Bicyclo [1.1.1] pentane compounds

Abstract

To provide a new compound having thyroid stimulating hormone receptor antagonist activity and useful for treating thyroid-related diseases.SOLUTION: The present invention relates to a bicyclo [1.1.1] pentane compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. Since the compound of the present invention or a pharmaceutically acceptable salt thereof has an antagonist activity against a thyroid stimulating hormone receptor, it is useful as a therapeutic agent for thyroid-related diseases (e.g., hyperthyroidism, Graves' disease, thyroid ophthalmopathy and thyroid cancer) and the like.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a bicyclo[1.1.1]pentane compound useful as a pharmaceutical. More specifically, the present invention relates to a bicyclo[1.1.1]pentane compound or a pharmacologically acceptable salt thereof that has antagonist activity against the thyroid-stimulating hormone receptor (TSHR) and is useful as a therapeutic agent for thyroid-related diseases. [Background technology]

[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 hormonal effects of this excess can cause a variety of undesirable physical and mental effects, including goiter, tachycardia, high blood pressure, fatigue, weight loss, palpitations, sleep disorders, and menstrual irregularities.

[0004] There are various causes of hyperthyroidism, but the most common is Graves' disease (Graves' disease). In Graves' disease, an autoimmune mechanism causes the thyroid gland to be recognized as a foreign body, resulting in the production of autoantibodies against the TSHR present on thyroid follicular cells, known as TSHR antibodies (TRAb). It is thought that these TRAb act as TSHR agonists, overstimulating the TSHR and resulting in the excessive production of thyroid hormones, leading to the development of hyperthyroidism.

[0005] Thyroid eye disease is also known to be associated with Graves' disease. Thyroid eye disease is an autoimmune inflammatory disease that presents with a variety of ocular symptoms and is thought to be primarily caused by the agonistic action of TRAb on TSHR in the orbital tissue. It often develops around the same time as hyperthyroidism, but may not be accompanied by thyroid dysfunction.

[0006] Currently, Graves' disease is treated with antithyroid drugs such as thiamazole and propylthiouracil, which inhibit the biosynthesis of thyroid hormones. However, these drugs have problems such as a low remission rate, a long treatment period until remission is achieved, and a high incidence of side effects. Therefore, there is a need for drugs with a new mechanism of action for the treatment of Graves' disease.

[0007] Blocking TSHR or inhibiting signal transduction induced through TSHR inhibits thyroid hormone secretion and thyroid cell proliferation. Therefore, TSHR antagonists are thought to have therapeutic effects on Graves' disease and thyroid eye disease, which are caused by the agonistic action of TRAb on TSHR (Patent Documents 1 and 2). NCGC00242364 is known as a TSHR antagonist, and has been shown to have a T4 concentration-reducing effect in mice administered with TSH-releasing hormone (TRH) and the thyroid-stimulating antibody M22 (Non-Patent Document 1).

[0008] Compounds with TSHR antagonist activity are described in Patent Documents 1 to 3 and Non-Patent Document 1. Patent Documents 4 to 6 describe or exemplify compounds containing bicyclo[1.1.1]pentane. Patent Document 7 describes cycloalkyl compounds, Patent Document 8 describes carbamate compounds, and Patent Document 9 describes compounds with kinase inhibitory activity, all of which describe a wide range of general formulas. However, the bicyclo[1.1.1]pentane compound of the present invention is not described in any of Patent Documents 1 to 9 and Non-Patent Document 1. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent Application Publication No. 2011 / 0172267 [Patent Document 2] US Patent Application Publication No. 2012 / 0315217 [Patent Document 3] US Patent Application Publication No. 2019 / 0134024 [Patent Document 4] International Publication No. 2019 / 032743 [Patent Document 5] US Patent Application Publication No. 2014 / 0275245 [Patent Document 6] US Patent Application Publication No. 2016 / 0075654 [Patent Document 7] US Patent Application Publication No. 2019 / 0060257 [Patent Document 8] US Patent Application Publication No. 2005 / 0203176 [Patent Document 9] US Patent Application Publication No. 2007 / 0208166 [Non-patent literature]

[0010] [Non-Patent Document 1] Susanne Neumann et al., Endocrinology 2014, Vol. 155, No. 1, pp. 310-314 Summary of the Invention [Problem to be solved by the invention]

[0011] An objective of the present invention is to provide novel compounds that have TSHR antagonist activity and are useful for treating thyroid-related diseases. [Means for solving the problem]

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

[0013] That is, the present invention relates to the following [1] to

[10] , etc. [1] Formula (I): [ka] [During the ceremony, V is -CR 4 R 4' - or a single bond; R 2 , R 2' , R 4 , and R 4' are each independently a hydrogen atom or C 1-6 is alkyl; Ring U is a group selected from the group consisting of the following (a) to (f): (a)C 6-10 aryl, (b) 5- or 6-membered heteroaryl, (c) 9- or 10-membered heteroaryl, (d)C 3-10 cycloalkyl, (e) 3- to 10-membered heterocycloalkyl, and (f) the following group: [ka] Ring W is C 5-8 cycloalkyl, or 5-8 membered heterocycloalkyl; R 2 or R 4 is combined with the ring U to form C 5-8 may form a cycloalkyl or a 5- to 8-membered heterocycloalkyl; n is an integer from 0 to 4; When n is an integer of 2 or more, each R 1 may be the same or different from each other; R 1 is a halogen atom, cyano, C 1-6 Alkyl, hydroxy, amino, -C(=O)OR 5 , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, C 3-10 Cycloalkyl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-10 Cycloalkyl C 2-6 Alkynyl, halohydroxy C 1-6 alkyl, or -SF5; R 5 is C 1-6 is alkyl; R 3 is a group selected from the group consisting of the following (i) to (vii): [ka] and [ka] R 6 , and R 6' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxy C 1-6 is alkyl; R 6 , and R 6'may be taken together to form a 3- to 10-membered heterocycloalkyl; R 7 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl or C 3-10 is cycloalkyl; R 8 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, or C 6-10 Aryl C 1-6 is alkyl; R 9 , and R 9’ are each independently a hydrogen atom, C 1-6 alkyl, or hydroxy] or a pharmacologically acceptable salt thereof. [2] The compound according to [1] above, Ring U is a group selected from the group consisting of the following (a) to (d): (a)C 6-10 aryl, (b) 5- or 6-membered heteroaryl, (c) 9- or 10-membered heteroaryl, and (d) the following group: [ka] Ring U and R 2 Together they form the following groups: [ka] may be formed; R 1 But halogen atoms, cyano, C 1-6 Alkyl, hydroxy, -C(=O)OR 5 , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl, or -SF5; R 6 , and R 6' are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 is alkyl; R 7 But C 1-6 is alkyl; R 8 But C 1-6 Alkyl or C 6-10 Aryl C 1-6 is alkyl; R 9 and R 9’ are each independently a hydrogen atom or hydroxy; R 2' , R 5 , V, and n are as defined in [1] above, or a pharmacologically acceptable salt thereof. [3] The compound according to [1] or [2] above, V is a single bond; Ring U is C 6-10 compounds that are aryl; or a pharmacologically acceptable salt thereof. [4] The compound according to any one of [1] to [3] above, R 3 is a group selected from the group consisting of the following (i) to (iii): [ka] and [ka] R 6 , and R 6' is the same as the compound [2] above; or a pharmacologically acceptable salt thereof. [5] The compound according to any one of the above [1] to [4], wherein the compound is represented by formula (II): [ka] [During the ceremony, R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, Cyano C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 alkoxy, 5- or 6-membered heteroaryl, or -SF5; n is an integer from 0 to 4; When n is an integer of 2 or more, each R 1a may be the same or different from each other; If n is an integer greater than or equal to 2, two R 1a Together, C 5-8 may form a cycloalkyl or a 5- to 8-membered heterocycloalkyl. or a pharmacologically acceptable salt thereof. [6] The compound according to any one of [1] to [5] above, R 1a But halogen atoms, haloC 1-6 Alkyl, HaloC 1-6 Alkoxy, or -SF5; A compound in which n is an integer of 1 to 3, or a pharmacologically acceptable salt thereof. [7] The compound according to any one of [1] to [6] above, A compound selected from the group consisting of the following compounds: [ka] [ka] and [ka] or a pharmacologically acceptable salt thereof. [8] A pharmaceutical composition comprising the compound according to any one of [1] to [7] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive. [9] The pharmaceutical composition according to [8] above, which is a pharmaceutical composition for treating a thyroid-related disease.

[10] The pharmaceutical composition according to [9] above, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

[0014] In one embodiment, the present invention relates to a method for treating a thyroid-related disease, comprising administering to a patient a required amount of the pharmaceutical composition described in [8] above.

[0015] In one embodiment, the present invention relates to use of the compound according to any one of the above [1] to [7] or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition for treating a thyroid-related disease. [Effects of the Invention]

[0016] The compound of the present invention has excellent TSHR antagonist activity, and therefore the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for thyroid-related diseases. DETAILED DESCRIPTION OF THE INVENTION

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

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

[0019] "Halogen atom" means a fluorine atom, chlorine atom, bromine atom, or iodine atom. "C 1-6 The term "alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. "C 2-6 The term "alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms and at least one triple bond. Examples include ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. "C 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, and isopropoxy.

[0020] "Haro C 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 identical or different halogen atoms. 1-6 It means alkyl, and examples thereof include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl. "Hydroxy C 1-6 "Alkyl" refers to a C substituted with 1 or 2 hydroxy groups. 1-6 It means alkyl, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. "C 1-6 Alkoxy C 1-6 "Alkyl" means one C 1-6Alkoxy-substituted C 1-6 It means alkyl, and examples thereof include methoxymethyl, methoxyethyl, ethoxymethyl, and ethoxyethyl. "Amino C 1-6 "Alkyl" refers to a C substituted with 1 or 2 amino groups. 1-6 It means alkyl, such as aminomethyl, aminoethyl, aminopropyl, and 2-aminopropan-2-yl. "Cyano C 1-6 "Alkyl" refers to a C substituted with one or two cyanos. 1-6 It means alkyl, for example, cyanomethyl, cyanoethyl, cyanopropyl, 2-cyanopropan-2-yl, etc.

[0021] "Haro C 1-6 "Alkoxy" refers to a C substituted with 1 to 5 identical or different halogen atoms. 1-6 It means alkoxy, for example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, etc.

[0022] "Halohydroxy C 1-6 "Alkyl" refers to a C alkyl group substituted with 1 to 6 identical or different halogen atoms and 1 or 2 hydroxyl groups. 1-6 It means alkyl, for example, 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl. "Haro C 1-6 Alkoxy C 1-6 "Alkyl" means one haloC 1-6 Alkoxy-substituted C 1-6 It means alkyl, for example, trifluoromethoxymethyl.

[0023] "C 6-10 "Aryl" means a phenyl or naphthyl group. The term "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include pyridyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl. The term "9- or 10-membered heteroaryl" refers to a bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, pryl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, and isochromenyl.

[0024] "C 3-10 "Cycloalkyl" means a 3- to 10-membered monocyclic or bicyclic hydrocarbon group. "C 5-8 "Cycloalkyl" refers to a 5- to 8-membered monocyclic or bicyclic hydrocarbon group. The monocyclic or bicyclic hydrocarbon group may be a saturated or partially unsaturated hydrocarbon group. The bicyclic hydrocarbon group may contain a spiro ring, a fused ring, or a bridged ring. Examples of monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0025] The term "3- to 10-membered heterocycloalkyl" refers to a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. The term "5- to 8-membered heterocycloalkyl" refers to a 5- to 8-membered monocyclic or bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in the ring. The monocyclic or bicyclic heterocyclic group may be saturated or partially unsaturated. The bicyclic heterocyclic group may include a spiro ring, a fused ring, and a bridged ring. Examples of monocyclic heterocyclic groups include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

[0026] "C 6-10 "Aryloxy" means (C 6-10 aryl)-O-. For example, phenoxy is mentioned. "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 It means alkyl, for example, benzyl. "C 6-10 Aryl C 2-6 "Alkynyl" means one C 6-10 Aryl-substituted C 2-6 It means alkynyl, for example, phenylethynyl. "C 6-10 Aryl C 1-6 "Alkoxy" means one C 6-10 Aryl-substituted C 1-6 It means alkoxy, for example, benzyloxy.

[0027] "5- or 6-membered heteroaryl C 1-6 "Alkyl" refers to a C substituted with one 5- or 6-membered heteroaryl. 1-6 It means alkyl, for example, pyridin-4-ylmethyl, thiophen-2-ylethyl, thiophen-3-ylethyl, etc. "5- or 6-membered heteroaryl C 2-6 "Alkynyl" refers to a C alkynyl group substituted with one 5- or 6-membered heteroaryl. 2-6 It means alkynyl, for example, pyridin-4-ylethynyl, pyridin-3-ylethynyl, etc.

[0028] "C 3-10 "Cycloalkoxy" means (C 3-10 cycloalkyl)-O-. For example, cyclopropyloxy. "C 3-10 Cycloalkyl C 1-6 "Alkyl" means one C 3-10 Cycloalkyl-substituted C 1-6 It means alkyl, and examples thereof include cyclopropylmethyl, cyclopropylethan-1-yl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. "C 3-10 Cycloalkyl C 2-6 "Alkynyl" means one C 3-10 Cycloalkyl-substituted C 2-6 It means alkynyl, for example, cyclopropylethynyl. "C 3-10 Cycloalkyl C 1-6 "Alkoxy" means one C 3-10 Cycloalkyl-substituted C 1-6 It means alkoxy, for example, cyclopropylmethyloxy.

[0029] The following abbreviations used in the text, figures, and tables have the following meanings: CDI: 1,1'-carbonyldiimidazole DAST: (Diethylamino)sulfur trifluoride DCE: 1,2-dichloroethane DCM: dichloromethane DIBAL-H: Diisobutylaluminum hydride DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EDC-HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole HOBt hydrate:HOBt monohydrate LDA: lithium diisopropylamide MeCN: acetonitrile NBS: N-bromosuccinimide NIS: N-iodosuccinimide Pd(amphos)2Cl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium(0) PMDTA: 1,1,4,7,7-pentamethyldiethylenetriamine T3P (registered trademark): Propylphosphonic anhydride (cyclic trimer) TBAF: Tetrabutylammonium fluoride TEA: Triethylamine TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl free radical THF: tetrahydrofuran 10% Pd / C: 10% palladium on carbon (approximately 55% water-wet) Aminosilicagel: Aminopropylated silica gel Method A: Column chromatography using a silica gel column connected to the bottom of an aminopropylated silica gel column Process: Process Scheme Ref. No.: Reference number Str.:Structural formula Ex. No.: Example number Phys. data: physical properties I C 50 :50% inhibitory concentration 1H-NMR: Proton nuclear magnetic resonance spectrum DMSO-d6: dimethyl sulfoxide-d6 CDCl3: chloroform-d1 MS: Mass spectrometry (The MS values ​​in the table were measured using the multi-ionization method of electrospray ionization-atmospheric pressure chemical ionization.) 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

[0030] When one or more asymmetric carbon atoms are present in the compound represented by formula (I), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0031] In the case where the compound represented by formula (I) has cis-trans isomers, the present invention encompasses both of the cis-trans isomers.

[0032] When tautomers exist in the compound represented by formula (I), the present invention includes all of the tautomers.

[0033] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0034] The compound represented by formula (I) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

[0035] 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.

[0036] 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.

[0037] Unless otherwise specified, a suffix to a chemical name or structural formula that refers to a salt, such as "hydrochloride" or "HCl," does not denote a stoichiometric description but simply denotes the salt form.

[0038] When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with an appropriate co-crystal former, etc.

[0039] In the compound represented by formula (I), some of the atoms may be replaced with the corresponding isotopes. The present invention also includes compounds replaced with these isotopes. Examples of isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18O, and 35 In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are isotopes of the hydrogen atom, carbon atom, chlorine atom, fluorine atom, iodine atom, nitrogen atom, oxygen atom, and sulfur atom represented by S. 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0040] In the compound represented by formula (I), a compound in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below, using a commercially available building block into which an isotope has been introduced. For example, a compound in which some hydrogen atoms of the compound represented by formula (I) are replaced with deuterium atoms can also be produced by the above method and a method described in the literature (see, for example, "Journal of the Society of Organic Synthetic Chemistry," 2007, Vol. 65, No. 12, pp. 1179-1190). In addition, for example, a compound in which some carbon atoms of the compound represented by formula (I) are replaced with 13 Compounds substituted at C can also be produced using the above method and methods described in the literature (see, for example, RADIOISOTOPES, 2007, Vol. 56, No. 11, pp. 741-750).

[0041] The compound of the present invention represented by formula (I) can be produced, for example, by the methods shown in Schemes 1 to 5 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compound of formula (I) corresponds to the compounds represented by compounds (I-1) to (I-7).

[0042] The compound of the present invention represented by formula (I) can be produced by the following method, but the following production method is an example of a general production method and is not intended to limit the production method.

[0043] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0044] In the reaction of each step, the reaction time varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 30 minutes to 3 days unless otherwise specified.

[0045] In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually −78° C. to reflux temperature unless otherwise specified.

[0046] In the reaction of each step, the pressure varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 1 to 20 atmospheres unless otherwise specified.

[0047] In the reactions of each step, a microwave reaction apparatus such as Initiator manufactured by Biotage may be used. When the reactions are carried out using a microwave reaction apparatus, the conditions vary depending on the raw materials, solvent, and model used, but the reactions can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0048] Unless otherwise specified, the reaction in each step is carried out without solvent or using an appropriate solvent. Examples of the appropriate solvent include solvents inert to the reaction. Specific examples of the solvent used include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Two or more of the following solvents may be mixed in an appropriate ratio and used. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, DME, 1,4-dioxane, cyclopentyl methyl ether, etc.; Aromatic hydrocarbons: benzene, chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, etc.; Amides: DMF, N,N-dimethylacetamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: DCM, DCE, carbon tetrachloride, etc.; Nitriles: MeCN, etc.; Sulfoxides: DMSO, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water.

[0049] When a base is used in the reaction of each step, the reaction is carried out using a base suitable for the reaction. Specific examples of the base to be used include the bases described in the Reference Examples or Examples corresponding to each step, and the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, etc.; Basic salts: sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; Organic bases: TEA, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; Organic magnesiums: isopropyl magnesium chloride, etc.; Organolithium compounds: n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0050] When an acid or an acid catalyst is used in the reaction of each step, the reaction is carried out using an acid or an acid catalyst suitable for the reaction. Specific examples of the acid or acid catalyst to be used include the acid or acid catalysts described in the Reference Examples and Examples corresponding to each step, and the following acid or acid catalysts. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0051] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent to be used include the condensing agents described in the Reference Examples or Examples corresponding to each step, and the following condensing agents. Carbodiimides: EDC-HCl, N,N'-dicyclohexylcarbodiimide, etc.; Imidazoles: CDI, etc.; Uronium salts, phosphonium salts: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: DMT-MM, etc.; Others: T3P, etc.

[0052] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, and the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, DIBAL-H, etc.; Boranes: BH3-THF complex, picoline borane complex, decaborane, etc.

[0053] When an oxidizing agent is used in the reaction of each step, the reaction is carried out using an oxidizing agent suitable for the reaction. Specific examples of the oxidizing agent to be used include the oxidizing agents described in the Reference Examples or Examples corresponding to each step, and the following oxidizing agents. Peracids: m-chloroperbenzoic acid, hydrogen peroxide, tert-butyl hydroperoxide, etc.; Chlorates: sodium hypochlorite, sodium chlorite, etc.; Iodates: sodium periodate, etc.; Hypervalent iodine reagents: iodobenzene diacetate, Dess-Martin periodinane, etc.; Chromium-containing reagents: pyridinium dichromate, Jones reagent, etc.; Manganese-containing reagents: manganese dioxide, potassium permanganate, etc.

[0054] When a carbonyl group-introducing reagent is used in the reaction of each step, the reaction is carried out using a carbonyl group-introducing reagent suitable for the reaction. Specific examples of the carbonyl group-introducing reagent to be used include the carbonyl group-introducing reagents described in the Reference Examples or Examples corresponding to each step, and the following carbonyl group-introducing reagents. Phosgenes: phosgene, diphosgene, triphosgene, etc.; Chloroformates: 4-nitrophenyl chloroformate, etc.; Imidazoles: CDI, etc.

[0055] In each step, when a protecting group is required depending on the type of functional group, the protective group may be introduced and removed in a suitable combination according to a conventional method. Regarding the type of protective group, protection, and deprotection, for example, the method described in "Greene's Protective Groups in Organic Synthesis," edited by Peter GM Wuts, fifth edition, Wiley-Interscience, 2014 can be mentioned.

[0056] When a hydrolysis reaction is carried out in each step, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base that can be used include those mentioned above.

[0057] In each step, when a catalytic reduction reaction is carried out, the reaction can be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc. If necessary, an acid may be used in the reaction.

[0058] When a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent to be used include the above-mentioned examples.

[0059] When an oxidation reaction is carried out in each step, the reaction can be carried out in the presence of an oxidizing agent. Examples of the oxidizing agent that can be used include those mentioned above. When a nitroxy radical oxidation catalyst is used, the reaction can be carried out in the presence of a reoxidizing agent. Examples of the nitroxy radical oxidation catalyst that can be used include TEMPO and 2-azaadamantane-N-oxyl. Examples of the reoxidizing agent that can be used include sodium hypochlorite and iodobenzene diacetate. If necessary, the reaction can be carried out by adding an additive such as tetrabutylammonium hydrogen sulfate or potassium bromide.

[0060] In each step, when an amidation reaction is carried out, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base to be used include those mentioned above. When a carbodiimide is used as the condensing agent, the reaction may be carried out by adding an additive such as HOBt or DMAP as necessary. The reaction can also be carried out using an acyl halide or an acid anhydride in the presence or absence of a base.

[0061] When a reductive amination reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent that can be used include those mentioned above. The reaction can also be carried out in the presence of hydrogen and a catalyst. Examples of the catalyst that can be used include palladium carbon powder, Pearlman's catalyst, platinum carbon powder, Raney nickel, etc.

[0062] In each step, when a carbamate reaction or a urea reaction is carried out, the reaction can be carried out using a carbonyl group-introducing reagent in the presence or absence of a base. Examples of the carbonyl group-introducing reagent and base to be used include those mentioned above.

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

[0064] [ka] The symbols in the formula have the same meanings as above. X is a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group. Y is a hydroxyl or chlorine atom.

[0065] Process 1-1 Compound (1-3) can also be produced by reacting compound (1-1) with compound (1-2) in the presence of a base. Process 1-2 R 2' When is a hydrogen atom, compound (1-3) can also be produced by a reductive amination reaction of compound (1-1) with compound (1-4).

[0066] Process 1-3 Compound (I) can also be produced by an amidation reaction of compound (1-3) and compound (1-5).

[0067] The compound represented by formula (I-1) can be produced, for example, according to the method described in Scheme 2.

[0068] [ka] The symbols in the formula have the same meanings as above. 1 is a protecting group.

[0069] Process 2-1 The compound (2-2) can also be produced by an amidation reaction between the compound (1-3) and the compound (2-1).

[0070] Process 2-2 Compound (2-3) can also be prepared by removing the protecting group of compound (2-2).

[0071] Process 2-3 Compound (I-1) can also be produced by an amidation reaction of compound (2-3) and compound (2-4).

[0072] The compound represented by formula (I-2) can be produced, for example, according to the method described in Scheme 3.

[0073] [ka] The symbols in the formula have the same meanings as above. 2 is a protecting group.

[0074] Process 3-1 Compound (3-2) can also be produced by an amidation reaction between compound (1-3) and compound (3-1).

[0075] Process 3-2 Compound (3-3) can also be prepared by removing the protecting group of compound (3-2).

[0076] Process 3-3 Compound (I-2) can also be produced by an amidation reaction of compound (3-3) and compound (2-4).

[0077] The compounds represented by formula (I-3), formula (I-4), formula (I-5), and formula (I-6) can be produced, for example, according to the method described in Scheme 4.

[0078] [ka] The symbols in the formula have the same meanings as above, and Z is a protected amino group.

[0079] Process 4-1 Compound (4-2) can also be produced by an amidation reaction of compound (1-3) and compound (4-1).

[0080] Process 4-2 Compound (4-3) can also be prepared by removing the protecting group of compound (4-2).

[0081] Process 4-3 Compound (I-3) can also be produced by reacting compound (4-3) with trimethylsilyl isocyanate or an alkali cyanate such as potassium cyanate or sodium cyanate.

[0082] Process 4-4 Compound (I-4) can also be produced by subjecting compound (4-3) and compound (2-4) to a urea reaction.

[0083] Process 4-5 Compound (I-5) can also be produced by an amidation reaction of compound (4-3) and compound (4-4).

[0084] Process 4-6 Compound (I-6) can also be produced by a carbamate reaction of compound (4-3) and compound (4-5).

[0085] The compound represented by formula (I-7) can be produced, for example, according to the method described in Scheme 5.

[0086] [ka] The symbols in the formula have the same meanings as above. 3 is a protecting group.

[0087] Process 5-1 Compound (5-2) can also be produced by an amidation reaction between compound (1-3) and compound (5-1).

[0088] Process 5-2 Compound (5-3) can also be prepared by removing the protecting group of compound (5-2).

[0089] Process 5-3 Compound (I-7) can also be produced by a carbamate reaction of compound (5-3) and compound (2-4).

[0090] The scheme shown above is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The scheme can be modified in various ways that can be easily understood by those skilled in the art.

[0091] The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc.

[0092] The compounds of the present invention have excellent TSHR antagonist activity and can 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, Vol. 155, No. 1, pp. 310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

[0093] In one embodiment, hyperthyroidism includes hyperthyroidism caused by, for example, Graves' disease, thyroiditis, Plummer's disease, toxic multinodular goiter, TSH-producing pituitary adenoma, hyperemesis gravidarum, ovarian goiter, gestational trophoblastic tumor, or germ cell tumor. Preferably, the compound of the present invention can be used as a therapeutic agent for hyperthyroidism caused by Graves' disease.

[0094] In one embodiment, the thyroid-related disease is a disease or condition associated with abnormal thyroid hormone levels. Diseases and conditions associated with abnormal thyroid hormone levels include, for example, diseases and conditions caused by TRAb.

[0095] In the present invention, "treatment" includes the meaning of "prevention." For example, treatment of hyperthyroidism, Graves' disease, or thyroid eye disease includes the meanings of "prevention of relapse or recurrence" and "maintenance of remission." In addition, in one embodiment, the compounds of the present invention can be used to prevent the onset of thyroid eye disease in patients with Graves' disease.

[0096] In the present invention, the term "antagonist" refers to a drug that inhibits or blocks the function of a target protein, regardless of its binding site. For example, the term "antagonist" includes the meanings of "allosteric antagonist" and "negative allosteric modulator (NAM)."

[0097] The therapeutic effect of the compound of the present invention on thyroid-related diseases can be confirmed by methods well known in the art. For example, a method for confirming the effect in an animal model of hyperthyroidism or Graves' disease includes the method described in "Endocrinology," 2007, Vol. 148, No. 5, pp. 2335-2344, or a method modified therefrom.

[0098] The pharmaceutical composition of the present invention may be used in various dosage forms depending on the intended use, including, for example, powders, granules, fine granules, dry syrup, tablets, capsules, injections, liquids, ointments, suppositories, patches, eye drops, and enemas.

[0099] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0100] The pharmaceutical compositions of the present invention are prepared using a compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving the compound with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, using methods known in pharmaceutical sciences depending on the dosage form.

[0101] When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is determined appropriately depending on the patient's age, sex, weight, disease, degree of treatment, etc. The daily dosage may be administered in one, two, three, or four divided doses. In the case of oral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 5000 mg / day. In one embodiment, the oral dosage can be set in the range of 1 to 1500 mg / day, preferably in the range of 1 to 500 mg / day, and more preferably in the range of 10 to 500 mg / day. In the case of parenteral administration, the dosage for an adult can be set, for example, in the range of 0.01 to 5000 mg / day. In one embodiment, the parenteral dosage can be set in the range of 0.1 to 1500 mg / day, preferably in the range of 0.1 to 500 mg / day, and more preferably in the range of 1 to 500 mg / day.

[0102] In one embodiment, the pharmaceutical composition of the present invention can be used in combination with drugs other than TSHR antagonists. Examples of other drugs that can be used in combination for the treatment of thyroid-related diseases include antithyroid drugs (e.g., thiamazole, propylthiouracil, etc.), inorganic iodine, lithium carbonate, thyroid hormone preparations, etc.

[0103] When the compound represented by formula (I) or its pharmacologically acceptable salt is used in combination with other drugs, these active ingredients can be administered as a preparation containing them together, or as a preparation in which each of these active ingredients is separately formulated. When formulated separately, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or its pharmacologically acceptable salt may be appropriately reduced depending on the dosage of the other drug used in combination.

[0104] The compound represented by formula (I) may be appropriately converted into a prodrug for use. For example, a prodrug of the compound represented by formula (I) can be produced by introducing a group constituting a prodrug using a prodrug-forming reagent such as a corresponding halide, followed by purification. Examples of the group constituting a prodrug include the groups described in "Drug Development," Hirokawa Shoten, 1990, Vol. 7, pp. 163-198. [Example]

[0105] The present invention will be explained in more detail below based on Reference Examples, Examples and Test Examples, but the present invention is not limited to the contents thereof.

[0106] The names of compounds described in the following Reference Examples and Examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

[0107] Reference example 1 1-chloro-3-(chloromethyl)-2-fluoro-5-(trifluoromethyl)benzene To a mixture of 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid (0.200 g) and THF (2 mL), BH3-THF complex (0.91 mol / L in THF) (2.04 mL) was slowly added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes and then at 60 °C for 1 hour, and then allowed to cool to room temperature. Methanol (1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water 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, TEA (0.113 g), and DCM (2 mL) was added methanesulfonyl chloride (0.118 g) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.160 g).

[0108] Reference example 2 1-chloro-3-(difluoromethyl)-5-methylbenzene To a mixture of 3-chloro-5-methylbenzaldehyde (0.500 g) and DCM (20 mL) was slowly added DAST (1.15 g) at -78 °C. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture, DAST (1.15 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture, DAST (1.15 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.192 g).

[0109] Reference example 3 1-(Bromomethyl)-3-chloro-5-(difluoromethyl)benzene A mixture of Reference Example 2 (0.192 g), NBS (0.213 g), benzoyl peroxide (0.026 g), and carbon tetrachloride (10 mL) was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature, and insoluble matter was removed by filtration. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were added to the filtrate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.153 g).

[0110] Reference example 4 3,5-Dichloro-2-fluorobenzaldehyde To a mixture of 2,4-dichlorofluorobenzene (1.41 g) and THF (20 mL), LDA (1.08 mol / L in n-hexane / THF) (8.7 mL) was slowly added at -78 °C. The reaction mixture was stirred at the same temperature for 10 minutes. DMF (1 mL) was added to the reaction mixture at -78 °C. The reaction mixture was stirred at the same temperature for 5 minutes and then under ice-cooling for 30 minutes. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2 to 90 / 10) to give the title compound (0.831 g).

[0111] Reference example 5 2,3-Difluoro-5-(trifluoromethyl)benzaldehyde NIS (1.36 g) was added to a mixture of 1,2-difluoro-4-(trifluoromethyl)benzene (1.00 g) and 20% fuming sulfuric acid (2 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to ice water, and the mixture was extracted twice with n-hexane. The combined extracts were washed with 10% aqueous sodium sulfite solution, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and THF (8 mL), n-butyllithium (2.8 mol / L in n-hexane) (1.91 mL) was added at -78 °C. The reaction mixture was stirred at the same temperature for 5 minutes. DMF (1.38 mL) was added to the reaction mixture at -78 °C. The reaction mixture was stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0-99 / 1) to obtain the title compound (0.850 g).

[0112] Reference example 6 2-chloro-4-(difluoromethyl)-1-fluorobenzene To a mixture of 3-chloro-4-fluorobenzaldehyde (0.500 g) and DCM (30 mL), DAST (1.41 g) was slowly added at -78 °C. The reaction mixture was stirred at room temperature for 2 hours. DAST (3.86 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate 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) to obtain the title compound (0.648 g).

[0113] Reference example 7 3-chloro-5-(difluoromethyl)-2-fluorobenzaldehyde To a mixture of Reference Example 6 (0.218 g) and THF (5 mL), n-butyllithium (2.8 mol / L in n-hexane) (1.29 mL) was added at -78 °C. The reaction mixture was stirred at the same temperature for 5 minutes. DMF (0.467 mL) was added to the reaction mixture at -78 °C. The reaction mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain the title compound (0.208 g).

[0114] Reference example 8 2-Fluoro-5-(1-hydroxyethyl)benzonitrile Under an argon atmosphere, methylmagnesium bromide (3 mol / L in diethyl ether) (1.23 mL) was added to a mixture of 2-fluoro-5-formylbenzonitrile (0.500 g) and THF (20 mL) at -78 °C. The reaction mixture was stirred at the same temperature for 1 hour. Saturated brine was added to the reaction mixture at -78 °C, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20 - 50 / 50) to give the title compound (0.439 g).

[0115] Reference example 9 5-Acetyl-2-fluorobenzonitrile To a mixture of Reference Example 8 (0.439 g) and DCM (8 mL), Dess-Martin periodinane (1.69 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. 1 mol / L aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate 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. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to give the title compound (0.373 g).

[0116] Reference example 10 5-(1,1-difluoroethyl)-2-fluorobenzonitrile A mixture of Reference Example 9 (0.173 g) and DAST (1.22 g) was stirred at 50° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and added dropwise to a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.152 g).

[0117] Reference example 11 5-(1,1-difluoroethyl)-2-fluorobenzaldehyde Under an argon atmosphere, DIBAL-H (1.03 mol / L in n-hexane) (1.61 mL) was added to a mixture of Reference Example 10 (0.152 g) and toluene (2 mL) at -78 °C. The reaction mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (5 mL) and 2 mol / L hydrochloric acid (4 mL) were added to the reaction mixture at -78 °C. The mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0-85 / 15) to give the title compound (0.100 g).

[0118] Reference example 12 2-Bromo-1-fluoro-4-(1,1,2,2-tetrafluoroethoxy)benzene Cesium carbonate (0.384 g) was added to a mixture of 3-bromo-4-fluorophenol (0.150 g), 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.408 g), and DMSO (2 mL) at room temperature. The reaction mixture was stirred at 140 °C for 10 minutes under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To the residue, acetic acid (1 mL) and zinc (0.154 g) were added at room temperature. The reaction mixture was stirred at 50 °C for 30 minutes and then allowed to cool to room temperature. Water and DCM were added to the reaction mixture. The mixture was stirred at room temperature for 10 minutes and then filtered through Celite. The organic layer of the filtrate was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.046 g).

[0119] Reference example 13 N-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)bicyclo[1.1.1]pentan-1-amine Under an argon atmosphere, n-butyllithium (1.55 mol / L in n-hexane) (0.102 mL) was added to a mixture of Reference Example 12 (0.046 g) and diethyl ether (1 mL) at -78°C. The reaction mixture was stirred at the same temperature for 30 minutes. DMF (0.015 mL) was added to the reaction mixture at -78°C. The reaction mixture was stirred at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture at -78°C, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, bicyclo[1.1.1]pentan-1-amine hydrochloride (0.019 g), TEA (0.019 g), and methanol (1 mL) was stirred at room temperature for 30 minutes. Sodium borohydride (0.006 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 98 / 2-80 / 20) to give the title compound (0.016 g).

[0120] Reference example 14 (3-chloro-4-fluorophenoxy)triisopropylsilane To a mixture of 3-chloro-4-fluorophenol (2.10 g), imidazole (0.977 g), and DMF (20 mL) was added triisopropylsilyl chloride (2.77 g) at room temperature. The reaction mixture was stirred at 70 °C for 4 hours. Triisopropylsilyl chloride (2.77 g) and imidazole (0.977 g) were added to the reaction mixture at 70 °C. The reaction mixture was stirred at the same temperature for 2 hours and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-80 / 20) to obtain the title compound (6.67 g).

[0121] Reference example 15 (3-chloro-2-fluoro-5-((triisopropylsilyl)oxy)phenyl)methanol To a mixture of PMDTA (2.48 g) and THF (20 mL), sec-butyllithium (1.04 mol / L in n-hexane / cyclohexane) (17.9 mL) was added at -78 °C. The reaction mixture was stirred at the same temperature for 10 minutes. Reference Example 14 (6.67 g) was slowly added to the reaction mixture at -78 °C. The reaction mixture was stirred at the same temperature for 1 hour. Dry ice was added to the reaction mixture at -78 °C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 16 hours. Water and 2 mol / L hydrochloric acid were added to the reaction mixture at room temperature to adjust the pH to approximately 5. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and THF (20 mL), BH3-THF complex (0.91 mol / L in THF) (31.5 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the title compound (0.671 g).

[0122] Reference example 16 3-chloro-4-fluoro-5-(hydroxymethyl)phenol To a mixture of Reference Example 15 (0.671 g) and THF (10 mL), TBAF (1 mol / L in THF) (5.04 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol / L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 - 0 / 100) to give the title compound (0.049 g).

[0123] Reference example 17 (3-chloro-5-(difluoromethoxy)-2-fluorophenyl)methanol A mixture of Reference Example 16 (0.049 g), sodium chlorodifluoroacetate (0.126 g), potassium carbonate (0.152 g), water (0.5 mL), and DMF (4 mL) was stirred at 120° C. for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 20 / 80) to give the title compound (0.025 g).

[0124] Reference example 18 N-(3-(difluoromethoxy)-5-(trifluoromethyl)benzyl)bicyclo[1.1.1]pentan-1-amine hydrochloride To a mixture of methyl 3-hydroxy-5-(trifluoromethyl)benzoate (0.250 g), potassium hydroxide (1.27 g), water (3 mL), and MeCN (3 mL), diethyl (bromodifluoromethyl)phosphonate (1.52 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 15 hours. Diethyl (bromodifluoromethyl)phosphonate (0.303 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. 2 mol / L hydrochloric acid (10 mL) was slowly added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-90 / 10) to give 3-(difluoromethoxy)-5-(trifluoromethyl)benzoic acid. To a mixture of the resulting 3-(difluoromethoxy)-5-(trifluoromethyl)benzoic acid and THF (5 mL), BH3-THF complex (0.91 mol / L in THF) (3.74 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for 1 hour. To the reaction mixture, BH3-THF complex (0.91 mol / L in THF) (3.74 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20-0 / 100) to obtain the alcohol. To a mixture of the obtained alcohol and DCM (1 mL), Dess-Martin periodinane (0.110 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. 1 mol / L aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), TEA (0.030 g), and methanol (1 mL) was stirred at room temperature for 1 hour. Sodium borohydride (0.014 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Sodium borohydride (0.014 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at the same temperature for 1 hour. 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (1 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (0.186 mL) was slowly added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure to give the title compound (0.067 g).

[0125] Reference example 19 3-((trifluoromethoxy)methyl)benzaldehyde Under an argon atmosphere, DIBAL-H (1.03 mol / L in n-hexane) (2.19 mL) was slowly added to a mixture of 3-((trifluoromethoxy)methyl)benzonitrile (0.182 g) and DCM (6 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 2.5 hours. 2 mol / L hydrochloric acid was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0-86 / 14) to give the title compound (0.113 g).

[0126] Reference example 20 N-(1-(3-(trifluoromethyl)phenyl)ethyl)bicyclo[1.1.1]pentan-1-amine To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.043 g), TEA (0.049 g), and methanol (1.6 mL) was added 1-(3-(trifluoromethyl)phenyl)ethan-1-one (0.061 g) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. Titanium(IV) isopropoxide (0.101 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature overnight. Sodium borohydride (0.018 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30-0 / 100) to give the title compound (0.050 g).

[0127] Reference example 21 N-(bicyclo[1.1.1]pentan-1-yl)-2-(1,3-dioxoisoindolin-2-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)acetamide To a mixture of Reference Example 20 (0.050 g), DIPEA (0.051 g), and THF (2 mL), phthalylglycyl chloride (0.057 g) was added under ice-cooling. The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50 / 50 - 0 / 100) to give the title compound (0.061 g).

[0128] Reference example 22 N-(6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)bicyclo[1.1.1]pentan-1-amine To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.032 g), TEA (0.037 g), and methanol (0.63 mL) was added 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (0.048 g) at room temperature. The reaction mixture was stirred at the same temperature for 4 days. Sodium borohydride (0.014 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30-0 / 100) to obtain the title compound (0.016 g).

[0129] Reference Example 23 was synthesized in the same manner as in Reference Example 21, except that Reference Example 22 was used instead of Reference Example 20.

[0130] Reference example 24 N-(3-(trifluoromethyl)benzyl)bicyclo[1.1.1]pentan-1-amine To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.250 g), DIPEA (0.675 g), and MeCN (6 mL) was added 3-(trifluoromethyl)benzyl bromide (0.500 g) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-70 / 30) to give the title compound (0.215 g).

[0131] Reference example 25 2-Amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)acetamide Under an argon atmosphere, 10% Pd / C (0.023 g) was added to a mixture of Example 51 (0.113 g) and THF (1.5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.078 g).

[0132] Reference example 26 N-(3-(trifluoromethyl)benzyl)bicyclo[1.1.1]pentan-1-amine hydrochloride To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.501 g) and methanol (5 mL), TEA (0.423 g) and 3-(trifluoromethyl)benzaldehyde (0.728 g) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours. Sodium borohydride (0.236 g) was added to the reaction mixture under water cooling. The reaction mixture was stirred at room temperature for 3 hours. Sodium borohydride (0.079 g) was added to the reaction mixture under water cooling. The reaction mixture was stirred at room temperature for 2 hours. 1 mol / L aqueous sodium hydroxide solution and water were added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (10 mL), hydrogen chloride (4 mol / L in ethyl acetate) (3.14 mL) was slowly added at room temperature. The reaction mixture was stirred at the same temperature for 40 minutes, and the insoluble matter was filtered off. The resulting solid was dried under reduced pressure to give the title compound (0.876 g).

[0133] Reference example 27 2-Amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)acetamide methanesulfonate To a mixture of Example 53 (0.100 g) and ethyl acetate (1 mL), methanesulfonic acid (0.036 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours and then at 50 °C for 2.5 hours. To the reaction mixture, methanesulfonic acid (0.015 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (0.2 mL) was added to the reaction mixture, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (0.087 g).

[0134] Reference example 28 2-(benzyloxy)-N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)acetamide To a mixture of Reference Example 24 (0.060 g), DIPEA (0.096 g), and MeCN (1 mL) was added 2-(benzyloxy)acetic acid (0.062 g) at room temperature. The reaction mixture was stirred at the same temperature for 5 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.293 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10-70 / 30) to obtain the title compound (0.086 g).

[0135] Reference example 29 N-(bicyclo[1.1.1]pentan-1-yl)-2-hydroxy-N-(3-(trifluoromethyl)benzyl)acetamide Under an argon atmosphere, 10% Pd / C (0.017 g) was added to a mixture of Reference Example 28 (0.085 g) and ethanol (1.5 mL) at room temperature. The reaction mixture was stirred at 60 °C under a hydrogen atmosphere for 45 minutes. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (0.059 g).

[0136] Reference example 30 (E)-4-(bicyclo[1.1.1]pentan-1-yl(3-(trifluoromethyl)benzyl)amino)-4-oxobut-2-enoic acid ethyl ester To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.025 g), DIPEA (0.108 g), and MeCN (1 mL) was added 3-(trifluoromethyl)benzyl bromide (0.052 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.108 g), and MeCN (1 mL), ethyl (E)-4-chloro-4-oxobut-2-enoate (0.041 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 30 / 70-0 / 100) to give the title compound (0.038 g).

[0137] Reference Examples 31 and 32 were synthesized in the same manner as in Reference Example 28, except that corresponding starting materials were used instead of 2-(benzyloxy)acetic acid.

[0138] Reference example 33 Methanesulfonic acid 3-(benzyloxy)benzyl ester To a mixture of (3-(benzyloxy)phenyl)methanol (0.054 g), TEA (0.030 g), and DCM (1 mL) was added methanesulfonyl chloride (0.032 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes and then diluted with DCM. The mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.074 g).

[0139] Reference example 34 Methanesulfonic acid (2-(trifluoromethyl)pyridin-4-yl)methyl ester To a mixture of (2-(trifluoromethyl)pyridin-4-yl)methanol (0.076 g) and DCM (2 mL) was added DIPEA (0.067 g) at room temperature. Methanesulfonyl chloride (0.059 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20-32 / 68) to give the title compound (0.094 g).

[0140] Reference example 35 N-(2-fluoro-5-(trifluoromethyl)benzyl)bicyclo[1.1.1]pentan-1-amine hydrochloride A solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (1.95 g) in methanol (2.5 mL) was added to a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (1.05 g), triethanolamine (0.891 g), and methanol (8 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Sodium borohydride (0.201 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 5 minutes under ice-cooling. Sodium borohydride (0.200 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 5 minutes under ice-cooling. Sodium borohydride (0.200 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 3 hours at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a mixture of the residue and ethyl acetate (11 mL), hydrogen chloride (4 mol / L in ethyl acetate) (6.60 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, and the insoluble matter was filtered off. The resulting solid was dried under reduced pressure to give the title compound (2.29 g).

[0141] Reference example 36 2-Amino-N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)acetamide To a mixture of Reference Example 35 (0.100 g), N-(tert-butoxycarbonyl)glycine (0.077 g), TEA (0.103 g), and MeCN (1.7 mL) was added T3P (1.7 mol / L in ethyl acetate) (0.299 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 days. The reaction mixture was partitioned with saturated aqueous sodium bicarbonate and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-50 / 50) to obtain the amide compound. To a mixture of the obtained amide compound and ethyl acetate (2.5 mL), hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was added at room temperature. The reaction mixture was stirred at the same temperature overnight. A saturated aqueous solution of sodium bicarbonate was slowly added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.071 g).

[0142] The structural formulas of the reference examples are shown in the table below.

[0143] [Table 1] [Table 2] [Table 3] [Table 4]

[0144] Example 1 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.029 g), DIPEA (0.127 g), and MeCN (0.5 mL) was added 3-(trifluoromethyl)benzyl bromide (0.061 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was 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, DIPEA (0.127 g), and MeCN (0.5 mL) was added N-carbamoylglycine (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.288 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.030 g).

[0145] Example 2 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethoxy)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.029 g), DIPEA (0.127 g), and MeCN (0.5 mL) was added 3-(trifluoromethoxy)benzyl bromide (0.066 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was 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, DIPEA (0.127 g), and MeCN (0.5 mL) was added N-carbamoylglycine (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.288 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.030 g).

[0146] Example 3 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-fluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.029 g), DIPEA (0.095 g), and MeCN (0.5 mL) was added 3-fluoro-5-(trifluoromethyl)benzyl bromide (0.063 g) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was 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, DIPEA (0.095 g), and MeCN (0.5 mL) was added N-carbamoylglycine (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.288 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.038 g).

[0147] Example 4 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.029 g), DIPEA (0.095 g), and MeCN (0.5 mL) was added 2-fluoro-5-(trifluoromethyl)benzyl bromide (0.058 g) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was 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, DIPEA (0.095 g), and MeCN (0.5 mL) was added N-carbamoylglycine (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.288 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.032 g).

[0148] Example 5 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.029 g), DIPEA (0.095 g), and MeCN (0.5 mL) was added 3-chloro-5-(trifluoromethyl)benzyl bromide (0.067 g) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was 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, DIPEA (0.095 g), and MeCN (0.5 mL) was added N-carbamoylglycine (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.288 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.044 g).

[0149] Example 6 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-chloro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.029 g), DIPEA (0.095 g), and MeCN (0.5 mL) was added 2-chloro-5-(trifluoromethyl)benzyl bromide (0.067 g) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was 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, DIPEA (0.095 g), and MeCN (0.5 mL) was added N-carbamoylglycine (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added T3P (1.7 mol / L in ethyl acetate) (0.288 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.041 g).

[0150] Example 7 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3,5-dichlorobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.015 g), TEA (0.015 g), 3,5-dichlorobenzaldehyde (0.022 g), and methanol (1 mL) was stirred at room temperature for 1 hour. Sodium borohydride (0.005 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.024 g), and MeCN (1 mL) was stirred at room temperature for 10 minutes. N-carbamoylglycine (0.019 g) and T3P (1.7 mol / L in ethyl acetate) (0.110 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-70 / 30) to give the title compound (0.034 g).

[0151] Example 8 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-fluoro-5-(trifluoromethoxy)benzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), TEA (0.025 g), 2-fluoro-5-(trifluoromethoxy)benzaldehyde (0.052 g), sodium triacetoxyborohydride (0.106 g), and MeCN (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.071 g), N-carbamoylglycine (0.034 g), T3P (1.7 mol / L in ethyl acetate) (0.195 mL), and MeCN (2 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 70 / 30) to give the title compound (0.031 g).

[0152] Example 9 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-5-(trifluoromethoxy)benzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.081 g), and MeCN (1 mL) was stirred at room temperature for 10 minutes. 3-Chloro-5-(trifluoromethoxy)benzyl bromide (0.073 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. N-carbamoylglycine (0.039 g) and T3P (1.7 mol / L in ethyl acetate) (0.221 mL) were added sequentially to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-70 / 30) to give the title compound (0.034 g).

[0153] Example 10 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.075 g), TEA (0.070 g), and DMF (2 mL) was added Reference Example 1 (0.160 g) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours. N-carbamoylglycine (0.111 g), TEA (0.190 g), and T3P (1.6 mol / L in DMF) (0.510 mL) were added to the reaction mixture at 50 °C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into water. The mixture was extracted twice with diethyl ether. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (eluent: ethyl acetate / methanol=100 / 0-80 / 20) and silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-80 / 20) to give the title compound (0.097 g).

[0154] Example 11 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2,6-difluoro-3-(trifluoromethyl)benzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), TEA (0.025 g), 2,6-difluoro-3-(trifluoromethyl)benzaldehyde (0.053 g), sodium triacetoxyborohydride (0.106 g), and MeCN (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.081 g), N-carbamoylglycine (0.039 g), T3P (1.7 mol / L in ethyl acetate) (0.221 mL), and MeCN (2 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-70 / 30) to give the title compound (0.030 g).

[0155] Example 12 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(pentafluorosulfanyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g) and MeCN (0.8 mL) was added DIPEA (0.081 g) at room temperature. To the reaction mixture was added a mixture of 3-(pentafluorosulfanyl)benzyl bromide (0.082 g) and MeCN (0.2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added N-carbamoylglycine (0.039 g) and T3P (1.7 mol / L in ethyl acetate) (0.192 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous sodium bicarbonate 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 amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.031 g).

[0156] Example 13 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-5-(difluoromethyl)benzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.081 g), and MeCN (1 mL) was stirred at room temperature for 10 minutes. Reference Example 3 (0.153 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. N-carbamoylglycine (0.039 g) and T3P (1.7 mol / L in ethyl acetate) (0.221 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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 give the title compound (0.012 g).

[0157] Example 14 N-(bicyclo[1.1.1]pentan-1-yl)-N-(5-(difluoromethyl)-2-fluorobenzyl)-2-ureidoacetamide To a mixture of 5-(difluoromethyl)-2-fluorobenzonitrile (0.420 g) and toluene (10 mL), DIBAL-H (1 mol / L in n-hexane) (6.14 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1.5 hours. 2 mol / L hydrochloric acid was added to the reaction mixture under ice-cooling to adjust the pH to approximately 5. The mixture was stirred under ice-cooling for 5 minutes and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, bicyclo[1.1.1]pentan-1-amine hydrochloride (0.060 g), TEA (0.051 g), sodium triacetoxyborohydride (0.213 g), and MeCN (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.162 g), N-carbamoylglycine (0.077 g), T3P (1.7 mol / L in ethyl acetate) (0.443 mL), and MeCN (2 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 80 / 20), amino silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 90 / 10), and silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 90 / 10) to give the title compound (0.019 g).

[0158] Example 15 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-5-(difluoromethoxy)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.080 g), TEA (0.092 g), and methanol (3 mL) was added 3-chloro-5-(difluoromethoxy)benzaldehyde (0.126 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Sodium borohydride (0.036 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was 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 and MeCN (3 mL), N-carbamoylglycine (0.108 g), DIPEA (0.157 g), and T3P (1.7 mol / L in ethyl acetate) (0.465 mL) were added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was allowed to cool to room temperature and partitioned with saturated aqueous ammonium chloride and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.095 g).

[0159] Example 16 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3,5-dichloro-2-fluorobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), TEA (0.030 g), Reference Example 4 (0.048 g), and methanol (1 mL) was stirred at room temperature for 1 hour. Sodium borohydride (0.010 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. Sodium borohydride (0.047 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was 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, N-carbamoylglycine (0.030 g), T3P (1.7 mol / L in ethyl acetate) (0.221 mL), and MeCN (1 mL) was added DIPEA (0.065 g) at room temperature. The reaction mixture was stirred at 40 °C for 1 hour and then allowed to cool to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.038 g).

[0160] Example 17 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2,3-difluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.050 g), TEA (0.051 g), sodium triacetoxyborohydride (0.177 g), and MeCN (2 mL) was added Reference Example 5 (0.268 g) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes and then at 50 °C for 30 minutes. To the reaction mixture was added sodium triacetoxyborohydride (0.089 g) at 50 °C. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added sodium triacetoxyborohydride (0.089 g) at 50 °C. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added sodium triacetoxyborohydride (0.177 g) at 50 °C. The reaction mixture was stirred at the same temperature for 10 minutes. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. To a mixture of the residue, DIPEA (0.135 g), N-carbamoylglycine (0.064 g), and MeCN (2 mL) was added T3P (1.7 mol / L in ethyl acetate) (0.369 mL) at room temperature. The reaction mixture was stirred at 50 °C for 30 minutes and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.056 g).

[0161] Example 18 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-5-(difluoromethyl)-2-fluorobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.080 g), TEA (0.068 g), sodium triacetoxyborohydride (0.284 g), Reference Example 7 (0.140 g), and MeCN (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.216 g), N-carbamoylglycine (0.103 g), T3P (1.7 mol / L in ethyl acetate) (0.590 mL), and MeCN (2 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 80 / 20), amino silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 90 / 10), and silica gel column chromatography (eluent: ethyl acetate / methanol = 95 / 5) to give the title compound (0.014 g).

[0162] Example 19 N-(bicyclo[1.1.1]pentan-1-yl)-N-(5-(1,1-difluoroethyl)-2-fluorobenzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.060 g), TEA (0.061 g), sodium triacetoxyborohydride (0.213 g), and MeCN (3 mL) was added Reference Example 11 (0.100 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Sodium triacetoxyborohydride (0.213 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 30 minutes and then allowed to cool to room temperature. A saturated aqueous solution of sodium bicarbonate was 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, DIPEA (0.162 g), N-carbamoylglycine (0.077 g), and MeCN (3 mL), T3P (1.7 mol / L in ethyl acetate) (0.443 mL) was added at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.085 g).

[0163] Example 20 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-2-ureidoacetamide To a mixture of Reference Example 13 (0.016 g), DIPEA (0.010 g), N-carbamoylglycine (0.008 g), and MeCN (1 mL) was added T3P (1.7 mol / L in ethyl acetate) (0.046 mL) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 98 / 2 to 70 / 30) to give the title compound (0.016 g).

[0164] Example 21 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2,4-difluoro-5-(trifluoromethyl)benzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), TEA (0.030 g), 2,4-difluoro-5-(trifluoromethyl)benzaldehyde (0.053 g), and methanol (1 mL) was stirred at room temperature for 15 minutes. Sodium borohydride (0.010 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was 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, DIPEA (0.049 g), N-carbamoylglycine (0.039 g), and MeCN (1 mL) was added T3P (1.7 mol / L in ethyl acetate) (0.221 mL) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-70 / 30) to give the title compound (0.038 g).

[0165] Example 22 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-5-(difluoromethoxy)-2-fluorobenzyl)-2-ureidoacetamide To a mixture of Reference Example 17 (0.025 g) and DCM (1 mL), Dess-Martin periodinane (0.071 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, bicyclo[1.1.1]pentan-1-amine hydrochloride (0.020 g), TEA (0.022 g), sodium triacetoxyborohydride (0.094 g), and MeCN (2 mL) was stirred at 50 °C for 1 hour. Sodium triacetoxyborohydride (0.047 g) was added to the reaction mixture at 50 °C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.043 g), N-carbamoylglycine (0.020 g), T3P (1.7 mol / L in ethyl acetate) (0.090 mL), and MeCN (2 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 90 / 10) to give the title compound (0.008 g).

[0166] Example 23 N-(bicyclo[1.1.1]pentan-1-yl)-N-(5-(difluoromethoxy)-2-fluorobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.070 g), 5-(difluoromethoxy)-2-fluorobenzaldehyde (0.111 g), TEA (0.118 g), sodium triacetoxyborohydride (0.248 g), and MeCN (2 mL) was stirred at 50 °C for 1 hour. Sodium triacetoxyborohydride (0.248 g) was added to the reaction mixture at 50 °C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, DIPEA (0.227 g), N-carbamoylglycine (0.104 g), T3P (1.7 mol / L in ethyl acetate) (0.476 mL), and MeCN (2 mL) was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-80 / 20) to give the title compound (0.093 g).

[0167] Example 24 N-(bicyclo[1.1.1]pentan-1-yl)-N-phenethyl-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.040 g), TEA (0.102 g), and MeCN (2 mL) was added (2-bromoethyl)benzene (0.074 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. N-Carbamoylglycine (0.051 g) and T3P (1.7 mol / L in ethyl acetate) (0.256 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.008 g).

[0168] Example 25 N-Benzyl-N-(bicyclo[1.1.1]pentan-1-yl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.081 g), and MeCN (1 mL) was stirred at room temperature for 10 minutes. Benzyl bromide (0.041 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. N-carbamoylglycine (0.039 g) was added to the reaction mixture at room temperature. T3P (1.7 mol / L in ethyl acetate) (0.221 mL) was added to the reaction mixture at 50 °C. The reaction mixture was stirred at the same temperature for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.024 g).

[0169] Example 26 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-bromobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.040 g), TEA (0.041 g), 3-bromobenzaldehyde (0.124 g), and methanol (1 mL) was stirred at room temperature for 1 hour. Sodium borohydride (0.013 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was 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, N-carbamoylglycine (0.039 g), T3P (1.7 mol / L in ethyl acetate) (0.295 mL), and MeCN (1 mL) was added DIPEA (0.086 g) at room temperature. The reaction mixture was stirred at 40 °C for 1 hour and then allowed to cool to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.100 g).

[0170] Example 27 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-iodobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.060 g), DIPEA (0.130 g), 3-iodobenzyl bromide (0.149 g), and MeCN (1 mL) was stirred at room temperature for 1.5 hours. N-carbamoylglycine (0.059 g), T3P (1.7 mol / L in ethyl acetate) (0.443 mL), and DIPEA (0.130 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.078 g).

[0171] Example 28 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-chloro-2-fluorobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.081 g), and MeCN (1 mL) was stirred at room temperature for 10 minutes. 3-Chloro-2-fluorobenzyl bromide (0.056 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. N-carbamoylglycine (0.039 g) and T3P (1.6 mol / L in DMF) (0.235 mL) were added sequentially to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol=98 / 2-70 / 30) and amino silica gel column chromatography (eluent: ethyl acetate / methanol=98 / 2-70 / 30) to give the title compound (0.014 g).

[0172] Example 29 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-cyanobenzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.065 g), 3-cyanobenzyl bromide (0.049 g), and MeCN (0.5 mL) was stirred at 40 °C for 2 hours. N-carbamoylglycine (0.030 g), T3P (1.7 mol / L in ethyl acetate) (0.221 mL), and DIPEA (0.065 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.031 g).

[0173] Example 30 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-propylbenzyl)-2-ureidoacetamide To a mixture of Example 27 (0.030 g), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.015 g), 2 mol / L aqueous sodium carbonate (0.075 mL), and 1,4-dioxane (1 mL) was added Pd(PPh3)4 (0.009 g) at room temperature. The reaction mixture was stirred at 100 °C for 2 hours and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to obtain the coupling product. A mixture of the resulting coupling product, 10% Pd / C (0.004 g), and methanol (1 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using Method A (eluent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.011 g).

[0174] Example 31 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(benzyloxy)benzyl)-2-ureidoacetamide A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.081 g), and MeCN (1 mL) was stirred at room temperature for 10 minutes. Reference Example 33 (0.073 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Sodium iodide (0.038 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. N-carbamoylglycine (0.039 g) and T3P (1.6 mol / L in DMF) (0.235 mL) were added sequentially to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol=98 / 2-70 / 30) to obtain the title compound (0.016 g).

[0175] Example 32 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-hydroxybenzyl)-2-ureidoacetamide A mixture of Example 31 (0.015 g), 10% Pd / C (0.015 g), and THF (1 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 70 / 30) and amino silica gel column chromatography (eluent: ethyl acetate / methanol = 95 / 5 to 70 / 30) to give the title compound (0.003 g).

[0176] Example 33 3-((N-(bicyclo[1.1.1]pentan-1-yl)-2-ureidoacetamido)methyl)benzoic acid methyl ester A mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.030 g), DIPEA (0.065 g), methyl 3-(bromomethyl)benzoate (0.057 g), and MeCN (0.5 mL) was stirred at 40 °C for 1.5 hours. N-carbamoylglycine (0.030 g), T3P (1.7 mol / L in ethyl acetate) (0.221 mL), and DIPEA (0.065 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 40 °C for 1 hour and then allowed to cool to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.040 g).

[0177] Example 34 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-cyclopropylbenzyl)-2-ureidoacetamide Palladium(II) acetate (0.001 g) was added to a mixture of Example 27 (0.020 g), cyclopropylboronic acid (0.013 g), tricyclohexylphosphine (0.6 mol / L in toluene) (0.017 mL), tripotassium phosphate (0.037 g), water (0.032 mL), and toluene (1 mL) at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under an argon atmosphere and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by Method A (eluent: ethyl acetate / methanol = 98 / 2 to 85 / 15) and amino silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 85 / 15) to give the title compound (0.004 g).

[0178] Example 35 was synthesized in the same manner as in Example 27, except that 3-(bromomethyl)-1,1′-biphenyl was used instead of 3-iodobenzyl bromide.

[0179] Example 36 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(pyridin-4-yl)benzyl)-2-ureidoacetamide A mixture of Example 27 (0.036 g), pyridin-4-ylboronic acid (0.013 g), Pd(PPh3)4 (0.022 g), sodium carbonate (0.020 g), water (0.25 mL), ethanol (0.5 mL), and toluene (1 mL) was stirred at 100 °C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.021 g).

[0180] Example 37 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(thiophen-3-yl)benzyl)-2-ureidoacetamide A mixture of Example 27 (0.022 g), thiophen-3-ylboronic acid (0.009 g), Pd(PPh3)4 (0.013 g), sodium carbonate (0.013 g), water (0.1 mL), and 1,4-dioxane (1 mL) was stirred at 100 °C for 1 hour under microwave irradiation. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.010 g).

[0181] Example 38 was synthesized in the same manner as in Example 9, except that 4-methyl-3-(trifluoromethyl)benzyl bromide was used instead of 3-chloro-5-(trifluoromethoxy)benzyl bromide.

[0182] Example 39 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-methoxy-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.033 g), DIPEA (0.106 g), and MeCN (1.4 mL) was added 2-methoxy-5-(trifluoromethyl)benzyl bromide (0.075 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. N-carbamoylglycine (0.048 g), T3P (1.7 mol / L in ethyl acetate) (0.209 mL), and DIPEA (0.071 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 40 °C for 3 hours. The reaction mixture was allowed to cool to room temperature and partitioned with saturated aqueous ammonium chloride and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.029 g).

[0183] Example 40 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(difluoromethoxy)-5-(trifluoromethyl)benzyl)-2-ureidoacetamide To a mixture of Reference Example 18 (0.067 g), TEA (0.079 g), N-carbamoylglycine (0.030 g), and MeCN (1 mL) was added T3P (1.7 mol / L in ethyl acetate) (0.229 mL) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour and then allowed to cool to room temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.051 g).

[0184] Example 41 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(2-cyanopropan-2-yl)benzyl)-2-ureidoacetamide Under an argon atmosphere, Pd(amphos)2Cl2 (0.009 g) was added to a mixture of Example 26 (0.090 g), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.052 g), 2 mol / L aqueous sodium carbonate (0.256 mL), and DME (1 mL) at room temperature. The reaction mixture was refluxed for 7 hours and then allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to obtain the coupling product. Under an argon atmosphere, p-toluenesulfonyl cyanide (0.139 g), phenylsilane (0.036 g), and 1,1,2,2-tetramethyl-1,2-ethanediamino-N,N'-bis(3,5-di-tert-butylsalicylidene)-cobalt(II) (0.005 g) were added to a mixture of the resulting coupling product and ethanol (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 14 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by Method A (eluent: ethyl acetate / methanol = 98 / 2 to 85 / 15) and amino silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 88 / 12) to give the title compound (0.010 g).

[0185] Example 42 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(2-hydroxypropan-2-yl)benzyl)-2-ureidoacetamide To a mixture of Example 33 (0.040 g) and THF (1 mL), methylmagnesium bromide (3 mol / L in diethyl ether) (0.121 mL) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for 2 hours. Saturated aqueous ammonium chloride 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 sequentially by Method A (eluent: ethyl acetate / methanol = 98 / 2 to 80 / 20) and amino silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 85 / 15) to give the title compound (0.013 g).

[0186] Example 43 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(methoxymethyl)benzyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.033 g), TEA (0.038 g), and methanol (1 mL) was added 3-(methoxymethyl)benzaldehyde (0.038 g) at room temperature. The reaction mixture was stirred at the same temperature overnight. Sodium borohydride (0.015 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was 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 and MeCN (1 mL), N-carbamoylglycine (0.046 g), T3P (1.7 mol / L in ethyl acetate) (0.193 mL), and DIPEA (0.065 g) were added at room temperature. The reaction mixture was stirred at 40 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and partitioned with saturated aqueous ammonium chloride and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.036 g).

[0187] Example 44 N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-((trifluoromethoxy)methyl)benzyl)-2-ureidoacetamide A solution of Reference Example 19 (0.065 g) in methanol (0.5 mL) was added to a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.036 g), TEA (0.036 g), and methanol (0.5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. Sodium borohydride (0.020 g) was added to the reaction mixture in three portions under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into 1 mol / L aqueous sodium hydroxide solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a mixture of the residue and MeCN (1.5 mL), DIPEA (0.113 g) and N-carbamoylglycine (0.052 g) were added sequentially at room temperature. The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture, T3P (1.7 mol / L in ethyl acetate) (0.344 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 92 / 8) to give the title compound (0.082 g).

[0188] Example 45 N-(bicyclo[1.1.1]pentan-1-yl)-N-(naphthalen-1-ylmethyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.025 g), DIPEA (0.068 g), and MeCN (0.5 mL) was added 1-(chloromethyl)naphthalene (0.037 g) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. N-carbamoylglycine (0.037 g), T3P (1.7 mol / L in ethyl acetate) (0.160 mL), and DIPEA (0.054 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then at 50 °C for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 80 / 20) and silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-80 / 20) to obtain the title compound (0.009 g).

[0189] Example 46 N-(bicyclo[1.1.1]pentan-1-yl)-N-((2-(trifluoromethyl)pyridin-4-yl)methyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.025 g) and MeCN (1 mL) was added TEA (0.053 g) at room temperature. To the reaction mixture was added a mixture of Reference Example 34 (0.053 g) and MeCN (0.2 mL) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added N-carbamoylglycine (0.032 g) and T3P (1.7 mol / L in ethyl acetate) (0.184 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water and saturated aqueous sodium bicarbonate 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 amino silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 80 / 20) to give the title compound (0.023 g).

[0190] Example 47 N-(bicyclo[1.1.1]pentan-1-yl)-N-((4-(trifluoromethyl)thiophen-2-yl)methyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.055 g), DIPEA (0.149 g), and MeCN (1 mL) was added 2-(chloromethyl)-4-(trifluoromethyl)thiophene (0.092 g) at room temperature. The reaction mixture was stirred at 50 °C for 2 hours. N-carbamoylglycine (0.081 g), T3P (1.7 mol / L in ethyl acetate) (0.352 mL), and DIPEA (0.119 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 50 °C for 2.5 hours. The reaction mixture was allowed to cool to room temperature and poured into 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.024 g).

[0191] Example 48 N-(bicyclo[1.1.1]pentan-1-yl)-N-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-2-ureidoacetamide To a mixture of bicyclo[1.1.1]pentan-1-amine hydrochloride (0.025 g), DIPEA (0.068 g), and MeCN (0.5 mL) was added 4-(bromomethyl)-2,2-difluorobenzo[d][1,3]dioxole (0.052 g) at room temperature. The reaction mixture was stirred at 50 °C for 1 hour. N-carbamoylglycine (0.037 g), T3P (1.7 mol / L in ethyl acetate) (0.160 mL), and DIPEA (0.054 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into 1 mol / L hydrochloric acid, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=30 / 70 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.022 g).

[0192] Example 49 N-(bicyclo[1.1.1]pentan-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-2-ureidoacetamide To a mixture of Reference Example 21 (0.061 g) and ethanol (1.4 mL), hydrazine monohydrate (0.035 g) was added at room temperature. The reaction mixture was stirred at 70° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. To a mixture of the residue and THF (1.4 mL), trimethylsilyl isocyanate (0.080 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.041 g).

[0193] Example 50 was synthesized in the same manner as in Example 49, except that Reference Example 23 was used instead of Reference Example 21.

[0194] Example 51 was synthesized in the same manner as in Reference Example 28, except that ((benzyloxy)carbonyl)glycine was used instead of 2-(benzyloxy)acetic acid.

[0195] Example 52 Methyl (2-(bicyclo[1.1.1]pentan-1-yl(3-(trifluoromethyl)benzyl)amino)-2-oxoethyl)carbamate To a mixture of Reference Example 25 (0.025 g), DIPEA (0.028 g), and THF (1 mL) was added methyl chloroformate (0.010 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added methyl chloroformate (0.004 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1.5 hours. The reaction mixture was poured into water, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 93 / 7) to give the title compound (0.027 g).

[0196] Example 53 tert-Butyl (2-(bicyclo[1.1.1]pentan-1-yl(3-(trifluoromethyl)benzyl)amino)-2-oxoethyl)carbamate To a mixture of Reference Example 26 (0.364 g), N-(tert-butoxycarbonyl)glycine (0.276 g), EDC-HCl (0.400 g), HOBt hydrate (0.261 g), and DMF (5 mL) was added TEA (0.332 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0-65 / 35) to give the title compound (0.553 g).

[0197] Example 54 N-(bicyclo[1.1.1]pentan-1-yl)-2-(3-methylureido)-N-(3-(trifluoromethyl)benzyl)acetamide To a mixture of Reference Example 25 (0.031 g), DIPEA (0.047 g), and THF (1 mL) was added triphosgene (0.012 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. Methylamine hydrochloride (0.010 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, 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 / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.008 g).

[0198] Example 55 was synthesized in the same manner as in Example 54, except that dimethylamine hydrochloride was used instead of methylamine hydrochloride.

[0199] Example 56 N-(bicyclo[1.1.1]pentan-1-yl)-2-(3-(2-hydroxyethyl)ureido)-N-(3-(trifluoromethyl)benzyl)acetamide To a mixture of Reference Example 25 (0.025 g), DIPEA (0.027 g), and THF (1 mL) was added triphosgene (0.010 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 20 minutes. 2-(benzyloxy)ethan-1-amine hydrochloride (0.016 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then at 50°C for 1.5 hours. DIPEA (0.011 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 50°C for 2 hours and then at 60°C for 1 hour. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 90 / 10) and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the urea compound. Under an argon atmosphere, 10% Pd / C (0.003 g) was added to a mixture of the obtained urea compound and ethanol (1 mL) at room temperature. The reaction mixture was stirred at 45 °C under a hydrogen atmosphere for 45 minutes. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.005 g).

[0200] Example 57 2-Acetamido-N-(bicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)acetamide To a mixture of Reference Example 25 (0.025 g), TEA (0.013 g), and DCM (0.5 mL) was added acetyl chloride (0.008 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.026 g).

[0201] Example 58 (E)-N-(bicyclo[1.1.1]pentan-1-yl)-2-(2-cyanoguanidino)-N-(3-(trifluoromethyl)benzyl)acetamide To a mixture of Reference Example 27 (0.040 g), TEA (0.031 g), and DCM (1 mL) was added N-cyanocarbonimidate diphenyl (0.025 g) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours and then concentrated under reduced pressure. To a mixture of the residue and MeCN (1 mL), 15 mol / L aqueous ammonia (0.204 mL) was added at room temperature. The reaction mixture was stirred at 50 °C for 2 hours and then at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 95 / 5) to give the title compound (0.015 g).

[0202] Example 59 Carbamic acid 2-(bicyclo[1.1.1]pentan-1-yl(3-(trifluoromethyl)benzyl)amino)-2-oxoethyl ester To a mixture of Reference Example 29 (0.035 g), TEA (0.018 g), DMAP (0.003 g), and DCM (1 mL) was added 4-nitrophenyl chloroformate (0.028 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. 15 mol / L aqueous ammonia (0.684 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 19 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed with 2 mol / L aqueous potassium carbonate and then concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.023 g).

[0203] Example 60 N 1 -(bicyclo[1.1.1]pentan-1-yl)-N 1 -(3-(trifluoromethyl)benzyl)fumaramide To a mixture of Reference Example 30 (0.038 g), methanol (0.5 mL), and THF (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.077 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours. Water and 1 mol / L hydrochloric acid (0.5 mL) 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, 15 mol / L aqueous ammonia (0.021 mL), and MeCN (1 mL) was added DMT-MM (0.043 g) at room temperature. The reaction mixture was stirred at the same temperature for 45 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) and silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 90 / 10) to give the title compound (0.020 g).

[0204] Example 61 N 1 -(bicyclo[1.1.1]pentan-1-yl)-N 1 -(3-(trifluoromethyl)benzyl)succinamide Under an argon atmosphere, 10% Pd / C (0.009 g) was added to a mixture of Example 60 (0.019 g) and methanol (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours and then at 50 °C for 2 hours under a hydrogen atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 75 / 25) to give the title compound (0.010 g).

[0205] Example 62 (R)-N 1 -(bicyclo[1.1.1]pentan-1-yl)-3-hydroxy-N 1 -(3-(trifluoromethyl)benzyl)succinamide To a mixture of Reference Example 31 (0.020 g), methanol (0.265 mL), and THF (0.265 mL), 4 mol / L aqueous lithium hydroxide solution (0.040 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Water and 1 mol / L hydrochloric acid (0.5 mL) 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, 15 mol / L aqueous ammonia (0.021 mL), and MeCN (1 mL) was added DMT-MM (0.022 g) at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15), silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15), and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 85 / 15) to give the title compound (0.001 g).

[0206] Example 63 was synthesized in the same manner as in Example 60, except that Reference Example 32 was used instead of Reference Example 30.

[0207] Example 64 N-(bicyclo[1.1.1]pentan-1-yl)-N-(2-fluoro-5-(trifluoromethyl)benzyl)-2-(3-methoxyureido)acetamide To a mixture of Reference Example 36 (0.035 g) and THF (1.1 mL), 4-nitrophenyl chloroformate (0.024 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 40 minutes. O-Methylhydroxylamine hydrochloride (0.011 g) and DIPEA (0.043 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred overnight at the same temperature. The reaction mixture was partitioned with saturated aqueous sodium bicarbonate and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70 / 30 - 0 / 100) to give the title compound (0.030 g).

[0208] The structural formulas, physical properties, and TSHR antagonist activity (see Test Example 1) of the examples are shown in the table below.

[0209] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0210] Test Example 1 Measurement of antagonist activity using TSH-induced cAMP production in CHO cells stably expressing human TSHR

[0211] 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 the lipofection method to establish CHO cells stably expressing human TSHR. The resulting cells were plated at 5 x 10 in a 96-well poly-D-lysine-coated plate. 4Cells were seeded at 100 μL / well and cultured in F12 medium containing 10% FBS, 400 μg / mL G418, 50 U / mL penicillin, and 50 μg / mL streptomycin at 37°C and 5% CO2 for 1 day. After removing the medium, the cells were washed twice with 100 μL of assay buffer (Hanks' Balanced Salt Solution containing 20 mM HEPES and 1 mM IBMX) per well. 30 μL of assay buffer containing the test compound was added to the well and incubated at room temperature for 15 minutes. Next, 30 μL of assay buffer containing 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. According to the instructions for the cAMP Gs HiRange kit (Cisbio), cell lysates were reacted with d2-labeled cAMP and anti-cAMP Europium Cryptate labeled antibodies (Cisbio) in a 384-well white microplate. The fluorescence intensity ratio (measurement wavelength: 665 nm / 620 nm) was then measured using a multiplate reader (PHERAstar FSX, BMG LABTECH Japan). The fluorescence intensity ratio for each sample was converted to cAMP content using a standard curve. The cAMP content was converted as a percentage of the control value to calculate the cAMP production rate. The cAMP production rate was plotted against the test compound concentration using Prism (Graph Pad Software Inc.), and the IC 50 The IC values ​​were calculated for each test compound. 50 are shown in the table above. In the table, IC 50 <3.0 μM:A, 3.0 μM ≤ IC 50 <30 μM:B. The IC 50 If the value could not be calculated, it was expressed as C.

[0212] As shown in the above table, the compounds of the present invention were found to have human TSHR antagonist activity. [Industrial Applicability]

[0213] The compound of the present invention or a pharmacologically acceptable salt thereof has TSHR antagonist activity and is therefore useful as a therapeutic agent for thyroid-related diseases.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, V is -CR 4 R 4' - or a single bond; R 2 , R 2' , R 4 , and R 4' are each independently a hydrogen atom or C 1-6 is alkyl; Ring U is a group selected from the group consisting of the following (a) to (f): (a)C 6-10 aryl, (b) 5- or 6-membered heteroaryl, (c) 9- or 10-membered heteroaryl, (d)C 3-10 cycloalkyl, (e) 3- to 10-membered heterocycloalkyl, and (f) the following group: 【Chemistry 2】 Ring W is C 5-8 cycloalkyl, or 5- to 8-membered heterocycloalkyl; R 2 or R 4 is combined with the ring U to form C 5-8 may form a cycloalkyl, or a 5- to 8-membered heterocycloalkyl; n is an integer from 0 to 4; When n is an integer of 2 or more, each R 1 may be the same or different from each other; R 1 is a halogen atom, cyano, C 1-6 Alkyl, hydroxy, amino, -C(=O)OR 5 , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkyl C 1-6 Alkyl, C 3-10 Cycloalkyl C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkyl, C 6-10 Aryl C 2-6 Alkynyl, C 6-10 Aryloxy, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylC 1-6 Alkyl, 5- or 6-membered heteroaryl C 2-6 Alkynyl, C 3-10 Cycloalkyl C 2-6 Alkynyl, halohydroxy C 1-6 Alkyl, or -SF 5 and R 5 is C 1-6 is alkyl; R 3 is a group selected from the group consisting of the following (i) to (vii): 【Transformation 3】 and 【Chemistry 4】 R 6 , and R 6' are each independently a hydrogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl or hydroxy C 1-6 is alkyl; R 6 , and R 6' may be taken together to form a 3- to 10-membered heterocycloalkyl; R 7 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, or C 3-10 is cycloalkyl; R 8 is C 1-6 Alkyl, HaloC 1-6 Alkyl, C 3-10 Cycloalkyl, or C 6-10 Aryl C 1-6 is alkyl; R 9 , and R 9’ are each independently a hydrogen atom, C 1-6 alkyl, or hydroxy] or a pharmacologically acceptable salt thereof.

2. 2. The compound of claim 1 , Ring U is a group selected from the group consisting of the following (a) to (d): (a)C 6-10 aryl, (b) 5- or 6-membered heteroaryl, (c) 9- or 10-membered heteroaryl, and (d) a group: 【Transformation 5】 Ring U and R 2 The following groups are taken together: 【Transformation 6】 may form R 1 But halogen atoms, cyano, C 1-6 Alkyl, hydroxy, -C(=O)OR 5 , Haro C 1-6 Alkyl, Cyano C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl, or -SF 5 and R 6 , and R 6' are each independently a hydrogen atom, C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 is alkyl; R 7 But C 1-6 is alkyl; R 8 But C 1-6 Alkyl or C 6-10 Aryl C 1-6 is alkyl; R 9 , and R 9’ are each independently a hydrogen atom or hydroxy; R 2' , R 5 , V, and n have the same meanings as in claim 1, or a pharmacologically acceptable salt thereof.

3. 3. The compound of claim 2, V is a single bond; Ring U is C 6-10 Compounds which are aryl; or a pharmacologically acceptable salt thereof.

4. 4. The compound of claim 3, R 3 is a group selected from the group consisting of the following (i) to (iii): 【Transformation 7】 and 【Transformation 8】 R 6 , and R 6' has the same meaning as in claim 2; or a pharmacologically acceptable salt thereof.

5. Formula (II): 【Chemistry 9】 [During the ceremony, R 1a is a halogen atom, C 1-6 Alkyl, HaloC 1-6 Alkyl, Cyano C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, C 1-6 Alkoxy C 1-6 Alkyl, HaloC 1-6 Alkoxy C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl C 1-6 Alkoxy, 5- or 6-membered heteroaryl, or -SF 5 and n is an integer from 0 to 4; When n is an integer of 2 or more, each R 1a may be the same or different from each other; If n is an integer greater than or equal to 2, two R 1a Together, C 5-8 It may form a cycloalkyl or a 5- to 8-membered heterocycloalkyl. or a pharmacologically acceptable salt thereof.

6. 6. The compound of claim 5, R 1a But halogen atoms, haloC 1-6 Alkyl, HaloC 1-6 Alkoxy or -SF 5 and A compound in which n is an integer of 1 to 3, or a pharmacologically acceptable salt thereof.

7. A compound selected from the group consisting of the following compounds: 【Chemistry 10】 【Chemistry 11】 and 【Chemistry 12】 or a pharmacologically acceptable salt thereof.

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

9. The pharmaceutical composition according to claim 8, which is a pharmaceutical composition for treating a thyroid-related disease.

10. 10. The pharmaceutical composition according to claim 9, wherein the thyroid-related disease is hyperthyroidism, Graves' disease, or thyroid eye disease.

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