Substituted sulfonamide macrocyclic compound

Abstract

The present invention addresses the problem of providing a novel compound that has OX2R agonist activity.　The present invention relates to a substituted sulfonamide macrocyclic compound represented by formula (I) or a pharmacologically acceptable salt thereof. This compound, or a pharmacologically acceptable salt thereof, has agonist activity against OX2R, and is useful as a treatment agent, etc., for sleep disorders involving OX2R (e.g., narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a physical disease, hypersomnia associated with a mental disease, hypersomnia associated with a drug or a substance, circadian rhythm sleep-wake disorder, insufficient sleep syndrome, and extended sleep).

Description

Substituted sulfonamide macrocycles

[0001] The present invention relates to substituted sulfonamide macrocyclic compounds useful as pharmaceuticals. More specifically, the present invention relates to substituted sulfonamide macrocyclic compounds or pharmacologically acceptable salts thereof that have agonistic activity against the orexin 2 receptor (OX2R) and are useful as therapeutic agents for sleep disorders associated with OX2R.

[0002] Orexin is a neuropeptide produced and secreted by orexin neurons in the hypothalamus, and there are two subtypes: orexin A and orexin B. Orexin neurons project throughout the central nervous system, excluding the cerebellum, with prominent projections to areas involved in the wakefulness and sleep mechanisms, such as monoaminergic neurons and cholinergic neurons in the brainstem and the paraventricular nucleus of the thalamus. Orexin receptors are expressed in the projection sites, and two subtypes, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), are present in different tissue distributions. The orexin nervous system plays an important role in maintaining wakefulness, and its dysfunction is thought to be a cause of narcolepsy.

[0003] Narcolepsy is a chronic neurological sleep disorder characterized by excessive daytime sleepiness and sleep attacks. Narcolepsy is classified into two types: Type 1 (NT1), which is accompanied by cataplexy (a sudden episode of physical weakness due to strong emotions), and Type 2 (NT2), which is not. Currently, central nervous system stimulants such as modafinil, methylphenidate, and pemoline are used to treat hypersomnia. However, all of these drugs can cause paradoxical reactions, and methylphenidate and pemoline have strong side effects, including dependence. On the other hand, antidepressants are used to treat cataplexy because the aforementioned drugs are ineffective. However, these drugs are difficult to use due to their strong side effects, and discontinuing the medication can worsen the condition due to the rebound phenomenon characteristic of antidepressants. Thus, the current treatment for narcolepsy is limited to symptomatic treatment, and therapeutic options based on the etiology of narcolepsy are needed.

[0004] A study using postmortem brains of narcolepsy patients reported that orexin neurons in the hypothalamus were reduced compared to healthy controls (Non-Patent Document 1). Furthermore, in dogs, a model of hereditary narcolepsy, it has been reported that the causative gene for narcolepsy is the gene encoding OX2R (Non-Patent Document 2). OX1R-deficient mice do not develop narcoleptic symptoms, whereas OX2R-deficient mice do (Non-Patent Document 3). These findings strongly suggest that OX2R signaling is important for maintaining wakefulness and that its attenuation is involved in the development of narcolepsy. Therefore, OX2R agonists are expected to be therapeutic agents for narcolepsy and other sleep disorders.

[0005] TAK-925 is a known OX2R agonist, and subcutaneous administration of TAK-925 has been shown to prolong wakefulness in wild-type mice (Non-Patent Document 4). Furthermore, clinical trials have shown that TAK-925 maintains wakefulness and reduces daytime sleepiness in NT1 patients (Patent Document 1).

[0006] Compounds having OX2R agonist activity are described in Patent Documents 1 to 14 and Non-Patent Document 4. However, the substituted sulfonamide macrocyclic compounds of the present invention are not described in any of these documents.

[0007] International Publication No. 2021 / 048822 International Publication No. 2021 / 166934 International Publication No. 2021 / 142083 International Publication No. 2021 / 048821 U.S. Patent Application Publication No. 2020 / 0247747 U.S. Patent Application Publication No. 2019 / 0040010 U.S. Patent Application Publication No. 2020 / 0385346 U.S. Patent Application Publication No. 2017 / 0226137 International Publication No. 2022 / 109117 U.S. Patent Application Publication No. 2022 / 0056017 International Publication No. 2022 / 040058 International Publication No. 2021 / 026047 U.S. Patent Application Publication No. 2020 / 0255403 U.S. Patent Application Publication No. 2022 / 0144771

[0008] Thomas C. Thannickal et al., Neuron, 2000, Vol. 27, No. 3, pp. 469-474; Ling Lin et al., Cell, 1999, Vol. 98, No. 3, pp. 365-376; Michihiro Mieda et al., Proceedings of the National Academy of Sciences of the United States of America, 2004, Vol. 101, No. 13, pp. 4649-4654; Hiroshi Yukitake et al., Pharmacology, Biochemistry and Behavior, 2019, Vol. 187, pp. 172-794

[0009] An objective of the present invention is to provide a novel compound having OX2R agonist activity.

[0010] The present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof:

[0011] That is, the present invention relates to the following [1] to

[11] , etc. [1] A compound represented by formula (I): wherein ring V is C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Ring Z is a group represented by formula (1) or (2): Y 1 is a single bond, CR a1 R a2 , C.R. a1 , O, or NR b1 and Y 2 is CR 4 R 5 , or CR 4 and Y 3 is CR a1 or N; Y 4 is a single bond, CRa1 R a2 , O or NR b2 and represents a single or double bond; R a1 , R a2 , R a3 , and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R a1 and R a2 When there are two or more of each, each R a1 and R a2 may be the same or different; R b1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R b2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 4 and R 5 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy, or may be taken together to form a 3- to 8-membered saturated ring; R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 6 and R 7 When there are two or more of each, each R 6 and R 7 may be the same or different; p and q are each independently 1 or 2; r is an integer of 0 to 2; L 1 is a single bond, CR a5 R a6 , or NR b3 and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R b3 is a hydrogen atom, C1-6 Alkyl or haloC 1-6 alkyl; L 2 is -(CR a7 R a8 )s-, or * -(CR a7 R a8 )s-NR b4 - ** and the bond marked with * is L 3 the bond marked with ** is the bond to the carbonyl; R a7 and R a8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R a7 and R a8 When there are two or more of each, each R a7 and R a8 may be the same or different; R b4 is a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-6 cycloalkyl; R a7 is R a8 together with unsubstituted or 1 or 2 C 1-6 Forms a 3- to 8-membered saturated carbocyclic ring substituted with alkyl, or R b4 together with unsubstituted or 1 or 2 C 1-6 Optionally, the alkyl group forms a 4- to 8-membered saturated heterocyclic ring; s is an integer from 1 to 5; L 3 is a single bond, O, or NR b5 and R b5 is a hydrogen atom or C 1-6 alkyl; L 4 is a single bond or O; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C1-6 alkylamino; R 2 is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 m and n are each independently an integer from 0 to 2; when m is 2, each R 2 may be the same or different; when n is 2, each R 3 may be the same or different from each other] or a pharmacologically acceptable salt thereof. [2] The compound according to the above [1], which is represented by formula (I-I): wherein ring V is C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Y 1 is a single bond, CR a1 R a2 , C.R. a1 , O, or NR b1 and Y 2 is CR 4 R 5 , or CR 4 and represents a single or double bond; R a1 , and R a2 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R b1 is a hydrogen atom, C 1-6 Alkyl or haloC1-6 alkyl; R 4 and R 5 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy, or may be taken together to form a 3- to 8-membered saturated ring; R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 6 and R 7 When there are two or more of each, each R 6 and R 7 may be the same or different; p is 1 or 2; L 1 is a single bond, CR a5 R a6 , or NR b3 and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R b3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is -(CR a7 R a8 )s-, or * -(CR a7 R a8 )s-NR b4 - ** and the bond marked with * is L 3 the bond marked with ** is the bond to the carbonyl; R a7 and R a8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R a7 and R a8 When there are two or more of each, each R a7 and R a8 may be the same or different; R b4 is a hydrogen atom, C 1-6Alkyl, HaloC 1-6 Alkyl or C 3-6 cycloalkyl; R a7 is R a8 together with unsubstituted or 1 or 2 C 1-6 Forms a 3- to 8-membered saturated carbocyclic ring substituted with alkyl, or R b4 together with unsubstituted or 1 or 2 C 1-6 Optionally, the alkyl group forms a 4- to 8-membered saturated heterocyclic ring; s is an integer from 1 to 5; L 3 is a single bond, O, or NR b5 and R b5 is a hydrogen atom or C 1-6 alkyl; L 4 is a single bond or O; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 2 is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 m and n are each independently an integer from 0 to 2; when m is 2, each R 2 may be the same or different; when n is 2, each R 3 may be the same or different from each other] or a pharmacologically acceptable salt thereof. [3] The compound according to the above [1], which is represented by formula (I-II): wherein ring V is C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Y 3 is CR a1 or N; Y 4 is a single bond, CR a1 R a2 , O or NR b2 and R a1 , R a2 , R a3 , and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R a1 and R a2 When there are two or more of each, each R a1 and R a2 may be the same or different; R b2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 5 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy; R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 6 and R 7 When there are two or more of each, each R 6 and R 7 may be the same or different; q is 1 or 2; r is an integer from 0 to 2; L 1 is a single bond, CR a5 R a6 , or NR b3and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R b3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is -(CR a7 R a8 )s-, or * -(CR a7 R a8 )s-NR b4 - ** and the bond marked with * is L 3 the bond marked with ** is the bond to the carbonyl; R a7 and R a8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R a7 and R a8 When there are two or more of each, each R a7 and R a8 may be the same or different; R b4 is a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-6 cycloalkyl; R a7 is R a8 together with unsubstituted or 1 or 2 C 1-6 Forms a 3- to 8-membered saturated carbocyclic ring substituted with alkyl, or R b4 together with unsubstituted or 1 or 2 C 1-6 Optionally, the alkyl group forms a 4- to 8-membered saturated heterocyclic ring; s is an integer from 1 to 5; L 3 is a single bond, O, or NR b5 and R b5 is a hydrogen atom or C 1-6 alkyl; L 4 is a single bond or O; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 2 is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 m and n are each independently an integer from 0 to 2; when m is 2, each R 2 may be the same or different; when n is 2, each R 3 and Y may be the same or different from each other] or a pharmacologically acceptable salt thereof. [4] The compound according to any one of [1] to [3] above, wherein Y 3 is N; R a1 , R a2 , R a3 , and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 4 is a hydrogen atom or C 1-6 alkyl; R 5 is a hydrogen atom; R 6 and R 7 is a hydrogen atom; p and q are 1; s is an integer from 2 to 4; L 3 is a single bond or O, or a pharmacologically acceptable salt thereof. [5] The compound according to any one of [1] to [4] above, wherein ring V is C 6-10 aryl, or 5- or 6-membered heteroaryl; Ring W is C 3-8 Cycloalkyl, C 6-10aryl, or 5- or 6-membered heteroaryl; Y 1 But, CR a1 R a2 , or CR a1 and Y 4 But, CR a1 R a2 , O, or NR b2 and L 1 is a single bond or NR b3 r is 1 or 2; R b3 is a hydrogen atom; R a7 and R a8 are each independently a hydrogen atom or C 1-6 alkyl; R a7 is R b4 together with unsubstituted or 1 or 2 C 1-6 R may form a 4- to 8-membered saturated heterocyclic ring substituted with alkyl; b4 is a hydrogen atom, C 1-6 Alkyl or C 3-6 cycloalkyl; R 1 But C 1-6 Alkyl, C 3-8 Cycloalkyl, HaloC 1-6 Alkyl or C 1-6 alkylamino; R 2 is a halogen atom or C 1-6 alkyl; R 3 is a halogen atom or C 1-6 and m and n are each independently 0 or 1, or a pharmacologically acceptable salt thereof. [6] A compound according to [1], [2], [4], or [5] above, selected from the group consisting of the following compounds: and [7] The compound according to any one of [1] or [3] to [5] above, which is selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof. [8] The compound according to any one of [1], [2], or [5] above, which is selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof. [9] A pharmaceutical composition comprising the compound according to any one of [1] to [8] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.

[10] The pharmaceutical composition according to [9] above, which is a pharmaceutical composition for treating a sleep disorder associated with OX2R.

[11] The pharmaceutical composition according to

[10] above, wherein the sleep disorder associated with OX2R is narcolepsy.

[0012] In one embodiment, the present invention relates to a method for treating a sleep disorder associated with OX2R, comprising administering to a patient a required amount of the pharmaceutical composition according to [9] above.

[0013] In one embodiment, the present invention relates to use of the compound according to any one of [1] to [8] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating a sleep disorder involving OX2R.

[0014] The compound of the present invention has excellent OX2R agonist activity, and therefore the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for sleep disorders involving OX2R.

[0015] Hereinafter, embodiments of the present invention will be described in more detail.

[0016] In the present invention, each term has the following meaning unless otherwise specified.

[0017] "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. 2-6 "Alkenyl" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms. Examples include ethenyl, 1-propenyl, and 2-propenyl. 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0018] "Haro C 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 halogen atoms of the same or different types. 1-6 It means alkyl, and examples thereof include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl.

[0019] "C 6-10 "Aryl" means a phenyl group or a naphthyl group. "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include pyridyl, pyrimidyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl. "9- or 10-membered heteroaryl" means a 9- or 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, purinyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, cinnolyl, pteridinyl, chromenyl, and isochromenyl.

[0020] "C 3-6 "Cycloalkyl" means a 3- to 6-membered monocyclic saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, etc. 3-8 "Cycloalkyl" means a 3- to 8-membered monocyclic saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc. 5-10"Bicycloalkyl" means a 5- to 10-membered bicyclic saturated hydrocarbon group. Examples include bicyclo[1.1.1]pentyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, etc. "3- to 8-membered heterocycloalkyl" means a 3- to 8-membered cycloalkyl group in which carbon atoms in the ring are replaced with one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and also includes partially bridged structures. For example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[2.2.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrrolidonyl, piperidonyl, oxiranyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrole, and the like.

[0021] "3- to 8-membered saturated carbocycle" means a monocyclic or polycyclic saturated hydrocarbon ring having 3 to 8 carbon atoms. "3- to 8-membered saturated heterocycle" means a monocyclic or polycyclic 3- to 8-membered saturated ring having 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms in the ring. "3- to 8-membered saturated ring" means a 3- to 8-membered saturated carbocycle or a 3- to 8-membered saturated heterocycle.

[0022] The term "4- to 8-membered saturated heterocyclic ring" refers to a monocyclic or polycyclic 4- to 8-membered saturated ring having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.

[0023] "C 1-6 "Alkylamino" means (C 1-6 alkyl)-NH-, or (C 1-6 alkyl)N-, (C 1-6The two Cs of the group represented by alkyl)2N- 1-6 The alkyls may be the same or different, and examples thereof include methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, methylethylamino, and diethylamino.

[0024] The following abbreviations used in the text, figures, and tables have the following meanings: AZADOL®: 2-hydroxy-2-azaadamantane, Boc: tert-butoxycarbonyl, DCM: dichloromethane, DIPEA: N,N-diisopropylethylamine, DMAP: 4-dimethylaminopyridine, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, LDA: lithium diisopropylamide, MeCN: acetonitrile, NMP: N-methylpyrrolidone, 10% Pd / C: 10% palladium on carbon (approximately 55% water-wet), Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0), TBME: t-butyl methyl ether, TEA: triethylamine, THF: tetrahydrofuran Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xphos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate APS: Aminopropylated silica gel ODS: Octadecylsilylated silica gel Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical properties 1H-NMR: Proton nuclear magnetic resonance spectrum CDCl3: Chloroform-d1 MS: Mass spectrometry (The values ​​in the table were measured by electrospray ionization or electrospray ionization-atmospheric pressure chemical ionization multi-ionization method.) Act.: Activation rate of the test substance at a compound concentration of 10 μM, where the fluorescence intensity when 1 μM human orexin A peptide was added was taken as 100%, and the fluorescence intensity when only the vehicle was added was taken as 0%. CHO: Chinese hamster ovary HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid

[0025] When one or more asymmetric carbon atoms are present in the compound of formula (I), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0026] In the case where the compound represented by formula (I) has cis-trans isomers, the present invention encompasses both of the cis-trans isomers.

[0027] When tautomers exist in the compound represented by formula (I), the present invention includes all of the tautomers.

[0028] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0029] The compound represented by formula (I) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

[0030] Examples of acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

[0031] Examples of salts with bases include salts with inorganic bases such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0032] Unless otherwise specified, a suffix to a chemical name or structural formula referring to a salt, such as "hydrochloride" or "HCl," does not denote a stoichiometric description but simply refers to the salt form.

[0033] When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with a suitable co-crystal former, etc.

[0034] In the compound represented by formula (I), some of the atoms may be replaced with the corresponding isotopes. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O, and 35 In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are isotopes of the hydrogen atom, carbon atom, chlorine atom, fluorine atom, iodine atom, nitrogen atom, oxygen atom, and sulfur atom represented by S. 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0035] A compound represented by formula (I) in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below using a commercially available reagent containing an isotope. Alternatively, the compound can be produced by a method described in the literature (see, for example, Journal of Organic Synthesis, Vol. 65, No. 12, pp. 1179-1190, 2007, and RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

[0036] The compound of the present invention represented by formula (I) can be produced, for example, by the methods shown in Schemes 1 to 8 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compound of formula (I) corresponds to the compounds of formulae (I-1) to (I-3).

[0037] The compound of the present invention represented by formula (I) can be produced by the following method, but the following production method is an example of a general production method and is not intended to limit the production method.

[0038] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0039] In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified.

[0040] In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually −78° C. to reflux temperature unless otherwise specified.

[0041] In the reaction of each step, the pressure varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 1 to 20 atmospheres unless otherwise specified.

[0042] A microwave reactor such as Biotage Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0043] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, TBME, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, n-pentane, etc.; Amides: DMF, N,N-dimethylacetamide, NMP, etc.; Halogenated hydrocarbons: DCM, 1,2-dichloroethane, chloroform, carbon tetrachloride, etc.; Nitriles: MeCN, etc.; Sulfoxides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0044] When a base is used in the reaction of each step, the reaction is carried out using a base suitable for the reaction. Specific examples of the base to be used include the bases described in the Reference Examples or Examples corresponding to each step, and the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; organic magnesiums: isopropyl magnesium chloride, etc.; organic lithiums: methyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.

[0045] When an acid is used in the reaction of each step, the reaction is carried out using an acid suitable for the reaction. Specific examples of the acid used include the acids described in the Reference Examples and Examples corresponding to each step or the following acids: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0046] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent used include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents. Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: carbonyldiimidazole, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

[0047] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, or the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: borane-THF complex, picoline borane complex, decaborane, etc.

[0048] In each step, when a protecting group is required depending on the type of functional group, the protective group may be introduced and removed in a suitable combination according to a conventional method. Regarding the type of protective group, protection, and deprotection, for example, the method described in "Greene's Protective Groups in Organic Synthesis," edited by Peter GM Wuts, fifth edition, Wiley-Interscience, 2014 can be mentioned.

[0049] When hydrolysis is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0050] When catalytic reduction is carried out in each step, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. If necessary, an acid may be used in the reaction.

[0051] When oxidation is carried out in each step, the reaction can be carried out in the presence of an oxidizing agent. Examples of the oxidizing agent include metachloroperbenzoic acid and iodobenzene diacetate. If necessary, an oxidation catalyst such as AZADOL may be used in the reaction.

[0052] When reduction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include the examples mentioned above.

[0053] When amidation is carried out in each step, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base used include those mentioned above. When a carbodiimide is used as the condensing agent, the reaction may be carried out by adding an additive such as 1-hydroxybenzotriazole or DMAP, as necessary. The reaction can also be carried out using a halogenating agent in the presence or absence of a base. Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphoryl chloride, sulfuryl chloride, phosphorus trichloride, and phosphorus pentachloride.

[0054] When reductive amination is performed in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc.

[0055] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base include those mentioned above.

[0056] When a Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst include bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) and Pd(PPh3)4. Examples of the base used include those mentioned above.

[0057] When a Mitsunobu reaction is carried out in each step, the reaction can be carried out using an azodicarboxylic acid ester and triphenylphosphine. Examples of the azodicarboxylic acid ester to be used include diethyl azodicarboxylate and diisopropyl azodicarboxylate.

[0058] When sulfonylation is carried out in each step, the reaction can be carried out using a sulfonylating reagent in the presence of a base. Examples of the sulfonylating reagent that can be used include methanesulfonyl chloride, ethanesulfonyl chloride, etc. Examples of the base that can be used include the examples mentioned above.

[0059] When sulfamoylation is carried out in each step, the reaction can be carried out using a sulfamoylating reagent in the presence of a base. Examples of the sulfamoylating reagent that can be used include N-methylsulfamoyl chloride, dimethylsulfamoyl chloride, etc. Examples of the base that can be used include the examples mentioned above.

[0060] When the Staudinger reaction is carried out in each step, the reaction can be carried out using a phosphorus reagent, such as triphenylphosphine.

[0061] When a Curtius rearrangement reaction is carried out in each step, the reaction can be carried out by treating with an acid using an azide reagent. Examples of the azide reagent that can be used include diphenylphosphoryl azide. Examples of the acid that can be used include the above-mentioned examples.

[0062] When hydroboration is carried out in each step, the reaction can be carried out using a borane reagent, such as borane-THF complex.

[0063] The compound represented by formula (I-1) can be produced, for example, according to the method described in Scheme 1.

[0064] The symbols in the formula have the same meanings as above.

[0065] The compound represented by formula (I-1) can also be produced by intramolecular amidation of compound (1-1).

[0066] The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 2.

[0067] The symbols in the formula have the same meanings as above.

[0068] The compound represented by formula (I-2) can also be produced by intramolecular amidation of compound (2-1).

[0069] The compound represented by formula (I-3) can be produced, for example, according to the method described in Scheme 3.

[0070] The symbols in the formula have the same meanings as above.

[0071] The compound represented by formula (I-3) can also be produced by intramolecular amidation of compound (3-1).

[0072] Compound (1-1) can be produced, for example, according to the method described in Scheme 4.

[0073] The symbols in the formula have the same meanings as above. 1 and PG 2 represents a protecting group. 1 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group. 2 represents a chlorine atom or a bromine atom.

[0074] Compound (4-2) can also be produced by reacting compound (4-1) with compound (4-8) in the presence of a base.

[0075] Compound (4-3) can also be produced by removing the protecting group of compound (4-2), reacting the compound with methanesulfonyl chloride in the presence of a base, and then reacting the compound with sodium azide.

[0076] Compound (4-4) can also be produced by Staudinger reaction or catalytic reduction of compound (4-3).

[0077] Compound (4-5) can also be produced by sulfonylation or sulfamoylation of compound (4-4).

[0078] Compound (4-6) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (4-5) and compound (4-9).

[0079] Compound (4-7) can also be produced by hydrolysis of compound (4-6).

[0080] Compound (1-1) can also be prepared by removing the protecting group of compound (4-7).

[0081] Compound (2-1) can be produced, for example, according to the method described in Scheme 5.

[0082] The symbols in the formula have the same meanings as above.

[0083] The compound (5-2) can also be produced by subjecting the compound (5-1) to Curtius rearrangement reaction.

[0084] The compound (2-1) can also be produced by subjecting the compound (5-2) to reductive amination, if necessary, followed by reaction with an acid.

[0085] Compound (4-4) can be produced, for example, according to the method described in Scheme 6.

[0086] The symbols in the formula have the same meanings as above.

[0087] The compound (6-2) can also be produced by reacting the compound (6-1) with diphenylmethanimine.

[0088] Compound (6-3) can also be produced by reacting compound (6-2) with compound (4-8) in the presence of a base.

[0089] Compound (4-4) can also be produced by removing the diphenylmethylidene group from compound (6-3). The removal of the diphenylmethylidene group can be carried out, for example, by hydrolysis.

[0090] Compound (7-4) can be produced, for example, according to the method described in Scheme 7.

[0091] The symbols in the formula have the same meanings as above. 3 and PG 4 represents a protecting group. t is an integer of 1 or 2.

[0092] Compound (7-2) can also be produced by reacting compound (7-1) with compound (4-8) in the presence of a base.

[0093] Compound (7-3) can also be prepared by removing the acetal protecting group of compound (7-2).

[0094] Compound (7-4) can also be prepared by removing the protecting group of compound (7-3) and subjecting it to reductive amination.

[0095] Compound (8-6) can also be produced, for example, according to the method described in Scheme 8.

[0096] The symbols in the formula have the same meanings as above. 5 and PG 6 indicates a protecting group.

[0097] Compound (8-2) can also be prepared by hydroborating compound (8-1), followed by treatment with aqueous sodium hydroxide and aqueous hydrogen peroxide.

[0098] Compound (8-3) is a PG of compound (8-2). 6 and reacting with compound (8-7) in the presence of a base.

[0099] The compound (8-4) can also be produced by reacting the compound (8-3) with a base.

[0100] Compound (8-5) can also be produced by reacting compound (8-4) with compound (4-8) in the presence of a base.

[0101] Compound (8-6) can also be prepared by reducing the cyclic amide of compound (8-5).

[0102] The scheme shown above is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The scheme can be modified in various ways that can be easily understood by those skilled in the art.

[0103] The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0104] The compound of the present invention has excellent OX2R agonist activity and can therefore be used as a therapeutic agent for sleep disorders involving OX2R. In the present invention, examples of sleep disorders involving OX2R include narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to physical diseases (e.g., sleep apnea syndrome, periodic leg movements, Parkinson's disease, trauma, Niemann-Pick disease type C, Norrie disease, Prader-Willi syndrome, myotonic dystrophy, Moebius syndrome, fragile X syndrome, brain tumor, cerebral infarction, cerebral contusion, infection, hypothyroidism, hepatic encephalopathy, renal failure, adrenal insufficiency, pancreatic insufficiency, exposure to toxic substances, pediatric congenital metabolic disorders, progressive supranuclear palsy, hypoventilation syndrome, multiple sclerosis, Examples of hypersomnia include hypersomnia due to rheumatoid arthritis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy, dementia with Lewy bodies, Alzheimer's disease, migraine, headache, or neuropathic pain), hypersomnia due to psychiatric disorders (e.g., hypersomnia associated with depression, anxiety disorder, panic disorder, addiction, obsessive-compulsive disorder, eating disorder, bipolar disorder, epilepsy, schizophrenia, personality disorder, developmental disorder, or post-traumatic stress disorder), drug- or substance-induced hypersomnia, circadian rhythm sleep-wake disorder, insufficient sleep syndrome, and prolonged sleep. Preferably, the compound of the present invention can be used as a therapeutic agent for narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, or sleep apnea syndrome. More preferably, the compound of the present invention can be used as a therapeutic agent for narcolepsy (see Patent Document 1).

[0105] In the present invention, "treatment" includes the meaning of "prevention."

[0106] In the present invention, the term "agonist" refers to a drug that activates the function of a target protein regardless of its binding site. For example, the term "agonist" includes the meanings of "allosteric agonist" and "positive allosteric modulator (PAM)."

[0107] While OX2R is involved in maintaining wakefulness, signaling via OX1R is thought to be involved in the formation of drug addiction through the reward system (see, for example, PLoS One, 2022, Vol. 27, No. 7, e0271901). In one embodiment, the compounds of the present invention have selective agonist activity against OX2R among orexin receptors. Agonist activity against OX1R can be measured by methods well known in the art or methods equivalent thereto (see, for example, Non-Patent Document 4).

[0108] The therapeutic effect of the compound of the present invention on sleep disorders involving OX2R can be confirmed by methods well known in the art. For example, a method for confirming the effect in an animal model of narcolepsy includes the method described in Neuron, 2001, Vol. 30, No. 2, pp. 345-354, or a method similar thereto.

[0109] The pharmaceutical composition of the present invention may be used in various dosage forms depending on the intended use, including, for example, powders, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

[0110] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0111] The pharmaceutical compositions of the present invention are prepared using the compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving the compound with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, according to the dosage form, using methods known in pharmaceutical science.

[0112] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is determined appropriately depending on the patient's age, sex, weight, disease, and degree of treatment. The daily dosage may be administered once, twice, three times, or four times. When administered orally or parenterally, the dosage for an adult can be set, for example, in the range of 0.01 to 1000 mg / day. In one embodiment, the oral dosage can be set in the range of 0.01 to 500 mg / day, preferably 0.01 to 100 mg / day.

[0113] In one embodiment, the pharmaceutical composition of the present invention can be used in combination with drugs other than OX2R agonists. Examples of other drugs that can be used in combination to treat sleep disorders involving OX2R include drugs for treating narcolepsy (e.g., modafinil, methylphenidate, pemoline, amphetamine, sodium oxybate, pitolisant, solriamfetol, etc.), antidepressants (e.g., clomipramine, imipramine, paroxetine, fluvoxamine, milnacipran, etc.), caffeine, etc.

[0114] When the compound represented by formula (I) or its pharmacologically acceptable salt is used in combination with other drugs, these active ingredients can be administered as a preparation containing them together, or as a preparation in which each of these active ingredients is separately formulated. When formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or its pharmacologically acceptable salt may be appropriately reduced depending on the dosage of the other drug used in combination.

[0115] The compound represented by formula (I) may be appropriately converted into a prodrug for use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a group constituting the prodrug using a corresponding halide or the like, followed by purification. Examples of the group constituting the prodrug include the groups described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

[0116] The present invention will be explained in more detail below based on Reference Examples, Examples and Test Examples, but the present invention is not limited to the contents thereof.

[0117] The names of compounds described in the following examples, excluding commercially available reagents, were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc. The configuration of an asymmetric center marked with "*" in the compound name means that it is the relative configuration.

[0118] Reference Example A-1 tert-Butyl (4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butyl)carbamate To a mixture of 4-(tert-butoxycarbonylamino)-1-butanol (0.326 g), 2-bromophenol (0.894 g), triphenylphosphine (1.36 g), and THF (3 mL) was added diisopropyl azodicarboxylate (1.9 mol / L in toluene) (2.7 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give tert-butyl (4-(2-bromophenoxy)butyl)carbamate (0.655 g). A mixture of the obtained compound (0.200 g), bis(pinacolato)diboron (0.295 g), potassium acetate (0.171 g), Pd(dppf)Cl DCM adduct (0.047 g), and 1,4-dioxane (5 mL) was stirred under microwave irradiation at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (0.263 g).

[0119] Reference Example A-2 tert-Butyl methyl(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)carbamate A mixture of 2-chlorophenol (0.252 g), 3-(tert-butoxycarbonylamino)propyl bromide (0.607 g), cesium carbonate (1.93 g), and acetonitrile (4 mL) was stirred at 90°C for 6.5 hours and allowed to cool to room temperature. The reaction mixture was added to water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 70 / 30) to give tert-butyl (3-(2-chlorophenoxy)propyl)carbamate (0.578 g). To a mixture of the resulting compound (0.201 g) and DMF (2.3 mL), sodium hydride (approximately 60% in mineral oil) (0.042 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Methyl iodide (0.150 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to give tert-butyl (3-(2-chlorophenoxy)propyl)(methyl)carbamate (0.170 g). A mixture of the obtained compound (0.084 g), bis(pinacolato)diboron (0.143 g), potassium acetate (0.083 g), Pd(dppf)Cl DCM adduct (0.023 g), Xphos (0.027 g), and 1,4-dioxane (3 mL) was stirred at 110 °C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.076 g).

[0120] Reference Example A-3: tert-Butyl (2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)carbamate. A mixture of tert-butyl N-(2-(2-chlorophenoxy)ethyl)carbamate (0.073 g), bis(pinacolato)diboron (0.137 g), potassium acetate (0.079 g), Pd(dppf)Cl2DCM adduct (0.022 g), Xphos (0.026 g), and 1,4-dioxane (2 mL) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2 to 85 / 15) to obtain the title compound (0.059 g).

[0121] Reference Example A-4 1-(benzyloxy)-2-(cis-4-(chloromethoxy)cyclohexyl)benzene A mixture of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g), p-toluenesulfonyl hydrazide (26.2 g), and 1,4-dioxane (200 mL) was stirred at 120°C for 5 hours and then with water cooling for 2.5 hours. The reaction mixture was filtered, and the resulting solid was washed successively with 1,4-dioxane and n-hexane and then dried under reduced pressure at 50°C to give 4-methyl-N'-(1,4-dioxaspiro[4.5]decan-8-ylidene)benzenesulfonohydrazide (42.4 g). To a mixture of the resulting compound (10.4 g), (2-benzyloxyphenyl)boronic acid (5.60 g), and 1,4-dioxane (200 mL) was added cesium carbonate (24.0 g) at room temperature, and the mixture was stirred under an argon atmosphere at 110°C for 6 hours and at room temperature for 12 hours. The mixture was further stirred under an argon atmosphere at 110°C for 12 hours and at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to give 8-(2-(benzyloxy)phenyl)-1,4-dioxaspiro[4.5]decane (3.69 g). To a mixture of the obtained compound (3.69 g) and THF (35 mL), 6 mol / L hydrochloric acid (6.9 mL) was added at room temperature, and the mixture was stirred at 60°C for 4 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and THF (30 mL), lithium tri-sec-butylborohydride (1 mol / L in THF) (13.5 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, saturated aqueous ammonium chloride and water were added under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give cis-4-(2-(benzyloxy)phenyl)cyclohexan-1-ol (2.16 g). To a mixture of the obtained compound (2.60 g) and DCM (9.5 mL), paraformaldehyde (0.304 g) and chlorotrimethylsilane (3.00 g) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (3.38 g).

[0122] Reference Example A-5 tert-Butyl (2-(2-bromophenoxy)ethyl)(cyclopropyl)carbamate A mixture of 2-bromophenol (1.05 g), tert-butyl N-cyclopropyl-N-(2-hydroxyethyl)carbamate (1.34 g), (tributylphosphoranylidene)acetonitrile (2.20 g), and toluene (12 mL) was stirred at 110°C for 6 hours and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to obtain the title compound (0.459 g).

[0123] Reference Example A-6: 2'-(benzyloxy)-5-(bromomethyl)-2-fluoro-1,1'-biphenyl. A mixture of (3-bromo-4-fluorophenyl)methanol (1.50 g), (2-(benzyloxy)phenyl)boronic acid (1.67 g), palladium(II) acetate (0.164 g), triphenylphosphine (0.384 g), potassium carbonate (2.02 g), 1,4-dioxane (16 mL), and water (4 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was added to water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to give (2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methanol (1.91 g). To a mixture of the obtained compound (1.91 g), TEA (1.25 g), and ethyl acetate (30 mL), methanesulfonyl chloride (1.06 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered. To the filtrate, lithium bromide monohydrate (1.95 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.12 g).

[0124] Reference Example B-1 Methyl (1S,4R)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate A mixture of methyl (1S,4R)-4-((tert-butoxycarbonyl)amino)cyclopent-2-ene-1-carboxylate (3.00 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (31 mL), and methanol (30 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. A mixture of the residue, diphenylmethanimine (2.20 g), and DCM (24 mL) was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.74 g).

[0125] Reference Example B-2: Methyl (1R,4R)-4-amino-1-(3-bromobenzyl)cyclopent-2-ene-1-carboxylate. Under an argon atmosphere, to a mixture of Reference Example B-1 (1.23 g), 1-bromo-3-(bromomethyl)benzene (1.06 g), and THF (16 mL) was added lithium bis(trimethylsilyl)amide (1.5 mol / L in THF) (3.2 mL) at -78°C. The mixture was stirred at the same temperature for 5 minutes and then in an ice-salt bath for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 93 / 7) to give methyl (1R,4R)-1-(3-bromobenzyl)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate (1.03 g). To a mixture of the obtained compound (1.03 g) and methanol (5 mL), 6 mol / L hydrochloric acid (1.1 mL) was added at room temperature, and the mixture was stirred at the same temperature for 12 hours. Water and ethyl acetate were added to the reaction mixture, and the aqueous layer was separated. The aqueous layer was added to saturated aqueous sodium bicarbonate under ice-cooling and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.451 g).

[0126] Reference Example B-3: Methyl (1R,4R)-1-(3-bromo-4-fluorobenzyl)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate. Under an argon atmosphere, to a mixture of Reference Example B-1 (1.00 g), 2-bromo-4-(bromomethyl)-1-fluorobenzene (0.921 g), and THF (10 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (3.9 mL) at -78°C, and the mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous ammonium chloride were added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give the title compound (1.22 g).

[0127] Reference Example C-1: Methyl (1R,4R)-1-(3-bromobenzyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate. To a mixture of Reference Example B-2 (0.451 g), TEA (0.191 g), and DCM (4.5 mL), methanesulfonyl chloride (0.183 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 3.5 hours. The reaction mixture was added to water, extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to obtain the title compound (0.558 g).

[0128] Reference Example C-2: (1R,4R)-1-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate. A mixture of Reference Example B-3 (0.886 g), 2 mol / L hydrochloric acid (9 mL), and THF (12 mL) was stirred at room temperature for 30 minutes. 2 mol / L aqueous sodium hydroxide solution (9.9 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methanesulfonyl chloride (0.309 g) was added to a mixture of the residue, TEA (0.364 g), and DCM (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 50 / 50) to obtain the title compound (0.704 g).

[0129] Reference Example C-3: Methyl (1R,4R)-1-(5-chloro-2-fluorobenzyl)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate. Under an argon atmosphere, to a mixture of Reference Example B-1 (1.00 g), 2-(bromomethyl)-4-chloro-1-fluorobenzene (0.768 g), and THF (10 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (3.9 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give methyl (1R,4R)-1-(5-chloro-2-fluorobenzyl)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate (0.566 g). A mixture of the obtained compound (0.300 g), 2 mol / L hydrochloric acid (3.4 mL), and THF (12 mL) was stirred at room temperature for 30 minutes. 2 mol / L aqueous sodium hydroxide solution (3.7 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methanesulfonyl chloride (0.115 g) was added to a mixture of the residue, TEA (0.136 g), and DCM (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the title compound (0.225 g).

[0130] Reference Examples C-4 to C-5 Reference Examples C-4 to C-5 were synthesized in the same manner as in Reference Example C-3, except that corresponding reagents were used instead of 2-(bromomethyl)-4-chloro-1-fluorobenzene.

[0131] Reference Example C-6 Reference Example C-6 was synthesized in the same manner as in Reference Example C-3, except that Reference Example A-4 was used instead of 2-(bromomethyl)-4-chloro-1-fluorobenzene.

[0132] Reference Example C-7: Methyl (1R,4R)-1-(3-bromobenzyl)-4-((N,N-dimethylsulfamoyl)amino)cyclopent-2-ene-1-carboxylate. A mixture of Reference Example B-2 (0.220 g), dimethylsulfamoyl chloride (1.02 g), DMAP (0.260 g), and DIPEA (2 mL) was stirred at 60°C for 3.5 hours and allowed to cool to room temperature. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain the title compound (0.347 g).

[0133] Reference Example C-8: Methyl (1R,4R)-4-(((benzyloxy)carbonyl)amino)-1-(3-bromo-4-fluorobenzyl)cyclopent-2-ene-1-carboxylate. A mixture of Reference Example B-3 (0.870 g), 2 mol / L hydrochloric acid (5 mL), and THF (5 mL) was stirred at room temperature for 30 minutes. 2 mol / L aqueous sodium hydroxide solution (5.3 mL) was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Benzyl chloroformate (0.332 g) was added to a mixture of the residue, DIPEA (0.343 g), and DCM (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=90 / 10 to 50 / 50) to obtain the title compound (0.673 g).

[0134] Reference Example D-1 (1R,4R)-4-(methylsulfonamido)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopent-2-ene-1-carboxylate Reference Example C-1 (0.100 g), bis(pinacolato)diboron (0.131 g), potassium acetate (0.076 g), Pd(dppf)Cl DCM adduct (0.021 g), Xphos (0.025 g), and 1,4-dioxane (5 mL) were stirred at 110 ° C. for 1 hour under microwave irradiation and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to give the title compound (0.098 g).

[0135] Reference Example D-2: Benzyl (1R,4R)-4-(methylsulfonamido)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopent-2-ene-1-carboxylate. A mixture of Reference Example C-1 (0.640 g), 2 mol / L aqueous sodium hydroxide solution (10 mL), and methanol (10 mL) was stirred at 100°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Benzyl bromide (0.167 g) was added to a mixture of the residue (0.293 g), potassium carbonate (0.223 g), and acetone (8 mL) at room temperature, and the mixture was refluxed for 1 hour and allowed to cool to room temperature. A saturated aqueous ammonium solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to give benzyl (1R,4R)-1-(3-bromobenzyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.354 g). A mixture of the obtained compound (0.354 g), bis(pinacolato)diboron (0.385 g), potassium acetate (0.228 g), Pd(dppf)Cl2DCM adduct (0.063 g), Xphos (0.078 g), and 1,4-dioxane (12.5 mL) was stirred at 110 °C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=100 / 0 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.355 g).

[0136] Reference Example D-3 Reference Example D-3 was synthesized in the same manner as in Reference Example D-1, except that Reference Example C-2 was used instead of Reference Example C-1.

[0137] Reference Example E-1: (1R,4R)-1-((2'-(2-((tert-butoxycarbonyl)amino)ethyl)-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate. A mixture of Reference Example D-1 (0.155 g), tert-butyl (2-chlorophenethyl)carbamate (0.273 g), potassium phosphate tribasic (0.227 g), Xphos Pd G3 (0.030 g), 1,2-dimethoxyethane (2 mL), and water (2 mL) was stirred at 80°C for 30 minutes under microwave irradiation. The reaction mixture was added to a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 30 / 70) to obtain the title compound (0.061 g).

[0138] Reference Example E-2 Reference Example E-2 was synthesized in the same manner as in Reference Example E-1, except that tert-butyl (3-(2-chlorophenyl)propyl)carbamate was used instead of tert-butyl (2-chlorophenethyl)carbamate.

[0139] Reference Example E-3 (1R,4R)-1-((2'-(4-((tert-butoxycarbonyl)amino)butoxy)-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate A mixture of Reference Example A-1 (0.227 g), Reference Example C-1 (0.100 g), sodium carbonate (0.082 g), Pd(PPh3)4 (0.030 g), 1,4-dioxane (3.2 mL), and water (0.8 mL) was stirred at 110°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to give the title compound (0.137 g).

[0140] Reference Examples E-4 to E-5 Reference Examples E-4 to E-5 were synthesized in the same manner as in Reference Example E-3, except that the compounds of the corresponding Reference Examples were used instead of Reference Example A-1.

[0141] Reference Example E-6 (1R,4R)-1-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate Reference Example C-1 (0.855 g), (2-hydroxyphenyl)boronic acid (0.456 g), potassium carbonate (1.52 g), Pd(PPh3)4 (0.254 g), 1,4-dioxane (8 mL), and water (2 mL) were stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to obtain the title compound (0.855 g).

[0142] Reference Example E-7 (1R,4R)-1-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate Reference Example C-2 (0.704 g), (2-hydroxyphenyl)boronic acid (0.359 g), potassium carbonate (1.20 g), Pd(PPh3)4 (0.200 g), 1,4-dioxane (6 mL) and water (1.5 mL) were stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the title compound (0.642 g).

[0143] Reference Examples E-8 to E-9 Reference Examples E-8 to E-9 were synthesized in the same manner as in Reference Example E-7, except that the compounds of the corresponding Reference Examples were used instead of Reference Example C-2.

[0144] Reference Example E-10: (1R,4R)-1-((2-(2-hydroxyphenyl)pyridin-4-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate. A mixture of Reference Example C-5 (0.145 g), (2-hydroxyphenyl)boronic acid (0.087 g), tripotassium phosphate (0.268 g), Xphos Pd G3 (0.036 g), 1,2-dimethoxyethane (1 mL), and water (1 mL) was stirred at 80°C for 1 hour under microwave irradiation. The reaction mixture was added to a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (0.100 g).

[0145] Reference Example E-11 Reference Example E-11 was synthesized in the same manner as in Reference Example E-7, except that Reference Example C-1 and (3-fluoro-2-hydroxyphenyl)boronic acid were used instead of Reference Example C-2 and (2-hydroxyphenyl)boronic acid.

[0146] Reference Example E-12 Reference Example E-12 was synthesized in the same manner as in Reference Example E-7, except that 2-bromo-6-methylphenol and Reference Example D-1 were used instead of Reference Example C-2 and (2-hydroxyphenyl)boronic acid.

[0147] Reference Example E-13 Reference Example E-13 was synthesized in the same manner as in Reference Example E-7, except that 3-bromopyridin-2-ol and Reference Example D-1 were used instead of Reference Example C-2 and (2-hydroxyphenyl)boronic acid.

[0148] Reference Example E-14 (1R,4R)-1-((2'-(2-((tert-butoxycarbonyl)(cyclopropyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate A mixture of Reference Example D-3 (0.504 g), Reference Example A-5 (0.594 g), palladium(II) acetate (0.025 g), triphenylphosphine (0.058 g), potassium carbonate (0.307 g), 1,4-dioxane (12 mL), and water (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was added to water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 85 / 15) to obtain the title compound (0.459 g).

[0149] Reference Examples E-15 to E-16 Reference Examples E-15 to E-16 were synthesized in the same manner as in Reference Example E-7, except that the compounds of the corresponding Reference Examples were used instead of Reference Example C-2.

[0150] Reference Example F-1 (1R,3S)-1-((2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate A mixture of Reference Example E-6 (0.855 g), 10% Pd / C (0.500 g) and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.851 g).

[0151] Reference Example F-2 (1R,3S)-1-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate A mixture of Reference Example E-7 (0.642 g), 10% Pd / C (0.321 g) and THF (2 mL) was stirred under a hydrogen atmosphere at 50°C for 1 hour and allowed to cool to room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.580 g).

[0152] Reference Example F-3 (1R,3S)-1-((4-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate A mixture of Reference Example E-8 (0.219 g), 10% Pd / C (0.500 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the title compound (0.198 g).

[0153] Reference Example F-4 Reference Example F-4 was synthesized in the same manner as in Reference Example F-2, except that Reference Example E-9 was used instead of Reference Example E-7.

[0154] Reference Example F-5 Reference Example F-5 was synthesized in the same manner as in Reference Example F-3, except that Reference Example E-10 was used instead of Reference Example E-8.

[0155] Reference Examples F-6 to F-7 Reference Examples F-6 to F-7 were synthesized in the same manner as in Reference Example F-2, except that the compounds of the corresponding Reference Examples were used instead of Reference Example E-7.

[0156] Reference Example F-8 Reference Example F-8 was synthesized in the same manner as in Reference Example F-3, except that Reference Example E-15 was used instead of Reference Example E-8.

[0157] Reference Example F-9 (1R,3S)-3-amino-18'-fluoro-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-12'-one To a mixture of Reference Example E-16 (0.692 g), 2-(tert-butoxycarbonylamino)-1-ethanol (0.352 g) and toluene (12 mL), (tributylphosphoranylidene)acetonitrile (0.527 g) was added at room temperature, and the mixture was stirred at 100°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl (1R,4R)-4-(((benzyloxy)carbonyl)amino)-1-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)cyclopent-2-ene-1-carboxylate (0.737 g). A mixture of the obtained compound (0.737 g), 2 mol / L aqueous sodium hydroxide solution (7.3 mL), and methanol (10 mL) was stirred at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (3.6 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. HATU (0.601 g) was added to a mixture of the residue, DIPEA (0.557 g), and DMF (40 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to give N-[(1R,4R)-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0]. 2 , 7Benzyl ]nonadecane]-1'(19'),2,2',4',6',15',17'-heptaen-4-yl]carbamate (0.300 g) was obtained. A mixture of the obtained compound (0.300 g), 10% Pd / C (0.100 g), and THF (15 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.136 g).

[0158] Reference Example F-10: Ethyl (1R,3R,4R)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-methyl-4-(methylsulfonamido)cyclopentane-1-carboxylate. Under an argon atmosphere, to a mixture of ethyl cyclopent-3-ene-1-carboxylate (0.800 g) and THF (10 mL) was added LDA (1.1 mol / L in THF / n-hexane) (5.7 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a mixture of Reference Example A-6 (2.12 g) and THF (10 mL) at -78°C, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give ethyl 1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)cyclopent-3-ene-1-carboxylate (1.90 g). To a mixture of the obtained compound (1.90 g) and DCM (19 mL), metachloroperbenzoic acid (1.52 g) was added under ice-cooling. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. To the reaction mixture, 1 mol / L aqueous sodium thiosulfate solution (10 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water were added under ice-cooling. The mixture was extracted with DCM. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 75 / 25) to give (1R*,3s*,5S*)-3-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (0.997 g).Under an argon atmosphere, methyllithium (3.1 mol / L in 1,2-diethoxyethane) (3.17 mL) was added to a mixture of copper(I) cyanide (0.440 g) and THF (15 mL) at −78° C., and the mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added a mixture of (1R*,3s*,5S*)-3-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (0.997 g) and THF (10 mL) at −78° C., followed by the addition of boron trifluoride diethyl etherate (1.27 g). The mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to a saturated aqueous ammonium chloride solution at room temperature and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give ethyl (1R*,3R*,4R*)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-hydroxy-4-methylcyclopentane-1-carboxylate (0.845 g). To a mixture of the obtained compound (0.845 g), 4-nitrobenzoic acid (0.733 g), triphenylphosphine (1.15 g), and THF (18 mL) was added diisopropyl azodicarboxylate (1.9 mol / L in toluene) (2.3 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give (1S*,2R*,4R*)-4-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(ethoxycarbonyl)-2-methylcyclopentyl 4-nitrobenzoate (1.09 g). A mixture of the obtained compound (1.09 g), lithium hydroxide (0.087 g), and ethanol (18 mL) was stirred at room temperature for 30 minutes. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give ethyl (1R*,3S*,4R*)-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-hydroxy-4-methylcyclopentane-1-carboxylate (0.786 g). To a mixture of the obtained compound (0.786 g), TEA (0.344 g), and DCM (15 mL), methanesulfonyl chloride (0.292 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.331 g), and DMSO (15 mL) was stirred at 100 °C for 1 hour and allowed to cool to room temperature. The reaction mixture was added to water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give ethyl (1R*,3R*,4R*)-3-azido-1-((2'-(benzyloxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-methylcyclopentane-1-carboxylate (0.526 g). To a mixture of the obtained compound (0.526 g), methanol (10 mL), and water (0.034 mL), triphenylphosphine (0.424 g) was added at room temperature. The mixture was stirred at the same temperature for 13 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.437 g), and DCM (10 mL) was added methanesulfonyl chloride (0.247 g) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the title compound (0.379 g).

[0159] Reference Example G-1: 1-tert-Butyl 2-methyl (2S,4S)-5-oxo-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate. Triisopropylsilyl trifluoromethanesulfonate (15.0 g) was added to a mixture of 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g), imidazole (5.00 g), and DCM (50 mL) under ice cooling, and the mixture was stirred at room temperature for 2 days. Methanol (8.3 mL) and saturated brine were added to the reaction mixture, followed by extraction with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give 1-tert-butyl 2-methyl (2S,4S)-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (15.0 g). To a mixture of the resulting compound (15.0 g), sodium periodate (24.0 g), water (75 mL), and ethyl acetate (75 mL), ruthenium(III) chloride hydrate (0.421 g) was added at room temperature, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture, 1 mol / L aqueous sodium thiosulfate solution and 2-propanol were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes and filtered through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with 1 mol / L aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=95 / 5 to 80 / 20) to obtain the title compound (10.9 g).

[0160] Reference Example G-2: 1-tert-butyl 2-methyl (2S,4S,5S)-5-(2-(1,3-dioxolan-2-yl)ethyl)-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate. Under an argon atmosphere, a mixture of magnesium (0.611 g), iodine (1 piece), and THF (10 mL) was stirred at 50°C for 10 minutes. To the reaction mixture, a mixture of 2-(2-bromoethyl)-1,3-dioxolane (3.41 g) and THF (10 mL) was added dropwise at 50°C, and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture, a mixture of Reference Example G-1 (2.61 g) and THF (10 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 60 / 40) to give 1-tert-butyl 2-methyl (2S,4S)-5-(2-(1,3-dioxolan-2-yl)ethyl)-5-hydroxy-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.84 g). A mixture of the obtained compound (2.84 g), acetic acid (100 mL), and 5% platinum on carbon (0.852 g) was stirred under a hydrogen atmosphere at 50°C for 2 hours. 5% platinum on carbon (0.568 g) was added to the reaction mixture at room temperature, and the mixture was stirred under a hydrogen atmosphere at 50°C for 30 minutes and at 60°C for 15 minutes, and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=90 / 10 to 60 / 40) to obtain the title compound (2.01 g).

[0161] Reference Example G-3: (1R,3S,7aS)-3-(3-bromo-4-fluorobenzyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate. Under an argon atmosphere, lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (2.4 mL) was added to a mixture of Reference Example G-2 (1.00 g), 2-bromo-4-(bromomethyl)-1-fluorobenzene (0.561 g), and THF (20 mL) at -20°C, and the mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate 90 / 10 to 60 / 40) to give 1-tert-butyl 2-methyl (2S,4S,5S)-5-(2-(1,3-dioxolan-2-yl)ethyl)-2-(3-bromo-4-fluorobenzyl)-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (1.13 g). To a mixture of the resulting compound (1.13 g) and DCM (12 mL), trifluoroacetic acid (5.61 g) was added at room temperature, and the mixture was stirred at the same temperature for 20 hours and concentrated under reduced pressure. To a mixture of the residue and DCM (12 mL), sodium triacetoxyborohydride (0.695 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Sodium triacetoxyborohydride (0.695 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 80 / 20) to give methyl (1S,3S,7aS)-3-(3-bromo-4-fluorobenzyl)-1-((triisopropylsilyl)oxy)hexahydro-1H-pyrrolidine-3-carboxylate (0.780 g). 6 mol / L hydrochloric acid (25 mL) was added to a mixture of the resulting compound (0.780 g) and methanol (25 mL) at room temperature, and the mixture was stirred at 50 °C for 4 hours and allowed to cool to room temperature.Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to give methyl (1S,3S,7aS)-3-(3-bromo-4-fluorobenzyl)-1-hydroxyhexahydro-1H-pyrrolidine-3-carboxylate (0.430 g). Methanesulfonyl chloride (0.198 g) was added to a mixture of the resulting compound (0.430 g), TEA (0.234 g), and DCM (5 mL) under ice cooling, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.225 g), and DMSO (5 mL) was stirred at 100°C for 30 minutes and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to give methyl (1R,3S,7aS)-1-azido-3-(3-bromo-4-fluorobenzyl)hexahydro-1H-pyrrolidine-3-carboxylate (0.371 g). A mixture of the obtained compound (0.371 g), triphenylphosphine (0.367 g), methanol (5 mL), and water (0.034 mL) was stirred at room temperature for 58 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.189 g), and DCM (5 mL) was added methanesulfonyl chloride (0.160 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 30 / 70) to obtain the title compound (0.502 g).

[0162] Reference Example G-4 Reference Example G-4 was synthesized in the same manner as in Reference Example G-3, except that 1-bromo-3-(bromomethyl)benzene was used instead of 2-bromo-4-(bromomethyl)-1-fluorobenzene.

[0163] Reference Example G-5 (1R,3S,7aS)-3-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate Reference Example G-3 (0.420 g), (2-hydroxyphenyl)boronic acid (0.193 g), potassium carbonate (0.645 g), Pd(PPh3)4 (0.108 g), 1,4-dioxane (10 mL), and water (2 mL) were stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.343 g).

[0164] Reference Example G-6 Reference Example G-6 was synthesized in the same manner as in Reference Example G-5, except that Reference Example G-4 was used instead of Reference Example G-3.

[0165] Reference Example H-1: Methyl (6S,8S,8aS)-4-oxo-8-((triisopropylsilyl)oxy)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate. To a mixture of Reference Example G-1 (6.00 g), pyridine (2.28 g), and THF (15 mL), bis(cyclopentadienyl)dimethyltitanium (5% in toluene / THF) (135 mL) was added at room temperature, and the mixture was stirred at 80°C for 7 hours and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. n-Hexane was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) to give 1-tert-butyl 2-methyl (2S,4S)-5-methylene-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (4.63 g). To a mixture of the resulting compound (4.63 g) and THF (125 mL), borane-THF complex (0.93 mol / L in THF) (18 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. To the reaction mixture, a mixture of 2 mol / L aqueous sodium hydroxide (22 mL) and 35% aqueous hydrogen peroxide (16 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) to give 1-tert-butyl 2-methyl (2S,4S,5S)-5-(hydroxymethyl)-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (3.43 g). A mixture of the obtained compound (2.91 g), trifluoroacetic acid (15 mL), and DCM (30 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. DCM and saturated aqueous sodium bicarbonate were added to the residue, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.To a mixture of the residue, 2 mol / L aqueous sodium hydroxide (6.7 mL), and DCM (30 mL) was added chloroacetyl chloride (1.14 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 88 / 12 to 0 / 100) to give methyl (2S,4S,5S)-1-(2-chloroacetyl)-5-(hydroxymethyl)-4-((triisopropylsilyl)oxy)pyrrolidine-2-carboxylate (2.63 g). To a mixture of the resulting compound (2.63 g) and tert-butanol (50 mL), potassium tert-butoxide (1 mol / L in THF) (8.6 mL) was added at 40 °C, and the mixture was stirred at the same temperature for 5 minutes. Water and 2 mol / L hydrochloric acid were added to the reaction mixture, followed by extraction with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Methyl iodide (2.44 g) was added to a mixture of the residue, potassium carbonate (3.97 g), and DMF (50 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 82 / 18 to 0 / 100) to give the title compound (1.31 g).

[0166] Reference Example H-2: (6S,8R,8aR)-6-(3-bromo-4-fluorobenzyl)-8-(methylsulfonamido)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate. To a mixture of Reference Example H-1 (0.859 g), 2-bromo-4-(bromomethyl)-1-fluorobenzene (0.619 g), and THF (23 mL) was added lithium bis(trimethylsilyl)amide (1.0 mol / L in THF) (2.4 mL) at -20°C, and the mixture was stirred at the same temperature for 45 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 20 / 80) to give methyl (6S,8S,8aS)-6-(3-bromo-4-fluorobenzyl)-4-oxo-8-((triisopropylsilyl)oxy)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.574 g). To a mixture of the resulting compound (0.574 g) and THF (20 mL), borane-THF complex (0.93 mol / L in THF) (11 mL) was added at 60 °C. The mixture was stirred at the same temperature for 45 minutes and then allowed to cool to room temperature. Saturated aqueous ammonium chloride and water were added to the reaction mixture under water cooling, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and THF (10 mL), tetrabutylammonium fluoride (1 mol / L in THF) (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give methyl (6S,8S,8aS)-6-(3-bromo-4-fluorobenzyl)-8-hydroxyhexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.301 g).To a mixture of the obtained compound (0.301 g), TEA (0.143 g), and DCM (7 mL), methanesulfonyl chloride (0.122 g) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, sodium azide (0.138 g), and DMSO (10 mL) was stirred at 85°C for 3 hours under microwave irradiation. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give methyl (6S,8R,8aR)-8-azido-6-(3-bromo-4-fluorobenzyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylate (0.240 g). A mixture of the obtained compound (0.240 g), triphenylphosphine (0.143 g), methanol (5 mL), and water (0.028 mL) was stirred at 90 °C under microwave irradiation for 3 hours and then concentrated under reduced pressure. Methanesulfonyl chloride (0.119 g) was added to a mixture of the residue, TEA (0.157 g), and DCM (5.2 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (0.192 g).

[0167] Reference Example H-3 Reference Example H-3 was synthesized in the same manner as in Reference Example H-2, except that 1-bromo-3-(bromomethyl)benzene was used instead of 2-bromo-4-(bromomethyl)-1-fluorobenzene.

[0168] Reference Examples H-4 to H-5 Reference Examples H-4 to H-5 were synthesized in the same manner as in Reference Example G-5, except that the compounds of the corresponding Reference Examples were used instead of Reference Example G-3.

[0169] Reference Example I-1 tert-Butyl (2-(2-iodophenoxy)ethyl)carbamate Cesium carbonate (55.5 g) was added to a mixture of 2-iodophenol (25 g) and DMF (250 mL) at room temperature, and the mixture was stirred at the same temperature for 10 minutes. 1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide (17.8 g) was added to the mixture at room temperature, and the mixture was stirred at the same temperature for 10 minutes. 1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide (17.8 g) was added to the mixture at room temperature, and the mixture was stirred at the same temperature for 2 hours. 2 mol / L hydrochloric acid (199 mL) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and n-hexane. The extract was washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure to give the title compound (41.4 g).

[0170] Reference Example I-2 (2-(2-((tert-Butoxycarbonyl)amino)ethoxy)phenyl)boronic acid Under an argon atmosphere, isopropylmagnesium chloride-lithium chloride complex (1.3 mol / L in THF) (263 mL) was added dropwise to a mixture of Reference Example I-1 (41.4 g) and THF (166 mL) at −45° C., and the mixture was stirred at the same temperature for 30 minutes. Under an argon atmosphere, trimethyl borate (35.5 g) was added dropwise to the mixture at −45° C., and the mixture was stirred at the same temperature for 1 hour. 1 mol / L hydrochloric acid (228 mL) was added dropwise to the reaction mixture at −40° C., and the mixture was stirred under water-cooling and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was recrystallized using ethyl acetate (85 mL) and n-heptane (410 mL) to give the title compound (25.5 g).

[0171] Reference Example J-1 Ethyl 4-((triisopropylsilyl)oxy)cyclohexane-1-carboxylate To a mixture of ethyl 4-hydroxycyclohexanecarboxylate (1.0 g), imidazole (0.791 g), and DCM (15 mL) was added triisopropylsilyl trifluoromethanesulfonate (1.95 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the mixture were added imidazole (0.395 g) and triisopropylsilyl trifluoromethanesulfonate (1.77 g) successively under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (1.38 g).

[0172] Reference Example J-2 Ethyl 1-(3-bromo-4-fluorobenzyl)-4-((triisopropylsilyl)oxy)cyclohexane-1-carboxylate Under an argon atmosphere, lithium bis(trimethylsilyl)amide (1 mol / L in THF) (5.04 mL) was added dropwise to a mixture of Reference Example J-1 (1.38 g), 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.18 g), and THF (14 mL) at −15° C., and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. n-Heptane (5 mL) was added to the residue, and the mixture was stirred at 40° C. for 5 minutes and then at room temperature for 15 minutes. The mixture was filtered, and the filtrate was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 90 / 1) to obtain the title compound (1.54 g).

[0173] Reference Example J-3 Ethyl (1s,4s)-1-(3-bromo-4-fluorobenzyl)-4-hydroxycyclohexane-1-carboxylate. To a mixture of Reference Example J-2 (1.54 g) and THF (15 mL), tetrabutylammonium fluoride (1 mol / L in THF) (4.49 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give the title compound (0.625 g).

[0174] Reference Example J-4: Ethyl (1r,4r)-1-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamido)cyclohexane-1-carboxylate. To a mixture of Reference Example J-3 (0.625 g) and DCM (5 mL) was added TEA (0.282 g) at room temperature. Methanesulfonyl chloride (0.239 g) was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. TEA (0.085 g) and methanesulfonyl chloride (0.048 g) were added sequentially to the mixture at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Sodium azide (0.452 g) was added to a mixture of the residue and DMSO (3 mL), and the mixture was stirred at 90°C for 3 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and n-hexane. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15). Triphenylphosphine (0.730 g) and water (1.07 mL) were added to a mixture of the obtained compound (0.535 g) and toluene (5.35 mL) at room temperature, and the mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, DIPEA (0.360 g) was added to the reaction mixture under ice cooling. A mixture of methanesulfonyl chloride (0.239 g) and toluene (0.26 mL) was added to the mixture at the same temperature, and the mixture was stirred at room temperature for 1 hour. DIPEA (0.180 g) was added to the mixture under ice cooling. To this mixture was added a mixture of methanesulfonyl chloride (0.120 g) and toluene (0.26 mL) at the same temperature, and the mixture was stirred at room temperature for 30 minutes. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80) to give the title compound (0.486 g).

[0175] Reference Example J-5 Ethyl (1r,4r)-1-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclohexane-1-carboxylate Palladium(II) acetate (0.0048 g) was added to a mixture of Reference Example J-4 (0.250 g), Reference Example I-2 (0.169 g), XPhos (0.020 g), tripotassium phosphate (0.182 g), THF (1.31 mL), and water (1.31 mL). Under an argon atmosphere, the mixture was stirred at 75°C for 4 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was filtered through Celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (0.273 g).

[0176] Reference Example J-6 (1r,4r)-1-((2'-(2-aminoethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclohexane-1-carboxylic acid hydrochloride To a mixture of Reference Example J-5 (0.273 g), 2-propanol (2 mL), and water (2 mL), potassium hydroxide (0.089 g) was added at room temperature, and the mixture was stirred at 80°C for 4 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To a mixture of the residue (0.213 g), water (0.009 mL), tert-butyl alcohol (1 mL), and THF (0.5 mL), potassium tert-butoxide (0.114 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour. After cooling to room temperature, potassium tert-butoxide (0.114 g) and water (0.0091 mL) were added to the mixture, and the mixture was stirred at 60°C for 2 hours. After cooling to room temperature, tert-butyl alcohol (2 mL) and THF (1 mL) were added to the reaction mixture. The mixture was stirred at 60°C for 5 hours and then at 80°C for 8 hours. After cooling to room temperature, water (3 mL) was added to the reaction mixture. A mixture of di-tert-butyl dicarbonate (0.222 g) and THF (0.6 mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 1 hour. 2 mol / L hydrochloric acid (1.69 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and 1,4-dioxane (1.5 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 14 hours. Methanol (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to give the title compound (0.193 g).

[0177] Reference Example J-7 Reference Example J-7 was synthesized in the same manner as in Reference Example J-2, except that 1-bromo-3-(bromomethyl)benzene was used instead of 2-bromo-4-(bromomethyl)-1-fluorobenzene and ethyl 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate was used instead of Reference Example J-1.

[0178] Reference Example J-8 Reference Example J-8 was synthesized in the same manner as in Reference Example J-3, except that Reference Example J-7 was used instead of Reference Example J-2.

[0179] Reference Example J-9 Reference Example J-9 was synthesized in the same manner as in Reference Example J-4, except that Reference Example J-8 was used instead of Reference Example J-3.

[0180] Reference Example J-10 Reference Example J-10 was synthesized in the same manner as in Reference Example J-5, except that Reference Example J-9 was used instead of Reference Example J-4.

[0181] Reference Example J-11 Reference Example J-11 was synthesized in the same manner as in Reference Example J-6, except that Reference Example J-10 was used instead of Reference Example J-5.

[0182] Reference Example K-1: 1-tert-butyl 2-methyl (2S,4S)-2-(3-bromo-4-fluorobenzyl)-4-hydroxypyrrolidine-1,2-dicarboxylate. Under an argon atmosphere, to a mixture of Reference Example G-1 (2.00 g) and THF (15 mL) was added LDA (1.0 mol / L in THF) (5.92 mL) at −78°C, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a mixture of 2-bromo-4-(bromomethyl)-1-fluorobenzene (1.46 g) and THF (5 mL) at −78°C, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10) to give 1-tert-butyl 2-methyl (2S,4S)-2-(3-bromo-4-fluorobenzyl)-4-((triisopropylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (2.50 g). To a mixture of the obtained compound (2.50 g) and THF (10 mL), tetrabutylammonium fluoride (1 mol / L in THF) (5.10 mL) was added at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to give the title compound (0.899 g).

[0183] Reference Example K-2: 1-tert-butyl 2-methyl (2S,4R)-2-(3-bromo-4-fluorobenzyl)-4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate. To a mixture of Reference Example K-1 (0.899 g) and DCM (9 mL) was added TEA (0.402 g) at room temperature. Methanesulfonyl chloride (0.341 g) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. Sodium azide (0.387 g) was added to a mixture of the residue and DMSO (4.5 mL), and the mixture was stirred at 100°C for 3 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give 1-tert-butyl 2-methyl (2S,4R)-4-azido-2-(3-bromo-4-fluorobenzyl)pyrrolidine-1,2-dicarboxylate (0.896 g). To a mixture of the resulting compound (0.896 g) and toluene (12.6 mL), triphenylphosphine (0.965 g) and water (2.52 mL) were added sequentially at room temperature, and the mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, methanesulfonyl chloride (1.41 g) was added to the reaction mixture under ice cooling. DIPEA (1.43 g) was added to the mixture at the same temperature, and the mixture was stirred at room temperature for 15 minutes. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=50 / 50 to 20 / 80) to obtain the title compound (0.651 g).

[0184] Reference Example K-3 1-tert-butyl 2-methyl (2S,4R)-2-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)pyrrolidine-1,2-dicarboxylate Reference Example K-2 (0.250 g), Reference Example I-2 (0.193 g), XPhos (0.023 g), tripotassium phosphate (0.208 g), THF (1.75 mL), and water (1.75 mL) were mixed and palladium(II) acetate (0.0055 g) was added. Under an argon atmosphere, the mixture was stirred at 75°C for 4 hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture, and the mixture was filtered through Celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by APS silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.264 g).

[0185] Reference Example K-4 (2S,4R)-2-((2'-(2-aminoethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)pyrrolidine-2-carboxylic acid dihydrochloride. To a mixture of Reference Example K-3 (0.264 g), 2-propanol (2 mL), and water (2 mL), potassium hydroxide (0.087 g) was added at room temperature, and the mixture was stirred at 80°C for 15 hours. After cooling to room temperature, 2 mol / L hydrochloric acid (1.11 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a mixture of the residue and 1,4-dioxane (1.5 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.228 g).

[0186] Reference Example K-5 Reference Example K-5 was synthesized in the same manner as in Reference Example K-1, except that 1-bromo-3-(bromomethyl)benzene was used instead of 2-bromo-4-(bromomethyl)-1-fluorobenzene.

[0187] Reference Example K-6 Reference Example K-6 was synthesized in the same manner as in Reference Example K-2, except that Reference Example K-5 was used instead of Reference Example K-1.

[0188] Reference Example K-7 Reference Example K-7 was synthesized in the same manner as in Reference Example K-3, except that Reference Example K-6 was used instead of Reference Example K-2.

[0189] Reference Example K-8 Reference Example K-8 was synthesized in the same manner as in Reference Example K-4, except that Reference Example K-7 was used instead of Reference Example K-3.

[0190] The structural formulas of the reference examples are shown in the table below.

[0191] The stereochemistry of Reference Example F-10 in the table indicates the relative configuration.

[0192] Example 1 N-[(1R,3S)-11'-oxo-10'-azaspiro[cyclopentane-1,12'-tricyclo[12.3.1.0 2 , 7[Octadecane]-1'(18'),2',4',6',14',16'-hexaen-3-yl]methanesulfonamide. A mixture of Reference Example E-1 (0.061 g), 10% Pd / C (0.011 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (1 mL), and methanol (2 mL) was stirred at 70°C for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes. Ethyl acetate and 2 mol / L hydrochloric acid were added to the reaction mixture. The aqueous layer was separated and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.010 g), and DMF (5 mL) was added HATU (0.006 g) at room temperature, and the mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (1.3 mg).

[0193] Example 2 N-[(1R,3S)-12'-oxo-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7[nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide. A mixture of Reference Example E-2 (0.039 g), 10% Pd / C (0.020 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (1.1 mL), and methanol (1 mL) was stirred at 70°C for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour. Ethyl acetate and 2 mol / L hydrochloric acid were added to the reaction mixture. The aqueous layer was separated and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.007 g), and DMF (20 mL) was added HATU (0.005 g) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (2.0 mg).

[0194] Example 3 N-[(1R,3S)-14'-oxo-8'-oxa-13'-azaspiro[cyclopentane-1,15'-tricyclo[15.3.1.0 2 , 7[heneicosane]-1'(21'),2',4',6',17',19'-hexaen-3-yl]methanesulfonamide. A mixture of Reference Example E-3 (0.137 g), 10% Pd / C (0.135 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (1 mL), and methanol (4 mL) was stirred at 120°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.156 g), and DMF (10 mL) was added HATU (0.101 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.020 g).

[0195] Example 4 N-[(1R,3S)-12'-methyl-13'-oxo-8'-oxa-12'-azaspiro[cyclopentane-1,14'-tricyclo[14.3.1.0 2 , 7A mixture of Reference Example E-4 (0.064 g), 10% Pd / C (0.019 g), and methanol (1.1 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to give methyl (1R,3S)-1-((2'-(3-((tert-butoxycarbonyl)(methyl)amino)propoxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.060 g). A mixture of the obtained compound (0.060 g), 2 mol / L aqueous sodium hydroxide solution (1 mL), and methanol (1 mL) was stirred at 60°C for 4 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (2 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, hydrogen chloride (4 mol / L in 1,4-dioxane) (0.526 mL), and 1,4-dioxane (1 mL) was stirred at room temperature for 16 hours and concentrated under reduced pressure. HATU (0.060 g) was added to a mixture of the residue, DIPEA (0.068 g), and DMF (100 mL) at room temperature, and the mixture was stirred at the same temperature for 14 hours. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=50 / 50 to 0 / 100) to obtain the title compound (0.036 g).

[0196] Example 5 Example 5 was synthesized in the same manner as in Example 4, except that Reference Example E-5 was used instead of Reference Example E-4.

[0197] Example 6 N-[(1R,3S)-11'-methyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 ,7 ]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example F-1 (0.062 g), tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.027 g), and toluene (2 mL), (tributylphosphoranylidene)acetonitrile (0.110 g) was added at room temperature, and the mixture was stirred at 100°C for 1 hour and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl (1R,3S)-1-((2'-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.085 g). A mixture of the obtained compound (0.085 g), 2 mol / L aqueous sodium hydroxide solution (0.762 mL), and methanol (2 mL) was stirred at 100 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, hydrogen chloride (4 mol / L in 1,4-dioxane) (0.381 mL), and THF (2 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. A mixture of the residue, DIPEA (0.098 g), HATU (0.064 g), and DMF (15 mL) was stirred at room temperature for 30 minutes. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (0.015 g).

[0198] Example 7 N-[(1R,3S,10'R)-10'-methyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example E-6 (0.026 g), Boc-D-alaninol (0.034 g), and toluene (2 mL), (tributylphosphoranylidene)acetonitrile (0.047 g) was added at room temperature, and the mixture was stirred at 100°C for 1 hour and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to give methyl (1R,4R)-1-((2'-((R)-2-((tert-butoxycarbonyl)amino)propoxy)-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.041 g). A mixture of the obtained compound (0.041 g), 10% Pd / C (0.020 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue, 2 mol / L aqueous sodium hydroxide solution (2 mL), methanol (2 mL), and THF (1 mL) was stirred at 120 °C for 30 minutes under microwave irradiation. To the reaction mixture, 2 mol / L hydrochloric acid was added, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. HATU (0.024 g) was added to a mixture of the residue, DIPEA (0.037 g), and DMF (10 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (0.010 g).

[0199] Example 8 N-[(1R,3S,9'R)-9'-methyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.02 , 7 ]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example F-1 (0.050 g), N-Boc-(S)-1-amino-2-propanol (0.065 g) and toluene (2 mL), (tributylphosphoranylidene)acetonitrile (0.090 g) was added at room temperature, and the mixture was stirred at 100°C for 1 hour and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to give methyl (1R,3S)-1-((2'-(((R)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.104 g). A mixture of the obtained compound (0.104 g), 2 mol / L aqueous sodium hydroxide solution (2 mL), methanol (2 mL), and THF (1 mL) was stirred at 120 °C for 30 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. HATU (0.052 g) was added to a mixture of the residue, DIPEA (0.080 g), and DMF (10 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.022 g).

[0200] Example 9 N-[(1R,3S,10'S)-15'-oxo-8'-oxa-14'-azaspiro[cyclopentane-1,16'-tetracyclo[16.3.1.0 2 , 7 .0 10 ,14 ]docosane]-1'(22'),2',4',6',18',20'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example F-1 (0.062 g), (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl (0.062 g), and toluene (2 mL), (tributylphosphoranylidene)acetonitrile (0.112 g) was added at room temperature, and the mixture was stirred at 80°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give tert-butyl (S)-2-(((3'-(((1R,3S)-1-(methoxycarbonyl)-3-(methylsulfonamido)cyclopentyl)methyl)-[1,1'-biphenyl]-2-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.091 g). A mixture of the obtained compound (0.091 g), 2 mol / L aqueous sodium hydroxide solution (0.772 mL), and methanol (2 mL) was stirred at 80 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, hydrogen chloride (4 mol / L in 1,4-dioxane) (0.386 mL), and THF (2 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. A mixture of the residue, DIPEA (0.100 g), HATU (0.065 g), and DMF (21 mL) was stirred at room temperature for 30 minutes. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (0.018 g).

[0201] Example 10 N-[(1R,3S,9'R,11'R)-11'-methyl-13'-oxo-8'-oxa-12'-azaspiro[cyclopentane-1,14'-tetracyclo[14.3.1.1 9 , 12 .0 2 ,7]henicosane]-1'(20'),2',4',6',16',18'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example F-1 (0.067 g), tert-butyl (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (0.100 g) and toluene (1 mL), (tributylphosphoranylidene)acetonitrile (0.120 g) was added at room temperature, and the mixture was stirred at 80°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give tert-butyl (2R,4R)-4-((3'-(((1R,3S)-3-methanesulfonamido-1-(methoxycarbonyl)cyclopentyl)methyl)-[1,1'-biphenyl]-2-yl)oxy)-2-methylpyrrolidine-1-carboxylate (0.211 g). A mixture of the obtained compound (0.211 g), 2 mol / L aqueous sodium hydroxide solution (0.829 mL), and methanol (1 mL) was stirred at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 0 / 100) to give (1R,3S)-1-((2'-(((3R,5R)-1-(tert-butoxycarbonyl)-5-methylpyrrolidin-3-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)-3-methanesulfonamidocyclopentane-1-carboxylic acid (0.092 g). A mixture of the obtained compound (0.092 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.139 g), and DCM (17 mL), phosphoryl chloride (0.038 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with DCM, the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 0 / 100) to obtain the title compound (0.006 g).

[0202] Example 11 N-[(1R,3S)-11'-oxo-8'-oxa-12'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7A mixture of Reference Example D-2 (0.149 g), tert-butyl 3-(2-bromophenoxy)propanoate (0.177 g), potassium carbonate (0.202 g), Pd(PPh3)4 (0.034 g), 1,4-dioxane (8 mL), and water (2 mL) was stirred at 100°C for 75 minutes under microwave irradiation. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give benzyl (1R,4R)-1-((2'-(3-(tert-butoxy)-3-oxopropoxy)-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.129 g). A mixture of the obtained compound (0.129 g), 10% Pd / C (0.067 g), and THF (5 mL) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give (1R,3S)-1-((2'-(3-(tert-butoxy)-3-oxopropoxy)-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid (0.095 g). A mixture of the obtained compound (0.049 g), diphenylphosphoryl azide (0.029 g), TEA (0.014 g), and 1,4-dioxane (1 mL) was stirred at 100°C for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid (1 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 90 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to give tert-butyl 3-((3'-(((1R,3S)-1-amino-3-(methylsulfonamido)cyclopentyl)methyl)-[1,1'-biphenyl]-2-yl)oxy)propanoate (0.013 g). A mixture of the obtained compound (0.013 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (0.5 mL) was stirred at room temperature for 100 minutes and concentrated under reduced pressure. HATU (0.012 g) was added to a mixture of the residue, DIPEA (0.017 g), and DMF (3 mL) at room temperature, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added to water, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to give the title compound (2.9 mg).

[0203] Example 12 N-[(1R,3S)-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example F-2 (0.050 g), 2-(tert-butoxycarbonylamino)-1-ethanol (0.048 g) and toluene (2 mL), (tributylphosphoranylidene)acetonitrile (0.086 g) was added at room temperature, and the mixture was stirred at 80°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl (1R,3S)-1-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.081 g). A mixture of the obtained compound (0.081 g), 2 mol / L aqueous sodium hydroxide solution (0.593 mL), and methanol (2 mL) was stirred at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 0 / 100) to give (1R,3S)-1-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid (0.059 g). A mixture of the obtained compound (0.059 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (0.297 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. A mixture of the residue, DIPEA (0.077 g), HATU (0.050 g), and DMF (20 mL) was stirred at room temperature for 30 minutes. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 0 / 100) to obtain the title compound (0.011 g).

[0204] Examples 13 and 14 Examples 13 and 14 were synthesized in the same manner as in Example 12, except that the compounds of the corresponding Reference Examples were used instead of Reference Example F-2.

[0205] Example 15 N-[(1R,3S)-18'-fluoro-11'-methyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example F-2 (0.580 g), tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.289 g), and toluene (14 mL), (tributylphosphoranylidene)acetonitrile (1.66 g) was added at room temperature, and the mixture was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give methyl (1R,3S)-1-((2'-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.796 g). A mixture of the obtained compound (0.796 g), 2 mol / L aqueous sodium hydroxide solution (6.9 mL), and methanol (14 mL) was stirred at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 0 / 100) to give (1R,3S)-1-((2'-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid (0.777 g). A mixture of the obtained compound (0.777 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (10 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue, DIPEA (1.16 g), and DCM (138 mL), phosphoryl chloride (0.316 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0 to 0 / 100) to obtain the title compound (0.089 g).

[0206] Example 16 Example 16 was synthesized in the same manner as in Example 15, except that Reference Example F-4 and 2-(tert-butoxycarbonylamino)-1-ethanol were used instead of Reference Example F-2 and tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate, respectively.

[0207] Example 17 Example 17 was synthesized in the same manner as in Example 15, except that Reference Example F-4 was used instead of Reference Example F-2.

[0208] Example 18 N-[(1S,1's,3S,16's)-12'-oxo-8',15'-dioxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[14.2.2.0 2 , 7]icosane]-2',4',6'-trien-3-yl]methanesulfonamide. Reference Example C-6 (0.983 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.957 mL), and 2-propanol (10 mL) were mixed at room temperature with 20% palladium hydroxide on carbon (approximately 50% water-wet) (0.197 g), and the mixture was stirred under a hydrogen atmosphere at the same temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give methyl (1R,4R)-1-((((1s,4S)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.501 g). To a mixture of the obtained compound (0.193 g), 2-(tert-butoxycarbonylamino)-1-ethanol (0.095 g), and toluene (4 mL), (tributylphosphoranylidene)acetonitrile (0.330 g) was added at room temperature, and the mixture was stirred at 100° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give methyl (1R,4R)-1-((((1s,4S)-4-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)phenyl)cyclohexyl)oxy)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.258 g). A mixture of the obtained compound (0.258 g), 2 mol / L aqueous sodium hydroxide solution (2.3 mL), and methanol (2.5 mL) was stirred at 80°C for 20 minutes under microwave irradiation. The reaction mixture was added to 2 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1.1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.383 g), and DCM (46 mL), phosphoryl chloride (0.105 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water and extracted with DCM.The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give N-[(1R,1's,4R,16's)-12'-oxo-8',15'-dioxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[14.2.2.0]. 2 , 7 ]icosane]-2,2',4',6'-tetraen-4-yl]methanesulfonamide (0.005 g) was obtained. To a mixture of the obtained compound (0.005 g), ethanol (0.25 mL), and THF (0.25 mL), 10% Pd / C (1.1 mg) was added at room temperature, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (2.5 mg).

[0209] Example 19 Example 19 was synthesized in the same manner as in Example 12, except that Reference Example F-6 was used instead of Reference Example F-2.

[0210] Examples 20 to 21 Examples 20 to 21 were synthesized in the same manner as in Example 15, except that the compounds of the corresponding Reference Examples were used instead of Reference Example F-2.

[0211] Example 22 N-[(1R,3S)-12'-oxo-8'-oxa-6',11'-diazaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example E-13 (0.073 g), 2-(tert-butoxycarbonylamino)-1-ethanol (0.038 g) and toluene (1 mL), (tributylphosphoranylidene)acetonitrile (0.130 g) was added at room temperature, and the mixture was stirred at 110°C for 1.5 hours and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl (1R,4R)-1-(3-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)pyridin-3-yl)benzyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.098 g). A mixture of the obtained compound (0.098 g), 2 mol / L aqueous sodium hydroxide solution (0.901 mL), and methanol (1 mL) was stirred at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.151 g), and DMF (4.5 mL), HATU (0.102 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and extracted with DCM. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain N-[(1R,4R)-12'-oxo-8'-oxa-6',11'-diazaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0]]. 2 , 7]nonadecane]-1'(19'),2,2',4',6',15',17'-heptaen-4-yl]methanesulfonamide (0.009 g) was obtained. To a mixture of the obtained compound (0.009 g), ethanol (0.5 mL), and THF (0.5 mL), 10% platinum on carbon (approximately 55% water-wet) (0.007 g) was added at room temperature, and the mixture was stirred under a hydrogen atmosphere at the same temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (3.0 mg).

[0212] Example 23 N-[(1R,3S)-11'-ethyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide To a mixture of Reference Example E-6 (0.056 g), tert-butyl N-ethyl-N-(2-hydroxyethyl)carbamate (0.053 g), and toluene (1 mL), (tributylphosphoranylidene)acetonitrile (0.101 g) was added at room temperature, and the mixture was stirred at 100°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl (1R,4R)-1-((2'-(2-((tert-butoxycarbonyl)(ethyl)amino)ethoxy)-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.080 g). A mixture of the obtained compound (0.080 g), 2 mol / L aqueous sodium hydroxide solution (2 mL), and methanol (3 mL) was stirred at 100 °C for 15 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.092 g), and DCM (2 mL), phosphoryl chloride (0.025 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70) to obtain N-[(1R,4R)-11'-ethyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0]. 2 , 7]nonadecane]-1'(19'),2,2',4',6',15',17'-heptaen-4-yl]methanesulfonamide was obtained. A mixture of the obtained compound, 10% Pd / C (0.012 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70) followed by APS column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70) to obtain the title compound (0.012 g).

[0213] Example 24 N-[(1R,3S)-11'-cyclopropyl-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7 [nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide. A mixture of Reference Example E-14 (0.459 g), 2 mol / L aqueous sodium hydroxide solution (3.8 mL), and methanol (1 mL) was stirred at 80°C for 15 minutes under microwave irradiation. The reaction mixture was added to 2 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.640 g), and DCM (25 mL), phosphoryl chloride (0.175 g) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to water and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give N-[(1R,4R)-11'-cyclopropyl-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2,2',4',6',15',17'-heptaen-4-yl]methanesulfonamide (0.048 g) was obtained. To a mixture of the obtained compound (0.012 g), ethanol (0.5 mL), and THF (0.5 mL), 10% platinum on carbon (approximately 55% water-wet) (0.005 g) was added at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 1 hour and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.012 g).

[0214] Example 25 Example 25 was synthesized in the same manner as in Example 12, except that Reference Example F-8 was used instead of Reference Example F-2.

[0215] Example 26 N-[(1R,3S)-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7 ]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]ethane-1-sulfonamide. To a mixture of Reference Example F-9 (0.030 g), DIPEA (0.033 g), and DCM (2 mL), ethanesulfonyl chloride (0.013 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added to water, extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to obtain the title compound (0.025 g).

[0216] Example 27 Example 27 was synthesized in the same manner as in Example 26, except that fluoromethanesulfonyl chloride was used instead of ethanesulfonyl chloride.

[0217] Example 28 N-[(1R,3S)-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]cyclopropanesulfonamide. To a mixture of Reference Example F-9 (0.015 g), 1,8-diazabicyclo[5.4.0]-7-undecene (0.052 g), and DCM (2 mL), cyclopropanesulfonyl chloride (0.030 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to obtain the title compound (0.013 g).

[0218] Example 29 N-[(1R,4R)-11'-ethyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2,2',4',6',15',17'-heptaen-4-yl]methanesulfonamide To a mixture of Reference Example E-6 (0.056 g), tert-butyl N-ethyl-N-(2-hydroxyethyl)carbamate (0.053 g), and toluene (1 mL), (tributylphosphoranylidene)acetonitrile (0.101 g) was added at room temperature, and the mixture was stirred at 100°C for 30 minutes and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give methyl (1R,4R)-1-((2'-(2-((tert-butoxycarbonyl)(ethyl)amino)ethoxy)-[1,1'-biphenyl]-3-yl)methyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate (0.080 g). A mixture of the obtained compound (0.080 g), 2 mol / L aqueous sodium hydroxide solution (2 mL), and methanol (3 mL) was stirred at 100 °C for 15 minutes under microwave irradiation. The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. To a mixture of the residue (0.027 g), DIPEA (0.046 g), and DCM (2 mL), phosphoryl chloride (0.013 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70) to give the title compound (3.0 mg).

[0219] Example 30 N-[(1R*,3R*,4R*)-18'-fluoro-4-methyl-12'-oxo-8'-oxa-11'-azaspiro[cyclopentane-1,13'-tricyclo[13.3.1.0 2 , 7[nonadecane]-1'(19'),2',4',6',15',17'-hexaen-3-yl]methanesulfonamide Reference Example F-10 (0.379 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.351 mL), and ethanol (7 mL) were added with 20% palladium hydroxide on carbon (approximately 50% water-wet) (0.076 g) at room temperature, and the mixture was stirred at the same temperature under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give ethyl (1R*,3R*,4R*)-1-((6-fluoro-2'-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3-methyl-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.322 g). To a mixture of the obtained compound (0.160 g), 2-(tert-butoxycarbonylamino)-1-ethanol (0.080 g), and toluene (3.6 mL), (tributylphosphoranylidene)acetonitrile (0.258 g) was added at room temperature, and the mixture was stirred at 90 °C under microwave irradiation for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give ethyl (1R*,3R*,4R*)-1-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-methyl-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.211 g). A mixture of the obtained compound (0.211 g), 2 mol / L aqueous sodium hydroxide solution (1.8 mL), and methanol (2 mL) was stirred at 90 °C for 30 minutes under microwave irradiation. The reaction mixture was added to 2 mol / L hydrochloric acid and extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (0.890 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. A mixture of the residue, DIPEA (0.230 g), HATU (0.203 g), and DMF (36 mL) was stirred at room temperature for 30 minutes.The reaction mixture was added to 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to give the title compound (0.057 g).

[0220] Example 31 N-[(1R,3S,7aS)-18'-fluoro-12'-oxo-1,2,5,6,7,7a-hexahydro-8'-oxa-11'-azaspiro[pyrrolidine-3,13'-tricyclo[13.3.1.0 2 , 7]nonadecane]-1'(19'),2',4',6',15',17'-hexaen-1-yl]methanesulfonamide To a mixture of Reference Example G-5 (0.343 g), 2-(tert-butoxycarbonylamino)-1-ethanol (0.179 g) and toluene (5 mL), (tributylphosphoranylidene)acetonitrile (0.537 g) was added at room temperature, and the mixture was stirred at 100°C for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give methyl (1R,3S,7aS)-3-((2'-(2-((tert-butoxycarbonyl)amino)ethoxy)-6-fluoro-[1,1'-biphenyl]-3-yl)methyl)-1-(methylsulfonamido)hexahydro-1H-pyrrolidine-3-carboxylate (0.297 g). A mixture of the obtained compound (0.297 g), 2 mol / L aqueous sodium hydroxide solution (1.9 mL), and methanol (3 mL) was stirred at 100 °C for 1 hour under microwave irradiation. Water and 2 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (5 mL) was stirred at room temperature for 30 minutes and concentrated under reduced pressure. A mixture of the residue, DIPEA (0.480 g), and DMF (30 mL) was added to a mixture of DIPEA (0.480 g), HATU (0.310 g), and DMF (30 mL) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give the title compound (0.028 g).

[0221] Examples 32 to 34 Examples 32 to 34 were synthesized in the same manner as in Example 31, except that the compounds of the corresponding Reference Examples were used instead of Reference Example G-5.

[0222] Example 35 N-[(1r,4r)-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[cyclohexane-1,13'-tricyclo[13.3.1.0 2,7 [nonadecane]-1'(19'),2',4',6',15',17'-hexaen-4-yl]methanesulfonamide. DIPEA (0.172 g) was added to a mixture of HATU (0.190 g) and acetonitrile (25 mL) at room temperature. A mixture of Reference Example J-6 (0.193 g), acetonitrile (1.7 mL), and DMF (1.7 mL) was added dropwise to the mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate, water, and saturated aqueous sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 0.2% NH in H O / 0.2% NH in MeCN = 69.4 / 30.6 to 5 / 95) to obtain the title compound (0.079 g).

[0223] Example 36 Example 36 was synthesized in the same manner as in Example 35, except that Reference Example J-11 was used instead of Reference Example J-6.

[0224] Example 37 N-[(2S,4R)-18'-fluoro-12'-oxo-8'-oxa-11'-azaspiro[pyrrolidine-2,13'-tricyclo[13.3.1.0 2,7[nonadecane]-1'(19'),2',4',6',15',17'-hexaen-4-yl]methanesulfonamide. DIPEA (0.241 g) was added to a mixture of HATU (0.213 g) and acetonitrile (29 mL) at room temperature. A mixture of Reference Example K-4 (0.196 g), acetonitrile (2 mL), and DMF (2 mL) was added dropwise to the mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Ethyl acetate, water, and saturated aqueous sodium bicarbonate were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain (0.099 g).

[0225] Example 38 N-[(2S,4R)-18'-fluoro-1-methyl-12'-oxo-8'-oxa-11'-azaspiro[pyrrolidine-2,13'-tricyclo[13.3.1.0 2,7 To a mixture of [nonadecane]-1'(19'),2',4',6',15',17'-hexaen-4-yl]methanesulfonamide Example 37 (0.076 g) and methanol (1 mL), formaldehyde solution (37%) (0.047 mL) was added at room temperature and stirred at the same temperature for 20 minutes. Sodium triacetoxyborohydride (0.084 g) was added to the mixture at room temperature and stirred at the same temperature for 1 hour. Sodium triacetoxyborohydride (0.021 g) was added to the mixture at room temperature and stirred at room temperature for 15 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: 0.2% NH in H O / 0.2% NH in MeCN = 72.4 / 27.6 to 5 / 95) to obtain the title compound (0.058 g).

[0226] Example 39 Example 39 was synthesized in the same manner as in Example 37, except that Reference Example K-8 was used instead of Reference Example K-4.

[0227] Example 40 Example 40 was synthesized in the same manner as in Example 38, except that Example 39 was used instead of Example 37.

[0228] The structural formulas, physical properties, and OX2R agonist activity (see Test Example 1) of the examples are shown in the table below.

[0229] The stereochemistry designation for Example 30 in the table indicates the relative configuration.

[0230] Test Example 1

[0231] 1) Obtaining Human OX2R-Expressing Cells. The human OX2R sequence (Accession No. NM_001526.4) was inserted into the multicloning site of pcDNA3.4 (Life Technologies Japan, Inc.) to clone a human OX2R expression plasmid vector. This plasmid was then introduced into CHO-K1 cells using Lipofectamine 2000 (Life Technologies Japan, Inc.). After two days, the transfected CHO-K1 cells were passaged into 175T flasks and selectively cultured for six days. The selective medium used was Ham's F-12 Nutrient Mix (Life Technologies Japan, Inc.) containing Geneticin® (Life Technologies Japan, Inc.) at a final concentration of 1 mg / mL and heat-inactivated fetal bovine serum (Biowest) at a final concentration of 10%. After selective culture, the cells were replated onto 96-well plates, and human OX2R-expressing cell lines were obtained by limiting dilution.

[0232] 2) Measurement of OX2R agonist activity The agonist activity of the test substance on human OX2R was evaluated using the change in intracellular calcium concentration upon stimulation as an index. On the day before measuring the intracellular calcium concentration, 5 × 10 human OX2R-expressing cells suspended in medium were cultured. 3Cells were seeded into a 384-well plate at 50 μL / well and cultured overnight in an incubator set at 37°C and 5% CO2. After incubation, the medium was removed and replaced with 20 μL of loading buffer. The loading buffer used was an assay buffer containing Fluo4-AM (Dojindo Laboratories, Inc.) at a final concentration of 1.14 μM, Cremophor® EL (Nacalai Tesque, Inc.) at a final concentration of 0.02%, probenecid (Life Technologies Japan, Inc.) at a final concentration of 1.5 mM, and amaranth (Sigma-Aldrich Japan, LLC) at a final concentration of 0.5 mg / mL. The assay buffer used was Hank's balanced salt solution containing 20 mM HEPES, 1.5 mM CaCl2, 0.5 mM MgCl2, and 0.4 mM MgSO4, adjusted to pH 7.4. After incubating the cells at 37°C for 45 minutes, fluorescence intensity was measured over time using an FDSS® 7000 (Hamamatsu Photonics) (excitation wavelength: 480 nm, emission wavelength: 540 nm). Twenty seconds after the start of the measurement, a vehicle containing the test substance (final concentration: 10 μM) or vehicle alone was added, and the measurement was continued for 2 minutes. The vehicle was a solution prepared by diluting dimethyl sulfoxide to a final concentration of 0.1% in assay buffer containing a final concentration of 0.1% bovine serum albumin (Fujifilm Wako Pure Chemical Corporation). The fluorescence intensity upon addition of a final concentration of 1 μM human orexin A peptide (Peptide Institute, Inc.) was set as 100%, and the fluorescence intensity upon addition of vehicle alone was set as 0%. The agonist activity of the test substance against human OX2R was calculated by setting the fluorescence intensity upon addition of a final concentration of 1 μM human orexin A peptide (Peptide Institute, Inc.) as 100% and that upon addition of vehicle alone as 0%. The table above shows the activation rate of each test substance at a compound concentration of 10 μM. In the table, Act. ≧ 75%: A, 75% > Act. ≧ 50%: B, 50% > Act. ≧ 30%: C. These results demonstrated that the compounds of the present invention have agonistic activity against human OX2R.

[0233] The compound of the present invention or a pharmacologically acceptable salt thereof has OX2R agonist activity and is therefore useful as a therapeutic agent for sleep disorders involving OX2R.

Claims

1. A compound represented by formula (I): wherein ring V is C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Ring W is C 3-8 Cycloalkyl, C 5-10 Bicycloalkyl, 3- to 8-membered heterocycloalkyl, C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; Ring Z is a group represented by formula (1) or (2): Y 1 is a single bond, CR a1 R a2 , C.R. a1 , O, or NR b1 and Y 2 is CR 4 R 5 , or CR 4 and Y 3 is CR a1 or N; Y 4 is a single bond, CR a1 R a2 , O or NR b2 and represents a single or double bond; R a1 , R a2 , R a3 , and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R a1 and R a2 When there are two or more of each, each R a1 and R a2 may be the same or different; R b1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R b2 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; R 4 and R 5 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, HaloC 1-6 Alkyl or C 1-6 alkoxy, or may be taken together to form a 3- to 8-membered saturated ring; R 6 and R 7 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 6 and R 7 When there are two or more of each, each R 6 and R 7 may be the same or different; p and q are each independently 1 or 2; r is an integer of 0 to 2; L 1 is a single bond, CR a5 R a6 , or NR b3 and R a5 and R a6 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl or haloC 1-6 alkyl; R b3 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 alkyl; L 2 is -(CR a7 R a8 )s-, or * -(CR a7 R a8 )s-NR b4 - ** and the bond marked with * is L 3 the bond marked with ** is the bond to the carbonyl; R a7 and R a8 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R a7 and R a8 When there are two or more of each, each R a7 and R a8 may be the same or different; R b4 is a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl or C 3-6 cycloalkyl; R a7 is R a8 together with unsubstituted or 1 or 2 C 1-6 forming a 3- to 8-membered saturated carbocyclic ring substituted with alkyl, or R b4 together with unsubstituted or 1 or 2 C 1-6 Optionally, the alkyl group forms a 4- to 8-membered saturated heterocyclic ring; s is an integer from 1 to 5; L 3 is a single bond, O, or NR b5 and R b5 is a hydrogen atom or C 1-6 alkyl; L 4 is a single bond or O; R 1 is C 1-6 Alkyl, C 2-6 Alkenyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted C 3-8 Cycloalkyl, unsubstituted or 1 to 3 C 1-6 Alkyl-substituted 3- to 8-membered heterocycloalkyl, haloC 1-6 Alkyl or C 1-6 alkylamino; R 2 is a halogen atom, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl or C 1-6 alkylamino; R 3 is a halogen atom, hydroxy, amino, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 m and n are each independently an integer from 0 to 2; when m is 2, each R 2 may be the same or different; when n is 2, each R 3 may be the same or different] or a pharmacologically acceptable salt thereof.

2. The compound of claim 1, comprising: Y 3 is N; R a1 , R a2 , R a3 , and R a4 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 4 is a hydrogen atom or C 1-6 alkyl; R 5 is a hydrogen atom; R 6 and R 7 is a hydrogen atom; p and q are 1; s is an integer from 2 to 4; L 3 is a single bond or O, or a pharmacologically acceptable salt thereof.

3. The compound according to claim 2, wherein ring V is C 6-10 aryl, or 5- or 6-membered heteroaryl; Ring W is C 3-8 Cycloalkyl, C 6-10 aryl, or 5- or 6-membered heteroaryl; Y 1 But, CR a1 R a2 , or CR a1 and Y 4 But, CR a1 R a2 , O, or NR b2 and L 1 is a single bond or NR b3 r is 1 or 2; R b3 is a hydrogen atom; R a7 and R a8 are each independently a hydrogen atom or C 1-6 alkyl; R a7 is R b4 together with unsubstituted or 1 or 2 C 1-6 R may form a 4- to 8-membered saturated heterocyclic ring substituted with alkyl; b4 is a hydrogen atom, C 1-6 Alkyl or C 3-6 cycloalkyl; R 1 But C 1-6 Alkyl, C 3-8 Cycloalkyl, HaloC 1-6 Alkyl or C 1-6 alkylamino; R 2 is a halogen atom or C 1-6 alkyl; R 3 is a halogen atom or C 1-6 alkyl; and m and n are each independently 0 or 1, or a pharmaceutically acceptable salt thereof.

4. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

5. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

6. A compound selected from the group consisting of the following compounds: and or a pharmacologically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmacologically acceptable salt thereof, and pharmaceutical additives.

8. The pharmaceutical composition according to claim 7, which is a pharmaceutical composition for treating sleep disorders involving OX2R.

9. The pharmaceutical composition according to claim 8, wherein the sleep disorder involving OX2R is narcolepsy.

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