TW201718480A - Urea derivatives and use thereof - Google Patents

Abstract

The purpose of the present invention is to provide a compound having an inhibition activity against discoidin domain receptor 1. The present invention provides a urea derivative represented by the formula and a pharmacologically acceptable salt thereof.

Description

Urea derivative and its use

The present invention relates to urea derivatives and uses thereof.

Discoidin domain receptor 1 (hereinafter, DDR1) is a receptor-type tyrosine kinase which is activated by insoluble collagen which is a ligand, and each has collagen outside the cell. The disc-like domain of binding ability has a receptor-type tyrosine kinase domain in cells (Non-Patent Documents 1 and 2).

Activation of DDR1 has been reported to promote cell infiltration, metastasis or survival (Non-Patent Documents 3 to 5). In clinical practice, DDR1 has been reported to be hyperactive in non-small cell lung cancer, glioma, and breast cancer. In non-small cell lung cancer, the association between hyperactivity and poor prognosis has been reported. Correlation of infiltration (Non-Patent Documents 6 to 9).

It has been reported that DDR1 is knocked down by using RNA interference, and bone metastasis of lung cancer cells is suppressed (Non-Patent Document 6) and tumor production ability of colorectal cancer is lowered (Non-Patent Document 10).

For a compound having an inhibitory activity against DDR1, for example, a 3-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamide derivative has been reported (Patent Document 1 and Non-patent literature 11), 4-((4-ethylperidazole) Methyl)-3-trifluoromethylbenzylamine derivative (Non-Patent Document 12) and 4-piperider Methyl-3-trifluoromethylbenzylamine derivatives (Patent Documents 2 and 3).

On the other hand, in the case of a compound having a urea skeleton, for example, as a compound having p38MAPK inhibitory activity, a 2,3-dihydro-1H-indol-2-ylurea derivative has been reported (Patent Document 4), and As a compound having inhibitory activity against FLT3 (Fms-like tyrosine kinase 3) and VEGFR2 (vascular endothelial growth factor receptor 2), pentacene has been reported. A pentafluorosulfanyl phenyl urea derivative (Patent Document 5).

Prior technical literature Patent literature

Patent Document 1 International Publication No. 2012/000304

Patent Document 2 International Publication No. 2013/161851

Patent Document 3 International Publication No. 2013/161853

Patent Document 4 International Publication No. 2011/040509

Patent Document 5 International Publication No. 2012/094451

Non-patent literature

Non-Patent Document 1 Vogel et al., British Journal of Cancer, 2007, Vol. 96, p. 808-814

Non-Patent Document 2 Vogel et al., Cellular Signalling, 2006, Vol. 18, p. 1108-1116

Non-Patent Document 3 Vogel et al., FASEB Journal, 1999, Vol. 13, p. S77-S82

Non-Patent Document 4 Valiathan et al., Cancer Metastasis Review, 2012, Vol. 31, p. 295-321

Non-Patent Document 5 Vogel et al., Molecular Cell, 1997, Vol. 1, p. 13-23

Non-Patent Document 6 Valencia et al., Clinical Cancer Research, 2012, Vol. 18, p. 969-980

Non-Patent Document 7 Barker et al., Oncogene, 1995, Vol. 10, p. 569-575

Non-Patent Document 8 Yamanaka et al., Oncogene, 2006, Vol. 25, p. 5994-6002

Non-Patent Document 9 Miao et al., Medical Oncology, 2013, Vol. 30, p. 626

Non-Patent Document 10 Hung-Gu et al., Journal of Biological Chemistry, 2011, Vol. 286, p. 17672-17681

Non-Patent Document 11 Ding et al., Journal of Medicinal Chemistry, 2013, Vol. 56, p. 3281-3295

Non-Patent Document 12 Gray et al., ACS Chemical Biology, 2013, Vol. 8, p. 2145-2150

Summary of invention

However, among the compounds having a urea skeleton, compounds having an inhibitory activity against DDR1 have not been reported so far.

Accordingly, the present invention is intended to provide a compound having an inhibitory activity against DDR1.

In order to achieve the above-mentioned problems, 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), and has completed the present invention.

That is, the present invention provides the urea derivative represented by the following 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 a carbon in which one to four hydrogen atoms are each independently replaceable by a halogen atom or a hydroxyl group; Alkyl groups of 1 to 3, R ² represents a hydrogen atom, a halogen atom, a 4-pyridyl group, a 4-hydroxy-1-piperidinyl group, and 4 Olinyl, 3-oxo-1-piperidin , tetrahydro-4-piperidyl, (2-hydroxyethyl)(methyl)amine, (2-acetoxyethyl)(methyl)amine or R ⁴ -(CH ₂ ) _n -O-, or a phenyl group in which 1 to 3 hydrogen atoms are each independently substituted by a hydroxyl group or a methoxy group, R ³ represents a hydrogen atom or a halogen atom, n represents 0 or 1, and R ⁴ represents a methyl group, a phenyl group, N-Ethyl-3-indenyl, N-methylsulfonyl-3-indenyl or 3-oxinyl].

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

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

Further, in the urea derivative represented by the above formula (I), R ¹ is preferably a hydrogen atom or a methylol group, and R ² is a 4-pyridyl group or a 3-oxo-1-piped. Or R ⁴ O-, R ³ is a hydrogen atom or a fluorine atom, and R ⁴ is methyl, N-ethylindol-3-yl, N-methylsulfonyl-3-indenyl or 3-oxo呾基.

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

Further, in the urea derivative represented by the above formula (I), it is more preferred that R ¹ is a hydrogen atom or a methylol group, and R ² is a 4-pyridyl group or a 3-sideoxy-1-piperidyl group. Or R ⁴ O-, R ³ is a hydrogen atom or a fluorine atom, and R ⁴ is methyl, N-ethylindol-3-yl, N-methylsulfonyl-3-indenyl or 3-oxo呾 base, one of k and m is 1 and the other is 0.

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

Further, the present invention provides an inhibitor of DDR1 comprising the urea derivative represented by the above 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.

Form for implementing the invention

The urea derivative of the present invention is characterized 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 a carbon in which one to four hydrogen atoms are each independently replaceable by a halogen atom or a hydroxyl group; Alkyl groups of 1 to 3, R ² represents a hydrogen atom, a halogen atom, a 4-pyridyl group, a 4-hydroxy-1-piperidinyl group, and 4 Olinyl, 3-oxo-1-piperidin , tetrahydro-4-piperidyl, (2-hydroxyethyl)(methyl)amine, (2-acetoxyethyl)(methyl)amine or R ⁴ -(CH ₂ ) _n -O-, or a phenyl group in which 1 to 3 hydrogen atoms are each independently substituted by a hydroxyl group or a methoxy group, R ³ represents a hydrogen atom or a halogen atom, n represents 0 or 1, and R ⁴ represents a methyl group, a phenyl group, N-Ethyl-3-indenyl, N-methylsulfonyl-3-indenyl or 3-oxinyl].

The following terms used in the specification are as defined below unless otherwise specified.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "alkyl group having 1 to 3 carbon atoms" means methyl, ethyl, 1-propyl or isopropyl.

"Alkyl groups having 1 to 3 carbon atoms independently substituted by a halogen atom or a hydroxyl group" means that 1 to 4 hydrogen atoms of the above alkyl group having 1 to 3 carbon atoms are independently and independently The group which may be substituted by a halogen atom or a hydroxyl group may, for example, be a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 2-chloroethyl group, a 2,2,2-trifluoroethyl group or a 1-hydroxy group. Base or 2-hydroxyethyl.

The "phenyl group in which one to three hydrogen atoms may be independently substituted with a hydroxyl group or a methoxy group" means a group in which one to three hydrogen atoms of the phenyl group are independently independently substituted with a hydroxyl group or a methoxy group, for example, Listed: 2-hydroxyphenyl, 4-hydroxyphenyl or 4-methoxyphenyl.

Specific examples of the preferred compound of the urea derivative represented by the above formula (I) are shown in Table 1, but the present invention is not limited thereto.

The urea derivative represented by the above formula (I) (hereinafter, the urea derivative (I)) has an optical isomer or a non-image isomer, but includes not only a single isomer but also a foreign product. A mixture of polar and non-image isomers.

Further, the present invention contains a prodrug of the urea derivative (I) or a pharmacologically acceptable salt thereof. The urea derivative (I) is a compound which is converted to a urea derivative (I) in an enzyme form in vivo or chemically. The active bulk of the urea derivative (I) prodrug is the urea derivative (I), but the urea derivative (I) prodrug itself may be active.

As the prodrug of the urea derivative (I), for example, a compound in which the hydroxyl group of the urea derivative (I) is alkylated, phosphorylated or borated can be mentioned. These compounds can be synthesized from the urea derivative (I) by a known method.

Further, the urea derivative (I) may be a well-known document ("Development of Pharmaceutical Products", Hirokawa Shoten, 1990, Vol. 7, p. 163-198 and Progress in Medicine, Vol. 5, 1985 , p. 2157~2161) The physiological conditions described are converted into urea derivatives (I).

The urea derivative (I) may be identified by an isotope. For the identified isotope, for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁵ O, ¹⁸ O and/or ¹²⁵ I may be mentioned.

The "pharmacologically acceptable salt" of the urea derivative (I) may, for example, be a mineral acid such as a hydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide or a phosphate. Salt; or oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleic acid Salt, gluconate, benzoate, ascorbate, glutarate, mandelic acid, citrate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate, An organic acid salt of camphor sulfonate, aspartate, glutamate or cinnamate, but preferably hydrochloride, sulfate, hydrobromide, maleate, benzoate Acid salt or methanesulfonate.

The urea derivative (I) or a pharmacologically acceptable salt thereof may be an anhydride, and a solvate such as a hydrate or the like may be formed. Here, as the solvate, a pharmacologically acceptable solvate is preferred. The pharmacologically acceptable solvate is either a hydrate or a non-hydrate, but a hydrate is preferred. The solvent constituting the solvate may, for example, be an alcohol solvent such as methanol, ethanol or n-propanol, N,N-dimethylformamide, dimethylhydrazine or water.

The urea derivative (I) can be produced by a suitable method based on characteristics derived from the basic skeleton or the kind of the substituent. Further, the starting materials and reagents used in the manufacture of such compounds can be generally obtained or can be produced by a known method.

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

In the case where the urea derivative (I) contains an optical isomer or a stereoisomer, the respective isomers of the single compounds can be obtained by a known method. As the well-known method, for example, crystallization, enzymatic resolution, or palm chromatography can be cited.

In the reaction of the production method described below, when the raw material compound has a hydroxyl group, an amine group or a carboxyl group, a protecting group may be introduced into the group, and the target compound may be obtained by deprotecting the protective group after the reaction.

Examples of the protective group of the hydroxyl group include a trityl group, an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group) or a substituted nonyl group (for example). For example, trimethyldecyl, triethyldecyl or tert-butyldimethylmethylalkyl).

Examples of the protecting group of the amine group include an alkylcarbonyl group having 2 to 6 carbon atoms (for example, an ethyl fluorenyl group), a benzinyl group, and an alkoxycarbonyl group having 2 to 8 carbon atoms (for example, a tertiary butyl group). An oxycarbonyl group or a benzyloxycarbonyl group, an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group) or a fluorenyl group.

The protective group of the carboxyl group may, for example, be an alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group or a tertiary butyl group) or a carbon number 7 to 10 aralkyl group (for example, a benzyl group).

The deprotection of the protecting group varies depending on the type of the protecting group, but can be carried out by a known method (for example, Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method according thereto.

The urea derivative (I) can be obtained, for example, by the urea formation reaction of the aniline derivative (II) and the amino alcohol derivative (III) in the presence of a ureazing agent and a base, as shown in Scheme 1.

[wherein, R ¹ to R ³ are the same as defined above].

The above-described amino alcohol derivative (III) can be purchased as an optically active or racemic form as necessary. Moreover, it can also be manufactured by a known method or according to the method thereof.

Among the amino alcohol derivatives (III), a derivative in which k is 0 and m is 1 can be, for example, from the literature (Tetrahedron Letters, 1993, Vol. 34 (52), p. 8399-8402; Journal of Pharmaceutical Sciences, 1979, vol. 99 (11), p. 1111-1115; Tetrahedron: Asymmetry, 1995, vol. 6 (7), p. 1535-1538, etc.), manufactured by the method (Tetrahedron) : Asymmetry, 1995, Vol. 6 (7), p. 1535-1538, etc.) The optical resolution is carried out using an optically active acid, and an amine of an optically active substance can also be obtained. The optically active acid used herein may, for example, be a carboxylic acid such as lactic acid, tartaric acid, 2-phenylpropionic acid or mandelic acid; or an acidic amino acid such as glutamic acid or aspartic acid. Or a sulfonic acid such as camphorsulfonic acid, and an acid can be appropriately selected by the reaction of the compound, and a satisfactory result can be obtained.

The amount of the amino alcohol derivative (III) used in the urea conversion reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the aniline derivative (II).

Examples of the ureazing agent used in the urea-forming reaction include chloroformate such as 2,2,2-trichloroethyl chloroformate, phenyl chloroformate or p-nitrophenyl chloroformate. a derivative; triphosgene, phosgene, N,N'-carbonyldiimidazole or N,N'-disuccinimide carbonate, but preferably 2,2,2-trichloroethyl chloroformate, chlorine a chloroformate derivative such as phenyl formate or p-nitrophenyl chloroformate or triphosgene.

The amount of the ureazing agent used in the urea-forming reaction is preferably 0.1 to 100 equivalents, more preferably 0.3 to 30 equivalents, based on the aniline derivative (II).

Examples of the base used in the urea conversion reaction include an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium hydrogencarbonate or potassium carbonate; sodium hydride or potassium hydride or A hydrogenated metal compound such as calcium hydride; an alkyl lithium such as methyl lithium or butyl lithium; or amination of lithium hexamethyldisilazide or lithium diisopropylamide Lithium amide or a mixture thereof, but is preferably an organic base such as triethylamine or diisopropylethylamine.

The amount of the base used in the urea-forming reaction is preferably from 1 to 100 equivalents, more preferably from 2 to 30 equivalents, based on the aniline derivative (II).

The reaction solvent to be used in the urea-forming reaction can be appropriately selected depending on the type of the reagent to be used. However, the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include N,N-dimethylformamidine. An aprotic polar solvent such as amine, N,N-dimethylacetamide or dimethylhydrazine; diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-two An ether solvent such as an alkane; an ester solvent such as ethyl acetate or propyl acetate; a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane; or a nitrile solvent such as acetonitrile or propionitrile; The solvent mixture is preferably a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane or a nitrile solvent such as acetonitrile or propionitrile.

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

The reaction time of the urea-forming reaction can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.

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

The aniline derivative (II) used in the urealation reaction is commercially available, but it can also be produced by a known method.

The aniline derivative (II) is, for example, as shown in Scheme 2, and can be obtained by a reduction reaction of a nitrobenzene derivative (IV).

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

The reduction reaction may, for example, be a catalytic hydrogenation reaction in the presence of a metal catalyst such as palladium, nickel or platinum under a hydrogen atmosphere; using lithium aluminum hydride, boron hydride dimethyl sulfide complex or hydrogenation a hydride reduction reaction of a hydrogenation metal reagent such as a boron tetrahydrofuran complex; or a single electron reduction reaction using a metal catalyst such as zinc, iron or tin in the presence of an acid, but preferably in a hydrogen atmosphere A single-electron reduction reaction using a metal catalyst such as zinc, iron or tin in the presence of a catalytic hydrogenation reaction in the presence of a metal catalyst such as palladium, nickel or platinum or in the presence of an acid.

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

The amount of the metal catalyst used in the catalytic hydrogenation reaction is preferably 0.001 to 5 equivalents, more preferably 0.01 to 1 equivalent, based on the nitrobenzene derivative (IV).

The reaction solvent to be used in the catalytic hydrogenation reaction is appropriately selected depending on the type of the reagent to be used. However, the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include an alcohol solvent such as methanol or ethanol; a nitrile solvent such as acetonitrile or propionitrile; an aprotic polar solvent such as N,N-dimethylformamide or N,N-dimethylacetamide; diethyl ether, tetrahydrofuran, dimethoxy Ethane or 1,4-two An ether solvent such as an alkane; 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, preferably An alcohol solvent such as methanol or ethanol.

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

The reaction temperature of the catalytic hydrogenation reaction is preferably from 0 to 200 ° C, more preferably from 0 to 100 ° C.

The reaction time of the catalytic hydrogenation reaction can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 72 hours.

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

The metal catalyst used in the one-electron reduction reaction may, for example, be zinc, iron, tin or a halide thereof.

The amount of the metal catalyst used in the one-electron reduction reaction is preferably 0.1 to 100 equivalents, more preferably 1 to 50 equivalents, based on the nitrobenzene derivative (IV).

The reaction solvent to be used in the one-electron reduction reaction may be appropriately selected depending on the type of the reagent to be used. However, the reaction solvent is not particularly limited, and examples thereof include an acidic solvent such as hydrochloric acid or acetic acid; An alcohol solvent such as methanol or ethanol; a nitrile solvent such as acetonitrile or propionitrile; an aprotic polar solvent such as N,N-dimethylformamide or N,N-dimethylacetamide; Ether, tetrahydrofuran, dimethoxyethane or 1,4-two An ether solvent such as an alkane; 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, preferably An acidic solvent such as hydrochloric acid or acetic acid or an alcohol solvent such as methanol or ethanol.

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

The reaction time of the one-electron reduction reaction can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 72 hours.

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

Among the above nitrobenzene derivatives (IV), the nitrobenzene derivative (IVa) wherein R ¹ is a hydrogen atom is, for example, as shown in the scheme 3, and in the presence of a metal catalyst, 2-chloro- Coupling reaction of 5-pentafluorosulfanylnitrobenzene (V) with a boronic acid derivative (VI) derivative or a pinacolborane derivative (VII) or by 2-chloro-5-five The fluorosulfanylnitrobenzene (V) is obtained by a nucleophilic substitution reaction using a nucleophile (VIII).

[wherein R ² is as defined above, and R ⁵ each 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 a lithium atom].

The 2-chloro-5-pentafluorosulfanylnitrobenzene (V) used in the coupling reaction and the nucleophilic substitution reaction is commercially available. Moreover, it can also be manufactured by a known method or according to the method thereof.

The boric acid derivative (VI) and the pinacol borane derivative (VII) used in the coupling reaction are commercially available. Moreover, it can also be manufactured by a known method or according to the method thereof.

The amount of the boric acid derivative (VI) and the pinacol borane derivative (VII) used in the coupling reaction is 0.5 to 20 with respect to 2-chloro-5-pentafluorosulfanylnitrobenzene (V). The equivalent is preferably, and 1 to 3 equivalents are more preferred.

The metal catalyst used in the coupling reaction may, for example, be cerium triphenylphosphine palladium (0), ginseng (dibenzylideneacetone) dipalladium (0) or bis(dibenzylideneacetone)palladium. (0) A zero-valent palladium complex catalyst, etc., but preferably triphenylphosphine palladium (0).

The amount of the metal catalyst used in the coupling reaction is preferably 0.001 to 10 equivalents, more preferably 0.01 to 1 equivalent, based on the 2-chloro-5-pentafluorosulfanylnitrobenzene (V).

The coupling reaction can use a base as required. Examples of the base to be used include inorganic bases such as sodium hydroxide or sodium carbonate; metal alkoxides such as tertiary sodium butoxide or tertiary potassium butoxide; and carboxylic acids such as sodium acetate or potassium acetate. A salt or the like or an aqueous solution thereof is preferably an inorganic base such as sodium hydroxide or sodium carbonate or an aqueous solution thereof.

The amount of the base to be used in the coupling reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, based on the 2-chloro-5-pentafluorosulfanylnitrobenzene (V).

The reaction solvent to be used in the coupling reaction is appropriately selected depending on the type of the reagent to be used, and is not particularly limited as long as the reaction is not inhibited. For example, an aromatic hydrocarbon solvent such as benzene or toluene may be mentioned. An alcohol solvent such as methanol or ethanol; a nitrile solvent such as acetonitrile or propionitrile; or a non-N,N-dimethylformamide, N,N-dimethylacetamide or dimethylammonium Protic polar solvent; diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-two An ether solvent such as an alkane; 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, preferably An aromatic hydrocarbon solvent such as benzene or toluene, an alcohol solvent such as methanol or ethanol, or a mixed solvent thereof.

The reaction temperature of the coupling reaction is preferably from 0 to 300 ° C, more preferably from 20 to 200 ° C.

The reaction time of the coupling reaction can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 48 hours.

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

The nucleophile (VIII) used in the nucleophilic substitution reaction is commercially available. Moreover, it can also be manufactured by a known method or according to the method thereof.

The amount of the nucleophilic agent (VIII) used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents, preferably 1 to 3 equivalents based on 2-chloro-5-pentafluorosulfanylnitrobenzene (V). For better.

The nucleophilic substitution reaction system can use a base as required. The base to be used may, for example, be an inorganic base such as sodium hydride, sodium hydrogencarbonate or potassium carbonate; an organic base such as triethylamine, diisopropylethylamine or pyridine or a mixture thereof.

The amount of the base to be used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 3 equivalents, based on the 2-chloro-5-pentafluorosulfanylnitrobenzene (V).

The reaction solvent to be used for the nucleophilic substitution reaction is appropriately selected depending on the type of the reagent to be used. However, the reaction is not particularly limited as long as the reaction is not inhibited, and examples thereof include an alcohol solvent such as methanol or ethanol. a nitrile solvent such as acetonitrile or propionitrile; an aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethylhydrazine; diethyl ether , tetrahydrofuran, dimethoxyethane or 1,4-two An ether solvent such as an alkane; 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, preferably An alcohol solvent such as methanol or ethanol; an aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethylhydrazine; or diethyl ether, Tetrahydrofuran, dimethoxyethane or 1,4-two An ether solvent such as an alkane.

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 may be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 30 hours.

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

Among the above nitrobenzene derivatives (IV), the nitrobenzene derivative (IVb) wherein R ¹ is a methylol group is, for example, as shown in Scheme 4, and can be substituted by 3-methylindenyl-5-pentafluoro Obtained by a reduction reaction of a thioalkylnitrobenzene derivative (IX).

[wherein R ² is as defined above].

The reducing agent to be used in the reduction reaction may, for example, be an aluminum-based reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride or a boron-based reducing agent such as sodium borohydride or lithium borohydride. It is a boron-based reducing agent such as sodium borohydride or lithium borohydride.

The amount of the reducing agent used in the reduction reaction is preferably 0.2 to 20 equivalents, more preferably 1 to 10 equivalents, based on the 3-methylindolyl-5-pentafluorosulfanylnitrobenzene derivative (IX). good.

The reaction solvent to be used in the reduction reaction may be appropriately selected depending on the type of the reagent to be used. However, the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include methanol, ethanol, isopropanol or tertiary. An alcohol solvent such as butanol; an aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or dimethylhydrazine; diethyl ether, tetrahydrofuran, Dimethoxyethane or 1,4-two An ether solvent such as an alkane or a mixed solvent thereof, preferably an alcohol solvent such as methanol, ethanol, isopropyl or tributyl.

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

The reaction time of the reduction reaction can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 30 hours.

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

Among the above nitrobenzene derivatives (IV), the nitrobenzene derivative (IVc) wherein R ¹ is 2,2,2-trifluoro-1-hydroxyethyl is, for example, as shown in the scheme 5, It is obtained by the trifluoromethylation reaction of the above 3-methylindolyl-5-pentafluorosulfanylnitrobenzene derivative (IX).

[wherein R ² is as defined above].

The trifluoromethylating agent to be used in the trifluoromethylation reaction may, for example, be a trifluoromethyl bromide or a trimethyl(trifluoromethyl)decane, but is preferably a trimethyl group (three Fluoromethyl) decane.

The amount of the trifluoromethylating agent used in the trifluoromethylation reaction is preferably 0.5 to 10 equivalents based on the 3-methylindolyl-5-pentafluorosulfanylnitrobenzene derivative (IX). 0.5 to 5 equivalents is more preferred.

The trifluoromethylation reaction can be carried out using fluoride salts as required. As the fluoride salt to be used, for example, sodium fluoride or fluorine can be cited. An alkali metal salt such as potassium or an ammonium salt such as tetramethylammonium fluoride or tetra-n-butylammonium fluoride is preferred, but an ammonium salt such as tetra-n-butylammonium fluoride is preferred.

The amount of the fluoride salt used in the trifluoromethylation reaction is preferably 0.01 to 2 equivalents based on the 3-methylindolyl-5-pentafluorosulfanylnitrobenzene derivative (IX), 0.05~. 1 equivalent is more preferred.

The reaction solvent to be used in the trifluoromethylation reaction can be appropriately selected depending on the type of the reagent to be used. However, the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran and 1,4-diene. An ether solvent such as an alkane or ethylene glycol dimethyl ether; an aromatic hydrocarbon solvent such as benzene or toluene; or a mixed solvent thereof, preferably tetrahydrofuran or 1,4-di An ether solvent such as an alkane or ethylene glycol dimethyl ether.

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 can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably 30 minutes to 30 hours.

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

The above nitrobenzene derivative (IV) can be obtained, for example, by the nitration reaction of the 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 to be used in the nitration reaction include nitric acid such as concentrated nitric acid or fuming nitric acid or nitrium salt such as nitrium tetrafluoroborate, but it is preferably concentrated. Nitric acid such as nitric acid or fuming nitric acid.

The amount of the nitrating agent to be used in the nitration reaction is preferably 0.5 to 20 equivalents, more preferably 0.5 to 10 equivalents, based on the pentafluorosulfanylbenzene derivative (X).

The reaction solvent to be used for the nitration reaction is appropriately selected depending on the type of the reagent to be used. However, the reaction solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include an acid solvent such as concentrated sulfuric acid or acetic anhydride. Further, it is a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane, but is preferably an acid solvent such as concentrated sulfuric acid or acetic anhydride.

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 can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 72 hours.

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

Among the above-mentioned pentafluorosulfanylbenzene derivatives (X), R ¹ is a methyl group and R ² is a methoxy group of 3-methylindenyl-2-methoxy-5-pentafluorosulfanyl nitrate The benzene (Xa) is obtained, for example, as shown in Scheme 7, in the presence of an acid by a mercaptolation reaction of 4-pentafluorosulfanylanisole (XI).

4-pentafluorosulfanylanisole (XI) used in the methylation reaction is commercially available. Moreover, it can also be manufactured by a known method or according to the method thereof.

The mercapto grouping agent used for the methylation reaction may, for example, be a dihalomethylalkyl group such as dichloromethyl methyl ether, dichloromethyl ethyl ether or dichloromethyl isopropyl ether. An ether derivative or a formamide derivative such as dimethylformamide or N-methylmercaptopiperidine, but preferably dichloromethyl methyl ether, dichloromethyl ethyl ether or dichloromethyl A dihalomethyl alkyl ether derivative such as isopropyl ether.

The amount of the formazylating agent to be used in the methylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, based on the 4-pentafluorosulfanylanisole (XI).

Examples of the acid used in the methylation reaction include Lewis acid such as aluminum trichloride, tin tetrachloride, titanium tetrachloride or boron trifluoride or phosphorus oxychloride or oxybromination. A phosphorus compound such as phosphorus, but preferably a Lewis acid such as aluminum trichloride, tin tetrachloride, titanium tetrachloride or boron trifluoride.

The amount of the acid used in the methylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, based on the 4-pentafluorosulfanylanisole (XI).

The reaction solvent to be used for the methylation reaction may be appropriately selected depending on the type of the reagent to be used. However, the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include dichloromethane, chloroform and 1, a halogen-based solvent such as 2-dichloroethane or carbon tetrachloride; or tetrahydrofuran, diethyl ether, 1,4-two An ether solvent such as an alkane or ethylene glycol dimethyl ether, preferably a halogen-based solvent such as dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride.

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

Although the reaction time of the thiolation reaction can be appropriately selected depending on the conditions such as the reaction temperature, it is preferably from 10 minutes to 30 hours.

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

The nitrobenzene derivative (XIII) is, for example, as shown in Scheme 8, which can be obtained by the above 3-methylindol-5-pentafluorosulfanylnitrobenzene derivative (IX) and 3-aminopyrrolidine. Obtained by the amination reaction of the derivative (XII).

[wherein, PG represents a protecting group, and R ² is as defined above].

The amount of the 3-aminopyrrolidine derivative (XII) used in the reduction amination reaction is based on the above 3-methylindolyl-5-pentafluorosulfanylnitrobenzene derivative (IX). 0.5 to 10 equivalents are preferred, and 1 to 3 equivalents are more preferred.

The reducing agent used in the reduction amination reaction may, for example, be lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. However, sodium triethoxy borohydride is preferred.

The amount of the reducing agent to be used in the reduction amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, based on the 3-aminopyrrolidine derivative (XII).

The reaction solvent to be used for the reduction of the amination reaction is appropriately selected depending on the type of the reducing agent to be used. However, the reaction is not particularly limited as long as the reaction is not inhibited, and examples thereof include an alcohol system such as methanol or ethanol. Solvent; diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-two An ether solvent such as an alkane; a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane; or a mixed solvent thereof, preferably an alcohol solvent such as methanol or ethanol.

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

The reaction time of the reduced amination reaction can be appropriately selected depending on the conditions such as the reaction temperature, but it is preferably from 1 to 30 hours.

The concentration at the start of the reaction of the 3-aminopyrrolidine derivative (XII) used in the reduction amination 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.

The "inhibitor of DDR1" means a compound which inhibits the kinase activity of DDR1.

Since the urea derivative (I) or a pharmacologically acceptable salt thereof has a DDR1 inhibitory activity, it can be expected as a therapeutic drug for a disease in which an improvement in symptoms or a symptom can be expected based on the action mechanism, for example, cancer.

"Cancer" refers to, for example, pharyngeal cancer, laryngeal cancer, tongue cancer, non-small cell lung cancer, breast cancer, esophageal cancer, gastric cancer, colon cancer, uterine cancer, endometrial cancer, ovarian cancer, liver cancer, pancreatic cancer. , biliary cancer, cholangiocarcinoma, renal pelvic cancer, pelvic ureteral cancer, bladder cancer, prostate cancer, malignant melanoma, thyroid cancer, neuroosteosarcoma, chondrosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, glioma, leukemia or Malignant lymphoma, neuroblastoma, myeloma or brain tumor.

The urea derivative (I) or a pharmacologically acceptable salt thereof having a DDR1 inhibitory activity can be evaluated using an in vitro test. For the in vitro test, for example, a method for evaluating the activity of DDR1 kinase by quantitatively phosphorylating the base 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, as a method for evaluating the kinase activity of DDR1, for example, a method in which a purified protein of an intracellular domain of DDR1, a matrix peptide, and ATP are mixed and reacted, and a phosphorylated matrix peptide is quantified is exemplified. . Be Phosphorylated matrix peptides can be quantified, for example, by measurement using fluorescence resonance energy transfer using a matrix peptide previously identified by biotin or a fluorescent substance.

[Examples]

Hereinafter, the present invention will be described in detail using examples and reference examples, but the invention is not limited thereto.

Further, as for the compound used in the synthesis of the compound of the example, there is no synthetic method, and a commercially available compound is used. The solvent name shown in the NMR data indicates the solvent used for the measurement. Further, the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (Japan Electronics Co., Ltd.) or a JNM-ECS400 type nuclear magnetic resonance apparatus (Japan Electronics Co., Ltd.). The chemical shift is based on tetramethyl decane and expressed in δ (unit: ppm). The signal is s (single peak), d (double peak), t (triplet), q (quadruple), m. (Multiple peaks), br (wide peaks), dd (double doublets), dt (double triplets), ddd (double double doublets), dq (double quadruple peaks) or tt (triple triplets). The ESI-MS spectrum was measured using an Agilent Technologies 1200 series, G6130A (manufactured by Agilent Technologies). All of the solvents are commercially available. The rapid chromatography system uses YFLC W-prep2XY (Shanshan Company). Monowave 300 manufactured by Anton Paar Co., Ltd. was used for the microwave synthesizing apparatus.

The raw material and intermediate system of the urea derivative (I) were synthesized by the methods described in the following Reference Examples. Further, as for the compound used in the synthesis of the reference compound, there is no synthetic method, and a commercially available compound is used.

(Reference Example 1) Synthesis of phenyl 5-pentafluorosulfanylphenylcarbamate:

3-Pentafluorosulfanylaniline (438 mg, 2.00 mmol) was dissolved in tetrahydrofuran (5 mL), and sodium hydrogencarbonate (252 mg, 3.00 mmol) and phenyl chloroformate (251 μL, 2.00 mmol) were added. After stirring at room temperature for 16 hours, 1 M hydrochloric acid was added to the mixture and acidified, and ethyl acetate. The organic layer was dried with EtOAc EtOAcjjjjjjjjjj

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).

(Example 1) Synthesis of 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(3-pentafluorosulfanylphenyl)urea :

Add (1R,2S)-1-amino-2-hydrofurfuryl alcohol (indanol) to a solution of phenyl 5-pentafluorosulfanylphenylcarbamate (290 mg, 0.816 mmol) in tetrahydrofuran (5 mL) (121 mg , 0.816 mmol), triethylamine (455 μL, 3.26 mmol). After heating to reflux for 2 hours, it was cooled to room temperature. A saturated aqueous solution of ammonium chloride was added to the mixture and the mixture was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated to give crude The product was purified by silica gel column chromatography (EtOAc) elute

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, 5.2 Hz), 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.

(Reference Example 2) Synthesis of 2-chloro-5-pentafluorosulfanylnitrobenzene:

To a suspension of 4-pentafluorosulfanylchlorobenzene (5.00 g, 21.0 mmol) in concentrated sulfuric acid (10 mL) was added EtOAc (10 mL). After stirring at room temperature for 18 hours, ice was added to the mixture and extracted with chloroform. The title compound (5.94 g) was obtained.

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).

(Reference Example 3) Synthesis of 2-methoxy-5-pentafluorosulfanylnitrobenzene:

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). After stirring at room temperature for 2 hours, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium

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 = 2.7Hz).

MS (ESI) [M+H] ⁺ : 280.

(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% by weight of palladium-carbon (50% by weight aqueous, 50 mg) in ethanol (3 mL). After stirring at room temperature for 5 hours under a hydrogen atmosphere, the catalyst was filtered. The residue was washed with EtOAc (EtOAc m.

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.

(Example 2) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(2-methoxy-5-pentafluorosulfanyl Synthesis of phenyl)urea:

Add triphosgene (47.0 mg, 0.158 mmol), triethylamine (66 μL) to a solution of 2-methoxy-5-pentafluorosulfanylaniline (118 mg, 0.470 mmol) in dichloromethane (3 mL). , 0.47 mmol), and stirred for 1 hour. Next, (1R,2S)-1-amino-2-hydrofurfuryl alcohol (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 solution of ammonium chloride was added to the mixture. The organic layer was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjjjjj ).

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 = 9.0 Hz), 7.05 (1H, brs), 7.35-7.40 (2H, m), 8.75 (1H, d, J = 2.7 Hz).

MS (ESI) [M+H] ⁺ : 425.

(Example 3) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(2-methoxy-5-pentafluorosulfanyl Synthesis of phenyl)urea:

To a solution of 2-methoxy-5-pentafluorosulfanylaniline (546 mg, 2.19 mmol) in dichloromethane (20 mL), EtOAc (EtOAc) 1.08 mmol) and stirred for 1 hour. Next, (1S,2R)-2-amino-1-hydrofurfuryl alcohol (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 solution of ammonium chloride was added to the mixture. The organic layer was dried over anhydrous sodium sulfate (MgSO4), EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .

^{1 H-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 , 7.3 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, [MH] ^- :423.

(Reference Example 5) Synthesis of 2-phenoxy-5-pentafluorosulfanylnitrobenzene:

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), and the mixture was stirred for 30 minutes, then 2-chloro-5-pentafluorobenzene was added. Sulfur-alkyl nitrate Base benzene (283 mg, 1.00 mmol). After stirring at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium

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.

(Reference Example 6) Synthesis of 2-phenoxy-5-pentafluorosulfanylaniline:

The title compound (287 mg) was obtained from m. m.

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.

(Example 4) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(3-pentafluorosulfanyl-6-phenoxy Synthesis of phenyl)urea:

The title compound (hereinafter, the compound of Example 4) was obtained as a pale yellow amorphous form from 2-phenoxy-5-pentafluorosulfanylaniline (286 mg, 0.920 mmol). 361mg).

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.

(Reference Example 7) Synthesis of 3-pentafluorosulfanyl-6-phenylnitrobenzene:

2-Chloro-5-pentafluorosulfanylnitrobenzene (100 mg, 0.353 mmol), triphenylphosphine palladium (0) (12.2 mg, 0.0106 mmol), phenylboronic acid (55.9 mg, 0.458 mmol) To a solution of toluene (1.9 mL), ethanol (0.3 mL) and a 2M sodium carbonate aqueous solution (1.9 mL) were added. After stirring at 100 ° C for 15 hours, the reaction mixture was allowed to cool and liquid-separated. The organic layer was washed with brine, dried, evaporated, evaporated, evaporated .

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).

(Reference Example 8) Synthesis of 3-pentafluorosulfanyl-6-phenylaniline:

The title compound (85 mg) was obtained from m.j.

¹ H-NMR (400 MHz, 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 9) Synthesis of 2-pentafluorosulfanyl-6-phenylaminocarbamic acid 2,2,2-trichloroethyl ester:

Diisopropylethylamine (75 μL, 0.43 mmol), chloroformic acid 2, 2 was added to a solution of 3-pentafluorosulfanyl-6-phenylaniline (85.0 mg, 0.288 mmol) in tetrahydrofuran (1.0 mL). , 2-trichloroethyl ester (51 μL, 0.37 mmol). After stirring at room temperature for 17 hours, water was added to the mixture and extracted with ethyl acetate. After washing the organic layer with saturated brine, drying and concentrating, the obtained crude product was chromatographed on a silica gel column. Purification of the title compound (124 mg)

^{1 H-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°C.

(Example 5) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(3-pentafluorosulfanyl-6-phenylbenzene Synthesis of urea

Add diisopropylethylamine to a solution of 2,2,2-trichloroethyl 3-pentafluorosulfanyl-6-phenylcarbamate (60.0 mg, 0.127 mmol) in acetonitrile (1.0 mL) (44 μL, 0.25 mmol), (1R, 2S)-1-amino-2-hydrofurfuryl alcohol (30.4 mg, 0.191 mmol). After stirring at 80 ° C for 14 hours, the reaction mixture was cooled and extracted with ethyl acetate. The organic layer was washed successively with 1 M hydrochloric acid and brine, dried, and concentrated, and the obtained crude product was purified by silica gel column chromatography (chloroform/methanol) by using diethyl ether. The title compound (hereinafter, the compound of Example 5) (40.2 mg) was obtained 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.

Mp226.3-228.6 °C.

(Reference Example 10) Synthesis of 2-(4-methoxyphenyl)-5-pentafluorosulfanylnitrobenzene:

Obtained as a yellow solid from 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) and 4-methoxyphenylboronic acid (209 mg, 1.38 mmol). The title compound (314 mg).

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).

Mp83.6-84.2°C.

(Reference Example 11) Synthesis of 2-(4-methoxyphenyl)-5-pentafluorosulfanylaniline:

The title compound (268 mg) was obtained from m.

¹ H-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°C.

(Reference Example 12) Synthesis of 2,2,2-trichloroethyl 2-(4-methoxyphenyl)-5-pentafluorosulfanylphenylcarbamate:

The title compound (434 mg) was obtained from m.

¹ H-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, 2.3 Hz), 8.58 (1H, s).

Mp85.8-95.2°C.

(Example 6) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(2-(4-methoxyphenyl)-5 Synthesis of -pentafluorosulfanylphenyl)urea:

2,2,2-trichloroethyl 2-(4-methoxyphenyl)-5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.150 mmol) in the same manner as in Example 5. The title compound (hereinafter, the compound of Example 6) (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, 5.0 Hz), 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.

Mp220.5-222.0 °C.

(Example 7) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(2-(4-methoxyphenyl)-5 Synthesis of -pentafluorosulfanylphenyl)urea:

a solution of 2,2,2-trichloroethyl 2-(4-methoxyphenyl)-5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.150 mmol) in EtOAc (1 mL) Add diisopropylethylamine (52 μL, 0.30 mmol), (1S, 2R)-2- Amino-1-hydrofurfuryl alcohol (33.5 mg, 0.225 mmol). After stirring at 100 ° C for 22 hours, the reaction mixture was cooled and extracted with EtOAc. The organic layer was washed with 1 M hydrochloric acid and brine, and dried, and then evaporated, and the obtained crude product was purified by silica gel column chromatography (chloroform/methanol) to give the title compound as colorless solid. Compound of Example 7) (69.4 mg).

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 (3H, s) , 4.39 (1H, dt, J = 7.4, 5.6 Hz), 4.96 (1H, 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 = 8.5 Hz), 7.49 (1H, dd, J = 8.5, 2.4 Hz), 8.54 (1H, d, J = 2.4 Hz).

MS (ESI) [MH] ^- :499.

Mp185.5-187.1 °C.

(Reference Example 13) Synthesis of 2,2,2-trichloroethyl 2-(4-hydroxyphenyl)-5-pentafluorosulfanylphenylcarbamic acid:

a solution of 2,2,2-trichloroethyl 2-(4-methoxyphenyl)-5-pentafluorosulfanylphenylcarbamate (160 mg, 0.320 mmol) in dichloromethane (1.5 mL) Cool to -78 °C. Boron tribromide (1.0 M dichloromethane solution, 1.1 mL, 1.1 mmol) was added and stirred under ice cold for 2 hr. After the reaction mixture was again cooled to -78 ° C, methanol and water were added in that order. Mix the reaction After warming to room temperature, the mixture was extracted with dichloromethane. The organic layer was washed with EtOAc EtOAc EtOAc.

^{1 H-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 = 8.3 Hz), 7.55 (1H, dd, J = 8.5, 2.2 Hz), 8.58 (1H, s).

MS (ESI) [M+H] ⁺ : 486.

Mp181.3-182.6°C.

(Example 8) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(2-(4-hydroxyphenyl)-5-f Synthesis of fluorosulfanylphenyl)urea:

2,2,2-trichloroethyl 2-(4-hydroxyphenyl)-5-pentafluorosulfanylphenylcarbamate (75.0 mg, 0.154 mmol), in the same manner as in Example 5 The title compound (hereinafter, the compound of Example 8) (75 mg) was obtained as a colorless crystal.

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.

(Reference Example 14) Synthesis of 2-(4-pyridyl)-5-pentafluorosulfanylnitrobenzene:

Obtained as a black oil from 2-chloro-5-pentafluorosulfanyl nitrobenzene (500 mg, 1.76 mmol) and 4-pyridylboronic acid (325 mg, 2.64 mmol). The title compound (56.6 mg).

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.

(Reference Example 15) Synthesis of 2-(4-pyridyl)-5-pentafluorosulfanylaniline:

The title compound (64.8 mg) was obtained from m.

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.

(Reference Example 16) Synthesis of 2,2,2-trichloroethyl 2-(4-pyridyl)-5-pentafluorosulfanylphenylcarbamic acid:

The title compound (31.7 mg) was obtained from m.

^{1 H-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°C.

(Example 9) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(2-(4-pyridyl)-5-pentafluoro Synthesis of thioalkylphenyl)urea:

Obtained from 2,2,2-trichloroethyl 2-(4-pyridyl)-5-pentafluorosulfanylphenylcarbamate (15.0 mg, 0.0320 mmol) in the same manner as in Example 5. 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, 5.0 Hz), 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.

Mp227.9-229.3 °C.

(Example 10) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(2-(4-pyridyl)-5-pentafluoro Synthesis of thioalkylphenyl)urea:

Obtained from 2,2,2-trichloroethyl 2-(4-pyridyl)-5-pentafluorosulfanylphenylcarbamate (15.0 mg, 0.0320 mmol) in the same manner as in Example 7. 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 (1H, m), 4.96 (1H, d, J = 5.4 Hz), 7.20-7.25 (3H, m), 7.41 (2H, 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.

Mp237.4-238.1°C.

(Reference Example 17) Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylnitrobenzene:

2-Chloro-5-pentafluorosulfanylnitrobenzene (500 mg, 1.76 mmol), triphenylphosphine palladium (0) (102 mg, 0.0883 mmol), 3,6-dihydro-2H-pyran- To a solution of 4-boronic acid decyl alcohol (481 mg, 2.29 mmol) in toluene (9 mL), EtOAc (EtOAc) After stirring at 100 ° C for 20 hours, the reaction mixture was allowed to cool and liquid-separated. The organic layer was washed with brine, dried, evaporated, evaporated.

^{1 H-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 = 2.8 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.

(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) mL), water (2.8mL), ammonium chloride (457mg, 8.54mmol), iron Powder (1.91 g, 34.1 mmol). 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 cooled and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine, and then evaporated and evaporated. (256mg).

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 =2.8Hz), 5.87-5.89 (1H, m), 7.07 (3H, m).

MS (ESI) [M+H] ⁺ : 302.

Mp133.6-137.2 °C.

(Reference Example 19) Synthesis of 2,2,2-trichloroethyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylphenylcarbamate:

In the same manner as in Reference Example 9, from 2-(3,6-dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylaniline (250 mg, 0.830 mmol), as a colorless solid. The title compound (333 mg).

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 (1H, dd, J = 8.5, 2.2 Hz), 8.49 (1H) , s).

MS (ESI) [M+H] ⁺ :476.

Mp153.9-156.0 °C.

(Reference Example 20) 1-(2-(3,6-Dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylphenyl)-3-((1R,2S)-2- Synthesis of hydroxy-2,3-dihydro-1H-indol-1-yl)urea:

2,2,2-trichloroethyl 2-(3,6-dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylcarbamate as in the same manner as in Example 5. (150 mg, 0.315 mmol).

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.

Mp208.8-211.1°C.

(Example 11) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(5-pentafluorosulfanyl-2-(tetrahydro) Synthesis of -2H-piperidin-4-yl)phenyl)urea:

In 1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylphenyl)-3-((1R,2S)-2-hydroxy-2, 3-Dihydro-1H-indol-1-yl)urea (60.0 mg, 0.126 mmol) in methanol (4.0 mL), 10% by weight of palladium-carbon (50% by weight aqueous, 12 mg) in a hydrogen atmosphere Stir at room temperature for 2 hours. After filtering the catalyst, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (chloroform/methanol) with diethyl ether/cyclohexane (1/1). The slurry was washed to give the title compound (yield compound of Example 11) (47.6 mg).

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=8.3,5.1Hz), 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, 2.4Hz), 7.96 (1H, d, J = 2.4Hz).

MS (ESI) [M+H] ⁺ : 479.

(Reference Example 21) 1-(2-(3,6-Dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylphenyl)-3-((1S,2R)-1- Synthesis of hydroxy-2,3-dihydro-1H-indol-2-yl)urea:

2,2,2-trichloroethyl 2-(3,6-dihydro-2H-piperazin-4-yl)-5-pentafluorosulfanylcarbamate was used in the same manner as in Example 7. (150 mg, 0.315 mmol).

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 (1H, d, J = 2.4 Hz).

MS (ESI) [MH] ^- : 475.

Mp200.1-202.0 °C.

(Example 12) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(5-pentafluorosulfanyl-2-(tetrahydro) Synthesis of -2H-piperidin-4-yl)phenyl)urea:

In the same manner as in Example 11, from 1-(2-(3,6-dihydro-2H-pyran-4-yl)-5-pentafluorosulfanylphenyl)-3-((1S, 2R)-1-Hydroxy-2,3-dihydro-1H-indol-2-yl)urea (60.0 mg, 0.126 mmol) afforded the title compound (m. ).

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 =2.4Hz).

MS (ESI) [MH] ^- : 477.

Mp219.9-221.9 °C.

(Reference Example 22) Synthesis of 2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanylnitrobenzene:

Add 3-ethylamine (221 μL, 1.59 mmol), 4-hydroxypiperidine to a solution of 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) in dimethylhydrazine (2 mL) (139 mg, 1.38 mmol). After stirring at 50 ° C for 4 hours, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried, evaporated, evaporated, evaporated

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.

Mp96.9-98.4°C.

(Reference Example 23) Synthesis of 2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanylaniline:

The title compound was obtained as a red amorphous material from (2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanyl nitrobenzene (345 mg, 0.991 mmol). 314mg).

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 = 9.0 Hz), 7.08-7.11 (2H, m).

MS (ESI) [M+H] ⁺ : 319.

(Reference Example 24) Synthesis of (2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanylphenyl)carbamic acid 2,2,2-trichloroethyl ester:

The title compound (390 mg) was obtained as a pale red amorphous material from 2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanylaniline (314 mg, 0.986 mmol). ).

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.

(Example 13) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(2-(4-hydroxypiperidin-1-yl) Synthesis of 5-5-pentafluorosulfanylphenyl)urea:

In the same manner as in Example 5, 2,2,2-trichloroethyl (2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanylphenyl)carbamate (190 mg) The title compound (hereinafter, the compound of Example 13) (134 mg) was obtained as a colorless amorphous material.

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.

(Example 14) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(2-(4-hydroxypiperidin-1-yl) Synthesis of 5-5-pentafluorosulfanylphenyl)urea:

In the same manner as in Example 7, 2,2,2-trichloroethyl (2-(4-hydroxypiperidin-1-yl)-5-pentafluorosulfanylphenyl)carbamate (190 mg) The title compound (hereinafter, the compound of Example 14) (163 mg) was obtained as a colorless amorphous material.

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 (1H, m), 4.46 (1H, dt, J = 7.6, 5.6 Hz), 5.02 (1H, d, J = 5.4 Hz), 7.23 - 7.28 (4H, m), 7.37 (1H, dd, J = 8.8, 2.7 Hz), 7.42 (1H, d, J = 6.8 Hz), 8.57 (1H, d, J = 2.7 Hz).

MS (ESI) [M+H] ⁺ : 494.

(Reference Example 25) 2-( Synthesis of phenyl-4-yl)-5-pentafluorosulfanylnitrobenzene:

In the same manner as in Reference Example 22, from 2-chloro-5-pentafluorosulfanylnitrobenzene (100 mg, 0.353 mmol) and The title compound (118 mg) was obtained.

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.

(Reference Example 26) 2-( Synthesis of phenyl-4-yl)-5-pentafluorosulfanylaniline:

According to the same method as Reference Example 4, from 2-( The title compound (95.3 mg) was obtained as a colorless solid.

^{1 H-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 = 8.5 Hz), 7.12 (2H, dt, J = 10.1, 3.5 Hz).

MS (ESI) [M+H] ⁺ : 305.

Mp152.8-155.0 °C.

(Reference Example 27) (5-pentafluorosulfanyl-2-() Synthesis of 2,2,2-trichloroethyl ester of phenyl-4-yl)phenyl)carbamic acid:

In the same manner as in Reference Example 9, from 2-( The title compound (146 mg) was obtained as a colorless solid.

^{1 H-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 = 8.8 Hz), 7.49 (1H, dd, J = 8.8, 2.7 Hz), 7.88 (1H, s), 8.53 (1H, s).

MS (ESI) [M+H] ⁺ : 479.

Mp103.3-105.4°C.

(Example 15) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(5-pentafluorosulfanyl-2-() Synthesis of phenyl-4-yl)phenyl)urea:

In the same manner as in Example 5, from (5-pentafluorosulfanyl-2-() To the title compound (hereinafter, the compound of Example 15) (115 mg) was obtained as a colorless solid.

^{1 H-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, 5.2 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.

Mp192.6-194.0 °C.

(Example 16) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(5-pentafluorosulfanyl-2-() Synthesis of phenyl-4-yl)phenyl)urea:

In the same manner as in Example 7, from (5-pentafluorosulfanyl-2-() The title compound (hereinafter, the compound of Example 16) (145 mg) was obtained as a colorless crystals of the title compound (1,2,2-dichloroethyl ester).

^{1 H-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, 7.2 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 = 2.7Hz).

MS (ESI) [M+H] ⁺ : 480.

(Reference Example 28) 2-(3- side oxygen piperazine Synthesis of -1-yl)-5-pentafluorosulfanylnitrobenzene:

The same procedure as in Reference Example 22, from 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) and 2-piper The ketone (138 mg, 1.38 mmol The obtained crude product was not further purified, and the next step was carried out.

^{1 H-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 = 9.0 Hz), 7.86 (1H, dd, J = 9.0, 2.7 Hz), 8.26 (1H, d, J = 2.7 Hz).

MS (ESI) [M+H] ⁺ : 248.

(Reference Example 29) 2-(3- side oxygen piperazine Synthesis of -1-yl)-5-pentafluorosulfanylaniline:

According to the same method as Reference Example 4, from 2-(3-oxopiperidin) -1-yl)-5-pentafluorosulfanyl nitrobenzene (345 mg, 0.993 mmol) gave the title compound (353 mg). The obtained crude product was not further purified, and the next step was carried out.

^{1 H-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 = 8.8 Hz), 7.27 (1H, dd, J = 8.8, 2.7 Hz), 7.48 (1H, d, J = 2.7 Hz), 7.93 (1H, s), 8.27 (1H, s), 8.80 ( 1H, d, J = 1.7Hz).

(Reference Example 30) 2-(3- side oxygen piperazine Synthesis of -2-yl)-5-pentafluorosulfanylphenylaminocarbamic acid 2,2,2-trichloroethyl ester:

In the same manner as in Reference Example 9, from 2-(3-oxopiperidin) -1-yl)-5-pentafluorosulfanylaniline (353 mg, 1.11 mmol) gave the title compound (152 mg).

^{1 H-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 = 8.8 Hz), 7.51 (1H, dd, J = 8.9, 206 Hz), 7.74 (1H, s), 8.58 (1H, s).

MS (ESI) [M+H] ⁺ : 492.

(Example 17) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-3-(5-pentafluorosulfanyl-2-(3- Side oxygen piperazine Synthesis of -1-yl)phenyl)urea:

In the same manner as in Example 5, from 2-(3-oxopiperidin) 2-(1)-5-pentafluorosulfanylphenylaminocarbamic acid 2,2,2-trichloroethyl ester (75.0 mg, 0.152 mmol) afforded the title compound (yield Compound) (32.3 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, d, J = 15.9 Hz), 3.04-3.14 (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 (1H, d, J = 3.9 Hz), 7.18-7.25 (4H, m), 7.29 (1H, 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.

Mp245.3-246.9 °C.

(Example 18) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(5-pentafluorosulfanyl-2-(3- Side oxygen piperazine Synthesis of -1-yl)phenyl)urea:

In the same manner as in Example 7, from 2-(3-oxopiperidin) 2,2,2-trichloroethyl ester (75.0 mg, 0.152 mmol), mp. Compound) (39.5 mg).

^{1 H-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 = 5.4 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) [MH] ^- : 491.

Mp222.5-240.0 °C.

(Reference Example 31) Synthesis of 2-(oxaindole-3-yloxy)-5-pentafluorosulfanylnitrobenzene:

To a solution of oxetanol (94.0 mg, 1.27 mmol) in tetrahydrofuran (1 mL), sodium hydride (55% by weight in mineral oil, 69.2 mg, 1.59 mmol). After stirring at room temperature for 30 minutes, 2-chloro-5-pentafluorosulfanylnitrobenzene (300 mg, 1.06 mmol) was added to the mixture. After stirring at room temperature for 4 hours, water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc. The obtained crude product was not further purified, and the next step was carried out.

¹ H-NMR (400 MHz, CD ₃ OD) 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 = 9.1 Hz), 8.04 (1H, dd, J = 9.1, 2.8 Hz), 8.39 (1H, d, J = 2.8 Hz).

MS (ESI) [M + H ] +: 322.

(Reference Example 32) Synthesis of 2-(oxaindole-3-yloxy)-5-pentafluorosulfanylaniline:

The title compound was obtained as a brown oil (yield (yield (yield) 305mg).

^{1 H-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 = 8.8 Hz), 7.05 (1H, dd, J = 8.8, 2.7 Hz), 7.12 (1H, d, J = 2.7 Hz).

MS (ESI) [M+H] ⁺ : 292.

(Reference Example 33) Synthesis of 2,2,2-trichloroethyl 2-(oxaindole-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid:

The title compound (318 mg) was obtained from m.

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 (1H, s).

MS (ESI) [M+H] ⁺ : 466.

Mp167.0-169.0°C.

(Example 19) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(5-pentafluorosulfanyl-2-(oxonium) Synthesis of -3-yloxy)phenyl)urea:

2,2,2-trichloroethyl 2-(oxaindole-3-yloxy)-5-pentafluorosulfanylphenylcarbamate (150 mg, 0.321 mmol) in the same manner as in Example 5. 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.

Mp112.9-119.8°C.

(Example 20) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(5-pentafluorosulfanyl-2-(oxonium) Synthesis of -3-yloxy)phenyl)urea:

2,2,2-trichloroethyl 2-(oxaindole-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid was used in the same manner as in Example 7. (150 mg, 0.321 mmol), m.

^{1 H-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, 4.8 Hz), 4.91-4.98 (3H, 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) [MH] ^- : 465.

Mp239.0-241.5 °C.

(Reference Example 34) Synthesis of 2-(oxaindole-3-ylmethoxy)-5-pentafluorosulfanylnitrobenzene:

Obtained as an orange oil from 2-chloro-5-pentafluorosulfanyl nitrobenzene (300 mg, 1.06 mmol) and 3-oxoethanol (112 mg, 1.27 mmol). The title compound (357 mg).

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.

(Reference Example 35) Synthesis of 2-(oxaindole-3-ylmethoxy)-5-pentafluorosulfanylaniline:

The title compound was obtained as a purple solid (354 mg, m. ).

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.

(Reference Example 36) Synthesis of 2,2,2-trichloroethyl 2-(oxaindole-3-ylmethoxy)-5-pentafluorosulfanylphenylcarbamic acid:

The title compound (378 mg) was obtained from m.

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.

Mp130.4-133.3 °C.

(Example 21) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(5-pentafluorosulfanyl-2-(oxindole) Synthesis of -3-ylmethoxy)phenyl)urea:

2,2,2-trichloroethyl 2-(oxaindole-3-ylmethoxy)-5-pentafluorosulfanylphenylcarbamate (70.0 mg, in the same manner as in Example 5) The title compound (hereinafter, the compound of Example 21) (50.6 mg) was obtained.

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 (1H, m ), 3.94 (1H, d, J = 4.6 Hz), 4.03 (1H, 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 (3H, m), 5.25 (1H, t, J = 7.0 Hz), 6.58 (1H, 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 = 2.7 Hz).

MS (ESI) [M+H] ⁺ : 481.

(Example 22) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(5-pentafluorosulfanyl-2-(oxonium) Synthesis of -3-ylmethoxy)phenyl)urea:

In the same manner as in Example 7, 2,2,2-trichloroethyl 2-(oxaindole-3-ylmethoxy)-5-pentafluorosulfanylphenylcarbamic acid (70.0 mg, The title compound (hereinafter, 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 (1H, m ), 3.98 (1H, dd, J = 9.8, 3.4 Hz), 4.19 (1H, dd, J = 9.8, 2.9 Hz), 4.44 - 4.52 (1H, m), 4.67 (1H, s), 4.75 (1H, t, J = 6.0 Hz), 4.90 (1H, t, J = 6.1 Hz), 5.00-5.07 (2H, m), 5.18 (1H, t, J = 5.9 Hz), 6.65 (1H, 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), 7.38 (1H, d , J = 7.1 Hz), 7.45 (1H, s), 8.84 (1H, d, J = 2.7 Hz).

MS (ESI) [MH] ^- : 479.

Mp157.2-183.6 °C.

(Reference Example 37) Synthesis of 2-(1-(tris-butoxycarbonyl)indol-3-yloxy)-5-pentafluorosulfanylnitrobenzene:

In the same manner as in Reference Example 31, 2-chloro-5-pentafluorosulfanylnitrobenzene (600 mg, 2.12 mmol) and 1-(tert-butoxycarbonyl)-3-hydroxyindole (440 mg, The title compound (884 mg) was obtained 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 = 2.7Hz).

(Reference Example 38) Synthesis of 2-(1-(tertiary butoxycarbonyl)indol-3-yloxy)-5-pentafluorosulfanylaniline:

In the same manner as in Reference Example 4, from 2-(1-(tertiarybutoxycarbonyl)indol-3-yloxy)-5-pentafluorosulfanylnitrobenzene (889 mg, 2.12 mmol), The title compound (886 mg) was obtained as a yellow solid.

^{1 H-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, 1.1 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=2.5Hz).

(Reference Example 39) 2-(1-(tertiary butoxycarbonyl)indol-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid 2,2,2-trichloroethyl ester Synthesis:

In the same manner as in Reference Example 9, from 2-(1-(tertiarybutoxycarbonyl)indol-3-yloxy)-5-pentafluorosulfanylaniline (886 mg, 2.12 mmol), Colorless amorphous title compound (938 mg).

^{1 H-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, 2.9 Hz), 6.55 (1H, d, J = 9.1 Hz), 7.39 (1H, brs), 7.44 (1H, dd, J = 8.8, 2.5 Hz) , 8.65 (1H, s).

MS (ESI) [MH] ^- : 563.

(Reference Example 40) Synthesis of 2,2,2-trichloroethyl 2-(indol-3-yloxy)-5-pentafluorosulfanylphenylcarbamate:

2,2,2-trichloroethyl 2-(1-(tris-butoxycarbonyl)indol-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid under ice cooling ( A solution of 500 mg, 0.884 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.02 mL, 13.3 mmol). After stirring at room temperature for 2 hours, in the reverse A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was separated. The organic layer was washed with EtOAcqqqqqqqq The obtained crude product was not further purified, and the next step was carried out.

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.

Mp137.0-140.5 °C.

(Reference Example 41) Synthesis of 2-(2-ethylindolyl-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid 2,2,2-trichloroethyl ester:

Ethyl acetate (2 mL) solution of 2,2,2-trichloroethyl 2-(indol-3-yloxy)-5-pentafluorosulfanylphenylcarbamate (130 mg, 0.279 mmol) Pyridine (47.4 μL, 0.586 mmol) and acetic anhydride (27.7 μL, 0.293 mmol) were added. After stirring at room temperature for 2 hours, water was added to the reaction mixture, and the mixture was separated. The organic layer was washed with EtOAc EtOAc EtOAcjjjjjj The obtained crude product was not further purified, and the next step was carried out.

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.

Mp226.1-227.4 °C.

(Example 23) 1-(2-(1-Ethylindol-3-yloxy)-5-pentafluorosulfanylphenyl)-3-((1R,2S)-2-hydroxy- Synthesis of 2,3-dihydro-1H-indol-1-yl)urea:

2,2,2-trichloroethyl 2-(1-ethylindolyl-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid was used in the same manner as in Example 5. (65.0 mg, 0.128 mmol), the title compound (m.

^{1 H-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, 3.3 Hz), 4.31 (1H, 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.

(Example 24) 1-(2-(1-Ethylindol-3-yloxy)-5-pentafluorosulfanylphenyl)-3-((1S,2R)-1-hydroxy- Synthesis of 2,3-dihydro-1H-indol-2-yl)urea:

2,2,2-trichloroethyl 2-(1-ethylindolyl-3-yloxy)-5-pentafluorosulfanylphenylcarbamate as in the same manner as in Example 7. (65.0 mg, 0.128 mmol), m.

^{1 H-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 = 10.7 Hz), 4.16 (1H, d, J = 9.5 Hz), 4.29-4.38 (2H, m), 4.58 (1.0H, t, J = 7.8 Hz), 4.92 ( 1H, t, J = 5.5 Hz), 5.14 - 5.17 (1H, 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) [MH] ^- : 506.

Mp249.6-252.4°C.

(Reference Example 42) Synthesis of 2,2,2-trichloroethyl 2-(1-methylsulfonylindol-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid:

Ethyl acetate (3 mL) solution of 2,2,2-trichloroethyl 2-(p--3-yloxy)-5-pentafluorosulfanylphenylcarbamate (135 mg, 0.290 mmol) Among them, pyridine (49.2 μL, 0.609 mmol) and methanesulfonium chloride (23.7 μL, 0.304 mmol) were added. After stirring at room temperature for 2 hours, water was added to the reaction mixture, and the mixture was separated. The organic layer was washed with EtOAc EtOAc EtOAc.

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) [MH] ^- : 541.

Mp179.4-181.1 °C.

(Example 25) 1-(2-(1-Methanesulfonylindole-3-yloxy)-5-pentafluorosulfanylphenyl)-3-((1R,2S)-2-hydroxyl Synthesis of -2,3-dihydro-1H-indol-1-yl)urea:

In the same manner as in Example 5, from 2,2,2-trichloroethyl 2-(1-methylsulfonylindol-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid The ester (60.0 mg, 0.110 mmol) gave the title compound (m.

^{1 H-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 = 4.5 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.

(Example 26) 1-(2-(1-Methanesulfonylindole-3-yloxy)-5-pentafluorosulfanylphenyl)-3-((1S,2R)-1-hydroxyl Synthesis of -2,3-dihydro-1H-indol-2-yl)urea:

In the same manner as in Example 7, 2,2,2-trichloroethane from 2-(1-methanesulfonylindole-3-yloxy)-5-pentafluorosulfanylphenylcarbamic acid The ester (60.0 mg, 0.110 mmol) was obtained (yield of the compound of Example 26) (62.9 mg).

^{1 H-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 = 9.1 Hz), 7.20-7.28 (3H, m), 7.31-7.39 (3H, m), 8.50 (1H, s), 8.90 (1H, d, J = 3.2 Hz).

MS (ESI) [MH] ^- : 542.

(Example 27) 1-((1S,2R)-4-fluoro-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(5-pentafluorosulfanyl-2 Synthesis of (-oxo-3-yloxy)phenyl)urea:

a solution of 2,2,2-trichloroethyl 2-(oxaindole-3-yloxy)-5-pentafluorosulfanylphenylcarbamate (100 mg, 0.214 mmol) in EtOAc (1 mL) Diisopropylethylamine (75 μL, 0.43 mmol), (1S, 2R)-2-amino-4-fluoro-1-hydrofurfuryl alcohol (53.7 mg, 0.321 mmol) was added. After stirring at 100 ° C for 23 hours, the reaction mixture was cooled, water was added, and ethyl acetate was evaporated. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (chloroform/methanol) to give the title compound as a colorless solid (hereinafter, compound of Example 27) (86.9 mg).

^{1 H-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, 6.5 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) [MH] ^- : 483.

Mp227.2-229.6°C.

(Reference Example 43) Synthesis of 2-chloro-5-pentafluorosulfanylaniline:

The title compound (263 mg) was obtained from yyyyyyyyyyyyyyyyyyyyyyyyyyyyyy

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.

(Example 28) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(2-chloro-5-pentafluorosulfanylphenyl) ) Synthesis of urea:

The title compound (hereinafter, the compound of Example 28) (221 mg) was obtained as a colorless solid (yield: 262 mg).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.81 (1H, d, J = 16.1 Hz), 3.08 (1H, 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.

(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 extracted with diethyl ether. The organic layer was dried over anhydrous sodium

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.

(Reference Example 45) Synthesis of 2-methylmercapto-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 for 10 min Titanium tetrachloride (1.46 mL, 13.35 mmol) was added to make the temperature of the reaction solution -20 to -22 °C. After stirring at the same temperature for 30 minutes, water was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to give crude The resultant was purified by EtOAc EtOAc (EtOAc)

^{1 H-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 46) Synthesis of 3-methylindenyl-2-methoxy-5-pentafluorosulfanylnitrobenzene:

To a suspension of 2-methylmercapto-4-pentafluorosulfanylanisole (5.00 g, 19.3 mmol) in concentrated sulfuric acid (60 mL) was added EtOAc (1 mL). After stirring at the same temperature for 3 hours, ice was added to the reaction mixture and extracted with chloroform. The title compound (5.28 g) m.

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.

(Reference Example 47) Synthesis of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylnitrobenzene:

Addition of hydroboration to a solution of 3-mercapto-2-methoxy-5-pentafluorosulfanylnitrobenzene (70.0 mg, 0.228 mmol) in methanol (2 mL) Sodium (10.4 mg, 0.273 mmol). After stirring at the same temperature for 1 hour, 1 M hydrochloric acid was added to the reaction mixture and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate ).

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.

(Reference Example 48) Synthesis of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylaniline:

To a solution of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanyl nitrobenzene (57.0 mg, 0.184 mmol) in MeOH (1 mL), EtOAc. After stirring for 30 minutes under a hydrogen atmosphere, the title compound (49 mg) was obtained.

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.

(Reference 49) Synthesis of 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate:

Add 2,2,2-trichloroethyl chloroformate to a solution of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylaniline (49.0 mg, 0.175 mmol) in tetrahydrofuran (2 mL) 0.0240 mL, 0.175 mmol), diisopropylethylamine (0.153 mL, 0.877 mmol). After stirring at room temperature for 3 hours, water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with aq. EtOAc (EtOAc) (71 mg).

^{1 H-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.

(Example 29) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(3-hydroxymethyl-2-methoxy-5 Synthesis of -pentafluorosulfanylphenyl)urea:

In the same manner as in Example 5, 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate (20.0 mg, 0.0440 mmol) The title compound (hereinafter, the compound of Example 29) (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.

(Example 30) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(3-hydroxymethyl-2-methoxy-5 Synthesis of -pentafluorosulfanylphenyl)urea:

In the same manner as in Example 7, 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate (20.0 mg, 0.0440 mmol) The title compound (hereinafter, 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=6.8Hz),7.44-7.45(1H,m),8.63( 1H, d, J = 3.2Hz).

MS (ESI) [M+H] ⁺ : 455.

(Example 31) 1-((1S,2R)-4-fluoro-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(3-hydroxymethyl-2-methyl Synthesis of oxy-5-pentafluorosulfanylphenyl)urea:

To a solution of 2,2,2-trichloroethyl 3-hydroxymethyl-2-methoxy-5-pentafluorosulfanylphenylcarbamate (20.0 mg, 0.0440 mmol) in EtOAc (1 mL) Diisopropylethylamine (15.3 μL, 0.0880 mmol), (1S, 2R)-2-amino-4-fluoro-1-hydrofurfuryl alcohol (11.0 mg, 0.0660 mmol) was added. After stirring at 100 ° C for 6 hours, the reaction mixture was cooled, water was added, and ethyl acetate was evaporated. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (chloroform/methanol) to give the title compound as a colorless solid (hereinafter, compound of Example 31) (11.2 mg).

^{1 H-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 = 5.9 Hz), 4.96 (1H, 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

Mp184.6-186.8°C.

(Reference Example 50) Synthesis of 3-(2,2,2-trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylnitrobenzene:

Trimethyl (trifluoromethyl) was added to a solution of 3-mercapto-2-methoxy-5-pentafluorosulfanylnitrobenzene (340 mg, 1.11 mmol) in tetrahydrofuran (3 mL). Decane (0.327 mL, 2.21 mmol), tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 0.11 mL, 0.11 mmol). The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour, then concentrated. The obtained crude product was purified by EtOAcjjjjjjjjj

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).

(Reference Example 51) Synthesis of 3-(2,2,2-trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylaniline:

In the same manner as in Reference Example 4, from 3-(2,2,2-trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylnitrobenzene (404 mg, 1.07 mmol) The title compound (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.

(Reference Example 52) 3-(2,2,2-Trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylphenylcarbamic acid 2,2,2-trichloro Synthesis of ethyl ester:

In the same manner as in Reference Example 9, from 3-(2,2,2-trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylaniline (393 mg, 1.13 mmol), The title compound (470 mg) was obtained as a yellow oil.

¹ H NMR (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).

(Example 32) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)-3-(3-(2,2,2-trifluoro-1) Synthesis of -hydroxyethyl)-2-methoxy-5-pentafluorosulfanylphenyl)urea:

In the same manner as in Example 5, from 3-(2,2,2-trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylphenylcarbamic acid 2,2 , 2-trichloroethyl ester (225 mg, 0.430 mmol), to obtain the title compound (hereinafter, the compound of the low polarity side of Example 32) (110 mg) and the highly polar side of the low-polarity side of the colorless amorphous form. The title compound (hereinafter, the compound on the highly polar side of Example 32) (111 mg).

Compound of the low polarity side of Example 32:

^{1 H-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 = 4.1 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 of the high 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, 4.5 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) [MH] ^- : 521.

(Example 33) 1-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(3-(2,2,2-trifluoro-1) Synthesis of -hydroxyethyl)-2-methoxy-5-pentafluorosulfanylphenyl)urea:

In the same manner as in Example 7, from 3-(2,2,2-trifluoro-1-hydroxyethyl)-2-methoxy-5-pentafluorosulfanylphenylcarbamic acid 2,2 , 2-trichloroethyl ester (233 mg, 0.450 mmol), to obtain the title compound (hereinafter, the compound on the low polarity side of Example 33) (112 mg) of the low polarity side of the colorless amorphous form, and the highly polar side The title compound (hereinafter, the compound on the highly polar side of Example 33) (102 mg).

Compound of the low polarity side of Example 33:

^{1 H-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 = 5.7 Hz), 5.37-5.43 (1H, m), 5.55 (1H, d, J = 5.4 Hz), 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).

Compound of the high polarity side of Example 33:

^{1 H-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 = 5.4 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) [MH] ^- : 521.

(Reference Example 53) Synthesis of 2-((4-pentafluorosulfanyl-2-nitrophenyl)(methyl)amino)ethanol:

The title compound (341 mg) was obtained from m.

^{1 H-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 = 5.4 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.

(Reference Example 54) Synthesis of 2-((4-pentafluorosulfanyl-2-nitrophenyl)(methyl)amino)ethyl acetate:

Add pyridine (0.207 mL) to a solution of 2-((4-pentafluorosulfanyl-2-nitrophenyl)(methyl)amino)ethanol (341 mg, 1.06 mmol) in ethyl acetate (2.1 mL) 2.54 mmol), acetic anhydride (0.121 mL, 1.27 mmol), 4-dimethylaminopyridine (1.2 mg, 0.010 mmol), and stirred at room temperature for 2 hr. Water (5 mL) was added to the mixture, and ethyl acetate (5 mL) was evaporated. The organic layer was washed with saturated brine (2 mL), evaporated, evaporated, evaporated. (350mg).

^{1 H-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 = 5.7 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.

(Reference Example 55) Synthesis of 2-((2-amino-(4-pentafluorosulfanyl)phenyl)(methyl)amino)ethyl acetate:

According to the same procedure as Reference Example 4, 2-((4-pentafluorosulfanyl-2-nitrophenyl)(methyl)amino)ethyl acetate (350 mg, 0.960 mmol) was obtained. The title compound (306 mg) was obtained.

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.

(Reference Example 56) 2-((4-(pentafluorosulfanyl)-2-((2,2,2-trichloroethoxy)carbonyl)amino)phenyl)(methyl)amino group Synthesis of ethyl acetate:

In the same manner as in Reference Example 9, from 2-((2-amino-(4-pentafluorosulfanyl)phenyl)(methyl)amino)ethyl acetate (305 mg, 0.910 mmol), The title compound (447 mg) was obtained as a white solid.

^{1 H-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 = 5.4 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.

Mp51.5-53.0 °C.

(Example 34) 2-((2-(3-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-1-yl)ureido)-4-(pentafluorosulfur Synthesis of alkyl)phenyl)(methyl)amino)ethyl acetate:

In the same manner as in Example 5, from 2-((4-(pentafluorosulfanyl)-2-((2,2,2-trichloroethoxy)carbonyl)amino)phenyl) ( The title compound (hereinafter, the compound of Example 34) (131 mg) was obtained 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.

Mp139.9-141.1 °C.

(Example 35) 2-((2-(3-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)ureido)-4-(pentafluorosulfur Synthesis of alkyl)phenyl)(methyl)amino)ethyl acetate:

In the same manner as in Example 7, from 2-((4-(pentafluorosulfanyl)-2-((2,2,2-trichloroethoxy)carbonyl)amino)phenyl) ( Methyl)amino)ethyl acetate (150 mg, 0.294 mmol) gave the title compound (m.

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 (1H, 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.

(Example 36) 1-((1R,2S)-2-hydroxy-2,3-dihydro-1H-indol-2-yl)-3-(2-((2-hydroxyethyl))methyl Synthesis of Amino)-5-(pentafluorosulfanyl)phenyl)urea:

A solution of the compound (118 mg, 0.232 mmol) in MeOH (MeOH) (EtOAc) bell. 1 M hydrochloric acid was added to the reaction mixture, the pH was adjusted to 7, and then concentrated under reduced pressure. The residue was extracted with ethyl acetate. EtOAc (EtOAc m. (hereinafter, the compound of Example 36) (76.9 mg).

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 (1H, d, J = 4.6 Hz), 7.19-7.27 (4H, m), 7.31 (1H, 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.

Mp211.1-213.4 °C.

(Reference Example 57) Synthesis of (1-(2-methoxy-5-pentafluorosulfanyl-3-nitrobenzyl)pyrrolidin-3-yl)carbamic acid (R)-tertiary butyl ester:

Add pyrrrolidin-3-ylaminocarboxylic acid (R) to a solution of 3-mercapto-2-methoxy-5-pentafluorosulfanyl nitrobenzene (100 mg, 0.330 mmol) in tetrahydrofuran (5 mL) Tri-tert-butyl ester (67 mg, 0.36 mmol), and sodium triethoxysulfonyl borohydride (104 mg, 0.49 mmol). After warming to room temperature and stirring for one night, the reaction solution was concentrated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc)

^{1 H-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 = 2.7 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=2.7Hz).

ESI-MSm/z[M+H] ⁺ :478.

(Reference 58) (((R)-1-(3-(3-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)))) Synthesis of 3-methoxybutyl 5-methoxy-5-(pentafluorosulfanyl)benzyl)pyrrolidin-3-yl)carbamate:

(1-(2-Methoxy-5-pentafluorosulfanyl-3-nitrobenzyl)pyrrolidin-3-yl)carbamic acid (R)-tertiary butyl ester (163 mg under hydrogen atmosphere) An ethanol suspension of 0.330 mmol) and platinum oxide (6 mg) was stirred at room temperature for 1 hour. The catalyst was filtered with diatomaceous earth (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). After stirring at room temperature for 1 hour, (1S,2R)-2-amino-1-hydrofurfuryl alcohol (25 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate (mjjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH .

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.

(Example 37) 1-(3-((R)-3-Aminopyrrolidin-1-yl)methyl)-2-methoxy-5-pentafluorosulfanylphenyl)-3- Synthesis of ((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)urea:

(((R)-1-(3-(3-((1S,2R)-1-hydroxy-2,3-dihydro-1H-indol-2-yl)ureido)-2-methoxy -5-(Pentafluorosulfanyl)benzyl)pyrrolidin-3-yl)carbamic acid tert-butyl butyl ester (32 mg, 0.051 mmol) was dissolved in ethyl acetate (0.5 mL). After the reaction mixture was stirred at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated. The organic layer was dried over anhydrous sodium sulfate and evaporated. The title compound (10.7 mg) (yield, the compound of Example 37) was obtained as a pale yellow-yield (yield of chloroform/methanol).

^{1 H-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, 6.1 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 = 2.7 Hz), 8.57 (1H) , d, J = 2.7 Hz).

(Example 38) Evaluation of DDR1 inhibitory activity:

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 hydrazine (hereinafter, DMSO) and used in the following evaluation. In addition, the test substance and each test drug were diluted with a Kinase buffer (Cisbio Bioassays), which was 5 mmol/L for MgCl _{2 and} 0.5 mmol/L for MnCl ₂ , and DTT was used. 0.25 mmol/L, a supplemental enzyme buffer (Cisbio Bioassays) was added and prepared in a manner of 50 nmol/L. In a 384-well black disk (Corning), the test substance (final DMSO concentration 1%), DDR1 intracellular domain (final concentration 5 ng/μL) (Carna Biosciences), ATP as a phosphate donor (final concentration) were added. 25 μmol/L (SIGMA) and TK Substrate-biotin (final concentration: 1000 nmol/L) (Cisbio Bioassays) as a substrate were allowed to react at room temperature for 1 hour. After the reaction, TK antibody-cryptate (Cisbio Bioassays) and streptavidin-XL665 (Cisbio Bioassays) were added and allowed to react at room temperature for 1 hour. . In addition, wells to which the test substance was not added, and wells in which the DDR1 intracellular domain was not added and the test substance was not added were prepared.

The fluorescence intensity (excitation wavelength: 320 nm, measurement wavelength: 665 nm and 620 nm) of each well was measured using Multilabel Counter (Envision, PerkinElmer Co., Ltd.), and the ratio (fluorescence intensity of 665 nm / fluorescence intensity of 620 nm) was calculated. The inhibition rate (%) of each concentration of the test substance was calculated by the following formula.

Inhibition rate (%) = ([ratio of unexamined substances] - [ratio of substances to be tested]) / ([ ratio of substances not added] - [DDR1 intracellular domain was not added and the substance to be tested was not Ratio of addition]) × 100

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

The IC ₅₀ values of the respective substances to be tested are shown in Table 2. As is apparent from the results of Table 2, the urea derivative (I) of the present invention or a pharmacologically acceptable salt thereof exhibits high DDR1 inhibitory activity.

[Industrial availability]

The urea derivative (I) of the present invention and its pharmacologically acceptable salt can be utilized as an inhibitor of DDR1 because of its high DDR1 inhibitory activity.

Claims (4)

a urea derivative represented by the following 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 a carbon in which one to four hydrogen atoms are each independently replaceable by a halogen atom or a hydroxyl group; Alkyl groups of 1 to 3, R ² represents a hydrogen atom, a halogen atom, a 4-pyridyl group, a 4-hydroxy-1-piperidinyl group, and 4 Olinyl, 3-oxo-1-piperidin , tetrahydro-4-piperidyl, (2-hydroxyethyl)(methyl)amine, (2-acetoxyethyl)(methyl)amine or R ⁴ -(CH ₂ ) _n -O-, or a phenyl group in which 1 to 3 hydrogen atoms are each independently substituted by a hydroxyl group or a methoxy group, R ³ represents a hydrogen atom or a halogen atom, n represents 0 or 1, and R ⁴ represents a methyl group, a phenyl group, N-Ethyl-3-indenyl, N-methylsulfonyl-3-indenyl or 3-oxinyl]. The urea derivative of claim 1, or a pharmacologically acceptable salt thereof, wherein one of k and m is 1 and the other is 0. A urea derivative according to claim 1 or 2, wherein R ¹ is a hydrogen atom or a hydroxymethyl group, and R ² is a 4-pyridyl group, 3-oxo-oxyl- ¹ , or a pharmacologically acceptable salt thereof. Or R ⁴ O-, R ³ is a hydrogen atom or a fluorine atom, and R ⁴ is methyl, N-ethylindol-3-yl, N-methylsulfonyl-3-indenyl or 3-oxo呾基. An inhibitor of discoidin domain receptor 1 which contains the urea derivative of any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.