N-substituted piperidone compound

Abstract

The present invention addresses the problem of providing a novel compound that has an antagonistic activity against a thyroid-stimulating hormone receptor and is useful for the treatment of thyroid-related diseases. The present invention relates to an N-substituted piperidone compound represented by the following formula or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof according to the present invention has an antagonistic activity against a thyroid-stimulating hormone receptor and is useful, for example, as a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer).

Description

N-substituted piperidone compounds

[0001] The present invention relates to N-substituted piperidone compounds useful as pharmaceuticals. More specifically, the present invention relates to N-substituted piperidone compounds or pharmacoagulably acceptable salts thereof that have antagonist activity against thyroid-stimulating hormone receptors (TSHR) and are useful as therapeutic agents for thyroid-related diseases.

[0002] The thyroid hormones triiodothyronine (T3) and thyroxine (T4) play important roles in development, growth, and metabolism, and their synthesis and secretion are strictly regulated by thyroid-stimulating hormone (TSH) secreted from the pituitary gland.

[0003] In hyperthyroidism, these thyroid hormones are secreted in excess for some reason, and the effects of these hormones cause a variety of undesirable physical and mental effects, such as goiter, tachycardia, hypertension, fatigue, weight loss, palpitations, sleep disturbances, and menstrual irregularities.

[0004] There are various causes of hyperthyroidism, but Graves' disease is the most common. In Graves' disease, an autoimmune mechanism causes the body to mistakenly recognize its own thyroid gland as a foreign substance, producing autoantibodies against TSHR present on thyroid follicular cells, known as TSHR antibodies (TRAb). It is believed that these TRAb act as agonists against TSHR, excessively stimulating it, leading to the over-secretion of thyroid hormones and the development of hyperthyroidism.

[0005] Another disease associated with Graves' disease is thyroid eye disease. Thyroid eye disease is an autoimmune inflammatory disease that presents with a variety of ocular symptoms, and is thought to be mainly caused by the agonist effect of TRAb on TSHR in orbital tissue. It often develops at roughly the same time as hyperthyroidism, but it can also occur without thyroid dysfunction.

[0006] Currently, drug therapy for Graves' disease involves antithyroid drugs that inhibit the biosynthesis of thyroid hormones, such as thiamazole and propylthiouracil. However, these drugs have drawbacks, including a low remission rate, a long treatment period to achieve remission, and a high frequency of side effects. Therefore, there is a need for new drugs for Graves' disease with novel mechanisms of action.

[0007] Blocking TSHR, or inhibiting TSHR-induced signaling, inhibits the production, secretion, and proliferation of thyroid hormones. Therefore, TSHR antagonists are thought to have therapeutic effects against Graves' disease and thyroid eye disease caused by the agonist effect of TRAb on TSHR (Patent Documents 1 and 2). NCGC00242364 is a known TSHR antagonist, and it has been shown to reduce blood T4 levels in mice administered with TSH-releasing hormone (TRH) and mice administered with the thyroid-stimulating antibody M22 (Non-Patent Document 1).

[0008] Compounds having TSHR antagonist activity are described in Patent Documents 1 to 3 and Non-Patent Document 1. However, the N-substituted piperidone compound of the present invention is not described in any of Patent Documents 1 to 3 or Non-Patent Document 1.

[0009] U.S. Patent Application Publication No. 2011 / 0172267, U.S. Patent Application Publication No. 2012 / 0315217, U.S. Patent Application Publication No. 2019 / 0134024

[0010] Susanne Neumann et al., "Endocrinology," 2014, Vol. 155, No. 1, pp. 310-314.

[0011] The object of this invention is to provide a novel compound that has TSHR antagonist activity and is useful for the treatment of thyroid-related diseases.

[0012] The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In other words, the present invention relates to the following [1] to

[22] , etc. [1] Compound represented by formula (I): [wherein, Y is C 3-8 , 5 , 1-6 , 3-8 , 1-6 , 5 , 1 , 5' , 3-8 , 1-6 , 1-6 , 1-6 , 2 , 5' alkyl, haloC 1-6 alkyl, or ring X; ring X is a group selected from the group consisting of the following (i) to (iv): (i) C 6-10 aryl substituted with 1 to 3 groups selected from unsubstituted or substituent group A; (ii) 5- to 10-membered heteroaryl substituted with 1 to 3 groups selected from unsubstituted or substituent group A; (iii) C 3-8 cycloalkyl; and (iv) 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A (however, excluding the group in which the atom bonded to L 4 is a nitrogen atom); substituent group A is a halogen atom, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-8 cycloalkyl, and C 3-8 cycloalkoxy; ring Z is C 6-10 aryl, or 5- to 10-membered heteroaryl; R 1 is a halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, or C 3-8 cycloalkoxy; n is an integer from 0 to 2; when n is 2, each R 1 may be the same as or different from each other; R 2 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, or -NR 5 R 5' ; R 5 and R 5' are each independently a hydrogen atom, C1-6 Alkyl, or C 3-8 It is a cycloalkyl group; R 3 and R 3' Each of these is independently a hydrogen atom, or C 1-6 It is alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, Halo C 1-6 Alkyl, Halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 It is a cycloalkoxy or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 -and; R 6 and R 6' Each of these is independently a hydrogen atom, or C 1-6 Alkyl; L 2 C 1-6 Alkylene, or Halo C 1-6 It is alkylene; L 3 is a single bond, or -O-; L 4 C is a single bond. 1-6 Alkylene, or Halo C 1-6 It is an alkylene; m is an integer from 0 to 3; if m is 2 or greater, each R 4 They may be the same or different from each other; however, L 2 C 1-6 It is alkylene and L 3 If is -O-, then Y is C 1-6 Not alkyl; L 3 If Y is a single bond, then Y is ring X] or a pharmacologically acceptable salt thereof.

[0014] [2] A compound described in [1] above, which is represented by formula (II): [In the formula, ring X is a group selected from the group consisting of (i) to (iv) below: (i) C is unsubstituted or substituted with 1 to 3 groups selected from substituent group A] 6-10Aryl; (ii) a 5- to 10-member heteroaryl unsubstituted or substituted with 1 to 3 groups selected from substituent group A; (iii) a C 3-8 cycloalkyl; and (iv) a 3- to 8-member heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group A (excluding groups in which the atom bonded to L 4 is a nitrogen atom); substituent group A consists of a halogen atom, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-8 cycloalkyl, and C 3-8 cycloalkoxy; ring Z is C 6-10 aryl, or 5- to 10-member heteroaryl; R 1 is a halogen atom, hydroxy, C 1-6 [[ID=二十一]]alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, or C 3-8 cycloalkoxy; n is an integer from 0 to 2; when n is 2, each R 1 may be the same as or different from each other; R 2 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, or -NR 5 R 5' ; R 5 and R 5' are each independently a hydrogen atom, C 1-6 alkyl, or C 3-8 cycloalkyl; R 3 and R 3' are each independently a hydrogen atom, or C 1-6 alkyl; R 4 is a halogen atom, cyano, C 1-6Alkyl, Halo C 1-6 Alkyl, Halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 It is a cycloalkoxy or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 -and; R 6 and R 6' Each of these is independently a hydrogen atom, or C 1-6 Alkyl; L 2 C 1-6 Alkylene, or Halo C 1-6 It is alkylene; L 3 is a single bond, or -O-; L 4 C is a single bond. 1-6 Alkylene, or Halo C 1-6 It is an alkylene; m is an integer from 0 to 3; if m is 2 or greater, each R 4 [These may be identical or different from each other] or a pharmaceutically acceptable salt thereof. [3] A compound according to [1] or [2] above, wherein ring X is unsubstituted or substituted with 1 to 3 groups selected from substituent group A. 3-8 A compound that is cycloalkyl; wherein substituent group A has the same meaning as in [1] above, or a pharmacoposly acceptable salt thereof.

[0015] [4] A compound described in [1] above, which is represented by formula (III): [In the formula, Y a C 1-6 Alkyl, or halo C 1-6 It is alkyl; ring Z is C 6-10 It is an aryl or a 5- to 10-membered heteroaryl; R 1 is a halogen atom, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 Alkyl, Halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, or C 3-8It is a cycloalkoxy; n is an integer from 0 to 2; if n is 2, then each R 1 They may be the same or different from each other; R 2 C 1-6 Alkyl, Halo C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, or -NR 5 R 5' And; R 5 and R 5' These are, independently, hydrogen atoms and C 1-6 Alkyl, or C 3-8 It is a cycloalkyl group; R 3 and R 3' Each of these is independently a hydrogen atom, or C 1-6 It is alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, Halo C 1-6 Alkyl, Halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 It is a cycloalkoxy or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 -and; R 6 and R 6' Each of these is independently a hydrogen atom, or C 1-6 Alkyl; L 2 C 1-6 Alkylene, or Halo C 1-6 It is an alkylene; m is an integer from 0 to 3; if m is 2 or greater, each R 4 They may be the same or different from each other; however, L 2 C 1-6 If it is an alkylene, Y a is Hello C 1-6 Alkyl compounds or their pharmacologically acceptable salts.

[0016] [5] A compound described in any of [1] to [4] above, R 2 ga-NHR 5 A compound that is or a pharmacoposly acceptable salt thereof. [6] A compound according to any of [1] to [5] above, R 5 A compound in which is a hydrogen atom or a pharmacoposly acceptable salt thereof. [7] A compound according to any of [1] to [6] above, L 1 A compound in which is -NH- or a pharmacoposly acceptable salt thereof. [8] A compound according to any of [1] to [7] above, where R 3 and R 3' A compound in which the atom is a hydrogen atom, or a pharmacokinetically acceptable salt thereof.

[0017] [9] A compound according to any of [1] to [8] above, wherein ring Z is C 6-10 A compound that is an aryl compound or a pharmaceutically acceptable salt thereof.

[10] A compound according to any of [1] to [9] above, R 4 is a halogen atom, or halo C 1-6 A compound that is alkyl or a pharmacokinetically acceptable salt thereof.

[11] A compound according to any one of [1] to

[10] above, wherein n is 0, or a pharmacokinetically acceptable salt thereof.

[0018]

[12] A compound according to any of [1] to

[11] above, wherein Y is halo C 1-6 A compound or a pharmaceutically acceptable salt thereof in which ring X is alkyl or ring X is the same as in [1] above.

[13] A compound according to any of [1] to

[12] above, where Y is halo C 1-6 A compound that is alkyl or a pharmaceutically acceptable salt thereof.

[14] A compound according to any one of [1] to

[12] above, wherein ring X is (i) or (ii): (i) unsubstituted or substituted with 1 to 3 groups selected from substituent group A. 3-8 Cycloalkyl; (ii) Unsubstituted or 3- to 8-membered heterocycloalkyl (where L 4(Excluding groups in which the atom bonded is a nitrogen atom); Compounds in which substituent group A has the same meaning as in [1] above, or pharmacologically acceptable salts thereof.

[15] Compounds according to any of [1] to

[12] above, wherein ring X is (i) or (ii) below: (i) Unsubstituted or C substituted with 1 to 3 groups selected from substituent group A 6-10 (ii) an unsubstituted or 5- to 10-membered heteroaryl compound having 1 to 3 groups selected from substituent group A; a compound or a pharmaceutically acceptable salt thereof in which substituent group A has the same meaning as in [1] above.

[16] A compound according to any of [1] to

[15] above, wherein substituent group A is a halogen atom, cyano, C 1-6 alkyl and halo C 1-6 A compound consisting of alkyl groups, or a pharmacokinetically acceptable salt thereof.

[0019]

[17] A compound selected from the group consisting of the following compounds, according to any one of [1] to

[16] above: and or its pharmacologically acceptable salt.

[0020]

[18] A compound selected from the group consisting of the following compounds, according to any one of [1] to

[16] above: and or its pharmacologically acceptable salt.

[0021]

[19] A compound selected from the group consisting of the following compounds, according to any one of [1] to

[16] above: and or its pharmacologically acceptable salt.

[0022]

[20] A pharmaceutical composition comprising a compound described in any of [1] to

[19] above or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive.

[0023]

[21] The pharmaceutical composition according to

[20] , which is a pharmaceutical composition for the treatment of thyroid-related diseases.

[0024]

[22] A pharmaceutical composition according to

[21] above, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

[0025] As one embodiment, the present invention relates to a method for treating thyroid-related diseases, comprising administering a required amount of the pharmaceutical composition described in

[20] above to a patient.

[0026] As one embodiment, the present invention relates to the use of any of the compounds described in [1] to

[19] above or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition for the treatment of thyroid-related diseases.

[0027] The compounds of the present invention possess excellent TSHR antagonist activity. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts are useful as therapeutic agents for thyroid-related diseases.

[0028] Embodiments of the present invention will be described in more detail below.

[0029] In this invention, unless otherwise specified, each term has the following meanings.

[0030] "Halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom. 1-6 "Alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-6 "Alkylene" refers to a linear or branched alkylene group having 1 to 6 carbon atoms. Examples include methylene, ethylene, and 1-propylene. 1-6 "Alkoxy" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, and isopropoxy. 1-6 "Alkyl" refers to a carbon atom substituted with 1 to 5 identical or heterogeneous halogen atoms. 1-6 This refers to alkyl groups. Examples include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl. 1-6"Alkylene" refers to a carbon atom substituted with 1 to 5 identical or heterogeneous halogen atoms. 1-6 This refers to alkylene. Examples include difluoromethylene, 1,1-difluoroethylene, and 1,1-difluoropropylene. 1-6 "Alkoxy" refers to a carbon atom substituted with 1 to 5 identical or heterogeneous halogen atoms. 1-6 This refers to alkoxy compounds. Examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluoroethoxy. 1-6 Alkoxy C 1-6 "Alkyl" refers to a single C 1-6 alkoxy-substituted C 1-6 It means alkyl. Examples include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl. 1-6 "Alkyl" refers to a carbon atom substituted with 1 to 6 identical or different halogen atoms and 1 or 2 hydroxyls. 1-6 It means alkyl. For example, 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl is one such example.

[0031] "C 6-10 "Aryl" means a phenyl group or a naphthyl group. "5-10 membered heteroaryl" means a 5- to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring, and part of the ring may be partially saturated. Examples include pyridyl, pyrimidyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolyl, and 1,2,3,4-tetrahydroisoquinolyl. 3-8"Cycloalkyl" refers to a saturated hydrocarbon group with 3 to 8 members, including those with partially cross-linked structures. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, and bicyclo[2.2.2]octyl. 3-8 "Cycloalkoxy" means (C 3-8 This refers to a group represented by (cycloalkyl)-O-. For example, cyclopropyloxy is one such group. "3- to 8-membered heterocycloalkyl" refers to a cycloalkyl group in which the carbon atoms in the ring are substituted with one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and also includes those with partially cross-linked structures. Examples include azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanil, 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, oxyranil, oxetyl, tetrahydrofuranil, and tetrahydropyranil.

[0032] The following abbreviations used in this specification have the following meanings: BH3-THF: Borane-tetrahydrofuran complex Boc: tert-butoxycarbonyl Boc2O: Ditert-butyl dicarbonate DBU: Diazabicycloundecene DCM: Dichloromethane DIBAL-H: Diisobutylaluminum hydride DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DPPA: Diphenyl phosphoryl azide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate LDA: Lithium diisopropylamide MeCN: Acetonitrile MTBE: Methyltert-butyl ether NMP: N-methylpyrrolidone TBAF: Tetrabutylammonium fluoride TBDPS: tert-butyldiphenylsilyl TBDPSCl: tert-butyldiphenylsilyl chloride TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran 10% Pd / C: 10% palladium carbon (approx. 55% water-moistened) APS: aminopropylated silica gel Method A: Column chromatography with a silica gel column attached to the bottom of an aminopropylated silica gel column ODS: octadecylsilylated silica gel Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical properties IC 50 : 50% inhibitory concentration 1H-NMR: Proton nuclear magnetic resonance spectrum DMSO: Dimethyl sulfoxide CD3OD: Methanol-d4 DMSO-d6: Dimethyl sulfoxide-d6 CDCl3: Chloroform-d1 MS: Mass spectrometry (Measurements in the table were taken by electrospray ionization or electrospray ionization-atmospheric pressure chemical ionization multi-ionization method.) cAMP: Adenosine 3',5'-cyclic monophosphate CHO: Chinese hamster ovary FBS: Fetal bovine serum HEPES: 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid IBMX: 3-Isobutyl-1-methylxanthine

[0033] In compounds represented by formulas (I) to (III), where one or more chiral carbon atoms are present, the present invention also includes compounds in which each chiral carbon atom is in an R configuration, an S configuration, and any combination thereof. Furthermore, racemic compounds, racemic mixtures, single enantiomers, and diastereomer mixtures thereof are also within the scope of the present invention.

[0034] In the case of compounds represented by formulas (I) to (III), if cis-trans isomers exist, the present invention encompasses all of those cis-trans isomers.

[0035] If tautomers exist in the compounds represented by formulas (I) to (III), the present invention includes any of those tautomers.

[0036] In this invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0037] The compounds represented by formulas (I) to (III) can be prepared, if necessary, by conventional methods to obtain pharmacologically acceptable salts. Examples of such salts include acid addition salts or salts with bases.

[0038] 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.

[0039] 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, TEA, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0040] Unless otherwise specified, chemical names or structural formula suffixes related to salts, such as "hydrochloride" or "HCl," do not represent stoichiometric descriptions but simply indicate the salt form.

[0041] If the compounds represented by formulas (I) to (III) or their pharmacologically acceptable salts exist, for example, as crystals, then all crystalline forms are included. Pharmacologically acceptable salts of the compounds represented by formulas (I) to (III) also include cocrystals or cocrystalline salts with a suitable co-crystal-forming agent. A cocrystal or cocrystalline salt means a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.). Cocrystals or cocrystalline salts can be produced according to known co-crystallization methods. Compounds represented by formulas (I) to (III) or their pharmacologically acceptable salts also include hydrates or solvates with water or a pharmaceutically acceptable solvent such as ethanol.

[0042] In the compounds represented by formulas (I) to (III), some of each atom may be replaced by its corresponding isotope. The present invention also includes compounds in which these isotopes have been replaced. Examples of isotopes are, 2 H, 3 H, 11 C, 13C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, and 35 Examples include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, and sulfur atoms represented by S. In one embodiment, some hydrogen atoms of the compounds represented by formulas (I) to (III) are 2 Examples include compounds in which H (D: deuterium atom) is substituted.

[0043] Compounds represented by formulas (I) to (III), in which some atoms are replaced by isotopes, can be produced using commercially available isotopic building blocks in a manner similar to the production method described below. They can also be produced using methods described in the literature (for example, see Journal of Synthetic Organic Chemistry, Japan, Vol. 65, No. 12, pp. 1179-1190, 2007, and RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

[0044] The compounds represented by formulas (I) to (III) of the present invention can be produced, for example, by the methods shown in Schemes 1 to 3 or similar methods, or by methods described in the literature or similar methods. In the Schemes, the compounds represented by formulas (I) to (III) correspond to the compounds represented by formulas (I-1a) to (I-1d).

[0045] The compounds represented by formulas (I) to (III) of the present invention can be produced by the following methods, but the following production methods are illustrative of general production methods and are not limited to any particular method.

[0046] In the reactions of each step, if the raw materials or reagents are commercially available, commercially available products can be used.

[0047] In each step of the reaction, the reaction time varies depending on the raw materials used, solvent, and reaction temperature, but unless otherwise specified, it is usually between 30 minutes and 3 days.

[0048] In each step of the reaction, the reaction temperature varies depending on the raw materials and solvents used, but unless otherwise specified, it is usually between -78°C and reflux temperature.

[0049] The pressure in each reaction step varies depending on the raw materials used, solvent, and reaction temperature, but unless otherwise specified, it is usually between 1 and 20 bar.

[0050] Microwave reactors, such as Biotage Initiators, may be used in each step of the reaction. When using a microwave reactor, the reaction can be carried out under conditions that vary depending on the raw materials, solvents, and model used, but typically include a pressure range of 1 to 30 bar, an output range of 1 to 400 W, a reaction temperature of room temperature to 300°C, and a reaction time of 1 minute to 1 day.

[0051] Unless otherwise specified, the reactions in each step shall be carried out without a solvent or using a suitable solvent. Examples of suitable solvents include solvents that are inert to the reaction. Specific examples of solvents used include those described in the reference examples or examples corresponding to each step, or the following solvents. Two or more of the following solvents may be used in a mixture in appropriate proportions. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, DME, 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, 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.

[0052] When a base is used in the reaction of each step, the reaction shall be carried out using a base suitable for the reaction. Specific examples of bases used include the bases described in the reference examples or examples corresponding to each step, or 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, DBU, 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.; Organomagnesiums: isopropylmagnesium chloride, etc.; Organolithiums: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0053] When an acid is used in the reaction of each step, the reaction shall be carried out using an acid suitable for the reaction. Specific examples of acids used include those listed in the reference examples and examples corresponding to each step, or the following acids: Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, 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.

[0054] When a condensing agent is used in each step of the reaction, the reaction shall be carried out using a condensing agent suitable for the reaction. Specific examples of condensing agents used include those described in the reference examples or examples corresponding to each step, or the following condensing agents: Carbodiimides: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: carbonyldiimidazole, etc.; Uronium salts, phosphonium salts: HATU, 1H-benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: DMT-MM, etc.; Others: propylphosphonic anhydride (cyclic trimer), etc.

[0055] When a reducing agent is used in each step of the reaction, the reaction shall be carried out using a reducing agent suitable for the reaction. Specific examples of reducing agents used include those described in the reference examples or examples corresponding to each step, or the following reducing agents: Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, DIBAL-H, etc.; Boranes: BH3-THF, picoline borane complex, decaborane, etc.

[0056] When a carbonyl group introduction reagent is used in each step of the reaction, the reaction shall be carried out using a carbonyl group introduction reagent suitable for the reaction. Specific examples of carbonyl group introduction reagents used include those described in the reference examples or examples corresponding to each step, or the following carbonyl group introduction reagents: Phosgenes: phosgene, diphosgene, triphosgene, etc.; Chloroformate esters: 4-nitrophenyl chloroformate, etc.; Imidazoles: carbonyldiimidazole, etc.

[0057] In each step, if a protecting group is required depending on the type of functional group, it can be carried out by combining introduction and removal operations as appropriate according to conventional methods. For information on the types of protecting groups, protection, and deprotection, see, for example, the methods described in Peter GM Wuts (ed.), "Greene's Protective Groups in Organic Synthesis," fifth edition, Wiley-Interscience, 2014.

[0058] When reduction is performed in each step, the reaction can be carried out in the presence of a reducing agent. Examples of reducing agents that can be used are those mentioned above.

[0059] In each step, when amidation is performed, the reaction can be carried out using a coupling agent, either in the presence or absence of a base. Examples of coupling agents and bases used are given above. When carbodiimides are used as coupling agents, additives such as 1-hydroxybenzotriazole and DMAP may be added as needed. The reaction can also be carried out using acyl halides or acid anhydrides, either in the presence or absence of a base.

[0060] When carbamate or urea formation is performed in each step, the reaction can be carried out using a carbonyl group introduction reagent, either in the presence or absence of a base. Examples of carbonyl group introduction reagents and bases used are given above.

[0061] When sulfonylation is performed in each step, the reaction can be carried out using a sulfonylation reagent, either in the presence or absence of a base. Examples of sulfonylation reagents that can be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, and trifluoromethanesulfonic anhydride.

[0062] When the Appel reaction is carried out in each step, the reaction can be carried out using triphenylphosphine and a halogen source, either in the presence or absence of a base. Examples of halogen sources that can be used include carbon tetrachloride, carbon tetrabromide, and iodine.

[0063] In each step, when esterification is performed, the reaction can be carried out using a coupling agent, either in the presence or absence of a base. Examples of coupling agents and bases used are given above. When carbodiimides are used as coupling agents, additives such as 1-hydroxybenzotriazole and DMAP may be added as needed. The reaction can also be carried out using acyl halides or acid anhydrides, either in the presence or absence of a base. Furthermore, the reaction can also be carried out using alcohols in the presence of an acid.

[0064] The compounds represented by formulas (I-1a) to (I-1d) can be prepared, for example, by the method described in Scheme 1.

[0065] The symbols in the formula have the same meaning as above. R P1 C 1-6 It is alkyl, R P1' C 1-6 Alkyl, Halo C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 1-6 Alkoxy C 1-6 It is alkyl, PG 1 It is a protecting group.

[0066] Process 1-1 Compound (1-2) can also be prepared by removing the protecting group from compound (1-1).

[0067] Process 1-2 Compound (I-1a) can also be produced by reacting compound (1-2) with trimethylsilyl isocyanate. Alternatively, compound (I-1a) can be produced by reacting compound (1-2) with potassium cyanate or sodium cyanate in the presence of an acid.

[0068] Process 1-3 Compound (I-1b) can also be produced by urea conversion of compounds (1-2) and (1-3).

[0069] Process 1-4 Compound (I-1c) can also be produced by carbamate of compound (1-2) and compound (1-4).

[0070] Process 1-5 Compound (I-1d) can also be produced by amidation of compound (1-2) and compound (1-5).

[0071] The compound represented by formula (1-1a) can be prepared, for example, by the method described in Scheme 2.

[0072] The symbols in the formula have the same meaning as above. LG 2 and LG 2' This is a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group.

[0073] Process 2-1 Compound (1-1a) can also be produced by reacting compound (2-1) and compound (2-2) in the presence of a base.

[0074] Process 2-2 Compound (2-3) can also be produced by sulfonylation or Appel reaction of compound (2-1).

[0075] Process 2-3 Compound (1-1a) can also be produced by reacting compound (2-3) and compound (2-4) in the presence of a base.

[0076] The compound represented by formula (2-1a) can be prepared, for example, by the method described in Scheme 3.

[0077] The symbols in the formula have the same meaning as above. LG 3 R is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group. P3 is C 1-6 It is alkyl, PG 3 It is a protecting group.

[0078] Process 3-1 Compound (3-2) can also be produced by esterification of compound (3-1).

[0079] Process 3-2 Compound (3-3) can also be produced by reducing the ester of compound (3-2).

[0080] Process 3-3 Compound (3-4) can also be produced by protecting the hydroxyl group of compound (3-3).

[0081] Process 3-4 Compound (3-6) can also be produced by reacting compound (3-4) and compound (3-5) in the presence of a base.

[0082] Process 3-5 Compounds (3-7) can also be prepared by reacting compound (3-6) with DPPA and Boc2O in the presence of a base.

[0083] Process 3-6 Compound (2-1a) is the PG of compound (3-7) 3 It can also be manufactured by removing [a certain component].

[0084] Each of the schemes shown above is an example of a method for producing the compounds represented by formulas (I) to (III) or their intermediates. Each of the schemes shown above can be modified in various ways to become a scheme that is easily understood by those skilled in the art.

[0085] The compounds represented by formulas (I) to (III) and their manufacturing intermediates may, if necessary, be isolated and purified by isolation and purification methods well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, and preparative high-performance liquid chromatography.

[0086] The compounds of the present invention have excellent TSHR antagonist activity and can therefore be used as therapeutic agents for thyroid-related diseases. In the present invention, thyroid-related diseases include, for example, hyperthyroidism, Graves' disease, thyroid eye disease, and thyroid cancer. Preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism, Graves' disease, or thyroid eye disease (see Endocrinology, 2014, 155 (1), pp. 310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

[0087] Furthermore, in one embodiment, hyperthyroidism includes, for example, hyperthyroidism caused by any of the following: Graves' disease, thyroiditis, Plummer's disease, toxic multinodular goiter, TSH-producing pituitary adenoma, hyperemesis gravidarum, ovarian goiter, gestational trophoblastic neoplasm, or germ cell tumor. Preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism caused by Graves' disease.

[0088] Furthermore, in one embodiment, thyroid-related diseases are diseases and symptoms associated with abnormal thyroid hormone levels. Diseases and symptoms associated with abnormal thyroid hormone levels include, for example, diseases and symptoms caused by TRAb.

[0089] In this invention, "treatment" includes the meaning of "prevention." For example, the treatment of hyperthyroidism, Graves' disease, or thyroid eye disease includes the meanings of "prevention of relapse / recurrence" and "maintenance of remission." Furthermore, as one embodiment, the compounds of this invention can be used to prevent the onset of thyroid eye disease in patients with Graves' disease.

[0090] In this invention, "antagonist" refers to a drug that inhibits or blocks the function of a target protein, regardless of its binding site. For example, "antagonist" includes both "allosteric antagonists" and "negative allosteric modulators (NAMs)."

[0091] The therapeutic effect of the compounds of the present invention on thyroid-related diseases can be confirmed according to methods well known in the art. For example, methods for confirming the effect in animal models of hyperthyroidism or Graves' disease include those described in Endocrinology 2007, 148(5), p.2335-2344, or similar methods.

[0092] The pharmaceutical composition of the present invention can be used in various dosage forms depending on the method of use. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

[0093] The pharmaceutical composition of the present invention contains a compound represented by formula (I) to (III) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0094] The pharmaceutical compositions of the present invention are prepared using compounds represented by formulas (I) to (III) or pharmaceutically acceptable salts thereof, and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving them with appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, using pharmaceutically known methods depending on the dosage form.

[0095] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formulas (I) to (III) or its pharmacopositically acceptable salt is appropriately determined based on the patient's age, sex, weight, disease, and the degree of treatment. The daily dose may be divided into one, two, three, or four doses. For oral administration, the dose for adults can be set in the range of, for example, 0.1 to 5000 mg / day. In one embodiment, the oral dose can also be set in the range of 1 to 1500 mg / day, preferably in the range of 1 to 500 mg / day. For parenteral administration, the dose for adults can be set in the range of, for example, 0.01 to 5000 mg / day. In one embodiment, the parenteral dose can also be set in the range of 0.1 to 1500 mg / day, preferably in the range of 0.1 to 500 mg / day.

[0096] In one embodiment, the pharmaceutical composition of the present invention can also be used in combination with other agents other than TSHR antagonists. Other agents that can be used in combination in the treatment of thyroid-related diseases include, for example, antithyroid drugs (e.g., thiamazole, propylthiouracil, etc.), inorganic iodine, lithium carbonate, and thyroid hormone preparations.

[0097] When compounds represented by formulas (I) to (III) or their pharmacologically acceptable salts are used in combination with other drugs, they can be administered as a preparation containing these active ingredients together, or as preparations in which each of these active ingredients is formulated separately. If they are formulated separately, these preparations can be administered separately or simultaneously. Furthermore, the dosage of compounds represented by formulas (I) to (III) or their pharmacologically acceptable salts may be appropriately reduced in accordance with the dosage of the other drugs used in combination.

[0098] The compounds represented by formulas (I) to (III) may be used after being converted into prodrugs as appropriate. For example, prodrugs of the compounds represented by formulas (I) to (III) can be produced by introducing the groups constituting the prodrug using a prodrug reagent such as a corresponding halide, and then purifying the compound. Examples of groups constituting prodrugs include those described in "Pharmaceutical Development" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

[0099] The present invention will be described in more detail below based on reference examples, examples, and test examples, but the present invention is not limited thereto.

[0100] The compound names listed in the following examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., with the exception of commercially available reagents.

[0101] Reference Example A-1 (S)-6-(hydroxymethyl)piperidine-2-one A mixture of (S)-6-oxopiperidine-2-carboxylic acid (1.00 g) and methanol (4.0 mL) was mixed with thionyl chloride (2.49 g) under ice cooling and stirred at 60°C for 8 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Sodium borohydride (1.06 g) was added to a mixture of the residue and ethanol (20 mL) under ice cooling and stirred at room temperature for 65 hours. A small amount of acetic acid was added to the reaction mixture and the mixture was concentrated under reduced pressure. The residue was suspended in DCM and insoluble matter was filtered off. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.783 g).

[0102] Reference Example A-2 (S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-2-one A mixture of Reference Example A-1 (0.783 g), imidazole (0.825 g), TBDPSCl (1.83 g), DMAP (0.074 g), and DCM (20 mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into water 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 (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100) to obtain the title compound (1.21 g).

[0103] Reference Example A-3: (S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidine-2-one. A mixture of Reference Example A-2 (1.21 g) and DMF (24 mL) was mixed with approximately 60% sodium hydride (0.145 g) under ice cooling and stirred at room temperature for 30 minutes. 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (1.02 g) was added to the reaction mixture and stirred at room temperature for 4 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain the title compound (0.684 g).

[0104] Reference Example A-4: ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)carbamate tert-butyl. A mixture of Reference Example A-3 (1.32 g) and THF (20 mL) was mixed with LDA (1.01 mol / L in THF / n-hexane) (4.80 mL) at -78°C and stirred at the same temperature for 10 minutes. DPPA (1.33 g) was added to the reaction mixture at -78°C and stirred at the same temperature for 45 minutes. A mixture of Boc2O (0.741 g) and THF (10 mL) was added to the reaction mixture at -78°C and stirred at the same temperature for 10 minutes, then under ice cooling for 1 hour. Water was added to the reaction mixture and stirred at 50°C for 1 hour. After allowing the reaction mixture to cool to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain the title compound (0.897 g).

[0105] Reference Example A-5: (S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidine-2-one. A mixture of Reference Example A-2 (0.507 g), 1-(bromomethyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzene (0.482 g), and DMF (5.0 mL) was mixed with approximately 60% sodium hydride (0.090 g) under ice cooling and stirred at room temperature for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) to obtain the title compound (0.642 g).

[0106] Reference Example A-6: (S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)piperidine-2-one. A mixture of Reference Example A-5 (0.891 g) and THF (10 mL) was mixed with TBAF (1 mol / L in THF) (2.31 mL) at room temperature and stirred for 20 minutes at the same temperature. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted by DCM. 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 30 / 70) to obtain the title compound (0.440 g).

[0107] Reference Example A-7 (S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((difluoromethoxy)methyl)piperidine-2-one A mixture of Reference Example A-6 (0.197 g), copper(I) iodide (0.033 g), and MeCN (1.5 mL) was stirred at 50°C for 5 minutes. A mixture of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.207 g) and MeCN (4.1 mL) was added to the reaction mixture and stirred at 50°C for 1.5 hours. 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.103 g) was added to the reaction mixture and stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 39 / 61) to obtain the title compound (0.087 g).

[0108] Reference Example A-8: ((3R,6S)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)carbamate tert-butyl. A mixture of Reference Example A-5 (2.01 g) and THF (10 mL) was mixed with LDA (1.01 mol / L in THF / n-hexane) (3.79 mL) at -78°C and stirred at the same temperature for 30 minutes. A mixture of DPPA (1.05 g) and THF (4.0 mL) was added to the reaction mixture at -78°C and stirred at the same temperature for 30 minutes. A mixture of Boc2O (1.06 g) and THF (4.0 mL) was added to the reaction mixture at -78°C and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture and stirred at 50°C for 1 hour. After allowing the reaction mixture to cool to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 85 / 15) to obtain the title compound (0.999 g).

[0109] Reference Example A-9: A mixture of Reference Example A-8 (0.999 g) and THF (5.0 mL) was mixed with TBAF (1 mol / L in THF) (2.16 mL) at room temperature and stirred for 30 minutes at the same temperature. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to obtain the title compound (0.578 g).

[0110] Reference Example A-10: A mixture of Reference Example A-4 (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain the title compound (0.308 g).

[0111] Reference Example A-11: Trifluoromethanesulfonic acid ((2S,5R)-5-((tert-butoxycarbonyl)amino)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidine-2-yl) was added to a mixture of Reference Example A-10 (0.146 g), DIPEA (0.180 g), and DCM (3.0 mL) under a methylargon atmosphere at -78°C. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water and saturated ammonium chloride aqueous solution was added. The mixture was extracted with DCM, and the extract was concentrated under reduced pressure to obtain the title compound (0.192 g).

[0112] Reference Example A-12 A mixture of pyrimidine-2-ylmethylpyrimidine-2-carboxylate methyl methanesulfonate (0.075 g) and ethanol (2.0 mL) was mixed with sodium borohydride (0.025 g) at room temperature and stirred for 25 minutes at the same temperature. Acetic acid (0.082 g) was added to the reaction mixture under ice cooling, and the mixture was concentrated under reduced pressure. Methanesulfonyl chloride (0.187 g) was added to a mixture of the residue, TEA (0.275 g), and DCM (2.0 mL) under ice cooling, and stirred for 30 minutes at room temperature. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure to obtain the title compound (0.102 g).

[0113] Reference Example A-13 5-Fluoro-6-oxo-1,6-dihydropyridine-3-carbonitrile A mixture of 5,6-difluoronicotinonitrile (0.100 g) and 2 mol / L hydrochloric acid (0.892 mL) was stirred at 150°C for 5 minutes under microwave irradiation. Water was added to the reaction mixture and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and then dried under reduced pressure to obtain the title compound (0.080 g).

[0114] The structural formulas of the example are shown in the table below.

[0115]

[0116] Example A-1 A mixture of 1-((3R,6S)-6-(cyclopropoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea (Reference Example A-4) (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.308 g). Under an argon atmosphere, the mixture of the obtained compound (0.100 g), silver(I) acetate (0.040 g), (triphenylphosphine)gold(I) chloride (0.118 g) and n-butyl vinyl ether (3.0 mL) was stirred at 60°C for 30 minutes and at 80°C for 3 hours. After the reaction mixture was allowed to cool to room temperature, it was filtered and the insoluble matter was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((vinyloxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.057 g). Under an argon atmosphere, a mixture of diethylzinc (1 mol / L in n-hexane) (0.383 mL), TFA (0.044 g), and DCM (1.0 mL) was stirred on ice for 5 minutes. Diiodomethane (0.103 g) was added to the reaction mixture on ice and stirred on ice for 10 minutes.The reaction mixture was mixed with the above-mentioned ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((vinyloxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.057 g) and DCM (0.8 mL), and stirred under ice for 1 hour and at room temperature for 8 hours. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain ((3R,6S)-6-(cyclopropoxymethyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.015 g). To a mixture of the obtained compound (0.015 g) and DCM (1.0 mL), TFA (0.296 g) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue, water (0.012 mL), and THF (1.0 mL), potassium cyanate (0.003 g) and acetic acid (0.004 g) were added and the mixture was stirred at room temperature for 18 hours. Potassium cyanate (0.003 g) was added to the reaction mixture and the mixture was stirred at room temperature for 1.5 hours. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 90 / 10 to 80 / 20) and ODS column chromatography (elution solvent: water / MeCN = 30 / 70 to 10 / 90) to obtain the title compound (0.003 g).

[0117] Example A-2 A mixture of 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((2,2,2-trifluoroethoxy)methyl)piperidine-3-yl)urea (Reference Example A-4) (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.308 g). To a mixture of the obtained compound (0.114 g), 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (0.189 g), and DMF (1.5 mL), sodium hydride (approximately 60%) (0.014 g) was added at room temperature and the mixture was stirred for 30 minutes at the same temperature. 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (0.629 g) and sodium hydride (approximately 60%) (0.035 g) were added to the reaction mixture and stirred at room temperature for 30 minutes. Sodium hydride (approximately 60%) (0.024 g) was added to the reaction mixture and stirred at room temperature for 1 hour. Water and saturated aqueous ammonium chloride were added to the reaction mixture and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 88 / 12 to 0 / 100) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((2,2,2-trifluoroethoxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.084 g).To a mixture of the obtained compound (0.084 g) and DCM (1.0 mL), TFA (0.296 g) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue, water (0.060 mL), and THF (1.0 mL), potassium cyanate (0.027 g) and acetic acid (0.020 g) were added and the mixture was stirred at room temperature for 3 hours. Potassium cyanate (0.014 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (elution solvent: 0.2% NH₃). 3 in water / 0.2% NH 3 The compound was purified in MeCN (68.3 / 31.7–5 / 95) to obtain the title compound (0.010 g).

[0118] Example A-3 A mixture of 1-((3R,6S)-6-((difluoromethoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea (Reference Example A-4) (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.308 g). Under an argon atmosphere, a mixture of the obtained compound (0.068 g), copper(I) iodide (0.009 g), and MeCN (1.4 mL) was added to a mixture of 2-(fluorosulfonyl)difluoroacetic acid (0.058 g) and MeCN (0.7 mL) at room temperature, and the mixture was stirred at 50°C for 1 hour. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30-40 / 60) to obtain ((3R,6S)-6-((difluoromethoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.010 g). The obtained compound (0.010 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.0 mL), and methanol (1.0 mL) were mixed and stirred at room temperature for 40 minutes. Under ice cooling, 2 mol / L aqueous sodium hydroxide solution (2.0 mL) and saturated aqueous sodium bicarbonate solution (1.5 mL) were added to the reaction mixture, and the mixture was extracted by DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.To a mixture of residue, water (0.008 mL), and THF (1.0 mL), potassium cyanate (0.003 g) and acetic acid (0.003 g) were added at room temperature, and the mixture was stirred at the same temperature for 3.5 hours. 0.5 mol / L hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.005 g).

[0119] Example A-4: A mixture of 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((trifluoromethoxy)methyl)piperidine-3-yl)urea (Reference Example A-4) (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.308 g). Under an argon atmosphere, the obtained compound (0.150 g), DIPEA (0.184 g), and DCM (3.0 mL) were mixed, to which anhydrous trifluoromethanesulfonic acid (0.201 g) was added under ice cooling, and the mixture was stirred under ice cooling for 25 minutes. The reaction mixture was poured into ice water, and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain trifluoromethanesulfonic acid ((2S,5R)-5-((tert-butoxycarbonyl)amino)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-oxopiperidine-2-yl)methyl (0.282 g). Under an argon atmosphere, the obtained compound (0.198 g), 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid trifluoromethyl (0.185 g), and MeCN (3.0 mL) were mixed with silver(I) fluoride (0.054 g) at room temperature and stirred for 30 minutes at the same temperature. The reaction mixture was poured into water and extracted with DCM. The extract was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((trifluoromethoxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.037 g). The obtained compound (0.012 g), hydrogen chloride (4 mol / L in 1,4-dioxane) (1.0 mL), and methanol (1.0 mL) were mixed and stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted by DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a mixture of residue, water (0.009 mL), and THF (1.0 mL), potassium cyanate (0.004 g) and acetic acid (0.005 g) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 90 / 10 to 10 / 90) to obtain the title compound (0.004 g).

[0120] Example A-5 A mixture of 1-((3R,6S)-6-((2,2-difluoroethoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea (Reference Example A-4) (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.308 g). To a mixture of the obtained compound (0.080 g), 2,2-difluoroethyl trifluoromethanesulfonic acid (0.244 g), and DMF (1.0 mL), sodium hydride (approximately 60%) (0.025 g) was added at room temperature and the mixture was stirred for 20 minutes at the same temperature. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). After washing the extract with saturated brine, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of residue and DCM (1.0 mL), TFA (0.296 g) was added and the mixture was stirred at room temperature for 10 minutes. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of residue, water (0.069 mL), acetic acid (0.023 g), and THF (1.5 mL), potassium cyanate (0.031 g) was added and the mixture was stirred at room temperature for 1 hour. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (elution solvent: 0.2% NH₄). 3 in water / 0.2% NH 3 The compound was purified in MeCN (72.4 / 27.6–5 / 95) to obtain the title compound (0.009 g).

[0121] Example A-6 A mixture of 1-((3R,6S)-6-((3,3-difluorocyclobutoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea (Reference Example A-4) (0.897 g) and THF (15 mL) was mixed with TBAF (1 mol / L in THF) (4.85 mL) and stirred at room temperature for 20 minutes. Saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 60 / 40) and silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-(hydroxymethyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.308 g). To a mixture of the obtained compound (0.015 g), DIPEA (0.018 g), and DCM (1.0 mL), anhydrous trifluoromethanesulfonic acid (0.020 g) was added at -78°C and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was poured into ice water and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue, 3,3-difluorocyclobutanol (0.008 g), and THF (1.0 mL), sodium hydride (approximately 60%) (0.005 g) was added at room temperature and the mixture was stirred for 30 minutes at the same temperature. Water and saturated ammonium chloride aqueous solution were added to the reaction mixture under ice cooling, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 50 / 50) to obtain ((3R,6S)-6-((3,3-difluorocyclobutoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.008 g). The obtained compound (0.008 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1.0 mL) were mixed and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure.A saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was then subjected to ODS column chromatography (elution solvent: 0.2% NH4). 3 in water / 0.2% NH 3 The compound was purified in MeCN (64.2 / 35.8–5 / 95) to obtain (3R,6S)-3-amino-6-((3,3-difluorocyclobutoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidine-2-one (0.002 g). To a mixture of the obtained compound (0.002 g), water (0.005 mL), and THF (1.0 mL), potassium cyanate (0.002 g) and acetic acid (0.005 g) were added, and the mixture was stirred at room temperature for 1 hour. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was analyzed by ODS column chromatography (elution solvent: 0.2% NH₄). 3 in water / 0.2% NH 3 The compound was purified in MeCN (67.3 / 32.7–5 / 95) to obtain the title compound (0.001 g).

[0122] Example A-7 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((difluoromethoxy)methyl)-2-oxopiperidine-3-yl)urea Under an argon atmosphere, a mixture of Reference Example A-7 (0.081 g) and THF (2.0 mL) was mixed with LDA (1.01 mol / L in THF / n-hexane) (0.226 mL) at -78°C and stirred at the same temperature for 10 minutes. DPPA (0.063 g) was added to the reaction mixture at -78°C and stirred at the same temperature for 5 minutes. A mixture of Boc2O (0.054 g) and THF (0.4 mL) was added to the reaction mixture at -78°C and stirred under ice cooling for 10 minutes. Water was added to the reaction mixture and stirred at 50°C for 40 minutes. After allowing the reaction mixture to cool to room temperature, saturated ammonium chloride aqueous solution and water were added, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((difluoromethoxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.039 g). To a mixture of the obtained compound (0.037 g) and DCM (1.0 mL), TFA (0.148 g) was added at room temperature, and the mixture was stirred for 30 minutes at the same temperature. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. Potassium cyanate (0.008 g) was added to a mixture of residue, water (0.027 mL), acetic acid (0.009 g), and THF (1.0 mL), and the mixture was stirred at room temperature for 2.5 hours. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.011 g).

[0123] Example A-8 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((trifluoromethoxy)methyl)piperidine-3-yl)urea Under an argon atmosphere, a mixture of Reference Example A-9 (0.052 g), DIPEA (0.074 g), and DCM (1.0 mL) was mixed with trifluoromethanesulfonic anhydride (0.097 g) at -78°C and stirred at the same temperature for 10 minutes. The reaction mixture was poured into ice water and water and saturated ammonium chloride aqueous solution were added. The mixture was extracted with DCM and the extract was concentrated under reduced pressure. DCM, water, and 2 mol / L hydrochloric acid were added to the residue and the organic layer was separated. The organic layer was concentrated under reduced pressure. Under an argon atmosphere, a mixture of the residue and MeCN (1.0 mL) was mixed with 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid trifluoromethyl (0.084 g) and silver(I) fluoride (0.025 g), and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((trifluoromethoxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.031 g). To a mixture of the obtained compound (0.031 g) and DCM (1.0 mL), TFA (0.296 g) was added at room temperature and the mixture was stirred for 10 minutes at the same temperature. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.021 mL), acetic acid (0.007 g), and THF (1.0 mL), potassium cyanate (0.005 g) was added and the mixture was stirred at room temperature for 12 hours. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by ODS column chromatography (elution solvent: water / MeCN = 70 / 30 to 10 / 90) to obtain the title compound (0.007 g).

[0124] Example A-9 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(cyclopropoxymethyl)-2-oxopiperidine-3-yl)urea A mixture of Reference Example A-9 (0.477 g), silver(I) acetate (0.175 g), chloro(triphenylphosphine)gold(I) (0.519 g) and n-butyl vinyl ether (9.0 mL) was stirred at 80°C for 5 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by APS column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((vinyloxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.334 g). Under an argon atmosphere, TFA (0.616 g) was added to a mixture of diethylzinc (1 mol / L in n-hexane) (5.40 mL) and DCM (2.5 mL) under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. Diiodomethane (1.45 g) was added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. To the reaction mixture, a mixture of ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((vinyloxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.150 g) and DCM (2.5 mL) was added under ice cooling and stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture and the mixture was extracted with DCM. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0 to 0 / 100 / 0 to 0 / 70 / 30) to obtain (3R,6S)-3-amino-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(cyclopropoxymethyl)piperidine-2-one (0.055 g). To a mixture of the obtained compound (0.096 g), water (0.096 mL), and THF (0.96 mL), potassium cyanate (0.026 g) and acetic acid (0.015 g) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours.Water was added to the reaction mixture, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 70 / 30 / 0 to 0 / 100 / 0 to 0 / 80 / 20) to obtain the title compound (0.086 g).

[0125] Example A-10 1-((3R,6S)-6-((cyclopentylmethoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea Under an argon atmosphere, a mixture of Reference Example A-11 (0.064 g), cyclopentanemethanol (0.023 g), and THF (1.0 mL) was mixed with sodium hydride (approximately 60%) (0.014 g) at room temperature and stirred at the same temperature for 1 hour. Saturated ammonium chloride aqueous solution was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20) to obtain ((3R,6S)-6-((cyclopentyl methoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.002 g). To a mixture of the obtained compound (0.002 g) and DCM (0.5 mL), TFA (0.010 g) was added at room temperature and the mixture was stirred at the same temperature for 1 hour. TFA (0.148 g) was added to the reaction mixture at room temperature and the mixture was stirred at the same temperature for 15 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture under ice cooling and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of residue, water (0.001 mL), and THF (0.5 mL), potassium cyanate (0.0003 g) and acetic acid (0.0002 g) were added at room temperature, and the mixture was stirred at the same temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.001 g).

[0126] Example A-11 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((((S)tetrahydrofuran-3-yl)oxy)methyl)piperidine-3-yl)urea Under an argon atmosphere, a mixture of (S)-tetrahydrofuran-3-ol (0.016 g) and THF (1.5 mL) was mixed with sodium hydride (approximately 60%) (0.011 g) under ice cooling and stirred at room temperature for 15 minutes. A mixture of Reference Example A-11 (0.056 g) and THF (1.0 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes. A mixture of (S)-tetrahydrofuran-3-ol (0.016 g), sodium hydride (approximately 60%) (0.011 g) and THF (1.0 mL) was added to the reaction mixture at room temperature and stirred at the same temperature for 1.5 hours. Water and saturated ammonium chloride aqueous solution were added to the reaction mixture, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 51 / 49 to 30 / 70) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((((S)tetrahydrofuran-3-yl)oxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.007 g). To a mixture of the obtained compound (0.041 g) and DCM (1.0 mL), TFA (0.296 g) was added at room temperature, and the mixture was stirred for 15 minutes at the same temperature. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. Potassium cyanate (0.009 g) was added to a mixture of the residue, acetic acid (0.010 g), water (0.030 mL), and THF (1.0 mL), and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was sequentially purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 70 / 30) and silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to obtain the title compound (0.004 g).

[0127] Example A-12 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(((tetrahydrofuran-3-yl)methoxy)methyl)piperidine-3-yl)urea Under an argon atmosphere, a mixture of (tetrahydrofuran-3-yl)methanol (0.066 g) and THF (3.0 mL) was mixed with sodium hydride (approximately 60%) (0.030 g) under ice cooling and stirred at room temperature for 15 minutes. A mixture of Reference Example A-11 (0.119 g) and THF (1.5 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes. Water and saturated ammonium chloride aqueous solution were added to the reaction mixture and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 39 / 61) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(((tetrahydrofuran-3-yl)methoxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.012 g). To a mixture of the obtained compound (0.032 g) and DCM (1.0 mL), TFA (0.296 g) was added at room temperature and the mixture was stirred for 15 minutes at the same temperature. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, acetic acid (0.008 g), water (0.023 mL), and THF (1.0 mL), potassium cyanate (0.007 g) was added and the mixture was stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted using DCM. 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 (0.002 g).

[0128] Example A-13 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((pyrimidine-2-ylmethoxy)methyl)piperidine-3-yl)urea A mixture of Reference Example A-10 (0.037 g), Reference Example A-12 (0.102 g), and DMF (1.0 mL) was mixed with approximately 60% sodium hydride (0.005 g) and stirred at room temperature for 1 hour. Approximately 60% sodium hydride (0.007 g) was added to the reaction mixture and stirred at room temperature for 1 hour. Approximately 60% sodium hydride (0.007 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Water, saturated ammonium chloride aqueous solution, and saturated saline solution were added to the reaction mixture and the mixture was extracted with n-hexane / ethyl acetate (1 / 1). The extract was washed with saturated saline solution, 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 = 19 / 81 to 0 / 100) to obtain ((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((pyrimidine-2-ylmethoxy)methyl)piperidine-3-yl)carbamate tert-butyl (0.013 g). To a mixture of the obtained compound (0.013 g) and DCM (1.0 mL), TFA (0.296 g) was added at room temperature and the mixture was stirred at the same temperature for 10 minutes. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, acetic acid (0.003 g), water (0.009 mL), and THF (1.0 mL), potassium cyanate (0.002 g) was added and the mixture was stirred at room temperature for 11 hours. A saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted using DCM. 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 (0.002 g).

[0129] Example A-14 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((5-fluoropyridine-2-yl)oxy)methyl)-2-oxopiperidine-3-yl)urea Reference Example A-9 (0.070 g), 5-fluoropyridine-2-ol (0.026 g), and toluene (1.0 mL) were mixed with cyanomethylenetributylphosphoran (0.111 g) at room temperature and stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((5-fluoropyridine-2-yl)oxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.061 g). To a mixture of the obtained compound (0.061 g) and DCM (2.0 mL), TFA (0.296 g) was added at room temperature and the mixture was stirred at the same temperature for 1.5 hours. Saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, acetic acid (0.013 g), water (0.040 mL), and THF (1.0 mL), potassium cyanate (0.012 g) was added and the mixture was stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution and water were added to the reaction mixture, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (elution solvent: 0.2% NH₄). 3 in water / 0.2% NH 3 The compound was purified in MeCN (64.2 / 35.8–5 / 95) to obtain the title compound (0.021 g).

[0130] Example A-15 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-(((4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)piperidine-3-yl)urea Example A-15 was synthesized in the same manner as Example A-14, using 4-(trifluoromethyl)pyridine-2-ol instead of 5-fluoropyridine-2-ol.

[0131] Example A-16 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((3,5-difluoropyridine-2-yl)oxy)methyl)-2-oxopiperidine-3-yl)urea Reference Example A-9 (0.108 g), 3,5-difluoropyridine-2-ol (0.047 g), and toluene (1.5 mL) were mixed with cyanomethylenetributylphosphoran (0.172 g) at room temperature and stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((3,5-difluoropyridine-2-yl)oxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.100 g). To a mixture of the obtained compound (0.100 g) and DCM (1.0 mL), TFA (0.402 g) was added at room temperature and the mixture was stirred at the same temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture under ice cooling, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of residue, water (0.063 mL), and THF (1.0 mL), acetic acid (0.011 g) and potassium cyanate (0.019 g) were added at room temperature, and the mixture was stirred at the same temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted by DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.056 g).

[0132] Example A-17 1-((3R,6S)-6-(((3,5-difluoropyridine-2-yl)oxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea Under an argon atmosphere, 10% Pd / C (0.004 g) was added to a mixture of Example A-16 (0.022 g), TEA (0.007 g), and methanol (1.0 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 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 (elution solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0 to 0 / 100 / 0 to 0 / 90 / 10) to obtain the title compound (0.019 g).

[0133] Example A-18 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-6-((pyridine-2-yloxy)methyl)piperidine-3-yl)urea Example A-18 was synthesized in the same manner as in Example A-16, using pyridine-2-ol instead of 3,5-difluoropyridine-2-ol.

[0134] Example A-19 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-cyano-3-fluorophenoxy)methyl)-2-oxopiperidine-3-yl)urea Example A-19 was synthesized in the same manner as in Example A-16, using 2-fluoro-4-hydroxybenzonitrile instead of 3,5-difluoropyridine-2-ol.

[0135] Example A-20: A mixture of 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((5-cyano-3-fluoropyridine-2-yl)oxy)methyl)-2-oxopiperidine-3-yl)urea, Reference Example A-9 (0.100 g), Reference Example A-13 (0.046 g), and toluene (2.0 mL) was mixed with cyanomethylenetributylphosphoran (0.159 g) at room temperature and stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 85 / 15 to 65 / 35) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((5-cyano-3-fluoropyridine-2-yl)oxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.050 g). To a mixture of the obtained compound (0.050 g) and DCM (1.0 mL), TFA (0.190 g) was added at room temperature and the mixture was stirred for 1 hour at the same temperature. DCM and saturated sodium bicarbonate aqueous solution were added to the reaction mixture and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. To a mixture of residue, water (0.030 mL), and THF (1.0 mL), acetic acid (0.005 g) and potassium cyanate (0.009 g) were added at room temperature, and the mixture was stirred at the same temperature for 22 hours. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted using 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: ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.036 g).

[0136] Example A-21 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-(((5-methylisoxazole-3-yl)oxy)methyl)-2-oxopiperidine-3-yl)urea Example A-21 was synthesized in the same manner as in Example A-14, using 5-methylisoxazole-3-ol instead of 5-fluoropyridine-2-ol.

[0137] Example A-22 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-cyanophenoxy)methyl)-2-oxopiperidine-3-yl)urea Reference Example A-9 (0.100 g), 4-hydroxybenzonitrile (0.039 g), and toluene (1.5 mL) were mixed with cyanomethylenetributylphosphoran (0.159 g) at room temperature and stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-cyanophenoxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.095 g). To a mixture of the obtained compound (0.095 g) and DCM (2.0 mL), TFA (0.501 g) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.062 mL), and THF (1.0 mL), acetic acid (0.021 g) and potassium cyanate (0.021 g) were added under ice cooling and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted using DCM. The extract was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (elution solvent: 0.2% NH₄). 3 in water / 0.2% NH 3 The compound was purified in MeCN (67.3 / 32.7–47.5 / 52.5) ​​to obtain the title compound (0.051 g).

[0138] Example A-23 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-cyano-2-fluorophenoxy)methyl)-2-oxopiperidine-3-yl)urea Example A-23 was synthesized in the same manner as in Example A-22, using 3-fluoro-4-hydroxybenzonitrile instead of 4-hydroxybenzonitrile.

[0139] Example A-24 1-((3R,6S)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-fluorophenoxy)methyl)-2-oxopiperidine-3-yl)urea Reference Example A-9 (0.200 g), 4-fluorophenol (0.074 g), and toluene (2.0 mL) were mixed with cyanomethylene tributylphosphoran (0.318 g) at room temperature and stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-fluorophenoxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.173 g). To a mixture of the obtained compound (0.173 g) and DCM (2.0 mL), TFA (1.00 g) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, water (0.113 mL), and THF (1.0 mL), acetic acid (0.038 g) and potassium cyanate (0.038 g) were added under ice cooling and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. By concentrating the extract under reduced pressure, 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((4-fluorophenoxy)methyl)-2-oxopiperidine-3-yl)urea (0.155 g) was obtained. Under an argon atmosphere, a mixture of the obtained compound (0.079 g), TEA (0.024 g), and methanol (2.0 mL) was mixed with 10% Pd / C (0.050 g) at room temperature and stirred at the same 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 subjected to ODS column chromatography (elution solvent: 0.2% NH4). 3 in water / 0.2% NH 3 The compound was purified in MeCN (65.3 / 34.7–45.3 / 54.7) to obtain the title compound (0.037 g).

[0140] Example A-25 1-((3R,6S)-6-((2,4-difluorophenoxy)methyl)-1-(2-fluoro-5-(trifluoromethyl)benzyl)-2-oxopiperidine-3-yl)urea Reference Example A-9 (0.100 g), 2,4-difluorophenol (0.043 g), and toluene (2.0 mL) were mixed with cyanomethylenetributylphosphoran (0.159 g) at room temperature and stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 60 / 40) to obtain ((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((2,4-difluorophenoxy)methyl)-2-oxopiperidine-3-yl)carbamate tert-butyl (0.056 g). To a mixture of the obtained compound (0.056 g) and DCM (1.0 mL), TFA (0.216 g) was added at room temperature and the mixture was stirred at the same temperature for 1 hour. DCM and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue, water (0.034 mL), and THF (1.0 mL), acetic acid (0.006 g) and potassium cyanate (0.010 g) were added at room temperature, and the mixture was stirred at the same temperature for 5 hours. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted by 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: ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain 1-((3R,6S)-1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-6-((2,4-difluorophenoxy)methyl)-2-oxopiperidine-3-yl)urea (0.034 g). To a mixture of the obtained compound (0.033 g), TEA (0.009 g), and methanol (1.0 mL), 10% Pd / C (0.006 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 90 / 10) to obtain the title compound (0.026 g).

[0141] The structural formulas, physical properties, and TSHR antagonist activity (see Test Example 1) of the examples are shown in the table below.

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] Test Example 1: Measurement of antagonist activity using TSH-induced cAMP production as an indicator in human TSHR-stable expressing CHO cells.

[0150] The human TSHR gene sequence (reference number NM_000369.2) was inserted into the multicloning site of pcDNA3.1(+). The constructed plasmid vector was introduced into CHO cells using lipofection, and human TSHR stable expression CHO cells were established. The obtained cells were placed in 96-well poly-D-lysine coated plates in a 5 x 10⁶ arrangement. 4Cells were seeded at 1 cell / well and cultured for 1 day at 37°C under 5% CO2 conditions in F12 medium containing 10% FBS, 400 μg / mL G418, 50 U / mL penicillin, and 50 μg / mL streptomycin. After removing the medium, the cells were washed twice with 100 μL of assay buffer per well (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX). 30 μL of assay buffer containing the test compound was added to each well and incubated at room temperature for 15 minutes. Then, assay buffer containing 30 μL of human TSH (R&D Systems, Inc., final concentration 50 ng / mL) was added and incubated at 37°C for 1 hour. The supernatant was removed, and cell lysates were prepared by adding Lysis and Detection Buffer 2 (Cisbio) and incubating at room temperature for 1 hour. Following the instructions for use of the cAMP Gs HiRange kit (Cisbio), cell lysates were reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate labeled antibody (Cisbio) in a 384-well white microplate. The fluorescence intensity ratio (measurement wavelength 665 nm / 620 nm) was then measured using a multiplate reader (PHERAstarFSX, BMG LABTECH Japan). The fluorescence intensity ratio of each sample was converted to cAMP content using a standard curve. The cAMP generation rate was calculated by converting the cAMP content to a percentage of the control value. The cAMP generation rate was plotted against the test compound concentration using Prism (Graph Pad Software Inc.), and IC50 was calculated. 50 The values ​​were calculated for each test compound's IC (Impulse Control Value). 50 This is shown in the table above. In the table, IC 50 <0.5 μM: A, 0.5 μM ≤ IC 50 : Denoted as B. IC of those that showed activity. 50 If a value could not be calculated, it was indicated as C.

[0151] As shown in the table above, the compounds of the present invention have been found to possess human TSHR antagonist activity.

[0152] The compounds of the present invention or their pharmaceutically acceptable salts have TSHR antagonist activity and are therefore useful as therapeutic agents for thyroid-related diseases.

Claims

1. A compound represented by formula (I): [In the formula, Y is C 3-8 , 1-6 , 5 , 1-6 , 3-8 , 1-6 , 5 , 1 , 5' , 3-8 , 1-6 , 1-6 , 1-6 , 1-6 , 2 , 5' alkyl, haloC 1-6 alkyl, or ring X; ring X is a group selected from the group consisting of the following (i) to (iv): (i) C 6-10 aryl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A; (ii) 5- to 10-membered heteroaryl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A; (iii) C 3-8 cycloalkyl; and (iv) 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A (however, excluding the group in which the atom bonded to L 4 is a nitrogen atom); the substituent group A is a group consisting of a halogen atom, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-8 cycloalkyl, and C 3-8 cycloalkoxy; ring Z is C 6-10 aryl, or 5- to 10-membered heteroaryl; R 1 is a halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 3-8 cycloalkyl, or C 3-8 cycloalkoxy; n is an integer from 0 to 2; when n is 2, each R​​​​​​​​​​​​​​​​​​​​​​​These are, independently, hydrogen atoms and C 1-6 Alkyl, or C 3-8 It is a cycloalkyl group; R 3 and R 3' Each of these is independently a hydrogen atom, or C 1-6 It is alkyl; R 4 is a halogen atom, cyano, C 1-6 Alkyl, Halo C 1-6 Alkyl, Halohydroxy C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 3-8 It is a cycloalkoxy or -SF5; L 1 -CR 6 R 6' -, -O-, or -NR 6 -and; R 6 and R 6' Each of these is independently a hydrogen atom, or C 1-6 Alkyl; L 2 C 1-6 Alkylene, or Halo C 1-6 It is alkylene; L 3 is a single bond, or -O-; L 4 C is a single bond. 1-6 Alkylene, or Halo C 1-6 It is an alkylene; m is an integer from 0 to 3; if m is 2 or greater, each R 4 They may be the same or different from each other; however, L 2 C 1-6 It is alkylene and L 3 If is -O-, then Y is C 1-6 Not alkyl; L 3 If Y is a single bond, then Y is ring X] or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1, R 2 ga-NHR 5 A compound that is or a pharmacologically acceptable salt thereof.

3. The compound according to claim 2, wherein R 5 A compound in which the atom is a hydrogen atom, or a pharmacokinetically acceptable salt thereof.

4. The compound according to claim 3, L 1 A compound having -NH- or a pharmacoposly acceptable salt thereof.

5. The compound according to claim 4, wherein R 3 and R 3' A compound in which the atom is a hydrogen atom, or a pharmacokinetically acceptable salt thereof.

6. The compound according to claim 5, wherein ring Z is C 6-10 A compound that is aryl or a pharmacoposly acceptable salt thereof.

7. The compound according to claim 6, wherein R 4 is a halogen atom, or halo C 1-6 A compound that is alkyl or a pharmacokinetically acceptable salt thereof.

8. The compound according to claim 7, wherein n is 0, or a pharmaceutically acceptable salt thereof.

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

10. Compounds selected from the group consisting of the following compounds: and or its pharmacologically acceptable salt.

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

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive.

13. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for the treatment of thyroid-related diseases.

14. A pharmaceutical composition according to claim 13, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

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