Entitled urea derivatives and use thereof

Technical field

[0001]

　The present invention relates to urea derivatives and their use.

Background technique

[0002]

　Discoidin domain receptor 1 (hereinafter, DDR1) is a receptor tyrosine kinase that is activated by collagen is a ligand, a discoidin domain having collagen binding to extracellular receptor tyrosine kinase domain into a cell and each have (non-Patent documents 1 and 2).

[0003]

　Activation of DDR1 is to promote invasion and metastasis and cell survival has been reported (Non-Patent Documents 3-5). In clinical, non-small cell lung cancer, it has been reported that expression in glioma and breast cancer DDR1 is increased in non-small cell lung cancer, a correlation between it and the poor prognosis expression is enhanced and correlation with the infiltration of cells have been reported (non-Patent documents 6-9).

[0004]

　DDR1 to by knockdown by RNA interference, the bone metastasis of lung cancer cells is inhibited tumorigenicity of (Non-Patent Document 6) and colon cancer has been reported to decrease (Non-Patent Document 10).

[0005]

　As compounds having an inhibitory activity against DDR1, for example, 3- (2- (pyrazolo [1,5-a] pyrimidin-6-yl) ethynyl) benzamide derivatives (Patent Document 1 and Non-Patent Document 11), 4- ((4-ethyl-piperazinyl) methyl) -3-trifluoromethyl benzal bromide derivative (non-Patent Document 12) and 4-piperazinyl-3-trifluoromethyl benzal bromide derivative (Patent documents 2 and 3) It has been reported.

[0006]

　On the other hand, the compound having a urea skeleton, for example, as a compound having an inhibitory activity against p38MAPK, 2,3-dihydro -1H- inden-2-ylurea derivative (Patent Document 4), but also, FLT3 (Fms-like tyrosine kinase as compounds having an inhibitory activity against 3) and VEGFR2 (vascular endothelial growth factor receptor 2), pentafluorosulfur sulfonyl phenyl urea derivatives (Patent Document 5) have been reported.

CITATION

Patent Literature

[0007]

Patent Document 1: WO 2012/000304 Patent
Patent Document 2: WO 2013/161851
Patent Document 3: WO 2013/161853 Patent
Patent Document 4: WO 2011/040509 Patent
Patent Document 5: International Publication No. 2012/094451

Non-Patent Document

[0008]

Non-Patent Document 1: Vogel ra, British Journal of Cancer, 2007, Volume 96, p. 808-814
Non-Patent Document 2: Vogel ra, Cellular Signaling, 2006, Volume 18, p. 1108-1116
Non-Patent Document 3: Vogel ra, FASEB Journal, 1999, Volume 13, p. S77-S82
Non-Patent Document 4: Valiathan ra, Cancer Metastasis Review, 2012, Volume 31, p. 295-321
Non-Patent Document 5: Vogel ra, Molecular Cell, 1997, Volume 1, p. 13-23
Non-Patent Document 6: Valencia ra, Clinical Cancer Research, 2012 year Volume 18, p. 969-980
Non-Patent Document 7: Barker ra, Oncogene, 1995 year Volume 10, p. 569-575
Non-Patent Document 8: Yamanaka ra, Oncogene, 2006, Volume 25, p. 5994-6002
Non-Patent Document 9: Miao ra, Medical Oncology, 2013 year Volume 30, p. 626
Non-Patent Document 10: Hung-Gu ra, Journal of Biological Chemistry, 2011 year Volume 286, p. 17672-17681
Non-Patent Document 11: Ding ra, Journal of Medicinal Chemistry, 2013 year Volume 56, p. 3281-3295
Non-Patent Document 12: Gray ra, ACS Chemical Biology, 2013 years Volume 8, p. 2145-2150

Summary of the Invention

Problems that the Invention is to Solve

[0009]

　However, in the compound having a urea skeleton so far, compounds having an inhibitory activity against DDR1 has not been reported.

[0010]

　The present invention aims at providing a compound having inhibitory activity against DDR1.

Means for Solving the Problems

[0011]

　The present inventors have made intensive investigations to achieve the above objects, a novel urea derivative or a pharmacologically acceptable salt thereof, found to have inhibitory activity against DDR1 (hereinafter, DDR1 inhibitory activity) this has led to the completion of the present invention.

[0012]

　That is, the present invention provides a urea derivative or a pharmacologically acceptable salt thereof represented by the following general formula (I).
[Chemical formula 1]

wherein, m represents 0 or 1, R 1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group or pentafluorosulfur sulfonyl group, R 2 is a hydrogen atom, or , one hydrogen atom, a hydroxyl group, a piperazinyl group or a 4-methylpiperazinyl group, in substituted methyl group, R 3 is a hydrogen atom or R 5 represents O-, R 4 is a substituted may be, a phenyl group, a pyridyl group or pyrimidinyl group, R 5 represents an alkyl group having 1 to 3 carbon atoms, represents a 3-oxetanyl group or a 4-piperidyl group (wherein, m is 0, R 1 is a halogen atom, a trifluoromethyl group or a trifluoromethoxy group, and, R 4 except when it is pyridyl group which may be substituted.). ]

[0013]

　In the urea derivative represented by the above general formula (I), R 4 is 3-or 4-carbamoylphenyl group, 4-N-methylcarbamoyl-phenyl group, 4-pyridyl or 2-(1H-imidazolyl) -4 - it is preferably a pyrimidinyl group.

[0014]

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

[0015]

　Further, in the urea derivative represented by the above formula (I), m is preferably 0.

[0016]

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

[0017]

　Furthermore, in the urea derivative represented by the above general formula (I), R 4 is 3-or 4-carbamoylphenyl group, 4-N-methylcarbamoyl-phenyl group, 4-pyridyl or 2-(1H-imidazolyl ) -4-pyrimidinyl group, m is more preferably 0.

[0018]

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

[0019]

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

Effect of the invention

[0020]

　Urea derivatives and their pharmacologically acceptable salts of the present invention has a high DDR1 inhibitory activity, can be used as inhibitors of DDR1.

DESCRIPTION OF THE INVENTION

[0021]

　Urea derivatives of the present invention is characterized in that the following general formula (I).
[Formula 2]

wherein, m represents 0 or 1, R 1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group or pentafluorosulfur sulfonyl group, R 2 is a hydrogen atom, or , one hydrogen atom, a hydroxyl group, a piperazinyl group or a 4-methylpiperazinyl group, in substituted methyl group, R 3 is a hydrogen atom or R 5 represents O-, R 4 is a substituted may be, a phenyl group, a pyridyl group or pyrimidinyl group, R 5 represents an alkyl group having 1 to 3 carbon atoms, represents a 3-oxetanyl group or a 4-piperidyl group (wherein, m is 0, R 1 is a halogen atom, a trifluoromethyl group or a trifluoromethoxy group, and, R 4 except when it is pyridyl group which may be substituted.). ]

[0022]

　The following terms used herein, unless otherwise specified, are as defined below.

[0023]

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

[0024]

　The "which may be substituted phenyl group" refers to one substituted group with which hydrogen atoms have been substituted with a carbonyl group of the phenyl group, for example, a phenyl group, 3- or 4-carboxyl phenyl group, 3- or 4-carbamoylphenyl group, 4-N-methylcarbamoyl-phenyl group, 4-N- (2- (methylamino) ethyl) carbamoyl phenyl group, 4-N- (2- (dimethylamino) ethyl) carbamoyl phenyl group, 4-N- (2- (diethylamino) ethyl) carbamoyl phenyl group, 4-N, N- dimethylcarbamoyl-phenyl group or a 3- or 4-methoxycarbonylphenyl group and the like.

[0025]

　The "which may be substituted pyridyl group" means one group which may be hydrogen atoms have been substituted with a carbonyl group of a pyridyl group, such as pyridyl group, 2-carbamoyl-4-pyridyl group, 3-carbamoyl-6-pyridyl, or 3-N-methylcarbamoyl-6-pyridyl group.

[0026]

　The "which may pyrimidinyl group substituted" means one hydrogen atom group which may be substituted by an imidazolyl group of a pyrimidinyl group, for example, pyrimidinyl or 2-(1H-imidazolyl) -4 - it includes pyrimidinyl group.

[0027]

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

[0028]

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

[0029]

[Table 1-1]

[0030]

[Table 1-2]

[0031]

[Table 1-3]

[0032]

　Urea derivative represented by the above general formula (I) (hereinafter, urea derivatives (I)) is, there are cases where optical isomers and diastereomers exist, not the single isomer alone, racemates and diastereomers also includes diastereomeric mixture.

[0033]

　The present invention includes prodrug thereof, or a pharmaceutically acceptable salt of the urea derivative (I). Prodrugs of the urea derivative (I), enzymatically or chemically in vivo, is a compound that is converted into a urea derivative (I). Active principle of the prodrug of the urea derivative (I) is a urea derivative (I), a prodrug itself urea derivative (I) may have activity.

[0034]

　Examples of the prodrug of the urea derivative (I), for example, hydroxyl groups of the urea derivative (I) is alkylated, compounds phosphorylated or borated and the like. These compounds according to known methods, can be synthesized from urea derivatives (I).

[0035]

　In addition, the prodrug of the urea derivative (I), known in the literature ( "Development of Pharmaceuticals", Hirokawa Shoten, 1990, Vol. 7, p.163 ~ 198 and Progress in Medicine, Vol. 5, 1985, p. under physiological conditions described in 2157-2161), or it may be changed to urea derivatives (I).

[0036]

　Urea derivatives (I) may be labeled with isotope, the isotope labeled, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 15 O, 18 O and / or 125 I and the like.

[0037]

　The "pharmacologically acceptable salt" of a urea derivative (I), for example, hydrochloride, sulfate, nitrate, hydrobromide, inorganic acid salts such as hydroiodic acid or phosphoric acid salt or oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate, glutaric, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, camphorsulfonate, aspartate, glutamate or organic salts such as cinnamic acid salts, hydrochlorides, sulfates, hydrobromides, maleate, benzoate or methanesulfonate is preferred.

[0038]

　Urea derivatives (I) or a pharmacologically acceptable salt thereof, may be may be an anhydride, to form a solvate of hydrate. Examples of the solvate, pharmaceutically acceptable solvates are preferred. Solvate pharmacologically acceptable, but may be either a hydrate or non-hydrate, hydrate is preferable. As the solvent constituting the solvate include methanol, alcohol solvents such as ethanol or n- propanol, N, N- dimethylformamide, and dimethyl sulfoxide, or water.

[0039]

　Urea derivatives (I) can be prepared by an appropriate method based on features derived from the type of the basic skeleton or substituents. Note that it is prepared in the starting materials and reagents can generally be purchased or known methods used for the preparation of these compounds.

[0040]

　Urea derivatives (I), as well as intermediates and starting materials used in their preparation, can be isolated and purified by known means. Known means for isolation and purification such as solvent extraction, recrystallization or chromatography.

[0041]

　Urea derivatives (I) is, when it contains an optical isomer or stereoisomers by known methods, it is possible to obtain the respective isomers as a single compound. Known methods, such as crystallization, enzymes split or chiral chromatography.

[0042]

　In each reaction of the production methods described below, if the raw material compound has a hydroxyl group, an amino group or carboxyl group, it may be a protective group into these groups have been introduced, the protecting group as necessary after the reaction removing it is possible to obtain the desired compound by protecting.

[0043]

　As the protective group for hydroxyl groups, for example, a trityl group, an aralkyl group having 7 to 10 carbon atoms (e.g., benzyl group) include or substituted silyl group (e.g., trimethylsilyl group, triethylsilyl group or tert- butyldimethylsilyl group) It is.

[0044]

　As the amino-protecting group, for example, an alkylcarbonyl group having 2 to 6 carbon atoms (e.g., acetyl group), a benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (e.g., tert- butoxycarbonyl group or benzyloxycarbonyl carbonyl group), an aralkyl group having 7 to 10 carbon atoms (e.g., benzyl group) or a phthaloyl group.

[0045]

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

[0046]

　Deprotection of the protecting group varies depending on the kind of protecting group, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience Co.) performed in accordance with or methods analogous thereto be able to.

[0047]

　Urea derivatives (I) are, for example, as shown in Scheme 1, a urea agent and the presence of a base can be obtained by urea reaction of aniline derivative (II) and benzylamine derivative (III).
[Chemical Formula 3]

[wherein, m and R 1 ~ R 4 are defined the same as above. ]

[0048]

　The amount of benzylamine derivative (III) used in the urea reaction is preferably 0.5 to 10 equivalents relative to the aniline derivative (II), more preferably 1 to 3 equivalents.

[0049]

　The urea bond forming agent used in the urea reaction, for example, 2,2,2-trichloroethyl chloroformate, ester derivatives such as phenyl chloroformate or chloroformate p- nitrophenyl, triphosgene, phosgene, N, N' carbonyldiimidazole or N, N'disuccinimidyl but succinimidyl carbonate and the like, 2,2,2-trichloroethyl chloroformate, are chloroformic acid ester derivatives or triphosgene such as phenyl chloroformate or chloroformate p- nitrophenyl preferable.

[0050]

　The amount of urea bond forming agent used in the urea reaction is preferably 0.1 to 100 equivalents with respect to the aniline derivative (II), more preferably 0.3 to 30 equivalents.

[0051]

　Examples of the bases used in the urea reaction, for example, organic bases, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, sodium hydride, metal hydride compounds such as potassium hydride or calcium hydride, such as triethylamine or diisopropylethylamine, methyl alkyl lithium such as lithium or butyl lithium, lithium amide or a mixture thereof such as lithium hexamethyldisilazide or lithium diisopropylamide and the like, organic bases are preferred, such as triethylamine or diisopropylethylamine.

[0052]

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

[0053]

　As the reaction solvent used in the urea reaction is appropriately selected depending on the type of reagent used is not particularly limited as long as it does not inhibit the reaction, for example, N, N-dimethylformamide, N, N-dimethyl acetamide, N- methyl-2-pyrrolidone or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chlorinated solvents such as chloroform or 1,2-dichloroethane, including but nitrile solvent or a mixed solvent thereof such as acetonitrile or propionitrile, dichloromethane, a chlorinated solvent such as chloroform or 1,2-dichloroethane, or A Nitrile solvents such as Tonitoriru or propionitrile are preferred.

[0054]

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

[0055]

　The reaction time of the urea reaction is appropriately selected depending on the conditions such as reaction temperature, preferably 30 minutes to 30 hours.

[0056]

　Concentration at the start of the reaction of the aniline derivative (II) used for the urea reaction are, 1mmol / L ~ 1mol / L is preferred.

[0057]

　Urea reaction may be used microwave reactor as needed.

[0058]

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

[0059]

　Of aniline derivative (II), R 2 is a hydroxymethyl group in which derivative (IIb), for example, as shown in Scheme 2, can be obtained by a reduction reaction of the alkyl ester derivatives (IIa).
[Formula 4]

[wherein, X represents a methyl group or an ethyl group, and other symbols are the same as defined above. ]

[0060]

　The reduction reaction, for example, under a hydrogen atmosphere, palladium, catalytic hydrogenation in the presence of a metal catalyst nickel or platinum, lithium aluminum hydride, such as borohydride dimethyl sulfide complex or boron hydride tetrahydrofuran complex under hydride reduction reaction or an acid present with metal reagents, zinc, although a one-electron reduction reaction with a metal catalyst iron or tin, and the like, lithium aluminum hydride, borohydride-dimethyl sulfide complex or hydrogen, such as boron hydride-tetrahydrofuran complex of metal reagent is preferred.

[0061]

　As the reaction solvent used in the reduction reaction used is appropriately selected depending on the kind of the reagent, as long as it does not inhibit the reaction is not particularly limited, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or propionitrile nitrile solvents such as nitriles, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1,4 - an ether solvent such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-but chlorinated solvent or a mixed solvent thereof dichloroethane and the like, diethyl ether, tetrahydrofuran Down, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0062]

　The reaction temperature of the reduction reaction is preferably from 0 ~ 200 ℃, 0 ~ 100 ℃ is more preferable.

[0063]

　Concentration at the start of the reaction of the alkyl ester derivative used in the reduction reaction (IIa) is, 1mmol / L ~ 1mol / L is preferred.

[0064]

　Aniline derivative (II) is, for example, as shown in Scheme 3, can be obtained by a reduction reaction of nitrobenzene derivative (IV).
[Chemical Formula 5]

[wherein each symbol is defined the same as above. ]

[0065]

　The reduction reaction, for example, under a hydrogen atmosphere, palladium, catalytic hydrogenation in the presence of a metal catalyst nickel or platinum, lithium aluminum hydride, such as borohydride dimethyl sulfide complex or boron hydride tetrahydrofuran complex presence hydride reduction reaction or an acid by a metal reagent, zinc, although one-electron reduction reaction with a metal catalyst iron or tin, and the like, under hydrogen atmosphere, palladium, catalytic hydrogenation in the presence of a metal catalyst nickel or platinum under reaction or acid present, zinc, one-electron reduction reaction or the like with a metal catalyst iron or tin is preferable.

[0066]

　The metal catalyst used for catalytic hydrogenation, for example, palladium, nickel, platinum or a carbon support and the like.

[0067]

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

[0068]

　As the reaction solvent used in the catalytic hydrogenation reaction is appropriately selected depending on the type of reagent used is not particularly limited as long as it does not inhibit the reaction, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-but chlorinated solvent or a mixed solvent thereof dichloroethane and the like, methanol or ethanol Alcohol solvents are preferred.

[0069]

　The pressure of the hydrogen gas used in catalytic hydrogenation reactions is preferably from 1 to 10 atmospheres, 1-3 atm is more preferred.

[0070]

　The reaction temperature of the catalytic hydrogenation is preferably 0 ~ 200 ℃, 0 ~ 100 ℃ is more preferable.

[0071]

　The reaction time of the catalytic hydrogenation reaction is appropriately selected depending on the conditions such as reaction temperature, 1-72 hours is preferable.

[0072]

　The acid used in the one-electron reduction reaction, for example, acetic acid, hydrochloric acid or ammonium chloride.

[0073]

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

[0074]

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

[0075]

　Examples of the reaction solvent used in the one-electron reduction reaction is appropriately selected depending on the kind of reagents used, as long as it does not inhibit the reaction is not particularly limited, for example, an acidic solvent such as hydrochloric acid or acetic acid, methanol or ethanol alcohol solvents, acetonitrile or nitriles such as propionitrile and the like, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or aprotic polar solvents such as dimethyl sulfoxide, diethyl include ether, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chlorine-based solvent or a mixed solvent thereof or the like chloroform or 1,2-dichloroethane It is , Alcohol solvents acidic solvents or methanol or ethanol, such as hydrochloric acid or acetic acid is preferred.

[0076]

　First reaction temperature in the electron reduction reaction is preferably 0 ~ 200 ℃, 0 ~ 100 ℃ is more preferable.

[0077]

　First reaction time of electron reduction, is appropriately selected depending on the conditions such as reaction temperature, 1-72 hours is preferable.

[0078]

　Concentration at the start of the reaction of nitrobenzene derivative used in the reduction reaction (IV) is, 1mmol / L ~ 1mol / L is preferred.

[0079]

　Of the above nitrobenzene derivative (IV), R 3 derivative is an alkoxy group (IVa), for example, as shown in Scheme 4, a nucleophilic substitution reaction with an alcohol (VI) to the halogenation nitrobenzene derivative (V) it can be obtained by.
[Formula 6]

[wherein, Y represents a fluorine atom or a chlorine atom, and the other symbols are the same as defined above. ]

[0080]

　The alcohol used in the nucleophilic substitution reaction (VI) can be purchased. It can also be produced by a known method or a method analogous thereto.

[0081]

　The amount of alcohol (VI) used in the nucleophilic substitution reaction for the halogenated nitrobenzene derivative (V), preferably 0.5 to 20 equivalents, more preferably 1 to 3 equivalents.

[0082]

　Nucleophilic substitution reaction may be used if desired base. The base used, for example, sodium hydride, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, triethylamine, organic bases or mixtures thereof, such as diisopropylethylamine or pyridine.

[0083]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents with respect to the halogenated nitrobenzene derivative (V), more preferably 1 to 3 equivalents.

[0084]

　As the reaction solvent used in the nucleophilic substitution reaction is appropriately selected depending on the kind of reagents used, the reaction is not particularly limited as long as it does not inhibit, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0085]

　The reaction temperature of the nucleophilic substitution reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0086]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0087]

　Concentration at the start of the reaction of the halogenated nitrobenzene derivative used in the nucleophilic substitution reaction (V) is, 1mmol / L ~ 1mol / L is preferred.

[0088]

　Of the above nitrobenzene derivative (IV), 3-hydroxymethyl nitrobenzene derivative (IVb) can be, for example, as shown in Scheme 5, it can be obtained by a reduction reaction of 3-formyl nitrobenzene derivative (VII).
[Chemical Formula 7]

wherein each symbol is defined the same as above. ]

[0089]

　The reducing agent used in the reduction reaction, for example, although boron-based reducing agent of aluminum-based reducing agent or with sodium borohydride or lithium borohydride such as lithium aluminum hydride or diisobutylaluminum hydride and the like, boron hydride boron-based reducing agent such as sodium or lithium borohydride is preferred.

[0090]

　The amount of reducing agent used in the reduction reaction, 3-formyl 0.2-20 equivalents relative to nitrobenzene derivative (VII), and more preferably 1 to 10 equivalents.

[0091]

　As the reaction solvent used in the reduction reaction is appropriately selected depending on the kind of reagents used, as long as it does not inhibit the reaction is not particularly limited, for example, methanol, ethanol, or isopropyl alcohol or tert- butyl alcohol alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvent or mixtures solvent thereof, methanol, ethanol, alcohol solvents such as isopropyl alcohol or tert- butyl alcohol.

[0092]

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

[0093]

　The reaction time of the reduction reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0094]

　Concentration at the start of the reaction used in the reduction reaction 3-formyl nitrobenzene derivative (VII) is, 1mmol / L ~ 1mol / L is preferred.

[0095]

　Additional 3-formyl nitrobenzene derivative (VII) is, for example, as shown in Scheme 6, 2-formyl - can be obtained by nitration reaction of anisole derivative (VIII).
[Formula 8]

wherein each symbol is defined the same as above. ]

[0096]

　The nitrating agent used in the nitration reaction, for example, there may be mentioned nitronium salts such as nitrates or nitronium tetrafluoroborate concentrated nitric acid or fuming nitric acid, nitric acid such as concentrated nitric acid or fuming nitric acid are preferred.

[0097]

　The amount of nitrating agent used in the nitration reaction, 2-formyl - preferably 0.5 to 20 equivalents relative to anisole derivative (VIII), and more preferably 0.5 to 10 equivalents.

[0098]

　As the reaction solvent used in the nitration reaction, using is appropriately selected depending on the kind of the reagent is not particularly limited as long as it does not inhibit the reaction, for example, acid solvent or dichloromethane etc. concentrated sulfuric or acetic anhydride, a chlorine solvents such as chloroform or 1,2-dichloroethane, but acid solvent such as concentrated sulfuric acid or acetic anhydride is preferred.

[0099]

　The reaction temperature of the nitration reaction is preferably -20 ℃ ~ 200 ℃, 0 ~ 100 ℃ is more preferable.

[0100]

　The reaction time of the nitration reaction is appropriately selected depending on the conditions such as reaction temperature, 1-72 hours is preferable.

[0101]

　Used in the nitration reaction 2-formyl - concentration at the beginning of the reaction of anisole derivative (VIII) is, 1mmol / L ~ 1mol / L is preferred.

[0102]

　Additional 2-formyl - anisole derivative (VIII), for example, as shown in Scheme 7, the presence of an acid, can be obtained by formylation of anisole derivative (IX).
[Formula 9]

[wherein each symbol is defined the same as above. ]

[0103]

　Anisole derivative used in the formylation reaction (IX) can be purchased. It can also be produced by a known method or a method analogous thereto.

[0104]

　Formylation agent used in the formylation reaction, for example, dichloromethyl methyl ether, di-halomethyl alkyl ether derivative or N, such as dichloromethyl ethyl ether or dichloromethyl isopropyl ether, N- dimethylformamide or N- formyl formamide derivatives such as mill piperidine Although the like, dichloromethyl methyl ether, di-halomethyl alkyl ether derivatives such as dichloromethyl ethyl ether or dichloromethyl isopropyl ether.

[0105]

　The amount of formylating agent used in the formylation reaction is preferably 0.5 to 20 equivalents relative to anisole derivative (IX), and more preferably 1 to 5 equivalents.

[0106]

　The acid used in the formylation reaction, for example, aluminum trichloride, tin tetrachloride, phosphorus compounds of the Lewis acid or phosphorus oxychloride or phosphorus oxybromide or the like of titanium tetrachloride or boron trifluoride, and the like, the three aluminum chloride, tin tetrachloride, a Lewis acid titanium chloride or boron trifluoride and the like are preferable.

[0107]

　The amount of acid used in the formylation reaction is preferably 0.5 to 20 equivalents relative to anisole derivative (IX), and more preferably 1 to 5 equivalents.

[0108]

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

[0109]

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

[0110]

　The reaction time of the formylation reaction is appropriately selected depending on the conditions such as reaction temperature, preferably 10 minutes to 30 hours.

[0111]

　Concentration at the start of the reaction of anisole derivative used in the formylation reaction (IX) is, 1mmol / L ~ 1mol / L is preferred.

[0112]

　It benzylamine derivative (III) is, for example, as shown in Scheme 8, the protected benzylamine derivative (X) can be obtained by deprotection.
[Formula 10]

wherein, PG represents a protecting group, and other symbols are the same as defined above. ]

[0113]

　Deprotection of the protecting group varies depending on the kind of protecting group, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience Co.) performed in accordance with or methods analogous thereto be able to.

[0114]

　Among the protected benzylamine derivative (X), m is a 0, R 4 is a derivative having a carbamoyl group which may be substituted (Xa) is, for example, as shown in Scheme 9, it can be obtained by condensation reaction of a carboxylic acid derivative (Xb) with an amine derivative (XI).
[Formula 11]

wherein, R 6 and R 7 are each independently hydrogen atom, an alkyl group having 1 to 3 carbon atoms, 2- (methylamino) ethyl group, 2- (dimethylamino) ethyl group, or It represents 2- (diethylamino) ethyl group, Z is represents CH or N, and the other symbols are the same as defined above. ]

[0115]

　The amount of the amine derivative used in the condensation reaction (XI) is preferably 0.5 to 10 equivalents relative to the carboxylic acid derivative (Xb), more preferably 1 to 3 equivalents.

[0116]

　The condensing agent used in the condensation reaction, for example, ethyl chloroformate, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, hexafluorophosphate 2- (7-aza -1H- benzotriazole - 1-yl) -1,1,3,3-tetramethyluronium, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate, 1H- benzotriazol-1-yl, but oxytripyrrolidinophosphonium hexafluorophosphate and the like, 2-ethyl chloroformate or hexafluorophosphate (7-aza -1H- benzotriazole-1-yl) -1,1, 3,3-tetramethyluronium are preferred.

[0117]

　The amount of condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents relative to the carboxylic acid derivative (Xb), more preferably 0.3 to 30 equivalents.

[0118]

　As the reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used is not particularly limited as long as it does not inhibit the reaction, for example, N, N-dimethylformamide, N, N- dimethylacetamide aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane chlorine solvents such as chloroform or 1,2-dichloroethane, including but nitrile solvent or a mixed solvent thereof such as acetonitrile or propionitrile, dichloromethane, chloroform or N, N- dimethylformamide, N, N-dimethyl Acetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.

[0119]

　The reaction temperature of the condensation reaction is preferably -40 ° C. ~ 200 ° C., more preferably -20 ℃ ~ 150 ℃.

[0120]

　The reaction time of the condensation reaction is appropriately selected depending on the conditions such as reaction temperature, preferably 30 minutes to 30 hours.

[0121]

　Concentration at the start of the reaction of the carboxylic acid derivative used in the condensation reaction (Xb) may, 1mmol / L ~ 1mol / L is preferred.

[0122]

　The above carboxylic acid derivative (Xb) may, for example, as shown in Scheme 10, the presence of a base can be obtained by hydrolysis of the alkyl ester derivatives (Xc).
[Formula 12]

wherein each symbol is defined the same as above. ]

[0123]

　The base used in the hydrolysis reaction, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and inorganic bases such as barium hydroxide or potassium carbonate.

[0124]

　The amount of base used in the hydrolysis reaction is preferably 0.5 to 20 equivalents relative to the alkyl ester derivative (Xc), and more preferably 1 to 3 equivalents.

[0125]

　As the reaction solvent used in the hydrolysis reaction, is used is appropriately selected depending on the kind of the reagent, as long as it does not inhibit the reaction is not particularly limited, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or pro nitrile solvents such as Pionitoriru, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1, ether solvents 4- dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0126]

　The reaction temperature of Kasui Bunkai Han'no is Konomashiku is -20 ℃ ~ 200 ℃, more preferably 0 ~ 150 ℃.

[0127]

　The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0128]

　Concentration at the start of the reaction of the alkyl ester derivatives (Xc) used in the hydrolysis reaction, 1mmol / L ~ 1mol / L is preferred.

[0129]

　The above alkyl ester derivative (Xc), for example, as shown in Scheme 11, can be obtained by protection reaction that leads reduction reaction of benzonitrile derivatives (XI).
[Formula 13]

wherein each symbol is defined the same as above. ]

[0130]

　The reduction reaction, for example, under a hydrogen atmosphere, palladium, catalytic hydrogenation in the presence of a metal catalyst nickel or platinum, lithium aluminum hydride, such as borohydride dimethyl sulfide complex or boron hydride tetrahydrofuran complex presence hydride reduction reaction or an acid by a metal reagent, zinc, although one-electron reduction reaction with a metal catalyst iron or tin, and the like, under hydrogen atmosphere, palladium, catalytic hydrogenation in the presence of a metal catalyst nickel or platinum reaction is preferred.

[0131]

　The metal catalyst used for catalytic hydrogenation, for example, palladium, nickel, platinum or a carbon support and the like.

[0132]

　The amount of metal catalyst used in the catalytic hydrogenation reaction is preferably from 0.001 to 5 equivalents relative benzonitrile derivative (XI), more preferably 0.01 to 1 equivalent.

[0133]

　As the reaction solvent used in the catalytic hydrogenation reaction is appropriately selected depending on the type of reagent used is not particularly limited as long as it does not inhibit the reaction, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-but chlorinated solvent or a mixed solvent thereof dichloroethane and the like, methanol or ethanol Alcohol solvents are preferred.

[0134]

　The pressure of the hydrogen gas used in catalytic hydrogenation reactions is preferably from 1 to 10 atmospheres, 1-3 atm is more preferred.

[0135]

　The reaction temperature of the catalytic hydrogenation is preferably 0 ~ 200 ℃, 0 ~ 100 ℃ is more preferable.

[0136]

　The reaction time of the catalytic hydrogenation reaction is appropriately selected depending on the conditions such as reaction temperature, 1-72 hours is preferable.

[0137]

　Concentration at the start of the reaction of benzonitrile derivatives used in the reduction reaction (XI) is, 1mmol / L ~ 1mol / L is preferred.

[0138]

　Protection of benzylamine varies depending on the kind of protecting group, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience, Inc.) be carried out according or methods analogous thereto can.

[0139]

　Among the above benzonitrile derivative (XI), Z is CH derivative (XIa), for example, as shown in Scheme 12, by nucleophilic substitution reaction of benzonitrile derivatives (XII) and the phenol derivative (XIII) it is possible to obtain.
[Formula 14]

wherein each symbol is defined the same as above. ]

[0140]

　Benzonitrile derivative used in the nucleophilic substitution reaction (XII) may be purchased. It can also be produced by a known method.

[0141]

　The amount of benzonitrile derivatives used in the nucleophilic substitution reaction (XII) is preferably from 0.2 to 10 equivalents relative to the phenol derivative (XIII), and more preferably 0.5 to 3 equivalents.

[0142]

　Nucleophilic substitution reaction may be used if desired base. The base used, for example, sodium hydride, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, triethylamine, organic bases or mixtures thereof, such as diisopropylethylamine or pyridine.

[0143]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents relative to the phenol derivative (XIII), and more preferably 1 to 3 equivalents.

[0144]

　As the reaction solvent used in the nucleophilic substitution reaction is appropriately selected depending on the kind of reagents used, the reaction is not particularly limited as long as it does not inhibit, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0145]

　The reaction temperature of the nucleophilic substitution reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0146]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0147]

　Concentration at the start of the reaction of a phenol derivative used in the nucleophilic substitution reaction (XIII) is, 1mmol / L ~ 1mol / L is preferred.

[0148]

　Among the above benzonitrile derivative (XI), Z is N derivative (XIb) is, for example, as shown in Scheme 13, determined with 2-hydroxybenzonitrile (XIV) with a halogenated pyridine derivative (XV) it can be obtained by nuclear substitution reaction.
Formula 15]

wherein each symbol is defined the same as above. ]

[0149]

　Used in the nucleophilic substitution reaction of 2-hydroxybenzonitrile (XIV) may be purchased. It can also be produced by a known method.

[0150]

　The amount of used nucleophilic substitution reaction of 2-hydroxy benzonitrile (XIV) is preferably from 0.2 to 10 equivalents to the halogenated pyridine derivative (XV), more preferably from 0.5 to 3 equivalents.

[0151]

　Nucleophilic substitution reaction may be used if desired base. The base used, for example, sodium hydride, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, triethylamine, organic bases or mixtures thereof, such as diisopropylethylamine or pyridine.

[0152]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents relative to 2-hydroxybenzonitrile (XIV), 1 ~ 3 equivalents being more preferred.

[0153]

　As the reaction solvent used in the nucleophilic substitution reaction is appropriately selected depending on the kind of reagents used, the reaction is not particularly limited as long as it does not inhibit, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0154]

　The reaction temperature of the nucleophilic substitution reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0155]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0156]

　Concentration at the start of the reaction of the halogenated pyridine derivative used in the nucleophilic substitution reaction (XV) is, 1mmol / L ~ 1mol / L is preferred.

[0157]

　Among the above-mentioned urea derivative (I), m is 1 derivative (Ia) is, for example, as shown in Scheme 14, the presence of a base, determined the phenol derivative (XVI) and the alkyl halide derivative (XVII) it can be obtained by nuclear substitution reaction.
[Formula 16]

wherein each symbol is defined the same as above. ]

[0158]

　The above phenol derivative (XVI) may be prepared by a method analogous to known methods or scheme 1.

[0159]

　Alkyl halide derivative used in the nucleophilic substitution reaction (XVII) may be purchased. It can also be produced by a known method.

[0160]

　The amount of alkyl halide derivative (XVII) used in the nucleophilic substitution reaction is preferably 0.2 to 10 equivalents relative to the phenol derivative (XVI), more preferably from 0.5 to 3 equivalents.

[0161]

　Nucleophilic substitution reaction may be used if desired base. The base used, for example, sodium hydride, sodium bicarbonate, inorganic base such as cesium carbonate or potassium carbonate, triethylamine, organic bases or mixtures thereof, such as diisopropylethylamine or pyridine.

[0162]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents relative to the phenol derivative (XVI), more preferably 1 to 3 equivalents.

[0163]

　As the reaction solvent used in the nucleophilic substitution reaction is appropriately selected depending on the kind of reagents used, the reaction is not particularly limited as long as it does not inhibit, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0164]

　The reaction temperature of the nucleophilic substitution reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0165]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0166]

　Concentration at the start of the reaction of a phenol derivative used in the nucleophilic substitution reaction (XVI) may, 1mmol / L ~ 1mol / L is preferred.

[0167]

　Among the above-mentioned urea derivative (I), m is 0 derivative (Ib) is, for example, as shown in Scheme 15, the presence of a base, with a phenol derivative (XVI), aryl halide or heteroaryl halide derivative it can be obtained by nucleophilic substitution reaction with (XVIII).
[Formula 17]

wherein each symbol is defined the same as above. ]

[0168]

　The amount of the phenol derivative used in the nucleophilic substitution reaction (XVI) is preferably from 0.2 to 10 equivalents relative to aryl halide or heteroaryl halide derivative (XVIII), more preferably from 0.5 to 3 equivalents.

[0169]

　Nucleophilic substitution reaction may be used if desired base. The base used, for example, sodium hydride, sodium bicarbonate, inorganic base such as cesium carbonate or potassium carbonate, triethylamine, organic bases or mixtures thereof, such as diisopropylethylamine or pyridine.

[0170]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents relative to the phenol derivative (XVI), more preferably 1 to 3 equivalents.

[0171]

　As the reaction solvent used in the nucleophilic substitution reaction is appropriately selected depending on the kind of reagents used, the reaction is not particularly limited as long as it does not inhibit, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0172]

　The reaction temperature of the nucleophilic substitution reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0173]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0174]

　Concentration at the start of the reaction of a phenol derivative used in the nucleophilic substitution reaction (XVI) may, 1mmol / L ~ 1mol / L is preferred.

[0175]

　Nucleophilic substitution reaction may be using a microwave reaction device as needed.

[0176]

　Among the above-mentioned urea derivative (Ia), R 4 , a derivative having a carbamoyl group which may be substituted (Iaa), for example, as shown in Scheme 16, the carboxylic acid derivative (Iab) with an amine derivative (XI ) can be obtained by condensation reaction of.
[Formula 18]

wherein each symbol is defined the same as above. ]

[0177]

　The amount of the amine derivative used in the condensation reaction (XI) is preferably 0.5 to 10 equivalents relative to the carboxylic acid derivative (Iab), more preferably 1 to 3 equivalents.

[0178]

　The condensing agent used in the condensation reaction, for example, ethyl chloroformate, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, hexafluorophosphate 2- (7-aza -1H- benzotriazole - 1-yl) -1,1,3,3-tetramethyluronium, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate, 1H- benzotriazol-1-yl, but oxytripyrrolidinophosphonium hexafluorophosphate and the like, 2-ethyl chloroformate or hexafluorophosphate (7-aza -1H- benzotriazole-1-yl) -1,1, 3,3-tetramethyluronium are preferred.

[0179]

　The amount of condensing agent used in the condensation reaction is preferably 0.1 to 100 equivalents relative to the carboxylic acid derivative (Iab), more preferably 0.3 to 30 equivalents.

[0180]

　As the reaction solvent used in the condensation reaction is appropriately selected depending on the type of reagent used is not particularly limited as long as it does not inhibit the reaction, for example, N, N-dimethylformamide, N, N-dimethylformamide , N, N- dimethylacetamide, N- methyl-2-aprotic polar solvents such as diethyl ether pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, ether solvents, ethyl acetate or propyl acetate and dimethoxyethane or 1,4-dioxane ester solvents etc., dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane, including but nitrile solvent or a mixed solvent thereof such as acetonitrile or propionitrile, dichloromethane, chloroform or N, N-dimethyl Formamide, N, N- dimethylacetamide, aprotic polar solvents such as N- methyl-2-pyrrolidone or dimethyl sulfoxide is preferable.

[0181]

　The reaction temperature of the condensation reaction is preferably -40 ° C. ~ 200 ° C., more preferably -20 ℃ ~ 150 ℃.

[0182]

　The reaction time of the condensation reaction is appropriately selected depending on the conditions such as reaction temperature, preferably 30 minutes to 30 hours.

[0183]

　Concentration at the start of the reaction of the carboxylic acid derivative used in the condensation reaction (Iab) is, 1mmol / L ~ 1mol / L is preferred.

[0184]

　Among the above-mentioned urea derivative (Ia), R 4 , a derivative having a carboxylic acid (Iab) can be, for example, as shown in Scheme 17, the presence of a base, to obtain the hydrolysis of the alkyl ester derivatives (Iac) can.
[Formula 19]

wherein each symbol is defined the same as above. ]

[0185]

　The base used in the hydrolysis reaction, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and inorganic bases such as barium hydroxide or potassium carbonate.

[0186]

　The amount of base used in the hydrolysis reaction is preferably 0.5 to 20 equivalents relative to the ester derivative (Iac), and more preferably 1 to 3 equivalents.

[0187]

　As the reaction solvent used in the hydrolysis reaction, is used is appropriately selected depending on the kind of the reagent, as long as it does not inhibit the reaction is not particularly limited, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or pro nitrile solvents such as Pionitoriru, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1, ether solvents 4- dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0188]

　The reaction temperature of Kasui Bunkai Han'no is Konomashiku is -20 ℃ ~ 200 ℃, more preferably 0 ~ 150 ℃.

[0189]

　The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0190]

　Concentration at the start of the reaction of the ester derivative used in the hydrolysis reaction (Iac) is, 1mmol / L ~ 1mol / L is preferred.

[0191]

　Among the above-mentioned urea derivative (Ib), R 4 nucleophilic, the derivatives having a pyrimidinyl group substituted in position 2 (Ibb), for example, as shown in Scheme 18, 2-chloropyrimidine derivative (Iba) it can be obtained by nucleophilic substitution reaction with agent (XIX).
[Formula 20]

wherein, R 8 represents a 1H- imidazolyl group, the other symbols are the same as defined above. ]

[0192]

　The amount of the nucleophilic agent used in the nucleophilic substitution reaction (XIX) is preferably from 0.2 to 10 equivalents relative to 2-chloropyrimidine derivative (Iba), more preferably from 0.5 to 3 equivalents.

[0193]

　Nucleophilic substitution reaction may be used if desired base. The base used, for example, sodium hydride, sodium bicarbonate, inorganic base such as cesium carbonate or potassium carbonate, triethylamine, organic bases or mixtures thereof, such as diisopropylethylamine or pyridine.

[0194]

　The amount of base used in the nucleophilic substitution reaction, 2-chloropyrimidine derivative (Iba) is preferably 0.5 to 20 equivalents with respect to, and more preferably 1 to 3 equivalents.

[0195]

　As the reaction solvent used in the nucleophilic substitution reaction is appropriately selected depending on the kind of reagents used, the reaction is not particularly limited as long as it does not inhibit, for example, alcoholic solvent such as methanol or ethanol, acetonitrile or nitrile solvents such as propionitrile, N, N- dimethylformamide, N, N- dimethylacetamide, N- aprotic polar solvents, diethyl ether and methyl-2-pyrrolidone or dimethyl sulfoxide, tetrahydrofuran, dimethoxyethane or 1 , 4-ether solvents such as dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or 1,2-chlorinated solvents dichloroethane and the like or mixtures solvent thereof, methanol or ethanol Alcohol solvents, N, N- dimethylformamide, N, N- dimethylacetamide, N- methyl-2-pyrrolidone or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents etc. are preferred.

[0196]

　The reaction temperature of the nucleophilic substitution reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0197]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, for 1 to 30 hours is preferred.

[0198]

　Concentration at the start of the reaction used in the nucleophilic substitution reaction of 2-chloro pyrimidine derivative (Iba) is, 1mmol / L ~ 1mol / L is preferred.

[0199]

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

[0200]

　"Inhibitors of DDR1" refers to compounds that inhibit the kinase activity of DDR1.

[0201]

　Urea derivatives (I) or a pharmaceutically acceptable salt thereof pharmacologically because with DDR1 inhibitory activity, disease remission or improved symptoms of the condition based on the mechanism of action can be expected, for example, expected as therapeutic agents for cancer it can.

[0202]

　"Ga san" と ha, Example え ba, pharyngeal cancer, laryngeal cancer, tongue cancer, non-small cell lung cancer, breast cancer, esophageal cancer, stomach cancer, colon cancer, uterine cancer, endometrial cancer, egg Chao cancer, liver Zang cancer, pancreas Zang cancer, gall Nang cancer, bile duct cancer, kidney Zang cancer, renal pelvis and ureter cancer, bladder cancer, before Li adenocarcinoma, E of black color swelling, thyroid cancer, Neurology flesh swollen, soft flesh swollen, striated muscle swelling, blood vessel flesh swollen, Xian-dimensional flesh swollen, Neurology gum swelling, leukemia ya E pa swelling of Surlyn, Neurology bud cell types, bone marrow neoplasm swollen and Nao ha ra ge ga Ju DomNode- ru.

[0203]

　The urea derivative (I) or a pharmacologically acceptable salt thereof having a DDR1 inhibitory activity can be assessed using the in vitro test. The in vitro tests, for example, a method of assessing the kinase activity of DDR1 by quantifying the phosphorylated substrate amount or consumed amount of ATP (Analytical Biochemistry, 1999 years, 269 vol, P.94-104) , and a method to evaluate the binding to DDR1 (Journal of Biomolecular Screening, 2009 years, Vol. 14, p.924-935), and the like. More specifically, as a method of assessing the kinase activity of DDR1, for example, include a method of intracellular domain of the purified protein of DDR1, to the substrate peptide and ATP were mixed reaction to quantify the phosphorylated substrate peptide It is. Substrate peptide is phosphorylated, for example, by using a labeled substrate peptide at a pre-biotin or fluorescent substance can be quantified by measurement of fluorescence resonance energy transfer.
Example

[0204]

　Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, the present invention is not limited thereto.

[0205]

　As for those not described in the synthesis method in compounds used in the synthesis of Example compounds were used commercially available compounds. Solvents name indicated in the NMR data show the solvents for measurement. Further, 400 MHz NMR spectra were measured using JNM-AL400 type nuclear magnetic resonance apparatus (Nippon Denshi) or JNM-ECS400 type nuclear magnetic resonance apparatus (Nippon Denshi). Chemical shift, based on tetramethylsilane, [delta] (Unit: ppm) expressed by each signal s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double doublet), dt (double triplet), ddd (double double doublet), dq (double quartet) or tt (triplet It expressed as a triplet). ESI-MS spectra were measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). The solvent using all commercially available. Flash chromatography was used YFLC W-prep2XY (Yamazen Corporation). If it is described as an amino silica gel, using an aminopropyl silane bonded silica gel. Microwave synthesizer used was AntonPaar Co. Monowave300.

[0206]

　Materials and intermediates of the urea derivative (I) was synthesized according to the methods described in the following Reference Examples. As for those not described in the synthesis method in compounds used in the synthesis of Reference Example compounds were used commercially available compounds.

[0207]

(Reference Example 1) 1- (2-hydroxybenzyl) -3-(2-methoxy-5- (pentafluorosulfanyl) phenyl) urea:
[Formula 21]

　Under ice-cooling, 2-methoxy-5-pentafluoro sulfur sulfonyl aniline (7.44 g, 29.9 mmol) in dichloromethane (30 mL) was added triphosgene (2.96 g, 9.95 mmol), triethylamine (0.42 mL, 0.47 mmol) was added and stirred for 1 hour. Subsequently, 2-hydroxy-benzylamine (3.61 g, 29.6 mmol), was added triethylamine (2.99 g, 29.6 mmol). After stirring for 16 h at room temperature, the reaction mixture, a saturated aqueous solution of ammonium chloride was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the resultant crude product was purified by silica gel column chromatography (chloroform: methanol = 10 1, Rf = 0.42) , the title compound (11.6 g, 97 %) (hereinafter, to give the compound) of reference example 1 as a pale yellow solid.
MS (ESI) [M Tasu H] Tasu : 399.

[0208]

(Example 1) 1- (2-methoxy-5 - ((Synthesis of pentafluorosulfanyl) phenyl) -3- (2- (pyridin-4-ylmethoxy) benzyl) urea:
[formula 22]

　the compound of Reference Example 1 (2.0g, 5.0mmol), 4- (bromomethyl) pyridine hydrobromide (1.52g, 6.0mmol), N cesium carbonate (4.1g, 13mmol), N- dimethylformamide (10 mL) the solution was stirred overnight at room temperature, the reaction solution, water was added, extracted with diethyl ether. the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. the resulting crude the product was purified by silica gel column chromatography (ethyl acetate, Rf = 0.32) to obtain the desired compound (140 mg, 5.6%) (hereinafter, the compound of example 1) as a white solid
. And 1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.87 (3H, s), 4.58 (2H, d, J = 4.0 Hz), 5.16 (2H, s), 6.81 (2H, m), 6.88 (1H, d, J = 8.0Hz), 7.00 (1H, t, J = 8.0Hz), 7.35-7.40 (4H, m ), 8.62 (IH, dd, J = 8.0,4.0Hz), 8.69
(IH, d, J = 4.0 Hz). MS (ESI) [M + H] + : 490.

[0209]

Synthesis of Reference Example 2 4-pentafluorosulfur sulfonyl anisole:
[Chem

　23] 4-pentafluorosulfur sulfonyl nitrobenzene (20 g, 80 mmol) N, and N- dimethylformamide (100 mL) was added sodium methoxide (13 g, 240mmol) was added. After stirring for 1 hour at room temperature, water was added to the reaction mixture and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane, Rf = 0.25), the title compound (16.3 g, 87%) (hereinafter, reference the example compound 2) was obtained as a colorless oily substance.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.85 (3H, s), 6.91 (2H, d, J = 9.6 Hz), 7.68 (2H, d, J = 9 .6Hz).
MS (ESI) [M Tasu H] Tasu : 235.

[0210]

(Reference Example 3) 2-formyl-4-Synthesis of pentafluorosulfur sulfonyl anisole:
Formula 24]

　the compound of Reference Example 2 (1.25 g, 5.34 mmol) and dichloromethyl methyl ether (1.18 mL, 13.4 mmol dichloromethane) (10 mL) was cooled to -20 ° C. was added over titanium tetrachloride (1.46mL, 13.35mmol) 10 minutes so that the temperature of the reaction solution becomes -20 ~ -22 ° C. the. After stirring for 30 minutes at the same temperature, water was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, Rf = 0.41 ) to give the title compound (521 mg, 37% ) (hereinafter, to give the compound) of reference example 3 as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.02 (3H, s), 7.04-7.08 (IH, m), 7.90-7.95 (IH, m), 8.22-8.24 (1H, m), 10.5 (1H, s).
MS (ESI) [M Tasu H] Tasu : 263.

[0211]

(Reference Example 4) 3-formyl-2-methoxy -5-pentafluorosulfur sulfonyl nitrobenzene:
Formula 25]

　Under ice-cooling, suspension concentrated sulfuric acid (60 mL) of the compound of Reference Example 3 (5 g, 19.3 mmol) the Nigoeki was added fuming nitric acid (1.0 mL). After stirring for 3 hours at the same temperature, ice was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried and concentrated to give the title compound (5.28 g, 89%) (hereinafter, the compound of Reference Example 4) as a yellow oily substance.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.15 (3H, s), 8.43-8.47 (2H, m), 10.4 (IH, s).
MS (ESI) [M Tasu H] Tasu : 308.

[0212]

(Reference Example 5) Synthesis of 3-hydroxymethyl-2-methoxy-5-pentafluorosulfur sulfonyl nitrobenzene:
[Chemical Formula 26]

　under ice cooling, methanol (2mL of the compound of Reference Example 4 (70.0 mg, 0.228 mmol) ) solution was added sodium borohydride (10.4 mg, 0.273 mmol). After stirring for 1 hour at the same temperature, the 1.0N hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography, (hexane: 1, Rf = 0.23: ethyl acetate = 3) the title compound (67 mg, 95%) (hereinafter, the compound of reference example 5) was obtained as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.97 (3H, s), 4.82-4.87 (2H, m), 8.12-8.21 (2H, m).
MS (ESI) [M Tasu H] Tasu : 310.

[0213]

Synthesis of Reference Example 6 3-hydroxy-2-methoxy-5-pentafluorosulfur sulfonyl aniline:
[formula 27]

　methanol (1.0 mL) solution of the compound of Reference Example 5 (57.0 mg, 0.184 mmol) to, platinum oxide (4.20mg, 0.0184mmol) was added. Under a hydrogen atmosphere, followed by stirring for 30 minutes, the catalyst is filtered, concentrated, and the resultant crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, Rf = 0.31 ) to give the title compound (49 mg, 95%) (hereinafter, the compound of reference example 6) was obtained as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (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 Tasu H] Tasu : 280.

[0214]

(Reference Example 7) 2,2,2-trichloroethyl (3-hydroxy-2-methoxy-5-pentafluorosulfur sulfonyl phenyl) carbamate:
[Formula 28]

　the compound of Reference Example 7 (49 mg, 0.18 mmol under ice-cooling in tetrahydrofuran (5.0 mL) in), chloroformate 2,2,2-trichloroethyl (0.02 mL, 0.21 mmol), was added diisopropylethylamine (0.04 mL, 0.21 mmol). After stirring for 3 hours at room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography, (hexane: 1, Rf = 0.38: ethyl acetate = 4) the title compound (71 mg, 87%) (hereinafter, the compound of reference example 7) was obtained as a colorless solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.88 (3H, s), 4.77-4.88 (4H, m), 7.37-7.47 (IH, m), 7.59-7.62 (1H, m), 8.46-8.58 (1H, m).
MS (ESI) [M Tasu H] Tasu : 455.

[0215]

(Reference Example 8) 1- (2-hydroxybenzyl) -3-(3- (hydroxymethyl) -2-methoxy-5- (pentafluorosulfanyl) phenyl) urea:
[Formula 29]

　the same manner as in Reference Example 1 according to the method, the compound of reference example 6 (200 mg), the title compound (73.3 mg) (hereinafter, the compound of reference example 8) was obtained as a colorless amorphous. (Chloroform: methanol 10
=: 1, Rf = 0.45) 1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.78 (3H, s), 4.41 (2H, d, J = 8 .0Hz), 4.75 (2H, d , J = 4.0Hz), 5.47 (1H, m), 6.83-6.87 (2H, m), 6.96 (1H, d, J = 8.0Hz), 7.10 (1H, dd, J = 8.0,4.0Hz), 7.53 (1H, d, J = 4.0Hz), 8.50 (1H, d, J = 4.0Hz), 8.93 (1H, brs ).
MS (ESI) [M Tasu H] Tasu : 429.

[0216]

(Example 2) 1- (3- (hydroxymethyl) -2-methoxy-5 - ((pentafluorosulfanyl) phenyl) -3- (2- (pyridin-4-ylmethoxy) benzyl) urea::
Formula 30]

　according to the same manner as in example 1, from the compound of reference example 8 (73 mg), to give the title compound (10 mg) (hereinafter, the compound of example 2) as a white oil (chloroform:. methanol = 10:
1, Rf = 0.42) 1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.62 (3H, s), 4.56 (2H, d, J = 4.0 Hz), 4.68 (2H, s), 5.10 ( 2H, s), 5.63 (1H, t, J = 8.0Hz), 6.89 (2H, d, J = 8.0Hz), 6.99 (1H , t, J = 8.0Hz), 7.08 (1H, s), 7.38 (IH, d, J = 4.0 Hz), 7.45 (IH, m), 8.52 (IH, d, J = 4.0 Hz), 8.56
(IH, m). MS (ESI) [ Tasu H M]

[0217]

(Reference Example 9) 2,2,2-trichloroethyl (2-methoxy-5- (trifluoromethoxy) phenyl) carbamate:
[Formula 31]

　according to the same manner as in Reference Example 7, 2-methoxy-5- from (trifluoromethoxy) aniline (3.0 g), the title compound (4.0 g) (hereinafter, the compound of reference example 9) was obtained.
(Hexane: ethyl acetate
1 =: 1, Rf = 0.31) MS (ESI) [M + H] + : 383.

[0218]

(Reference Example 10) 1- (2-hydroxybenzyl) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) urea:
[formula 32]

　according to the same manner as in Reference Example 1, 2-methoxy from 5- (trifluoromethoxy) aniline (500 mg), the title compound (427 mg) (hereinafter, the compound of reference example 10) was obtained as a colorless amorphous.
(Hexane: ethyl acetate
1 =: 1, Rf = 0.33) MS (ESI) [M + H] + : 357.

[0219]

(Example 3) 1- (2-methoxy-5- (trifluoromethoxy) phenyl) -3- (3-pyridin - ylmethoxy) benzyl) urea::
Formula 33]

　according to the same manner as in Example 1, from the compound of reference example 10 (100 mg) and 3- (bromomethyl) pyridine hydrobromide (106 mg), the title compound (55 mg) (hereinafter, the compound of example 3) was obtained as a white solid. (Hexane: ethyl acetate 1
=: 4, Rf = 0.28) 1 H-NMR (CDCl 3 , 400 MHz) [delta]: 3.76 (3H, s), 4.50 (2H, d, J = 4.0 Hz ), 5.10 (2H, s) , 5.29 (1H, t, J = 4.0Hz), 6.72-6.79 (2H, m), 6.93-6.99 (3H, m ), 7.25-7.32 (2H, m) , 7.37 (1H, dd, J = 8.0,4.0Hz), 7.78 (1H, d, J = 8.0Hz), 8 .15 (1H, d, J = 4.0Hz), 8.56 (1H, d, J = 4.0Hz), 8.64 (1H, s).
MS (ESI) [M Tasu H] Tasu : 448.

[0220]

(Example 4) 1- (2-methoxy-5- (trifluoromethoxy) phenyl) -3- (4-pyridin - ylmethoxy) benzyl) urea::
Formula 34]

　according to the same manner as in Example 1, from the compound of reference example 10 and (100 mg) 4-(chloromethyl) pyridine hydrobromide (106 mg), to give the title compound (48 mg) (hereinafter, the compound of example 4) as a white solid. (Hexane: ethyl acetate 1
=: 4, Rf = 0.24) 1 H-NMR (CDCl 3 , 400 MHz) [delta]: 3.77 (3H, s), 4.57 (2H, d, J = 4.0 Hz ), 5.13 (2H, s) , 5.36 (1H, t, J = 4.0Hz), 6.73-6.80 (2H, m), 6.87 (1H, d, J = 8 .0Hz), 6.97 (1H, t , J = 8.0Hz), 7.03 (1H, br), 7.25 (1H, td, J = 8.0,4.0Hz), 7.32 (2H, dd, J = 8.0,4.0Hz ), 7.40 (1H, dd, J = 8.0,4.0Hz), 8.17 (1H, d, J = 4.0Hz), 8.58 (2H, dd, J = 8.0,4.0Hz).
MS (ESI) [M Tasu H] Tasu : 448.

[0221]

(Reference Example 11) Ethyl 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) Synthesis of picolinic acid ester:
[of 35]

　Example according to the same manner as in 1, the compound of reference example 10 (67 mg) and ethyl 4- (chloromethyl) Pikorine - from preparative hydrochloride (30 mg), the title compound (40 mg) (hereinafter, the compound of reference example 11) as a white solid It was obtained as a. (Hexane: ethyl acetate
1 =: 1, Rf = 0.32) MS (ESI) [M + H] + : 520.

[0222]

(Example 5) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) Synthesis of picolinic acid amide:
[Chem 36]

　Reference Example 11 compound (30 mg, 0.06 mmol) in tetrahydrofuran / methanol solution, aqueous sodium hydroxide 1.0 N, was stirred overnight at room temperature. The pH was added to 1.0N hydrochloric acid to the reaction mixture was 5 or less, and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. N of the resulting crude product and hexafluorophosphate 2- (7-aza -1H- benzotriazole-1-yl) -1,1,3,3-tetramethyluronium (10 mg), N-dimethylformamide It was added triethylamine (5.2 mg) was added and stirred for 30 minutes at room temperature. Aqueous ammonia excess, and the mixture was stirred for 30 min followed. To the reaction solution, 1.0N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 10 1, Rf = 0.29) , the objective compound (10 mg, 35%) (hereinafter, compound of Example 5) as a white solid It was obtained as a.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.86 (3H, s), 4.50 (2H, d, J = 4.0 Hz), 5.30 (2H, s), 6.79 (1H, d, J = 8.0Hz ), 6.92-7.00 (3H, m), 7.24 (1H, t, J = 8.0Hz), 7.33 (1H, d, J = 8.0Hz), 7.69 (1H, d , J = 4.0Hz), 8.09 (1H, m), 8.18 (1H, s), 8.57 (1H, d, J = 8. 0Hz).
　　　　　　　MS (ESI) [M Tasu H] Tasu : 491.

[0223]

(Reference Example 12) 1- (2-hydroxybenzyl) -3- (2-methoxy-5- (trifluoromethyl) phenyl) urea:
[Formula 37]

　according to the same manner as in Reference Example 1, 2-methoxy -5-trifluoromethyl aniline (310 mg), the title compound (50 mg) (hereinafter, the compound of reference example 12) was obtained as a colorless foam. (Hexane: ethyl acetate
1 =: 1, Rf = 0.30) MS (ESI) [M + H] + : 341.

[0224]

(Example 6) 1- (2-methoxy-5- (trifluoromethyl) phenyl) -3- (3-pyridin - ylmethoxy) benzyl) urea::
Formula 38]

　according to the same manner as in Example 1, from the compound of reference example 12 (100 mg) and 3- (bromomethyl) pyridine hydrobromide (106 mg), the title compound (55 mg) (hereinafter, the compound of example 6) was obtained as a white solid. (Hexane: ethyl acetate 1
=: 4, Rf = 0.28) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.34 (3H, s), 4.34 (2H, d, J = 4 .0Hz), 4.58-4.71 (2H, m ), 4.96 (1H, t, J = 4.0Hz), 5.38-5.44 (1H, m), 6.76 (1H , d, J = 8.0Hz), 6.93 (1H, d, J = 8.0Hz), 7.12-7.24 (3H, m), 7.32 (1H, dd, J = 8. 0,4.0Hz), 7.40-7.51 (5H, m ), 7.63 (1H, d, J = 8.0Hz), 8.01 (1H, s), 8.29 (1H, s), 8.54 (1H, d , J = 2.0Hz).
MS (ESI) [M Tasu H] Tasu : 432.

[0225]

(Example 7) Methyl 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzoic acid ester:
Chemical Formula 39]

　Example according to the same manner as in 1, from methyl and the compound of reference example 10 (100mg) 4- (bromomethyl) benzoate (70.7 mg), the title compound (72 mg) (hereinafter, the compound of example 7) as a white solid Obtained. (Hexane: ethyl acetate 1
=: 1, Rf = 0.61) 1 H-NMR (CDCl 3 , 400 MHz) [delta]: 3.82 (3H, s), 3.92 (3H, s), 4.53 ( 2H, d, J = 8.0Hz) , 5.08 (1H, t, J = 4.0Hz), 5.19 (2H, s), 6.74-6.99 (3H, m), 6. 92 (1H, d, J = 8.0Hz), 6.97 (1H, t, J = 8.0Hz), 7.37 (1H, d, J = 8.0Hz), 7.50 (2H, d , J = 8.0Hz), 8.05 ( 2H, d, J = 8.0Hz), 8.14 (1H, s).
MS (ESI) [M Tasu H] Tasu : 505.

[0226]

(Example 8) 4 - Synthesis of - ((2 ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzoic acid:
Formula 40]

　Example 7 compound (60 mg, 0.12 mmol) in tetrahydrofuran / methanol solution, aqueous sodium hydroxide 1.0 N, was stirred overnight at room temperature. The pH was added to 1.0N hydrochloric acid to the reaction mixture was 5 or less, and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1, and purified by Rf = 0.48, title compound (18 mg, 31%)) (hereinafter, the compound of Example 8) as a white solid It was obtained as a.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.86 (3H, s), 4.36 (2H, d, J = 8.0 Hz), 5.27 (2H, s), 6.84 (1H, dd, J = 8.0,4.0Hz ), 6.94 (1H, t, J = 4.0Hz), 7.02-7.07 (2H, m), 7.22-7. 28 (2H, m), 7.34 (1H, t, J = 8.0Hz), 7.94 (2H, d, J = 8.0Hz), 8.21 (1H, s), 8.35 ( 1H, s).
MS (ESI) [M Tasu H] Tasu : 491.

[0227]

(Reference Example 13) Methyl 3 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzoic acid ester:
Chemical Formula 41]

　Example according to the same manner as in 1, from methyl and the compound of reference example 10 (100 mg) 3- (bromomethyl) benzoate (70.7 mg), the title compound (92 mg) (hereinafter, the compound of reference example 13) as a white solid Obtained. (Hexane: ethyl acetate 1
=: 1, Rf = 0.58) 1 H-NMR (CDCl 3 , 400 MHz) [delta]: 3.80 (3H, s), 3.91 (3H, s), 4.52 ( 2H, d, J = 8.0Hz) , 5.13 (1H, t, J = 4.0Hz), 5.18 (2H, s), 6.73-6.79 (2H, m), 6. 87 (1H, br), 6.93-6.99 (2H, m), 7.38 (1H, dd, J = 8.0,4.0Hz), 7.47 (1H, t, J = 8 .0Hz), 7.64 (2H, d , J = 8.0Hz), 8.00 (2H, d, J = 8.0Hz), 8.11 (1H, s), 8.15 (1H, s ).
MS (ESI) [M Tasu H] Tasu : 505.

[0228]

(Example 9) 3 - - (((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl (2) benzoic acid
[Formula 42]

　Example 8 according to a similar method, the compound of reference example 13 (92 mg), to give the title compound (62 mg) (hereinafter, the compound of example 9) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.45) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.86 (3H, s), 4.34 (2H, d, J = 4. 0Hz), 5.26 (2H, s ), 6.84 (1H, d, J = 8.0Hz), 6.95 (1H, t, J = 8.0Hz), 7.02 (1H, d, J = 12.0Hz), 7.08 (1H , d, J = 8.0Hz), 7.22-7.27 (3H, m), 7.36 (1H, br), 7.48-7. 52 (1H, m), 7.74 (1H, br), 7.89 (1H, d, J = 8.0Hz), 8.06 (1H, s), 8.19 (1H, d, J = 4.0Hz), 8.36 (1H, s ).
MS (ESI) [M Tasu H] Tasu : 491.

[0229]

(Reference Example 14) 2-methoxy-3-nitro-5- (trifluoromethyl) benzaldehyde Synthesis of:
Formula 43]

　according to the same manner as in Reference Example 4, 2-methoxy-5- (trifluoromethyl) benzaldehyde ( from 3.0 g), the title compound (3.2 g) (hereinafter, the compound of reference example 14) was obtained.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.15 (3H, s), 8.33 (2H, d, J = 2.2 Hz), 8.35 (2H, d, J = 2 .4Hz), 10.43 (1H, s ).

[0230]

(Reference Example 15) (2-methoxy-3-nitro-5- (trifluoromethyl) phenyl) methanol:
[Formula 44]

　according to the same manner as in Reference Example 5, the compound of Reference Example 14 (2.0 g) from the title compound (1.9 g) (hereinafter, the compound of reference example 15) was obtained. (Hexane: ethyl acetate 3
=: 1, Rf = 0.28) 1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 2.01 (IH, t, J = 5.9 Hz), 3.98 ( 3H, s), 4.87 (2H , d, J = 5.9Hz), 8.01 (1H, d, J = 1.8Hz), 8.06 (1H, d, J = 1.8Hz).

[0231]

(Reference Example 16) Synthesis of (3-amino-2-methoxy-5- (trifluoromethyl) phenyl) methanol:
[Chem 45]

　according to the same manner as in Reference Example 6, the compound of Reference Example 15 (1.0 g) from the title compound (0.84 g) (hereinafter, the compound of reference example 16) was obtained. (Hexane: ethyl acetate 2
=: 1, Rf = 0.32) 1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.96 (IH, s), 3.83 (3H, s), 3 .97 (2H, s), 4.74 (2H, s), 6.95 (1H, d, J = 1.4Hz), 7.04 (1H, s).
MS (ESI) [M Tasu H] Tasu : 222.

[0232]

(Reference Example 17) 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) Karubame - DOO Synthesis:
[Formula 46]

　in the same manner as in Reference Example 7 according to the method, the compound of reference example 16 (0.84 g), the title compound (1.2 g) (hereinafter, the compound of reference example 17) was obtained. (Hexane: ethyl acetate 2
=: 1, Rf = 0.43) 1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.90 (IH, t, J = 6.1 Hz), 3.89 ( 3H, s), 4.80 (2H , d, J = 5.9Hz), 4.87 (2H, s), 7.43 (1H, s), 7.46 (1H, d, J = 1. 4Hz), 8.37 (1H, s ).

[0233]

(Example 10) Methyl 4 - ((2 - ((3- (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzoic acid ester :
Formula 47]

　the compound of reference example 17 (30 mg, 0.08 mmol), methyl 4 - acetonitrile ((2- (aminomethyl) phenoxy) methyl) benzoate hydrochloride (21 mg), diisopropylethylamine (0.02 ml) ( 10mL) solution was stirred for 30 minutes at 0.99 ° C. using a microwave reaction device was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2, Rf = 0.71 ) to give the title compound (31 mg, 75%) white (hereinafter the compound of Example 10) It was obtained as a solid.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.70 (3H, s), 3.84 (3H, s), 4.39 (2H, d, J = 4.0 Hz), 4.59 (2H, d, J = 4.0Hz ), 5.28 (2H, s), 5.35 (1H, t, J = 4.0Hz), 6.96 (1H, t, J = 8.0Hz) , 7.07 (2H, d, J = 8.0Hz), 7.24-7.35 (4H, m), 7.64 (1H, d, J = 8.0Hz), 7.95 (2H, d, J = 8.0Hz), 8.43 (1H, s), 8.52 (1H, s).
MS (ESI) [M Tasu H] Tasu : 519.

[0234]

(Example 11) 4 - ((2 - ((3- (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzoic acid:
[ of 48]

　according to the same manner as in example 8, the compound of example 10 from (20 mg), to give the title compound (17 mg) (hereinafter, the compound of example 11) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.41) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.71 (3H, s), 4.38 (2H, d, J = 4. 0Hz), 4.59 (2H, s ), 5.28 (2H, s), 6.96 (1H, t, J = 8.0Hz), 7.07 (2H, d, J = 8.0Hz) , 7.22-7.36 (4H, m), 7.60 (2H, d, J = 8.0Hz), 7.95 (2H, d, J = 4.0Hz), 8.45 (1H, s), 8.52 (1H, d ).
MS (ESI) [M Tasu H] Tasu : 505.

[0235]

(Example 12) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzamide:
[Formula 49]

　The compound of Example 8 (20 mg, 0.04 mmol) and hexafluorophosphate 2- (7-aza -1H- benzotriazole-1-yl)-1,1,3,3 N tetramethyl uronium (23 mg, 0.06 mmol) , N- dimethylformamide solution, diisopropylethylamine (5.3 mg, 0.04 mmol) was added and stirred for 30 minutes at room temperature. Aqueous ammonia excess, and the mixture was stirred for 30 min followed. To the reaction solution, 1.0N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 10 1, Rf = 0.42) , the title compound (18 mg, 90%) (hereinafter, the compound of Example 12) as a white solid It was obtained as a.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.86 (3H, s), 4.35 (2H, d, J = 4.0 Hz), 5.24 (2H, s), 6.85 (1H, d, J = 8.0Hz ), 6.94 (1H, t, J = 8.0Hz), 7.02-7.06 (2H, m), 7.22-7.27 (2H, m), 7.30-7.40 (2H, m ), 7.56 (2H, d, J = 8.0Hz), 7.88 (2H, d, J = 8.0Hz), 7.96 ( 1H, br), 8.21 (1H , d, J = 4.0Hz), 8.36 (1H, s).
MS (ESI) [M Tasu H] Tasu : 490.

[0236]

(Example 13) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) -N- synthesis methylbenzamide:
[Chem 50]

　Embodiment compound of example 8 (12 mg, 0.04 mmol) and hexafluorophosphate 2- (7-aza -1H- benzotriazole-1-yl) -1,1,3,3-tetramethyluronium (14 mg, 0. N of 04Mmol), N- dimethylformamide was added triethylamine (5.2 mg, 0.04 mmol) was added and stirred for 30 minutes at room temperature. 40% methanol solution of dimethylamine excess was added and stirred for 30 min followed. To the reaction solution, water and 1.0N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4, Rf = 0.52 ) to give the title compound (7.2 mg, 58%) (hereinafter, the compound of Example 13) as a white solid.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 2.77 (3H, d, J = 8.0 Hz), 3.86 (3H, s), 4.35 (2H, d, J = 4. 0Hz), 5.24 (2H, s ), 6.85 (1H, d, J = 8.0Hz), 6.94 (1H, t, J = 8.0Hz), 7.02-7.06 ( 2H, m), 7.22-7.27 (2H , m), 7.34 (1H, t, J = 4.0Hz), 7.57 (2H, d, J = 8.0Hz), 7. 83 (2H, d, J = 8.0Hz), 8.21 (1H, d, J = 4.0Hz), 8.35 (1H, s), 8.40-8.50 (1H, m).
MS (ESI) [M + H] + : 504.

[0237]

(Example 14) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) -N, of N- dimethylbenzamide synthesized:
[Formula 51 ]

　according to the same manner as in example 13, the compound of example 8 from (20 mg), to give the title compound (17 mg) (hereinafter, the compound of example 14) as a white solid. (Chloroform: methanol 20
=: 1, Rf = 0.82) 1 H-NMR (MeOH-d 4 , 400 MHz) [delta]: 2.80 (3H, d, J = 8.0 Hz), 2.96 (3H, s), 3.08 (3H, s ), 3.87 (3H, s), 4.44 (2H, s), 5.21 (2H, s), 6.80 (1H, d, J = 8 .0Hz), 6.90-6.97 (2H, m ), 7.02 (1H, d, J = 8.0Hz), 7.23 (1H, t, J = 4.0Hz), 7.30 (2H, d, J = 8.0Hz ), 7.57 (2H, d, J = 12.0Hz), 8.11 (1H, d, J = 4.0Hz).
MS (ESI) [M Tasu H] Tasu : 518.

[0238]

(Example 15) N-(2-(diethylamino) ethyl) -4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzamide Synthesis of :
Formula 52]

　according to the same manner as in example 13, the compound of example 8 from (20 mg), the title compound (17 mg) (hereinafter, the compound of example 15) was obtained as a foam. (Amino silica gel, chloroform: methanol 20
=: 1, Rf = 0.75) 1 H-NMR (MeOH-d 4 , 400 MHz) [delta]: of 0.99 (6H, t, J = 8.0 Hz), 2.52 -2.63 (6H, m), 3.39 (2H, t, J = 8.0Hz), 3.77 (3H, s), 4.36 (2H, s), 5.14 (2H, s ), 6.70 (1H, dd, J = 8.0,4.0Hz), 6.82-6.86 (2H, m), 6.91 (1H, d, J = 8.0Hz), 7 .13 (1H, t, J = 4.0Hz), 7.21 (2H, dd, J = 8.0,4.0Hz), 7.48 (2H, d, J = 8.0Hz), 7. 71 (2H, d, J = 8.0Hz), 8.00 (1H, d, J = 4.0Hz).
MS (ESI) [M Tasu H] Tasu : 589.

[0239]

(Example 16) N-(2- (dimethylamino) ethyl) -4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzamide synthesis of:
Formula 53]

　according to the same manner as in example 13, the compound of example 8 from (20 mg), the title compound (17 mg) (hereinafter, the compound of example 16) was obtained as a foam. (Amino silica gel, chloroform: methanol 20
=: 1, Rf = 0.68) 1 H-NMR (MeOH-d 4 , 400 MHz) [delta]: 2.31 (6H, s), 2.57 (2H, t, J = 8.0Hz), 3.51 (2H, t, J = 8.0Hz), 3.87 (3H, s), 4.45 (2H, s), 5.23 (2H, s), 6. 78 (1H, dd, J = 8.0,4.0Hz), 6.91-6.96 (2H, m), 7.01 (1H, d, J = 8.0Hz), 7.22 (1H , t, J = 4.0Hz), 7.30 (1H, dd, J = 8.0,4.0Hz), 7.58 (2H, d, J = 8.0Hz), 7.82 (2H, d, J = 8.0Hz), 8.09 (1H, d, J = 4.0Hz).
MS (ESI) [M Tasu H] Tasu : 561.

[0240]

(Reference Example 18) tert-butyl (2- (4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) benzamido) ethyl) (methyl ) Karubame - DOO synthesis:
[Chem 54]

　according to the same manner as in example 5, to give the compound of example 8 from (50 mg), the title compound (32 mg) (hereinafter, the compound of reference example 18) as a foam It was. (Chloroform: methanol
20 =: 1, Rf = 0.70) MS (ESI) [M + H] + : 647.

[0241]

(Example 17) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) methyl) N- of (2- (methylamino) ethyl) benzamide synthesis:
[of 55]

　the compound of reference example 18 (15 mg, 0.02 mmol) in methanol was added hydrogen chloride 4.0 N - dioxane, and the mixture was allowed to stand at room temperature for one hour. After the reaction mixture was concentrated, basified conditions, methanol-containing chloroform (chloroform: methanol = 95: 5, v / v ) and extracted with. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino silica gel, chloroform: methanol = 10: 1, Rf = 0.52 ) to give the title compound (8.2 mg) (hereinafter, the compound of Example 17) It was obtained as an oily substance.
1 H-NMR (MeOH-d 4 , 400 MHz) [delta]: 2.41 (3H, s), 2.78 (2H, br), 3.51 (2H, br), 3.87 (3H, s), 4.45 (2H, s), 5.23 (2H, s), 6.80 (1H, d, J = 8.0Hz), 6.91-6.96 (2H, m), 7.01 ( 1H, d, J = 8.0Hz) , 7.22 (1H, t, J = 4.0Hz), 7.30 (1H, d, J = 8.0Hz), 7.58 (2H, d, J = 8.0Hz), 7.82 (2H, d, J = 8.0Hz), 8.09 (1H, d, J = 4.0Hz).
MS (ESI) [M Tasu H] Tasu : 547.

[0242]

(Reference Example 19) 2,2,2-trichloroethyl (2-methoxy-5- (trifluoromethyl) phenyl) carbamate:
[Formula 56]

　according to the same manner as in Reference Example 7, 2-methoxy-5- (trifluoromethyl) aniline (5.0 g), the title compound (7.8 g) (hereinafter, the compound of reference example 19) was obtained.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.97 (3H, s), 4.86 (2H, s), 6.95 (IH, d, J = 8.5 Hz), 7. 33 (1H, dd, J = 8.9,1.8Hz), 7.52 (1H, s), 8.42 (1H, s).
MS (ESI) [M Tasu H] Tasu : 366.

[0243]

(Example 18) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzamide:
[Formula 57]

　as in Example 10 according to the method, the compound of reference example 19 and (30 mg) 4 - from ((2- (aminomethyl) phenoxy) methyl) benzamide hydrochloride (23 mg), the title compound (21 mg) (hereinafter, the compound of example 18) It was obtained as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.32) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.92 (3H, s), 4.37 (2H, d, J = 4. 0Hz), 5.25 (2H, s ), 6.94 (1H, t, J = 8.0Hz), 7.06 (1H, d, J = 8.0Hz), 7.14 (2H, d, J = 8.0Hz), 7.22-7.27 (3H , m), 7.33-7.40 (2H, m), 7.56 (2H, d, J = 8.0Hz), 7. 88 (2H, d, J = 8.0Hz), 7.97 (1H, br), 8.36 (1H, s), 8.54 (1H, d, J = 4.0Hz).
MS (ESI) [M Tasu H] Tasu : 474.

[0244]

(Example 19) 4 - ((2 - ((3- (3- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzamide:
[Formula 58]

　according to the same manner as in Example 10, 2,2,2-trichloroethyl and (3- (trifluoromethyl) phenyl) carbamate (30 mg) 4 - ((2-(aminomethyl) phenoxy) methyl) benzamide hydrochloride (23 mg), the title compound (23 mg) (hereinafter, the compound of example 19) was obtained as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.49) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.37 (2H, d, J = 4.0 Hz), 5.25 (2H, s), 6.62 (1H, t , J = 4.0Hz), 6.94 (1H, t, J = 8.0Hz), 7.05 (1H, d, J = 8.0Hz), 7. 21-7.27 (3H, m), 7.37 (1H, br), 7.43-7.51 (2H, m), 7.57 (2H, d, J = 8.0Hz), 7. 89 (2H, d, J = 8.0Hz), 7.98 (1H, br).
MS (ESI) [M Tasu H] Tasu : 444.

[0245]

(Example 20) 4 - ((2 - ((3- (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzamide:
[Formula 59]

　according to the same manner as in example 10, the compound of reference example 17 (30 mg) and 4 - from ((2- (aminomethyl) phenoxy) methyl) benzamide hydrochloride (19 mg), the title compound (21 mg) (hereinafter, the compounds) of example 20 was obtained as a white solid. (Hexane: ethyl acetate 1
=: 4, Rf = 0.27) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.72 (3H, s), 4.36 (2H, d, J = 8 .0Hz), 4.59 (2H, d , J = 8.0Hz), 5.25 (2H, s), 5.34 (1H, t, J = 4.0Hz), 6.95 (1H, t , J = 8.0Hz), 7.06 ( 2H, d, J = 8.0Hz), 7.22-7.36 (5H, m), 7.56 (2H, d, J = 8.0Hz) , 7.88 (2H, d, J = 8.0Hz), 8.46 (1H, s), 8.52 (1H, d, J = 4.0Hz).
MS (ESI) [M + H] + : 504.

[0246]

(Example 21) 3 - ((2 - ((3- (2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzamide:
[Formula 60]

　as in Example 10 according to the method, the compound of reference example 19 and (30 mg) 3 - from ((2- (aminomethyl) phenoxy) methyl) benzamide hydrochloride (21 mg), the title compound (21 mg) (hereinafter, the compound of example 21) It was obtained as a foam-like substance. (Chloroform: methanol 10
=: 1, Rf = 0.53) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.91 (3H, s), 4.35 (2H, d, J = 4. 0Hz), 5.22 (2H, s ), 6.95 (1H, t, J = 8.0Hz), 7.09 (1H, d, J = 12.0Hz), 7.13 (1H, d, J = 8.0Hz), 7.22-7.27 (3H , m), 7.34 (1H, t, J = 8.0Hz), 7.40-7.52 (2H, m), 8. 39 (1H, s), 8.53 (1H, d, J = 2.0Hz).
MS (ESI) [M Tasu H] Tasu : 474.

[0247]

(Example 22) 3 - ((2 - ((3- (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) methyl) benzamide:
[Formula 61]

　according to the same manner as in example 10, the compound of reference example 17 (30 mg) and 3 - from ((2- (aminomethyl) phenoxy) methyl) benzamide hydrochloride (19 mg), the title compound (19 mg) (hereinafter, to give the compound) of example 22 as a foam. (Chloroform: methanol 10
=: 1, Rf = 0.50) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.71 (3H, s), 4.36 (2H, d, J = 8. 0Hz), 4.59 (2H, d , J = 8.0Hz), 5.23 (2H, s), 5.35 (1H, t, J = 4.0Hz), 6.96 (1H, t, J = 8.0Hz), 7.08 (1H , d, J = 8.0Hz), 7.22-7.30 (3H, m), 7.40-7.50 (3H, m), 7. 66 (2H, d, J = 8.0Hz), 7.82 (2H, d, J = 8.0Hz), 7.998.10 (2H, m), 8.45 (1H, s), 8. 51 (1H, d, J = 2.0Hz).
MS (ESI) [M + H] + : 504.

[0248]

(Example 23) 1- (2-methoxy-5-pentafluorosulfur sulfonyl) -3- (2- (pyridin-4-yloxy) benzyl) urea: hydrochloride
[formula 62]

　the compound of Reference Example 1 (815 mg, 2.05 mmol) N, N-dimethylformamide (3.0 mL) of sodium hydride (mineral oil in 55 wt%, 98 mg, 2.3 mmol) of was added under ice cooling, stirred for 15 minutes at room temperature did. Again, ice-cooled, 2-chloro-4-nitropyridine (389 mg, 2.45 mmol) and the mixture was stirred for 2 hours at room temperature. After the reaction was terminated by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting diethyl ether was added to the crude product, the precipitated white solid was collected by filtration (510mg, 49%). The resulting intermediate was dissolved in methanol (5.0 mL), 10 wt% palladium - carbon (50 wt% water, 50 mg) was added, under hydrogen atmosphere and stirred overnight at room temperature. The reaction mixture was through Celite® filtration, the filtrate was concentrated under reduced pressure. The resulting residue diethyl ether was added, and the precipitated solid was collected by filtration to give the title compound by drying (490 mg, quant) (hereinafter, the compound of Example 23) was obtained as a white solid.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta] (ppm): 3.92 (3H, s), 4.25 (2H, d, J = 4.0 Hz), 7.12 (2H, d, J = 8.0Hz), 7.25-7.35 (3H, m), 7.39-7.49 (4H, m), 7.55 (1H, d, J = 8.0Hz), 8.22 (1H, brs), 8.65 ( 1H, brs), 8.70 (2H, brs).
MS (ESI) [M Tasu H] Tasu : 476.

[0249]

(Reference Example 20) 1- (2 - ((2-chloro-4-yl) oxy) benzyl) -3- (2-methoxy-5- (pentafluorosulfanyl) phenyl) urea:
[Formula 63]

　under ice-cooling, the compound (5.0 g, 12.6 mmol) of reference example 1 N of, N- dimethylformamide (10 mL) sodium hydride solution (mineral oil in 55 wt%, 602 mg, 13.8 mmol) was added, It was stirred at room temperature for 15 minutes. Then 2,4-dichloropyrimidine (2.24 g, 15.1 mmol) was added. After stirring for 2 hours at room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, diethyl ether was added and stirred overnight at room temperature. The precipitated white solid was collected by filtration to give the title compound (3.6 g, 56%) (hereinafter, the compound of Reference Example 20) was obtained.
MS (ESI) [M Tasu H] Tasu : 511.

[0250]

(Example 24) 1-(2 - ((2- (1H-imidazo - 1-yl) pyrimidin-4-yl) oxy) benzyl) -3- (2-methoxy-5- (pentafluorosulfanyl) phenyl) urea:
[Formula

　64] the compound of reference example 20 under 60 ℃ (20mg, 0.039mmol), 1H- imidazole (35 mg, 0.52 mmol), ethanol triethylamine (0.077 mL, 0.55 mmol) (4.0 mL) the solution was stirred for 192 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20 1, Rf = 0.40) , the title compound (9.9 mg, 47%) (hereinafter, the compound of Example 24) Obtained.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta] (ppm): 3.86 (3H, s), 4.28 (2H, d, J = 5.4 Hz), 6.97-7.08 (3H , m), 7.29-7.60 (7H, m), 8.21-8.23 (2H, m), 8.62-8.64 (2H, m).

[0251]

(Example 25) Methyl 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) benzoic acid ester:
Chemical Formula 65]

　Reference Example 11 compound (400mg, 1.04mmol), methyl 4-fluoro-benzoic acid (208mg, 1.55mmol), 150 ℃ using a microwave reaction device N, N- dimethylformamide solution of potassium carbonate (326 mg, 2.36 mmol) after stirring in 30 minutes, and concentrated under reduced pressure to give crude product was purified by silica gel column chromatography. (hexane: ethyl acetate = 1: 1, Rf = 0.49 ) to give the title compound (19 mg, 3.4 %) (hereinafter, the compound) of example 25 was obtained as a white
solid. 1 H-NMR (CDCl 3 , 400 MHz) [delta]: 3.8 1 (3H, s), 3.89 (3H, s), 4.45 (2H, d, J = 4.0Hz), 4.95 (1H, t, J = 4.0Hz), 6.73- 6.79 (3H, m), 6.94-6.99 (3H, m), 7.21 (1H, td, J = 8.0,4.0Hz), 7.32 (1H, t, J 8.0 Hz =), 7.54 (IH, dd, J = 8.0,4.0Hz), 8.00 (2H, d, J = 8.0 Hz), 8.09 (IH,
s). MS (ESI) [M Tasu H] Tasu : 491.

[0252]

(Example 26) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) benzoic acid:
[formula 66]

　in the same manner as in Example 8 according to the method, the compound of example 25 from (20 mg), to give the title compound (16 mg) (hereinafter, the compound of example 26) as a white solid. (chloroform: methanol = 10: 1, Rf =
0.34) 1 -NMR H (DMSO-d 6 , 400 MHz) [delta]: 3.86 (3H, s), 4.25 (2H, d, J = 4.0 Hz), 6.84 (IH, dd, J = 8.0 , 4.0Hz), 6.97-7.00 (3H, m), 7.03-7.06 (2H, m), 7.26 (1H, td, J = 8.0,4.0Hz) , 7.32-7.41 (2H, m), 7.45 (1H, dd, J = 8.0
. 4.0 Hz), 7.93 (2H, d, J = 8.0 Hz), 8.15 (IH, s), 8.29 (IH, s) MS (ESI) [M + H] + : 477.

[0253]

(Example 27) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 67]

　the same manner as in Example 12 according, the compound of example 26 from (15 mg), the title compound (11 mg) (hereinafter, the compound of example 27) was obtained as a foam. (chloroform: methanol = 10: 1, R =
0.43) 1 -NMR H (DMSO-d 6 , 400 MHz) [delta]: 3.86 (3H, s), 4.26 (2H, d, J = 4.0 Hz), 6.85 (IH, dd, J = 8.0 , 4.0Hz), 6.94-7.04 (3H, m), 7.22-7.35 (3H, m), 7.42-7.45 (2H, m), 7.90 (2H , d, J = 8.0Hz), 8.15 (1H, s), 8.33 (1H, s .
MS (ESI) [M Tasu H] Tasu : 476.

[0254]

Synthesis of (Example 21) Ethyl 4- (2-cyanophenoxy) benzoate:
[of 68]

　Ethyl 4-fluorobenzoate (2.0 g, 13.5 mmol), 2-hydroxybenzonitrile (3.11 g, 26 .0Mmol) and potassium carbonate (3.48 g, 25.0 mmol) of N- methyl-2-pyrrolidone solution (10 mL) for 8 hours at 170 ° C., the mixture was stirred under heating. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica The resulting crude product was gel column chromatography (hexane: ethyl acetate = 1: 1, Rf = 0.71) to give the title compound (1. 2 g, 33%) (hereinafter, the compound of reference example 21) was obtained as an oily substance.
MS (ESI) [M Tasu H] Tasu : 268.

[0255]

Synthesis of (Reference Example 22) Ethyl 4- (2- (aminomethyl) phenoxy) benzoate:
[of 69]

　compound (0.15 g, 0.56 mmol) of Reference Example 21 Raney nickel in methanol (10 mL) of ( dispersion in water 50 wt%, 3.0 ml) was added, under hydrogen atmosphere and stirred at room temperature for 10 hours. After removal of Raney Nickel by Celite® filtration, concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amino silica gel, chloroform: methanol = 10: 1, Rf = 0.28 ) to give the title compound (0.082 g, 54%) (hereinafter, Reference Example 22 compound) as an oily substance.
MS (ESI) [M Tasu H] Tasu : 272.

[0256]

(Reference Example 23) 4- (2 - (( (tert- butoxycarbonyl) amino) methyl) phenoxy) benzoic acid:
[Chem 70]

　the compound of Reference Example 21 (1.5 g, 5.6 mmol) and Reference Example perform catalytic reduction under the same conditions as 22, it was added celite (R) saturated sodium bicarbonate solution which corresponds to half volume in methanol solution obtained after filtration. There di tert- butyl (1.35 g, 6.2 mmol) was added and stirred at room temperature overnight. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product (1.5 g). In tetrahydrofuran / methanol solution of the resulting crude product was added sodium hydroxide solution 1.0 N, was stirred overnight at room temperature. The pH was adjusted to 5 or less with 1.0N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 10 1, Rf = 0.32) , the title compound (1.41 g, 73%) (hereinafter, the compound of Reference Example 23) and as a pale yellow solid.
MS (ESI) [M Tasu H] Tasu : 344.

[0257]

(Reference Example 24) Methyl 4- Synthesis of (2- (aminomethyl) phenoxy) benzoate:
[of 71]

　in a methanol solution of the compound of Reference Example 23 (90 mg), hydrogen chloride 4.0 N-1,4 - dioxane solution, and the mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (80 mg) (hereinafter, the compound of Reference Example 24) as a white solid.
MS (ESI) [M Tasu H] Tasu : 258.

[0258]

(Reference Example 25) Synthesis of 4 (2- (aminomethyl) phenoxy) benzamide hydrochloride
[formula 72]

　the compound of Reference Example 23 (0.2 g, 0.58 mmol) and hexafluorophosphate 2- (7- aza -1H- benzotriazole-1-yl) -1,1,3,3-tetramethyluronium (244 mg, N of 0.64 mmol), N- dimethylformamide solution, diisopropylethylamine (113 mg) was added, at room temperature in the mixture was stirred for 30 minutes. Ammonia 7.0 N - methanol solution excess added, and the mixture was stirred for 30 min followed. To the reaction solution, water and 1.0N hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10 1, Rf = 0.42) , to give the intermediate as a white solid. The methanol solution of the resulting white solid was added hydrogen chloride-1,4-dioxane solution of 4.0 N, and allowed to stand overnight at room temperature. Concentrated under reduced pressure to give the title compound (80 mg, 57%) (hereinafter, the compound of Reference Example 25) as a white solid.
MS (ESI) [M Tasu H] Tasu : 243.

[0259]

(Example 28) 4 - ((2 - ((3- (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzoic acid:
[Formula 73 ]

　according to a similar manner to example 10, from the compound of reference example 17 (42 mg) and the compound of reference example 22 (27 mg), according to the same manner as was obtained. example 8 ethyl ester derivative (35 mg) as an intermediate , from the obtained ethyl ester derivative (27 mg), the title compound (21 mg) (hereinafter, the compound of example 28) was obtained as a white solid. (chloroform: methanol = 10: 1, Rf =
0.28) 1 H- NMR (DMSO-d 6 , 400 MHz) [delta]: 3.69 (3H, s), 4.28 (2H, d, J = 4.0 Hz), 4.58 (2H, s), 5.33 (IH, rs), 6.99 (2H, dd , J = 8.0,4.0Hz), 7.04 (1H, d, J = 8.0Hz), 7.25-7.29 (2H, m), 7.34-7.41 (2H, m), 7.48 (1H, d, J = 8.0Hz), 7.93 (2H, dd, J = 8.0,4.0Hz), 8.40
. (IH, s), 8.44 (IH, d, J = 2.0 Hz) MS (ESI) [M + H] + : 491.

[0260]

(Example 29) 4 - ((2 - ((3- (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 74]

　according to the same manner as in example 12, the compound of example 28 from (30 mg), to give the title compound (18 mg) (hereinafter, the compound of example 29) as a white solid (chloroform:. methanol = 10: 1, Rf 0.32
=) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.70 (3H, s), 4.29 (2H, d, J = 4.0 Hz), 6.95-7.01 (3H, m), 7.23-7.48 ( 6H, m), 7.89 (1H, s), 7.91 (2H, s), 8.43 (1H, s), 8.45 ( IH,
d, J = 2.0 Hz). MS (ESI) [M + H] + 490.

[0261]

(Example 30) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzoic acid:
[formula 75]

　in the same manner as in Example 10 according to the method, the compound (42 mg) and the compound of reference example 22, reference example 19 (27 mg), was obtained ethyl ester derivative (32 mg) as an intermediate. according to the same manner as in example 8, the obtained ethyl ester derivative ( from 32 mg), to give the title compound (23 mg) (hereinafter, the compound of example 30) as a white solid (chloroform:. methanol =
10: 1, Rf = 0.42) 1 H-NMR (DMSO-d 6 , 400MHz) δ: 3.91 (3H, s), 4.26 (2H, d, J = 8.0Hz), 6.99 (2H, dd, J = 8.0,4.0Hz), 7.04 (1H, , J = 8.0Hz), 7.12 ( 1H, d, J = 8.0Hz), 7.22-7.29 (2H, m), 7.34-7.47 (3H, m), 7 .93 (2H, dd, J = 8.0,4.0Hz), 8.32 (IH, s), 8.49 (IH,
d, J = 2.0 Hz). MS (ESI) [M + H] + : 461.

[0262]

(Example 31) 4 - ((2 - ((3- (2-methoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 76]

　the same manner as in Example 13 according, the compound of example 30 from (30 mg), to give the title compound (19 mg) (hereinafter, the compound of example 31) as a white solid. (chloroform: methanol = 10: 1, Rf =
0.40) 1 H -NMR (DMSO-d 6 , 400 MHz) [delta]: 3.92 (3H, s), 4.27 (2H, d, J = 8.0 Hz), 6.96-7.00 (3H, m), 7 .13 (1H, d, J = 8.0Hz), 7.22-7.36 (4H, m), 7.40-7.45 (2H, m), 7.90 (3H, d, J = 8.0Hz), 8.36 (1H, s ), 8.49 (1H, d, J = 2.
. Hz) MS (ESI) [M Tasu H] Tasu : 460.

[0263]

(Example 32) 4 - ((2 - ((3- (5- (Synthesis of trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide
[reduction 77]

　according to the same manner as in Example 10, phenyl ( 3- (trifluoromethyl) phenyl) Karubame -. DOO (30 mg) and the compound of reference example 22 from (29 mg), was obtained ethyl ester derivative according to the same manner as in example 8, the carboxylic acid from the obtained ethyl ester derivative . following the same method as derivatives obtained in example 12, from the obtained carboxylic acid derivative to give the title compound (18 mg) (hereinafter, the compound of example 32) as a white solid (chloroform:. methanol = 10: 1 ,
Rf = 0.47) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.28 (2H, d, J = 8.0 Hz), 6.7 (1H, t, J = 8.0Hz ), 6.96-7.00 (3H, m), 7.22-7.36 (4H, m), 7.42-7.51 (3H, m) , 7.90 (3H, d, J = 8.0
Hz), 7.96 (IH, s). MS (ESI) [M + H] + : 430.

[0264]

(Reference Example 26) 2,2,2-trichloroethyl (2- (oxetan-3-yloxy) -5- (trifluoromethyl) phenyl) carbamate:
[Formula 78]

　under ice-cooling with 1-chloro-2 - N nitro-4- (trifluoromethyl) benzene (3.2 g, 5.2 mmol), N-dimethylformamide solution (20 mL), sodium hydride (in mineral oil 55 wt%, 0.41g, 7. 6mmol) was added. After stirring for 30 minutes at room temperature, it was added oxetane-3-ol (3.2 g, 43 mmol). After stirring overnight at room temperature, the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. In methanol (20 mL) of the crude product obtained under room temperature, 10 wt% palladium - carbon (50 wt% water, 0.10 g) was added, under hydrogen atmosphere and stirred for 5 hours. The reaction mixture was Celite® filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. Under ice-cooling, the crude product obtained, diisopropylethylamine (3.8 mL, 22 mmol) in tetrahydrofuran (30 mL) of was added chloroformate 2,2,2-trichloroethyl (3.3 g, 16 mmol). After stirring overnight at room temperature, the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product with hexane: diethyl ether (20: 1) was recrystallized from a mixed solution of, and the precipitated solid is isolated by filtration to give the title compound (3.8 g, 66%) (hereinafter, Reference Example 26 the compound) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.83 (2H, dd, J = 8.3,5.1Hz), 4.88 (2H, s), 5.05 (2H, dd , J = 7.7,6.7Hz), 5.29-5.35 ( 1H, m), 6.49 (1H, d, J = 8.5Hz), 7.29 (1H, d, J = 2.0Hz), 7.46 (1H, s ), 8.47 (1H, s).
MS (ESI) [M + H] + : 408.

[0265]

(Reference Example 27) 2,2,2-trichloroethyl (2- (oxetan-3-yloxy) -5- (trifluoromethoxy) phenyl) carbamate:
[Formula 79]

　according to the same manner as in Reference Example 26, from 1-chloro-2-nitro-4- (trifluoromethoxy) benzene (0.5 g), the title compound (0.12 g) (hereinafter, the compound of reference example 27) was obtained as an oily substance. Incidentally, purification of title compound was performed by column chromatography. (Hexane: ethyl acetate
1 =: 1, Rf = 0.40) MS (ESI) [M + H] + : 424.

[0266]

(Example 33) 4- (2 - ((3- (2- (oxetan-3-yloxy) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 80]

　Example according to the same manner as 10, the compound of reference example 25 (30 mg) and the compound of reference example 26 (20 mg), to give the title compound (21 mg) (hereinafter, the compound of example 33) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.35) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.31 (2H, d, J = 8.0 Hz), 4.63-4. 67 (2H, m), 4.98 (2H, t, J = 8.0Hz), 5.41 (1H, t, J = 4.0Hz), 6.76 (1H, d, J = 8.0Hz ), 6.94-7.01 (3H, m) , 7.18 (1H, d, J = 8.0Hz), 7.24-7.37 (3H, m), 7.45-7.50 (2H, m), 7.80-7.90 ( 3H, m), 8.29 (1H, s), 8.54 (1H, s).
MS (ESI) [M + H] + : 502.

[0267]

(Example 34) 4- (2 - ((3- (2- (oxetan-3-yloxy) -5- (trifluoromethoxy) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 81]

　Example according to the same manner as 10, from the compound of reference example 25 (40 mg) and the compound of reference example 27 (42 mg), to give the title compound (16 mg) (hereinafter, the compound of example 34) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.32) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.29 (2H, d, J = 8.0 Hz), 4.62-4. 68 (2H, m), 4.95 (2H, t, J = 8.0Hz), 5.33 (1H, t, J = 4.0Hz), 6.66 (1H, d, J = 8.0Hz ), 6.80 (1H, dd, J = 8.0,4.0Hz), 6.95-7.01 (3H, m), 7.24-7.37 (3H, m), 7.47 -7.50 (2H, m), 7.89-7.91 (3H, m), 8.21 (1H, d, J = 2.0Hz), 8.24 (1H, s).
MS (ESI) [M Tasu H] Tasu : 518.

[0268]

(Reference Example 28) Methyl 3-amino-5- (trifluoromethyl) benzoic acid ester:
Chemical Formula

　82] 3-nitro-5- (trifluoromethyl) benzoic acid (1.0 g, 4.2 mmol) and 8 hours a methanol solution of p- toluenesulfonic acid (0.05 g), while heating under reflux and stirred. After returning to room temperature and concentrated in vacuo. The resulting residue was dissolved in methanol, 5.0 wt% palladium - carbon (50 wt% water, 0.2 g) was added, under hydrogen atmosphere for 3 hours, and stirred at room temperature. The reaction mixture was through Celite® filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, Rf = 0.47 ) to give the title compound (0.85 g, 91%) (hereinafter, the compound of Reference Example 28) It was obtained as an oily substance.
MS (ESI) [M Tasu H] Tasu : 220.

[0269]

(Reference Example 29) Synthesis of methyl 4-amino-2- (trifluoromethyl) benzoate:
[of 83]

　according to the same manner as in Reference Example 28, 4-nitro-6- (trifluoromethyl) benzoic acid ( from 1.0 g), the title compound (0.9 g) (hereinafter, the compound of reference example 29) was obtained in oily substance.
(Hexane: ethyl acetate
2 =: 1, Rf = 0.48) MS (ESI) [M + H] + : 220.

[0270]

(Reference Example 30) (3-amino-5- (trifluoromethyl) phenyl) methanol:
[Formula 84]

　the compound of Reference Example 28 (0.4 g, 1.8 mmol) under ice cooling tetrahydrofuran, lithium aluminum hydride (0.22 g, 5.7 mmol) was added portionwise number of times. The resulting reaction mixture was returned to room temperature and stirred for 1 hour. Water was added to the reaction mixture, after stopping the reaction, and extracted with ethyl acetate, saturated aqueous ammonium chloride solution, and a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, Rf = 0.32 ) to give the title compound (0. 32 g, 92%) (hereinafter, to give the compound) of reference example 30 as a white solid.
MS (ESI) [M Tasu H] Tasu : 192.

[0271]

(Reference Example 31) (4-amino-2- (trifluoromethyl) phenyl) methanol:
[Formula 85]

　according to the same manner as in Reference Example 30, from the compound of Reference Example 29 (0.4 g), the title compound (0.31 g) (hereinafter, the compound of reference example 31) was obtained as an oily substance.
(Hexane: ethyl acetate
2 =: 1, Rf = 0.49) MS (ESI) [M + H] + : 192.

[0272]

(Reference Example 32) 2,2,2-trichloroethyl (3- (hydroxymethyl) -5- (trifluoromethyl) phenyl) Karubame - DOO Synthesis:
[Chem 86]

　according to the same manner as in Reference Example 7, reference compound of example 30 from (0.32 g), the title compound (0.13 g) (hereinafter, the compound of reference example 32) as a white solid.
(Hexane: ethyl acetate
2 =: 1, Rf = 0.51) MS (ESI) [M + Na] + : 388.

[0273]

(Reference Example 33) 2,2,2-trichloroethyl (4- (hydroxymethyl) -3- (trifluoromethyl) phenyl) Karubame - DOO Synthesis:
[Chem 87]

　according to the same manner as in Reference Example 32, Reference compound of example 31 from (0.13 g), the title compound (0.16 g) (hereinafter, the compound of reference example 33) as a white solid. (Hexane: ethyl acetate
2 =: 1, Rf = 0.61) MS (ESI) [M + H] + : 348.

[0274]

(Example 35) 4 - ((3- (3- (hydroxymethyl) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide - ((2
[formula 88]

　Example 10 according to a similar method, the compound of reference example 25 (40 mg) and the compound of reference example 32 (61 mg), to give the title compound (46 mg) (hereinafter, the compound of example 35) as a white solid (chloroform:. methanol =
10: 1, Rf = 0.27) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.27 (2H, d, J = 4.0 Hz), 4.51 (2H, d, J = 8 .0Hz), 5.36 (1H, t , J = 4.0Hz), 6.68 (1H, br), 6.99-7.00 (3H, m), 7.17 (1H, br), 7.23 (1H, t, J = 8.0Hz), 7.3 -7.35 (2H, m), 7.24-7.45 (2H, m), 7.82 (1H, s), 7.90 (3H, d, J = 8.0Hz), 9.02
. (IH, s) MS (ESI) [M + H] + : 460.

[0275]

(Example 36) 4- (2 - ((3- (4- (hydroxymethyl) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 89]

　as in Example 10 according to the method, the compound of reference example 25 (40 mg) and the compound of reference example 33 (61 mg), to give the title compound (42 mg) (hereinafter, the compound of example 36) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.26) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.27 (2H, d, J = 4.0 Hz), 4.56 (2H, d, J = 4.0Hz), 5.32 (1H, t, J = 4.0Hz), 6.66 (1H, br), 6.96-7.00 (3H, m), 7.23 ( 1H, t, J = 8.0Hz) , 7.29-7.35 (2H, m), 7.43 (2H, d, J = 8.0Hz), 7.51 (2H, d, J = 8 .0Hz), 7.58 (2H, d , J = 8.0Hz), 7.90 (4H, d, J = 8.0Hz), 8.94 (1H, s).
MS (ESI) [M-OH] Tasu : 452.

[0276]

(Example 37) 4- (2 - ((3- (3 - ((4-methylpiperazin-1-yl) methyl) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide Synthesis of:
Formula 90]

　the compound of example 35 (20 mg, 0.04 mmol) and diisopropylethylamine (5.5 mg, 0.042 mmol) in tetrahydrofuran, under ice-cooling, methanesulfonyl chloride (5.5 mg, 0.048 mmol) added. After stirring for 30 min, 1-methylpiperazine (10 mg, 0.1 mmol) was added, while returning to room temperature and stirred overnight. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica The resulting crude product was gel column chromatography (amino silica gel, chloroform: methanol = 10: 1, Rf = 0.52 ) to give the title compound ( 5.0 mg, 21%) (hereinafter, to give the compound) of example 37 as a white solid.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 2.14 (3H, s), 2.35 (6H, bs), 3.43 (2H, s), 4.27 (2H, d, J = 4.0Hz), 6.66 (1H, t, J = 4.0Hz), 6.95-7.00 (3H, m), 7.10 (1H, br), 7.23 (1H, t , J = 8.0Hz), 7.26-7.35 ( 2H, m), 7.43 (2H, br), 7.82 (1H, s), 7.90 (3H, d, J = 8 .0Hz), 9.05 (1H, s ).
MS (ESI) [M Tasu H] Tasu : 542.

[0277]

(Example 38) 4- (2 - ((3- (4 - ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide Synthesis of:
Formula 91]

　according to the same manner as in example 35, the compound of example 36 from (20 mg), to give the title compound (5.0 mg) (hereinafter, the compound of example 38) as a white solid.
(Amino silica gel, chloroform: methanol 10
=: 1, Rf = 0.48) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 2.14 (3H, s), 2.35 (6H, br), 3.49 (2H, s), 4.27 (2H, d, J = 4.0Hz), 6.69 (1H, t, J = 4.0Hz), 6.95-7.00 (3H, m ), 7.23 (1H, t, J = 8.0Hz), 7.26-7.35 (2H, m), 7.41 (1H, d, J = 4.0Hz), 7.48 (1H , d, J = 8.0Hz), 7.50-7.56 (1H, m), 7.89-7.91 (4H, m), 8.99 (1H, s).
MS (ESI) [M Tasu H] Tasu : 542.

[0278]

(Reference Example 34) tert-butyl 4- (3 - (((2,2,2-trichloroethoxycarbonyl) carbonyl) amino) -5- (trifluoromethyl) benzyl) piperazine-1-carboxylate The synthesis of:
[Formula 92]

　the compound of reference example 32 (140 mg, 0.4 mmol) and diisopropylethylamine (223 mg, 1.7 mmol) in tetrahydrofuran, under ice-cooling, methanesulfonyl chloride (98 mg, 0.85 mmol) was added. After stirring 30 minutes, N-tert-butoxycarbonyl - piperazine (200 mg, 1.1 mmol) and potassium carbonate (98 mg, 0.71 mmol) was added, at room temperature and stirred overnight. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (amino silica gel, hexane: ethyl acetate = 1: 1, Rf = 0.43 ) to give the title compound (180 mg, 48%) (hereinafter, the compound of reference example 34) was obtained as a foam.
MS (ESI) [M Tasu H] Tasu : 535.

[0279]

(Reference Example 35) tert-butyl 4- (4 - (((2,2,2-trichloroethoxycarbonyl) carbonyl) amino) -5- (trifluoromethyl) benzyl) piperazin-1-carboxylate - DOO Synthesis:
Formula 93]

　according to the same manner as in reference example 34, the compound of example 33 from (140 mg), the title compound (180 mg) (hereinafter, the compound of reference example 35) was obtained as a foam. (Amino silica gel, hexane: ethyl acetate
1 =: 1, Rf = 0.43)) MS (ESI) [M + H] + : 535.

[0280]

(Example 39) 4- (2 - ((3- (3 - ((piperazin-1-ylmethyl) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide hydrochloride
[formula 94 ]

　according to the same manner as in example 10, compound (15 mg) and the compound of reference example 34 reference example 25 (30 mg), as an intermediate, to give the tert- butoxycarbonyl protected compound (chloroform: methanol = 10: 1 , Rf = 0.27). following the same procedure as in example 17, tert-butoxide from alkoxycarbonyl protected form, the title compound (15 mg) (hereinafter, the compound) of example 39 was obtained as an oily
substance. 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.43 (2H, s), 4.16 (6H, brs), 4.29 (2H, d, J = 4.0 Hz), 4.43 ( H, s), 6.97-7.00 (3H , m), 7.10-7.38 (4H, m), 7.45 (1H, dd, J = 8.0,4.0Hz), 7.60 (1H, br), 7.74 (1H, br), 7.90 (2H, d, J = 8.0Hz), 8.02 (1H, br), 9.61 (2H, s) . MS (ESI) [M Tasu H] Tasu : 528.

[0281]

(Example 40) 4- (2 - ((3- (4 - ((piperazin-1-ylmethyl) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide hydrochloride
[formula 95 ]

　according to the same manner as in example 10, compound (15 mg) and the compound of reference example 35 reference example 25 (30 mg), as an intermediate, to give the tert- butoxycarbonyl protected compound (chloroform: methanol = 10: 1 , Rf = 0.32). following the same procedure as in example 17, tert from butoxycarbonyl protecting member, the title compound (13 mg) (hereinafter, the compound) of example 40 was obtained as an oily
substance. 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.20-3.50 (8H, m), 4.05-4.39 (11H, m), 6.98 (3H, d, J = 8.0 z), 7.20-7.35 (3H, m ), 7.44 (1H, d, J = 8.0Hz), 7.61 (1H, d, J = 8.0Hz), 7.89 ( . 3H, d, J = 8.0 Hz), 8.02 (2H, br), 9.61 (2H, s) MS (ESI) [M + H] + : 528.

[0282]

Synthesis of (Reference Example 36) tert-butyl 4- (2-nitro-4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate:
[Chem 96]

　Under ice-cooling, tert- butyl 4-hydroxypiperidine -1 - carboxylate (89 mg, 0.4 mmol) in N, N- dimethylformamide (5.0 mL) of sodium hydride was added (mineral oil in 55 wt%, 35 mg, 0.65 mmol) was added and after stirring for 30 minutes, 1-chloro-2-nitro-4- (trifluoromethyl) benzene (100 mg, 0.4 mmol) was added. After stirring overnight at room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography, (hexane: 1, Rf = 0.25: ethyl acetate = 4) the title compound (113 mg, 65%) (hereinafter, the compound of reference example 36) as a yellow oily substance.
MS (ESI) [M Tasu H] Tasu : 391.

[0283]

(Reference Example 37) tert-butyl 4- (2-amino-4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate The synthesis of:
[Formula 97]

　the compound of Reference Example 36 (200 mg, 0.51 mmol) in methanol solution, 10 wt% palladium - carbon (50 wt% water, 0.05 g) was added, under hydrogen atmosphere and stirred for 5 hours. The reaction mixture was Celite® filtration, the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, Rf = 0.34 ) to give the title compound (110 mg, 60%) (hereinafter, the compound of reference example 37) was obtained as an oily substance.
MS (ESI) [M-TBu] Tasu : 305.

[0284]

(Reference Example 38) tert-butyl (2 - (((2,2,2-trichloroethoxycarbonyl) carbonyl) amino-4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate The synthesis of:
[Formula 98]

　Reference according to the same manner as in example 7, the compound of reference example 37 (109 mg), the title compound (0.13 g) (hereinafter, the compound of reference example 38) as a white solid.
(hexane: ethyl acetate = 2: 1 ,
Rf = 0.40) MS (ESI) [M-Boc] Tasu : 437.

[0285]

(Example 41) 4- (2 - ((3- (2- (piperidin-4-yloxy) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 99]

　Example according to the same manner as 10, the compound of reference example 25 (45 mg) and the compound of reference example 38 from (80 mg), to give the tert- butoxycarbonyl protected compound as an intermediate (chloroform: methanol = 10: 1, Rf = 0 .37). According to a similar manner to Example 17, from tert- butoxycarbonyl protecting member, the title compound (23 mg) (hereinafter, the compound of Example 41) was obtained as a foam. (Amino silica gel, chloroform: methanol 10
=: 1, Rf = 0.48) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 1.54-1.62 (2H, m), 1.95-1 .99 (2H, m), 2.50-2.70 (2H, m), 2.73 (1H, s), 2.89 (1H, s), 3.01-3.05 (2H, m ), 4.29 (2H, d, J = 4.0Hz), 4.54-4.59 (1H, m), 6.95-7.00 (3H, m), 7.18-7.4 (5H, m), 7.47 ( 1H, d, J = 8.0Hz), 7.65-7.67 (1H, m), 7.89-7.95 (3H, m), 8.02 (1H, s), 8.49 ( 1H, s).
MS (ESI) [M Tasu H] Tasu : 529.

[0286]

(Reference Example 39) Synthesis of 4 (2- (aminomethyl) phenoxy) -N- methylbenzamide hydrochloride
[formula 100]

　according to the same manner as in Reference Example 25, from the compound of Reference Example 23 (0.2 g) , the title compound (80 mg) (hereinafter, the compound of reference example 39) as a white solid.
MS (ESI) [M Tasu H] Tasu : 257

[0287]

(Example 42) 4 - ((2 - ((3- (5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) -N- methyl - benzamide:
[Formula 101]

　as in Example 10 according to the method, a phenyl (3- (trifluoromethyl) phenyl) carbamate (20 mg) of reference example 39 (22 mg), to give the title compound (16 mg) (hereinafter, the compound of example 42) as a white solid. (chloroform : methanol 10
=: 1, Rf = 0.52) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 2.78 (3H, d, J = 8.0 Hz), 4.28 (2H, d, J = 8.0Hz), 6.71 (1H , t, J = 8.0Hz), 6.98 (3H, d, J = 8.0Hz), 7.33 (1H, td, J = 8.0 , 2.0Hz), 7.42-7.51
. (3H, m), 8.35 (IH, d, J = 4.0 Hz), 9.02 (IH, s) MS (ESI) [M + H] + : 444.

[0288]

(Example 43) 4- (2 - ((3- (2- (oxetan-3-yloxy) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) -N- methyl - benzamide Synthesis of:
[ of 102]

　according to the same manner as in example 10, to give the compound of reference example 26 (20 mg) and the compound of reference example 39 from (15 mg), the title compound (13 mg) (hereinafter, the compound of example 43) as a white solid It was. (Chloroform: methanol 10
=: 1, Rf = 0.35) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 2.76 (3H, d, J = 8.0 Hz), 4.31 (2H, d, J = 8.0Hz), 4.63-4.67 (2H, m), 4.98 (2H, t, J = 8.0Hz), 5.41 (1H, t, J = 4.0Hz ), 6.75 (1H, d, J = 8.0Hz), 6.92-7.01 (3H, m), 7.16 (1H, d, J = 8.0Hz), 7.25 (1H , t, J = 8.0Hz), 7.37 (1H, td, J = 8.0,4.0Hz), 7.46-7.50 (2H, m), 8.28 (1H, s) , 8.36 (1H, d, J = 4.0Hz), 8.54 (1H, d, J = 4.0Hz).
MS (ESI) [M Tasu H] Tasu : 516.

[0289]

(Reference Example 40) Methyl 3- (2-cyanophenoxy) benzoic acid ester:
Chemical Formula 103]

　Methyl 3-hydroxybenzoate (0.6 g, 4.1 mmol), 2-fluorobenzonitrile (0.5 g, 4 .1Mmol) and potassium carbonate (0.89 g, 6.4 mmol) of N- methyl-2-pyrrolidone solution 8 hours at 170 ° C. and was heated and stirred. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, Rf = 0.68 ) to give the title compound (0. 58 g, 56%) (hereinafter, the compound of reference example 40) was obtained as an oily substance.
MS (ESI) [M Tasu H] Tasu : 254.

[0290]

(Reference Example 41) 3- (2 - (((tert-butoxycarbonyl) amino) methyl) phenoxy) benzoic acid:
Formula 104]

　according to the same manner as in Reference Example 23, the compound of Reference Example 40 (0. from 58 g), the title compound (0.28 g) (hereinafter, to give the compound) of reference example 41 as a pale yellow solid.
MS (ESI) [M Tasu H] Tasu : 343.

[0291]

(Reference Example 42) Synthesis of 4 (2- (aminomethyl) phenoxy) benzamide hydrochloride
[formula 105]

　according to the same manner as in Reference Example 26, from the compound of Reference Example 41 (0.15 g), the title compound ( 85 mg) (hereinafter, the compound of reference example 42) as a white solid. (Chloroform: methanol
10 =: 1, Rf = 0.30) MS (ESI) [M + H] + : 243.

[0292]

(Example 44) 3 - ((2 - ((3- (3- (Synthesis of trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide
[reduction 106]

　according to the same manner as in Example 10, phenyl ( . 3- (trifluoromethyl) phenyl) Karubame - from preparative (20 mg) and the compound of reference example 42 (22 mg), to give the title compound (16 mg) (hereinafter, the compound of example 44) as a white solid (chloroform: methanol 10
=: 1, Rf = 0.52) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.31 (2H, d, J = 8.0 Hz), 6.73 (IH, t, J = 8.0Hz), 6.91 (1H, d, J = 8.0Hz), 7.13 (1H, dd, J = 8.0,2.0Hz), 7.18-7.25 (2H, m), 7.30 (1H, td , J = 8. 0,2.0Hz), 7.41-7.51 (6H, m ), 7.65 (1H, d, J = 8.0Hz), 7.96 (1H, s), 8.02 (1H,
. s), 9.03 (IH, s) MS (ESI) [M + H] + : 430.

[0293]

(Example 45) 3- (2 - ((3- (3- (oxetan-3-yloxy) -5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 107]

　Example according to the same manner as 10, the compound of reference example 26 (20 mg) and the compound of reference example 42 from (15 mg), to give the title compound (13 mg) (hereinafter, the compound of example 45) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.42) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.35 (2H, d, J = 8.0 Hz), 4.58-4. 71 (2H, m), 4.96 (2H, t, J = 8.0Hz), 5.41 (1H, t, J = 4.0Hz), 6.76 (1H, d, J = 8.0Hz ), 6.93 (1H, d, J = 8.0Hz), 7.12-7.24 (3H, m), 7.33 (1H, td, J = 8.0,2.0Hz), 7 .44-7.10 (5H, m), 7.63 (1H, d, J = 8.0Hz), 8.01 (1H, s), 8.29 (1H, s), 8.54 (1H , d, J = 4.0Hz).
MS (ESI) [M + H] + : 502

[0294]

(Reference Example 43) 2,2,2-trichloroethyl (5-chloro-2- (trifluoromethyl) phenyl) Karubame - DOO Synthesis:
Formula 108]

　according to the same manner as in Reference Example 37, 1-ethoxy - It was obtained intermediate from 2-nitro-4- (trifluoromethyl) benzene (0.139 g). According to the same manner as in Reference Example 7, the resulting crude product, the title compound (0.14 g) (hereinafter, the compound of Reference Example 43) as a white solid. (Hexane: ethyl acetate
1 =: 1, Rf = 0.63) MS (ESI) [M + H] + : 381.

[0295]

(Example 46) 4 - ((2 - ((3- (2-ethoxy-5- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) benzamide:
[Formula 109]

　the same manner as in Example 10 according, from the compound of reference example 25 (31 mg) and the compound of reference example 43 (40 mg), to give the title compound (28 mg) (hereinafter, the compound of example 46) as a white solid (chloroform:. methanol = 10: 1 ,
Rf = 0.36) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 1.41 (3H, t, J = 8.0 Hz), 4.18 (2H, q, J = 8.0 Hz) , 4.27 (2H, d, J = 8.0Hz), 6.94-7.00 (3H, m), 7.11 (1H, d, J = 8.0Hz), 7.20-7. 39 (4H, m), 7.47 (1H, dd, J = 8.0, .0Hz), 7.56 (1H, t , J = 8.0Hz), 7.90 (3H, d, J = 8.0Hz), 8.16 (1H, s), 8.50 (1H, d ,
J = 2.0 Hz). MS (ESI) [M + H] + : 474.

[0296]

(Reference Example 44) Ethyl 6- (2-cyanophenoxy) nicotinate Synthesis of:
Formula 110]

　according to the same manner as in Reference Example 21, from ethyl 4-chloro-nicotinate (224 mg), the title compound (200 mg) (hereinafter, to give the compound) of reference example 44 as an oil.
MS (ESI) [M Tasu H] Tasu : 269.

[0297]

(Reference Example 45) Ethyl 6- (2- (aminomethyl) phenoxy) nicotinate Synthesis of:
Formula 111]

　according to the same manner as in Reference Example 22, from the compound of Reference Example 44 (0.8 g), the title compound (110 mg ) (hereinafter, to give the compound) of reference example 45 as an oil. (Amino silica gel, chloroform: methanol
10 =: 1, Rf = 0.12) MS (ESI) [M + H] + : 273.

[0298]

(Example 47) 6 - Synthesis of (2 ((3- (3- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) nicotinamide:
Formula 112]

　The compound of Reference Example 45 (80 mg, 0.29 mmol ) and diisopropylethylamine (50 mg, N of 0.38 mmol), N-dimethylformamide solution of 1-trifluoromethyl-3 isocyanatobenzene (55 mg, 0.29 mmol) and the mixture was stirred at room temperature for 3 hours. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica The resulting crude product was gel column chromatography (chloroform: methanol = 10 1, Rf = 0.42) , the intermediate ethyl ester obtained as (50mg, 52%). According to the same manner as in Example 8 and 13, from the obtained intermediate, the title compound (21 mg, 32%) was obtained (hereinafter, the compound of Example 47) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.31) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.20 (2H, d, J = 8.0 Hz), 6.64 (IH, t, J = 4.0Hz), 7.08-7.14 (2H, m), 7.22 (1H, d, J = 8.0Hz), 7.27 (1H, td, J = 8.0 , 2.0Hz), 7.34 (1H, td, J = 8.0,2.0Hz), 7.42-7.48 (4H, m) 7.95 (1H, s), 8.03 ( 1H, br), 8.27 (1H , dd, J = 8.0,4.0Hz), 8.61 (1H, d, J = 2.0Hz), 8.99 (1H, s).
MS (ESI) [M Tasu H] Tasu : 431.

[0299]

(Example 48) N-methyl-6 - Synthesis of (2 ((3- (3- (trifluoromethyl) phenyl) ureido) methyl) phenoxy) nicotinamide:
Formula 113]

　the same manner as in Example 47 according, the compound of reference example 45 from (80 mg), to give the title compound (16 mg) (hereinafter, the compound of example 48) as a white solid. (Chloroform: methanol 10
=: 1, Rf = 0.42) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 2.78 (3H, d, J = 8.0 Hz), 4.20 (2H, d, J = 8.0Hz), 6.62 (1H, t, J = 4.0Hz), 7.08-7.14 (2H, m), 7.22 (1H, d, J = 8.0Hz ), 7.27 (1H, td, J = 8.0,2.0Hz), 7.34 (1H, td, J = 8.0,2.0Hz), 7.42-7.48 (4H, m) 7.94 (1H, s) , 8.23 (1H, dd, J = 8.0,4.0Hz), 8.49 (1H, d, J = 8.0Hz), 8.56 (1H , d, J = 4.0Hz), 8.98 (1H, s).
MS (ESI) [M Tasu H] Tasu : 445.

[0300]

(Reference Example 46) 2,2,2-trichloroethyl (5-chloro-2-methoxy phenyl) carbamate:
[Formula 114]

　according to the same manner as in Reference Example 7, 5-chloro-2-methoxyaniline (120 mg from), the title compound (203 mg) (hereinafter, to give the compound) of reference example 46 as a white solid. (Hexane: ethyl acetate
1 =: 1, Rf = 0.58) MS (ESI) [M + H] + : 333.

[0301]

Synthesis of (Example 47) 2,2,2-trichloroethyl (5-chloro-2-ethoxyphenyl) carbamate:
[Chem 115]

　according to the same manner as in Reference Example 7, 5-chloro-2- ethoxy-aniline (160 mg from), the title compound (0.15 g) (hereinafter, to give the compound) of reference example 47 as a white solid. (Hexane: ethyl acetate
1 =: 1, Rf = 0.61) MS (ESI) [M + H] + : 348.

[0302]

: - (((3- (3-chlorophenyl) ureido) methyl) phenoxy 2) benzamide (Example 49) 4-
[of 116]

　N of the compound of Reference Example 25 (24 mg) and diisopropylethylamine (20 mg), N- dimethylformamide in 1-chloro-3-isocyanatobenzene and (0.012 ml) was added, followed by stirring at room temperature for 3 hours. After the reaction was terminated by adding saturated ammonium chloride solution, the reaction mixture was extracted with ethyl acetate, washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica The resulting crude product was gel column chromatography (chloroform: methanol = 10 1, Rf = 0.30) , the title compound (0.015 g , 39%) (hereinafter, to give the compound) of example 49 as a white solid.
1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 4.27 (2H, d, J = 8.0 Hz), 6.67 (IH, d, J = 8.0 Hz), 6.92-7. 00 (4H, m), 7.17 (1H, d, J = 8.0Hz), 7.23 (2H, t, J = 8.0Hz), 7.31-7.34 (2H, m), 7.43 (1H, d, J = 8.0Hz), 7.66 (1H, t, J = 4.0Hz), 7.90 (3H, d, J = 8.0Hz), 8.86 (1H , s).
MS (ESI) [M Tasu H] Tasu : 396.

[0303]

(Example 50) 4 - ((2 - ((3- (5-chloro-2-methoxyphenyl) ureido) methyl) phenoxy) benzamide:
[Formula 117]

　according to the same manner as in Example 10, Reference Example from the compound of 25 (17 mg) and the compound of reference example 46 (20 mg), to give the title compound (11 mg) (hereinafter, the compound of example 50) as a white solid (chloroform:. methanol = 10: 1, Rf = 0
.36) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 3.83 (3H, s), 4.25 (2H, d, J = 8.0 Hz), 6.90 (IH, dd, J = 8.0,4.0Hz), 6.95-7.00 (4H, m), 7.22-7.45 (5H, m), 7.90 (3H, d, J = 8.0Hz) , 8.17 (1H, d, J = 2.0Hz), 8.25 (1H, s .
MS (ESI) [M Tasu H] Tasu : 426.

[0304]

(Example 51) 4 - ((2 - ((3- (5-chloro-2-ethoxyphenyl) ureido) methyl) phenoxy) benzamide:
[Formula 118]

　according to the same manner as in Example 10, Reference Example from the compound of 25 (33 mg) and the compound of reference example 47 (40 mg), to give the title compound (31 mg) (hereinafter, the compound of example 51) as a white solid (chloroform:. methanol = 10: 1, Rf = 0
.40) 1 H-NMR (DMSO-d 6 , 400 MHz) [delta]: 1.37 (3H, t, J = 8.0 Hz), 4.08 (2H, q, J = 8.0 Hz), 4.27 (2H, d, J = 8.0Hz ), 6.87 (1H, dd, J = 8.0,4.0Hz), 6.94-7.00 (4H, m), 7.23-7. 36 (3H, m), 7.46 (1H, dd, J = 8.0,2.0 z), 7.52 (1H, t , J = 8.0Hz), 7.90 (3H, d, J = 8.0Hz), 8.05 (1H, s), 8.18 (1H, d,
. J = 2.0 Hz) MS (ESI) [M + H] + : 440.

[0305]

(Example 52) DDR1 inhibitory activity evaluation:
　the DDR1 inhibitory activity of the compounds of Examples 1-51 using the HTRF (R) KinEASE-TK kit (Cisbio bioassay Inc.), it was evaluated.

[0306]

　The test substance dimethyl sulfoxide (hereinafter, DMSO) were dissolved in, and used in the following evaluation. Further, the test substance and the reagent, MgCl 2 and 5 mmol / L, MnCl 2 and 0.5 mmol / L, the DTT 0.25mmol / L, Supplemental Enzyme buffer (Cisbio bioassay Inc.) so as to be 50 nmol / L of It was used after dilution with and added to the prepared of Kinase buffer (Cisbio bioassay Inc.). In 384-well black plate (Corning Co.), test substance (final DMSO concentration 1%), DDR1 intracellular domain (final concentration 5 ng / [mu] L) (Carna Biosciences), ATP phosphate donor (final concentration 25 [mu] mol / L) (Sigma Co.) and a substrate TK substrate-biotin (final concentration 1000 nmol / L) (Cisbio bioassay Inc.) was added and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the addition of TK antibody-cryptate (Cisbio bioassay Inc.) and streptavidin-XL665 (Cisbio bioassay Inc.), was reacted at room temperature for 1 hour. Incidentally, the test substance non-addition of the well, and, provided the DDR1 intracellular domain not added and a test substance non-addition of the wells.

[0307]

　Using a multi-label counter (Envision, PerkinElmer, Inc.), fluorescence intensity (excitation wavelength 320 nm, measurement wavelength 665nm and 620 nm) of each well was measured, to calculate the Ratio (the fluorescence intensity of the fluorescence intensity / 620 nm of 665nm). Inhibition rate at each concentration of the test substance (%) was calculated by the following equation.
　Inhibition rate (%) = ([Ratio of the test substance non-addition] - [Ratio of test substance]) / ([Ratio of the test substance non-addition] - [DDR1 Ratio of the intracellular domain was not added and a test substance non-addition]) × 100

[0308]

　The calculated percent inhibition Prism 5.04 (GraphPad Software, Inc) was used to return to the sigmoidal dose-response, IC of the test article 50 was calculated value.

[0309]

IC　of each test substance 50 the value shown in Table 2. As apparent from the results in Table 2, urea derivatives (I) or a pharmacologically acceptable salt thereof of the present invention have been shown to have a high DDR1 inhibitory activity.

[0310]

[table 2-1]

[0311]

[Table 2-2]

Industrial Applicability

[0312]

　Urea derivatives (I) and its pharmacologically acceptable salts of the present invention has a high DDR1 inhibitory activity, can be used as inhibitors of DDR1.

The scope of the claims

[Claim 1]

　Urea derivative or a pharmacologically acceptable salt thereof represented by the following general formula (I).
[Chemical formula 1]

wherein, m represents 0 or 1, R 1 represents a halogen atom, a trifluoromethyl group, a trifluoromethoxy group or pentafluorosulfur sulfonyl group, R 2 is a hydrogen atom, or , one hydrogen atom, a hydroxyl group, a piperazinyl group or a 4-methylpiperazinyl group, in substituted methyl group, R 3 is a hydrogen atom or R 5 represents O-, R 4 is a substituted may be, a phenyl group, a pyridyl group or pyrimidinyl group, R 5 represents an alkyl group having 1 to 3 carbon atoms, represents a 3-oxetanyl group or a 4-piperidyl group (wherein, m is 0, R 1 is a halogen atom, a trifluoromethyl group or a trifluoromethoxy group, and, R 4 except when it is pyridyl group which may be substituted.). ]

[Claim 2]

　R 4 is 3- or 4-carbamoylphenyl group, 4-N-methylcarbamoyl-phenyl group, a 4-pyridyl group or 2-(1H-imidazolyl) -4-pyrimidinyl group, a urea derivative according to claim 1, wherein or a pharmacologically acceptable salt thereof.

[Claim 3]

　m is 0, claim 1 or 2 urea derivative or a pharmacologically acceptable salt thereof.

[Claim 4]

　Containing claims 1 to urea derivative or a pharmacologically acceptable salt thereof according to any one claim of 3 as an active ingredient, an inhibitor of discoidin domain receptor 1.