JPWO2017038870A1 - Urea derivatives and uses thereof - Google Patents

Abstract

An object of the present invention is to provide a compound having an inhibitory activity against the discoidin domain receptor 1. The present invention provides a urea derivative represented by the following formula or a pharmacologically acceptable salt thereof.

Description

  The present invention relates to urea derivatives and uses thereof.

  Discoidin domain receptor 1 (hereinafter referred to as DDR1) is a receptor tyrosine kinase that is activated by insoluble collagen as a ligand. Each has a domain (Non-patent Documents 1 and 2).

  It has been reported that the activation of DDR1 promotes cell infiltration / metastasis and survival (Non-Patent Documents 3 to 5). Clinically, it has been reported that DDR1 expression is increased in non-small cell lung cancer, glioma and breast cancer, and in non-small cell lung cancer the correlation between increased expression and poor prognosis And the correlation with the infiltration of a cell has been reported (nonpatent literature 6-9).

  It has been reported that knocking down DDR1 by RNA interference suppresses bone metastasis of lung cancer cells (Non-patent Document 6) and decreases the tumorigenic ability of colorectal cancer (Non-patent Document 10).

  Examples of compounds having inhibitory activity against DDR1 include 3- (2- (pyrazolo [1,5-a] pyrimidin-6-yl) ethynyl) benzamide derivatives (Patent Document 1 and Non-Patent Document 11), 4- ((4-ethylpiperazinyl) methyl) -3-trifluoromethylbenzamide derivative (Non-patent Document 12) and 4-piperazinylmethyl-3-trifluoromethylbenzamide derivative (Patent Documents 2 and 3) It has been reported.

  On the other hand, as a compound having a urea skeleton, for example, as a compound having p38 MAPK inhibitory activity, 2,3-dihydro-1H-inden-2-ylurea derivative (Patent Document 4), FLT3 (Fms-like tyrosine kinase 3) ) And VEGFR2 (vascular endothelial growth factor receptor 2) have been reported as pentafluorosulfanylphenylurea derivatives (Patent Document 5).

International Publication No. 2012/000304 International Publication No. 2013/161851 International Publication No. 2013/161853 International Publication No. 2011/040509 International Publication No. 2012/094541

Vogel et al., British Journal of Cancer, 2007, 96, p. 808-814 Vogel et al., Cellular Signaling, 2006, Vol. 18, p. 1108-1116 Vogel et al., FASEB Journal, 1999, Vol. 13, p. S77-S82 Variathan et al., Cancer Metastasis Review, 2012, Vol. 31, p. 295-321 Vogel et al., Molecular Cell, 1997, Volume 1, p. 13-23 Valencia et al., Clinical Cancer Research, 2012, Vol. 18, p. 969-980 Barker et al., Oncogene, 1995, volume 10, p. 569-575 Yamanaka et al., Oncogene, 2006, 25, p. 5994-6002 Miao et al., Medical Oncology, 2013, Vol. 30, p. 626 Hung-Gu et al., Journal of Biological Chemistry, 2011, 286, p. 17672-17681 Ding et al., Journal of Medicinal Chemistry, 2013, Vol. 56, p. 3281-3295 Gray et al., ACS Chemical Biology, 2013, Vol. 8, p. 2145-2150

  However, no compound having an inhibitory activity against DDR1 has been reported so far.

  Then, an object of this invention is to provide the compound which has inhibitory activity with respect to DDR1.

  As a result of intensive studies to achieve the above object, the present inventors have found that a novel urea derivative or a pharmacologically acceptable salt thereof has an inhibitory activity against DDR1 (hereinafter, DDR1 inhibitory activity) The present invention has been completed.

［式中、ｋ及びｍは、それぞれ独立して、０又は１を表し、Ｒ^１は、水素原子若しくは３−アミノピロリジニルメチル基、又は、１〜４個の水素原子がそれぞれ独立にハロゲン原子若しくはヒドロキシ基で置換されていてもよい炭素数１〜３のアルキル基、を表し、Ｒ^２は、水素原子、ハロゲン原子、４−ピリジル基、４−ヒドロキシ−１−ピペリジニル基、４−モルホリニル基、３−オキソ−１−ピペラジニル基、テトラヒドロ−４−ピラニル基、（２−ヒドロキシエチル）（メチル）アミノ基、（２−アセトキシエチル）（メチル）アミノ基若しくはＲ^４−（ＣＨ_２）_ｎ−Ｏ−、又は、１〜３個の水素原子がそれぞれ独立にヒドロキシ基若しくはメトキシ基で置換されていてもよいフェニル基、を表し、Ｒ^３は、水素原子又はハロゲン原子を表し、ｎは、０又は１を表し、Ｒ^４は、メチル基、フェニル基、Ｎ−アセチル−３−アゼチジニル基、Ｎ−メタンスルホニル−３−アゼチジニル基又は３−オキセタニル基を表す。］That is, the present invention provides a urea derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein, k and m each independently represent 0 or 1, and R ¹ represents a hydrogen atom or a 3-aminopyrrolidinylmethyl group, or 1 to 4 hydrogen atoms each independently a halogen atom. Represents an alkyl group having 1 to 3 carbon atoms which may be substituted with an atom or a hydroxy group, and R ² represents a hydrogen atom, a halogen atom, a 4-pyridyl group, a 4-hydroxy-1-piperidinyl group, or 4-morpholinyl. Group, 3-oxo-1-piperazinyl group, tetrahydro-4-pyranyl group, (2-hydroxyethyl) (methyl) amino group, (2-acetoxyethyl) (methyl) amino group or R ⁴ — (CH ₂ ) _n -O-, or one to three hydrogen atoms are each independently a hydroxy group or a methoxy group optionally substituted by a phenyl group, a, R ³ is a hydrogen atom or a halo Represents a down atom, n is 0 or 1, ^{R 4} represents a methyl group, a phenyl group, N- acetyl-3-azetidinyl group, N- methanesulfonyl-3- azetidinyl group or a 3-oxetanyl group. ]

  In the urea derivative represented by the above general formula (I), it is preferable that one of k and m is 1 and the other is 0.

  In this case, high DDR1 inhibitory activity can be expected.

In the urea derivative represented by the above general formula (I), R ¹ is a hydrogen atom or a hydroxymethyl group, and R ² is a 4-pyridyl group, a 3-oxo-1-piperazinyl group or an R ⁴ O. R ³ is a hydrogen atom or a fluorine atom, and R ⁴ is a methyl group, an N-acetyl-3-azetidinyl group, an N-methanesulfonyl-3-azetidinyl group or a 3-oxetanyl group. preferable.

  In this case, higher DDR1 inhibitory activity can be expected.

Furthermore, in the urea derivative represented by the above general formula (I), R ¹ is a hydrogen atom or a hydroxymethyl group, and R ² is a 4-pyridyl group, a 3-oxo-1-piperazinyl group or R ^4. O—, R ³ is a hydrogen atom or a fluorine atom, R ⁴ is a methyl group, an N-acetyl-3-azetidinyl group, an N-methanesulfonyl-3-azetidinyl group or a 3-oxetanyl group, More preferably, one of k and m is 1 and the other is 0.

  In this case, higher DDR1 inhibitory activity can be expected.

  The present invention also provides an inhibitor of DDR1 containing the urea derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

  The urea derivative of the present invention and a pharmacologically acceptable salt thereof have high DDR1 inhibitory activity and can be used as an inhibitor of DDR1.

［式中、ｋ及びｍは、それぞれ独立して、０又は１を表し、Ｒ^１は、水素原子若しくは３−アミノピロリジニルメチル基、又は、１〜４個の水素原子がそれぞれ独立にハロゲン原子若しくはヒドロキシ基で置換されていてもよい炭素数１〜３のアルキル基、を表し、Ｒ^２は、水素原子、ハロゲン原子、４−ピリジル基、４−ヒドロキシ−１−ピペリジニル基、４−モルホリニル基、３−オキソ−１−ピペラジニル基、テトラヒドロ−４−ピラニル基、（２−ヒドロキシエチル）（メチル）アミノ基、（２−アセトキシエチル）（メチル）アミノ基若しくはＲ^４−（ＣＨ_２）_ｎ−Ｏ−、又は、１〜３個の水素原子がそれぞれ独立にヒドロキシ基若しくはメトキシ基で置換されていてもよいフェニル基、を表し、Ｒ^３は、水素原子又はハロゲン原子を表し、ｎは、０又は１を表し、Ｒ^４は、メチル基、フェニル基、Ｎ−アセチル−３−アゼチジニル基、Ｎ−メタンスルホニル−３−アゼチジニル基又は３−オキセタニル基を表す。］The urea derivative of the present invention is characterized by being represented by the following general formula (I).

[Wherein, k and m each independently represent 0 or 1, and R ¹ represents a hydrogen atom or a 3-aminopyrrolidinylmethyl group, or 1 to 4 hydrogen atoms each independently a halogen atom. Represents an alkyl group having 1 to 3 carbon atoms which may be substituted with an atom or a hydroxy group, and R ² represents a hydrogen atom, a halogen atom, a 4-pyridyl group, a 4-hydroxy-1-piperidinyl group, or 4-morpholinyl. Group, 3-oxo-1-piperazinyl group, tetrahydro-4-pyranyl group, (2-hydroxyethyl) (methyl) amino group, (2-acetoxyethyl) (methyl) amino group or R ⁴ — (CH ₂ ) _n -O-, or one to three hydrogen atoms are each independently a hydroxy group or a methoxy group optionally substituted by a phenyl group, a, R ³ is a hydrogen atom or a halo Represents a down atom, n is 0 or 1, ^{R 4} represents a methyl group, a phenyl group, N- acetyl-3-azetidinyl group, N- methanesulfonyl-3- azetidinyl group or a 3-oxetanyl group. ]

  The following terms used in this specification are defined as follows unless otherwise specified.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  The “C1-C3 alkyl group” means a methyl group, an ethyl group, a 1-propyl group or an isopropyl group.

  “1 to 4 hydrogen atoms, each of which may be independently substituted with a halogen atom or a hydroxy group” refers to 1 to 4 of the above alkyl group of 1 to 3 carbon atoms. Each hydrogen atom independently represents a group which may be substituted with a halogen atom or a hydroxy group, for example, methyl group, ethyl group, 1-propyl group, isopropyl group, 2-chloroethyl group, 2,2, A 2-trifluoroethyl group, a 1-hydroxyethyl group, or a 2-hydroxyethyl group may be mentioned.

  “A phenyl group in which 1 to 3 hydrogen atoms may be independently substituted with a hydroxy group or a methoxy group” means that 1 to 3 hydrogen atoms of the phenyl group are each independently a hydroxy group or a methoxy group. It means a group which may be substituted, and examples thereof include 2-hydroxyphenyl group, 4-hydroxyphenyl group and 4-methoxyphenyl group.

  Although the specific example of the preferable compound of the urea derivative shown by said general formula (I) is shown in Table 1, this invention is not limited to these.

  The urea derivative represented by the above general formula (I) (hereinafter referred to as urea derivative (I)) may have optical isomers and diastereomers, but not only single isomers but also racemates and diastereomers. Also includes stereomeric mixtures.

  The present invention also includes a prodrug of the urea derivative (I) or a pharmacologically acceptable salt thereof. The prodrug of urea derivative (I) is a compound that is enzymatically or chemically converted into urea derivative (I) in vivo. The active body of the prodrug of the urea derivative (I) is the urea derivative (I), but the prodrug itself of the urea derivative (I) may have activity.

  Examples of the prodrug of the urea derivative (I) include compounds in which the hydroxy group of the urea derivative (I) is alkylated, phosphorylated or borated. These compounds can be synthesized from the urea derivative (I) according to a known method.

  In addition, prodrugs of urea derivatives (I) are disclosed in known literature (“Development of Pharmaceuticals”, Hirokawa Shoten, 1990, Vol. 7, p.163-198, and Progress in Medicine, Vol. 5, 1985, p. 2157 to 2161) may be changed to the urea derivative (I).

The urea derivative (I) may be labeled with an isotope, and examples of the labeled isotope include ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁵ O, ¹⁸ O and / or ¹²⁵ I is mentioned.

  Examples of the “pharmacologically acceptable salt” of the urea derivative (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, or Oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, Ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate or Organic acid salts such as cinnamate are exemplified, and hydrochloride, sulfate, hydrobromide, maleate, benzoate or methanesulfonate is preferable.

  The urea derivative (I) or a pharmacologically acceptable salt thereof may be an anhydride, or may form a solvate such as a hydrate. Here, the solvate is preferably a pharmacologically acceptable solvate. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferable. Examples of the solvent constituting the solvate include alcohol solvents such as methanol, ethanol, and n-propanol, N, N-dimethylformamide, dimethyl sulfoxide, and water.

  The urea derivative (I) can be produced by an appropriate method based on characteristics derived from the basic skeleton and the type of substituent. The starting materials and reagents used for the production of these compounds can be generally purchased or can be produced by known methods.

  The urea derivative (I) and intermediates and starting materials used for the production thereof can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

  When the urea derivative (I) contains an optical isomer or a stereoisomer, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.

  In each reaction of the production method described below, when the raw material compound has a hydroxy group, an amino group or a carboxyl group, a protective group may be introduced into these groups, and the protective group may be removed as necessary after the reaction. By protecting, the target compound can be obtained.

  Examples of the protective group for the hydroxy group include a trityl group, an aralkyl group having 7 to 10 carbon atoms (for example, benzyl group), or a substituted silyl group (for example, trimethylsilyl group, triethylsilyl group, or tert-butyldimethylsilyl group). It is done.

  Examples of the amino-protecting group include an alkylcarbonyl group having 2 to 6 carbon atoms (for example, acetyl group), a benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (for example, tert-butoxycarbonyl group or benzyloxy). Carbonyl group), an aralkyl group having 7 to 10 carbon atoms (for example, benzyl group) or a phthaloyl group.

  Examples of the protecting group for the carboxyl group include an alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group or a tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group).

  The deprotection of the protecting group varies depending on the kind of the protecting group, but is performed according to a known method (for example, Greene, TW, “Green's Protective Groups in Organic Synthesis”, Wiley-Interscience) or a method equivalent thereto. be able to.

［式中、Ｒ^１〜Ｒ^３は、上記定義に同じである。］As shown in Scheme 1, the urea derivative (I) can be obtained, for example, by a ureaation reaction between an aniline derivative (II) and an amino alcohol derivative (III) in the presence of a urea agent and a base.

[Wherein R ^{1 to} R ³ are the same as defined above. ]

  Said amino alcohol derivative (III) can be purchased as an optically active substance or a racemic body as needed. Moreover, it can also manufacture by a well-known method or the method according to it.

  Among the aminoalcohol derivatives (III), derivatives in which k is 0 and m is 1, for example, literature (Tetrahedron Letters, 1993, Vol. 34 (52), p. 8399-8402; Pharmaceutical Journal, 1979 1999, Vol. 99 (11), p. 1111-1115; Tetrahedron: Asymmetry, 1995, Vol. 6 (7), p. 1535-1538, etc.), and further (Tetrahedron: Asymmetry, (1995, Vol. 6 (7), p. 1535-1538, etc.) The optically active amine can be obtained by optical resolution using an optically active acid. Examples of the optically active acid used herein include carboxylic acids such as lactic acid, tartaric acid, 2-phenylpropionic acid and mandelic acid, acidic amino acids such as glutamic acid and aspartic acid, and sulfonic acids such as camphorsulfonic acid, and the like. Satisfactory results can be obtained by appropriately selecting the acid according to the above.

  0.5-10 equivalent is preferable with respect to aniline derivative (II), and, as for the quantity of amino alcohol derivative (III) used for a urea-ized reaction, 1-3 equivalent is more preferable.

  Examples of ureating agents used in the ureation reaction include chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate, triphosgene, phosgene, N, N'- Examples include carbonyldiimidazole or N, N′-disuccinimidyl carbonate, but chloroformate derivatives such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate or triphosgene preferable.

  0.1-100 equivalent is preferable with respect to aniline derivative (II), and, as for the quantity of the urea agent used for a urea-ized reaction, 0.3-30 equivalent is more preferable.

  Examples of the base used in the urea reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, methyl Examples thereof include alkyllithium such as lithium or butyllithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, and an organic base such as triethylamine or diisopropylethylamine is preferable.

  The amount of the base used for the urea reaction is preferably 1 to 100 equivalents and more preferably 2 to 30 equivalents with respect to the aniline derivative (II).

  The reaction solvent used for the urea reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, N, N-dimethylformamide, N, N-dimethyl Aprotic polar solvents such as acetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2- Examples include chlorinated solvents such as dichloroethane, nitrile solvents such as acetonitrile or propionitrile, or mixed solvents thereof. Chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, acetonitrile or propio Nitriles tolyl are preferred.

  The reaction temperature of the urea reaction is preferably −40 ° C. to 200 ° C., more preferably −20 ° C. to 150 ° C.

  The reaction time of the urea reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 30 hours.

  The concentration of the aniline derivative (II) used for the urea reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

  The aniline derivative (II) used in the urea reaction can be purchased, but can also be produced by a known method.

［式中、Ｒ^１及びＲ^２は、上記定義に同じである。］The aniline derivative (II) can be obtained, for example, by a reduction reaction of the nitrobenzene derivative (IV) as shown in Scheme 2.

[Wherein, R ¹ and R ² are the same as defined above. ]

  As the reduction reaction, for example, catalytic hydrogenation reaction in the presence of a metal catalyst such as palladium, nickel or platinum in a hydrogen atmosphere, hydrogenation of lithium aluminum hydride, borohydride dimethyl sulfide complex or borohydride tetrahydrofuran complex, etc. Examples include hydride reduction reaction with metal reagents or one-electron reduction reaction with metal catalysts such as zinc, iron or tin in the presence of acid, but catalytic hydrogenation in the presence of metal catalysts such as palladium, nickel or platinum under hydrogen atmosphere. A one-electron reduction reaction with a metal catalyst such as zinc, iron or tin in the presence of a reaction or acid is preferred.

  Examples of the metal catalyst used for the catalytic hydrogenation reaction include palladium, nickel, platinum, or a carbon support thereof.

  0.001-5 equivalent is preferable with respect to nitrobenzene derivative (IV), and, as for the quantity of the metal catalyst used for a catalytic hydrogenation reaction, 0.01-1 equivalent is more preferable.

  The reaction solvent used in the catalytic hydrogenation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, alcohol solvents such as methanol or ethanol, acetonitrile or Nitrile solvents such as propionitrile, aprotic polar solvents such as N, N-dimethylformamide or N, N-dimethylacetamide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, acetic acid An ester solvent such as ethyl or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof may be mentioned, and an alcohol solvent such as methanol or ethanol is preferable.

  The pressure of the hydrogen gas used for the catalytic hydrogenation reaction is preferably 1 to 10 atm, and more preferably 1 to 3 atm.

  0-200 degreeC is preferable and, as for the reaction temperature of a catalytic hydrogenation reaction, 0-100 degreeC is more preferable.

  The reaction time of the catalytic hydrogenation reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 72 hours.

  Examples of the acid used for the one-electron reduction reaction include acetic acid, hydrochloric acid, and ammonium chloride.

  Examples of the metal catalyst used for the one-electron reduction reaction include zinc, iron, tin, and halides thereof.

  0.1-100 equivalent is preferable with respect to nitrobenzene derivative (IV), and, as for the quantity of the metal catalyst used for one-electron reduction reaction, 1-50 equivalent is more preferable.

  The reaction solvent used in the one-electron reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, an acidic solvent such as hydrochloric acid or acetic acid, methanol or ethanol Alcohol solvents such as acetonitrile, nitrile solvents such as acetonitrile or propionitrile, aprotic polar solvents such as N, N-dimethylformamide or N, N-dimethylacetamide, diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4- An ether solvent such as dioxane, an ester solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof includes an acidic solvent such as hydrochloric acid or acetic acid, or Methanol Alcohol solvents such as ethanol is preferred.

  The reaction temperature of the one-electron reduction reaction is preferably 0 to 200 ° C, more preferably 0 to 100 ° C.

  The reaction time of the one-electron reduction reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 72 hours.

  The concentration of the nitrobenzene derivative (IV) used for the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

［式中、Ｒ^２は、上記定義に同じであり、Ｒ^５は、それぞれ独立して、水素原子又は炭素数１〜３のアルキル基を表し、Ｘは、水素原子、ナトリウム原子、カリウム原子又はリチウム原子を表す。］Among the above nitrobenzene derivatives (IV), a nitrobenzene derivative (IVa) in which R ¹ is a hydrogen atom is, for example, 2-chloro-5-pentafluorosulfanylnitrobenzene (in the presence of a metal catalyst, as shown in Scheme 3). V) and coupling reaction of boronic acid derivative (VI) derivative or pinacol borane derivative (VII) or nucleophilic substitution reaction of 2-chloro-5-pentafluorosulfanylnitrobenzene (V) with nucleophile (VIII) Can be obtained.

[Wherein, R ² is the same as defined above, R ⁵ independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and X represents a hydrogen atom, a sodium atom, a potassium atom or Represents a lithium atom. ]

  2-Chloro-5-pentafluorosulfanylnitrobenzene (V) used for the coupling reaction and the nucleophilic substitution reaction can be purchased. Moreover, it can also manufacture by a well-known method or the method according to it.

  The boronic acid derivative (VI) and pinacol borane derivative (VII) used for the coupling reaction can be purchased. Moreover, it can also manufacture by a well-known method or the method according to it.

  The amount of boronic acid derivative (VI) and pinacolborane derivative (VII) used in the coupling reaction is preferably 0.5 to 20 equivalents relative to 2-chloro-5-pentafluorosulfanylnitrobenzene (V). ˜3 equivalents are more preferred.

  Examples of the metal catalyst used in the coupling reaction include zero-valent palladium complex catalysts such as tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0), and bis (dibenzylideneacetone) palladium (0). Among them, tetrakistriphenylphosphine palladium (0) is preferable.

  0.001-10 equivalent is preferable with respect to 2-chloro-5-pentafluorosulfanyl nitrobenzene (V), and, as for the quantity of the metal catalyst used for a coupling reaction, 0.01-1 equivalent is more preferable.

  In the coupling reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydroxide and sodium carbonate, metal alkoxides such as tert-butoxy sodium and tert-butoxy potassium, carboxylates such as sodium acetate and potassium acetate, and aqueous solutions thereof. An inorganic base such as sodium hydroxide or sodium carbonate or an aqueous solution thereof is preferred.

  0.5-100 equivalent is preferable with respect to 2-chloro-5-pentafluorosulfanyl nitrobenzene (V), and, as for the quantity of the base used for a coupling reaction, 1-30 equivalent is more preferable.

  The reaction solvent used for the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, an aromatic hydrocarbon solvent such as benzene or toluene, Alcohol solvents such as methanol or ethanol, nitrile solvents such as acetonitrile or propionitrile, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, diethyl ether, tetrahydrofuran, dimethoxy An ether solvent such as ethane or 1,4-dioxane, an ester solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or a mixed solvent thereof may be mentioned. Zen or aromatic hydrocarbon solvent such as toluene, an alcoholic solvent or a mixed solvent thereof as methanol or ethanol and the like are preferable.

  0-300 degreeC is preferable and, as for the reaction temperature of a coupling reaction, 20-200 degreeC is more preferable.

  The reaction time for the coupling reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 48 hours.

  The concentration at the start of the reaction of 2-chloro-5-pentafluorosulfanylnitrobenzene (V) used for the coupling reaction is preferably 1 mmol / L to 1 mol / L.

  The nucleophile (VIII) used for the nucleophilic substitution reaction can be purchased. Moreover, it can also manufacture by a well-known method or the method according to it.

  The amount of the nucleophilic agent (VIII) used for the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 3 equivalents with respect to 2-chloro-5-pentafluorosulfanylnitrobenzene (V). .

  In the nucleophilic substitution reaction, a base may be used if desired. Examples of the base to be used include inorganic bases such as sodium hydride, sodium hydrogen carbonate and potassium carbonate, organic bases such as triethylamine, diisopropylethylamine and pyridine, and mixtures thereof.

  0.5-20 equivalent is preferable with respect to 2-chloro-5-pentafluorosulfanyl nitrobenzene (V), and, as for the quantity of the base used for nucleophilic substitution reaction, 1-3 equivalent is more preferable.

  The reaction solvent used for the nucleophilic substitution reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, acetonitrile or Nitrile solvents such as propionitrile, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide, ether systems such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane Examples include solvents, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or mixed solvents thereof. Alcohol solvents such as methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

  The reaction temperature of the nucleophilic substitution reaction is preferably −20 ° C. to 200 ° C., more preferably 0 to 150 ° C.

  The reaction time of the nucleophilic substitution reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.

  The concentration at the start of the reaction of 2-chloro-5-pentafluorosulfanylnitrobenzene (V) used for the nucleophilic substitution reaction is preferably 1 mmol / L to 1 mol / L.

［式中、Ｒ^２は、上記定義に同じである。］Among the above nitrobenzene derivatives (IV), the nitrobenzene derivative (IVb) in which R ¹ is a hydroxymethyl group is, for example, a 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX) as shown in Scheme 4. It can be obtained by a reduction reaction.

[Wherein R ² is the same as defined above. ]

  Examples of the reducing agent used in the reduction reaction include aluminum-based reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride, and boron-based reducing agents such as sodium borohydride or lithium borohydride. Boron-based reducing agents such as sodium or lithium borohydride are preferred.

  The amount of the reducing agent used in the reduction reaction is preferably 0.2 to 20 equivalents and more preferably 1 to 10 equivalents with respect to the 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX).

  The reaction solvent used in the reduction reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc. Alcohol solvents, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane or mixtures thereof Examples of the solvent include alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butyl alcohol.

  The reaction temperature of the reduction reaction is preferably -78 ° C to 200 ° C, more preferably -20 ° C to 100 ° C.

  The reaction time for the reduction reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 30 hours.

  The concentration of 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX) used for the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

［式中、Ｒ^２は、上記定義に同じである。］Among the above nitrobenzene derivatives (IV), the nitrobenzene derivative (IVc) in which R ¹ is a 2,2,2-trifluoro-1-hydroxyethyl group is, for example, the above 3-formyl as shown in Scheme 5. It can be obtained by a trifluoromethylation reaction of a -5-pentafluorosulfanylnitrobenzene derivative (IX).

[Wherein R ² is the same as defined above. ]

  Examples of the trifluoromethylating agent used for the trifluoromethylation reaction include trifluoromethyl bromide and trimethyl (trifluoromethyl) silane, and trimethyl (trifluoromethyl) silane is preferable.

  The amount of the trifluoromethylating agent used in the trifluoromethylation reaction is preferably 0.5 to 10 equivalents relative to the 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX), and 0.5 to 5 equivalents. More preferred.

  In the trifluoromethylation reaction, a fluoride salt may be used if desired. Examples of the fluoride salt to be used include alkali metal salts such as sodium fluoride and potassium fluoride, and ammonium salts such as tetramethylammonium fluoride and tetra n-butylammonium fluoride, but tetra n-butylammonium fluoride. Ammonium salts such as dodo are preferred.

  The amount of the fluoride salt used for the trifluoromethylation reaction is preferably 0.01 to 2 equivalents, more preferably 0.05 to 1 equivalents with respect to the 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX). .

  The reaction solvent used in the trifluoromethylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, tetrahydrofuran, 1,4-dioxane or ethylene glycol Examples include ether solvents such as dimethyl ether, aromatic hydrocarbon solvents such as benzene or toluene, or mixed solvents thereof, and ether solvents such as tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether are preferable.

  The reaction temperature of the trifluoromethylation reaction is preferably -78 ° C to 50 ° C, more preferably -30 ° C to 30 ° C.

  The reaction time of the trifluoromethylation reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 30 minutes to 30 hours.

  The concentration of 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX) used for the trifluoromethylation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

［式中、Ｒ^１及びＲ^２は、上記定義に同じである。］The nitrobenzene derivative (IV) can be obtained, for example, by a nitration reaction of a pentafluorosulfanylbenzene derivative (X) as shown in Scheme 6.

[Wherein, R ¹ and R ² are the same as defined above. ]

  Examples of the nitrating agent used in the nitration reaction include nitric acids such as concentrated nitric acid or fuming nitric acid or nitronium salts such as nitronium tetrafluoroborate, but nitric acids such as concentrated nitric acid or fuming nitric acid are preferable.

  The amount of the nitrating agent used for the nitration reaction is preferably 0.5 to 20 equivalents and more preferably 0.5 to 10 equivalents with respect to the pentafluorosulfanylbenzene derivative (X).

  The reaction solvent used in the nitration reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, an acid solvent such as concentrated sulfuric acid or acetic anhydride or dichloromethane, Chlorinated solvents such as chloroform or 1,2-dichloroethane can be mentioned, and acid solvents such as concentrated sulfuric acid or acetic anhydride are preferred.

  The reaction temperature of the nitration reaction is preferably −20 ° C. to 200 ° C., more preferably 0 to 100 ° C.

  The reaction time of the nitration reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 1 to 72 hours.

  The concentration at the start of the reaction of the pentafluorosulfanylbenzene derivative (X) used for the nitration reaction is preferably 1 mmol / L to 1 mol / L.

Among the above pentafluorosulfanylbenzene derivatives (X), 3-formyl-2-methoxy-5-pentafluorosulfanylnitrobenzene (Xa) in which R ¹ is a formyl group and R ² is a methoxy group is, for example, As shown in Scheme 7, it can be obtained by a formylation reaction of 4-pentafluorosulfanylanisole (XI) in the presence of an acid.

  4-Pentafluorosulfanylanisole (XI) used for the formylation reaction can be purchased. Moreover, it can also manufacture by a well-known method or the method according to it.

  Examples of the formylating agent used in the formylation reaction include dihalomethyl alkyl ether derivatives such as dichloromethyl methyl ether, dichloromethyl ethyl ether or dichloromethyl isopropyl ether, or formamide derivatives such as dimethylformamide or N-formylpiperidine. Dihalomethyl alkyl ether derivatives such as dichloromethyl methyl ether, dichloromethyl ethyl ether or dichloromethyl isopropyl ether are preferred.

  The amount of the formylating agent used in the formylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to 4-pentafluorosulfanylanisole (XI).

  Examples of the acid used in the formylation reaction include Lewis acids such as aluminum trichloride, tin tetrachloride, titanium tetrachloride and boron trifluoride, and phosphorus compounds such as phosphorus oxychloride and phosphorus oxybromide. Lewis acids such as aluminum chloride, tin tetrachloride, titanium tetrachloride or boron trifluoride are preferred.

  The amount of acid used for the formylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to 4-pentafluorosulfanylanisole (XI).

  The reaction solvent used for the formylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, dichloromethane, chloroform, 1,2-dichloroethane or tetrachloride Examples include halogen solvents such as carbon or ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane or ethylene glycol dimethyl ether, but halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride. preferable.

  The reaction temperature of the formylation reaction is preferably -78 ° C to 100 ° C, more preferably -30 ° C to 50 ° C.

  The reaction time of the formylation reaction is appropriately selected according to the reaction temperature and other conditions, but is preferably 10 minutes to 30 hours.

  The concentration of 4-pentafluorosulfanylanisole (XI) used for the formylation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

［式中、ＰＧは、保護基を表し、Ｒ^２は、上記定義に同じである。］Nitrobenzene derivative (XIII) can be obtained, for example, by reductive amination reaction of 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX) and 3-aminopyrrolidine derivative (XII) as shown in Scheme 8. Can be obtained.

[Wherein, PG represents a protecting group, and R ² has the same definition as above. ]

  The amount of 3-aminopyrrolidine derivative (XII) used for the reductive amination reaction is preferably 0.5 to 10 equivalents relative to the above-mentioned 3-formyl-5-pentafluorosulfanylnitrobenzene derivative (IX). 3 equivalents are more preferred.

  Examples of the reducing agent used in the reductive amination reaction include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, and sodium triacetoxyborohydride is preferable.

  0.5-10 equivalent is preferable with respect to 3-aminopyrrolidine derivative (XII), and, as for the quantity of the reducing agent used for reductive amination reaction, 1-3 equivalent is more preferable.

  The reaction solvent used for the reductive amination reaction is appropriately selected depending on the type of the reducing agent used, but is not particularly limited as long as it does not inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, Examples include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or mixed solvents thereof, but alcohols such as methanol or ethanol. A solvent is preferred.

  The reaction temperature of the reductive amination reaction is preferably -78 ° C to 200 ° C, more preferably 0 to 100 ° C.

  The reaction time of the reductive amination reaction is appropriately selected according to conditions such as the reaction temperature, but is preferably 1 to 30 hours.

  The concentration of the 3-aminopyrrolidine derivative (XII) used for the reductive amination reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

  The DDR1 inhibitor of the present invention is characterized by containing a urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient.

  “Inhibitor of DDR1” means a compound that inhibits the kinase activity of DDR1.

  Since the urea derivative (I) or a pharmacologically acceptable salt thereof has DDR1 inhibitory activity, it is expected as a therapeutic agent for diseases that can be expected to improve the pathological condition or to relieve symptoms based on the mechanism of action. it can.

  “Cancer” means, for example, pharyngeal cancer, laryngeal cancer, tongue cancer, non-small cell lung cancer, breast cancer, esophageal cancer, stomach cancer, colon cancer, uterine cancer, endometrial cancer, ovarian cancer, liver cancer, pancreatic cancer, Gallbladder cancer, bile duct cancer, kidney cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, malignant melanoma, thyroid cancer, neuroosteosarcoma, chondrosarcoma, rhabdomyosarcoma, hemangiosarcoma, fibrosarcoma, glioma, leukemia And malignant lymphoma, neuroblastoma, myeloma or brain tumor.

  It can be evaluated using an in vitro test that the urea derivative (I) or a pharmacologically acceptable salt thereof has DDR1 inhibitory activity. As an in vitro test, for example, a method for evaluating the kinase activity of DDR1 by quantifying the phosphorylated substrate mass or the amount of ATP consumed (Analytical Biochemistry, 1999, Vol. 269, p. 94-104). And a method for evaluating the binding to DDR1 (Journal of Biomolecular Screening, 2009, Vol. 14, p. 924-935). More specifically, the method for evaluating the kinase activity of DDR1 includes, for example, a method in which a purified protein of DDR1 intracellular domain, a substrate peptide, and ATP are mixed and reacted to quantify the phosphorylated substrate peptide. It is done. The phosphorylated substrate peptide can be quantified by measurement of fluorescence resonance energy transfer, for example, by using a substrate peptide previously labeled with biotin or a fluorescent substance.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example and a reference example, this invention is not limited to these.

  In addition, the commercially available compound was used about the compound which is not described in the synthesis method by the compound used for the synthesis | combination of an Example compound. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.) or a JNM-ECS400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), m, respectively. (Multiple line), br (wide), dd (double double line), dt (double triple line), ddd (double double line), dq (double quadruple line) or tt (triple line) (Triple line). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technologies). All solvents were commercially available. For flash chromatography, YFLC W-prep2XY (Yamazensha) was used. As the microwave synthesizer, Monowave 300 manufactured by Anton Paar was used.

  The raw materials and intermediates of the urea derivative (I) were synthesized by the method described in the following reference examples. In addition, the commercially available compound was used about the compound which is used for the synthesis | combination of a reference example compound and there is no description of a synthesis method.

３−ペンタフルオロサルファニルアニリン（４３８ｍｇ，２．００ｍｍｏｌ）をテトラヒドロフラン（５ｍＬ）に溶解し、炭酸水素ナトリウム（２５２ｍｇ，３．００ｍｍｏｌ）、クロロギ酸フェニル（２５１μＬ，２．００ｍｍｏｌ）を加えた。室温で１６時間撹拌した後、反応混合物に１Ｍ塩酸を加え酸性とし、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（６８５ｍｇ）を無色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：７．１８−７．２０（２Ｈ，ｍ），７．２５−７．２９（１Ｈ，ｍ），７．３７（１Ｈ，ｂｒｓ），７．３９−７．４５（３Ｈ，ｍ），７．４９−７．５１（１Ｈ，ｍ），７．５９−７．６１（１Ｈ，ｍ），７．９６（１Ｈ，ｓ）．Reference Example 1 Synthesis of phenyl 3-pentafluorosulfanylphenylcarbamate:

3-Pentafluorosulfanylaniline (438 mg, 2.00 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogen carbonate (252 mg, 3.00 mmol) and phenyl chloroformate (251 μL, 2.00 mmol) were added. After stirring at room temperature for 16 hours, the reaction mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (685 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.18-7.20 (2H, m), 7.25-7.29 (1H, m), 7.37 (1H, brs), 7.39-7.45 (3H, m), 7.49-7.51 (1H, m), 7.59-7.61 (1H, m), 7.96 (1H, s).

３−ペンタフルオロサルファニルフェニルカルバミン酸フェニル（２９０ｍｇ，０．８１６ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に（１Ｒ，２Ｓ）−１−アミノ−２−インダノール（１２１ｍｇ，０．８１６ｍｍｏｌ）、トリエチルアミン（４５５μＬ，３．２６ｍｍｏｌ）を加えた。２時間加熱還流した後、室温に冷却した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、得られた固体をジエチルエーテルで洗浄し、表題化合物（以下、実施例１の化合物）（１８４ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．８９（１Ｈ，ｄｄ，Ｊ＝１６．７，４．０Ｈｚ），３．１６（１Ｈ，ｄｄ，Ｊ＝１６．７，５．２Ｈｚ），４．５８（１Ｈ，ｍ），５．２９（１Ｈ，ｍ），５．４９（１Ｈ，ｂｒｓ），６．９１（１Ｈ，ｂｒｓ），７．１０−７．２６（３Ｈ，ｍ），７．３０−７．５２（４Ｈ，ｍ），７．８０（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３９５．Example 1 Synthesis of 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (3-pentafluorosulfanylphenyl) urea:

To a solution of phenyl 3-pentafluorosulfanylphenylcarbamate (290 mg, 0.816 mmol) in tetrahydrofuran (5 mL) (1R, 2S) -1-amino-2-indanol (121 mg, 0.816 mmol), triethylamine (455 μL, 3 .26 mmol) was added. The mixture was heated to reflux for 2 hours and then cooled to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol), and the resulting solid was washed with diethyl ether to give the title compound (hereinafter, Examples). 1 compound) (184 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.89 (1H, dd, J = 16.7, 4.0 Hz), 3.16 (1H, dd, J = 16.7, 5. 2Hz), 4.58 (1H, m), 5.29 (1H, m), 5.49 (1H, brs), 6.91 (1H, brs), 7.10-7.26 (3H, m ), 7.30-7.52 (4H, m), 7.80 (1H, m).
MS (ESI) [M + H] ⁺ : 395.

４−ペンタフルオロサルファニルクロロベンゼン（５．００ｇ，２１．０ｍｍｏｌ）の濃硫酸（１０ｍＬ）懸濁液に、発煙硝酸（１０ｍＬ）を加えた。室温で１８時間撹拌した後、反応混合物に氷を加え、クロロホルムで抽出した。有機層を乾燥、濃縮し、表題化合物（５．９４ｇ）を黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：７．７１（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．９２（１Ｈ，ｄｄ，Ｊ＝８．６，２．７Ｈｚ），８．３１（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．Reference Example 2 Synthesis of 2-chloro-5-pentafluorosulfanylnitrobenzene:

Fuming nitric acid (10 mL) was added to a concentrated sulfuric acid (10 mL) suspension of 4-pentafluorosulfanylchlorobenzene (5.00 g, 21.0 mmol). After stirring at room temperature for 18 hours, ice was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated to give the title compound (5.94 g) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.71 (1H, d, J = 8.6 Hz), 7.92 (1H, dd, J = 8.6, 2.7 Hz), 8 .31 (1H, d, J = 2.7 Hz).

氷冷下、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（２．９６ｇ，１０．４ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液に、ナトリウムメトキシド（２８％メタノール溶液、２．４１ｇ，１２．５ｍｍｏｌ）を加えた。室温で２時間撹拌した後、反応混合物に飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をヘキサンで洗浄し、表題化合物（２．５４ｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．０４（３Ｈ，ｓ），７．１６（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．９４（１Ｈ，ｄｄ，Ｊ＝９．３，２．７Ｈｚ），８．２９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２８０．Reference Example 3 Synthesis of 2-methoxy-5-pentafluorosulfanylnitrobenzene:

Under ice cooling, sodium methoxide (28% methanol solution, 2.41 g, 12.5 mmol) was added to a solution of 2-chloro-5-pentafluorosulfanylnitrobenzene (2.96 g, 10.4 mmol) in tetrahydrofuran (30 mL). added. After stirring at room temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was washed with hexane to obtain the title compound (2.54 g) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.04 (3H, s), 7.16 (1H, d, J = 9.3 Hz), 7.94 (1H, dd, J = 9) .3, 2.7 Hz), 8.29 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 280.

１０重量％パラジウム−炭素（５０重量％含水，５０ｍｇ）のエタノール（３ｍＬ）懸濁液に２−メトキシ−５−ペンタフルオロサルファニルニトロベンゼン（５１１ｍｇ，１．８３ｍｍｏｌ）を加えた。水素雰囲気下、室温で５時間撹拌した後、触媒をろ過した。残渣をジクロロメタンで洗浄、濃縮し、表題化合物（４５１ｍｇ）を淡褐色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．９０（３Ｈ，ｓ），６．７５（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），７．０９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），７．１３（１Ｈ，ｄｄ，Ｊ＝９．１，２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２５０．Reference Example 4 Synthesis of 2-methoxy-5-pentafluorosulfanylaniline:

2-Methoxy-5-pentafluorosulfanylnitrobenzene (511 mg, 1.83 mmol) was added to a suspension of 10 wt% palladium-carbon (containing 50 wt% water, 50 mg) in ethanol (3 mL). After stirring for 5 hours at room temperature under a hydrogen atmosphere, the catalyst was filtered. The residue was washed with dichloromethane and concentrated to give the title compound (451 mg) as a light brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.90 (3H, s), 6.75 (1H, d, J = 9.1 Hz), 7.09 (1H, d, J = 2) .7 Hz), 7.13 (1H, dd, J = 9.1, 2.7 Hz).
MS (ESI) [M + H] ⁺ : 250.

氷冷下、２−メトキシ−５−ペンタフルオロサルファニルアニリン（１１８ｍｇ，０．４７０ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液にトリホスゲン（４７．０ｍｇ，０．１５８ｍｍｏｌ）、トリエチルアミン（６６μＬ，０．４７ｍｍｏｌ）を加え１時間撹拌した。続いて（１Ｒ，２Ｓ）−１−アミノ−２−インダノール（７１ｍｇ，０．４７ｍｍｏｌ）、トリエチルアミン（１３２μＬ，０．９５０ｍｍｏｌ）を加えた。室温で１６時間撹拌した後、反応混合物に飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、表題化合物（以下、実施例２の化合物）（８２．９ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．０７（１Ｈ，ｂｒｓ），２．９５（１Ｈ，ｄｄ，Ｊ＝１６．５，２．２Ｈｚ），３．２１（１Ｈ，ｄｄ，Ｊ＝１６．５，５．２Ｈｚ），３．９２（３Ｈ，ｓ），４．６９（１Ｈ，ｂｒｓ），５．３６（２Ｈ，ｍ），６．８５（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．０５（１Ｈ，ｂｒｓ），７．３５−７．４０（２Ｈ，ｍ），８．７５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４２５．Example 2 of 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (2-methoxy-5-pentafluorosulfanylphenyl) urea Synthesis:

Under ice-cooling, triphosgene (47.0 mg, 0.158 mmol) and triethylamine (66 μL, 0.47 mmol) were added to a solution of 2-methoxy-5-pentafluorosulfanylaniline (118 mg, 0.470 mmol) in dichloromethane (3 mL). Stir for 1 hour. Subsequently, (1R, 2S) -1-amino-2-indanol (71 mg, 0.47 mmol) and triethylamine (132 μL, 0.950 mmol) were added. After stirring at room temperature for 16 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (hereinafter, the compound of Example 2) (82.9 mg) Obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.07 (1H, brs), 2.95 (1H, dd, J = 16.5, 2.2 Hz), 3.21 (1H, dd , J = 16.5, 5.2 Hz), 3.92 (3H, s), 4.69 (1H, brs), 5.36 (2H, m), 6.85 (1H, d, J = 9). .0Hz), 7.05 (1H, brs), 7.35-7.40 (2H, m), 8.75 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 425.

氷冷下、２−メトキシ−５−ペンタフルオロサルファニルアニリン（５４６ｍｇ，２．１９ｍｍｏｌ）のジクロロメタン（２０ｍＬ）溶液にトリホスゲン（１０６ｍｇ，０．３５８ｍｍｏｌ）、トリエチルアミン（１５０μＬ，１．０８ｍｍｏｌ）を加え１時間撹拌した。続いて（１Ｓ，２Ｒ）−２−アミノ−１−インダノール（２４１ｍｇ，１．０８ｍｍｏｌ）、トリエチルアミン（７４９μＬ，１１．０ｍｍｏｌ）を加えた。室温で１６時間撹拌した後、反応混合物に飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、表題化合物（以下、実施例３の化合物）（３２７ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．４２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），２．８３（１Ｈ，ｄｄ，Ｊ＝１６．０，６．７Ｈｚ），３．２４（１Ｈ，ｄｄ，Ｊ＝１６．０，７．３Ｈｚ），３．８６（３Ｈ，ｓ），４．５３−４．６０（１Ｈ，ｍ），５．１１（１Ｈ，ｔ，Ｊ＝５．２Ｈｚ），５．６５（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．７６（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．１１（１Ｈ，ｂｒｓ），７．２０−７．３２（４Ｈ，ｍ），７．３９（１Ｈ，ｄ，Ｊ＝９．５Ｈｚ），８．６８（１Ｈ，ｄ，Ｊ＝２．１Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｎａ］^＋：４４７，［Ｍ−Ｈ］⁻：４２３．Example 3 of 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (2-methoxy-5-pentafluorosulfanylphenyl) urea Synthesis:

Under ice cooling, triphosgene (106 mg, 0.358 mmol) and triethylamine (150 μL, 1.08 mmol) were added to a solution of 2-methoxy-5-pentafluorosulfanylaniline (546 mg, 2.19 mmol) in dichloromethane (20 mL) for 1 hour. Stir. Subsequently, (1S, 2R) -2-amino-1-indanol (241 mg, 1.08 mmol) and triethylamine (749 μL, 11.0 mmol) were added. After stirring at room temperature for 16 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (hereinafter, the compound of Example 3) (327 mg) as a colorless amorphous product. Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.42 (1H, d, J = 4.9 Hz), 2.83 (1H, dd, J = 16.0, 6.7 Hz), 3 .24 (1H, dd, J = 16.0, 7.3 Hz), 3.86 (3H, s), 4.53-4.60 (1H, m), 5.11 (1H, t, J = 5.2 Hz), 5.65 (1H, d, J = 7.6 Hz), 6.76 (1H, d, J = 9.0 Hz), 7.11 (1H, brs), 7.20-7. 32 (4H, m), 7.39 (1H, d, J = 9.5 Hz), 8.68 (1H, d, J = 2.1 Hz).
MS (ESI) [M + Na] ⁺ : 447, [M−H] ⁻ : 423.

氷冷下、水素化ナトリウム（５５重量％ｉｎ ｍｉｎｅｒａｌ ｏｉｌ，６５ｍｇ，１．５ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）懸濁液にフェノール（１０３ｍｇ，１．１０ｍｍｏｌ）を加え、３０分間撹拌した後、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（２８３ｍｇ，１．００ｍｍｏｌ）を加えた。室温で３時間撹拌した後、反応混合物に飽和塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（３２７ｍｇ）を黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：６．９９（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．１２（２Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．３０（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．４６（２Ｈ，ｄ，Ｊ＝７．５Ｈｚ），７．８２（１Ｈ，ｄｄ，Ｊ＝９．３，２．７Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３４２．Reference Example 5 Synthesis of 2-phenoxy-5-pentafluorosulfanylnitrobenzene:

Under ice-cooling, phenol (103 mg, 1.10 mmol) was added to a suspension of sodium hydride (55 wt% in mineral oil, 65 mg, 1.5 mmol) in tetrahydrofuran (2 mL), stirred for 30 minutes, and then 2-chloro -5-Pentafluorosulfanylnitrobenzene (283 mg, 1.00 mmol) was added. After stirring at room temperature for 3 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (327 mg) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.99 (1H, d, J = 9.3 Hz), 7.12 (2H, d, J = 7.5 Hz), 7.30 (1H , D, J = 7.5 Hz), 7.46 (2H, d, J = 7.5 Hz), 7.82 (1H, dd, J = 9.3, 2.7 Hz), 8.38 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 342.

参考例４と同様の方法に従い、２−フェノキシ−５−ペンタフルオロサルファニルニトロベンゼン（３２５ｍｇ，０．９５ｍｍｏｌ）から、表題化合物（２８７ｍｇ）を淡褐色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．０６（２Ｈ，ｂｒｓ），６．７６（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），７．０１−７．０６（３Ｈ，ｍ），７．１５−７．１８（１Ｈ，ｍ），７．２０（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），７．３５−７．４０（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３１２．Reference Example 6 Synthesis of 2-phenoxy-5-pentafluorosulfanylaniline:

The title compound (287 mg) was obtained as a pale brown oil from 2-phenoxy-5-pentafluorosulfanylnitrobenzene (325 mg, 0.95 mmol) according to the same method as in Reference Example 4.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.06 (2H, brs), 6.76 (1H, d, J = 9.1 Hz), 7.01-7.06 (3H, m ), 7.15-7.18 (1H, m), 7.20 (1H, d, J = 2.7 Hz), 7.35-7.40 (2H, m).
MS (ESI) [M + H] ⁺ : 312.

実施例２と同様の方法に従い、２−フェノキシ−５−ペンタフルオロサルファニルアニリン（２８６ｍｇ，０．９２０ｍｍｏｌ）から、表題化合物（以下、実施例４の化合物）（３６１ｍｇ）を淡黄色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．１６（１Ｈ，ｄ，Ｊ＝４．０Ｈｚ），２．８５（１Ｈ，ｄｄ，Ｊ＝１６．６，２．０Ｈｚ），３．１０（１Ｈ，ｄｄ，Ｊ＝１６．６，５．２Ｈｚ），４．５５（１Ｈ，ｂｒｓ），５．２７（１Ｈ，ｄｄ，Ｊ＝８．０，５．１Ｈｚ），５．６１（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），６．７３（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．０２（２Ｈ，ｍ），７．１８−７．２８（５Ｈ，ｍ），７．３６−７．４０（３Ｈ，ｍ），８．８４（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８７．Example 4 of 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (3-pentafluorosulfanyl-6-phenoxyphenyl) urea Synthesis:

The title compound (hereinafter, the compound of Example 4) (361 mg) was obtained as a pale yellow amorphous form from 2-phenoxy-5-pentafluorosulfanylaniline (286 mg, 0.920 mmol) according to the same method as in Example 2. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.16 (1H, d, J = 4.0 Hz), 2.85 (1H, dd, J = 16.6, 2.0 Hz), 3 .10 (1H, dd, J = 16.6, 5.2 Hz), 4.55 (1H, brs), 5.27 (1H, dd, J = 8.0, 5.1 Hz), 5.61 ( 1H, d, J = 8.0 Hz), 6.73 (1H, d, J = 9.0 Hz), 7.02 (2H, m), 7.18-7.28 (5H, m), 7. 36-7.40 (3H, m), 8.84 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 487.

２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（１００ｍｇ，０．３５３ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１２．２ｍｇ，０．０１０６ｍｍｏｌ）、フェニルボロン酸（５５．９ｍｇ，０．４５８ｍｍｏｌ）のトルエン（１．９ｍＬ）溶液に、エタノール（０．３ｍＬ）、２Ｍ炭酸ナトリウム水溶液（１．９ｍＬ）を加えた。１００℃で１５時間撹拌した後、反応混合物を放冷、分液した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（９９．５ｍｇ）を黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：７．３０−７．３４（２Ｈ，ｍ），７．４６−７．４８（３Ｈ，ｍ），７．５９（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．００（１Ｈ，ｄｄ，Ｊ＝８．４，２．３Ｈｚ），８．２７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．Reference Example 7 Synthesis of 3-pentafluorosulfanyl-6-phenylnitrobenzene:

2-chloro-5-pentafluorosulfanylnitrobenzene (100 mg, 0.353 mmol), tetrakistriphenylphosphine palladium (0) (12.2 mg, 0.0106 mmol), phenylboronic acid (55.9 mg, 0.458 mmol) Ethanol (0.3 mL) and 2M aqueous sodium carbonate solution (1.9 mL) were added to a toluene (1.9 mL) solution. After stirring at 100 ° C. for 15 hours, the reaction mixture was allowed to cool and separated. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (99.5 mg) as a yellow oil. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.30-7.34 (2H, m), 7.46-7.48 (3H, m), 7.59 (1H, d, J = 8.5 Hz), 8.00 (1H, dd, J = 8.4, 2.3 Hz), 8.27 (1H, d, J = 2.4 Hz).

参考例４と同様の方法に従い、３−ペンタフルオロサルファニル−６−フェニルニトロベンゼン（９８．０ｍｇ，０．３０１ｍｍｏｌ）から、表題化合物（８５ｍｇ）を橙色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．９５（２Ｈ，ｓ），７．１３−７．１７（３Ｈ，ｍ），７．３８−７．５０（５Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２９６．Reference Example 8 Synthesis of 3-pentafluorosulfanyl-6-phenylaniline:

In the same manner as in Reference Example 4, the title compound (85 mg) was obtained as an orange oil from 3-pentafluorosulfanyl-6-phenylnitrobenzene (98.0 mg, 0.301 mmol).
^{1 H-NMR (400MHz, CDCl} 3) δ (ppm): 3.95 (2H, s), 7.13-7.17 (3H, m), 7.38-7.50 (5H, m).
MS (ESI) [M + H] ⁺ : 296.

３−ペンタフルオロサルファニル−６−フェニルアニリン（８５．０ｍｇ，０．２８８ｍｍｏｌ）のテトラヒドロフラン溶液（１．０ｍＬ）に、ジイソプロピルエチルアミン（７５μＬ，０．４３ｍｍｏｌ）、クロロギ酸２，２，２−トリクロロエチル（５１μＬ，０．３７ｍｍｏｌ）を加えた。室温で１７時間撹拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（１２４ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．８１（２Ｈ，ｓ），６．９０（１Ｈ，ｓ），７．３６−７．３９（３Ｈ，ｍ），７．４９−７．５９（４Ｈ，ｍ），８．６０（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７０．
ｍｐ８７．０−１１８．０℃．Reference Example 9 Synthesis of 2,2,2-trichloroethyl 3-pentafluorosulfanyl-6-phenylcarbamate:

To a tetrahydrofuran solution (1.0 mL) of 3-pentafluorosulfanyl-6-phenylaniline (85.0 mg, 0.288 mmol), diisopropylethylamine (75 μL, 0.43 mmol), 2,2,2-trichloroethyl chloroformate (51 μL, 0.37 mmol) was added. After stirring at room temperature for 17 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (124 mg) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.81 (2H, s), 6.90 (1H, s), 7.36-7.39 (3H, m), 7.49- 7.59 (4H, m), 8.60 (1H, s).
MS (ESI) [M + H] ⁺ : 470.
mp 87.0-118.0 ° C.

３−ペンタフルオロサルファニル−６−フェニルカルバミン酸２，２，２−トリクロロエチル（６０．０ｍｇ，０．１２７ｍｍｏｌ）のアセトニトリル（１．０ｍＬ）溶液に、ジイソプロピルエチルアミン（４４μＬ，０．２５ｍｍｏｌ）、（１Ｒ，２Ｓ）−１−アミノ−２−インダノール（３０．４ｍｇ，０．１９１ｍｍｏｌ）を加えた。８０℃で１４時間撹拌した後、反応混合物を放冷、酢酸エチルで抽出した。有機層を１Ｍ塩酸、飽和食塩水で順次洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、得られた目的物をジエチルエーテル／シクロヘキサン（＝１／１）でスラリー洗浄することで表題化合物（以下、実施例５の化合物）（４０．２ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．８８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），２．８８（１Ｈ，ｄ，Ｊ＝１６．６Ｈｚ），３．１５（１Ｈ，ｄｄ，Ｊ＝１６．６，５．４Ｈｚ），４．５９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），５．１１（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），５．２６（１Ｈ，ｔ，Ｊ＝６．５Ｈｚ），６．４５（１Ｈ，ｓ），７．２２−７．３０（５Ｈ，ｍ），７．３５−７．３７（２Ｈ，ｍ），７．４２−７．５１（４Ｈ，ｍ），８．６９（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７１．
ｍｐ２２６．３−２２８．６℃．Example 5 of 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (3-pentafluorosulfanyl-6-phenylphenyl) urea Synthesis:

To a solution of 2,2,2-trichloroethyl 3-pentafluorosulfanyl-6-phenylcarbamate (60.0 mg, 0.127 mmol) in acetonitrile (1.0 mL), diisopropylethylamine (44 μL, 0.25 mmol), ( 1R, 2S) -1-Amino-2-indanol (30.4 mg, 0.191 mmol) was added. After stirring at 80 ° C. for 14 hours, the reaction mixture was allowed to cool and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid and saturated brine, dried and concentrated, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol). The obtained target product was diethyl ether / cyclohexane ( = 1/1) to give the title compound (hereinafter, the compound of Example 5) (40.2 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.88 (1H, d, J = 4.9 Hz), 2.88 (1H, d, J = 16.6 Hz), 3.15 (1H , Dd, J = 16.6, 5.4 Hz), 4.59 (1H, d, J = 2.7 Hz), 5.11 (1H, d, J = 7.6 Hz), 5.26 (1H, t, J = 6.5 Hz), 6.45 (1H, s), 7.22-7.30 (5H, m), 7.35-7.37 (2H, m), 7.42-7. 51 (4H, m), 8.69 (1H, d, J = 2.0 Hz).
MS (ESI) [M + H] ⁺ : 471.
mp 226.3-228.6 ° C.

参考例７と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３００ｍｇ，１．０６ｍｍｏｌ）及び４−メトキシフェニルボロン酸（２０９ｍｇ，１．３８ｍｍｏｌ）から、表題化合物（３１４ｍｇ）を黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８６（３Ｈ，ｓ），６．９７−７．００（２Ｈ，ｍ），７．２４−７．２７（２Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．９６（１Ｈ，ｄｄ，Ｊ＝８．５，２．２Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ）．
ｍｐ８３．６−８４．２℃．Reference Example 10 Synthesis of 2- (4-methoxyphenyl) -5-pentafluorosulfanylnitrobenzene:

According to the same method as in Reference Example 7, the title compound (314 mg) was converted to yellow from 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) and 4-methoxyphenylboronic acid (209 mg, 1.38 mmol). Obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.86 (3H, s), 6.97-7.00 (2H, m), 7.24-7.27 (2H, m), 7.57 (1H, d, J = 8.5 Hz), 7.96 (1H, dd, J = 8.5, 2.2 Hz), 8.21 (1H, d, J = 2.2 Hz).
mp 83.6-84.2 ° C.

参考例４と同様の方法に従い、２−（４−メトキシフェニル）−５−ペンタフルオロサルファニルニトロベンゼン（３１０ｍｇ，０．８７３ｍｍｏｌ）から、表題化合物（２６８ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８６（３Ｈ，ｓ），３．９３（２Ｈ，ｓ），６．９９−７．０１（２Ｈ，ｍ），７．１２−７．１７（３Ｈ，ｍ），７．３４−７．３６（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３２６．
ｍｐ１０５．５−１０７．９℃．Reference Example 11 Synthesis of 2- (4-methoxyphenyl) -5-pentafluorosulfanylaniline:

The title compound (268 mg) was obtained as a colorless solid from 2- (4-methoxyphenyl) -5-pentafluorosulfanylnitrobenzene (310 mg, 0.873 mmol) according to the same method as in Reference Example 4.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.86 (3H, s), 3.93 (2H, s), 6.99-7.01 (2H, m), 7.12- 7.17 (3H, m), 7.34-7.36 (2H, m).
MS (ESI) [M + H] ⁺ : 326.
mp 105.5-107.9 ° C.

参考例９と同様の方法に従い、２−（４−メトキシフェニル）−５−ペンタフルオロサルファニルアニリン（２６５ｍｇ，０．８１５ｍｍｏｌ）から、表題化合物（４３４ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８９（３Ｈ，ｓ），４．８２（２Ｈ，ｓ），６．９２（１Ｈ，ｓ），７．０５−７．０７（２Ｈ，ｍ），７．２８−７．３３（３Ｈ，ｍ），７．５５（１Ｈ，ｄｄ，Ｊ＝８．４，２．３Ｈｚ），８．５８（１Ｈ，ｓ）．
ｍｐ８５．８−９５．２℃．Reference Example 12 Synthesis of 2, (2-methoxyphenyl) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

The title compound (434 mg) was obtained as a pale yellow solid from 2- (4-methoxyphenyl) -5-pentafluorosulfanylaniline (265 mg, 0.815 mmol) in the same manner as in Reference Example 9.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.89 (3H, s), 4.82 (2H, s), 6.92 (1H, s), 7.05-7.07 ( 2H, m), 7.28-7.33 (3H, m), 7.55 (1H, dd, J = 8.4, 2.3 Hz), 8.58 (1H, s).
mp 85.8-95.2 ° C.

実施例５と同様の方法に従い、２−（４−メトキシフェニル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７５．０ｍｇ，０．１５０ｍｍｏｌ）から、表題化合物（以下、実施例６の化合物）（７５ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８７（１Ｈ，ｄｄ，Ｊ＝１６．５，１．３Ｈｚ），３．１２（１Ｈ，ｄｄ，Ｊ＝１６．５，５．０Ｈｚ），３．８４（３Ｈ，ｓ），４．５４（１Ｈ，ｄｔ，Ｊ＝５．０，１．５Ｈｚ），５．１７（１Ｈ，ｄ，Ｊ＝５．１Ｈｚ），７．０４−７．０６（２Ｈ，ｍ），７．１７−７．２２（４Ｈ，ｍ），７．３４−７．３７（３Ｈ，ｍ），７．５２（１Ｈ，ｄｄ，Ｊ＝８．５，２．４Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５０１．
ｍｐ２２０．５−２２２．０℃．Example 6 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (2- (4-methoxyphenyl) -5-pentafluorosulfur Synthesis of (nylphenyl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (4-methoxyphenyl) -5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.150 mmol) , Example 6 compound) (75 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.87 (1H, dd, J = 16.5, 1.3 Hz), 3.12 (1H, dd, J = 16.5, 5) .0Hz), 3.84 (3H, s), 4.54 (1H, dt, J = 5.0, 1.5 Hz), 5.17 (1H, d, J = 5.1 Hz), 7.04 -7.06 (2H, m), 7.17-7.22 (4H, m), 7.34-7.37 (3H, m), 7.52 (1H, dd, J = 8.5) 2.4 Hz), 8.54 (1H, d, J = 2.2 Hz).
MS (ESI) [M + H] ⁺ : 501.
mp 220.5-222.0 ° C.

２−（４−メトキシフェニル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７５．０ｍｇ，０．１５０ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、ジイソプロピルエチルアミン（５２μＬ，０．３０ｍｍｏｌ）、（１Ｓ，２Ｒ）−２−アミノ−１−インダノール（３３．５ｍｇ，０．２２５ｍｍｏｌ）を加えた。１００℃で２２時間撹拌した後、反応混合物を放冷し、酢酸エチルで抽出した。有機層を１Ｍ塩酸、飽和食塩水で順次洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、表題化合物（以下、実施例７の化合物）（６９．４ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８４（１Ｈ，ｄｄ，Ｊ＝１５．６，７．８Ｈｚ），３．１３（１Ｈ，ｄｄ，Ｊ＝１５．４，７．３Ｈｚ），３．８５（３Ｈ，ｓ），４．３９（１Ｈ，ｄｔ，Ｊ＝７．４，５．６Ｈｚ），４．９６（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．０４−７．０６（２Ｈ，ｍ），７．１９−７．２７（３Ｈ，ｍ），７．３０−７．３４（３Ｈ，ｍ），７．３８（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．４９（１Ｈ，ｄｄ，Ｊ＝８．５，２．４Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４９９．
ｍｐ１８５．５−１８７．１℃．Example 7 1-((1S, 2R) -1-Hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (2- (4-methoxyphenyl) -5-pentafluorosulfur Synthesis of (nylphenyl) urea:

To a solution of 2,2,2-trichloroethyl 2- (4-methoxyphenyl) -5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.150 mmol) in acetonitrile (1 mL) was added diisopropylethylamine (52 μL,. 30 mmol), (1S, 2R) -2-amino-1-indanol (33.5 mg, 0.225 mmol) was added. After stirring at 100 ° C. for 22 hours, the reaction mixture was allowed to cool and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid and saturated brine, dried and concentrated, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (hereinafter referred to as the compound of Example 7). (69.4 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.84 (1H, dd, J = 15.6, 7.8 Hz), 3.13 (1H, dd, J = 15.4, 7 .3 Hz), 3.85 (3 H, s), 4.39 (1 H, dt, J = 7.4, 5.6 Hz), 4.96 (1 H, d, J = 5.6 Hz), 7.04 -7.06 (2H, m), 7.19-7.27 (3H, m), 7.30-7.34 (3H, m), 7.38 (1H, d, J = 8.5Hz) 7.49 (1H, dd, J = 8.5, 2.4 Hz), 8.54 (1H, d, J = 2.4 Hz).
MS (ESI) [M−H] ⁻ : 499.
mp 185.5-187.1 [deg.] C.

２−（４−メトキシフェニル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１６０ｍｇ，０．３２０ｍｍｏｌ）のジクロロメタン（１．５ｍＬ）溶液を−７８℃に冷却した。三臭化ホウ素（１．０Ｍジクロロメタン溶液，１．１ｍＬ，１．１ｍｍｏｌ）を加え、氷冷下、２時間撹拌した。反応混合物を再度−７８℃に冷却した後、メタノール、水を順次加えた。反応混合物を室温に昇温後、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（１２７ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．８２（２Ｈ，ｓ），５．０５（１Ｈ，ｄ，Ｊ＝１．５Ｈｚ），６．９０（１Ｈ，ｓ），６．９８−７．００（２Ｈ，ｍ），７．２４−７．２６（２Ｈ，ｍ），７．３１（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．５５（１Ｈ，ｄｄ，Ｊ＝８．５，２．２Ｈｚ），８．５８（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８６．
ｍｐ１８１．３−１８２．６℃．Reference Example 13 Synthesis of 2,2,2-trichloroethyl 2- (4-hydroxyphenyl) -5-pentafluorosulfanylphenylcarbamate:

A solution of 2,2,2-trichloroethyl 2- (4-methoxyphenyl) -5-pentafluorosulfanylphenylcarbamate (160 mg, 0.320 mmol) in dichloromethane (1.5 mL) was cooled to -78 ° C. Boron tribromide (1.0 M dichloromethane solution, 1.1 mL, 1.1 mmol) was added, and the mixture was stirred for 2 hours under ice cooling. The reaction mixture was cooled again to −78 ° C., and methanol and water were sequentially added. The reaction mixture was warmed to room temperature and extracted with dichloromethane. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (127 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.82 (2H, s), 5.05 (1H, d, J = 1.5 Hz), 6.90 (1H, s), 6. 98-7.00 (2H, m), 7.24-7.26 (2H, m), 7.31 (1H, d, J = 8.3 Hz), 7.55 (1H, dd, J = 8) .5, 2.2 Hz), 8.58 (1H, s).
MS (ESI) [M + H] ⁺ : 486.
mp 181.3-182.6 ° C.

実施例５と同様の方法に従い、２−（４−ヒドロキシフェニル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７５．０ｍｇ，０．１５４ｍｍｏｌ）から、表題化合物（以下、実施例８の化合物）（７５ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８８（１Ｈ，ｄｄ，Ｊ＝１６．５，１．３Ｈｚ），３．１２（１Ｈ，ｄｄ，Ｊ＝１６．５，４．８Ｈｚ），４．５４（１Ｈ，ｄｔ，Ｊ＝４．９，１．６Ｈｚ），５．１８（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），６．９０−６．９２（２Ｈ，ｍ），７．１８−７．２８（６Ｈ，ｍ），７．３３（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５１（１Ｈ，ｄｄ，Ｊ＝８．５，２．４Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８７．Example 8 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (2- (4-hydroxyphenyl) -5-pentafluorosulfur Synthesis of (nylphenyl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (4-hydroxyphenyl) -5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.154 mmol) , Example 8 compound) (75 mg) was obtained as a colorless amorphous.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.88 (1H, dd, J = 16.5, 1.3 Hz), 3.12 (1H, dd, J = 16.5, 4) .8 Hz), 4.54 (1H, dt, J = 4.9, 1.6 Hz), 5.18 (1H, d, J = 4.9 Hz), 6.90-6.92 (2H, m) 7.18-7.28 (6H, m), 7.33 (1H, d, J = 8.5 Hz), 7.51 (1H, dd, J = 8.5, 2.4 Hz), 8. 51 (1H, d, J = 2.4 Hz).
MS (ESI) [M + H] ⁺ : 487.

参考例７と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（５００ｍｇ，１．７６ｍｍｏｌ）及び４−ピリジルボロン酸（３２５ｍｇ，２．６４ｍｍｏｌ）から、表題化合物（５６．６ｍｇ）を黒色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：７．２４−７．２５（２Ｈ，ｍ），７．５７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．０８（１Ｈ，ｄｄ，Ｊ＝８．５，２．２Ｈｚ），８．４１（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ），８．７３−８．７５（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３２７．Reference Example 14 Synthesis of 2- (4-pyridyl) -5-pentafluorosulfanylnitrobenzene:

The title compound (56.6 mg) was obtained from 2-chloro-5-pentafluorosulfanylnitrobenzene (500 mg, 1.76 mmol) and 4-pyridylboronic acid (325 mg, 2.64 mmol) in the same manner as in Reference Example 7. Obtained as a black oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.24-7.25 (2H, m), 7.57 (1H, d, J = 8.5 Hz), 8.08 (1H, dd , J = 8.5, 2.2 Hz), 8.41 (1H, d, J = 2.2 Hz), 8.73-8.75 (2H, m).
MS (ESI) [M + H] ⁺ : 327.

参考例４と同様の方法に従い、２−（４−ピリジル）−５−ペンタフルオロサルファニルニトロベンゼン（１５０ｍｇ，０．４６０ｍｍｏｌ）から、表題化合物（６４．８ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．９８（２Ｈ，ｂｒｓ），７．１６−７．２２（３Ｈ，ｍ），７．３８−７．４０（２Ｈ，ｍ），８．７２−８．７４（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２９７．Reference Example 15 Synthesis of 2- (4-pyridyl) -5-pentafluorosulfanylaniline:

In the same manner as in Reference Example 4, the title compound (64.8 mg) was obtained as a pale yellow solid from 2- (4-pyridyl) -5-pentafluorosulfanylnitrobenzene (150 mg, 0.460 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.98 (2H, brs), 7.16-7.22 (3H, m), 7.38-7.40 (2H, m), 8.72-8.74 (2H, m).
MS (ESI) [M + H] ⁺ : 297.

参考例９と同様の方法に従い、２−（４−ピリジル）−５−ペンタフルオロサルファニルアニリン（６５．０ｍｇ，０．２１９ｍｍｏｌ）から、表題化合物（３１．７ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．８２（２Ｈ，ｓ），７．３１−７．３７（３Ｈ，ｍ），７．６４（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５３（１Ｈ，ｓ），８．７２−８．８０（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７１．
ｍｐ１６６．４−１６９．０℃．Reference Example 16 Synthesis of 2,2,2-trichloroethyl 2- (4-pyridyl) -5-pentafluorosulfanylphenylcarbamate:

In the same manner as in Reference Example 9, the title compound (31.7 mg) was obtained as a colorless solid from 2- (4-pyridyl) -5-pentafluorosulfanylaniline (65.0 mg, 0.219 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.82 (2H, s), 7.31-7.37 (3H, m), 7.64 (1H, d, J = 8.6 Hz) ), 8.53 (1H, s), 8.72-8.80 (2H, m).
MS (ESI) [M + H] ⁺ : 471.
mp 166.4-169.0 ° C.

実施例５と同様の方法に従い、２−（４−ピリジル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１５．０ｍｇ，０．０３２０ｍｍｏｌ）から、表題化合物（以下、実施例９の化合物）（１２．７ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８８（１Ｈ，ｄｄ，Ｊ＝１６．３，１．８Ｈｚ），３．１２（１Ｈ，ｄｄ，Ｊ＝１６．３，５．０Ｈｚ），４．５３（１Ｈ，ｄｔ，Ｊ＝５．０，１．４Ｈｚ），５．１５（１Ｈ，ｄ，Ｊ＝５．０Ｈｚ），７．１４−７．２３（４Ｈ，ｍ），７．４６（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．５３−７．５５（２Ｈ，ｍ），７．６３（１Ｈ，ｄｄ，Ｊ＝８．６，２．３Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），８．６６−８．６７（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７２．
ｍｐ２２７．９−２２９．３℃．Example 9 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (2- (4-pyridyl) -5-pentafluorosulfanyl Synthesis of phenyl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (4-pyridyl) -5-pentafluorosulfanylphenylcarbamate (15.0 mg, 0.0320 mmol), the title compound (hereinafter, The compound of Example 9) (12.7 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.88 (1H, dd, J = 16.3, 1.8 Hz), 3.12 (1H, dd, J = 16.3, 5) .0Hz), 4.53 (1H, dt, J = 5.0, 1.4 Hz), 5.15 (1H, d, J = 5.0 Hz), 7.14-7.23 (4H, m) 7.46 (1H, d, J = 8.6 Hz), 7.53-7.55 (2H, m), 7.63 (1H, dd, J = 8.6, 2.3 Hz), 8. 54 (1H, d, J = 2.3 Hz), 8.66-8.67 (2H, m).
MS (ESI) [M + H] ^< +>: 472.
mp 227.9-229.3 ° C.

実施例７と同様の方法に従い、２−（４−ピリジル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１５．０ｍｇ，０．０３２０ｍｍｏｌ）から、表題化合物（以下、実施例１０の化合物）（１１．４ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８２（１Ｈ，ｄｄ，Ｊ＝１５．６，７．５Ｈｚ），３．１３（１Ｈ，ｄｄ，Ｊ＝１５．４，７．２Ｈｚ），４．３５−４．４０（１Ｈ，ｍ），４．９６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．２０−７．２５（３Ｈ，ｍ），７．４１（２Ｈ，ｄｄ，Ｊ＝１６．８，７．７Ｈｚ），７．４９−７．５１（２Ｈ，ｍ），７．６０（１Ｈ，ｄｄ，Ｊ＝８．６，２．３Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），８．６５−８．６６（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７２．
ｍｐ２３７．４−２３８．１℃．Example 10 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (2- (4-pyridyl) -5-pentafluorosulfanyl Synthesis of phenyl) urea:

In the same manner as in Example 7, from 2,2,2-trichloroethyl 2- (4-pyridyl) -5-pentafluorosulfanylphenylcarbamate (15.0 mg, 0.0320 mmol), the title compound (hereinafter, The compound of Example 10) (11.4 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.82 (1H, dd, J = 15.6, 7.5 Hz), 3.13 (1H, dd, J = 15.4, 7 .2 Hz), 4.35-4.40 (1 H, m), 4.96 (1 H, d, J = 5.4 Hz), 7.20-7.25 (3 H, m), 7.41 (2 H) , Dd, J = 16.8, 7.7 Hz), 7.49-7.51 (2H, m), 7.60 (1H, dd, J = 8.6, 2.3 Hz), 8.53 ( 1H, d, J = 2.3 Hz), 8.65-8.66 (2H, m).
MS (ESI) [M + H] ^< +>: 472.
mp 237.4-248.1 ° C.

２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（５００ｍｇ，１．７６ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１０２ｍｇ，０．０８８３ｍｍｏｌ）、３，６−ジヒドロ−２Ｈ−ピラン−４−ボロン酸ピナコール（４８１ｍｇ，２．２９ｍｍｏｌ）のトルエン（９ｍＬ）溶液に、エタノール（１．４ｍＬ）２Ｍ炭酸ナトリウム水溶液（９ｍＬ）を加えた。１００℃で２０時間撹拌した後、反応混合物を放冷し、分液した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（５６６ｍｇ）を黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．３５（２Ｈ，ｄｔ，Ｊ＝４．９，２．３Ｈｚ），３．９４（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），４．２９（２Ｈ，ｑ，Ｊ＝２．８Ｈｚ），５．７５（１Ｈ，ｓ），７．４６（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．９５（１Ｈ，ｄｄ，Ｊ＝８．５，２．２Ｈｚ），８．３１（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３３２．Reference Example 17 Synthesis of 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylnitrobenzene:

2-chloro-5-pentafluorosulfanylnitrobenzene (500 mg, 1.76 mmol), tetrakistriphenylphosphine palladium (0) (102 mg, 0.0883 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol To a solution of (481 mg, 2.29 mmol) in toluene (9 mL) was added ethanol (1.4 mL) 2M aqueous sodium carbonate solution (9 mL). After stirring at 100 ° C. for 20 hours, the reaction mixture was allowed to cool and separated. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (566 mg) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.35 (2H, dt, J = 4.9, 2.3 Hz), 3.94 (2H, t, J = 5.4 Hz), 4 .29 (2H, q, J = 2.8 Hz), 5.75 (1H, s), 7.46 (1H, d, J = 8.3 Hz), 7.95 (1H, dd, J = 8. 5, 2.2 Hz), 8.31 (1H, d, J = 2.2 Hz).
MS (ESI) [M + H] ⁺ : 332.

２−（３，６−ジヒドロ−２Ｈ−ピラン−４−イル）−５−ペンタフルオロサルファニルニトロベンゼン（５６５ｍｇ，１．７１ｍｍｏｌ）のテトラヒドロフラン（８．５ｍＬ）溶液に、エタノール（８．５ｍＬ）、水（２．８ｍＬ）、塩化アンモニウム（４５７ｍｇ，８．５４ｍｍｏｌ）、鉄粉（１．９１ｇ，３４．１ｍｍｏｌ）を加えた。８０℃で６時間撹拌した後、さらに、濃塩酸（１．４ｍＬ）、鉄粉（４．７５ｇ，８５．１ｍｍｏｌ）を加えた。８０℃で１３時間撹拌した後、反応混合物を放冷し、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（２５６ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．３５−２．４０（２Ｈ，ｍ），３．９４（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），３．９８（２Ｈ，ｂｒｓ），４．３０（２Ｈ，ｑ，Ｊ＝２．８Ｈｚ），５．８７−５．８９（１Ｈ，ｍ），７．０７（３Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３０２．
ｍｐ１３３．６−１３７．２℃．Reference Example 18 Synthesis of 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylaniline:

To a solution of 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylnitrobenzene (565 mg, 1.71 mmol) in tetrahydrofuran (8.5 mL), ethanol (8.5 mL), water (2.8 mL), ammonium chloride (457 mg, 8.54 mmol), and iron powder (1.91 g, 34.1 mmol) were added. After stirring at 80 ° C. for 6 hours, concentrated hydrochloric acid (1.4 mL) and iron powder (4.75 g, 85.1 mmol) were further added. After stirring at 80 ° C. for 13 hours, the reaction mixture was allowed to cool and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (256 mg) as a colorless solid. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.35-2.40 (2H, m), 3.94 (2H, t, J = 5.4 Hz), 3.98 (2H, brs) ), 4.30 (2H, q, J = 2.8 Hz), 5.87-5.89 (1H, m), 7.07 (3H, m).
MS (ESI) [M + H] ⁺ : 302.
mp 133.6-137.2 ° C.

参考例９と同様の方法に従い、２−（３，６−ジヒドロ−２Ｈ−ピラン−４−イル）−５−ペンタフルオロサルファニルアニリン（２５０ｍｇ，０．８３０ｍｍｏｌ）から、表題化合物（３３３ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．３５−２．３９（２Ｈ，ｍ），３．９６（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），４．３４（２Ｈ，ｑ，Ｊ＝２．８Ｈｚ），４．８６（２Ｈ，ｓ），５．９０−５．９２（１Ｈ，ｍ），７．１１（１Ｈ，ｓ），７．２２（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５０（１Ｈ，ｄｄ，Ｊ＝８．５，２．２Ｈｚ），８．４９（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７６．
ｍｐ１５３．９−１５６．０℃．Reference Example 19 Synthesis of 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

The title compound (333 mg) was purified from 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylaniline (250 mg, 0.830 mmol) in the same manner as in Reference Example 9. Obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.35-2.39 (2H, m), 3.96 (2H, t, J = 5.4 Hz), 4.34 (2H, q , J = 2.8 Hz), 4.86 (2H, s), 5.90-5.92 (1H, m), 7.11 (1H, s), 7.22 (1H, d, J = 8). .5 Hz), 7.50 (1 H, dd, J = 8.5, 2.2 Hz), 8.49 (1 H, s).
MS (ESI) [M + H] ⁺ : 476.
mp 153.9-156.0 ° C.

実施例５と同様の方法に従い、２−（３，６−ジヒドロ−２Ｈ−ピラン−４−イル）−５−ペンタフルオロサルファニルカルバミン酸２，２，２−トリクロロエチル（１５０ｍｇ，０．３１５ｍｍｏｌ）から、表題化合物（１２８ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．３７−２．４２（２Ｈ，ｍ），２．９２（１Ｈ，ｄｄ，Ｊ＝１６．５，１．６Ｈｚ），３．１５（１Ｈ，ｄｄ，Ｊ＝１６．５，５．０Ｈｚ），３．９４（２Ｈ，ｔ，Ｊ＝５．５Ｈｚ），４．２９（２Ｈ，ｑ，Ｊ＝２．８Ｈｚ），４．５８（１Ｈ，ｄｔ，Ｊ＝５．０，１．７Ｈｚ），５．２２（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），５．８７−５．８９（１Ｈ，ｍ），７．１９−７．３１（５Ｈ，ｍ），７．４６（１Ｈ，ｄｄ，Ｊ＝８．５，２．４Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７７．
ｍｐ２０８．８−２１１．１℃．Reference Example 20 1- (2- (3,6-Dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylphenyl) -3-((1R, 2S) -2-hydroxy-2, Synthesis of 3-dihydro-1H-inden-1-yl) urea:

According to the same method as in Example 5, 2,2,2-trichloroethyl 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylcarbamate (150 mg, 0.315 mmol) Gave the title compound (128 mg) as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.37-2.42 (2H, m), 2.92 (1H, dd, J = 16.5, 1.6 Hz), 3. 15 (1H, dd, J = 16.5, 5.0 Hz), 3.94 (2H, t, J = 5.5 Hz), 4.29 (2H, q, J = 2.8 Hz), 4.58 (1H, dt, J = 5.0, 1.7 Hz), 5.22 (1H, d, J = 4.9 Hz), 5.87-5.89 (1H, m), 7.19-7. 31 (5H, m), 7.46 (1H, dd, J = 8.5, 2.4 Hz), 8.51 (1H, d, J = 2.4 Hz).
MS (ESI) [M + H] ⁺ : 477.
mp 208.8-211.1 ° C.

１−（２−（３，６−ジヒドロ−２Ｈ−ピラン−４−イル）−５−ペンタフルオロサルファニルフェニル）−３−（（１Ｒ，２Ｓ）−２−ヒドロキシ−２，３−ジヒドロ−１Ｈ−インデン−１−イル）ウレア（６０．０ｍｇ，０．１２６ｍｍｏｌ）のメタノール（４．０ｍＬ）溶液に１０重量％パラジウム−炭素（５０重量％含水，１２ｍｇ）を加え、水素雰囲気下、室温で２時間撹拌した。触媒をろ過した後、ろ液を濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、得られた目的物をジエチルエーテル／シクロヘキサン（１／１）でスラリー洗浄することで表題化合物（以下、実施例１１の化合物）（４７．６ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．７２−１．８２（２Ｈ，ｍ），２．３０（１Ｈ，ｄ，Ｊ＝３．２Ｈｚ），２．８４（１Ｈ，ｄｄ，Ｊ＝１６．６，２．０Ｈｚ），３．０３−３．１６（２Ｈ，ｍ），３．４６−３．５４（２Ｈ，ｍ），４．０２−４．０７（２Ｈ，ｍ），４．５３−４．５６（１Ｈ，ｍ），５．２７（１Ｈ，ｄｄ，Ｊ＝８．３，５．１Ｈｚ），５．５８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），６．８１（１Ｈ，ｓ），７．２０−７．２８（４Ｈ，ｍ），７．３４（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．５６（１Ｈ，ｄｄ，Ｊ＝８．８，２．４Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７９．Example 11 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (5-pentafluorosulfanyl-2- (tetrahydro-2H-) Synthesis of pyran-4-yl) phenyl) urea:

1- (2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylphenyl) -3-((1R, 2S) -2-hydroxy-2,3-dihydro-1H -Inden-1-yl) urea (60.0 mg, 0.126 mmol) in methanol (4.0 mL) was added 10 wt% palladium-carbon (50 wt% water content, 12 mg), and 2% at room temperature under hydrogen atmosphere. Stir for hours. After filtering the catalyst, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (chloroform / methanol). The obtained target product was washed with slurry in diethyl ether / cyclohexane (1/1). As a result, the title compound (hereinafter referred to as the compound of Example 11) (47.6 mg) was obtained as a colorless amorphous substance.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.72-1.82 (2H, m), 2.30 (1H, d, J = 3.2 Hz), 2.84 (1H, dd , J = 16.6, 2.0 Hz), 3.03-3.16 (2H, m), 3.46-3.54 (2H, m), 4.02-4.07 (2H, m) , 4.53-4.56 (1H, m), 5.27 (1H, dd, J = 8.3, 5.1 Hz), 5.58 (1H, d, J = 8.0 Hz), 6. 81 (1H, s), 7.20-7.28 (4H, m), 7.34 (1H, d, J = 8.5 Hz), 7.56 (1H, dd, J = 8.8, 2) .4 Hz), 7.96 (1H, d, J = 2.4 Hz).
MS (ESI) [M + H] ⁺ : 479.

実施例７と同様の方法に従い、２−（３，６−ジヒドロ−２Ｈ−ピラン−４−イル）−５−ペンタフルオロサルファニルカルバミン酸２，２，２−トリクロロエチル（１５０ｍｇ，０．３１５ｍｍｏｌ）から、表題化合物（１３０ｍｇ）無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．３５−２．３８（２Ｈ，ｍ），２．９２（１Ｈ，ｄｄ，Ｊ＝１５．６，７．６Ｈｚ），３．１９（１Ｈ，ｄｄ，Ｊ＝１５．５，７．２Ｈｚ），３．９３（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），４．２８（２Ｈ，ｑ，Ｊ＝２．７Ｈｚ），４．４４（１Ｈ，ｄｔ，Ｊ＝７．３，５．６Ｈｚ），５．０１（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），５．８４−５．８６（１Ｈ，ｍ），７．２１−７．２９（４Ｈ，ｍ），７．４１−７．４５（２Ｈ，ｍ），８．４９（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４７５．
ｍｐ２００．１−２０２．０℃．Reference Example 21 1- (2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylphenyl) -3-((1S, 2R) -1-hydroxy-2, Synthesis of 3-dihydro-1H-inden-2-yl) urea:

According to the same method as in Example 7, 2,2,2-trichloroethyl 2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylcarbamate (150 mg, 0.315 mmol) Gave the title compound (130 mg) as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.35-2.38 (2H, m), 2.92 (1H, dd, J = 15.6, 7.6 Hz), 3. 19 (1H, dd, J = 15.5, 7.2 Hz), 3.93 (2H, t, J = 5.4 Hz), 4.28 (2H, q, J = 2.7 Hz), 4.44 (1H, dt, J = 7.3, 5.6 Hz), 5.01 (1H, d, J = 5.4 Hz), 5.84-5.86 (1H, m), 7.21-7. 29 (4H, m), 7.41-7.45 (2H, m), 8.49 (1 H, d, J = 2.4 Hz).
MS (ESI) [M−H] ⁻ : 475.
mp200.1-202.0 ° C.

実施例１１と同様の方法に従い、１−（２−（３，６−ジヒドロ−２Ｈ−ピラン−４−イル）−５−ペンタフルオロサルファニルフェニル）−３−（（１Ｓ，２Ｒ）−１−ヒドロキシ−２，３−ジヒドロ−１Ｈ−インデン−２−イル）ウレア（６０．０ｍｇ，０．１２６ｍｍｏｌ）から、表題化合物（以下、実施例１２の化合物）（３５．４ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：１．６８−１．８２（４Ｈ，ｍ），２．９４（１Ｈ，ｄｄ，Ｊ＝１５．５，７．４Ｈｚ），３．０７−３．１２（１Ｈ，ｍ），３．２１（１Ｈ，ｄｄ，Ｊ＝１５．６，７．１Ｈｚ），３．５９（２Ｈ，ｄｔ，Ｊ＝１１．６，２．３Ｈｚ），４．０３−４．０７（２Ｈ，ｍ），４．４６（１Ｈ，ｄｔ，Ｊ＝７．２，５．７Ｈｚ），５．０２（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．２４−７．２８（３Ｈ，ｍ），７．４１−７．４６（２Ｈ，ｍ），７．５２（１Ｈ，ｄｄ，Ｊ＝８．８，２．４Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４７７．
ｍｐ２１９．９−２２１．９℃．Example 12 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (5-pentafluorosulfanyl-2- (tetrahydro-2H-) Synthesis of pyran-4-yl) phenyl) urea:

According to a method similar to that in Example 11, 1- (2- (3,6-dihydro-2H-pyran-4-yl) -5-pentafluorosulfanylphenyl) -3-((1S, 2R) -1- The title compound (hereinafter, the compound of Example 12) (35.4 mg) was obtained as a colorless solid from hydroxy-2,3-dihydro-1H-inden-2-yl) urea (60.0 mg, 0.126 mmol). .
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.68-1.82 (4H, m), 2.94 (1H, dd, J = 15.5, 7.4 Hz), 3. 07-3.12 (1H, m), 3.21 (1H, dd, J = 15.6, 7.1 Hz), 3.59 (2H, dt, J = 11.6, 2.3 Hz), 4 .03-4.07 (2H, m), 4.46 (1H, dt, J = 7.2, 5.7 Hz), 5.02 (1H, d, J = 5.6 Hz), 7.24- 7.28 (3H, m), 7.41-7.46 (2H, m), 7.52 (1H, dd, J = 8.8, 2.4 Hz), 8.21 (1H, d, J = 2.4 Hz).
MS (ESI) [M−H] ⁻ : 477.
mp 219.9-221.9 ° C.

２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３００ｍｇ，１．０６ｍｍｏｌ）のジメチルスルホキシド（２ｍＬ）溶液に、トリエチルアミン（２２１μＬ，１．５９ｍｍｏｌ）、４−ヒドロキシピペリジン（１３９ｍｇ，１．３８ｍｍｏｌ）を加えた。５０℃で４時間撹拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（３４６ｍｇ）を黄色固体として得た
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．５０（１Ｈ，ｄ，Ｊ＝３．７Ｈｚ），１．７２−１．７８（２Ｈ，ｍ），２．００−２．０７（２Ｈ，ｍ），３．０２−３．０８（２Ｈ，ｍ），３．３６−３．４１（２Ｈ，ｍ），３．９９（１Ｈ，ｄｔ，Ｊ＝７．６，３．８Ｈｚ），７．１０（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．７６（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．２０（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３４９．
ｍｐ９６．９−９８．４℃．Reference Example 22 Synthesis of 2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylnitrobenzene:

To a solution of 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) in dimethyl sulfoxide (2 mL) was added triethylamine (221 μL, 1.59 mmol) and 4-hydroxypiperidine (139 mg, 1.38 mmol). . After stirring at 50 ° C. for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (346 mg) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.50 (1H, d, J = 3.7 Hz), 1.72-1.78 (2H, m), 2.00-2.07 (2H, m), 3.02-3.08 (2H, m), 3.36-3.41 (2H, m), 3.99 (1H, dt, J = 7.6, 3.8 Hz) 7.10 (1H, d, J = 9.0 Hz), 7.76 (1H, dd, J = 9.0, 2.7 Hz), 8.20 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 349.
mp 96.9-98.4 ° C.

参考例４と同様の方法に従い、２−（４−ヒドロキシピペリジン−１−イル）−５−ペンタフルオロサルファニルニトロベンゼン（３４５ｍｇ，０．９９１ｍｍｏｌ）から、表題化合物（３１４ｍｇ）を赤色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．６７−１．７６（２Ｈ，ｍ），２．０３−２．０６（２Ｈ，ｍ），２．７０−２．７４（２Ｈ，ｍ），３．１３−３．１８（２Ｈ，ｍ），３．８６−３．９０（１Ｈ，ｍ），４．０６（２Ｈ，ｓ），６．９６（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．０８−７．１１（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３１９．Reference Example 23 Synthesis of 2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylaniline:

The title compound (314 mg) was obtained as a red amorphous form from 2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylnitrobenzene (345 mg, 0.991 mmol) in the same manner as in Reference Example 4.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.67-1.76 (2H, m), 2.03-2.06 (2H, m), 2.70-2.74 (2H M), 3.13-3.18 (2H, m), 3.86-3.90 (1H, m), 4.06 (2H, s), 6.96 (1H, d, J = 9). .0Hz), 7.08-7.11 (2H, m).
MS (ESI) [M + H] ⁺ : 319.

参考例９と同様の方法に従い、２−（４−ヒドロキシピペリジン−１−イル）−５−ペンタフルオロサルファニルアニリン（３１４ｍｇ，０．９８６ｍｍｏｌ）から、表題化合物（３９０ｍｇ）を淡赤色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．７８−１．８１（２Ｈ，ｍ），２．０４−２．１０（２Ｈ，ｍ），２．７５−２．７９（２Ｈ，ｍ），３．０６−３．１１（２Ｈ，ｍ），３．９５（１Ｈ，ｓ），４．８７（２Ｈ，ｓ），７．１７（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝８．８，２．４Ｈｚ），７．８４（１Ｈ，ｓ），８．５０（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４９３．Reference Example 24 Synthesis of (2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylphenyl) carbamate 2,2,2-trichloroethyl:

The title compound (390 mg) was obtained as a pale red amorphous form from 2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylaniline (314 mg, 0.986 mmol) in the same manner as in Reference Example 9. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.78-1.81 (2H, m), 2.04-2.10 (2H, m), 2.75-2.79 (2H M), 3.06-3.11 (2H, m), 3.95 (1H, s), 4.87 (2H, s), 7.17 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8, 2.4 Hz), 7.84 (1H, s), 8.50 (1H, s).
MS (ESI) [M + H] ⁺ : 493.

実施例５と同様の方法に従い、（２−（４−ヒドロキシピペリジン−１−イル）−５−ペンタフルオロサルファニルフェニル）カルバミン酸２，２，２−トリクロロエチル（１９０ｍｇ，０．３８５ｍｍｏｌ）から、表題化合物（以下、実施例１３の化合物）（１３４ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：１．７７−１．８４（２Ｈ，ｍ），２．００−２．０１（２Ｈ，ｍ），２．７３−２．８１（２Ｈ，ｍ），２．９１−２．９５（１Ｈ，ｍ），３．０８−３．１８（３Ｈ，ｍ），３．７７−３．８１（１Ｈ，ｍ），４．６０（１Ｈ，ｄｔ，Ｊ＝５．１，１．９Ｈｚ），５．２４（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），７．２２−７．２８（５Ｈ，ｍ），７．４０（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．５７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４９４．Example 13 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (2- (4-hydroxypiperidin-1-yl) -5 Synthesis of -pentafluorosulfanylphenyl) urea:

According to a method similar to that of Example 5, from 2,2,2-trichloroethyl (190 mg, 0.385 mmol) of (2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylphenyl) carbamate The title compound (hereinafter referred to as the compound of Example 13) (134 mg) was obtained as a colorless amorphous product.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.77-1.84 (2H, m), 2.00-2.01 (2H, m), 2.73-2.81 ( 2H, m), 2.91-2.95 (1H, m), 3.08-3.18 (3H, m), 3.77-3.81 (1H, m), 4.60 (1H, dt, J = 5.1, 1.9 Hz), 5.24 (1H, d, J = 4.9 Hz), 7.22-7.28 (5H, m), 7.40 (1H, dd, J = 9.0, 2.7 Hz), 8.57 (1H, d, J = 2.4 Hz).
MS (ESI) [M + H] ⁺ : 494.

実施例７と同様の方法に従い、（２−（４−ヒドロキシピペリジン−１−イル）−５−ペンタフルオロサルファニルフェニル）カルバミン酸２，２，２−トリクロロエチル（１９０ｍｇ，０．３８５ｍｍｏｌ）から、表題化合物（以下、実施例１４の化合物）（１６３ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：１．７７−１．８３（２Ｈ，ｍ），１．９９−２．００（２Ｈ，ｍ），２．７３−２．７６（２Ｈ，ｍ），２．９６（１Ｈ，ｄｄ，Ｊ＝１５．６，７．８Ｈｚ），３．０６−３．０９（２Ｈ，ｍ），３．１９（１Ｈ，ｄｄ，Ｊ＝１５．６，７．３Ｈｚ），３．７６−３．８２（１Ｈ，ｍ），４．４６（１Ｈ，ｄｔ，Ｊ＝７．６，５．６Ｈｚ），５．０２（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．２３−７．２８（４Ｈ，ｍ），７．３７（１Ｈ，ｄｄ，Ｊ＝８．８，２．７Ｈｚ），７．４２（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），８．５７（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４９４．Example 14 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (2- (4-hydroxypiperidin-1-yl) -5 Synthesis of -pentafluorosulfanylphenyl) urea:

According to a method similar to that in Example 7, from 2,2,2-trichloroethyl (190 mg, 0.385 mmol) of (2- (4-hydroxypiperidin-1-yl) -5-pentafluorosulfanylphenyl) carbamate The title compound (hereinafter, the compound of Example 14) (163 mg) was obtained as a colorless amorphous substance.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 1.77-1.83 (2H, m), 1.99-2.00 (2H, m), 2.73-2.76 ( 2H, m), 2.96 (1H, dd, J = 15.6, 7.8 Hz), 3.06-3.09 (2H, m), 3.19 (1H, dd, J = 15.6). , 7.3 Hz), 3.76-3.82 (1 H, m), 4.46 (1 H, dt, J = 7.6, 5.6 Hz), 5.02 (1 H, d, J = 5. 4 Hz), 7.23-7.28 (4 H, m), 7.37 (1 H, dd, J = 8.8, 2.7 Hz), 7.42 (1 H, d, J = 6.8 Hz), 8.57 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 494.

参考例２２と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（１００ｍｇ，０．３５３ｍｍｏｌ）及びモルホリン（４０μＬ，０．４６ｍｍｏｌ）から、表題化合物（１１８ｍｇ）を橙色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．１６（４Ｈ，ｔ，Ｊ＝４．８Ｈｚ），３．８６（４Ｈ，ｔ，Ｊ＝４．６Ｈｚ），７．１０（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．８２（１Ｈ，ｄｄ，Ｊ＝９．３，２．７Ｈｚ），８．２２（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３３５．Reference Example 25 Synthesis of 2- (morpholin-4-yl) -5-pentafluorosulfanylnitrobenzene:

The title compound (118 mg) was obtained as an orange oil from 2-chloro-5-pentafluorosulfanylnitrobenzene (100 mg, 0.353 mmol) and morpholine (40 μL, 0.46 mmol) in the same manner as in Reference Example 22. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.16 (4H, t, J = 4.8 Hz), 3.86 (4H, t, J = 4.6 Hz), 7.10 (1H , D, J = 9.3 Hz), 7.82 (1H, dd, J = 9.3, 2.7 Hz), 8.22 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 335.

参考例４と同様の方法に従い、２−（モルホリン−４−イル）−５−ペンタフルオロサルファニルニトロベンゼン（１１８ｍｇ，０．３５３ｍｍｏｌ）から、表題化合物（９５．３ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．９４（４Ｈ，ｔ，Ｊ＝４．６Ｈｚ），３．８６（４Ｈ，ｔ，Ｊ＝４．５Ｈｚ），４．０８（２Ｈ，ｓ），６．９７（１Ｈ，ｄ，Ｊ＝８．５Ｈｚ），７．１２（２Ｈ，ｄｔ，Ｊ＝１０．１，３．５Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３０５．
ｍｐ１５２．８−１５５．０℃．Reference Example 26 Synthesis of 2- (morpholin-4-yl) -5-pentafluorosulfanylaniline:

In the same manner as in Reference Example 4, the title compound (95.3 mg) was obtained as a colorless solid from 2- (morpholin-4-yl) -5-pentafluorosulfanylnitrobenzene (118 mg, 0.353 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.94 (4H, t, J = 4.6 Hz), 3.86 (4H, t, J = 4.5 Hz), 4.08 (2H , S), 6.97 (1H, d, J = 8.5 Hz), 7.12 (2H, dt, J = 10.1, 3.5 Hz).
MS (ESI) [M + H] ⁺ : 305.
mp 152.8-155.0 ° C.

参考例９と同様の方法に従い、２−（モルホリン−４−イル）−５−ペンタフルオロサルファニルアニリン（９５．０ｍｇ，０．３１２ｍｍｏｌ）から、表題化合物（１４６ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．９１（４Ｈ，ｔ，Ｊ＝４．６Ｈｚ），３．９０（４Ｈ，ｔ，Ｊ＝４．６Ｈｚ），４．８８（２Ｈ，ｓ），７．２０（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４９（１Ｈ，ｄｄ，Ｊ＝８．８，２．７Ｈｚ），７．８８（１Ｈ，ｓ），８．５３（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７９．
ｍｐ１０３．３−１０５．４℃．Reference Example 27 Synthesis of (5-pentafluorosulfanyl-2- (morpholin-4-yl) phenyl) carbamate 2,2,2-trichloroethyl:

In the same manner as in Reference Example 9, the title compound (146 mg) was obtained as a colorless solid from 2- (morpholin-4-yl) -5-pentafluorosulfanylaniline (95.0 mg, 0.312 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.91 (4H, t, J = 4.6 Hz), 3.90 (4H, t, J = 4.6 Hz), 4.88 (2H , S), 7.20 (1H, d, J = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.7 Hz), 7.88 (1H, s), 8.53 (1H, s).
MS (ESI) [M + H] ⁺ : 479.
mp 103.3-105.4 ° C.

実施例５と同様の方法に従い、（５−ペンタフルオロサルファニル−２−（モルホリン−４−イル）フェニル）カルバミン酸２，２，２−トリクロロエチル（１３５ｍｇ，０．２８１ｍｍｏｌ）から、表題化合物（以下、実施例１５の化合物）（１１５ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．０９（１Ｈ，ｄ，Ｊ＝５．１Ｈｚ），２．８８−２．９０（４Ｈ，ｍ），２．９６（１Ｈ，ｄｄ，Ｊ＝１６．７，２．６Ｈｚ），３．２２（１Ｈ，ｄｄ，Ｊ＝１６．５，５．２Ｈｚ），３．８４（４Ｈ，ｔ，Ｊ＝４．６Ｈｚ），４．７０（１Ｈ，ｄｑ，Ｊ＝１０．２，２．５Ｈｚ），５．３４（１Ｈ，ｄｄ，Ｊ＝７．８，５．１Ｈｚ），５．４３（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ），７．１６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２６−７．２９（３Ｈ，ｍ），７．３６（１Ｈ，ｄ，Ｊ＝６．３Ｈｚ），７．４１（１Ｈ，ｄｄ，Ｊ＝８．８，２．７Ｈｚ），７．５４（１Ｈ，ｓ），８．６９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８０．
ｍｐ１９２．６−１９４．０℃．Example 15 1-((1R, 2S) -2-Hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (5-pentafluorosulfanyl-2- (morpholine-4-) Synthesis of yl) phenyl) urea:

According to a method similar to that in Example 5, 2,5-trichloroethyl (135 mg, 0.281 mmol) of (5-pentafluorosulfanyl-2- (morpholin-4-yl) phenyl) carbamate (135 mg, 0.281 mmol) was used. The compound of Example 15) (115 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.09 (1H, d, J = 5.1 Hz), 2.88-2.90 (4H, m), 2.96 (1H, dd , J = 16.7, 2.6 Hz), 3.22 (1H, dd, J = 16.5, 5.2 Hz), 3.84 (4H, t, J = 4.6 Hz), 4.70 ( 1H, dq, J = 10.2, 2.5 Hz), 5.34 (1H, dd, J = 7.8, 5.1 Hz), 5.43 (1H, d, J = 8.3 Hz), 7 .16 (1H, d, J = 8.8 Hz), 7.26-7.29 (3H, m), 7.36 (1H, d, J = 6.3 Hz), 7.41 (1H, dd, J = 8.8, 2.7 Hz), 7.54 (1H, s), 8.69 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 480.
mp 192.6-194.0 ° C.

実施例７と同様の方法に従い、（５−ペンタフルオロサルファニル−２−（モルホリン−４−イル）フェニル）カルバミン酸２，２，２−トリクロロエチル（１４５ｍｇ，０．３０２ｍｍｏｌ）から、表題化合物（以下、実施例１６の化合物）（１４５ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．０４（１Ｈ，ｓ），２．８９（４Ｈ，ｔ，Ｊ＝４．６Ｈｚ），２．９６（１Ｈ，ｄｄ，Ｊ＝１６．１，６．６Ｈｚ），３．３６（１Ｈ，ｄｄ，Ｊ＝１６．０，７．２Ｈｚ），３．８７（４Ｈ，ｔ，Ｊ＝４．５Ｈｚ），４．５８−４．６４（１Ｈ，ｍ），５．１６（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），５．４６（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．１５（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２６−７．３５（３Ｈ，ｍ），７．３９（１Ｈ，ｄｄ，Ｊ＝８．９，２．６Ｈｚ），７．４４−７．４６（２Ｈ，ｍ），８．６５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８０．Example 16 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (5-pentafluorosulfanyl-2- (morpholine-4-) Synthesis of yl) phenyl) urea:

According to a method similar to that in Example 7, from 2,2-trichloroethyl (145 mg, 0.302 mmol) of (5-pentafluorosulfanyl-2- (morpholin-4-yl) phenyl) carbamate (145 mg, 0.302 mmol), the title compound ( Hereinafter, the compound of Example 16) (145 mg) was obtained as a colorless amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.04 (1H, s), 2.89 (4H, t, J = 4.6 Hz), 2.96 (1H, dd, J = 16) .1, 6.6 Hz), 3.36 (1H, dd, J = 16.0, 7.2 Hz), 3.87 (4H, t, J = 4.5 Hz), 4.58-4.64 ( 1H, m), 5.16 (1H, t, J = 5.5 Hz), 5.46 (1H, d, J = 7.6 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.26-7.35 (3H, m), 7.39 (1H, dd, J = 8.9, 2.6 Hz), 7.44-7.46 (2H, m), 8.65 (1H , D, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 480.

参考例２２と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３００ｍｇ，１．０６ｍｍｏｌ）及び２−ピペラジノン（１３８ｍｇ，１．３８ｍｍｏｌ）から、表題化合物の粗生成物（３４５ｍｇ）を黄色固体として得た。得られた粗生成物をさらに精製することなく、次工程を実施した。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．４０（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），３．５６−３．５９（２Ｈ，ｍ），３．９１（２Ｈ，ｓ），６．１８（１Ｈ，ｓ），７．１１（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．８６（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．２６（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２４８．Reference Example 28 Synthesis of 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylnitrobenzene:

According to the same method as in Reference Example 22, the crude product (345 mg) of the title compound was obtained from 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) and 2-piperazinone (138 mg, 1.38 mmol). Obtained as a yellow solid. The next step was carried out without further purification of the obtained crude product.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.40 (2H, t, J = 5.2 Hz), 3.56-3.59 (2H, m), 3.91 (2H, s ), 6.18 (1H, s), 7.11 (1H, d, J = 9.0 Hz), 7.86 (1H, dd, J = 9.0, 2.7 Hz), 8.26 (1H) , D, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 248.

参考例４と同様の方法に従い、２−（３−オキソピペラジン−１−イル）−５−ペンタフルオロサルファニルニトロベンゼン（３４５ｍｇ，０．９９３ｍｍｏｌ）から、表題化合物の粗生成物（３５３ｍｇ）を黄色固体として得た。得られた粗生成物をさらに精製することなく、次工程を実施した。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：３．１２（１．８Ｈ，ｔ，Ｊ＝５．２Ｈｚ），３．２７−３．３２（２Ｈ，ｍ），３．４９（２Ｈ，ｓ），７．０５（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２７（１Ｈ，ｄｄ，Ｊ＝８．８，２．７Ｈｚ），７．４８（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），７．９３（１Ｈ，ｓ），８．２７（１Ｈ，ｓ），８．８０（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ）．Reference Example 29 Synthesis of 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylaniline:

According to the same method as in Reference Example 4, the crude product (353 mg) of the title compound was obtained as a yellow solid from 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylnitrobenzene (345 mg, 0.993 mmol). Got as. The next step was carried out without further purification of the obtained crude product.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.12 (1.8 H, t, J = 5.2 Hz), 3.27-3.32 (2H, m), 3.49 (2H, s), 7.05 (1H, d, J = 8.8 Hz), 7.27 (1H, dd, J = 8.8, 2.7 Hz), 7.48 (1H, d, J = 2.7 Hz), 7.93 (1 H, s), 8.27 (1 H, s), 8.80 (1 H, d, J = 1.7 Hz).

参考例９と同様の方法に従い、２−（３−オキソピペラジン−１−イル）−５−ペンタフルオロサルファニルアニリン（３５３ｍｇ，１．１１ｍｍｏｌ）から、表題化合物（１５２ｍｇ）を橙色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．１９（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），３．５２−３．５５（２Ｈ，ｍ），３．６６（２Ｈ，ｓ），４．８８（２Ｈ，ｓ），６．３６（１Ｈ，ｂｒｓ），７．１９（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５１（１Ｈ，ｄｄ，Ｊ＝８．９，２０６Ｈｚ），７．７４（１Ｈ，ｓ），８．５８（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４９２．Reference Example 30 Synthesis of 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

The title compound (152 mg) was obtained as an orange amorphous form from 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylaniline (353 mg, 1.11 mmol) in the same manner as in Reference Example 9.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.19 (2H, t, J = 5.4 Hz), 3.52-3.55 (2H, m), 3.66 (2H, s ), 4.88 (2H, s), 6.36 (1H, brs), 7.19 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.9, 206 Hz) ), 7.74 (1H, s), 8.58 (1H, s).
MS (ESI) [M + H] ⁺ : 492.

実施例５と同様の方法に従い、２−（３−オキソピペラジン−１−イル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７５．０ｍｇ，０．１５２ｍｍｏｌ）から、表題化合物（以下、実施例１７の化合物）（３２．３ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄ，Ｊ＝１５．９Ｈｚ），３．０４−３．１４（３Ｈ，ｍ），３．３３−３．３６（２Ｈ，ｍ），３．４１（２Ｈ，ｓ），４．４６（１Ｈ，ｄｄ，Ｊ＝８．５，３．４Ｈｚ），５．１３（１Ｈ，ｄｄ，Ｊ＝８．８，４．９Ｈｚ），５．１９（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），７．１８−７．２５（４Ｈ，ｍ），７．２９（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４３（１Ｈ，ｄｄ，Ｊ＝８．９，２．８Ｈｚ），７．６８（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．００（１Ｈ，ｓ），８．５２（１Ｈ，ｓ），８．８８（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４９３．
ｍｐ２４５．３−２４６．９℃．Example 17 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (5-pentafluorosulfanyl-2- (3-oxopiperazine) Synthesis of -1-yl) phenyl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.152 mmol), The title compound (hereinafter, the compound of Example 17) (32.3 mg) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, d, J = 15.9 Hz), 3.04 to 3.14 (3H, m), 3.33-3 .36 (2H, m), 3.41 (2H, s), 4.46 (1H, dd, J = 8.5, 3.4 Hz), 5.13 (1H, dd, J = 8.8, 4.9 Hz), 5.19 (1 H, d, J = 3.9 Hz), 7.18-7.25 (4 H, m), 7.29 (1 H, d, J = 8.8 Hz), 7. 43 (1H, dd, J = 8.9, 2.8 Hz), 7.68 (1H, d, J = 8.8 Hz), 8.00 (1H, s), 8.52 (1H, s), 8.88 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 493.
mp 245.3-246.9 ° C.

実施例７と同様の方法に従い、２−（３−オキソピペラジン−１−イル）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７５．０ｍｇ，０．１５２ｍｍｏｌ）から、表題化合物（以下、実施例１８の化合物）（３９．５ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄｄ，Ｊ＝１５．５，７．２Ｈｚ），３．０５−３．１１（３Ｈ，ｍ），３．３３−３．３６（２Ｈ，ｍ），３．３８（２Ｈ，ｓ），４．３０−４．３７（１Ｈ，ｍ），４．９０（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），５．４９（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．２４−７．２８（４Ｈ，ｍ），７．３７（１Ｈ，ｄ，Ｊ＝６．６Ｈｚ），７．４１（１Ｈ，ｄｄ，Ｊ＝８．８，２．７Ｈｚ），７．５５（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．０１（１Ｈ，ｓ），８．４７（１Ｈ，ｓ），８．８６（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４９１．
ｍｐ２２２．５−２４０．０℃．Example 18 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (5-pentafluorosulfanyl-2- (3-oxopiperazine) Synthesis of -1-yl) phenyl) urea:

According to a method similar to that in Example 7, from 2,2,2-trichloroethyl 2- (3-oxopiperazin-1-yl) -5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.152 mmol), The title compound (hereinafter, the compound of Example 18) (39.5 mg) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, dd, J = 15.5, 7.2 Hz), 3.05 to 3.11 (3H, m), 3 33-3.36 (2H, m), 3.38 (2H, s), 4.30-4.37 (1H, m), 4.90 (1H, t, J = 5.4 Hz), 5 .49 (1H, d, J = 5.4 Hz), 7.24-7.28 (4H, m), 7.37 (1H, d, J = 6.6 Hz), 7.41 (1H, dd, J = 8.8, 2.7 Hz), 7.55 (1H, d, J = 7.8 Hz), 8.01 (1H, s), 8.47 (1H, s), 8.86 (1H, d, J = 2.7 Hz).
MS (ESI) [M−H] ⁻ : 491.
mp 222.5-240.0 ° C.

３−オキセタノール（９４．０ｍｇ，１．２７ｍｍｏｌ）のテトラヒドロフラン（１ｍＬ）溶液に、水素化ナトリウム（５５重量％ｉｎ ｍｉｎｅｒａｌ ｏｉｌ，６９．２ｍｇ，１．５９ｍｍｏｌ）を加えた。室温で３０分撹拌した後、反応混合物に２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３００ｍｇ，１．０６ｍｍｏｌ）を加えた。室温で４時間撹拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、表題化合物（３４０ｍｇ）を橙色油状物として得た。得られた粗生成物を精製することなく、次工程を実施した。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：４．７２−４．７５（２Ｈ，ｍ），５．０３−５．０７（２Ｈ，ｍ），５．５２−５．５７（１Ｈ，ｍ），７．０６（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），８．０４（１Ｈ，ｄｄ，Ｊ＝９．１，２．８Ｈｚ），８．３９（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３２２．Reference Example 31 Synthesis of 2- (oxetane-3-yloxy) -5-pentafluorosulfanylnitrobenzene:

Sodium hydride (55 wt% in mineral oil, 69.2 mg, 1.59 mmol) was added to a solution of 3-oxetanol (94.0 mg, 1.27 mmol) in tetrahydrofuran (1 mL). After stirring at room temperature for 30 minutes, 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) was added to the reaction mixture. After stirring at room temperature for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated to give the title compound (340 mg) as an orange oil. The next step was carried out without purifying the resulting crude product.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 4.72 to 4.75 (2H, m), 5.03 to 5.07 (2H, m), 5.52 to 5.57 ( 1H, m), 7.06 (1H, d, J = 9.1 Hz), 8.04 (1H, dd, J = 9.1, 2.8 Hz), 8.39 (1H, d, J = 2) .8 Hz).
MS (ESI) [M + H] ⁺ : 322.

参考例４と同様の方法に従い、２−（オキセタン−３−イルオキシ）−５−ペンタフルオロサルファニルニトロベンゼン（３４０ｍｇ，１．０６ｍｍｏｌ）から、表題化合物（３０５ｍｇ）を茶色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．０３（２Ｈ，ｂｒｓ），４．７６−４．７９（２Ｈ，ｍ），４．９９−５．０３（２Ｈ，ｍ），５．２４−５．２９（１Ｈ，ｍ），６．３０（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．０５（１Ｈ，ｄｄ，Ｊ＝８．８，２．７Ｈｚ），７．１２（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２９２．Reference Example 32 Synthesis of 2- (oxetane-3-yloxy) -5-pentafluorosulfanylaniline:

The title compound (305 mg) was obtained as a brown oil from 2- (oxetane-3-yloxy) -5-pentafluorosulfanylnitrobenzene (340 mg, 1.06 mmol) in the same manner as in Reference Example 4.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.03 (2H, brs), 4.76-4.79 (2H, m), 4.99-5.03 (2H, m), 5.24-5.29 (1H, m), 6.30 (1H, d, J = 8.8 Hz), 7.05 (1H, dd, J = 8.8, 2.7 Hz), 7.12 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 292.

参考例９と同様の方法に従い、２−（オキセタン−３−イルオキシ）−５−ペンタフルオロサルファニルアニリン（３０８ｍｇ，１．０６ｍｍｏｌ）から、表題化合物（３１８ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．８２（２Ｈ，ｄｄ，Ｊ＝８．３，４．９Ｈｚ），４．８８（２Ｈ，ｓ），５．０３−５．０７（２Ｈ，ｍ），５．３０−５．３５（１Ｈ，ｍ），６．４５（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４２（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．６６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４６６．
ｍｐ１６７．０−１６９．０℃．Reference Example 33 Synthesis of 2- (oxetane-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

According to the same method as in Reference Example 9, the title compound (318 mg) was obtained as a colorless solid from 2- (oxetane-3-yloxy) -5-pentafluorosulfanylaniline (308 mg, 1.06 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.82 (2H, dd, J = 8.3, 4.9 Hz), 4.88 (2H, s), 5.03-5.07 (2H, m), 5.30-5.35 (1H, m), 6.45 (1H, d, J = 9.0 Hz), 7.42 (1H, dd, J = 9.0,2. 7 Hz), 8.66 (1 H, s).
MS (ESI) [M + H] ⁺ : 466.
mp167.0-169.0 ° C.

実施例５と同様の方法に従い、２−（オキセタン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１５０ｍｇ，０．３２１ｍｍｏｌ）から、表題化合物（以下、実施例１９の化合物）（１２７ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８２（１Ｈ，ｄ，Ｊ＝１６．１Ｈｚ），３．０７（１Ｈ，ｄｄ，Ｊ＝１６．１，４．９Ｈｚ），４．４６（１Ｈ，ｑ，Ｊ＝４．６Ｈｚ），４．６６（２Ｈ，ｄｔ，Ｊ＝７．６，４．８Ｈｚ），４．９７（２Ｈ，ｔ，Ｊ＝６．７Ｈｚ），５．１４（１Ｈ，ｄｄ，Ｊ＝８．７，５．０Ｈｚ），５．２５（１Ｈ，ｄ，Ｊ＝３．９Ｈｚ），５．４１−５．４６（１Ｈ，ｍ），６．７６（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．１９−７．２６（４Ｈ，ｍ），７．３６（１Ｈ，ｄｄ，Ｊ＝９．１，２．６Ｈｚ），７．５１（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．６１（１Ｈ，ｓ），８．９４（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４６７．
ｍｐ１１２．９−１１９．８℃．Example 19 1-((1R, 2S) -2-Hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (5-pentafluorosulfanyl-2- (oxetane-3-) Synthesis of yloxy) phenyl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (oxetane-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (150 mg, 0.321 mmol), the title compound (hereinafter, The compound of Example 19) (127 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.82 (1H, d, J = 16.1 Hz), 3.07 (1H, dd, J = 16.1, 4.9 Hz) 4.46 (1H, q, J = 4.6 Hz), 4.66 (2H, dt, J = 7.6, 4.8 Hz), 4.97 (2H, t, J = 6.7 Hz), 5.14 (1H, dd, J = 8.7, 5.0 Hz), 5.25 (1H, d, J = 3.9 Hz), 5.41-5.46 (1H, m), 6.76 (1H, d, J = 9.0 Hz), 7.19-7.26 (4H, m), 7.36 (1H, dd, J = 9.1, 2.6 Hz), 7.51 (1H, d, J = 8.8 Hz), 8.61 (1H, s), 8.94 (1H, d, J = 2.9 Hz).
MS (ESI) [M + H] ⁺ : 467.
mp 112.9-119.8 ° C.

実施例７と同様の方法に従い、２−（オキセタン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１５０ｍｇ，０．３２１ｍｍｏｌ）から、表題化合物（以下、実施例２０の化合物）（１１０ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８２（１Ｈ，ｄｄ，Ｊ＝１５．５，７．０Ｈｚ），３．０９（１Ｈ，ｄｄ，Ｊ＝１５．６，６．８Ｈｚ），４．３１−４．３８（１Ｈ，ｍ），４．６５（２Ｈ，ｄｄ，Ｊ＝７．４，４．８Ｈｚ），４．９１−４．９８（３Ｈ，ｍ），５．３９−５．４４（１Ｈ，ｍ），５．５７（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），６．７４（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２１−７．２６（３Ｈ，ｍ），７．３２−７．３９（３Ｈ，ｍ），８．５８（１Ｈ，ｓ），８．８９（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４６５．
ｍｐ２３９．０−２４１．５℃．Example 20 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (5-pentafluorosulfanyl-2- (oxetane-3-) Synthesis of yloxy) phenyl) urea:

According to the same method as in Example 7, from 2,2,2-trichloroethyl 2- (oxetane-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (150 mg, 0.321 mmol), the title compound (hereinafter, The compound of Example 20) (110 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.82 (1H, dd, J = 15.5, 7.0 Hz), 3.09 (1H, dd, J = 15.6, 6.8 Hz), 4.31-4.38 (1 H, m), 4.65 (2 H, dd, J = 7.4, 4.8 Hz), 4.91-4.98 (3 H, m), 5.39-5.44 (1H, m), 5.57 (1H, d, J = 5.4 Hz), 6.74 (1H, d, J = 9.0 Hz), 7.21-7.26 (3H, m), 7.32-7.39 (3H, m), 8.58 (1H, s), 8.89 (1H, d, J = 2.9 Hz).
MS (ESI) [M−H] ⁻ : 465.
mp 239.0-241.5 ° C.

参考例３１と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３００ｍｇ，１．０６ｍｍｏｌ）及び３−オキセタンメタノール（１１２ｍｇ，１．２７ｍｍｏｌ）から、表題化合物（３５７ｍｇ）を橙色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．４８−３．５６（１Ｈ，ｍ），４．４３（２Ｈ，ｄ，Ｊ＝６．８Ｈｚ），４．５５（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），４．９１（２Ｈ，ｄｄ，Ｊ＝７．６，６．６Ｈｚ），７．１８（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９４（１Ｈ，ｄｄ，Ｊ＝９．３，２．７Ｈｚ），８．２８（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３３６．Reference Example 34 Synthesis of 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylnitrobenzene:

The title compound (357 mg) was obtained as an orange oil from 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) and 3-oxetanemethanol (112 mg, 1.27 mmol) in the same manner as in Reference Example 31. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.48-3.56 (1H, m), 4.43 (2H, d, J = 6.8 Hz), 4.55 (2H, t , J = 6.1 Hz), 4.91 (2H, dd, J = 7.6, 6.6 Hz), 7.18 (1H, d, J = 9.0 Hz), 7.94 (1H, dd, J = 9.3, 2.7 Hz), 8.28 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 336.

参考例４と同様の方法に従い、２−（オキセタン−３−イルメトキシ）−５−ペンタフルオロサルファニルニトロベンゼン（３５５ｍｇ，１．０６ｍｍｏｌ）から表題化合物を（３５４ｍｇ）紫色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．４１−３．５１（１Ｈ，ｍ），３．９７（２Ｈ，ｂｒｓ），４．２７（２Ｈ，ｄ，Ｊ＝６．１Ｈｚ），４．５９（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．９１（２Ｈ，ｄｄ，Ｊ＝７．８，６．３Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．０９−７．１３（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３０６．Reference Example 35 Synthesis of 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylaniline:

In the same manner as in Reference Example 4, the title compound (354 mg) was obtained as a purple solid from 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylnitrobenzene (355 mg, 1.06 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.41-3.51 (1H, m), 3.97 (2H, brs), 4.27 (2H, d, J = 6.1 Hz) ), 4.59 (2H, t, J = 6.0 Hz), 4.91 (2H, dd, J = 7.8, 6.3 Hz), 6.78 (1H, d, J = 8.8 Hz) 7.09-7.13 (2H, m).
MS (ESI) [M + H] ⁺ : 306.

参考例９と同様の方法に従い、２−（オキセタン−３−イルメトキシ）−５−ペンタフルオロサルファニルアニリン（３５４ｍｇ，１．１６ｍｍｏｌ）から、表題化合物（３７８ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．４５−３．５５（１Ｈ，ｍ），４．３９（２Ｈ，ｄ，Ｊ＝６．３Ｈｚ），４．５５（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．８６（２Ｈ，ｓ），４．９６（２Ｈ，ｄｄ，Ｊ＝７．７，６．５Ｈｚ），６．９４（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４１（１Ｈ，ｓ），７．４８（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．６０（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８０．
ｍｐ１３０．４−１３３．３℃．Reference Example 36 Synthesis of 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

According to the same method as in Reference Example 9, the title compound (378 mg) was obtained as a colorless solid from 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylaniline (354 mg, 1.16 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.45-3.55 (1H, m), 4.39 (2H, d, J = 6.3 Hz), 4.55 (2H, t , J = 6.0 Hz), 4.86 (2H, s), 4.96 (2H, dd, J = 7.7, 6.5 Hz), 6.94 (1H, d, J = 9.0 Hz) , 7.41 (1H, s), 7.48 (1H, dd, J = 9.0, 2.7 Hz), 8.60 (1H, s).
MS (ESI) [M + H] ⁺ : 480.
mp 130.4-133.3 ° C.

実施例５と同様の方法に従い、２−（オキセタン−３−イルメトキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７０．０ｍｇ，０．１４６ｍｍｏｌ）から、表題化合物（以下、実施例２１の化合物）（５０．６ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．４９（１Ｈ，ｄｄ，Ｊ＝１６．７，２．８Ｈｚ），２．９３（１Ｈ，ｄｄ，Ｊ＝１６．８，６．１Ｈｚ），３．３５−３．３９（１Ｈ，ｍ），３．９４（１Ｈ，ｄ，Ｊ＝４．６Ｈｚ），４．０３（１Ｈ，ｄｄ，Ｊ＝９．８，３．４Ｈｚ），４．１８（１Ｈ，ｄｄ，Ｊ＝９．８，３．２Ｈｚ），４．５７（１Ｈ，ｄｔ，Ｊ＝１０．２，４．５Ｈｚ），４．７１（１Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．８９−５．０１（３Ｈ，ｍ），５．２５（１Ｈ，ｔ，Ｊ＝７．０Ｈｚ），６．５８（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），６．６９（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．０５−７．０７（１Ｈ，ｍ），７．１７−７．２４（３Ｈ，ｍ），７．５８（１Ｈ，ｓ），８．７９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４８１．Example 21 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (5-pentafluorosulfanyl-2- (oxetane-3-) Synthesis of ylmethoxy) phenyl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylphenylcarbamate (70.0 mg, 0.146 mmol), the title compound ( Hereinafter, the compound of Example 21 (50.6 mg) was obtained as a colorless amorphous substance.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.49 (1H, dd, J = 16.7, 2.8 Hz), 2.93 (1H, dd, J = 16.8, 6. 1 Hz), 3.35-3.39 (1 H, m), 3.94 (1 H, d, J = 4.6 Hz), 4.03 (1 H, dd, J = 9.8, 3.4 Hz), 4.18 (1H, dd, J = 9.8, 3.2 Hz), 4.57 (1H, dt, J = 10.2, 4.5 Hz), 4.71 (1H, t, J = 6. 0 Hz), 4.89-5.01 (3 H, m), 5.25 (1 H, t, J = 7.0 Hz), 6.58 (1 H, d, J = 7.6 Hz), 6.69 ( 1H, d, J = 9.0 Hz), 7.05-7.07 (1H, m), 7.17-7.24 (3H, m), 7.58 (1H, s), 8.79 ( 1H, d, J = .7Hz).
MS (ESI) [M + H] ⁺ : 481.

実施例７と同様の方法に従い、２−（オキセタン−３−イルメトキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（７０．０ｍｇ，０．１４６ｍｍｏｌ）から、表題化合物（以下、実施例２２の化合物）（６６．５ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．５４（１Ｈ，ｄｄ，Ｊ＝１６．１，７．８Ｈｚ），３．０４（１Ｈ，ｄｄ，Ｊ＝１６．３，８．０Ｈｚ），３．３８−３．４２（１Ｈ，ｍ），３．９８（１Ｈ，ｄｄ，Ｊ＝９．８，３．４Ｈｚ），４．１９（１Ｈ，ｄｄ，Ｊ＝９．８，２．９Ｈｚ），４．４４−４．５２（１Ｈ，ｍ），４．６７（１Ｈ，ｓ），４．７５（１Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．９０（１Ｈ，ｔ，Ｊ＝６．１Ｈｚ），５．００−５．０７（２Ｈ，ｍ），５．１８（１Ｈ，ｔ，Ｊ＝５．９Ｈｚ），６．６５（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），６．７１（１Ｈ，ｓ），７．０７（１Ｈ，ｄ，Ｊ＝７．１Ｈｚ），７．１６（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），７．２３−７．２９（１Ｈ，ｍ），７．３８（１Ｈ，ｄ，Ｊ＝７．１Ｈｚ），７．４５（１Ｈ，ｓ），８．８４（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４７９．
ｍｐ１５７．２−１８３．６℃．Example 22 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (5-pentafluorosulfanyl-2- (oxetane-3- Synthesis of ylmethoxy) phenyl) urea:

According to a method similar to that in Example 7, 2- (oxetane-3-ylmethoxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl (70.0 mg, 0.146 mmol) was used to give the title compound ( Then, the compound of Example 22) (66.5 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.54 (1H, dd, J = 16.1, 7.8 Hz), 3.04 (1H, dd, J = 16.3, 8. 0 Hz), 3.38-3.42 (1 H, m), 3.98 (1 H, dd, J = 9.8, 3.4 Hz), 4.19 (1 H, dd, J = 9.8, 2) 0.9 Hz), 4.44-4.52 (1 H, m), 4.67 (1 H, s), 4.75 (1 H, t, J = 6.0 Hz), 4.90 (1 H, t, J = 6.1 Hz), 5.00-5.07 (2 H, m), 5.18 (1 H, t, J = 5.9 Hz), 6.65 (1 H, d, J = 8.8 Hz), 6 .71 (1H, s), 7.07 (1H, d, J = 7.1 Hz), 7.16 (1H, dd, J = 9.0, 2.7 Hz), 7.23-7.29 ( 1H, m), 7. 8 (1H, d, J = 7.1Hz), 7.45 (1H, s), 8.84 (1H, d, J = 2.7Hz).
MS (ESI) [M−H] ⁻ : 479.
mp 157.2-183.6 ° C.

参考例３１と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（６００ｍｇ，２．１２ｍｍｏｌ）及び１−（ｔｅｒｔ−ブトキシカルボニル）−３−ヒドロキシアゼチジン（４４０ｍｇ，２．５４ｍｍｏｌ）から、表題化合物（８８４ｍｇ）を黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．４６（９Ｈ，ｓ），４．１１（２Ｈ，ｄｄ，Ｊ＝１０．６，４．０Ｈｚ），４．３８（２Ｈ，ｄｄｄ，Ｊ＝１０．０，６．３，１．０Ｈｚ），５．０５（１Ｈ，ｔｔ，Ｊ＝６．５，２．９Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．９２（１Ｈ，ｄｄ，Ｊ＝９．１，２．８Ｈｚ），８．３２（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．Reference Example 37 Synthesis of 2- (1- (tert-butoxycarbonyl) azetidin-3-yloxy) -5-pentafluorosulfanylnitrobenzene:

According to the same method as in Reference Example 31, from 2-chloro-5-pentafluorosulfanylnitrobenzene (600 mg, 2.12 mmol) and 1- (tert-butoxycarbonyl) -3-hydroxyazetidine (440 mg, 2.54 mmol) To give the title compound (884 mg) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.46 (9H, s), 4.11 (2H, dd, J = 10.6, 4.0 Hz), 4.38 (2H, ddd , J = 10.0, 6.3, 1.0 Hz), 5.05 (1H, tt, J = 6.5, 2.9 Hz), 6.78 (1H, d, J = 9.0 Hz), 7.92 (1H, dd, J = 9.1, 2.8 Hz), 8.32 (1H, d, J = 2.7 Hz).

参考例４と同様の方法に従い、２−（１−（ｔｅｒｔ−ブトキシカルボニル）アゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルニトロベンゼン（８８９ｍｇ，２．１２ｍｍｏｌ）から、表題化合物（８８６ｍｇ）を黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．４５（９Ｈ，ｓ），４．０１（２Ｈ，ｂｒｓ），４．０１−４．０３（２Ｈ，ｍ），４．３４（２Ｈ，ｄｄｄ，Ｊ＝９．７，６．３，１．１Ｈｚ），４．９４（１Ｈ，ｔｔ，Ｊ＝６．６，２．９Ｈｚ），６．４０（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．０７（１Ｈ，ｄｄ，Ｊ＝８．６，２．５Ｈｚ），７．１２（１Ｈ，ｄ，Ｊ＝２．５Ｈｚ）．Reference Example 38 Synthesis of 2- (1- (tert-butoxycarbonyl) azetidin-3-yloxy) -5-pentafluorosulfanylaniline:

According to the same method as in Reference Example 4, the title compound (886 mg) was obtained from 2- (1- (tert-butoxycarbonyl) azetidin-3-yloxy) -5-pentafluorosulfanylnitrobenzene (889 mg, 2.12 mmol) in yellow Obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.45 (9H, s), 4.01 (2H, brs), 4.01-4.03 (2H, m), 4.34 ( 2H, ddd, J = 9.7, 6.3, 1.1 Hz), 4.94 (1H, tt, J = 6.6, 2.9 Hz), 6.40 (1H, d, J = 8. 6 Hz), 7.07 (1H, dd, J = 8.6, 2.5 Hz), 7.12 (1H, d, J = 2.5 Hz).

参考例９と同様の方法に従い、２−（１−（ｔｅｒｔ−ブトキシカルボニル）アゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルアニリン（８８６ｍｇ，２．１２ｍｍｏｌ）から、表題化合物（９３８ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．４６（９Ｈ，ｓ），４．０７−４．１１（２Ｈ，ｍ），４．３９（２Ｈ，ｄｄｄ，Ｊ＝１０．０，６．３，０．９Ｈｚ），４．８８（２Ｈ，ｓ），５．００（１Ｈ，ｔｔ，Ｊ＝６．３，２．９Ｈｚ），６．５５（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），７．３９（１Ｈ，ｂｒｓ），７．４４（１Ｈ，ｄｄ，Ｊ＝８．８，２．５Ｈｚ），８．６５（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：５６３．Reference Example 39 Synthesis of 2- (1- (tert-butoxycarbonyl) azetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

The title compound (938 mg) was purified from 2- (1- (tert-butoxycarbonyl) azetidin-3-yloxy) -5-pentafluorosulfanylaniline (886 mg, 2.12 mmol) in the same manner as in Reference Example 9. Obtained as amorphous.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.46 (9H, s), 4.07-4.11 (2H, m), 4.39 (2H, ddd, J = 10.0 , 6.3, 0.9 Hz), 4.88 (2H, s), 5.00 (1H, tt, J = 6.3, 2.9 Hz), 6.55 (1H, d, J = 9. 1 Hz), 7.39 (1 H, brs), 7.44 (1 H, dd, J = 8.8, 2.5 Hz), 8.65 (1 H, s).
MS (ESI) [M−H] ⁻ : 563.

氷冷下、２−（１−（ｔｅｒｔ−ブトキシカルボニル）アゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（５００ｍｇ，０．８８４ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、トリフルオロ酢酸（１．０２ｍＬ，１３．３ｍｍｏｌ）を加えた。室温で２時間撹拌した後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、分液した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、表題化合物（４０８ｍｇ）を無色固体として得た。得られた粗生成物を精製することなく、次工程を実施した。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８４−３．８８（２Ｈ，ｍ），４．０１−４．０５（２Ｈ，ｍ），４．８７（２Ｈ，ｓ），５．０８−５．１３（１Ｈ，ｍ），６．５９（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．４２（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），７．４７（１Ｈ，ｓ），８．６３（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４６５．
ｍｐ１３７．０−１４０．５℃．Reference Example 40 Synthesis of 2- (azetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

Under ice cooling, 2- (1- (tert-butoxycarbonyl) azetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl (500 mg, 0.884 mmol) in dichloromethane (3 mL) ) To the solution was added trifluoroacetic acid (1.02 mL, 13.3 mmol). After stirring at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by liquid separation. The organic layer was washed with saturated brine, dried and concentrated to give the title compound (408 mg) as a colorless solid. The next step was carried out without purifying the resulting crude product.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.84-3.88 (2H, m), 4.01-4.05 (2H, m), 4.87 (2H, s), 5.08-5.13 (1H, m), 6.59 (1H, d, J = 9.0 Hz), 7.42 (1H, dd, J = 9.0, 2.7 Hz), 7.47 (1H, s), 8.63 (1H, s).
MS (ESI) [M + H] ⁺ : 465.
mp 137.0-140.5 ° C.

２−（アゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１３０ｍｇ，０．２７９ｍｍｏｌ）の酢酸エチル（２ｍＬ）溶液に、ピリジン（４７．４μＬ，０．５８６ｍｍｏｌ）、無水酢酸（２７．７μＬ，０．２９３ｍｍｏｌ）を加えた。室温で２時間撹拌した後、反応混合物に水を加え、分液した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、表題化合物（１３７ｍｇ）を無色固体として得た。得られた粗生成物を精製することなく、次工程を実施した。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．９４（３Ｈ，ｓ），４．１６（１Ｈ，ｄｄ，Ｊ＝９．５，３．４Ｈｚ），４．２７（１Ｈ，ｄｄ，Ｊ＝９．５，３．４Ｈｚ），４．４７（１Ｈ，ｄｄ，Ｊ＝１０．９，６．７Ｈｚ），４．５９（１Ｈ，ｄｄ，Ｊ＝９．０，７．１Ｈｚ），４．８８（２Ｈ，ｓ），５．０４−５．０９（１Ｈ，ｍ），６．５７（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．３５（１Ｈ，ｓ），７．４６（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．６６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５０７．
ｍｐ２２６．１−２２７．４℃．Reference Example 41 Synthesis of 2- (1-acetylazetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

To a solution of 2- (azetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl (130 mg, 0.279 mmol) in ethyl acetate (2 mL) was added pyridine (47.4 μL, 0 586 mmol), acetic anhydride (27.7 μL, 0.293 mmol) was added. After stirring at room temperature for 2 hours, water was added to the reaction mixture for liquid separation. The organic layer was washed with saturated brine, dried and concentrated to give the title compound (137 mg) as a colorless solid. The next step was carried out without purifying the resulting crude product.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.94 (3H, s), 4.16 (1H, dd, J = 9.5, 3.4 Hz), 4.27 (1H, dd , J = 9.5, 3.4 Hz), 4.47 (1H, dd, J = 10.9, 6.7 Hz), 4.59 (1H, dd, J = 9.0, 7.1 Hz), 4.88 (2H, s), 5.04-5.09 (1H, m), 6.57 (1H, d, J = 8.8 Hz), 7.35 (1H, s), 7.46 ( 1H, dd, J = 9.0, 2.7 Hz), 8.66 (1H, s).
MS (ESI) [M + H] ⁺ : 507.
mp 226.1-227.4 ° C.

実施例５と同様の方法に従い、２−（１−アセチルアゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（６５．０ｍｇ，０．１２８ｍｍｏｌ）から、表題化合物（以下、実施例２３の化合物）（４５．３ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：１．７９（３Ｈ，ｓ），２．８２（１Ｈ，ｄ，Ｊ＝１５．９Ｈｚ），３．０７（１Ｈ，ｄｄ，Ｊ＝１６．２，４．８Ｈｚ），３．９４−３．９８（１Ｈ，ｍ），４．１７（１Ｈ，ｄｔ，Ｊ＝８．９，３．３Ｈｚ），４．３１（１Ｈ，ｄｄ，Ｊ＝１０．６，６．５Ｈｚ），４．４５（１Ｈ，ｑ，Ｊ＝４．５Ｈｚ），４．６０（１Ｈ，ｄｄ，Ｊ＝９．１，６．７Ｈｚ），５．１３−５．２０（２Ｈ，ｍ），５．２５（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），６．８８（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．１９−７．２５（４Ｈ，ｍ），７．３９（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．５４（１Ｈ，ｄ，Ｊ＝１．７Ｈｚ），８．９５（１Ｈ，ｔ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５０８．Example 23 1- (2- (1-Acetylazetidin-3-yloxy) -5-pentafluorosulfanylphenyl) -3-((1R, 2S) -2-hydroxy-2,3-dihydro- Synthesis of 1H-inden-1-yl) urea:

According to the same method as in Example 5, from 2,2,2-trichloroethyl 2- (1-acetylazetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (65.0 mg, 0.128 mmol) The title compound (hereinafter, the compound of Example 23) (45.3 mg) was obtained as a colorless amorphous product.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.79 (3H, s), 2.82 (1H, d, J = 15.9 Hz), 3.07 (1H, dd, J = 16.2, 4.8 Hz), 3.94-3.98 (1 H, m), 4.17 (1 H, dt, J = 8.9, 3.3 Hz), 4.31 (1 H, dd, J = 10.6, 6.5 Hz), 4.45 (1H, q, J = 4.5 Hz), 4.60 (1H, dd, J = 9.1, 6.7 Hz), 5.13-5. .20 (2H, m), 5.25 (1H, d, J = 4.1 Hz), 6.88 (1H, d, J = 9.3 Hz), 7.19-7.25 (4H, m) 7.39 (1H, dd, J = 9.0, 2.7 Hz), 7.47 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J = 1.7 Hz), 8.95 (1H t, J = 2.4Hz).
MS (ESI) [M + H] ⁺ : 508.

実施例７と同様の方法に従い、２−（１−アセチルアゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（６５．０ｍｇ，０．１２８ｍｍｏｌ）から、表題化合物（以下、実施例２４の化合物）（５０．５ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：１．７９（３Ｈ，ｓ），２．８１（１Ｈ，ｄｄ，Ｊ＝１５．７，７．０Ｈｚ），３．０８（１Ｈ，ｄｄ，Ｊ＝１５．５，７．０Ｈｚ），３．９６（１Ｈ，ｄ，Ｊ＝１０．７Ｈｚ），４．１６（１Ｈ，ｄ，Ｊ＝９．５Ｈｚ），４．２９−４．３８（２Ｈ，ｍ），４．５８（１．０Ｈ，ｔ，Ｊ＝７．８Ｈｚ），４．９２（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ），５．１４−５．１７（１Ｈ，ｍ），５．５７（１Ｈ，ｄ，Ｊ＝４．９Ｈｚ），６．８６（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２１−７．２６（３Ｈ，ｍ），７．３１（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．３５−７．３９（２Ｈ，ｍ），８．５２（１Ｈ，ｓ），８．８９（１Ｈ，ｄｄ，Ｊ＝２．８，１．１Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：５０６．
ｍｐ２４９．６−２５２．４℃．Example 24 1- (2- (1-Acetylazetidin-3-yloxy) -5-pentafluorosulfanylphenyl) -3-((1S, 2R) -1-hydroxy-2,3-dihydro- Synthesis of 1H-inden-2-yl) urea:

According to the same method as in Example 7, from 2,2,2-trichloroethyl 2- (1-acetylazetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (65.0 mg, 0.128 mmol) The title compound (hereinafter, the compound of Example 24) (50.5 mg) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.79 (3H, s), 2.81 (1H, dd, J = 15.7, 7.0 Hz), 3.08 (1H , Dd, J = 15.5, 7.0 Hz), 3.96 (1H, d, J = 10.7 Hz), 4.16 (1H, d, J = 9.5 Hz), 4.29-4. 38 (2H, m), 4.58 (1.0 H, t, J = 7.8 Hz), 4.92 (1 H, t, J = 5.5 Hz), 5.14-5.17 (1 H, m ), 5.57 (1H, d, J = 4.9 Hz), 6.86 (1H, d, J = 9.0 Hz), 7.21-7.26 (3H, m), 7.31 (1H) , D, J = 7.6 Hz), 7.35-7.39 (2H, m), 8.52 (1H, s), 8.89 (1H, dd, J = 2.8, 1.1 Hz) .
MS (ESI) [M−H] ⁻ : 506.
mp 249.6-252.4 ° C.

２−（アゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１３５ｍｇ，０．２９０ｍｍｏｌ）の酢酸エチル（３ｍＬ）溶液に、ピリジン（４９．２μＬ，０．６０９ｍｍｏｌ）、メタンスルホニルクロリド（２３．７μＬ，０．３０４ｍｍｏｌ）を加えた。室温で２時間撹拌した後、反応混合物に水を加え、分液した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（１３２ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．９５（３Ｈ，ｓ），４．１７（２Ｈ，ｄｄ，Ｊ＝９．６，４．８Ｈｚ），４．３８（２Ｈ，ｄｄ，Ｊ＝９．９，６．５Ｈｚ），４．８８（２Ｈ，ｓ），５．０２−５．０８（１Ｈ，ｍ），６．５７（１Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．３６（１Ｈ，ｓ），７．４５（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．６６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：５４１．
ｍｐ１７９．４−１８１．１℃．Reference Example 42 Synthesis of 2- (1-methanesulfonylazetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl:

To a solution of 2- (azetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate 2,2,2-trichloroethyl (135 mg, 0.290 mmol) in ethyl acetate (3 mL) was added pyridine (49.2 μL, 0 609 mmol), methanesulfonyl chloride (23.7 μL, 0.304 mmol) was added. After stirring at room temperature for 2 hours, water was added to the reaction mixture for liquid separation. The organic layer was washed with saturated brine, dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (132 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.95 (3H, s), 4.17 (2H, dd, J = 9.6, 4.8 Hz), 4.38 (2H, dd , J = 9.9, 6.5 Hz), 4.88 (2H, s), 5.02-5.08 (1H, m), 6.57 (1H, d, J = 9.0 Hz), 7 .36 (1H, s), 7.45 (1H, dd, J = 9.0, 2.7 Hz), 8.66 (1H, s).
MS (ESI) [M−H] ⁻ : 541.
mp 179.4-181.1 ° C.

実施例５と同様の方法に従い、２−（１−メタンスルホニルアゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（６０．０ｍｇ，０．１１０ｍｍｏｌ）から、表題化合物（以下、実施例２５の化合物）（６０．０ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８２（１Ｈ，ｄ，Ｊ＝１５．９Ｈｚ），３．０５−３．１０（１Ｈ，ｍ），３．０８（３Ｈ，ｓ），４．００−４．０６（２Ｈ，ｍ），４．３７−４．４１（２Ｈ，ｍ），４．４６（１Ｈ，ｑ，Ｊ＝４．５Ｈｚ），５．１２−５．１８（２Ｈ，ｍ），５．２８（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），７．１９−７．２６（４Ｈ，ｍ），７．３９（１Ｈ，ｄｄ，Ｊ＝９．１，３．２Ｈｚ），７．４７（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），８．５１（１Ｈ，ｓ），８．９５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５４４．Example 25 1- (2- (1-Methanesulfonylazetidin-3-yloxy) -5-pentafluorosulfanylphenyl) -3-((1R, 2S) -2-hydroxy-2,3-dihydro Synthesis of -1H-inden-1-yl) urea:

According to the same method as in Example 5, 2,2,2-trichloroethyl 2- (1-methanesulfonylazetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (60.0 mg, 0.110 mmol) From the above, the title compound (hereinafter, the compound of Example 25) (60.0 mg) was obtained as a colorless amorphous substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.82 (1H, d, J = 15.9 Hz), 3.05 to 3.10 (1H, m), 3.08 (3H , S), 4.00-4.06 (2H, m), 4.37-4.41 (2H, m), 4.46 (1H, q, J = 4.5 Hz), 5.12-5 .18 (2H, m), 5.28 (1H, d, J = 4.1 Hz), 6.90 (1H, d, J = 9.1 Hz), 7.19-7.26 (4H, m) , 7.39 (1H, dd, J = 9.1, 3.2 Hz), 7.47 (1H, d, J = 8.6 Hz), 8.51 (1H, s), 8.95 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 544.

実施例７と同様の方法に従い、２−（１−メタンスルホニルアゼチジン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（６０．０ｍｇ，０．１１０ｍｍｏｌ）から、表題化合物（以下、実施例２６の化合物）（６２．９ｍｇ）を無色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８２（１Ｈ，ｄｄ，Ｊ＝１５．６，７．０Ｈｚ），３．０６−３．１０（１Ｈ，ｍ），３．０８（３Ｈ，ｓ），４．０２（２Ｈ，ｄｄ，Ｊ＝９．５，４．５Ｈｚ），４．３１−４．４０（３Ｈ，ｍ），４．９２（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），５．１３−５．１９（１Ｈ，ｍ），５．６０（１Ｈｄ，Ｊ＝５．０Ｈｚ），６．８７（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ），７．２０−７．２８（３Ｈ，ｍ），７．３１−７．３９（３Ｈ，ｍ），８．５０（１Ｈ，ｓ），８．９０（１Ｈ，ｄ，Ｊ＝３．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：５４２．Example 26 1- (2- (1-Methanesulfonylazetidin-3-yloxy) -5-pentafluorosulfanylphenyl) -3-((1S, 2R) -1-hydroxy-2,3-dihydro Synthesis of -1H-inden-2-yl) urea:

According to the same method as in Example 7, 2,2,2-trichloroethyl 2- (1-methanesulfonylazetidin-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (60.0 mg, 0.110 mmol) From the above, the title compound (hereinafter, the compound of Example 26) (62.9 mg) was obtained as a colorless amorphous substance.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.82 (1H, dd, J = 15.6, 7.0 Hz), 3.06 to 3.10 (1H, m), 3 .08 (3H, s), 4.02 (2H, dd, J = 9.5, 4.5 Hz), 4.31-4.40 (3H, m), 4.92 (1H, t, J = 5.4 Hz), 5.13-5.19 (1 H, m), 5.60 (1 Hd, J = 5.0 Hz), 6.87 (1 H, d, J = 9.1 Hz), 7.20- 7.28 (3H, m), 7.31-7.39 (3H, m), 8.50 (1 H, s), 8.90 (1 H, d, J = 3.2 Hz).
MS (ESI) [M−H] ⁻ : 542.

２−（オキセタン−３−イルオキシ）−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（１００ｍｇ，０．２１４ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、ジイソプロピルエチルアミン（７５μＬ，０．４３ｍｍｏｌ）、（１Ｓ，２Ｒ）−２−アミノ−４−フルオロ−１−インダノール（５３．７ｍｇ，０．３２１ｍｍｏｌ）を加えた。１００℃で２３時間撹拌した後、反応混合物を放冷し、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、表題化合物（以下、実施例２７の化合物）（８６．９ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．７８（１Ｈ，ｄｄ，Ｊ＝１５．７，６．５Ｈｚ），３．１６（１Ｈ，ｄｄ，Ｊ＝１５．９，７．１Ｈｚ），４．３７−４．４４（１Ｈ，ｍ），４．６５（２Ｈ，ｄｄ，Ｊ＝７．３，６．５Ｈｚ），４．９４−４．９８（３Ｈ，ｍ），５．３９−５．４５（１Ｈ，ｍ），５．７５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），６．７４（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．０９（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．２４（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．２９−７．３５（２Ｈ，ｍ），７．４０（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），８．５９（１Ｈ，ｓ），８．８９（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：４８３．
ｍｐ２２７．２−２２９．６℃．Example 27 1-((1S, 2R) -4-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (5-pentafluorosulfanyl-2- ( Synthesis of oxetane-3-yloxy) phenyl) urea:

To a solution of 2,2,2-trichloroethyl 2- (oxetane-3-yloxy) -5-pentafluorosulfanylphenylcarbamate (100 mg, 0.214 mmol) in acetonitrile (1 mL) was added diisopropylethylamine (75 μL, 0.43 mmol). ), (1S, 2R) -2-amino-4-fluoro-1-indanol (53.7 mg, 0.321 mmol) was added. After stirring at 100 ° C. for 23 hours, the reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (hereinafter referred to as the compound of Example 27) (86.9 mg). ) Was obtained as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.78 (1H, dd, J = 15.7, 6.5 Hz), 3.16 (1H, dd, J = 15.9, 7.1 Hz), 4.37-4.44 (1H, m), 4.65 (2H, dd, J = 7.3, 6.5 Hz), 4.94-4.98 (3H, m), 5.39-5.45 (1H, m), 5.75 (1H, d, J = 5.6 Hz), 6.74 (1H, d, J = 8.8 Hz), 7.09 (1H, d , J = 8.8 Hz), 7.24 (1H, d, J = 8.4 Hz), 7.29-7.35 (2H, m), 7.40 (1H, d, J = 7.6 Hz) , 8.59 (1H, s), 8.89 (1H, d, J = 2.9 Hz).
MS (ESI) [M−H] ⁻ : 483.
mp 227.2-229.6 ° C.

参考例１８と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３２２ｍｇ，１．１７ｍｍｏｌ）から表題化合物（２６３ｍｇ）を淡褐色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．２６（２Ｈ，ｂｒｓ），７．０５（１Ｈ，ｄｄ，Ｊ＝９．１，２．７Ｈｚ），７．１５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），７．３１（１Ｈ，ｄ，Ｊ＝９．１Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２５４．Reference Example 43 Synthesis of 2-chloro-5-pentafluorosulfanylaniline:

In the same manner as in Reference Example 18, the title compound (263 mg) was obtained as a light brown amorphous substance from 2-chloro-5-pentafluorosulfanylnitrobenzene (322 mg, 1.17 mmol).
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.26 (2H, brs), 7.05 (1H, dd, J = 9.1, 2.7 Hz), 7.15 (1H, d , J = 2.7 Hz), 7.31 (1H, d, J = 9.1 Hz).
MS (ESI) [M + H] ⁺ : 254.

実施例２と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルアニリン（２６２ｍｇ，１．０３ｍｍｏｌ）から、表題化合物（以下、実施例２８の化合物）（２２１ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄ，Ｊ＝１６．１Ｈｚ），３．０８（１Ｈ，ｄｄ，Ｊ＝１６．１，５．０Ｈｚ），４．４９−４．４５（１Ｈ，ｍ），５．１１（１Ｈ，ｄｄ，Ｊ＝８．３，５．０Ｈｚ），５．２４（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），７．２６−７．１８（４Ｈ，ｍ），７．４７（１Ｈ，ｄｄ，Ｊ＝８．５，２．７Ｈｚ），７．６８（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．８１（１Ｈ，ｂｒｓ），８．９９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４２９．Example 28 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (2-chloro-5-pentafluorosulfanylphenyl) urea Synthesis:

The title compound (hereinafter, the compound of Example 28) (221 mg) was obtained as a colorless solid from 2-chloro-5-pentafluorosulfanylaniline (262 mg, 1.03 mmol) in the same manner as in Example 2.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, d, J = 16.1 Hz), 3.08 (1 H, dd, J = 16.1, 5.0 Hz) 4.49-4.45 (1H, m), 5.11 (1H, dd, J = 8.3, 5.0 Hz), 5.24 (1H, d, J = 4.1 Hz), 7. 26-7.18 (4H, m), 7.47 (1H, dd, J = 8.5, 2.7 Hz), 7.68 (2H, d, J = 8.5 Hz), 8.81 (1H , Brs), 8.99 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 429.

４−ペンタフルオロサルファニルクロロベンゼン（２０．０ｇ，８０．３ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１００ｍＬ）溶液に、ナトリウムメトキシド（１３．０ｇ，２４０ｍｍｏｌ）を加えた。室温で１時間撹拌した後、反応混合物に水を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン）で精製し、表題化合物（１６．３ｇ）を無色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８５（３Ｈ，ｓ），６．９１（２Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．６８（２Ｈ，ｄ，Ｊ＝９．６Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２３５．Reference Example 44 Synthesis of 4-pentafluorosulfanylanisole:

Sodium methoxide (13.0 g, 240 mmol) was added to a solution of 4-pentafluorosulfanylchlorobenzene (20.0 g, 80.3 mmol) in N, N-dimethylformamide (100 mL). After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane) to give the title compound (16.3 g) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.85 (3H, s), 6.91 (2H, d, J = 9.6 Hz), 7.68 (2H, d, J = 9) .6 Hz).
MS (ESI) [M + H] ⁺ : 235.

４−ペンタフルオロサルファニルアニソール（１．２５ｇ，５．３４ｍｍｏｌ）とジクロロメチルメチルエーテル（１．１８０ｍＬ，１３．３５ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液を−２０℃に冷却し、四塩化チタン（１．４６ｍＬ，１３．３５ｍｍｏｌ）を反応溶液の温度が−２０〜−２２℃になるよう１０分間かけて加えた。同温度で３０分間撹拌した後、反応混合物に水を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（５２１ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．０２（３Ｈ，ｓ），７．０４−７．０８（１Ｈ，ｍ），７．９０−７．９５（１Ｈ，ｍ），８．２２−８．２４（１Ｈ，ｍ），１０．５（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２６３．Reference Example 45 Synthesis of 2-formyl-4-pentafluorosulfanylanisole:

A solution of 4-pentafluorosulfanylanisole (1.25 g, 5.34 mmol) and dichloromethyl methyl ether (1.180 mL, 13.35 mmol) in dichloromethane (10 mL) was cooled to −20 ° C., and titanium tetrachloride (1. 46 mL, 13.35 mmol) was added over 10 minutes so that the temperature of the reaction solution was -20 to -22 ° C. After stirring at the same temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (521 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.02 (3H, s), 7.04-7.08 (1H, m), 7.90-7.95 (1H, m), 8.22-8.24 (1H, m), 10.5 (1H, s).
MS (ESI) [M + H] ⁺ : 263.

氷冷下、２−ホルミル−４−ペンタフルオロサルファニルアニソール（５．００ｇ，１９．３ｍｍｏｌ）の濃硫酸（６０ｍＬ）懸濁液に、発煙硝酸（１ｍＬ）を加えた。同温度で３時間撹拌した後、反応混合物に氷を加え、クロロホルムで抽出した。有機層を乾燥、濃縮し、表題化合物（５．２８ｇ）を黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：４．１５（３Ｈ，ｓ），８．４３−８．４７（２Ｈ，ｍ），１０．４（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３０８．Reference Example 46 Synthesis of 3-formyl-2-methoxy-5-pentafluorosulfanylnitrobenzene:

Fuming nitric acid (1 mL) was added to a suspension of 2-formyl-4-pentafluorosulfanylanisole (5.00 g, 19.3 mmol) in concentrated sulfuric acid (60 mL) under ice cooling. After stirring at the same temperature for 3 hours, ice was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried and concentrated to give the title compound (5.28 g) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 4.15 (3H, s), 8.43-8.47 (2H, m), 10.4 (1H, s).
MS (ESI) [M + H] ⁺ : 308.

氷冷下、３−ホルミル−２−メトキシ−５−ペンタフルオロサルファニルニトロベンゼン（７０．０ｍｇ，０．２２８ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、水素化ホウ素ナトリウム（１０．４ｍｇ，０．２７３ｍｍｏｌ）を加えた。同温度で１時間撹拌した後、反応溶混合物に１Ｍ塩酸を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（６７ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．９７（３Ｈ，ｓ），４．８２−４．８７（２Ｈ，ｍ），８．１２−８．２１（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３１０．Reference Example 47 Synthesis of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylnitrobenzene:

Under ice-cooling, sodium borohydride (10.4 mg, 0.273 mmol) was added to a solution of 3-formyl-2-methoxy-5-pentafluorosulfanylnitrobenzene (70.0 mg, 0.228 mmol) in methanol (2 mL). added. After stirring at the same temperature for 1 hour, 1M hydrochloric acid was added to the reaction solution mixture, followed by extraction with chloroform. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (67 mg) as a colorless solid. It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.97 (3H, s), 4.82-4.87 (2H, m), 8.12-8.21 (2H, m).
MS (ESI) [M + H] ⁺ : 310.

３−ヒドロキシメチル−２−メトキシ−５−ペンタフルオロサルファニルニトロベンゼン（５７．０ｍｇ，０．１８４ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、酸化白金（４．２０ｍｇ，０．０１８４ｍｍｏｌ）を加えた。水素雰囲気下、３０分間撹拌した後、触媒を濾過、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（４９ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８２（３Ｈ，ｓ），３．９４−４．０２（２Ｈ，ｍ），４．７１−４．７４（２Ｈ，ｍ），７．０８−７．１２（１Ｈ，ｍ），７．１６−７．２０（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：２８０．Reference Example 48 Synthesis of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylaniline:

Platinum oxide (4.20 mg, 0.0184 mmol) was added to a methanol (1 mL) solution of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylnitrobenzene (57.0 mg, 0.184 mmol). After stirring for 30 minutes under a hydrogen atmosphere, the catalyst was filtered and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (49 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.82 (3H, s), 3.94-4.02 (2H, m), 4.71-4.74 (2H, m), 7.08-7.12 (1H, m), 7.16-7.20 (1H, m).
MS (ESI) [M + H] ⁺ : 280.

３−ヒドロキシメチル−２−メトキシ−５−ペンタフルオロサルファニルアニリン（４９．０ｍｇ，０．１７５ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）溶液に、クロロギ酸２，２，２−トリクロロエチル（０．０２４０ｍＬ，０．１７５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１５３ｍＬ，０．８７７ｍｍｏｌ）を加えた。室温で３時間撹拌した後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（７１ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．８８（３Ｈ，ｓ），４．７７−４．８８（４Ｈ，ｍ），７．３７−７．４７（１Ｈ，ｍ），７．５９−７．６２（１Ｈ，ｍ），８．４６−８．５８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４５５．Reference Example 49 Synthesis of 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate:

To a solution of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylaniline (49.0 mg, 0.175 mmol) in tetrahydrofuran (2 mL) was added 2,2,2-trichloroethyl chloroformate (0.0240 mL,. 175 mmol), diisopropylethylamine (0.153 mL, 0.877 mmol) was added. After stirring at room temperature for 3 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product is purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (71 mg) as a colorless solid. It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.88 (3H, s), 4.77-4.88 (4H, m), 7.37-7.47 (1H, m), 7.59-7.62 (1H, m), 8.46-8.58 (1H, m).
MS (ESI) [M + H] ⁺ : 455.

実施例５と同様の方法に従い、３−ヒドロキシメチル−２−メトキシ−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（２０．０ｍｇ，０．０４４０ｍｍｏｌ）から、表題化合物（以下、実施例２９の化合物）（１４．７ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８３−２．９０（１Ｈ，ｍ），３．０５−３．１３（１Ｈ，ｍ），３．７６（３Ｈ，ｓ），４．５０−４．５５（１Ｈ，ｍ），４．６４−４．６８（２Ｈ，ｍ），５．１６−５．２０（１Ｈ，ｍ），７．１３−７．２７（４Ｈ，ｍ），７．４７−７．４９（１Ｈ，ｍ），８．６８（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４５５．Example 29 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (3-hydroxymethyl-2-methoxy-5-pentafluorosulfur Synthesis of (nylphenyl) urea:

According to the same method as in Example 5, from the 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate (20.0 mg, 0.0440 mmol), the title compound , Example 29 compound) (14.7 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.83-2.90 (1H, m), 3.05-3.13 (1H, m), 3.76 (3H, s) , 4.50-4.55 (1H, m), 4.64-4.68 (2H, m), 5.16-5.20 (1H, m), 7.13-7.27 (4H, m), 7.47-7.49 (1H, m), 8.68 (1H, d, J = 2.8 Hz).
MS (ESI) [M + H] ⁺ : 455.

実施例７と同様の方法に従い、３−ヒドロキシメチル−２−メトキシ−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（２０．０ｍｇ，０．０４４０ｍｍｏｌ）から表題化合物（以下、実施例３０の化合物）（１５．５ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δ（ｐｐｍ）：２．８２−２．９０（１Ｈ，ｍ），３．０８−３．１６（１Ｈ，ｍ），３．７３（３Ｈ，ｓ），４．３５−４．４２（１Ｈ，ｍ），４．６２−４．６３（２Ｈ，ｍ），４．９２−４．９５（１Ｈ，ｍ），７．１４−７．２３（３Ｈ，ｍ），７．３５（１Ｈ，ｄ，Ｊ＝６．８Ｈｚ），７．４４−７．４５（１Ｈ，ｍ），８．６３（１Ｈ，ｄ，Ｊ＝３．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４５５．Example 30 1-((1S, 2R) -1-Hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (3-hydroxymethyl-2-methoxy-5-pentafluorosulfur Synthesis of (nylphenyl) urea:

According to the same method as in Example 7, the title compound (hereinafter referred to as the following) was obtained from 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate (20.0 mg, 0.0440 mmol). The compound of Example 30) (15.5 mg) was obtained as a colorless solid.
¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 2.82-2.90 (1H, m), 3.08-3.16 (1H, m), 3.73 (3H, s) , 4.35-4.42 (1H, m), 4.62-4.63 (2H, m), 4.92-4.95 (1H, m), 7.14-7.23 (3H, m), 7.35 (1H, d, J = 6.8 Hz), 7.44-7.45 (1H, m), 8.63 (1H, d, J = 3.2 Hz).
MS (ESI) [M + H] ⁺ : 455.

３−ヒドロキシメチル−２−メトキシ−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（２０．０ｍｇ，０．０４４０ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、ジイソプロピルエチルアミン（１５．３μＬ，０．０８８０ｍｍｏｌ）、（１Ｓ，２Ｒ）−２−アミノ−４−フルオロ−１−インダノール（１１．０ｍｇ，０．０６６０ｍｍｏｌ）を加えた。１００℃で６時間撹拌した後、反応混合物を放冷、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、乾燥、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、表題化合物（以下、実施例３１の化合物）（１１．２ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．７７（１Ｈ，ｄｄ，Ｊ＝１５．９，６．６Ｈｚ），３．１５（１Ｈ，ｄｄ，Ｊ＝１５．９，７．１Ｈｚ），３．７１（３Ｈ，ｓ），４．３５−４．４２（１Ｈ，ｍ），４．５９（２Ｈ，ｄ，Ｊ＝５．９Ｈｚ），４．９６（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），５．４２（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），５．７１（１Ｈ，ｄ，Ｊ＝５．１Ｈｚ），７．０９（１Ｈ，ｔ，Ｊ＝８．５Ｈｚ），７．２３（１Ｈ，ｄ，Ｊ＝７．１Ｈｚ），７．２７−７．３２（１Ｈ，ｍ），７．４０−７．４５（２Ｈ，ｍ），８．７０（１Ｈ，ｓ），８．８２（１Ｈ，ｄ，Ｊ＝２．９Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４７３
ｍｐ１８４．６−１８６．８℃．Example 31 1-((1S, 2R) -4-fluoro-1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (3-hydroxymethyl-2-methoxy-5 Synthesis of -pentafluorosulfanylphenyl) urea:

To a solution of 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate (20.0 mg, 0.0440 mmol) in acetonitrile (1 mL) was added diisopropylethylamine (15.3 μL, 0.0880 mmol), (1S, 2R) -2-amino-4-fluoro-1-indanol (11.0 mg, 0.0660 mmol) was added. After stirring at 100 ° C. for 6 hours, the reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (hereinafter referred to as the compound of Example 31) (11.2 mg). ) Was obtained as a colorless solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.77 (1H, dd, J = 15.9, 6.6 Hz), 3.15 (1H, dd, J = 15.9, 7.1 Hz), 3.71 (3H, s), 4.35-4.42 (1 H, m), 4.59 (2 H, d, J = 5.9 Hz), 4.96 (1 H, t, J = 5.1 Hz), 5.42 (1H, t, J = 5.7 Hz), 5.71 (1H, d, J = 5.1 Hz), 7.09 (1H, t, J = 8.5 Hz) ), 7.23 (1H, d, J = 7.1 Hz), 7.27-7.32 (1H, m), 7.40-7.45 (2H, m), 8.70 (1H, s) ), 8.82 (1H, d, J = 2.9 Hz).
MS (ESI) [M + H] ⁺ : 473
mp 184.6-186.8 ° C.

氷冷下、３−ホルミル−２−メトキシ−５−ペンタフルオロサルファニルニトロベンゼン（３４０ｍｇ，１．１１ｍｍｏｌ）のテトラヒドロフラン（３ｍＬ）溶液に、トリメチル（トリフルオロメチル）シラン（０．３２７ｍＬ，２．２１ｍｍｏｌ）、テトラｎ−ブチルアンモニウムフルオリド（１Ｍテトラヒドロフラン溶液、０．１１ｍＬ、０．１１ｍｍｏｌ）を加えた。反応混合物を同温度で３０分間、室温で１時間撹拌した後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（４０５ｍｇ）を淡黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．３４（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），３．９７（３Ｈ，ｓ），５．６５−５．５９（１Ｈ，ｍ），８．２５（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），８．３１（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．Reference Example 50 Synthesis of 3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylnitrobenzene:

Under ice-cooling, a solution of 3-formyl-2-methoxy-5-pentafluorosulfanylnitrobenzene (340 mg, 1.11 mmol) in tetrahydrofuran (3 mL) was added to trimethyl (trifluoromethyl) silane (0.327 mL, 2.21 mmol). Tetra n-butylammonium fluoride (1M tetrahydrofuran solution, 0.11 mL, 0.11 mmol) was added. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour, and then concentrated. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (405 mg) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.34 (1H, d, J = 5.4 Hz), 3.97 (3H, s), 5.65-5.59 (1H, m ), 8.25 (1H, d, J = 2.7 Hz), 8.31 (1H, d, J = 2.7 Hz).

参考例４と同様の方法に従い、３−（２，２，２−トリフルオロ−１−ヒドロキシエチル）−２−メトキシ−５−ペンタフルオロサルファニルニトロベンゼン（４０４ｍｇ，１．０７ｍｍｏｌ）から、表題化合物（３９３ｍｇ）を淡黄色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．１７（１Ｈ，ｂｒｓ），３．８３（３Ｈ，ｓ），４．００（１Ｈ，ｂｒｓ），５．３８（１Ｈ，ｑ，Ｊ＝６．８Ｈｚ），７．１８（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ），７．３１（１Ｈ，ｂｒｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３４８．Reference Example 51 Synthesis of 3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylaniline:

According to the same method as in Reference Example 4, from the title compound (3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylnitrobenzene (404 mg, 1.07 mmol) 393 mg) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 3.17 (1H, brs), 3.83 (3H, s), 4.00 (1H, brs), 5.38 (1H, q, J = 6.8 Hz), 7.18 (1H, d, J = 2.4 Hz), 7.31 (1H, brd, J = 2.4 Hz).
MS (ESI) [M + H] ⁺ : 348.

参考例９と同様の方法に従い、３−（２，２，２−トリフルオロ−１−ヒドロキシエチル）−２−メトキシ−５−ペンタフルオロサルファニルアニリン（３９３ｍｇ，１．１３ｍｍｏｌ）から、表題化合物（４７０ｍｇ）を黄色油状物として得た。
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：３．１６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），３．８９（３Ｈ，ｓ），４．８１−４．９２（２Ｈ，ｍ），５．４２−５．４８（１Ｈ，ｍ），７．３２（１Ｈ，ｂｒｓ），７．７６（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ），８．６１（１Ｈ，ｂｒｓ）．Reference Example 52 Synthesis of 2,2,2-trichloroethyl 3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylphenylcarbamate:

According to the same method as in Reference Example 9, from the 3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylaniline (393 mg, 1.13 mmol), the title compound ( 470 mg) as a yellow oil.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 3.16 (1H, d, J = 5.4 Hz), 3.89 (3H, s), 4.81-4.92 (2H, m), 5.42-5.48 (1H, m), 7.32 (1H, brs), 7.76 (1H, d, J = 2.3 Hz), 8.61 (1H, brs).

実施例５と同様の方法に従い、３−（２，２，２−トリフルオロ−１−ヒドロキシエチル）−２−メトキシ−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（２２５ｍｇ，０．４３０ｍｍｏｌ）から、低極性側の表題化合物（以下、実施例３２の低極性側の化合物）（１１０ｍｇ）及び高極性側の表題化合物（以下、実施例３２の高極性側の化合物）（１１１ｍｇ）をいずれも無色アモルファスとして得た。
実施例３２の低極性側の化合物：
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄ，Ｊ＝１６．３Ｈｚ），３．０８（１Ｈ，ｄｄ，Ｊ＝１６．３，４．１Ｈｚ），３．７７（３Ｈ，ｓ），４．４７（１Ｈ，ｑ，Ｊ＝４．１Ｈｚ），５．１２（１Ｈ，ｄｄ，Ｊ＝８．４，４．８Ｈｚ），５．２４（１Ｈ，ｄ，Ｊ＝４．１Ｈｚ），５．３９−５．４６（１Ｈ，ｍ），７．１７−７．２６（５Ｈ，ｍ），７．４８−７．５１（２Ｈ，ｍ），８．８６（１Ｈ，ｂｒｓ），８．９７（１Ｈ，ｄ，Ｊ＝３．２Ｈｚ）．
実施例３２の高極性側の化合物：
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄ，Ｊ＝１６．３Ｈｚ），３．０８（１Ｈ，ｄｄ，Ｊ＝１６．３，４．５Ｈｚ），３．７８（３Ｈ，ｓ），４．４７（１Ｈ，ｑ，Ｊ＝４．２Ｈｚ），５．１２（１Ｈ，ｄｄ，Ｊ＝８．４，４．８Ｈｚ），５．２３（１Ｈ，ｄ，Ｊ＝４．５Ｈｚ），５．３９−５．４６（１Ｈ，ｍ），７．１７−７．２２（５Ｈ，ｍ），７．４９−７．５１（２Ｈ，ｍ），８．８３（１Ｈ，ｂｒｓ），８．９９（１Ｈ，ｄ，Ｊ＝３．２Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：５２１．Example 32 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) -3- (3- (2,2,2-trifluoro-1- Synthesis of hydroxyethyl) -2-methoxy-5-pentafluorosulfanylphenyl) urea:

According to a method similar to that in Example 5, 2,2,2-trichloroethyl 3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylphenylcarbamate (225 mg) , 0.430 mmol) from the low-polarity-side title compound (hereinafter, the low-polarity-side compound of Example 32) (110 mg) and the high-polarity-side title compound (hereinafter, the high-polarity-side compound of Example 32) ( 111 mg) was obtained as colorless amorphous.
Compound on the low polarity side of Example 32:
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, d, J = 16.3 Hz), 3.08 (1H, dd, J = 16.3, 4.1 Hz) , 3.77 (3H, s), 4.47 (1H, q, J = 4.1 Hz), 5.12 (1H, dd, J = 8.4, 4.8 Hz), 5.24 (1H, d, J = 4.1 Hz), 5.39-5.46 (1H, m), 7.17-7.26 (5H, m), 7.48-7.51 (2H, m), 8. 86 (1H, brs), 8.97 (1H, d, J = 3.2 Hz).
Compound on the highly polar side of Example 32:
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, d, J = 16.3 Hz), 3.08 (1 H, dd, J = 16.3, 4.5 Hz) , 3.78 (3H, s), 4.47 (1H, q, J = 4.2 Hz), 5.12 (1H, dd, J = 8.4, 4.8 Hz), 5.23 (1H, d, J = 4.5 Hz), 5.39-5.46 (1H, m), 7.17-7.22 (5H, m), 7.49-7.51 (2H, m), 8. 83 (1H, brs), 8.99 (1H, d, J = 3.2 Hz).
MS (ESI) [M−H] ⁻ : 521.

実施例７と同様の方法に従い、３−（２，２，２−トリフルオロ−１−ヒドロキシエチル）−２−メトキシ−５−ペンタフルオロサルファニルフェニルカルバミン酸２，２，２−トリクロロエチル（２３３ｍｇ，０．４５０ｍｍｏｌ）から、低極性側の表題化合物（以下、実施例３３の低極性側の化合物）（１１２ｍｇ）及び高極性側の表題化合物（以下、実施例３３の高極性側の化合物）（１０２ｍｇ）をいずれも無色アモルファスとして得た。
実施例３３の低極性側の化合物：
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄｄ，Ｊ＝１５．９，７．０Ｈｚ），３．０９（１Ｈ，ｄｄ，Ｊ＝１５．９，７．０Ｈｚ），３．７３（３Ｈ，ｓ），４．３０−４．３７（１Ｈ，ｍ），４．９２（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），５．３７−５．４３（１Ｈ，ｍ），５．５５（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．１６（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．２０−７．２５（３Ｈ，ｍ），７．３６−７．４０（２Ｈ，ｍ），７．４７（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），８．８１（１Ｈ，ｂｒｓ），８．９７（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
実施例３３の高極性側の化合物：
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：２．８１（１Ｈ，ｄｄ，Ｊ＝１５．９，６．８Ｈｚ），３．１１（１Ｈ，ｄｄ，Ｊ＝１５．９，６．８Ｈｚ），３．７４（３Ｈ，ｓ），４．２９−４．３６（１Ｈ，ｍ），４．９２（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），５．３８−５．４２（１Ｈ，ｍ），５．５６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．１６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．２０−７．２５（３Ｈ，ｍ），７．３６−７．４０（２Ｈ，ｍ），７．４８（１Ｈ，ｂｒｓ），８．８０（１Ｈ，ｂｒｓ），８．９６（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ−Ｈ］⁻：５２１．Example 33 1-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (3- (2,2,2-trifluoro-1- Synthesis of hydroxyethyl) -2-methoxy-5-pentafluorosulfanylphenyl) urea:

According to a method similar to that in Example 7, 2,2,2-trichloroethyl 3- (2,2,2-trifluoro-1-hydroxyethyl) -2-methoxy-5-pentafluorosulfanylphenylcarbamate (233 mg) , 0.450 mmol) from the low-polarity-side title compound (hereinafter, the low-polarity-side compound of Example 33) (112 mg) and the high-polarity-side title compound (hereinafter, the high-polarity-side compound of Example 33) ( 102 mg) were obtained as colorless amorphous.
Compound on the low polarity side of Example 33:
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, dd, J = 15.9, 7.0 Hz), 3.09 (1H, dd, J = 15.9, 7.0 Hz), 3.73 (3H, s), 4.30-4.37 (1 H, m), 4.92 (1 H, d, J = 5.7 Hz), 5.37-5.43 ( 1H, m), 5.55 (1H, d, J = 5.4 Hz), 7.16 (1H, d, J = 5.9 Hz), 7.20-7.25 (3H, m), 7. 36-7.40 (2H, m), 7.47 (1H, d, J = 2.7 Hz), 8.81 (1H, brs), 8.97 (1H, d, J = 2.7 Hz).
High polarity compound of Example 33:
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, dd, J = 15.9, 6.8 Hz), 3.11 (1H, dd, J = 15.9, 6.8 Hz), 3.74 (3 H, s), 4.29-4.36 (1 H, m), 4.92 (1 H, d, J = 5.4 Hz), 5.38-5.42 ( 1H, m), 5.56 (1H, d, J = 5.4 Hz), 7.16 (1H, d, J = 5.4 Hz), 7.20-7.25 (3H, m), 7. 36-7.40 (2H, m), 7.48 (1H, brs), 8.80 (1H, brs), 8.96 (1H, d, J = 2.3 Hz).
MS (ESI) [M−H] ⁻ : 521.

参考例２２と同様の方法に従い、２−クロロ−５−ペンタフルオロサルファニルニトロベンゼン（３００ｍｇ，１．０６ｍｍｏｌ）から、表題化合物（３４１ｍｇ）を橙色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．９２（１Ｈ，ｔ，Ｊ＝６．０Ｈｚ），２．９２（３Ｈ，ｓ），３．５４（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），３．８７（２Ｈ，ｑ．Ｊ＝５．４Ｈｚ），７．１９（１Ｈ，ｄ，Ｊ＝９．３Ｈｚ），７．７３（１Ｈ，ｄｄ，９．３，２．７Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３２３．Reference Example 53 Synthesis of 2-((4-pentafluorosulfanyl-2-nitrophenyl) (methyl) amino) ethanol:

The title compound (341 mg) was obtained as an orange oil from 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) in the same manner as in Reference Example 22.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.92 (1H, t, J = 6.0 Hz), 2.92 (3H, s), 3.54 (2H, t, J = 5) .2 Hz), 3.87 (2H, q.J = 5.4 Hz), 7.19 (1H, d, J = 9.3 Hz), 7.73 (1H, dd, 9.3, 2.7 Hz) 8.17 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 323.

２−（（４−ペンタフルオロサルファニル−２−ニトロフェニル）（メチル）アミノ）エタノール（３４１ｍｇ，１．０６ｍｍｏｌ）の酢酸エチル溶液（２．１ｍＬ）に、ピリジン（０．２０７ｍＬ，２．５４ｍｍｏｌ）、無水酢酸（０．１２１ｍＬ，１．２７ｍｍｏｌ）、４−ジメチルアミノピリジン（１．２ｍｇ，０．０１０ｍｍｏｌ）を加え、室温で２時間攪拌した。反応混合液に水（５ｍＬ）を加え、酢酸エチル（５ｍＬ）で抽出した。有機層を飽和食塩水（２ｍＬ）で洗浄後、乾燥、濃縮後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（３５０ｍｇ）を黄色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．９９（３Ｈ，ｓ），２．９４（３Ｈ，ｓ），３．５６（２Ｈ，ｔ，Ｊ＝５．９Ｈｚ），４．３１（２Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．１２（１Ｈ，ｄ，Ｊ＝９．５Ｈｚ），７．７３（１Ｈ，ｄｄ，Ｊ＝９．３，２．７Ｈｚ），８．１５（１Ｈ，ｄ，２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３６５．Reference Example 54 Synthesis of 2-((4-pentafluorosulfanyl-2-nitrophenyl) (methyl) amino) ethyl acetate:

2-((4-Pentafluorosulfanyl-2-nitrophenyl) (methyl) amino) ethanol (341 mg, 1.06 mmol) in ethyl acetate (2.1 mL) was added to pyridine (0.207 mL, 2.54 mmol). , Acetic anhydride (0.121 mL, 1.27 mmol) and 4-dimethylaminopyridine (1.2 mg, 0.010 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (2 mL), dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (350 mg) as a yellow oil. It was.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.99 (3H, s), 2.94 (3H, s), 3.56 (2H, t, J = 5.9 Hz), 4. 31 (2H, t, J = 5.7 Hz), 7.12 (1H, d, J = 9.5 Hz), 7.73 (1H, dd, J = 9.3, 2.7 Hz), 8.15 (1H, d, 2.7 Hz).
MS (ESI) [M + H] ⁺ : 365.

参考例４と同様の方法に従い、２−（（４−ペンタフルオロサルファニル−２−ニトロフェニル）（メチル）アミノ）エチルアセタート（３５０ｍｇ，０．９６０ｍｍｏｌ）から、表題化合物（３０６ｍｇ）を無色油状物として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．０３（３Ｈ，ｓ）, ２．７４（３Ｈ，ｓ），３．１６（２Ｈ，ｔ，Ｊ＝５．６Ｈｚ），４．１９（２Ｈ，ｓ），４．２２（２Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．００（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．０８−７．１０（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：３３５．Reference Example 55 Synthesis of 2-((2-amino- (4-pentafluorosulfanyl) phenyl) (methyl) amino) ethyl acetate:

According to the same method as in Reference Example 4, the title compound (306 mg) was obtained from 2-((4-pentafluorosulfanyl-2-nitrophenyl) (methyl) amino) ethyl acetate (350 mg, 0.960 mmol) as a colorless oil. Obtained as a thing.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.03 (3H, s), 2.74 (3H, s), 3.16 (2H, t, J = 5.6 Hz), 4. 19 (2H, s), 4.22 (2H, d, J = 5.6 Hz), 7.00 (1H, d, J = 8.8 Hz), 7.08-7.10 (2H, m).
MS (ESI) [M + H] ⁺ : 335.

参考例９と同様の方法に従い、２−（（２−アミノ−（４−ペンタフルオロサルファニル）フェニル）（メチル）アミノ）エチルアセタート（３０５ｍｇ，０．９１０ｍｍｏｌ）から、表題化合物（４４７ｍｇ）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．１２（３Ｈ，ｓ），２．７４（３Ｈ，ｓ），３．１２（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ）,４．１９（１Ｈ，ｔ，Ｊ＝５．４Ｈｚ），４．８９（２Ｈ，ｓ），７．２３（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝８．８，２．４Ｈｚ），８．２３（１Ｈ，ｓ），８．６３（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５０９．
ｍｐ５１．５−５３．０℃．Reference Example 56 Synthesis of 2-((4- (pentafluorosulfanyl) -2-(((2,2,2-trichloroethoxy) carbonyl) amino) phenyl) (methyl) amino) ethyl acetate:

The title compound (447 mg) was obtained from 2-((2-amino- (4-pentafluorosulfanyl) phenyl) (methyl) amino) ethyl acetate (305 mg, 0.910 mmol) in the same manner as in Reference Example 9. Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.12 (3H, s), 2.74 (3H, s), 3.12 (2H, t, J = 5.4 Hz), 4. 19 (1H, t, J = 5.4 Hz), 4.89 (2H, s), 7.23 (1H, d, J = 8.8 Hz), 7.46 (1H, dd, J = 8.8) , 2.4 Hz), 8.23 (1H, s), 8.63 (1H, s).
MS (ESI) [M + H] ⁺ : 509.
mp 51.5-53.0 ° C.

実施例５と同様の方法に従い、２−（（４−（ペンタフルオロサルファニル）−２−（（（２，２，２−トリクロロエトキシ）カルボニル）アミノ）フェニル）（メチル）アミノ）エチルアセタート（１５０ｍｇ，０．２９４ｍｍｏｌ）から、表題化合物（以下、実施例３４の化合物）（１３１ｍｇ）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．９７（３Ｈ，ｓ），２．３４（１Ｈ，ｄ，Ｊ＝４．５Ｈｚ），２．７０（３Ｈ，ｓ），２．９７（１Ｈ，ｄｄ，Ｊ＝１６．５，２．０Ｈｚ），３．１２（２Ｈ，ｄｔ，Ｊ＝１４．８，４．１Ｈｚ），３．２１（１Ｈ，ｄｄ，Ｊ＝１６．５，５．２Ｈｚ），４．２０−４．３２（２Ｈ，ｍ），４．７０−４．７２（１Ｈ，ｍ），５．３８（１Ｈ，ｄｄ，Ｊ＝７．７，５．０Ｈｚ），５．７０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），５．７０（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），７．１５（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２３−７．２７（３Ｈ，ｍ），７．３４−７．３７（２Ｈ，ｍ），７．９４（１Ｈ，ｓ），８．８０（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５１０．
ｍｐ１３９．９−１４１．１℃．Example 34 2-((2- (3-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-1-yl) ureido) -4- (pentafluorosulfanyl) Synthesis of phenyl) (methyl) amino) ethyl acetate:

According to a method similar to that in Example 5, 2-((4- (pentafluorosulfanyl) -2-(((2,2,2-trichloroethoxy) carbonyl) amino) phenyl) (methyl) amino) ethyl acetate (150 mg, 0.294 mmol) gave the title compound (hereinafter, the compound of Example 34) (131 mg) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.97 (3H, s), 2.34 (1H, d, J = 4.5 Hz), 2.70 (3H, s), 2. 97 (1H, dd, J = 16.5, 2.0 Hz), 3.12 (2H, dt, J = 14.8, 4.1 Hz), 3.21 (1H, dd, J = 16.5, 5.2 Hz), 4.20-4.32 (2H, m), 4.70-4.72 (1H, m), 5.38 (1H, dd, J = 7.7, 5.0 Hz), 5.70 (1H, d, J = 8.2 Hz), 5.70 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 8.6 Hz), 7.23-7 .27 (3H, m), 7.34-7.37 (2H, m), 7.94 (1H, s), 8.80 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 510.
mp 139.9-141.1 ° C.

実施例７と同様の方法に従い、２−（（４−（ペンタフルオロサルファニル）−２−（（（２，２，２−トリクロロエトキシ）カルボニル）アミノ）フェニル）（メチル）アミノ）エチルアセタート（１５０ｍｇ，０．２９４ｍｍｏｌ）から、表題化合物（以下、実施例３５の化合物）（１３５ｍｇ）を白色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．９９（３Ｈ，ｓ），２．２８（１Ｈ，ｄ，Ｊ＝４．５Ｈｚ），２．６８（３Ｈ，ｓ），２．９６（１Ｈ，ｄ，Ｊ＝１５．９，６．３Ｈｚ），３．０８−３．１３（ｓＨ，ｍ），３．３３（１Ｈ，ｄｄ，Ｊ＝１５．９，７．２Ｈｚ），４．１８−４．３０（２Ｈ，ｍ），４．６１−４．６８（１Ｈ，ｍ），５．１６（１Ｈ，ｔ，Ｊ＝５．２Ｈｚ），５．７４（１Ｈ，ｄ，Ｊ＝７．７Ｈｚ），７．１３（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ），７．２７−７．３５（４Ｈ，ｍ），７．３４−７．４５（１Ｈ，ｍ），７．８５（１Ｈ，ｓ），８．７８（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：５１０．Example 35 2-((2- (3-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) ureido) -4- (pentafluorosulfanyl) Synthesis of phenyl) (methyl) amino) ethyl acetate:

According to a method similar to that in Example 7, 2-((4- (pentafluorosulfanyl) -2-(((2,2,2-trichloroethoxy) carbonyl) amino) phenyl) (methyl) amino) ethyl acetate From (150 mg, 0.294 mmol), the title compound (hereinafter, the compound of Example 35) (135 mg) was obtained as a white amorphous substance.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.99 (3H, s), 2.28 (1H, d, J = 4.5 Hz), 2.68 (3H, s), 2. 96 (1H, d, J = 15.9, 6.3 Hz), 3.08-3.13 (sH, m), 3.33 (1 H, dd, J = 15.9, 7.2 Hz), 4 18-4.30 (2H, m), 4.61-4.68 (1H, m), 5.16 (1H, t, J = 5.2 Hz), 5.74 (1H, d, J = 7.7 Hz), 7.13 (1H, d, J = 8.6 Hz), 7.27-7.35 (4H, m), 7.34-7.45 (1H, m), 7.85 ( 1H, s), 8.78 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 510.

実施例３４の化合物（１１８ｍｇ，０．２３２ｍｍｏｌ）のメタノール（１．０ｍＬ）及びテトラヒドロフラン（１．０ｍＬ）溶液に、１Ｍ水酸化ナトリウム水溶液（０．４６０ｍＬ，０．４６０ｍｍｏｌ）を加え、室温で２時間２０分撹拌した。反応混合物に１Ｍ塩酸を加え、ｐＨを７に調整後、減圧濃縮した。残渣を酢酸エチルで抽出し、有機層を飽和食塩水（５ｍＬ）で洗浄後、乾燥、濃縮し、得られた粗生成物をジエチルエーテルでスラリー洗浄し、表題化合物（以下、実施例３６の化合物）（７６．９ｍｇ）を白色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：２．７５（３Ｈ，ｓ），２．９２（１Ｈ，ｄｄ，Ｊ＝１６．５，１．１Ｈｚ），３．００−３．０６（２Ｈ，ｍ），３．１５（１Ｈ，ｄｄ，Ｊ＝１６．５，５．０Ｈｚ），３．７４（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），４．５９（１Ｈ，ｔｄ，Ｊ＝５．０，１．５Ｈｚ），５．２３（１Ｈ，ｄ，Ｊ＝４．６Ｈｚ），７．１９−７．２７（４Ｈ，ｍ），７．３１（１Ｈ，ｔ，Ｊ＝４．４Ｈｚ），７．２８（１Ｈ，ｄｄ，Ｊ＝９．０，２．７Ｈｚ），８．７３（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：４６８．
ｍｐ２１１．１−２１３．４℃．Example 36 1-((1R, 2S) -2-hydroxy-2,3-dihydro-1H-inden-2-yl) -3- (2-((2-hydroxyethyl) (methyl) amino) Synthesis of -5- (pentafluorosulfanyl) phenyl) urea:

To a solution of the compound of Example 34 (118 mg, 0.232 mmol) in methanol (1.0 mL) and tetrahydrofuran (1.0 mL) was added 1M aqueous sodium hydroxide solution (0.460 mL, 0.460 mmol), and the mixture was stirred at room temperature for 2 hours. Stir for 20 minutes. 1M hydrochloric acid was added to the reaction mixture to adjust the pH to 7, and then concentrated under reduced pressure. The residue was extracted with ethyl acetate, the organic layer was washed with saturated brine (5 mL), dried and concentrated, and the resulting crude product was slurry washed with diethyl ether to give the title compound (hereinafter referred to as the compound of Example 36). ) (76.9 mg) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 2.75 (3H, s), 2.92 (1H, dd, J = 16.5, 1.1 Hz), 3.00-3.06 (2H, m), 3.15 (1H, dd, J = 16.5, 5.0 Hz), 3.74 (2H, t, J = 5.2 Hz), 4.59 (1H, td, J = 5.0, 1.5 Hz), 5.23 (1 H, d, J = 4.6 Hz), 7.19-7.27 (4 H, m), 7.31 (1 H, t, J = 4.4 Hz) ), 7.28 (1H, dd, J = 9.0, 2.7 Hz), 8.73 (1H, d, J = 2.7 Hz).
MS (ESI) [M + H] ⁺ : 468.
mp 211.1-213.4 ° C.

３−ホルミル−２−メトキシ−５−ペンタフルオロサルファニルニトロベンゼン（１００ｍｇ，０．３３０ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に，（Ｒ）−ｔｅｒｔ−ブチル ピロリジン−３−イルカルバマート（６７ｍｇ，０．３６ｍｍｏｌ）を加え、氷冷下、トリアセトキシ水素化ホウ素ナトリウム（１０４ｍｇ，０．４９ｍｍｏｌ）を加えた。室温に昇温して一晩撹拌した後、反応液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、表題化合物（１６３ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．５９（９Ｈ，ｓ），１．６５（１Ｈ，ｍ），２．２９−２．４２（２Ｈ，ｍ），２．５８−２．６７（２Ｈ，ｍ），８．１４（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），２．８４（１Ｈ，ｍ），３．７４（２Ｈ，ｂｒｓ），３．９６（３Ｈ，ｓ），４．２１（１Ｈ，ｂｒｓ），４．７７（１Ｈ，ｂｒｓ），８．０９（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．
ＥＳＩ−ＭＳｍ／ｚ［Ｍ＋Ｈ］^＋：４７８．Reference Example 57 Synthesis of (R) -tert-butyl (1- (2-methoxy-5-pentafluorosulfanyl-3-nitrobenzyl) pyrrolidin-3-yl) carbamate:

To a solution of 3-formyl-2-methoxy-5-pentafluorosulfanylnitrobenzene (100 mg, 0.330 mmol) in tetrahydrofuran (5 mL) was added (R) -tert-butyl pyrrolidin-3-ylcarbamate (67 mg, 0.36 mmol). ) And sodium triacetoxyborohydride (104 mg, 0.49 mmol) was added under ice cooling. After warming to room temperature and stirring overnight, the reaction solution was concentrated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (163 mg) as a colorless solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.59 (9H, s), 1.65 (1H, m), 2.29-2.42 (2H, m), 2.58- 2.67 (2H, m), 8.14 (1H, d, J = 2.7 Hz), 2.84 (1H, m), 3.74 (2H, brs), 3.96 (3H, s) , 4.21 (1H, brs), 4.77 (1H, brs), 8.09 (1H, d, J = 2.7 Hz).
ESI-MS m / z [M + H] ⁺ : 478.

水素雰囲気下、（Ｒ）−ｔｅｒｔ−ブチル （１−（２−メトキシ−５−ペンタフルオロスルファニル−３−ニトロベンジル）ピロリジン−３−イル）カルバマート（１６３ｍｇ，０．３３０ｍｍｏｌ）及び酸化白金（６ｍｇ）のエタノール懸濁液を室温で1時間撹拌した。触媒をセライト（登録商標）ろ過し、溶液を濃縮し粗生成物を得た。得られた粗生成物（７４ｍｇ，０．１７ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、氷冷下、トリエチルアミン（０．０４６ｍＬ，０．３３ｍｍｏｌ）及びトリホスゲン（１６ｍｇ，０．０５５ｍｍｏｌ）を加えた。室温で1時間撹拌した後、（１Ｓ，２Ｒ）−２−アミノ−１−インダノール（２５ｍｇ，０．１７ｍｍｏｌ）を加え、さらに室温で1時間撹拌した。反応液に塩化アンモニウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）及びプレパラティブＴＬＣ（クロロホルム／メタノール）で精製し、表題化合物（２０ｍｇ）を無色固体として得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ（ｐｐｍ）：１．４２（９Ｈ，ｓ），１．５８（１Ｈ，ｍ），２．２４−２．３２（２Ｈ，ｍ），２．５６（２Ｈ，ｍ），２．８１（１Ｈ，ｍ），２．９１（１Ｈ，ｄｄ，Ｊ＝１５．９，６．６Ｈｚ），３．２９（１Ｈ，ｄｄ，Ｊ＝１５．９，７．２Ｈｚ），３．６２（２Ｈ，ｄｄ，Ｊ＝１８．３，１３．４Ｈｚ），３．７６（３Ｈ，ｓ），４．１５（１Ｈ，ｂｒｍ），４．５５−４．６２（１Ｈ，ｍ），４．８５（１Ｈ，ｄ，Ｊ＝８．２Ｈｚ），５．１１（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），５．８２（１Ｈ，ｂｒｓ），７．２６−７．２９（３Ｈ，ｍ），７．４０−７．４４（２Ｈ，ｍ），８．５８（１Ｈ，ｂｒｓ）．
ＭＳ（ＥＳＩ）［Ｍ＋Ｈ］^＋：６２３．Reference Example 58 tert-butyl (((R) -1- (3- (3-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) ureido)- Synthesis of 2-methoxy-5- (pentafluorosulfanyl) benzyl) pyrrolidin-3-yl) carbamate:

Under a hydrogen atmosphere, (R) -tert-butyl (1- (2-methoxy-5-pentafluorosulfanyl-3-nitrobenzyl) pyrrolidin-3-yl) carbamate (163 mg, 0.330 mmol) and platinum oxide (6 mg) Was stirred at room temperature for 1 hour. The catalyst was filtered through Celite (registered trademark), and the solution was concentrated to obtain a crude product. The obtained crude product (74 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.046 mL, 0.33 mmol) and triphosgene (16 mg, 0.055 mmol) were added under ice cooling. After stirring at room temperature for 1 hour, (1S, 2R) -2-amino-1-indanol (25 mg, 0.17 mmol) was added, and the mixture was further stirred at room temperature for 1 hour. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) and preparative TLC (chloroform / methanol) to obtain the title compound (20 mg) as a colorless solid. .
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.42 (9H, s), 1.58 (1H, m), 2.24-2.32 (2H, m), 2.56 ( 2H, m), 2.81 (1H, m), 2.91 (1H, dd, J = 15.9, 6.6 Hz), 3.29 (1H, dd, J = 15.9, 7.2 Hz) ), 3.62 (2H, dd, J = 18.3, 13.4 Hz), 3.76 (3H, s), 4.15 (1H, brm), 4.55-4.62 (1H, m ), 4.85 (1H, d, J = 8.2 Hz), 5.11 (1H, d, J = 5.9 Hz), 5.82 (1H, brs), 7.26-7.29 (3H) M), 7.40-7.44 (2H, m), 8.58 (1H, brs).
MS (ESI) [M + H] ⁺ : 623.

ｔｅｒｔ−ブチル （（（Ｒ）−１−（３−（３−（（１Ｓ，２Ｒ）−１−ヒドロキシ−２，３−ジヒドロ−１Ｈ−インデン−２−イル）ウレイド）−２−メトキシ−５−（ペンタフルオロスルファニル）ベンジル）ピロリジン−３−イル）カルバマート（３２ｍｇ，０．０５１ｍｍｏｌ）を酢酸エチル（０．５ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（０．５ｍＬ）を加えた。反応混合物を室温で２時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）及びプレパラティブＴＬＣ（クロロホルム／メタノール）で精製し、表題化合物（１０．７ｍｇ）（以下、実施例３７の化合物）を淡黄色アモルファスとして得た。
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ_６）δ（ｐｐｍ）：１．４７（１Ｈ，ｍ），２．３３（１Ｈ，ｄｄ，Ｊ＝９．３，３．９Ｈｚ），２．４４（１Ｈ，ｄｄ，Ｊ＝１５．０，８．６Ｈｚ），２．６６（１Ｈ，ｄｄ，Ｊ＝９．３，６．１Ｈｚ），２．７２-２．７８（１Ｈ，ｍ），２．９０（１Ｈ，ｄｄ，Ｊ＝１５．９，６．８Ｈｚ），３．３０（１Ｈ，ｄｄ，Ｊ＝１５．９，７．２Ｈｚ），３．４８（１Ｈ，ｍ），３．６２（２Ｈ，ｄｄ，Ｊ＝２１．１，１３．４Ｈｚ），３．７９（３Ｈ，ｓ），４．５４−４．６１（１Ｈ，ｍ），５．１０（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），５．８１（１Ｈ，ｔ，Ｊ＝７．２Ｈｚ），７．２０−７．３２（４Ｈ，ｍ），７．４０（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），７．４３（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ），８．５７（１Ｈ，ｄ，Ｊ＝２．７Ｈｚ）．Example 37 1- (3-(((R) -3-Aminopyrrolidin-1-yl) methyl) -2-methoxy-5-pentafluorosulfanylphenyl) -3-((1S, 2R) -1 Synthesis of -hydroxy-2,3-dihydro-1H-inden-2-yl) urea:

tert-butyl (((R) -1- (3- (3-((1S, 2R) -1-hydroxy-2,3-dihydro-1H-inden-2-yl) ureido) -2-methoxy-5 -(Pentafluorosulfanyl) benzyl) pyrrolidin-3-yl) carbamate (32 mg, 0.051 mmol) was dissolved in ethyl acetate (0.5 mL), and 4N hydrogen chloride-ethyl acetate solution (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform / methanol). ) And preparative TLC (chloroform / methanol) to give the title compound (10.7 mg) (hereinafter referred to as Example 37). Compound) was obtained as a pale yellow amorphous.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 1.47 (1H, m), 2.33 (1H, dd, J = 9.3, 3.9 Hz), 2.44 (1H , Dd, J = 15.0, 8.6 Hz), 2.66 (1H, dd, J = 9.3, 6.1 Hz), 2.72-2.78 (1H, m), 2.90 ( 1H, dd, J = 15.9, 6.8 Hz), 3.30 (1H, dd, J = 15.9, 7.2 Hz), 3.48 (1H, m), 3.62 (2H, dd) , J = 21.1, 13.4 Hz), 3.79 (3H, s), 4.54-4.61 (1H, m), 5.10 (1H, d, J = 5.4 Hz), 5 .81 (1H, t, J = 7.2 Hz), 7.20-7.32 (4H, m), 7.40 (1H, d, J = 7.2 Hz), 7.43 (1H, d, J = 2.7Hz , 8.57 (1H, d, J = 2.7Hz).

(Example 38) DDR1 inhibitory activity evaluation:
The DDR1 inhibitory activity of the compounds of Examples 1 to 37 was evaluated using HTRF (registered trademark) KinEASE-TK kit (Cisbio Bioassays).

The test substance was dissolved in dimethyl sulfoxide (hereinafter DMSO) and used for the following evaluation. In addition, the test substance and each reagent have MgCl ₂ at 5 mmol / L, MnCl ₂ at 0.5 mmol / L, DTT at 0.25 mmol / L, and Supplemental Enzyme buffer (Cisbio Bioassay) at 50 nmol / L. It was diluted with Kinase buffer (Cisbio Bioassays) prepared by adding to the solution. A test substance (final DMSO concentration of 1%), DDR1 intracellular domain (final concentration of 5 ng / μL) (Carna Biosciences), phosphate donor ATP (final concentration of 25 μmol / mL) was added to a 384-well black plate (Corning). L) (Sigma) and a substrate TK Substrate-biotin (final concentration 1000 nmol / L) (Cisbio Bioassay) were added and reacted at room temperature for 1 hour. After completion of the reaction, TK antibody-cryptate (Cisbio Bioassay) and streptavidin-XL665 (Cisbio Bioassay) were added and reacted at room temperature for 1 hour. In addition, a well with no test substance added and a well with no DDR1 intracellular domain added and no test substance added were provided.

Using a multi-label counter (Envision, PerkinElmer), the fluorescence intensity (excitation wavelength 320 nm, measurement wavelengths 665 nm and 620 nm) of each well was measured, and Ratio (fluorescence intensity of 665 nm / fluorescence intensity of 620 nm) was calculated. The inhibition rate (%) at each concentration of the test substance was calculated by the following formula.
Inhibition rate (%) = ([Ratio without addition of test substance] − [Ratio of test substance]) / ([Ratio without addition of test substance] − [Ratio without addition of DDR1 intracellular domain and without addition of test substance]) × 100

The calculated inhibition rate was returned to sigmoidal dose-response using Prism 5.04 (GraphPad Software, Inc), and the IC ₅₀ value of the test substance was calculated.

The IC ₅₀ value of each test substance is shown in Table 2. As is clear from the results in Table 2, it was shown that the urea derivative (I) of the present invention or a pharmacologically acceptable salt thereof has a high DDR1 inhibitory activity.

  Since the urea derivative (I) and pharmacologically acceptable salt thereof of the present invention have high DDR1 inhibitory activity, they can be used as inhibitors of DDR1.

Claims (4)

A urea derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[Wherein, k and m each independently represent 0 or 1, and R ¹ represents a hydrogen atom or a 3-aminopyrrolidinylmethyl group, or 1 to 4 hydrogen atoms each independently a halogen atom. Represents an alkyl group having 1 to 3 carbon atoms which may be substituted with an atom or a hydroxy group, and R ² represents a hydrogen atom, a halogen atom, a 4-pyridyl group, a 4-hydroxy-1-piperidinyl group, or 4-morpholinyl. Group, 3-oxo-1-piperazinyl group, tetrahydro-4-pyranyl group, (2-hydroxyethyl) (methyl) amino group, (2-acetoxyethyl) (methyl) amino group or R ⁴ — (CH ₂ ) _n -O-, or one to three hydrogen atoms are each independently a hydroxy group or a methoxy group optionally substituted by a phenyl group, a, R ³ is a hydrogen atom or a halo Represents a down atom, n is 0 or 1, ^{R 4} represents a methyl group, a phenyl group, N- acetyl-3-azetidinyl group, N- methanesulfonyl-3- azetidinyl group or a 3-oxetanyl group. ]   The urea derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein one of k and m is 1 and the other is 0. R ¹ is a hydrogen atom or a hydroxymethyl group, R ² is a 4-pyridyl group, 3-oxo-1-piperazinyl group or R ⁴ O—, R ³ is a hydrogen atom or a fluorine atom, R ⁴ is a methyl group, an N-acetyl-3-azetidinyl group, an N-methanesulfonyl-3-azetidinyl group or a 3-oxetanyl group, or the urea derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. Salt.   The inhibitor of the discoidin domain receptor 1 which contains the urea derivative as described in any one of Claims 1-3, or its pharmacologically acceptable salt as an active ingredient.