Biaryl compound

Abstract

The present invention addresses the problem of providing a novel compound that has thyroid-stimulating hormone receptor antagonist activity and is useful for treating thyroid-related diseases.　The present invention pertains to a biaryl compound represented by formula (I) or a pharmacologically acceptable salt thereof. The compound according to the present invention or the pharmacologically acceptable salt thereof has antagonist activity with respect to thyroid-stimulating hormone receptors, and is therefor useful as a therapeutic agent and the like for thyroid-related diseases (for example, hyperthyroidism, Graves disease, thyroid-associated ophthalmopathy, and thyroid cancer).

Description

Biaryl Compounds

[0001] The present invention relates to a biaryl compound useful as a pharmaceutical. More specifically, the present invention relates to a biaryl 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.

[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 be effective in treating Graves' disease and thyroid eye disease, which are caused by the agonistic action of TRAb on TSHR (Patent Documents 1 and 2). NCGC00242364 is a known TSHR antagonist, and has been shown to reduce T4 levels in mice treated with TSH-releasing hormone (TRH) and the thyroid-stimulating antibody M22 (Non-Patent Document 1).

[0008] Compounds having TSHR antagonist activity are described in Patent Documents 1 to 3 and Non-Patent Document 1. Biaryl-containing compounds are described or exemplified in Patent Documents 4 and 5. However, the biaryl compound of the present invention is not described in any of Patent Documents 1 to 5 or Non-Patent Document 1.

[0009] US Patent Application Publication No. 2011 / 0172267 US Patent Application Publication No. 2012 / 0315217 US Patent Application Publication No. 2019 / 0134024 US Patent Application Publication No. 2014 / 0193906 International Publication No. 2010 / 036316

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

[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.

[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): [Wherein, ring Z is C 6-10 Aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 3- to 8-membered heterocycloalkyl; V 1 is =CR v1 - or =N-; V 2 is =CR v2 - or =N-; V 3 is =CR v3 - or =N-; R v1 , R v2 and R v3 are each independently a hydrogen atom, C 1-6 Alkyl or hydroxy C 1-6 alkyl; X is -CR x R x' -, -O-, or -C(=O)-; R x and R x' are each independently a hydrogen atom or C 1-6 alkyl; m and n are each independently an integer from 0 to 2; R A is a halogen atom, a cyano group, a hydroxyl group, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy or C 1-6 alkylsulfonyl; when n is 2, each R A may be the same or different; R B is a halogen atom or C 1-6 alkyl; when m is 2, each R B may be the same or different; R C is -NHC(O)OR c1 , -NHC(O)R c2 , -NHC(O)NR c2 R c2' , or -NHC(O)NR c2 (ORc2' ) and R c1 is a group selected from the group consisting of the following (a) to (g): (a) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 (b) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 (c) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 (d) unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 Aryl C 1-6 (e) a 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A; (f) a 3- to 8-membered heterocycloalkyl C that is unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 1-6 alkyl, and (g) a 5- or 6-membered heteroaryl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 1-6 Alkyl; Substituent group A is a halogen atom, a cyano group, a hydroxyl group, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 cycloalkyl; when substituted with two or more groups selected from the substituent group A, each group may be the same or different; R c2 and R c2' are each independently a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom, (b) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 (c) unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 (d) unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl C 1-6(e) 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and (f) the following groups which are unsubstituted or substituted with 1 to 3 groups selected from the substituent group B: Substituent group B is a halogen atom, a cyano group, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, and C 3-8 cycloalkyl; when substituted with two or three groups selected from the substituent group B, each group may be the same or different; R D is a group selected from the group consisting of the following (a) to (e): 1-6 Alkyl, (b) Hydroxy C 1-6 Alkyl, and R d and R d' are each independently a hydrogen atom or C 1-6 [2] The compound according to [1] above, wherein: V is an alkyl group; or a pharmacologically acceptable salt thereof. 2 But, =CR v2 - and R v1 , R v2 and R v3 are each independently a hydrogen atom or C 1-6 alkyl; R A However, halogen atoms, cyano groups, hydroxyl groups, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy or C 1-6 alkylsulfonyl; R c1 is a group selected from the group consisting of the following (a) to (f): (a) C unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 1-6 (b) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 (c) unsubstituted or substituted with 1 to 6 groups selected from the substituent group A 3-8 Cycloalkyl C1-6 (d) unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 Aryl C 1-6 (e) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group A, and (f) 3- to 8-membered heterocycloalkyl C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 1-6 alkyl; the substituent group A has the same meaning as in [1] above; R c2 and R c2' are each independently a group selected from the group consisting of the following (a) to (e): (a) a hydrogen atom, (b) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 (c) unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 (d) 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, and (e) the following groups which are unsubstituted or substituted with 1 to 3 groups selected from the substituent group B: The substituent group B is a halogen atom and C 1-6 alkyl; R d and R d' is a hydrogen atom, or a pharmacologically acceptable salt thereof. [3] The compound according to [1] or [2] above, wherein: ring Z is C 6-10 aryl, or 5- or 6-membered heteroaryl; V 1 is ═CH— or ═N—; V 2 , and V 3 is ═CH—; R x and R x' is a hydrogen atom; m is 1; R B is a halogen atom; R C But -NHC(O)OR c1 and R c1 is a group selected from the group consisting of the following (a) to (e): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 1-6(b) unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 3-8 (c) unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 3-8 Cycloalkyl C 1-6 (d) unsubstituted or substituted with 1 to 3 groups selected from the substituent group A 6-10 Aryl C 1-6 alkyl, and (e) a 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from Substituent Group A; Substituent Group A has the same meaning as in [1] above; R D is a group represented by the following (a) or (b): or or a pharmacologically acceptable salt thereof. [4] The compound according to any one of [1] to [3] above, which is represented by formula (II): [In the formula, V 1a is =CH- or =N-; W is -CH2- or -NH-; X a is -CH2-, -O-, or -C(=O)-; Y is ═CR a2 - or =N-; R a1 and R a2 are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy or C 1-6 alkylsulfonyl; R c1a is a group selected from the group consisting of the following (a) to (e): (a) unsubstituted or substituted group A a C substituted with 1 to 3 groups selected from 1-6 (b) unsubstituted or substituted group A a C substituted with 1 to 3 groups selected from 3-8 cycloalkyl, (c) unsubstituted or substituted group A a C substituted with 1 to 3 groups selected from 3-8 Cycloalkyl C 1-6alkyl, (d) unsubstituted or substituted group A a C substituted with 1 to 3 groups selected from 6-10 Aryl C 1-6 alkyl, and (e) unsubstituted or substituted group A a 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from: Substituent Group A a is a halogen atom, a cyano group, a hydroxyl group, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 Substituent Group A is a group consisting of cycloalkyl; a [5] A compound represented by the formula (III): or a pharmacologically acceptable salt thereof. [In the formula, V 1b is ═CH— or ═N—; W b is -CH2- or -NH-; X b is -CH2- or -O-; R a1b and R a2b are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, or C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy or C 1-6 alkylsulfonyl; R c1b is a group selected from the group consisting of the following (a) to (e): (a) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from 1-6 (b) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from 3-8 cycloalkyl, (c) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from3-8 Cycloalkyl C 1-6 alkyl, (d) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from 6-10 Aryl C 1-6 alkyl, and (e) unsubstituted or substituted group A b 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from: Substituent Group A b is a halogen atom, a cyano group, a hydroxyl group, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkoxy, and C 3-8 Substituent Group A is a group consisting of cycloalkyl; b [6] A compound represented by the formula (I) or a pharmacologically acceptable salt thereof, wherein R a1b and R a2b are each independently a hydrogen atom, a halogen atom, or a cyano group; R ｃ1b is a group selected from the group consisting of the following (a) to (c): (a) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from 1-6 (b) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from 3-8 cycloalkyl, and (c) unsubstituted or substituted group A b C substituted with 1 to 3 groups selected from 3-8 Cycloalkyl C 1-6 Alkyl; Substituent Group A b However, halogen atoms, cyano groups, C 1-6 Alkyl or haloC 1-6 [7] The compound according to any one of [1] to [6] above, wherein the compound is selected from the group consisting of the following compounds: and 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 ophthalmopathy.

[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.

[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.

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

[0020] "Haro C 1-6 "Alkyl" means a C alkyl group substituted with 1 to 5 halogen atoms of the same or different types. 1-6Examples of the hydroxy group include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and pentafluoroethyl. 1-6 "Alkyl" refers to a C alkyl group substituted with one or two hydroxyl groups. 1-6 "HaloC" refers to alkyl. Examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, etc. 1-6 "Alkoxy" means a C substituted with 1 to 5 identical or different halogen atoms. 1-6 "C" means alkoxy. Examples thereof include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, etc. 1-6 "Alkylsulfonyl" means (C 1-6 It means a group represented by the formula (alkyl)-SO2-. Examples include methylsulfonyl and ethylsulfonyl.

[0021] "C 6-10 "Aryl" means a phenyl group or a naphthyl group. "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atoms, nitrogen atoms, 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. "C 3-8 "Cycloalkyl" means a saturated hydrocarbon group having 3 to 8 ring members, including those having a partially bridged structure. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, etc. "3 to 8-membered heterocycloalkyl" means a C 1 -C 2 -C 3 -C 8 -C ...3-8 It refers to a cycloalkyl group, including those with a partially bridged structure. Examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, azabicyclo[2.2.2]octyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[2.2.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, pyrrolidonyl, piperidonyl, oxiranyl, oxetyl, tetrahydrofuranyl, and tetrahydropyranyl. Preferable examples include 1-pyrrolidinyl, 1-piperidinyl, and 4-morpholinyl.

[0022] "C 6-10 Aryl C 1-6 "Alkoxy" means one C 6-10 Aryl-substituted C 1-6 It means alkoxy, for example, benzyloxy.

[0023] "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 "5- or 6-membered heteroaryl C" means an alkyl group. For example, benzyl is mentioned. 1-6 "Alkyl" refers to a C alkyl substituted with one 5- or 6-membered heteroaryl. 1-6 Examples include 2-pyridylmethyl, 3-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, and 2-thiazolylmethyl. 3-8 Cycloalkyl C 1-6 "Alkyl" means one C 3-8 Cycloalkyl-substituted C 1-6 Examples include cyclopropylmethyl, cyclopropylethan-1-yl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. "3- to 8-membered heterocycloalkyl C 1-6"Alkyl" refers to a C substituted with one 3- to 8-membered heterocycloalkyl. 1-6 It means alkyl, for example, tetrahydrofuranylmethyl.

[0024] When a group containing an acyclic structure and a cyclic structure is substituted with a group selected from Substituent Group A, one or both of the acyclic structure and the cyclic structure may be substituted. For example, C substituted with 1 to 3 groups selected from Substituent Group A 3-8 Cycloalkyl C 1-6 Examples of alkyl include (1-cyanocyclopropyl)methyl, (1-methylcyclopropyl)methyl, (2-fluorocyclopropyl)methyl, (2,2-difluorocyclopropyl)methyl, (1-(fluoromethyl)cyclopropyl)methyl, (1-(difluoromethyl)cyclopropyl)methyl, (2,2-difluoro-1-methylcyclopropyl)methyl, (2,2-difluorocyclobutyl)methyl, (3,3-difluorocyclobutyl)methyl, 1-cyclopropyl-2,2,2-trifluoroethan-1-yl, and the like.

[0025] The following abbreviations used in the text, figures, and tables have the following meanings: Boc2O: di-tert-butyl dicarbonate CDI: 1,1'-carbonyldiimidazole DCE: 1,2-dichloroethane DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EDC-HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et2O: diethyl ether HOBt: 1-hydroxybenzotriazole HOBt hydrate: HOBt monohydrate KHMDS: potassium bis(trimethylsilyl)amide LiHMDS: lithium bis(trimethylsilyl)amide MeCN: acetonitrile MTBE: methyl tert-butyl ether NaHMDS: sodium bis(trimethylsilyl)amide NBS: N-bromosuccinimide Pd(amphos)2Cl2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1); Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0); T3P®: propylphosphonic anhydride (cyclic trimer); TBAF: tetrabutylammonium fluoride; TEA: triethylamine; TEMPO: 2,2,6,6-tetramethylpiperidine 1-oxyl free radical; TFA: trifluoroacetic acid; THF: tetrahydrofuran; Xantphos: 4,5-bis(diphenylphosphino)-9,9-Dimethylxanthene 10% Pd / C: 10% palladium carbon (approximately 55% water-wet) Amino silica gel: Aminopropylated silica gel Diamine silica gel: CHROMATOREX Q-PACK DNH60 (Fuji Silysia Chemical) ODS: Octadecylsilylated silica gel Method A: Column chromatography using a silica gel column connected to the bottom of an aminopropylated silica gel column Method B: Column chromatography using an aminopropylated silica gel column connected to the bottom of a silica gel column Process: Process Scheme: Scheme Ref. No.: Reference example number Str.: Structural formula Ex. No.: Example number Phys. data: Physical property values ​​IC, 50 : 50% inhibitory concentration (The numbers with "*" in the table indicate the inhibition rate at a compound concentration of 30 μM.) 1 H-NMR: Proton nuclear magnetic resonance spectrum DMSO: Dimethyl sulfoxide 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

[0026] When one or more asymmetric carbon atoms are present in the compound of formula (I), the present invention encompasses compounds in which each asymmetric carbon atom is in the R configuration, compounds in the S configuration, and any combination thereof. Furthermore, their racemates, racemic mixtures, single enantiomers, and diastereomeric mixtures are also included within the scope of the present invention.

[0027] In the case where the compound represented by formula (I) has cis-trans isomers, the present invention includes both of the cis-trans isomers.

[0028] When tautomers exist in the compound represented by formula (I), the present invention includes all of the tautomers.

[0029] In the present invention, the determination of stereochemistry can also be carried out by methods well known in the art.

[0030] 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.

[0031] 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, TFA, 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.

[0032] 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.

[0033] 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.

[0034] When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, the present invention includes any crystalline form. For example, pharmacologically acceptable salts also include solvates with pharmaceutically acceptable solvents such as water or ethanol, co-crystals with a suitable co-crystal former, etc.

[0035] 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. 13C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O, and 35 In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are isotopes of the hydrogen atom, carbon atom, chlorine atom, fluorine atom, iodine atom, nitrogen atom, oxygen atom, and sulfur atom represented by S. 2 Examples include compounds in which hydrogen is replaced by H (D: deuterium atom).

[0036] A compound represented by formula (I) in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below, using commercially available building blocks containing isotopes. For example, a compound represented by formula (I) in which some hydrogen atoms are replaced with deuterium atoms can also be produced by the above-mentioned method and methods described in the literature (see, for example, Journal of Organic Synthetic Chemistry, Vol. 65, No. 12, pp. 1179-1190, 2007). In addition, for example, a compound represented by formula (I) in which some carbon atoms are replaced with 13 Compounds substituted at C can also be prepared using the above method and methods described in the literature (see, for example, RADIOISOTOPES, Vol. 56, No. 11, pp. 741-750, 2007).

[0037] The compound of the present invention represented by formula (I) can be produced, for example, by the methods shown in Schemes 1 to 12 or methods similar thereto, or by methods described in the literature or methods similar thereto. In the schemes, the compound of formula (I) corresponds to the compounds represented by compounds (Ia) to (In) and compound (I').

[0038] 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.

[0039] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used.

[0040] In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified.

[0041] 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.

[0042] In the reaction of each step, the pressure varies depending on the starting materials, solvent, reaction temperature, etc. used, but is usually 1 to 20 atmospheres unless otherwise specified.

[0043] A microwave reactor such as Biotage's Initiator may be used in the reactions of each step. When a microwave reactor is used, the conditions vary depending on the raw materials, solvent, and model used, but the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day.

[0044] 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: Et2O, 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, TFA, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; Water.

[0045] 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, cesium fluoride, 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, sodium tert-butoxide, potassium tert-butoxide, etc.; alkali metal hydrides: sodium hydride, etc.; metal amides: sodium amide, lithium diisopropylamide, LiHMDS, NaHMDS, KHMDS, etc.; organic magnesiums: isopropyl magnesium chloride, etc.; organic lithiums: n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0046] When an acid or acidic catalyst is used in the reaction of each step, the reaction is carried out using an acid or acidic catalyst suitable for the reaction. Specific examples of the acid or acidic catalyst used include the acid or acidic catalysts described in the Reference Examples and Examples corresponding to each step, as well as the following acid or acidic catalysts: inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; organic acids: acetic acid, TFA, citric acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: BF3-Et2O complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0047] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of the condensing agent used include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents: carbodiimides: 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.

[0048] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of the reducing agent to be used include the reducing agents described in the Reference Examples or Examples corresponding to each step, or the following reducing agents. Metal hydrides: lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: BH3-THF complex, picoline borane complex, decaborane, etc.

[0049] 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 used include the oxidizing agents described in the Reference Examples or Examples corresponding to each step, or 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.

[0050] 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, or the following carbonyl group-introducing reagents: phosgene, diphosgene, triphosgene, etc.; chloroformates: 4-nitrophenyl chloroformate, etc.; imidazoles: CDI, etc.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] When a metal reduction reaction is carried out in each step, the reaction can be carried out in the presence of a metal or the like. Examples of the metal or the like that can be used include iron powder, zinc powder, tin chloride, titanium trichloride, etc. If necessary, an acid may be used in the reaction.

[0055] 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.

[0056] 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.

[0057] When an amidation reaction is carried out in each step, the reaction can be carried out using a condensing agent in the presence or absence of a base. Examples of the condensing agent and base 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.

[0058] 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.

[0059] When the Staudinger reaction is carried out in each step, the reaction can be carried out in the presence of a phosphine compound, such as triphenylphosphine.

[0060] When a Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. The palladium catalyst used is Pd(amphos)Cl 2、 Pd(PPh3)4, etc. Examples of the base that can be used include the examples mentioned above.

[0061] When a Migita-Kosugi-Stille cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst, such as Pd(PPh3)4.

[0062] When a bromination reaction is carried out in each step, the reaction can be carried out in the presence of a bromination reagent, such as NBS.

[0063] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base that can be used include those mentioned above.

[0064] When the Horner-Wadsworth-Emmons reaction is carried out in each step, the reaction can be carried out in the presence of a base. Examples of the base that can be used include those mentioned above.

[0065] In each step, when the Appel reaction is carried out, the reaction can be carried out in the presence of a halogen source and a phosphine compound. Examples of the halogen source that can be used include carbon tetrachloride, carbon tetrabromide, and iodine. Examples of the phosphine compound that can be used include triphenylphosphine.

[0066] When a Curtius rearrangement reaction is carried out in each step, the reaction can be carried out in the presence of an azide source, such as sodium azide or diphenylphosphoryl azide.

[0067] In each step, when a diazotization reaction followed by a Sandmeyer reaction is performed, the reaction can be carried out in the presence of a nitrite ester and a copper salt. Examples of the nitrite ester that can be used include tert-butyl nitrite. Examples of the copper salt that can be used include copper(II) bromide.

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

[0069] The symbols in the formula have the same meanings as above.

[0070] Process 1-1 Compound (I) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-1) and compound (1-2).

[0071] Process 1-2 Compound (I) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (1-3) and compound (1-4).

[0072] The compounds represented by formula (Ia), formula (Ib), formula (Ic), and formula (Id) can be produced, for example, according to the method described in Scheme 2.

[0073] The symbols in the formula have the same meanings as above. P is a protected amino group.

[0074] Process 2-1 Compound (2-1) can also be prepared by removing the protecting group of compound (I').

[0075] Process 2-2 Compound (Ia) can also be produced by a carbamate reaction of compound (2-1) and compound (2-2).

[0076] Process 2-3 Compound (Ib) can also be produced by an amidation reaction of compound (2-1) and compound (2-3).

[0077] Process 2-4 Compound (Ic) can also be produced by subjecting compound (2-1) and compound (2-4) to a urea reaction.

[0078] Process 2-5 Compound (Id) can also be produced by subjecting compound (2-1) and compound (2-5) to a urea reaction.

[0079] The compounds represented by formula (Ie) and formula (If) can be produced, for example, according to the method described in Scheme 3.

[0080] The symbols in the formula have the same meanings as above. 1 is a protecting group.

[0081] Process 3-1 The compound (3-2) can also be produced by introducing a protecting group into the hydroxyl group of the compound (3-1).

[0082] Process 3-2 The compound (3-3) can also be produced by reacting the compound (3-2) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0083] Process 3-3 The compound (3-4) can also be produced by subjecting the compound (3-3) and the compound (1-3) to Suzuki-Miyaura cross-coupling reaction.

[0084] Process 3-4 Compound (Ie) can also be prepared by removing the protecting group of compound (3-4).

[0085] Process 3-5 Compound (3-5) can also be produced by reacting compound (Ie) with methanesulfonyl chloride in the presence of a base.

[0086] Process 3-6 The compound (3-6) can also be produced by reacting the compound (3-5) with sodium azide.

[0087] Process 3-7 The compound (3-7) can also be produced by subjecting the compound (3-6) to the Staudinger reaction.

[0088] Process 3-8 Compound (If) can also be produced by reacting compound (3-7) with trimethylsilyl isocyanate. Alternatively, compound (If) can be produced by reacting compound (3-7) with potassium cyanate, sodium cyanate, or the like in the presence of an acid.

[0089] The compounds represented by formula (Ig) and formula (Ih) can be produced, for example, according to the method described in Scheme 4.

[0090] The symbols in the formula have the same meanings as above. 2 is a protecting group.

[0091] Process 4-1 The compound (4-2) can also be produced by subjecting the compound (4-1) to Horner-Wadsworth-Emmons reaction.

[0092] Process 4-2 The compound (4-3) can also be produced by reacting the compound (4-2) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0093] Process 4-3 The compound (4-4) can also be produced by subjecting the compound (4-3) and the compound (1-3) to Suzuki-Miyaura cross-coupling reaction.

[0094] Process 4-4 The compound (4-5) can also be prepared by removing the protecting group of the compound (4-4).

[0095] Process 4-5 Compound (Ig) can also be produced by the amidation reaction of compound (4-5) and compound (4-6).

[0096] Process 4-6 Compound (Ih) can also be produced by catalytic reduction of compound (Ig).

[0097] The compound represented by formula (Ii) can be produced, for example, according to the method described in Scheme 5.

[0098] The symbols in the formula have the same meanings as above. X P1 is a chlorine atom or a bromine atom.

[0099] Process 5-1 The compound (5-2) can also be produced by subjecting the compound (5-1) to an aromatic nucleophilic substitution reaction.

[0100] Process 5-2 The compound (5-3) can also be produced by the reduction reaction of the compound (5-2).

[0101] Process 5-3 The compound (5-4) can also be produced by reacting the compound (5-3) with methanesulfonyl chloride in the presence of a base.

[0102] Process 5-4 The compound (5-5) can also be produced by reacting the compound (5-4) with phthalimide in the presence of a base.

[0103] Process 5-5 The compound (5-6) can also be produced by catalytic reduction of the compound (5-5).

[0104] Process 5-6 The compound (5-7) can also be produced by reacting the compound (5-6) with phosphorus oxychloride or phosphorus oxybromide.

[0105] Process 5-7 The compound (5-8) can also be produced by subjecting the compound (5-7) and the compound (1-1) to Suzuki-Miyaura cross-coupling reaction.

[0106] Process 5-8 The compound (5-9) can also be produced by removing the phthaloyl group of the compound (5-8).

[0107] Process 5-9 Compound (Ii) can also be produced by reacting compound (5-9) with trimethylsilyl isocyanate. Alternatively, compound (Ii) can be produced by reacting compound (5-9) with potassium cyanate or sodium cyanate in the presence of an acid.

[0108] The compounds represented by formula (Ij), formula (Ik), and formula (Il) can be produced, for example, according to the method described in Scheme 6.

[0109] The symbols in the formula have the same meanings as above. P2 is C 1-6 It is alkyl.

[0110] Process 6-1 The compound (6-2) can also be produced by subjecting the compound (6-1) and the compound (1-1) to Suzuki-Miyaura cross-coupling reaction.

[0111] Process 6-2 The compound (6-3) can also be produced by catalytic reduction of the compound (6-2).

[0112] Process 6-3 The compound (6-4) can also be produced by reacting the compound (6-3) with N-phenylbis(trifluoromethanesulfonimide).

[0113] Process 6-4 Compound (Ij) can also be produced by Migita-Kosugi-Stiel cross-coupling reaction of compound (6-4) and compound (6-5).

[0114] Process 6-5 The compound (6-7) can also be produced by subjecting the compound (6-4) and the compound (6-6) to Suzuki-Miyaura cross-coupling reaction.

[0115] Process 6-6 The compound (6-8) can also be prepared by removing the protecting group of the compound (6-7).

[0116] Process 6-7 Compound (Ik) can also be produced by an amidation reaction of compound (6-8) and compound (4-6).

[0117] Process 6-8 Compound (Il) can also be produced by catalytic reduction of compound (Ik).

[0118] The compounds represented by formula (Im) and formula (In) can be produced, for example, according to the method described in Scheme 7.

[0119] The symbols in the formula have the same meanings as above. 3 is a protecting group. X P2 is a chlorine atom, a bromine atom, or an iodine atom.

[0120] Process 7-1 The compound (7-2) can also be produced by introducing a protecting group into the hydroxyl group of the compound (7-1).

[0121] Process 7-2 The compound (7-3) can also be produced by catalytic reduction or metal reduction of the compound (7-2).

[0122] Process 7-3 The compound (7-4) can also be produced by bromination of the compound (7-3).

[0123] Process 7-4 The compound (7-5) can also be produced by subjecting the compound (7-4) to a carbamate reaction.

[0124] Process 7-5 The compound (7-6) can also be produced by reacting the compound (7-5) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0125] Process 7-6 The compound (7-7) can also be produced by subjecting the compound (7-6) to Suzuki-Miyaura cross-coupling reaction with the compound (1-2).

[0126] Process 7-7 The compound (7-8) can also be produced by removing the protecting group of the compound (7-7).

[0127] Process 7-8 The compound (7-9) can also be produced by the Appel reaction of the compound (7-8).

[0128] Process 7-9 The compound (7-10) can also be produced by reacting the compound (7-8) with methanesulfonyl chloride in the presence of a base.

[0129] Process 7-10 Compound (Im) can also be produced by reacting compound (7-9) with compound (7-11).

[0130] Process 7-11 Compound (Im) can also be produced by reacting compound (7-10) with compound (7-11) in the presence of a base.

[0131] Process 7-12 Compound (In) can also be produced by Suzuki-Miyaura cross-coupling reaction of compound (7-9) and compound (7-12).

[0132] Compound (1-2a) and compound (1-2b) can be produced, for example, according to the method described in Scheme 8.

[0133] The symbols in the formula have the same meanings as above.

[0134] Process 8-1 Compound (1-2a) can also be produced by reacting compound (8-1) with trimethylsilyl isocyanate. Alternatively, compound (1-2a) can be produced by reacting compound (8-1) with potassium cyanate, sodium cyanate, or the like in the presence of an acid.

[0135] Process 8-2 The compound (8-2) can also be prepared by removing the protecting group of the compound (4-2).

[0136] Process 8-3 The compound (1-2b) can also be produced by an amidation reaction of the compound (8-2) with the compound (4-6).

[0137] Compound (1-3a) and compound (1-1a) can be produced, for example, according to the method described in Scheme 9.

[0138] The symbols in the formula have the same meanings as above, and M is a lithium atom, a sodium atom, or a potassium atom.

[0139] Process 9-1 The compound (9-2) can also be produced by reacting the compound (9-1) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0140] Process 9-2 The compound (9-4) can also be produced by subjecting the compound (9-2) and the compound (9-3) to Suzuki-Miyaura cross-coupling reaction.

[0141] Process 9-3 The compound (9-4) can also be produced by reacting the compound (9-2) with the compound (9-5) in the presence of a palladium catalyst.

[0142] Process 9-4 The compound (9-6) can also be produced by catalytic reduction or metal reduction of the compound (9-4).

[0143] Process 9-5 The compound (9-7) can also be produced by bromination of the compound (9-6).

[0144] Process 9-6 The compound (1-3a) can also be produced by subjecting the compound (9-7) to a carbamate reaction.

[0145] Process 9-7 The compound (1-1a) can also be produced by reacting the compound (1-3a) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0146] Compounds (1-3b) and (1-1b) can be produced, for example, according to the method described in Scheme 10.

[0147] The symbols in the formula have the same meanings as above. 4 is a protecting group.

[0148] Process 10-1 The compound (10-3) can also be produced by subjecting the compound (10-1) and the compound (10-2) to a nucleophilic aromatic substitution reaction.

[0149] Process 10-2 The compound (10-4) can also be produced by reacting the compound (10-3) with aqueous ammonia.

[0150] Process 10-3 The compound (10-6) can also be produced by subjecting the compound (10-5) and the compound (2-2) to a Curtius rearrangement reaction.

[0151] Process 10-4 The compound (10-7) can also be produced by subjecting the compound (10-4) to a carbamate reaction.

[0152] Process 10-5 The compound (10-7) can also be produced by subjecting the compound (10-6) to a nucleophilic aromatic substitution reaction with the compound (10-2).

[0153] Process 10-6 The compound (10-8) can also be produced by catalytic reduction or metal reduction of the compound (10-7).

[0154] Process 10-7 The compound (10-11) can also be produced by reacting the compound (10-9) with the compound (10-10) in the presence of a copper salt such as copper(II) acetate.

[0155] Process 10-8 The compound (10-12) can also be produced by removing the protecting group of the compound (10-11).

[0156] Process 10-9 The compound (1-3b) can also be produced by subjecting the compound (10-8) to a diazotization reaction followed by a Sandmeyer reaction.

[0157] Process 10-10 The compound (1-3b) can also be produced by the Curtius rearrangement reaction of the compound (10-12) and the compound (2-2).

[0158] Process 10-11 The compound (1-1b) can also be produced by reacting the compound (1-3b) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0159] Compound (1-3c), compound (1-1c), and compound (1-1d) can be produced, for example, according to the method described in Scheme 11.

[0160] The symbols in the formula have the same meanings as above, except that R x is C 1-6 It is alkyl. R P3 is a hydrogen atom or alkyl.

[0161] Process 11-1 The compound (11-1) can also be prepared by removing the protecting group of the compound (7-5a).

[0162] Process 11-2 The compound (11-2) can also be produced by the oxidation reaction of the compound (11-1).

[0163] Process 11-3 The compound (11-4) can also be produced by reacting the compound (11-2) with a Grignard reagent (11-3).

[0164] Process 11-4 The compound (1-3c) can also be produced by the oxidation reaction of the compound (11-4).

[0165] Process 11-5 The compound (1-1c) can also be produced by reacting the compound (1-3c) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0166] Process 11-6 The compound (11-6) can also be produced by reacting the compound (1-3c) with a Grignard reagent (11-5).

[0167] Process 11-7 The compound (11-7) can also be produced by reacting the compound (11-6) with triethylsilane in the presence of an acid.

[0168] Process 11-8 The compound (11-8) can also be produced by reacting the compound (11-7) with bis(pinacolato)diboron in the presence of a palladium catalyst.

[0169] Process 11-9 The compound (1-1d) can also be produced by catalytic reduction of the compound (11-8).

[0170] Compound (9-4a) and compound (1-3e) can be produced, for example, according to the method described in Scheme 12.

[0171] The symbols in the formula have the same meanings as above.

[0172] Process 12-1 The compound (9-4a) can also be produced by reacting the compound (12-1) with the compound (7-11).

[0173] Process 12-2 The compound (12-3) can also be produced by an amidation reaction of the compound (12-2) with the compound (7-11).

[0174] Process 12-3 The compound (12-4) can also be produced by catalytic reduction or metal reduction of the compound (12-3).

[0175] Process 12-4 The compound (12-5) can also be produced by bromination of the compound (12-4).

[0176] Process 12-5 The compound (1-3e) can also be produced by subjecting the compound (12-5) to a carbamate reaction.

[0177] 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.

[0178] 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.

[0179] 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, 155 (1), pp. 310-314). More preferably, the compounds of the present invention can be used as therapeutic agents for hyperthyroidism or Graves' disease.

[0180] 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.

[0181] 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.

[0182] 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 / 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.

[0183] 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)."

[0184] 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, the effect can be confirmed in an animal model of hyperthyroidism or Graves' disease by the method described in Endocrinology 2007, 148(5), pp. 2335-2344 or a method modified therefrom.

[0185] 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.

[0186] The pharmaceutical composition of the present invention comprises a compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[0187] The pharmaceutical compositions of the present invention are prepared using the compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting, or dissolving the compound with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers, according to the dosage form, using methods known in pharmaceutical science.

[0188] 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, body weight, disease, and degree of treatment. The daily dosage may be administered once, twice, three times, or four times. When administered orally, the dosage for an adult may be determined, for example, in the range of 0.1 to 5000 mg / day. In one embodiment, the oral dosage may be determined in the range of 1 to 1500 mg / day, preferably 1 to 500 mg / day, and more preferably 10 to 500 mg / day. When administered parenterally, the dosage for an adult may be determined, for example, in the range of 0.01 to 5000 mg / day. In one embodiment, the parenteral dosage may be determined in the range of 0.1 to 1500 mg / day, preferably 0.1 to 500 mg / day, and more preferably 1 to 500 mg / day.

[0189] 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.

[0190] 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.

[0191] 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 prodrug-constituting group using a prodrug-converting reagent such as a corresponding halide, followed by purification. Examples of the prodrug-constituting group include those described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990), Vol. 7, pp. 163-198.

[0192] 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.

[0193] 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.

[0194] Reference Example A-1 2-Fluoro-1-(2-fluorobenzyl)-3-nitrobenzene Under an argon atmosphere, Pd(PPh3)4 (0.065 g) was added to a mixture of 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.300 g), 2-fluorobenzyl bromide (0.234 g), 2 mol / L aqueous sodium carbonate (1.12 mL), and DME (2 mL) at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. 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 by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.240 g).

[0195] Reference Example A-2 2-Fluoro-3-(2-fluorobenzyl)aniline Under a hydrogen atmosphere, a mixture of Reference Example A-1 (0.240 g), 10% Pd / C (0.050 g), methanol (2 mL), and THF (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-60 / 40) to obtain the title compound (0.210 g).

[0196] Reference Example A-3 4-Bromo-2-fluoro-3-(2-fluorobenzyl)aniline To a mixture of Reference Example A-2 (0.210 g) and DCM (3 mL), NBS (0.188 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.210 g). 1 H-NMR (CDCl3) δ ppm : 2.64-4.63 (4H, m), 6.62 (1H, t, J=8.9Hz), 6.84-7.10 (3H, m), 7.11-7.22 (2H, m)

[0197] Reference Example A-4 tert-Butyl (4-bromo-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate To a mixture of Reference Example A-3 (0.210 g), TEA (0.214 g), DMAP (0.017 g), and THF (2 mL), BocO (0.338 g) was added under water cooling. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.292 g), and methanol (2 mL) was stirred at 50°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.170 g).

[0198] Reference Example A-5: tert-Butyl (2-fluoro-3-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-4 (0.170 g), bis(pinacolato)diboron (0.141 g), potassium acetate (0.126 g), and 1,4-dioxane (2 mL), Pd(dppf)Cl.DCM (0.031 g) was added at room temperature. The reaction mixture was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride and water were added. 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 = 98 / 2-80 / 20) to obtain the title compound (0.160 g).

[0199] Reference Example A-6 2-(2-Fluoro-3-nitrobenzyl)benzonitrile Under an argon atmosphere, Pd(PPh3)4 (0.065 g) was added to a mixture of 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.300 g), 2-(bromomethyl)benzonitrile (0.242 g), 2 mol / L aqueous sodium carbonate (1.12 mL), and DME (2 mL) at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. 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: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.240 g).

[0200] Reference Example A-7 2-(3-amino-2-fluorobenzyl)benzonitrile Under a hydrogen atmosphere, a mixture of Reference Example A-6 (0.240 g), 10% Pd / C (0.050 g), methanol (2 mL), and THF (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using Method A (eluent: n-hexane / ethyl acetate = 90 / 10-60 / 40) to give the title compound (0.210 g).

[0201] Reference Example A-8 2-(3-amino-6-bromo-2-fluorobenzyl)benzonitrile To a mixture of Reference Example A-7 (0.210 g) and DCM (3 mL), NBS (0.198 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were 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: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.180 g). 1H-NMR (CDCl3) δ ppm : 3.78 (2H, br), 4.35-4.44 (2H, m), 6.61-6.70 (1H, m), 7.02 (1H, d, J=7.8Hz), 7.19 (1H, dd, J=1.5, 8.5Hz), 7.25-7.35 (1H, m), 7.40-7.49 (1H, m), 7.61-7.72 (1H, m)

[0202] Reference Example A-9: tert-Butyl (4-bromo-3-(2-cyanobenzyl)-2-fluorophenyl)carbamate. To a mixture of Reference Example A-8 (0.180 g), TEA (0.179 g), DMAP (0.014 g), and THF (2 mL), BocO (0.283 g) was added under water cooling. The reaction mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.245 g), and methanol (2 mL) was stirred at room temperature for 1 hour and then at 50°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (eluent: n-hexane / ethyl acetate=95 / 5-70 / 30) to obtain the title compound (0.180 g).

[0203] Reference Example A-10 was synthesized in the same manner as in Reference Example A-5, except that Reference Example A-9 was used instead of Reference Example A-4.

[0204] Reference Example A-11 3-Fluoro-2-(2-fluoro-3-nitrobenzyl)benzonitrile Pd(PPh3)4 (0.087 g) was added to a mixture of 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.400 g), 2-(bromomethyl)-3-fluorobenzonitrile (0.321 g), sodium carbonate (0.317 g), water (3 mL), and DME (8 mL) at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. The reaction mixture was refluxed overnight. The reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, 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 Method A (elution solvent: n-hexane / ethyl acetate=100 / 0-85 / 15) to obtain the title compound (0.083 g).

[0205] Reference Example A-12 2-(3-amino-2-fluorobenzyl)-3-fluorobenzonitrile Under a hydrogen atmosphere, a mixture of Reference Example A-11 (0.276 g), 10% Pd / C (0.083 g), methanol (1.5 mL), and THF (1.5 mL) was stirred at room temperature for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0-80 / 20) to obtain the title compound (0.234 g).

[0206] Reference Example A-13 2-(3-amino-6-bromo-2-fluorobenzyl)-3-fluorobenzonitrile To a mixture of Reference Example A-12 (0.233 g) and DCM (6 mL), NBS (0.170 g) was added at -45°C. The reaction mixture was stirred for 2 hours while slowly warming to room temperature. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-80 / 20) to obtain the title compound (0.261 g). 1H-NMR (CDCl3) δ ppm : 3.71 (2H, br), 4.37 (2H, s), 6.56-6.65 (1H, m), 7.11-7.17 (1H, m), 7.19-7.25 (1H, m), 7.28-7.37 (1H, m), 7.43-7.49 (1H, m)

[0207] Reference Example A-14 tert-Butyl (4-bromo-3-(2-cyano-6-fluorobenzyl)-2-fluorophenyl)carbamate To a mixture of Reference Example A-13 (0.261 g), TEA (0.245 g), DMAP (0.020 g), and THF (4 mL), BocO (0.423 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. DMAP (0.049 g) and BocO (0.176 g) were added to the reaction mixture 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 saturated aqueous ammonium chloride and water were added. The mixture was extracted with ethyl acetate. The extract was washed with 1 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.335 g), and methanol (4 mL) was stirred at 50 °C for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to give the title compound (0.270 g).

[0208] Reference Example A-15 1-Methylcyclopropyl (4-bromo-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate To a mixture of Reference Example A-3 (0.161 g), Reference Example I-1 (0.385 g), and THF (5 mL), NaHMDS (1 mol / L in THF) (1.62 mL) was slowly added under ice-cooling. The reaction mixture was stirred for 1 hour under ice-cooling. Saturated brine and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0 to 70 / 30) to obtain the title compound (0.136 g).

[0209] Reference Example A-16: 1-Methylcyclopropyl (2-fluoro-3-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-15 (0.136 g), bis(pinacolato)diboron (0.130 g), potassium acetate (0.101 g), and 1,4-dioxane (5 mL), Pd(dppf)Cl.DCM (0.028 g) was added at room temperature. The reaction mixture was refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium bicarbonate and water were added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2-85 / 15) to obtain the title compound (0.109 g).

[0210] Reference Example A-17 3-Benzyl-2-fluoroaniline Under an argon atmosphere, Pd(dppf)Cl2·DCM (0.645 g) was added to a mixture of 3-bromo-2-fluoroaniline (3.00 g), potassium benzyltrifluoroborate (6.25 g), cesium carbonate (10.3 g), water (6 mL), and 1,4-dioxane (60 mL) at room temperature. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride and water were added. 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 = 95 / 5-70 / 30) to obtain the title compound (2.44 g).

[0211] Reference Example A-18 was synthesized in the same manner as in Reference Example A-3, except that Reference Example A-17 was used instead of Reference Example A-2. 1 H-NMR (CDCl3) δ ppm : 3.72 (2H, br), 4.14 (2H, d, J=2.8Hz), 6.48-6.68 (1H, m), 6.90-7.54 (6H, m)

[0212] Reference Example A-19: tert-Butyl (3-benzyl-4-bromo-2-fluorophenyl)carbamate. To a mixture of Reference Example A-18 (1.80 g), TEA (1.95 g), DMAP (0.157 g), and DCM (20 mL), BocO (3.09 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. 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. A mixture of the residue, potassium carbonate (2.66 g), and methanol (10 mL) was stirred at 50°C for 5 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2-85 / 15) to obtain the title compound (1.60 g).

[0213] Reference Example A-20 tert-Butyl (3-benzyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-19 (1.60 g), bis(pinacolato)diboron (1.60 g), potassium acetate (1.24 g), and 1,4-dioxane (10 mL), Pd(dppf)Cl.DCM (0.308 g) was added at room temperature. The reaction mixture was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride, water, and ethyl acetate were added. The mixture was stirred at the same temperature for 10 minutes and then filtered through Celite. The filtrate 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=98 / 2-85 / 15) to obtain the title compound (1.58 g).

[0214] Reference Example A-21 tert-Butyl (3-benzoyl-4-bromophenyl)carbamate. To a mixture of 2-bromo-5-nitrobenzaldehyde (3.00 g) and THF (60 mL), phenylmagnesium bromide (3 mol / L in EtO) (4.78 mL) was added under ice-salt bath conditions. The reaction mixture was stirred for 2 hours under ice-cooling. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-60 / 40) to obtain (2-bromo-5-nitrophenyl)(phenyl)methanol. To a mixture of the obtained compound and DCM (30 mL), Dess-Martin periodinane (4.09 g) was added under ice-cooling conditions. The reaction mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were 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: n-hexane / ethyl acetate = 90 / 10 - 60 / 40) to obtain (2-bromo-5-nitrophenyl)(phenyl)methanone. To a mixture of the obtained compound and methanol (20 mL), iron powder (1.78 g) and 2 mol / L hydrochloric acid (23.9 mL) were added under ice-cooling. The reaction mixture was stirred at 85 °C for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through Celite. 2 mol / L aqueous sodium hydroxide (25 mL) and ethyl acetate were added to the filtrate, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 - 60 / 40) to obtain (5-amino-2-bromophenyl)(phenyl)methanone. To a mixture of the obtained compound, TEA (1.47 g), DMAP (0.088 g), and DCM (20 mL), BocO (1.90 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 hours. 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.A mixture of the residue, potassium carbonate (1.00 g), and methanol (20 mL) was stirred at 50° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30) to give the title compound (2.00 g).

[0215] Reference Example A-22 tert-Butyl (4-bromo-3-(1-hydroxy-1-phenylethyl)phenyl)carbamate To a mixture of Reference Example A-21 (1.05 g) and THF (10 mL), methylmagnesium bromide (3 mol / L in EtO) (1.40 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 6 hours. To the reaction mixture, methylmagnesium bromide (3 mol / L in EtO) (1.40 mL) was added under ice-cooling. The reaction mixture was stirred at 40 °C for 1 hour. 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 (elution solvent: n-hexane / ethyl acetate = 90 / 10-60 / 40) to obtain the title compound (1.15 g).

[0216] Reference Example A-23 tert-Butyl (4-bromo-3-(1-phenylvinyl)phenyl)carbamate To a mixture of Reference Example A-22 (1.15 g) and DCM (10 mL), triethylsilane (0.971 g) and TFA (0.381 g) were added under ice-cooling. The reaction mixture was stirred at room temperature for 5 days. 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 (elution solvent: n-hexane / ethyl acetate = 95 / 5-60 / 40) to obtain the title compound (0.640 g).

[0217] Reference Example A-24: tert-Butyl (3-(1-phenylvinyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. Under an argon atmosphere, Pd(PPh3)4 (0.031 g) was added to a mixture of Reference Example A-23 (0.200 g), bis(pinacolato)diboron (0.156 g), cesium fluoride (0.191 g), and THF (20 mL) at room temperature. The reaction mixture was stirred at 110 °C for 3 hours under microwave irradiation. The reaction mixture was poured into water, and the mixture was extracted with Et2O. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-90 / 10) to obtain the title compound (0.088 g).

[0218] Reference Example A-25: tert-Butyl (3-(1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. Under an argon atmosphere, 10% Pd / C (0.016 g) was added to a mixture of Reference Example A-24 (0.035 g) and ethyl acetate (1 mL) at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-85 / 15) to obtain the title compound (0.022 g).

[0219] Reference Example A-26: 1-(2-Fluorobenzyl)-2-methyl-3-nitrobenzene. Under an argon atmosphere, Pd(PPh3)4 (0.132 g) was added to a mixture of 4,4,5,5-tetramethyl-2-(2-methyl-3-nitrophenyl)-1,3,2-dioxaborolane (0.600 g), 1-(bromomethyl)-2-fluorobenzene (0.474 g), 2 mol / L aqueous sodium carbonate (2.28 mL), and DME (6 mL) at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.590 g).

[0220] Reference Example A-27 3-(2-Fluorobenzyl)-2-methylaniline Under a hydrogen atmosphere, a mixture of Reference Example A-26 (0.590 g), 10% Pd / C (0.050 g), methanol (5 mL), and THF (5 mL) was stirred at room temperature for 4 hours and then at 50 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and allowed to stand for 62 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using Method A (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.450 g).

[0221] Reference Example A-28 was synthesized in the same manner as in Reference Example A-8, except that Reference Example A-27 was used instead of Reference Example A-7. 1 H-NMR (CDCl3) δ ppm : 2.02 (3H, s), 3.62 (2H, br), 4.24 (2H, s), 6.56 (1H, d, J=8.4Hz), 6.68-6.79 (1H, m), 6.92-6.99 (1H, m), 7.01-7.09 (1H, m), 7.12-7.21 (1H, m), 7.29 (1H, d, J=8.4Hz)

[0222] Reference Example A-29: tert-Butyl (4-bromo-3-(2-fluorobenzyl)-2-methylphenyl)carbamate. To a mixture of Reference Example A-28 (0.500 g), TEA (0.516 g), DMAP (0.021 g), and THF (3 mL), BocO (0.816 g) was added under water cooling. The reaction mixture was stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 0.5 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.705 g), and methanol (3 mL) was stirred at 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and a saturated aqueous ammonium chloride solution and water were added. The mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate=98 / 2-80 / 20) to obtain the title compound (0.530 g).

[0223] Reference Example A-30 tert-Butyl (3-(2-fluorobenzyl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-29 (0.530 g), bis(pinacolato)diboron (0.512 g), potassium acetate (0.396 g), and 1,4-dioxane (3 mL), Pd(dppf)Cl.DCM (0.220 g) was added at room temperature. The reaction mixture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium bicarbonate and ethyl acetate were added. The mixture was stirred at the same temperature for 10 minutes and then filtered through Celite. The filtrate 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=98 / 2-85 / 15) to obtain the title compound (0.260 g).

[0224] Reference Example A-31 2-(2,4-Difluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a mixture of 1-bromo-2,4-difluoro-3-nitrobenzene (2.49 g), bis(pinacolato)diboron (3.99 g), potassium acetate (3.08 g), and 1,4-dioxane (30 mL), Pd(dppf)Cl2·DCM (0.854 g) was added at room temperature. The reaction mixture was refluxed for 2.5 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium bicarbonate, water, and ethyl acetate were added. The mixture was stirred at the same temperature for 10 minutes and then filtered through Celite. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=90 / 10-40 / 60) to obtain the title compound (0.860 g).

[0225] Instead of 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-(bromomethyl)benzonitrile, Reference Example A-31 and 1-(bromomethyl)-2-fluorobenzene were used, and Reference Example A-32 was synthesized in the same manner as Reference Example A-6.

[0226] Reference Example A-33 was synthesized in the same manner as in Reference Example A-7, except that Reference Example A-32 was used instead of Reference Example A-6.

[0227] Reference Example A-34 was synthesized in the same manner as in Reference Example A-8, except that Reference Example A-33 was used instead of Reference Example A-7. 1 H-NMR (CDCl3) δ ppm : 3.75 (2H, br), 4.07-4.22 (2H, m), 6.87-6.96 (1H, m), 6.97-7.08 (2H, m), 7.12 (1H, dd, J=2.1, 9.9Hz), 7.15-7.23 (1H, m)

[0228] Reference Example A-35: tert-Butyl (4-bromo-2,6-difluoro-3-(2-fluorobenzyl)phenyl)carbamate. To a mixture of Reference Example A-34 (0.230 g), TEA (0.221 g), DMAP (0.009 g), and THF (3 mL), BocO (0.349 g) was added under water cooling. The reaction mixture was stirred at room temperature for 1 hour and then at 50°C for 4 hours. The reaction mixture was allowed to cool to room temperature and stirred for 12 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 0.5 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.302 g), and methanol (3 mL) was stirred at 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature, a saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and the residue was purified by Method A (elution solvent: n-hexane / ethyl acetate=95 / 5-70 / 30) to obtain the title compound (0.280 g).

[0229] Reference Example A-36: tert-Butyl (2,6-difluoro-3-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. Reference Example A-35 (0.280 g), bis(pinacolato)diboron (0.256 g), potassium acetate (0.198 g), and 1,4-dioxane (2 mL) were mixed and added with Pd(dppf)Cl.DCM (0.110 g) at room temperature. The reaction mixture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium hydrogen carbonate and water were added. 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 = 98 / 2-85 / 15) to give the title compound (0.270 g).

[0230] Reference Example A-37 was synthesized in the same manner as in Reference Example A-1, except that 3-fluorobenzyl bromide was used instead of 2-fluorobenzyl bromide.

[0231] Reference Example A-38 was synthesized in the same manner as in Reference Example A-2, except that Reference Example A-37 was used instead of Reference Example A-1.

[0232] Reference Example A-39 was synthesized in the same manner as in Reference Example A-3, except that Reference Example A-38 was used instead of Reference Example A-2. 1 H-NMR (CDCl3) δ ppm : 2.80-4.56 (4H, m), 6.54-6.67 (1H, m), 6.83-7.10 (3H, m), 7.15 (1H, dd, J=1.8, 8.5Hz), 7.18-7.34 (1H, m)

[0233] Reference Example A-40 was synthesized in the same manner as in Reference Example A-4, except that Reference Example A-39 was used instead of Reference Example A-3.

[0234] Reference Example A-41 was synthesized in the same manner as in Reference Example A-5, except that Reference Example A-40 was used instead of Reference Example A-4.

[0235] Reference Example A-42 was synthesized in the same manner as in Reference Example A-1, except that 4-fluorobenzyl bromide was used instead of 2-fluorobenzyl bromide.

[0236] Reference Example A-43 was synthesized in the same manner as in Reference Example A-2, except that Reference Example A-42 was used instead of Reference Example A-1.

[0237] Reference Example A-44 was synthesized in the same manner as in Reference Example A-3, except that Reference Example A-43 was used instead of Reference Example A-2. 1 H-NMR (CDCl3) δ ppm : 2.94-4.27 (4H, m), 6.54-6.64 (1H, m), 6.90-7.02 (2H, m), 7.14 (1H, dd, J=1.6, 8.7Hz), 7.18-7.29 (2H, m)

[0238] Reference Example A-45 was synthesized in the same manner as in Reference Example A-4, except that Reference Example A-44 was used instead of Reference Example A-3.

[0239] Reference Example A-46 was synthesized in the same manner as in Reference Example A-5, except that Reference Example A-45 was used instead of Reference Example A-4.

[0240] Reference Example A-47 3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-fluoroaniline To a mixture of (2-fluoro-3-nitrophenyl)methanol (0.920 g), imidazole (0.439 g), and DCM (10 mL), tert-butyldimethylsilyl chloride (0.851 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, 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. Under a hydrogen atmosphere, a mixture of the residue, 10% Pd / C (0.200 g), methanol (5 mL), and THF (5 mL) was stirred at room temperature for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate = 98 / 2-80 / 20) to obtain the title compound (1.20 g).

[0241] Reference Example A-48 tert-Butyl (4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorophenyl)carbamate To a mixture of Reference Example A-47 (1.20 g) and DCM (10 mL), NBS (0.753 g) was added at −20° C. The reaction mixture was stirred at the same temperature for 20 minutes. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate 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, TEA (1.43 g), DMAP (0.057 g), and THF (10 mL), BocO (2.26 g) was added under water-cooling. The reaction mixture was stirred at room temperature for 13 hours. Saturated aqueous ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (1.95 g), and methanol (5 mL) was stirred at room temperature for 5 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 = 90 / 10 - 75 / 25) to give the title compound (1.31 g). 1H-NMR (CDCl3) δ ppm : 0.11 (6H, s), 0.91 (9H, s), 1.52 (9H, s), 4.81 (2H, d, J=2.5Hz), 6.69 (1H, br), 7.30 (1H, dd, J=1.6, 8.9Hz), 7.85-8.04 (1H, m)

[0242] Reference Example A-49 tert-Butyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate Reference Example A-48 (0.500 g), bis(pinacolato)diboron (0.380 g), Pd(dppf)Cl.DCM (0.042 g), and 1,4-dioxane (2 mL) were mixed and added with potassium acetate (0.339 g) at room temperature. The reaction mixture was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride and water were added. 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 = 98 / 2-90 / 10) to obtain the title compound (0.400 g).

[0243] Reference Example A-50 1-(benzyloxy)-2-methylpropan-2-yl (4-bromo-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate. To a mixture of Reference Example A-3 (0.118 g), Reference Example I-2 (0.151 g), and THF (4 mL), NaHMDS (1 mol / L in THF) (0.791 mL) was slowly added under ice-cooling. The reaction mixture was stirred for 1 hour under ice-cooling. Saturated brine and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 100 / 0-86 / 14) to give the title compound (0.200 g).

[0244] Reference Example A-51: 1-(benzyloxy)-2-methylpropan-2-yl (2-fluoro-3-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. A mixture of Reference Example A-50 (0.102 g), bis(pinacolato)diboron (0.065 g), potassium acetate (0.058 g), Pd(dppf)Cl.DCM (0.016 g), and 1,4-dioxane (1 mL) was stirred at 120° C. for 1.5 hours under microwave irradiation. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0-89 / 11) to obtain the title compound (0.078 g).

[0245] Reference Example A-52 2-Fluoro-1-(2-(methylsulfonyl)benzyl)-3-nitrobenzene Under an argon atmosphere, 1-(bromomethyl)-2-(methylsulfonyl)benzene (0.089 g) was added to a mixture of 4,4,5,5-tetramethyl-2-(2-fluoro-3-nitrophenyl)-1,3,2-dioxaborolane (0.095 g), Pd(PPh3)4 (0.021 g), 2 mol / L aqueous sodium carbonate solution (0.356 mL), and DME (2 mL) at room temperature. The reaction mixture was stirred at 110 °C for 1 hour under microwave irradiation. 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 silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10-40 / 60) to obtain the title compound (0.095 g).

[0246] Reference Example A-53 4-Bromo-2-fluoro-3-(2-(methylsulfonyl)benzyl)aniline Under a hydrogen atmosphere, a mixture of Reference Example A-52 (0.095 g), 10% Pd / C (0.020 g), methanol (1 mL), and THF (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue, THF (0.5 mL), and DCM (1 mL), NBS (0.046 g) was added at -20 °C. The reaction mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate and a 1 mol / L aqueous solution of sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10-45 / 55) to obtain the title compound (0.072 g). 1 H-NMR (CDCl3) δ ppm : 3.24 (3H, s), 3.77 (2H, br), 4.60 (2H, d, J=2.3Hz), 6.65-6.74 (1H, m), 6.84-6.94 (1H, m), 7.22 (1H, dd, J=1.5, 8.5Hz), 7.37-7.55 (2H, m), 8.11 (1H, dd, J=1.6, 7.7Hz)

[0247] Reference Example A-54 tert-Butyl (4-bromo-2-fluoro-3-(2-(methylsulfonyl)benzyl)phenyl)carbamate To a mixture of Reference Example A-53 (0.072 g), TEA (0.061 g), DMAP (0.003 g), and THF (1 mL), BocO (0.097 g) was added under water cooling. The reaction mixture was stirred at room temperature for 16 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.083 g), and methanol (1 mL) was stirred at room temperature for 2 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 (elution solvent: n-hexane / ethyl acetate = 90 / 10-70 / 30) to obtain the title compound (0.045 g).

[0248] Reference Example A-55: tert-Butyl (2-fluoro-3-(2-(methylsulfonyl)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-54 (0.045 g), bis(pinacolato)diboron (0.037 g), Pd(dppf)Cl.DCM (0.004 g), and 1,4-dioxane (2 mL), potassium acetate (0.029 g) was added at room temperature. The reaction mixture was stirred at 120°C for 1 hour under microwave irradiation. A saturated aqueous ammonium chloride solution 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 (elution solvent: n-hexane / ethyl acetate = 90 / 10-60 / 40) to obtain the title compound (0.027 g).

[0249] Reference Example A-56 [1,1'-bi(cyclopropane)]-1-yl (4-bromo-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate. To a mixture of Reference Example A-3 (0.200 g), Reference Example I-6 (0.229 g), and THF (5 mL), NaHMDS (1 mol / L in THF) (1.34 mL) was slowly added under ice-cooling. The reaction mixture was stirred for 1 hour under ice-cooling. Reference Example I-6 (0.050 g) and NaHMDS (1 mol / L in THF) (1.34 mL) were added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 1 hour under ice-cooling. Saturated brine and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0-70 / 30) to obtain the title compound (0.193 g).

[0250] Reference Example A-57 was synthesized in the same manner as in Reference Example A-16, except that Reference Example A-56 was used instead of Reference Example A-15.

[0251] Reference Example A-58 tert-Butyl (4-bromo-2-fluoro-3-(hydroxymethyl)phenyl)carbamate To a mixture of Reference Example A-48 (3.85 g) and THF (20 mL), TBAF (1 mol / L in THF) (9.75 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (2.42 g).

[0252] Reference Example A-59 tert-Butyl (4-bromo-2-fluoro-3-formylphenyl)carbamate. To a mixture of Reference Example A-58 (0.500 g) and DCM (5 mL), Dess-Martin periodinane (0.795 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.470 g).

[0253] Reference Example A-60 tert-Butyl (4-bromo-2-fluoro-3-(hydroxy(o-tolyl)methyl)phenyl)carbamate To a mixture of 1-iodo-2-methylbenzene (0.181 g) and THF (1 mL), isopropylmagnesium chloride (2 mol / L in THF) (0.377 mL) was added at -40 ° C. The reaction mixture was stirred under ice-cooling for 30 minutes. A solution of Reference Example A-59 (0.150 g) in THF (1 mL) was added at -40 ° C. The reaction mixture was stirred at the same temperature for 10 minutes and then under ice-cooling for 2 hours. A saturated aqueous ammonium chloride solution 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 Method A (elution solvent: n-hexane / ethyl acetate = 95 / 5-60 / 40) to obtain the title compound (0.090 g).

[0254] Reference Example A-61 tert-Butyl (4-bromo-2-fluoro-3-(2-methylbenzoyl)phenyl)carbamate To a mixture of Reference Example A-60 (0.090 g) and DCM (1 mL), Dess-Martin periodinane (0.112 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. Dess-Martin periodinane (0.056 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 and a 1 mol / L aqueous solution of sodium thiosulfate 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 Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2-85 / 15) to obtain the title compound (0.040 g).

[0255] Reference Example A-62 was synthesized in the same manner as in Reference Example A-36, except that Reference Example A-61 was used instead of Reference Example A-35.

[0256] Reference Example A-63 was synthesized in the same manner as in Reference Example A-60, except that 1-iodo-2-(trifluoromethyl)benzene was used instead of 1-iodo-2-methylbenzene.

[0257] Reference Example A-64 tert-Butyl (4-bromo-2-fluoro-3-(2-(trifluoromethyl)benzoyl)phenyl)carbamate To a mixture of Reference Example A-63 (0.660 g) and DCM (3 mL), Dess-Martin periodinane (0.724 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and a 1 mol / L aqueous solution of sodium thiosulfate 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 Method A (elution solvent: n-hexane / ethyl acetate = 98 / 2-85 / 15) to obtain the title compound (0.610 g).

[0258] Reference Example A-65 was synthesized in the same manner as in Reference Example A-5, except that Reference Example A-64 was used instead of Reference Example A-4.

[0259] Reference Example A-66 was synthesized in the same manner as in Reference Example A-60, except that 1-fluoro-2-iodobenzene was used instead of 1-iodo-2-methylbenzene.

[0260] Reference Example A-67 was synthesized in the same manner as in Reference Example A-64, except that Reference Example A-66 was used instead of Reference Example A-63.

[0261] Reference Example A-68 was synthesized in the same manner as in Reference Example A-5, except that Reference Example A-67 was used instead of Reference Example A-4.

[0262] Reference Example A-69: Potassium 2-(3-fluoropyridin-2-yl)acetate. A mixture of 2,3-difluoropyridine (2.00 g), cesium carbonate (13.6 g), diethyl malonate (6.68 g), and DMSO (20 mL) was stirred at 100 °C for 4.5 hours. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with n-hexane / ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain diethyl 2-(3-fluoropyridin-2-yl)malonate. A mixture of the obtained compound, sodium chloride (0.831 g), water (0.466 mL), and DMSO (20 mL) was stirred at 140 °C for 10 hours, at room temperature for 14 hours, and then at 140 °C for 8 hours, and then allowed to cool to room temperature. n-Hexane and ethyl acetate were added to the reaction mixture. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20-50 / 50) to obtain ethyl 2-(3-fluoropyridin-2-yl)acetate. To a mixture of the obtained compound, water (0.274 mL), and ethanol (20 mL), a solution of potassium tert-butoxide (1.71 g) in ethanol (10 mL) was added at 60 °C over 30 minutes. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtO (20 mL) was added to the residue, and the insoluble matter was collected by filtration. The resulting solid was washed sequentially with EtO / ethanol (1 / 1) (10 mL) and EtO (30 mL) and then dried under reduced pressure to obtain the title compound (2.15 g). Reference Example A-70 3-Fluoro-2-(2-fluoro-3-nitrobenzyl)pyridine Under an argon atmosphere, 1-bromo-2-fluoro-3-nitrobenzene (0.500 g), Reference Example A-69 (0.527 g), Xantphos (0.079 g) and 2-methoxyethyl ether (4 mL) were added to a mixture of tris(dibenzylideneacetone)dipalladium(0) (0.042 g) at room temperature. The reaction mixture was stirred at 150 ° C. for 1 hour under microwave irradiation.The reaction mixture was filtered through Celite, and the filtrate was partitioned with water and ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to give the title compound (0.440 g).

[0263] Reference Example A-71 was synthesized in the same manner as in Reference Example A-7, except that Reference Example A-70 was used instead of Reference Example A-6.

[0264] Reference Example A-72 was synthesized in the same manner as in Reference Example A-8, except that Reference Example A-71 was used instead of Reference Example A-7. 1 H-NMR (CDCl3) δ ppm : 3.74 (2H, br), 4.31-4.44 (2H, m), 6.56-6.68 (1H, m), 7.10-7.22 (2H, m), 7.31-7.43 (1H, m), 8.25-8.40 (1H, m)

[0265] Reference Example A-73 was synthesized in the same manner as in Reference Example A-29, except that Reference Example A-72 was used instead of Reference Example A-28.

[0266] Reference Example A-74 tert-Butyl (2-fluoro-3-((3-fluoropyridin-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-73 (0.220 g), bis(pinacolato)diboron (0.210 g), potassium acetate (0.162 g), and 1,4-dioxane (2 mL), Pd(dppf)Cl.DCM (0.045 g) was added at room temperature. The reaction mixture was refluxed for 4 hours. To the reaction mixture, Pd(dppf)Cl.DCM (0.045 g) was added at room temperature. The reaction mixture was refluxed for 2.5 hours. The reaction mixture was allowed to cool to room temperature and purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=90 / 10-60 / 40) to obtain the title compound (0.160 g).

[0267] Reference Example A-75: 4-Bromo-2-fluoro-3-(morpholinomethyl)aniline. Morpholine (0.083 g) was added to a mixture of 1-(chloromethyl)-2-fluoro-3-nitrobenzene (0.090 g) and THF (1 mL) at room temperature. The reaction mixture was refluxed for 6 hours. The reaction mixture was allowed to cool to room temperature and 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 = 80 / 20-10 / 90) to obtain 4-(2-fluoro-3-nitrobenzyl)morpholine. A mixture of the obtained compound, 10% Pd / C (0.050 g), methanol (2 mL), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. To a mixture of the residue and DCM (3 mL), NBS (0.052 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. Saturated aqueous sodium bicarbonate and 1 mol / L aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.051 g). 1 H-NMR (CDCl3) δ ppm : 2.43-2.68 (4H, m), 3.58-3.84 (8H, m), 6.56-6.69 (1H, m), 7.14 (1H, dd, J=1.5, 8.5Hz)

[0268] Reference Example A-76 was synthesized in the same manner as in Reference Example A-54, except that Reference Example A-75 was used instead of Reference Example A-53.

[0269] Reference Example A-77: tert-Butyl (2-fluoro-3-(morpholinomethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-76 (0.060 g), bis(pinacolato)diboron (0.051 g), Pd(dppf)Cl.DCM (0.011 g), and 1,4-dioxane (2 mL), potassium acetate (0.045 g) was added at room temperature. The reaction mixture was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride and water were added. 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 = 50 / 50 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (0.030 g).

[0270] Reference Example A-78 (2-Fluoro-3-nitrophenyl)(morpholino)methanone To a mixture of 2-fluoro-3-nitrobenzoic acid (0.300 g), morpholine (0.141 g), DIPEA (0.419 g), and DCM (5 mL), T3P (1.7 mol / L in ethyl acetate) (1.91 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 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 = 40 / 60-0 / 100) to obtain the title compound (0.380 g).

[0271] Reference Example A-79 (3-amino-2-fluorophenyl)(morpholino)methanone Under a hydrogen atmosphere, a mixture of Reference Example A-78 (0.380 g), 10% Pd / C (0.100 g), methanol (4 mL), and THF (4 mL) was stirred at room temperature for 3 hours. The reaction mixture was 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 = 40 / 60-0 / 100) to give the title compound (0.300 g).

[0272] Reference Example A-80 was synthesized in the same manner as in Reference Example A-48, except that Reference Example A-79 was used instead of Reference Example A-47. 1 H-NMR (CDCl3) δ ppm : 1.53 (9H, s), 3.19-3.36 (2H, m), 3.57-3.94 (6H, m), 6.69 (1H, br), 7.34 (1H, dd, J=1.5, 9.0Hz), 7.98-8.14 (1H, m)

[0273] Reference Example A-81 was synthesized in the same manner as in Reference Example A-55, except that Reference Example A-80 was used instead of Reference Example A-54.

[0274] Reference Example A-82 1-Allyl-2-fluoro-3-nitrobenzene A mixture of 3-bromo-2-fluoronitrobenzene (0.515 g), Pd(PPh3)4 (0.541 g), allyltri-n-butyltin (0.929 g) and toluene (10 mL) was stirred at 130 ° C for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 100 / 0-80 / 20) to obtain the title compound (0.321 g).

[0275] Reference Example A-83 1-(Cyclopropylmethyl)-2-fluoro-3-nitrobenzene Under an argon atmosphere, a solution of TFA (1.08 g) in DCM (20 mL) was slowly added to a mixture of diethylzinc (1 mol / L in n-hexane) (9.49 mL) and DCM (20 mL) under ice-cooling. The reaction mixture was stirred for 20 minutes under ice-cooling. A solution of diiodomethane (2.54 g) in DCM (20 mL) was slowly added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 20 minutes under ice-cooling. A solution of Reference Example A-82 (0.215 g) in DCM (10 mL) was slowly added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. 1 mol / L hydrochloric acid was added to the reaction mixture under ice-cooling, and the mixture was extracted with DCM. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0-90 / 10) to obtain the title compound (0.166 g).

[0276] Reference Example A-84: 4-Bromo-3-(cyclopropylmethyl)-2-fluoroaniline. To a mixture of Reference Example A-83 (0.130 g), zinc powder (0.261 g), and methanol (5 mL) was added ammonium chloride (0.142 g) under ice-cooling. The reaction mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 100 / 0 to 90 / 10) to obtain 3-(cyclopropylmethyl)-2-fluoroaniline. To a mixture of the obtained compound and DMF (1 mL), a solution of NBS (0.044 g) in DMF (0.5 mL) was slowly added under ice-cooling. The reaction mixture was stirred for 30 minutes under ice-cooling. Water was added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (3 / 1). The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0-97 / 3) to obtain the title compound (0.052 g). 1H-NMR (CDCl3) δ ppm : 0.26-0.36 (2H, m), 0.37-0.50 (2H, m), 1.02-1.15 (1H, m), 2.70 (2H, dd, J=2.6, 7.0Hz), 3.70 (2H, br), 6.49-6.61 (1H, m), 7.08-7.18 (1H, m)

[0277] Reference Example A-85: tert-Butyl (4-bromo-3-(cyclopropylmethyl)-2-fluorophenyl)carbamate. To a mixture of Reference Example A-84 (0.052 g) and THF (2 mL), TEA (0.065 g), DMAP (0.003 g), and BocO (0.121 g) were added at room temperature. The reaction mixture was refluxed for 3 hours. To the reaction mixture, DMAP (0.003 g) and BocO (0.121 g) were added at room temperature. The reaction mixture was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride and water were added. The mixture was extracted with ethyl acetate. The extract was washed with 1 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixture of the residue, potassium carbonate (0.088 g), and methanol (2 mL) was stirred at 60° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added, 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 95 / 5) to give the title compound (0.058 g).

[0278] Reference Example A-86: tert-Butyl (3-(cyclopropylmethyl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example A-85 (0.046 g), bis(pinacolato)diboron (0.068 g), potassium acetate (0.046 g), and 1,4-dioxane (4 mL), Pd(dppf)Cl.DCM (0.022 g) was added at room temperature. The reaction mixture was stirred at 100° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride solution, water, and DCM were added. The mixture was stirred at the same temperature for 10 minutes and then filtered through Celite. The filtrate was extracted with DCM, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=100 / 0-95 / 5) to obtain the title compound (0.025 g).

[0279] Reference Example B-1 1,2-Difluoro-4-nitro-3-phenoxybenzene Under an argon atmosphere, sodium tert-butoxide (1.63 g) was added to a mixture of phenol (1.59 g) and THF (34 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 15 minutes. 2,3,4-Trifluoronitrobenzene (3.00 g) was slowly added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (4.45 g).

[0280] Reference Example B-2 2-Fluoro-4-nitro-3-phenoxyaniline A mixture of Reference Example B-1 (4.38 g) and 15 mol / L aqueous ammonia (24 mL) was stirred at 130 ° C. for 30 minutes under microwave irradiation. The insoluble matter was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to obtain the title compound (3.93 g).

[0281] Reference Example B-3: tert-Butyl (2-fluoro-4-nitro-3-phenoxyphenyl)carbamate. To a mixture of Reference Example B-2 (3.92 g), TEA (4.79 g), DMAP (1.93 g), and THF (40 mL), BocO (5.52 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 9 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol / L hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Potassium carbonate (6.56 g) was added to a mixture of the residue and methanol (40 mL) at room temperature. The reaction mixture was stirred at 60°C for 30 minutes. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was washed with water, 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 / 0-84 / 16) to obtain the title compound (4.39 g).

[0282] Reference Example B-4: tert-Butyl (4-amino-2-fluoro-3-phenoxyphenyl)carbamate. Under an argon atmosphere, 10% Pd / C (0.131 g) was added to a mixture of Reference Example B-3 (4.38 g) and methanol (42 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5-75 / 25) to give the title compound (3.55 g).

[0283] Reference Example B-5: tert-Butyl (4-bromo-2-fluoro-3-phenoxyphenyl)carbamate. To a mixture of Reference Example B-4 (3.55 g), copper(II) bromide (2.62 g), and MeCN (50 mL) was slowly added tert-butyl nitrite (1.21 g) at room temperature. The reaction mixture was stirred at 77°C for 1 hour. The reaction mixture was allowed to cool to room temperature, 1 mol / L hydrochloric acid was added, 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 / 0-92 / 8) to give the title compound (3.50 g).

[0284] Reference Example B-6 tert-Butyl (2,3-difluoro-4-nitrophenyl)carbamate Diphenylphosphoryl azide (0.407 g) was added to a mixture of 2,3-difluoro-4-nitrobenzoic acid (0.200 g), tert-butyl alcohol (0.365 g), TEA (0.149 g), and toluene (3 mL) at room temperature. The reaction mixture was refluxed for 3 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90 / 10-75 / 25) to give the title compound (0.044 g).

[0285] Reference Example B-7 tert-Butyl (4-amino-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate To a mixture of 2-fluorophenol (0.117 g) and THF (1 mL), sodium tert-butoxide (0.100 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, a mixture of Reference Example B-6 (0.260 g) and THF (2 mL) was slowly added under ice-cooling. The reaction mixture was stirred at room temperature for 13 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. Under a hydrogen atmosphere, a mixture of the residue, 10% Pd / C (0.010 g), methanol (2 mL), and THF (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was 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=95 / 5-65 / 35) to obtain the title compound (0.240 g).

[0286] Reference Example B-8 tert-Butyl (4-bromo-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate To a mixture of Reference Example B-7 (0.230 g), copper(II) bromide (0.153 g), and MeCN (3 mL), tert-butyl nitrite (0.085 g) was slowly 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, 1 mol / L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-70 / 30) to obtain the title compound (0.200 g).

[0287] Reference Example B-9: tert-Butyl (2-fluoro-3-(2-fluorophenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate. To a mixture of Reference Example B-8 (0.200 g), bis(pinacolato)diboron (0.165 g), Pd(dppf)Cl.DCM (0.018 g), and 1,4-dioxane (3 mL), potassium acetate (0.147 g) was added at room temperature. The reaction mixture was stirred at 135°C for 1 hour under microwave irradiation. A saturated aqueous ammonium chloride solution 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 (elution solvent: n-hexane / ethyl acetate = 90 / 10-55 / 45) to obtain the title compound (0.034 g).

[0288] Reference Example B-10: Methyl 4-bromo-3-phenoxybenzoate. A mixture of methyl 4-bromo-3-hydroxybenzoate (2.00 g), phenylboronic acid (2.11 g), copper(II) acetate (1.73 g), TEA (4.38 g), molecular sieves 4A (10.0 g), and DCM (80 mL) was stirred at room temperature for 36 hours. Phenylboronic acid (0.633 g), copper(II) acetate (0.629 g), and TEA (1.40 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 8 hours. The reaction mixture was filtered through Celite. Saturated aqueous ammonium chloride and water 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 (elution solvent: n-hexane / ethyl acetate = 95 / 5-60 / 40) to give the title compound (2.30 g).

[0289] Reference Example B-11 4-Bromo-3-phenoxybenzoic acid A mixture of Reference Example B-10 (2.30 g), 4 mol / L aqueous lithium hydroxide solution (5.62 mL), methanol (10 mL), and THF (10 mL) was stirred at room temperature for 18 hours. Water and 2 mol / L hydrochloric acid (15 mL) were added to the reaction mixture under ice-cooling. The mixture was stirred at the same temperature for 10 minutes, and the insoluble matter was filtered off. The resulting solid was dried under reduced pressure to give the title compound (1.84 g).

[0290] Reference Example B-12 tert-Butyl (4-bromo-3-phenoxyphenyl)carbamate A mixture of Reference Example B-11 (1.83 g), diphenylphosphoryl azide (2.06 g), TEA (1.39 g), and tert-butyl alcohol (30 mL) was refluxed for 7 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10-60 / 40) to obtain the title compound (1.71 g).

[0291] Reference Example B-13 was synthesized in the same manner as in Reference Example A-5, except that Reference Example B-12 was used instead of Reference Example A-4.

[0292] Reference Example C-1 1-((3-Bromopyridin-2-yl)methyl)urea To a mixture of 2-(aminomethyl)-3-bromopyridine hydrochloride (0.388 g), TEA (0.264 g), and THF (4.4 mL), trimethylsilyl isocyanate (0.600 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 3 days. The reaction mixture was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2-75 / 25) to obtain the title compound (0.306 g).

[0293] Reference Example C-2 3-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)pyridine To a mixture of (3-bromopyridin-2-yl)methanol (0.415 g) and DCM (5 mL), imidazole (0.376 g) and tert-butyldimethylsilyl chloride (0.399 g) were added 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 DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-90 / 10) to obtain the title compound (0.530 g).

[0294] Reference Example C-3 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. To a mixture of Reference Example C-2 (0.529 g), bis(pinacolato)diboron (0.578 g), potassium acetate (0.515 g), and 1,4-dioxane (10 mL), Pd(dppf)Cl.DCM (0.143 g) was added at room temperature. The reaction mixture was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous ammonium chloride solution, 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 aminosilica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-50 / 50) to obtain the title compound (0.297 g).

[0295] Reference Example C-4 1-((3-Bromo-4-methylpyridin-2-yl)methyl)urea To a mixture of (3-bromo-4-methylpyridin-2-yl)methanamine hydrochloride (0.200 g), TEA (0.085 g), and THF (2 mL), trimethylsilyl isocyanate (0.194 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 12 hours. The reaction mixture was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 90 / 10) to give the title compound (0.048 g).

[0296] Reference Example C-5 1-((3-Bromo-5-methylpyridin-2-yl)methyl)urea A mixture of (3-bromo-5-methylpyridin-2-yl)methanamine hydrochloride (0.100 g), DIPEA (0.071 g) and THF (3 mL) was stirred at room temperature for 10 minutes. Trimethylsilyl isocyanate (0.243 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (0.126 g).

[0297] Reference Example C-6: Ethyl (E)-3-(3-bromopyridin-2-yl)acrylate. To a mixture of triethyl phosphonoacetate (0.663 g) and THF (10 mL), sodium hydride (approximately 60%) (0.129 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. 3-Bromopicolinaldehyde (0.500 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. 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 (elution solvent: n-hexane / ethyl acetate = 95 / 5-70 / 30) to give the title compound (0.450 g).

[0298] Reference Example C-7 (E)-3-(3-bromopyridin-2-yl)acrylamide To a mixture of Reference Example C-6 (0.450 g), methanol (3 mL), and THF (3 mL), 4 mol / L aqueous lithium hydroxide solution (1.32 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Water and 1 mol / L hydrochloric acid (5.5 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, DMT-MM (0.730 g), and MeCN (6 mL), 15 mol / L aqueous ammonia (0.176 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. 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 silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=50 / 50 / 0-0 / 100 / 0-0 / 97 / 3) and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate=50 / 50-0 / 100) to obtain the title compound (0.305 g).

[0299] Reference Example C-8: Ethyl (E)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylate. To a mixture of Reference Example C-6 (0.620 g), bis(pinacolato)diboron (0.922 g), potassium acetate (0.713 g), and 1,4-dioxane (5 mL), Pd(dppf)Cl.DCM (0.198 g) was added at room temperature. The reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium bicarbonate, water, and ethyl acetate were added. The mixture was stirred at the same temperature for 10 minutes and then filtered through Celite. The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=90 / 10-60 / 40) to obtain the title compound (0.550 g).

[0300] Reference Example C-9: Ethyl 3-(3-bromopyridin-2-yl)-3-oxopropanoate. To a mixture of 3-bromopyridine-2-carboxylic acid (2.00 g) and THF (10 mL), CDI (1.69 g) was added portionwise at room temperature. The reaction mixture was stirred at the same temperature for 21 hours (Solution A). To a mixture of potassium ethyl malonate (3.37 g), TEA (3.01 g), and MeCN (40 mL), magnesium(II) chloride (2.36 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 5 hours. Solution A was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 19 hours and then at 90 °C for 1 hour. The reaction mixture was allowed to cool to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. A mixture of the residue, 2 mol / L hydrochloric acid (50 mL), and toluene (50 mL) was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 85 / 15 to 50 / 50) to give the title compound (1.73 g).

[0301] Reference Example D-1: Methyl 4-(benzyloxy)-6-chloropyridazine-3-carboxylate. A mixture of methyl 4,6-dichloropyridazine-3-carboxylate (1.00 g), potassium carbonate (1.34 g), benzyl alcohol (0.575 g), and DMF (10 mL) was stirred at room temperature for 1 hour and then at 50°C for 6 hours. Benzyl alcohol (0.104 g) was added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 62 hours and then at 50°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and saturated aqueous ammonium chloride, water, ethyl acetate, and n-hexane were added. The mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-60 / 40) to give the title compound (0.340 g). 1 H-NMR (CDCl3) δ ppm : 4.03 (3H, s), 5.26 (2H, s), 7.08 (1H, s), 7.33-7.52 (5H, m)

[0302] Reference Example D-2 (4-(benzyloxy)-6-chloropyridazin-3-yl)methanol To a mixture of Reference Example D-1 (0.340 g) and methanol (5 mL), sodium borohydride (0.092 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol = 59 / 39 / 2 - 0 / 98 / 2) to obtain the title compound (0.240 g).

[0303] Reference Example D-3 2-((4-(benzyloxy)-6-chloropyridazin-3-yl)methyl)isoindoline-1,3-dione To a mixture of Reference Example D-2 (0.240 g), TEA (0.194 g), and DCM (3 mL), methanesulfonyl chloride (0.143 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium bicarbonate and water 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, phthalimide (0.169 g), cesium carbonate (0.624 g), and MeCN (3 mL) was stirred at room temperature for 1 hour and then at 50° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, a saturated aqueous solution of ammonium chloride and water were added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. MTBE was added to the residue, and the insoluble matter was collected by filtration. The obtained solid was washed with water and MTBE and then dried under reduced pressure to obtain the title compound (0.290 g).

[0304] Reference Example D-4 2-((4-hydroxypyridazin-3-yl)methyl)isoindoline-1,3-dione hydrochloride A mixture of Reference Example D-3 (0.290 g), 10% Pd / C (0.050 g), methanol (2 mL), and THF (2 mL) was stirred at 50° C. for 10 minutes. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 13 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.072 g).

[0305] Reference Example D-5 2-((4-chloropyridazin-3-yl)methyl)isoindoline-1,3-dione A mixture of Reference Example D-4 (0.040 g), phosphorus oxychloride (0.823 g), and DMF (0.53 mL) was stirred at 90° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue, 5 mol / L aqueous sodium hydroxide solution and saturated aqueous sodium bicarbonate solution were added, and the mixture was extracted with DCM. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. MTBE was added to the residue, and the insoluble matter was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (0.027 g).

[0306] Reference Example D-6 2-((4-bromopyridazin-3-yl)methyl)isoindoline-1,3-dione To a mixture of Reference Example D-4 (0.020 g), DIPEA (0.027 g), and toluene (1 mL), phosphorus oxybromide (0.079 g) was added at room temperature. The reaction mixture was stirred at 80° C. for 1 hour. Water and saturated aqueous sodium bicarbonate solution were slowly added to the reaction mixture under ice-cooling. The mixture was stirred at room temperature for 10 minutes. DCM and a small amount of methanol were added to the mixture at room temperature. The mixture was stirred at the same temperature for 10 minutes. The mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: DCM / ethyl acetate=90 / 10-40 / 60) to obtain the title compound (0.012 g).

[0307] Reference Example E-1 tert-Butyl (4-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-3-(2-cyano-6-fluorobenzyl)-2-fluorophenyl)carbamate. To a mixture of Reference Example A-14 (0.056 g), Reference Example C-3 (0.046 g), potassium carbonate (0.055 g), water (0.4 mL), ethanol (0.4 mL), and toluene (2 mL), Pd(PPh3)4 (0.031 g) was added at room temperature. The reaction mixture was stirred at 100°C for 2 hours under microwave irradiation. 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 (0.028 g).

[0308] Reference Example E-2 (4-(2-(azidomethyl)pyridin-3-yl)-3-(2-cyano-6-fluorobenzyl)-2-fluorophenyl)carbamate tert-butyl To a mixture of Reference Example E-1 (0.041 g) and THF (1 mL), TBAF (1 mol / L in THF) (0.217 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10-40 / 60) to give tert-butyl (3-(2-cyano-6-fluorobenzyl)-2-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)phenyl)carbamate. To a mixture of the obtained compound, TEA (0.021 g), and DCM (1 mL) was added methanesulfonyl chloride (0.012 g) 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 DCM. The extract was concentrated under reduced pressure. To a mixture of the residue and DMF (1 mL), sodium azide (0.007 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into water, 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 70 / 30) to give the title compound (0.028 g).

[0309] Reference Example E-3 tert-Butyl (4-(2-(aminomethyl)pyridin-3-yl)-3-(2-cyano-6-fluorobenzyl)-2-fluorophenyl)carbamate To a mixture of Reference Example E-2 (0.028 g), water (0.1 mL), and THF (1 mL), triphenylphosphine (0.023 g) was added at room temperature. The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (elution solvent: n-hexane / ethyl acetate=65 / 35-0 / 100) to obtain the title compound (0.026 g).

[0310] Reference Example E-4 1-((3-(4-amino-3-fluoro-2-(2-fluorobenzyl)phenyl)pyridin-2-yl)methyl)urea A mixture of Example A-1 (0.953 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluting solvent: ethyl acetate / methanol=98 / 2-70 / 30) to obtain the title compound (0.704 g).

[0311] Reference Example E-5 tert-Butyl (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate. To a mixture of Reference Example A-49 (0.190 g), Reference Example C-1 (0.100 g), 2 mol / L aqueous potassium carbonate solution (0.592 mL), ethanol (0.592 mL), and toluene (3 mL), Pd(PPh3)4 (0.091 g) was added at room temperature. The reaction mixture was stirred at 110°C for 1 hour under microwave irradiation. 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: ethyl acetate / methanol = 100 / 0-85 / 15) to obtain the title compound (0.161 g).

[0312] Reference Example E-6 tert-Butyl (2-fluoro-3-(hydroxymethyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example E-5 (0.160 g) and THF (2 mL), TBAF (1 mol / L in THF) (0.951 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with THF. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.246 g).

[0313] Reference Example E-7 tert-Butyl (3-(bromomethyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate Reference Example E-6 (0.246 g) and DCM (5 mL) were added to a mixture of carbon tetrabromide (0.263 g) and triphenylphosphine (0.208 g) at room temperature. The reaction mixture was stirred at the same temperature for 2 hours and then refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature and stirred overnight. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, 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 (eluting solvent: ethyl acetate / methanol=100 / 0-80 / 20) to obtain the title compound (0.089 g).

[0314] Reference Example E-8 1-((3-(4-amino-2-(2-cyanobenzyl)-3-fluorophenyl)pyridin-2-yl)methyl)urea hydrochloride A mixture of Example A-2 (0.126 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1.2 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.159 g).

[0315] Reference Example E-9 was synthesized in the same manner as in Reference Example E-4, except that Example E-3 was used instead of Example A-1.

[0316] Reference Example E-10 was synthesized in the same manner as in Reference Example E-4, except that Example E-8 was used instead of Example A-1.

[0317] Reference Example E-11 (E)-3-(3-(4-((tert-butoxycarbonyl)amino)-3-fluoro-2-((3-fluoropyridin-2-yl)methyl)phenyl)pyridin-2-yl)acrylate Ethyl (E)-3-(3-(4-((tert-butoxycarbonyl)amino)-3-fluoro-2-((3-fluoropyridin-2-yl)methyl)phenyl)pyridin-2-yl)acrylate To a mixture of Reference Example A-73 (0.150 g), Reference Example C-8 (0.114 g), 2 mol / L aqueous potassium carbonate solution (0.564 mL), ethanol (0.564 mL) and toluene (1.5 mL), Pd(PPh3)4 (0.087 g) was added at room temperature. The reaction mixture was stirred at 110 °C for 1 hour under microwave irradiation. 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 Method A (elution solvent: n-hexane / ethyl acetate = 95 / 5-50 / 50) to obtain the title compound (0.072 g).

[0318] Reference Example E-12 3-(3-(4-amino-3-fluoro-2-((3-fluoropyridin-2-yl)methyl)phenyl)pyridin-2-yl)propanamide To a mixture of Reference Example E-11 (0.072 g), THF (0.5 mL), and methanol (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.109 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water and 1 mol / L hydrochloric acid 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 and MeCN (1 mL), DMT-MM (0.060 g) and 15 mol / L aqueous ammonia (0.015 mL) were added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. 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 using Method A (elution solvent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2-0 / 98 / 2-0 / 86 / 14) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-((3-fluoropyridin-2-yl)methyl)phenyl)carbamate. Under a hydrogen atmosphere, a mixture of the obtained compound, 10% Pd / C (0.005 g), methanol (1 mL), and THF (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A mixture of the residue and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at 40 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol=98 / 2-80 / 20) to obtain the title compound (0.027 g).

[0319] Reference Example F-1 tert-Butyl (4-(2-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-3-yl)-2-fluoro-3-phenoxyphenyl)carbamate Reference Example B-5 (0.206 g), Reference Example C-3 (0.183 g), Pd(PPh3)4 (0.122 g), 0.84 mol / L aqueous potassium carbonate solution (1.87 mL), and 1,4-dioxane (7.5 mL) were stirred at 120 °C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 100 / 0-82 / 18) to obtain the title compound (0.125 g).

[0320] Reference Example F-2 tert-Butyl (4-(2-(azidomethyl)pyridin-3-yl)-2-fluoro-3-phenoxyphenyl)carbamate To a mixture of Reference Example F-1 (0.123 g) and THF (3.4 mL), TBAF (1 mol / L in THF) (0.705 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate = 100 / 0-25 / 75) to obtain tert-butyl (2-fluoro-4-(2-(hydroxymethyl)pyridin-3-yl)-3-phenoxyphenyl)carbamate. To a mixture of the obtained compound, TEA (0.066 g), and DCM (3 mL), methanesulfonyl chloride (0.037 g) was added 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 DCM. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Sodium azide (0.021 g) was added to a mixture of the residue and DMF (3 mL) at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5-75 / 25) to give the title compound (0.085 g).

[0321] Reference Example F-3 tert-Butyl (4-(2-(aminomethyl)pyridin-3-yl)-2-fluoro-3-phenoxyphenyl)carbamate To a mixture of Reference Example F-2 (0.083 g), water (0.33 mL), and THF (3.3 mL), triphenylphosphine (0.076 g) was added at room temperature. The reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol=99 / 1-91 / 9) to obtain the title compound (0.045 g).

[0322] Reference Example F-4 1-((3-(4-amino-3-fluoro-2-(2-fluorophenoxy)phenyl)pyridin-2-yl)methyl)urea A mixture of Example B-2 (0.105 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol=100 / 0-70 / 30) to obtain the title compound (0.065 g).

[0323] Reference Example F-5: tert-Butyl (4-(2-acetylpyridin-3-yl)-3-phenoxyphenyl)carbamate. To a mixture of Reference Example B-13 (0.100 g), Reference Example C-9 (0.066 g), 2 mol / L aqueous sodium carbonate solution (0.243 mL), and toluene (1 mL), Pd(amphos)Cl (0.017 g) was added at room temperature. The reaction mixture was stirred under microwave irradiation at 120°C for 1 hour and then at 150°C 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 using Method A (elution solvent: n-hexane / ethyl acetate = 90 / 10-50 / 50) to obtain the title compound (0.055 g).

[0324] Reference Example G-1 tert-Butyl (4-(3-((1,3-dioxoisoindolin-2-yl)methyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate Reference Example A-5 (0.178 g), Reference Example D-5 (0.089 g), 2 mol / L aqueous potassium carbonate solution (0.444 mL), ethanol (0.444 mL), and toluene (1 mL) were mixed and Pd(amphos)Cl (0.042 g) was added at room temperature. The reaction mixture was stirred at 100° C. for 1 hour under microwave irradiation. 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 Method A (elution solvent: n-hexane / ethyl acetate=80 / 20-20 / 80) to obtain the title compound (0.038 g).

[0325] Reference Example G-2 1-((4-(4-amino-3-fluoro-2-(2-fluorobenzyl)phenyl)pyridazin-3-yl)methyl)urea A mixture of Example C-1 (0.015 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol=98 / 2-80 / 20) to obtain the title compound (0.010 g).

[0326] Reference Example G-3 1-Methylcyclopropyl (4-(3-((1,3-dioxoisoindolin-2-yl)methyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate Reference Example A-16 (0.109 g), Reference Example D-6 (0.047 g), Pd(PPh3)4 (0.034 g), 2 mol / L aqueous potassium carbonate solution (0.222 mL), ethanol (0.222 mL), and toluene (1 mL) were stirred at 100°C for 1 hour under microwave irradiation. 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 / 20-20 / 80) to obtain the title compound (0.014 g).

[0327] Reference Example G-4: tert-Butyl (4-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate. Reference Example A-5 (0.400 g), 4-bromo-6-chloropyridazin-3(2H)-one (0.151 g), 2 mol / L aqueous potassium carbonate solution (0.984 mL), and 1,4-dioxane (3 mL) were mixed and Pd(PPh3)4 (0.152 g) was added at room temperature. The reaction mixture was stirred at 160°C for 30 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. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20-60 / 40) to obtain the title compound (0.036 g). 1 H-NMR (CDCl3) δ ppm : 1.53 (9H, s), 4.04 (2H, s), 6.76-7.02 (6H, m), 7.10-7.20 (1H, m), 8.05-8.18 (1H, m), 10.29 (1H, br)

[0328] Reference Example G-5 tert-butyl (2-fluoro-3-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydropyridazin-4-yl)phenyl)carbamate. Under a hydrogen atmosphere, a mixture of Reference Example G-4 (0.036 g), 10% Pd / C (0.020 g), and methanol (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-90 / 10) to give the title compound (0.030 g).

[0329] Reference Example G-6 4-(4-((tert-butoxycarbonyl)amino)-3-fluoro-2-(2-fluorobenzyl)phenyl)pyridazin-3-yl trifluoromethanesulfonate To a mixture of Reference Example G-5 (0.030 g), cesium carbonate (0.047 g) and DMF (1 mL), N-phenylbis(trifluoromethanesulfonimide) (0.031 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into water, 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 (elution solvent: n-hexane / ethyl acetate = 80 / 20-30 / 70) to obtain the title compound (0.036 g).

[0330] Reference Example G-7: Ethyl (E)-3-(4-(4-((tert-butoxycarbonyl)amino)-3-fluoro-2-(2-fluorobenzyl)phenyl)pyridazin-3-yl)acrylate. To a mixture of Reference Example G-6 (0.036 g), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (0.016 g), 2 mol / L aqueous potassium carbonate solution (0.099 mL), ethanol (0.1 mL), and DME (1 mL), Pd(PPh3)4 (0.015 g) was added at room temperature. The reaction mixture was stirred at 110°C for 30 minutes under microwave irradiation. 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 Method A (elution solvent: n-hexane / ethyl acetate=80 / 20-10 / 90) to obtain the title compound (0.011 g).

[0331] Reference Example G-8 3-(4-(4-amino-3-fluoro-2-(2-fluorobenzyl)phenyl)pyridazin-3-yl)propanamide A mixture of Example C-4 (0.017 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-60 / 40) to obtain the title compound (0.009 g).

[0332] Reference Example G-9 [1,1'-bi(cyclopropane)]-1-yl (4-(3-((1,3-dioxoisoindolin-2-yl)methyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate [1,1'-bi(cyclopropane)]-1-yl Reference Example A-57 (0.050 g), Reference Example D-5 (0.029 g), 2 mol / L aqueous potassium carbonate solution (0.160 mL), ethanol (0.160 mL), and toluene (2 mL) were mixed and added with Pd(amphos)Cl (0.015 g) at room temperature. The reaction mixture was stirred at 100°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 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 / methanol=70 / 30 / 0-0 / 100 / 0-0 / 98 / 2) to obtain the title compound (0.009 g).

[0333] Reference Example H-1 tert-Butyl (4-(3-((1,3-dioxoisoindolin-2-yl)methyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate. To a mixture of Reference Example B-9 (0.120 g), Reference Example D-5 (0.086 g), 2 mol / L aqueous potassium carbonate solution (0.469 mL), ethanol (0.469 mL), and toluene (1.5 mL), Pd(amphos)Cl (0.044 g) was added at room temperature. The reaction mixture was stirred at 100°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 saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol=69 / 29 / 2-0 / 98 / 2) to obtain the title compound (0.062 g).

[0334] Reference Example H-2 1-((4-(4-amino-3-fluoro-2-(2-fluorophenoxy)phenyl)pyridazin-3-yl)methyl)urea A mixture of Example D-1 (0.020 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (1 mL) was stirred at room temperature for 30 minutes and then at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (elution solvent: ethyl acetate / methanol=98 / 2-80 / 20) to obtain the title compound (0.016 g).

[0335] Reference Example H-3 was synthesized in the same manner as in Reference Example G-4, except that Reference Example B-9 was used instead of Reference Example A-5. 1 H-NMR (CDCl3) δ ppm : 1.53 (9H, s), 6.71-6.89 (2H, m), 6.92-7.04 (2H, m), 7.06-7.38 (1H, m), 7.45 (1H, s), 7.47-7.53 (1H, m), 8.01-8.20 (1H, m), 10.56 (1H, br)

[0336] Reference Example H-4 tert-Butyl (2-fluoro-3-(2-fluorophenoxy)-4-(3-oxo-2,3-dihydropyridazin-4-yl)phenyl)carbamate. Under a hydrogen atmosphere, a mixture of Reference Example H-3 (0.064 g), 10% Pd / C (0.064 g), potassium carbonate (0.020 g), and 1,4-dioxane (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95 / 5-50 / 50) to give the title compound (0.058 g).

[0337] Reference Example H-5 4-(4-((tert-butoxycarbonyl)amino)-3-fluoro-2-(2-fluorophenoxy)phenyl)pyridazin-3-yl trifluoromethanesulfonate To a mixture of Reference Example H-4 (0.058 g), cesium carbonate (0.136 g), and DMF (2 mL), N-phenylbis(trifluoromethanesulfonimide) (0.075 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into water, 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 (elution solvent: n-hexane / ethyl acetate = 80 / 20-30 / 70) to obtain the title compound (0.040 g).

[0338] Reference Example H-6: Ethyl (E)-3-(4-(4-((tert-butoxycarbonyl)amino)-3-fluoro-2-(2-fluorophenoxy)phenyl)pyridazin-3-yl)acrylate. To a mixture of Reference Example H-5 (0.040 g), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (0.025 g), 2 mol / L aqueous potassium carbonate solution (0.110 mL), ethanol (0.1 mL), and DME (2 mL), Pd(PPh3)4 (0.017 g) was added at room temperature. The reaction mixture was stirred at 110°C for 30 minutes under microwave irradiation. 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 Method A (elution solvent: n-hexane / ethyl acetate=80 / 20-10 / 90) to obtain the title compound (0.034 g).

[0339] Reference Example H-7 3-(4-(4-amino-3-fluoro-2-(2-fluorophenoxy)phenyl)pyridazin-3-yl)propanamide A mixture of Example D-3 (0.019 g) and hydrogen chloride (4 mol / L in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-60 / 40) to give the title compound (0.008 g).

[0340] Reference Example I-1 (4-Nitrophenyl) 1-Methylcyclopropyl Carbonate Under an argon atmosphere, 4-nitrophenyl chloroformate (1.54 g) was added to a mixture of 1-methylcyclopropan-1-ol (0.500 g), pyridine (1.10 g), and DCM (10 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. n-Hexane was added to the residue, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.31 g).

[0341] Reference Example I-2 (4-Nitrophenyl) 1-(benzyloxy)-2-methylpropan-2-yl Carbonate To a mixture of 1-(benzyloxy)-2-methylpropan-2-ol (0.101 g) and DCM (1 mL), pyridine (0.088 g) and 4-nitrophenyl chloroformate (0.124 g) were added sequentially under ice-cooling. The reaction mixture was stirred at room temperature for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was washed three times with saturated aqueous ammonium chloride solution, 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 / 0-88 / 12) to obtain the title compound (0.153 g).

[0342] Reference Example I-3 Carbonochloridic acid quinuclidin-3-yl hydrochloride To a mixture of 3-quinuclidinol (0.201 g) and MeCN (16 mL), trichloromethyl chloroformate (0.404 g) was slowly added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.357 g).

[0343] Reference Example I-4 (4-Nitrophenyl) 1,1-difluoro-2-methylpropan-2-yl Carbonate Pyridine (0.158 g) and 4-nitrophenyl chloroformate (0.222 g) were added to a mixture of 1,1-difluoro-2-methylpropan-2-ol (0.110 g) and DCM (5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure, and a small amount of ethyl acetate was added to the residue. n-Hexane was added to the mixture, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.099 g).

[0344] Reference Example I-5 was synthesized in the same manner as in Reference Example I-2, except that bicyclo[2.2.2]octan-3-ol was used instead of 1-(benzyloxy)-2-methylpropan-2-ol.

[0345] Reference Example I-6 was synthesized in the same manner as in Reference Example I-4, except that [1,1'-bi(cyclopropane)]-1-ol was used instead of 1,1-difluoro-2-methylpropan-2-ol.

[0346] Reference Example J-1: Ethyl (E)-3-(3-bromopyrazin-2-yl)acrylate. Under an argon atmosphere, sodium hydride (approximately 60%) (0.021 g) was added to a mixture of triethyl phosphonoacetate (0.121 g) and THF (2.5 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. A solution of 3-bromopyrazine-2-carbaldehyde (0.084 g) in THF (2 mL) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 98 / 2-75 / 25) to give the title compound (0.076 g).

[0347] Reference Example J-2 (E)-3-(3-bromopyrazin-2-yl)acrylamide To a mixture of Reference Example J-1 (0.075 g), THF (1 mL), and methanol (1 mL), 4 mol / L aqueous lithium hydroxide solution (0.219 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Water and 1 mol / L hydrochloric acid (1 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 and MeCN (1 mL), DMT-MM (0.121 g) and 15 mol / L aqueous ammonia (0.029 mL) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride solution and DCM were added to the reaction mixture at room temperature. The mixture was stirred at the same temperature for 10 minutes, and the insoluble matter was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (0.026 g).

[0348] The structural formulas of the reference examples are shown in the table below.

[0349]

[0350] Example A-1 tert-Butyl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate. To a mixture of Reference Example A-5 (0.060 g), Reference Example C-1 (0.023 g), 2 mol / L aqueous potassium carbonate solution (0.150 mL), ethanol (0.150 mL), and toluene (2 mL), Pd(PPh3)4 (0.023 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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: ethyl acetate / methanol = 98 / 2-85 / 15) to obtain the title compound (0.032 g).

[0351] Example A-2 tert-Butyl (3-(2-cyanobenzyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate. To a mixture of Reference Example A-10 (0.160 g), Reference Example C-1 (0.058 g), 2 mol / L aqueous potassium carbonate solution (0.377 mL), ethanol (0.377 mL), and toluene (2 mL), Pd(PPh3)4 (0.058 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2 to 85 / 15) and amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 85 / 15) to obtain the title compound (0.070 g).

[0352] Example A-3 (3-(2-cyano-6-fluorobenzyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl To a mixture of Reference Example E-3 (0.026 g) and THF (0.75 mL), trimethylsilyl isocyanate (0.017 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.019 g).

[0353] Example A-4 1-methylcyclopropyl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example E-4 (0.040 g), Reference Example I-1 (0.471 g), and MeCN (2 mL), HOBt hydrate (0.042 g) and DIPEA (0.049 g) were added at room temperature. The reaction mixture was stirred at 80° C. for 70 hours. 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. The residue was purified by Method A (elution solvent: ethyl acetate / methanol=100 / 0-90 / 10) to give the title compound (0.008 g).

[0354] Example A-5 trans-3-fluorocyclobutyl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate A mixture of Reference Example E-4 (0.020 g), 4-nitrophenyl chloroformate (0.016 g) and THF (1 mL) was stirred under ice-cooling for 15 minutes, then at room temperature for 15 minutes. To the reaction mixture were added trans-3-fluorocyclobutan-1-ol (0.024 g) and DMAP (0.010 g) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. 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 Method A (elution solvent: ethyl acetate / methanol = 100 / 0-90 / 10) to obtain the title compound (0.013 g).

[0355] Examples A-6 to A-8 were synthesized in the same manner as in Example A-5, except that the corresponding starting materials were used instead of trans-3-fluorocyclobutan-1-ol.

[0356] Example A-9 (3-benzyl-2-fluoro-4-(4-methyl-2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-Butyl Reference Example A-20 (0.035 g), Reference Example C-4 (0.020 g), 2 mol / L aqueous potassium carbonate solution (0.123 mL), ethanol (0.123 mL), and DME (0.5 mL) were mixed and Pd(PPh3)4 (0.019 g) was added at room temperature. The reaction mixture was stirred at 120 °C for 30 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. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0-85 / 15) to obtain the title compound (0.009 g).

[0357] Example A-10 (2-fluoro-3-(2-fluorobenzyl)-4-(5-methyl-2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl Under an argon atmosphere, a mixture of Reference Example A-5 (0.030 g), Reference Example C-5 (0.016 g), Pd(PPh3)4 (0.016 g), potassium carbonate (0.028 g), water (0.2 mL), ethanol (0.2 mL), and toluene (2 mL) was refluxed for 30 minutes. The reaction mixture 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 / 70 / 30) to obtain the title compound (0.009 g).

[0358] Example A-11 (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-3-(1-phenylethyl)phenyl)carbamate tert-Butyl Ester Under an argon atmosphere, Pd(PPh3)4 (0.011 g) was added to a mixture of Reference Example A-25 (0.021 g), Reference Example C-7 (0.012 g), potassium carbonate (0.021 g), water (0.14 mL), ethanol (0.14 mL), and toluene (0.56 mL) at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=70 / 30 / 0-0 / 100 / 0-0 / 95 / 5) and diamine silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=70 / 30 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (0.006 g).

[0359] Example A-12 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-3-(1-phenylethyl)phenyl)carbamate Under an argon atmosphere, 10% Pd / C (0.012 g) was added to a mixture of Example A-11 (0.011 g), ethanol (1 mL), and THF (1 mL) at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.010 g).

[0360] Example A-13 tert-Butyl (3-(2-fluorobenzyl)-2-methyl-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate. To a mixture of Reference Example A-30 (0.050 g), Reference Example C-1 (0.023 g), 2 mol / L aqueous potassium carbonate solution (0.148 mL), ethanol (0.170 mL), and toluene (1 mL), Pd(PPh3)4 (0.023 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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: n-hexane / ethyl acetate / methanol = 49 / 49 / 2-0 / 98 / 2-0 / 86 / 14) to obtain the title compound (0.034 g).

[0361] Example A-14 (2,6-difluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl ester Reference Example A-36 (0.060 g), Reference Example C-1 (0.029 g), 2 mol / L aqueous potassium carbonate solution (0.169 mL), ethanol (0.169 mL), and toluene (0.5 mL) were mixed and Pd(PPh3)4 (0.026 g) was added at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. 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: n-hexane / ethyl acetate / methanol = 49 / 49 / 2-0 / 98 / 2-0 / 86 / 14) to obtain the title compound (0.043 g).

[0362] Example A-15 was synthesized in the same manner as in Example A-1, except that Reference Example A-41 was used instead of Reference Example A-5.

[0363] Example A-16 was synthesized in the same manner as in Example A-1, except that Reference Example A-46 was used instead of Reference Example A-5.

[0364] Example A-17 (2-fluoro-3-(2-methoxybenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl ester Reference Example E-7 (0.050 g), 2-methoxyphenylboronic acid (0.017 g), sodium carbonate (0.023 g), water (0.25 mL), and DME (0.66 mL) were mixed and Pd(PPh3)4 (0.006 g) was added at room temperature. The reaction mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. A 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 by silica gel column chromatography (eluting solvent: ethyl acetate / methanol = 100 / 0-94 / 6) to obtain the title compound (0.006 g).

[0365] Example A-18 (3-(2-(benzyloxy)benzyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl ester. Reference Example E-7 (0.030 g), (2-benzyloxyphenyl)boronic acid (0.015 g), sodium carbonate (0.014 g), water (0.125 mL), and DME (0.33 mL) were mixed and Pd(PPh3)4 (0.003 g) was added at room temperature. The reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. A 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 by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-93 / 7) to obtain the title compound (0.019 g).

[0366] Example A-19 tert-Butyl (2-fluoro-3-(2-hydroxybenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate Example A-18 (0.017 g) and methanol (1 mL) were added to a mixture of 10% Pd / C (0.005 g) at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at the same temperature for 30 minutes and then at 60 ° C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-90 / 10) to obtain the title compound (0.011 g).

[0367] Example A-20 (2-Fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate 1-(benzyloxy)-2-methylpropan-2-yl Under microwave irradiation, a mixture of Reference Example A-51 (0.076 g), Reference Example C-1 (0.023 g), potassium carbonate (0.041 g), Pd(PPh3)4 (0.023 g), water (0.21 mL), ethanol (0.21 mL) and DME (0.84 mL) was stirred at 100 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / methanol = 100 / 0-92 / 8) to obtain the title compound (0.020 g).

[0368] Example A-21 1-hydroxy-2-methylpropan-2-yl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate Under an argon atmosphere, 10% Pd / C (0.007 g) was added to a mixture of Example A-20 (0.017 g), ethanol (1 mL), and THF (1 mL) at room temperature. Under a hydrogen atmosphere, the reaction mixture was stirred at the same temperature for 2.5 hours and then at 70 ° C. for 9 hours. The reaction mixture was allowed to cool to room temperature and stirred for 10 hours. The reaction mixture was stirred at 70 ° C. for 12 hours. After allowing the reaction mixture to cool to room temperature, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-89 / 11) to obtain the title compound (0.011 g).

[0369] Examples A-22 to A-24 were synthesized in the same manner as in Example A-5, except that the corresponding starting materials were used instead of trans-3-fluorocyclobutan-1-ol.

[0370] Example A-25 (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate (S)-1-methoxypropan-2-yl A mixture of Reference Example E-4 (0.020 g), 4-nitrophenyl chloroformate (0.016 g) and THF (1 mL) was stirred under ice-cooling for 15 minutes, then at room temperature for 15 minutes. To the reaction mixture were added (S)-1-methoxypropan-2-ol (0.024 g) and DMAP (0.010 g) at room temperature. The reaction mixture was stirred at 50 ° C. for 3 hours. 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. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-85 / 15) to obtain the title compound (0.015 g).

[0371] Example A-26 (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate Cyclopropyl A mixture of Reference Example E-4 (0.018 g), 4-nitrophenyl chloroformate (0.015 g) and THF (1 mL) was stirred under ice-cooling for 15 minutes, then at room temperature for 15 minutes. Cyclopropanol (0.0029 g) and DMAP (0.009 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 4 hours. 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 sequentially by amino silica gel column chromatography (eluting solvent: ethyl acetate / methanol=100 / 0-95 / 5) and silica gel column chromatography (eluting solvent: ethyl acetate / methanol=100 / 0-95 / 5) to give the title compound (0.003 g).

[0372] Example A-27 3,3-difluorocyclopentyl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate 4-Nitrophenyl chloroformate (0.014 g) was added to a mixture of Reference Example E-4 (0.020 g) and THF (0.5 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. 3,3-Difluorocyclopentanol (0.033 g) and DMAP (0.009 g) were added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours. 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 Method A (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.012 g).

[0373] Example A-28 was synthesized in the same manner as in Example A-5, except that tetrahydrofuran-3-ol was used instead of trans-3-fluorocyclobutan-1-ol.

[0374] Example A-29 Quinuclidin-3-yl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example E-4 (0.031 g), Reference Example I-3 (0.028 g), and THF (1 mL), NaHMDS (1 mol / L in THF) (0.081 mL) was slowly added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. Reference Example I-3 (0.018 g) was added to the reaction mixture under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by amino silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-89 / 11) and amino silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-89 / 11) to obtain the title compound (0.003 g).

[0375] Example A-30 3-(dimethylamino)propyl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate 4-Nitrophenyl chloroformate (0.025 g) was added to a mixture of Reference Example E-4 (0.030 g) and THF (1 mL) under ice-cooling. The reaction mixture was stirred for 15 minutes under ice-cooling. 3-Dimethylamino-1-propanol (0.042 g) and DMAP (0.010 g) were added to the reaction mixture under ice-cooling. The reaction mixture was stirred overnight at 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 amino silica gel column chromatography (eluting solvent: ethyl acetate / methanol=100 / 0-48 / 52) to obtain the title compound (0.040 g).

[0376] Example A-31 Cyclopropylmethyl (2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example E-4 (0.030 g) and THF (1 mL), 4-nitrophenyl chloroformate (0.025 g) was added under ice-cooling. The reaction mixture was stirred for 25 minutes under ice-cooling and then at room temperature for 10 minutes. Cyclopropylmethanol (0.029 g) and DMAP (0.015 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The extract was washed with saturated aqueous sodium bicarbonate solution and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluting solvent: n-hexane / ethyl acetate / methanol = 30 / 70 / 0-0 / 100 / 0-0 / 95 / 5) to obtain the title compound (0.031 g).

[0377] Examples A-32 to A-35 were synthesized in the same manner as in Example A-5, except that the corresponding starting materials were used instead of trans-3-fluorocyclobutan-1-ol.

[0378] Example A-36 was synthesized in the same manner as in Example A-31, except that (2-fluorophenyl)methanol was used instead of cyclopropylmethanol.

[0379] Example A-37 1,1-difluoro-2-methylpropan-2-yl (3-(2-cyanobenzyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example E-8 (0.025 g), Reference Example I-4 (0.033 g), and MeCN (2 mL), HOBt hydrate (0.023 g) and TEA (0.022 g) were added at room temperature. The reaction mixture was stirred at 80° C. for 31 hours. 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. The residue was purified sequentially by Method A (elution solvent: n-hexane / ethyl acetate / methanol = 10 / 90 / 0-0 / 100 / 0-0 / 90 / 10) and amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 100 / 0 / 0-0 / 100 / 0-0 / 90 / 10) to give the title compound (0.007 g).

[0380] Example A-38 Bicyclo[2.2.2]octan-2-yl (3-(2-cyanobenzyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example E-8 (0.030 g), Reference Example I-5 (0.064 g), and MeCN (1.2 mL), HOBt hydrate (0.022 g) and TEA (0.026 g) were added sequentially at room temperature. The reaction mixture was refluxed for 27 hours. TEA (0.011 g) was added to the reaction mixture at room temperature. The reaction mixture was refluxed for 10 hours. The reaction mixture was allowed to cool to room temperature and diluted with DCM. The mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified sequentially by Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 87 / 13), silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 87 / 13), and amino silica gel column chromatography (elution solvent: ethyl acetate / methanol = 100 / 0 to 89 / 11) to give the title compound (0.002 g).

[0381] Example A-39 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-3-(2-cyanobenzyl)-2-fluorophenyl)carbamate To a mixture of Reference Example A-10 (0.112 g), Reference Example C-7 (0.019 g), 2 mol / L aqueous potassium carbonate solution (0.115 mL), ethanol (0.122 mL), and DME (0.5 mL), Pd(PPh3)4 (0.018 g) was added at room temperature. The reaction mixture was stirred at 120°C for 1 hour under microwave irradiation. 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: ethyl acetate / methanol = 100 / 0-90 / 10) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-3-(2-cyanobenzyl)-2-fluorophenyl)carbamate. To a mixture of the obtained compound and methanol (1 mL), 10% Pd / C (0.003 g) was added at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-90 / 10) to give the title compound (0.019 g).

[0382] Example A-40 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-(methylsulfonyl)benzyl)phenyl)carbamate. To a mixture of Reference Example A-55 (0.027 g), Reference Example C-7 (0.007 g), 2 mol / L aqueous potassium carbonate solution (0.043 mL), ethanol (0.043 mL), and toluene (2 mL), Pd(PPh3)4 (0.007 g) was added at room temperature. The reaction mixture was stirred at 110°C for 1 hour under microwave irradiation. 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: ethyl acetate / methanol = 100 / 0-75 / 25) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-(2-(methylsulfonyl)benzyl)phenyl)carbamate. To a mixture of the obtained compound, methanol (1 mL), and THF (1 mL), 10% Pd / C (0.010 g) was added at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified sequentially by amino silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-85 / 15) and silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-70 / 30) to give the title compound (0.002 g).

[0383] Example B-1 tert-Butyl (2-fluoro-3-phenoxy-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example F-3 (0.044 g) and THF (1 mL), trimethylsilyl isocyanate (0.037 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-92 / 8) to obtain the title compound (0.041 g).

[0384] Example B-2 tert-Butyl (2-fluoro-3-(2-fluorophenoxy)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate. To a mixture of Reference Example B-9 (0.034 g), Reference Example C-1 (0.017 g), 2 mol / L aqueous potassium carbonate solution (0.114 mL), ethanol (0.114 mL), and toluene (2 mL), Pd(PPh3)4 (0.018 g) was added at room temperature. The reaction mixture was stirred at 110°C for 1 hour under microwave irradiation. 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: ethyl acetate / methanol = 100 / 0-65 / 35) to obtain the title compound (0.014 g).

[0385] Example B-3 (2-Fluoro-3-(2-fluorophenoxy)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate (S)-1,1,1-trifluoropropan-2-yl To a mixture of Reference Example F-4 (0.025 g) and THF (2 mL), 4-nitrophenyl chloroformate (0.020 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour and then at room temperature for 15 minutes. To the reaction mixture, (S)-1,1,1-trifluoropropan-2-ol (0.038 g) and DMAP (0.025 g) were added 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 solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol=100 / 0 to 85 / 15) to give the title compound (0.016 g).

[0386] Example B-4 was synthesized in the same manner as in Example B-3, except that (3,3-difluorocyclobutyl)methanol was used instead of (S)-1,1,1-trifluoropropan-2-ol.

[0387] Example B-5 was synthesized in the same manner as in Example A-5, except that Reference Example F-4 and 3,3-difluorocyclobutan-1-ol were used instead of Reference Example E-4 and trans-3-fluorocyclobutan-1-ol.

[0388] Example B-6 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate A mixture of Reference Example B-9 (0.021 g), Reference Example C-7 (0.010 g), Pd(PPh3)4 (0.010 g), 2 mol / L aqueous potassium carbonate solution (0.069 mL), ethanol (0.069 mL), and toluene (1.2 mL) was stirred at 110 °C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with DCM. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 0 / 10 / 90-0 / 100 / 0-0 / 98 / 2) and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 95 / 5) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate. Under an argon atmosphere, 10% Pd / C (0.006 g) was added to a mixture of the obtained compound and methanol (1 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2.5 hours 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: n-hexane / ethyl acetate / methanol=10 / 90 / 0-0 / 100 / 0-0 / 91 / 9) and ODS column chromatography (eluent: water / MeCN=90 / 10-10 / 90) to obtain the title compound (0.003 g).

[0389] Example B-7 tert-Butyl (4-(2-(1-hydroxyethyl)pyridin-3-yl)-3-phenoxyphenyl)carbamate To a mixture of Reference Example F-5 (0.020 g) and methanol (1 mL), sodium borohydride (0.004 g) was added under ice-cooling. The reaction mixture was stirred at the same temperature for 30 minutes. 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 Method A (elution solvent: n-hexane / ethyl acetate = 80 / 20-30 / 70) to obtain the title compound (0.018 g).

[0390] Example C-1 tert-Butyl (2-fluoro-3-(2-fluorobenzyl)-4-(3-(ureidomethyl)pyridazin-4-yl)phenyl)carbamate A mixture of Reference Example G-1 (0.085 g), hydrazine monohydrate (0.076 g), and ethanol (1 mL) was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, trimethylsilyl isocyanate (0.053 g), and THF (1 mL) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to obtain the title compound (0.054 g).

[0391] Example C-2 (S)-1,1,1-trifluoropropan-2-yl (2-fluoro-3-(2-fluorobenzyl)-4-(3-(ureidomethyl)pyridazin-4-yl)phenyl)carbamate 4-Nitrophenyl chloroformate (0.008 g) was added to a mixture of Reference Example G-2 (0.010 g) and THF (0.5 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. (S)-1,1,1-trifluoropropan-2-ol (0.015 g) and DMAP (0.010 g) were added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 14 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 Method A (elution solvent: ethyl acetate / methanol=98 / 2-85 / 15) to obtain the title compound (0.007 g).

[0392] Example C-3 1-methylcyclopropyl (2-fluoro-3-(2-fluorobenzyl)-4-(3-(ureidomethyl)pyridazin-4-yl)phenyl)carbamate A mixture of Reference Example G-3 (0.014 g), hydrazine monohydrate (0.012 g), and ethanol (1 mL) was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, trimethylsilyl isocyanate (0.009 g), and THF (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.007 g).

[0393] Example C-4 tert-Butyl (4-(3-(3-amino-3-oxopropyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate To a mixture of Reference Example G-7 (0.011 g), THF (0.5 mL), and methanol (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.055 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 4 hours. Water and 2 mol / L hydrochloric acid 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, DMT-MM (0.010 g), and MeCN (1 mL), 15 mol / L aqueous ammonia (0.015 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. 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 (eluent: ethyl acetate / methanol = 90 / 10 to 60 / 40) to give tert-butyl (E)-(4-(3-(3-amino-3-oxoprop-1-en-1-yl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate. To a mixture of the obtained compound, methanol (1 mL), and THF (1 mL), 10% Pd / C (0.010 g) was added at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.003 g).

[0394] Example C-5 (4-(3-(3-amino-3-oxopropyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate (S)-1,1,1-trifluoropropan-2-yl To a mixture of Reference Example G-8 (0.009 g) and THF (1 mL), 4-nitrophenyl chloroformate (0.008 g) and pyridine (0.004 g) were added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. To the reaction mixture, (S)-1,1,1-trifluoropropan-2-ol (0.015 g) and DMAP (0.005 g) were added under ice-cooling. The reaction mixture was stirred at room temperature for 40 minutes. To the reaction mixture, (S)-1,1,1-trifluoropropan-2-ol (0.015 g) and TEA (0.008 g) were added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0 to 70 / 30) to give the title compound (0.008 g).

[0395] Example C-6 (4-(3-(3-amino-3-oxopropyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate (R)-1-Cyclopropylethyl ester To a mixture of Reference Example G-8 (0.010 g) and THF (1 mL), 4-nitrophenyl chloroformate (0.008 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, (R)-1-cyclopropylethan-1-ol (0.012 g) and DMAP (0.010 g) were added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol=100 / 0 to 90 / 10) to obtain the title compound (0.004 g).

[0396] Example C-7 trans-3-fluorocyclobutyl (4-(3-(3-amino-3-oxopropyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorobenzyl)phenyl)carbamate To a mixture of Reference Example G-8 (0.004 g) and THF (1 mL), 4-nitrophenyl chloroformate (0.003 g) was added under ice-cooling. The reaction mixture was stirred at room temperature for 5 minutes. trans-3-Fluorocyclobutan-1-ol (0.006 g) and DMAP (0.002 g) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into a saturated aqueous solution of 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 (eluting solvent: ethyl acetate / methanol=100 / 0-70 / 30) to obtain the title compound (0.002 g).

[0397] Example C-8 was synthesized in the same manner as in Example C-6, except that 3,3-difluorocyclobutan-1-ol was used instead of (R)-1-cyclopropylethan-1-ol.

[0398] Example C-9 tert-butyl (2-fluoro-3-(2-fluorobenzyl)-4-(3-methylpyridazin-4-yl)phenyl)carbamate. A mixture of Reference Example G-6 (0.020 g), Pd(PPh3)4 (0.005 g), tetramethyltin (0.013 g), and N-methylpyrrolidone (1 mL) was stirred at 140 ° C. for 10 minutes under microwave irradiation. The reaction mixture was poured into water, 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 sequentially by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 80 / 20-10 / 90) and amino silica gel column chromatography (eluent: n-hexane / ethyl acetate = 70 / 30-20 / 80) to give the title compound (0.004 g).

[0399] Example C-10 was synthesized in the same manner as in Example C-3, except that Reference Example G-9 was used instead of Reference Example G-3.

[0400] Example D-1 tert-Butyl (2-fluoro-3-(2-fluorophenoxy)-4-(3-(ureidomethyl)pyridazin-4-yl)phenyl)carbamate A mixture of Reference Example H-1 (0.060 g), hydrazine monohydrate (0.054 g), and ethanol (1 mL) was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. A mixture of the residue, trimethylsilyl isocyanate (0.037 g), and THF (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified sequentially by Method A (elution solvent: ethyl acetate / methanol = 98 / 2-85 / 15) and ODS column chromatography (elution solvent: water / MeCN = 70 / 30-10 / 90) to obtain the title compound (0.020 g).

[0401] Example D-2 (2-Fluoro-3-(2-fluorophenoxy)-4-(3-(ureidomethyl)pyridazin-4-yl)phenyl)carbamate (S)-1,1,1-trifluoropropan-2-yl To a mixture of Reference Example H-2 (0.016 g) and THF (0.5 mL), 4-nitrophenyl chloroformate (0.013 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. To the reaction mixture, (S)-1,1,1-trifluoropropan-2-ol (0.025 g) and DMAP (0.016 g) were 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. The residue was purified by Method A (elution solvent: ethyl acetate / methanol=98 / 2-85 / 15) to obtain the title compound (0.014 g).

[0402] Example D-3 tert-Butyl (4-(3-(3-amino-3-oxopropyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate To a mixture of Reference Example H-6 (0.034 g), THF (0.5 mL), and methanol (0.5 mL), 4 mol / L aqueous lithium hydroxide solution (0.171 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 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, DMT-MM (0.028 g), and MeCN (1 mL), 15 mol / L aqueous ammonia (0.046 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 15 minutes. 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. A mixture of the residue, 10% Pd / C (0.032 g), and THF (2 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 95 / 5-70 / 30) to give the title compound (0.020 g).

[0403] Example D-4 (4-(3-(3-amino-3-oxopropyl)pyridazin-4-yl)-2-fluoro-3-(2-fluorophenoxy)phenyl)carbamate (S)-1,1,1-trifluoropropan-2-yl To a mixture of Reference Example H-7 (0.008 g) and THF (2 mL), 4-nitrophenyl chloroformate (0.007 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 15 minutes. To the reaction mixture were added (S)-1,1,1-trifluoropropan-2-ol (0.012 g) and DMAP (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 solution, and the mixture was extracted with DCM. 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 obtain the title compound (0.007 g).

[0404] Example E-1 tert-Butyl (2-fluoro-3-(2-methylbenzoyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example A-62 (0.025 g), Reference Example C-1 (0.014 g), 2 mol / L aqueous potassium carbonate solution (0.082 mL), ethanol (0.082 mL), and toluene (0.5 mL), Pd(PPh3)4 (0.013 g) was added at room temperature. The reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified sequentially by Method A (eluent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2-0 / 98 / 2-0 / 86 / 14) and silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-85 / 15) to obtain the title compound (0.008 g).

[0405] Example E-2 was synthesized in the same manner as in Example A-14, except that Reference Example A-65 was used instead of Reference Example A-36.

[0406] Example E-3 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-fluorobenzoyl)phenyl)carbamate To a mixture of Reference Example A-68 (0.050 g), Reference Example C-7 (0.027 g), 2 mol / L aqueous potassium carbonate solution (0.163 mL), ethanol (0.163 mL), and toluene (1 mL), Pd(PPh3)4 (0.025 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 Method A (eluent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2-0 / 98 / 2-0 / 86 / 14) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-(2-fluorobenzoyl)phenyl)carbamate. Under a hydrogen atmosphere, a mixture of the obtained compound, 10% Pd / C (0.005 g), and methanol (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (eluent: ethyl acetate / methanol = 98 / 2-88 / 12) to give the title compound (0.022 g).

[0407] Example E-4 (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-fluorobenzoyl)phenyl)carbamate (S)-1,1,1-trifluoropropan-2-yl To a mixture of Reference Example E-9 (0.016 g) and THF (1 mL), 4-nitrophenyl chloroformate (0.013 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. To the reaction mixture, (S)-1,1,1-trifluoropropan-2-ol (0.023 g), DMAP (0.007 g), and TEA (0.012 g) were added under ice-cooling. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol=100 / 0 to 80 / 20) to obtain the title compound (0.010 g).

[0408] Example E-5 (S)-1-Cyclopropylethyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-fluorobenzoyl)phenyl)carbamate 4-Nitrophenyl chloroformate (0.014 g) was added to a mixture of Reference Example E-9 (0.017 g) and THF (1.2 mL) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour. (S)-1-Cyclopropylethan-1-ol (0.019 g), DMAP (0.009 g), and TEA (0.014 g) were added to the reaction mixture sequentially under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: n-hexane / ethyl acetate / methanol=5 / 95 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (0.014 g).

[0409] Examples E-6 to E-7 were synthesized in the same manner as in Example E-5, except that the corresponding starting materials were used instead of (S)-1-cyclopropylethan-1-ol.

[0410] Example E-8 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-(trifluoromethyl)benzoyl)phenyl)carbamate. To a mixture of Reference Example A-65 (0.100 g), Reference Example C-7 (0.045 g), 2 mol / L aqueous potassium carbonate solution (0.295 mL), ethanol (0.295 mL), and toluene (1.5 mL), Pd(PPh3)4 (0.045 g) was added at room temperature. The reaction mixture was stirred at 110°C for 1 hour under microwave irradiation. 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: ethyl acetate / methanol = 98 / 2-85 / 15) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-(2-(trifluoromethyl)benzoyl)phenyl)carbamate. To a mixture of the obtained compound and methanol (2 mL), 10% Pd / C (0.008 g) was added at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 1.5 hours. To the reaction mixture, 10% Pd / C (0.008 g) was added at room temperature. The reaction mixture was stirred at the same temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was allowed to stand at room temperature for 64 hours under an argon atmosphere. The reaction mixture was stirred at the same temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 98 / 2-85 / 15) to give a mixture of tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-(2-(trifluoromethyl)benzoyl)phenyl)carbamate and the title compound. Under a hydrogen atmosphere, a mixture of the resulting mixture, 10% Pd / C (0.016 g), and methanol (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 100 / 0-85 / 15) to give the title compound (0.045 g).

[0411] Example E-9 3,3-difluorocyclobutyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-(2-(trifluoromethyl)benzoyl)phenyl)carbamate A mixture of Reference Example E-10 (0.015 g), 4-nitrophenyl chloroformate (0.011 g) and THF (2 mL) was stirred under ice-cooling for 15 minutes, then at room temperature for 15 minutes. 3,3-Difluorocyclobutan-1-ol (0.019 g) and DMAP (0.013 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 saturated aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method B (elution solvent: ethyl acetate / methanol = 100 / 0-85 / 15) to obtain the title compound (0.012 g).

[0412] Example F-1 tert-Butyl (2-fluoro-3-((3-fluoropyridin-2-yl)methyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example A-74 (0.080 g), Reference Example C-1 (0.031 g), 2 mol / L aqueous potassium carbonate solution (0.134 mL), ethanol (0.134 mL), and toluene (1 mL), Pd(PPh3)4 (0.021 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 aminosilica gel column chromatography (eluent: n-hexane / ethyl acetate / methanol=29 / 69 / 2-0 / 98 / 2-0 / 83 / 17) and silica gel column chromatography (eluent: ethyl acetate / methanol=98 / 2-85 / 15) to obtain the title compound (0.012 g).

[0413] Example F-2 tert-Butyl (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-((3-fluoropyridin-2-yl)methyl)phenyl)carbamate To a mixture of Reference Example A-74 (0.035 g), Reference Example C-7 (0.020 g), 2 mol / L aqueous sodium carbonate solution (0.078 mL), and 4-methyltetrahydropyran (1 mL), Pd(amphos)Cl (0.011 g) was added at room temperature. The reaction mixture was stirred at 100° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (eluent: n-hexane / ethyl acetate / methanol = 49 / 49 / 2-0 / 98 / 2-0 / 86 / 14) to give tert-butyl (E)-(4-(2-(3-amino-3-oxoprop-1-en-1-yl)pyridin-3-yl)-2-fluoro-3-((3-fluoropyridin-2-yl)methyl)phenyl)carbamate. Under a hydrogen atmosphere, a mixture of the obtained compound, 10% Pd / C (0.005 g), and methanol (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (eluent: ethyl acetate / methanol = 98 / 2-85 / 15) to give the title compound (0.005 g).

[0414] Example F-3 (4-(2-(3-amino-3-oxopropyl)pyridin-3-yl)-2-fluoro-3-((3-fluoropyridin-2-yl)methyl)phenyl)carbamate (R)-1-Cyclopropylethyl ester To a mixture of Reference Example E-12 (0.013 g) and THF (0.5 mL), 4-nitrophenyl chloroformate (0.011 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture, (R)-1-cyclopropylethan-1-ol (0.015 g) and DMAP (0.013 g) were added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture, TEA (0.011 g) was added 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, and the mixture was extracted with DCM. The extract was concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol=98 / 2-85 / 15) to obtain the title compound (0.005 g).

[0415] Example F-4 tert-Butyl (2-fluoro-3-(morpholinomethyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example A-77 (0.030 g), Reference Example C-1 (0.014 g), 2 mol / L aqueous potassium carbonate solution (0.103 mL), ethanol (0.103 mL), and toluene (2 mL), Pd(PPh3)4 (0.016 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 amino silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-75 / 25), silica gel column chromatography (eluent: ethyl acetate / methanol=95 / 5-60 / 40), and ODS column chromatography (eluent: water / MeCN=90 / 10-10 / 90) to obtain the title compound (0.005 g).

[0416] Example F-5 (S)-(2-fluoro-3-((2-methylmorpholino)methyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl To a mixture of Reference Example E-7 (0.010 g) and THF (0.5 mL), (S)-2-methylmorpholine (0.007 g) was added 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 DCM. The extract was concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluting solvent: ethyl acetate / methanol = 100 / 0-90 / 10) to obtain the title compound (0.011 g).

[0417] Example F-6 tert-Butyl (3-((3,3-difluoropiperidin-1-yl)methyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate Reference Example E-6 (0.022 g), TEA (0.016 g) and DCM (1 mL) were mixed and added with methanesulfonyl chloride (0.009 g) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. Water 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 THF (1 mL), 3,3-difluoropiperidine hydrochloride (0.025 g) and sodium hydride (about 60%) (0.013 g) were added at room temperature. The reaction mixture was stirred at 60 ° C. for 5 hours. Potassium iodide (0.017 g) was added to the reaction mixture at 60 ° 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, 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 / 0-93 / 7) to give the title compound (0.003 g).

[0418] Example F-7 (3-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate tert-butyl ester Reference Example E-7 (0.020 g) and THF (1 mL) were added to a mixture of 8-oxa-3-aza-bicyclo[3.2.1]octane (0.010 g) at room temperature. The reaction mixture was stirred at 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / methanol = 95 / 5-70 / 30) to obtain the title compound (0.017 g).

[0419] Example F-8 tert-Butyl (2-fluoro-3-(morpholine-4-carbonyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example A-81 (0.100 g), Reference Example C-1 (0.051 g), 2 mol / L aqueous potassium carbonate solution (0.333 mL), ethanol (0.333 mL), and toluene (2 mL), Pd(PPh3)4 (0.051 g) was added at room temperature. The reaction mixture was stirred at 110°C for 1 hour under microwave irradiation. 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 silica gel column chromatography (eluent: ethyl acetate / methanol=100 / 0-75 / 25) and ODS column chromatography (eluent: water / MeCN=80 / 20-30 / 70) to obtain the title compound (0.010 g).

[0420] Example F-9 tert-Butyl (3-(cyclopropylmethyl)-2-fluoro-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)carbamate To a mixture of Reference Example A-86 (0.025 g), Reference Example C-1 (0.015 g), potassium carbonate (0.027 g), water (0.089 mL), ethanol (0.089 mL), and toluene (0.5 mL), Pd(PPh3)4 (0.015 g) was added at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 aminosilica gel column chromatography (eluent: ethyl acetate / methanol=90 / 10-50 / 50) and ODS column chromatography (eluent: water / MeCN=70 / 30-10 / 90) to obtain the title compound (0.006 g).

[0421] Example G-1 N-(2-Fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)-1-methylcyclopropane-1-carboxamide A mixture of Reference Example E-4 (0.020 g), 1-methylcyclopropane-1-carboxylic acid (0.011 g), DIPEA (0.021 g), T3P (1.6 mol / L in DMF) (0.068 mL), and DCM (1 mL) was stirred at room temperature for 16 hours. 1-Methylcyclopropane-1-carboxylic acid (0.011 g), DIPEA (0.021 g), and T3P (1.6 mol / L in DMF) (0.068 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 24 hours. A saturated aqueous ammonium chloride solution 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 Method A (elution solvent: ethyl acetate / methanol=100 / 0 to 90 / 10) to obtain the title compound (0.010 g).

[0422] Example G-2 N-(2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)isobutyramide A mixture of Reference Example E-4 (0.020 g), isobutyric acid (0.010 g), DIPEA (0.021 g), T3P (1.6 mol / L in DMF) (0.068 mL), and DCM (1 mL) was stirred at room temperature for 3 hours. Isobutyric acid (0.010 g) and T3P (1.6 mol / L in DMF) (0.068 mL) were added to the reaction mixture at room temperature. The reaction mixture was stirred at the same temperature for 1 hour and then refluxed for 30 minutes. The reaction mixture was allowed to cool to room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution 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 / methanol=50 / 50 / 0-0 / 100 / 0-0 / 85 / 15) to obtain the title compound (0.010 g).

[0423] Example G-3 N-(2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)cyclopropanecarboxamide A mixture of Reference Example E-4 (0.020 g), cyclopropanecarboxylic acid (0.009 g), DIPEA (0.021 g), T3P (1.6 mol / L in DMF) (0.068 mL) and DCM (1 mL) was stirred at room temperature for 24 hours. A saturated aqueous ammonium chloride solution 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 Method A (elution solvent: n-hexane / ethyl acetate / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 88 / 12) to obtain the title compound (0.015 g).

[0424] Example G-4 3,3-Difluoro-N-(2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)cyclobutane-1-carboxamide A mixture of Reference Example E-4 (0.020 g), 3,3-difluorocyclobutane-1-carboxylic acid (0.015 g), DIPEA (0.021 g), T3P (1.6 mol / L in DMF) (0.068 mL) and DCM (1 mL) was stirred at room temperature for 24 hours. A saturated aqueous ammonium chloride solution 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 / methanol = 50 / 50 / 0-0 / 100 / 0-0 / 88 / 12) to give the title compound (0.019 g).

[0425] Example G-5 was synthesized in the same manner as in Example G-4, except that tetrahydrofuran-2-carboxylic acid was used instead of 3,3-difluorocyclobutane-1-carboxylic acid.

[0426] Example G-6 was synthesized in the same manner as in Example A-30, except that pyrrolidine was used instead of 3-dimethylamino-1-propanol.

[0427] Example G-7 N-(2-Fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)-2-azaspiro[3.3]heptane-2-carboxamide To a mixture of Reference Example E-4 (0.024 g) and THF (0.7 mL), 4-nitrophenyl chloroformate (0.021 g) was added at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. 2-Azaspiro[3.3]heptane (0.033 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 ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-85 / 15) to obtain the title compound (0.024 g).

[0428] Example G-8 1-cyclopentyl-3-(2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)urea To a mixture of Reference Example E-4 (0.017 g) and THF (0.5 mL), 4-nitrophenyl chloroformate (0.014 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 15 minutes. To the reaction mixture, cyclopentylamine (0.019 g) was added under ice-cooling. The reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was partitioned with saturated aqueous sodium bicarbonate solution and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-95 / 5) to obtain the title compound (0.018 g).

[0429] Example G-9 1-cyclopentyl-3-(2-fluoro-3-(2-fluorobenzyl)-4-(2-(ureidomethyl)pyridin-3-yl)phenyl)-1-methoxyurea To a mixture of Reference Example E-4 (0.022 g) and THF (1 mL), 4-nitrophenyl chloroformate (0.014 g) was added under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 minutes. N-Cyclopentyl-O-methylhydroxylamine hydrochloride (0.015 g) and DIPEA (0.024 g) were added to the reaction mixture under ice-cooling. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with saturated aqueous sodium bicarbonate solution and DCM. The organic layer was separated and concentrated under reduced pressure. The residue was purified by Method A (elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20) to obtain the title compound (0.027 g).

[0430] Example H-1 tert-Butyl (4-(3-(3-amino-3-oxopropyl)pyrazin-2-yl)-3-benzyl-2-fluorophenyl)carbamate Pd(PPh3)4 (0.027 g) was added to a mixture of Reference Example A-20 (0.060 g), Reference Example J-2 (0.026 g), 2 mol / L aqueous potassium carbonate solution (0.173 mL), ethanol (0.173 mL), and toluene (1 mL) at room temperature. The reaction mixture was stirred at 100°C for 1 hour under microwave irradiation. 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 Method A (eluent: n-hexane / ethyl acetate / methanol = 48.5 / 48.5 / 3-0 / 97 / 3) to give tert-butyl (E)-(4-(3-(3-amino-3-oxoprop-1-en-1-yl)pyrazin-2-yl)-3-benzyl-2-fluorophenyl)carbamate. Under a hydrogen atmosphere, a mixture of the obtained compound, 10% Pd / C (0.006 g), methanol (1 mL), and THF (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by Method A (eluent: ethyl acetate / methanol = 98 / 2-88 / 12) to give the title compound (0.016 g).

[0431] The structural formulas, physical properties, and TSHR antagonist activity (see Test Example 1) of the examples are shown in the table below.

[0432] The structural formula of Example A-32 in the table shows the relative configuration.

[0433] Test Example 1: Measurement of antagonist activity using TSH-induced cAMP production as an index in human TSHR stably expressing CHO cells

[0434] 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. 4 Cells 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 for 15 minutes at room temperature. Next, 30 μL of assay buffer containing human TSH (R&D Systems, Inc., final concentration 50 ng / mL) was added and incubated for 1 hour at 37°C. 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 50The IC values ​​were calculated for each test compound. 50 are shown in the table above. In the table, IC 50 <0.3 μM: A, 0.3 μM ≤ IC 50 <30 μM: Expressed as B. IC 50 If the value could not be calculated, it was expressed as C.

[0435] As shown in the above table, the compounds of the present invention were found to have human TSHR antagonist activity.

[0436] 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): [In the formula, ring Z is C 6-10 aryl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; V 1 is =CR v1 -, or =N-; V 2 is =CR v2 -, or =N-; V 3 is =CR v3 -, or =N-; R v1 , R v2 and R v3 are each independently a hydrogen atom, C 1-6 alkyl, or hydroxy C 1-6 alkyl; X is -CR x R x' -, -O-, or -C(=O)-; R x and R x' are each independently a hydrogen atom, or C 1-6 alkyl; m and n are each independently an integer from 0 to 2; R A is a halogen atom, cyano group, hydroxyl group, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 6-10 aryl C 1-6 alkoxy, or C 1-6 alkylsulfonyl; when n is 2, each R A may be the same as or different from each other; R B is a halogen atom, or C 1-6 alkyl; when m is 2, each R B may be the same as or different from each other; R C is -NHC(O)OR c1 , -NHC(O)R c2 , -NHC(O)NR c2 R c2' , or -NHC(O)NR c2 (OR c2' ) and; R c1 is a group selected from the group consisting of the following (a) to (g): (a) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 1-6 alkyl, (b) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 3-8 cycloalkyl, (c) C substituted with 1 to 6 groups selected from unsubstituted or substituent group A 3-8 cycloalkylC 1-6 alkyl, (d) C substituted with 1 to 3 groups selected from unsubstituted or substituent group A 6-10 arylC 1-6 alkyl, (e) 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A, (f) 3- to 8-membered heterocycloalkylC 1-6 alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A, and (g) 5- or 6-membered heteroarylC 1-6 alkyl; The substituent group A is a group consisting of a halogen atom, a cyano group, a hydroxyl group, -N(C 1-6 alkyl)2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 6-10 arylC 1-6 alkoxy, and C 3-8 cycloalkyl; When substituted with 2 or more groups selected from the substituent group A, each group may be the same or different; R c2 and R c2' are each independently a group selected from the group consisting of the following (a) to (f): (a) a hydrogen atom, (b) C substituted with 1 to 3 groups selected from unsubstituted or substituent group B 1-6 alkyl, (c) C substituted with 1 to 3 groups selected from unsubstituted or substituent group B 3-8 cycloalkyl, (d) C substituted with 1 to 3 groups selected from unsubstituted or substituent group B 3-8 cycloalkylC 1-6 alkyl, (e) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group B, and (f) the following group unsubstituted or substituted with 1 to 3 groups selected from substituent group B: Substituent group B consists of a halogen atom, a cyano group, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and C 3-8 cycloalkyl; when substituted with 2 or 3 groups selected from substituent group B, each group may be the same or different; R D is a group selected from the group consisting of the following (a) to (e): (a) C 1-6 alkyl, (b) hydroxyC 1-6 alkyl, and R d and R d' are each independently a hydrogen atom or C 1-6 alkyl), or a pharmacologically acceptable salt thereof.

2. The compound according to claim 1, wherein: V 2 is =CR v2 -; R v1 , R v2 and R v3 are each independently a hydrogen atom or C 1-6 alkyl; R A is a halogen atom, cyano group, hydroxyl group, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl C 1-6 alkoxy, or C 1-6 alkylsulfonyl; R c1 is a group selected from the group consisting of the following (a) to (f): (a) C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from substituent group A, (b) C 3-8 cycloalkyl unsubstituted or substituted with 1 to 6 groups selected from substituent group A, (c) C 3-8 cycloalkyl C 1-6 alkyl unsubstituted or substituted with 1 to 6 groups selected from substituent group A, (d) C 6-10 aryl C 1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group A, (e) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group A, and (f) 3- to 8-membered heterocycloalkyl C 1-6 alkyl; substituent group A has the same meaning as in claim 1; R c2 and R c2' are each independently a group selected from the group consisting of the following (a) to (e): (a) hydrogen atom, (b) C 1-6 alkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group B, (c) C 3-8 Cycloalkyl, (d) a 3- to 8-membered heterocycloalkyl optionally substituted with 1 to 3 groups selected from substituent group B, and (e) the following group optionally substituted with 1 to 3 groups selected from substituent group B: The substituent group B is a group consisting of a halogen atom and C 1-6 alkyl; R d and R d' is a hydrogen atom, or a pharmacologically acceptable salt thereof.

3. The compound according to claim 2, wherein: Ring Z is C 6-10 aryl, or 5- or 6-membered heteroaryl; V 1 is =CH-, or =N-; V 2 , and V 3 is =CH-; R x and R x' are hydrogen atoms; m is 1; R B is a halogen atom; R C is -NHC(O)OR c1 ; R c1 is a group selected from the group consisting of the following (a) to (e): (a) C 1-6 alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A, (b) C 3-8 cycloalkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A, (c) C 3-8 cycloalkylC 1-6 alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A, (d) C 6-10 arylC 1-6 alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A, and (e) 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A; Substituent group A has the same meaning as in claim 1; R D is a compound represented by the following (a) or (b): or or a pharmaceutically acceptable salt thereof.

4. Formula (II): [wherein, V 1a is =CH-, or =N-; W is -CH2-, or -NH-; X a is -CH2-, -O-, or -C(=O)-; Y is =CR a2 -, or =N-; R a1 and R a2 are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl C 1-6 alkoxy, or C 1-6 alkylsulfonyl; R c1a is a group selected from the group consisting of the following (a) to (e): (a) C a alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A 1-6 alkyl, (b) C a cycloalkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A 3-8 cycloalkyl, (c) C a cycloalkyl C 3-8 alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A 1-6 alkyl, (d) C a aryl C 6-10 alkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A 1-6 alkyl, and (e) 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from unsubstituted or substituent group A a ; Substituent group A a is a group consisting of a halogen atom, a cyano group, a hydroxyl group, -N(C 1-6 alkyl)2, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl C 1-6 alkoxy, and C 3-8 cycloalkyl; Substituent group A a When substituted with 2 or 3 groups selected from, each group may be the same or different〕 a compound represented by or a pharmaceutically acceptable salt thereof.

5. Formula (III): [wherein, V 1b is =CH-, or =N-; W b is -CH2-, or -NH-; X b is -CH2-, or -O-; R a1b and R a2b are each independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 6-10 arylC 1-6 alkoxy, or C 1-6 alkylsulfonyl; R ｃ1b is a group selected from the group consisting of the following (a) to (e): (a) C b alkyl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A 1-6 , (b) C b cycloalkyl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A 3-8 , (c) C b cycloalkylC 3-8 alkyl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A 1-6 , (d) C b arylC 6-10 alkyl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A 1-6 , and (e) 3- to 8-membered heterocycloalkyl substituted with 1 to 3 groups selected from the unsubstituted or substituent group A b ; The substituent group A b is a group consisting of a halogen atom, a cyano group, a hydroxyl group, -N(C 1-6 alkyl)2, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 6-10 arylC 1-6 alkoxy, and C 3-8 cycloalkyl; The substituent group A b When substituted with 2 or 3 groups selected from, each group may be the same or different〕 a compound represented by or a pharmacologically acceptable salt thereof.

6. The compound according to claim 5, wherein: R a1b and R a2b are each independently a hydrogen atom, a halogen atom, or a cyano group; R c1b is a group selected from the group consisting of the following (a) to (c): (a) C b alkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group A 1-6 , (b) C b cycloalkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group A 3-8 , and (c) C b cycloalkyl C 3-8 alkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group A 1-6 ; substituent group A b is a halogen atom, a cyano group, C 1-6 alkyl, or halo C 1-6 alkyl; a compound or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of the following compounds: and or a pharmaceutically 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 the treatment of thyroid-related diseases.

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

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