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 an insoluble collagen, a ligand, a discoidin domain having collagen binding to extracellular receptor tyrosine kinases in the cell domains, respectively 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 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) There has been reported.

[0006]

　On the other hand, the compound having a urea skeleton, for example, as a compound having a p38MAPK inhibitor activity, 2,3-dihydro -1H- inden-2-ylurea derivative (Patent Document 4) 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

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 object, the 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, R 1 is trifluoromethyl group, a trifluoromethoxy group, or pentafluorosulfur sulfonyl group,
　R 2 are each independently a hydrogen atom, or, one hydroxyl or one It represents a ring-constituting atom C 4-6 saturated heterocyclyl group optionally substituted methyl group,
　R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms, which may have an oxo group good ring member atom number of 4-6 saturated heterocyclyl group, or R 5 O-a represents,
　R 4 , one of R 6 may be substituted with, represents a phenyl group, a pyridyl group, a pyridazinyl group or a pyrimidinyl group,
　m and n each independently represent 0 or
　1, R 5 represents an alkyl group having 1 to 3 carbon atoms, or represents a saturated heterocyclyl group having a ring-constituting atoms 4-6 (however, R 5 of ring configuration Hara If There is a nitrogen atom, i.e., R 5 if ring members contains a nitrogen atom, the nitrogen atom may be substituted with an acetyl group.),
　R 6 is a carbamoyl group, a phenyl group, ring constituting atom number of 5 or 6 heteroaryl group, ring members having 4 to 6 saturated heterocyclyl group, or (R 7 ) R 8 N-a
　represents, R 7 and R 8 are each independently hydrogen atom, or , be substituted with a hydroxyl group represents an alkyl group having 1 to 3 carbon atoms (provided that, m and n are 0, and, R 4 is substituted with a carbamoyl group, is a phenyl group or a pyridyl group except in the case.). ]

[0013]

　In the urea derivative represented by the above general formula (I), R 2 are each independently a hydrogen atom or a hydroxymethyl group,
　R 3 represents a hydrogen atom, a morpholinyl group, 2-oxo-piperazinyl group, or R 5 is
　O-, R 4 , one of R 6 may be substituted by a pyridyl group or pyrimidinyl
　group, R 5 represents an alkyl group having 1 to 3 carbon atoms, 3-oxetanyl group, or , nitrogen atom may be substituted with an acetyl group, a 3-azetidinyl group, 3-pyrrolidinyl or 4-piperidinyl
　group, R 6 is a carbamoyl group, a pyridyl group, morpholinyl group, or (R 7 ) R 8 is preferably N-.

[0014]

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

[0015]

　Further, in the urea derivative represented by the above general formula (I), R 4 of the general formula (IIa) ~ a group represented by one formula selected from (IIc),
　m and n are 0 there it is more preferable.
[Formula 2]

wherein, R 9 is a carbamoyl group, a pyridyl group, morpholinyl group, or (R 7 ) R 8 N-a represents the wavy line represents the point of attachment to formula (I). ]

[0016]

　Further, R 4 is a group represented by the general formula (IId) or (IIe),
　m and n, one is a 0, it is also preferable the other is 1.
[Chemical Formula 3]

[wherein, R 10 represents a hydrogen atom or a carbamoyl group, the wavy line represents the point of attachment to formula (I). ]

[0017]

　In these cases, it can be expected even higher DDR1 inhibitory activity.

[0018]

　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

[0019]

　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

[0020]

　Urea derivatives of the present invention is characterized in that the following general formula (I).
[Formula 4]

[wherein, R 1 is trifluoromethyl group, a trifluoromethoxy group, or pentafluorosulfur sulfonyl group,
　R 2 are each independently a hydrogen atom, or, one hydroxyl or one It represents a ring-constituting atom C 4-6 saturated heterocyclyl group optionally substituted methyl group,
　R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms, which may have an oxo group good ring member atom number of 4-6 saturated heterocyclyl group, or R 5 O-a represents,
　R 4 , one of R 6 may be substituted with, represents a phenyl group, a pyridyl group, a pyridazinyl group or a pyrimidinyl group,
　m and n each independently represent 0 or
　1, R 5 represents an alkyl group having 1 to 3 carbon atoms, or represents a saturated heterocyclyl group having a ring-constituting atoms 4-6 (however, R 5 of ring configuration Hara If There is a nitrogen atom, i.e., R 5 if ring members contains a nitrogen atom, the nitrogen atom may be substituted with an acetyl group.),
　R 6 is a carbamoyl group, a phenyl group, ring constituting atom number of 5 or 6 heteroaryl group, ring members having 4 to 6 saturated heterocyclyl group, or (R 7 ) R 8 N-a
　represents, R 7 and R 8 are each independently hydrogen atom, or , be substituted with a hydroxyl group represents an alkyl group having 1 to 3 carbon atoms (provided that, m and n are 0, and, R 4 is substituted with a carbamoyl group, is a phenyl group or a pyridyl group except in the case.). ]

[0021]

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

[0022]

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

[0023]

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

[0024]

　"Saturated heterocyclyl group ring members C 4-6", an oxygen atom, from one or more atoms and 1 to 5 carbon atoms which is identical to or different selected from the group consisting of a sulfur atom and a nitrogen atom consisting of 4 to having a six-membered ring, it means a monocyclic saturated heterocyclic group, for example, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group or morpholinyl group It is. Incidentally, ring members contains a nitrogen atom, the saturated heterocyclyl group ring members C 4-6, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl group or morpholinyl group.

[0025]

　"Saturated heterocyclyl group ring which may have an oxo group configuration atoms 4-6", two hydrogen atoms of the methylene group portion of saturated heterocyclyl groups of the ring members C 4-6 oxo means a group which may be substituted with a group, for example, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, morpholinyl group, 2-oxo azetidinyloxyimino group, oxopyrrolidinyl group, 2-oxopiperidinyl group, 2-oxo-oxetanyl group, 2-oxo-tetrahydrofuranyl group, 2-oxo-tetrahydropyranyl group, 2-oxo-piperazinyl group or a 3 Okisomoruhori It includes group.

[0026]

　The "heteroaryl group ring members having 5 or 6", an oxygen atom, from one or more atoms and 1 to 5 carbon atoms which is identical to or different selected from the group consisting of a sulfur atom and a nitrogen atom comprising 5 or with a 6-membered ring, means a monocyclic aromatic heterocyclic group, for example, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, thiazolyl group, thiadiazolyl group, a pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, or triazinyl group.

[0027]

　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.

[0028]

[Table 1-1]

[0029]

[Table 1-2]

[0030]

[Table 1-3]

[0031]

[Table 1-4]

[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 group 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]

　If configuration of the compounds described in the urea derivative (I) and Reference Examples are revealed show by the following equation (IIIa) or (IIIb).
[Of 5]

[0040]

　The configuration of a compound according to the urea derivative (I) and reference examples, the formula (IIIa) are preferred.

[0041]

　Urea derivatives (I) can be prepared by an appropriate method based on features derived from the type of the basic skeleton or substituents. Incidentally, the starting materials and reagents used in preparing these compounds may be prepared in general can be purchased or known methods.

[0042]

　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.

[0043]

　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.

[0044]

　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, deprotecting the protecting group as necessary after the reaction it is possible to obtain the desired compound by.

[0045]

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

[0046]

　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.

[0047]

　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).

[0048]

　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.

[0049]

　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 (IV) and the cyclohexane derivative (V).
[Formula 6]

[wherein each symbol has the same meaning as defined above. ]

[0050]

　Aniline derivative used in the urea reaction (IV) can be prepared by known methods or methods analogous thereto.

[0051]

　Cyclohexane derivatives used in the urea reaction (V) may be purchased as a mixture of single isomers or isomer as needed. It can also be produced by a known method or a method analogous thereto.

[0052]

　The amount of cyclohexane amine derivative used in the urea reaction (V) is preferably 0.5 to 10 equivalents relative to the aniline derivative (IV), more preferably 1 to 3 equivalents.

[0053]

　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.

[0054]

　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 (IV), more preferably 0.3 to 30 equivalents.

[0055]

　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.

[0056]

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

[0057]

　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 aprotic polar solvents such as acetamide 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, chloroform or 1,2 chlorinated solvents dichloroethane, including but nitrile solvent or a mixed solvent thereof such as acetonitrile or propionitrile, dichloromethane, chloroform or 1,2-chlorinated solvent or acetonitrile or propionitrile of dichloroethane Nitriles tolyl are preferred.

[0058]

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

[0059]

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

[0060]

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

[0061]

　Aniline derivative (IV) is, for example, as shown in Scheme 2, it can be obtained by a reduction reaction of nitrobenzene derivative (VI).
[Chemical Formula 7]

[wherein each symbol has the same meaning as defined above. ]

[0062]

　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 with a metal catalyst iron or tin is preferable.

[0063]

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

[0064]

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

[0065]

　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 or N, N-aprotic polar solvents, diethyl ether dimethylacetamide, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane, acetic acid ester solvents such as ethyl or propyl acetate, dichloromethane, chloroform or 1,2-but chlorinated solvent or a mixed solvent thereof dichloroethane and the like, alcohol solvents such as methanol or ethanol are preferred.

[0066]

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

[0067]

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

[0068]

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

[0069]

　The metal hydride reagent used in the hydride reduction reaction, for example, lithium aluminum hydride, and a boron hydride dimethyl sulphide complex or boron hydride tetrahydrofuran complex.

[0070]

　The amount of hydrogenation metal reagent used to hydride reduction reaction is preferably 0.1 to 20 equivalents, relative to nitrobenzene derivative (VI), more preferably 0.1 to 10 equivalents.

[0071]

　As the reaction solvent used in the hydride reduction 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, benzene, aromatic hydrocarbons such as toluene or xylene the solvent, diethyl ether, tetrahydrofuran and the like ether solvents or a mixed solvent thereof and dimethoxyethane or 1,4-dioxane, diethyl ether, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred .

[0072]

　The reaction temperature of the hydride reduction reaction is preferably from -78 ° C. ~ 0.99 ° C., more preferably -20 ℃ ~ 100 ℃.

[0073]

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

[0074]

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

[0075]

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

[0076]

　One amount of electron reduction used in the reaction the acid is preferably 0.1 to 20 equivalents, relative to nitrobenzene derivative (VI), more preferably 0.1 to 10 equivalents.

[0077]

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

[0078]

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

[0079]

　As 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 or N, aprotic polar solvents such as N- dimethylacetamide, diethyl ether, 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, an acidic solvent such as hydrochloric acid or acetic acid, or methanol Wakashi Alcohol solvents such as ethanol is preferred.

[0080]

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

[0081]

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

[0082]

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

[0083]

　Nitrobenzene derivative (VI), for example, as shown in Scheme 3, the presence or absence of a base can be obtained by nucleophilic substitution reaction with a nucleophilic agent and nitrobenzene derivatives (VIA).
[Formula 8]

[wherein each symbol has the same meaning as defined above. ]

[0084]

　Nucleophile used in the nucleophilic substitution reaction may be purchased. It can also be produced by a known method.

[0085]

　The amount of the nucleophilic agent used in the nucleophilic substitution reaction is preferably 0.2 to 10 equivalents, relative to nitrobenzene derivative (VIA), more preferably from 0.5 to 3 equivalents.

[0086]

　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.

[0087]

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

[0088]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0089]

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

[0090]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, 1-60 hours is preferable.

[0091]

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

[0092]

　Cyclohexane derivative (V) is, for example, as shown in Scheme 4, it can be obtained by deprotection reaction of cyclohexane derivative (VII).
[Formula 9]

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

[0093]

　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.

[0094]

　Of cyclohexane derivative (VII), cyclohexane derivatives m and n are 0 (VIIA), for example, as shown in Scheme 5, the presence or absence of a base, with an alcohol derivative halogenated heteroaryl derivative (IX) it can be obtained by nucleophilic substitution reaction with (VIIIA).
[Formula 10]

[wherein, X represents a halogen atom, and other symbols have the same meanings as defined above. ]

[0095]

　Alcohol derivatives used in the nucleophilic substitution reaction (VIIIA), can be purchased as a mixture of single isomers or isomer as needed. It can also be produced by a known method or a method analogous thereto.

[0096]

　Halogenated heteroaryl derivative used in the nucleophilic substitution reaction (IX) can be purchased. It can also be produced by a known method.

[0097]

　The amount of the halogenated heteroaryl derivative used in the nucleophilic substitution reaction (IX) is preferably from 0.2 to 10 equivalents to the alcohol derivative (VIIIA), more preferably from 0.5 to 3 equivalents.

[0098]

　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.

[0099]

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

[0100]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0101]

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

[0102]

　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.

[0103]

　Concentration at the start of the reaction of an alcohol derivative used in the nucleophilic substitution reaction (VIIIA) is, 1mmol / L ~ 1mol / L is preferred.

[0104]

　Of cyclohexane derivative (VII), cyclohexane derivatives m is is 1 n is 0 (VIIB) are, for example, as shown in Scheme 6, azo compounds and organic phosphorus compounds presence, the alcohol derivative (X) alcohol derivative (VIIIB) and the Mitsunobu reaction or a base the presence or absence of, can be obtained by nucleophilic substitution reaction of a halogenated heteroaryl derivative (IX) with an alcohol derivative (VIIIB).
[Formula 11]

wherein each symbol has the same meaning as defined above. ]

[0105]

　Mitsunobu alcohol derivative used in the reaction or nucleophilic substitution reaction (VIIIB) can be purchased as needed as a mixture of a single isomer or isomers. It can also be produced by a known method or a method analogous thereto.

[0106]

　The Mitsunobu reaction, for example, a method using an azo compound such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and an organic phosphorus compound such as triphenylphosphine or tributylphosphine and the like (Ref:. Chem Rev. 2009 years, the 109 Volume, p.2551-2651).

[0107]

　Alcohol derivatives used in the Mitsunobu reaction (X), azo compounds and organic phosphorus compounds can be purchased. It can also be produced by a known method.

[0108]

　The amount of the alcohol derivative (X) used in the Mitsunobu reaction is preferably 0.5 to 20 equivalents to the alcohol derivative (VIIIB), more preferably 1-5 equivalents.

[0109]

　The azo compound used in the Mitsunobu reaction include diethyl azodicarboxylate, diisopropyl azodicarboxylate, azodicarboxylic acid bis (2,2,2-trichloroethyl), N, N, N ', N'- tetramethyl azodicarbonyl carboxamide, azodicarboxylic acid bis (2-methoxyethyl) or include azodicarboxylate di -tert- butyl.

[0110]

　The amount of the azo compound used in the Mitsunobu reaction is preferably 0.5 to 20 equivalents to the alcohol derivative (VIIIB), more preferably 1-5 equivalents.

[0111]

　The organic phosphorus compound used in the Mitsunobu reaction, for example, triphenylphosphine, and tributyl phosphine or tricyclohexylphosphine.

[0112]

　The amount of the organic phosphorus compound used in the Mitsunobu reaction is preferably 1 to 20 equivalents to the alcohol derivative (VIIIB), more preferably from 0.5 to 5 equivalents.

[0113]

　As the reaction solvent used in the Mitsunobu 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, benzene, aromatic hydrocarbon solvents such as toluene or xylene , nitrile solvents such as acetonitrile or propionitrile, N, N-dimethylformamide, N, N- dimethylacetamide or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane ether solvents, 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, aromatic such as benzene, toluene or xylene carbide water Ether solvents such as system solvent or diethyl ether or tetrahydrofuran is preferred.

[0114]

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

[0115]

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

[0116]

　Mitsunobu concentration at the beginning of the reaction of the alcohol derivative used in the reaction (VIIIB) is, 1mmol / L ~ 1mol / L is preferred.

[0117]

　The amount of the halogenated heteroaryl derivative used in the nucleophilic substitution reaction (IX) is preferably from 0.2 to 10 equivalents to the alcohol derivative (VIIIB), more preferably from 0.5 to 3 equivalents.

[0118]

　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.

[0119]

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

[0120]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0121]

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

[0122]

　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.

[0123]

　Concentration at the start of the reaction of an alcohol derivative used in the nucleophilic substitution reaction (VIIIB) is, 1mmol / L ~ 1mol / L is preferred.

[0124]

　Of cyclohexane derivative (VII), n is 1 cyclohexane (VIIC) may be, for example, as shown in Scheme 7, the presence or absence of a base, with an alkyl halide derivative (XI), the alcohol derivative (VIIIA) or it can be obtained by nucleophilic substitution reaction with (VIIIB).
[Formula 12]

wherein each symbol has the same meaning as defined above. ]

[0125]

　The above alcohol derivative (VIIIA) and (VIIIB) can be purchased as needed as a mixture of a single isomer or isomers. It can also be produced by a known method or a method analogous thereto.

[0126]

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

[0127]

　The amount of alkyl halide derivative (XI) used in the nucleophilic substitution reaction is preferably 0.2 to 10 equivalents to the alcohol derivative (VIIIA) or (VIIIB), more preferably from 0.5 to 3 equivalents.

[0128]

　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.

[0129]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents to the alcohol derivative (VIIIA) or (VIIIB), more preferably 1 to 3 equivalents.

[0130]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0131]

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

[0132]

　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.

[0133]

　Concentration at the start of the reaction of an alcohol derivative used in the nucleophilic substitution reaction (VIIIA) or (VIIIB) is, 1mmol / L ~ 1mol / L is preferred.

[0134]

　Of cyclohexane derivative (VIIA), R 4 is heteroaryl halide in a cyclohexane derivative (VIIA-b), for example, as shown in Scheme 8, the presence or absence of a base, dihalogenated heteroaryl derivative ( and XII), can be obtained by nucleophilic substitution reaction with an alcohol derivative (VIIIA).
[Formula 13]

[wherein, X represents a halogen atom, R 11 represents a phenyl group, a pyridyl group, pyridazinyl group or pyrimidinyl group, and other symbols have the same meanings as defined above. ]

[0135]

　Alcohol derivatives used in the nucleophilic substitution reaction (VIIIA), can be purchased as a mixture of single isomers or isomer as needed. It can also be produced by a known method or a method analogous thereto.

[0136]

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

[0137]

　The amount of dihalogenated heteroaryl derivative used in the nucleophilic substitution reaction (XII) is preferably from 0.2 to 10 equivalents to the alcohol derivative (VIIIA), more preferably from 0.5 to 3 equivalents.

[0138]

　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.

[0139]

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

[0140]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0141]

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

[0142]

　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.

[0143]

　Concentration at the start of the reaction of an alcohol derivative used in the nucleophilic substitution reaction (VIIIA) is, 1mmol / L ~ 1mol / L is preferred.

[0144]

　Nucleophilic of cyclohexane derivative (VII), derivatives represented by formula (VIIA-a), for example, as shown in Scheme 9, the presence or absence of a base, using a cyclohexane derivative (VIIA-b) it can be obtained by substitution reaction or coupling reaction.
[Formula 14]

wherein each symbol has the same meaning as defined above. ]

[0145]

　The cyclohexane derivative (VIIA-b), for example, as shown in above Scheme 5, the presence of a base can be obtained by nucleophilic substitution reaction of a halogenated heteroaryl derivative (IX) with an alcohol derivative (VIIIA).

[0146]

　Nucleophile used in the nucleophilic substitution reaction may be purchased. It can also be produced by a known method.

[0147]

　The amount of the nucleophilic agent used in the nucleophilic substitution reaction is preferably 0.2 to 10 equivalents relative to cyclohexane derivatives (VIIA-b), more preferably from 0.5 to 3 equivalents.

[0148]

　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.

[0149]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents relative to cyclohexane derivatives (VIIA-b), more preferably 1 to 3 equivalents.

[0150]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0151]

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

[0152]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, 1-60 hours is preferable.

[0153]

　Concentration at the start of the reaction the cyclohexane derivative used in the nucleophilic substitution reaction (VIIA-b) may, 1mmol / L ~ 1mol / L is preferred.

[0154]

　As the coupling reaction, for example, the presence of a metal catalyst, an organic magnesium compound, an organometallic compound such as an organic zinc compound or organoboron compound and an aryl halide, a method using a halide such as a halogenated heteroaryl or alkyl halides mentioned are (reference:.. Angewante Chem Int.Ed. 2005 years, Vol. 44, p.4442-4489).

[0155]

　Metal catalysts, organometallic compound used in the coupling reaction may be purchased. It can also be produced by a known method or a method analogous thereto.

[0156]

　The amount of the organometallic compound used in the coupling reaction, to the cyclohexane derivative (VIIA-b), preferably 0.5 to 20 equivalents, more preferably 1 to 3 equivalents.

[0157]

　The metal catalyst used in the coupling reaction, for example, tetrakis triphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0) or bis (dibenzylideneacetone) palladium (0) 0-valent palladium complex catalyst such as Although the like, tetrakistriphenylphosphine palladium (0) are preferred.

[0158]

　The amount of metal catalyst used in the coupling reaction is preferably from 0.001 to 10 equivalents relative to cyclohexane derivatives (VIIA-b), more preferably 0.01 to 1 equivalent.

[0159]

　The coupling reaction may be used if desired base. The base used, for example, an inorganic base such as sodium carbonate or sodium hydroxide, tert- butoxy sodium or tert- butoxy potassium or the like of the metal alkoxide, although carboxylates, etc., or aqueous solutions thereof, such as sodium acetate or potassium acetate and the like , an inorganic base or an aqueous solution thereof such as sodium hydroxide or sodium carbonate are preferred.

[0160]

　The amount of base used in the coupling reaction is preferably 0.5 to 100 equivalents relative to cyclohexane derivatives (VIIA-b), more preferably 1 to 30 equivalents.

[0161]

　As the reaction solvent used in the coupling 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, aromatic hydrocarbon solvents such as benzene or toluene, alcohol solvent such as methanol or ethanol or the like, a nitrile solvent such as acetonitrile or propionitrile, N, N-dimethylformamide, N, N- dimethylacetamide or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, dimethoxyethane ether solvents such ethane or 1,4-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, base Zen or aromatic solvents such as toluene, alcohol solvents methanol or ethanol, diethyl ether, tetrahydrofuran, ether solvents or a mixed solvent thereof and dimethoxyethane or 1,4-dioxane are preferred.

[0162]

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

[0163]

　The reaction time of the coupling reaction is appropriately selected depending on the conditions such as reaction temperature, 1-48 hours is preferable.

[0164]

　Concentration at the start of the reaction the cyclohexane derivative used in the coupling reaction (VIIA-b) may, 1mmol / L ~ 1mol / L is preferred.

[0165]

　Among the urea derivatives (I), R 4 is a morpholinyl group, or (R 7 ) R 8 R is substituted with N- 11 urea derivative is (IA-a) is, for example, as shown in Scheme 10 , urea agent and the presence of a base, urea reaction of aniline derivative (IV) and the cyclohexane derivative (VA) (step 1) and a base the presence or absence, urea derivatives (IA-b) with a nucleophilic agent it can be obtained by nucleophilic substitution reaction using a (step 2) (IX).
Formula 15]

wherein each symbol has the same meaning as defined above. ]

[0166]

(Step 1)
　above cyclohexane derivative (VA), for example, as shown in Scheme 4 above, can be obtained by deprotection reaction of cyclohexane derivative (VI).

[0167]

　Aniline derivative used in the urea reaction (IV) can be prepared by known methods or methods analogous thereto.

[0168]

　The amount of cyclohexane amine derivative used in the urea reaction (VA) is preferably 0.5 to 10 equivalents relative to the aniline derivative (IV), more preferably 1 to 3 equivalents.

[0169]

　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, triphosgene is preferred.

[0170]

　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 (IV), more preferably 0.3 to 30 equivalents.

[0171]

　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.

[0172]

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

[0173]

　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 aprotic polar solvents such as acetamide 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, chloroform or 1,2 chlorinated solvents dichloroethane, including but nitrile solvent or a mixed solvent thereof such as acetonitrile or propionitrile, dichloromethane, chloroform or 1,2-chlorinated solvent or acetonitrile or propionitrile of dichloroethane Nitriles tolyl are preferred.

[0174]

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

[0175]

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

[0176]

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

[0177]

(Step 2)
　nucleophiles used in the nucleophilic substitution reaction (IX) can be purchased. It can also be produced by a known method.

[0178]

　The amount of the nucleophilic agent used in the nucleophilic substitution reaction (IX) is preferably from 0.2 to 10 equivalents relative to the urea derivative (IA-b), more preferably from 0.5 to 3 equivalents.

[0179]

　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.

[0180]

　The amount of base used in the nucleophilic substitution reaction is preferably 0.5 to 20 equivalents with respect to the urea derivative (IA-b), more preferably 1 to 3 equivalents.

[0181]

　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 or aprotic polar solvents such as dimethyl sulfoxide, diethyl ether, tetrahydrofuran, ethers such as dimethoxyethane or 1,4-dioxane-based solvents, 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, alcohol solvents methanol or ethanol, N, N Dimethylformamide, N, N- dimethylacetamide or dimethylsulfoxide aprotic polar solvent or diethyl ether, etc. De, tetrahydrofuran, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.

[0182]

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

[0183]

　The reaction time of the nucleophilic substitution reaction is appropriately selected depending on the conditions such as reaction temperature, 1-60 hours is preferable.

[0184]

　Concentration at the start of the reaction of the urea derivative used in the nucleophilic substitution reaction (IA-b) may, 1mmol / L ~ 1mol / L is preferred.

[0185]

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

[0186]

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

[0187]

　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.

[0188]

　"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.

[0189]

　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 test, 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

[0190]

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

[0191]

　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 AgilentTechnologies1200Series, G6130A (manufactured AgilentTechnology). The solvent using all commercially available. Flash chromatography was used YFLCW-prep2XY (Yamazen Corporation). Microwave synthesizer used was AntonPaar Co. Monowave300.

[0192]

　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.

[0193]

(Reference Example 1) tert-butyl trans- (4-hydroxycyclohexyl) carbamate Synthesis:
[Chemical Formula 16]

　under ice-cooling with trans-4- amino-hexanol (10 g, 87 mmol), dichloromethane triethylamine (18 mL, 0.13 mol) in (44 mL) solution was added di -tert- butyl (21g, 96 mmol). After stirring for 6.5 hours at room temperature, the reaction solution, water and 1 N hydrochloric acid was added, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by recrystallization with a hexane / ethyl acetate mixed solvent, the precipitated solid was collected by filtration to give the title compound (13 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.12-1.21 (2H, m), 1.33-1.44 (11H, m), 1.97-2.01 (4H , m), 3.40-3.43 (1H, m), 3.60-3.61 (1H, m), 4.33-4.35 (1H, m).

[0194]

(Reference Example 2) tert- butyl trans- (4 - ((2-chloro-4-yl) oxy) cyclohexyl) carbamate and tert- butyl trans- (4 - ((4-chloro-2-yl) oxy ) cyclohexyl) carbamate synthesis:
[Formula 17]

[Formula 18]

　under ice-cooling with tert- butyl trans- (4-hydroxycyclohexyl) carbamate (0.59 g, 2.7 mmol) in tetrahydrofuran (hereinafter, THF) (10 mL) was added sodium hydride (55 wt% in mineral oil, 0.36g) was added. After stirring 1.5 hours at room temperature, the reaction solution was added 2,4-dichloropyrimidine (0.45 g, 3.0 mmol) and THF (5 mL) solution of. After stirring for 2 hours at 40 ° was stirred under 60 ° for 7 hours. To the reaction solution under ice-cooling, water 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 (eluent; hexane: ethyl acetate = 95: 5 → 85: 15 ) was purified by, tert- butyl trans- (4 - ((2-chloro-4-yl was obtained ((4-chloro-2-yl) oxy) cyclohexyl) carbamate (0.17 g) -) oxy) cyclohexyl) carbamate (0.32 g) and tert- butyl trans- (4.
　tert- butyl trans- (4 - ((2- chloro-4-yl) oxy) cyclohexyl) carbamate
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.34 (2H, t, J = 11 .7Hz), 1.45 (11H, s ), 2.09-2.13 (4H, m), 3.50-3.53 (1H, m), 4.40-4.43 (1H, m ), 5.07-5.09 (1H, m) , 6.59 (1H, d, J = 6.3Hz), 8.26 (1H, d, J = 6.3Hz).
　tert- butyl trans- (4 - ((4- chloro-2-yl) oxy) cyclohexyl) carbamate
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.31-1.36 (2H, m ), 1.44-1.46 (9H, m) , 1.63-1.66 (2H, m), 2.10-2.16 (4H, m), 3.53 (1H, brs), 4.40 (1H, brs), 4.93-4.98 (1H, m), 6.95 (1H, d, J = 5.1Hz), 8.36 (1H, d, J = 5.1Hz ).

[0195]

(Reference Example 3) trans-4 - (( 2- chloro-4-yl) oxy) cyclohexanecarboxylic hydrochloride:
[formula

　19] tert-butyl trans- (4 - ((2-chloro-4- yl) oxy) cyclohexyl) carbamate (0.33 g, 0.99 mmol) of 4 N hydrogen chloride / ethyl acetate solution (2 mL) was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound.

[0196]

(Reference Example 4) 1- (trans-4 - ((2- chloro-4-yl) oxy) cyclohexyl) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) urea:
[Formula 20]

　under ice-cooling triphosgene (0.037 g, 0.13 mmol) in dichloromethane (3 mL) solution of dichloromethane (0 of 2-methoxy-5- (trifluoromethoxy) aniline (0.79 g, 0.38 mmol). 9 mL) solution of triethylamine (0.053 mL, 0.38 mmol) was added. After stirring for 1 hour under ice-cooling, to the reaction solution, trans-4 - ((2- chloro-4-yl) oxy) crude cyclohexane hydrochloride (0.10 g) N, N-dimethyl formamide was added (hereinafter, DMF) (0.6 mL) solution of triethylamine (0.26 mL, 1.9 mmol). After stirring 1.5 hours at room temperature, the reaction solution, water was added and extracted with chloroform. 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 (eluent; hexane: ethyl acetate = 99: 1 → 50: 50 ) to afford the title compound (0.015 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.35-1.40 (2H, m), 1.58-1.68 (2H, m), 2.16-2.18 (4H , m), 3.76-3.80 (1H, m), 3.88 (3H, s), 4.47 (1H, d, J = 7.6Hz), 5.08-5.14 (1H , m), 6.61 (1H, d, J = 5.9Hz), 6.79-6.81 (3H, m), 8.14 (1H, s), 8.27 (1H, d, J = 5.9Hz).

[0197]

(Example 1) 1- (2-methoxy-5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (-4- 2- morpholino-yl) oxy) cyclohexyl) urea::
Formula

　21] 1-(trans-4 - ((2-chloro-4-yl) oxy) cyclohexyl) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) urea (0.016 g, 0.034 mmol ), morpholine (0.0032 g, 0.037 mmol), sodium carbonate (0.068 g, ethanol (0.17 mL) solution of 0.064 mmol) after stirring for 1 hour at room temperature, the reaction solution, morpholine (0.010 g , 0.11mmol) was added. After stirring overnight at room temperature, the reaction solution, aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate 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 was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 40: 60 ) to give the give the title compound (0.0073G) (hereinafter, the compound of Example 1) It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.24-1.39 (2H, m), 1.59-1.64 (2H, m), 2.15-2.17 (4H , m), 3.75 (9H, brs), 3.87 (3H, s), 4.52-4.54 (1H, m), 4.93-4.96 (1H, m), 5. 97 (1H, d, J = 5.6Hz), 6.79-6.81 (3H, m), 8.06 (1H, d, J = 5.6Hz), 8.13 (1H, s).
MS (ESI) [M Tasu H] Tasu : 512.

[0198]

(Example 2) 1- (2-methoxy-5- (trifluoromethoxy) phenyl)-3-(trans-4-(pyrimidin-4-yloxy) cyclohexyl) urea Synthesis of:
[Chem

　22] 1- (trans -4 - ((2-chloro-4-yl) oxy) cyclohexyl) -3- (2-methoxy-5- (trifluoromethoxy) phenyl) urea (0.020 g, 0.043 mmol), 10 wt% palladium - carbon (50 wt% water, 0.0046 g), ammonium formate (0.0055 g, 0.087 mmol) in ethanol (0.33 mL) solution was stirred at room temperature overnight, the reaction mixture through Celite® filtration and, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 0: 100 ) to give the give the title compound (0.014 g) (hereinafter, the compound of Example 2) It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.35-1.42 (2H, m), 1.56-1.66 (2H, m), 2.15-2.19 (4H , m), 3.76-3.80 (1H, m), 3.88 (3H, s), 4.45-4.49 (1H, m), 5.07-5.11 (1H, m ), 6.68 (1H, d, J = 6.0Hz), 6.79-6.82 (3H, m), 8.14 (1H, s), 8.40 (1H, d, J = 6 .0Hz), 8.74 (1H, s ).
MS (ESI) [M Tasu H] Tasu : 425.

[0199]

(Example 3) 1- (2-methoxy-5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (2- ( methylamino) pyrimidin-4-yl) oxy) cyclohexyl) urea: :
Formula

　23] 1.0 N methylamine / THF solution using (0.20 mL), 1-(2-methoxy-5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (2 - morpholino-4-yl) oxy) cyclohexyl) the title compound was prepared in a similar manner as in the synthesis of urea (example 1) (0.010 g) (hereinafter, the compound of example 3) was obtained.
1 H-NMR (400 MHz, CD 3 OD) [delta] (ppm): 1.37-1.40 (2H, m), 1.58-1.61 (2H, m), 2.06-2.15 ( 4H, m), 2.88 (3H , s), 3.61-3.64 (1H, m), 3.90 (3H, s), 4.59 (1H, brs), 5.06 (1H , brs), 5.97 (1H, d, J = 5.9Hz), 6.80 (1H, dd, J = 9.1,2.6Hz), 6.96 (1H, d, J = 8. 8Hz), 7.91 (1H, d , J = 5.9Hz), 8.09 (1H, d, J = 2.9Hz).
MS (ESI) [M Tasu H] Tasu : 456.

[0200]

(Reference Example 5) 2-methoxy-3-nitro-5- (trifluoromethyl) benzaldehyde:
[Formula 24]

　under ice-cooling with 2-methoxy-5- (trifluoromethyl) benzaldehyde (3.0 g, 15 mmol concentrated sulfuric acid (44 mL) solution of), was added fuming nitric acid (0.79 mL). After stirring for 1 hour under ice-cooling, to a ice-cold water, the reaction solution was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 99: 1 → 90: 10 ) to afford the title compound (3.2 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.15 (3H, s), 8.33 (IH, d, J = 2.2 Hz), 8.35 (IH, d, J = 2 .4Hz), 10.43 (1H, s ).

[0201]

(Reference Example 6) (2-methoxy-3-nitro-5- (trifluoromethyl) phenyl) methanol:
Formula 25]

　under ice-cooling with 2-methoxy-3-nitro-5- (trifluoromethyl) benzaldehyde (2.0 g, 8.0 mmol) in methanol (40 mL) solution of sodium borohydride was added (0.15 g, 4.0 mmol). After stirring for 10 minutes under ice-cooling, to the reaction solution, 1N hydrochloric acid was added, and the reaction solution was concentrated under reduced pressure. To the resulting crude product, water 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 (eluent; hexane: ethyl acetate = 90: 10 → 75: 25 ) to afford the title compound (1.9 g).
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).

[0202]

(Reference Example 7) (3-amino-2-methoxy-5- (trifluoromethyl) phenyl) methanol:
[Chemical Formula

　26] under 90 degrees (2-methoxy-3-nitro-5- (trifluoromethyl ) phenyl) methanol (1.0 g, 4.0 mmol), iron powder (1.1 g, 20 mmol), ethanol / water mixed solvent of ammonium chloride (1.1 g, 20 mmol) (ethanol: water = 2: 1, v / v, after a 60 mL) solution was stirred for 1.5 hours, the reaction mixture was celite filtered, and the filtrate was concentrated under reduced pressure. To the resulting crude product, a saturated aqueous sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.84 g).
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.

[0203]

(Reference Example 8) 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) carbamate Synthesis:
[Formula 27]

　under ice-cooling (3-amino 2-methoxy-5- (trifluoromethyl) phenyl) methanol (0.84 g, 3.8 mmol), diisopropylethylamine (hereinafter, DIPEA) (0.99 mL, in THF (38 mL) solution of 5.7 mmol), chloroformate acid 2,2,2-trichloroethyl (0.80 g, 3.8 mmol) was added. After stirring 14 hours at room temperature, the reaction solution, 1N 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 (eluent; hexane: ethyl acetate = 90: 10 → 65: 35 ) to afford the title compound (1.2 g).
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).

[0204]

(Reference Example 9) 2-methoxy-3-nitro-5- (trifluoromethoxy) benzaldehyde Synthesis of:
[formula

　28] 2-methoxy-5- (trifluoromethoxy) benzaldehyde (25 g, 0.11 mol) with to give 2-methoxy-3-nitro-5- (trifluoromethyl) the title compound was prepared in a similar manner to the synthesis of benzaldehyde (reference example 5) (21g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.11 (3H, s), 7.95-7.97 (2H, m), 10.40 (IH, t, J = 3.5 Hz ).

[0205]

(Reference Example 10) (2-methoxy-3-nitro-5- (trifluoromethoxy) phenyl) methanol:
[Formula

　29] 2-methoxy-3-nitro-5- (trifluoromethoxy) benzaldehyde (21g, 0.081 mol) by using the obtained (2-methoxy-3-nitro-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of methanol (reference example 6) (19 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 2.01 (IH, t, J = 5.9 Hz), 3.94 (3H, s), 4.84 (2H, d, J = 5 .6Hz), 7.64-7.67 (2H, m ).

[0206]

(Reference Example 11) (3-amino-2-methoxy-5- (trifluoromethoxy) phenyl) methanol:
[Formula

　30] (2-methoxy-3-nitro-5- (trifluoromethoxy) phenyl) methanol It was obtained (19 g, 0.069 mol) with (3-amino-2-methoxy-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of methanol (reference example 7) (13 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.97 (IH, t, J = 6.2 Hz), 3.79 (3H, s), 3.92 (2H, s), 4. 69 (2H, d, J = 6.3Hz), 6.56 (1H, s), 6.62 (1H, s).

[0207]

(Reference Example 12) 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethoxy) phenyl) carbamate Synthesis:
[Formula

　31] (2-methoxy-3-nitro 5- (trifluoromethoxy) phenyl) methanol (13 g, 0.057 mol) with 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) to give the title compound (11g) in the same manner as in the synthesis of carbamate (example 8).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.89 (IH, t, J = 6.0 Hz), 3.84 (3H, s), 4.77 (2H, d, J = 5 .9Hz), 4.86 (2H, s ), 7.05 (1H, s), 7.40 (1H, s), 8.00 (1H, s).

[0208]

(Reference Example 13) 1-methoxy-4- (pentafluorosulfur sulfonyl) Synthesis of Benzene:
[formula

　32] 1-nitro-4- (pentafluorosulfur) benzene (20 g, 80 mmol) in DMF (100 mL) solution of It was added over sodium methoxide (13 g, 24 mmol) for 30 minutes. After stirring for 1 hour at room temperature, the reaction solution, water was added and extracted with diethyl ether. 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 (eluent: hexane) to afford the title compound (16g).
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.

[0209]

(Reference Example 14) 2-methoxy-5- (pentafluorosulfur yl) benzaldehyde:
[formula

　33] at -20 ° with 4-pentafluorosulfur sulfonyl anisole (1.3 g, 5.3 mmol) and dichloromethyl methyl ether (1.2 mL, 13 mmol) in dichloromethane (10 mL) was added titanium tetrachloride (1.5 mL, 13 mmol) was added over 10 minutes such that the temperature of the reaction solution is -20 to -22 degrees. After stirring for 30 minutes at -20 °, the reaction solution, water was added and extracted with dichloromethane. 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 (eluent; hexane: ethyl acetate = 95: 5 → 80: 20 ) to afford the title compound (0.52 g).
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.

[0210]

(Reference Example 15) 2-methoxy-3-nitro-5- (pentafluorosulfur yl) benzaldehyde:
[Formula

　34] 2-methoxy-5- (pentafluorosulfur sulfonyl) benzaldehyde (0.10 g, 0.38 mol ) to give the title compound (0.070 g) in the same manner as 2-methoxy-3-nitro-5 using (synthesis of trifluoromethyl) benzaldehyde (reference example 5).
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.

[0211]

(Reference Example 16) (2-methoxy-3-nitro-5- (pentafluorosulfur) phenyl) methanol A mixture of:
[formula

　35] 2-methoxy-3-nitro-5- (pentafluorosulfur sulfonyl) benzaldehyde ( 0.070 g, with 0.23 mmol) (2-methoxy-3-nitro-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of methanol (reference example 6) (0.067 g) Obtained.
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.

[0212]

(Reference Example 17) (3-amino-2-methoxy-5- (pentafluorosulfur) phenyl) methanol A mixture of:
[Formula

　36] (3-amino-2-methoxy-5- (pentafluorosulfur) phenyl ) methanol (0.057 g, methanol (1 mL) solution of 0.18 mmol), platinum oxide (0.0042 g, 0.018 mmol) was added, under hydrogen atmosphere and stirred at room temperature for 30 minutes. The reaction solution was Celite filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 95: 5 → 70: 30 ) to afford the title compound (0.049 g).
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.

[0213]

(Reference Example 18) 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (pentafluorosulfur) phenyl) carbamate Synthesis:
[Formula

　37] (3-amino-2- methoxy-5- (pentafluorosulfur) phenyl) methanol (0.049 g, 0.18 mmol) with 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl to give the title compound (0.071 g) in the same manner as in the synthesis of methyl) phenyl) carbamate (example 8).
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.

[0214]

(Reference Example 19) 4- (2-nitro-4- (trifluoromethyl) phenyl) piperazin-2-one Synthesis of:
Formula

　38] 1-chloro-2-nitro-4- (trifluoromethyl) benzene ( 0.30 g, 1.3 mmol), piperazin-2-one (0.17 mL, 1.7 mmol), triethylamine (0.28 mL, 2.0 mmol) in dimethyl sulfoxide (hereinafter, DMSO) (5 mL) solution for 2 hours with stirring after, the reaction solution, water 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 (eluent; hexane: ethyl acetate = 95: 5 → 0: 100 ) to give 4- (2-nitro-4- (trifluoromethyl) phenyl) piperazine - to give 2-one and (0.32 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.38-3.39 (2H, m), 3.56-3.58 (2H, m), 3.91 (2H, d, J = 3.7Hz), 7.17-7.18 (1H, m), 7.72-7.75 (1H, m), 8.11-8.13 (1H, m).

[0215]

(Reference Example 20) 4- (2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one Synthesis of:
[Formula 39]

　at room temperature 4- (2-nitro-4- (trifluoromethyl) phenyl) piperazin-2-one (0.15 g, methanol (11 mL) solution of 0.58 mol), 10 wt% palladium - carbon (50 wt% water, 0.062 g) was added, under a hydrogen atmosphere at room temperature for 1 and the mixture was stirred time. The reaction was Celite® filtration, the filtrate was concentrated under reduced pressure to give the title compound (0.15 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.22-3.23 (2H, m), 3.47-3.50 (2H, m), 3.68 (2H, s), 4.09 (1H, s), 5.95 (1H, s), 6.97 (1H, s), 7.01 (2H, s).

[0216]

(Reference Example 21) 2,2,2-trichloroethyl (2- (3-oxo-piperazin-1-yl) -5- (trifluoromethyl) phenyl) carbamate Synthesis:
Formula

　40] 4- (2-amino 4- (trifluoromethyl) phenyl) piperazin-2-one (0.15 g, 0.57 mmol) with 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- ( to give the title compound (0.17 g) trifluoromethyl) phenyl) carbamate (synthesis similar to the method of reference example 8).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.18-3.20 (2H, m), 3.53-3.55 (2H, m), 3.67 (2H, s), 4.88 (2H, s), 6.01 (1H, s), 7.21-7.24 (1H, m), 7.38 (1H, d, J = 8.3Hz), 7.79 ( 1H, s), 8.40 (1H , s).

[0217]

(Reference Example 22) 2,2,2-trichloroethyl (2- (oxetan-3-yloxy) -5- (trifluoromethyl) phenyl) carbamate Synthesis:
Formula 41]

　under ice-cooling with 1-chloro-2 - nitro-4- (trifluoromethyl) benzene (1.2 g, 5.2 mmol) in DMF was added sodium hydride (55 wt% in mineral oil, 0.41g) 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. The methanol solution 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 was Celite® filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product obtained under ice-cooling and DIPEA (3.8 mL, 22 mmol) in THF solution 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 was purified by recrystallization with a hexane / diethyl ether mixed solvent, the precipitated solid was collected by filtration to give the title compound (3.8 g).
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.

[0218]

(Reference Example 23) 1-chloro-2-nitro-4- (pentafluorosulfur sulfonyl) Synthesis of Benzene:
Formula

　42] 1-chloro-4- (pentafluorosulfur) benzene (5.0 g, 21 mmol) used to give 2-methoxy-3-nitro-5- (trifluoromethyl) benzaldehyde (reference example 5) as the title compound in a similar manner (5.9 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 7.71 (IH, d, J = 8.6 Hz), 7.92 (IH, dd, J = 8.6, 2.7 Hz), 8 .31 (1H, d, J = 2.7Hz).

[0219]

(Reference Example 24) 3- (2-nitro-4- (pentafluorosulfur) phenoxy) Synthesis of oxetane:
Formula 43]

　THF (1 mL) solution of oxetane-3-ol (94.0 mg, 1.27 mmol) to, sodium hydride (55 wt% in mineral oil, 0.069g) was added. After stirring for 30 minutes at room temperature, the reaction solution was added 1-chloro-2-nitro-4- (pentafluorosulfur) benzene (0.030 g, 1.1 mmol) and. After stirring for 4 hours at room temperature, the reaction solution, water was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.34 g).
1 H-NMR (400 MHz, CD 3 OD) [delta] (ppm): 4.72-4.75 (2H, m), 5.03-5.07 (2H, m), 5.52-5.57 ( 1H, m), 7.06 (1H , d, J = 9.1Hz), 8.04 (1H, dd, J = 9.1,2.8Hz), 8.39 (1H, d, J = 2 .8Hz).
MS (ESI) [M Tasu H] Tasu : 322.

[0220]

(Reference Example 25) 2- (oxetane-3-yloxy) -5- (pentafluorosulfur sulfonyl) Synthesis of aniline:
[Chem

　44] 3- (2-nitro-4- (pentafluorosulfur) phenoxy) oxetane ( 0.34 g, 1.1 mmol) with 4- (2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one synthesis of (reference example 20) and title compound was prepared in a similar manner (0.31 g ) was obtained.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.03 (2H, brs), 4.76-4.79 (2H, m), 4.99-5.03 (2H, m), 5.24-5.29 (1H, m), 6.30 (1H, d, J = 8.8Hz), 7.05 (1H, dd, J = 8.8,2.7Hz), 7.12 (1H, d, J = 2.7Hz ).
MS (ESI) [M Tasu H] Tasu : 292.

[0221]

(Reference Example 26) 2,2,2-trichloroethyl (2- (oxetan-3-yloxy) -5- (pentafluorosulfur) phenyl) carbamate Synthesis:
[Chem

　45] 2- (oxetane-3-yloxy ) -5-pentafluorosulfur sulfonyl aniline (0.31 g, 1.1 mmol) using 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) to give the title compound (0.32 g) in the same manner as in the synthesis of carbamate (example 8).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.82 (2H, dd, J = 8.3,4.9Hz), 4.88 (2H, s), 5.03-5.07 (2H, m), 5.30-5.35 ( 1H, m), 6.45 (1H, d, J = 9.0Hz), 7.42 (1H, dd, J = 9.0,2. 7Hz), 8.66 (1H, s ).
MS (ESI) [M Tasu H] Tasu : 466.

[0222]

(Reference Example 27) 1-methoxy-2-nitro-4- (pentafluorosulfur sulfonyl) Synthesis of Benzene:
Formula 46]

　under ice-cooling with 1-chloro-2-nitro-4- (pentafluorosulfur) benzene (3.0 g, 10 mmol) in THF (30 mL) was added sodium methoxide / methanol solution (28 wt%, 2.4 g, 13 mmol) was added. After stirring for 2 hours at room temperature, the reaction solution, a saturated aqueous ammonium chloride solution was added, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.5 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 4.04 (3H, s), 7.16 (IH, d, J = 9.3 Hz), 7.94 (IH, dd, J = 9 .3,2.7Hz), 8.29 (1H, d , J = 2.7Hz).
MS (ESI) [M Tasu H] Tasu : 280.

[0223]

(Reference Example 28) 2-methoxy-5- (pentafluorosulfur sulfonyl) Synthesis of aniline:
[Chem

　47] 1-methoxy-2-nitro-4- (pentafluorosulfur) benzene (0.34 g, 1.1 mmol ) to give the title compound (0.45 g) in the same manner as with synthesis of 4- (2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one (reference example 20).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.90 (3H, s), 6.75 (IH, d, J = 9.1 Hz), 7.09 (IH, d, J = 2 .7Hz), 7.13 (1H, dd , J = 9.1,2.7Hz).
MS (ESI) [M Tasu H] Tasu : 250.

[0224]

Synthesis of (Example 29) 2,2,2-trichloroethyl (2-methoxy-5- (pentafluorosulfur) phenyl) carbamate:
[formula

　48] 2-methoxy-5- (pentafluorosulfur) aniline ( 4.5 g, the same method as 2,2,2-trichloroethyl using 18 mmol) synthesis of (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) carbamate (example 8) in to give the title compound (5.0 g).

[0225]

(Reference Example 30) 2,2,2-trichloroethyl (2-methoxy-5- (trifluoromethoxy) phenyl) carbamate Synthesis:
[Chem

　49] 2-methoxy-5- (trifluoromethoxy) aniline (5. 0 g, 24 mmol) with 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) carbamate (title in reference example 8) in the same manner as compound (7.0 g) was obtained.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 3.92 (3H, s), 4.85 (2H, s), 6.86-6.91 (2H, m), 7.51 ( 1H, d, J = 8.0Hz) , 8.08 (1H, s).
MS (ESI) [M Tasu H] Tasu : 382.

[0226]

(Reference Example 31) 2,2,2-trichloroethyl (2-methoxy-5- (trifluoromethyl) phenyl) carbamate Synthesis:
Formula

　50] 2-methoxy-5- (trifluoromethyl) aniline (5. 0 g, 26 mmol) with 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) carbamate (title in reference example 8) in the same manner as compound (7.8 g) 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).

[0227]

(Reference Example 32) tert-butyl 4- (2-nitro-4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate:
[Chem

　51] 1-chloro-2-nitro-4- (trifluoromethyl methyl) benzene (0.10 g, 0.44 mmol), using tert- butyl 4-hydroxypiperidine-1-carboxylate (0.089 g, 0.044 mmol), tert- butyl trans- (4 - ((2- to give chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.11 g).
MS (ESI) [M-TBu] Tasu : 335.

[0228]

(Reference Example 33) tert-butyl 4- (2-amino-4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate:
[Chem

　52] tert-butyl 4- (2-nitro-4- ( trifluoromethyl) phenoxy) piperidine-1-carboxylate (0.20 g, 0.51 mmol) with 4- (2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one synthesis of (reference example to give the title compound (0.19 g) in a similar manner as 20).
MS (ESI) [M Tasu H] Tasu : 437.

[0229]

(Reference Example 34) tert-butyl 4- (2 - (((2,2,2-trichloroethoxycarbonyl) carbonyl) amino) -4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate:
[formula

　53] tert-butyl 4- using (2-amino-4- (trifluoromethyl) phenoxy) piperidine-1-carboxylate (0.11 g, 0.30 mmol) and 2,2,2-trichloroethyl (3 - (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of carbamate (reference example 8) (0.13 g).
MS (ESI) [M Tasu H] Tasu : 534.

[0230]

(Reference Example 35) tert-butyl 3- (2-nitro-4- (trifluoromethyl) phenoxy) azetidine-1-carboxylate Synthesis of acrylate:
Formula

　54] 1-chloro-2-nitro-4- (trifluoromethyl methyl) benzene (0.10 g, 0.44 mmol) and tert- butyl 3-hydroxy-azetidine-1-carboxylate (0.08 g, 0.44 mmol) using tert- butyl trans- (4 - ((2- to give chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.12 g).
MS (ESI) [M-TBu] Tasu : 307.

[0231]

(Reference Example 36) (S)-tert-butyl-3- (2-nitro-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate Synthesis of acrylate:
Formula

　55] 1-chloro-2-nitro-4 - (trifluoromethyl) benzene (0.50 g, 2.22 mmol) using the the (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.50 g, 2.66 mmol) tert-butyl trans- yield - (4 ((2-chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.62 g).
MS (ESI) [M-TBu] Tasu : 321.

[0232]

(Reference Example 37) (R)-tert-butyl-3- (2-nitro-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate Synthesis of acrylate:
Formula

　56] 1-chloro-2-nitro-4 - (trifluoromethyl) benzene (0.50 g, 2.22 mmol) and (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.50 g, 2.66 mmol), tert-butyl trans - give - (4 ((2-chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.6 g).
MS (ESI) [M-TBu] Tasu : 321.

[0233]

(Reference Example 38) tert-butyl 3- (2-amino-4- (trifluoromethyl) phenoxy) azetidine-1-carboxylate Synthesis of acrylate:
Formula

　57] tert-butyl 3- (2-nitro-4- ( trifluoromethyl) phenoxy) azetidine-1-carboxylate (0.19 g, 0.51 mmol) with 4- (2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one synthesis of (reference example to give the title compound (0.15 g) in a similar manner as 20).
MS (ESI) [M-TBu] Tasu : 277.

[0234]

(Reference Example 39) (S)-tert-butyl-3- (2-amino-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate Synthesis of acrylate:
[Formula

　58] (S)-tert-butyl 3- (2-nitro-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (0.62 g, 1.65 mmol) with 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine - to give the title compound (0.5 g) in the same manner as 2-one synthesis of (example 20).
MS (ESI) [M-TBu] Tasu : 291.

[0235]

(Reference Example 40) (R)-tert-butyl-3- (2-amino-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate Synthesis of acrylate:
[Formula

　59] (R)-tert-butyl 3- (2-nitro-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (0.61 g, 1.62 mmol) with 4- (2-amino-4- (trifluoromethyl) phenyl) piperazine - to give the title compound (0.51 g) in the same manner as 2-one synthesis of (example 20).
MS (ESI) [M-TBu] Tasu : 291.

[0236]

(Reference Example 41) tert-butyl 3- (2 - (((2,2,2-trichloroethyl) carbonyl) amino) -4- (trifluoromethyl) phenoxy) azetidine-1-carboxylate Synthesis of acrylate:
Formula

　60] tert-butyl 3- (2-amino-4- (trifluoromethyl) phenoxy) azetidine-1-carboxylate (0.10 g, 0.30 mmol) with 2,2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of carbamate (reference example 8) (0.15 g).
MS (ESI) [M-TBu] Tasu : 451.

[0237]

(Reference Example 42) (S)-tert-Butyl 3- (2 - (((2,2,2-trichloroethyl) carbonyl) amino) -4- (trifluoromethyl l) phenoxy) pyrrolidine-1-carboxylate synthesis:
[Formula

　61] (S)-tert-butyl-3- (2-amino-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (0.34 g, 1.59 mmol) using 2, to give 2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of carbamate (reference example 8) (0.49 g) .
MS (ESI) [M-Boc] Tasu : 421.

[0238]

(Reference Example 43) (R)-tert-butyl 3- (2 - (((2,2,2-trichloroethyl) carbonyl) amino) -4- (trifluoromethyl l) phenoxy) pyrrolidine-1-carboxylate synthesis:
[Formula

　62] (R)-tert-butyl-3- (2-amino-4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (0.50 g, 1.44 mmol) using 2, to give 2,2-trichloroethyl (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) the title compound was prepared in a similar manner as in the synthesis of carbamate (reference example 8) (0.51 g) .
MS (ESI) [M-Boc] Tasu : 421.

[0239]

(Reference Example 44) 2,2,2-trichloroethyl (2-methyl-5- (trifluoromethyl) phenyl) carbamate Synthesis:
[Chem

　63] 2-methyl-5- (trifluoromethyl) aniline (0. 20g, the same method as 2,2,2-trichloroethyl using 1.05 mmol) synthesis of (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) carbamate (example 8) in to give the title compound (0.18 g).
MS (ESI) [M Tasu H] Tasu : 349.

[0240]

(Reference Example 45) 2,2,2-trichloroethyl (2-fluoro-5- (trifluoromethyl) phenyl) carbamate Synthesis:
[Chem

　64] 2-fluoro-5- (trifluoromethyl) aniline (0. 26 g, the same method as 2,2,2-trichloroethyl using 1.23 mmol) synthesis of (3- (hydroxymethyl) -2-methoxy-5- (trifluoromethyl) phenyl) carbamate (example 8) in to give the title compound (0.15 g).
MS (ESI) [M Tasu H] Tasu : 354.

[0241]

(Reference Example 46) 2,2,2-trichloroethyl Synthesis of (2-chloro-5- (trifluoromethyl) phenyl) carbamate:
[Chem 65]

　under ice-cooling with 2-chloro-5- (trifluoromethyl) aniline (0.24 g, 1.1 mmol), diazabicycloundecene (hereinafter, DBU) (0.20 g, 1.3 mmol) in THF solution of chloroformate 2,2,2-trichloroethyl (0.20 g, 1.0mmol) was added. 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 was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 60: 40 ) to afford the title compound (0.12 g).
MS (ESI) [M Tasu H] Tasu : 505.

[0242]

(Reference Example 47) 2,2,2-trichloroethyl (2- (oxetan-3-yloxy) -5- (trifluoromethoxy) phenyl) carbamate Synthesis:
[Chem

　66] 1-chloro-2-nitro-4 - (trifluoromethoxy) benzene (0.50 g, 1.79 mmol) 2,2,2-trichloroethyl using (2- (oxetan-3-yloxy) -5- (trifluoromethyl) phenyl) carbamate (reference to give the title compound (0.12 g) in example 22) and similar methods.
MS (ESI) [M Tasu H] Tasu : 424

[0243]

(Reference Example 48) tert-butyl (trans-4 - ((2-morpholino-4-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　67] tert-butyl trans- (4 - ((2-chloro-pyrimidine 4-yl) oxy) cyclohexyl) carbamate (0.020 g, 0.061 mmol) with 1- (2-methoxy-5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (2- to give the title compound (0.54 g) in morpholino-4-yl) oxy) cyclohexyl) urea: (example 1) and similar methods.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.25-1.46 (13H, m), 2.10 (4H, m), 3.50 (IH, brs), 3.74- 3.78 (8H, m), 4.41 (1H, brs), 4.92 (1H, brs), 5.96 (1H, d, J = 5.6Hz), 8.05 (1H, d, J = 5.6Hz).

[0244]

(Reference Example 49) tert- butyl (trans-4-(pyrimidin-2-yloxy) cyclohexyl) carbamate Synthesis:
[Chem

　68] 2-chloropyrimidine (0.30 g, 1.4 mmol) using tert- butyl trans - give - (4 ((2-chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.35 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.24-1.31 (2H, m), 1.42 (9H, s), 1.60-1.64 (2H, m), 2.07-2.15 (4H, m), 3.51 (1H, brs), 4.39 (1H, brs), 4.89-4.94 (1H, m), 6.86 (1H, t, J = 4.8Hz), 8.46 (2H, d, J = 4.8Hz).

[0245]

(Reference Example 50) tert-butyl (trans-4-(6- phenyl-3-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　69] 3-chloro-6-phenyl-pyridazine (0.093 g, 0. 49 mmol) using tert- butyl trans- - give (4 ((2-chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.060 g) It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.33-1.36 (2H, m), 1.46 (9H, s), 1.61-1.64 (2H, m), 2.08-2.11 (2H, m), 2.29-2.31 (2H, m), 3.55 (1H, brs), 4.43 (1H, brs), 5.33 (1H, brs), 6.98 (1H, d , J = 9.3Hz), 7.48-7.50 (3H, m), 7.78 (1H, d, J = 9.5Hz), 8.00- 8.02 (2H, m).

[0246]

(Reference Example 51) trans-4 - (( 2- morpholino-4-yl) oxy) cyclohexane Synthesis of amine:
[Formula 70]

　at room temperature tert- butyl (trans-4 - ((2-morpholino-4 - yl) oxy) cyclohexyl) carbamate (0.54 g, was stirred for 2 hours at 4 N hydrogen chloride / ethyl acetate solution (4 mL) of 1.4 mmol). The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate, and extracted with chloroform / methanol mixed solvent. The organic layer was washed with saturated aqueous sodium bicarbonate 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 title compound (0.40 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.24-1.34 (2H, m), 1.48-1.55 (2H, m), 1.95-1.97 (2H , m), 2.12-2.15 (2H, m), 2.79-2.84 (1H, m), 3.75 (8H, s), 4.90-4.98 (1H, m ), 5.95 (1H, d, J = 5.6Hz), 8.05 (1H, d, J = 5.6Hz).

[0247]

(Reference Example 52) trans-4-Synthesis of (pyrimidin-2-yloxy) cyclohexanamine:
Formula

　71] tert-butyl (trans-4-(pyrimidin-2-yloxy) cyclohexyl) carbamate (0.35 g, 1. trans-4 using 2 mmol) - was obtained ((2-morpholino-4-yl) oxy) the title compound was prepared in a similar manner as in the synthesis of cyclohexanamine (reference example 51) and (0.020 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.20-1.32 (2H, m), 1.55-1.60 (2H, m), 1.90-1.93 (2H , m), 2.14-2.16 (2H, m), 2.76-2.78 (1H, m), 4.92-4.94 (1H, m), 6.86 (1H, t , J = 4.8Hz), 8.46 ( 2H, d, J = 4.9Hz).

[0248]

(Reference Example 53) trans-4- (6- phenyl-3-yl) oxy) cyclohexanecarboxylic amine:
[Chem

　72] tert-butyl (trans-4-(6- phenyl-3-yl) oxy) cyclohexyl) carbamate (0.060 g, 0.16 mmol) with trans-4 - ((2-morpholino-4-yl) oxy) the title compound was prepared in a similar manner as in the synthesis of cyclohexanamine (reference example 51) the crude to give the product (0.069 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.32-1.35 (2H, m), 1.53-1.56 (2H, m), 1.94-1.97 (2H , m), 2.30-2.33 (2H, m), 2.80 (1H, brs), 5.33 (1H, brs), 6.98 (1H, d, J = 9.0Hz), 7.47-7.50 (3H, m), 7.78 (1H, d, J = 9.0Hz), 8.00-8.03 (2H, m).

[0249]

(Reference Example 54) tert-butyl (trans-4-(4-(methylamino) pyrimidin-2-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　73] tert-butyl trans- (4 - ((4- chloro-2-yl) oxy) cyclohexyl) carbamate (0.050 g, 0.15 mmol) with 1- (2-methoxy-5- (trifluoromethoxy) phenyl)-3-(trans-4-( to give (2-morpholino-4-yl) oxy) cyclohexyl) the title compound was prepared in a similar manner as in the synthesis of urea (example 1) (0.048 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.25-1.30 (2H, m), 1.43-1.46 (2H, m), 1.45 (9H, s), 2.06-2.15 (4H, m), 2.94 (3H, d, J = 4.9Hz), 3.50 (1H, brs), 4.39 (1H, brs), 4.85- 4.91 (1H, m), 5.97 (1H ,, d, J = 5.9Hz), 7.96 (1H, d, J = 5.9Hz).

[0250]

(Reference Example 55) 2 - Synthesis of ((trans-4-aminocyclohexyl) oxy) -N- methyl-pyrimidin-4-amine dihydrochloride:
[formula

　74] tert-butyl (trans-4-(4-(methyl amino) -2-yl) oxy) cyclohexyl) carbamate (0.087 g, trans-4 using 0.27 mmol) - ((2-chloro-4-yl) oxy) cyclohexanecarboxylic hydrochloride (reference example 3) the same method to give the crude product of the title compound (0.056 g).

[0251]

(Reference Example 56) trans-4 - (( 4- morpholino-2-yl) oxy) cyclohexanecarboxylic amine:
[Chem

　75] tert-butyl trans- (4 - ((4-chloro-2-yl) oxy) cyclohexyl) carbamate (0.020 g, 0.043 mmol) with 1- (2-methoxy-5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (2- morpholino-4 to give the title compound (0.048 g) in yl) oxy) cyclohexyl) in a similar manner to the synthesis of urea (example 1).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.25-1.28 (2H, m), 1.43-1.46 (11H, m), 2.05-2.17 (4H , m), 3.50 (1H, brs) 3.59-3.61 (4H, m), 3.75-3.76 (4H, m), 4.39 (1H, brs), 4.87 (1H, brs), 6.13 ( 1H, d, J = 6.1Hz), 8.02 (1H, d, J = 6.1Hz).

[0252]

(Reference Example 57) trans-4 - (( 4- morpholino-2-yl) oxy) cyclohexanecarboxylic dihydrochloride:
[formula

　76] tert-butyl (trans-4 - ((4-morpholino pyrimidin-2 - yl) oxy) cyclohexyl) carbamate (0.066 g, trans-4 using 0.15 mmol) - same as ((synthesis of 2-chloro-4-yl) oxy) cyclohexane hydrochloride (reference example 3) to give crude product of the title compound (0.056 g) in manner.

[0253]

(Reference Example 58) tert-butyl trans- (4 - ((6- chloro-4-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　77] 4,6-dichloropyrimidine (0.35 g, 2.3 mmol ) using, tert- butyl trans- - give (4 ((2-chloro-4-yl) oxy) cyclohexyl) synthesis of the carbamate (reference example 2) and the title compound was prepared in a similar manner to (0.56 g) It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.29-1.32 (2H, m), 1.44-1.46 (11H, m), 2.05-2.13 (4H , m), 3.50 (1H, s), 4.42 (1H, s), 5.06 (1H, s), 6.71 (1H, d, J = 1.0Hz), 8.53 ( 1H, d, J = 0.7Hz) .

[0254]

(Reference Example 59) tert-butyl (trans-4 - ((6- morpholino-4-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　78] tert-butyl trans- (4 - ((6- chloropyrimidine 4-yl) oxy) cyclohexyl) carbamate (0.050 g, with 0.15 mmol) 1-(2-methoxy-5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (2- to give the title compound (0.058 g) in morpholino-4-yl) oxy) cyclohexyl) urea: (example 1) and similar methods.
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.17-1.35 (2H, m), 1.41-1.48 (11H, m), 2.07-2.10 (4H , m), 3.52-3.56 (4H, m), 3.74-3.58 (4H, m), 4.41 (1H, brs), 4.98 (1H, brs), 5. 76 (1H, s), 8.29 (1H, s).

[0255]

(Reference Example 60) trans-4 - (( 6- morpholino-4-yl) oxy) cyclohexanecarboxylic dihydrochloride:
[formula

　79] tert-butyl (trans-4 - ((6- morpholino-4 - yl) oxy) cyclohexyl) carbamate (0.059 g, trans-4 using 0.16 mmol) - same as ((synthesis of 2-chloro-4-yl) oxy) cyclohexane hydrochloride (reference example 3) to give crude product of the title compound (0.061 g) in manner.

[0256]

(Reference Example 61) tert-butyl (trans-4-(6- (methylamino) pyrimidin-4-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　80] tert-butyl trans- (4 - ((6- chloro-4-yl) oxy) cyclohexyl) carbamate (0.050 g, 0.15 mmol) with 1- (2-methoxy-5- (trifluoromethoxy) phenyl)-3-(trans-4-( to give (2-morpholino-4-yl) oxy) cyclohexyl) the title compound was prepared in a similar manner as in the synthesis of urea (example 1) (0.56 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.30-1.32 (2H, m), 1.43-1.47 (11H, m), 2.07-2.11 (4H , m), 2.87 (3H, d, J = 5.1Hz), 3.50 (1H, brs), 4.42 (1H, brs), 4.83 (1H, brs), 4.99 ( 1H, brs), 5.60 (1H , d, J = 0.7Hz), 8.20 (1H, s).

[0257]

(Reference Example 62) 6 - Synthesis of ((trans-4-aminocyclohexyl) oxy) -N- methyl-pyrimidin-4-amine dihydrochloride:
[formula

　81] tert-butyl (trans-4-(6- (methyl amino) pyrimidin-4-yl) oxy) cyclohexyl) carbamate (0.029 g, 0.089 mmol) using, trans-4 - synthesis of ((2-chloro-4-yl) oxy) cyclohexane hydrochloride ( to give crude product of the title compound (0.031 g) in reference example 3) in the same manner as.

[0258]

(Reference Example 63) tert- butyl (trans-4-(2-(methylamino) pyrimidin-4-yl) oxy) cyclohexyl) carbamate Synthesis:
[Formula 82]

　at room temperature tert- butyl trans- (4-( (2-chloro-4-yl) oxy) cyclohexyl) carbamate (0.12 g, methylamine / methanol solution (40 wt% of 0.37 mmol), 0.37 mL) solution was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 99: 1 → 60: 40 ) to afford the title compound (0.087 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.25-1.29 (2H, m), 1.45 (9H, s), 1.51-1.55 (2H, m), 2.08-2.12 (4H, m), 2.96 (3H, d, J = 5.1Hz), 3.49 (1H, brs), 4.40 (1H, brs), 4.92 ( 1H, brs), 5.94 (1H , d, J = 5.9Hz), 8.00 (1H, d, J = 5.6Hz).

[0259]

(Reference Example 64) 4 - Synthesis of ((trans-4-aminocyclohexyl) oxy) -N- methyl-2-amine dihydrochloride:
[formula

　83] tert-butyl (trans-4-(2-(methyl amino) -4-yl) oxy) cyclohexyl) carbamate (0.087 g, 0.27 mmol) using, trans-4 - ((2- chloro-4-yl) oxy) cyclohexanecarboxylic hydrochloride (reference to give crude product of the title compound (0.078 g) in example 3) and similar methods.

[0260]

(Reference Example 65) tert-butyl (trans-4 - ((2 - ((2- hydroxymethyl) amino) pyrimidin-4-yl) oxy) cyclohexyl) carbamate Synthesis:
[Chem

　84] 2-aminoethanol (55 mL , 0.92 mmol), tert-butyl trans- (4 - ((2-chloro-4-yl) oxy) cyclohexyl) carbamate (0.15 g, 0.46 mmol) with 1- (2-methoxy - 5- (trifluoromethoxy) phenyl) -3- (trans-4 - ( (2- morpholino-4-yl) oxy) cyclohexyl) produced the crude title compound was prepared in a similar manner to the synthesis of urea (example 1) to obtain a thing (0.15g).

[0261]

(Reference Example 66) tert-butyl (trans-4 - ((2 - ((2- hydroxymethyl) amino) pyrimidin-4-yl) oxy) cyclohexyl) carbamate 2 Synthesis of hydrochloride
[formula

　85] tert-butyl (trans-4 - ((2 - ((2- hydroxymethyl) amino) pyrimidin-4-yl) oxy) cyclohexyl) carbamate (0.15 g, 0.43 mmol) using, trans-4 - ((2- to give chloro-4-yl) oxy) cyclohexanecarboxylic hydrochloride (reference example 3) as a crude product of the title compound in a similar manner (0.11 g).

[0262]

(Reference Example 67) tert-butyl (trans-4-(pyridin-4-ylmethoxy) cyclohexyl) carbamate Synthesis:
[Chem

　86] tert-butyl trans- (4-hydroxycyclohexyl) carbamate (0.20 g, 0.93 mmol ), a DMF solution of 4- (bromomethyl) pyridine hydrobromide (0.18 g, 0.72 mmol), sodium hydride (55 wt% in mineral oil, 0.096g) was added. After stirring 1.5 hours at room temperature, the reaction solution, water was added, followed by extraction with ethyl acetate, saturated aqueous ammonium chloride solution, a saturated aqueous sodium chloride solution. 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 (eluent; hexane: ethyl acetate = 95: 5 → 35: 65 ) to afford the title compound (0.053 g).
MS (ESI) [M Tasu H] Tasu : 307.

[0263]

(Reference Example 68) trans-4-Synthesis of (pyridin-4-ylmethoxy) cyclohexane dihydrochloride:
[formula

　87] tert-butyl (trans-4-(pyridin-4-ylmethoxy) cyclohexyl) carbamate (0.017 g , using 0.055 mmol), trans-4 - a ((2-chloro-4-yl) oxy) the title compound was prepared in a similar manner as in the synthesis of cyclohexane hydrochloride (reference example 3) (0.012 g) Obtained.
MS (ESI) [M Tasu H] Tasu : 207.

[0264]

(Reference Example 69) tert-butyl (trans-4-(pyridin-3-ylmethoxy) cyclohexyl) Synthesis of carbamate:
[Formula

　88] 3- (bromomethyl) pyridine hydrobromide (0.53 g, 2.1 mmol) to give the title compound (0.094 g) in the same manner as tert- butyl using (trans-4-(pyridin-4-ylmethoxy) cyclohexyl) synthesis of the carbamate (example 67).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.13-1.16 (2H, m), 1.42-1.46 (11H, s), 2.05-2.06 (4H , m), 3.33 (1H, brs), 3.45 (1H, brs), 4.37 (1H, brs), 4.55 (2H, s), 7.25-7.28 (1H, m), 7.68 (1H, d , J = 8.0Hz), 8.54-8.56 (2H, m).

[0265]

(Reference Example 70) trans-4-Synthesis of (pyridin-3-ylmethoxy) cyclohexane dihydrochloride:
[formula

　89] tert-butyl (trans-4-(pyridin-3-ylmethoxy) cyclohexyl) carbamate (0.029 g , trans-4 with 0.089 mmol) - ((2-chloro-4-yl) oxy) cyclohexanecarboxylic hydrochloride (reference example 3) as a crude product of the title compound was prepared in a similar manner (0. 078g) was obtained.

[0266]

(Reference Example 71) tert-butyl - Synthesis of (trans-4 ((pyridin-3-ylmethoxy) methyl) cyclohexyl) carbamate:
[Chem

　90] tert-butyl (trans-4-(hydroxymethyl) cyclohexyl) carbamate (0 .20g, 0.87mmol), 3- (bromomethyl) pyridine hydrobromide (0.20 g, 0.79 mmol) using tert- butyl (trans-4- (pyridin-4-ylmethoxy) cyclohexyl) carbamate to give the title compound (0.12 g) in the same manner as in synthesis (reference example 67).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.03-1.11 (4H, m), 1.44 (9H, s), 1.53-1.57 (IH, m), 1.83-1.86 (2H, m), 2.02-2.04 (2H, m), 3.29-3.30 (2H, m), 3.38-3.41 (1H, m ), 4.37 (1H, brs) , 4.50 (2H, brs), 7.28-7.29 (1H, m), 7.66 (1H, d, J = 8.0Hz), 8. 53-8.55 (2H, m).

[0267]

(Reference Example 72) trans-4 - Synthesis of ((pyridin-3-ylmethoxy) methyl) cyclohexane dihydrochloride:
[formula

　91] tert-butyl (trans-4 - ((pyridin-3-ylmethoxy) methyl) cyclohexyl ) carbamate (0.12 g, trans-4 using 0.38 mmol) - ((-4-2-chloro-pyrimidin-yl) oxy) cyclohexanecarboxylic hydrochloride (the title compound in reference example 3) in the same manner as the crude product (0.084 g) was obtained.

[0268]

(Reference Example 73) tert-butyl - Synthesis of (trans-4 ((pyridin-4-ylmethoxy) methyl) cyclohexyl) carbamate:
[Chem

　92] tert-butyl (trans-4-(hydroxymethyl) cyclohexyl) carbamate (0 .20g, 0.87mmol), 4- (bromomethyl) pyridine hydrobromide (0.20 g, 0.79 mmol) using tert- butyl (trans-4- (pyridin-4-ylmethoxy) cyclohexyl) carbamate to give the title compound (0.14 g) in the same manner as in synthesis (reference example 67).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.07-1.16 (4H, m), 1.44 (9H, s), 1.53-1.57 (IH, m), 1.85-1.87 (2H, m), 2.03-2.05 (2H, m), 3.31 (2H, d, J = 6.6Hz), 3.39 (1H, brs), 4.38 (1H, brs), 4.50 (2H, s), 7.24 (2H, dd, J = 3.4,2.7Hz), 8.56 (2H, dd, J = 4.4 , 1.5Hz).

[0269]

(Reference Example 74) trans-4 - Synthesis of ((pyridin-4-ylmethoxy) methyl) cyclohexane dihydrochloride:
[formula

　93] tert-butyl (trans-4 - ((pyridin-4-ylmethoxy) methyl) cyclohexyl ) carbamate (0.14 g, trans-4 using 0.44 mmol) - ((-4-2-chloro-pyrimidin-yl) oxy) cyclohexanecarboxylic hydrochloride (the title compound in reference example 3) in the same manner as the crude product (0.097 g) was obtained.

[0270]

(Reference Example 75) 5 - ((trans- 4 - ((tert- butoxycarbonyl) amino) cyclohexyl) methoxy) Synthesis of methyl nicotinate:
[Chem 94]

　under ice-cooling tert- butyl (trans-4-(hydroxy methyl) cyclohexyl) carbamate (0.10g, 0.44mmol), 5- hydroxymethyl nicotinic acid methyl (0.10 g, 0.65 mmol), triphenylphosphine (0.17 g, in THF (5 mL) solution of 0.65 mmol) It was added bis (2-methoxyethyl) azodicarboxylate (0.15 g, 0.65 mmol). After stirring over night at room temperature, the reaction solution, water 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 (eluent; hexane: ethyl acetate = 80: 20 → 55: 45 ) to afford the title compound (0.12 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.13-1.24 (4H, m), 1.45 (9H, s), 1.76-1.80 (IH, m), 1.94-1.96 (2H, m), 2.06-2.09 (2H, m), 3.42 (1H, brs), 3.84 (2H, d, J = 6.3Hz), 3.95 (3H, s), 4.41 (1H, brs), 7.73-7.73 (1H, m), 8.45 (1H, d, J = 2.9Hz), 8.81 ( 1H, d, J = 1.5Hz) .

[0271]

(Reference Example 76) 5 - ((trans- 4 - ((tert- butoxycarbonyl) amino) cyclohexyl) methoxy) Synthesis of nicotinic acid:
[Chem

　95] 5 - ((trans-4 - ((tert-butoxycarbonyl) amino) cyclohexyl) methoxy) THF / methanol mixed solvent of methyl nicotinate (0.092 g, 0.25 mmol) (THF: methanol = 1: 1, v / v , 2mL) was added 1 N sodium hydroxide solution (0 .50mL) was added. After stirring over night at room temperature, the reaction solution, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product of the title compound (0.086 g).

[0272]

(Reference Example 77) tert-butyl (trans-4 - (((5-carbamoyl-pyridin-3-yl) oxy) methyl) cyclohexyl) carbamate Synthesis:
[Formula 96]

　under ice-cooling 5 - ((trans-4 - ((tert-butoxycarbonyl) amino) cyclohexyl) methoxy) nicotinic acid (0.086 g, 0.25 mmol), ammonium chloride (0.13 g, 2.5 mmol), hexafluorophosphate 2- (7-aza -1H - benzotriazol-1-yl) -1,1,3,3-tetramethyluronium, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate Fato (hereinafter, HATU) (0.14g, 0.37mmol) in DMF (2 mL) solution of, DIPEA (0.48mL, 3. mmol) was added. After stirring over night at room temperature, the reaction solution, water, 1N 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 (eluent; chloroform: methanol = 99: 1 → 95: 5 ) to afford the title compound (0.019 g).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.14-1.19 (4H, m), 1.45 (9H, s), 1.76-1.80 (IH, m), 1.93-1.96 (2H, m), 2.08-2.11 (2H, m), 3.42 (1H, brs), 3.86 (2H, d, J = 6.3Hz), 4.41 (1H, brs), 7.66 (1H, s), 8.43 (1H, d, J = 2.9Hz), 8.53 (1H, d, J = 1.7Hz).

[0273]

(Reference Example 78) 5 - ((trans- 4- aminocyclohexyl) methoxy) Synthesis of nicotinamide dihydrochloride:
[formula

　97] tert-butyl (trans-4 - (((5-carbamoyl-pyridin-3-yl ) oxy) methyl) cyclohexyl) carbamate (0.019 g, trans-4 with 0.054 mmol) - same as ((synthesis of 2-chloro-4-yl) oxy) cyclohexane hydrochloride (reference example 3) to give crude product of the title compound (0.014 g) in manner.

[0274]

(Reference Example 79) 3 - ((trans- 4 - ((tert- butoxycarbonyl) amino) cyclohexyl) methoxy) benzoic acid methyl:
Formula

　98] 3-hydroxybenzoate (0.10 g, 0.65 mmol ) using a 5 - to give a - (((tert-butoxycarbonyl) amino) cyclohexyl (trans-4) methoxy) synthesis of methyl nicotinate (example 75) and title compound was prepared in a similar manner (0.092 g) .
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.12-1.20 (4H, m), 1.45 (9H, s), 1.76 (IH, brs), 1.94- 1.96 (2H, m), 2.06-2.08 (2H, m), 3.42 (1H, brs), 3.80 (2H, d, J = 6.3Hz), 3.91 ( 3H, s), 4.40 (1H , brs), 7.07 (1H, dt, J = 8.3,1.2Hz), 7.33 (1H, t, J = 7.9 Hz), 7 .52 (1H, t, J = 2.0Hz), 7.61 (1H, dt, J = 7.6,1.2Hz).

[0275]

(Reference Example 80) 3 - ((trans- 4 - ((tert- butoxycarbonyl) amino) cyclohexyl) methoxy) benzoic acid:
[Formula

　99] 3 - ((trans-4 - ((tert-butoxycarbonyl) amino) cyclohexyl) methoxy) benzoate (0.092 g, 0.25 mmol) using, 5 - ((trans-4 - ((tert- butoxycarbonyl) synthesis of amino) cyclohexyl) methoxy) nicotinic acid (reference example to give the title compound (0.081 g) in the same manner as in 76).

[0276]

(Reference Example 81) tert-butyl (trans-4 - ((3- carbamoyl) methyl) cyclohexyl) carbamate Synthesis:
[Formula

　100] 3 - ((trans-4 - ((tert-butoxycarbonyl) amino) cyclohexyl ) methoxy) benzoic acid (0.081 g, 0.23 mmol) using, tert- butyl (trans-4 - (((5-carbamoyl-pyridin-3-yl) oxy) methyl) cyclohexyl) synthesis of the carbamate (example to give the title compound (0.081 g) in the same manner as in 77).
1 H-NMR (400 MHz, CDCl 3 ) [delta] (ppm): 1.12-1.22 (4H, m), 1.76 (IH, s), 1.94 (2H, d, J = 8.5 Hz ), 2.08 (2H, s) , 3.42 (1H, s), 3.81 (2H, d, J = 6.3Hz), 4.41 (1H, s), 5.58 (1H, s), 6.02 (1H, s ), 7.03-7.06 (1H, m), 7.31-7.34 (3H, m).

[0277]

(Reference Example 82) 3 - ((trans- 4- aminocyclohexyl) methoxy) benzamide Synthesis of hydrochloride
[formula

　101] 3 - ((trans-4 - ((tert-butoxycarbonyl) amino) cyclohexyl) methoxy) benzoic acid (0.081g, 0.23mmol) trans-4 with - ((2-chloro-4-yl) oxy) crude title compound was prepared in a similar manner to the synthesis of cyclohexane hydrochloride (reference example 3) to give the product (0.045 g).

[0278]

(Reference Example 83) tert-butyl (trans-4 - ((2-chloropyridin-4-yl) oxy) cyclohexyl) carbamate Synthesis:
Formula

　102] 2-chloro-4-nitropyridine (0.10 g, 0 to give the title compound (0.082 g) in .46Mmol) using tert- butyl (trans-4-(pyridin-4-ylmethoxy) cyclohexyl) synthesis of the carbamate (reference example 67) and similar methods.
MS (ESI) [M Tasu H] Tasu : 327.

[0279]

(Reference Example 84) tert-butyl (trans-4 - ((-4- 2- chloro-yl) oxy) cyclohexyl) carbamate Synthesis:
Formula

　103] tert-butyl (trans-4 - ((2-chloro-pyridine 4-yl) oxy) cyclohexyl) carbamate (0.10 g, after stirring for 30 minutes under 170 degrees using a microwave synthesizer morpholine (5 mL) solution of 0.31 mmol), the reaction solution, water was added , and extracted with ethyl acetate, 0.01 N hydrochloric acid, a saturated aqueous sodium chloride solution. 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 (eluent; hexane: ethyl acetate = 80: 20 → 50: 50 ) to afford the title compound (0.025 g).
MS (ESI) [M Tasu H] Tasu : 378.

[0280]

(Reference Example 85) trans-4 - (( 2- morpholino-4-yl) oxy) cyclohexanecarboxylic dihydrochloride:
[formula

　104] tert-butyl (trans-4 - ((2-chloro-pyridin -4 - yl) oxy) cyclohexyl) carbamate (0.025 g, 0.066 mmol) using, trans-4 - and ((synthesis of 2-chloro-4-yl) oxy) cyclohexane hydrochloride (reference example 3) to give the title compound (0.010 g) in a similar manner.
MS (ESI) [M Tasu H] Tasu : 278.

[0281]

(Reference Example 86) tert-butyl (trans-4-(pyridin-4-yloxy) cyclohexyl) Synthesis of the carbamate hydrochloride
[formula

　105] tert-butyl (trans-4 - ((4-2-chloropyridin-yl ) oxy) cyclohexyl) carbamate (0.050 g, with 0.15 mmol) 4-(2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one synthesis of (example 20) in the same manner as in to give the title compound (0.042 g).
MS (ESI) [M Tasu H] Tasu : 293.

[0282]

(Reference Example 87) trans-4-Synthesis of (pyridin-4-yloxy) cyclohexane dihydrochloride:
[formula

　106] tert-butyl (trans-4-(pyridin-4-yloxy) cyclohexyl) carbamate (0.040 g , trans-4 using 0.14 mmol) - ((2-chloro-4-yl) oxy) cyclohexanecarboxylic hydrochloride (reference example 3) as a crude product of the title compound was prepared in a similar manner (0. 025g) was obtained.
MS (ESI) [M Tasu H] Tasu : 193.

[0283]

(Reference Example 88) tert-butyl (trans-4 - ((2- ( pyridin-3-yl) pyrimidin-4-yl) oxy) cyclohexyl) carbamate Synthesis:
Formula 107]

　Under a nitrogen atmosphere, at 105 ° tert- butyl trans- (4 - ((2- chloro-4-yl) oxy) cyclohexyl) carbamate (0.063 g, 0.19 mmol), pyridine-3-boronic acid (0.028 g, 0.23 mmol), PdCl 2 (PPh 3 ) 2 (0.0067G, 0.0096 mmol) and potassium carbonate (0.056 g, 0.40 mmol) in 1,4-dioxane / water mixed solvent (1,4-dioxane: water = 2: 1 after v / v) was stirred for 8 hours, 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 was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 60: 40 ) to give the title compound (0.047 g) was obtained.
MS (ESI) [M Tasu H] Tasu : 371.

[0284]

(Reference Example 89) tert-butyl (trans-4 - ((4- ( pyridin-3-yl) pyrimidin-2-yl) oxy) cyclohexyl) carbamate Synthesis:
Formula

　108] tert-butyl trans- (4- ((4-chloro-2-yl) oxy) cyclohexyl) carbamate (0.07 g, 0.21 mmol) using tert- butyl (trans-4 - ((2- ( pyridin-3-yl) pyrimidin-4 - yl) oxy) cyclohexyl) the title compound was prepared in a similar manner as in the synthesis of carbamate (reference example 88) and (0.05 g).
MS (ESI) [M Tasu H] Tasu : 371.

[0285]

(Reference Example 90) trans-4 - Synthesis of ((2- (pyridin-3-yl) pyrimidin-4-yl) oxy) cyclohexane dihydrochloride:
[formula

　109] tert-butyl (trans-4 - (( 2- (pyridin-3-yl) pyrimidin-4-yl) oxy) cyclohexyl) carbamate (0.05 g, trans-4 using 0.14 mmol) - ((2-chloro-4-yl) oxy) cyclohexane to give the title compound (0.03 g) in the same manner as in the synthesis of amine hydrochloride (reference example 3).

[0286]

(Reference Example 91) trans-4 - Synthesis of ((4- (pyridin-3-yl) pyrimidin-2-yl) oxy) cyclohexane dihydrochloride:
[formula

　110] tert-butyl (trans-4 - (( 4- (pyridin-3-yl) pyrimidin-2-yl) oxy) cyclohexyl) carbamate (0.047 g, trans-4 using 0.13 mmol) - ((2-chloro-4-yl) oxy) cyclohexane to give the title compound (0.03 g) in the same manner as in the synthesis of amine hydrochloride (reference example 3).

[0287]

(Reference Example 92) tert-butyl (trans-4 - ((2- ( pyridin-4-yl) pyrimidin-4-yl) oxy) cyclohexyl) carbamate Synthesis:
Formula

　111] tert-butyl trans- (4- ((4-chloro-2-yl) oxy) cyclohexyl) carbamate (0.2 g, using 0.61 mmol) and pyridine-4-boronic acid (0.09 g, 0.73 mmol) tert-butyl (trans- 4 - was obtained ((2- (pyridin-3-yl) pyrimidin-4-yl) oxy) cyclohexyl) the title compound was prepared in a similar manner as in the synthesis of carbamate (reference example 88) (0.10 g).
MS (ESI) [M Tasu H] Tasu : 371.

[0288]

(Reference Example 93) trans-4 - Synthesis of ((2- (pyridin-4-yl) pyrimidin-4-yl) oxy) cyclohexane dihydrochloride:
[formula

　112] tert-butyl (trans-4 - (( 2- (pyridin-3-yl) pyrimidin-4-yl) oxy) cyclohexyl) carbamate (0.2 g, trans-4 using 0.28 mmol) - ((2-chloro-4-yl) oxy) cyclohexane to give the title compound (0.059 g) in the same manner as in the synthesis of amine hydrochloride (reference example 3).

[0289]

(Reference Example 94) 2-morpholino-5- (trifluoromethyl) Synthesis of aniline:
Formula

　113] 1-chloro-2-nitro-4- (trifluoromethyl) benzene (0.4 g, 1.77 mmol) in morpholine (5.0 ml) was added and heated at 100 ° for 5 hours. After addition of 0.01 N hydrochloric acid to the reaction solution, and extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, using the obtained crude product 4- (2-amino-4- (trifluoromethyl) phenyl) piperazin-2-one Synthesis of (Reference Example 20 ) to give the title compound in the same manner as. Without purification, it was used in the next reaction.
MS (ESI) [M Tasu H] Tasu : 247.

The scope of the claims

[Claim 1]

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

wherein, R 1 is trifluoromethyl group, a trifluoromethoxy group, or pentafluorosulfur sulfonyl group,
　R 2 are each independently a hydrogen atom, or, one hydroxyl or one It represents a ring-constituting atom C 4-6 saturated heterocyclyl group optionally substituted methyl group,
　R 3 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms, which may have an oxo group good ring member atom number of 4-6 saturated heterocyclyl group, or R 5 O-a represents,
　R 4 , one of R 6 may be substituted with, represents a phenyl group, a pyridyl group, a pyridazinyl group or a pyrimidinyl group,
　m and n each independently represent 0 or
　1, R 5 represents an alkyl group having 1 to 3 carbon atoms, or represents a saturated heterocyclyl group having a ring-constituting atoms 4-6 (however, R 5 of ring configuration Hara If There containing a nitrogen atom, said nitrogen atom may be substituted with an acetyl group.),
　R 6 is a carbamoyl group, a phenyl group, ring members having 5 or 6 heteroaryl group, ring constituting atoms 4 to a saturated heterocyclyl group, or (R a 6 7 ) R 8 N-a 　represents, R 7 and R 8 are each independently a hydrogen atom or a hydroxyl group are carbon atoms and optionally 1 to 3 substituents at It represents an alkyl group (wherein, m and n are 0, and, R 4 except when is substituted with a carbamoyl group, a phenyl group or pyridyl group.). ]

[Claim 2]

　R 2 are each independently a hydrogen atom or a hydroxymethyl
　group, R 3 represents a hydrogen atom, a morpholinyl group, 3-oxopiperazinyl group, or R 5 is
　O-, R 4 , one of R 6 may be substituted by a pyridyl group or pyrimidinyl group,
　R 5 represents an alkyl group having 1 to 3 carbon atoms, 3-oxetanyl group, or a nitrogen atom may be substituted with an acetyl group, 3-azetidinyl group, a 3-pyrrolidinyl group or 4-piperidinyl
　group, R 6 is a carbamoyl group, a pyridyl group, morpholinyl group, or (R 7 ) R 8 is N-, urea derivative according to claim 1, wherein or pharmacologically acceptable salts.

[Claim 3]

　R 4 of the general formula (IIa) ~ a group represented by one formula selected from (IIc),
　m and n are 0, claim 2 urea derivative or a pharmacologically acceptable according salt.
[Formula 2]

wherein, R 9 is a carbamoyl group, a pyridyl group, morpholinyl group, or (R 7 ) R 8 N-a represents the wavy line represents the point of attachment to formula (I). ]

[Claim 4]

　R 4 is a group represented by the general formula (IId) or (IIe),
　m and n, one is a 0 and the other is 1, claim 2 urea derivative or a pharmacologically acceptable according salt.
[Chemical Formula 3]

[wherein, R 10 represents a hydrogen atom or a carbamoyl group, the wavy line represents the point of attachment to formula (I). ]

[Claim 5]

　Containing claims 1 to urea derivative or a pharmacologically acceptable salt thereof according to any one claim of 4 as an active ingredient, an inhibitor of discoidin domain receptor 1.