Pharmaceutical composition containing cyclopentane compound

Abstract

To provide a cyclopentane compound that exhibits agonist activity toward an orexin 2 receptor (OX2R) and is useful as a therapeutic agent for a sleep disorder associated with OX2R.SOLUTION: A pharmaceutical composition comprising a cyclopentane compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof is provided. A pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof has agonist activity for an orexin 2 receptor (OX2R) and is useful as a therapeutic agent for sleep disorders involving OX2R (for example, narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia caused by physical disease, hypersomnia caused by mental disorder, hypersomnia caused by drugs or substances, circadian rhythm sleep-wake disorder, sleep deprivation syndrome, and long sleep).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing a cyclopentane compound useful as a pharmaceutical. More specifically, the present invention relates to a pharmaceutical composition containing a cyclopentane compound or a pharmacologically acceptable salt thereof, which has agonist activity against orexin type 2 receptor (OX2R) and is useful as a therapeutic agent for sleep disorders associated with OX2R. [Background technology]

[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 except for 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 receptor 1 (OX1R) and orexin receptor 2 (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 the cause of narcolepsy.

[0003] Narcolepsy is a sleep disorder and a chronic neurological disease whose main symptoms are excessive daytime sleepiness and sleep attacks. Narcolepsy is classified into two types based on its symptoms: Type 1 (NT1) when cataplexy (attacks of sudden physical weakness caused by strong emotions) is present, and Type 2 (NT2) when it is not. Currently, in the treatment of narcolepsy, the central nervous system stimulants modafinil, methylphenidate, and pemoline are used for hypersomnia symptoms, but all of them can cause paradoxical reactions, and methylphenidate and pemoline have strong side effects such as dependency.On the other hand, for cataplexy, since the aforementioned drugs have no therapeutic effect, antidepressants are used, but they are difficult to use due to their strong side effects, and discontinuing the medication can cause exacerbation due to the rebound phenomenon characteristic of antidepressants. Thus, the current state of narcolepsy treatment is that only symptomatic treatment is available for all symptoms, and there is a need for therapeutic agents that address the etiology of narcolepsy.

[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 a gene encoding OX2R (Non-Patent Document 2), and that 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. In addition, Patent Document 15 and Non-Patent Document 5 describe compounds containing cyclopentane substituted with sulfonamide as a partial structure. However, the cyclopentane compound of the present invention is not described in any of Patent Documents 1 to 15, Non-Patent Document 4, or Non-Patent Document 5. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2021 / 048822 [Patent Document 2] International Publication No. 2021 / 166934 [Patent Document 3] International Publication No. 2021 / 142083 [Patent Document 4] International Publication No. 2021 / 048821 [Patent Document 5] US Patent Application Publication No. 2020 / 0247747 [Patent Document 6] U.S. Patent Application Publication No. 2019 / 0040010 [Patent Document 7] US Patent Application Publication No. 2020 / 0385346 [Patent Document 8] US Patent Application Publication No. 2017 / 0226137 [Patent Document 9] International Publication No. 2022 / 109117 [Patent Document 10] US Patent Application Publication No. 2022 / 0056017 [Patent Document 11] International Publication No. 2022 / 040058 [Patent Document 12] International Publication No. 2021 / 026047 [Patent Document 13] U.S. Patent Application Publication No. 2020 / 0255403 [Patent Document 14] US Patent Application Publication No. 2022 / 0144771 [Patent Document 15] US Patent Application Publication No. 2007 / 0149532 [Non-patent literature]

[0008] [Non-Patent Document 1] Thomas C. Thannickal et al., Neuron, 2000, Vol. 27, No. 3, pp. 469-474 [Non-patent document 2] Ling Lin et al., “Cell” 1999, Volume 98, No. 3, p. 365-376 [Non-patent document 3] 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 [Non-patent document 4] Hiroshi Yukitake et al., "Pharmacology, Biochemistry and Behavior," 2019, Vol. 187, p. 172794 [Non-patent document 5] Maris Vilums et al., European Journal of Medicinal Chemistry, 2015, Vol. 93, pp. 121-134 Summary of the Invention [Problem to be solved by the invention]

[0009] An objective of the present invention is to provide a pharmaceutical composition containing a novel compound having OX2R agonist activity. [Means for solving the problem]

[0010] The present invention relates to a pharmaceutical composition comprising 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] Compounds of formula (I): [ka] [During the ceremony, Ring A is C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; R 1 is a group selected from the group consisting of the following (a) to (c): (a) -NR a R a ', [ka] and [ka] R a and R a ' are each independently a hydrogen atom, a hydroxy group, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or haloC 1-6 is alkyl; R b is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or haloC 1-6 is alkyl; p is an integer from 1 to 3; When p is 2 or 3, each R b may be the same or different from each other; q is an integer from 1 to 3; r is 1 or 2; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, 1-3 C 1-6C optionally substituted with alkyl 3-8 Cycloalkyl, 1-3 C 1-6 3-8 membered heterocycloalkyl optionally substituted with alkyl, haloC 1-6 Alkyl, or C 1-6 With alkylamino; R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, or C 1-6 is alkoxy; R 5 and R 6 are each independently a hydrogen atom or a halogen atom; R 7 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 is alkylamino; R 8 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, or C 1-6 is alkylamino; n is 1 or 2; If n is 2, then each R 7 may be the same or different from each other; m is 1 or 2; If m is 2, then each R 8 may be the same or different from each other. or a pharmacologically acceptable salt thereof. [2] The pharmaceutical composition according to [1], Ring A is C 6-10 aryl, or 5- or 6-membered heteroaryl; R 5 and R 6 is a hydrogen atom; R 7However, hydrogen atoms, halogen atoms, hydroxyl groups, C 1-6 Alkyl, HaloC 1-6 Alkyl, or C 1-6 is alkoxy; A pharmaceutical composition comprising a compound wherein n is 1 or a pharmacologically acceptable salt thereof. [3] The pharmaceutical composition according to [1] or [2], R a and R a ' are each independently a hydrogen atom, a hydroxy group, or C 1-6 Alkyl, or C 1-6 is alkoxy; R b C 1-6 is alkyl; p is 1; q is 2; r is 1; R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or C 1-6 A pharmaceutical composition comprising a compound or a pharmacologically acceptable salt thereof, wherein R is an alkyl group; [4] The pharmaceutical composition according to any one of [1] to [3] above, comprising: R 1 But, -NR a R a 'And; R a and R a ', but independently, C 1-6 Alkyl, or C 1-6 A pharmaceutical composition comprising a compound which is alkoxy or a pharmacologically acceptable salt thereof. [5] The pharmaceutical composition according to any one of [1] to [4], comprising: A pharmaceutical composition comprising a compound or a pharmacologically acceptable salt thereof, wherein ring A is a 5- or 6-membered heteroaryl. [6] The pharmaceutical composition according to any one of [1] to [5], comprising: R 2 But C 1-6 Alkyl, 1-3 C1-6 C optionally substituted with alkyl 3-8 Cycloalkyl, 1-3 C 1-6 3-8 membered heterocycloalkyl optionally substituted with alkyl, or haloC 1-6 A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group; [7] The pharmaceutical composition according to any one of [1] to [6] above, comprising a compound represented by formula (II): [ka] [During the ceremony, R 2 is C 1-6 Alkyl, 1-3 C 1-6 C optionally substituted with alkyl 3-8 Cycloalkyl, 1-3 C 1-6 3-8 membered heterocycloalkyl optionally substituted with alkyl, or haloC 1-6 is alkyl; R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or C 1-6 is alkyl; R 7 is a hydrogen atom, a halogen atom, a hydroxy group, or C 1-6 is alkyl; R 8 is a hydrogen atom, a halogen atom, or C 1-6 alkyl] or a pharmacologically acceptable salt thereof. [8] The pharmaceutical composition according to any one of [1] to [7], wherein the compound is selected from the group consisting of the following compounds: [ka] and [ka] or a pharmacologically acceptable salt thereof. [9] The pharmaceutical composition according to any one of [1] to [7], wherein the compound is selected from the group consisting of the following compounds: [ka] and [ka] or a pharmacologically acceptable salt thereof.

[10] The pharmaceutical composition according to any one of [1] to [9] above, which is a pharmaceutical composition for treating a sleep disorder involving OX2R.

[11] The pharmaceutical composition according to

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

[0012] In one embodiment, among the compounds represented by formula (I), for example, a compound represented by the following formula (II) is preferred. [ka] [The symbols in the formula have the same meaning as in any one of [1] to [6] above.]

[0013] In one embodiment, among the compounds represented by formula (II), for example, a compound represented by the following formula (II-I) is preferred. [ka] [The symbols in the formula have the same meanings as in [7] above.]

[0014] In one embodiment, the present invention relates to a method for treating a sleep disorder involving OX2R, comprising administering to a patient a required amount of the pharmaceutical composition according to any one of [1] to [9] above.

[0015] In one embodiment, the present invention relates to use of the pharmaceutical composition according to any one of [1] to [9] above for producing a pharmaceutical composition for treating a sleep disorder involving OX2R. [Effects of the Invention]

[0016] The compound of the present invention has excellent OX2R agonist activity, and therefore, a pharmaceutical composition containing the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for sleep disorders involving OX2R. DETAILED DESCRIPTION OF THE INVENTION

[0017] Hereinafter, embodiments of the present invention will be described in more detail.

[0018] In the present invention, each term has the following meaning unless otherwise specified.

[0019] "Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom. "C 1-6 The term "alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. "C 2-6 The term "alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms. Examples include ethenyl, 1-propenyl, and 2-propenyl. "C 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, and isopropoxy.

[0020] "Haro C 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 identical or different halogen atoms. 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. "Hydroxy C 1-6"Alkyl" refers to a C alkyl group substituted with one or two hydroxy groups. 1-6 It means alkyl, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. "C 1-6 Alkoxy C 1-6 "Alkyl" means one C 1-6 Alkoxy-substituted C 1-6 It means alkyl, such as methoxymethyl, 2-methoxyethyl, ethoxymethyl, and 2-ethoxyethyl.

[0021] "C 1-6 "Alkylamino" means (C 1-6 alkyl)-NH-, or (C 1-6 alkyl)N-, (C 1-6 The 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.

[0022] "C 6-10 "Aryl" means a phenyl or naphthyl group. The term "5- or 6-membered heteroaryl" refers to 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. The term "9- or 10-membered heteroaryl" refers to a bicyclic 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, quinoxalyl, cinnolyl, pteridinyl, chromenyl, and isochromenyl. "C 3-8 "Cycloalkyl" refers to a saturated hydrocarbon group having a 3- to 8-membered ring, including those with a partially bridged structure. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.2.2]octyl. 3-8 1 to 3 cycloalkyl C 1-6 When substituted with alkyl, each substituent may be the same or different. 1-6 Alkyl-substituted C 3-8 Cycloalkyl includes, for example, 1-methylcyclopropyl, 2-methylcyclopropyl, and the like. The term "3- to 8-membered heterocycloalkyl" refers to a cycloalkyl group in which a carbon atom in the ring is substituted with one or two heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom, and also includes those having a partially bridged structure. 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, and the like.

[0023] The following abbreviations used in the text, figures, and tables have the following meanings: AZADOL®: 2-hydroxy-2-azaadamantane Boc2O: di-tert-butyl dicarbonate DIPEA: N,N-diisopropylethylamine DCM: dichloromethane DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide Deoxo-Fluor: Bis(2-methoxyethyl)aminosulfur trifluoride HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LDA: lithium diisopropylamide MeCN: acetonitrile Me4tBuXPhos: 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl MTBE: Methyl tert-butyl ether NMP: N-methylpyrrolidone PdCl2(PPh3)2: Dichlorobis(triphenylphosphine)palladium(II) Pd(dba)2: bis(dibenzylideneacetone)palladium(0) Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) TEA: Triethylamine TFA: Trifluoroacetic acid 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 10% Pd / C: 10% palladium on carbon (approximately 55% water-wet) APS: Aminopropylated silica gel ODS: Octadecylsilanized silica gel Method A: Column chromatography using an aminopropylated silica gel column followed by a silica gel column Chiral preparative column chromatography: Chiral preparative column chromatography using YMC CHIRALART Cellulose-SB Ref. No.: Reference number Str.:Structural formula Ex. No.: Example number Phys. data: physical properties 1 H-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 100%, and the fluorescence intensity when only the vehicle was added was 0%. CHO: Chinese hamster ovary HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid

[0024] When one or more asymmetric carbon atoms are present in the compounds represented by formula (I) or formula (II), 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.

[0025] In the case where the compound represented by formula (I) or formula (II) has cis-trans isomers, the present invention encompasses both of the cis-trans isomers.

[0026] When tautomers exist in the compounds represented by formula (I) or formula (II), the present invention includes all of the tautomers.

[0027] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0028] The compounds of formula (I) or (II) can be converted into their pharmacologically acceptable salts in accordance with conventional methods, if necessary. Examples of such salts include acid addition salts and salts with bases.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] When the compound represented by formula (I) or formula (II) 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 an appropriate co-crystal former, etc.

[0033] In the compounds represented by formula (I) or formula (II), 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).

[0034] In the compound represented by formula (I) or formula (II), a compound 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 into which an isotope has been incorporated. Alternatively, the compound can be produced by a method described in the literature (see, for example, Journal of Organic Synthetic Chemistry, Vol. 65, No. 12, pp. 1179-1190, 2007, and RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

[0035] The compounds of the present invention represented by formula (I) or formula (II) can be produced, for example, by the methods shown in Schemes 1 to 12 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compounds of formula (I) or formula (II) correspond to the compounds of formulas (I-1) to (I-10).

[0036] The compounds of the present invention represented by formula (I) or formula (II) can be produced by the following methods, which are merely examples of general production methods and are not intended to limit the scope of the present invention.

[0037] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0038] In the reaction of each step, the reaction time varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 30 minutes to 3 days unless otherwise specified.

[0039] 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.

[0040] In the reaction of each step, the pressure varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 1 to 20 atmospheres unless otherwise specified.

[0041] In the reactions of each step, a microwave reaction apparatus such as Initiator manufactured by Biotage may be used. When the reactions are carried out using a microwave reaction apparatus, the conditions vary depending on the raw materials, solvent, and model used, but the reactions 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.

[0042] 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, MTBE, 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, TFA, methanesulfonic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water.

[0043] 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.; Organolithium compounds: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0044] 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 to be used include the acids described in the Reference Examples and Examples corresponding to each step and the following acids. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, TFA, 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.

[0045] 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 to be used include the condensing agents described in the Reference Examples or Examples corresponding to each step, and 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.

[0046] 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, and 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] When fluorination is carried out in each step, the reaction can be carried out in the presence or absence of a base using a fluorination reagent, such as Deoxo-Fluor or N,N-diethylaminosulfur trifluoride.

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

[0062] [ka] The symbols in the formula have the same meanings as above. X 1 represents a chlorine atom, a bromine atom, or an iodine atom.

[0063] Process 1-1 Compound (I) can also be produced by sulfonylation or sulfamoylation of compound (1-1).

[0064] Process 1-2 Compound (I) can also be produced by amidation of compound (1-2).

[0065] Process 1-3 Compound (I) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-3) and compound (1-5).

[0066] Process 1-4 Compound (1-4) can also be produced by reacting compound (1-3) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0067] Process 1-5 Compound (I) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-4) and compound (1-6).

[0068] The compound represented by formula (I-1) can be produced, for example, according to the method described in Scheme 2.

[0069] [ka] The symbols in the formula have the same meanings as above. 1 indicates a protecting group.

[0070] Process 2-1 Compound (2-2) can also be produced by subjecting compound (2-1) to Staudinger reaction.

[0071] Process 2-2 Compound (2-3) can also be produced by sulfonylation of compound (2-2).

[0072] Process 2-3 Compound (2-4) can also be produced by reacting compound (2-3) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0073] Process 2-4 Compound (2-5) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (2-4) and compound (1-6).

[0074] Process 2-5 Compound (1-2a) can also be produced by hydrolysis of compound (2-5).

[0075] Process 2-6 Compound (I-1) can also be produced by amidation of compound (1-2a).

[0076] Process 2-7 Compound (2-6) can also be produced by hydrolysis of compound (2-3).

[0077] Process 2-8 Compound (1-3a) can also be produced by amidation of compound (2-6).

[0078] Process 2-9 Compound (1-4a) can also be produced by reacting compound (1-3a) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0079] Process 2-10 Compound (I-1) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-4a) and compound (1-6).

[0080] Process 2-11 Compound (I-1) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-3a) and compound (1-5).

[0081] Process 2-12 Compound (2-7) can also be prepared by protecting the amino group of compound (2-2).

[0082] Process 2-13 Compound (2-8) can also be produced by hydrolysis of compound (2-7).

[0083] Process 2-14 Compound (2-9) can also be produced by amidation of compound (2-8).

[0084] Process 2-15 Compound (2-10) can also be produced by reacting compound (2-9) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0085] Process 2-16 Compound (2-11) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (2-10) and compound (1-6).

[0086] Process 2-17 Compound (1-1a) can also be produced by removing the protecting group of compound (2-11).

[0087] Process 2-18 Compound (I-1) can also be produced by sulfonylation or sulfamoylation of compound (1-1a).

[0088] The compound represented by compound (2-1) can be produced, for example, according to the method described in Scheme 3.

[0089] [ka] The symbols in the formula have the same meanings as above. X 2 represents a chlorine atom or a bromine atom.

[0090] Process 3-1 Compound (3-3) can also be produced by reacting compound (3-1) with compound (3-2) in the presence of a base.

[0091] Process 3-2 Compound (3-4) can also be produced by hydrolysis of compound (3-3).

[0092] Process 3-3 Compound (3-5) can also be produced by reacting compound (3-4) with DMSO and bromotrimethylsilane in the presence of a base.

[0093] Process 3-4 Compound (3-6) can also be produced by reacting compound (3-5) with 2,2'-azobisisobutyronitrile and tris(trimethylsilyl)silane.

[0094] Process 3-5 Compound (3-7) can also be produced by reacting compound (3-6) with methanol in the presence of an acid.

[0095] Process 3-6 Compound (3-8) can also be produced by reacting compound (3-7) with methanesulfonyl chloride in the presence of a base.

[0096] Process 3-7 Compound (2-1) can also be produced by reacting compound (3-8) with sodium azide.

[0097] The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 4.

[0098] [ka] The symbols in the formula have the same meanings as above. The stereochemical notation in the formula indicates the relative configuration.

[0099] Process 4-1 Compound (4-2) can also be produced by reacting compound (3-1) with compound (4-1) in the presence of a base.

[0100] Process 4-2 The compound (4-3) and the compound (4-4) can also be produced by oxidizing the compound (4-2).

[0101] Process 4-3 Compound (4-5) can also be produced by reacting compound (4-4) with sodium azide.

[0102] Process 4-4 Compound (4-6) can also be produced by fluorination of compound (4-5).

[0103] Process 4-5 Compound (4-7) can also be produced by hydrolysis of compound (4-6).

[0104] Process 4-6 Compound (4-8) can also be produced by amidation of compound (4-7).

[0105] Process 4-7 Compound (1-1b) can also be produced by Staudinger reaction or catalytic reduction of compound (4-8).

[0106] Process 4-8 Compound (I-2) can also be produced by sulfonylation or sulfamoylation of compound (1-1b).

[0107] The compound represented by formula (I-3) can be produced, for example, according to the method described in Scheme 5.

[0108] [ka] The symbols in the formula have the same meanings as above. The stereochemical notation in the formula indicates the relative configuration.

[0109] Process 5-1 Compound (5-1) can also be produced by the Mitsunobu reaction of compound (4-5) with 4-nitrobenzoic acid.

[0110] Process 5-2 Compound (5-2) can also be produced by removing the p-nitrobenzoyl group from compound (5-1). The p-nitrobenzoyl group can be removed by, for example, hydrolysis.

[0111] Process 5-3 The compound (5-3) can also be produced by fluorinating the compound (5-2).

[0112] Process 5-4 Compound (5-4) can also be produced by hydrolysis of compound (5-3).

[0113] Process 5-5 Compound (5-5) can also be produced by amidation of compound (5-4).

[0114] Process 5-6 Compound (1-1c) can also be produced by subjecting compound (5-5) to Staudinger reaction or catalytic reduction.

[0115] Process 5-7 Compound (I-3) can also be produced by sulfonylation or sulfamoylation of compound (1-1c).

[0116] The compound represented by formula (I-4) can be produced, for example, according to the method described in Scheme 6.

[0117] [ka] The symbols in the formula have the same meanings as above. 2 indicates a protecting group. The stereochemistry in the formula indicates the relative configuration.

[0118] Process 6-1 Compound (6-1) can also be produced by Staudinger reaction or catalytic reduction of compound (4-5).

[0119] Process 6-2 Compound (6-2) can also be prepared by protecting the amino group of compound (6-1).

[0120] Process 6-3 Compound (6-3) can also be prepared by oxidation of compound (6-2).

[0121] Process 6-4 Compound (6-4) can also be produced by fluorination of compound (6-3).

[0122] Process 6-5 Compound (6-5) can also be prepared by hydrolysis of compound (6-4).

[0123] Process 6-6 Compound (6-6) can also be produced by amidation of compound (6-5).

[0124] Process 6-7 Compound (1-1d) can also be prepared by removing the protecting group of compound (6-6).

[0125] Process 6-8 Compound (I-4) can also be produced by sulfonylation or sulfamoylation of compound (1-1d).

[0126] The compound represented by compound (4-1) can be produced, for example, according to the method described in Scheme 7.

[0127] [ka] The symbols in the formula have the same meanings as above.

[0128] Process 7-1 Compound (7-2) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-6) and compound (7-1).

[0129] Process 7-2 Compound (7-4) can also be prepared by reduction of compound (7-2).

[0130] Process 7-3 Compound (7-4) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-6) and compound (7-3).

[0131] Process 7-4 Compound (7-5) can also be produced by reacting compound (7-4) with methanesulfonyl chloride in the presence of a base.

[0132] Process 7-5 Compound (4-1) can also be produced by reacting compound (7-5) with lithium bromide.

[0133] The compound represented by formula (I-5) can be produced, for example, according to the method described in Scheme 8.

[0134] [ka] The symbols in the formula have the same meanings as above. 3 represents a carbamate protecting group.

[0135] Process 8-1 Compound (8-2) can also be produced by removing the tert-butoxycarbonyl group of compound (8-1) in the presence of hydrogen chloride.

[0136] Process 8-2 Compound (8-3) can also be produced by reacting compound (8-2) with diphenylmethanimine.

[0137] Process 8-3 Compound (8-4) can also be produced by reacting compound (8-3) with compound (4-1) in the presence of a base.

[0138] Process 8-4 Compound (8-5) can also be produced by removing the diphenylmethylidene group from compound (8-4). The removal of the diphenylmethylidene group can be carried out, for example, by hydrolysis.

[0139] Process 8-5 Compound (8-6) can also be prepared by sulfonylation of compound (8-5).

[0140] Process 8-6 Compound (8-7) can also be prepared by catalytic reduction of compound (8-6).

[0141] Process 8-7 Compound (1-2b) can also be produced by hydrolysis of compound (8-7).

[0142] Process 8-8 Compound (I-5) can also be produced by amidation of compound (1-2b).

[0143] Process 8-9 Compound (8-8) can also be prepared by protecting the amino group of compound (8-5).

[0144] Process 8-10 Compound (8-9) can also be produced by catalytic reduction of compound (8-8).

[0145] Process 8-11 Compound (8-10) can also be prepared by hydrolysis of compound (8-9).

[0146] Process 8-12 Compound (8-11) can also be produced by amidation of compound (8-10).

[0147] Process 8-13 Compound (1-1e) can also be prepared by removing the protecting group of compound (8-11).

[0148] Process 8-14 Compound (I-5) can also be produced by sulfonylation or sulfamoylation of compound (1-1e).

[0149] Process 8-15 Compound (8-12) can also be prepared by removing the protecting group of compound (8-9).

[0150] Process 8-16 Compound (8-7) can also be prepared by sulfonylation or sulfamoylation of compound (8-12).

[0151] The compounds represented by formula (I-6) and formula (I-7) can be produced, for example, according to the method described in Scheme 9.

[0152] [ka] The symbols in the formula have the same meanings as above.

[0153] Process 9-1 Compound (9-1) can also be produced by reacting compound (8-8) with DMSO and bromotrimethylsilane in the presence of a base.

[0154] Process 9-2 Compound (9-2) can also be produced by reacting compound (9-1) with 2,2'-azobisisobutyronitrile and tris(trimethylsilyl)silane.

[0155] Process 9-3 Compound (9-3) can also be prepared by sulfonylation of compound (9-2).

[0156] Process 9-4 Compound (9-4a) can also be produced by reacting compound (9-3) with methanol in the presence of a base.

[0157] Process 9-5 Compound (9-5a) can also be produced by fluorination of compound (9-4a).

[0158] Process 9-6 Compound (1-2c) can also be produced by hydrolysis of compound (9-5a).

[0159] Process 9-7 Compound (I-6) can also be produced by amidation of compound (1-2c).

[0160] Process 9-8 Compound (9-6) can also be produced by the Mitsunobu reaction of compound (9-4a) with 4-nitrobenzoic acid.

[0161] Process 9-9 Compound (9-4b) can also be produced by removing the p-nitrobenzoyl group from compound (9-6). The p-nitrobenzoyl group can be removed by, for example, hydrolysis.

[0162] Process 9-10 Compound (9-5b) can also be produced by fluorination of compound (9-4b).

[0163] Process 9-11 Compound (1-2d) can also be produced by hydrolysis of compound (9-5b).

[0164] Process 9-12 Compound (I-7) can also be produced by amidation of compound (1-2d).

[0165] The compound represented by formula (I-8) can be produced, for example, according to the method described in Scheme 10.

[0166] [ka] The symbols in the formula have the same meanings as above. 4 indicates a protecting group.

[0167] Process 10-1 Compound (10-2) can also be produced by catalytic reduction of compound (10-1).

[0168] Process 10-2 Compound (10-3) can also be prepared by oxidation of compound (10-2).

[0169] Process 10-3 Compound (10-4) can also be produced by fluorination of compound (10-3).

[0170] Process 10-4 Compound (10-5) can also be prepared by removing the protecting group of compound (10-4).

[0171] Process 10-5 Compound (10-6) can also be produced by reacting compound (10-5) with diphenylmethanimine.

[0172] Process 10-6 Compound (10-7) can also be produced by reacting compound (10-6) with compound (4-1) in the presence of a base.

[0173] Process 10-7 Compound (10-8) can also be produced by removing the diphenylmethylidene group from compound (10-7). The removal of the diphenylmethylidene group can be carried out, for example, by hydrolysis.

[0174] Process 10-8 Compound (10-9) can also be prepared by sulfonylation of compound (10-8).

[0175] Process 10-9 Compound (1-2e) can also be produced by hydrolysis of compound (10-9).

[0176] Process 10-10 Compound (I-8) can also be produced by amidation of compound (1-2e).

[0177] The compound represented by formula (I-9) can be produced, for example, according to the method described in Scheme 11.

[0178] [ka] The symbols in the formula have the same meanings as above. 3a is C 1-6 The stereochemistry in the formula indicates the relative configuration.

[0179] Process 11-1 Compound (11-1) is a mixture of compound (4-4) and C 1-6 Alkyllithium reagent, or C 1-6 It can also be produced by reacting an alkylmagnesium reagent.

[0180] Process 11-2 Compound (11-2) can also be produced by reacting compound (11-1) with methanesulfonyl chloride in the presence of a base.

[0181] Process 11-3 Compound (11-3) can also be produced by reacting compound (11-2) with sodium azide.

[0182] Process 11-4 Compound (11-4) can also be produced by Staudinger reaction or catalytic reduction of compound (11-3).

[0183] Process 11-5 Compound (11-5) can also be prepared by sulfonylation of compound (11-4).

[0184] Process 11-6 Compound (1-2f) can also be prepared by hydrolysis of compound (11-5).

[0185] Process 11-7 Compound (I-9) can also be produced by amidation of compound (1-2f).

[0186] The compound represented by formula (I-10) can be produced, for example, according to the method described in Scheme 12.

[0187] [ka] The symbols in the formula have the same meanings as above. 5 , P.G. 6 indicates a protecting group. 3b is C 1-6 Indicates an alkyl group.

[0188] Process 12-1 Compound (12-1) can also be prepared by protecting the hydroxyl group of compound (9-4a).

[0189] Process 12-2 Compound (12-2) can also be prepared by protecting the sulfonamide NH of compound (12-1).

[0190] Process 12-3 Compound (12-3) can also be prepared by removing the protecting group of the hydroxyl group of compound (12-2).

[0191] Process 12-4 Compound (12-4) can be prepared by reacting compound (12-3) with halogenated C in the presence of a base. 1-6It can also be produced by reacting alkyl with halogenated C. 1-6 Examples of the alkyl include methyl iodide and ethyl iodide.

[0192] Process 12-5 Compound (12-5) can also be prepared by hydrolysis of compound (12-4).

[0193] Process 12-6 Compound (12-6) can also be prepared by amidation of compound (12-5).

[0194] Process 12-7 Compound (I-10) can also be prepared by removing the protecting group of compound (12-6).

[0195] The schemes shown above are examples of methods for producing compounds represented by formula (I) or formula (II) or their intermediates. The schemes can be modified in various ways that can be easily understood by those skilled in the art.

[0196] The compound represented by formula (I) or formula (II) 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.

[0197] The compounds of the present invention have excellent OX2R agonist activity and can therefore be used as therapeutic agents 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, and the like. 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).

[0198] In the present invention, "treatment" includes the meaning of "prevention."

[0199] 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)."

[0200] While OX2R is involved in maintaining wakefulness, signaling through 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 agonistic activity against OX2R among orexin receptors. The agonistic activity against OX1R can be measured by a method well known in the art or a method modified therefrom (see, for example, Non-Patent Document 4).

[0201] 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.

[0202] 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.

[0203] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or formula (II) or a pharmacologically acceptable salt thereof as an active ingredient.

[0204] The pharmaceutical compositions of the present invention are prepared using a compound represented by formula (I) or (II) 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, using methods known in pharmaceutical sciences depending on the dosage form.

[0205] When the pharmaceutical composition of the present invention is used for treatment, the dose of the compound represented by formula (I) or formula (II) or a pharmacologically acceptable salt thereof is appropriately determined depending on the patient's age, sex, weight, disease, degree of treatment, etc. The daily dose may be administered in one, two, three, or four divided doses. In the case of oral or parenteral administration, the dosage for an adult can be set within the range of, for example, 0.01 to 1000 mg / day. In one embodiment, the oral dosage can be set within the range of 0.01 to 500 mg / day, preferably 0.01 to 100 mg / day.

[0206] 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 for the treatment of 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.

[0207] When a compound represented by formula (I) or formula (II) or a pharmacologically acceptable salt thereof is used in combination with another drug, 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 a compound represented by formula (I) or formula (II) or a pharmacologically acceptable salt thereof may be appropriately reduced depending on the dosage of the other drug used in combination.

[0208] The compound represented by formula (I) or formula (II) 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. [Example]

[0209] 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.

[0210] The names of compounds described in the following examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents. The configuration of the asymmetric center marked with "*" in the compound name means the relative configuration. For example, (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-azidocyclopentane-1-carboxylate methyl ester (Reference Example A-1) indicates a mixture of (1R,3S)- and (1S,3R)-1-([1,1'-biphenyl]-3-ylmethyl)-3-azidocyclopentane-1-carboxylate methyl esters.

[0211] Reference example A-1 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-azidocyclopentane-1-carboxylate methyl ester Under an argon atmosphere, LDA (1.09 mol / L in THF / n-hexane) (7.85 mL) was added to a mixture of ethyl 3-cyclopentene-1-carboxylate (1.00 g) and THF (15 mL) at -78 °C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of 3-(bromomethyl)-1,1'-biphenyl (1.94 g) and THF (9 mL) was added to the reaction mixture at -78 °C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes. 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 sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5) to give ethyl 1-([1,1'-biphenyl]-3-ylmethyl)cyclopent-3-ene-1-carboxylate (2.31 g). A mixture of the obtained compound (2.19 g), 4 mol / L aqueous lithium hydroxide solution (5 mL), methanol (14 mL), and THF (7 mL) was stirred at 150 °C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid 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 sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 70 / 30) to give 1-([1,1'-biphenyl]-3-ylmethyl)cyclopent-3-ene-1-carboxylic acid (2.30 g). To a mixture of DMSO (0.911 g) and chloroform (18 mL), bromotrimethylsilane (1.79 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, a mixture of 1-([1,1'-biphenyl]-3-ylmethyl)cyclopent-3-ene-1-carboxylic acid (1.99 g) and chloroform (9 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, DIPEA (1.47 g) was added under ice-cooling. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5 to 50 / 50) to give (1S * ,4R * ,6S * )-4-([1,1'-biphenyl]-3-ylmethyl)-6-bromo-2-oxabicyclo[2.2.1]heptan-3-one (1.70 g) was obtained. To a mixture of the obtained compound (1.70 g), 2,2'-azobisisobutyronitrile (0.078 g), and toluene (10 mL) was added tris(trimethylsilyl)silane (1.78 g) at room temperature. The mixture was stirred at 90°C for 30 minutes and allowed to cool to room temperature. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture. 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 = 98 / 2 to 70 / 30) to obtain (1R * ,4R * )-4-([1,1'-biphenyl]-3-ylmethyl)-2-oxabicyclo[2.2.1]heptan-3-one (1.30 g) was obtained. A mixture of the obtained compound (1.30 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (5.84 mL), and methanol (10 mL) was stirred at 70°C for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to obtain (1R* ,3R * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-hydroxycyclopentane-1-carboxylate (1.07 g) was obtained. To a mixture of the obtained compound (1.07 g), TEA (0.698 g), and DCM (15 mL), methanesulfonyl chloride (0.592 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue and DMSO (15 mL) was added sodium azide (0.672 g) at room temperature. The mixture was stirred at 60°C for 30 minutes and allowed to cool to room temperature. Water was added to the reaction mixture. 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 80 / 20) to obtain the title compound (1.06 g).

[0212] Reference example A-2 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid To a mixture of Reference Example A-1 (0.400 g), methanol (6 mL), and water (0.043 mL) was added triphenylphosphine (0.469 g) at room temperature, and the mixture was stirred at the same temperature for 9 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.362 g), and DCM (10 mL) was added methanesulfonyl chloride (0.205 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 = 80 / 20 to 30 / 70) to obtain (1R * ,3S *)-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate (0.391 g) was obtained. A mixture of the obtained compound (0.230 g), 4 mol / L aqueous lithium hydroxide solution (0.742 mL), methanol (0.8 mL), THF (0.8 mL), and water (0.2 mL) was stirred at 100°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.222 g).

[0213] Reference example A-3 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid To a mixture of Reference Example A-1 (0.250 g), methanol (2 mL), and water (0.027 mL) was added triphenylphosphine (0.293 g) at room temperature, and the mixture was stirred at the same temperature for 15 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.226 g), and DCM (4 mL) was added BocO (0.179 g) at room temperature, and the mixture was stirred at the same temperature for 30 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 75 / 25) to obtain (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-(tert-butoxycarbonylamino)cyclopentane-1-carboxylate (0.300 g) was obtained. A mixture of the obtained compound (0.300 g), 4 mol / L aqueous lithium hydroxide solution (0.916 mL), methanol (0.8 mL), THF (0.8 mL), and water (0.2 mL) was stirred at 100°C for 15 minutes under microwave irradiation. 2 mol / L hydrochloric acid was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.289 g).

[0214] Reference example A-4 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-amino-N-methoxy-N-methylcyclopentane-1-carboxamide hydrochloride To a mixture of Reference Example A-3 (0.289 g), N,O-dimethylhydroxylamine hydrochloride (0.143 g), DIPEA (0.472 g), and DMF (4 mL) was added HATU (0.306 g) at room temperature. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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 50 / 50) to give ((1S * ,3R * )-3-([1,1'-biphenyl]-3-ylmethyl)-3-(methoxy(methyl)carbamoyl)cyclopentyl)carbamate tert-butyl ester (0.270 g) was obtained. A mixture of the obtained compound (0.270 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (0.230 g).

[0215] Reference example B-1 (1R * ,3S * )-3-Azido-1-(3-chlorobenzyl)cyclopentane-1-carboxylate methyl ester Under an argon atmosphere, LDA (1.09 mol / L in THF / n-hexane) (15.7 mL) was added to a mixture of ethyl 3-cyclopentene-1-carboxylate (2.00 g) and THF (32 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of 3-chlorobenzyl bromide (3.22 g) and THF (16 mL) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride and water were added to the reaction mixture under ice-cooling. 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 95 / 5) to give ethyl 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylate (3.50 g). A mixture of the obtained compound (3.50 g), 2 mol / L aqueous sodium hydroxide solution (33 mL), methanol (66 mL), and THF (33 mL) was stirred at 70°C for 3.5 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture. 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 to give 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylic acid (3.06 g). To a mixture of DMSO (1.31 g) and chloroform (25 mL), bromotrimethylsilane (2.57 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, a mixture of 1-(3-chlorobenzyl)cyclopent-3-ene-1-carboxylic acid (3.06 g) and chloroform (18 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, DIPEA (2.17 g) was added under ice-cooling. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture. The mixture was 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 = 98 / 2 to 80 / 20) to give (1S * ,4R * ,6S *)-6-Bromo-4-(3-chlorobenzyl)-2-oxabicyclo[2.2.1]heptan-3-one (2.20 g) was obtained. To a mixture of the obtained compound (2.20 g), 2,2'-azobisisobutyronitrile (0.115 g), and toluene (35 mL), tris(trimethylsilyl)silane (2.60 g) was added at room temperature. The mixture was stirred at 80°C for 1 hour and allowed to cool to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. 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 = 95 / 5 to 80 / 20) to obtain (1R * ,4R * )-4-(3-chlorobenzyl)-2-oxabicyclo[2.2.1]heptan-3-one (1.52 g) was obtained. A mixture of the obtained compound (1.52 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (16 mL), and methanol (13 mL) was stirred at 70°C for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to obtain (1R * ,3R * )-1-(3-chlorobenzyl)-3-hydroxycyclopentane-1-carboxylate (1.29 g) was obtained. To a mixture of the obtained compound (1.29 g), TEA (0.968 g), and DCM (16 mL), methanesulfonyl chloride (0.822 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 50 minutes. The reaction mixture was added to water and extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DMSO (16 mL) was added sodium azide (0.933 g) at room temperature. The mixture was stirred at 60°C for 30 minutes and allowed to cool to room temperature. Water was added to the reaction mixture. 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 90 / 10) to obtain the title compound (1.24 g).

[0216] Reference example B-2 (1R * ,3S * )-1-(3-chlorobenzyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate methyl ester To a mixture of Reference Example B-1 (1.00 g), methanol (8 mL), and water (0.123 mL) was added triphenylphosphine (1.34 g) at room temperature, and the mixture was stirred at the same temperature for 7 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (1.03 g), and DCM (8 mL) was added methanesulfonyl chloride (0.585 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 = 70 / 30 to 50 / 50) to give the title compound (1.00 g).

[0217] Reference example B-3 (1R * ,3S * )-1-(3-chlorobenzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example B-2 (1.38 g) and methanol (15 mL) was added 2 mol / L aqueous sodium hydroxide solution (10 mL) at room temperature. The mixture was stirred at 60°C for 4 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid was added to the reaction mixture. 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (1.51 g), DIPEA (2.50 g), and DMF (19 mL) was added HATU (1.62 g) at room temperature. The mixture was stirred at 70°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (1.25 g).

[0218] Reference example B-4 (1R * ,3S * )-N-Methoxy-N-methyl-3-(methylsulfonamido)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopentane-1-carboxamide A mixture of Reference Example B-3 (0.177 g), bis(pinacolato)diboron (0.359 g), potassium acetate (0.139 g), Pd(dppf)Cl DCM adduct (0.039 g), Xphos (0.045 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 = 50 / 50 to 0 / 100) to give the title compound (0.201 g).

[0219] Reference example B-5 Reference Example B-5 was synthesized in the same manner as in Reference Example B-4, except that Reference Example B-2 was used instead of Reference Example B-3.

[0220] Reference example B-6~Reference example B-9 Reference Examples B-6 to B-9 were synthesized in the same manner as in Reference Example B-1, except that the corresponding reagents were used instead of 3-chlorobenzyl bromide.

[0221] Reference example B-10 ~ Reference example B-13 Reference Examples B-10 to B-13 were synthesized in the same manner as in Reference Example B-2, except that the corresponding Reference Examples were used instead of Reference Example B-1.

[0222] Reference example B-14~Reference example B-17 Reference Examples B-14 to B-17 were synthesized in the same manner as in Reference Example B-3, except that the corresponding Reference Examples were used in place of Reference Example B-2.

[0223] Reference example B-18 ~ Reference example B-21 Reference Examples B-18 to B-21 were synthesized in the same manner as in Reference Example B-4, except that the corresponding Reference Examples were used instead of Reference Example B-3.

[0224] Reference example B-22 Reference Example B-22 was synthesized in the same manner as in Reference Example A-3, except that Reference Example B-1 was used instead of Reference Example A-1.

[0225] Reference example C-1 (1R * ,3S * )-3-(Methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxylic acid A mixture of Reference Example B-5 (0.030 g), 2-bromopyrimidine (0.022 g), sodium carbonate (0.022 g), Pd(dppf)Cl DCM adduct (0.006 g), 1,4-dioxane (1 mL), ethanol (0.5 mL), and water (0.25 mL) was stirred at 90°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 = 50 / 50 to 0 / 100) and then APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain (1R * ,3S * )-3-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.016 g) was obtained. To a mixture of the obtained compound (0.016 g) and methanol (1 mL), 2 mol / L aqueous sodium hydroxide solution (0.421 mL) was added at room temperature. The mixture was stirred at 60°C for 8.5 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid and water were added to the reaction mixture. 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 80 / 20) to give the title compound (0.015 g).

[0226] Reference example C-2 (1R * ,3S * )-3-Amino-N-methoxy-N-methyl-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide hydrochloride To a mixture of Reference Example B-22 (0.136 g) and DCM (3 mL), oxalyl chloride (0.058 g) and DMF (4.8 mg) were added at room temperature, followed by stirring at the same temperature for 30 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.187 g) and DIPEA (0.497 g) were added to the reaction mixture at room temperature, followed by stirring at the same temperature for 30 minutes. Water was added to the reaction mixture. The mixture was 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 give ((1S * ,3R * )-3-(3-chlorobenzyl)-3-(methoxy(methyl)carbamoyl)cyclopentyl)carbamate tert-butyl ester (0.104 g) was obtained. A mixture of the obtained compound (0.104 g), bis(pinacolato)diboron (0.203 g), potassium acetate (0.079 g), Pd(dppf)Cl2 (0.020 g), Xphos (0.025 g), and 1,4-dioxane (2 mL) was stirred at 110 °C for 1 hour under microwave irradiation. Water was added to the reaction mixture. 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 = 80 / 20 to 0 / 100) to give ((1S * ,3R * )-3-(methoxy(methyl)carbamoyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopentyl)carbamate tert-butyl ester (0.106 g) was obtained. A mixture of the obtained compound (0.052 g), 2-bromopyrimidine (0.068 g), sodium carbonate (0.068 g), Pd(dppf)Cl2DCM adduct (0.009 g), 1,4-dioxane (1 mL), ethanol (0.5 mL), and water (0.5 mL) was stirred at 90 °C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to give ((1S * ,3R* )-3-(methoxy(methyl)carbamoyl)-3-(3-(pyrimidin-2-yl)benzyl)cyclopentyl)carbamate tert-butyl ester (0.026 g) was obtained. A mixture of the obtained compound (0.026 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (0.021 g).

[0227] Reference example D-1 5-Bromo-2-(3-(bromomethyl)phenyl)pyrimidine To a mixture of (3-(5-bromopyrimidin-2-yl)phenyl)methanol (1.07 g), TEA (0.531 g), and ethyl acetate (30 mL) was added methanesulfonyl chloride (0.509 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered. To the filtrate was added lithium bromide monohydrate (1.27 g) at room temperature, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was added to water, 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 (1.13 g).

[0228] Reference example D-2 Reference Example D-2 was synthesized in the same manner as in Reference Example D-1, except that (3-(5-fluoropyrimidin-2-yl)phenyl)methanol was used instead of (3-(5-bromopyrimidin-2-yl)phenyl)methanol.

[0229] Reference example D-3 (4-fluoro-3-(5-fluoropyrimidin-2-yl)phenyl)methanol A mixture of (2-fluoro-5-(hydroxymethyl)phenyl)boronic acid (3.07 g), 2-chloro-5-fluoropyrimidine (3.17 g), cesium carbonate (8.83 g), Pd(PPh3)4 (0.418 g), DMF (45 mL), and water (9 mL) was stirred at 100°C for 2 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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 = 50 / 50 to 20 / 80) to obtain the title compound (2.17 g).

[0230] Reference example D-4 (2-fluoro-5-(5-fluoropyrimidin-2-yl)phenyl)methanol A mixture of (4-fluoro-3-(hydroxymethyl)phenyl)boronic acid (1.01 g), 2-chloro-5-fluoropyrimidine (1.02 g), cesium carbonate (2.90 g), Pd(PPh3)4 (0.137 g), DMF (15 mL), and water (3 mL) was stirred at 100 °C for 1.5 hours under microwave irradiation. 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 = 90 / 10 to 85 / 15) to give the title compound (1.05 g).

[0231] Reference example D-5 (3-(5-fluoropyrimidin-2-yl)-4-methoxyphenyl)methanol A mixture of (5-(hydroxymethyl)-2-methoxyphenyl)boronic acid (1.00 g), 2-chloro-5-fluoropyrimidine (0.947 g), cesium carbonate (2.69 g), Pd(PPh3)4 (0.127 g), DMF (15 mL), and water (2 mL) was stirred at 120 °C for 30 minutes under microwave irradiation. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 80 / 20) to give the title compound (0.466 g).

[0232] Reference example D-6 (5-(5-bromopyrimidin-2-yl)-2-fluorophenyl)methanol A mixture of (4-fluoro-3-(hydroxymethyl)phenyl)boronic acid (0.869 g), 5-bromo-2-iodopyrimidine (1.60 g), sodium carbonate (1.08 g), PdCl2(PPh3)2 (0.179 g), toluene (6 mL), ethanol (6 mL), and water (3 mL) was stirred at 90 °C for 2 hours under microwave irradiation. 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 = 90 / 10 to 80 / 20) to give the title compound (0.932 g).

[0233] Reference example D-7 (4-chloro-3-(5-fluoropyrimidin-2-yl)phenyl)methanol A mixture of (2-chloro-5-formylphenyl)boronic acid (0.300 g), 2-chloro-5-fluoropyrimidine (0.280 g), sodium carbonate (0.259 g), Pd(PPh3)4 (0.094 g), toluene (1.5 mL), ethanol (0.5 mL), and water (1.5 mL) was stirred at 110 °C for 3 h under microwave irradiation. 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 = 90 / 10 to 60 / 40) to give 4-chloro-3-(5-fluoropyrimidin-2-yl)benzaldehyde (0.081 g). To a mixture of the obtained compound (0.080 g) and ethanol (2 mL), sodium borohydride (0.013 g) was added at room temperature, and the mixture was stirred at the same temperature for 20 minutes. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture. The mixture was 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 = 50 / 50 to 20 / 80) to obtain the title compound (0.055 g).

[0234] Reference example D-8 (4-(benzyloxy)-3-(5-fluoropyrimidin-2-yl)phenyl)methanol A mixture of (2-(benzyloxy)-5-formylphenyl)boronic acid (3.00 g), 2-chloro-5-fluoropyrimidine (2.02 g), sodium carbonate (1.86 g), PdCl2(PPh3)2 (0.411 g), toluene (10 mL), ethanol (20 mL), and water (10 mL) was stirred at 80 °C for 45 minutes and allowed to cool to room temperature. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture. 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 10 / 90) to give 4-(benzyloxy)-3-(5-fluoropyrimidin-2-yl)benzaldehyde (3.23 g). To a mixture of the obtained compound (3.15 g), ethanol (30 mL), and THF (30 mL), sodium borohydride (0.193 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. Water was added to the reaction mixture under ice-cooling. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60) to obtain the title compound (1.05 g).

[0235] Reference example D-9 2-(5-(bromomethyl)-2-fluorophenyl)-5-fluoropyrimidine To a mixture of Reference Example D-3 (2.17 g), TEA (1.98 g), and ethyl acetate (30 mL) was added methanesulfonyl chloride (1.68 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (30 mL), lithium bromide monohydrate (3.07 g) was added at room temperature, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature and added to water. 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 (2.58 g).

[0236] Reference example D-10~Reference example D-14 Reference Examples D-10 to D-14 were synthesized in the same manner as in Reference Example D-9, except that the corresponding Reference Examples were used in place of Reference Example D-3.

[0237] Reference example E-1 ~ Reference example E-2 (1R,3s,5S)-3-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate ethyl (Reference Example E-1) (1R,3r,5S)-3-(3-(5-bromopyrimidin-2-yl)benzyl)-6-oxabicyclo[3.1.0]hexane-3-carboxylate ethyl (Reference Example E-2) Under an argon atmosphere, LDA (1.09 mol / L in THF / n-hexane) (7.2 mL) was added to a mixture of ethyl cyclopent-3-ene-1-carboxylate (1.00 g) and THF (20 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. A mixture of Reference Example D-1 (2.40 g) and THF (30 mL) was added to the reaction mixture 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-(3-(5-bromopyrimidin-2-yl)benzyl)cyclopent-3-ene-1-carboxylate (2.06 g). To a mixture of the obtained compound (2.00 g) and DCM (20 mL), metachloroperbenzoic acid (1.92 g) was added under ice cooling. The mixture was stirred at the same temperature for 1 hour 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, and water were added. The mixture was extracted with DCM. The extract was washed with saturated aqueous sodium bicarbonate solution 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 = 70 / 30) to obtain the title compound. Reference example E-1 (0.889 g); 1 H-NMR (CDCl3) δ ppm : 1.27 (3H, t, J=7.1Hz), 2.13-2.30 (4H, m), 3.17 (2H, s), 3.58 (2H, s), 4.16 (2H, q, J=7.1Hz), 7.16-7.31 (1H, m), 7.32-7.42 (1H, m), 8.14-8.21 (1H, m), 8.21-8.27 (1H, m), 8.81 (2H, s) Reference example E-2 (0.909 g); 1 H-NMR (CDCl3) δ ppm : 1.06-1.17 (3H, m), 1.71 (2H, d, J=14.3Hz), 2.88 (2H, d, J=14.3Hz), 2.96 (2H, s), 3.42 (2H, s), 3.98-4.09 (2H, m), 7.15-7.23 (1H, m), 7.34-7.44 (1H, m), 8.10-8.18 (1H, m), 8.23-8.32 (1H, m), 8.82 (2H, s)

[0238] Reference example E-3 (1R * ,3R * ,4R * )-3-Azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate ethyl A mixture of Reference Example E-2 (0.900 g), sodium azide (0.435 g), ammonium chloride (0.358 g), ethanol (10 mL), and water (1 mL) was stirred at 110°C for 1 hour under microwave irradiation. Water was 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 to give the title compound (0.936 g).

[0239] Reference example E-4 (1R * ,3R * ,4S *)-3-Azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-fluorocyclopentane-1-carboxylic acid To a mixture of Reference Example E-3 (0.150 g), pyridine (0.080 g), and 1,2-dichloroethane (3 mL) was added Deoxo-Fluor (0.112 g) at room temperature, and the mixture was stirred at 40°C for 1 hour. To the reaction mixture, saturated aqueous sodium bicarbonate solution and water were added under ice-cooling. 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 80 / 20) to obtain (1R * ,3R * ,4S * )-3-azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-fluorocyclopentane-1-carboxylate (0.066 g) was obtained. A mixture of the obtained compound (0.064 g), 2 mol / L aqueous sodium hydroxide solution (0.357 mL), and ethanol (1.4 mL) was stirred at 80°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (0.393 mL), water, and saturated brine were added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (0.055 g).

[0240] Reference example E-5 (1R * ,3R * ,4S * )-3-Azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-fluoro-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example E-4 (0.054 g), DMF (1 mg), and DCM (1.5 mL) was added oxalyl chloride (0.033 g) under ice-cooling. The mixture was stirred at room temperature for 45 minutes and concentrated under reduced pressure. A mixture of the residue and DCM (1 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.025 g), DIPEA (0.050 g), and DCM (1 mL) under ice-cooling. The mixture was stirred at room temperature for 10 minutes. Water and saturated brine were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to obtain the title compound (0.054 g).

[0241] Reference example E-6 (1R * ,3R * ,4S * )-3-Azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate ethyl To a mixture of Reference Example E-3 (0.500 g), 4-nitrobenzoic acid (0.225 g), triphenylphosphine (0.353 g), and THF (5 mL), diisopropyl azodicarboxylate (1.9 mol / L in toluene) (0.708 mL) was added at room temperature. The mixture was stirred at the same temperature for 22 hours 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 obtain 4-nitrobenzoic acid (1S * ,2R * ,4R * )-2-azido-4-(3-(5-bromopyrimidin-2-yl)benzyl)-4-(ethoxycarbonyl)cyclopentyl (0.526 g) was obtained. To a mixture of the obtained compound (0.520 g), ethanol (2 mL), and THF (2 mL), 2 mol / L aqueous sodium hydroxide solution (0.873 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.375 g).

[0242] Reference example E-7 (1R * ,3R * ,4R * )-3-Azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-fluorocyclopentane-1-carboxylic acid To a mixture of Reference Example E-6 (0.370 g), pyridine (0.197 g), and DCM (7 mL) was added Deoxo-Fluor (0.275 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, saturated aqueous sodium bicarbonate solution and water were added under ice-cooling. 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 80 / 20) to obtain (1R * ,3R * ,4R * )-3-azido-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-fluorocyclopentane-1-carboxylate (0.229 g) was obtained. A mixture of the obtained compound (0.225 g), 2 mol / L aqueous sodium hydroxide solution (1.26 mL), and ethanol (5 mL) was stirred at 80°C for 3 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (1.38 mL), water, and saturated brine were added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.192 g).

[0243] Reference example E-8 Reference Example E-8 was synthesized in the same manner as in Reference Example E-5, except that Reference Example E-7 was used instead of Reference Example E-4.

[0244] Reference example E-9~Reference example E-10 Reference Examples E-9 and E-10 were synthesized in the same manner as in Reference Examples E-1 and E-2, except that Reference Example D-2 was used instead of Reference Example D-1.

[0245] Reference example E-11 Reference Example E-11 was synthesized in the same manner as in Reference Example E-3, except that Reference Example E-10 was used instead of Reference Example E-2.

[0246] Reference example E-12 Reference Example E-12 was synthesized in the same manner as in Reference Example E-7, except that Reference Example E-11 was used instead of Reference Example E-6.

[0247] Reference example E-13 Reference Example E-13 was synthesized in the same manner as in Reference Example E-5, except that Reference Example E-12 was used instead of Reference Example E-4.

[0248] Reference example E-14 ~ Reference example E-15 Reference Examples E-14 and E-15 were synthesized in the same manner as in Reference Examples E-1 and E-2, except that Reference Example D-9 was used instead of Reference Example D-1.

[0249] Reference example E-16 Reference Example E-16 was synthesized in the same manner as in Reference Example E-3, except that Reference Example E-15 was used instead of Reference Example E-2.

[0250] Reference example E-17 (1R * ,3R * ,4S * )-3-Azido-4-fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)cyclopentane-1-carboxylic acid Deoxo-Fluor (0.312 g) was added to a mixture of Reference Example E-16 (0.379 g), pyridine (0.223 g), and DCM (7 mL) under ice-cooling. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours. The reaction mixture was added to a saturated aqueous solution of sodium bicarbonate under ice-cooling 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 = 95 / 5 to 80 / 20) to obtain (1R * ,3R * ,4S * )-3-azido-4-fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)ethyl cyclopentane-1-carboxylate (0.184 g) was obtained. A mixture of the obtained compound (0.184 g), 2 mol / L aqueous sodium hydroxide solution (1.14 ml), and 2-propanol (2 mL) was stirred at 60° C. for 3.5 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (1.25 mL) and water were added to the reaction mixture. The mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.196 g).

[0251] Reference example E-18 Reference Example E-18 was synthesized in the same manner as in Reference Example E-5, except that Reference Example E-17 was used instead of Reference Example E-4.

[0252] Reference example E-19 (1R * ,3R * ,4S * )-3-amino-4-fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example E-18 (0.175 g), ethanol (1.5 mL), and THF (1.5 mL), 10% Pd / C (0.035 g) was added under ice-cooling. The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (0.145 g).

[0253] Reference example E-20 ~ Reference example E-21 Reference Examples E-20 and E-21 were synthesized in the same manner as in Reference Examples E-1 and E-2, except that Reference Example D-10 was used instead of Reference Example D-1.

[0254] Reference example E-22 Reference Example E-22 was synthesized in the same manner as in Reference Example E-3, except that Reference Example E-21 was used instead of Reference Example E-2.

[0255] Reference example E-23 Reference Example E-23 was synthesized in the same manner as in Reference Example E-17, except that Reference Example E-22 was used instead of Reference Example E-16.

[0256] Reference example E-24 Reference Example E-24 was synthesized in the same manner as in Reference Example E-5, except that Reference Example E-23 was used instead of Reference Example E-4.

[0257] Reference example E-25 Reference Example E-25 was synthesized in the same manner as in Reference Example E-19, except that Reference Example E-24 was used instead of Reference Example E-18.

[0258] Reference example E-26 ~ Reference example E-27 Reference Examples E-26 and E-27 were synthesized in the same manner as in Reference Examples E-1 and E-2, except that Reference Example D-12 was used instead of Reference Example D-1.

[0259] Reference example E-28 (1R * ,3R * ,4R * )-3-Azido-1-(5-(5-bromopyrimidin-2-yl)-2-fluorobenzyl)-4-hydroxycyclopentane-1-carboxylate ethyl A mixture of Reference Example E-27 (1.01 g), sodium azide (0.468 g), ammonium chloride (0.385 g), ethanol (15 mL), and water (1.5 mL) was stirred at 110°C for 5 hours under microwave irradiation. 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 = 80 / 20) to give the title compound (1.10 g).

[0260] Reference example E-29 Reference Example E-29 was synthesized in the same manner as in Reference Example E-7, except that Reference Example E-28 was used instead of Reference Example E-6.

[0261] Reference example E-30 Reference Example E-30 was synthesized in the same manner as in Reference Example E-5, except that Reference Example E-29 was used instead of Reference Example E-4.

[0262] Reference example E-31 Reference Example E-31 was synthesized in the same manner as in Reference Example E-19, except that Reference Example E-30 was used instead of Reference Example E-18.

[0263] Reference example E-32 ~ Reference example E-33 Reference Examples E-32 and E-33 were synthesized in the same manner as in Reference Examples E-1 and E-2, except that Reference Example D-14 was used instead of Reference Example D-1.

[0264] Reference example E-34 (1R * ,3S * ,4R * )-3-Fluoro-1-(3-(5-fluoropyrimidin-2-yl)-4-hydroxybenzyl)-4-(methylsulfonamido)cyclopentane-1-carboxylate ethyl A mixture of Reference Example E-33 (0.152 g), sodium azide (0.054 g), ammonium chloride (0.045 g), 1,4-dioxane (1.5 mL), and water (0.15 mL) was stirred at 110°C for 2 hours under microwave irradiation. The reaction mixture was added to water and 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 = 80 / 20 to 70 / 30) to obtain (1R * ,3R * ,4R * )-3-azido-1-(4-(benzyloxy)-3-(5-fluoropyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate was obtained as a mixture with Reference Example E-33. A mixture of the obtained compound, sodium azide (0.054 g), ammonium chloride (0.045 g), 1,4-dioxane (1.5 mL), and water (0.15 mL) was stirred at 110°C for 1 hour under microwave irradiation. Water was 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, ethanol (0.9 mL), and THF (0.9 mL) was added 10% Pd / C (0.014 g) under ice-cooling. The mixture 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. To a mixture of the residue, TEA (0.021 g), and DCM (1 mL) was added methanesulfonyl chloride (0.015 g) under ice-cooling, and the mixture was stirred at room temperature for 15 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 = 70 / 30 to 60 / 40) to obtain (1R * ,3R * ,4R * )-1-(3-(5-fluoropyrimidin-2-yl)-4-hydroxybenzyl)-3-hydroxy-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.035 g) was obtained. To a mixture of the obtained compound (0.035 g), pyridine (0.018 g), and DCM (0.8 mL), Deoxo-Fluor (0.051 g) was added under ice-cooling. The mixture was stirred at the same temperature for 20 minutes and then at room temperature for 1 hour. The reaction mixture 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. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 to 60 / 40) to obtain the title compound (0.010 g).

[0265] Reference example E-35 (1R * ,3S * ,4R * )-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-methylcyclopentane-1-carboxylate ethyl Under an argon atmosphere, methyllithium (3.1 mol / L in 1,2-diethoxyethane) (1.24 mL) was added to a mixture of copper(I) cyanide (0.173 g) and THF (5 mL) at -78°C, and the mixture was stirred at room temperature for 5 minutes. A mixture of Reference Example E-9 (0.300 g) and THF (5 mL) was added to the reaction mixture at -78°C, followed by the addition of boron trifluoride diethyl ether complex (0.497 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 55 / 45) to give (1R * ,3R * ,4R * )-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-methylcyclopentane-1-carboxylate (0.250 g) was obtained. To a mixture of the obtained compound (0.250 g), 4-nitrobenzoic acid (0.280 g), triphenylphosphine (0.439 g), and THF (7 mL), diisopropyl azodicarboxylate (1.9 mol / L in toluene) (0.881 mL) was added 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 obtain 4-nitrobenzoic acid (1S * ,2R * ,4R * )-4-(ethoxycarbonyl)-4-(3-(5-fluoropyrimidin-2-yl)benzyl)-2-methylcyclopentyl (0.353 g) was obtained. A mixture of the obtained compound (0.353 g), 2 mol / L aqueous sodium hydroxide solution (0.698 mL), and ethanol (7 mL) was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride solution and water were 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 0 / 100) to obtain the title compound (0.078 g).

[0266] Reference example E-36 (1R * ,3R * ,4R * )-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-methyl-4-(methylsulfonamido)cyclopentane-1-carboxylate ethyl To a mixture of Reference Example E-35 (0.078 g), TEA (0.044 g), and DCM (1 mL), methanesulfonyl chloride (0.037 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 (0.042 g), and DMSO (1 mL) was stirred at 100°C for 2 hours. The reaction mixture was allowed to cool to room temperature, then 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 obtain (1R * ,3R * ,4R * )-3-azido-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-methylcyclopentane-1-carboxylate (0.058 g) was obtained. To a mixture of the obtained compound (0.058 g), methanol (1 mL), and water (0.005 mL) was added triphenylphosphine (0.060 g) at room temperature. The mixture was stirred at the same temperature for 13 hours and then concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 10 / 90). Obtained (1R * ,3R * ,4R * To a mixture of ethyl 2-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-methylcyclopentane-1-carboxylate, TEA (0.046 g), and DCM (1 mL), methanesulfonyl chloride (0.026 g) was added 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 70 / 30) to give the title compound (0.018 g).

[0267] Reference example E-37 (1R * ,3S * ,4S * )-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-methylcyclopentane-1-carboxylate ethyl Under an argon atmosphere, methyllithium (3.1 mol / L in 1,2-diethoxyethane) (1.95 mL) was added to a mixture of copper(I) cyanide (0.270 g) and THF (5 mL) at −78°C, and the mixture was stirred at room temperature for 5 minutes. A mixture of Reference Example E-10 (0.470 g) and THF (5 mL) was added to the reaction mixture at −78°C, followed by the addition of boron trifluoride diethyl ether complex (0.779 g). The mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to saturated aqueous ammonium chloride 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 55 / 45) to obtain the title compound (0.355 g).

[0268] Reference example E-38 Reference Example E-38 was synthesized in the same manner as in Reference Example E-36, except that Reference Example E-37 was used instead of Reference Example E-35.

[0269] Reference example F-1 (1R * ,4R * )-4-Azido-3,3-difluoro-N-methoxy-N-methyl-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example E-1 (0.950 g), benzyl alcohol (0.509 g), and DCM (10 mL), boron trifluoride diethyl ether complex (0.033 g) was added under ice-cooling. The mixture was stirred at 0°C for 16 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 75 / 25 to 55 / 45) to obtain (1S * ,3S * ,4S * )-3-(benzyloxy)-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate (0.739 g) was obtained. Azadol (0.010 g) was added to a mixture of the obtained compound (0.670 g), iodobenzene diacetate (0.633 g), and DCM (10 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. A 1 mol / L aqueous solution of sodium thiosulfate (2 mL), a saturated aqueous solution of sodium bicarbonate, and water were 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 = 90 / 10 to 70 / 30) to obtain (1R * ,3S * )-3-(benzyloxy)-1-(3-(5-bromopyrimidin-2-yl)benzyl)-4-oxocyclopentane-1-carboxylate (0.530 g) was obtained. To a mixture of the obtained compound (0.570 g) and DCM (3 mL), Deoxo-Fluor (0.545 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture, saturated aqueous sodium bicarbonate solution and water were added under ice-cooling. 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 80 / 20) to obtain (1R * ,4S * )-4-(benzyloxy)-1-(3-(5-bromopyrimidin-2-yl)benzyl)-3,3-difluorocyclopentane-1-carboxylate (0.550 g) was obtained. To a mixture of the obtained compound (0.550 g), ethanol (5 mL), and THF (5 mL), 10% Pd / C (0.110 g) was added under ice-cooling. The mixture was stirred at room temperature under a hydrogen atmosphere for 13 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 60 / 40) to obtain (1R * ,4S * )-4-(benzyloxy)-3,3-difluoro-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.259 g) was obtained. Under an argon atmosphere, to a mixture of the obtained compound (0.200 g) and DCM (8 mL) was added boron tribromide (1 mol / L in DCM) (1.77 mL) at -78°C, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture were added ethanol (0.2 mL), saturated aqueous sodium bicarbonate solution, and water at -78°C. 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 = 70 / 30 to 50 / 50) to obtain (1R * ,4S * )-3,3-Difluoro-4-hydroxy-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.151 g) was obtained. To a mixture of the obtained compound (0.165 g), TEA (0.092 g), and DCM (2 mL), methanesulfonyl chloride (0.078 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue and DMSO (2 mL) was added sodium azide (0.118 g) at room temperature. The mixture was stirred at 100°C for 12 hours, then at 150°C for 3 hours, and then allowed to cool to room temperature. Water was added to the reaction mixture. 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 = 70 / 30 to 50 / 50) to obtain (1R * ,4R * )-4-azido-3,3-difluoro-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.048 g) was obtained. A mixture of the obtained compound (0.045 g), 2 mol / L aqueous sodium hydroxide solution (0.290 mL), and ethanol (1 mL) was stirred at 80°C for 3 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (0.319 mL), water, and saturated brine were added to the reaction mixture. 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, DMF (1 mg), and DCM (1 mL) was added oxalyl chloride (0.030 g) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. A mixture of the residue and DCM (1 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.023 g), DIPEA (0.045 g), and DCM (1 mL) under ice-cooling. The mixture was stirred at room temperature for 30 minutes. Water and saturated brine were added to the reaction mixture. The mixture was 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 = 50 / 50 to 0 / 100) to obtain the title compound (0.043 g).

[0270] Reference example F-2 (1R * ,4R * )-4-Amino-3,3-difluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide A mixture of Reference Example E-11 (0.700 g), triphenylphosphine (0.572 g), THF (14 mL), and water (0.7 mL) was stirred at 70°C for 6 hours and allowed to cool to room temperature. To the reaction mixture was added a mixture of BocO (0.476 g) and THF (7 mL). To this mixture was added TEA (0.221 g). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50) to obtain (1R * ,3R * ,4R *)-3-((tert-butoxycarbonyl)amino)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate (0.773 g) was obtained. Azadol (0.013 g) was added to a mixture of the obtained compound (0.770 g), iodobenzene diacetate (0.810 g), and DCM (15 mL) at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture. The mixture was 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 = 80 / 20 to 60 / 40) to obtain (1R * ,3R * )-3-((tert-butoxycarbonyl)amino)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-oxocyclopentane-1-carboxylate (0.704 g) was obtained. To a mixture of the obtained compound (0.600 g) and 1,2-dichloroethane (3 mL), Deoxo-Fluor (1.16 g) was added at room temperature, and the mixture was stirred at 30°C for 24 hours. The reaction mixture was added to a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and water (10 mL) under ice-cooling. The mixture was stirred at room temperature for 10 minutes 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 = 90 / 10 to 70 / 30) to obtain (1R * ,4R * )-4-((tert-butoxycarbonyl)amino)-3,3-difluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.309 g) was obtained. A mixture of the obtained compound (0.300 g), 2 mol / L aqueous sodium hydroxide solution (1.56 mL), and 2-propanol (6 mL) was stirred at 60°C for 3 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (1.72 mL), water, and saturated brine were added to the reaction mixture. The mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.277 g), DIPEA (0.458 g), and DMF (3.2 mL) was added HATU (0.350 g) at room temperature. The mixture was stirred at 70°C for 1.5 hours and allowed to cool to room temperature. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. 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 = 70 / 30 to 50 / 50) to obtain (1R * ,4R * )-2,2-difluoro-4-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methoxy(methyl)carbamoyl)cyclopentyl)carbamate tert-butyl ester (0.271 g) was obtained. A mixture of the obtained compound (0.270 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.5 mL), and 1,4-dioxane (1.5 mL) was stirred at room temperature for 13 hours and diluted with DCM. A saturated aqueous solution of sodium bicarbonate, water, and saturated brine were added to the mixture. The mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.209 g).

[0271] Reference example F-3 ~ Reference example F-4 Reference Examples F-3 to F-4 were synthesized in the same manner as in Reference Example F-2, except that the corresponding Reference Examples were used in place of Reference Example E-11.

[0272] Reference example G-1 (1S,4R)-4-((diphenylmethylene)amino)cyclopent-2-ene-1-carboxylate methyl ester 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).

[0273] Reference example G-2 (1R,3S)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate methyl ester A mixture of (1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate (0.770 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (8 mL), and 1,4-dioxane (8 mL) was stirred at room temperature for 6 hours and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure. A mixture of the residue, diphenylmethanimine (0.545 g), and DCM (16 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give the title compound (0.921 g).

[0274] Reference example G-3 (4R)-4-((diphenylmethylene)amino)-3,3-difluorocyclopentane-1-carboxylate methyl ester To a mixture of methyl (3R,4R)-4-((tert-butoxycarbonyl)amino)-3-hydroxycyclopent-1-ene-1-carboxylate (1.36 g) and ethanol (20 mL) was added 10% Pd / C (0.408 g) at room temperature. The mixture 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. Azadol (0.081 g) was added to a mixture of the residue, iodobenzene diacetate (2.55 g), and DCM (21 mL) at room temperature, and the mixture was stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate 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 60 / 40) to give methyl (3R)-3-((tert-butoxycarbonyl)amino)-4-oxocyclopentane-1-carboxylate (1.06 g). To a mixture of the obtained compound (1.06 g) and 1,2-dichloroethane (15 mL), Deoxo-Fluor (3.65 g) was added at room temperature, and the mixture was stirred at 60°C for 13 hours and allowed to cool to room temperature. The reaction mixture was diluted with DCM. The mixture was added to saturated aqueous sodium bicarbonate solution under ice-cooling 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 60 / 40) to give methyl (4R)-4-((tert-butoxycarbonyl)amino)-3,3-difluorocyclopentane-1-carboxylate (0.499 g). A mixture of the obtained compound (0.499 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (8.93 mL), and methanol (7.5 mL) was stirred at room temperature for 1 hour and then 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 (4R)-4-amino-3,3-difluorocyclopentane-1-carboxylate (0.237 g). A mixture of the obtained compound (0.224 g), diphenylmethanimine (0.227 g), and DCM (3 mL) was stirred at room temperature for 40 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. DCM was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.337 g).

[0275] Reference example H-1 (1R,4R)-4-((diphenylmethylene)amino)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)cyclopent-2-ene-1-carboxylate methyl ester Under an argon atmosphere, to a mixture of Reference Example G-1 (2.26 g), Reference Example D-9 (2.22 g), and THF (23 mL) was added lithium bis(trimethylsilyl)amide (1.11 mol / L in THF) (8 mL) in an ice-salt bath. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added lithium bis(trimethylsilyl)amide (1.11 mol / L in THF) (2 mL) in an ice-salt bath. The mixture was stirred at the same temperature for 15 minutes. A saturated aqueous solution of ammonium chloride, saturated brine, and water were added to the reaction mixture. 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 = 100 / 0 to 80 / 20) to obtain the title compound (2.13 g).

[0276] Reference example H-2 (1R,4R)-4-((tert-butoxycarbonyl)amino)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)cyclopent-2-ene-1-carboxylate methyl ester A mixture of Reference Example H-1 (2.10 g), 6 mol / L hydrochloric acid (2.06 mL), and methanol (10 mL) was stirred at room temperature for 18 hours. To the reaction mixture, 5 mol / L aqueous sodium hydroxide (3.3 mL) was added under ice-cooling, followed by a mixture of BocO (1.17 g) and THF (10 mL). The mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2 mol / L aqueous sodium hydroxide (2.06 mL) was added at room temperature, followed by a mixture of BocO (0.450 g) and THF (2 mL). The mixture was stirred at the same temperature for 30 minutes. Water and saturated brine were added to the reaction mixture. 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 (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 60 / 40) to give the title compound (1.72 g).

[0277] Reference example H-3 (1R,3S)-3-((tert-butoxycarbonyl)amino)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate methyl ester To a mixture of Reference Example H-2 (1.71 g), ethanol (8.5 mL), and THF (8.5 mL), 5% platinum on carbon (0.342 g) was added under ice-cooling. The mixture 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 = 80 / 20 to 60 / 40) to obtain the title compound (1.63 g).

[0278] Reference example H-4 (1R,3S)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid A mixture of Reference Example H-3 (0.057 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.5 mL), and 1,4-dioxane (0.5 mL) was stirred at 40° C. for 1.5 hours and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue, TEA (0.039 g), and DCM (1 mL) was added methanesulfonyl chloride (0.022 g) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. A mixture of the residue, 6 mol / L hydrochloric acid (0.5 mL), and 1,4-dioxane (0.5 mL) was stirred at 80° C. for 2 hours and then at room temperature for 15 hours. The reaction mixture was stirred at 100° C. for 4 hours and allowed to cool to room temperature. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure to give the title compound (0.054 g).

[0279] Reference example H-5 (1R,3S)-3-amino-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide A mixture of Reference Example H-3 (0.210 g), 5 mol / L aqueous sodium hydroxide solution (0.939 mL), and 1,4-dioxane (4.2 mL) was stirred at 100°C for 6 hours and allowed to cool to room temperature. 6 mol / L hydrochloric acid (0.939 mL), water, and saturated brine were added to the reaction mixture under water cooling. 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, N,O-dimethylhydroxylamine hydrochloride (0.062 g), DIPEA (0.165 g), and DMF (2 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (0.274 g) at room temperature, and the mixture was stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture. 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60) to give tert-butyl ((1S,3R)-3-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-(methoxy(methyl)carbamoyl)cyclopentyl)carbamate (0.136 g). A mixture of the obtained compound (0.135 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL), and 1,4-dioxane (1 mL) was stirred at room temperature for 18 hours and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was 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 give the title compound (0.083 g).

[0280] Reference example H-6 (1R,3S)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-(methylsulfonamido)cyclopentane-1-carboxylate methyl ester Under an argon atmosphere, to a mixture of Reference Example G-2 (0.060 g), Reference Example D-13 (0.060 g), and THF (1 mL) was added lithium bis(trimethylsilyl)amide (1.1 mol / L in THF) (0.248 mL) in an ice-salt bath. The mixture was stirred at the same temperature for 1 hour. To the mixture was added lithium bis(trimethylsilyl)amide (1.1 mol / L in THF) (0.177 mL) in an ice-salt bath. The mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution, saturated brine, and water were added to the reaction mixture. 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to give (1R,3S)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-((diphenylmethylene)amino)cyclopentane-1-carboxylate (0.037 g). A mixture of the obtained compound (0.035 g), 2 mol / L hydrochloric acid (0.331 mL), and THF (1 mL) was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue, TEA (0.020 g), and DCM (1 mL), methanesulfonyl chloride (0.011 g) was added under ice-cooling, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction mixture. The mixture was 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 = 50 / 50 to 0 / 100) to obtain the title compound (0.019 g).

[0281] Reference example H-7 (1R,4R)-4-((diphenylmethylene)amino)-1-(3-(5-fluoropyrimidin-2-yl)-4-methoxybenzyl)cyclopent-2-ene-1-carboxylate methyl ester Under an argon atmosphere, to a mixture of Reference Example G-1 (0.493 g), Reference Example D-11 (0.505 g), and THF (7.3 mL) was added lithium bis(trimethylsilyl)amide (1.11 mol / L in THF) (1.84 mL) in an ice-salt bath. The mixture was stirred at the same 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 sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 40 / 60) to give the title compound (0.62 g).

[0282] Reference example H-8 (1R,4R)-1-(3-(5-fluoropyrimidin-2-yl)-4-methoxybenzyl)-4-(methylsulfonamido)cyclopent-2-ene-1-carboxylate methyl ester To a mixture of Reference Example H-7 (0.620 g) and THF (6 mL) was added 2 mol / L hydrochloric acid (1.78 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 2 mol / L aqueous sodium hydroxide solution (1.78 mL). The mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue and DCM (6 mL), TEA (0.241 g) and methanesulfonyl chloride (0.204 g) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture. The mixture was 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 / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 88 / 12) to give the title compound (0.476 g).

[0283] Reference example H-9 Reference Example H-9 was synthesized in the same manner as in Reference Example H-3, except that Reference Example H-8 was used instead of Reference Example H-2.

[0284] Reference example H-10 (1R,3S)-1-(3-(5-fluoropyrimidin-2-yl)-4-methoxybenzyl)-3-(methylsulfonamido)cyclopentane-1-carboxylic acid To a mixture of Reference Example H-9 (0.466 g) and 1,4-dioxane (5 mL), 5 mol / L aqueous sodium hydroxide solution (2.13 mL) was added at room temperature. The mixture was stirred at 100°C for 30 minutes and allowed to cool to room temperature. Concentrated hydrochloric acid (0.9 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure to give the title compound (0.125 g).

[0285] Reference example I-1 (3aR,5R,6aS)-5-(3-(5-fluoropyrimidin-2-yl)benzyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate methyl ester Under an argon atmosphere, lithium bis(trimethylsilyl)amide (1.1 mol / L in THF) (16.5 mL) was added to a mixture of Reference Example G-1 (2.80 g), Reference Example D-2 (2.57 g), and THF (42 mL) at -78°C. The mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture. 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 85 / 15) to give methyl (1R,4R)-4-((diphenylmethylene)amino)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclopent-2-ene-1-carboxylate (2.35 g). A mixture of the obtained compound (2.35 g), 2 mol / L hydrochloric acid (7.17 mL), and THF (28 mL) was stirred at room temperature for 30 minutes. To the reaction mixture, 2 mol / L aqueous sodium hydroxide (9.56 mL) was added at room temperature, followed by a mixture of BocO (1.25 g) and THF (28 mL). The mixture was stirred at room temperature for 20 minutes. Water was added to the reaction mixture. 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 = 90 / 10 to 50 / 50) to give methyl (1R,4R)-4-((tert-butoxycarbonyl)amino)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclopent-2-ene-1-carboxylate (2.04 g). To a mixture of the resulting compound (2.04 g), THF (24 mL), and water (2.4 mL), N-bromosuccinimide (1.11 g) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 1 mol / L aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate. 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 = 70 / 30 to 30 / 70) to give methyl (3aR,5S,6R,6aR)-6-bromo-5-(3-(5-fluoropyrimidin-2-yl)benzyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (1.59 g). Under an argon atmosphere, a mixture of the obtained compound (1.59 g), tris(trimethylsilyl)silane (1.32 g), 2,2'-azobisisobutyronitrile (0.058 g), and toluene (20 mL) was stirred at 90°C for 2 hours. The reaction mixture was allowed to cool to room temperature and 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 (1.16 g).

[0286] Reference example I-2 (3aR,5R,6aS)-5-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-(methylsulfonyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate To a mixture of Reference Example I-1 (0.392 g) and THF (20 mL), lithium bis(trimethylsilyl)amide (1.1 mol / L in THF) (2.0 mL) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methanesulfonyl chloride (0.206 g) was added to the reaction mixture at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Methanesulfonyl chloride (0.132 g) was added to the reaction mixture at -78°C, and the mixture was stirred at room temperature for 20 minutes. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture. 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 = 60 / 40) to obtain the title compound (0.364 g).

[0287] Reference example I-3 (1R,3S,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-(methylsulfonamido)cyclopentane-1-carboxylate methyl ester A mixture of Reference Example I-2 (0.364 g), cesium carbonate (0.792 g), and methanol (9 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. DCM and water were added to the residue. 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 = 30 / 70 to 20 / 80) to obtain the title compound (0.244 g).

[0288] Reference example I-4 (1R,3R,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-(methylsulfonamido)cyclopentane-1-carboxylate methyl ester Under an argon atmosphere, diisopropyl azodicarboxylate (1.9 mol / L in toluene) (0.728 mL) was added to a mixture of Reference Example I-3 (0.244 g), 4-nitrobenzoic acid (0.231 g), triphenylphosphine (0.363 g), and THF (5 mL) under ice-cooling. 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 = 60 / 40 to 50 / 50) to give (1R,2R,4R)-4-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methoxycarbonyl)-2-(methylsulfonamido)cyclopentyl 4-nitrobenzoate (0.299 g). A mixture of the obtained compound (0.287 g), 2 mol / L aqueous sodium hydroxide solution (0.501 mL), methanol (5 mL), and THF (6 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. DCM and water were added to the residue. 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 = 60 / 40 to 0 / 100) and then by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80) to obtain the title compound (0.140 g).

[0289] Reference example I-5 4-Nitrobenzoic acid (1R,2R,4R)-2-amino-4-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methoxycarbonyl)cyclopentyl ester hydrochloride To a mixture of Reference Example I-1 (1.16 g), DMAP (0.038 g), TEA (0.915 g), and THF (14 mL) was added BocO (0.818 g) at room temperature. 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 (eluent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to give (3aR,5R,6aS)-5-(3-(5-fluoropyrimidin-2-yl)benzyl)-2-oxotetrahydro-2H-cyclopenta[d]oxazole-3,5(3aH)-dicarboxylate (5-methyl 3-(tert-butyl)) (1.38 g). A mixture of the obtained compound (1.38 g), cesium carbonate (3.05 g), and methanol (28 mL) was stirred at room temperature for 1 hour. 2 mol / L hydrochloric acid (4.69 mL) and water were 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 = 70 / 30 to 0 / 100) to give methyl (1R,3R,4S)-3-((tert-butoxycarbonyl)amino)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate (0.910 g). To a mixture of the obtained compound (0.910 g), 4-nitrobenzoic acid (0.819 g), triphenylphosphine (1.29 g), and THF (10 mL) was added diisopropyl azodicarboxylate (1.9 mol / L in toluene) (2.58 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour and 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,2R,4R)-2-((tert-butoxycarbonyl)amino)-4-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methoxycarbonyl)cyclopentyl 4-nitrobenzoate (0.770 g). A mixture of the obtained compound (0.353 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (3 mL) was stirred at room temperature for 30 minutes, and the reaction mixture was concentrated under reduced pressure to give the title compound (0.315 g).

[0290] Reference example I-6 (1R,3R,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-((1-methylethyl)sulfonamido)cyclopentane-1-carboxylate methyl ester To a mixture of Reference Example I-5 (0.100 g), 1,8-diazabicyclo[5.4.0]-7-undecene (0.051 g), and DCM (2 mL), isopropylsulfonyl chloride (0.024 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, 1,8-diazabicyclo[5.4.0]-7-undecene (0.152 g) and isopropylsulfonyl chloride (0.071 g) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue and methanol (2 mL), 2 mol / L aqueous sodium hydroxide solution (0.111 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution and water were 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 = 50 / 50 to 0 / 100) to obtain the title compound (0.032 g).

[0291] Reference example I-7 (1R,3R,4R)-3-(ethylsulfonamido)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-hydroxycyclopentane-1-carboxylate methyl ester To a mixture of Reference Example I-5 (0.500 g), TEA (0.168 g), and DCM (7 mL), ethanesulfonyl chloride (0.107 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. To a mixture of the residue and methanol (7 mL), 2 mol / L aqueous sodium hydroxide solution (0.553 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. Saturated aqueous ammonium chloride solution and water were 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 = 50 / 50 to 30 / 70) to obtain the title compound (0.191 g).

[0292] Reference example I-8 Reference Example I-8 was synthesized in the same manner as in Reference Example I-6, except that cyclopropanesulfonyl chloride was used instead of isopropylsulfonyl chloride.

[0293] Reference example I-9 Reference Example I-9 was synthesized in the same manner as in Reference Example I-1, except that Reference Example D-12 was used instead of Reference Example D-2.

[0294] Reference example I-10 Reference Example I-10 was synthesized in the same manner as in Reference Example I-2, except that Reference Example I-9 and ethanesulfonyl chloride were used instead of Reference Example I-1 and methanesulfonyl chloride, respectively.

[0295] Reference example I-11 Reference Example I-11 was synthesized in the same manner as in Reference Example I-3, except that Reference Example I-10 was used instead of Reference Example I-2.

[0296] Reference example I-12 Reference Example I-12 was synthesized in the same manner as in Reference Example I-4, except that Reference Example I-11 was used instead of Reference Example I-3.

[0297] Reference example I-13 Reference Example I-13 was synthesized in the same manner as in Reference Example I-1, except that Reference Example D-13 was used instead of Reference Example D-2.

[0298] Reference example I-14 Reference Example I-14 was synthesized in the same manner as in Reference Example I-2, except that Reference Example I-13 was used instead of Reference Example I-1.

[0299] Reference example I-15 Reference Example I-15 was synthesized in the same manner as in Reference Example I-2, except that Reference Example I-13 and ethanesulfonyl chloride were used instead of Reference Example I-1 and methanesulfonyl chloride, respectively.

[0300] Reference example I-16 ~ Reference example I-17 Reference Examples I-16 and I-17 were synthesized in the same manner as in Reference Example I-3, except that the corresponding Reference Examples were used instead of Reference Example I-2.

[0301] Reference example I-18 ~ Reference example I-19 Reference Examples I-18 to I-19 were synthesized in the same manner as in Reference Example I-4, except that the corresponding Reference Examples were used instead of Reference Example I-3.

[0302] Reference example I-20 (3aR,5R,6aS)-5-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate methyl ester N-Bromosuccinimide (0.286 g) was added to a mixture of Reference Example H-2 (0.550 g), THF (5 mL), and water (0.5 mL) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 1 mol / L aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction mixture at room temperature. The mixture was extracted with ethyl acetate. 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 30 / 70) to give methyl (3aR,5S,6R,6aR)-6-bromo-5-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-2-oxohexahydro-2H-cyclopenta[d]oxazole-5-carboxylate (0.421 g). Under an argon atmosphere, a mixture of the obtained compound (0.421 g), tris(trimethylsilyl)silane (0.335 g), 2,2'-azobisisobutyronitrile (0.015 g), and toluene (9 mL) was stirred at 90°C for 1 hour. The reaction mixture was allowed to cool to room temperature 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 (0.117 g).

[0303] Reference example I-21 Reference Example I-21 was synthesized in the same manner as in Reference Example I-2, except that Reference Example I-20 was used instead of Reference Example I-1.

[0304] Reference example I-22 Reference Example I-22 was synthesized in the same manner as in Reference Example I-3, except that Reference Example I-21 was used instead of Reference Example I-2.

[0305] Reference example I-23 (1R,3S,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-methoxy-4-(N-(4-methoxybenzyl)methylsulfonamido)cyclopentane-1-carboxylate Under an argon atmosphere, tert-butyldimethylsilyl triflate (0.094 g) was added to a mixture of Reference Example I-3 (0.110 g), imidazole (0.032 g), and DCM (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. 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 60 / 40) to give methyl (1R,3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.087 g). To a mixture of the obtained compound (0.087 g), potassium carbonate (0.067 g), tetrabutylammonium iodide (0.012 g), and DMF (1 mL) was added 4-methoxybenzyl chloride (0.038 g) at room temperature. The mixture was stirred at 80 °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 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 80 / 20) to give methyl (1R,3S,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(N-(4-methoxybenzyl)methylsulfonamido)cyclopentane-1-carboxylate (0.066 g). A mixture of the obtained compound (0.066 g), tetrabutylammonium fluoride (1 mol / L in THF) (0.12 mL), and THF (1 mL) was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 60 / 40) to give methyl (1R,3S,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-3-hydroxy-4-(N-(4-methoxybenzyl)methylsulfonamido)cyclopentane-1-carboxylate (0.041 g). To a mixture of the obtained compound (0.041 g), methyl iodide (0.054 g), and THF (0.5 mL), sodium hydride (approximately 60% in mineral oil) (0.009 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 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 67 / 33) to obtain the title compound (0.021 g).

[0306] Reference example I-24 Reference Example I-24 was synthesized in the same manner as in Reference Example I-23, except that Reference Example I-4 was used instead of Reference Example I-3.

[0307] Reference example J-1 (1R,4R)-1-(3-(5-bromopyrimidin-2-yl)benzyl)-3,3-difluoro-4-(methylsulfonamido)cyclopentane-1-carboxylate methyl ester Under an argon atmosphere, LDA (1.09 mol / L in THF / n-hexane) (1.35 mL) was added to a mixture of Reference Example G-3 (0.337 g) and THF (5 mL) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. Reference Example D-1 (0.338 g) was added to the reaction mixture at -78°C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 40 minutes. A saturated aqueous solution of ammonium chloride 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. A mixture of the residue, hydrogen chloride (4 mol / L in 1,4-dioxane) (2.45 mL), and methanol (5 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give methyl (1R,4R)-4-amino-1-(3-(5-bromopyrimidin-2-yl)benzyl)-3,3-difluorocyclopentane-1-carboxylate (0.154 g) as a mixture with the (1S,4R)-isomer. To a mixture of the obtained compound (0.154 g), TEA (0.073 g), and DCM (2.3 mL), methanesulfonyl chloride (0.062 g) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 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 40 / 60) to give the title compound (0.153 g) as a mixture with the (1S,4R)-isomer.

[0308] Reference example J-2 (1R,4R)-1-(3-chlorobenzyl)-3,3-difluoro-4-(methylsulfonamido)cyclopentane-1-carboxylate methyl ester Under an argon atmosphere, LDA (1.09 mol / L in THF / n-hexane) (0.826 mL) was added to a mixture of Reference Example G-3 (0.206 g) and THF (6 mL) at -40°C, and the mixture was stirred at the same temperature for 30 minutes. 1-(Bromomethyl)-3-chlorobenzene (0.129 g) was added to the reaction mixture at -40°C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes. The reaction mixture was added to a 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 APS column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give methyl (1R,4R)-1-(3-chlorobenzyl)-4-((diphenylmethylene)amino)-3,3-difluorocyclopentane-1-carboxylate (0.185 g) as a mixture with the (1S,4R)-isomer. A mixture of the obtained compound (0.185 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (4.94 mL), and DCM (1 mL) was stirred at room temperature for 3 hours and concentrated under reduced pressure. To a mixture of the residue, TEA (0.160 g), and DCM (1 mL) was added methanesulfonyl chloride (0.136 g) at room temperature. The mixture was stirred at the same 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 the title compound (0.101 g) as a mixture with the (1S,4R)-isomer.

[0309] Reference example J-3 (1R,4R)-3,3-Difluoro-4-(methylsulfonamido)-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)cyclopentane-1-carboxylate A mixture of Reference Example J-2 (0.018 g), bis(pinacolato)diboron (0.036 g), potassium acetate (0.014 g), Pd(dba) (2.2 mg), Xphos (4.5 mg), and 1,4-dioxane (0.5 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 = 100 / 0 to 0 / 100) to give the title compound (0.025 g) as a mixture with the (1S,4R)-isomer.

[0310] The structural formulas of the reference examples are shown in the table below.

[0311] [Table 1]

[0312] [Table 2]

[0313] [Table 3]

[0314] [Table 4]

[0315]

Table 5

[0316]

Table 6

[0317]

Table 7

[0318]

Table 8

[0319]

Table 9

[0320]

Table 10

[0321]

Table 11

[0322]

Table 12

[0323]

Table 13

[0324]

Table 14

[0325] Example 1 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-N-ethyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example A-2 (0.006 g), ethylamine hydrochloride (0.003 g), DIPEA (0.010 g), and DMF (2 mL) was added HATU (0.007 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. 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 = 40 / 60 to 0 / 100) to obtain the title compound (0.006 g).

[0326] Example 2 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example A-2 (0.015 g), N,O-dimethylhydroxylamine hydrochloride (0.008 g), DIPEA (0.016 g), 1-hydroxybenzotriazole monohydrate (0.009 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.012 g), and DMF (0.5 mL) was stirred at 50°C for 24 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to give the title compound (0.013 g).

[0327] Example 3 (1R* ,3S * )-1-((2',6-difluoro-[1,1'-biphenyl]-3-yl)methyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example B-14 (0.015 g), 2-fluorophenylboronic acid (0.010 g), tripotassium phosphate (0.024 g), Xphos Pd G3 (3.2 mg), 1,2-dimethoxyethane (0.25 mL), and water (0.25 mL) was stirred at 80°C for 30 minutes under microwave irradiation. The reaction mixture was added to saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue. The 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 0 / 100) to obtain the title compound (0.016 g).

[0328] Examples 4 and 5 Examples 4 and 5 were synthesized in the same manner as in Example 3, except that corresponding reagents were used instead of 2-fluorophenylboronic acid.

[0329] Example 6 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-N-methoxy-N-methyl-3-((N-methylsulfamoyl)amino)cyclopentane-1-carboxamide To a mixture of Reference Example A-4 (0.014 g), DIPEA (0.030 g), and DCM (2 mL) was added N-methylsulfamoyl chloride (0.005 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. Water and DCM were added to the reaction mixture. The mixture was 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 = 50 / 50 to 0 / 100) to obtain the title compound (0.016 g).

[0330] Example 7 N-((1S * ,3R * )-3-([1,1'-biphenyl]-3-ylmethyl)-3-(isoxazolidine-2-carbonyl)cyclopentyl)methanesulfonamide To a mixture of Reference Example A-2 (0.015 g) and DCM (1 mL), oxalyl chloride (0.016 g) and DMF (4.7 mg) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Isoxazolidine hydrochloride (0.022 g) and DIPEA (0.104 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 20 / 80 to 0 / 100) to obtain the title compound (0.013 g).

[0331] Examples 8 to 9 Examples 8 and 9 were synthesized in the same manner as in Example 7, except that the corresponding reagents were used instead of isoxazolidine hydrochloride.

[0332] Example 10 (1R * ,3S * )-1-((2'-cyano-[1,1'-biphenyl]-3-yl)methyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example B-4 (0.019 g), 2-bromobenzonitrile (0.011 g), potassium carbonate (0.017 g), Pd(PPh3)4 (0.005 g), toluene (1 mL), ethanol (0.5 mL), and water (0.25 mL) was stirred at 120 °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 = 50 / 50 to 0 / 100) to obtain the title compound (0.013 g).

[0333] Example 11 Example 11 was synthesized in the same manner as in Example 10, except that 2-bromophenol was used instead of 2-bromobenzonitrile.

[0334] Example 12 (1R * ,3S * )-1-(3-(5-fluoropyridin-2-yl)benzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example B-4 (0.010 g), 2-bromo-5-fluoropyridine (0.006 g), sodium carbonate (0.007 g), Pd(dppf)Cl (2.0 mg), 1,4-dioxane (0.25 mL), ethanol (0.125 mL), and water (0.125 mL) was stirred at 100°C for 30 minutes under microwave irradiation. The reaction mixture was 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 (0.007 g).

[0335] Examples 13 to 14 Examples 13 and 14 were synthesized in the same manner as in Example 12, except that corresponding reagents were used instead of 2-bromo-5-fluoropyridine.

[0336] Example 15 (1R * ,3S * )-1-(3-(5-chloropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example B-4 (0.052 g), 2-bromo-5-chloropyrimidine (0.043 g), sodium carbonate (0.036 g), Pd(dppf)Cl DCM adduct (0.009 g), 1,4-dioxane (0.5 mL), ethanol (0.25 mL), and water (0.25 mL) was stirred at 90°C for 1 hour under microwave irradiation. The reaction mixture was added to saturated aqueous ammonium chloride solution. 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 40 / 60) to give the title compound (0.050 g).

[0337] Examples 16 to 20 Examples 16 to 20 were synthesized in the same manner as in Example 15, using the corresponding reagents instead of 2-bromo-5-chloropyrimidine.

[0338] Example 21 (1R * ,3S * )-1-(3-(5-(dimethylamino)pyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Example 15 (0.010 g), 9.5 mol / L aqueous dimethylamine solution (0.005 mL), Pd(dba)2 (0.6 mg), sodium tert-butoxide (0.006 g), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.5 mg), and 1,4-dioxane (0.5 mL) was stirred at 110 °C for 2 hours under microwave irradiation. 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 0 / 100) followed by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give the title compound (2.4 mg).

[0339] Examples 22 to 26 Examples 22 to 26 were synthesized in the same manner as in Example 15, except that the corresponding Reference Examples and reagents were used instead of Reference Example B-4 and 2-bromo-5-chloropyrimidine.

[0340] Example 27 (1R * ,3S * )-1-(3-(2H-1,2,3-triazol-2-yl)benzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example B-3 (0.034 g), 2H-1,2,3-triazole (0.019 g), tripotassium phosphate (0.096 g), Pd(dba)chloroform adduct (0.019 g), Me4tBuXPhos (0.017 g), and toluene (2 mL) was stirred at 140°C for 3 hours under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give the title compound (2.0 mg).

[0341] Example 28 (1R * ,3S * )-N-Ethyl-N-methyl-3-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide A mixture of Reference Example C-1 (0.035 g), N-methylethylamine (0.022 g), HATU (0.046 g), DIPEA (0.060 g), and NMP (0.6 mL) was stirred at 90°C for 1 hour under microwave irradiation. 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 (0.032 g).

[0342] Example 29 (1R * ,3S * )-N-Methoxy-3-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example C-1 (0.008 g), DMF (0.009 g), and DCM (0.5 mL) was added oxalyl chloride (0.006 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a mixture of methoxyamine hydrochloride (0.012 g), DIPEA (0.056 g), and DCM (0.5 mL) at room temperature. The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to obtain the title compound (0.006 g).

[0343] Example 30 (1R * ,3S * )-N-Hydroxy-N-methyl-3-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example C-1 (0.015 g), DMF (0.009 g), and DCM (0.5 mL) was added oxalyl chloride (0.011 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a mixture of N-methylhydroxyamine hydrochloride (0.024 g), DIPEA (0.104 g), and DCM (0.5 mL) at room temperature. The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 2 mol / L aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 5 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 95 / 5) to obtain the title compound (1.3 mg).

[0344] Example 31 (1R * ,3S * )-N-Methoxy-N-methyl-3-((1-methylcyclopropane)-1-sulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example C-2 (0.006 g), DIPEA (0.012 g), and DCM (2 mL) was added 1-methylcyclopropane-1-sulfonyl chloride (0.010 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, DIPEA (0.082 g) and 1-methylcyclopropane-1-sulfonyl chloride (0.048 g) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture. The mixture was 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) followed by APS column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70 to 0 / 100) to obtain the title compound (1.0 mg).

[0345] Example 32 (1R * ,3R * ,4R * )-3-Fluoro-N-methoxy-N-methyl-4-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example E-8 (0.053 g), TEA (0.017 g), ethanol (0.5 mL), and THF (0.5 mL), 10% Pd / C (0.011 g) was added under ice-cooling. The mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, TEA (0.035 g), and DCM (1 mL) was added methanesulfonyl chloride (0.020 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water and saturated brine were 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 / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 90 / 10) to give the title compound (0.035 g).

[0346] Example 33 Example 33 was synthesized in the same manner as in Example 32, except that Reference Example E-5 was used instead of Reference Example E-8.

[0347] Example 34 (1R * ,3R * ,4S * )-3-((N,N-dimethylsulfamoyl)amino)-4-fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide A mixture of Reference Example E-19 (0.013 g), dimethylsulfamoyl chloride (0.270 g), DMAP (0.012 g), and DIPEA (0.012 g) was stirred at 60°C for 5 hours. The reaction mixture was allowed to cool to room temperature and then added to saturated aqueous sodium bicarbonate solution. 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 = 40 / 60) to obtain the title compound (0.008 g).

[0348] Example 35 (1R * ,3R * ,4S * )-3-((N,N-dimethylsulfamoyl)amino)-4-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example E-13 (0.022 g), ethanol (0.5 mL), and THF (0.5 mL), 10% Pd / C (0.004 g) was added under ice-cooling. The mixture 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, dimethylsulfamoyl chloride (0.405 g), DMAP (0.020 g), and DIPEA (0.021 g) was stirred at 60°C for 3 hours and allowed to cool to room temperature. Water, saturated brine, and saturated aqueous sodium bicarbonate solution were added to the reaction mixture. 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 (0.008 g).

[0349] Example 36 (1R * ,3R * ,4S * )-3-(Ethylsulfonamido)-4-fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide Under an argon atmosphere, ethanesulfonyl chloride (0.065 g) was added to a mixture of Reference Example E-19 (0.067 g) and pyridine (1 mL) at room temperature, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was added to water. The mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 40 / 60) to obtain the title compound (0.039 g).

[0350] Example 37 (1R * ,3S * ,4R *)-3-Fluoro-1-(2-fluoro-5-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide Under an argon atmosphere, methanesulfonyl chloride (0.044 g) was added to a mixture of Reference Example E-25 (0.051 g), TEA (0.052 g), and DCM (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate 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 = 60 / 40) followed by APS column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50) to give the title compound (0.042 g).

[0351] Example 38 (1R * ,3S * ,4R * )-3-Fluoro-1-(2-fluoro-5-(pyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-((trifluoromethyl)sulfonamido)cyclopentane-1-carboxamide Under an argon atmosphere, a mixture of trifluoromethanesulfonyl chloride (0.010 g) and DCM (0.05 mL) was added to a mixture of Reference Example E-31 (0.015 g), TEA (0.008 g), and DCM (0.4 mL) under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, TEA (0.008 g) was added under ice-cooling, followed by a mixture of trifluoromethanesulfonyl chloride (0.010 g) and DCM (0.05 mL). The mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, TEA (0.020 g) was added under ice-cooling, followed by a mixture of trifluoromethanesulfonyl chloride (0.027 g) and DCM (0.05 mL). The mixture was stirred at the same temperature for 20 minutes. Water was added to the reaction mixture under ice-cooling. 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 = 70 / 30 to 50 / 50) to obtain the title compound (0.003 g).

[0352] Example 39 (1R * ,3S * ,4R * )-3-Fluoro-1-(3-(5-fluoropyrimidin-2-yl)-4-hydroxybenzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example E-34 (0.010 g), 6 mol / L hydrochloric acid (0.1 mL), and 1,4-dioxane (0.5 mL) was stirred at 100°C for 5 hours and then at room temperature for 18 hours. Concentrated hydrochloric acid (0.1 mL) was added to the reaction mixture at room temperature, and the mixture was stirred at 100°C for 4 hours and allowed to cool to room temperature. Concentrated hydrochloric acid (0.1 mL) and 1,4-dioxane (0.5 mL) were added to the reaction mixture at room temperature, and the mixture was stirred at 100°C for 1 hour and allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to make it basic. The mixture was washed with DCM. 2 mol / L hydrochloric acid was added to the aqueous layer to adjust the pH to 1-2. 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, N,O-dimethylhydroxylamine hydrochloride (0.007 g), DIPEA (0.012 g), and DMF (0.3 ml) was added HATU (0.009 g) at room temperature. The mixture was stirred at 70°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture. 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 = 60 / 40 to 20 / 80). Ethyl acetate and 2 mol / L hydrochloric acid were added to the obtained target product, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (0.006 g).

[0353] Example 40 (1R * ,4R * )-3,3-Difluoro-N-methoxy-N-methyl-4-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example F-1 (0.043 g), ethanol (0.5 mL), and THF (0.5 mL), 10% Pd / C (0.009 g) was added under ice-cooling. The mixture 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. To a mixture of the residue, TEA (0.022 g), and DCM (1 mL), methanesulfonyl chloride (0.012 g) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was 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 (0.011 g).

[0354] Example 41 Example 41 was synthesized in the same manner as in Example 34, except that Reference Example F-2 was used instead of Reference Example E-19.

[0355] Examples 42 to 43 Examples 42 and 43 were synthesized in the same manner as in Example 37, except that the corresponding Reference Examples were used instead of Reference Example E-25.

[0356] Example 44 (1R * ,3R * ,4R * )-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N,3-dimethyl-4-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example E-36 (0.018 g), 6 mol / L hydrochloric acid (1 mL), and 1,4-dioxane (1 mL) was stirred at 100° C. for 8 hours and allowed to cool to room temperature. 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. To a mixture of the residue, DMF (0.3 mg), and DCM (1 mL) was added oxalyl chloride (0.008 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and DCM (0.5 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.008 g), DIPEA (0.016 g), and DCM (0.5 mL) under ice-cooling. The mixture was stirred at room temperature for 15 minutes 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 the title compound (0.008 g).

[0357] Example 45 (1R * ,3S * ,4R * )-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N,3-dimethyl-4-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example E-38 (0.245 g), 6 mol / L hydrochloric acid (4 mL), and 1,4-dioxane (4 mL) was stirred at 100° C. for 8 hours and allowed to cool to room temperature. 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. To a mixture of the residue (0.051 g), DMF (0.9 mg), and DCM (1 mL), oxalyl chloride (0.048 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and DCM (0.5 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.024 g), DIPEA (0.113 g), and DCM (0.5 mL) under ice-cooling. The mixture was stirred at room temperature for 15 minutes 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 the title compound (0.036 g).

[0358] Examples 46 to 47 N-Methoxy-N-methyl-3-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide (Example 46, first peak) N-Methoxy-N-methyl-3-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide (Example 47, second peak) A mixture of Reference Example B-4 (0.305 g), 2-bromopyrimidine (0.208 g), sodium carbonate (0.208 g), Pd(dppf)Cl DCM adduct (0.053 g), 1,4-dioxane (5 mL), ethanol (2.5 mL), and water (2.5 mL) was stirred at 90 °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 = 100 / 0 to 0 / 100) followed by chiral preparative column chromatography (eluent: n-hexane / ethanol = 50 / 50). The first peak was identified as Example 46 (0.060 g), and the second peak was identified as Example 47 (0.056 g).

[0359] Example 48 (1R,3S)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example H-4 (0.151 g), DMF (2.7 mg), and DCM (1.5 mL) was added oxalyl chloride (0.070 g) under ice-cooling. The mixture was stirred at room temperature for 45 minutes and concentrated under reduced pressure. A mixture of the residue and DCM (1 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.071 g), DIPEA (0.142 g), and DCM (1 mL) under ice-cooling. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture. The mixture was 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 = 50 / 50 to 0 / 100) to obtain the title compound (0.066 g).

[0360] Example 49 (1R,3S)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example H-6 (0.019 g), 2 mol / L aqueous sodium hydroxide solution (0.215 mL), and 1,4-dioxane (1 mL) was stirred at 80° C. for 2 hours and then allowed to cool to room temperature. 2 mol / L hydrochloric acid (0.236 mL) and saturated brine were added to the reaction mixture. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.028 g), HATU (0.021 g), and DMF (1 mL) was stirred at 60°C for 1 hour and allowed to cool to room temperature. N,O-Dimethylhydroxylamine hydrochloride (0.017 g) was added to the reaction mixture at room temperature. The mixture was stirred at 70°C for 2 hours and then at room temperature for 22 hours. Water and saturated aqueous sodium bicarbonate solution 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 Method A (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) and then by ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.004 g).

[0361] Example 50 (1R,3S)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-((fluoromethyl)sulfonamido)-N-methoxy-N-methylcyclopentane-1-carboxamide Under an argon atmosphere, fluoromethanesulfonyl chloride (0.007 g) was added to a mixture of Reference Example H-5 (0.014 g), TEA (0.008 g), and DCM (0.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 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 = 60 / 40 to 50 / 50) to give the title compound (0.010 g).

[0362] Example 51 (1R,3S)-3-((difluoromethyl)sulfonamido)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide Under an argon atmosphere, difluoromethanesulfonyl chloride (0.008 g) was added to a mixture of Reference Example H-5 (0.017 g), pyridine (0.018 g), and MeCN (1 mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. Difluoromethanesulfonyl chloride (0.008 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. 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 (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 50 / 50) to obtain the title compound (0.004 g).

[0363] Example 52 (1R,3S)-3-(Ethylsulfonamido)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide Under an argon atmosphere, ethanesulfonyl chloride (0.033 g) was added to a mixture of Reference Example H-5 (0.032 g) and pyridine (0.8 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. 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. Toluene was added to the residue, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 40 / 60) to obtain the title compound (0.011 g).

[0364] Example 53 (1R,3S)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-3-(vinylsulfonamido)cyclopentane-1-carboxamide Under an argon atmosphere, 2-fluoroethane-1-sulfonyl chloride (0.009 g) was added to a mixture of Reference Example H-5 (0.016 g), TEA (0.009 g), and DCM (0.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. 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 = 60 / 40 to 40 / 60) to give the title compound (0.005 g).

[0365] Example 54 (1R,3S)-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-3-(oxetane-3-sulfonamido)cyclopentane-1-carboxamide Under an argon atmosphere, oxetane-3-sulfonyl chloride (0.018 g) was added to a mixture of Reference Example H-5 (0.022 g), 1,8-diazabicyclo[5.4.0]-7-undecene (0.036 g), and DCM (0.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 50 minutes. Oxetane-3-sulfonyl chloride (0.018 g) was added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 25 minutes. 1,8-diazabicyclo[5.4.0]-7-undecene (0.018 g) and oxetane-3-sulfonyl chloride (0.018 g) were added to the reaction mixture at room temperature, 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=80 / 20 to 60 / 40) to obtain the title compound (0.007 g).

[0366] Example 55 (1R,3S)-1-(3-(5-fluoropyrimidin-2-yl)-4-hydroxybenzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example H-10 (0.050 g) and DCM (1 mL), boron tribromide (1 mol / L in DCM) (0.236 mL) was added at -78°C, and the mixture was stirred at the same temperature for 1 hour. Water was added to the mixture at the same temperature, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.018 g), DIPEA (0.030 g), and DMF (1 mL) was added HATU (0.019 g) at room temperature. The mixture was stirred at 70°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.002 g).

[0367] Example 56 (1R,3S)-1-(3-(5-fluoropyrimidin-2-yl)-4-methoxybenzyl)-N-methoxy-N-methyl-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example H-10 (0.010 g), N,O-dimethylhydroxylamine hydrochloride (0.009 g), DIPEA (0.015 g), and DMF (1 mL) was added HATU (0.010 g) at room temperature. The mixture was stirred at the same temperature for 1 hour and then at 70°C for 2 hours, and then allowed to cool to room temperature. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.010 g).

[0368] Example 57 (1R,3S,4R)-3-Fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example I-4 (0.201 g) and DCM (10 mL) was added Deoxo-Fluor (0.158 g) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Deoxo-Fluor (0.158 g) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 15 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to give methyl (1R,3S,4R)-3-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.145 g). A mixture of the obtained compound (0.145 g), 2 mol / L aqueous sodium hydroxide solution (0.852 mL), and 2-propanol (4 mL) was stirred at 70°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (0.937 mL) 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.100 g), DIPEA (0.308 g), and DMF (2 mL) was added HATU (0.143 g) at room temperature. The mixture was stirred at 70 °C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture. 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100), silica gel column chromatography (eluent: n-hexane / ethyl acetate = 40 / 60), APS column chromatography (eluent: n-hexane / ethyl acetate = 40 / 60), and ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.042 g).

[0369] Example 58 (1R,3S,4R)-3-Fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-((1-methylethyl)sulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example I-6 (0.032 g) and DCM (2 mL), Deoxo-Fluor (0.024 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. The reaction mixture was added to saturated aqueous sodium bicarbonate. The mixture was 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 50 / 50) to give methyl (1R,3S,4R)-3-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-((1-methylethyl)sulfonamido)cyclopentane-1-carboxylate (0.020 g). A mixture of the obtained compound (0.020 g), 2 mol / L aqueous sodium hydroxide solution (0.110 mL), and 2-propanol (2 mL) was stirred at 70°C for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid (0.121 mL) 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.013 g), DIPEA (0.040 g), and DMF (2 mL) was added HATU (0.018 g) at room temperature. The mixture was stirred at 70°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture. 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 30 / 70) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.010 g).

[0370] Example 59 (1R,3R,4S)-3-(Ethylsulfonamido)-4-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example I-7 (0.191 g), pyridine (0.104 g), and DCM (4 mL) was added Deoxo-Fluor (0.145 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 20 hours. Saturated aqueous sodium bicarbonate and water were 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 = 80 / 20 to 50 / 50) to give methyl (1R,3R,4S)-3-(ethylsulfonamido)-4-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.168 g). A mixture of the obtained compound (0.168 g), 2 mol / L aqueous sodium hydroxide solution (0.437 mL), and 2-propanol (4 mL) was stirred at 70°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.128 g), DIPEA (0.282 g), and DMF (4 mL) was added HATU (0.183 g) at room temperature. The mixture was stirred at 80°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture. 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 20 / 80) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.041 g).

[0371] Example 60 (1R,3R,4S)-3-(Cyclopropanesulfonamido)-4-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example I-8 (0.027 g), pyridine (0.014 g), and DCM (2 mL) was added DeoxoFluor (0.020 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 17 hours. Saturated aqueous sodium bicarbonate and water were 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 = 70 / 30 to 50 / 50) to give methyl (1R,3R,4S)-3-(cyclopropanesulfonamido)-4-fluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)cyclopentane-1-carboxylate (0.023 g). A mixture of the obtained compound (0.023 g), 2 mol / L aqueous sodium hydroxide solution (0.060 mL), and 2-propanol (2 mL) was stirred at 70°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.018 g), DIPEA (0.039 g), and DMF (2 mL) was added HATU (0.025 g) at room temperature. The mixture was stirred at 80°C for 1 hour and allowed to cool to room temperature. Water was added to the reaction mixture. 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 20 / 80) and then ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.005 g).

[0372] Example 61 (1R,3R,4S)-3-(Ethylsulfonamido)-4-fluoro-1-(2-fluoro-5-(pyrimidin-2-yl)benzyl)-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example I-12 (0.169 g), pyridine (0.078 g), and DCM (7 mL) was added Deoxo-Fluor (0.109 g) under ice-cooling. The mixture was stirred at the same temperature for 5 minutes and then at room temperature for 3 hours. Saturated aqueous sodium bicarbonate and water were 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 = 80 / 20 to 50 / 50) to give methyl (1R,3R,4S)-1-(5-(5-bromopyrimidin-2-yl)-2-fluorobenzyl)-3-(ethylsulfonamido)-4-fluorocyclopentane-1-carboxylate (0.126 g). A mixture of the obtained compound (0.126 g), 2 mol / L aqueous sodium hydroxide solution (0.327 mL), and 2-propanol (4 mL) was stirred at 70°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.096 g), DIPEA (0.211 g), and DMF (4 mL) was added HATU (0.137 g) at room temperature. The mixture was stirred at 100°C for 1.5 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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 = 70 / 30 to 30 / 70) and then by ODS column chromatography (eluent: water / MeCN = 70 / 30 to 10 / 90) to give (1R,3R,4S)-1-(5-(5-bromopyrimidin-2-yl)-2-fluorobenzyl)-3-(ethylsulfonamido)-4-fluoro-N-methoxy-N-methylcyclopentane-1-carboxamide (0.081 g). A mixture of the obtained compound (0.073 g), TEA (0.020 g), ethanol (1.5 mL), THF (1.5 mL), and 10% Pd / C (0.014 g) was stirred under a hydrogen atmosphere at room temperature for 1 hour. 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 0 / 100) to give the title compound (0.055 g).

[0373] Example 62 (1R,3S,4R)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-fluoro-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example I-18 (0.237 g), pyridine (0.098 g), and DCM (7.6 mL) was added DeoxoFluor (0.137 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. The reaction mixture was added to saturated aqueous sodium bicarbonate 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 50 / 50) to give methyl (1R,3S,4R)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-fluoro-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.091 g). A mixture of the obtained compound (0.091 g), 5 mol / L aqueous sodium hydroxide solution (0.394 mL), and 1,4-dioxane (2 mL) was stirred at 80° C. for 1.5 hours and allowed to cool to room temperature. 6 mol / L hydrochloric acid (0.394 mL) 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.058 g), DIPEA (0.172 g), and DMF (2 mL) was added HATU (0.083 g) at room temperature. The mixture was stirred at 100°C for 1.5 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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) and then ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.033 g).

[0374] Example 63 (1R,3R,4S)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-(ethylsulfonamido)-4-fluoro-N-methoxy-N-methylcyclopentane-1-carboxamide To a mixture of Reference Example I-19 (0.251 g), pyridine (0.126 g), and DCM (2.5 mL) was added Deoxo-Fluor (0.177 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, then at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate and water were 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 give methyl (1R,3R,4S)-1-(4-chloro-3-(5-fluoropyrimidin-2-yl)benzyl)-3-(ethylsulfonamido)-4-fluorocyclopentane-1-carboxylate (0.200 g). A mixture of the obtained compound (0.200 g), 5 mol / L aqueous sodium hydroxide solution (0.571 mL), and 1,4-dioxane (2 mL) was stirred at 80° C. for 1.5 hours and allowed to cool to room temperature. 6 mol / L hydrochloric acid (0.571 mL) 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. To a mixture of the residue, N,O-dimethylhydroxylamine hydrochloride (0.083 g), DIPEA (0.184 g), and DMF (3 mL) was added HATU (0.119 g) at room temperature. The mixture was stirred at 100°C for 1.5 hours and allowed to cool to room temperature. Water was added to the reaction mixture. 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) and then ODS column chromatography (eluent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.060 g).

[0375] Example 64 (1R,3R,4R)-3-Fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example I-22 (0.033 g), pyridine (0.017 g), and DCM (1 mL) was added DeoxoFluor (0.024 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture under ice-cooling. 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 40 / 60) to give methyl (1R,3R,4R)-3-fluoro-1-(4-fluoro-3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.023 g). A mixture of the obtained compound (0.023 g), 6 mol / L hydrochloric acid (1 mL), and 1,4-dioxane (1 mL) was stirred at 100° C. for 8 hours and allowed to cool to room temperature. 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. To a mixture of the residue, DMF (0.4 mg), and DCM (1 mL), oxalyl chloride (0.010 g) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and DCM (0.5 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.010 g), DIPEA (0.020 g), and DCM (0.5 mL) under ice-cooling. The mixture was stirred at room temperature for 15 minutes 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 the title compound (0.011 g).

[0376] Example 65 (1R,4R)-3,3-Difluoro-N-methoxy-N-methyl-4-(methylsulfonamido)-1-(3-(pyrimidin-2-yl)benzyl)cyclopentane-1-carboxamide To a mixture of Reference Example J-1 (0.153 g), TEA (0.031 g), and ethanol (3 mL) was added 10% Pd / C (0.046 g) at room temperature. The mixture was stirred at the same temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate and DCM 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. A mixture of the residue, 5 mol / L aqueous sodium hydroxide solution (0.310 mL), THF (0.5 mL), and methanol (1 mL) was stirred at 110°C for 1 hour under microwave irradiation. 6 mol / L hydrochloric acid (0.259 mL) and water were added to the reaction mixture. The mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, DIPEA (0.201 g), HATU (0.154 g), and NMP (3 mL) was stirred at 90°C for 30 minutes under microwave irradiation. N,O-Dimethylhydroxylamine hydrochloride (0.121 g) and DIPEA (0.201 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 90°C for 1 hour under microwave irradiation. N,O-Dimethylhydroxylamine hydrochloride (0.121 g) and DIPEA (0.161 g) were added to the reaction mixture at room temperature, and the mixture was stirred at 90°C for 1 hour under microwave irradiation. The reaction mixture was poured into 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 0 / 100) and then by ODS column chromatography (eluent: water / MeCN=70 / 30 to 10 / 90) to obtain the title compound (0.020 g).

[0377] Example 66 (1R,4R)-3,3-Difluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N-methoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example J-3 (0.665 g), 2-bromo-5-fluoropyrimidine (0.497 g), sodium carbonate (0.447 g), Pd(dppf)Cl DCM adduct (0.115 g), 1,4-dioxane (5 mL), ethanol (2.5 mL), and water (2.5 mL) was stirred at 90 °C for 1 hour under microwave irradiation. The 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 50 / 50) to give methyl (1R,4R)-3,3-difluoro-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-4-(methylsulfonamido)cyclopentane-1-carboxylate (0.703 g) as a mixture with the (1S,4R)-isomer. A mixture of the obtained compound (0.703 g), 2 mol / L aqueous sodium hydroxide solution (3.57 mL), and 2-propanol (20 mL) was stirred at 60°C for 1 hour and allowed to cool to room temperature. 2 mol / L hydrochloric acid (3.96 mL), water, and saturated brine were added to the reaction mixture. The mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixture of the residue, DIPEA (1.05 g), HATU (0.805 g), and DMF (1 mL) was stirred at 60°C for 40 minutes. N,O-Dimethylhydroxylamine hydrochloride (0.635 g) was added to the reaction mixture at room temperature. The mixture was stirred at 60°C for 40 minutes 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 0 / 100) followed by chiral preparative column chromatography (eluent: n-hexane / ethanol = 70 / 30) to give the title compound (0.124 g).

[0378] Example 67 (1R,3S,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,3-dimethoxy-N-methyl-4-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example I-23 (0.021 g), 2 mol / L aqueous sodium hydroxide solution (0.190 mL), THF (0.5 mL), and 2-propanol (0.5 mL) was stirred at 60°C for 2 hours and allowed to cool to room temperature. 2 mol / L hydrochloric acid (0.228 mL), water, and saturated brine were added to the reaction mixture. 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, DMF (0.2 mg), and DCM (1 mL) was added oxalyl chloride (0.006 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A mixture of the residue and DCM (0.5 mL) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (0.006 g), DIPEA (0.012 g), and DCM (0.5 mL) under ice-cooling. The mixture was stirred at room temperature for 15 minutes 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 (1R,3S,4R)-1-(3-(5-fluoropyrimidin-2-yl)benzyl)-N,3-dimethoxy-4-(N-(4-methoxybenzyl)methylsulfonamido)-N-methylcyclopentane-1-carboxamide (0.013 g). A mixture of the obtained compound (0.013 g), triethylsilane (0.008 g), TFA (1.5 mL), and DCM (0.5 mL) was stirred at 40°C for 30 minutes. The reaction mixture was allowed to cool to room temperature and then 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 the title compound (0.009 g).

[0379] Example 68 Example 68 was synthesized in the same manner as in Example 67, except that Reference Example I-24 was used instead of Reference Example I-23.

[0380] Examples 69 to 70 Examples 69 and 70 were synthesized in the same manner as in Example 1, except that corresponding reagents were used instead of ethylamine hydrochloride.

[0381] Example 71 N-((1S * ,3R * )-3-([1,1'-biphenyl]-3-ylmethyl)-3-(2-(trifluoromethyl)pyrrolidine-1-carbonyl)cyclopentyl)methanesulfonamide To a mixture of Reference Example A-2 (0.011 g) and DCM (1 mL), oxalyl chloride (0.007 g) and DMF (4.7 mg) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. 2-(Trifluoromethyl)pyrrolidine hydrochloride (0.010 g) and DIPEA (0.074 g) were added to the reaction mixture at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture. The mixture was extracted with DCM, and the extract was 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 (0.007 g).

[0382] Example 72 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)cyclopentane-1-carboxamide To a mixture of Reference Example A-2 (0.035 g), ammonium chloride (0.025 g), DIPEA (0.097 g), and DMF (1.5 mL) was added HATU (0.039 g) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, DIPEA (0.048 g), ammonium chloride (0.013 g), and HATU (0.018 g) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. 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 = 20 / 80 to 0 / 100) and then APS column chromatography (eluent: ethyl acetate) to obtain the title compound (0.029 g).

[0383] Example 73 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-N-(2-hydroxyethyl)-3-(methylsulfonamido)cyclopentane-1-carboxamide A mixture of Reference Example A-2 (0.030 g), 2-(benzyloxy)-1-ethanamine hydrochloride (0.030 g), DIPEA (0.031 g), 1-hydroxybenzotriazole monohydrate (0.018 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.023 g), and DMF (1.0 mL) was stirred at 50°C for 13 hours and allowed to cool to room temperature. Water was added to the reaction mixture. The mixture was extracted with a mixed solvent of n-hexane / ethyl acetate (3 / 1). The extract was washed 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: ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-N-(2-(benzyloxy)ethyl)-3-(methylsulfonamido)cyclopentane-1-carboxamide (0.033 g) was obtained. To a mixture of the obtained compound (0.030 g) and ethanol (1.0 mL), 10% Pd / C (0.006 g) was added under ice-cooling. The mixture was stirred at room temperature under a hydrogen atmosphere for 6 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: ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.019 g).

[0384] Example 74 (1R * ,3S * )-1-([1,1'-biphenyl]-3-ylmethyl)-3-(methylsulfonamido)-N-(2,2,2-trifluoroethyl)cyclopentane-1-carboxamide To a mixture of 2,2,2-trifluoroethylamine (0.011 g), TEA (0.047 g), and DCM (0.5 mL) was added phosphoryl chloride (0.016 g) under ice-cooling. To this mixture was added a mixture of Reference Example A-2 (0.027 g) and DCM (0.5 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture. The mixture was 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 = 40 / 60 to 20 / 80) to obtain the title compound (0.010 g).

[0385] Example 75 Example 75 was synthesized in the same manner as in Example 71, except that 3,3-difluoropyrrolidine hydrochloride was used instead of 2-(trifluoromethyl)pyrrolidine hydrochloride.

[0386] The structural formulas, physical properties, and OX2R agonist activity (see Test Example 1) of the examples are shown in the table below.

[0387] [Table 15]

[0388] [Table 16]

[0389] [Table 17]

[0390] [Table 18]

[0391] [Table 19]

[0392] [Table 20]

[0393] [Table 21]

[0394] [Table 22]

[0395] [Table 23]

[0396] [Table 24]

[0397] [Table 25]

[0398] [Table 26]

[0399] [Table 27]

[0400] [Table 28] The stereochemistry notation of Ex. Nos. 1 to 45 and 69 to 75 in the table indicates the relative configuration.

[0401] Test Example 1

[0402] 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 isolated by limiting dilution.

[0403] 2) Measurement of OX2R agonist activity The agonistic effect of the test substance on human OX2R was evaluated using the change in intracellular calcium concentration due to stimulation as an index. On the day before measuring the intracellular calcium concentration, 5 × 10 human OX2R-expressing cells were suspended in medium. 3Cells were seeded into a 384-well plate at a concentration of 50 μL per well and cultured overnight in an incubator set at 37°C and 5% CO2. After culture, 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 measurement, a vehicle containing the test substance (final concentration: 10 μM) or vehicle alone was added, and measurements were performed 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 using the fluorescence intensity upon addition of human orexin A peptide (Peptide Institute, Inc.) at a final concentration of 1 μM 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. These results demonstrate that the compounds of the present invention have agonist activity against human OX2R. [Industrial Applicability]

[0404] Since the compound of the present invention or a pharmacologically acceptable salt thereof has OX2R agonist activity, the pharmaceutical composition of the present invention is useful as a therapeutic agent for sleep disorders associated with OX2R.

Claims

1. Compounds represented by formula (I): 【Chemical 1】 [During the ceremony, Ring A is C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; R 1 is a group selected from the group consisting of the following (a) to (c): (a) -NR a R a '、 【Chemistry 2】 and 【Chemistry 3】 R a and R a ' are each independently a hydrogen atom, a hydroxy group, or C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or haloC 1-6 is alkyl; R b is a hydrogen atom, a halogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or haloC 1-6 is alkyl; p is an integer from 1 to 3; When p is 2 or 3, each R b may be the same or different from each other; q is an integer from 1 to 3; r is 1 or 2; R 2 is C 1-6 Alkyl, C 2-6 Alkenyl, 1-3 C 1-6 C optionally substituted with alkyl 3-8 Cycloalkyl, 1 to 3 C 1-6 3- to 8-membered heterocycloalkyl optionally substituted with alkyl, haloC 1-6 Alkyl, or C 1-6 With alkylamino; R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, or C 1-6 is alkoxy; R 5 and R 6 are each independently a hydrogen atom or a halogen atom; R 7 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 alkylamino; R 8 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkyl, or C 1-6 alkylamino; n is 1 or 2; If n is 2, then each R 7 may be the same or different from each other; m is 1 or 2; If m is 2, then each R 8 may be the same or different from each other. or a pharmacologically acceptable salt thereof.

2. 10. The pharmaceutical composition of claim 1, comprising: Ring A is C 6-10 aryl, or 5- or 6-membered heteroaryl; R 5 and R 6 is a hydrogen atom; R 7 However, hydrogen atoms, halogen atoms, hydroxyl groups, C 1-6 Alkyl, HaloC 1-6 Alkyl, or C 1-6 is alkoxy; A pharmaceutical composition comprising a compound wherein n is 1 or a pharmacologically acceptable salt thereof.

3. A compound selected from the group consisting of the following compounds: 【Chemistry 4】 and 【Chemistry 5】 or a pharmacologically acceptable salt thereof.

4. A compound selected from the group consisting of the following compounds: 【Chemistry 6】 and 【Chemistry 7】 or a pharmacologically acceptable salt thereof.

5. The pharmaceutical composition according to any one of claims 1 to 4, which is a pharmaceutical composition for treating a sleep disorder involving OX2R.

6. 6. The pharmaceutical composition according to claim 5, wherein the sleep disorder involving OX2R is narcolepsy.

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