WO2007037010A1 - Phenoxyacetic acid derivatives and drugs using the same - Google Patents

Abstract

It is intended to provide a novel compound having an excellent agonism to PPARs α/Ϝ and desirable properties as a drug. An agonist to peroxisome proliferator-activated receptors α/Ϝ which is represented by the general formula (I) (wherein Q represents an optionally substituted benzene ring or pyridine ring; R1 and R2 represent each an optionally substituted phenyl group or a 5- to 6-membered aromatic heterocycle group; X, Y and Z independently represent each C, O, S or N; R3 to R9 represent each a hydrogen atom, a lower alkyl group, etc.; and n is an integer of from 0 to 3.

Description

 Phenoxyacetic acid derivatives and pharmaceutical technology using the same

 [0001] The present invention relates to a phenoxyacetic acid derivative, a salt thereof, and a solvate thereof effective as an agent for preventing or treating diabetes. More specifically, the present invention relates to a peroxisome proliferator-activated receptor / y agonist (PPAR / y agonist).

 Background art

 [0002] Diabetes mellitus is a disease that develops and develops various acute and chronic complications such as ischemic heart disease and cerebrovascular disorder, and causes a significant impairment in daily life. Therefore, it is necessary to prevent the onset and progression of these complications through early detection and strict glycemic control.

 Diabetes is impaired in the production and secretion of insulin to control blood sugar! Type 1 diabetes and the production of insulin 'secretion is at a high level from the normal range, but it is very sensitive to the target organ and tissue of insulin. It is classified as type 2 diabetes that is reduced (ie, increased insulin resistance).

 The main target organs and tissues of insulin are muscle, adipose tissue, and liver, which promotes glucose uptake and glycogen synthesis in muscle, and promotes uptake and utilization of dulose in adipose tissue. In the liver, it suppresses gluconeogenesis and promotes glycogen synthesis. Insulin is also involved in fat metabolism (facilitation of fat synthesis and inhibition of degradation) in adipose tissue that is not just for controlling sugar metabolism as described above.

 [0003] Recently, thiazolidinedione derivatives such as pioglitazone (non-patent document 1) having the following structure have been developed as drugs for improving insulin resistance, and patients with type 2 diabetes, particularly those with type 2 diabetes Widely used in the treatment of

[0004] [Chemical 1]

P i ogl i tazone

[0005] These thiazolidinedione derivatives have been clarified to be pergosomes of the peroxisome proliferator-activated receptor γ (PPAR y)! (Non-patent Document 2). The mechanism by which PPAR yagonists improve insulin resistance has not been fully elucidated, but it promotes apoptosis of hypertrophic adipocytes that produce and secrete free fatty acids that cause insulin resistance, and from preadipocytes to adipocytes Incorporation of free fatty acids by promoting differentiation into plants · Promoting storage is cited as a promising theory.

 [0006] PPAR Gamma-agonist pioglitazone is particularly high when administered to type 2 diabetic patients with obesity and has a therapeutic effect, while weight gain and fluid retention are in Watched! / Speak (Non-Patent Document 3). As mentioned above, diabetes causes and develops complications such as ischemic heart disease and cerebrovascular disorder, so such weight gain and fluid retention are not desirable. Recently, there has been active research on PPAR a / y agonists in which PPAR γ agonists have been subjected to PPAR α agonist action. It has also been suggested that it exhibits properties as an excellent anti-diabetic drug. For example, in a test using db / db mice, it has been shown that PPAR a / γagost KRP-297 significantly suppresses body weight gain compared to pioglitazone (Non-patent Document 4). . PPAR a / yagost LY465608 has been shown to increase high-density lipoprotein (HDL) in a dose-dependent manner and lower plasma triglycerides, reducing the risk of ischemic heart disease. (Non-Patent Document 5).

 Typical PPAR a / y agonists include the following compounds (Non-patent Documents 6 to 7 and Patent Documents 1 and 2).

[0007] [Chemical 2]

[0008] Non-patent literature l: Chem. Pharm. Bull, 39, 1440-1445 (1991)

 Non-Patent Document 2: J. Biol. Chem., 270, 12953-12956 (1995)

 Non-Patent Document 3: Am. J. Med., 115 (8A), 111S- 115S (2003)

 Non-Patent Document 4: Am. J. Physiol, 284, E966-E971 (2003)

 Non-Patent Document 5: Diabetes, 51, 1083-1087 (2002)

 Non-Patent Document 6: Bioorg. Med. Chem. Lett., 9, 533-538 (1999)

 Non-Patent Document 7: Chem. Pharm. Bull, 51, 138-151 (2003)

 Patent Literature l: WO2001-021602

 Patent Document 2: WO2004—000785

 Disclosure of the invention

 Problems to be solved by the invention

[0009] The object of the present invention is that the chemical structure is different from the above-mentioned known PPAR a / y agonist, has an excellent PPAR a / y agonist action, and is desirable and has properties as a pharmaceutical product. Is to provide a compound.

 Means for solving the problem

[0010] Therefore, as a result of various studies, the present inventor has shown that the compound represented by the following general formula (I) exhibits an excellent PPAR a / y agonist action and is useful as a prophylactic or therapeutic agent for diabetes. The headline and the present invention were completed. That is, the general formula (I)

[0011] [Chemical 3]

[0012] (In the above formula,

 Q is a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a pyrrolidinyl group, a piperidyl group, a piperazyl group, a morpholinyl group, a substituted group Or an unsubstituted phenol group and a substituted or unsubstituted pyridyl group, selected from one or two of the same or different groups, a benzene ring or a pyridine ring,

R ¹ is a halogen atom, a lower alkenyl group, a lower alkoxy group, a phenoxy group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted amino group, one selected from the same or two of the same or different A phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyradyl group, a chael group, a furyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, Represents isothiazolyl, isoxazolyl, oxaziazolyl or triazolyl,

R ² represents a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted pyridyl. A group selected from the following groups, which may be substituted with one, two, or the same or different groups, pyridyl group, pyrimidyl group, birazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, thiazolyl group, Oxazolyl group, isothiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, cinnolyl group, quinoxalyl group, phthalazinyl group, naphthyridinyl group, indolyl group, benzoimidazolyl group, indazolyl group, indazolyl group , Benzoxazolyl group, benzoiso Azolyl group, benzoisoxazolyl O hexa benzisoxazolyl group or base emission zone Toriazoriru group or substituted with one or allogeneic or two lower alkyl groups of different Will show the force rubermoyl group,

 X, Y and Z each independently represent C, 0, S or N (provided that at least one of X, Y and Z is 0, S or N);

R ^{3 to} R ⁶ each independently represent a hydrogen atom or a lower alkyl group, or R ³ and R ⁵ and R ⁶ together with the carbon atom they are substituted with 3 to 6 Indicates that a saturated ring of members may be formed,

R ⁸ and R ⁹ each independently represent a hydrogen atom or a lower alkyl group, and n represents an integer of 0 to 3. )

The compound represented by these, its salt, or those solvates are provided.

 The present invention also provides a compound, salt or solvate thereof, which is a 5-membered oxazole ring, thiazole ring or oxaziazole ring containing X, Y and Z in the general formula (I). .

 In the present invention, Q in the general formula (I) is one or more of the same or different selected from the group consisting of a halogen atom, a lower alkenyl group, a lower alkoxy group, and a substituted or unsubstituted lower alkyl group. A compound which is substituted with two groups and which is a benzene ring, a salt thereof or a solvate thereof is provided.

In the present invention, R ¹ in the above general formula (I) may be substituted with ^one of the halogen atoms and one of the same or different groups of the same or different groups selected from the substituted or unsubstituted lower alkyl groups. , A compound that is a phenyl group, a salt thereof, or a solvate thereof.

In the present invention, R ² in the above general formula (I) is selected from the group consisting of a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted phenyl group. Or a pyridyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isothiazolyl group, an isoxazolyl group, an oxadiazolyl group, a benzoimidazolyl group, a benzothiazolyl group, or a benzoyl group, which may be substituted with two groups of the same or different types The present invention provides a compound having a benzoxazolyl group, a salt thereof, or a solvate thereof.

In the present invention, R ² in the above general formula (I) is one or two lower groups of the same or different types. The present invention provides a compound, a salt thereof or a solvate thereof which is a carbamoyl group substituted with an alkyl group.

 [0014] The present invention also provides a pharmaceutical comprising the compound represented by the above general formula (I), a salt thereof or a solvate thereof as an active ingredient.

 The present invention also provides a pharmaceutical composition comprising a compound represented by the above general formula (I), a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier. Furthermore, the present invention provides use of a compound represented by the above general formula (I), a salt thereof or a solvate thereof for the production of a medicament.

 Furthermore, the present invention provides a method for treating a disease caused by insulin resistance, which comprises administering an effective amount of a compound represented by the above general formula (I), a salt thereof, or a solvate thereof. It is to provide.

[0015] Further, the present invention provides the following general formula (II)

[0016] [Chemical 4]

[0017] (In the above formula,

R ⁷ represents a hydrogen atom or an unsubstituted lower alkyl group,

R ^1QQ represents a methyl group or a methoxy group,

R ² ° represents a hydrogen atom or a methyl group. )

 The compound represented by these, its salt, and those solvates are provided.

[0018] Further, the present invention provides a medicament containing the compound represented by the above general formula (Π), a salt thereof, or a solvate thereof.

 The present invention also provides a pharmaceutical composition comprising a compound represented by the above general formula (Π), a salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier.

In addition, a compound represented by the above general formula (Π), a salt thereof, or a solvate thereof, The use for manufacturing is provided.

 The present invention also provides an insulin resistance improving agent containing the compound represented by the above general formula (Π), a salt thereof, or a solvate thereof.

 The present invention also provides a therapeutic agent for diabetes containing the compound represented by the above general formula (Π), a salt thereof or a solvate thereof.

 The present invention also provides a method for treating a disease caused by insulin resistance, which comprises administering an effective amount of a compound represented by the above general formula (Π), a salt thereof, or a solvate thereof.

 The invention's effect

 The compound represented by the general formula (I) of the present invention exhibits an excellent PPAR a Z agonist action, and is useful as a preventive / therapeutic agent for diabetes.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0020] The substituents in the general formula (I) will be described below.

 [0021] The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

 As the halogen atom, a fluorine atom and a chlorine atom are preferable.

 [0022] The unsubstituted lower alkyl group means a linear, branched and cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, a butyl group, and pentyl. Group, hexyl group, 1 methylethyl group, 1,1-dimethylethyl group, 1 methylpropyl group, 2-methylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group 1 methyl butyl group, 2 methyl butyl group, 3 methyl butyl group, 1, 1-dimethyl butyl group, 1, 2 dimethyl butyl group, 1, 3 dimethyl butyl group, 2, 2 dimethyl butyl group, 2, 3 dimethyl butyl group, 3 , 3 Dimethylbutyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4 methylpentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl It can be exemplified consequent opening cyclopropylmethyl group, cyclobutylmethyl group, and a cyclopentylmethyl group as a representative example. Of these, methyl, ethyl and propyl are preferred.

[0023] The substituted lower alkyl group is a hydroxyl group, a halogen atom, an amino group, an alkylamino group, dia Kilamino group, lower alkoxy group, carboxy group, lower alkoxy carbo group, carbamoyl group, alkyl strength rubamoyl group, dialkyl strength rubamoyl group, strength rubamoylamino group, alkyl strength rubamoylamino group, dialkyl strength rubamoylamino group, alkylsulfo-lumino Means a lower alkyl group substituted with 1 to 3 groups of the same or different types selected from a group, a lower alkoxycarbolumino group and a lower alkanoylamino group, such as a trifluoromethyl group, hydroxy Methyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-fluoroethyl group, 2-chloroethyl group, 3-fluoropropyl group, aminomethyl group, 2-aminoethyl group, 3-aminopropyl group, methylaminomethyl group Tyl group, 2-methylaminoethyl group, 3-methyl group Laminopropyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, 3-dimethylaminopropyl group, methoxymethyl group, 2-methoxyethyl group, 3-methoxypropyl group, carboxymethyl group, 2-carboxyethyl group, 3- Carboxypropyl group, methoxycarbomethyl group, 2-methoxycarboruethyl group, 3-methoxycarbopropyl group, strong rubamoylmethyl group, 2-carbamoylethyl group, 3-carbamoylpropyl group, methylcarbamoylmethyl group, 2 — Methylcarbamoylethyl, 3-methylcarbamoylpropyl, ethylcarbamoylmethyl, 2-ethylcarbamoylethyl, 3-ethylcarbamoylpropyl, dimethylcarbamoylmethyl, 2-dimethylcarbamoylethyl, 3— Dimethyl Lucal Vamoylpropyl group, Jetylcarbamoylmethyl group, 2-Detylcarbamoylethyl group, 3-Dethylcarbamoylpropyl group, Strong rumoamoylaminomethyl group, 2-Strong rumomoylaminoethyl group, 3-Strong ruberamoylaminopropyl Group, methylcarbamoylaminomethyl group, 2-methylcarbamoylaminoethyl group, 3-methylcarbamoylaminopropyl group, ethylcarbamoylaminomethyl group, 2-ethylcarbamoylaminoethyl group, 3-ethylcarbamoylaminopropyl group, dimethyl group Carbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, 3-dimethylcarbamoylaminopropyl group, jetylcarbamoylaminomethyl group, 2-jetylcarbamoylaminoethyl group, 3-jetylcarbamoylaminopropyl Group, methylsulfo-laminomethyl group, 2-methylsulfo-aminoamino group, 3-methylsulfo-laminopropyl group, methoxycarboaminomethyl group, 2-methoxycarbolaminoethyl group, 3-methoxycarboro group -Luaminopropyl group, ethoxycarboaminoamino group, 2-ethoxycarboaminoamino group, 3-ethoxycarbolaminopropyl group, acetylaminomethyl group, 2-acetylaminoethyl group, and 3-acetylaminoaminopropyl Groups can be mentioned as representative examples. Trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group, 2-fluoroethyl group, 2-chloroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, Dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, carboxymethyl group, 2-carboxetyl group, methoxycarboromethyl group, 2-methoxycarboruethyl group, rubamoylmethyl Group, 2-force rubamoylethyl, methylcarbamoylmethyl, 2-methylcarbamoylethyl, ethylcarbamoylmethyl, 2-ethylcarbamoylethyl, dimethylcarbamoylmethyl, 2-dimethylcarbamoylethyl, Tylcarbamoylmethyl group, 2-jetylcarbamoy Ethyl group, strong rubamoylaminomethyl group, 2-strong rubamoylaminoethyl group, methylcarbamoylaminomethyl group, 2-methylcarbamoylaminoethyl group, ethylcarbamoylaminomethyl group, 2-ethylcarbamoylaminoethyl group, dimethyl Carbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, jetylcarbamoylaminomethyl group, 2-jetylcarbamoylaminoethyl group, methylsulfo-luminaminomethyl group, 2-methylsulfoaminoamino group, methoxycarbo-luminaminomethyl group 2-methoxycarboroaminoethyl group, ethoxycarboaminoamino group, 2-ethoxycarboroaminoethyl group, acetylaminomethyl group, and 2-acetylethylaminoethyl group are preferred trifluoromethyl group, hydro Cymethyl group, 2-hydroxyethyl group, 2-fluoroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxy Methyl group, 2-methoxyethyl group, carbamoylmethyl group, 2-force rubamoylethyl group, methylcarbamoylmethyl group, 2-methylcarbamoylethyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoylethyl group, jetylcarbamoylmethyl group , Rubamoylaminomethyl group, methyl rubamoylaminomethyl group, ethylcarbamoylaminomethyl group, dimethylcarbamoylaminomethyl group, jetylcarbamoylaminomethyl group and methylsulfolamine The trifluoromethyl group, hydroxymethyl group, 2-hydroxyethyl group and 2-fluoroethyl group are particularly preferred, with the nomethyl group being more preferred.

[0024] The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a bur group, a allyl group, and a butenyl group. it can.

 [0025] The lower alkoxy group means an alkoxy group having a linear, branched and cyclic alkyl group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. Typical examples include butoxy group, isobutoxy group, pentoxy group, and cyclopentyloxy group. Of these, methoxy groups and methoxy groups are preferred, and methoxy groups are more preferred.

 [0026] The substituted amino group is an alkylamino group, a dialkylamino group, a lower alkoxycarboamino group, a strong ruberamoylamino group, an alkyl strength ruberamoylamino group, a dialkyl power ruberamoylamino group, an alkylsulfo-amino group, or a lower alkanoyl group. Mino group, for example, methylamino group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, 1-methylethylamino group, 1,1-dimethylethylamino group, 1 —Methylpropylamino group, dimethylamino group, jetylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, di (1 methylethyl) amino group, methylethylamino group, methoxycarbolumino group , Ethoxycarbo-lamino group, methyl Representative examples include carbamoylamino, ethylcarbamoylamino, dimethylcarbamoylamino, jetylcarbamoylamino, methylsulfo-lamino, ethylsulfo-lamino, acetylylamino, and propio-lamino groups. it can. Among them, methylamino group, ethylamino group, 1-methylethylamino group, dimethylamino group, jetylamino group, dipropylamino group, methylethylamino group, methoxycarbolumino group, ethoxycarbolumino group, methylcarbamoyla group A mino group, an ethylcarbamoylamino group, a dimethylcarbamoylamino group, a jetylcarbamoylamino group, a methylsulfo-lumino group, an ethylsulfo-lumino group, and an acetylylamino group are preferred.

[0027] The substituted phenol group is an alkyl group, a hydroxyl group, a halogen atom, an amino group, or an alkylamino group. It means a phenyl group substituted with one or two groups of the same or different types, wherein the intermediate force of a group, a dialkylamino group, a lower alkoxy group, a phenoxy group and a substituted or unsubstituted amino group is also selected. Specific examples of the mono-substituted phenyl group include methyl, trifluoromethyl, ethyl, hydroxy, fluoro, fluoro, chloro, bromo and aminophenyl groups. -Methyl group, methylaminophenyl group, ethylaminophenol group, dimethylaminophenol group, jetylaminophenol group, methoxyphenyl group, phenoxyphenyl group, methoxycarboaminophenol group, Carbamoylaminophenol groups, methylcarbamoylaminophenol groups, dimethylcarbamoylaminophenol groups, methylsulfoaminophenol groups and acetylaminophenol groups can be cited as representative examples. Specific examples of the thiol group include a fluoromethylphenol group, a black methylphenyl group, a fluorohydroxyphenyl group, a chloromethyl group, and a chloromethyl group. Mouth hydroxyphenol group, difluorophenol group, dichlorophenol group, black mouth fluorophenol group, aminofluorophenol group, aminochlorophenol group, fluoromethylaminophenol Group, chloromethylaminophenol group, dimethylamino-fluorophenol group, dimethylamino-chlorophenol group, jetylamino-fluorophenol group, chloromethylaminophenol group, fluorine Low methoxyphenyl group, chloromethoxyphenyl group, fluoromethoxycarboaminophenol group, chloromethoxycarbonylaminophenol group, strong rubamoylaminofluorophenol group, strong rubamoyl group Aminochrome mouth group, Fluoromethylcarbamoylaminophenol group, Chloromethylcarbamoylaminophenol group, Dimethylcarbamoyl Mino-fluorophenol group, Chloro-dimethylcarbamoylaminophenol group, Fluoromethylsulfo-luminophenol group, Chloro-methylsulfo-luminophenol group, Acetylaminofluorophenol group and Acetylamino group A black mouth phenyl group can be given as a representative example. The mono-substituted phenyl group includes methyl, trifluoromethyl, methoxy, phenoxy, fluoro and chlorophenols, and bromophenol. A methylphenol group, a trifluoromethylphenol group, a methoxyphenyl group, a phenoxyphenol group, a fluorophenol group, and a black mouthphenol group are preferred. Examples of the disubstituted phenol group include a fluoromethylphenol group, a chloromethylphenol group, and a difluorophenol group. Preferred are difluorophenol, dichlorophenol, and chlorophenol, chlorophenol, fluoromethoxy, fluoromethoxy, and methoxyphenol. Mouth Fluorophenol group is more preferred.

The substituted pyridyl group is selected from the group consisting of an alkyl group, a hydroxyl group, a halogen atom, an amino group, an alkylamino group, a dialkylamino group, a lower alkoxy group, a phenoxy group, and a substituted or unsubstituted amino group. Or it means that two different groups are substituted. Specific examples thereof include methylpyridyl group, trifluoromethylpyridyl group, ethylpyridyl group, hydroxypyridyl group, fluoropyridyl group, cyclopyridyl group, bromopyridyl group, aminoviridyl group, methylaminoviridyl group, and ethylamino. Biridyl group, dimethylaminopyridyl group, jetylaminopyridyl group, methoxypyridyl group, phenoxypyridyl group, methoxycarbolaminopyridyl group, rubamoylaminopyridyl group, methylcarbamoylaminopyridyl group, dimethylcarbamoylamino group Pyridyl, methylsulfonylamino, and acetylaminopyridyl groups can be listed as typical examples of mono-substituted pyridyl groups, such as fluoro-methylpyridyl, black-mouthed methylpyridyl, and fluoro-hydroxypyridyl. , Chlomouth 1 hydroxypyridyl group, difluoropyridyl group, dichloropyridyl group, chloro-fluoropyridyl group, aminofluoropyridyl group, aminochloropyridyl group, fluoro-methylaminopyridyl group, Aminoviridyl group, dimethylaminofluoropyridyl group, dimethylamino-cyclopyridyl group, jetylamino-fluoropyridyl group, chloro-jetylaminopyridyl group, fluoro-methoxypyridyl group, chloro-methoxypyridyl group, fluoro-methoxycarbo -Luminopyridyl group, Black-mouth methoxy-Carlo-amino-pyridyl group, Strong rumoylamino-Fluoropyridyl group, Strong rumo-molyaminopyridyl group, Fluoromethylcarbamoylaminopyridyl group, Chloromethylcarbamoylaminopi Dimethylcarbamoylaminofluoropyridyl group, dimethylcarbamoylaminopyridyl group, fluoromethylsulfonylaminopyridyl group, chloromethylsulfo-laminopyridyl group, acetylamino-fluoropyridyl group, and acetylamino A black-and-white pyridyl group can be listed as a typical example of a disubstituted pyridyl group. Mono-substituted pyridyl groups include methylpyridyl group, trifluoromethylpyridyl group, methoxypyridyl group, phenoxypyridyl group, fluoropyridyl group, A methylpyridyl group, a trifluoromethylpyridyl group, a methoxypyridyl group, a phenoxypyridyl group, a fluoropyridyl group, and a chloropyridyl group, which are preferred to a zyl group and a bromopyridyl group, are more preferred. Examples of the di-substituted pyridyl group include a fluoro-methylpyridyl group, a chloromethylpyridyl group, a difluoropyridyl group, a dichloropyridyl group, a black chloropyridyl group, a fluoro-methoxypyridyl group, and a chloro-methoxypyridyl group. Preferably, a difluoropyridyl group, a dichloropyridyl group, and a chlorofluoropyridyl group are more preferable.

[0029] R ¹ and R ² will be described below.

R ¹ is selected from the group consisting of a halogen atom, a lower alkenyl group, a lower alkoxy group, a phenoxy group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted amino group, one or the same or different 2 More specifically, phenyl group, pyridyl group, and chael group, which may be substituted with one group, are preferred, such as phenyl group, fluorophenyl group, chlorophenol group, and bromophenol. Preferred are, for example, the groups trifluoromethylphenyl, methylphenyl, dimethylphenyl, methoxyphenyl, phenoxyphenyl, and fluoromethylphenyl, and methylphenyl. be able to.

[0030] R ² represents a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted phenol group, and a substituted or non-substituted group. A pyridyl group, an imidazolyl group, an oxadiazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isothiazolyl group, which may be substituted with one, two, or the same or different groups selected from among substituted pyridyl groups Group, isoxazolyl group, benzimidazolyl group, indazolyl group, benzothiazolyl group, benzoxazolyl group, benzoisothiazolyl group and benzoisoxazolyl group, and one or two lower alkyl groups of the same or different kind More specifically, a carbamoyl group is preferred, and specifically, a pyridyl group, imidazolyl Group, methyl imidazolyl group, pyrazolyl group, methyl pyrazolyl group, thiazolyl group, methyl thiazolyl group, oxazolyl group, methyl oxazolyl group, methoxy oxazolyl group, foxoxazolyl group, methyl phe-loxa oxolyl group, hydroxy oxazia group Zolyl, methyloxadiazolyl, isothiazolyl, methylisothiazolyl, dimethylisothiazolyl, isoxazolyl, methyliso Oxazolyl group, dimethylisoxazolyl group, benzimidazolyl group, methylbenzoimidazolyl group, indazolyl group, methylindazolyl group, benzothiazolyl group, benzoxazolyl group, benzoisothiazolyl group, benzoisoxazolyl group, Strong rubamoyl group, methylcarbamoyl group, ethylcarbamoyl group, isopropyl strength rubamoyl group, butyl force rubamoyl group, cyclopropyl force rubamoyl group, cyclopropylmethylcarbamoyl group, dimethylcarbamoyl group, methyl-ethylcarbamoyl group, and jetylcarbamoyl group As preferred examples, pyridyl group, imidazolyl group, methyl imidazolyl group, thiazolyl group, methyl thiazolyl group, oxazolyl group, methyl oxazolyl group, methoxy oxoxy group Zolyl group, phenoxazolyl group, methylphenol-xazolyl group, hydroxyoxadiazolyl group, methyloxadiazolyl group, isoxazolyl group, methylisoxazolyl group, dimethylisoxazolyl group Group, benzimidazolyl group, methylbenzimidazolyl group, force rubamoyl group, methylcarbamoyl group, ethylcarbamoyl group, isopropyl force rubamoyl group, butylcarbamoyl group, cyclopropylcarbamoyl group, cyclopropylmethylcarbamoyl group, dimethylcarbamoyl group, jetylcarbamoyl group, And methyl-ethylcarbamoyl group is a more preferred example.

 Q will be explained below.

Q includes benzene ring, hydroxybenzene ring, fluorobenzene ring, black benzene ring, bromobenzene ring, bullbenzene ring, arylbenzene ring, methoxybenzene ring, ethoxybenzene ring, methylbenzene ring, ethylbenzene ring, methoxymethylbenzene. Ring, aminobenzene ring, methylaminobenzene ring, dimethylaminobenzene ring, pyrrolidylbenzene ring, piperidyl-benzene ring, piperazylbenzene ring, morpholinylbenzene ring, phenolbenzene ring, pyridylbenzene ring, etc. , Dimethylbenzene ring, methyl-ethylbenzene ring, methyl-methoxybenzene ring, methyl benzene ring, methoxy-fluorobenzene ring, difluorobenzene ring, dimethoxybenzene ring and other disubstituted benzene rings, pyridine Ring, hydroxy pyridine ring, fluoro pyridine ring, black pyridine ring, bromo pyridine ring, butyl pyridine ring, aryl pyridine ring, methoxy pyridine ring, ethoxy pyridine ring, methyl pyridine ring, ethyl pyridine ring, methoxy methyl pyridi Ring, aminopyridine, methylaminopyridine, dimethylaminopyridine, pyrrolidylpyridine, piperidyl-rubiridine, piperazylpyridine, morpholinylpyridine, phenolidine, and pyridylpyridine rings. Specific examples are benzene ring, hydroxybenzene ring, fluorobenzene ring, black benzene ring, arylbenzene, methoxybenzene ring, methylbenzene ring, phenylbenzene ring, pyridylbenzen ring, pyridine ring, hydroxypyridine. Preferred examples include a ring, a fluoropyridine ring, a black pyridine ring, an aryl pyridine ring, a methoxy pyridine ring, and a methyl pyridine ring. Among them, a benzene ring, a fluorobenzene ring, a black benzene ring, a bromobenzene ring, a Benzene ring, methoxybenzene ring, methylbenzene ring, difluorobenzene ring, dimethylbenzene ring, methyl-ethylbenzene ring, methyl-methoxybenzene ring, methyl-chlorobenzene ring, methoxy-fluorobenzene ring, dimethoxybenzene ring, and A more preferred example is a pyridine ring. Furthermore, among them, a benzene ring, an arylbenzene ring, a methoxybenzene ring, a methylbenzene ring, a dimethylbenzene ring, a methylethylbenzene ring, a methyl-methoxybenzene ring, a methylchlorobenzene ring, and a dimethoxybenzene ring are particularly preferable.

[0032] Hereinafter, R ^{3 to} R ⁹ and n will be described.

As R ³ and R ⁴ , a hydrogen atom in which a hydrogen atom, a methyl group and an ethyl group are preferable and a hydrogen atom in which a methyl group is more preferable are more preferable.

R ⁵ and R ⁶ are each preferably a hydrogen atom, a methyl group, or an ethyl group, or a 3- to 6-membered saturated ring formed by combining R ⁶ with a carbon atom. ,. R ⁵ and R ⁶ are each preferably a hydrogen atom and a methyl group, and more preferably a methyl group. R ⁵ and R ⁶ are both particularly preferably a methyl group.

R ⁷ is preferably a hydrogen atom, a methyl group, an ethyl group, or a tert-butyl group.

R ⁸ and R ⁹ are each preferably a hydrogen atom or a methyl group, more preferably a hydrogen atom, a methyl group, or an ethyl group.

 n is a force that is an integer of 0 to 3 0 to 2 force S, preferably 1 to 2.

[0033] The ring containing X, Y and Z in the general formula (I) means a 5-membered heterocyclic ring, and is a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an oxazole ring. Specific examples include an isothiazole ring, an isoxazole ring, an oxaziazole ring, and a triazole ring. When this 5-membered heterocyclic ring is a thiazole ring, an oxazole ring, an isothiazole ring, an isoxazole ring or a triazole ring, it is considered that there is no R ⁹ substituted for this heterocyclic ring. If is an oxadiazole ring, it is considered that there are no R ⁸ and R ⁹ substituted on this heterocycle.

[0034] The 5-membered heterocyclic ring in which the substituents R ⁸ and R ⁹ are substituted on the 5-membered heterocyclic ring includes a thiophene ring, a furan ring, a pyrrole ring, an imidazole substituted with one methyl group or one ethyl group. Preferred examples include rings, pyrazole rings, thiazole rings, oxazole rings, isothiazole rings, isoxazole rings and triazole rings, and thiophene rings, furan rings, pyrrole rings, imidazole rings, and pyrazole rings substituted with two methyl groups. be able to. Among them, a methyl group substituted by one methyl group, a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an oxazole ring, an isothiazole ring, an isoxazole ring and a triazole ring are more preferred. Particularly preferred are a thiazole ring and an oxazole ring substituted by one. In addition, when the substituents R ⁹ or R ⁸ and R ⁹ are not present in the 5-membered heterocyclic ring, an oxadiazole ring can be mentioned as the ring.

 [0035] Among the compounds represented by the general formula (I) of the present invention, as one of the particularly excellent compounds, the following general formula (II)

[0036] [Chemical 5]

(In the above formula,

R ⁷ represents a hydrogen atom or an unsubstituted lower alkyl group,

R ^1QQ represents a methyl group or a methoxy group,

R ² ° represents a hydrogen atom or a methyl group. ) The compound represented by these can be mentioned.

 [0038] Specifically,

 2- [4 [[Strengthened rubermoylmethyl- (5-methyl-2-p-tolyloxazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] 2 methylpropanoic acid (Ila),

2- [4 [[Strengthened rubermoylmethyl- [2- (4-methoxyphenol) -5-methyloxazol 4-ruylmethyl] amino] methyl] -2,6 dimethylphenoxy] -2-methylpropanoic acid ( IIb),

 2- [4 [[force rubermoylmethyl- (5-methyl-2-m-tolyloxazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] 2 methylpropanoic acid (IIc), and

 2— [4 [[Strong rubamoylmethyl- [2 -— (3,4 dimethylphenol) 5-methyloxazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] —2-methylpropanoic acid ( lid)

 In particular, (Ila) and (lie) have high safety.

[0039] Compound (Π) also showed a high blood glucose lowering effect in dbZdb mice, and decreased blood insulin levels. The decrease in blood insulin level is thought to be the result of improved insulin resistance as follows.

 That is, in dbZdb mice, insulin-dependent peripheral tissue uptake is impaired due to a decrease in insulin sensitivity (insulin resistance) in peripheral tissues, which is considered to be mainly caused by obesity. On the other hand, in order to compensate for insulin resistance, insulin secretion from spleen j8 cells is enhanced, and the insulin concentration in the blood is high (hyperinsulinemia). However, even if insulin secretion is increased, the blood glucose level cannot be lowered sufficiently due to insulin resistance. A decrease in blood insulin level due to administration of the above-mentioned compound (Π) is considered to result from a decrease (normalization) in insulin concentration as a result of an improvement in insulin resistance and a decrease in blood glucose level (normalization).

[0040] The compound represented by the general formula (I) of the present invention may have stereoisomers or optical isomers derived from asymmetric carbon atoms. These stereoisomers and optical isomers may exist. And deviations of these mixtures are also included in the present invention. [0041] The salt of the compound represented by the general formula (I) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specific examples include hydrochloride, hydrobromide, iodine, and the like. Organic sulfonates such as hydroacids, phosphates, nitrates and sulfates, mineral salts such as benzoates, methanesulfonates, 2-hydroxyethanesulfonates and p-toluenesulfonates And organic carboxylic acids such as acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and mandelate Examples thereof include salts.

[0042] When the compound represented by the general formula (I) has an acidic group, it may be a salt of an alkali metal ion or an alkaline earth metal ion. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.

 [0043] As described above, PPAR y receptor antigens have been found to have undesirable effects such as weight gain. On the other hand, the compound of the present invention suppresses excessive weight gain. The reason is that the compound of the present invention has a strong agonizing action on both the PPAR a receptor and the PPAR y receptor, and the insulin resistance is improved by the PPAR y receptor agonizing action. It is considered that excessive weight gain is suppressed by the action of PPAR a receptor agonist. Thus, the compound of the present invention has excellent qualities as a therapeutic agent for diabetes. In addition, when a compound having low solubility in water is orally administered, the absorption rate of gastrointestinal tract is generally low due to the low solubility. In addition, even if the absorption rate from the extinguishing tube is relatively high, there may be individual differences in the absorption rate in the administered animal or human due to its low solubility. In this respect, the compound of the present invention exhibits sufficient water solubility under acidic to neutral conditions and has excellent qualities as a pharmaceutical product.

 In addition, it is feared that a compound with high fat solubility may lack metabolic stability and may have an undesirable effect on liver function. However, the compound of the present invention has moderate fat solubility. Therefore, it is thought that it has the outstanding quality as a pharmaceutical.

[0044] Hereinafter, representative methods for synthesizing the compounds of the present invention will be described.

First, la and lb type compounds (R ² may be substituted, pyridyl group, pyrimidyl Group, birazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, isothiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, cinnolyl group, quinazolyl group, phthaloxalyl group Nyl group, naphthyridinyl group, indolyl group, benzoimidazolyl group, indazolyl group, benzothiazolyl group, benzoxazolyl group, benzoisothiazolyl group, benzoisoxazolyl group, or benzotriazolyl group) Natsu!

[0045] [Chemical 6]

 Synthesis method 1 1 1

(In the above formula, R ¹ R ² .R ^{5 to} RS, Q, X, Y, Ζ and η are as defined above.)

[0046] Compound 3 can be synthesized by reacting compound 1 and aldehyde 2 in the presence of a reducing agent. Compound 1 and aldehyde 2 are generated in the presence or absence of an acid such as acetic acid, and then a reducing agent is allowed to act to give compound 3. In this case, compound 3 can also be synthesized by dissolving compound 1 and aldehyde 2 in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, aldehyde 2 is used in an equimolar amount or an excess molar amount relative to compound 1. Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the compound 1 is usually equimolar or excess molar, preferably 3 Use from 5 to 5 moles of reducing agent. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, dichloromethane and chloroform-form alkane, and the like. The reaction temperature is up to the boiling point of the solvent which also uses 20 ° C force, preferably 0 ° C to 50 ° C, and the reaction time is 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.

[0047] Synthesis of compound la from compound 3 is achieved by reacting compound 3 and aldehyde 4 in the presence of a reducing agent. Usually, an equimolar amount or an excess molar amount of aldehyde 4 is used with respect to compound 3. Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, preferably sodium triacetoxyborohydride, and usually equimolar or excess to compound 3. Mol, preferably 2 to 3 moles of reducing agent is used. Examples of the reaction solvent include halogenated alkanes such as dichloromethane and black mouth form, the reaction temperature is 0 ° C force up to 40 ° C, preferably 0 ° C to 30 ° C, and the reaction time is 1 hour force. 48 hours, preferably 1 to 30 hours.

[0048] The synthesis of compound lb depends on the type of ester, but the method described in the literature [Protective Groups in Organic Synthesis, 2nd edition, TW Green (TW Green), PGM Wuts, John Wiley & Son (1991)] or similar methods. Examples thereof include a hydrolysis reaction using an acid or a base, a hydrogenation reaction performed in the presence of a catalyst such as palladium carbon, and a method using trifluoroacetic acid. For example, in a hydrolysis reaction using a base, a metal hydroxide salt such as lithium hydroxide or sodium hydroxide or a carbonate salt such as sodium carbonate or potassium carbonate is allowed to act on the compound la in an equimolar or excess molar manner. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and mixed solvents thereof. The reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 60 ° C. The reaction time varies depending on the type of ester, and is usually 1 to 72 hours, preferably 1 to 24 hours. When R ^{7 of} compound la is a tert butyl group, the reaction can be carried out by a method of reacting an acid such as trifluoroacetic acid or hydrochloric acid. Trifluoroacetic acid, hydrochloric acid Uses molar excess. Examples of the solvent include solvents such as dichloromethane and dioxane. The reaction temperature is 0 ° C up to the boiling point of the solvent to be used, preferably 0 ° C to 30 ° C, and the reaction time is 1 hour at 48 hours, preferably 1 to 24 hours.

[0049] In the synthesis method 1-1, the compound la is synthesized from the compound 3 by the following synthesis method 1.

 As shown in 2, it can also be carried out by allowing compound 5 to act on compound 3.

 [0050] [Chemical 7]

 Synthesis method 1 1 2

R.

X X R ^S R ⁶

0

 (Hal: Br or CI)

(In the above formula, RR ² , R ^{5 to} R ^S , Q, ^x , Y, Z and n represent the above-mentioned ones.)

[0051] Synthesis of compound la from compound 3 is carried out by allowing compound 5 to act on compound 3 in an equimolar to excess mole, preferably equimolar to 2 moles in the presence of a base. Reaction accelerators such as -um and yodo potassium can be used. As the base, tertiary amines such as triethylamine, carbonates such as potassium carbonate and cesium carbonate are used in equimolar or excess moles. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, solvents such as N, N dimethylformamide, and acetonitrile. The reaction temperature is from 20 ° C to the boiling point of the solvent used, preferably from room temperature to 80 ° C, and the reaction time is from 1 hour to 7 days, preferably from 1 hour to 48 hours.

 As a method for synthesizing compound la, synthesis method 1-1 is preferred.

[0052] Next, a method for synthesizing Ic and Id type compounds (when R ² represents a carbamoyl group which may be substituted with 1 or 2 lower alkyl groups) will be described.

[0053] [Chemical 8] Synthesis method 2

 (I d)

(In the above formula, R ¹ R ² , R ^{5 to} R ⁹ , X, Υ, Ζ and η represent the above, and R ¹⁰ and R ¹¹ represent a hydrogen atom or a lower alkyl group. .)

[0054] Synthesis of compound 7 from compound 3 is carried out by synthesizing compound 3 and darioxylic acid 6 with a metal hydride complex such as sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, preferably sodium triacetoxyborohydride. It is done by acting. Usually, equimolar or excess molar amount of dalioxylic acid 6 is used with respect to compound 3. The metal hydride complex is usually used in an equimolar amount or an excess molar amount, preferably 2 to 3 moles, relative to Compound 3. Examples of the reaction solvent include inert solvents such as tetrahydrofuran, dichloromethane, and chloroform. The reaction temperature is 0 ° C force up to 40 ° C, preferably about 0 ° C to 30 ° C, and the reaction time is 1 The time is 48 hours, preferably 1 hour to 10 hours.

[0055] The compound Ic can be synthesized from the compound 7 by allowing the amine 7 to act on the compound 7 in the presence of a condensing agent. For example, equimolar to excess molar amount of amine 8 with respect to compound 7 is −50 ° C. in an inert solvent! This is done by acting in the presence. The reaction time is about 10 minutes to 48 hours, preferably about 30 minutes to 12 hours. Condensation agents include N, N'-dicyclo Xylcarbodiimide, 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide, cetyl cyanophosphate, benzotriazolyloxy-tris [pyrrolidino] -phospho-um hexafluorophosphate, 2- (1H benzotriazole 1 — 1, 1, 3, 3-Tetramethinore mouth-um Tetrafluoroborate, etc.

 The compound 7 is used in an equimolar to excess molar amount, preferably 1 to 5 molar relative to compound 7. Examples of the inert solvent include solvents such as dichloromethane, N, N-dimethylformamide, tetrahydrofuran, and ethyl acetate, or a mixture thereof. If necessary, it can be carried out in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine or 4-dimethylaminopyridine. In addition, N-hydroxy compounds such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, etc., or 4-nitrophenol, 2,4 dinitrophenol, 2,4,5 triclonal phenol, pentachromic Phenolic compounds such as phenol can be added as a reaction accelerator.

 Compound Ic Force Compound Id can be synthesized by the same method as in the synthesis of Compound la force Compound lb in Synthesis Method 11.

[0057] The synthesis method of the compound 2 used in the synthesis method 11 can be synthesized according to the following synthesis method 3.

[0058] [Chemical 9] Synthesis method 3

(In the above formula, R ^{5 to} R ⁷ and Q are as defined above.) Compound 2 can be synthesized by reacting compound 10 with compound 10 in the presence of a base. Compound 10 with an excess molar amount of cesium carbonate and potassium carbonate with respect to compound 9 In the presence of a tertiary amine such as carbonate or triethylamine. As the solvent, an inert solvent such as N, N dimethylformamide or dichloromethane is used. The reaction temperature is up to the boiling point of the solvent used at room temperature, and the reaction time is from 1 hour to 3 days, preferably from about 1 hour to 1 day.

 [0060] The compound of the present invention can be administered as a prophylactic / therapeutic agent for diabetes by various methods such as oral administration. In the case of oral administration, it may be a free form or a salt form. As a preparation method of the preparation containing the compound of the present invention, an appropriate preparation can be selected according to the administration method, and it can be prepared by various preparation methods commonly used. When the compound represented by the general formula (I) of the present invention, a salt thereof, and a solvate thereof are used as a preparation, examples of the form of the preparation include tablets, fine granules, powders, granules, turnips. Cell agents and the like can be exemplified as oral preparations, among which tablets are preferable. Solid preparations include active pharmaceutical ingredients and pharmaceutically acceptable additives, such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants. It is possible to select and mix types as necessary to prepare a formulation.

[0061] Also, when administered as a prophylactic or therapeutic agent for diabetes, the dosage is preferably 0.1 mg to 1500 mg, more preferably 1 mg to 500 mg per person per person. This dose may be administered once a day or divided into 2 to 3 times.

 Example

 [0062] The present invention will be described below with reference to examples.

 [Reference Example 1]

 (1) 4 Azidomethyl-2- (3-bromophenol) 5 Methyloxazole [0063] [Chemical 10]

2- (3 Bromophenyl) -4 chloromethyl-5 Methylphenyloxazole (5. Og) was dissolved in dimethylformamide (30 ml), sodium azide (1.71 g), rhodium iodide, (2.17 g) was added at room temperature, heated to 80 ° C. and stirred for 7 hours.

 After cooling to 0 ° C., water was stirred in the reaction solution. The precipitated solid was collected by filtration to give the title compound (5.3 g) as a pale yellow solid.

[0065] 'H-NMR (400MHz, CDC1) δ: 2.43 (3Η, s), 4.28 (2Η, s), 7.32 (1H, t

 Three

 , J = 7.8Hz), 7.54-7.58 (1H, m), 7.94 (1H, dd, J = 7.9Hz, 1.3Hz), 8

16 (1H, s) .MSm / z: 293 (M + H) ⁺ .

[0066] (2) [2- (3 Bromophenol) 5-Methyloxazole-4-ylmethyl] strength rubamic acid tert butyl ester

[0067] [Chemical 11]

[0068] Reference Example 1— Dissolving the compound (5.3 g) in (1) in tetrahydrofuran (150 ml) and adding triphenylphosphine (6. Og) and water (1. Oml) at 0 ° C. And stirred at room temperature all day and night. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane (100 ml), ditert-butyl dicarbonate (8. Oml) and saturated aqueous sodium hydrogen carbonate (50 ml) were added, and the mixture was stirred at room temperature for 1 hr. After extraction with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate) to give the title compound (6. Og) as a colorless solid.

 [0069] 'H-NMR (400MHz, CDC1) δ: 1.48 (9Η, s), 2.41 (3Η, s), 4.19 (2H,

 Three

d, J = 5.4Hz), 7.31 (1H, t, J = 8.0Hz), 7.52— 7.56 (1H, m), 7.88— 7. 92 (1H, m), 8.13 (1H, s) .MSm / z : 369 (M + H) ⁺ .

[0070] (3) C- [2- (3 Bromophenyl) 5-methyloxazole-4-yl] methylamine

[0071] [Chemical 12]

 Reference Example 1 The compound (6. Og) of 1 (2) was dissolved in dichloromethane (100 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred overnight at room temperature. After evaporation of the solvent under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound. (4.12 g) was obtained as a pale yellow solid.

MSm / z: 296 (M + H) ⁺ .

 [0073] [Reference Example 2]

 2— (4 formylphenoxy) 2 methylpropionic acid tert butyl ester

[0074] [Chemical 13]

 [0075] 4-hydroxybenzaldehyde (20 g), 2 bromo-2 methylpropanoic acid tert-butyl ester (40 ml) was dissolved in dimethylformamide (10 ml), cesium carbonate (100 g) and triethylamine (50 ml) were added, The mixture was stirred at 80 ° C all day and night. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane acetate) to give the title compound (15.4 g) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.41 (9Η, s), 1.64 (6Η, s), 6. 91 (2H,

 Three

 d, J = 8. 82Hz), 7. 78 (2H, d, J = 8. 82Hz), 9. 88 (1H, s).

 [0076] [Reference Example 3]

2- [4- [[[2- (3 Bromophenol) 5-methyloxazole-4-ylmethyl] amino] methyl Ίphenoxy] -2-methylpropionic acid tert butyl ester [0077] [Chemical 14]

 Reference Example 1 The compound (2. Og) of 1 (3) and the compound of Reference Example 2 (2.4 g) were dissolved in black mouth form (30 ml) and heated to reflux for 5 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in methanol (40 ml), sodium borohydride (0.85 g) was added at 0 ° C, and the mixture was stirred for 1 hour while gradually returning to room temperature. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous layer and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form methanol) to give the title compound (4.21 g) as a yellow oil.

 [0079] 'H-NMR (400MHz, CDC1) δ: 1. 44 (9Η, s), 1. 56 (6Η, s), 2. 32 (3H, s

 Three

 ), 3.66 (2H, s), 3.75 (2H, s), 6.82 (2H, d, J = 8.55Hz), 7.20 (2H, d, J = 8.79Hz), 7.30 (1H, t, J = 7. 81Hz), 7.52 (1H, d, J = 8.06Hz), 7. 91 (1H, d, J = 7.81Hz), 8. 15 (1H , s).

MSm / z: 517 (M + H) ⁺ .

[0080] [Reference Example 4]

 2- (4-Formylphenoxy) 2-methylpropionic acid ethyl ester

[0081] [Chemical 15]

参考例 2と同様にして、 4ーヒドロキシベンズアルデヒド（10g)と 2 ブロモー 2—メチ ルプロパン酸 ェチルエステル（18ml)力も合成し、標題ィ匕合物（8. 91g)を淡黄色 油状物質として得た。 Ή- NMR (400MHz, CDCl) δ :1.21 (3H, t, J = 7. 1Hz), 1.67 (6H, s),

In the same manner as in Reference Example 2, 4-hydroxybenzaldehyde (10 g) and 2-bromo-2-methylpropanoic acid ethyl ester (18 ml) were also synthesized to give the title compound (8.91 g) as a pale yellow oily substance. NMR-NMR (400MHz, CDCl) δ: 1.21 (3H, t, J = 7.1 Hz), 1.67 (6H, s),

 Three

 4.23 (2H, q, J = 7.1Hz), 6.90 (2H, d, J = 8.8Hz), 7.79 (2H, d, J = 8.8H z), 9.88 (1H, s).

[0083] [Reference Example 5]

 2- [4-[[[2- (3 Bromophenyl) 5-methyloxazole-4-ylmethyl] amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

[0084] [Chemical 16]

[0085] In the same manner as in Reference Example 3, the compound of Reference Example 1— (3) (1.42 g) and the compound of Reference Example 4 (1.

 51g) to give the title compound (3.02g) as a yellow oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.25 (3Η, t, J = 7.1 Hz), 1.58 (6H, s),

 Three

 2.31 (3H, s), 3.66 (2H, s), 3.75 (2H, s), 4.24 (2H, q, J = 7.2Hz), 4.6 1 (1H, s), 6.81 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.6Hz), 7.30 (1H, t, J = 7.8Hz), 7.51-7.55 (1H, m), 7.89— 7.93 (1H, m), 8.15 (1H, s ) .MSm / z: 489 (M + H) +.

[0086] [Reference Example 6]

 2- [4-[[[2- (3 Bromophenyl) 5-methyloxazole-4-ylmethyl] carboxymethylamino] methyl] phenoxy] 2-methylpropionic acid tert butyl ester

[0087] [Chemical 17]

[0088] 参考例 3の化合物（3. Og)とグリオキシル酸（696mg)をテトラヒドロフラン（30ml) に溶解し、トリァセトキシ水素化ホウ素ナトリウム（2.47g)を加え一昼夜攪拌した。溶 媒を減圧留去し、残渣を酢酸ェチルにて希釈し、水、飽和食塩水の順に洗浄後、無 水硫酸ナトリウムで乾燥して溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグ ラフィー（クロ口ホルム一メタノール）にて精製し、アセトン一へキサンにより再結晶し標 題化合物（2. lg)を無色固体として得た。

[0088] The compound of Reference Example 3 (3. Og) and glyoxylic acid (696 mg) were dissolved in tetrahydrofuran (30 ml), sodium triacetoxyborohydride (2.47 g) was added, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed in turn with water and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form-methanol) and recrystallized from acetone-hexane to give the title compound (2.lg) as a colorless solid.

 [0089] 'H-NMR (400MHz, CDC1) δ: 1.43 (9Η, s), 1.56 (6Η, s), 2.44 (3H, s

 Three

 ), 3.59 (2H, s), 4.24 (2H, s), 4.37 (2H, s), 6.89 (2H, d, J = 8.6Hz), 7.43 (1H, t, J = 8.0Hz), 7.51 (2H, d, J = 8.6Hz), 7.65 (1H, d, J = 6.8Hz), 7.98 (1H, d, J = 7.8Hz), 8.16 (1H, s).

MSm / z: 575 (M + H) ⁺ .

[0090] [Reference Example 7]

 2- (2-aryl-formylphenoxy) -2-methylpropanoic acid tert-butyl ester

[0091] [Chemical 18]

 [0092] In the same manner as in Reference Example 2, 3-aryl-1-hydroxybenzaldehyde (5. Og) and 2-bromo-2-methylpropanoic acid tert-butyl ester (10 ml) were synthesized to give the title compound. (3.6 g) was obtained as an oily substance.

 'H-NMR (400MHz, CDC1) δ: 1.39 (9Η, s), 1.68 (6Η, s), 3.43 (2H,

 Three

 d, J = 6.6Hz), 5.05-5.13 (2H, m), 5.93— 6.05 (1H, m), 6.76 (1H, d, J = 8.3Hz), 7.64 (1H, dd, J = 2.2, 8.3Hz ), 7.70 (1H, d, J = 2.2Hz), 9. 87 (1H, s).

[0093] [Reference Example 8] 2— [2 aryl 4 [[((5 Methyl 2 phenoxazole 4 ylmethyl) amino] methyl] phenoxy] −2-methylpropanoic acid tert butyl ester

 [Chemical 19]

[0095] In the same manner as in Reference Example 3, the compound of Reference Example 7 (304.4 mg) and 5-methyl-2-phenoloxazole-4-ylmethylamine (188.2 mg) were also synthesized to give the title compound (420. 1 mg). Obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 1.39 (9Η, s), 1.56 (6Η, s), 1.55—1.7

 Three

 0 (1H, brs), 2.30 (3H, s), 3.35 (2H, d, J = 6.6Hz), 3.62 (2H, s), 3.75 (2H, s), 4.97-5.01 (2H, m), 5.85 — 6.00 (1H, m), 6.65 (1H, d, J = 8.5 Hz), 7.02 (1H, dd, J = 2.2, 8.5Hz), 7.07 (1H, d, J = 8.5Hz), 7.40— 7. 50 (3H, m), 7.97— 8.03 (2H, m).

[0096] [Reference Example 9]

 2- [2 allyluo 4 [[carboxymethyl- (5-methyl-2-phenoloxalulu 4-ylmethyl) amino] methyl] phenoxy] —2-methylpropanoic acid tert-butylenoestenole

 [0097] [Chemical 20]

In the same manner as in Reference Example 6, the title compound was synthesized from the compound of Reference Example 8 (420. Img) and darioxylic acid (81. Omg), and used as such in the next reaction. [0099] [Reference Example 10]

 2— [2 aryl 4 [[[5-Methyl-2- (3 bromophenol) oxazol-4-ylmethyl] amino] methyl] phenoxy] -2-methylpropanoic acid tert butyl ester

 [0100] [Chemical 21]

[0101] In the same manner as in Reference Example 3, the compound of Reference Example 7 (304.4 mg) was synthesized from the compound of Reference Example 1- (3) (267. Img) to give the title compound (212. Omg). Obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 1.39 (9Η, s), 1.56 (6Η, s), 1.55—1.7

 Three

 0 (1H, brs), 2.30 (3H, s), 3.35 (2H, d, J = 6.6Hz), 3.62 (2H, s), 3.75 (2H, s), 4.97-5.01 (2H, m), 5.85 — 6.00 (1H, m), 6.65 (1H, d, J = 8.5 Hz), 7.02 (1H, dd, J = 2.2, 8.5Hz), 7.07 (1H, d, J = 8.5Hz), 7.25— 7. 30 (1H, m), 7.50-7.60 (1H, m), 7.90— 8.00 (1H, m), 8.15— 8.17 (1 H, m).

 [0102] [Reference Example 11]

 2- [2 aryl-4-[[carboxymethyl- [5-methyl-2- (3-bromophenol) oxazole-4-ylmethyl] amino] methyl] phenoxy] -2 methylpropanoic acid t ert butyl ester

 [0103] [Chemical 22]

[0104] 参考例 6と同様にして、参考例 10の化合物とダリオキシル酸 (81. Omg)から合成し

[0104] In the same manner as in Reference Example 6, it was synthesized from the compound of Reference Example 10 and darioxylic acid (81. Omg).

The title compound was obtained and used as such in the next reaction.

[0105] [Reference Example 12]

 2— (4 formyl-2,6 dimethylphenoxy) -2 methyl propellate ester

[0106] [Chemical 23]

[0107] 3,5 Dimethyl-4-hydroxybenzaldehyde (5. Og) was dissolved in N, N dimethylformamide (20 ml), and cesium carbonate (10 g) and 2 bromo-2-methylpropanoic acid ethyl ester (10 ml) were added. The mixture was stirred at ° C for 12 hours. After returning to room temperature, ethyl acetate (200 ml) and water (40 ml) were added and separated. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (6.2 g) as a pale yellow oil.

 iH—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2 Hz), 1. 50 (6H, s),

 Three

 2.31 (6H, s), 4.30 (2H, q, J = 7.2 Hz), 7.52 (2H, s), 9.85 (1H, s).

[0108] [Reference Example 13]

 (1) Oxazole 2-carbaldehyde

ォキサゾール（3. Og)をテトラヒドロフラン（120ml)に溶解し、 78°Cに冷却攪拌 下、 n—ブチルリチウム（1. 6Mへキサン溶液、 41ml)を滴下した。反応液を— 10°C で 10分間攪拌後、再び— 78°Cに冷却して 6時間攪拌した。反応液に 4 ホルミルモ ルホリン（22ml)を滴下し、室温で 15時間攪拌した。氷水冷却下、反応液に飽和塩 化アンモ-ゥム水溶液をカ卩えて、酢酸ェチルにて希釈後、酒石酸ナトリウムカリウム 水溶液を加えて、有機層を分取した。有機層を飽和食塩水にて洗浄後、無水硫酸ナ トリウムで乾燥し、標題化合物の酢酸ェチル溶液を得て、そのまま次の反応に用いた [0109] [Chemical 24]

Oxazole (3. Og) was dissolved in tetrahydrofuran (120 ml), and n-butyllithium (1.6 M hexane solution, 41 ml) was added dropwise with stirring at 78 ° C. The reaction solution was stirred at −10 ° C. for 10 minutes, then cooled again to −78 ° C. and stirred for 6 hours. 4 formylmol in the reaction solution Ruphorin (22 ml) was added dropwise and stirred at room temperature for 15 hours. Under cooling with ice water, a saturated aqueous ammonium chloride solution was added to the reaction solution, diluted with ethyl acetate, an aqueous sodium potassium tartrate solution was added, and the organic layer was separated. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate to obtain an ethyl acetate solution of the title compound, which was directly used in the next reaction.

[0111] (2) (5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole-2-ylmethylcarbamic acid tert butyl ester

[0112] [Chemical 25]

[0113] C- (5-Methyl-2phenoloxol-4-yl) methylamine (2.05 g) was dissolved in tetrahydrofuran (30 ml) to give oxazole 2 obtained in Reference Example 13- (1). —Force Rubaldehyde (ethyl acetate solution) was added and heated to reflux for 6 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in methanol, sodium borohydride (1.24 g) was added under ice water cooling, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with saturated multilayer water and saturated brine. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (50 ml), di-tertbutyl dicarbonate (2.86 g) and saturated aqueous sodium hydrogen carbonate (50 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound (1.51 g) as a colorless solid.

 [0114] 'H-NMR (400MHz, CDC1) δ: 1.56 (9Η, s), 2.35— 2.39 (3Η, m), 4.

 Three

45 -4. 49 (2H, m), 4. 64—4. 73 (2H, m), 7. 06 (1H, s), 7. 41— 7. 44 (3 H, m), 7. 59 (1H, s), 7. 96- 7. 98 (2H, m). MS m / z: 370 (M + H) ⁺ .

[0115] (3) (5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole-2-ylmethylamine

[0116] [Chemical 26]

Reference Example 13— The compound (1.5 lg) of (2) was dissolved in dichloromethane (20 ml), trifluoroacetic acid (10 ml) was added with cooling with ice water, and the mixture was stirred at room temperature for 12 hours. Under cooling with ice water, 50% aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, followed by extraction with ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.87 g) as a pale yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.36 (3Η, s), 3.74 (2Η, s), 3.97 (2H, s

 Three

 ), 7.07 (1H, s), 7.40-7.45 (3H, m), 7.61 (1H, d, J = 0.7Hz), 7.98— 8.01 (2H, m).

MS m / z: 270 (M + H) ⁺ .

[0118] [Reference Example 14]

 (1) 2- [4 [(tert-Butoxycarboromethylamino) methyl] -2,6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0119] [Chemical 27]

参考例 12の化合物（15.8g)をテトラヒドロフラン（300ml)に溶解し、グリシン tert —ブチル エステル（9ml)と硫酸マグネシウム （50g)加えて 4時間加熱還流した。 反応液を室温に戻し、セライトを使用してろ過後、ろ液を減圧濃縮した。残渣をメタノ ール（100ml)に溶解し、氷水冷却下に水素化ホウ素ナトリウム（2.3g)をカ卩え、室温 で 4時間攪拌した。反応液に水を加えて減圧濃縮後、残渣を酢酸ェチルにて希釈し 、飽和重曹水、飽和食塩水の順に洗浄した後、無水硫酸ナトリウムで乾燥して溶媒を 減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（クロ口ホルム:メタノール = 19:1)にて精製し、標題化合物 (21.6g)を淡黄色油状物質として得た。

The compound of Reference Example 12 (15.8 g) was dissolved in tetrahydrofuran (300 ml), glycine tert-butyl ester (9 ml) and magnesium sulfate (50 g) were added, and the mixture was heated to reflux for 4 hours. The reaction solution was returned to room temperature, filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (100 ml), sodium borohydride (2.3 g) was added while cooling with ice water, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 19: 1) to obtain the title compound (21.6 g) as a pale yellow oily substance.

[0121] 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.46 (6H, s),

 Three

 1.48 (9H, s), 2.18 (6H, s), 3.30 (2H, s), 3.65 (2H, s), 4.29 (2H, q, J

= 7.1 Hz), 6.93 (2H, s).

 MS m / z: 380 (M + H) +.

[0122] (2) 2- [4 -— [[tert-Butoxycarboromethyl- (5-methyl-2-phenols-4-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] -2-methylpropanoic acid Ethyl ester

[0123] [Chemical 28]

[0124] 4 Chloromethyl-5-methyl-2-phenoloxol (1.87 g) and Reference Example 14

 The compound (3.9 g) of (1) was dissolved in acetonitrile (30 ml), potassium carbonate (2.5 g) was added, and the mixture was heated to reflux for 24 hours. After the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (4. Og) as a yellow oil.

 [0125] 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

1.48 (9H, s), 2.17 (6H, s), 2.30 (3H, s), 3.30 (2H, s), 3.71 (2H, s), 3.75 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.99 (2H, s), 7.38— 7.46 (3H, m ), 8. 00-8. 02 (2H, m).

 MS m / z: 551 (M + H) +.

[0126] (3) 2- [4 [[Carboxymethyl- (5-methyl-2-phenolazole-4-ylmethyl) amino] methyl] 2,6 dimethylphenoxy] 2 methylpropanoic acid ethyl ester

 [0127] [Chemical 29]

Reference Example 14— The compound (4. Og) of (2) was dissolved in dichloromethane (30 ml), 4N hydrochloric acid-dioxane solution (30 ml) was added with cooling with ice water, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from hexane to give the title compound hydrochloride (3.17 g) as a pale yellow solid.

 MS m / z: 495 (M + H) +.

[0129] [Reference Example 15]

 (5Methyl-2-phenoloxal-4-ylmethyl) thiazole-2-ylmethylamine

[0130] [Chemical 30]

C- (5-Methyl-2-phenoloxal-4-yl) methylamine (5.17 g) and thiazol-2-strong rubaldehyde (3.1 lg) were dissolved in black mouth form (50 ml) and concentrated under reduced pressure. The residue was dissolved in methanol (100 ml), sodium borohydride (1.5 g) was added, and the mixture was stirred at room temperature for 10 hr. Ethyl acetate and water were added for liquid separation, and the organic layer was washed with anhydrous sodium sulfate. Dry with thorium. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol: dichloromethane = 1: 30) to obtain the title compound (4.8 g) as a pale yellow oil.

[0132] [Reference Example 16]

 (1) 2- [4 [[[2- (Ν '— tert-butoxycarbo-hydrazino) 2-oxoethyl]-((5-methyl-2phenoloxol-4-ylmethyl) amino] methyl] -2,

6 Dimethylphenoxy] 2 Methylpropanoic acid ethyl ester

[0133] [Chemical 31]

[0134] Reference Example 14 Compound (1. Og) of (3) was dissolved in N, N dimethylformamide (3 ml), and hydrazinecarboxylic acid tert-butyl ester (400 mg), 1- (3-dimethylaminopropyl pill) ) -3-Ethylcarbodiimide hydrochloride (776 mg) and 1-hydroxybenzotriazole (622 mg) were added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed successively with water, 10% aqueous citrate solution, saturated multilayered water, and saturated brine. After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound as a yellow oil, which was directly used in the next reaction.

 MS m / z: 609 (M + H) +.

 [0135] (2) 2- [4 [[Hydrazinocarbomethyl- (5-methyl-2-phenolazol 4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropenoate Estenole

[0136] [Chemical 32]

[0137] The compound of Reference Example 16- (1) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 14 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (1.14 g) as a yellow oil.

 MS m / z: 509 (M + H) +.

 [0138] [Reference Example 17]

 2— [4 — [[[[2- (Ν '—Acetylhydrazino) 2-oxoethyl]-((5-Methyl-2-phenol-l-azole) -4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] 2-Methylpropanoic acid ethyl ester

 [0139] [Chemical 33]

Reference Example 16—In the same manner as in (1), the compound of Reference Example 14- (3) (400 mg) and acetic hydrazide (77 mg) title compound (503 mg) were obtained as a pale yellow oil. Got as.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.02 (3H, s), 2.18 (6H, s), 2.23 (3H, s), 3.40 (2H, s), 3.60 (2H, s), 3.65 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.42—7.45 (3H, m), 8.00-8.02 (2H, m).

 MS m / z: 551 (M + H) +.

[0141] [Reference Example 18] 2- (4 formylphenoxy) hexanoic acid ethyl ester

[0142] [Chemical 34]

[0143] In the same manner as in Reference Example 12, the title compound (2.24g) was obtained as a colorless oil from 2hydroxybenzaldehyde (1.22g) and 2bromohexanoic acid ethyl ester (2.23g).

 'H-NMR (400MHz, CDC1) δ: 0.93 (3Η, t, J = 7.2Hz), 1.23 (3H, t, J

 Three

 = 7.1Hz), 1.25-1.60 (6H, m), 4.24 (2H, q, J = 7.1Hz), 4.50—4.42 (1 H, m), 6.70 (2H, d, J = 8.1Hz), 7.65 ( 2H, d, J = 8.1Hz), 9.85 (1H, s).

[0144] [Reference Example 19]

 2- [2, 6 Dimethyl-4 [[2- (5-Methyl-2-phenoloxazole-4-yl) -ethylamino] methyl] phenoxy] -2-methyl-propionate ethyl ester

 [0145] [Chemical 35]

2- (5 Methyl 2-phenoloxol 4-yl) ethylamine (400 mg) and Reference Example 12 (523 mg) were dissolved in tetrahydrofuran (10 ml), and magnesium sulfate (5 g) was dissolved in Stir at room temperature for 17 hours. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml), sodium borohydride (225 mg) was added under cooling with ice water, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (1. Og) as a pale yellow oil. Got as.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.33 (3H, s), 2.71 (2H, t, J = 6.9Hz), 2.95 (2H, t, J = 6.

9Hz), 3.70 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.91 (2H, s), 7.40—7.4

4 (3H, m), 7.96-7.99 (2H, m).

[0147] [Reference Example 20]

 2— [2, 6 Dimethyl 4— [[(5 Methyl 2 phenoxyxazole 4 yl methyl) amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

[0148] [Chemical 36]

[0149] In the same manner as in Reference Example 19, C— (5-methyl-2-phenoloxazole-4-yl) methylamine (1.43 g) and the compound (2. Og) of Reference Example 12 were also combined with the title compound (2.9 g) was obtained as a yellow oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

2.18 (6H, s), 2.31 (3H, s), 3.67 (2H, s), 3.70 (2H, s), 4.29 (2H, q, J = 7.2Hz), 6.95 (2H, s), 7.40 — 7.45 (3H, m), 7.98— 8.00 (2H, m). MSm / z: 437 (M + H) ⁺ .

[0150] [Reference Example 21]

(1) 2- (4-Hydroxyiminomethyl 2,6 dimethylphenoxy) 2-methylpropi Ethyl onion ester

 [0151] [Chemical 37]

[0152] The compound of Reference Example 12 (3. Og), hydroxylamine hydrochloride (3.15 g) and N-methylmorpholine (5 ml) were dissolved in methanol (100 ml), and magnesium sulfate (20 g) was added. Heated to reflux for hours. After cooling, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 0.5N aqueous hydrochloric acid solution and then with saturated brine.

 After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (2.8 g) as a pale yellow oil. It was.

MSm / z: 280 (M + H) ⁺ .

 [0153] (2) 2- (4 Aminomethyl-2,6 dimethylphenoxy) -2 Methylpropionic acid ethynole ester

 [0154] [Chemical 38]

[0155] Reference Example 21— (1) Compound (2.8 g) was dissolved in a mixture of ethanol (50 ml) and tetrahydrofuran (10 ml), 10% palladium-carbon (2 g) was added, and about 30 atm. It was allowed to stand at room temperature for 12 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate and hexane were added to the residue, and the solid was collected by filtration to give the title compound (1.72 g) as a colorless solid. Ή-NMR (400MHz, CDC1) δ: 1.26 (3H, t, J = 7.2Hz), 1.38 (6H, s),

 Three

 2.13 (6H, s), 3.88 (2H, brs), 4.19 (2H, q, J = 7.1Hz), 7.15 (2H, s), 8.37 (2H, brs).

[0156] [Reference Example 22]

 (1) 2- [4 -— [[[((2 Hydroxy 1-methylethylcarbamoyl) methyl] (5 methyl —2 phe-loxazol-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] 2-methylpropanoic acid Ethyl ester

[0157] [Chemical 39]

Reference Example 14 The compound (0.200 g) obtained in 1 (3) and 2 amino-1 propanol (0.063 ml) were dissolved in methanol (3 ml), and 4- (4, 6 dimethoxy-1, 3, 5 Triazine 2-yl) -4 methylmorpholine n hydrate (0.224 g) was added and stirred at room temperature for 24 hours. Again 2-amino-1-propanol (0.063 ml) and salt 4- (4, 6 dimethoxy-1, 3, 5 triazine-2-yl) -4-methylmorpholine n hydrate (0.224 g) And stirred for another 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0

.292 g) was obtained as a colorless oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.19 (3Η, d, J = 6.9Hz), 1.34 (3H, t, J

 Three

= 7. 1Hz), 1.43 (6H, s), 2.14 (6H, s), 2.32 (3H, s), 3.02—4.01 (9H, m), 4. 10 (1H, s), 4.27 (2H, q , J = 7.2Hz), 4.59 (1H, s), 6.85 (2H, s), 7.45—7.52 (3H, m), 8.00—8.05 (3H, m). MSm / z: 552 (M + H) +.

[0159] (2) 2— [2, 6 Dimethyl-4- [ 2-—Methylpropanoic acid ethyl ester

[0160] [Chemical 40]

[0161] A solution of dioxalyl chloride (0.45 ml) in dichloromethane (10 ml) was stirred at 178 ° C, and a solution of dimethyl sulfoxide (0.52 ml) in dichloromethane (l ml) was added dropwise. After 10 minutes, a dichloromethane solution (5 ml) of the compound (0.292 g) obtained in Reference Example 22- (1) was added and stirred for 1 hour. Triethylamine (1.7 ml) was added and the temperature was raised to room temperature and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give the title compound (0.247 g) as a yellow oil Obtained as a thing.

 'H-NMR (400MHz, CDC1) δ: 1.31— 1.36 (6Η, m), 1.44 (6Η, s), 2.

 Three

 17 (6H, s), 2.29 (3H, s), 3.29 (2H, s), 3.54 (1H, d, J = 13.9Hz), 3.59 (1H, d, J = 13.9Hz), 3.61 (2H, s ), 4.27 (2H, q, J = 7.1Hz), 4.43 (1H, quin, J = 7.3Hz), 6.95 (2H, s), 7.42— 7.45 (3H, m), 7.95— 7.97 (2H, m) , 8.34 (1H, d, J = 7.3Hz), 9.51 (1H, s).

 MSm / z: 550 (M + H) +.

[0162] [Reference Example 23]

 2- [2, 6 Dimethyl-4 [[(Oxazol-Ruylmethyl) amino] methyl] phenoxy] 2-Methylpropanoic acid ethyl ester

[0163] [Chemical 41]

[0164] The compound (2.70 g) obtained in Reference Example 21- (2) and N-methylmorpholine (1.7 ml) were dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (20 ml). To this were added an oxazole-2 carbaldehyde ethyl acetate solution and magnesium sulfate (30 g) synthesized from oxazole (1.73 g) in the same manner as in Reference Example 13 1 (1), and the mixture was heated to reflux for 14 hours. After cooling, the insoluble material was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (30 ml), sodium borohydride (2.84 g) was added while cooling with ice water, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate and then saturated brine. It dried with the anhydrous sodium sulfate and the solvent was depressurizingly distilled. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (2.35 g) as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2 Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 3.71 (2H, s), 3.93 (2H, s), 4.29 (2H, q, J = 7.2 Hz), 6.93 (2H, s), 7. 07 (1H, s), 7. 61 (1H, d, J = l. OHz).

MSm / z: 347 (M + H) ⁺ .

[0165] [Reference Example 24]

 (1) 2- [4 [(Carboxymethyloxazoline 2-methylmethylamino) methyl] -2,6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0166] [Chemical 42]

参考例 6と同様にして、参考例 23で得たィ匕合物（0. 5g)とダリオキシル酸 (0. 2g) から標題ィ匕合物を得た。このものを少量のジクロロメタンに溶解し、過剰量の 4規定塩 酸 ジォキサン溶液をカ卩えて減圧濃縮した。残渣をエーテル 酢酸ェチル一へキサ ンの混合溶媒より結晶化して標題ィ匕合物の塩酸塩 (0.43g)を黄色固体として得た。 'H-NMR (400MHz, CDC1) δ :1.32 (3Η, t, J = 7. 1Hz), 1.47 (6H, s), 2

In the same manner as in Reference Example 6, the title compound was obtained from the compound (0.5 g) obtained in Reference Example 23 and darioxylic acid (0.2 g). Dissolve this in a small amount of dichloromethane and add an excess amount of 4N salt. The acid dioxane solution was added and concentrated under reduced pressure. The residue was crystallized from a mixed solvent of ether, ethyl acetate and hexane to give the title compound hydrochloride (0.43 g) as a yellow solid. 'H-NMR (400MHz, CDC1) δ: 1.32 (3Η, t, J = 7.1 Hz), 1.47 (6H, s), 2

 Three

 .23 (6H, s), 4.27-4.21 (4H, m), 4.43 (2H, s), 4.60 (2H, s), 7.24 (2 H, s), 7.33 (1H, s), 8.07 (1H, d, J = 0.7Hz).

 MS m / z: 405 (M + H) +.

[0168] (2) 2- [4-[[[2- (Ν 'Benzylhydrazino) 2-oxoethyl] oxazole —2-ylmethylamino] methyl] —2, 6-dimethylphenoxy] —2— Methyl propanoic acid ester

 [0169] [Chemical 43]

Reference Example 24— Dissolve the compound (0.15 g) obtained in (1), benzoic acid hydrazide (0.070 g) and 1 hydroxybenztriazole (0.079 g) in N, N dimethylformamide (2 ml). —Ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.098 g) was added and stirred at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, an aqueous solution of citrate, saturated aqueous sodium hydrogen carbonate, and saturated brine in this order. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0.115 g) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.3Hz), 1.45 (6H, s), 2

 Three

.20 (6H, s), 3.45 (2H, s), 3.71 (2H, s), 3.95 (2H, s), 4.27 (2H, q, J = 7.2Hz), 7.03 (2H, s), 7.12 ( 1H, s), 7.47 (2H, t, J = 7.7Hz), 7.52—7.58 (1H, m), 7.67 (1H, s), 7.83 (2H, d, J = 7.1Hz), 8.54 ( 1H, br s), 10.00 (1H, br s). MSm / z: 523 (M + H) +.

 [0171] [Reference Example 25]

 2- [2, 6 Dimethyl-4-[[Oxazol 2-ylmethyl-[(2 oxo-2-phenyl-carbamoyl) methyl] amino] methyl] phenoxy] 2-methylpropanoic acid ethinole ester

 [0172] [Chemical 44]

Reference Example 24- In the same manner as (2), the compound (0.15 g) obtained in Reference Example 24- (1), 2-aminoacetophenone hydrochloride (0.064 g), and N-methylmorpholine (0.083 ml) Force The title compound (0.122 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.6Hz), 1.45 (6H, s), 2

 Three

 .21 (6H, s), 3.35 (2H, s), 3.68 (2H, s), 3.91 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 4.76 (2H, d, J = 4.7Hz), 7.08 (2H, s), 7.09 (1H, s), 7.51 (2H, t, J = 8.0Hz), 7.62 (1H, t, J = 6.7Hz), 7.65 (1H, s), 7.99 (2H, d, J = 8.3Hz).

MSm / z: 522 (M + H) ⁺ .

 [0174] [Reference Example 26]

 2- [2, 6 Dimethyl-4 [[Oxazol 2-ylmethyl-[[2 Oxazo2-—N, 1- (thiophene2-carbol) hydrazino] ethyl] amino] methyl] amino] methyl] phenoxy] 2— Methyl propanoic acid ethyl ester

[0175] [Chemical 45]

[0176] Reference Example 24— In the same manner as (2), the compound (0.15 g) obtained in Reference Example 24 (1) and 2-thiophenecarboxylic acid hydrazide (0.053 g) were also used in the title compound. (0.12 g) was obtained as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 .20 (6H, s), 3.43 (2H, s), 3.69 (2H, s), 3.94 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.99 (2H, s), 7.12 — 7.10 (2H, m), 7.55 (1H, d, J = 4.9Hz), 7.62 (1H, d, J = 3.7Hz), 7.66 (1H, s), 8.31 (1H, s), 9.81 ( 1H, s).

MSm / z: 529 (M + H) ⁺ .

 [0177] [Reference Example 27]

 (1) N-hydroxythiophene 2-force noreboxyamidine

 [0178] [Chem 46]

[0179] 2 Thiophenecarbo-tolyl (1. Og) was dissolved in ethanol (20 ml), 50% hydroxyamine (1.2 ml) was added, and the mixture was heated to reflux for 18 hours. After cooling, the reaction mixture was concentrated under reduced pressure, ether monohexane was added to the residue and the insoluble material was filtered off to give the title compound (1. l _g ) as a colorless solid.

 'H-NMR (400MHz, CD OD) δ: 7.05— 7.02 (1H, m), 7.37— 7.40 (2H

 Three

 , m).

 MS m / z: 143 (M + H) +.

[0180] (2) 2- [2, 6 Dimethyl-4 [[Oxazolru 2-ylmethyl- [2 Oxa-2- [(Thiophene 2-carboxymidoyl) aminoxy] ethyl] amino] methyl] phenoxy] mono-2-methylpropanoic acid ethyl ester

[0181] [Chemical 47]

Reference Example 24—In the same manner as (2), the compound (0.15 g) obtained in Reference Example 24- (1) and Reference Example 2 7- (1) (0.053 g) The title compound was obtained as a brown oil and used directly in the next reaction.

 MS m / z: 529 (M + H) +.

[0183] [Reference Example 28]

 2- (2 Fluoro-4-formyl 1-methoxyphenoxy) 2-methylpropenoic acid ester

 [0184] [Chemical 48]

[0185] In the same manner as in Reference Example 12, it was synthesized from 3 fluoro-4-hydroxy-5-methoxybenzaldehyde (0.50 g) and 2 bromo-2-methylpropanoic acid ethyl ester (1.8 g), and the title compound (0.78 g) was colorless. Obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.32 (3Η, t, J = 7.1 Hz), 1.55 (6H, s), 3

 Three

 .86 (3H, s), 4.26 (2H, q, J = 7.1Hz), 7.22— 7.26 (2H, m), 9.85 (1H, d, J = l.2Hz).

MSm / z: 285 (M + H) ⁺ .

[0186] [Reference Example 29] 2- (4 formyl-2-methoxy-6-methylphenoxy) -2 methylpropanoic acid ethyl ester

 [0187] [Chemical 49]

[0188] In the same manner as in Reference Example 12, 4-hydroxy-3-methoxy-5-methylbenzaldehyde (11.5g) and 2-bromo-2-methylpropanoic acid ethyl ester (30ml) were also synthesized to give the title compound (21.5g) as a colorless solid. Got as.

 iH—NMR (400MHz, CDC1) δ: 1.32 (3Η, t, J = 7.3Hz), 1.50 (6H, s), 2

 Three

 .30 (3H, s), 3.78 (3H, s), 4.28 (2H, q, J = 7.3Hz), 7.22 (1H, s), 7.30 (1H, s), 9.78 (1H, s).

MSm / z: 281 (M + H) ⁺ .

[0189] [Reference Example 30]

 (1) 2— [4 — [[tert-Butoxycarboromethyl- (9H fluorene-9-ilmethoxycarbonyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropenoic acid ester

 [0190] [Chemical 50]

参考例 14— (1)で得たィ匕合物（3.5g)をァセトニトリル（30ml)に溶解し、氷水冷 却下に N— (9—フルォレ -ルメトキシカルボ-ルォキシ）スクシンイミド（3.74g)を加 えて、室温で 4時間攪拌した。反応液を減圧濃縮後、残渣を酢酸ェチルで抽出し、 有機層を水、飽和重曹水、クェン酸水溶液、飽和食塩水の順で洗浄した。無水硫酸 ナトリウムで乾燥後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトダラ フィ一で精製する（酢酸ェチル：へキサン = 1： 1)ことにより標題ィ匕合物（5.24g)を淡 黄色油状物として得た。

Reference Example 14— The compound (3.5 g) obtained in (1) was dissolved in acetonitrile (30 ml), and N— (9-fluormethoxycarbo-loxy) succinimide (3.74 g) was added while cooling with ice water. In addition, the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was extracted with ethyl acetate, The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, aqueous citrate solution and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (5.24 g) Was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.34—1.38 (3Η, m), 1.43—1.54 (15Η)

 Three

 , m), 2.17 (3Η, s), 2.18 (3Η, s), 3.78 (1Η, s), 3.84 (1H, s), 4.26—4. 30 (3H, m), 4.44—4.49 (4H, m ), 6.77 (1H, s), 6.85 (1H, s), 7.25—7.31 (2H, m), 7.41—7.35 (2H, m), 7.53 (1H, d, J = 7.4Hz), 7.59 ( 1H, d, J = 7.4Hz), 7.73 (1H, d, J = 7.6Hz), 7.76 (1H, d, J = 7.6Hz).

 MSm / z: 624 (M + Na) +.

[0192] (2) 2— [4 [[Carboxymethyl- (9H-fluorene-9-ylmethoxycarbol) amino] methyl] —2, 6-dimethylphenoxy] —2-methylpropanoic acid ethyl ester

 [0193] [Chemical 51]

Reference Example 30— The compound (5.24 g) obtained in (1) was dissolved in dichloromethane (60 ml), trifluoroacetic acid (20 ml) was added under ice water cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with water and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (5.70 g). Obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.33— 1.38 (3Η, m), 1.45 (3Η, s), 1.4

 Three

6 (3H, s), 2.17 (6H, s), 3.77 (1H, s), 3.98 (1H, s), 4.25—4.32 (3H, m), 4.44 (2H, s), 4.52-4.55 ( 2H, m), 6.75 (1H, s), 6.82 (1H, s), 7.23 -7.31 (2H, m), 7.38 (2H, t, J = 7.4Hz), 7.56—7.53 (2H, m), 7.74 (2H, d, J = 7.3Hz).

MSm / z: 568 (M + H) ⁺ .

 [0195] (3) 2— [4— [[[2- (N, -acetyl-hydrazino) -1-2-oxoethyl] -1- (9H-fluorene-9-ylmethoxycarbol) amino] methyl] —2,6-Dimethylphenoxy] 1-2-methylpropanoic acid ethyl ester

 [0196] [Chemical 52]

[0197] In the same manner as in Reference Example 17, the title compound (1. lg) was colorless from the compound (1.5 g) obtained in Reference Example 30- (2) and acetic hydrazide (0.31 g). Obtained as a solid.

MSm / z: 602 (M + H) ⁺ .

 [0198] (4) 2— [4— [[(9H-Fluorene-9-ylmethoxycarbol) mono (5-methyl- [1,

 3, 4] Oxadiazo 2-ruyl) amino] methyl] -1,2,6-dimethylphenoxy] 1-2-methylpropanoic acid ethyl ester

 [0199] [Chemical 53]

Example 18—In the same manner as (1), the title compound (1. Og) was obtained as a colorless solid from the compound (1. lg) obtained in Reference Example 30- (3). It was.

^! H-NMR (400MHz, CDCl) δ: 1.36 (3Η, t, J = 7.1 Hz), 1.46 (6H, s), 2 16 (6H, s), 2.46, 2.49 (3H, each s), 4.26—4.31 (3H, m), 4.39—4.

44 (3H, m), 4.55—4.59 (3H, m), 6.73, 6.85 (2H, each s), 7.36— 7.

40 (2H, m), 7.46— 7.49 (1H, m), 7.53— 7.57 (3H, m), 7.65— 7.70 (1

H, m), 7.75-7.73 (2H, m).

MSm / z: 584 (M + H) ⁺ .

[0201] (5) 2— [2, 6 Dimethyl-4-] [[(5-Methyl- [1, 3, 4] oxadiazole-2-ylmethyl) amino] methyl] phenoxy] -2-methylpropane Acid ethyl ester

[0202] [Chemical 54]

[0203] Reference Example 30— The compound (1. Og) obtained in (4) was dissolved in tetrahydrofuran (50 ml), and 1,8 diazabicyclo [5.4.0] undane 7 sen (2%) was cooled with ice water. Tetrahydrofuran solution (42.2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0.54 g). Obtained as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.46 (7H, s), 2

 Three

 19 (6H, s), 2.53 (3H, s), 3.73 (2H, s), 3.98 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.92 (2H, s).

MSm / z: 362 (M + H) +.

[0204] [Reference Example 31]

 2— [2, 6 Dimethyl 4 [[((thiazole-2-ylmethyl) amino] methyl] phenoxy) 2-methylpropanoic acid ethyl ester

[0205] [Chemical 55]

[0206] In tetrahydrofuran (20 ml), the compound obtained in Reference Example 21- (2) (hydrochloride, 1. Og), 2-thiazolecarbaldehyde (0.46 g) and N-methylmorpholine (0.40 ml) were added. It was heated and refluxed for 2 hours. After cooling, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol (30 ml), sodium borohydride (0.38 g) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (1.2 g ) Was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1. 46 (7H, s), 2

 Three

 19 (7H, s), 3.76 (2H, s), 4.14 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6. 95 (2H, s), 7. 28 (1H, d, J = 3.4 Hz), 7. 73 (1H, d, J = 3.2 Hz).

 MSm / z: 363 (M + H) +.

[0207] [Reference Example 32]

 4 Chloromethyl 5 Methyl 2 -— (5 Methylthiophene 2-yl) oxazole [0208] [Chemical 56]

5-Methyl-2-thiophenecarbaldehyde (1.07 ml) and 2,3 butanedione monooxime (2. Og) were mixed, and 4N hydrochloric acid-dioxane solution (10 ml) was added and stirred at room temperature for 14 hours. 4N hydrochloric acid-dioxane solution (10 ml) was added, and the mixture was further stirred for 3 days. Under cooling with ice water, the solid is filtered off with the addition of jetyl ether to give 4,5-dimethyl-2- (2-methylthiophene-5yl) oxazole 3-oxide hydrochloride (2. 3 g) was obtained as a brown solid. This was dissolved in black mouth form (30 ml), phosphorus oxychloride (2 ml) was added, and the mixture was heated to reflux for 4 hours. After cooling, it was diluted with chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (1.34 g) as a pale yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 2.52 (3Η, s), 4.51 (2H, s

 Three

 ), 6.74 (1H, d, J = 3.7Hz), 7.42 (1H, d, J = 3.7Hz).

MSm / z: 228 (M + H) ⁺ .

[0210] [Reference Example 33]

 (1) 2- [4 -— [[(9H-Fluorene 9-ylmethoxycarbol) [(2 Hydroxypropyl rubamoyl) methyl] amino] methyl] -2, 6 Dimethylphenoxy] 2 Methylpropane Acid ethyl ester

[0211] [Chemical 57]

[0212] Reference Example 30— The compound (1.70 g) obtained in (2) was dissolved in methanol (30 ml).

 (4,6 dimethoxy-1,3,5 triazine-2-yl) -4-methylmorpholine n hydrate (1.29 g) and 1-amino-2-propanol (0.36 ml) were added at room temperature. Stir for hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with water, 10% aqueous citrate solution, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (1.89 g) as a pale yellow oil.

 MSm / z: 603 (M + H) +.

[0213] (2) 2— [4— [[(9H—Fluorene 9-ylmethoxycarbol) [(2 oxopro Pill force rubermoyl) methyl] amino] methyl] —2,6-dimethylphenoxy] —2-methylpropanoic acid ethyl ester

[0214] [Chemical 58]

Reference Example 22—In the same manner as in (2), the title compound (1.lg) was obtained as a pale yellow solid from the compound (1.89 g) obtained in Reference Example 33- (1).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 16-2.18 (9H, m), 3.69—4.13 (4H, m), 4.26—4.31 (3H, m), 4.42 (

2H, s), 4.56 (2H, d, J = 6.6Hz), 6.73 (1H, s), 6.83 (1H, s), 7.23— 7.

29 (9H, m), 7.38 (2H, t, J = 7.5Hz), 7.56— 7.54 (2H, m), 7.74 (2H, d

, J = 7.6Hz).

 MSm / z: 601 (M + H) +.

[0216] (3) 2— [4— [[(9H-Fluorene-9-ylmethoxycarbol)-((5-methyloxazole-2-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] — 2-Methylpropyl ethyl ester

[0217] [Chemical 59]

[0218] Triphenylphosphine (1. Olg) was dissolved in dichloromethane (50 ml), and hexachloroethane (0.78 g) and triethylamine (0.51 ml) were added under cooling with ice water. Further, the compound (1.10 g) obtained in Reference Example 33- (2) was added, stirred for 1 hour, and then stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, 10% aqueous citrate solution, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to obtain the title compound (0.71 g) as a pale yellow oil.

 MSm / z: 583 (M + H) +.

 [0219] (4) 2- [2,6 Dimethyl-4 [[(5-Methyloxazole-2-ylmethyl) amino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

 [0220] [Chemical 60]

参考例 33— (3)で得たィ匕合物（0. 71g)をテトラヒドロフラン（10ml)に溶解し、氷 水冷却下にジェチルァミン（1. 26ml)をカ卩えて、室温で 23時間攪拌した。溶媒を減 圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製 (メタノール:ク ロロホルム = 1： 9)して標題化合物（0. 44g)を淡黄色油状物として得た。 MSm/z:361(M+H)+.

Reference Example 33— The compound (0.71 g) obtained in (3) was dissolved in tetrahydrofuran (10 ml), and jetylamine (1.26 ml) was added while cooling with ice water, followed by stirring at room temperature for 23 hours. . The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to obtain the title compound (0.44 g) as a pale yellow oil. MS m / z: 361 (M + H) +.

[0222] [Reference Example 34]

 (1) 2— [4— [[tert-Butoxycarboromethyl (5 methyl 2-p-trioxazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylethyl ethyl ester Ester

[0223] [Chemical 61]

[0224] 4 Chloromethyl-5-methyl-2-p-tolylazole (0.127 g) and Reference Example 14 — Compound (0.198 g) obtained in (1) were dissolved in acetonitrile (5 ml). Potassium carbonate (0.08 7 g) was added and stirred at 50 ° C. overnight and then at 70 ° C. for 4 days. After cooling, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (13% ethyl acetate-hexane) to give the title compound (0.258 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 1.47 (9H, s), 2.17 (6H, s), 2.29 (3H, s), 2.38 (3H, s), 3.30 (2H, s), 3.71 (2H, br s), 3.74 (2H, br s), 4.28 (2Hq, J = 7.2Hz), 6.99 (2H, s), 7.23 (2H, d, J = 8.3Hz), 7.89 (2H, d, J = 8.3Hz).

 MSm / z: 565 (M + H) +.

[0225] (2) 2- [4 -— [[Carboxymethyl- (5-methyl-2-p-trioxazole-4-ylmethyl) amino] methyl] 2,6 dimethylphenoxy] 2 methylpropanoic acid Echi Nore Esther

[0226] [Chemical 62]

[0227] Reference Example 34— The compound (0.258 g) obtained in (1) was dissolved in dichloromethane (5.2 ml), 4N hydrochloric acid-dioxane solution (5.2 ml) was added, and the mixture was stirred at room temperature for 2 days. Stir. After drying under reduced pressure, the title compound (0.232 g) was obtained as a colorless oil.

 [0228] [Reference Example 35]

 (1) 2- [4 [[tert-Butoxycarboromethyl- [2- (4-Chlorophenyl) 5-Methyloxazol 4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] -2 Methylpropane Acid ethyl ester

[0229] [Chemical 63]

[0230] In the same manner as in Reference Example 34- (1), the compound (0.208) obtained from 4-chloromethyl-2- (4-chlorophenol) -5-methyloxazole (0.146 g) and Reference Example 14- (1) From g), the title compound (0.289 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.1 Hz), 1.44 (6H, s), 1

 Three

 .47 (9H, s), 2.17 (6H, s), 2.29 (3H, s), 3.29 (2H, s), 3.71 (2H, br s), 3.73 (2H, br s), 4.27 (2H, q , J = 7.1Hz), 6.98 (2H, s), 7.36—7.42 (2H, m), 7.90-7.96 (2H, m).

 MSm / z: 585 (M + H) +.

[0231] (2) 2— [4 [[Carboxymethyl- [2- (4 Black Mole)]-5-Methyloxazo 1-L 4-methylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] — 2-Methylpro Nonethyl ester

 [0232] [Chemical 64]

[0233] In the same manner as in Reference Example 34- (2), the title compound (0.26 lg) was obtained as a colorless oil from the compound (0.289 g) obtained in Reference Example 35- (1).

[0234] [Reference Example 36]

 (1) 2— [4— [[tert-Butoxycarboromethyl] [2— (3 Phlorophenyl) -5-methyloxazol 4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy ] -2 Methylpropanoic acid ethyl ester

[0235] [Chemical 65]

参考例 34— (1)と同様にして、 4 クロロメチル一 2— (3 クロ口フエ-ル） 5—メ チルォキサゾール (0.134g)と参考例 14— (1)で得た化合物（0.190g)から標題 化合物（0.236g)を無色油状物として得た。

Reference Example 34—In the same manner as (1), 4-chloromethyl-2- (3-chlorophenol) 5-methyloxazole (0.134 g) and Reference Example 14- (1) compound (0.190 g) Gave the title compound (0.236 g) as a colorless oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 1

 Three

 .48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.30 (2H, s), 3.71 (2H, br s), 3.75 (2H, br s), 4.28 (2H, q , J = 7.2Hz), 6.99 (2H, s), 7.34— 7.38 (2H, m), 7.85— 7.91 (1H, m), 8.00— 8.02 (1H, m).

MSm / z: 585 (M + H) +. [0237] (2) 2— [4— [[Carboxymethyl mono [2- (3-chloromethyl)] 5-methyloxazo-ru 4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] — 2-Methylpronoic acid ethyl ester

 [0238] [Chemical 66]

Reference Example 34—In the same manner as in (2), the compound (0.236 g) force obtained in Reference Example 36- (1) was also used to give the title compound (0.214 g) as a colorless oil.

[0240] [Reference Example 37]

 (1) 2- (4 Formyl-2-methoxy-6-methylphenoxy) -2 Methylpropanoic acid tert-Butinole Estenole

[0241] [Chemical 67]

4-hydroxy mono 3-methyl 5-methoxybenzaldehyde (7. Og) is dissolved in N, N dimethylformamide (110 ml), potassium carbonate (17.4 g) and 2-bromo 2-methylpropanoic acid tert-butyl ester (23.5 ml) was added and stirred at 80 ° C. for 27 hours. After cooling, the mixture was filtered using celite. The filtrate was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed twice with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (4.25 g) as a pale yellow oil. Obtained as a product.

 'H-NMR (400MHz, CDCl) δ: 1.47 (6Η, s), 2.31 (3Η, s), 3.80 (3H, s

 Three

 ), 7.24-7.30 (2H, m), 9.84 (1H, s).

 MS m / z: 309 (M + H) +.

 [0243] (2) 2- [2-Methoxy-6-methyl-4-] [[(5-Methyl-2-phenolox-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid tert-butyl ester

 [0244] [Chemical 68]

[0245] In the same manner as in Reference Example 19, C- [5-Methyl-2 phe-loxazol-4-yl] methylamine (1. Og) and Reference Example 37- Compound obtained in (1) (1.63 g ) To give the title compound (2.3 g) as a brown oil.

 'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 1.51 (9Η, s), 2.21 (3H, s

 Three

 ), 2.31 (3H, s), 3.67 (2H, s), 3.70 (3H, s), 3.73 (2H, s), 6.70— 6.73 (2H, m), 7.38-7.49 (3H, m), 8.01— 7.97 (2H, m).

 MS m / z: 481 (M + H) +.

[0246] (3) 2— [4— [[Carboxymethyl- (5-methyl-2-phenolazole-4-ylmethyl) amino] methyl] -2-methoxy-6 Methylphenoxy-2 Methylpropanoic acid tert-Butinore Estenole

[0247] [Chem 69]

[0248] In the same manner as in Reference Example 6, the title compound (0.12 g) was obtained as a pale yellow oil from the compound (0.20 g) obtained in Reference Example 37- (2).

 'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 1.50 (9Η, s), 2.21 (3H, s

 Three

 ), 2.27 (3H, s), 3.44 (2H, s), 3.67 (2H, s), 3.68 (3H, s), 3.76 (2H, s), 6.67 (1H, s), 6.69 (1H, s) , 7.43— 7.47 (3H, m), 7.97— 8.01 (2H, m).

 MS m / z: 539 (M + H) +.

 [0249] [Reference Example 38]

 2— (2 Fluoro-4-formylphenoxy) -2 Ethyl methyl propanoate

 [0250] [Chemical 70]

[0251] In the same manner as in Reference Example 3, 3 fluoro-4-hydroxybenzaldehyde (2.5 g) and 2-bromo-2-methylpropanoic acid ethyl ester (7. Og) were used to give the title compound (1.54 g) as a colorless oil. Obtained.

MSm / z: 255 (M + H) ⁺ .

 [0252] [Reference Example 39]

 Methanesulfonic acid 5-phenylisoxazole 3-ylmethyl ester

[0253] [Chemical 71]

[0254] 3 Hydroxymethyl-15-phenyl isoxazole (0.101g) was dissolved in dichloromethane (4ml), and methanesulfuryl chloride (0.048ml) and triethylamine (0.094ml) were added under ice water cooling and stirred for 1 hour. did. Saturated aqueous sodium bicarbonate was added and extracted three times with dichloroethane, followed by washing with saturated brine. After drying over anhydrous sodium sulfate and distilling off the solvent under reduced pressure, the title compound was obtained as an oil. The title compound was used in the next reaction without formation.

 [0255] [Reference Example 40]

 2- (2-ethyl 4-formyl 6-methylphenoxy) 2-methyl propanoic acid ethyl ester

 [0256] [Chemical 72]

[0257] In the same manner as in Reference Example 12, 3-ethyl 4-hydroxy-5-methylbenzaldehyde (2.08 g) and 2-bromo-2-methylpropanoic acid ethyl ester (7. Og) were also used as a pale yellow compound. Obtained as an oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.4Hz), 1.36 (3H, t, J

 Three

 = 7. 1Hz), 1.50 (6H, s), 2.28 (3H, s), 2.65 (2H, q, J = 7.4Hz), 4.30 (2 H, q, J = 7.1Hz), 7.53 (1H, d , J = 2.2Hz), 7.58 (1H, d, J = 2.2Hz), 9.90 (1H, s).

MSm / z: 279 (M + H) ⁺ .

[0258] [Reference Example 41]

(1) 2- (4-Formyl-2,6 dimethylphenoxy) -2-methylpropanoic acid tert-butyl ester

[0260] Reference Example 37— In the same manner as (1), 3, 5 dimethyl-4-hydroxybenzaldehyde (1 5. Og) and 2 bromo-2-methylpropanoic acid tert butyl ester (56 ml) were added to potassium carbonate (55.3 g). The title compound (4.47 g) was obtained as a pale yellow oil by treatment at 80 ° C for 2 days in the presence of.

 'H-NMR (400MHz, CDCl) δ: 1.41 (6Η, s), 1.47 (9Η, s), 2.25 (6H, s

 Three

 ), 7.48 (2H, s), 9.83 (1H, s).

 (2) 2- [2,6-Dimethyl 4-[[[(5-Methyl-2-phenoloxol-4-ylmethyl) amino] methyl] phenoxy] —2-methylpropanoic acid tert-butyl ester [0261] [Chemical 74]

[0262] In the same manner as in Reference Example 19, C— (5-methyl-2-phenol-azole-4-yl) methylamine (1.94 g) and Reference Example 41—the compound obtained in (1) (3. Og) Power also title compound (5.8 g

) Was obtained as a pale yellow oil.

 MSm / z: 465 (M + H) +.

[0263] (3) 2— [4 [[Carboxymethyl- (5-methyl-2-phenoloxol-4-ylmethyl) amino] methyl] 2, 6 dimethylphenoxy] 2 methylpropanoic acid tert

—Butyl ester

[0264] [Chemical 75]

[0265] In the same manner as in Reference Example 6, the title compound (0.90 g) was obtained as a colorless oil from the compound (1. OOg) obtained in Reference Example 41- (2).

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s

 Three

 ), 2.25 (3H, s), 3.45 (2H, s), 3.67 (2H, s), 3.74 (2H, s), 6.92 (2H, s)

, 7.44-7.47 (3H, m), 8.01— 7.98 (2H, m).

MSm / z: 523 (M + H) ⁺ .

[0266] (4) 2- [2, 6 Dimethyl-4-[[[(5-Methyl-2-phenoloxazole-4-ylmethyl)] [Ν'- (2, 2, 2-trifluoroacetyl) monohydrazinocarboromethyl] Amino] methyl] phenoxy] —2-methylpropanoic acid tert-butyl ester

[0267] [Chemical 76]

[0268] In the same manner as in Reference Example 16- (1), the compound (0.150 g) obtained in Reference Example 41- (3) and trifluoroacetic acid hydrazide (0.046 g) were also used in the title compound ( 0.135 g) was obtained as a pale yellow oil.

MSm / z: 633 (M + H) +.

[0269] [Reference Example 42]

(1) 2— [4 — [[[2— [N, 1 (9H-Fluorene-9-ylmethoxycarbol) hydrazide No] — 2-oxoethyl] mono (5-methyl-2 phenol-azole-4-aminomethyl) amino] methyl] 2, 6-dimethylphenoxy] —2-methylpropanoic acid tert-butyl ester

 [Chemical 77]

[0271] Reference Example 16—In the same manner as (1), the compound (0.350 g) obtained in Reference Example 41 (3) and hydrazine carboxylic acid 9H fluorene-9-ylmethyl ester (0.24 g) The compound (0.48 g) was obtained as a yellow oil.

 [0272] 'H-NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.2Hz), 1.40 (6H, s), 1

 Three

 .50 (9H, s), 2.04 (2H, s), 2.18 (6H, s), 2.23 (3H, s), 3.40 (2H, s), 3.

57-3.65 (4H, m), 4.12 (2H, q, J = 7.2Hz), 4.43 (2H, d, J = 7.3Hz), 6

.90 (2H, s), 7.26 (2H, s), 7.42—7.40 (5H, m), 7.56—7.58 (2H, m),

7.72-7.75 (2H, m), 7.97—7.99 (2H, m).

[0273] (2) 2— [4 [[Hydrazinocarboromethyl- (5-methyl-2-phenoloxazole)

—4-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] —2-methylpropanoic acid tert butyl ester

[0274] [Chemical 78]

[0275] Reference Example 42— The compound (0.48 g) obtained in (1) was dissolved in tetrahydrofuran (20 ml), and jetylamine (0.98 ml) was added while cooling with ice water, followed by stirring at room temperature for 2 hours. did. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0.3 g) as a yellow oil.

MSm / z: 537 (M + H) ⁺ .

 [0276] [Reference Example 43]

 2- (2, 6 difluoro-4 formylphenoxy) -2 methylpropanoic acid tert-butyl ester

 [0277] [Chemical 79]

参考例 12と同様にして、 3, 5 ジフルオロー 4ーヒドロキシベンズアルデヒド（3.8g )と 2—ブロモー 2—メチルプロパン酸 tert ブチル エステル（20g)を炭酸セシゥ ム（12.6g)の存在下に 80°Cで 3日間処理することにより標題化合物（6.68g)を無 色油状物として得た。

In the same manner as in Reference Example 12, 3,5 difluoro-4-hydroxybenzaldehyde (3.8 g) and 2-bromo-2-methylpropanoic acid tert butyl ester (20 g) were added at 80 ° C in the presence of cesium carbonate (12.6 g). For 3 days to give the title compound (6.68 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.48 (9Η, s), 1.59 (6Η, s), 7.44 (2H, d

 Three

 , J = 7.8Hz), 9.85 (1H, t, J = l.6Hz).

MSm / z: 323 (M + H) +. [0279] [Reference Example 44]

 2- (3-formyl 4-methoxyphenoxy) 2-methylpropanoic acid tert-butyl ester

[0280] [Chemical 80]

[0281] In the same manner as in Reference Example 12, 5-hydroxy-2-methoxybenzaldehyde (2. lg) and 2-bromo-2-methylpropanoic acid tert-butyl ester (9 g) were added to the title compound (2.6 2 g) as a pale yellow oil. Obtained as a thing.

 'H-NMR (400MHz, CDCl) δ: 1.48 (9Η, s), 1.53 (6Η, s), 3.89 (3H, s

 Three

 ), 6.89 (1H, d, J = 9.1Hz), 7.16 (1H, dd, J = 9.1, 3.2Hz), 7.34 (1H, d

, J = 3.2Hz), 10.41 (1H, s).

MSm / z: 295 (M + H) +.

[0282] [Reference Example 45]

 (1) 2— [4 [(Benzyloxycarboru tert butoxycarboromethylamino) methyl] -2,6 dimethylphenoxy] 2 methylpropanoic acid ethyl ester

[0283] [Chemical 81]

参考例 14— (1)で得たィ匕合物（1. Og)のジクロロメタン（20ml)溶液と飽和重曹水 ( 20ml)を混合し、氷水冷却下に塩化べンジロキシカルボ-ル（0.49ml)を加えて、 室温で 18時間攪拌した。反応液を酢酸ェチルで希釈し、水、次いで飽和食塩水で 洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲ ルカラムクロマトグラフィーで精製 (酢酸ェチル：へキサン = 1： 2)することにより標題 化合物（1. 35g)を無色油状物として得た。

Reference Example 14— A solution of the compound (1. Og) obtained in (1) in dichloromethane (20 ml) and a saturated aqueous sodium bicarbonate solution (20 ml) were mixed, and benzyloxycarbon chloride (0.49 ml) was added while cooling with ice water. in addition, Stir at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (1.35 g) as a colorless oil.

 MSm / z: 536 (M + Na) +.

 [0285] (2) 2- [4- [(Benzyloxycarbo-ru force ruberamoylmethylamino) methyl] -2,6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

 [0286] [Chemical 82]

Reference Example 45— The compound (1.35 g) obtained in (1) was dissolved in dichloromethane (20 ml), trifluoroacetic acid (5 ml) was added under ice water cooling, and the mixture was stirred at room temperature for 18 hours. . The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give 2- [4 [(benzyloxycarbo-rucarboxymethylamino) methyl. ] -2,6 Dimethylphenoxy] 2 Methylpropanoic acid ethyl ester (1.2 g) was obtained as a colorless oil. Dissolve this in acetonitrile (20 ml) and add salt form (0.28 g), 1- (3 dimethylaminopropyl) -3 ethylcarbodiimide hydrochloride (0.76 g), 1-hydroxy Benzotriazole (0.61 g) and N-methylmorpholine (0.58 ml) were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed successively with water, 10% aqueous citrate solution, saturated aqueous sodium hydrogen carbonate, and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanolol: chlorophonolem = 1: 9) to give the title compound (1.lg) as a colorless oil Obtained as a thing.

MSm / z: 457 (M + H) ⁺ . [0288] (3) 2— [4 [[Benzyloxycarboru (3-methyl- [1, 2, 4] oxadiazole —5-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] —2— Methylpropanoic acid ethynole ester

 [0289] [Chemical 83]

Example 19—In the same manner as (2), the title compound (0.73 g) was obtained as a pale yellow oil from the compound (1.10 g) obtained in Reference Example 45- (2). .

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2 Hz), 1.45 (6H, s), 2

 Three

 12, 2. 16 (6H, each s), 2. 35, 2. 38 (3H, each s), 4. 28 (2H, q, J = 7.2

Hz), 4. 51 (2H, s), 4. 55, 4.60 (2H, each s), 5. 20, 5. 24 (2H, each s

), 6. 75, 6.86 (2H, each s), 7. 36— 7. 29 (5H, m).

 MS m / z: 496 (M + H) +.

[0291] (4) 2- [2,6 Dimethyl 4-[[[(3-Methyl- [1, 2, 4] oxadiazol 5-ylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[0292] [Chemical 84]

参考例 45— (3)で得たィ匕合物（0. 73g)をジクロロメタン（5ml)に溶解し、氷水冷 却下に臭化水素（30%酢酸溶液、 5ml)を加えて、室温で 6時間攪拌した。減圧濃縮 乾固することにより標題化合物の臭化水素塩 (0.345g)を褐色油状物として得、そ のまま次の反応に用いた。

Reference Example 45— The compound (0.73 g) obtained in (3) was dissolved in dichloromethane (5 ml), and hydrogen bromide (30% acetic acid solution, 5 ml) was added while cooling with ice water. Stir for hours. Vacuum concentration After drying, the title compound hydrobromide (0.345 g) was obtained as a brown oil and used as such in the next reaction.

 ^ H—NMR (400MHz, CD OD) δ: 1.23 (3H, t, J = 7.1Hz), 1.36 (6H, s),

 Three

 2.13 (6H, s), 2.32 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 4.22 (2H, s), 4.7

7 (2H, s), 7.10 (2H, s).

[0294] [Reference Example 46]

 2— [2, 6 Dimethyl 4— [[(5 Methyl 2 -Feloxazole 4 dimethyl) [2-Oxo 2 — [Ν'— (Pyridine 1-carbol) hydrazino] ethyl] amino

] Methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[0295] [Chemical 85]

[0296] In the same manner as in Reference Example 16- (1), the compound (0.200 g) obtained in Reference Example 14- (3) and nicotinic acid hydrazide (0.078 g) had the same forces (0 170 g) was obtained as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.04 (3Η, t, J = 7.2Hz), 1.15 (6H, s),

 Three

 1.89 (6H, s), 1.96 (3H, s), 3.16 (2H, s), 3.35 (2H, s), 3.39 (2H, s), 3.97 (2H, q, J = 7.0Hz), 6.71 (2H, s), 7.07-7.11 (3H, m), 7.70-7.7 3 (2H, m), 7.76-7.79 (1H, m), 8.23-8.22 (1H, m), 8.45-8.47 (1H, m ), 8.70 (1H, s).

MSm / z: 614 (M + H) ⁺ .

[0297] [Reference Example 47]

 (1) 2— [4 [[tert Butoxycarboromethyl- [2- (4-methoxyphenol) -5-methyloxazole-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2— Methyl propanoic acid ethyl ester

[0298] [Chemical 86]

[0299] Reference Example 14 In the same manner as in (2), 4-chloromethyl-2- (4-methoxyphenyl) -5-methyloxazole (0.194 g) and Reference Example 14- The combined force (0.238 g) gave the title compound (0.357 g) as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.41—1.52 (1

 Three

 5H, m), 2.18 (6H, s), 2.28 (3H, s), 3.30 (2H, s), 3.65—3.79 (4H, m)

, 3.84 (3H, s), 4.28 (2H, q, J = 7.2Hz), 6.94 (2H, q, J = 8.3Hz), 7.00 (

2H, s), 7.94 (2H, d, J = 8.3Hz).

 MS m / z: 581 (M + H) +.

[0300] (2) 2— [4— [[Carboxymethyl mono [2- (4-methoxyphenyl) 5-methyloxazol 4-ruylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] —2 —Methylpronoic acid ethyl ester

[0301] [Chemical 87]

[0302] Reference Example 14- In the same manner as (3), the compound (0.173 g) strength obtained in Reference Example 47- (1) was also used to obtain the hydrochloride of the title compound as a colorless oil, Used for.

 [0303] [Reference Example 48]

(1) 2— [4— [[tert-Butoxycarboromethyl (5 methyl 2- m triloxazol-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] -2-methylpropanoic acid ethyl ester [0304] [Chemical 88]

To 〇

[0305] Reference Example 14— In the same manner as (2), 4-chloromethyl mono 5-methyl 2-m-tolylazole (0.175 g) and Reference compound 14- (1) compound (0.23 lg The title compound (0.335 g) was also obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.41—1.51 (1

 Three

 5H, m), 2.18 (6H, s), 2.30 (3H, s), 2.40 (3H, s), 3.30 (2H, s), 3.72 (2H, s), 3.75 (2H, s), 4.28 (2H , q, J = 7.2Hz), 7.00 (2H, s), 7.21 (1H, d, J = 7.6Hz), 7.28-7.34 (1H, m), 7.80 (1H, d, J = 7.8Hz), 7.86 (1H, s).

 MS m / z: 565 (M + H) +.

[0306] (2) 2- [4 -— [[Carboxymethyl- (5-methyl-2-m-triloxazol-4-ylmethyl) amino] methyl] 2,6 dimethylphenoxy] 2 methylpropanoic acid Ethyl ester

 [0307] [Chemical 89]

To 0

Reference Example 14— In the same manner as in (3), the compound (0.160 g) strength obtained in Reference Example 48- (1) was also used to obtain the hydrochloride of the title compound as a colorless oil, Used for.

 [0309] [Reference Example 49]

(1) 2— [4 -— [[tert-Butoxycarboromethyl]-[5-Methyl-2-((4 trifluoromethylphenol) oxazole-4-ylmethyl] amino] methyl] —2, 6 Enoxy] 2-Methylpropanoic acid ethyl ester

[0310] [Chemical 90]

[0311] Reference Example 14- In the same manner as in (2), the compound (0.236) obtained from 4-chloromethyl-1,5-methyl 2- (4 trifluoromethylphenol) oxazole (0.223 g) and Reference Example 14- (1) g) The title compound (0.356 g) was also obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s),

 Three

 1.48 (9H, s), 2.17 (6H, s), 2.32 (3H, s), 3.30 (2H, s), 3.72 (2H, s), 3.76 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.68 (2H, d, J = 8.1 Hz), 8.12 (2H, d, J = 8.1Hz).

 MS m / z: 619 (M + H) +.

[0312] (2) 2— [4— [[Carboxymethyl— [5-methyl-2-] (4 trifluoromethylphenol) oxazole-4-ylmethyl] amino] methyl] —2, 6 dimethylphenol Si] -2-Methylpropanoic acid ethyl ester

 [0313] [Chem 91]

Reference Example 14—Similar to (3), Reference Example 49—The compound (0.173 g) obtained in (1) was also used to obtain the hydrochloride of the title compound as a colorless oil, and the reaction Used for.

 [0315] [Reference Example 50]

(1) 2— [4 [[tert Butoxycarboromethyl- [2— (4 fluorophenyl) 5 —Methyloxazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0316] [Chemical 92]

What

[0317] In the same manner as in Reference Example 14 2), 4-chloromethyl-2- (4 fluorophenyl) 5 -methyloxazole (0.71 g) and Reference Example 14- Compound obtained in (1) (1 The title compound (1. Og) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s)

 Three

 , 1.48 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.30 (2H, s), 3.72 (2H, s), 3.74 (2H, s), 4.28 (2H, q, J = 7.08Hz), 6.99 (2H, s), 7.12 (2H, m), 8.00 (2H, m).

 MS m / z: 569 (M + H) +.

[0318] (2) 2— [4— [[Carboxymethyl— [5-methyl-2-] (4 trifluoromethylphenol) oxazole-4-ylmethyl] amino] methyl] —2, 6 dimethylphenol Si] -2-Methylpropanoic acid ethyl ester

 [0319] [Chemical 93]

To 0

参考例 14— (3)と同様にして、参考例 50— (1)で得たィ匕合物（1. Og)力も標題ィ匕 合物の塩酸塩 (0.92g)を無色固体として得た。

Reference Example 14- In the same manner as in (3), the compound (1. Og) force obtained in Reference Example 50- (1) was also obtained as the title compound compound hydrochloride (0.92 g) as a colorless solid. .

'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.47 (6H, s) [S6 ^] [SSSO]

 /

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 · (

^ 'Η2) 00 8' ( ^s ' UZ) Z 'L' (m 'HS) 9I' L '(' HS) S9 'UZ) L £'

'( ^Z H80 · = Γ'¾' UZ) SZ ''('HS) Z6 Έ' ( ^s 'U £) Z' Z '( ^s ' H9) SS 'Z'

9Z

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA To 〇

Reference Example 14— In the same manner as in (3), the hydrochloride of the title compound was obtained as a pale yellow oil from the compound (0.215 g) obtained in Reference Example 51— (1). Used for reaction.

[0327] [Reference Example 52]

 (1) 2- [4 [[tert-Butoxycarboromethyl- [2- (3-Methoxyphenol) -5-Methyloxazole-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] 2 —Methylpropanoic acid ethyl ester

[0328] [Chemical 96]

[0329] Reference Example 14 In the same manner as in (2), 4-chloromethyl-2- (3-methoxyphenol) -5-methyloxazole (0.232 g) and Reference Example 14- Combined (0.336 g) strength gave the title compound (0.442 g) as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 1.48 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 3.30 (2H, s), 3.72 (2H, s), 3.75 (2H, s), 3.87 (3H, s) , 4.28 (2H, q, J = 7.2Hz), 6.92— 6.98 (1H, m), 6.99 (2H, s), 7.33 (1H, t, J = 8.1Hz), 7.52— 7.57 (1H, m), 7.57—7.63 (1H, m).

 MS m / z: 581 (M + H) +.

[0330] (2) 2— [4— [[Carboxymethyl mono [2- (3-methoxyphenyl) 5-methyloxazol 4-ruylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] —2 —Methylpro Nonethyl ester

 [0331] [Chemical 97]

[0332] Reference Example 14- In the same manner as in (3), the hydrochloride of the title compound was obtained as a colorless oil from the compound (0.217 g) obtained in Reference Example 52- (1), and was directly used in the next reaction. Used for.

 [0333] [Reference Example 53]

 (1) 4 Chloromethyl-2- (3 fluorophenyl) -5 methyloxazole

 [0334] [Chemical 98]

[0335] In the same manner as in Reference Example 32, 4,5-dimethyl-2- (3 fluorophenol) oxazole 3-oxide hydrochloride (19.3 g) was obtained from 3 fluorobenzaldehyde (17.6 g). This was treated with phosphorus oxychloride (22.6 g) to give the title compound (15.6 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.57 (3Η, s), 2.44 (2Η, s), 7.10—7.1

 Three

 6 (1H, m), 7.38-7.43 (1H, m), 7.68— 7.71 (1H, m), 7.78— 7.80 (1H, m).

 [0336] (2) 2— [4 [[tert Butoxycarboromethyl- [2- (3 Fluorophenol) 5 -Methyloxazole- 4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] 2-Methylpropanoic acid ethyl ester

[0337] [Chemical 99] To 0

[0338] Reference Example 14—In the same manner as (2), Reference Example 53—The compound obtained in (1) (0.71 g) and Reference Example 14—The compound obtained in (1) ( 1. Og) The title compound (1.26 g) was also obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s)

 Three

 , 1.48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.30 (2H, s), 3.71 (2H, s),

3.74 (2H, s), 4.28 (2H, q, J = 7.08Hz), 6.99 (2H, s), 7.11 (1H, m), 7.

40 (1H, m), 7.70 (1H, d, J = 9.64Hz), 7.79 (1H, d, J = 8.81Hz).

 MS m / z: 569 (M + H) +.

[0339] (3) 2— [4 [[Carboxymethyl- [2- (3 fluorophenol) 5 Methyloxazole-4-ylmethyl] amino] methyl] -2,6 Dimethylphenoxy] -2-methyl Ethyl panate ester

[0340] [Chemical 100]

To 0

Reference Example 14- In the same manner as in (3), the hydrochloride (1.20 g) of the title compound was obtained as a colorless oil from the compound (1.26 g) obtained in Reference Example 53- (2). .

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.08Hz), 1.47 (6H, s)

 Three

 , 2.22 (6H, s), 2.44 (3H, s), 3.96 (2H, br), 4.28 (2H, q, J = 7.08Hz), 4.38 (2H, br), 4.53 (2H, br), 7.11 ( 1H, m), 7.44 (3H, m), 7.68 (1H, m), 7.79 (1H, d, J = 7.94Hz).

MS m / z: 513 (M + H) +. [0342] [Reference Example 54]

 (1) 2— [4 [[tert Butoxycarboromethyl- [2- (2 fluorophenyl) 5 —methyloxazole-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methyl Propanoic acid ethyl ester

 [0343] [Chemical 101]

To 〇

[0344] In the same manner as in Reference Example 14-1 (2), 4-chloromethyl-2- (2 fluorophenyl) -5-methyloxazole (0.71 g) and Reference Example 14- The compound (1. Og) force also gave the title compound (1.13 g) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s)

 Three

 , 1.48 (9H, s), 2.18 (6H, s), 2.33 (3H, s), 3.29 (2H, s), 3.71 (2H, s),

3.77 (2H, s), 4.28 (2H, q, J = 7.08Hz), 7.00 (2H, s), 7.18 (2H, m), 7.

38 (1H, m), 8.02 (1H, m).

 MS m / z: 569 (M + H) +.

[0345] (2) 2— [4 [[Carboxymethyl- [2- (2 fluorophenol) 5 Methyloxazole-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] -2-methyl Ethyl panate ester

[0346] [Chemical 102]

To 〇

Reference Example 14— In the same manner as (3), the hydrochloride salt (1. llg) of the title compound was obtained as a colorless oil from the compound (1.13 g) obtained in Reference Example 54- (1). It was. NMR-NMR (400MHz, CDCl) δ: 1.35 (3H, t, J = 7.08Hz), 1.48 (6H, s)

 Three

 , 2.23 (6H, s), 2.46 (3H, s), 3.97 (2H, br), 4.28 (2H, q, J = 7.08Hz),

4.40 (2H, br), 4.55 (2H, br), 7.18 (2H, m), 7.48 (3H, m), 7.99 (1H, t

, J = 7.69Hz).

 MSm / z: 513 (M + H) +.

[0348] [Reference Example 55]

 (1) 4 Chloromethyl-2- (4-ethoxyphenyl) -5 methyloxazole

[0349] [Chemical 103]

[0350] In the same manner as in Reference Example 32, 4 ethoxybenzaldehyde (0.92 g) force and 4,5 dimethyl 2- (4 ethoxyphenol) oxazole 3-oxide hydrochloride (1.57 g) were obtained. This was treated with phosphorus oxychloride (1.34 g) to give the title compound (0.80 g) as a pale yellow solid.

 'H-NMR (400MHz, CDCl) δ: 1.44 (3Η, t, J = 7.OHz), 2.40 (3H, s),

 Three

 4.08 (2H, q, J = 7. OHz), 4.54 (2H, s), 6.93 (2H, d, J = 8.8Hz), 7.92 (2

(H, d, J = 8.8Hz).

MSm / z: 252 (M + H) ⁺ .

[0351] (2) 2— [4 [[tert Butoxycarboromethyl] [2— (4 Ethoxyphenol) -5

—Methyloxazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0352] [Chemical 104]

Reference Example 14—In the same manner as in (2), Reference Example 55—The compound obtained in (1) (0.242 g) and Reference Example 14—in the compound obtained in (1) (0.333). g) The title compound (0.435 g) was also obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.40-1.50 (1

 Three

 8H, m), 2.17 (6H, s), 2.28 (3H, s), 3.30 (2H, s), 3.67— 3.78 (4H, m)

, 4.08 (2H, q, J = 7. OHz), 4.28 (2H, q, J = 7.2Hz), 6.92 (2H, d, J = 9.0

Hz), 6.99 (2H, s), 7.93 (2H, d, J = 9. OHz).

 MS m / z: 595 (M + H) +.

[0354] (3) 2— [4— [[Carboxymethyl- [2- (4 ethoxyphenol) -5 Methyloxazol-4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] —2— Methylpropyl ethyl ester

[0355] [Chemical 105]

Reference Example 14—In the same manner as in (3), the compound (0.214 g) obtained in Reference Example 55— (2) was also used to obtain the hydrochloride of the title compound as a colorless oil, which was directly used in the next reaction. .

 [0357] [Reference Example 56]

 (1) 4 Chloromethyl-2- (3,4-dimethylphenol) -5 methyloxazole

[0358] [Chem 106]

[0359] In the same manner as in Reference Example 32, 3, 4 dimethylbenzaldehyde (1. Olg) force 4,5 dimethyl-2- (3,4, dimethylphenol) oxazole 3-oxide hydrochloride (1.37 g) was added. Obtained. This was treated with phosphorus oxychloride (1.24 g) to give the title compound (1.19 g) as a light brown solid.

 'H-NMR (400MHz, CDC1) δ: 2.30 (3Η, s), 2.31 (3Η, s), 2.42 (3H, s

 Three

 ), 4.55 (2H, s), 7.19 (1H, d, J = 7.8Hz), 7.71 (1H, d, J = 7.8Hz), 7.80 (1H, s).

MS m / z: 236 (M + H) ⁺ .

[0360] (2) 2— [4 [[tert Butoxycarboromethyl] [2— (3, 4 Dimethylphenol)

5-Methyloxazole-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy

] 2-Methylpropanoic acid ethyl ester

[0361] [Chemical 107]

参考例 14— (2)と同様にして、参考例 56— (1)で得たィ匕合物 (0.226g)と参考例 14— (1)で得たィ匕合物（0.33 lg)力 標題ィ匕合物（0.460g)を淡黄色油状物とし て得た。

Reference Example 14—Same as (2), Reference Example 56—Compound (0.226 g) obtained in (1) and Reference Example 14—Compound (0.33 lg) force obtained in (1). The title compound (0.460 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

1.47 (9H, s), 2.17 (6H, s), 2.27— 2.33 (9H, m), 3.29 (2H, s), 3.71 (2 H, s), 3.74 (2H, s), 4.28 (2H, q , J = 7.2Hz), 6.99 (2H, s), 7.18 (1H, d, J = 8.1Hz), 7.70-7.74 (1H, m), 7.79—7.82 (1H, m). MS m / z: 579 (M + H) ⁺ .

[0363] (3) 2— [4 [[Carboxymethyl- [2— (3,4 Dimethylphenol) 5-Methyloxazol-4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] —2— Methyl propanoic acid ethyl ester

[0364] [Chemical 108]

to o

Reference Example 14- In the same manner as in (3), the hydrochloride of the title compound was obtained as a colorless oil from the compound (0.241 g) obtained in Reference Example 56- (2), and used as such in the next reaction. .

 [0366] [Reference Example 57]

 (1) 4 Chloromethyl-2- (3-chloro-4-methylphenol) -5-methyloxazole

 [0367] [Chem 109]

参考例 32と同様にして、 3 クロロー 4 メチルベンズアルデヒド（1.59g)力ら 2— (3—クロロー 4 メチルフエ-ル）—4, 5—ジメチルォキサゾール 3—ォキシド 塩 酸塩（2.20g)を得た。このものをォキシ塩化リン（3.07g)で処理することにより標題 化合物（1.97g)を淡黄色固体として得た。

In the same manner as in Reference Example 32, 3 Chloro-4-methylbenzaldehyde (1.59 g) was added to 2- (3-Chloro-4-methylphenol) -4,5-dimethyloxazole 3-oxide hydrochloride (2.20 g). Obtained. This was treated with phosphorus oxychloride (3.07 g) to give the title compound (1.97 g) as a pale yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.40—2.43 (6Η, m), 4.54 (2Η, s), 7.

 Three

 29 (1H, d, J = 8. OHz), 7.79 (1H, dd, J = 8.0, 1.7Hz), 7.99 (1H, d, J = l .7Hz).

MSm / z: 256 (M + H) ⁺ . [0369] (2) 2— [4— [[tert-Butoxycarboromethyl] [2— (3 Chromium 1-Methylphenol) -5-Methyloxazole-4-ylmethyl] amino] methyl] —2 , 6-Dimethylphenoxy] 2-Methylpropanoic acid ethyl ester

 [0370] [Chem 110]

[0371] Reference Example 14— In the same manner as (2), Reference Example 57—The compound (0.251 g) obtained in (1) and Reference Example 14— g) The title compound (0.466 g) was also obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s),

 Three

 1.48 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 2.41 (3H, s), 3.29 (2H, s), 3.71 (2H, s), 3.74 (2H, s) , 4.28 (2H, q, J = 7.1 Hz), 6.99 (2H, s), 7.24 -7.32 (1H, m), 7.75- 7.81 (1H, m), 8.00 (1H, s).

 MS m / z: 599 (M + H) +.

 [0372] (3) 2— [4 [[Carboxymethyl- [2- (3 Chloro-4-methylphenol) -5-methyloxazol-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] -2 — Methylpropanoic acid ethyl ester

 [0373] [Chem 111]

Reference Example 14— In the same manner as in (3), the hydrochloride of the title compound was obtained as a colorless oil from the compound (0.244 g) obtained in Reference Example 57— (2) and used as such in the next reaction. .

[0375] [Reference Example 58] (1) 4 Chloromethyl-1- (4-methoxy-1-3-methylphenol) 5-Methyloxazo

[0376] [Chem 112]

In the same manner as in Reference Example 32, 4-methoxy-3-methylbenzaldehyde (1.02 g), 4,5 dimethyl-2- (4-methoxy-3-methylphenyl) oxazole 3-oxide hydrochloride (1.81 g) was obtained. This was treated with phosphorus oxychloride (1.54 g) to give the title compound (1.37 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.25 (3Η, s), 2.40 (3Η, s), 3.88 (3H, s

 Three

 ), 4.54 (2H, s), 6.84-6.87 (1H, m), 7.82-7.79 (2H, m).

MSm / z: 252 (M + H) ⁺ .

[0378] (2) 2— [4 [[tert Butoxycarboromethyl- [2- (4-Methoxy-3-methylphenol

-L) -5-Methyloxazole-4-ylmethyl] amino] methyl] -2,6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0379] [Chem 113]

What

参考例 14— (2)と同様にして、参考例 58— (1)で得たィ匕合物 (0.247g)と参考例 14— (1)で得たィ匕合物（0.338g)力 標題ィ匕合物（0.441g)を淡黄色油状物とし て得た。

Reference Example 14—Same as (2), Reference Example 58—Compound (0.247g) obtained in (1) and Reference Example 14—Compound (0.338g) force obtained in (1). The title compound (0.441 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

1.47 (9H, s), 2.17 (6H, s), 2.25 (3H, s), 2.29 (3H, s), 3.29 (2H, s), 3 71 (2H, s), 3. 74 (2H, s), 3. 87 (3H, s), 4. 28 (2H, q, J = 7.2 Hz), 6. 81

-6. 88 (1H, m), 6. 99 (2H, s), 7. 77— 7. 84 (2H, m).

 MS m / z: 595 (M + H) +.

[0381] (3) 2— [4 [[Carboxymethyl- [2- (4-Methoxy-3-methylphenol) 5-Methyloxazol 4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] — 2 Methylpropanoic acid ethyl ester

[0382] [Chem 114]

What

Reference Example 14— In the same manner as in (3), the hydrochloride of the title compound was obtained as a colorless oil from the compound (0.183 g) obtained in Reference Example 58— (2) and used as such for the next reaction. It was.

[0384] [Reference Example 59]

 (1) 2— [4 [[tert Butoxycarboromethyl- [2— (3,5 difluorophenol) —5-Methyloxazole-4-ylmethyl] amino] methyl] —2, 6 dimethylphenol ] 2-Methylpropanoic acid ethyl ester

[0385] [Chemical 115]

参考例 14一（2)と同様にして、 4 クロロメチルー 2— (3, 5 ジフルオロフェ -ル) 一 5 メチルォキサゾール（0. 224g)と参考例 14一（1)で得た化合物（0. 318g)力 ^ ら標題化合物（0. 439g)を無色油状物として得た。 Ή- NMR (400MHz, CDCl ) δ :1.35 (3H, t, J=7.2Hz), 1.45 (6H, s), What

Reference Example 14 In the same manner as in 1 (2), the compound (0) of 4 chloromethyl-2- (3,5 difluorophenol) 15 methyloxazole (0.224 g) and Reference Example 14 1 (1) 318 g) gave the title compound (0.439 g) as a colorless oil. NMR-NMR (400MHz, CDCl) δ: 1.35 (3H, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 1.48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.30 (2H, s), 3.71 (2H, s), 3.74 (2H, s), 4.29 (2H, q, J = 7.2Hz), 6.79- 6.88 (1H, m), 6.98 (2H, s), 7.48-7.56 (2H, m).

MS m / z: 587 (M + H) ⁺ .

[0387] (2) 2— [4 [[Carboxymethyl- [2— (3,5 Difluorophenol) 5-Methyloxazol 4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] —2—Methylpropanoic acid ethyl ester

 [0388] [Chem 116]

What

[0389] In the same manner as in Reference Example 14- (3), the hydrochloride of the title compound was obtained as a colorless oil from the compound (0.213g) obtained in Reference Example 59- (1). Used for.

 [0390] [Reference Example 60]

 (1) 2— [4— [[tert-Butoxycarboromethyl] [2— (3, 5 dichlororophenol) —5-Methyloxazole-4-ylmethyl] amino] methyl] —2, 6 Dimethylphenol 2] 2-Methylpropanoic acid ethyl ester

 [0391] [Chemical 117]

To 〇

[0392] 参考例 14— (2)と同様にして、 4 クロロメチル一 2— (3, 5 ジクロロフエ-ル） - 5—メチルォキサゾール（0.258g)と参考例 14— (1)で得た化合物（0.322g)から 標題化合物 (0.406g)を淡黄色油状物として得た。

[0392] Reference Example 14— Obtained in the same manner as (2) using 4-chloromethyl-1- (3,5 dichlorophenol) -5-methyloxazole (0.258 g) and Reference Example 14- (1). The title compound (0.406 g) was obtained as a pale yellow oil from the obtained compound (0.322 g).

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s),

 Three

 1.48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.29 (2H, s), 3.70 (2H, s), 3

.74 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.36— 7.39 (1H, m

), 7.88-7.92 (2H, m).

 MS m / z: 619 (M + H) +.

[0393] (2) 2— [4 [[Carboxymethyl- [2— (3,5 Diclonal Methanol) 5-Methyloxazol-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] — 2-Methylpropanoic acid ethyl ester

[0394] [Chemical 118]

Reference Example 14—In the same manner as in (3), the compound (0.209 g) obtained in Reference Example 60— (1) was also used to obtain the hydrochloride of the title compound as a colorless oil, Used for.

 [0396] [Reference Example 61]

 (1) 2- (3 Bromo-4-methoxyphenol) -4 Chloromethyl-5-methyloxazo

 [0397] [Chemical 119]

[0398] 参考例 32と同様にして、 3 ブロモー 4ーメトキシベンズアルデヒド（2.17g)から 2 一（3—ブロモー 4ーメトキシフエニル）—4, 5—ジメチルォキサゾール 3—ォキシド 塩酸塩（2.86g)を得た。このものをォキシ塩化リン（3.07g)で処理することにより標 題化合物（2.48g)を無色固体として得た。 Br

[0398] In the same manner as in Reference Example 32, from 3 bromo-4-methoxybenzaldehyde (2.17 g) to 2 mono (3-bromo-4-methoxyphenyl) -4,5-dimethyloxazole 3-oxide hydrochloride (2.86 g) was obtained. This was treated with phosphorus oxychloride (3.07 g) to give the title compound (2.48 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.95 (3Η, s), 4.53 (2H, s

 Three

 ), 6.91-6.98 (1H, m), 7.89— 7.97 (1H, m), 8.19— 8.24 (1H, m). MSm / z: 316 (M + H) +.

[0399] (2) 2— [4— [[[2— (3 Bromo 4-methoxyphenol) -5-Methyloxazole

4-ylmethyl] -tert-butoxycarbo-methylmethylamino] methyl] -2,6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0400] [Chemical 120]

[0401] Reference Example 14— In the same manner as in (2), Reference Example 61—The compound (0.334 g) obtained in (1) and Reference Example 14— g) The title compound (0.471 g) was also obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 1.48 (9H, s), 2.17 (6H, s), 2.29 (3H, s), 3.29 (2H, s), 3.71 (2H, s), 3.73 (2H, s), 3.94 (3H, s) , 4.28 (2H, q, J = 7.1 Hz), 6.93 (1H, d, J = 8.5 Hz), 6.98 (2H, s), 7.92 (1H, dd, J = 8.5, 2. OHz), 8.22 ( (1H, d, J = 2.0 Hz).

 MS m / z: 660 (M + H) +.

[0402] (3) 2- [4-[[[2- (3 Bromo-4-methoxyphenol) -5-methyloxazole-4-ylmethyl] carboxymethylamino] methyl] -2, 6 dimethylphenol Si] -2-Methylpropanoic acid ethyl ester [0403] [Chemical 121]

[0404] Reference Example 14- In the same manner as (3), the compound (0.236 g) force obtained in Reference Example 61- (2) was also used to obtain the hydrochloride of the title compound as a pale yellow solid, Used for.

 [0405] [Reference Example 62]

 (1) 2- [4- [6-Butoxycarboromethyl- (3--trilu [1,2,4] oxadiazo-l 5-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methyl Rupropanoic acid ethyl ester

 [0406] [Chemical 122]

[0407] Reference Example 14— Obtained in the same manner as (2) in 5-chloromethyl-1-p-tolyl [1,2,4] oxadiazole (0.66 g) and Reference Example 14- (1) Compound (1. Og) force The title compound (1.29 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.20Hz), 1.47 (15H, s

 Three

 ), 2.19 (6H, s), 2.42 (3H, s), 3.42 (2H, s), 3.82 (2H, s), 4.19 (2H, s), 4.28 (2H, q, J = 7.08Hz), 7.02 (2H, s), 7.29 (2H, d, J = 8.06Hz), 7.99 (2H, d, J = 8.06Hz).

MS m / z: 552 (M + H) ⁺ .

[0408] (2) 2— [4 — [[Carboxymethyl- (3-p-tolyl- [1,2,4] oxadiazole-5-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] —2—Methylpropanoic acid Echinore Estenore

 [0409] [Chemical 123]

To 〇

Reference Example 14- In the same manner as in (3), the hydrochloride (1.16 g) of the title compound was obtained as a colorless solid from the compound (1.29 g) obtained in Reference Example 62- (1).

 'H-NMR (400MHz, CDCl) δ: 1.33 (3Η, t, J = 7.08Hz), 1.44 (6H, s)

 Three

 , 2.18 (6H, s), 2.41 (3H, s), 4.25 (2H, q, J = 7.08Hz), 4.33 (2H, s), 4.55 (2H, s), 4.80 (2H, s), 7.20 (2H, s), 7.28 (2H, d, J = 8.18Hz), 7.9 4 (2H, d, J = 8.06Hz).

 MS m / z: 496 (M + H) +.

[0411] [Reference Example 63]

 (1) 2- [4- [6-Butoxycarbonylmethyl- (3-111-trilu [1,2,4] oxadiazol 5-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] — 2-Methylpropanoic acid ethyl ester

 [0412] [Chemical 124]

参考例 14— (2)と同様にして、 5—クロロメチル— 3— m—トリル— [1, 2, 4]ォキサ ジァゾール (0.54g)と参考例 14— (1)で得たィ匕合物（0.90g)から標題ィ匕合物（1. 15g)を淡黄色油状物として得た。

Reference Example 14—In the same manner as (2), 5-chloromethyl-3-m-tolyl- [1, 2, 4] oxadiazole (0.54 g) was combined with Reference Example 14- (1). The title compound (1.15 g) was obtained as a pale yellow oil from the product (0.90 g).

'H-NMR (400MHz, CDCl) δ: 1.36 (3Η, t, J = 7.08Hz), 1.48 (15H, s

[8 0]

 D ^ D

^ ^ ー 9 — [^ [^ (^ / —S— / —,; ^ ^ ['Z'!]-(/-É c ^ —) — ε] -Λ ^ Λ ^^ Λ ^^^- ^- _→ -] -ζ {\)

 [^ 9p}%] [ΐ ^ Ο]

• ₊ (H + V) 96: ^z Z ^ra SPV

(Ra 'UZ) L' L '(m' UZ) l £ 'L' ( ^s ' HS) OI 'L' ( ^s ' HS) S '' ( ^Z H80 'L =

Γ '¾' HS) 9S '' ( ^s ' UZ) Z '' ( ^S 'HS) SO''( ^s ¾ε) ε' Ζ '( ^S ' Η9) 8Ι 'Ζ'

(s ¾9) s · χ '(ZH80 Ί = ί'-¾ε) ε · ΐ: 9 (\ οαο ^<z HPVOO ^) HPVN-H _x

oM ^ m ^ ^ ( ^§ 6ο -Dw m ^ ^

®¾ ^ ( ^§ 9ΐ -D ^ -M ^)-mm 爾 (ε) → nm

Yes

Λ ^ Υ: · Χ / ^ e 邈 be ΰ: ^ — é ^ — 9 'Z-s— / —,; ^ ^ [' ζ Ί]-fi4-ra-e)-/ ^^^ / ^- ^ _-Ζ (ζ) [ww)]

• ₊ (H + PV) sgg: z / ^ra SPV

• (ra 'HS) I6' L '(m' HS) 9S 'L'(s' HS) SO 'L' (Z H80 · Ζ = Γ¾ 'UZ) SZ''(s' UZ) OZ''( ^s ' HS) S8 Έ '( ^s ' UZ) Z Έ' ( ^s ¾ε) ε 'Ζ' ( ^s ' Η9) 6 Ι 'Ζ' (

86

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV

[0419] Reference Example 14— Obtained in the same manner as (2) in 5 Chloromethyl-3— (4 Black Mole) [1, 2, 4] oxadiazole (1.45 g) and Reference Example 14— (1) The compound (2. Og) strength also gave the title compound (2.6 lg) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.46 (15H, s

 Three

 ), 2.19 (6H, s), 3.42 (2H, s), 3.83 (2H, s), 4.20 (2H, s), 4.28 (2H, q,

J = 7.08Hz), 7.01 (2H, s), 7.46 (2H, d, J = 8.6Hz), 8.04 (2H, d, J = 8.

67Hz).

MS m / z: 572 (M + H) ⁺ .

[0420] (2) 2— [4 [[Carboxymethyl- [3- (4 Black-mouthed phenol) [1, 2, 4] Oxadiazol-5-ylmethyl) amino] methyl] -2, 6 Enoxy] —2-Methylpropylethyl ester

[0421] [Chemical 127]

参考例 14— (3)と同様にして、参考例 64— (1)で得たィ匕合物（1.36g)から標題 化合物の塩酸塩を黄色固体として得、そのまま次の反応に使用した。

Reference Example 14- The hydrochloride of the title compound was obtained as a yellow solid from the compound (1.36 g) obtained in Reference Example 64-(1) in the same manner as in (3), and used as it was in the next reaction.

 'H-NMR (400MHz, CDCl) δ: 1.33 (3Η, t, J = 7.08Hz), 1.42 (6H, s)

 Three

, 2.15 (6H, s), 4.25 (2H, q, J = 7.08Hz), 4.41 (2H, br), 4.61 (2H, br), 4.90 (2H, br), 7.21 (2H, s), 7.44 ( 2H, d, J = 8.06Hz), 7.96 (2H, d, J = 8.28Hz).

[6Zl ^ [LZfO ^^ e / ^ e ^ ^

[ ^ [ ^ （ ^ / — S— /— 、 、 ^ [ 'ζ Ί] - {Λ^—^^ ^-Ζ) -ε] -S (S) [92^0]

[^ [^ (^ / — S— / —,, ^ ['ζ Ί]-{Λ ^ — ^^ ^ -Ζ) -ε] -S (S) [92 ^ 0]

一 ^ ' • ₊ (H +) S 9: ^z / ^ra SPV • (^ 'HI) II · 8' (m 'HI) 66' L '(^' HS) S 'L' ( ^s ' HS) IO 'L' ( m 'HS) 8S''( ^s ' HS) OS''( ^s ' HS) S8 Έ' ( ^s ' HS) S Έ '( ^s ' H9) 6I' Z '( ^s ' H9I) 9 ^ Ί' ( ^ 'HS) 9S'!: 9 (lOOO 'ZH OO ^ H NH,

One ^ '

D ^ E 邈 cl cl l ^ s— ^ ー 9 — [^ [^ (^ / —S— / —,; ^ ^ ['Z'!]-(/-É clE ^ ε) -S]- Λ ^ Λ ^^ Λ ^^^-^- _→ -] -ζ {\)

 [99pi}%] [ZZfO

96

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV NMR-NMR (400MHz, CDCl) δ: 1.33 (3H, t, J = 7.08Hz), 1.44 (6H, s)

 Three

 , 2.17 (6H, s), 4.26 (2H, q, J = 7.08Hz), 4.27 (2H, br), 4.49 (2H, br), 4.78 (2H, br), 7.18 (2H, s), 7.46 ( 2H, m), 7.95 (1H, d, J = 7.45Hz), 8.05 (1H, s).

[0429] [Reference Example 66]

 2- (2 Chloro-4-formyl 6-methylphenoxy) 2-methylpropanoic acid ester

 [0430] [Chemical 130]

[0431] In the same manner as in Reference Example 12, the title compound (3.20 g) was obtained as a yellow oil from 3 chloro-4-hydroxy-5 methylbenzaldehyde (2.08 g).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, q, J = 6.4Hz), 1.57 (6H, s),

 Three

 2.33 (3H, s), 4.30 (2H, q, J = 7.1Hz), 7.61 (1H, d, J = 2.2Hz), 7.73 (1 H, d, J = 2.2Hz), 9.87 (1H, s) .

MS m / z: 285 (M + H) ⁺ .

[0432] [Reference Example 67]

 (1) [tert-Butoxycarboru (5-methyl-2phenoloxol-4-ylmethyl) amino] acetic acid methyl ester

[0433] [Chemical 131]

[0434] 水素化ナトリウム（55%油性， 760mg)を N, N—ジメチルホルムアミド（30ml)に懸 濁し、氷水冷却下に tert—ブトキシカルボ-ルァミノ酢酸 メチル エステル（3. Og) の N—ジメチルホルムアミド（15ml)溶液を滴下した。同温にて 30分攪拌後、 4— クロロメチル— 5—メチル—2—フエ-ルォキサゾール（3. 29g)の N, N—ジメチルホ ルムアミド（15ml)溶液を滴下し、室温にて一晩攪拌した。反応液を酢酸ェチルにて 希釈して、飽和塩化アンモ-ゥムを加えた。有機層を水と飽和食塩水にて洗浄後、 無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して、残渣をシリカゲルカラムクロ マトグラフィー（酢酸ェチル：へキサン = 1 :4)にて精製して、標題化合物（2. 43g)を 淡黄色油状物として得た。

[0434] Suspension of sodium hydride (55% oil, 760 mg) in N, N-dimethylformamide (30 ml), and cooling with ice water, tert-butoxycarbolamaminoacetic acid methyl ester (3. Og) N-dimethylformamide (15 ml) solution was added dropwise. After stirring at the same temperature for 30 minutes, a solution of 4-chloromethyl-5-methyl-2-phenoloxazole (3.29 g) in N, N-dimethylformamide (15 ml) was added dropwise and stirred overnight at room temperature. . The reaction solution was diluted with ethyl acetate and saturated ammonium chloride was added. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (2.43 g) as a pale yellow oil.

 [0435] 'H-NMR (400MHz, CDC1) δ: 1. 43, 1. 52 (total 9Η, s), 2. 38, 2. 41 (

 Three

 total 3H, s), 3. 69, 3. 71 (total 3H, s), 4. 08, 4. 17 (total 2H, s), 4. 4 2, 4. 44 (total 2H, s), 7 39— 7. 46 (3H, m), 7. 95— 7. 99 (2H, m). MS m / z: 361 (M + H) +.

 [0436] (2) [tert-Butoxycarboru (5-methyl-2-phenol-4-methyl) amino] acetic acid

 [0437] [Chemical 132]

[0438] To a solution of the compound (2.43 g) obtained in Reference Example 67- (1) in ethanol (20 ml) was added 1N aqueous sodium hydroxide solution (10 mL) at room temperature, and the mixture was stirred for 2 hours. 1N Hydrochloric acid (10m 1) was added, and the solvent was evaporated under reduced pressure. The residue was extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.19 g) as a colorless solid.

'H-NMR (400MHz, CDC1) δ: 1.45 (9Η, s), 2.40 (3Η, s), 4.09 (2H, s ), 4.42 (2H, s), 7.44-7.49 (3H, m), 7.93- 8.00 (2H, m).

MS m / z: 347 (M + H) ⁺ .

[0439] (3) Methylcarbamoylmethyl- (5-methyl-2-phenoloxol-4-ylmethyl) rubamic acid tert butyl ester

[0440] [Chemical 133]

[0441] Reference Example 67— Dissolving the compound (1.07g) obtained in (2) and methylamine hydrochloride (313mg) in a mixture of dichloromethane (10ml) and acetonitrile (10ml) to give 1-hydroxybenzotriazole Hydrate (473 mg), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (888 mg) and triethylamine (0.65 ml) were added and stirred at room temperature. The solvent was distilled off under reduced pressure, and the residue was suspended in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 3: 1 to 4: 1) to give the title compound. The compound (989 mg) was obtained as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.42 (9Η, s), 2.39 (3Η, s), 2.81 (3H, d

 Three

 , J = 4.9Hz), 3.94 (2H, brs), 4.32 (2H, s), 7.42— 7.47 (3H, m), 7.83 (

1H, s), 7.93-7.99 (2H, m).

 MS m / z: 360 (M + H) +.

[0442] (4) N-Methyl-2-[[(5-Methyl-2-phenoloxal-4-ylmethyl) amino] acetamide

[0443] [Chemical 134]

[0444] To a solution of the compound (987 mg) obtained in Reference Example 67- (3) in dichloromethane (10 ml) was added 4N hydrochloric acid-dioxane solution (10 ml), and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure to obtain hydrochloride (817 mg) of the title compound as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.43 (3Η, s), 2.67 (3Η, s), 3.75 (2H, s

 Three

 ), 4.13 (2H, s), 7.52-7.57 (3H, m), 7.93- 7.98 (2H, m), 8.34 (1H, d, J = 4.9Hz), 9.25 (2H, s).

MS m / z: 260 (M + H) ⁺ .

[0445] [Reference Example 68]

 (1) [(5-Methyl-2phenoloxazole-4-ylmethyl) amino] acetic acid methyl ester

[0446] [Chemical 135]

Reference Example 67— To a solution of the compound obtained in (1) (5.16 g) in dichloromethane (50 ml) was added 4N hydrochloric acid-dioxane solution (50 ml), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain the hydrochloride of the title compound (4.3 g) as a pale yellow solid.

 [0448] (2) 2- [2 Chloro-4 [[Methoxycarboromethyl- (5-methyl-2-phenolazol 4-ylmethyl) amino] methyl] -6-methylphenoxy] -2-methylpronoate Ester

[0449] [Chemical 136]

In the same manner as in Example 102- (1), the compound (544 mg) obtained in Reference Example 68- (1) and the compound (520 mg) obtained in Reference Example 66 were treated with sodium triacetoxyborohydride. Treatment gave the title compound (233 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.51 (6H, s),

 Three

 2.21 (3H, s), 2.29 (3H, s), 3.46 (2H, s), 3.71 (4H, s), 3.74 (3H, s), 4.28 (2H, q, J = 7. OHz), 7.09 (1H, s), 7.24 (1H, s), 7.39— 7.46 (3H, m), 7.98-8.02 (2H, m).

MS m / z: 529 (M + H) ⁺ .

[0451] (3) 2— [4 [[Carboxymethyl- (5-methyl-2-phenoloxol-4-ylmethyl) amino] methyl] 2 Chloro-6 methylphenoxy] 2 Methylpropanoic acid ethinole ester

 [0452] [Chemical 137]

[0453] To a solution of the compound (230 mg) obtained in Reference Example 68- (2) in ethanol (10 ml) was added 1N aqueous sodium hydroxide solution (5 ml) at room temperature, and the mixture was stirred for 30 minutes. 1N Aqueous hydrochloric acid solution (5 ml) was added, and the solvent was evaporated under reduced pressure. The residue was extracted with dichloromethane and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (223 mg) as a colorless oil.

 [0454] [Reference Example 69]

(1) 2— [5 Methyl 2- (4 trifluoromethylphenol) oxazole 4 yl] ethylamine [0455] [Chemical 138]

[0456] [5-Methyl-2- (4 trifluoromethylphenol) oxazole-4-yl] acetate A solution of nitrile (3.17 g) in tetrahydrofuran (30 ml) added to borane monotetrahydrofuran complex (1 M tetrahydrofuran) The solution, 26 ml) was collected and stirred at room temperature overnight. While cooling with ice water, 1N aqueous hydrochloric acid solution (100 ml) was added and stirred for 30 minutes. It was extracted with ethyl acetate as alkalinity with 1N aqueous sodium hydroxide solution. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.16 g) as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 2. 37 (3Η, s), 2. 66 (2Η, t, J = 6.5Hz),

 Three

 3.06 (2H, t, J = 6.6Hz), 7.68 (2H, d, J = 8.1 Hz), 8.08 (2H, d, J = 8.1 Hz)

MS m / z: 271 (M + H) ⁺ .

[0457] (2) 2— [2, 6 Dimethyl 4— [[2— [5-Methyl-2- (4-Trifluoromethylphenol) oxazole 4-ethyl] ethylamino] methyl] phenoxy] 2 methyl Propenoic acid ethyl ester

[0458] [Chemical 139]

参考例 3と同様にして、参考例 69— (1)で得られた化合物（2. 14g)と参考例 12の 化合物（1. 57g)から標題ィ匕合物（2. 42g)を淡黄色油状物として得た。 Ή-NMR (400MHz, CDC1 ) δ : 1. 34 (3H, t, J= 7. 1Hz) , 1. 43 (6H, s) ,

In the same manner as in Reference Example 3, the title compound (2.42 g) was pale yellow from the compound (2.14 g) obtained in Reference Example 69- (1) and the compound of Reference Example 12 (1.57 g). Obtained as an oil. NMR-NMR (400MHz, CDC1) δ: 1.34 (3H, t, J = 7.1 Hz), 1.43 (6H, s),

 Three

 2. 09 (6H, s), 2. 24 (3H, s), 2. 67 (2H, t, J = 6. 6Hz), 2. 80 (2H, t, J = 6.

4Hz), 3.52 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 6.75 (2H, s), 7.71 (2H, d

, J = 8.3Hz), 8.06 (2H, d, J = 8.3Hz).

 MS m / z: 519 (M + H) +.

[0460] (3) 2— [4 [[Carboxymethyl- [2-[5-Methyl-2- (4 trifluoromethyl-) -oxazol-4-yl] ethyl] amino] methyl] —2, 6 —Dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0461] [Chemical 140]

[0462] In the same manner as in Reference Example 6, the compound (658 mg) obtained in Reference Example 69- (2) and darioxylic acid (240 mg) title compound (430 mg) as a pale yellow oil were obtained. Obtained.

 [0463] [Reference Example 70]

 (1) 2— (5 Methyl 2-p-trioxazole 4-yl) ethylamine

 [0464] [Chem 141]

4 Chloromethyl-5-methyl-2-p-trioxazole (18. Og) was dissolved in N, N dimethylformamide (90 ml) and sodium cyanide (4.2 g) and potassium iodide (4.6 7 g) was added and stirred at 85 ° C. for 1 hour. The reaction solution was returned to room temperature, water (150 ml) and potassium carbonate (2. lg) were added, and the mixture was vigorously stirred for 15 minutes. The precipitated solid is collected by filtration and washed twice with water. Then, (5-methyl 2-p-trioxazole 4-yl) acetononitrile was obtained as a pale yellow solid by drying.

 The obtained (5-methyl-2-p-tolyloxazole-4-yl) acetonitrile (2.18 g) was used in the same manner as in Reference Example 69- (1). , 33 ml) to give the title compound (2.18 g) as a yellow oil.

 'H-NMR (400MHz, CDCl) δ: 2.34 (3Η, s), 2.39 (3Η, s), 2.62 (2H, t

 Three

 , J = 6.6Hz), 3.02 (2H, t, J = 6.6Hz), 7.23 (2H, d, J = 8.3Hz), 7.87 (2

(H, d, J = 8.3Hz).

MS m / z: 217 (M + H) ⁺ .

[0466] (2) 2- [2, 6 Dimethyl-4-[[2- (5-Methyl-2-p-trioxazole-4-yl) ethylamino] methyl] phenoxy] -2-methylpropanoate Ester [0467] [Chem 142]

[0468] In the same manner as in Reference Example 3, the title compound (1.59g) was pale yellow from the compound (1.5g) obtained in Reference Example 70- (1) and the compound of Reference Example 12 (1.28g). Obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.32 (3H, s), 2.39 (3H, s), 2.70 (2H, t, J = 6.9Hz), 2.9 5 (2H, t, J = 6.9Hz), 3.71 ( 2H, s), 4.28 (2H, q, J = 7.1Hz), 6.91 (2H, s), 7.23 (2H, d, J = 8.1Hz), 7.86 (2H, d, J = 8.1Hz).

 MS m / z: 465 (M + H) +.

[0469] (3) 2— [4 — [[Carboxymethyl— [2- (5-Methyl-2-p-trioxazole-4-yl) ethyl] amino] methyl] —2, 6 dimethylphenol Si] -2-Methylpropanoic acid Echinore Estenore

 [0470] [Chemical 143]

[0471] In the same manner as in Reference Example 6, the compound (431 mg) obtained in Reference Example 70- (2) and darioxylic acid (170 mg) and the title compound (366 mg) as a pale yellow oil were obtained. Obtained.

 'H-NMR (400MHz, CDC1) δ: 1.33 (3Η, t, J = 7.4Hz), 1.39 (6H, s),

 Three

 1.95 (6H, s), 2.19 (3H, s), 2.41 (3H, s), 2.61 (2H, t, J = 5.9Hz), 2.7 6 (2H, t, J = 5.9Hz), 3.40 (2H, s), 3.55 (2H, s), 4.26 (2H, q, J = 7.4Hz), 6.66 (2H, s), 7.27 (2H, d, J = 8.1 Hz), 7.94 (2H, d, J = 8.3Hz).

MS m / z: 523 (M + H) ⁺ .

[0472] [Reference Example 71]

 2— [2,6 Dimethyl 4— [[((5 Methyl 2 phenoxazole 4 dimethyl) [2-Oxo 2— (Ν, 1-propio-hydrazino) 1-ethyl] amino] methyl] phenoxy] 2-methylpropane Acid ethyl ester

[0473] [Chemical 144]

[0474] Reference Example 16— The compound (0.200 g) obtained in (2) was dissolved in dichloromethane (5 ml) and cooled with ice water. On the rejection, pyridine (0.11 ml) and propionic anhydride (0.058 ml) were added, and the mixture was stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0.190 g) as a pale yellow oil. Got as.

 MS m / z: 565 (M + H) +.

 [0475] [Reference Example 72]

 2— [4 [[[[2- (N, 1 acetylhydrazino) 2 oxoethyl] (5 Methyl 2 Phenyloxazole-4-ylmethyl) amino] methyl] —2 Chloro 6-methylphenoxy] 2 -Methyl Propanoic acid ethyl ester

 [0476] [Chemical 145]

Reference Example 17—In the same manner as in (1), the compound (107 mg) obtained in Reference Example 68- (3) and the acetate hydrazide (31 mg) and the title compound (57 mg) were obtained. Obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.52 (6H, s),

 Three

 2.04 (3H, s), 2.22 (3H, s), 2.25 (3H, s), 3.41 (2H, s), 3.61 (2H, s), 3.68 (2H, s), 4.28 (2H, q, J = 7.1Hz), 7.11 (1H, s), 7.20 (1H, s), 7.

42-7.48 (4H, m), 7.75 (1H, s), 7.99— 8.03 (2H, m).

MS m / z: 571 (M + H) ⁺ .

[0478] [Reference Example 73]

 2- [4-[[[2- (Ν'-Acetylhydrazino) 2-oxoethyl] [2- (5 methyl

— 2— ρ Tolyloxazole-4-yl) ethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropanoic acid ethyl ester [0479] [Chemical 146]

[0480] Reference Example 17— In the same manner as in (1), the compound (265 mg) obtained in Reference Example 70 (3) and acetohydrazide (56 mg) and the title compound (192 mg) were combined. Obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.34 (3Η, t, J = 7.2Hz), 1.42 (6H, s),

 Three

 1.88 (3H, s), 2.09 (6H, s), 2.20 (3H, s), 2.39 (3H, s), 2.65 (2H, t, J = 6. OHz), 2.81 (2H, t, J = 6 OHz), 3.27 (2H, s), 3.54 (2H, s), 4.27 (3H, q, J = 7.2Hz), 6.84 (2H, s), 7.23 (1H, d, J = 8.1Hz), 7.39 (1H, s), 7.86 (2H, d, J = 8.1Hz), 10.07 (1H, s).

MS m / z: 579 (M + H) ⁺ .

[0481] [Reference Example 74]

 2- [4-[[[2- (Ν'-Acetylhydrazino) -2-oxoxetyl] (3-ρ-Tolyl- [1,2,4] oxadiazo-l-5ylmethyl) amino] methyl] -2, 6-Dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0482] [Chemical 147]

[0483] Reference Example 17- In the same manner as in (1), the compound (400 mg) obtained in Reference Example 62- (2) and acetohydrazide (70 mg) were also treated with the title compound (370 mg) as a colorless solid. Got as.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s)

 Three

 , 2.07 (3H, s), 2.19 (6H, s), 2.42 (3H, s), 3.52 (2H, s), 3.73 (2H, s), 4.07 (2H, s), 4.27 (2H, q, J = 7.08Hz), 7.01 (2H, s), 7.29 (2H, d, J = 8.18Hz), 7.97 (2H, d, J = 8.18Hz), 8.50 (1H, d, J = 5.13Hz) , 9.57 (1H, d, J = 5.25Hz).

MS m / z: 552 (M + H) ⁺ .

[0484] [Reference Example 75]

 2- [4-[[[2- (Ν'-Acetylhydrazino) -2-oxoxetyl]-(3-m-tolyl- [1, 2, 4] oxadiazo 5-ylmethyl) amino] methyl] — 2, 6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0485] [Chemical 148]

[0486] 参考例 17— (1)と同様にして、参考例 63— (2)で得たィ匕合物 (460mg)とァセトヒ ドラジド（80mg)力も標題ィ匕合物（500mg)を無色固体として得た。

[0486] In the same manner as Reference Example 17- (1), the compound (460mg) obtained in Reference Example 63- (2) and acetohydrazide (80mg) were also treated with the title compound (500mg) as a colorless solid. Got as.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s)

 Three

 , 2.07 (3H, s), 2.20 (6H, s), 2.44 (3H, s), 3.53 (2H, s), 3.74 (2H, s), 4.09 (2H, s), 4.27 (2H, q, J = 7.08Hz), 7.01 (2H, s), 7.35 (2H, m), 7.90 (2H, m), 8.58 (1H, s), 9.58 (1H, d, J = 5.13Hz).

MS m / z: 552 (M + H) ⁺ .

[Example 1]

 (1) 2- [4 -— [[[2- (3 Bromophenol) 5-Methyloxazole- 4-methyl] thiazol-2-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid tert Butinores Estenole

[0488] [Chemical 149]

[0489] The compound of Reference Example 3 (75 mg) and 2 formylthiazole (19 μ1) were dissolved in dichloromethane (l ml), sodium triacetoxyborohydride (62 mg) was added, and the mixture was stirred overnight. The reaction solution was diluted with dichloromethane, washed successively with layered water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane acetate) to give the title compound (64 mg) as a pale yellow oil.

[0490] 'H-NMR (400MHz, CDC1) δ: 1.43 (9Η, s), 1.57 (6Η, s), 2.27 (3H, s

 Three

 ), 3.64 (2H, s), 3.69 (2H, s), 4.06 (2H, s), 6.83 (2H, d, J = 8.6Hz), 7.28-7.31 (4H, m), 7.53 (1H, d, J = 9.1Hz), 7.69 (1H, d, J = 3.4Hz), 7.92 (1H, d, J = 7.8Hz), 8. 14 (1H, s).

MSm / z: 614 (M + H) ⁺ . [0491] (2) 2— [4— [[[2— (3 Promomol) 5-Methyloxazole- 4-methyl] thiazole-2-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid hydrochloride

 [0492] [Chemical 150]

Example 1 The compound (64 mg) of (1) was dissolved in dichloromethane (1.Oml), 4N hydrochloric acid-dioxane solution (2ml) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone monohexane to obtain the title compound (55 mg) as a pale yellow solid.

'H-NMR (400MHz, DMSO-d) δ: 1.50 (6Η, s), 2.32 (3Η, s), 4.10 (

 6

 2H, s), 4.25 (2H, s), 4.53 (2H, s), 6.84 (2H, d, J = 8.8Hz), 7.48—7.53 (3H, m), 7.72—7.74 (1H, m) , 7.84—7.96 (3H, m), 8.08 (1H, s) .MSm / z: 556 (M + H) +.

[0494] [Example 2]

 (1) 2— [4— [[[2— (3-Bromophenoxy) 5-methyloxazole-4-ylmethyl] one (1-methyl-1H-imidazol-2-ylmethyl) amino] methyl] phenoxy] 2— Methyl propionic acid ethyl ester

[0495] [Chemical 151]

[0496] The compound of Reference Example 5 (95 mg) and 1-methyl-2-imidazolecarboxaldehyde (3 2 mg) was dissolved in methylene chloride (2. Oml), sodium triacetoxyborohydride (83 mg) was added, and the mixture was stirred overnight. The reaction solution was diluted with methylene chloride, washed successively with layered water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane acetate) to give the title compound (76 mg) as a pale yellow oil.

 iH—NMR (400MHz, CDC1) δ: 1.25 (3Η, t, J = 7.2Hz), 1.57 (6H, s),

 Three

 2.21 (3H, s), 3.50 (2H, s), 3.53 (3H, s), 3.59 (2H, s), 3.74 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.77 (1H, d, J = l.2Hz), 6.79 (2H, d, J = 7.0Hz), 6.89 (1H, d, J = l.0Hz), 7.19 (12H, d, J = 8.6Hz), 7.30 (1H, t, J = 8.0Hz), 7.53 (1H, d, J = 9.1Hz), 7.91 (1H, d, J = 7.8Hz), 8.14 (1H, s)

MS m / z: 583 (M + H) +.

[0497] (2) 2- [4-[[[2- (3 Bromophenoxy) 5-methyloxazole-4-ylmethyl] one (1-Methyl-1H-imidazole-2-ylmethyl) amino] methyl] phenoxy] 2-Methylpropionic acid

[0498] [Chemical 152]

Example 2— Dissolving the compound of (1) (70 mg) in ethanol (10 ml), adding 1N aqueous sodium hydroxide solution (lml) and 5N aqueous sodium hydroxide solution (0.2 ml), Heated for a whole day and night. The solvent was distilled off under reduced pressure, neutralized with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography and recrystallized from acetone-hexane to give the title compound (29 mg) as a pale yellow solid.

iH—NMR (400MHz, DMSO d) δ: 1.46 (6H, s), 2.25 (3H, s), 3.33 -3.39 (5H, m), 3.43— 3.46 (2H, m), 3.63— 3.66 (2H, m), 6.76— 6. 78 (3H, m), 7.04 (1H, s), 7.19— 7.22 (2H, m), 7.48 (1H, t, J = 8.1Hz), 7.69 (1H, d, J = 7.8Hz), 7.92 (1H, d, J = 7.8Hz), 8.03 (1H, s).

 MSm / z: 555 (M + H) +.

 Elemental analysis value C H BrN O -H O

 27 29 4 4 2

 Calculated values: C, 56.75; H, 5.47; N, 9.80.

 Found: C, 57.01; H, 5.47; N, 9.30.

[0500] [Example 3]

 (1) 2— [4— [[[2— (3-Bromophenol) 5-methyloxazole-4-ylmethyl] one (1-methyl-1H-benzimidazol-2-ylmethyl) amino] methyl] Phenoxy] 2-Methylpropionic acid ethyl ester

[0501] [Chemical 153]

 [0502] In the same manner as in Example 2- (1), the compound of Reference Example 5 (95 mg) and 1-methyl-2-formylbenzimidazole (47 mg) were synthesized to give the title compound (89 mg) as a colorless oil Obtained as material.

 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1 Hz), 1.56 (6H, s),

 Three

 2.17 (3H, s), 3.56 (2H, s), 3.66, (2H, s), 3.73 (3H, s), 3.99 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.79 (2H, d, J = 8.6Hz), 7.20— 7.32 (6H, m), 7.53 (1H, d, J = 6.0Hz), 7.70 (1H, d, J = 5.8Hz), 7.89 (1H, d , J = 8.1 Hz), 8.11 (1H, s).

 MSm / z: 633 (M + H) +.

[0503] (2) 2- [4-[[[2- (3 Bromophenyl) 5-Methyloxazole-4-ylmethyl] one (1-Methyl-1H-Benzimidazole-2-ylmethyl) amino] Methyl] fueno Xyl] 2-methylpropionic acid

 [Chemical 154]

Example 2- In the same manner as in (2), synthesis was performed from the compound of Example 3- (1) (85 mg) to obtain the title compound (26 mg) as a pale yellow solid.

 iH—NMR (400MHz, DMSO d) δ: 1.46 (6H, s), 2.25 (3H, s), 3.33

 6

 -3.39 (5H, m), 3.43— 3.46 (2H, m), 3.63— 3.66 (2H, m), 6.76— 6. 78 (3H, m), 7.04 (1H, s), 7.19— 7.22 (2H, m), 7.48 (1H, t, J = 8.1Hz), 7.69 (1H, d, J = 7.8Hz), 7.92 (1H, d, J = 7.8Hz), 8.03 (1H, s).

 MSm / z: 605 (M + H) +.

 Elemental analysis value C H BrN O 0.75H O

 33 31 4 5 2

 Calculated value: C, 60.34; H, 5.31; N, 9.08.

 Found: C, 60.74; H, 5.31; N, 8.63.

[0506] [Example 4]

 (1) 2- [4 -— [[[2- (3 Bromophenyl) 5-Methyloxazole-4-ylmethyl] pyridine-4-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

 [0507] [Chemical 155]

[0508] 実施例 2— (1)と同様にして、参考例 5の化合物（75mg)とピリジン 4 アルデヒド (22 μ 1)カゝら合成し、標題化合物（69mg)を無色油状物質として得た。

Example 2—Synthesis of the compound of Reference Example 5 (75 mg) and pyridine 4-aldehyde (22 μ 1) in the same manner as (1) to give the title compound (69 mg) as a colorless oil .

 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1 Hz), 1.56 (6H, s),

 Three

 2.22 (3H, s), 3.52 (2H, s), 3.59, (2H, s), 3.59 (2H, s), 3.67 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.81 ( 2H, d, J = 8.6Hz), 7.24- 7.35 (5H, m), 7.53 (1H, d, J = 9.8Hz), 7.91 (1H, d, J = 7.8Hz), 8.14 (1H, s), 8.53 (2H, d, J = 5.9Hz).

 MS m / z: 580 (M + H) +.

 [0509] (2) 2- [4-[[[2- (3 Bromophenyl)] 5-Methyloxazole- 4-methyl] pyridine- 4-methylmethylamino] methyl] phenoxy] 2 methylpropionic acid

 [0510] [Chemical 156]

Example 2- Synthesis in the same manner as (2) from Example 4- (1) compound (67 mg) gave the title compound (51 mg) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.47 (6Η, s), 2.24 (3Η, s), 3.48 (

 6

 2H, s), 3.56 (2H, s), 3.64 (2H, s), 6.79 (2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.1 Hz), 7.40 (2H, d, J = 5.4Hz), 7.49 (1H, t, J = 7.8Hz), 7.70 (1 H, d, J = 9.1Hz), 7.92 (1H, d, J = 7.8Hz), 8.03 (1H, s), 8.49 (2H, d, J = 4.9Hz).

 MSm / z: 550 (M + H) +.

 Elemental analysis value as C H BrNO -0.25H O-O.5EtOH

 28 28 3 4 2

 Calculated values: C, 60.26; H, 5.49; N, 7.27.

 Found: C, 60.32; H, 5.55; N, 6.82.

[0512] [Example 5] (1) 2— [4— [[[2— (3-Bromophenol) 5-Methyloxazol-4-ylmethyl] thiazole 4-methylmethylamino] methyl] phenoxy] 2 Methylpropionic acid tert Butinolesthenole

 [Chemical 157]

[0514] The compound of Reference Example 3 (300 mg) and 4 (chloromethyl) thiazole hydrochloride (129 mg) were dissolved in tetrahydrofuran (5 ml), and then tetrabutylammonium (108 mg) and triethylamine were dissolved. (3 ml) was heated to reflux for 5 days. The reaction solution was diluted with ethyl acetate, washed successively with layered water, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane ethyl acetate) to give the title compound (140 mg) as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.43 (9Η, s), 1.45 (6Η, s), 2.26 (3H, s

 Three

 ), 3.59 (2H, s), 3.64 (2H, s), 3.95 (2H, s), 6.81 (2H, d, J = 8.3Hz), 7

.22-7.35 (4H, m), 7.50—7.55 (1H, m), 7.91—7.95 (1H, m), 8.15 (

1H, s), 8.78 (1H, s).

MSm / z: 614 (M + H) ⁺ .

[0515] (2) 2- [4-[[[2- (3 Bromophenyl) 5-methyloxazole-4-ylmethyl] thiazole 4-methylmethylamino] methyl] phenoxy] 2 methylpropionic acid hydrochloride

[0516] [Chemical 158]

[0517] 実施例 5— (1)の化合物（141mg)をジクロロメタン（3. Oml)に溶解し、 4規定塩酸 —ジォキサン溶液（5ml)を加え、室温にて一昼夜撹拌した。溶媒を減圧留去し、残 渣をシリカゲルカラムクロマトグラフィー（クロ口ホルム一メタノール）にて精製後、 4規 定塩酸—ジォキサン溶液に溶解した。得られた溶液を減圧留去し、アセトン—酢酸 ェチルーへキサンにて再結晶し、標題化合物（83mg)を無色固体として得た。

Example 5— The compound (141 mg) of (1) was dissolved in dichloromethane (3. Oml), 4N hydrochloric acid-dioxane solution (5 ml) was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (black mouth form-methanol) and then dissolved in 4N hydrochloric acid-dioxane solution. The obtained solution was evaporated under reduced pressure and recrystallized from acetone-ethyl acetate-hexane to give the title compound (83 mg) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.53 (6Η, s), 2.34 (3Η, s), 4.19 (

 6

 2H, s), 4.39 (2H, s), 4.49 (2H, s), 6.86 (2H, d, J = 8.3Hz), 7.50—7.57 (3H, m), 7.76 (1H, d, J = 4.7Hz), 7.99 (1H, d, J = 7.8Hz), 8.02 (1H, s), 8.11 (1H, s), 9.26 (1H, s).

 MS m / z: 558 (M + H) +.

[0518] [Example 6]

 (1) 2— [4 — [[[2— (3 Bromophenyl) 5-methyloxazole-4-ylmethyl] mono (2-methylthiazole-4-ylmethyl) amino] methyl] phenoxy] 2-methyl Propionic acid tert butyl ester

[0519] [Chemical 159]

実施例 5— (1)と同様にして、参考例 3の化合物（300mg)と 4 クロロメチル— 2— メチルチアゾール塩酸塩（140mg)カゝら合成し、標題化合物（212mg)を黄色油状物 質として得た。

Example 5—Synthesis of the compound of Reference Example 3 (300 mg) and 4 chloromethyl-2-methylthiazole hydrochloride (140 mg) in the same manner as in (1), and the title compound (212 mg) was synthesized as a yellow oily substance. Got as.

 'H-NMR (400MHz, CDCl) δ: 1.43 (9Η, s), 1.53 (6Η, s), 2.26 (3H, s

 Three

), 2.70 (3H, s), 3.59 (2H, s), 3.64 (2H, s), 3.85 (2H, s), 6.81 (2H, d, J = 8.3Hz), 7.10 (1H, s), 7.24 (2H, d, J = 6.9Hz), 7.30 (1H, t, J = 7.8 Hz), 7.50-7.54 (1H, m), 7.91- 7.95 (1H, m), 8. 15 (1H, s). MSm / z: 628 (M + H) +.

[0521] (2) 2- [4-[[[2- (3 Bromophenyl) 5-Methyloxazole-4-ylmethyl] mono (2-methylthiazole-4-ylmethyl) amino] methyl] phenoxy] 2 —Methylpropionic acid hydrochloride

[0522] [Chemical 160]

Example 5- Synthesis was performed in a similar manner to (2) from the compound (210 mg) of Example 6- (1) to obtain the title compound (148 mg) as a colorless solid.

 ^ H—NMR (400MHz, DMSO d) δ: 1.53 (6H, s), 2.35 (3H, s), 2.69 (

 6

 3H, s), 4.21 (2H, s), 4.39 (4H, bs), 6.87 (2H, d, J = 8.8Hz), 7.50—7.56 (3H, m), 7.77 (2H, d, J = 7.4Hz), 7.99 (1H, d, J = 7.8Hz), 8.11 (1 H, s).

MSm / z: 570 (M + H) ⁺ .

 Elemental analysis value as C H BrN O S'2H O'HCl

 27 28 3 4 2

 Calculated value: C, 50.44; H, 5.17; N, 6.54.

 measured value:. , 50.44; H, 5.28; N, 6.12.

[0524] [Example 7]

 (1) 2— [4— [[[2— (3-Bromophenol) 5-Methyloxazole- 4-methyl]]-(3,5-Dimethylisoxazole-4-ylmethyl) amino] methyl] Phenoxy] -2-methylpropionic acid tert butyl ester

[0525] [Chem 161]

Example 5—Similar to (1), the compound of Reference Example 3 (300 mg) and 4 chloromethyl-3,5-dimethylisoxazole (11 lmg) were synthesized to give the title compound (324 mg ) Was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.44 (9Η, s), 1.54 (6Η, s), 2.17 (3H, s

 Three

), 2.19 (3H, s), 2.36 (3H, s), 3.41 (2H, s), 3.42 (2H, s), 3.46 (2H, s), 6.81 (2H, d, J = 8.5Hz), 7.15 (2H, d, J = 8.5Hz), 6.31 (IH, t, J = 8.1 Hz), 7.53 (1H, d, J = 9.8Hz), 7.91 (IH, d, J = 7.8Hz), 8.13 (1H, s) .MSm / z: 626 (M + H) ⁺ .

 [0527] (2) 2- [4-[[[2- (3 Bromophenyl) 5-Methyloxazole-4-ylmethyl]-(3,5-Dimethylisoxazole-4-ylmethyl) amino] Methyl] phenoxy] -2-methylpropionic acid hydrochloride

 [0528] [Chemical 162]

実施例 1— (2)と同様にして、実施例 7— (1)の化合物（141mg)から合成し、標題 化合物（237mg)を無色固体として得た。

Example 1- Synthesis was performed in the same manner as in (2) from the compound (141 mg) of Example 7- (1) to obtain the title compound (237 mg) as a colorless solid.

 ^ H—NMR (400MHz, DMSO d) δ: 1.52 (6H, s), 2.10 (3H, s), 2.32

 6

-2.43 (4H, m), 4.08—4.26 (4H, m), 4.31—4.48 (2H, m), 6.90 (2H, bs), 7.54 (3H, bs), 7.76 (IH, bs), 7.98 (1H , d, J = 5.4Hz), 8.12 (1H, s MSm / z: 570 (M + H) ⁺ .

 Elemental analysis value as C H BrN O 'HC1

 28 30 3 5

 Calculated values: C, 55.59; H, 5.17; N, 6.95.

 measured value:. , 55.53; H, 5.36; N, 6.52.

[0530] [Example 8]

 (1) 2— [4— [[[2— (3-Bromophenol) 5-Methyloxazole-4-ylmethyl] -methylcarbamoylmethylamino] methylphenoxy] 2-methylpropionic acid t ert butyl ester

[0531] [Chemical 163]

[0532] The compound of Reference Example 6 (lOOmg) was dissolved in dimethylformamide (2 ml), methylamine hydrochloride (20 mg), N-methylmorpholine (30 μ 1), 1 (3 dimethylaminopropyl) 3 -ethyl Carbodiimide hydrochloride (50 mg) and 1-hydroxybenzotriazole (35 mg) were added and stirred overnight. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (black mouth form-methanol) to obtain the title compound (97 mg) as a colorless oily substance.

 [0533] 'H-NMR (400MHz, CDC1) δ: 1.43 (9Η, s), 1.58 (6Η, s), 2.29 (3H, s

 Three

 ), 2.79 (3H, d, J = 4.9Hz), 3.18 (2H, s), 3.51 (2H, s), 3.63 (2H, s), 6.81 (2H, d, J = 8.3Hz), 7 15 (2H, d, J = 8.3Hz), 7.33 (1H, t, J = 7.8Hz), 7.56 (1H, d, J = 7.8Hz), 7.63— 7.69 (1H, m), 7.92 (1H, d, J = 7.8H z), 8.15 (1H, s).

 MSm / z: 588 (M + H) +.

[0534] (2) 2- [4-[[[2- (3 Bromophenol) 5-Methyloxazole- 4-methyl L] -Methylcarbamoylmethylamino] methylphenoxy] 2-methylpropionic acid hydrochloride

 [Chemical 164]

Example 1—Synthesized from the compound (95 mg) of Example 8- (1) in the same manner as (2), and recrystallized from acetone monohexane to give the title compound (87 mg). Obtained as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.53 (6Η, s), 2.43 (3Η, s), 2.59 (3H,

 Three

 d, J = 3.7Hz), 3.82 (2H, s), 4.28—4.39 (4H, m), 6.87 (2H, d, J = 8.6 Hz), 7.51-7.55 (3H, m), 7.76 (1H, d , J = 8.1Hz), 7.97 (1H, d, J = 7.8Hz), 8.11 (1H, s).

MSm / z: 532 (M + H) ⁺ .

 Elemental analysis value as C H BrNO '2HO'HCl

 25 28 3 5 2

 Calculated values: C, 49.80; H, 5.52; N, 6.97.

 measured value:. , 50.31; H, 5.23; N, 6.55.

[0537] [Example 9]

 (1) 2— [4 — [[[2— (3 Bromophenol) 5-Methyloxazole-4-ylmethyl] dimethylcarbamoylmethylamino] methyl] phenoxy] 2-methylpropionic acid tert Butinolesthenole

[0538] [Chemical 165]

Br Example 8— Synthesis was performed in the same manner as in (1) from the compound of Reference Example 6 (lOOmg) to give the title compound (75mg) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.44 (9Η, s), 1.58 (6Η, s), 2.29 (3H, s

 Three

 ), 2.89 (6H, d, J = 5.9Hz), 3.36 (2H, s), 3.66 (2H, s), 3.71 (2H, s), 6.81 (2H, d, J = 6.9Hz), 7.23 (2H, d, J = 8.3Hz), 7.29 (1H, t, J = 7.8Hz), 7.53 (1H, d, J = 7.4Hz), 7.89— 7.94 (1H, m), 8.15 (1H, s) .

MSm / z: 602 (M + H) ⁺ .

 [0540] (2) 2- [4-[[[2- (3 Bromophenyl) 5-methyloxazole-4-methyl] dimethylcarbamoylmethylamino] methyl] phenoxy] 2-methylpropionic acid hydrochloride

 [0541] [Chemical 166]

 In the same manner as in Example 1- (2), synthesis was performed from Example 9- (1) (70 mg) to give the title compound (60 mg) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.54 (6Η, s), 2.46 (3Η, s), 2.82 (3H, s

 Three

 ), 2.88 (3H, s), 4.19-4.39 (6H, m), 6.88 (2H, d, J = 8.6Hz), 7.52—7.60 (3H, m), 7.76 (1H, d, J = 9.1Hz) , 7.98 (1H, d, J = 7.8Hz), 8.10 (1H, s).

 MS m / z: 546 (M + H) +.

[0543] [Example 10]

 (1) 2— [2 aryl 4 [[methyl carbamoylmethyl mono (5-methyl-2-phenoloxal-4-ylmethyl) amino] methyl] phenoxy] -2 methylpropanoic acid t ert butyl ester

[0544] [Chemical 167]

実施例 8— (1)と同様にして、参考例 9で得たィ匕合物と N—メチルァミン塩酸塩（10 Omg)から合成し、標題化合物（120.5mg)を固体として得た。

Example 8—Synthesis of the compound obtained in Reference Example 9 and N-methylamine hydrochloride (10 Omg) in the same manner as (1) to give the title compound (120.5 mg) as a solid.

 'H-NMR (400MHz, CDC1) δ: 1.39 (9Η, s), 1.56 (6Η, s), 2.30 (3H, s

 Three

 ), 2.77 (3H, d, J = 6.6Hz), 3.20 (2H, s), 3.35 (2H, d, J = 6.6Hz), 3.50 (2H, s), 3.61 (2H, s), 4.97— 5.01 (2H, m), 5.85- 6.00 (1H, m), 6.6 5 (1H, d, J = 8.5Hz), 6.98 (1H, dd, J = 2.2, 8.5Hz), 7.07 (1H, d, J = 8.5Hz), 7.40-7.50 (3H, m), 7.72— 7.80 (1H, m), 7.97— 8.03 (2H, m)

[0546] (2) 2— [2 Allyru 4 [[Methylcarbamoylmethyl mono (5-methyl-2-phenolazol- 4-methyl) amino] methyl] phenoxy] -2 Methylpropanoic acid trifluoroacetate

 [0547] [Chemical 168]

 Example 10— Trifluoroacetic acid (lml) was added to a solution of the compound of (1) (125. Omg) in dichloromethane (3ml) and stirred for 4 hours. The solvent was distilled off under reduced pressure to obtain the title compound (12 2. Omg) as an oily substance.

 'H-NMR (400MHz, CDC1) δ: 1.64 (6Η, s), 2.36 (3Η, s), 2.64 (3H, s

 Three

), 3.36 (2H, d, J = 6.6Hz), 3.87 (2H, s), 4.25 (2H, s), 4.36 (2H, s), 5 .00-5.10 (2H, m), 5.87— 5.98 (1H, m), 6.60— 7.05 (3H, m), 7.34 (1H, s), 7.43-7.48 (3H, m), 7.92— 7.98 (2H, m), 8.17-8.27 (1H, m).

 [0549] [Example 11]

 (1) 2- [2 Allyru 4 [[Methylcarbamoylmethyl- [5-Methyl-2- (3 Bromophenyl) oxazole 4-ylmethyl] amino] methyl] phenoxy] 2 Methylpropanoic acid tert butyl ester

[0550] [Chemical 169]

Example 8—Similarly to (1), the title compound (140. Img) was synthesized from the compound obtained in Reference Example 11 and N-methylamine hydrochloride (1 OOmg). Obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 1.39 (9Η, s), 1.56 (6Η, s), 2.30 (3H, s

 Three

 ), 2.77 (3H, d, J = 6.6Hz), 3.20 (2H, s), 3.35 (2H, d, J = 6.6Hz), 3.50 (2H, s), 3.61 (2H, s), 4.95—5.05 (2H, m), 5.85- 6.00 (1H, m), 6.6 5 (1H, d, J = 8.5Hz), 6.98 (1H, dd, J = 2.2, 8.5Hz), 7.07 (1H, d, J = 8.5Hz), 7.30-7.35 (1H, m), 7.50— 7.75 (2H, m), 7.92— 7.98 (1H, m), 8.17-8.27 (2H, m).

[0552] (2) 2- [2 Allyru 4 [[Methylcarbamoylmethyl- [5-Methyl-2- (3 Bromophenyl) oxazole 4-methyl] amino] methyl] phenoxy] 2 Methylpropanoic acid trifluoroacetate

[0553] [Chemical 170]

Example 10- In the same manner as in (2), trifluoroacetic acid (1 ml) was added to a solution of the compound of Example 11 (141. Omg) in dichloromethane (3 ml), and the mixture was stirred for 4 hours. The solvent was distilled off under reduced pressure to obtain the title compound (122. Omg) as an oily substance.

 'H-NMR (400MHz, CDC1) δ: 1.64 (6Η, s), 2.37 (3Η, s), 2.71 (3H, s

 Three

 ), 3.37 (2H, d, J = 6.4Hz), 3.88 (2H, s), 4.29 (2H, s), 4.39 (2H, s), 5.00-5.10 (2H, m), 5.88—5.98 ( 1H, m), 6.62— 7.05 (2H, m), 7.34 (1H, s), 7.43-7.68 (3H, m), 7.92— 7.98 (1H, m), 8.17— 8.27 (2H, m).

 [0555] [Example 12]

 (1) 2— [4— [[[2— (3 Bromophenol) 5-Methyloxazole-4-ylmethyl] oxazole 2-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid tert butyl ester

[0556] [Chemical 171]

実施例 1一（1)と同様にして、参考例 3の化合物（1.3g)とォキサゾールー 2 カル ボアルデヒド（244mg)カゝら合成し、標題ィ匕合物（193mg)を無色油状物質として得 た。

Example 1 In the same manner as in 1 (1), the compound of Reference Example 3 (1.3 g) and oxazole-2-carbaldehyde (244 mg) were synthesized to give the title compound (193 mg) as a colorless oily substance. It was.

'H-NMR (400MHz, CDC1) δ: 1.45 (9Η, s), 1.56 (6Η, s), 2.30 (3H, s ), 3.65 (2H, s), 3.68 (2H, s), 3.88 (2H, s), 6.82 (1H, d, J = 8.6Hz), 6.85 (2H, d, J = 8.6Hz), 7.24 (2H, d, J = 8.3Hz), 7.30 (1H, t, J = 7.9 Hz), 7.53 (1H, d, J = 6.8Hz), 7.64 (1H, s), 7.93 (1H, d, J = 7.8Hz), 8.16 (1H, s).

 MS m / z: 598 (M + H) +.

 [0558] (2) 2- [4-[[[2- (3 Bromophenol) 5-Methyloxazole- 4-methyl] oxazole 2-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid hydrochloride

 [0559] [Chemical 172]

Example 1—Synthesis of the compound of Example 12- (1) (190 mg) in the same manner as in (2) to give the title compound (50 mg) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.52 (6Η, s), 2.36 (3Η, s), 4.07-4.2

 Three

 5 (6H, s), 6.84 (2H, d, J = 8.8Hz), 7.32 (1H, bs), 7.44 (2H, d, J = 9.0 Hz), 7.94 (1H, d, J = 8.1Hz), 8.07 (1H, bs), 8.20 (1H, s).

MS m / z: 542 (M + H) ⁺ .

 Elemental analysis value C H BrNO -0.75H O'HCl

 26 26 3 5 2

 Calculated value: C, 52.90; H, 4.87; N, 7.12.

 measured value:. , 52.91; H, 4.94; N, 6.77.

[Example 15] [Example 13]

 (1) 2- [2,6 Dimethyl-4-[[[(5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy] -2-methylpronoyl ethyl ester

[0562] [Chemical 173]

[0563] The compound of Reference Example 12 (162 mg) and the compound of Reference Example 13- (3) (150 mg) were dissolved in dichloromethan (3 ml), and sodium triacetoxyborohydride (180 mg) was added to the solution at room temperature. Stir overnight. The reaction solution was extracted with ethyl acetate, washed successively with layered water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (307 mg) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.27 (3H, s), 3.63 (2H, s), 3.65 (2H, s), 3.93 (2H, s), 4

.28 (2H, q, J = 6.9Hz), 6.98 (2H, s), 7.08 (1H, s), 7.41—7.43 (3H, m

), 7.64 (1H, s), 8.00-8.02 (2H, m).

 MS m / z: 518 (M + H) +.

[0564] (2) 2- [2, 6-Dimethyl-4-[[[(5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy]-2-methylpropanoic acid

[0565] [Chemical 174]

Example 13— The compound (300 mg) of (1) was dissolved in methanol (2 ml), 2N aqueous sodium hydroxide solution (l ml) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was neutralized with 1N aqueous hydrochloric acid solution. The mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 9: 1). Obtained The title compound was dissolved in dichloromethane, 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and hexane to give the hydrochloride of the title compound ( 201 mg) was obtained as a colorless solid.

[0567] 'H-NMR (400MHz, DMSO— d) δ: 1.33 (6H, s), 2.14 (6H, s), 2.32 (

 6

 3H, s), 4.11-4.35 (6H, m), 7.14 (2H, s), 7.30 (1H, s), 7.51—7.55 (3H, m), 7.93-7.95 (2H, m), 8.19 ( 1H, s).

 MS m / z: 490 (M + H) +.

 Elemental analysis value as C H NO 'HC1

 28 31 3 5

 Calculated value: C, 63.93; H, 6.13; N, 7.99.

 measured value:. 63.63; H, 6.42; N, 7.58.

[0568] [Example 14]

 (1) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2phenoloxylmethyl) amino] methyl] phenoxy] 2 Methylpropenoic acid Ethenole Estenole

[0569] [Chemical 175]

[0570] Reference Example 14 The compound of (3) (3. Og) was dissolved in N, N dimethylformamide (10 ml) and methylamine (2M tetrahydrofuran solution, 4.5 ml), 1 (3 dimethylaminopropyl)- 3 Ethylcarbodiimide hydrochloride (2.27 g) and 1-hydroxybenzotriazole (1.82 g) were added, and the mixture was stirred at room temperature for 13 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in ethyl acetate and washed with water, 10% aqueous citrate solution, water, saturated multistory water, and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate) to give the title compound (2.59 g) as a yellow oil. [0571] NMR-NMR (400MHz, CDC1) δ: 1.35 (3H, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.25 (3H, s), 2.80 (3H, d, J = 4.9 Hz), 3.22 (2H, s), 3.4

9 (2H, s), 3.60 (2H, s), 4.28 (2H, q, J = 7.2 Hz), 6.89 (2H, s), 7.43— 7

.47 (3H, m), 7.80 (1H, s), 7.99—8.01 (2H, m).

 MS m / z: 508 (M + H) +.

[0572] (2) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-phenolazole 4-methyl) amino] methyl] phenoxy] 2 Methylpropanoic acid

[0573] [Chemical 176]

Example 14— Compound (2.59 g) of (1) was dissolved in methanol (2. Oml), and 1N aqueous sodium hydroxide solution (5ml) and 5N aqueous sodium hydroxide solution (2ml) were added. After stirring, the mixture was stirred at room temperature for 13 hours. The reaction was concentrated under reduced pressure, and the residue was neutralized with 1N aqueous hydrochloric acid. This was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 7: 1) and recrystallized from a mixed solution of ethyl acetate and hexane to obtain the title compound (1.85 g) as a colorless solid.

 [0575] iH—NMR (400MHz, DMSO d) δ: 1.31 (6H, s), 2. 12 (6H, s), 2. 22 (

 6

 3H, s), 2.60 (3H, d, J = 4.6Hz), 3.09 (2H, s), 3.50 (2H, s), 3.56 (2H, s), 6.99 (2H, s), 7.48-7. 53 (3H, m), 7. 74-7. 78 (1H, m), 7. 91—7.93 (2H, m).

 MS m / z: 480 (M + H) +.

 Elemental analysis value as C H NO

 27 33 3 5

 Calculated values: C, 67.62; H, 6. 94; N, 8. 76.

Measurements: C, 67. 57; H, 7.09; N, 8. 56. [0576] [Example 15]

 (1) 2- [4 [[Dimethylcarbamoylmethyl- (5-methyl-2-phenoloxazol 4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpronoyl ester

[0577] [Chemical 177]

In the same manner as in Example 14 (1), the title compound (1.80 g) was pale yellow from the compound of Reference Example 14 (3) (2.37 g) and dimethylamine (40% aqueous solution, 0.76 ml). Obtained as an oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.26 (3H, s), 2.89 (6H, s), 3.39 (2H, s), 3.66 (4H, s), 4

.29 (2H, q, J = 7.1Hz), 6.97 (2H, s), 7.40— 7.46 (3H, m), 7.98— 8.0

1 (2H, m).

MS m / z: 522 (M + H) ⁺ .

[0579] (2) 2- [4 [[Dimethylcarbamoylmethyl- (5-methyl-2-phenoloxal-l-ylmethyl) amino] methyl] -2,6 Dimethylphenoxy] -2-methylpropanoic acid

[0580] [Chemical 178]

実施例 13— (2)と同様にして、実施例 15— (1)の化合物（1.8g)を処理後、ジクロ ロメタン 酢酸ェチルーへキサンの混合溶媒より再結晶することにより標題ィ匕合物の 塩酸塩（1.3g)を無色固体として得た。

In the same manner as in Example 13- (2), the compound of Example 15- (1) (1.8 g) was treated and then recrystallized from a mixed solvent of dichloromethane, ethyl acetate and hexane to give the title compound. The hydrochloride (1.3 g) was obtained as a colorless solid.

'H-NMR (400MHz, DMSO-d) δ: 1.36 (6Η, s), 2.18 (6Η, s), 2.42 ( 3H, s), 2.84 (3H, s), 2.89 (3H, s), 4.11—4.40 (6H, m), 7.31 (2H, s), 7.54-7.59 (3H, m), 7.97—7.99 (2H, m).

 MS m / z: 494 (M + H) +.

 Elemental analysis value C H N O · Η O-HCl-0.2CH CI

 28 35 3 5 2 2 2

 Calculated values: C, 59.94; H, 6.85; CI, 8.78; N, 7.44.

 measured value:. , 60.15; H, 6.74; CI, 9.12; N, 7.36.

[0582] [Example 16]

 (1) 2- [2, 6 Dimethyl-4-[[[(5-Methyl-2-phenoloxazole-4-ylmethyl) thiazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropenoic acid Ethenole

[0583] [Chemical 179]

[0584] In the same manner as in Example 13- (1), the compound of Reference Example 12 (264 mg) and the compound of Reference Example 15

 (285 mg) The title compound (499 mg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.20 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.22 (6H, s), 2.28 (3H, s), 3.63 (2H, s), 3.65 (2H, s), 4.10 (2H, s), 4.24 (2H, q, J = 7.1Hz) , 7.05 (2H, s), 7.28 (1H, d, J = 3.4Hz), 7.35—7.45 (3H, m), 7.70 (1H, d, J = 3.4Hz), 7.96—8.00 (2H, m ).

 [0585] (2) 2- [2,6 Dimethyl-4-[[[(5-Methyl-2-phenoloxazole-4-ylmethyl) thiazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid

 [0586] [Chemical 180]

[0587] 実施例 16— (1)の化合物（499mg)をテトラヒドロフラン (4ml)に溶解し、メタノール (2ml)と 1規定水酸ィ匕ナトリウム水溶液 (2ml)を加えた後、室温にて 1時間攪拌した。 1規定塩酸水溶液にて中和後、酢酸ェチルにて抽出し、無水硫酸ナトリウムにて乾 燥した。減圧下溶媒を留去することにより標題化合物 (452mg)を淡黄色固体として 得た。

Example 16— Dissolving the compound of (1) (499 mg) in tetrahydrofuran (4 ml), adding methanol (2 ml) and 1N aqueous sodium hydroxide solution (2 ml), and then at room temperature for 1 hour Stir. The mixture was neutralized with 1N aqueous hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (452 mg) as a pale yellow solid.

 NMR (400MH, CDC1) δ: 1.50 (6Η, s), 2.22 (6H, s), 2.28 (3H, s)

 Three

 , 3.63 (2H, s), 3.65-3.68 (3H, br s), 4.10 (2H, s), 7.05 (2H, s), 7.

28 (1H, d, J = 3.4Hz), 7.40—7.45 (3H, m), 7.78 (1H, d, J = 3.4Hz), 7

.98-8.02 (2H, m).

[0588] [Example 17]

 (1) 2- [2,6 Dimethyl-4-[[((5-Methyl-2-phenoloxazole-4-ylmethyl) -one (5--oxo-4,5-dihydro-1, [1, 3, 4] oxaziazo-one-ru 2-ylme Til) amino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[0589] [Chemical 181]

[0590] The compound of Reference Example 16- (2) (200 mg) was dissolved in dioxane (5 ml), triphosgene (234 mg) was added, and the mixture was stirred at room temperature. Further, triphosgene (234 mg) was added and stirred at 60 ° C for 4 hours, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (176 mg) as a colorless oil. It was.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.57 (6H, s),

 Three

2.18 (6H, s), 2.28 (3H, s), 3.65 (2H, s), 3.67 (2H, s), 3.73 (2H, s), 4.28 (2H, q, J = 7.1Hz) , 6.97 (2H, s), 7.40- 7.46 (3H, m), 7.99- 8.0 1 (2H, m), 8.54 (1H, s). MS m / z: 535 (M + H) +.

[0591] (2) 2- [2, 6 Dimethyl-4-[[((5-Methyl-2phenoloxazole-4-ylmethyl)] (5-oxo-4,5-dihydro- [1,3,4] oxaziazolo-2ilmethyl ) Amino] methyl] phenoxy] -2-methylpropanoic acid

[0592] [Chemical 182]

Example 14- In the same manner as in (2), the title compound (lOOmg) was obtained as a colorless solid from the compound (170 mg) of Example 17- (1).

 ^ H—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2.12 (6H, s), 2.26 (

 6

 3H, s), 3.57 (2H, s), 3.59 (2H, s), 3.62 (2H, s), 6.95 (2H, s), 7.46— 7.53 (3H, m), 7.90— 7.92 (2H, m) .

 MS m / z: 505 (M-H) ".

[0594] [Example 18]

 (1) 2— [2,6 Dimethyl—4 -— [[(5-Methyl- [1, 3, 4] oxadiazole—2-ylmethyl)-(5-Methyl-2 pheoloxazole-4-ylmethyl) amino ] Methyl] phenoxy] —2-methylpropanoic acid ethyl ester

[0595] [Chemical 183]

トリフエ-ルホスフィン（675mg)をジクロロメタン（15ml)に溶解し、氷水冷却攪拌 下にへキサクロロェタン（510mg)とトリエチルァミン（716mg)を加えた。更に参考例 17の化合物（0.5g)のジクロロメタン（5ml)溶液をカ卩えて、室温で 13時間攪拌した。 飽和重曹水を加えて 1時間攪拌後、ジクロロメタンで 3回抽出した。飽和食塩水で洗 浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトフ ラフィ一で精製 (酢酸ェチル：へキサン = 2： 1)することにより標題ィ匕合物（577mg)を 淡黄色油状物として得た。

Triphenylphosphine (675 mg) was dissolved in dichloromethane (15 ml), and hexachloroethane (510 mg) and triethylamine (716 mg) were added with ice water cooling and stirring. Further, a dichloromethane (5 ml) solution of the compound of Reference Example 17 (0.5 g) was collected and stirred at room temperature for 13 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was stirred for 1 hour, and extracted with dichloromethane three times. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound (577 mg) as a pale yellow oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2. 18 (6H, s), 2.27 (3H, s), 2.51 (3H, s), 3.67 (4H, br s), 3.99 (2H, s

), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.40— 7.45 (3H, m), 8.00—

8.02 (2H, m).

 MS m / z: 533 (M + H) +.

[0597] (2) 2- [2, 6 Dimethyl 4-[[[(5-Methyl- [1, 3, 4] oxaziazol 2-ylmethyl)-(5-Methyl-2 pheoloxazole- 4-ylmethyl) amino] [Methyl] phenoxy] 2-methylpropanoic acid

[0598] [Chemical 184]

Example 13- In the same manner as in (2), hydrochloride (315 mg) of the title compound was obtained as a colorless solid from the compound (0.57 g) of Example 18- (1).

 ^ H—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2.13 (6H, s), 2.29 (

 6

 3H, s), 2.46 (3H, s), 3.66-4.26 (6H, m), 7.05 (2H, s), 7.50- 7.52 (3H, m), 7.91- 7.93 (2H, m).

 MS m / z: 505 (M + H) +.

[0600] [Example 19]

 (1) 2- [4 [[Strengthened rubermoylmethyl- (5-methyl-2-phenoloxazole- 4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropenoic acid ester

[0601] [Chemical 185]

[0602] In the same manner as Reference Example 16- (1), the compound of Reference Example 14-1 (3) (400 mg) and salt ammonium (55 mg) title compound containing slightly impurities ( 528 mg) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.25 (3H, s), 3.24 (2H, s), 3.54 (2H, s), 3.60 (2H, s), 4

.28 (2H, q, J = 7.1Hz), 6.91 (2H, s), 7.44—7.45 (3H, m), 7.98—8.0

2 (2H, m).

 MS m / z: 494 (M + H) +.

[0603] (2) 2- [2, 6 Dimethyl 4-[[[(3-Methyl- [1, 2, 4] oxadiazolu 5-ylmethyl)-(5-Methyl-2 pheluoxazole 4-ylmethyl) amino] Methyl] -phenoxy] -2-methylpropanoic acid ethyl ester

[0604] [Chemical 186]

Example 19— N, N-dimethylacetamide dimethylacetal (5 ml) was added to the compound (528 mg) of (1) and heated at 120 ° C. for 2 hours. The solvent was evaporated under reduced pressure, 50% aqueous hydroxylamine solution (70 ml) and 70% aqueous acetic acid solution (6 ml) were added to the residue, and the mixture was stirred at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (379 mg) as a colorless oil. NMR-NMR (400MHz, CDCl) δ: 1.35 (3H, t, J = 7.1 Hz)

 Three

 1.45 (6H, s), 2.18 (6H, s), 2.27 (3H, s), 2.41 (3H, s), 3.67 (2H, s), 3

.70 (2H, s), 4.04 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 7.00 (2H, s), 7.40

-7.46 (3H, m), 7.99— 8.01 (2H, m).

 MS m / z: 533 (M + H) +.

[0606] (3) 2- [2, 6 Dimethyl 4-[[[(3-Methyl- [1, 2, 4] oxadiazoru 5-ylmethyl)-(5-Methyl-2 pheoloxazole- 4-ylmethyl) amino] Methyl] phenoxy] 2-methylpropanoic acid

[0607] [Chemical 187]

Example 13- In the same manner as in (2), hydrochloride (273 mg) of the title compound was obtained as a colorless solid from the compound (375 mg) of Example 19- (2).

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.13 (6Η, s), 2.27 (

 6

 3H, s), 2.31 (3H, s), 3.81 (4H, br s), 4. 15 (2H, br s), 7.01 (2H, s), 7.49-7.53 (3H, m), 7.90— 7.92 (2H, m).

 MS m / z: 505 (M + H) +.

 Elemental analysis value as C H C1NO -1.4HO-HC1

 28 33 4 5 2

 Calculated values: C, 61.65; H, 6.19; N, 10.27.

 measured value:. 62.02; H, 6.53; N, 9.87.

[Example 20]

 (l) 2- [4-[[(5-Methyl-2-phenoloxol-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy] hexanoic acid ethyl ester

[0610] [Chemical 188]

[0611] In the same manner as in Example 13- (1), the compound of Reference Example 13- (3) (50 mg) and the compound of Reference Example 18 (54 mg) were combined with the title compound (96 mg). Obtained as a colorless oil.

 iH—NMR (400MHz, CDCl) δ: 0.92 (3Η, t, J = 7.2Hz), 1.24 (3H, t, J

 Three

 = 7. 1Hz), 1.35-1.42 (4H, m), 1.90—1.97 (2H, m), 2.31 (3H, s), 3.66 (2H, s), 3.69 (2H, s), 3.87 (2H , s), 4.20 (2H, q, J = 7.1Hz), 4.54 —4.58 (1H, m), 6.83 (2H, d, J = 8.5Hz), 7.08 (1H, d, J = 0.7Hz), 7.3 1 (2H, d, J = 8.8Hz), 7.41- 7.43 (3H, m), 7.63 (1H, d, J = 0.7Hz), 7. 99-8.01 (2H, m).

 MS m / z: 518 (M + H) +.

 [0612] (2) 2— [4— [[(5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy] hexanoic acid

 [0613] [Chemical 189]

実施例 13— (2)と同様にして、実施例 20— (1)の化合物（95mg)から標題ィ匕合物 の塩酸塩（51mg)を無色固体として得た。

Example 13- In the same manner as in (2), hydrochloride (51 mg) of the title compound was obtained as a colorless solid from the compound (95 mg) of Example 20- (1).

 'H-NMR (400MHz, CDCl) δ: 0.87 (3Η, t, J = 7.1 Hz), 1.14—1.45 (4

 Three

H, m), 1.74-1.93 (3H, m), 2.34 (3H, s), 4.03—4.23 (6H, m), 4.67 —4.70 (1H, m), 6.90 (2H, d, J = 8.3Hz) , 7.30 (1H, s), 7.43 (2H, brs), 7.51-7.54 (3H, m), 7.93-7.95 (2H, m), 8.18 (1H, s). MSm / z: 488 (MH) —.

[0615] [Example 21]

 (1) 2- [2,6 Dimethyl-4 [[[2- (5-Methyl-2-phenoloxazole-4-yl) ethyl] thiazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropionate Ethenole Estenole

[0616] [Chemical 190]

[0617] Compound of Reference Example 19 (200 mg) and 2 formylthiazole (0.06 ml) in dichloromethane

 (5 ml), sodium triacetoxyborohydride (188 mg) was added, and the mixture was stirred at room temperature for 23 hours. After dilution with ethyl acetate, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (223 mg) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.1 Hz), 1.43 (6H, s),

 Three

 2.15 (6H, s), 2.24 (3H, s), 2.70 (2H, t, J = 7.4Hz), 2.86 (2H, t, J = 7.

2Hz), 3.64 (2H, s), 3.98 (2H, s), 4.27 (2H, q, J = 7.1Hz), 6.97 (2H, s

), 7.22 (1H, d, J = 3.4Hz), 7.38- 7.44 (3H, m), 7.66 (1H, d, J = 3.2H z), 7.93-7.95 (2H, m).

 MSm / z: 548 (M + H) +.

[0618] (2) 2- [2, 6 Dimethyl-4-[[[[2- (5-Methyl-2-phenoloxazo

 1ru 4 yl) ethyl] thiazole 2-ylmethylamino] methyl] phenoxy]-

2-Methylpropionic acid

[0619] [Chemical 191]

Example 13- In the same manner as in (2), hydrochloride (167 mg) of the title compound was obtained as a colorless solid from the compound (220 mg) of Example 21- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.35 (6Η, s), 2.15 (6Η, s), 2.34 (

 6

 3H, s), 3.06 (2H, t, J = 7.6Hz), 3.34 (2H, t, J = 7.8Hz), 4.41 (2H, s), 4.82 (2H, s), 7.28 (2H, s), 7.50— 7.54 (3H, m), 7.88— 7.90 (2H, m), 7.94 (1H, d, J = 3.4Hz), 8.02 (1H, d, J = 3.2Hz).

MSm / z: 520 (M + H) ⁺ .

 Elemental analysis value C H C1N O S'2HC1

 29 34 3 4

 Calculated value: C, 58.78; H, 5.95; N, 7.09.

 measured value:. 58.75; H, 5.99; N, 7.01.

[0621] [Example 22]

 (1) 2- [4 [[Benzoxazole-2-ylmethyl- (methyl-2-phenol-azol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionate ethinole Estenole

[0622] [Chemical 192]

[0623] The compound of Reference Example 20 (200 mg) and 2 chloromethylbenzoxazole (77 mg) were mixed with N It was dissolved in N dimethylformamide (5 ml), cesium carbonate (300 mg) was added, and the mixture was stirred at 70 ° C. for 20 hours. After dilution with ethyl acetate, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (lOOmg) as a pale yellow oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.43 (6H, s),

 Three

 2.17 (6H, s), 2.26 (3H, s), 3.74 (2H, s), 3.76 (2H, s), 4.11 (2H, s), 4.28 (2H, q, J = 7.2Hz), 7.02 (2H, s), 7.31-7.33 (2H, m), 7.40-7.43 (3H, m), 7.52-7.54 (1H, m), 7.70-7.73 (1H, m), 7.98-8.00 (2H, m).

 MS m / z: 568 (M + H) +.

[0624] (2) 2- [4 [[Benzoxazol-2-ylmethyl- (methyl-2phenol--4-methyl) amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid

[0625] [Chemical 193]

 Example 13- In the same manner as in (2), the hydrochloride (49 mg) of the title compound was obtained as a colorless solid from the compound (lOOmg) of Example 22- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.13 (6Η, s), 2.33 (

 6

 3H, s), 4.02-4.46 (6H, m), 7.15 (2H, s), 7.38— 7.45 (2H, m), 7.51 -7.53 (3H, m), 7.73— 7.79 (2H, m), 7.87— 8.00 (2H, m).

MSm / z: 520 (M + H) ⁺ .

 Elemental analysis value C H C1NO 3 / 4Η O'HCl

 32 34 3 5 2

 Calculated value: C, 65.19; H, 6.07; N, 7.13.

Measurements: C, 65.31; H, 6.11; N, 7.00. [0627] [Example 23]

 (1) 2— [4 [[Bis- (5 Methyl 2 phenoxazole 4 ylmethyl) amino] methyl] -2, 6 Dimethylphenoxy] —2-Methylpropionate Ethyl ester

 [0628] [Chemical 194]

[0629] Reference Example 21— (2) Compound (50 mg) and 5 Methyl 2-phenoloxal 4 Carbaldehyde (75 mg) were dissolved in dichloromethane (2 ml), and sodium triacetoxyborohydride (120 mg) was added at room temperature. For 17 hours. After dilution with ethyl acetate, the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (105 mg) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.44 (6H, s),

 Three

 2.17 (6H, s), 2.29 (6H, s), 3.61 (2H, s), 3.68 (4H, s), 4.28 (2H, q, J = 7.1 Hz), 7.00 (2H, s), 7.40— 7.45 (6H, m), 8.00— 8.02 (4H, m). MSm / z: 608 (M + H) +.

 [0630] (2) 2— [4 [[Bis- (5 Methyl 2 phe-loxazol 4 ylmethyl) amino] methyl] 2,6 dimethylphenoxy] 2 Methylpropionic acid

[0631] [Chemical 195]

[0632] In the same manner as in Example 13- (2), hydrochloride (57 mg) of the title compound was obtained as a colorless solid from the compound (lOOmg) of Example 23- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.34 (6Η, s), 2.15 (6Η, s), 2.38 (

 6

 6H, s), 4.32-4.51 (6H, m), 7.29 (2H, s), 7.53—7.57 (6H, m), 7.96 -7.98 (4H, m).

 Elemental analysis value C H C1NO 5 / 4Η O'HCl

 35 38 3 5 2

 Calculated value: C, 65.82; H, 6.39; N, 6.58.

 measured value:. , 65.94; H, 6.44; N, 6.32.

 [0633] [Example 24]

 (1) 2- [2,6-Dimethyl-4-[[[(4-Methyloxazole-2-ylmethyl) (5-Methyl-2-phenol-lazole) -4-ylmethyl) amino] methyl] phenoxy] — 2-Methylpropanoic acid ethyl ester

 [0634] [Chemical 196]

[0635] Triphenylphosphine (0.341 g), hexachloroethane (0.2 ml) in dichloromethane (10 ml) 60 g) and triethylamine (0.361 ml) were added and stirred for 15 minutes under cooling with ice water, then the compound (0.242 g) obtained in Reference Example 22- (2) was added and the mixture was warmed to room temperature overnight. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and then saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (0.085 g) as pale yellow Obtained as an oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2.16 (3H, s), 2.17 (6H, s), 2.26 (3H, s), 3.62 (2H, s), 3.63 (2H, s), 3

.88 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.99 (2H, s), 7.34 (1H, s), 7.40

-7.44 (3H, m), 8.02—7.99 (2H, m).

MSm / z: 532 (M + H) ⁺ .

[0636] (2) 2- [2, 6-Dimethyl-4-[[[(4-Methyloxazole-2-ylmethyl) (5-Methyl-2-phenol-xazole-4-ylmethyl) amino] methyl] Phenoxy] — 2-Methylpropanoic acid

[0637] [Chemical 197]

Example 24— The compound (0.080 g) obtained in (1) was dissolved in methanol (5 ml), 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled, neutralized with 1N aqueous hydrochloric acid, and concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to obtain the title compound. This was dissolved in 4N hydrochloric acid-dioxane (lml) and dried under reduced pressure to give the hydrochloride of the title compound (0.060g) as a colorless solid.

^ H—NMR (400MHz, DMSO—d) δ: 1.35 (6H, s), 2.09 (3H, s), 2.16 ( 6H, s), 2.33 (3H, s), 3.54-3.60 (4H, m), 4.07-4.32 (3H, m), 7.14 (2H, s), 7.52-7.55 (3H, m), 7.86 ( 1H, s), 7.96—7.92 (2H, m).

MSm / z: 504 (M + H) ⁺ .

 Elemental analysis value as C H NO 'HCl'2HO

 29 33 3 5 2

 Calculated values: C, 60.46; H, 6.65; N, 7.29.

 Analytical values: C, 60.94; H, 6.82; N, 6.76.

[0639] [Example 25]

 (1) 2— [2, 6 Dimethyl 4 [[oxazole 2-methyl] (5-phenol [1, 3, 4] oxadiazol 2-methyl) amino] methyl] phenoxy] 2 methyl pronoyl ester

[0640] [Chemical 198]

[0641] In the same manner as in Example 24- (1), the title compound (0.090g) was obtained as a yellow oil by treating the compound (0.115g) obtained in Reference Example 24- (2). Obtained.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 6.6Hz), 1.45 (6H, s),

 Three

 2.18 (6H, s), 3.75 (2H, s), 4.02 (2H, s), 4.11 (2H, d, J = 4.4Hz), 4.2 8 (2H, q, J = 7.2Hz), 7.00 ( 2H, s), 7.08 (1H, d, J = l.0Hz), 7.49- 7.5 5 (3H, m), 7.64 (1H, d, J = l.0Hz), 8.07- 8.05 (2H, m).

 MSm / z: 505 (M + H) +.

 [0642] (2) 2— [2, 6 Dimethyl-4 [[Oxazol 2-ylmethyl- (5-phenol [1, 3, 4] Oxadiazol 2-ylmethyl) amino] methyl] phenoxy] 2 Methylpropanoic acid

[0643] [Chemical 199]

Example 24-—In the same manner as in (2), the compound (0.090 g) obtained in Example 25- (1) and the hydrochloride of the title compound (0.050 g) were obtained as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.30 (6Η, s), 2.11 (6Η, s), 3.71 (

 6

 2H, s), 3.98 (2H, s), 4.08 (2H, s), 6.96 (2H, s), 7.17 (1H, d, J = 0.7H z), 7.65-7.59 (3H, m), 7.96— 7.98 (2H, m), 8.08 (1H, d, J = l.0Hz)

MSm / z: 477 (M + H) ⁺ .

 Elemental analysis value as C H NO '1Z4HC1'3Z4H O

 26 28 4 5 2

 Calculated value: C, 62.56; H, 6.01; N, 11.22.

 Analytical values: C, 62.98; H, 5.87; N, 10.79.

[0645] [Example 26]

 (1) 2- [2, 6 Dimethyl-4 [[Oxazol-Lu 2-ylmethyl- (5-phenolox-2-ylmethyl) amino] methyl] phenoxy] -2-Methylpropanoic acid ester

 [0646] [Chemical 200]

実施例 24— (1)と同様にして、参考例 25で得たィ匕合物 (0.12g)を処理することに より標題化合物 (0.06g)を黄色油状物として得た。

Example 24—The title compound (0.06 g) was obtained as a yellow oil by treating the compound (0.12 g) obtained in Reference Example 25 in the same manner as (1).

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

18 (6H, s), 3.72 (2H, s), 3.98 (2H, s), 4.00 (2H, s), 4.28 (2H, q, J = 7.1Hz), 7.02 (2H, s), 7.09 (IH, s), 7.28 (IH, s), 7.34 (1H, d, J = 7.3

Hz), 7.44-7.40 (2H, m), 7.63—7.65 (3H, m).

MSm / z: 504 (M + H) ⁺ .

[0648] (2) 2 -— [2, 6 Dimethyl-4 [[Oxazol 2-ylmethyl- (5-phenolox-2-ylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid

[0649] [Chemical 201]

Example 24—In the same manner as (2), hydrochloride (0.04 g) of the title compound was obtained as a pale yellow solid from the compound (0.06 g) obtained in Example 26 (1). .

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.12 (6Η, s), 3.67 (

 6

 2Η, s), 3.92 (2Η, s), 3.95 (2H, s), 6.96 (2H, s), 7.18 (1H, s), 7.35— 7.39 (1H, m), 7.48 (2H, t, J = 7.6Hz), 7.60 (1H, s), 7.70— 7.68 (2H, m), 8.08 (IH, d, J = 0.7Hz).

MSm / z: 476 (M + H) ⁺ .

 Elemental analysis value as C H NO '3Z4HC1

 27 29 3 5

 Calculated values: C, 64.49; H, 5.96; N, 8.36.

 Analytical values: C, 64.33; H, 6.13; N, 7.94.

[0651] [Example 27]

 (1) 2— [2, 6 Dimethyl 4 [[Oxazol 2-ylmethyl (5 Thiophene 2-yl- [1, 3, 4] oxadiazole— 2-ylmethyl) amino] methyl] phenoxy] — 2-Methylpropane Acid ethyl ester

[0652] [Chem 202]

Example 24— By treating the compound (0.12 g) obtained in Reference Example 26 in the same manner as in (1), the title compound (0.09 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.18 (6H, s), 3.74 (2H, s), 4.00 (2H, s), 4.08 (2H, s), 4.28 (2H, q, J = 7.2Hz), 7.00 (2H, s), 7.09 (IH, s), 7.18 (1H, dd, J = 4.9, 3.9Hz), 7.56 (1H, dd, J = 5.1, 1.2Hz), 7.64 (1H, s), 7.76 (IH, dd, J = 3.8, 1.1 Hz).

 MS m / z: 511 (M + H) +.

[0654] (2) 2— [2, 6 Dimethyl-4 [[Oxazolru 2-ylmethyl- (5 Thiophene

2-yl- [1, 3, 4] oxadiazole-2-ylmethyl) amino] methyl] phenoxy] —

2-Methylpropanoic acid

[0655] [Chemical 203]

実施例 24— (2)と同様にして、実施例 27— (1)で得たィ匕合物 (0.09g)から標題 化合物の塩酸塩 (0.06g)を無色固体として得た。

Example 24- In the same manner as in (2), the hydrochloride (0.06 g) of the title compound was obtained as a colorless solid from the compound (0.09 g) obtained in Example 27- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.12 (6Η, s), 3.69 (

 6

2Η, s), 3.96 (2H, s), 4.05 (2H, s), 6.95 (2H, s), 7.17 (1H, d, J = 0.7H z), 7.30 (1H, dd, J = 4.9, 3.7 Hz), 7.78 (IH, dd, J = 3.7, 1.2Hz), 7.95 (1H, dd, J = 5.1, 1.2Hz), 8.07 (1H, d, J = 0.7Hz).

 MS m / z: 483 (M + H) +.

 Elemental analysis value C H N O S'1 / 2HC1'1 / 5CH O

 24 26 4 5 4 8 2

 Calculated values: C, 57.46; H, 5.46; N, 10.81; S, 6.19.

 Analytical values: C, 57.45; H, 5.26; N, 10.44; S, 6.11.

 [0657] [Example 28]

 (1) 2— [2, 6 Dimethyl 4 [[Oxazol 2-ylmethyl (3 Thiophene 2-yl- [1, 2, 4] Oxadiazol-5-ylmethyl) amino] methyl] phenoxy] — 2-Methylpropane Acid ethyl ester

[0658] [Chemical 204]

[0659] Reference Example 27— The compound obtained in (2) was dissolved in tetrahydrofuran (5 ml), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.034 ml) was added and stirred at room temperature for 3 days. did. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give the title compound (0.14 g) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2. 19 (6H, s), 3.76 (2H, s), 4.04 (2H, s), 4.11 (2H, s), 4.28 (2H, q, J = 7.2Hz), 7.00 (2H, s), 7.09 (1H, d, J = 0.7Hz), 7.17- 7.15 (1H, m), 7.51 (1H, dd, J = 5.0, 1.1 Hz), 7.64 (1H, d, J = 0.7Hz), 7.82 (1H , dd, J = 3.8, 1.1 Hz).

MS m / z: 511 (M + H) +. [0660] (2) 2— [2, 6 Dimethyl-4 [[Oxazol 2-ylmethyl (3 thiophene 2-yl- [1, 2, 4] oxadiazole-5-ylmethyl) amino] methyl] phenoxy ] — 2-Methylpropanoic acid

 [0661] [Chemical 205]

Example 24-—In the same manner as (2), the title compound (0.091 g) was obtained as a pale yellow solid from the compound (0.14 g) obtained in Example 28- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.13 (6Η, s), 3.72 (

 6

 2H, s), 3.97 (2H, s), 4.14 (2H, s), 6.96 (2H, s), 7.17 (1H, s), 7.27 (1 H, dd, J = 4.9, 3.7Hz), 7.79 ( 1H, dd, J = 3.7, 1.2Hz), 7.88 (1H, dd, J = 4.9, 1.2Hz), 8.07 (1H, d, J = 0.7Hz).

 MS m / z: 483 (M + H) +.

 Elemental analysis value C H NO S

 24 26 4 5

 Calculated values: C, 59.74; H, 5.43; N, 11.61.

 Analytical values: C, 60.31; H, 5.79; N, 11.08.

[0663] [Example 29]

 (1) 2- [2 Fluoro-6-methoxy-4-] [[(5-Methyl-2 pheluoxazole —4-ylmethyl) oxazole 2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

[0664] [Chemical 206]

Example 13— In the same manner as in (1), the title compound was obtained from the compound (0. llg) obtained in Reference Example 28 and the compound (0. lOg) obtained in Reference Example 13- (3). The compound (0.14 g) was obtained as a colorless oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.32 (3Η, t, J = 7.2Hz), 1.49 (6H, s),

 Three

 2.31 (3H, s), 3.68 (2H, s), 3.70 (2H, s), 3.78 (3H, s), 3.91 (2H, s), 4.25 (2H, q, J = 7.1Hz), 6.76 (1H, d, J = 9.8Hz), 7.09 (1H, s), 7.23 (1 H, s), 7.40-7.44 (3H, m), 7.64 (1H, s), 7.98— 8.02 (2H, m) .

 MS m / z: 538 (M + H) +.

[0666] (2) 2- [2-Fluoro-6-methoxy-4] [[(5-Methyl-2-phenyl-xazole-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy] —2-methylpropane Acid

 [0667] [Chemical 207]

実施例 24— (2)と同様にして、実施例 29— (1)で得たィ匕合物 (0.14g)から標題 化合物の塩酸塩 (0.04g)を無色固体として得た。

Example 24- In the same manner as in (2), the hydrochloride (0.04 g) of the title compound was obtained as a colorless solid from the compound (0.14 g) obtained in Example 29- (1).

 'H-NMR (400MHz, CDCl) δ: 1.55 (6Η, s), 2.48 (3Η, s), 4.01 (3H ,!

 Three

), 4.06-4.30 (6H, m), 6.96 (1H, d, J = 10.0Hz), 7.22 (1H, s), 7.26 (1H, s), 7.43-7.48 (3H, m), 7.75 (1H, s), 7.98—7.94 (2H, m). MSm / z: 510 (M + H) ⁺ .

 Elemental analysis value as C H FNO -HCM / 4CH O -1 / 2HO

 27 28 3 6 2 8 2 2

 Calculated value: C, 58.28; H, 5.59; N, 7.28.

 Analytical values: C, 58.75; H, 5.66; N, 6.85.

[0669] [Example 30]

 (1) 2— [2-Methoxy-6-methyl-4-] [[(5-Methyl-2-phenol-xazole-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy] —2-methylpropanoic acid ethyl ester

[0670] [Chemical 208]

In the same manner as in Example 13- (1), the title was obtained from the compound (0.093 g) obtained in Reference Example 29 and the compound (0.10g) obtained in Reference Example 13- (3). Compound (0.16 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.4Hz), 1.43 (6H, s),

 Three

 2.20 (3H, s), 2.29 (3H, s), 3.66 (2H, s), 3.67 (2H, s), 3.70 (3H, s), 3.91 (2H, s), 4.28 (2H, q, J = 7.4Hz), 6.74 (1H, s), 6.82 (1H, s), 7.08 (1H, s), 7.39-7.45 (3H, m), 7.63 (1H, s), 8.02—7.98 (2H, m ).

MSm / z: 534 (M + H) ⁺ .

[0672] (2) 2— [2-Methoxy-6-methyl-4-] [[(5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole-2-ylmethylamino] methyl] phenoxy] —2-methylpropanoic acid

[0673] [Chemical 209]

Example 24— In the same manner as in (2), the hydrochloride salt (0.112 g) of the title compound was obtained as a colorless solid from the compound (0.154 g) obtained in Example 30 (1).

 'H-NMR (400MHz, CDCl) δ: 1.51 (6Η, s), 2.26 (3Η, s), 2.48 (3H, s

 Three

 ), 3.93 (3H, s), 4.08-4.66 (6H, m), 6.93 (1H, s), 7.23 (1H, s), 7.26 (1H, s), 7.43-7.47 (3H, m), 7.76 ( 1H, s), 7.98—7.93 (2H, m).

 MSm / z: 506 (M + H) +.

 Elemental analysis value C H NO -HCM / 4C H O

 28 31 3 6 4 8 2 2

 Calculated values: C, 60.78; H, 6.16; N, 7.33.

 Analytical values: C, 60.67; H, 6.26; N, 6.83.

[0675] [Example 31]

 (1) 2— [2, 6 Dimethyl— 4— [[(5—Methyl— [1, 3, 4] oxadiazole—2-ylmethyl)-(5-methyl-2-p-tolylazole) — 4-ylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[0676] [Chemical 210]

参考例 30—（5)で得た化合物（0.147g)と 4 クロロメチルー 5—メチルー 2— p— トリルォキサゾール（0.09g)を N, N ジメチルホルムアミド（3ml)に溶解し、炭酸セ シゥム（0.198g)とようィ匕カリウム（0.02g)をカ卩えて、 60°Cにて 3日間攪拌した。反 応液を酢酸ェチルで希釈し、水、飽和食塩水の順に洗浄した。無水硫酸ナトリウムで 乾燥後、溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィーで精 製する（酢酸ェチル：へキサン = 3:1)ことにより標題ィ匕合物（0. 15g)を黄色油状物 として得た。

Reference Example 30—Dissolve the compound (0.147 g) obtained in (5) and 4 chloromethyl-5-methyl-2-p-tolylazole (0.09 g) in N, N dimethylformamide (3 ml) and add cesium carbonate ( 0.198 g) and potassium chloride (0.02 g) were added and stirred at 60 ° C for 3 days. Anti The reaction solution was diluted with ethyl acetate and washed with water and saturated brine in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to give the title compound (0.15 g). Was obtained as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.26 (3H, s), 2.39 (4H, s), 2.51 (3H, s), 3.66 (4H, br s)

, 3.99 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.98 (2H, s), 7.24 (2H, d, J = 8

1Hz), 7.89 (2H, d, J = 8.1 Hz).

MSm / z: 547 (M + H) ⁺ .

[0678] (2) 2— [2, 6 Dimethyl— 4— [[(5—Methyl— [1, 3, 4] oxadiazole—2-ylmethyl)-(5—Methyl—2— p Tolyro Xazol-4-ylmethyl) amino] methyl

] Phenoxy] 2-Methylpropanoic acid

[0679] [Chemical 211]

Example 31— The compound (0.15 g) obtained in (1) was dissolved in methanol (10 ml), 1N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 19 hours. Thereafter, the mixture was heated to reflux for 5 hours. After cooling, 1N aqueous hydrochloric acid solution (2 ml) was added, and the mixture was evaporated under reduced pressure. The residue was extracted with ethyl acetate and washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methanol: black-mouthed form = 1: 9) to give the title compound (0.082 g) was obtained as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.25 (3

 6

H, s), 2.36 (3H, s), 2.45 (3H, s), 3.57 (2H, s), 3.61 (2H, s), 3.91 (2H, s), 6.96 (2H, s), 7.32 (2H , d, J = 8.1Hz), 7.81 (2H, d, J = 8.1Hz). MS m / z: 519 (M + H) +.

 Elemental analysis value as C H NO 3Ζ5ΗΟ

 29 34 4 5 2

 Calculated values: C, 65.79; H, 6.70; N, 10.58.

 Analytical values: C, 66.10; H, 6.75; N, 10.10.

[0681] [Example 32]

 (l) 2- [4-[[[2- (4-Chlorophenyl) 5-methyloxazole-4-ylmethyl]-(5-methyl- [1, 3, 4] oxadiazol 2-ylmethyl) amino] methyl] 2, 6-dimethylphenoxy] 2-methylpropanoic acid ethyl ester

[0682] [Chem 212]

 [0683] Example 31— In the same manner as (1), the compound (0.147 g) obtained in Reference Example 30— (5) and 4-chloromethyl-2- (4-chlorophage) 5-methyl Oxazole (0.098 g) was obtained as a pale yellow oily product (0.18 g).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (5H, s),

 Three

 2. 18 (5H, s), 2.27 (2H, s), 2.51 (3H, d, J = 0.7Hz), 3.66 (1H, s), 3.6

6 (2H, s), 3.98 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.97 (2H, s), 7.41 (2

H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.3Hz).

MSm / z: 567 (M + H) ⁺ .

[0684] (2) 2- [4-[[[2- (4 Black Mole) 5 -Methyloxazole-4-methyl

]-(5-Methyl- [1, 3, 4] Oxadiazo 2-ylmethyl) amino] methyl] 2,

6 Dimethylphenoxy] 2 Methylpropanoic acid

[0685] [Chemical 213]

[0686] 実施例 31— (2)と同様にして、実施例 32— (1)で得たィ匕合物（0.18g)から標題 化合物（0.094g)を無色固体として得た。

Example 31— In the same manner as in (2), the title compound (0.094 g) was obtained as a colorless solid from the compound (0.18 g) obtained in Example 32 (1).

 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2.13 (6H, s), 2.26 (

 6

 3H, s), 2.46 (3H, s), 3.59 (2H, s), 3.61 (2H, s), 3.91 (2H, s), 6.96 (2 H, s), 7.58 (2H, d, J = 8.6 Hz), 7.92 (2H, d, J = 8.6Hz).

MSm / z: 540 (M + H) ⁺ .

 Elemental analysis value as C H C1NO 3 / 4ΗΟ

 28 31 4 5 2

 Calculated values: C, 60.87; H, 5.93; N, 10.14.

 Analytical values: C, 61.36; H, 5.92; N, 9.64.

[0687] [Example 33]

 (1) 2- [2,6 Dimethyl-4-[[[(3 Phenyl [1,2,4] oxadiazole-5-ylmethyl) thiazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropenoic acid

[0688] [Chemical 214]

[0689] In the same manner as in Example 31- (1), from 5 chloromethyl-3 phenol [1, 2, 4] oxadiazole (0.070 g) and the compound (0.13 g) obtained in Reference Example 31 The title compound (0.080 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

 2.20 (5H, s), 3.78 (2H, s), 4.10 (2H, s), 4.22 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 7.05 (2H, s), 7.33 ( 1H, d, J = 3.4Hz), 7.49- 7.52 (4H, m), 7.72 (1H, d, J = 3.2Hz), 8.12-8.10 (2H, m).

MSm / z: 521 (M + H) ⁺ .

[0690] (2) 2— [2, 6 Dimethyl— 4— [[(3 Phenol [1, 2, 4] oxadiazole— 5— Rumethyl) thiazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid

 [Chemical 215]

In the same manner as in Example 31- (2), the compound (0.080 g) force obtained in Example 33- (1) also gave the title compound (0.038 g) as a pale yellow oil.

 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.14 (6Η, s), 3.74 (2

 6

 H, s), 4.15 (2H, s), 4.17 (2H, s), 7.03 (2H, s), 7.61—7.57 (3H, m), 7.69 (1H, d, J = 3.2Hz) , 7.74 (1H, d, J = 3.4Hz), 8.01— 8.03 (2H, m). MSm / z: 493 (M + H) +.

 [0693] [Example 34]

 (1) 2-[2, 6 Dimethyl 4-[[((5 -Fluxol-2-ylmethyl) thiazol-2-ylmethylamino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

 [0694] [Chemical 216]

実施例 31—（1)と同様にして、 2 クロロメチルー 5 フエ-ルォキサゾール（0.04 5g)と参考例 31で得たィ匕合物（0.084g)力も標題ィ匕合物（0.053g)を淡黄色油状 物として得た。

Example 31—Similarly to (1), 2 chloromethyl-5-phenoloxazole (0.04 5 g) and the compound (0.084 g) obtained in Reference Example 31 were also used in the same manner as the title compound (0.053 g). Obtained as an oil.

'H-NMR (400MHz, CDCl) δ: 1.35 (4Η, t, J = 7.1 Hz), 1.45 (7H, s), 2. 19 (6H, s), 3.73 (2H, s), 3.96 (2H, s), 4.16 (2H, s), 4.28 (2H, q, J

= 7.2Hz), 7.07 (2H, s), 7.27— 7.36 (4H, m), 7.43 (2H, t, J = 7.6Hz)

, 7.66-7.64 (2H, m), 7.71 (1H, d, J = 3.4Hz).

 MSm / z: 520 (M + H) +.

[0696] (2) 2- [2, 6 Dimethyl-4-[[[(5-Phenoxazole-2-ylmethyl) thiazol-2-ylmethylamino] methyl] phenoxy] -2-methylpropanoic acid

[0697] [Chemical 217]

Example 31—In the same manner as in (2), the compound (0.050 g) force obtained in Example 34- (1) was also used to obtain the title compound (0.034 g) as a pale yellow solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.14 (6Η, s), 3.66 (2

 6

 H, s), 3.91 (2H, s), 4.10 (2H, s), 7.04 (2H, s), 7.40— 7.36 (1H, m), 7.49 (2H, t, J = 7.7Hz), 7.62 (1H, s), 7.67— 7.73 (4H, m).

MSm / z: 492 (M + H) ⁺ .

[0699] [Example 35]

 (1) 2- [2, 6 Dimethyl-4-[[[5-Methyl-2- (5-Methylthiophen-2-yl) oxazole-4-ylmethyl] thiazole-2-ylmethylamino] methyl] phenoxy] 2— Methyl propanoic acid ethyl ester

[0700] [Chemical 218]

[0701] 実施例 31— (1)と同様にして、参考例 31で得たィ匕合物（0.143g)と参考例 32で 得た化合物（0.090g)力も標題ィ匕合物（0.155g)を淡黄色油状物として得た。 'H-NMR (400MHz, CDC1) δ :1.35 (3Η, t, J = 7. 1Hz), 1.45 (7H, s), 2

[0701] Example 31— In the same manner as (1), the compound (0.143 g) obtained in Reference Example 31 and the compound (0.090 g) obtained in Reference Example 32 were also treated with the title compound (0.155 g). ) Was obtained as a pale yellow oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (7H, s), 2

 Three

 19 (7H, s), 2.21 (3H, s), 2.51 (3H, s), 3.60 (2H, s), 3.63 (2H, s), 4.

06 (2H, s), 4.28 (2H, q, J = 7. OHz), 6.73 (1H, d, J = 3.2Hz), 7.03 (2H

, s), 7.27 (1H, d, J = 2.9Hz), 7.38 (1H, d, J = 3.4Hz), 7.68 (1H, d, J =

3.2Hz).

MSm / z: 554 (M + H) ⁺ .

[0702] (2) 2- [2, 6 Dimethyl-4-[[[[5-Methyl-2-] (5-Methylthiophene-2-yl

) Oxazol-4-ylmethyl] thiazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid

[0703] [Chemical 219]

Example 31— In the same manner as in (2), the title compound (0.114 g) was obtained as a colorless solid from the compound (0.15 g) obtained in Example 35 (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.15 (6Η, s), 2.19 (

 6

 3H, s), 3.29 (2H, s), 3.53 (2H, s), 3.57 (3H, s), 3.99 (2H, s), 6.88 (1 H, dd, J = 3.6, 1.1Hz), 7.03 ( 2H, s), 7.40 (1H, d, J = 3.4Hz), 7.64 (1 H, d, J = 3.2Hz), 7.71 (1H, d, J = 3.4Hz).

 MSm / z: 526 (M + H) +.

 Elemental analysis value C H N O S · 1 / 2H O

 27 31 3 4 2 2

 Calculated values: C, 60.65; H, 6.03; N, 7.86; S, 11.99.

 Analytical values: C, 60.70; H, 5.90; N, 7.66; S, 11.68.

[0705] [Example 36] (1) 2- [2,6 Dimethyl-4 [[[5-Methyl-2- (5-methylthiophen-2-yl) oxazole 4-ylmethyl] oxazole 2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

 [Chemical 220]

Example 31— In the same manner as in (1), the title compound (0.296 g) was obtained from the compound (0.23 g) obtained in Reference Example 23 and the compound (0.15 g) obtained in Reference Example 32. ) Was obtained as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.23 (3H, s), 2.51 (3H, s), 3.61 (4H, s), 3.90 (2H, s), 4.

28 (2H, q, J = 7.1Hz), 6.73 (1H, d, J = 2.7Hz), 6.98 (2H, s), 7.07 (1H

, s), 7.39 (1H, d, J = 3.7Hz), 7.63 (1H, s).

 MS m / z: 538 (M + H) +.

[0708] (2) 2- [2, 6 Dimethyl 4- [[[[5-Methyl-2-] (5-Methylthiophene-2-yl

) Oxazole 4ylmethyl] oxazole 2ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid

[0709] [Chem 221]

実施例 31— (2)と同様にして、実施例 36— (1)で得たィ匕合物 (0.296g)力も標題 化合物 (0. 150g)を淡黄色固体として得た。

Example 31—In the same manner as (2), the compound (0.296 g) force obtained in Example 36 (1) was also used to obtain the title compound (0.150 g) as a pale yellow solid.

'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (6Η, s), 2.21 ( 3H, s), 3.51 (2H, s), 3.56 (2H, s), 3.57 (3H, s), 3.79 (2H, s), 6.88 (1 H, dd, J = 3.7, 1. OHz), 6.95 (2H, s), 7.18 (1H, d, J = 0.7Hz), 7.39 (1 H, d, J = 3.7Hz), 8.07 (1H, d, J = 0.7Hz).

MSm / z: 510 (M + H) ⁺ .

 Elemental analysis value C H NOS.1Z2HO

 27 31 3 5 2

 Calculated values: C, 62.53; H, 6.22; N, 8.10; S, 6.18.

 Analytical values: C, 62.73; H, 6.15; N, 7.77; S, 6.00.

[0711] [Example 37]

 (1) 2- [2, 6 Dimethyl-4-[[[5-Methyl-2- (5-Methylthiophene-2-yl) oxazoline 4-ylmethyl]-(5-methyloxazole-2-ylmethyl) amino ] Methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[0712] [Chemical 222]

[0713] In the same manner as in (31), the title compound was obtained from the compound (0.090 g) obtained in Reference Example 32 and the compound (0.142 g) obtained in Reference Example 33 (4). (0.16 g) was obtained as a pale yellow oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s),

 Three

 2.18 (6H, s), 2.24 (3H, s), 2.30 (3H, s), 2.51 (3H, s), 3.61 (2H, s), 3.61 (2H, s), 3.82 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.65 (1H, d, J = l.2 Hz), 6.73 (1H, dd, J = 3.7, 1. OHz), 6.98 (2H, s) , 7.39 (1H, d, J = 3.7 Hz).

MSm / z: 552 (M + H) ⁺ .

[0714] (2) 2- [2, 6 Dimethyl-4-[[[[5-Methyl-2- (5-Methylthiophene-2-yl)] oxazol 4-ylmethyl] 1- (5-Methyloxazole-2 Ylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid [0715] [Chemical 223]

[0716] In the same manner as in Example 31- (2), the title compound was obtained from the compound (0.16 g) obtained in Example 37- (1), and further 4N hydrochloric acid-dioxane was added and dried under reduced pressure. Solidification gave the title compound hydrochloride (0. llg) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.35 (6H, s), 2.16 (6H, s), 2.27

 6

 -2.28 (6H, m), 2.49— 2.51 (3H, m), 4.21—4.01 (6H, m), 6.89— 6. 92 (2H, m), 7.12 (2H, s), 7.45 (1H, d, J = 3.7Hz).

MSm / z: 524 (M + H) ⁺ .

 Elemental analysis value C H N O S'HC1'1 / 2H O

 28 33 3 5 2

 Calculated values: C, 59.09; H, 6.20; N, 7.38; S, 5.63.

 Analytical values: C, 59.20; H, 6.04; N, 7.13; S, 5.65.

[0717] [Example 38]

 (1) 2- [2,6 Dimethyl-4-[[[(5-Methyloxazole-2-ylmethyl)-((3-phenyl [1, 2, 4] oxadiazo-l-ylmethyl) amino] methyl] phenoxy] —2 Methylpropanoic acid ethyl ester

[0718] [Chemical 224]

[0719] In the same manner as in Example 31- (1), it was obtained in 5 chloromethyl-3-phenol [1, 2, 4] oxadiazole (0.070 g) and Reference Example 33- (4). Title compound (0.13g) to title compound (0. 12 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 19 (6H, s), 2.29 (3H, d, J = l.2Hz), 3.77 (2H, s), 3.98 (2H, s), 4.12 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.66 (1H, d, J = l.2Hz), 7.01 (2H, s), 7.52-7.48 (3H, m), 8.09— 8.12 (2H, m).

 MS m / z: 519 (M + H) +.

 (2) 2- [2, 6 dimethyl-4-[[((5-methyloxazole-2-ylmethyl)-((3-phenyl [1, 2, 4] oxadiazo-l-ylmethyl) amino] methyl] phenoxy] —2 Methylpropanoic acid

 [Chemical 225]

[0721] In the same manner as in Example 31- (2), the title compound was obtained from the compound (0.12g) obtained in Example 38- (1), and further 4N hydrochloric acid-dioxane was added and dried under reduced pressure. Solidification afforded the title compound hydrochloride (0.082 g) as a pale yellow oil.

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.14 (6Η, s), 2.22 (

 6

 3H, s), 3.76 (2H, s), 3.91 (2H, s), 4.17 (2H, s), 6.73 (1H, d, J = l.2H z), 6.98 (2H, s), 7.56—7.61 (3H, m), 7.99— 8.01 (2H, m).

 MS m / z: 491 (M + H) +.

 [0722] [Example 39]

 (1) 2- [2, 6 Dimethyl-4-[[[(5-Methyloxazol-2-ylmethyl)-((5--Feloxazol-2-ylmethyl) amino] methyl] phenoxy]-2-methylpropanoic acid Echinore Estenore

[0723] [Chem 226]

[0724] In the same manner as in Example 31- (1), 2-chloromethyl-5-phenoloxazole (0.04

5g) and Reference Example 33- Compound (0.084 g) obtained in (4) also gave the title compound (0. llg) as a pale yellow oil.

 MS m / z: 518 (M + H) +.

[0725] (2) 2- [2, 6-Dimethyl-4-[[(5-Methyloxazol-2-ylmethyl)-((5-Feloxazolo-2-ylmethyl) amino] methyl] phenoxy] — 2-Methylpropanoic acid

[0726] [Chemical 227]

Example 31—In the same manner as (2), the title compound was obtained from the compound (0. llg) obtained in Example 39- (1), and further 4N hydrochloric acid-dioxane was added to reduce the pressure. Drying gave the title compound hydrochloride (0.033 g) as a pale yellow solid.

 ^ H—NMR (400MHz, DMSO—d) δ: 1.32 (6H, s), 2.13 (6H, s), 2.25 (

 6

 3H, s), 3.76 (2H, s), 3.95 (2H, s), 4.00 (2H, s), 6.78 (1H, d, J = l.2H z), 6.99 (2H, s), 7.37—7.40 (1H, m), 7.46- 7.50 (2H, m), 7.62 (1H, s), 7.68-7.72 (2H, m).

MSm / z: 490 (M + H) ⁺ .

[0728] [Example 40] (l) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl-

 Trioloxazole-4-ylmethyl) amino] methyl] phenoxy]

 Acid ester

 [0729] [Chemical 228]

Example 14— In the same manner as (1), the compound (0.232 g) obtained in Reference Example 34 (2), methylamine hydrochloride (0.037 g) and triethylamine (0.172 ml) Compound (0.084 g) was obtained as a colorless oil.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.25 (3H, s), 2.41 (3H, s), 2.79 (3H, d, J = 4.9Hz), 3.2 6 (2H, s), 3.55 (2H, s), 3.66 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.92 (2 H, s), 7.26 (2H, d, J = 7.8Hz), 7.80—7.94 (3H, m).

MSm / z: 522 (M + H) ⁺ .

[0731] (2) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-p-triloxazole-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropane

[0732] [Chemical 229]

実施例 16— (2)と同様にして、実施例 40— (1)で得たィ匕合物（0.084g)を処理後 、シリカゲルカラムクロマトグラフィー精製（11%メタノール一クロ口ホルム）により標題 化合物（0.072g)を無色固体として得た。

Example 16- The compound (0.084 g) obtained in Example 40- (1) was treated in the same manner as in (2), and then purified by silica gel column chromatography purification (11% methanol / chloroform form). The compound (0.072g) was obtained as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.49 (6Η, s), 2.20 (6Η, s), 2.27 (3H, s

 Three

 ), 2.40 (3H, s), 2.78 (3H, d, J = 4.9Hz), 3.24 (2H, br s), 3.53 (2H, br s), 3.63 (2H, br s), 6.92 (2H, s ), 7.22— 7.29 (2H, m), 7.85— 8.01 (

3H, m).

MSm / z: 494 (M + H) ⁺ .

 Elemental analysis value C H N O

 28 35 3 5 2

 Calculated values: C, 66.91; H, 7.22; N, 8.36.

 Analytical values: C, 67.10; H, 7.28; N, 8.09.

[0734] [Example 41]

 (l) 2- [4-[[[2- (4-Chlorophenyl) 5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] -2 Methyl propanoic acid ethyl ester

[0735] [Chem 230]

In the same manner as in Example 40- (1), the title compound (0.220 g) was obtained as a pale yellow oil from the compound (0.261 g) obtained in Reference Example 35- (2).

 ^ H—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.24 (3H, s), 2.79 (3H, d, J = 5.1 Hz), 3.22 (2H, s), 3.50 (2H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.88 (2H, s), 7.40— 7.46 (2H, m), 7.64— 7.75 (1H, m), 7.90— 7.96 (2H, m).

MSm / z: 542 (M + H) ⁺ .

[0737] (2) 2— [4— [[[2— (4 Black Mouth-Fuel)] 5-Methyloxazol-4-ylmethyl] methylcarbamoylmethylamino] methyl Ί-2, 6 Dimethylphenoxy ] 2 Methyl [0738] [Chemical 231]

In the same manner as in Example 40- (2), the title compound (0.180 g) was obtained as a colorless solid from the compound (0.220 g) obtained in Example 41- (1).

 'H-NMR (400MHz, CDCl) δ: 1.49 (6Η, s), 2.20 (6Η, s), 2.28 (3H, s)

 Three

 , 2.79 (3H, d, J = 4.9Hz), 3.24 (2H, br s), 3.53 (2H, br s), 3.63 (2H, br s), 6.92 (2H, br s), 7.40— 7.47 (2H , m), 7.76— 7.89 (1H, m), 7. 90-7.97 (2H, m).

MSm / z: 514 (M + H) ⁺ .

 Elemental analysis value C H C1NO

 As 27 32 3 5

 Calculated values: C, 63.09; H, 6.27; CI, 6.90; N, 8.17.

 Analytical values: C, 63.02; H, 6.30; CI, 6.97; N, 8.10.

[0740] [Example 42]

 (l) 2- [4-[[[2- (3-Chlorophenol) 5 Methyloxazole 4-methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] -2-methyl Propanoic acid ethyl ester

[0741] [Chemical 232]

[0742] 実施例 40— (1)と同様にして、参考例 36— (2)で得た化合物 (0.214g)力も標題 化合物（0. 194g)を淡黄色油状物として得た。

In the same manner as in Example 40- (1), the compound (0.214 g) obtained in Reference Example 36- (2) also gave the title compound (0.194 g) as a pale yellow oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.25 (3H, s), 2.81 (3H, d, J = 4.9Hz), 3.22 (2H, s), 3.5 0 (2H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.89 (2H, br s), 7.36 -7.43 (2H, m), 7.65— 7.75 (1H, m), 7.84— 7.91 (1H, m), 7.97— 8 .00 (1H, m).

MSm / z: 542 (M + H) ⁺ .

[0743] (2) 2- [4-[[[2- (3-Chroophthalate) 5-Methyloxazole 4-ylmethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenol Enoxy] —2-methylpropanoic acid

 [0744] [Chemical 233]

実施例 40— (2)と同様にして、実施例 42— (1)で得たィ匕合物 (0.194g)力も標題 化合物（0. 156g)を無色固体として得た。

Example 40—In the same manner as in (2), the compound (0.194 g) force obtained in Example 42— (1) was also used to obtain the title compound (0.156 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.49 (6Η, s), 2.20 (6Η, s), 2.29 (3H, s

 Three

 ), 2.80 (3H, d, J = 4.9Hz), 3.24 (2H, s), 3.53 (2H, s), 3.62 (2H, s), 6.92 (2H, s), 7.36-7.44 (2H, m), 7.76—7.92 (2H, m), 7.97—8.01 (1 H, m).

MSm / z: 514 (M + H) ⁺ .

 Elemental analysis value C H C1N O · 1 / 4H O

 27 32 3 5 2

 Calculated values: C, 62.54; H, 6.32; CI, 6.84; N, 8.10.

Analytical values: C, 62.45; H, 6.36; CI, 6.71; N, 7.80. [0746] [Example 43]

 (1) 2- [2-Methoxy-6 methyl 4 [[Methylcarbamoylmethyl mono (5 methyl 2-phenoxazole 4-methyl) amino] methyl] phenoxy] 2 methyl propanoic acid tert-butyl ester

[0747] [Chemical 234]

Example 14— In the same manner as in (1), the title compound (0.109 g) was obtained as a colorless oil from the compound (0.118 g) obtained in Reference Example 37 (3).

 'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 1.50 (9Η, s), 2.20 (3H, s

 Three

 ), 2.28 (3H, s), 2.79 (3H, d, J = 4.9Hz), 3.22 (2H, s), 3.52 (2H, s), 3.62 (2H, s), 3.68 (3H, s) , 6.65 (1H, d, J = l.7Hz), 6.68 (1H, d, J = l.7 Hz), 7.41-7.48 (3H, m), 7.85 (1H, q, J = 4.9Hz), 7.97 — 8.02 (2H, m).

MSm / z: 552 (M + H) ⁺ .

[0749] (2) 2— [2-Methoxy 6-methyl-4 [[methylcarbamoylmethyl- (5-methyl-

2—Phenoloxazole 4-methyl) amino] methyl] phenoxy] 2 methyl propanoic acid

[0750] [Chemical 235]

ΉΖ)ΖΟ 'S-L6 ' L '(^ΖΗ Έ = Γ'Ρ 'ΗΙ)69 ' L '(^ 'HS)S 'LS£ ' L '(^ΖΗ

ΉΖ) ΖΟ 'S-L6' L '( ^Ζ Η Έ = Γ'Ρ' ΗΙ) 69 'L' (^ 'HS) S' LS £ 'L' ( ^Ζ Η

Z Έ = Γ'Ρ 'HI) 8S' L '( ^Ζ ΗΖΗΖ = ΓΡ' ΗΙ) 06 9 '( ^Ζ ΗΖΗΖ = ΓΡ' ΗΙ) ΖΖ 9 '( ^s ' Η2) 80 '' ( ^s ' HS) 9Z Έ '( ^s ' Η2) 89 Έ' ( ^s ' Η2) 99 Έ '( ^s ' HS) 8S' Ζ '( ^s Ήε) ΖΖ' Ζ '( ^s ' Η6) Ι9 Ί' ( ^s 'Η9) 0 · ΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

oM ^ ^ w ^ ( ^§ 89ο -o) ^

[9S2 ^] [SSZO] d cl cl ^^-z-[[^ [^ ^ / — s— / —, ^

1 / —, ^ / -e — / ^ ー 9)]] ー — ^ ー 9 一 ^ ー

 [Pain ¾ϊ 第] [2SZ0] • 91 · 8 'Ν'ΙΖ · 9' Η '^ ε 9'

 • εε · 8 'Ν' βζ · 9 'H' S · 9 '

 ^ O HZ / l · O N H O UMl ^ ^ 峯 ^

• ₊ (H + PV) 96 ^: ^z / ^ra SPV • (ra 'HS) 96 Ί-ΙΟ · 8' ( ^Ζ Η9 · = Γ¾ 'ΗΙ) 06' L '(^ ¾ε) 8 · L →' L '( ^Ζ ΗΖ · Ι = Γ'Ρ' ΗΙ) 9Ζ 9 '( ^Ζ ΗΖ · ΐ = ΓΡ' HI) SZ 9 '( ^s ' U £) LL · S' ( ^s ' Η2) 99 Έ '( ^s ΉΖ) Έ '( ^s ΉΖ) ΙΖ Έ' ( ^Ζ Η6 · = ΓΡ 'HS) I8' Ζ '( ^s Ήε) τε' ζ '( ^s ' uz) z 'ζ' ( ^s ¾9) 8 9 (\ οαο 'ZH OO ^) H NH _T

Z9I-

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV [8S2 ^] [6SZ0]

 /

 1 ^ S [^ [^ ^ / S— / —, ^

 →-/ —, ^ / é -Ζ- -9)]]-^-J ^ -Z -Z {\)

 imm

 Έ6 '9' S-S9 'L' Ν · Ζ6 '9' H-S6 Έ9 ':

 • 60 · 9 'S' 66 'L' N 'SO · 9' Η · 26 Έ 9 'one: military

 ^ O H ^ / I-S O N H O UMl ^ ^ 峯 ^

• ₊ (H +) SSg: z / ^ra S

• (ra 'UZ) L6 Ί-10 8' ( ^Z HS Έ = Γ 'Ρ' HI) 0Z 'L' (m 'U £) L' L- 'L' ( ^Z UZ Έ = Γ'Ρ ' (Ul) 6Z 'L' ( ^s 'HI) 10' L '( ^s ' HI) 98 9 '( ^s ' UZ) L0 '' ( ^s 'HS) Z8 Έ' ( ^s 'UZ) L Έ' ( ^s 'HS) 69 Έ' ( ^s ' HS) IS '( ^s ' U £) LZ' Z '( ^s ' H9) 6 9-9 (\ OaO' ZH 00 ^) H NH _T

[S2 ^] [9SZ0] Difficult zci

 ^^-z-[[^ [^ ^ / — s— / —, ^

1 / —, ^ / e / ^ ー 9)]]] — — ^ 9 1 ^ ー [SSZ0]

• ₊ (H + PV) 8 9: ^z / ^ra SPV

891 ·

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA

Example 13— Similar to (1), the compound (0.094 g) obtained in Reference Example 38 and the compound compound force obtained in Reference Example 13 (3) Title compound ( 0.082 g) was obtained as a colorless oil.

 iH—NMR (400MHz, CDC1) δ: 1.28 (3Η, t, J = 7.1 Hz), 1.56 (6H, s), 2

 Three

 .31 (3H, s), 3.67 (2H, s), 3.70 (2H, s), 3.89 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 6.92 (1H, t, J = 8.4Hz), 7.03 (1H, d, J = 8.3Hz), 7.08 (1H, s), 7.19 (1H, dd, J = ll.8, 1.7Hz), 7.38- 7.46 (3H, m), 7.64 ( 1H, s), 8.03-7.98 (2H, m).

 MSm / z: 508 (M + H) +.

[0761] (2) 2— [2 Fluoro 4 [[(5 Methyl 12 Phenolazole 4-ilmethyl) oxazole-2-ylmethylamino] Methyl] phenoxy] 2-Methylpropanoic acid

 [0762] [Chemical 239]

Example 24— In the same manner as in (2), the hydrochloride (0.059 g) of the title compound was obtained as a colorless solid from the compound (0.082 g) obtained in Example 45- (1).

MSm / z: 450 (M + H) ⁺ .

 Elemental analysis value C H FNO 'HC1

 26 26 3 5

 Calculated value: C, 60.52; H, 5.27; N, 8.14.

Analytical values: C, 60.38: H, 5.23: N, 7.98. [0764] [Example 46]

 (1) 2- [2, 6 Dimethyl-4 [[[2- (5-Methyl-2-phenoloxazole-4-yl) ethyl] oxazol-2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

 [0765] [Chemical 240]

Example 31— Similar to (1), the compound (0.lOOg) obtained in Reference Example 23 and toluene-4-sulfonic acid 2- (5-methyl-2-phenoloxol-4-yl) The title compound (0.069 g) was obtained as a colorless oil from ethyl ester (0.206 g).

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.44 (6H, s), 2

 Three

 15 (6H, s), 2.28 (3H, s), 2.67— 2.74 (2H, m), 2.81— 2.87 (2H, m), 3.64 (2H, s), 3.86 (2H, s), 4.28 (2H , q, J = 7.1 Hz), 6.93 (2H, s), 7.0 6 (1H, d, J = 0.7 Hz), 7.37—7.44 (3H, m), 7.61 (1H, d, J = 0.7 Hz) , 7. 99-7.93 (2H, m).

MSm / z: 532 (M + H) ⁺ .

[0767] (2) 2- [2,6 Dimethyl-4-[[[[2- (5-Methyl-2-phenoloxazole-4-yl) ethyl] oxazole-2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid

[0768] [Chemical 241]

Example 31- In the same manner as in (2), the title compound (0.026 g) was obtained as a pale yellow oil from the compound (0.069 g) obtained in Example 46- (1).

 'H-NMR (400MHz, CDCl) δ: 1.46 (6Η, s), 2.16 (6Η, s), 2.30 (3H, s

 Three

 ), 2.66 (2H, t, J = 7.2Hz), 2.83 (2H, t, J = 7.2Hz), 3.63 (2H, s), 3.88 (2H, s), 6.93 (2H, s), 7.08 (1H , s), 7.44— 7.38 (3H, m), 7.63 (1H, d, J = 0.7Hz), 7.95-7.90 (2H, m).

MSm / z: 504 (M + H) ⁺ .

[0770] [Example 47]

 (1) 2- [2,6-Dimethyl-4-[[Oxazol 2-ylmethyl- (5-phenolisoxazol 3-ylmethyl) amino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

 [0771] [Chemical 242]

炭酸セシウムに代えて炭酸カリウムを使用する以外は実施例 31— (1)と同様にして 、参考例 23で得たィ匕合物 (0.166g)と参考例 39で得たィ匕合物力も標題ィ匕合物 (0. 142g)を淡黄色油状物として得た。

In the same manner as in Example 31- (1) except that potassium carbonate was used in place of cesium carbonate, the compound (0.166 g) obtained in Reference Example 23 and the compound strength obtained in Reference Example 39 were also obtained. The title compound (0.142 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s),

 Three

2. 19 (6H, s), 3.64 (2H, s), 3.81 (2H, s), 3.85 (2H, s), 4.28 (2H, q, J = 7. 1Hz), 6.59 (1H, s), 6.99 (2H, s), 7.09 (1H, s), 7.41— 7.48 (3H, m), 7.65 (IH, s), 7.79 (2H, d, J = 8.3Hz).

MSm / z: 504 (M + H) ⁺ .

[0773] (2) 2— [2, 6-Dimethyl-4-] [[Oxazol 2-ylmethyl- (5-phenolisoxazol 3-ylmethyl) amino] methyl] phenoxy] — 2-methylpropanoic acid

[0774] [Chemical 243]

Example 31—In the same manner as in (2), the compound (0.138 g) force obtained in Example 47- (1) was also used to obtain the title compound (0.083 g) as a colorless solid.

 ^ H—NMR (400MHz, DMSO— d) δ: 1.33 (6H, s), 2.15 (6H, s), 3.59 (

 6

2H, s), 3.80 (2H, s), 3.81 (2H, s), 6.98 (2H, s), 7.01 (IH, s), 7. 19 (1 H, s), 7.48—7.57 (3H, m ), 7.88 (2H, d, J = 7.3Hz), 8.08 (1H, s) .MSm / z: 476 (M + H) ⁺ .

 Elemental analysis value as C H NO -1 / 4C H O -3 / 4H O

 27 29 3 5 4 8 2 2

 Calculated values: C, 66.98; H, 6.32; N, 8.37.

 Analytical values: C, 67.15; H, 6.31; N, 8.01.

[0776] [Example 48]

 (1) 2- [2-Ethyl 4-[[[(5-Methyl-2-phenyl-tetrazol-4-ylmethyl) -oxazol-2-ylmethylamino] methyl] phenoxy] -2-methylpropenoic acid ester

[0777] [Chemical 244]

 [0778] Example 13— Similar to (1), Reference Compound 13- (3.) Compound (0. lOOg) and 2- (2-ethyl-4-formylphenoxy) 2 methylpropanoic acid obtained in (3) Ethyl ester (0.0 99 g) gave the title compound (0.107 g) as a colorless oil.

 iH—NMR (400MHz, CDC1) δ: 1.19 (3Η, t, J = 7.6Hz), 1.23 (3H, t, J

 Three

 = 7. 1Hz), 1.58 (6H, s), 2.30 (3H, s), 2.63 (2H, q, J = 7.4Hz), 3.66 (2 H, s), 3.67 (2H, s), 3.89 (2H , s), 4.22 (2H, q, J = 7.1Hz), 6.59 (1H, d, J = 8.1Hz), 7.09-7.04 (2H, m), 7.19 (1H, d, J = l.7Hz), 7.45— 7.3 6 (3H, m), 7.63 (1H, s), 8.02— 7.97 (2H, m).

 MS m / z: 518 (M + H) +.

 [0779] (2) 2— [2 Ethyl 4 [[(5 Methyl 2 Phenyloxazole 4 lMethyl) -Oxazol-2-ylmethylamino] Methyl] phenoxy] 2 -Methylpropanoic acid

 [0780] [Chemical 245]

実施例 31— (2)と同様にして、実施例 48— (1)で得たィ匕合物 (0.107g)力も標題 化合物を得、更に 4規定塩酸一ジォキサンを加えて減圧乾固することにより標題ィ匕合 物の塩酸塩 (0.075g)を無色固体として得た。

Example 31- In the same manner as (2), the compound (0.107 g) strength obtained in Example 48- (1) was also used to obtain the title compound, and further 4N hydrochloric acid monodioxane was added to dryness under reduced pressure. Gave the hydrochloride salt of the title compound (0.075 g) as a colorless solid.

MSm / z: 490 (M + H) +. Elemental analysis value as CH NO 'HC1

 28 31 3 5

 Calculated value: C, 63.93; H, 6.13; C1, 6.74; N, 7.99.

 Analytical values: C, 63.74; H, 6.19; C1, 6.46; N, 7.64.

[0782] [Example 49]

 (1) 2- [2 Ethyl-6-methyl-4-] [[(5-Methyl-2-phenoloxazole-4-ylmethyl) oxazole 2-ylmethylamino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

[0783] [Chemical 246]

Example 13— In the same manner as (1), the force of the compound (0.120 g) obtained in Reference Example 13- (3) and the compound (0.124 g) obtained in Reference Example 40 were also Compound (0.156 g) was obtained as a colorless oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.18 (3Η, t, J = 7.6Hz), 1.35 (3H, t, J

 Three

 = 7.4Hz), 1.44 (6H, s), 2.18 (3H, s), 2.28 (3H, s), 2.56 (2H, q, J = 7.5 Hz), 3.66 (2H, s), 3.66 (2H, s), 3.93 (2H, s), 4.28 (2H, q, J = 7.1Hz), 7.00 (1H, s), 7.04 (1H, s), 7.08 (1H, s), 7.39—7.45 (3H, m ), 7.64 (1H, s), 8.03— 7.98 (2H, m).

 MSm / z: 532 (M + H) +.

[0785] (2) 2— [2 Ethyl 6 Methyl 4 [[(5 Methyl 2 Phenoloxazole 4-ylmethyl) oxazole 2-ylmethylamino] Methyl] phenoxy] 2-Methylpropanoic acid

[0786] [Chemical 247]

Example 31—In the same manner as (2), the title compound was obtained from the compound (0.154 g) obtained in Example 49- (1), and further 4N dioxane hydrochloride was added and dried under reduced pressure. After solidification, crystallization from ethyl acetate-hexane gave the title compound hydrochloride (0.094 g) as a colorless solid.

MSm / z: 504 (M + H) ⁺ .

 Elemental analysis value C H N O 0. 85HC1-0.

 29 33 3 5 2

 Calculated values: C, 64. 08; H, 6. 46; CI, 5. 54; N, 7. 70.

 Analytical values: C, 64. 33; H, 6. 64; CI, 5. 56; N, 7. 28.

[0788] [Example 50]

 (1) 2— [2, 6 Dimethyl 4 — [[(5 Methyl 2 pheluoxazole 4 yl methyl) (5 Trifluoromethyl — [1, 3, 4] oxadiazole 2 ylmethyl) amino ] Methyl] phenoxy] —2-methylpropanoic acid tert-butyl ester

[0789] [Chemical 248]

[0790] In the same manner as in Example 18, the compound (0.135 g) obtained in Reference Example 41- (4) also gave the title compound (0.036 g) as a pale yellow oil. NMR-NMR (400MHz, CDC1) δ: 1.41 (6H, s), 1.51 (9H, s), 2.21 (6H, s

 Three

 ), 2.28 (3H, s), 3.70 (2H, s), 3.72 (2H, s), 4.12 (2H, s), 6.96 (2H, s

), 7.42-7.44 (3H, m), 8.00— 7.98 (2H, m).

 MSm / z: 615 (M + H) +.

[0791] (2) 2- [2, 6 Dimethyl-4-[[[(5-Methyl-2-phenoloxazole-4-ylmethyl) (5-Trifluoromethyl- [1, 3, 4] oxadiazole-2-ylmethyl ) Amino] methyl] phenoxy] -2-methylpropanoic acid

[0792] [Chemical 249]

Example 50— The compound (0.035 g) obtained in (1) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (lml) was added under ice water cooling, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methanol: chloroform = 1: 19) to give the title compound. 4N Hydrochloric acid-dioxane solution was added to this and dissolved, and then dried under reduced pressure to obtain the hydrochloride of the title compound (0.030 g) as a colorless solid.

 ^ H—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2.13 (6H, s), 2.29 (

 6

 3H, s), 3.72 (4H, s), 4.13 (2H, s), 6.98 (2H, s), 7.49- 7.53 (3H, m), 7.92-7.89 (2H, m).

 MS m / z: 559 (M + H) +.

[0794] [Example 51]

(1) 2— [2, 6 Dimethyl 4 — [[(5 Methyl 2 -Feloxazole 4-ylmethyl) mono (5 oxo 4, 5 dihydro- [1, 3, 4] oxaziazo lu 2-ylmethyl ) Amino] methyl] phenoxy] -2-methylpropanoic acid tert-butyl ester

[0795] [Chemical 250]

[0796] In the same manner as in Example 17- (1), the title compound (0.052g) was obtained as a pale yellow oil in the same manner as in Example 42- (2).

 MSm / z: 563 (M + H) +.

[0797] (2) 2— [2, 6 Dimethyl 4— [[(4-Methyl 5-oxo 4,5 Dihydro [1, 3,

4] Oxadiazo leu-2-ylmethyl) one (5-methyl-2-phenoloxazole)

4-ylmethyl) amino] methyl] phenoxy] —2-methylpropanoic acid tert-butyl ester

[0798] [Chemical 251]

Example 51—The compound obtained in (1) (0.052 g), methanol (0.50 ml) and triphenylphosphine (0.038 g) were dissolved in tetrahydrofuran (5 ml) at 78 ° C. After adding azodicarboxylic acid diisopropyl ester (0.03 ml) dropwise, the mixture was warmed to room temperature and stirred for 19 hours. The reaction mixture was diluted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to give the title compound (0.055 g). Obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s

 Three

 ), 2.28 (3H, s), 3.37 (3H, s), 3.64 (2H, s), 3.65 (2H, s), 3.72 (2H, s), 6.97 (2H, s), 7.42-7.45 (3H, m), 8.01-7.98 (2H, m).

MSm / z: 577 (M + H) ⁺ .

 [0800] (3) 2- [2, 6 Dimethyl-4-[[(4-Methyl-5-oxo-4,5-dihydro- [1,3,4] -oxadiazolu-2-ylmethyl) mono (5-methyl-2-phenoloxazole-4-ylmethyl ) Amino] methyl] phenoxy] -2-methylpropanoic acid

 [0801] [Chemical 252]

In the same manner as in Example 50- (2), the compound (0.052 g) obtained in Example 51- (2) and the hydrochloride of the title compound (0.036 g) were obtained as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.34 (6Η, s), 2.15 (6Η, s), 2.30 (

 6

 3H, s), 3.27 (3H, s), 3.56— 3.71 (4H, m), 3.87— 3.95 (2H, m), 7.07 (2H, s), 7.52-7.54 (3H, m), 7.95— 7.92 ( 2H, m).

MSm / z: 521 (M + H) ⁺ .

 Elemental analysis value as C H NO 'HC1'1 / 2H O

 28 32 4 6 2

 Calculated values: C, 59.41; H, 6.05; N, 9.90.

 Analytical values: C, 59.60; H, 6.15; N, 9.69.

[0803] [Example 52]

(1) 2-[2, 6 Difluoro 4-[[(5 Methyl 2-pheluoxazole 4-ylmethyl)-Oxazol-2-ylmethylamino] methyl] phenoxy]-2-Methyl propanoic acid tert-Butinole Estenole [0804] [Chemical 253]

Example 13— In the same manner as (1), from the compound (0.223 g) obtained in Reference Example 43 and the compound (0. lOOg) obtained in Reference Example 13 (3). The title compound (0.201 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.48 (9Η, s), 1.49 (6Η, s), 2.32 (3H, s

 Three

 ), 3.68 (2H, s), 3.71 (2H, s), 3.90 (2H, s), 7.00 (2H, d, J = 8.6Hz), 7

.09 (1H, s), 7.38-7.46 (3H, m), 7.65 (1H, d, J = 0.5Hz), 8.03—7.9

8 (2H, m).

MSm / z: 554 (M + H) ⁺ .

[0806] (2) 2- [2, 6-Difluoro-4-[[[(5-Methyl-2-phenoloxol-4-ylmethyl) -oxazole-2-ylmethylamino] methyl] phenoxy] -2-methylpropanoic acid

[0807] [Chemical 254]

Example 5—In the same manner as in (2), the compound (0.201 g) force obtained in Example 52- (1) was also used to obtain the hydrochloride of the title compound (0.150 g) as a colorless solid.

 MSm / z: 498 (M + H) +.

 Elemental analysis value C H FNO 'HC1

 26 25 2 3 5

 Calculated values: C, 58.49; H, 4.91; N, 7.87.

Analytical values: C, 58.38; H, 4.87; N, 7.69. [0809] [Example 53]

 (1) 2- [4-Methoxy-3] [[((5-Methyl-2-phenol-xazole-4-ylmethyl) -oxazole-2-ylmethylamino] methyl] phenoxy] -2-methylpropanoic acid tert-butyl ester

 [0810] [Chemical 255]

[0811] In the same manner as in Example 13- (1), from the compound (0.219g) obtained in Reference Example 44 and the compound (0.lOOg) obtained in Reference Example 13- (3). The title compound (0.183 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.44 (9Η, s), 1.50 (6Η, s), 2.31 (3H, s

 Three

 ), 3.69 (2H, s), 3.71 (3H, s), 3.75 (2H, s), 3.92 (2H, s), 6.69 (1H, d, J = 8.8Hz), 6.77 (1H, dd, J = 8.8, 2.9Hz), 7.06 (1H, s), 7.17 (1H, d, J = 2.9Hz), 7.45-7.36 (3H, m), 7.62 (1H, s), 8.02—7.98 (2H, m MSm / z: 548 (M + H) +.

[0812] (2) 2- [4-Methoxy-3] [[(5-Methyl-2-phenol-xazole-4-ylmethyl) -oxazole-2-ylmethylamino Ίmethyl] phenoxy Ί-2-methylpropane

[0813] [Chemical 256]

[0814] 実施例 53— (1)で得たィ匕合物（0.18 lg)をジクロロメタン（3ml)に溶解し、 4規定 塩酸 ジォキサン溶液 (5ml)を加えて、室温で一昼夜攪拌した。溶媒を減圧留去し 、得られた残渣をシリカゲルカラムクロマトグラフィーで精製 (メタノール：クロ口ホルム = 1:19)することにより標題ィ匕合物（0.090g)を無色固体として得た。

Example 08— The compound (0.18 lg) obtained in (1) was dissolved in dichloromethane (3 ml), 4N hydrochloric acid dioxane solution (5 ml) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 19) to give the title compound (0.090 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.58 (6Η, s), 2.35 (3Η, s), 3.57 (2H, s

 Three

 ), 3.75 (3H, s), 3.81 (2H, s), 3.86 (2H, s), 6.74 (1H, d, J = 8.6Hz), 6.86 (1H, d, J = 7.6Hz), 7 11 (1H, s), 7.49—7.43 (3H, m), 7.64 (1H, s), 7.72 (1H, d, J = 2.7Hz), 8.05—7.99 (2H, m).

MSm / z: 492 (M + H) ⁺ .

 Elemental analysis value C H N O

 27 29 3 6 2

 Calculated value: C, 64.79; H, 6.04; N, 8.39.

 Analytical values: C, 64.66; H, 6.03; N, 8.09.

[0815] [Example 54]

 (1) 2— [2, 6 Dimethyl— 4— [[(3—Methyl— [1, 2, 4] oxadiazole—5-Dimethyl)-(5-Methyl-2-p-tolyl-oxazole—4— Ylmethyl) amino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

[0816] [Chemical 257]

実施例 31— (1)と同様にして、参考例 45— (4)で得たィ匕合物（0.150g)と 4 クロ ロメチル— 5—メチル—2— p トリルォキサゾール（0.075g)から標題化合物（0.0 90g)を淡黄色油状物として得た。

Example 31—In the same manner as (1), the compound (0.150 g) obtained in Reference Example 45- (4) and 4-chloromethyl-5-methyl-2-p-tolylazole (0.075 g) Gave the title compound (0.090 g) as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

17 (6H, s), 2.26 (3H, s), 2.39 (6H, br s), 3.66 (2H, s), 3.69 (2H, s), 4.02 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.99 (2H, s), 7.23 (2H, d, J = 8.5Hz), 7.88 (2H, d, J = 8.1 Hz).

MSm / z: 547 (M + H) ⁺ .

[0818] (2) 2— [2,6 Dimethyl 4-[[((3-Methyl [1, 2, 4] oxadiazol 5-ylmethyl)-(5-Methyl-2-p-tolyl-oxazole) —4-ylmethyl) amino] methyl] phenoxy] 2-methylpropanoic acid

[0819] [Chemical 258]

In the same manner as in Example 31- (2), the compound (0.090 g) force obtained in Example 45- (1) was also used to give the title compound (0.047 g) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.50 (6Η, s), 2.22 (6Η, s), 2.28 (3H, s

 Three

 ), 2.39 (3H, s), 2.41 (3H, s), 3.69 (2H, s), 3.71 (2H, s), 4.03 (2H, s), 7.04 (2H, s), 7.22-7.24 (2H, m), 7.87—7.90 (2H, m).

 MS m / z: 519 (M + H) +.

[0821] [Example 55]

 2- [2, 6 Dimethyl 4-[[[[5-Methyl-2- (5-Methylthiophene-2-yl) oxazole- 4-methyl]] (3-Methyl- [1, 2, 4] oxaziazol 5-ylmethyl) Amino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[0822] [Chemical 259]

[0823] 実施例 31— (1)と同様にして、参考例 45— (4)で得たィ匕合物 (0.150g)と参考例 32で得たィ匕合物（0.077g)力 標題ィ匕合物（0.055g)を淡黄色油状物として得た iH—NMR (400MHz, CDC1 ) δ :1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

[0823] Example 31— Similar to (1), Reference Example 45—The compound (0.150 g) obtained in (4) and the compound (0.077 g) obtained in Reference Example 32 IH-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2.18 (6H, s), 2.23 (3H, s), 2.41 (3H, s), 2.51 (3H, s), 3.64 (2H, s), 3.66 (2H, s), 4.01 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.73 (1H, dd, J = 3. 7, 1.2Hz), 6.99 (2H, s), 7.39 (1H, d, J = 3.7Hz).

 MSm / z: 553 (M + H) +.

 [0824] [Example 56]

 (1) 2- [4 -— [[Cyclopropyl-powered rubermoylmethyl- (5-methyl-2-phenol-4-azolmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methyl Propanoic acid ethyl ester

 [0825] [Chemical 260]

In the same manner as in Example 14- (1), the compound (0.150 g) obtained in Reference Example 14- (3) and cyclopropylamine (0.030 ml) were also used in the same manner as the title compound (0. llOg) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 0.48— 0.52 (2Η, m), 0.71—0.76 (2Η

 Three

 , m), 1.26 (1Η, br s), 1.35 (3H, t, J = 7.1 Hz), 1.44 (6H, s), 2.16 (6H, s), 2.26 (3H, s), 3.18 (2H, s), 3.48 (2H, s), 3.57 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.86 (2H, s), 7.44— 7.48 (3H, m), 7.89 (1H, br s), 8.0 0-8.02 (2H, m).

MSm / z: 534 (M + H) ⁺ .

[0827] (2) 2— [4— [[Cyclopropyl-powered rubermoylmethyl (5-methyl-2-phenol) Sazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] propanoic acid

 [Chemical 261]

[0829] In the same manner as in Example 31- (2), the title compound (0.076g) was obtained as a colorless solid using the compound (0.llOg) force obtained in Example 56- (1).

 iH—NMR (400MHz, DMSO d) δ: 0.36— 0.40 (2H, m), 0.59— 0.63

 6

 (2H, m), 1.32 (6H, s), 2.11 (6H, s), 2.25 (3H, s), 2.66— 2.68 (1H, m), 3.06 (2H, s), 3.53 (2H, s), 3.57 (2H, s), 6.94 (2H, s), 7.50—7.5 5 (3H, m), 7.83 (1H, d, J = 4.2Hz), 7.95—7.92 (2H, m).

 MSm / z: 506 (M + H) +.

 Elemental analysis value as C H NO 3Ζ4ΗΟ

 29 35 3 5 2

 Calculated values: C, 67.10; H, 7.09; N, 8.09.

 Analytical values: C, 67.21; H, 6.60; N, 7.93.

[0830] [Example 57]

 (1) 2-[4 [[[(Cyclopropylmethylcarbamoyl) methyl] mono (5-methyl-2-furoxazole-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] 2-methylpropane Acid ethyl ester

[0831] [Chemical 262]

[0832] In the same manner as in Example 14- (1), the compound (0.150 g) obtained in Reference Example 14- (3) and cyclopropylmethylamine (0.040 ml) were also used in the title compound ( 0.075 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 0. 19— 0.21 (2Η, m), 0.44— 0.48 (2Η

 Three

 , m), 0.92-0.97 (1Η, m), 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2.17 (6H, s), 2.27 (3H, s), 3.10—3.13 (2H, m), 3.22 (2H, s), 3.53 (2H, s), 3.60 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.93 (2H, s), 7.42— 7.46 (3H, m), 7.81 (1H, br s), 8.01— 7.98 (2H, m).

 MSm / z: 548 (M + H) +.

 [0833] (2) 2— [4 [[[[(Cyclopropylmethylcarbamoyl) methyl]-((5-methyl-2-furoxazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] 2 —Methylpropanoic acid

 [0834] [Chemical 263]

In the same manner as in Example 31- (2), the compound (0.075 g) force obtained in Example 57- (1) The compound (0.058 g) was obtained as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 0. 12— 0.16 (2H, m), 0.34— 0.39

 6

 (2H, m), 1.32 (6H, s), 2.13 (6H, s), 2.26 (3H, s), 2.66— 2.68 (1H, m), 2.97 (2H, t, J = 6.3Hz), 3.10 ( 2H, s), 3.54 (2H, s), 3.58 (2H, s), 7.00 (2H, s), 7.49-7.55 (3H, m), 7.85 (1H, t, J = 5.6Hz), 7.95 — 7.92 (2H, m).

MSm / z: 520 (M + H) ⁺ .

 Elemental analysis value C H N O

 30 37 3 5 2

 Calculated value: C, 68.16; H, 7.25; N, 7.95.

 Analytical values: C, 68.22; H, 6.93; N, 7.86.

[0836] [Example 58]

 (1) 2— [4 [[Putylcarbamoylmethyl- (5-methyl-2-phenoloxol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropenoic acid ester

[0837] [Chemical 264]

実施例 14— (1)と同様にして、参考例 14— (3)で得たィ匕合物（0.150g)とブチル ァミン (0.042ml)力も標題ィ匕合物（0.120g)を淡黄色油状物として得た。

Example 14- In the same manner as in (1), the strength of the compound (0.150 g) obtained in Reference Example 14- (3) and butyramine (0.042 ml) was also reduced from that of the title compound (0.120 g) to a pale yellow color. Obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 0.88 (3Η, t, J = 7.4Hz), 1.30―1.36 (5

 Three

H, m), 1.44 (6H, s), 1.47—1.53 (2H, m), 2.17 (6H, s), 2.27 (3H, s), 3. 19-3.25 (4H, m), 3.51 (2H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.90 (2H, s), 7.43-7.46 (3H, m), 7.78 (1H, br s), 8.01— 7.99 (2 H, m). MSm / z: 550 (M + H) +.

[0839] (2) 2— [4 [[Putylcarbamoylmethyl- (5-methyl-2-phenoloxol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropanoic acid

 [0840] [Chemical 265]

Example 31—In the same manner as (2), the title compound (0.069 g) was obtained as a colorless solid from the compound (0.120 g) obtained in Example 58- (1).

 ^ H—NMR (400MHz, DMSO d) δ: 0.81 (3H, t, J = 7.2Hz), 1.19— 1.

 6

 28 (2H, m), 1.32 (6H, s), 1.33—1.41 (2H, m), 2.12 (6H, s), 2.26 (3H, s), 3.04—3.09 (4H, m), 3.54 (2H, s), 3.58 (2H, s), 6.98 (2H, s), 7.50—7.55 (3H, m), 7.79 (1H, t, J = 6.1Hz), 7.92—7.95 (2H, m).

MSm / z: 522 (M + H) ⁺ .

 Elemental analysis value C H N O

 30 39 3 5 2

 Calculated values: C, 67.90; H, 7.60; N, 7.92.

 Analytical values: C, 68.09; H, 7.23; N, 7.87.

[0842] [Example 59]

 (1) 2— [2, 6 Dimethyl 4— [[(5 Methyl-2-phenoloxol 4-ylmethyl) mono (5 Pyridine-3-yl [1, 3, 4] oxadiazolu-2-ylmethyl) amino] methyl] Phenoxy] -2-methylpropanoic acid ethyl ester

[0843] [Chemical 266]

[0844] In the same manner as in Example 18, the compound (0.170 g) force obtained in Reference Example 46 was also obtained as a mixture (0.62 g) with triphenylphosphine oxide.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s),

 Three

 2. 18 (6H, s), 2.31 (3H, s), 3.75 (6H, br s), 4.28 (2H, q, J = 7.1Hz), 7.03 (2H, s), 7.40—7.42 (3H , m), 7.96— 7.99 (2H, m), 8.33— 8.30 (1H, m), 8.76 (1H, dd, J = 4.7, 1.7Hz), 9.26 (1H, d, J = l.5Hz).

 MSm / z: 596 (M + H) +.

 [0845] (2) 2- [2,6 Dimethyl-4-[[((5-Methyl-2-phenoloxazole-4-ylmethyl)] (5 Pyridine-3-yl [1, 3, 4] oxaziazo lu 2-ylmethyl) amino ] Methyl] phenoxy] -2-methylpropanoic acid

 [0846] [Chemical 267]

実施例 31— (2)と同様にして、実施例 59— (1)で得た混合物 (0.62g)から標題 化合物（0.065g)を無色固体として得た。

Example 31- In the same manner as (2), the title compound (0.065 g) was obtained as a colorless solid from the mixture (0.62 g) obtained in Example 59- (1).

 ^ H—NMR (400MHz, DMSO d) δ: 1.28 (6H, s), 2.10 (6H, s), 2.29 (3

 6

H, s), 3.69 (2H, s), 3.71 (2H, s), 4.06 (2H, s), 7.00 (2H, s), 7.44—7.46 (3H, m), 7.59 (1H, dd, J = 8.0, 4.8Hz), 7.86- 7.84 (2H, m), 8.2 8 (1H, d, J = 7.8Hz), 8.76 (1H, d, J = 3.2 Hz), 9.09 (1H, s). MS m / z: 568 (M + H) +.

[0848] [Example 60]

 2- [4 [[Strengthened rubermoylmethyl- (5-methyl-2-phenolox-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] 2 methylpropionic acid

[0849] [Chemical 268]

Example 31—In the same manner as in (2), the compound (0.119 g) of Example 19- (1) was also used to obtain the title compound (0.080 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.13 (6Η, s), 2.24 (

 6

 3H, s), 3.07 (2H, s), 3.53 (2H, s), 3.57 (2H, s), 7.15 (1H, br s), 7.3 1 (1H, br s), 7.49— 7.53 (3H, m ), 7.94—7.91 (2H, m).

 MSm / z: 466 (M + H) +.

[0851] [Example 61]

 (1) 2-[4 [[Strong Rubamoylmethyl 5 Methyl 2-p-Trixoxol 4-ylmethyl) amino] methyl] 2,6 Dimethylphenoxy] 2 Methylpropanoic acid ethyl ester

 [0852] [Chemical 269]

参考例 34—（2)で得た化合物（0.150g)の N, N ジメチルホルムアミド（5. Oml) 溶液に塩化アンモ-ゥム（0.020g)、トリェチルァミン（0. 16ml)と 1—ヒドロキシベン ゾトリアゾール水和物（0.040g)を加えた。これに 1—ェチル—3— (3 ジメチルアミ ノプロピル)カルポジイミド 塩酸塩 (0.080g)を加え、室温にて 20時間攪拌した。反 応溶液に水をカ卩え、クロ口ホルムにて抽出、有機層を硫酸マグネシウムにて乾燥した 。減圧下溶媒を留去し、得られた残渣を分取用薄層シリカゲルクロマトグラフィー（ク ロロホルム:メタノール =20:1)にて精製し、標題化合物（0.133g)を無色油状物と して得た。

Reference Example 34—To a solution of the compound (0.150 g) obtained in (2) in N, N dimethylformamide (5. Oml), ammonium chloride (0.020 g), triethylamine (0.16 ml) and 1-hydroxybenzazol. Triazole hydrate (0.040 g) was added. 1-ethyl-3- (3 dimethylamino Nopropyl) carposimide hydrochloride (0.080 g) was added and stirred at room temperature for 20 hours. Water was added to the reaction solution, extracted with black mouth form, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (chloroform: methanol = 20: 1) to give the title compound (0.133 g) as a colorless oil. It was.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 16 (6H, s), 2.24 (3H, s), 2.40 (3H, s), 3.23 (2H, s), 3.53 (2H, s), 3.

60 (2H, s), 4.27 (2H, q, J = 7.1Hz), 5.44 (1H, br), 6.91 (2H, s), 7.25 (

2H, m), 7.69 (1H, br), 7.87 (2H, d, J = 8.2Hz).

 MS m / z: 508 (M + H) +.

[0854] (2) 2— [4 — [[Ruamoylmethyl- (5-methyl-2-p-trioxazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] 2 methyl Propanoic acid

[0855] [Chemical 270]

Example 61—Methanol (2. Oml) of Compound (0.130 g) obtained in (1) and Tetrahydrofuran

 To the mixed solution of (5. Oml) was added 1N sodium hydroxide aqueous solution (1.3 ml), and the mixture was heated to reflux for 15.5 hours. The temperature was returned to room temperature, and water was added to the reaction solution, followed by washing with jetyl ether. The aqueous layer was neutralized with 1N aqueous hydrochloric acid and extracted with black mouth form. The organic layer was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and hexane and diethyl ether were added to the obtained residue and crystallized to obtain the title compound (0.056 g) as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.50 (6Η, s), 2.20 (6Η, s), 2.28 (3H, s

 Three

), 2.40 (3H, s), 3.22 (2H, s), 3.57 (2H, s), 3.62 (2H, s), 5.75 (1H, br), 6.95 (2H, s), 7.26 (2H, m) , 7.75 (1H, br), 7.87 (2H, d, J = 8.2Hz). Elemental analysis value CHNO · Η As O Calculated value: C, 65.17; H, 7.09; N, 8.44.

 measured value:. 64.92; H, 6.73; N, 8.20.

[0857] [Example 62]

 (l) 2- [4-[[[2- (4-Methoxyphenol) 5-methyloxazole-4-methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] -2 —Methyl propanoic acid ethyl ester

 [0858] [Chemical 271]

[0859] Reference Example 47— The compound obtained in (2) was dissolved in dichloromethane (5 ml) to give methylamine hydrochloride

 (0.024g), 1-hydroxybenzotriazole hydrate (0.040g), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.086g) and triethylamine (0.112ml) at room temperature And stirred for 18 hours. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 20) to give the title compound (0.128 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 16 (6H, s), 2.23 (3H, s), 2.79 (3H, d, J = 4.9Hz), 3.21 (2H, s), 3.48 (2H, s), 3.59 (2H, s), 3.86 ( 3H, s), 4.28 (2H, q, J = 7.2Hz), 6.89 (2H, s), 6.97 (2H, d, J = 9.0Hz), 7.75— 7.86 (1H, m), 7.93 (2H, d , J = 9.0 Hz).

 MS m / z: 538 (M + H) +.

[0860] (2) 2- [4-[[[2- (4-Methoxyphenyl) 5-methyloxazole-4-methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy ] —2-Methylpropanoic acid [0861] [Chemical 272]

Example 62— The compound (0.128 g) obtained in (1) was dissolved in tetrahydrofuran (3 ml), 0.5 N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was heated to reflux for 22 hours. After cooling, the mixture was neutralized with 1N aqueous hydrochloric acid and extracted with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer silica gel chromatography (methanol: chloroform = 1: 10) to give an oil. This was dissolved in ethanol and dioxane and lyophilized to give the title compound (0.109 g) as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.45 (6 Η, s), 2.17 (6 Η, s), 2.26 (3 Η, s

 Three

 ), 2.77 (3H, d, J = 4.9Hz), 3.18 (2H, s), 3.50 (2H, s), 3.60 (2H, s), 3.86 (3H, s), 6.91 (2H, s) , 6.96 (2H, d, J = 8.8Hz), 7.77— 7.86 (1H, m), 7.93 (2H, d, J = 9. OHz).

 Elemental analysis value as C H N O -1.75H O

 28 35 3 6 2

 Calculated values: C, 62.15; H, 7.17; N, 7.77.

 measured value:. 62.13; H, 6.82; N, 7.46.

[0863] [Example 63]

 (1) 2- [4 [[Strengthened rubermoylmethyl- [2- (4-methoxyphenol) 5 Methyloxazole-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] -2-methyl Acid ethyl ester

[0864] [Chemical 273]

[0865] 実施例 61— (1)と同様にして、参考例 47— (2)の化合物力も標題ィ匕合物（0.122 g)を無色油状物として得た。

Example 61— In the same manner as in (1), the compound power of Reference Example 47- (2) was also obtained as the title compound (0.122 g) as a colorless oil.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

17 (6H, s), 2.23 (3H, s), 3.23 (2H, s), 3.52 (2H,), 3.60 (2H, s), 3.8 6 (3H, s), 4.28 (2H, q, J = 7.2Hz), 5.44— 5.54 (1H, m), 6.91 (2H, s), 6.96 (2H, d, J = 9. OHz), 7.65— 7.74 (1H, m), 7.89— 7.95 (2H, m MS m / z: 524 (M + H) ⁺ .

 [0866] (2) 2— [4 [[Strengthened rubermoylmethyl- [2- (4-methoxyphenyl) 5 methyloxazol-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] —2— Methyl propane

 [0867] [Chemical 274]

Example 62—In the same manner as in (2), the title compound (0.067 g) was obtained as a colorless solid from the compound (0.122 g) obtained in Example 63 (1).

 'H-NMR (400MHz, CDCl) δ: 1.36— 1.51 (6Η, m), 2.16 (6Η, s), 2.2

 Three

 6 (3H, s), 3.19 (2H, s), 3.54 (2H, s), 3.59 (2H, s), 3.85 (3H, s), 6. 12 -6.28 (1H, m), 6.83— 7.00 (4H, m), 7.64— 7.76 (1H, m), 7.91 (2H, d, J = 9. OHz).

 Elemental analysis value as C H NO · ΗΟ · 0.2 dioxane

 27 33 3 6 2

 Calculated values: C, 62.86; H, 6.94; N, 7.91.

 measured value:. 62.63; H, 6.79; N, 7.55.

[0869] [Example 64]

(1) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2m-trioxazole-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropane

, () 7.77.83H m.1

 ,,,, J ((((.82H s 6.872H s 7.217.271H m 7.331H 7.7Hz = 1

 ,, J ,, ((((2.13H S 2.763H.9HZ 3.172H s 3.02H s 3 =

 ,,,, () () () (δ HNMR OOMHZ CDC1: 1.396H S 2.16H S 2.263H sI

[] 0873

[] 0872

[]] 087075 ϊ, Η H Elemental analysis value CHNO · 1.25Η

 28 35 3 5 2

 Calculated value: C, 65.16; H, 7.32; N, 8.14.

 measured value:. 64.94; H, 7.06; N, 7.90.

[0875] [Example 65]

 (1) 2— [4 [[Strong Rubamoylmethyl 5-methyl 2-m-tolyloxazole 4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropenoic acid ester

 [0876] [Chemical 277]

Example 61— In the same manner as in (1), the compound power of Reference Example 48- (2) was also obtained as the title compound (0.125 g) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.24 (3H, s), 2.42 (3H, s), 3.24 (2H, s), 3.54 (2H, s), 3.

60 (2H, s), 4.28 (2H, q, J = 7.2Hz), 5.57— 5.75 (1H, m), 6.91 (2H, s)

, 7.21-7.28 (1H, m), 7.33 (1H, t, J = 7.6Hz), 7.59— 7.67 (1H, m), 7

.75-7.84 (2H, m).

 MS m / z: 508 (M + H) +.

[0878] (2) 2— [4— [[Strengthened rubermoylmethyl (5-methyl-2-m-triloxazol- 4

—Ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropanoic acid [0879] [Chemical 278]

[ ^ [ ^ [ ^ / — — /— 、 -^^ ^-9- ( / ェ cm — ε) -Ζ - ^ ^^ ^]] -S (2) 880]Example 62—Same as in (2), Example 65—Compound (0.125 g) force obtained in (1) [OSZ ^ [S880] Difficult zci

[^ [^ [^ / — — / —,-^^ ^ -9- (/ é cm — ε) -Ζ-^ ^^ ^]] -S (2) 880]

• ₊ (H + PV) 8S9: ^Z / ^RA SPV • ( ^s 'HI) 86' L '(m' HI) Z8 'L' HI) 89

'L' (m 'HS) 6S' L '( ^s ' HS) I6 9''HI) 8 ^' 9 '( ^Z H80 Ζ = Γ¾' UZ) SZ

'( ^S ' HS) 09 Έ '( ^S ' HS) S Έ '( ^S ' HS) S Έ '( ^S ' HS) 9S '( ^S ' H9) ZI

'( ^S ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 ('ιοαο' ZH OO ^) H NH _T

Ό)呦

Ό) 呦

[6 2 ^] [2880] ^^ e / ^ e ^ ^

[ ^ [ ^ [ ^ / — — /— 、 -^^ ^-9- ( / ェ crn^— ε) -Ζ — ^ / ¾ (ΐ)

[^ [^ [^ / — — / —,-^^ ^ -9- (/ é crn ^ — ε) -Ζ — ^ / ¾ (ΐ)

[99ί ^ ¾ϊ 第] [Ϊ880] • ₊ (H + V) 08: ^z / ra SPV • (ra * HS) 98 'L- £ L' L '(^' HI) 89 'Z-6

9 Ί '^' HI) 8S 'L' (^ 'HI) ZS · Ζ— S' L '( ^S ' HS) 6 · 9 '(^' HI

) 9Z '9-99' 9 '( ^S ' HS) I9 Έ '( ^S ' HS) 99 Έ '( ^S ' HS) 0S Έ '( ^S ' HS) I ^ 'Z' ( ^S 'HS) 6S' Z '( ^S ' H9) 6I 'Z' ( ^S 'Η9) 8 Ί-9 (\ OaO' ZH 00 ^) H NH _T

961 ·

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV • ( ^Ζ Η ^ 9 · 8 = ΓΡ ΉΖ) 16 'L' ΗΙ) 09 'L' ( ^Z HS 8 = Γ'Ρ 'HS)' L '( ^s ' HS) 06 · 9 '' HI) 19 '9' ( ^Z H80 · Ζ = Γ¾ 'UZ) SZ ·

'( ^s ' HS) 09 Έ' ( ^s ' HS) S9 Έ '( ^s ' UZ) Z Έ' ( ^s ¾ε) ΐ 'Ζ' ( ^s ' Η9) ΖΙ 'Ζ

'( ^S ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 ('ιοαο' ZH OO ^) H NH _T

(^§08ΐ Ό)呦

( ^§ 08ΐ Ό) 呦

[18] [8880] ^^ e / ^ e ^ ^

[ ^ [ ^ [ ^ / — — /— 、 -^^ ^-9- ( / ェ cm^— ） -Z — ^ / ¾ (ΐ)

[^ [^ [^ / — — / —,-^^ ^ -9- (/ é cm ^ —) -Z — ^ / ¾ (ΐ)

 m \ 880]

• 8 'L' Ν · 9Ι 'L ΊΟ'98' 9 'Η'ε ^ Ό9 thigh

 ΊΙ · 8 'Ν · 68 · 9 Ίθ'61 · 9' Η'ΙΖ Ό9 '

• ( ^s 'ΗΙ) 86' L '(m' ΗΙ) Ζ 8 'L' ΗΙ) Ζ 9 'L' ΉΖ) 6 £ 'L' ( ^s 'ΗΖ) Ρ 6 9'('ΗΙ) Ζ 0 9' ( ^s 'ΗΖ) Ζ9 Έ' ( ^s 'Η2) Ζ9 Έ' ( ^s 'ΗΖ) ΖΖ Έ' ( ^s Ήε) 6 Ζ 'Ζ' ( ^s 'Η9) Ι2' Ζ '( ^s ' Η9) 6 · ΐ: 9 (\ θαθ 'ZH 00 ^) H NH _T

oM ^ m ^ ^ ( ^§ 69ο -o) ^

16V

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV

Ζ-{_ [S82 ^] [, 680]

Ζ-{_

^ Ρ, e [^ [^ [^ / — — / — /: ^ (/ -e ^ / (Η-V) -2- ^ -9] ^ / ¾ ^]] — — ^ ー 9

 [89p «^] [S680] '91 'L' Ν · 80 · 8 'ΙΟ'ΟΟ · 9' Η · 6Ζ Ό9 Thigh

 '£ Ζ · 8' N'S9 'L' ΙΟ'ΟΙ · 9 'Η'εΐ Ί9'

( ^Ζ Η8Ζ 8 = ΓΡ 'Η2) Ι6' L '' ΗΙ) Ι 8 'L' ( ^Ζ Η8Ζ 8 = ΓΡ 'HS)''( ^s ' HS) S6 9'('ΗΙ) 09 9' Η2) 99 Έ '(ΉΖ) 09 Έ' ( ^s ' HS) S Έ '( ^s Ήε) 8 Ζ' Ζ '( ^s ' Η9) 6 Ι' Ζ '( ^s ' Η9) Ζ ΐΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

9 'S— [ ^ [ ^ [ ^ / — — /— 、 -^^ ^-9- ( / -ェ cm^ ） — ^ / ¾ (S) [0680][ZSZ ^ [Ϊ680] Difficult zci: ^ —

9 'S— [^ [^ [^ / — — / —,-^^ ^ -9- (/ -e cm ^) — ^ / ¾ (S) [0680]

• ₊ (H + PV) 8S9: ^z / ^ra SPV

861 ·

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA In the same manner as in Example 62- (1), the title compound (0.169 g) was obtained as a pale yellow oil from the compound (0.167 g) obtained in Reference Example 49- (2).

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, m),

 Three

 2.17 (6H, s), 2.27 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.23 (2H, s), 3.5

2 (2H, s), 3.60 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.89 (2H, s), 7.65— 7

.77 (3H, m), 8.11 (2H, d, J = 8.1 Hz)

MS m / z: 576 (M + H) ⁺ .

[0896] (2) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- [5-Methyl-2- (4 trifluoromethylphenol) oxazole-4-ylmethyl] amino] methyl] phenoxy] 2-Methyl Propanoic acid

[0897] [Chemical 284]

62—Similar to (2), Example 68—Compound (0.161 g) force obtained in (1) was also applied to the title compound.

 (0. 133 g) was obtained as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.43 (6Η, s), 2.17 (6Η, s), 2.30 (3Η, s

 Three

 ), 2.77 (3H, d, J = 4.6Hz), 3.19 (2H, s), 3.52 (2H, s), 3.60 (2H, s), 6.89 (2H, s), 7.64-7.75 (3H, m), 8.10 (2H, d, J = 8.3Hz).

 Elemental analysis value as C H FNO 1.25HO

 28 32 3 3 5 2

 Calculated values: C, 58.99; H, 6.10; F, 10.00; N, 7.37.

 measured value:. , 59.11; H, 5.94; F, 9.69; N, 7.08.

[0899] [Example 69]

(1) 2— [4 [[Strong rubermoylmethyl- [5-methyl-2- (4 trifluoromethylphenol) oxazole-4-ylmethyl] amino] methyl] -2, 6 dimethylphenoxy] -2 Methyl propanoic acid ethyl ester [0900] [Chemical 285]

[0901] In the same manner as in Example 61- (1), the compound of the reference Example 49- (2) (0.177 g) also gave the title compound (0.125 g) as a colorless oil.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.27 (3H, s), 3.25 (2H, s), 3.55 (2H, s), 3.61 (2H, s), 4.

28 (2H, q, J = 7.2Hz), 5.52— 5.69 (1H, m), 6.91 (2H, s), 7.52— 7.60

(1H, m), 7.70 (2H, d, J = 8.3Hz), 8.10 (2H, d, J = 8.3Hz).

 MS m / z: 562 (M + H) +.

[0902] (2) 2— [4 [[Strengthened rubermoylmethyl— [5-methyl-2— (4 trifluoromethylphenol) oxazole-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy ] -2 Methylpropanoic acid

[0903] [Chemical 286]

62—Similar to (2), Example 69—Compound (0.125 g) force obtained in (1) is the same as the title compound.

 (0.040 g) was obtained as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.47 (6Η, s), 2.20 (6Η, s), 2.31 (3H, s

 Three

 ), 3.22 (2H, s), 3.54-3.64 (4H, m), 6.16— 6.26 (1H, m), 6.92 (2H, s), 7.61-7.74 (3H, m), 8.10 (2H, d, J = 8.1Hz).

 MS m / z: 534 (M + H) +.

[0905] [Example 70] (1) 2- [4 [[Strong rubermoylmethyl- [2- (4 fluorophenyl) 5-methyloxazol-4-ylmethyl] amino] methyl] -2, 6 dimethylphenoxy] -2-methylpropanoic acid Ethyl ester

[0906] [Chemical 287]

Example 61— In the same manner as in (1), the compound (0.450 g) obtained in Reference Example 50- (2) also gave the title compound (0.300 g) as a colorless oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.24 (3H, s), 3.24 (2H, br), 3.53 (2H, s), 3.60 (2H, s), 4.28 (2H, q, J = 7.08Hz), 5.63 (1H, br), 6.91 (2H, s), 7.13 (2H, t, J = 8.66Hz), 7.64 (1H, br), 7.98 (2H, t, J = 8.66Hz).

MS m / z: 512 (M + H) ⁺ .

[0908] (2) 2— [4 [[Strong Rubamoylmethyl- [2- (4 Fluorophenol) 5-Methyloxazol-4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] —2— Methyl propanoic acid

 [0909] [Chemical 288]

[0910] Example 70— The compound (0.300 g) obtained in (1) was dissolved in a mixed solution of tetrahydrofuran (6 ml) and ethanol (6 ml), and 5N sodium hydroxide aqueous solution (0.24 ml) was added. In addition, the mixture was stirred at room temperature for 15.5 hours. 4N hydrochloric acid aqueous solution was added for neutralization, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to preparative thin layer silica gel chromatography (methanol: The title compound (0.153 g) was obtained as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.44 (6Η, s), 2.21 (6Η, s), 2.30 (3H, s

 Three

 ), 3.19 (2H, s), 3.60 (2H, s), 3.63 (2H, s), 6.99 (2H, s), 7.21 (2H, t, J = 8.78Hz), 8.01 (2H, dd, J = 5.25, 9.03Hz).

 Elemental analysis value as C H FN O -0.3H O

 26 30 3 5 2

 Calculated values: C, 63.87; H, 6.31; F, 3.89; N, 8.59.

 measured value:. 63.76; H, 6.27; F, 3.82; N, 8.33.

[0911] [Example 71]

 (l) 2- [4-[[[2- (4 Fluorophenyl) 5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2,6 dimethylphenoxy] 2-methyl Ethyl propanoic acid ester

 [0912] [Chemical 289]

[0913] In the same manner as in Example 62- (1), the compound (0.470 g) obtained in Reference Example 50- (2) also gave the title compound (0.260 g) as a colorless oil.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s),

 Three

 2.17 (6H, s), 2.24 (3H, s), 2.79 (3H, d, J = 3.30Hz), 3.22 (2H, br), 3.48 (2H, s), 3.59 (2H, s) , 4.28 (2H, q, J = 7.08Hz), 6.89 (2H, s), 7.1 4 (2H, m), 7.75 (1H, br), 7.98 (2H, m).

MS m / z: 525 (M + H) ⁺ .

[0914] (2) 2- [4-[[[2- (4 Fluorophenyl) 5-methyloxazole-4-methyl] methylcarbamoylmethylamino] methyl] -2, 6 dimethylphenoxy] 2-Methylpropanoic acid

[0915] [Chemical 290]

In the same manner as in Example 70- (2), the title compound (0.170 g) was obtained as a colorless solid from the compound (0.260 g) obtained in Example 71- (1).

 'H-NMR (400MHz, CDCl) δ: 1.50 (6Η, s), 2.21 (6Η, s), 2.28 (3H, s

 Three

 ), 2.80 (3H, d, J = 4.64Hz), 3.20 (2H, s), 3.51 (2H, s), 3.61 (2H, s), 6.94 (2H, s), 7.15 (2H, t, J = 8.78Hz), 7.76 (1H, br), 7.99 (2H, dd, J = 5.25, 8.78Hz).

 Elemental analysis value C H FN O -0. As IHO

 27 32 3 5 2

 Calculated values: C, 64.94; H, 6.50; F, 3.80; N, 8.41.

 measured value:. 64.65; H, 6.58; F, 3.73; N, 8.22.

[0917] [Example 72]

 (l) 2- [4-[[[2- (3,4-Dichlorophlephthalate) -5-Methyloxazole-4-yl Methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethyl Enoxy] —2— Methylpropanoic acid ethyl ester

[0918] [Chemical 291]

実施例 62— (1)と同様にして、参考例 51— (2)で得たィ匕合物 (0.208g)力も標題 化合物（0. 190g)を黄色油状物として得た。

Example 62—In the same manner as (1), the compound (0.208 g) force obtained in Reference Example 51— (2) also gave the title compound (0.190 g) as a yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

17 (6H, s), 2.25 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.22 (2H, s), 3.50 (2H, s), 3.59 (2H, s), 4.28 ( 2H, q, J = 7.1Hz), 6.88 (2H, s), 7.53 (1H , d, J = 8.3Hz), 7.58-7.68 (1H, m), 7.82 (1H, dd, J = 8.3, 2. OHz), 8

.08 (1H, d, J = 2. OHz).

MS m / z: 576 (M + H) ⁺ .

[0920] (2) 2- [4-[[[2- (3,4-Dichlorophlephthalate) 5-Methyloxazole-4-yl Methyl] methylcarbamoylmethylamino] methyl] -2, 6- Dimethylphenoxy] —2-methylpropanoic acid

[0921] [Chemical 292]

[0922] In the same manner as in Example 70- (2), the compound (0.190 g) obtained in Example 72- (1) was also converted from the title compound (0.156 g) as a pale yellow solid. Obtained.

 'H-NMR (400MHz, CDCl) δ: 1.38 (6Η, s), 2.14 (6Η, s), 2.27 (3H, s

 Three

 ), 2.76 (3H, d, J = 4.9Hz), 3.16 (2H, s), 3.50 (2H, s), 3.57 (2H, s), 6.86 (2H, s), 7.52 (1H, d, J = 8.3Hz), 7.60- 7.70 (1H, m), 7.81 (1H, dd, J = 8.3, 2. OHz), 8.07 (1H, d, J = 2. OHz).

 Elemental analysis value as C H C1NO 1.75HO

 27 31 2 3 5 2

 Calculated values: C, 55.91; H, 6.00; CI, 12.23; N, 7.24.

 measured value:. , 55.95; H, 5.71; C1, 12.13; N, 6.93.

[0923] [Example 73]

 (1) 2— [4 [[Strengthened rubermoylmethyl- [2 -— (3,4-dichlorophage)-5-methyloxazol 4-ylmethyl] amino] methyl] -2, 6 dimethylphenoxy ] —2-Methylpropanoic acid ethyl ester

[0924] [Chemical 293]

[0925] In the same manner as in Example 61- (1), the compound (0.204g) strength obtained in Reference Example 51- (2) also gave the title compound (0.166g) as a pale yellow oil.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.25 (3H, s), 3.23 (2H, s), 3.53 (2H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.2Hz), 5.71— 5.88 (1H, m), 6.90 (2H, s), 7.48— 7.56 (2H, m), 7.81 (1H, dd, J = 8.3, 2. OHz), 8.07 (1H, d, J = 2. OHz).

[0926] (2) 2— [4 [[Strong Rubamoyl Methyl- [2— (3, 4-Diclonal Methanol) -5-Methyloxazol-Lu 4-ylmethyl] amino] methyl] —2, 6 Dimethyl Phenoxy] —2-methylpropanoic acid

 [0927] [Chemical 294]

In the same manner as in Example 70- (2), the title compound (0.155 g) was obtained as a colorless solid from the compound (0.166 g) obtained in Example 73- (1).

 'H-NMR (400MHz, CDCl) δ: 1.45 (6Η, s), 2.18 (6Η, s), 2.28 (3H, s

 Three

 ), 3.20 (2H, s), 3.47-3.64 (4H, m), 6.04— 6.38 (1H, m), 6.90 (2H, s), 7.50 (1H, d, J = 8.3Hz), 7.53— 7.62 ( 1H, m), 7.80 (1H, d, J = 8.3 Hz), 8.06 (1H, s).

[0929] [Example 74]

(l) 2- [4-[[[2- (3-Methoxyphenyl) 5-methyloxazole-4-methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] — 2—Mech ^Ζ ΗΙ '8 = Γ' Ί- 'HI) 9S' L '' ΗΙ) 20 'Z-96 9' ( ^s ' Η2) 88 9 '( ^s ' HS) Z8 ε' ( ^S 'HS) 89 · ε '( ^S ' HS) 09 · ε '( ^S ' HS) ZI · ε '( ^Ζ Η6 · = ΓΡ' HS) 9Z 'Ζ' ( ^s Ή £) ΙΖ 'Ζ' ( ^s ' Η9) 9Ι 'Ζ' ( ^s 'Η9) ΐ · ΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

 邈 ΰ 1 /

 [^ [^ ^ / ¾ ^ [→-Λ ^ ^^ Λ ^-9-(/ ェ ^ ΕΗ ー S) [2S60]

• ₊ (H + PV) 8S9: ^z / ^ra SPV • (m 'Ηΐ) 8' L- L 'L' ( ^Ζ ΗΙ · 8 = ΓΡ 'ΗΙ) 69' L '(^' ΗΙ) 99 • Ζ- ^{Ι9 'L' (Ζ ΗΙ ·} 8 = Γ 'HI) 9S' L '(Ζ ΗΖ' 2 Ί '8 = Γ' ΡΡ 'ΗΙ) 86 · 9' (s 'HS) 68 · 9' (Ζ Η2 · = Γ'¾ 'HS) 8S''( ^s ' HS) 68 Έ '( ^s ' Η2) 09 Έ '( ^s ' Η2)

09 Έ '( ^S ΉΖ) Έ Έ' ( ^Ζ Η6 · = ΓΡ ¾ε) 08 'Ζ' ( ^S 'HS) 9S' Ζ '( ^S ' Η9) 9 Ζ Ζ '( ^s ' H9) S Ί' ( ^Ζ Η2 · = Γ'ΐ 'HS) 9S · !: 9 (ΐΟΟΟ' ZH 00 ^) H NH _T

Ό)呦

Ό) 呦

[362 ^] [0S60] D ^ D

903

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA ), 7.49-7.54 (1H, m), 7.55-7.62 (1H, m), 7.75-7.85 (1H, m). Elemental analysis value as CH NO 2ΗΟ

 28 35 3 6 2

 Calculated values: C, 61.64; H, 7.20; N, 7.70.

 measured value:. 61.83; H, 6.98; N, 7.60.

[0935] [Example 75]

 (1) 2- [4 [[Strengthened rubermoylmethyl- [2- (3-methoxyphenyl) -5-methyloxazole-4-ylmethyl] amino] methyl] -2,6 Dimethylphenoxy] -2-methyl Ethyl panate ester

[0936] [Chemical 297]

Example 61—In the same manner as in (1), the compound (0.196 g) obtained in Reference Example 52- (2) also gave the title compound (0.119 g) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.25 (3H, s), 3.24 (2H, s), 3.54 (2H, s), 3.60 (2H, s), 3.88 (3H, s), 4.28 (2H, q , J = 7.2Hz), 5.39— 5.51 (1H, m), 6.91 (2H, s), 6.95-7.01 (1H, m), 7.36 (1H, t, J = 7.9Hz), 7.49— 7.54 (1H, m), 7.56-7.61 (1H, m), 7.63-7.68 (1H, m).

MS m / z: 524 (M + H) ⁺ .

 [0938] (2) 2— [4 [[Strong Rubamoylmethyl- [2- (3-Methoxyphenol) 5 Methyloxazole-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] -2 —Methylpropyl

[0939] [Chemical 298] 'L' (m 'HI) SI' L '( ^s ' HS) I6 9''HI)S9' 9 '( ^Z H80 Ζ = Γ¾' UZ) SZ

'( ^s ' HS) 09 Έ '( ^s ' HS) S Έ '( ^s ' UZ) Z Έ '( ^s ' HS) 9S 'Z' ( ^s 'Η9) ΖΙ' Z

'( ^S ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 ('ιοαο' ZH OO ^) H NH _T

®¾ ^ ( ^§ 09 Ό) 呦 (ε) -S9p}% # ^ O # ^^ (I) -I9p «^

[66] β 60]

[ ^ [ ^ [ ^ / — — /— 、

[^ [^ [^ / — — / —,

 Jp ^ ^ -9- (/-é cl / — ε) -Ζ-^ ^^ ^]] -S (I)

 [9Ζί ^ ¾ϊ 第] [ΐ½0] • 19 'L' N'S8 · 9 'Η · 28 Ί9 Thigh

 · 6 'L' Ν · 86 · 9 'Η · 29 Ί 9'

 O H9Z 'I- O N H O UMl ^ ^ 峯 ^

 • (ra 'HI) 99' Z-09

^{'L' (Z HI · 8} = ΓΡ 'ΗΙ) 89' L '(s' HI) 19' L '(Ζ ΗΙ · 8 = Γ' HI) 9S 'L' (^

'HI) 66' 9-Z6 9 '(^' HS) 96 9 9 88 9 '(^' Ηΐ) 0 '9-9Ζ' 9 '( ^s ' HS)

88 Έ '(' Η) 9 Έ '( ^s ' Η2) 6 Ι Έ '( ^s ' HS) 6S 'Ζ' ( ^s 'HS) 6I' Ζ '( ^s ' Ηε) ζχ 'ζ' ( ^s ¾ε) ζ · Χ '( ^s ¾ε) 9 · ΐ: 9 (ιοαο' ZH OO ^) H NH _T

⁰ -M ^ m ^ ^ ( ^§ οχ Ό) 呦

^{®¾ ^ (§ 6ΙΙ Ό) ^^} ^ (Ι) -9 p} «, Ekko; (S) -0 p}« [0 ^ 60]

803

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV [TOS ^] [8 ^ 60] d ^ d cl cl l / ^ ー S over ^ ー 9 — [^ [^ ^ / ¾ ^ [^

 / — One / —, ^ / ^ ー S— (-e ci / — —]

 mm [6o]

'L · 8' Ν · 90 '' ή'-ΙΖ · 9 'Η · 92 · 9': Army Thigh

 • 69 · 8 'Ν'εβ Έ' ή ^ Ζ · 9 'Η · 89 · 9': Military

I) 8Z 'L'('HI)0Z'L'(m'HI)69'L'(^' HI) S'L '(^' HI) SI'L '( ^s

'HS) 96 9'('HI) S0 9' ( ^s ' HS) S9 Έ '( ^s ' HS) 89 Έ' ( ^s ΉΖ) £ Ζ Έ '( ^s

¾ε) οε 'ζ' ( ^s 'H9) xs' z '( ^s ¾9) 6 · χ ： 9 (\ oao' ZH OO ^) H NH _T

[60]

[ ^ [ ^ [ ^ / — — /— 、 [οοε ^] [s 60] 邈 1

[^ [^ [^ / — — / —,

Jp ^ ^ -9- (/ ΰ ΰ / —ε) -Ζ ^ / ¾]] ー] (S) [„60]

• ₊ (H + PV) Sig: z / ^ra SPV • (ra 'ΗΙ) 8Ζ' L '(m HI) 69' L '(^ q' HI) S9 'L' (^ 'Ηΐ) ε

603

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV CH FN〇H.

 ,) () 7.801H br.

 ,,,, () () ,,,, () () (, 6.932H s 7.11H m 7.31H m 7.681H m 7.791H m

 ,, J,) () ,,,, () () (,,) 2.803H. Oopiz 3.232H s 3.32H s 3.622H s =

 , () ,,,, () () (, δ: HNMR ^ OOMHZ CDCl: 1.506H s 2.216H s 2.293H sI

 g) Painting.翁 ^^ τ 270

 [S0,] ≠ ss room sis ^^ 0952p ^^ 77l1 <

[] 0949 Calculated values: C, 64.71; H, 6.52; F, 3.79; N, 8.38.

 measured value:. 64.45; H, 6.44; F, 3.98; N, 8.18.

[0953] [Example 78]

 (1) 2- [4 -— [[[2- (2-Fluorophenyl) 5-methyloxazole- 4-methyl] methylcarbamoylmethylamino] methyl] -2,6 dimethylphenoxy] 2-methyl Ethyl propanoic acid ester

 [0954] [Chem 303]

To 〇

Example 62—In the same manner as in (1), the title compound (0.43 g) was obtained as a colorless oil from the compound (0.55 g) obtained in Reference Example 54- (2).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s),

 Three

 2.16 (6H, s), 2.27 (3H, s), 2.81 (3H, d, J = 4.76Hz), 3.23 (2H, br), 3.52 (2H, s), 3.60 (2H, s) , 4.27 (2H, q, J = 7.08Hz), 6.90 (2H, s), 7.1 9 (2H, m), 7.42 (1H, m), 7.97 (2H, m).

 MS m / z: 526 (M + H) +.

[0956] (2) 2- [4-[[[2- (2 Fluorophenyl) 5-methyloxazole-4-methyl] methylcarbamoylmethylamino] methyl] -2, 6 dimethylphenoxy] 2-Methylpropanoic acid

 [0957] [Chem 304]

[ ^ [ ^ [ ^ / — — /— 、 Example 70—In the same manner as (2), the title was obtained from the compound (0.43 g) obtained in Example 78— (1). [90S ^] [S960]

[^ [^ [^ / — — / —,

 Jp ^ ^ -9- {^ — ^ J ^ -Z) -Z ^ / ¾]]]] (S) [2960]

• ₊ (H + PV) Sig: z / ^ra SPV • (ra 'ΗΙ) 86' L '(' Ηΐ) 8 'L' (^ 'Ηΐ) ΐ · L' (m 'HS) 8I' L '( ^s ' HS) S6 9 '' HI) OZ '9' ( ^Z H80Ζ = Γ¾ 'UZ) SZ'

'( ^s ' HS) I9 Έ '( ^s ' HS) 99 Έ 'HS) S Έ' ( ^s 'U £) LZ' Z '( ^s ' H9) ZI

'( ^S ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 ('ιοαο' ZH OO ^) H NH _T

[S0S ^] [0960]

[ ^ [ ^ [ ^ / — — /— 、

[^ [^ [^ / — — / —,

[6Ζί ^ ¾ϊ 第] [6S60] ΌΖ · 8 'Ν · 96 Έ' J'S9 · 9 'Η: 8 · 9': Army Thigh

 • S · 8 'N-S8 Έ' 8 · 9 'Η · 8 Ι '99'

 ε 2ε

 Λ.Λ U D ϊ ^ ^

(Ra 'HS) 86' L '(m' Ηΐ) ε 'L' (m 'UZ) ZZ' L '( ^s ' HS) 96 9

'( ^s ' HS) S9 Έ' ( ^s ' HS) 99 Έ '( ^s ' HS) IS Έ' ( ^Ζ Η 9 · = ΓΡ 'HS) S8' Z '( ^s ¾ε) οε' ζ '( ^S ' H9) os' z '( ^S ' H9) 09 '!: 9 (\ oao' ZH OO ^) H NH _T

31-3

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV (ra 'ΗΙ) 98 Ί-91' L '( ^Ζ Η0 6 = ΓΡ' Η2) 96 9 '( ^s ' Η2) 68 9' ( ^Z UZ Ί =

Γ'¾ 'UZ) SZ''( ^Ζ Η0 · = Γ'¾' Η2) 60 '( ^s ' Η2) 09 Έ' ( ^s ' HS) 8 Έ '( ^s

'HS) IS Έ' ( ^Ζ Η6 · = ΓΡ 'HS) 6Z' Ζ '( ^s Ή £) £ Ζ' Ζ '( ^s ' Η9) 9 Ι' Ζ '^' Η

6) 6, 'l- Ί' ( ^Ζ Η2 · = Γ'ΐ 'HS) 9S · ΐ: 9 (' ΐΟΟΟ 'ZH 00 ^) H NH _T

 .つ; ^ ^ Township (¾91

(S) -99p}%#、ェっコ ； （Ό -S9p}« Ό)

(S) -99p}% #, ecco; (Ό -S9p} «

[Z0S ^] [9960] D ^ D

^ ー e ^ — 9 [^ [^ ^ / ¾ ^ [

 →-Λ ^ ^^ Λ ^-9-(/ AE) -s]]]-^]-s (x)

 [08p «^] [S960] • 99 · 8 'Ν'ΖΟ' 'Λ'- Ζ · 9' Η · 98 Έ9 ': Army Thigh

 Έ9 · 8 'Ν · 06 Έ' ^ '62 · 9 'Η'ΙΙ · 9':

 ^ O HZ Ό · O H O UMl ^ ^ 峯 ^

 • (ra 'HI) 66' L '(' HI) 16 'L' (^ 'Ηΐ) ε' L '(^

'HS) 6I' L '( ^s ' HS) 96 9 'HI) 16' 9 '(' H 9 Έ '( ^s ΉΖ) £ Ζ Έ' ( ^s 'Ηε) χε' ζ '( ^s ' H9) xs 'z' ( ^s ¾9) 6 '!: 9 (ιοαο' ZH OO ^) H NH _T

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA , 7.92 (2H, d, J = 9. OHz).

 MS m / z: 552 (M + H) +.

[0968] (2) 2- [4-[[[2- (4 Ethoxyphenyl) 5-methyloxazole- 4-methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy ] —2-Methylpropanoic acid

 [0969] [Chemical 308]

Example 70- In the same manner as in (2), the title compound (0.135 g) was obtained as a colorless solid from the compound (0.152 g) obtained in Example 80- (1).

 'H-NMR (400MHz, CDC1) δ: 1.37—1.47 (9Η, m), 2.15 (6Η, s), 2.2

 Three

 5 (3H, s), 2.76 (3H, d, J = 4.9Hz), 3.17 (2H, s), 3.49 (2H, s), 3.58 (2 H, s), 4.08 (2H, q, J = 7. OHz), 6.88 (2H, s), 6.94 (2H, d, J = 8.8Hz), 7.79-7.87 (1H, m), 7.91 (2H, d, J = 8.8Hz).

 Elemental analysis value C H N O 1.5H O

 29 37 3 6 2

 Calculated value: C, 63.26; H, 7.32; N, 7.63.

 measured value:. 63.51; H, 7.14; N, 7.44.

[0971] [Example 81]

 (1) 2- [4 [[Strengthened rubermoylmethyl- [2- (4 ethoxyphenyl) -5-methyloxazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] -2-methylpropane Acid ethyl ester

[0972] [Chemical 309]

[0973] In the same manner as in Example 61- (1), the compound strength obtained in Reference Example 55- (3) was also the same as that of the title compound (0.

 150 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.38— 1.49 (9

 Three

 H, m), 2.17 (6H, s), 2.23 (3H, s), 3.23 (2H, s), 3.52 (2H, s), 3.60 (2 H, s), 4.09 (2H, q, J = 7 OHz), 4.28 (2H, q, J = 7.2Hz), 5.38— 5.51 (1 H, m), 6.84-7.00 (4H, m), 7.64— 7.76 (1H, m), 7.91 (2H, d, J = 8.5 Hz).

 MS m / z: 538 (M + H) +.

[0974] (2) 2— [4— [[Strong Rubamoylmethyl- [2- (4 Ethoxyphenol) -5-Methyloxazol-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] — 2-Methylpropanoic acid

 [0975] [Chem 310]

Example 70- The title compound (0.122 g) was obtained as a colorless solid from the compound (0.150 g) obtained in Example 81- (1) in the same manner as in (2).

 'H-NMR (400MHz, CDCl) δ: 1.36— 1.50 (9Η, m), 2.17 (6Η, s), 2.2

 Three

 6 (3Η, s), 3.18 (2Η, s), 3.54 (2H, s), 3.58 (2H, s), 4.07 (2H, q, J = 6.9Hz), 5.99-6.07 (1H, m ), 6.86— 6.98 (4H, m), 7.66— 7.73 (1H, m), 7.90 (2H, d, J = 8.8Hz).

MS m / z: 510 (M + H) ⁺ . [0977] [Example 82]

 (l) 2- [4-[[[2- (3,4-Dimethylphenol) 5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] —2— Methylpropanoic acid ethyl ester

[0978] [Chem 311]

 [0979] In the same manner as in Example 62- (1), the compound strength obtained in Reference Example 56- (3) was also determined using the title compound (0.

 156 g) was obtained as a colorless oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.24 (3H, s), 2.31— 2.33 (6H, m), 2.78 (3H, d, J = 5.1 Hz), 3.21 (2H, s), 3.50 (2H, s) , 3.60 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.89 (2H, s), 7.21 (1H, d, J = 7.8Hz), 7.68— 7.73 (1H, m), 7.74—7.8 2 (2H, m).

 MS m / z: 536 (M + H) +.

 [0980] (2) 2- [4-[[[2- (3,4-Dimethylphenol) 5-Methyloxazole-4-yl Methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenol Enoxy] —2—Methylpropanoic acid

 [0981] [Chem 312]

In the same manner as in Example 70- (2), the compound (0.156 g) force obtained in Example 82- (1) was also used to obtain the title compound (0.127 g) as a colorless solid. NMR-NMR (400MHz, CDCl) δ: 1.42 (6H, s), 2.16 (6H, s), 2.26 (3H, s

 Three

 ), 2.29-2.34 (6H, m), 2.75 (3H, d, J = 4.9Hz), 3.16 (2H, s), 3.50 (2 H, s), 3.59 (2H, s), 6.89 (2H, s ), 7.20 (1H, d, J = 8.1Hz), 7.67- 7.7 3 (1H, m), 7.75-7.84 (2H, m).

 Elemental analysis value as C H NO 2ΗΟ

 29 37 3 5 2

 Calculated values: C, 64.07; H, 7.60; N, 7.73.

 measured value:. 63.82; H, 7.32; N, 7.38.

[0983] [Example 83]

 (1) 2— [4 [[Strengthened rubermoylmethyl- [2— (3,4-dimethylphenol) 5-methyloxazol 4-ylmethyl] amino] methyl] —2,6 dimethylphenoxy] —2 —Methyl propanoic acid ethyl ester

 [0984] [Chem 313]

In the same manner as in Example 61- (1), the compound strength obtained in Reference Example 56- (3) was also determined using the title compound (0.

 167 g) was obtained as a pale yellow oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.24 (3H, s), 2.29— 2.34 (6H, m), 3.23 (2H, s), 3.53 (2 H, s), 3.60 (2H, s), 4.28 (2H, q, J = 7.2Hz), 5.41— 5.55 (1H, m), 6.9 1 (2H, s), 7.20 (1H, d, J = 7.8Hz), 7.61— 7.68 (1H, m), 7.68— 7.73 ( 1H, m), 7.75-7.79 (1H, m).

MS m / z: 522 (M + H) ⁺ .

[0986] (2) 2— [4 [[Strengthened rubermoylmethyl [2— (3,4 dimethylphenol) 5-Methyloxazol 4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy ] —2-Methylpropanoic acid

[0987] [Chem 314]

 In the same manner as in Example 70- (2), the title compound (0.133 g) was obtained as a colorless solid from the compound (0.167 g) obtained in Example 83- (1).

 'H-NMR (400MHz, CDCl) δ: 1.45 (6 Η, s), 2.17 (6 Η, s), 2.25— 2.3

 Three

 4 (9Η, m), 3.18 (2Η, s), 3.51— 3.62 (4H, m), 6.00— 6.08 (1H, m), 6. 91 (2H, s), 7. 19 (1H, d, J = 8.1Hz), 7.62— 7.73 (2H, m), 7.73— 7.78 (1H, m).

 MS m / z: 494 (M + H) +.

[0989] [Example 84]

 (1) 2- [4 -— [[[2- (3-Chloro-4-methylphenol) 5 Methyloxazole 4-ylmethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] 2 —Methylpropanoic acid ethyl ester

[0990] [Chemical 315]

実施例 62— (1)と同様にして、参考例 57— (3)で得たィ匕合物力も標題ィ匕合物 (0. 169g)を淡黄色油状物として得た。

In the same manner as in Example 62- (1), the compound strength obtained in Reference Example 57- (3) was also obtained as the title compound (0.169 g) as a pale yellow oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

17 (6H, s), 2.24 (3H, s), 2.43 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.21 (2H, s), 3.49 (2H, s), 3.59 ( 2H, s), 4.28 (2H, q, J = 7.2Hz), 6.89 (2H, s), 7.31 (1H, d, J = 8.1Hz), 7.68— 7.80 (2H, m), 7.98 (1H, d , J = l.5 Hz). MS m / z: 556 (M + H) +.

[0992] (2) 2— [4 [[[2— (3 Chloro-4 methylphenol) 5 Methyloxazole 4

—Ylmethyl] methylcarbamoylmethylamino] methyl] —2,6-dimethylphenoxy] 2-methylpropanoic acid

[0993] [Chem 316]

Example 70- The title compound (0.150 g) was obtained as a colorless solid from the compound (0.169 g) obtained in Example 84- (1) in the same manner as in (2).

 'H-NMR (400MHz, CDCl) δ: 1.41 (6Η, s), 2.16 (6Η, s), 2.26 (3H, s

 Three

 ), 2.42 (3H, s), 2.77 (3H, d, J = 4.9Hz), 3.18 (2H, s), 3.50 (2H, s), 3.58 (2H, s), 6.88 (2H, s) , 7.30 (1H, d, J = 8.1 Hz), 7.73-7.82 (2H, m), 7.97 (1H, d, J = l.7 Hz).

 Elemental analysis value as C H C1NO -1.25HO

 28 34 3 5 2

 Calculated values: C, 61.08; H, 6.68; N, 7.63.

 measured value:. , 60.81; H, 6.61; N, 7.27.

[0995] [Example 85]

 (1) 2— [4 [[Strong Rubamoyl Methyl [2— (3—Black Methyl 4-Methyl Phenol) 5 Methyloxazol 4-Methyl] amino] Methyl] —2, 6 Dimethylphenoxy] —2 Methyl propanoic acid ethyl ester

[0996] [Chemical 317]

エ ^エ 邈べ cl l ^ S—[ ^,ェ ^ — 9 [ ^ [ ^ ^ / ¾ ^ [ ^ / —

D ^ E 邈 cl cl l ^ S— [^, ^ ^ — 9 [^ [^ ^ / ¾ ^ [^ / —

/ —, ^ ^ -9-

 [98p «^] [ΐθθΐ]

• ₊ (H +) ^ xg: z / ^ra SPV

• ( ^Z H9 · Ι = Γ'Ρ 'ΗΙ) 96' L '( ^Ζ Η9 Ί Ί' 8 = Γ 'ΡΡ' ΗΙ) 9 ΖL '^' ΗΙ) 99 'Z-I9' L '( ^Ζ ΗΙ 8 = ΓΡ 'HI) OS' L '( ^s ' HS) S6 9 '(^' HI

) 26 9 1 8 '9' ( ^s ' Η2) 09 Έ '( ^s ' Η2) 99 Έ' ( ^s ' Η2) 02 Έ '( ^s ' HS) S' 2 '( ^s ' HS) 8S' ( ^s ' H9) 0S 'Ζ' ( ^s ' Η9) 8 ΐ: 9 (\ θαθ 'ZH 00 ^) H NH _T

oM ^ m ^ ^ ( ^§ χ ^ χ · ο) 呦 ^

 Ό) ^^ ^ (Ι) -98p} «っ こ 爾; (S) -O p}« [000Ϊ]

[8TS ^] [6660] 邈-

Over g- (- E ^ _{one, - ΰΕ ε) _2] -} Λ ^ Λ ^^ / Λ ^ -] -] - ^ -] - ζ {Ζ) [8660]

• ₊ (H +) S ^ g: z / ^ra SPV • ( ^Z HZ · Ι = Γ'Ρ 'ΗΙ) 96' L '( ^Ζ ΗΖ Ί

Ό 8 = Γ'ΡΡ 'ΗΙ) 9Ζ' L '^' Ηΐ) 9 'LL' L '( ^Ζ Η0 8 = ΓΡ' HI) 0S 'L' ( ^s ΉΖ) 06 9 '^' ΗΙ) 9 ^ '9-9S' 9 '( ^Ζ Η2ΖΖ = Γ¾' UZ) SZ '' ( ^s ' Η2) 69

Ε '( ^s ' Η2) ε9 · ε '( ^s Ήζ) £ ζ · ε' ( ^s 'uz) z' ζ '( ^S ' HS) 9S 'Ζ' ( ^S 'Η9) ΖΙ · ζ' ( ^s ¾9) s χ '( ^z HS = = Γ' ^ 'Ηε) 9ε χ: 9 (ιοαο' ZH OO ^) H NH _T

 .呦 ^^ 雜 ¾ (§

033

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV [ΟΟΐ]

• ₊ (H +) ^ g: z / ^ra SPV

(Ra 'HS) 98 Ί-1' L '' HS) S6 9 1 8 9 '( ^s ' HS) 88 Έ '( ^s ' H

2) 69 Έ '( ^s ' HS) 6 Έ '( ^s ' HS) 9I Έ '( ^Ζ Η6 · = ΓΡ' HS) ^ '(^' H9) 6

Z 'Z-ZZ' Z '( ^s ' H9) 9 I 'Z' ( ^s 'H9) S Ί-9 (\ OaO' zH OO ^) H NH _T

[OZZ ^ [SOOT] 1 1 ^ S— [^, é ^ — 9 [^ [^ ^ / ¾ ^ [^ / — One / —, ^ ^ S— (/ — ^ Δ / ^-£-^ i ^ →) [W) 0I]

• ₊ (H + PV) sgg: z / ^ra SPV • (ra 'HS) 98 · ζ-εζ' L '(m ¾ε) 6 · 9 ε8 ·' (m ΉΖ) ££ '-ZZ''( ^s ¾ε) 88 Έ '( ^s ' HS) 09 Έ '( ^s ' HS) 6 Έ '( ^s ' H

Z) IZ Έ '( ^Z HI 9 = Γ'Ρ' HS) 8Z 'Ζ' ( ^s ' U £) LZ 'Ζ' ( ^s ' U £) £ Z 'Z' ( ^s ' H9) Z

I 'z' ( ^s ¾9) s · χ '(m ¾ε) 6ε · χ-χε · ΐ: 9 (\ oao' ZH OO ^) H NH _T

 .つ; ^^ ^ Township (§091

 Ό) ^ mm ^ ^ -m ^ (ε)-m ^ m ^ ^ mM ^ d) -z m κοοι]

 Yes

[6ΐε ^] [200Ϊ]

1-33

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV

,,,, () () () δ HNMR OOMHZ CDC1: 1.26H S 2.166H s 2.222.2I1

9 (6H, m), 3.17 (2H, s), 3.54 (2H, s), 3.58 (2H, s), 3.87 (3H, s), 5.9 9-6.09 (1H, m), 6.85 (1H, d , J = 8.5Hz), 6.90 (2H, s), 7.58—7.66 (1H, m), 7.73-7.82 (2H, m).

 MS m / z: 510 (M + H) +.

[1013] [Example 88]

 (1) 2- [4 [[[[2- (3,5 Difluorophenol) 5 Methyloxazole 4-methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] — 2 Methylpropanoic acid ethyl ester

[1014] [Chemical 323]

[1015] In the same manner as in Example 62- (1), the compound strength obtained in Reference Example 59- (2) was also the same as that of the title compound (0.

 14 lg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.25 (3H, s), 2.81 (3H, d, J = 4.9Hz), 3.22 (2H, s), 3.50

(2H, s), 3.59 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.83— 6.94 (3H, m), 7

.46-7.55 (2H, m), 7.66 (1H, d, J = 4.9Hz).

 MS m / z: 544 (M + H) +.

[1016] (2) 2- [4-[[[2- (3, 5 Difluorophenol) -5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2, 6 —Dimethylphenoxy] —2 Methylpropanoic acid

[1017] [Chem 324] '(ra' HS) 69 'Shiichi

9 'L' (¾ε) 6 '9-28 9' (^ 'ΗΙ) 2Ζ' 9-Ζ9 '9' ( ^Ζ Η2 'Ζ = Γ' Η2) 82

'( ^S ' Η2) 69 Έ '( ^s ' HS) S9 Έ '( ^s ΉΖ) £ Ζ Έ' ( ^s 'HS) 9S' 2 '( ^s ' Η9) ΖΙ · Ζ '( ^s ' H9) S Ί '( ^Ζ Η2 · = Γ'ΐ' HS) 9S · !: 9 (ΐΟΟΟ 'ZH 00 ^) H NH _T

 .呦 ^^ 雜 ¾ (§

[S2S ^] [020Ϊ] d ^ d ci ci l / ^

 -^ ^ 9 'Z-[_Λ ^ →-

-s (I) (/ -E ci g 'ε)

-s (I)

[68p «^] [6Ϊ0Ϊ] • ₊ (H + PV) 9I9: ^z / ^ra SPV • (ra 'HI) SZ Ί-Ζ9' L '(m' HS) 99 'L' (^ ε) 6 · 9 S8

^{9 '(s' HS) 69} Έ '(s' HS) I9 Έ '(s' HS) 8I Έ '(Ζ Η6 · = ΓΡ' HS) 6Z '(s' HS) 8S '(s' H9) 8I 'Z' ( ^s 'Η9) Ί-9 (\ OaO' ZH 00 ^) H NH _T

zz

zz

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA MS m / z: 530 (M + H) +.

[1022] (2) 2— [4 [[Strong Rubamoylmethyl- [2— (3,5 Difluorophenol) 5 Methyloxazole-4-ylmethyl] amino] methyl] -2, 6 Dimethylphenoxy] —2—Methylpropanoic acid

 [1023] [Chemical 326]

[1024] In the same manner as in Example 70- (2), the title compound (0.124 g) was obtained as a colorless solid from the compound (0.133 g) obtained in Example 89- (1).

 'H-NMR (400MHz, CDCl) δ: 1.46 (6Η, s), 2.19 (6Η, s), 2.29 (3H, s

 Three

 ), 3.19 (2H, s), 3.56-3.59 (4H, m), 5.89—6.02 (1H, m), 6.83—6.9

4 (3H, m), 7.45-7.58 (3H, m).

 MS m / z: 502 (M + H) +.

[1025] [Example 90]

 (l) 2- [4-[[[2- (3,5 dichlorophenol) -5-methyloxazole-4-yl methyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy ] —2-Methylpropanoic acid ethyl ester

[1026] [Chemical 327]

[1027] In the same manner as in Example 62- (1), the compound strength obtained in Reference Example 60- (2) was also the same as that of the title compound (0. 169 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.25 (3H, s), 2.81 (3H, d, J = 5.1 Hz), 3.22 (2H, s), 3.50

(2H, s), 3.58 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.88 (2H, s), 7.37— 7.

45 (1H, m), 7.57-7.67 (1H, m), 7.86-7.89 (2H, m).

MS m / z: 576 (M + H) ⁺ .

[1028] (2) 2- [4-[[[2- (3,5-Dichlorophlephthal) -5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2, 6-Dimethylphenoxy] —2-Methylpropanoic acid

[1029] [Chem 328]

[1030] In the same manner as in Example 70- (2), the title compound (0.149 g) was obtained as a colorless solid from the compound (0.169 g) obtained in Example 90- (1).

 'H-NMR (400MHz, CDCl) δ: 1.46 (6Η, s), 2.19 (6Η, s), 2.29 (3H, s

 Three

 ), 2.79 (3H, d, J = 4.9Hz), 3.19 (2H, s), 3.51 (2H, s), 3.59 (2H, s), 6.90 (2H, s), 7.41 (1H, t, J = l.8Hz), 7.60— 7.67 (1H, m), 7.87 (2H, d, J = l.8Hz).

 MS m / z: 548 (M + H) +.

[1031] [Example 91]

 (1) 2— [4 — [[Strengthened rubermoylmethyl- [2 -— (3,5-Dichlorophlephthalate) -5-methyloxazoline 4-ylmethyl] amino] methyl] -2,6-dimethyl Phenoxy] -2-methylpropanoic acid ethyl ester

[1032] [Chemical 329] • ₊ (H +) ^ S9: ^z / ^ra SPV

( ^Z HZ Ι = Γ'Ρ 'HS) 98 Ί' (^ 'HI) 99' ー J 'L' (^ 'Ηΐ) ε' Z-8S 'L' ( ^s

'HS) S6 · 9'('HI) 10 · 9— ε8' 9 '(^' H) S9 Έ '( ^s ' Η2) 02 Έ' ( ^s ¾ε) θε 'Ζ' ( ^s ' Η9) 02 ' 2 '( ^s ' Η9) 8ΐΐ 9 (\ θαθ' ZH 00 ^) H NH _T

Ό)呦

Ό) 呦

[οεε ^] [δεοΐ] 邈 1

 [^ [^ [^ / — — / —, ^

 ^ — G— (-é cm ^^ — g 'ε) —s] — / ¾ [; ΟΪ]

• ₊ (H + PV) S99: ^z / ^ra SPV • ( ^Z H6 · Ι = Γ'Ρ 'HS) Z8' L '(^' ΗΙ) ^ 9 · Ζ— Ζ 'L' ( ^Ζ Η6 Ί = Γ '' Ηΐ) 'L' ( ^s 'HS) 06 9' (m 'HI) S9 9- ε' 9 '( ^Z UZ Ί = ί' UZ) Z

'( ^S ' HS) 69 Έ '( ^s ' HS) S9 Έ '( ^s ' HS) SS Έ '( ^s ' HS) 9S '( ^s ' H9) 8I · z '( ^s ¾9) s · χ' ( ^Z HS · = Γ '^' Ηε) 9εχ: 9 (ιοαο 'ZH OO ^) H NH _T

 .呦 ^^ 雜 ¾ (§

LZZ

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA [1037] [Example 92]

 (1) 2- [4 -— [[[2- (3-Bromo-4-methoxyphenyl) -5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy 2] 2-Methylpropanoic acid ethyl ester

[1038] [Chemical 331]

 [1039] In the same manner as in Example 62- (1), the compound strength obtained in Reference Example 61- (3) was also determined using the title compound (0.

 187 g) was obtained as a yellow oil.

 ^ H—NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.2Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.23 (3H, s), 2.79 (3H, d, J = 4.9Hz), 3.21 (2H, s), 3.48 (2H, s), 3.59 (2H, s), 3.96 ( 3H, s), 4.28 (2H, q, J = 7.2Hz), 6.88 (2H, s), 6.96 (1H, d, J = 8.5Hz), 7.67— 7.76 (1H, m), 7.91 (1H, dd , J = 8.5, 2.2Hz), 8.20 (1H, d, J = 2.2Hz).

MS m / z: 617 (M + H) ⁺ .

 [1040] (2) 2— [4— [[[2— (3-Bromo-4-methoxyphenyl) -5-methyloxazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6— Dimethylphenoxy] 2-methylpropanoic acid

 [1041] [Chemical 332]

[1042] In the same manner as in Example 70- (2), the title compound (0.156 g) was obtained as a pale yellow solid from the compound (0.187 g) obtained in Example 92- (1). [m ^ [Lfoi 邈-

[ ^ [ ^ ^ / ¾ [ ^ / — Z-

[^ [^ ^ / ¾ [^ / —

-— ^ Jp- ^ ^ -9- (-nr _{: /} J _E ; ^-^-¾ci: -S) -S]]]-^]-S (S) [9WH]

• ₊ (H + PV) S09: ^z / ^ra SPV • ( ^Ζ Η0 'Ζ = ΓΡ' ΗΙ) 8Ι · 8 '( ^Ζ Η0' Ζ

'9 8 = Γ'ΡΡ' ΗΙ) 06 'L' ^ 'Ηΐ) 9' LL 'L' ( ^Ζ Η 9 8 = ΓΡ 'ΗΙ) 96 9' ( ^s ' Η 2) 06 9 '^' HI) S9 ・ 9— ε '9' ( ^Ζ Η2 · Ζ = Γ¾ 'UZ) SZ''( ^s ' HS) 96

Έ '( ^S ' Η2) 69 Έ '( ^S ' HS) S9 Έ '( ^S ΉΖ) £ Ζ Έ' ( ^S 'U £) Z' Ζ '( ^S ' Η9) ΖΙ ζ ′ ( ^s ¾9) s · Χ '( ^z HS · = Γ' ^ 'Ηε) 9ε · χ: 9 (ιοαο' ZH OO ^) H NH _T

^エ 邈

^ D

[ ^ [ ^ ^ / ¾ [ ^ / — 一 /— 、 ^ ^ 一 s—( -ェ ^ ー 一 ¾ ci i一 ε )— s ] ] ]— ]一 s ( ΐ ) 2-

[^ [^ ^ / ¾ [^ / — One / —, ^ ^ One s— (-é ^ ー One ¾ ci i One ε) — s]]]]]]] s (ΐ)

 [S6p «^] [εκπ]

• S '9' N 'S8' ΖΙ ¾ · 28 '9' Η'ΟΙ · 9 thighs

 · 8 · 9 'Ν · 68 '21 ¾ · 0Ι · 9' Η '^ · 9'

( ^Z H0 2 = Γ'Ρ 'ΗΙ) 6Ι 8' ( ^Ζ Η0 '2' 9 8 = ΓΡΡ 'ΗΙ) 06' L '(^' ΗΙ) 8 Ζ 'L-OL' L '( ^Ζ Η9 8 = ΓΡ 'ΗΙ) 96 9' ( ^s 'Η2) 06 9' ( ^s 'HS) 96 ε' ( ^s 'HS) 69 ε' ( ^s ¾s) 6 ε '( ^s ' HS) ZI · ε '( ^Ζ Η6 · = ΓΡ' HS) ZZ 'Ζ' ( ^s ' HS) 9S 'Ζ' ( ^s ' Η9) ΖΙ '( ^s ' Η9) ΐΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

633

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV []

[¾104

[S105

[S105

〔〕1054 )uu入^^T/ / /2 rrr I— 1..

[] 1054) u ^^ T / / / 2 rrr I— 1 ..

() [[[] 1052224ll

[6εε ^] [290ΐ]

 Ϋ́: ^ — é ^ — 9 [^ [^ (^ / — S—

 / — ^ ['Z' I]-fi4-ra-e)-/ ^ ^^ / ^]--S (I)

[96p «^] [Ϊ90Ϊ] • ₊ (H + V): z / ui SPV

• ( ^Z H90 · 8

= Γ'Ρ ΉΖ) 6 'L' HI) 9S 'L' (ZH69ΖΖ = ΓΡ 'HS) OS' L '( ^s ' HS) 96

^{'(S' HS) 86 Έ} '(s' HS) IZ Έ'(s' HS) 8S Έ '(Z H88 · = ΓΡ' HS) Z8 'Z' (s ¾ε) ε 'ζ'(s' U9 ) zz 'z' ( ^s ¾9) 6ΐ: 9 (\ oao 'ZH OO ^) H NH _T

oM ^ m ^ ^ ( ^§ 08i -o) ^

 [o9oi]

[8εε ^] [6soi] ΰ: ^ S [[^ [^ (^ / S— / —,; ^ ^ [

[830ΐ]'Z' I]-fi4-dS)

[830ΐ]

• ₊ (H + PV) 609: ^z / ^ra SPV • ( ^Z H8I · 8 = ΓΡ 'HS) 96' L '( ^z HOS · 8 = ΓΡ' Η2)

OS 'L' ( ^s 'HS) S6 9' ( ^Z H80 Ζ = Γ¾ 'HS) 8S''( ^s ' UZ) L6 Έ '( ^s ' HS) 89

383

T86.l0 / S00Zdf / X3d 010.C0 / .00Z OAV [m ^ [8901]

 / / / 邈 邈 ΰ: ^ s [[^ [^ (^ / S / —,; ^ ^ [

• ₊ (H +) 9 ^: ^z / ^ra SPV • (ra 'HS) 68' L '(m' HS) 9S 'L' ( ^s ' HS) Z6 · 9 '(' HI) S6 '9' ( ^s 'HS) 0' ( ^s ' UZ) £ L Έ '( ^s ' HS) 6S Έ' ( ^s ¾ε) '( ^s Ή9) £ Ζ' Ζ '( ^s ' Η9) 09 · ΐ: 9 (\ θαθ' zH OO ^) H NH _T [9901]

[o ^ [S90T] m ΰ: ^ — é ^ — 9 [^ [^ (^ / — S—

 / — ^ ['Z' I]-fi4-ra-e)-/ ^ ^^ / ^]--S (S) 901]

• ₊ (H + PV) 96 ^: ^z / ^ra SPV • (ra 'HS) 88' L '(m' HS) 9S

'L'('HI)IS' L '( ^s ' HS) 6 9''HI)IZ' 9 '( ^Z H80 Ζ = Γ¾' UZ) SZ

'( ^s ' HS) IO''( ^s ' HS) IZ Έ' ( ^s ' HS) ZS Έ '( ^s ¾ε)' ( ^s ' Η9) 6 Ι 'Z

'( ^s ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 (\ oao 'ZH OO ^) H NH _T

εε3

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ Ο 'ζ' ΐ] (/ é —) ε] ^ / ¾

[86fii¾? No.] [εζοτ] • ₊ (H + V): z / ui SPV • (ra 'HS) Z8' L '(m' HS) 8S 'L' ( ^s ' HS) 96 · 9

'( ^S ' HS) 66 Έ '( ^S ' HS) OZ Έ '( ^S ' HS) 6S Έ '( ^Z H88 · = ΓΡ' HS) 88 'Z' ( ^s ¾ε) 'Ζ' ( ^s ' U9) ZZ 'Z' ( ^S 'H9) 6'!: 9 (\ θαθ 'ZH 00 ^) H NH _T

ΰ : ^ S ェ [ ^ [ ^ （ ^ / S— /—、 ; ^ ^ [

ΰ: ^ S [^ [^ (^ / S— / —,;

• ₊ (H + PV) 609: ^Z / ^RA SPV

 • ΉΖ) I

'L' (m 'HS) 9S' L '( ^s ' HS) S6 9' ( ^Z H80 · Ζ = Γ¾ 'HS) 6S' ( ^s ' HS) 66 · S '( ^S ' HS) 69 Έ ' ( ^S 'HS) ZS Έ' ( ^S 'HS) Z8' ( ^s ¾ε) 'Ζ' ( ^S 'Η9) 6Ι' Ζ

'( ^S ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 ('ιοαο' ZH OO ^) H NH _T

T86.l0 / S00Zdf / X3d 010.C0 / .00Z OAV Diazol 5-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] rupropanoic acid ethyl ester

 [Chemical 343]

To 〇

[1075] In the same manner as in Example 61- (1), the title compound (0.34g) was obtained as a yellow oil from the compound of Reference Example 64- (2) (0.62g).

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s).

 3 '

2.19 (6H, s), 3.38 (2H, s), 3.72 (2H, s), 4.02 (2H, s), 4.28 (2H, q, J = 7.08Hz), 5.55 (IH, br), 6.93 (2H, s), 7.18 (IH, br), 7.48 (2H, d, J = 8.54Hz), 8.02 (2H, d, J = 8.42Hz).

 MS m / z: 515 (M + H) +.

[1076] (2) 2— [4 [[Strengthened rubermoylmethyl- [3- (4 Black-mouthed phenol) [1, 2, 4] Oxadiazol-5-ylmethyl) amino] methyl] —2, 6-Dimethylphenoxy] —2-methylpropanoic acid

 [1077] [Chemical 344]

実施例 70— (2)と同様にして、実施例 98— (1)で得たィ匕合物 (0.34g)から標題 化合物（0. 160g)を無色固体として得た。

Example 70- The title compound (0.160 g) was obtained as a colorless solid from the compound (0.34 g) obtained in Example 98- (1) in the same manner as in (2).

 'H-NMR (400MHz, CDCl) δ: 1.50 (6Η, s), 2.23 (6Η, s), 3.39 (2H, s

 Three

), 3.74 (2H, s), 4.05 (2H, s), 6.04 (IH, br), 6.97 (2H, s), 7.21 (IH, br), 7.48 (2H, d, J = 8.42Hz), 8.02 (2H, d, J = 8.42 Hz). MS m / z: 487 (M + H) ⁺ .

[1079] [Example 99]

 (1) 2— [4— [[[3— (4 Chlorophenol) [1, 2, 4] Oxadiazol-5-methyl] methylcarbamoylmethylamino] methyl] —2, 6 dimethylphenoxy] 2-Methylpropanoic acid ethyl ester

 [1080] [ized 345]

[1081] In the same manner as in Example 62- (1), the title compound (0.63 g) was obtained as a pale yellow oil from the compound (0.63 g) of Reference Example 64- (2).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s),

 Three

 2. 19 (6H, s), 2.86 (3H, d, J = 5.01Hz), 3.37 (2H, s), 3.69 (2H, s), 3.99 (2H, s), 4.28 (2H, q, J = 7.08Hz), 6.91 (2H, s), 7.48 (2H, d, J = 8.7 9Hz), 8.02 (2H, d, J = 8.67Hz).

MS m / z: 529 (M + H) ⁺ .

[1082] (2) 2— [4— [[[3— (4 Black Mole)] [1, 2, 4] Oxadiazo 5-methyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropanoic acid

 [1083] [Chemical 346]

[1084] In the same manner as in Example 70- (2), the title was obtained from the compound (0.63 g) obtained in Example 99- (1). [S ^ [6801] Eve El: /

'ζ' ΐ] (/ ε) — ε] ^ / ¾ [8801]

• ₊ (H + PV) gig: z / ^ra SPV

• ( ^Z HS8 · Ι = Γ'Ρ 'ΗΙ) 80 · 8' ( ^Ζ Η69 · Ζ = ΓΡ 'ΗΙ) Ζ6' L

'(ra * HS) 9 ^' L '(' ΗΙ) 9Ι 'L' ( ^s 'HS) S6 9' ΗΙ) Ζ9 '9' ( ^Ζ Η80 Ί =

Γ'¾ 'UZ) Z''( ^s ' HS) SO '' ( ^s 'HS) IZ Έ' ( ^s 'UZ) L £ Έ' ( ^s 'Η9) 6 Ι' Z

:( ^s ¾9) s · χ '( ^Z H80 · = Γ' ^ 'Ηε) 9ε · χ: 9 (\ oao' ZH OO ^) H NH _T

[m ^ [9801] d ^ d / l /

'ζ' ΐ] (/ ε) — ε] ^ / ¾

• ₊ (H + PV) I09: ^z / ^ra SPV • ( ^Z H6Z · 8 = ΓΡ 'UZ) Z · 8' ( ^Z HZ9 · 8 = ΓΡ 'HS) 8 · L' ( ^s ' HS) 96 · 9 '( ^s ' HS) 00 '' ( ^s 'HS) IZ Έ' ( ^s 'HS) 6S Έ' ( ^Z H88

P 'HS) Z8' ( ^s ' H9) SS 'Z' ( ^s ' Η9) 09 Ί-9 (\ OaO 'zH OO ^) H NH _T

oM ^ m ^ ^ ( ^§ 09s Ό)

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA / — S— / —,; ^ ^ ['ζ' ΐ] — (/ écm ^ — ε) — ε]]] —] — 60 ΐ]

• ₊ (H + PV) 6S9: ^z / ^ra SPV • ( ^s ' ΗΙ) 80 8 '( ^Z HZ9' Ζ = Γ 'Ρ' ΗΖ)

L6 'L' (m 'HS) S' L '( ^s ' HS) I6 9' ( ^Z H80 · Ζ = Γ¾ 'HS) 8S''( ^s ' HS) 66

Έ '( ^s ' HS) 69 Έ '( ^s ' HS) ZS Έ '( ^Z H88 · = ΓΡ' HS) Z8 'Z' ( ^s 'Η9) 6 Ι' Z

'( ^S ¾9) s · χ' ( ^Z H80 · = Γ '^' Ηε) 9ε · χ: 9 (ιοαο 'ZH OO ^) H NH _T

Ό)呦

Ό) 呦

[6 ε ^] [260ΐ] d ^ d 邈 ci l / ^ ー S e ^ ー 9 — [^ [^ ^ / ¾ ^ [^

g ー — / _:, ^ ['z ^, I]-(-nr _{: clcl} ^ _g) _g]]] _ ^] _ 2 (i)

[XOIpM ^] [ΐ60ΐ] • ₊ (H +) 8 ^: ^z / ^ra SPV • ( ^s 'HI) 80 · 8' ( ^Z HZ9 · Ζ = Γ'Ρ 'ΗΙ) Ζ 6' L '(^' HS) 8 'L' q 'HI) SS' L '( ^s ' HS) Z6 9 'HI) 9I 9' ( ^s 'HS) 90' ( ^s 'HS) SZ Έ' ( ^s 'HS) 6S Έ' ( ^s 'H9) SS' ( ^s 'Η9) 09 · ΐ: 9 (\ θαθ' ZH 00) 丽 N— H _T

®¾ ^ (¾9 Ό) ^^ ^ (Ι) -OOIpM ^ kko ； (S) -OL, [0601]

883

T86.l0 / S00Zdf / X3d 010.C0 / .00Z OAV Til] methylcarbamoylmethylamino] methyl] -2,6-dimethylphenoxy] tyrupropanoic acid

 [Chem 350]

[1096] In the same manner as in Example 70- (2), the title compound (0.36 g) was obtained as a colorless solid from the compound (0.60 g) obtained in Example 101- (1).

 'H-NMR (400MHz, CDC1) δ: 1.49 (6Η, s), 2.23 (6Η, s), 2.88 (3H, d

 Three

 , J = 5.00Hz), 3.39 (2H, s), 3.71 (2H, s), 4.00 (2H, s), 6.95 (2H, s), 7.45 (2H, m), 7.96 (2H, d, J = 7.69Hz), 8.07 (1H, s).

 MS m / z: 501 (M + H) +.

 [1097] [Example 102]

 (1) 2— [2 Chloro-6 methyl 4 [[Methylcarbamoylmethyl mono (5 methyl 2 —phenoxazole 4-methyl) amino] methyl] phenoxy] 2 methyl propanoic acid ethyl ester

 [1098] [Chem 351]

[1099] Reference Example 67—The compound (lOOmg) obtained in (4) and the compound (115 mg) obtained in Reference Example 66 were dissolved in a mixture of dichloromethane (5 ml) and tetrahydrofuran (5 ml), and triacetoxy was added. Sodium borohydride (107 mg) was added, and the mixture was stirred at room temperature for 3 days. After evaporating the solvent under reduced pressure, the residue was suspended in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. Organic layer anhydrous After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 97: 3) to give the title compound (130 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.51 (6H, s), 2

 Three

 .20 (3H, s), 2.26 (3H, s), 2.82 (3H, d, J = 5.1Hz), 3.23 (2H, s), 3.5 1 (2H, s), 3.62 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.97 (1H, s), 7.16 (1 H, s), 7.43-7.48 (3H, m), 7.76 (1H, d, J = 5.1Hz), 7.98— 8.02 (2H, m).

MS m / z: 528 (M + H) ⁺ .

[1100] (2) 2 -— [2 Chloro-6 methyl 4 [[Methylcarbamoylmethyl mono (5 methyl 2

—Phenoloxazole 4-methyl) amino] methyl] phenoxy] 2 methyl propanoic acid

[1101] [Chem 352]

[1102] In the same manner as in Example 61- (2), the title compound (77 mg) was obtained as a colorless solid from the compound (128 mg) obtained in Example 102- (1).

 'H-NMR (400MHz, CDC1) δ: 1.56 (6Η, s), 2.26 (3Η, s), 2.29 (3H, s

 Three

 ), 2.83 (3H, d, J = 4.9Hz), 3.22 (2H, s), 3.53 (2H, s), 3.65 (2H, s), 7.04 (1H, s), 7.22 (1H, s) , 7.44— 7.50 (3H, m), 7.81 (1H, brs), 7.98 -8.03 (2H, m).

 Elemental analysis value C H C1NO · 0.5HO

 25 28 3 5 2

 Calculated values: C, 61.35; H, 6.14; CI, 6.96; N, 8.26.

 measured value:. 61.27; H, 6.20; CI, 6.97; N, 7.92.

[1103] [Example 103] (1) 2— [4 [[Strong rubermoylmethyl mono (5-methyl-2-phenolazol-4-ylmethyl) amino] methyl] —2-chloro-hexene 6-methylphenoxy] —2-methylpropanoic acid ester

 [Chemical 353]

[1105] In the same manner as in Example 61- (1), the title compound (85 mg) was obtained as a colorless oil from the compound (116 mg) obtained in Reference Example 68- (3).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.51 (6H, s), 2

 Three

 .20 (3H, s), 2.27 (3H, s), 3.25 (2H, s), 3.55 (2H, s), 3.63 (2H, s), 4.28 (2H, q, J = 7.2Hz), 5.40 (1H, br s), 7.00 (1H, s), 7.18 (1H, s), 7.4 2-7.47 (3H, m), 7.66 (1H, br s), 7.97— 8.01 (2H, m).

 MS m / z: 514 (M + H) +.

[1106] (2) 2— [4 [[Strength Rubamoylmethyl- (5-methyl-2-phenolox-4-ylmethyl) amino] methyl] —2 Chloromethyl 6-methylphenoxy] —2-Methylpropanoic acid

 [1107] [Chemical 354]

実施例 61— (2)と同様にして、実施例 103— (1)で得られた化合物（83mg)から 標題化合物（60mg)を無色固体として得た。

Example 61- In the same manner as (2), the title compound (60 mg) was obtained as a colorless solid from the compound (83 mg) obtained in Example 103- (1).

 'H-NMR (400MHz, CDCl) δ: 1.55 (6Η, s), 2.26 (3Η, s), 2.30 (3H, s

 Three

), 3.23 (2H, s), 3.58 (2H, s), 3.64 (2H, s), 5.87 (1H, d, J = 3.2Hz), 7 .05 (1H, s), 7.22 (1H, d, J = l.7Hz), 7.41— 7.49 (3H, m), 7.75 (1H, d

, J = 4.2Hz), 7.99-8.00 (2H, m).

 MS m / z: 486 (M + H) +.

[1109] [Example 104]

 (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl [2-[5 Methyl 2 mono (4 trifluoromethylphenol) oxazole 4 ethyl] ethyl] amino] methyl] phenoxy] 2-methyl Propanoic acid ethyl ester

[1110] [Chemical 355]

[1111] In the same manner as in Example 62- (1), the title compound (109 mg) was obtained as a colorless oil from the compound (128 mg) obtained in Reference Example 69- (3).

 'H-NMR (400MHz, CDCl) δ: 1.34 (3Η, t, J = 7.1 Hz), 1.44 (6H, s), 2

 Three

 .09 (6H, s), 2.26 (3H, s), 2.65 (2H, t, J = 6.6Hz), 2.70 (3H, d, J = 4.9 Hz), 2.78 (2H, t, J = 6.5Hz) , 3.14 (2H, s), 3.51 (2H, s), 4.28 (2H, q, J = 7.2Hz), 6.76 (2H, s), 7.50 (1H, d, J = 4.9Hz), 7.72 (2H, d, J = 8.3 Hz), 8.11 (2H, d, J = 8.3 Hz).

 MS m / z: 590 (M + H) +.

 [1112] (2) 2- [2, 6 Dimethyl-4 [(Methylcarbamoylmethyl- {2-— [5-Methyl-2-mono (4 trifluoromethylphenol) oxazole 4-yl] ethyl} amino) methyl] Phenoxy] 2-methylpropanoic acid

[1113] [Chemical 356]

[1114] In the same manner as in Example 62- (2), the title compound (81 mg) was obtained as a colorless solid from the compound (107 mg) obtained in Example 104- (1).

 'H-NMR (400MHz, CDCl) δ: 1.49 (6Η, s), 2.15 (6Η, s), 2.29 (3H, s

 Three

 ), 2.65-2.71 (5H, m), 2.80 (2H, t, J = 6.5Hz), 3.14 (2H, s), 3.54 (2 H, s), 6.82 (2H, s), 7.52 (1H, d , J = 4.7Hz), 7.72 (2H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz).

 MS m / z: 562 (M + H) +.

 Elemental analysis value as C H FNO 0.5HO

 29 34 3 3 5 2

 Calculated values: C, 61.04; H, 6.18; F, 9.98; N, 7.36.

 measured value:. 61.42; H, 6.21; F, 9.62; N, 7.24.

[1115] [Example 105]

 (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl [2 — (5 Methyl 2 — p Tolyloxazole — 4-yl) ethyl] amino] methyl] phenoxy] -2-methyl propanoate Ester

[1116] [Chemical 357]

/— 、 / (H— ^d— — S) -Z — / / ¾ ココ— コ (ΐ)

^{/ -, / (H- d -} - S) -Z - / / ¾ here - co (ΐ)

[90Ip «^] \ _ \ Z \ X \ • ₊ (H + PV) 809: ^z / ^ra SPV • ( ^Z HI · 8 = ΓΡ 'HS) 68' L '( ^Ζ Η6 · = ΓΡ' ΗΙ) ΙΖ 'L' ( ^Ζ ΗΙ8 = ΓΡ 'HS) 9S' L '( ^s ' HS) S8 9 '( ^s ' HS) S9 Έ '( ^s ' HS) SI Έ '( ^Ζ ΗΙ9 = Γ' ΗΖ)

SL 'Ζ' ( ^Ζ ΗΖ · = ΓΡ ¾ε) 89 'Ζ' ( ^Ζ Η9 = Γ 'HS) 9'('( ^s 'Ηε)' Ζ '( ^s Ήε) ΡΖ' Ζ '( ^s ' Η9 ) ΐ 'Ζ' ( ^s 'Η9) 6 ΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

[8SS ^] [6ΪΠ] l l l

-Z- [^ ^ Δ {Λ ^ {Π Λ (^ (/ →-/ —, ^ / (Η— ^d —

 -Ζ -Λ ^ Λ ^^ Λ ^ Λ ^}) → -Λ ^ ^ -9 'Ζ ~ Ζ {Ζ) [8ΐΐΐ]

• ₊ (H + PV) 9S9: ^z / ^ra SPV • (ζΗε · 8 = ΓΡ 'Η2) 06' L '( ^Ζ Η = ί' Ρ 'ΗΙ

), 9 'L' ( ^ζ Ηε · 8 = ΓΡ 'HS) 9S' L '( ^s ' Η2) 9Ζ 9' ( ^Ζ ΗΙ · ΗΙ = Γ¾ 'HS) 8S'

'( ^s ' Η2) 09 Έ' ( ^s ' Η2) 2Ι Έ '( ^Ζ Η9 = Γ' Η2) 9Ζ 'Ζ' ( ^Ζ Η6 · = ΓΡ 'ΗΖ

) 19 'Ζ' ( ^Ζ Η 9 = Γ 'HS) 9' Ζ '( ^s ¾ε) ΐ' Ζ '( ^s Ή £) ΖΖ' Ζ '( ^s ' Η9) 0 Ι ζ' ( ^s ¾9) χ '( ^ζ ΗΙ · = Γ' ^ 'Ηε) 9ε · χ: 9 (ιοαο' ZH OO ^) H NH _T

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OA —4—yl) ethyl] amino] methyl] —2,6-dimethylphenoxy] —2-methylpropanoic acid ethenole ester

 [Chemical 359]

[1123] Reference Example 70— To a solution of the compound obtained in (2) (166 mg) in N, N-dimethylformamide (5 mL) was added potassium carbonate (99 mg) and 2-bromoacetamide (99 mg), and the mixture was heated to 80 ° C. And stirred overnight. The reaction solution was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (black mouth form: methanol = 98: 2) to obtain the title compound (138 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.34 (3Η, t, J = 7.1 Hz), 1.43 (6H, s), 2

 Three

 .08 (6H, s), 2.20 (3H, s), 2.40 (3H, s), 2.66 (2H, t, J = 6. Hz), 2.78 (2 H, t, J = 6.5 Hz), 3. 14 (2H, s), 3.50 (2H, s), 4.27 (2H, q, J = 7.2Hz), 5.29 (1H, d, J = 4.7Hz), 6.73 (2H, s), 7.25 (2H , d, J = 8.8Hz), 7.88—7.81 (3H, m).

MS m / z: 522 (M + H) ⁺ .

[1124] (2) 2— [4— [[Strong Rubamoylmethyl- [2- (5-Methyl-2-p-triloxazol —4-yl) ethyl] amino] methyl] —2, 6— Dimethylphenoxy] -2-methylpropanoic acid

[1125] [Chemical 360]

[1126] In the same manner as in Example 70- (2), the title compound (67 mg) was obtained as a colorless solid from the compound of Example 106- (1) (136 mg).

 'H-NMR (400MHz, CDCl) δ: 1.48 (6Η, s), 2.11 (6Η, s), 2.23 (3H, s

 Three

 ), 2.39 (3H, s), 2.67 (2H, t, J = 6.5Hz), 2.82 (2H, t, J = 6.5Hz), 3.15 (2H, s), 3.52 (2H, s), 5.80 (1H , d, J = 3.9Hz), 6.76 (2H, s), 7.25 (2H, d, J = 8.3Hz), 7.83 (2H, d, J = 8.3Hz), 7.96 (1H, d, J = 4.4Hz ).

 Elemental analysis value C H N O 0.75H O

 28 35 3 5 2

 Calculated values: C, 66.31; H, 7.25; N, 8.29.

 measured value:. 66.57; H, 7.35; N, 7.97.

[1127] [Example 107]

 (l) 2- [4-[[[2- (4-Methoxyphenyl) 5-methyloxazole- 4-methyl]] (5-Methyl- [1, 3, 4] oxadiazo- 2-methyl) amino] Methyl] 2,6-dimethylphenoxy] -2-methylpropanoic acid ethyl ester

[1128] [Chemical 361]

[1129] Example 31— In the same manner as (1), the compound (0.150 g) obtained in Reference Example 30— (5) and 4 [] [] 363

[]

[] 1132

[]

[] 1130,,,) () () Hz 6.2H s 7.92H 8.8HZ.

 q ,,,,,,, () () () (3H s2H s.2H 1HZ2H

 ,,,,,,, () () () () () .186H s 2.23H s 2.13H s 3.62H s 3.662H s 3.

,,,,, () () () J δ: HNMR ^ 00MHZ CDCl: 1.33H 7.1HZ 1.6H s 2 = I to o

[1135] In the same manner as in Example 31- (1), Reference Example 30- Compound (0. lOOg) obtained in (5) and Reference Example 55- Compound (b) obtained in (1) ( 0.070 g) The title compound (0.115 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.42-1.45 (9

 Three

 H, m), 2.18 (6H, s), 2.25 (3H, s), 2.51 (3H, s), 3.65 (2H, s), 3.66 (2 H, s), 3.99 (2H, s), 4.08 ( 2H, q, J = 6.9Hz), 4.28 (2H, q, J = 7.2Hz), 6.93 (2H, d, J = 8.8Hz), 6.98 (2H, s), 7.92 (2H, d, J = 8.8 Hz).

MS m / z: 577 (M + H) ⁺ .

 [1136] (2) 2- [4-[[[2- (4 Ethoxyphenyl) 5-methyloxazole- 4-methyl] 5- (5-methyl- [1, 3, 4] oxadiazol 2-methyl ) Amino] methyl] 2, 6-dimethylphenoxy] -2-methylpropanoic acid

 [1137] [Chemical 364]

実施例 31— (2)と同様にして、実施例 108— (1)で得たィ匕合物 (0.115g)から標 題化合物（0.070g)を無色固体として得た。

Example 31- In the same manner as (2), the title compound (0.070 g) was obtained as a colorless solid from the compound (0.115 g) obtained in Example 108- (1).

 ^ H—NMR (400MHz, CDCl) δ: 1.44 (3Η, t, J = 7. OHz), 1.50 (6H, s), 2

 Three

.22 (6H, s), 2.28 (3H, s), 2.52 (3H, s), 3.67 (2H, s), 3.69 (2H, s), 3. 98 (2H, s), 4.08 (2H, q, J = 6.9Hz), 6.93 (2H, d, J = 8.8Hz), 7.04 (2H, s), 7.92 (2H, d, J = 8.8Hz).

 MS m / z: 549 (M + H) +.

 [1139] [Example 109]

 (1) 2— [2, 6 Dimethyl-4-[[((5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl) [5-Methyl-2- (4 trifluoromethylphenol) oxazole 4ylmethyl] amino] methyl] phenoxy] -2-methylpropanoic acid ethyl ester

[1140] [Chemical 365]

[1141] In the same manner as in Example 31- (1), the compound (0.100 g) obtained in Reference Example 30- (5) and 4-chloromethyl-5-methyl-2- (4 trifluoromethylphenol) were obtained. -L) oxazole (0.076 g) gave the title compound (0.128 g) as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.30 (3H, s), 2.52 (3H, s), 3.67— 3.68 (4H, m), 3.99 (2

H, s), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.69 (2H, d, J = 8.3Hz),

8.12 (2H, d, J = 8.1Hz).

 MS m / z: 601 (M + H) +.

[1142] (2) 2- [2, 6 Dimethyl 4-[[[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl) [5-Methyl-2- (4 trifluoromethyl phenol- L) oxazole-4-ylmethyl] amino] methyl] phenoxy] -2-methylpropanoic acid

[1143] [Chemical 366]

In the same manner as in Example 31- (2), the title compound (0.080 g) was obtained as a colorless solid from the compound (0.128 g) obtained in Example 109- (1).

 'H-NMR (400MHz, CDCl) δ: 1.51 (6Η, s), 2.23 (6Η, s), 2.33 (3H, s

 Three

 ), 2.53 (3H, s), 3.70-3.71 (4H, m), 3.98 (2H, s), 7.04 (2H, s), 7.70 (2H, d, J = 8.3Hz), 8.12 (2H, d, J = 8.1Hz).

MS m / z: 573 (M + H) ⁺ .

 [1145] [Example 110]

 (l) 2- [4-[[[2- (3,4-Dimethylphenol) 5-Methyloxazole-4-ylmethyl] one (5-Methyl- [1, 3, 4] oxadiazol-2-ylmethyl) Amino] methyl] —2, 6 dimethylphenoxy] 2 methyl propanoic acid ethyl ester

 [1146] [Chemical 367]

実施例 31— (1)と同様にして、参考例 30— (5)で得たィ匕合物 (0.100g)と参考例 56— (1)で得たィ匕合物（0.065g)力 標題ィ匕合物（0.135g)を淡黄色油状物とし て得た。

Example 31—Same as in (1), Reference Example 30—Compound (0.100 g) obtained in (5) and Reference Example 56—Compound (0.065 g) force obtained in (1) The title compound (0.135 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

18 (6H, s), 2.26 (3H, s), 2.30 (3H, s), 2.31 (3H, s), 2.51 (3H, s), 3. 66-3.67 (4H, m), 3.98 (2H , s), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s) , 7.19 (1H, d, J = 7.8Hz), 7.72 (1H, d, J = 7.8Hz), 7.80 (1H, s).

 MS m / z: 561 (M + H) +.

[1148] (2) 2- [4-[[[2- (3,4-Dimethylphenol) 5-methyloxazole- 4-ylmethyl] -one (5-methyl- [1, 3, 4] oxazodiazole 2ylmethyl) amino] methyl]

-2, 6 dimethylphenoxy] 2 methylpropanoic acid

[1149] [Chem 368]

[1150] In the same manner as in Example 31- (2), the compound (0.135 g) obtained in Example 110- (1) also gave the title compound (0.090 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.50 (6Η, s), 2.22 (6Η, s), 2.29 (3H, s

 Three

 ), 2.30 (3H, s), 2.32 (3H, s), 2.52 (3H, s), 3.68— 3.69 (4H, m), 3.98 (2H, s), 7.03 (2H, s), 7.19 (1H, d, J = 7.8Hz), 7.72 (1H, d, J = 7.8Hz), 7.80 (1H, s).

 MS m / z: 533 (M + H) +.

 [1151] [Example 111]

 (1) 2- [4 [[[[2- (4-Methoxy-3-methylphenol) 5 methyloxazole 4-ylmethyl] one (5-methyl- [1, 3, 4] oxaziazol 2-ylmethyl) amino] methyl] —2, 6 Dimethylphenoxy] -2 Methylpropanoic acid ethyl ester

[1152] [Chem 369]

[1153] 実施例 31— (1)と同様にして、参考例 30— (5)で得たィ匕合物 (0. lOOg)と参考例 58— (1)で得たィ匕合物（0.070g)力も標題ィ匕合物（0.118g)を淡黄色油状物とし て得た。

[1153] In the same manner as in Example 31- (1), Reference Example 30- Compound (0. lOOg) obtained in (5) and Reference Example 58- Compound (b) obtained in (1) ( 0.070 g) The title compound (0.118 g) was obtained as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.25-2.26 (6H, m), 2.51 (3H, s), 3.65—3.66 (4H, m), 3.88 (3H, s), 3.98 (2H, s), 4.28 (2H , q, J = 7.1 Hz), 6.86 (1H, d, J = 9.1 Hz), 6.98 (2H, s), 7.79—7.81 (2H, m).

MS m / z: 577 (M + H) ⁺ .

 [1154] (2) 2— [4— [[[2— (4-Methoxy-3-methylphenol) 5-methyloxazole 4-ylmethyl] one (5-methyl- [1, 3, 4] oxazodiazole 2-ylmethyl ) Amino] methyl] 2,6-dimethylphenoxy] -2-methylpropanoic acid

 [1155] [Chemical 370]

[1156] In the same manner as in Example 31- (2), the title compound (0.080 g) was obtained as a colorless solid from the compound (0.118 g) obtained in Example 111- (1).

 'H-NMR (400MHz, CDCl) δ: 1.50 (6Η, s), 2.22 (6Η, s), 2.26 (3H, s

 Three

 ), 2.28 (3H, s), 2.52 (3H, s), 3.67 (2H, s), 3.68 (2H, s), 3.88 (3H, s), 3.98 (2H, s), 6.86 (1H, d, J = 9.1Hz), 7.04 (2H, s), 7.80—7.81 (2H, m).

 MS m / z: 549 (M + H) +.

[1157] [Example 112]

(1) 2— [4 [[((5 ethyl [1, 3, 4] oxadiazo-l-ylmethyl)-((5-methyl-2-phenoloxol- 4-ylmethyl) amino) methyl] -2, 6 dimethyl Rufenoxy] 2-methylpropanoic acid ethyl ester

[1158] [Chemical 371]

[1159] In the same manner as in Example 18- (1), the compound (0.190 g) force obtained in Reference Example 71 was also obtained as the title compound (0.135 g) as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.33— 1.39 (6Η, m), 1.45 (6Η, s), 2.1

 Three

 8 (6H, s), 2.28 (3H, s), 2.86 (2H, q, J = 7.5Hz), 3.66 (2H, s), 3.67 (2

H, s), 3.99 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.99 (2H, s), 7.40—7.4

6 (3H, m), 7.99-8.02 (2H, m).

MS m / z: 547 (M + H) ⁺ .

[1160] (2) 2— [4 -1 [[(5 ethyl [1, 3, 4] oxadiazol 2 ylmethyl) -1- (5-methyl-2 pheluoxazole-4-ylmethyl) amino] methyl] -2, 6-Dimethylphenoxy] 2-methylpropanoic acid

[1161] [Chem 372]

実施例 70— (2)と同様にして、実施例 112— (1)で得たィ匕合物 (0.135g)カも標 題化合物（0.085g)を無色固体として得た。

Example 70- In the same manner as in (2), the compound (0.135 g) obtained in Example 112- (1) was also obtained as the colorless compound (0.085 g).

^ H—NMR (400MHz, CDCl) δ: 1.37 (3Η, t, J = 7.6Hz), 1.50 (6H, s), 2 22 (6H, s), 2. 31 (3H, s), 2. 87 (2H, q, J = 7.6Hz), 3.68—3.71 (3H, m), 3.71 (2H , s), 3.98 (2H, s), 7.03 (2H, s), 7.41—7.46 (3H, m), 7.99 -8. 02 (2H, m).

 MS m / z: 519 (M + H) +.

 [1163] [Example 113]

 (1) 2— [2 Chloro-6-methyl-4-[[[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(5-Methyl-2 phenol-loxazol-4-ylmethyl) amino] methyl ] Phenoxy] 2-Methylpropanoic acid ethyl ester

 [1164] [Chemical 373]

[1165] In the same manner as in Example 18- (1), the compound (0.080 g) force obtained in Reference Example 72 was also obtained as the title compound (0.070 g) as a pale yellow oil.

 ^ H—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1 Hz), 1.52 (6H, s), 2

 Three

 22 (3H, s), 2.29 (3H, s), 2.52 (3H, s), 3.68 (2H, s), 3.71 (2H, s), 3

99 (2H, s), 4. 28 (2H, q, J = 7.1 Hz), 7. 08 (1H, s), 7. 25 (1H, s), 7.40

-7. 46 (3H, m), 7. 98—8.03 (2H, m).

 MS m / z: 553 (M + H) +.

[1166] (2) 2— [2 Chloro-6-methyl-4-[[((5-methyl- [1, 3, 4] oxazodiazole)

2-ylmethyl)-(5-methyl-2phenoloxazole-4-ylmethyl) amino] methyl] phenoxy] 2-methylpropanoic acid

[1167] [Chemical 374]

[1168] In the same manner as in Example 61- (2), the compound (0.069 g) obtained in Example 113- (1) was also obtained as the title compound (0.057 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 1.56 (6Η, s), 2.28 (3Η, s), 2.32 (3H, s

 Three

 ), 2.53 (3H, s), 3.70 (2H, s), 3.73 (2H, s), 3.99 (2H, s), 7.14 (1H, d, J = 2. OHz), 7.31 (1H, d, J = 2. OHz), 7.41— 7.46 (3H, m), 7.98— 8.0 3 (2H, m).

MS m / z: 525 (M + H) ⁺ .

 [1169] [Example 114]

 (1) 2- [2, 6 Dimethyl-4-[[((5-Methyl- [1, 3, 4] oxaziazol 2-ylmethyl)-[2- (5-Methyl-2-p-triloxazole- 4-yl) ethyl] amino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

 [1170] [Chem 375]

実施例 18— (1)と同様にして、参考例 73で得たィ匕合物 (0.190g)力も標題ィ匕合 物（0. 160g)を無色油状物として得た。

Example 18—In the same manner as (1), the compound (0.190 g) obtained in Reference Example 73 was also used to obtain the title compound (0.160 g) as a colorless oil.

'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.44 (6H, s), 2

q, J ,, J, J () ((7.1HZ 6.922H s 7.222H 8.1HZ 7.82H8 = ==

,,,, ((() (.1HZ 2.882H 7.8HZ 3.62H s 3.2H s.282H ,,,,, (((((.166H s3H s3H s3H s2H [9th zone] [ΐΐ8Τ]

• ₊ (H + PV) 909: ^z / ^ra SPV

• ( ^Z H90 · 8 = ΓΡ 'UZ) L6' L

(ra 'HS) IS' L '( ^s ' HS) 0' L '( ^s ' H) SI''( ^s ' HS) S8 Έ' ( ^s ' HS) S9 'Z' ( ^s ¾ε) ε 'ζ '( ^S ' U9) zz 'z' ( ^S 'H9) 09 Ί-9 (\ oao' ZH OO ^) H NH _T

'ζ 'ΐ]一 / fH— ^d— ε) （ / [8 S ^] [6ΖΠ] 邈 I: ^ S [^ :,

'ζ' ΐ] ichi / fH— ^d — ε) (/

[8ζπ]yz- —

[8ζπ]

• ₊ (H +) ^ S9: ^z / ^ra SPV

 '(ra' HS) 8

Ί '^ ΉΖ) 6 Ζ' L '( ^s ' HS) 66 · 9' ( ^Z H80 · Ζ = Γ¾ 'HS) 8S''( ^s ' HS) 9I ·' ( ^s ' HS) SI '(s' HS ) 08 Έ '( ^s ' HS) I9' ( ^s ¾ε) ε 'Ζ' ( ^s ' Η9) 6Ι 'Ζ

'( ^s ' Η9) 9 Ί' ( ^Ζ Η80 · = Γ'ΐ 'HS) 9S · ΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

Yes

Z93

T86.l0 / S00Zdf / X3d οιο.εο / .οοζ OAV (1) 2- [2, 6 Dimethyl-4 [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(3-m-tolyl- [1, 2, 4] oxadiazole-5 —Ylmethyl) amino] methyl] phenoxy] 2-methylpropanoic acid ethyl ester

 [1182] [Chemical 379]

To 〇

[1183] In the same manner as in Example 18- (1), the compound (0.500 g) force obtained in Reference Example 75 also gave the title compound (0.38 g) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.08Hz), 1.45 (6H, s),

 Three

 2. 19 (6H, s), 2.44 (3H, s), 2.52 (3H, s), 3.80 (2H, s), 4.12 (2H, s), 4

15 (2H, s), 4.28 (2H, q, J = 7.08Hz), 7.00 (2H, s), 7.35 (2H, m), 7.9

0 (2H, m).

 MS m / z: 534 (M + H) +.

[1184] (2) 2- [2, 6 Dimethyl 4-[[[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(3-M-Tolyl- [1, 2, 4 ] Oxadiazole-5-ylmethyl) amino] methyl] phenoxy] 2-methylpropanoic acid

[1185] [Chemical 380]

[1186] Example 70- In the same manner as (2), the title was obtained from the compound (0.38 g) obtained in Example 116- (1). The compound (0.126 g) was obtained as a colorless solid.

 'H -NMR (400MHz, CDC1) δ: 1. 50 (6 Η, s), 2. 23 (6 Η, s), 2. 44 (3H, s)

 Three

 , 2. 53 (3H, s), 3. 83 (2H, s), 4. 16 (4H, s), 7. 04 (2H, s), 7. 35 (2H, m), 7. 91 ( 2H, m).

 MS m / z: 506 (M + H) +.

[1187] [Test Example 1]

 GAL4— hPPAR transactivation assembly (transient expression system)

 (a) Plasmid

 GAL4 DNA binding region PPAR ligand binding region fusion protein expression plasmids pFA -hPPAR a / GAL4 and pFA— hPPAR y / GAL4, respectively, hPPAR a and hPPAR y LBD cDNA, yeast GAL4 DNA binding under CMV promoter It was obtained by integrating into a commercially available expression vector (pFA-CMV, STRATAGE NE) having a region (GAL4 DBD). As the reporter protein expression plasmid, a commercially available plasmid (pFR-SEAP, STRATAGENE) having a GAL4 response region (GAL4 UAS) upstream of the cDNA of secretory alkaline phosphatase (SEAP) was used.

[1188] (b) Cell culture and transactivation assembly

Suspend HEK293T cells in high-Darcose Dulbecco's conditioned Eagle's medium (DMEM) containing 10% urine fetal serum (Hyclone or Cell Culture Technologies), 100 units ZmL penicillin G and lOOmgZmL streptomycin sulfate. Cell culture plates were seeded at a density of 8 × 10 ⁴ Zwells. 5% CO humidified atmosphere

 2

 Incubate for 24 hours at 37 ° C under air, and then transfer with lipofectionamine (Lipofectamine, Invitrogen) and Puffs reagent (Plus Reagent, Invitrogen) under serum-free conditions according to the manufacturer's instructions. Went. That is, in a 225 μL transfection medium (OPTI-MEM, Invitrogen) containing 0.48 μL of lipofectoamine pFA—PPARZGAL4 expression plasmid and 0.30 μg of pFR—SEAP Cells were incubated for 5 hours at 37 ° C in a 5% CO atmosphere. Next, 10% urine fetal serum,

2

100 units ZmL Penicillin G and lOOmg ZmL Streptomycin Sulfate and 2 volumes of the specified test compound at an equivalent volume of fresh high glucose DMEM are added to the cells. Was incubated for about 48 hours. Since the compounds were solubilized in DMSO, control cells were incubated with an equivalent concentration of DMSO. The final DMSO concentration is 0.1% or less, and it has been clarified that the concentration does not affect the transactivation activity. After completion of the incubation, the culture supernatant was collected, and SEAP activity was measured using a kit (Reporter assay kit SEAP, TOYOBO) according to the manufacturer's instructions. That is, add an equal volume of endogenous alkaline phosphatase inhibitor to 5 / zL of culture supernatant, incubate at 37 ° C for 30 minutes, and then add chemiluminescent substrate (Lumiphos PLUS, Lumigen) to 100 / L. After incubation and incubation at 37 ° C for 15 minutes, luminescence was measured using a multilabel counter (ARVOsx or ARVOmx, Perkin Elmer). Plot the relationship between the value obtained by the above operation and the concentration of the test compound.

 5 The value was obtained.

 0

 [1189] <Test results>

 As shown in the table below, the compounds of the present invention showed potent GAL4-hPPAR transactivation activity.

[1190] [Table 1] Table 1

[1191] [Test Example 2] Measurement of solubility

 <Measurement method>

Test compound lmg is weighed into a test tube, and the first solution of Japanese Pharmacopoeia Disintegration Test Method (artificial gastric juice, p Add 1 mL of HI. 2: JP, JP 1 liquid) and Japanese Pharmacopoeia Disintegration Test 2nd liquid (artificial intestinal fluid, pH 6.8, JP JP 2 liquid), shake, and then at room temperature for 12 hours It was left above. The sample after standing was filtered through a 0.45 μm membrane filter, and the filtrate was appropriately diluted with a DMSO-purified water mixture (1: 1) to obtain a solubility measurement solution.

 Separately, lmg of the test compound was placed in a 20mL volumetric flask and dissolved by adding DMSO-purified water mixture (1: 1) to prepare a 50 / z gZmL standard solution. This standard solution was diluted in several steps. A calibration curve was prepared using the solution.

 The above-mentioned solubility measurement solutions in JP 1 liquid and JP 2 liquid were analyzed by HPLC, and the solubility of the test compound was calculated using the above calibration curve.

 [1192] HPLC measurement conditions were as follows.

 HPLC system for Alliance analysis (Waters, USA); feed pump: 2795 separation module; UV detector: 2996 photodiode array detector; column: ODS C18 column (3.5 πι, 3. OmmlD X 30mm); Column temperature: 60 ° C; Mobile phase A: pH 4.5, 10 mM acetate buffer; Mobile phase B: 50% acetic acid-acetonitrile mixture (1: 999); Gradient condition: Mobile phase AZB ratio 95Z5 ~: L0Z90; flow rate: 1.5 mL / min; sample temperature: 25 ° C; injection volume: 5 μL; detection wavelength: maximum absorption wavelength in the range of 220-420 nm.

 [1193] <Measurement result>

 As shown in the table below, the compound of the present invention showed good solubility in JP 1 liquid and JP 2 liquid.

[1194] [Table 2]

Table 2

[試験例 3]脂溶性

[Test Example 3] Fat solubility

Measurement method>

 A mixture of n-octanol (hereinafter referred to as “octanol”) and pH 7.4 isotonic phosphate buffer (hereinafter referred to as “aqueous phase”) in the same volume was shaken in a suitable container and allowed to stand for 24 hours or longer. (Tanol) and lower layer (octanol saturated water) were collected.

1 mg of the test compound was weighed into a test tube, and 5 mL of water-saturated octanol was added and sonicated for 10 minutes, and then stirred for about 30 seconds. If insoluble matter was observed, it was filtered through a 0.45 zm membrane filter. 2 mL of a water-saturated octanol solution of the test compound was placed in a test tube, and 2 mL of octanol-saturated water was added, shaken for 30 minutes, and then centrifuged to separate the upper layer (octanol phase) and the lower layer (aqueous phase). The above octanol phase and aqueous phase were appropriately diluted with DMSO, and the concentration of the test compound was measured by UV detection HPLC or MS detection HPLC.

 Based on the measured concentration of both phases and the respective dilution factor, the partition coefficient was calculated. If the test compound is presumed to have high water solubility, dissolve the test compound in octanol-saturated water, add water-saturated octanol, and then shake and centrifuge to obtain the upper layer (octanol phase) and The lower layer (aqueous phase) was separated and the concentration of the test compound was measured.

[1196] HPLC equipment · Measurement conditions are as follows.

 <UV detection HPLC system>

 HPLC system for Alliance analysis (Waters, USA); liquid pump: 2795 separation module; UV detector: 2996 photodiode array detector.

 MS detection HPLC system>

 High-throughput LCZMS system (Agilent, USA); liquid pump: 1100 series / binary pump; MS detector: 1100 series LC / MSD SL.

 <Measurement conditions>

 Column: ODS C18 column (3.5 πι, 3. OmmlD X 30 mm); Column temperature: 60 ° C; Mobile phase A: pH 4.5, 10 mM acetate buffer; Mobile phase B: 50% acetate-acetonitrile mixture ( 1: 999); Gradient condition: Mobile phase AZB ratio 95Z5 ~: L0Z90; Flow rate: 1.5mL / min; Sample temperature: 25 ° C; Injection volume: 5L; UV detection wavelength: in the range of 220-420nm Maximum absorption wavelength.

 [1197] In the MS detection, the following conditions were used.

Moae: ¾IM; Drying gas flow: 12L / mm .; Nebulizer pressure: 55 psig .; Capillary voltage: 3000 V; Drying gas temp .: 350 ° C; Fragmenter vo ltage: 100V _o

[1198] <Measurement result>

 As shown in the table below, the compound of the present invention showed moderate fat solubility as a pharmaceutical product.

[1199] [Table 3] Table 3

[1200] [Test Example 4]

 GAL4— hPPAR transactivation assembly (constant expression system)

 (a) Plasmid

 The reporter protein expression plasmid (pFR-Luc-Zeo) is a commercially available plasmid (pFR-Luc, ST RATAGENE) with a GAL4 response region (GAL4 UAS) upstream of luciferase (Luc) cDN A. Zeocin resistance expression unit excised from Invitrogen).

[1201] (b) Production of constitutively expressing cells

Suspend HEK 293 cells in high-glucose DMEM containing 10% urine fetal serum (Cell Culture Technologies), 100 units ZmL penicillin G and lOOmgZmL streptomycin sulfate, and add 1.5 × 10 to a collagen-coated cell culture dish with a diameter of 60 mm. ⁶ seeds were seeded at a density of Z dish. Incubate for 24 hours at 37 ° C in a humidified atmosphere of 5% CO

 2

Subsequently, transfection was performed under serum-free conditions using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. That is, ribofeta Tomin 2000 20 pFA—PPAR a / GAL4 or pFA—PPAR y / GAL4 expression plasmid 0.38; zmL and pFR—Luc—Zeo In lmL transfection medium (OPTI—MEM, Invitrogen) containing 7.6 g In a 5% CO atmosphere at 37 ° C,

 2

Cells were incubated for 24 hours. Cells are diluted and passaged into a collagen-coated cell culture dish with a diameter of 150 mm, and after 24 hours, the medium is replaced with a selective medium (Zeocin 50 μg / mL, Geneticin 500 / z gZmL-containing 10% ushi fetal serum-containing DMEM) The culture was continued as it was, and the appearance of drug-resistant colonies was observed. About 100 drug-resistant colonies were picked up using a penicillin cup and seeded in a 96-well collagen-coated cell culture plate. Subculture was continued while expanding the scale to the same plate with 24 and 6 wells using selective medium, and highly stable for each PPAR agonist with luciferase assay (same method as described later). One colony that showed a reaction and was excellent in growth was selected. Next, 10 single clones were obtained from the selected colonies by limiting dilution, and one clone was finally obtained based on the results of these luciferase assays and growth. Selected.

(c) Luciferase Atsey

10% © Shi calf serum (Cell Culture Technologies, Inc.), were suspended each constitutive expression Itaipushironkappa 293 clonal cells to DMEM high glucose containing Zeocin 50 gZmL and Geneticin 500 μ g / mL, 1. 3 X 10 4 The cells were seeded in a 96-well black transparent bottom cell culture plate with collagen coating at a density of individual wells. The next day, an equal volume of fresh same medium containing the specified double concentration of the test compound was added and the cells were incubated. Since the compounds were soluble in DMSO, control cells were incubated with equivalent concentrations of DMSO. The final DMSO concentration is 0.1% or less, and it has been revealed that the concentration does not affect the transactivation activity. Remove the culture medium after 2 days, add 60 or 100 L of Pickergene LT2.0 (Toyo Ink), solubilize the cells, and simultaneously perform the luciferase activity measurement reaction. Measurement was performed using a counter (ARVOsx or ARVOmx, PerkinElmer).

Plot the relationship between the value obtained by the above procedure and the concentration of the test compound to obtain the EC50 value. [1203] <Test results>

 As shown in the table below, the compounds of the present invention exhibited potent GAL4-hPPAR transactivation activity.

[1204] [Table 4] Table 4

[1205] [Test Example 5]

 In vivo test using dbZdb mice

 <Test method>

Six female dbZdb mice (10-week-old C57BLZKsJ—dbZdb, Japan Claire) were raised per cage and allowed free access to F2 solid feed and drinking water. Animals weight was measured once a day, once daily by oral gavage with vehicle (1% methylcellulose) mechanic test compound was continuously administered for 9 days (10mgZkgZda _y). A drug suspension was prepared daily. The blood glucose concentration obtained by tail exsanguination on the 10th day during the test period and the blood force collected from the orbital venous plexus force on the 10th day were measured for the insulin concentration in the prepared serum. Glucose concentration was measured using a blood glucose measurement device (Anthosense IV, Neuel Sankyo), and insulin concentration was measured using a kit (Levis Insulin-Mouse-T, Shibayagi).

 [1206] <Test results>

 As shown in the table below, the compound of the present invention showed a strong blood glucose level lowering effect and blood insulin lowering effect in an in vivo test using dbZdb mice.

[1207] [Table 5] Table 5

[1208] Although the invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. is there.

 Industrial applicability

[1209] The compounds of the present invention, salts thereof and solvates thereof show excellent PPAR a / y agonist activity and are useful as preventive / therapeutic agents for diabetes.

Claims

Claim [1] General formula (I)  [Chemical 1]

(In the above formula,  Q is a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a pyrrolidinyl group, a piperidyl group, a piperazyl group, a morpholinyl group, a substituted group Or an unsubstituted phenol group and a substituted or unsubstituted pyridyl group, selected from one or two of the same or different groups, a benzene ring or a pyridine ring, R ¹ is a halogen atom, a lower alkenyl group, a lower alkoxy group, a phenoxy group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted amino group, one selected from the same or two of the same or different A phenyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyradyl group, a chael group, a furyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, Represents isothiazolyl, isoxazolyl, oxaziazolyl or triazolyl, R ² represents a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted pyridyl. A group selected from the following groups, which may be substituted with one, two, or the same or different groups, pyridyl group, pyrimidyl group, birazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, thiazolyl group, Oxazolyl group, isothiazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, cinnolyl group, quinoxalyl group, phthalazinyl group, naphthyridinyl group, indolyl group, benzoimidazolyl group, indazolyl group, indazolyl group The Benzoxazolyl group, benzoisothiazolyl group, benzoisoxazolyl group or benzotriazolyl group, or substituted with one or two lower alkyl groups of the same or different type, represents a rubamoyl group ,  X, Y and Z each independently represent C, 0, S or N (provided that at least one of X, Y and Z is 0, S or N); R ^{3 to} R ⁶ each independently represent a hydrogen atom or a lower alkyl group, or R ³ and R ⁵ and R ⁶ together with the carbon atom they are substituted with 3 to 6 Indicates that a saturated ring of members may be formed, R ⁸ and R ⁹ each independently represent a hydrogen atom or a lower alkyl group, n is an integer of 0-3. )  Or a salt or a solvate thereof. [2] The compound, its salt or solvate thereof according to claim 1, which is a 5-membered ring force containing X, Y and Z in the general formula (I), an oxazole ring, a thiazole ring or an oxaziazole ring.  [3] hydroxyl group, halogen atom, lower alkenyl group, lower alkoxy group, substituted or unsubstituted lower alkyl group, substituted or unsubstituted amino group, pyrrolidinyl group, piperidyl group, piperazyl group, morpholinyl group, substituted Or an unsubstituted phenyl group and a substituted or unsubstituted pyridyl group, the benzene ring may be substituted with one or two selected from the same or different groups. Or a salt or solvate thereof.  [4] Q force In the benzene ring which may be substituted with one or the same or different two groups of halogen atoms, lower alkenyl groups, lower alkoxy groups, and substituted or unsubstituted lower alkyl groups which are also selected. The compound according to claim 1 or 2, a salt thereof, or a solvate thereof. [5] R ¹ is selected from the group consisting of a halogen atom, a lower alkenyl group, a lower alkoxy group, a phenoxy group, a substituted or unsubstituted lower alkyl group and a substituted or unsubstituted amino group, one or the same or 5. The compound according to any one of claims 1 to 4, a salt thereof or a solvate thereof, which is a phenol group which may be substituted with two different groups. [6] R ¹ is selected from among halogen atoms and substituted or unsubstituted lower alkyl groups 5. The compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof, which is a phenyl group which may be substituted with one or two of the same or different groups. [7] R ² represents a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted phenyl group, and a substituted or non-substituted group. A pyridyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, an isothiazolyl group, an isoxazolyl group, which may be substituted with one, two, or the same or different groups selected from among substituted pyridyl groups The compound according to any one of claims 1 to 6, which is an oxadiazolyl group, a benzimidazolyl group, an indazolyl group, a benzothiazolyl group, a benzoxazolyl group, a benzisothiazolyl group, or a benzoisoxazolyl group. , Its salts or solvates thereof. [8] R ² is substituted with one selected from a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted phenyl group, or two of the same or different types The pyridyl group, imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, isothiazolyl group, isoxazolyl group, oxadiazolyl group, benzoimidazolyl group, benzothiazolyl group, or benzoxazolyl group, which may be substituted! , Any of the compounds, salts thereof or solvates thereof. [9] The compound, salt or solvent thereof according to any one of claims 1 to 6, wherein R ² is a carbamoyl group which may be substituted with one or the same or different two lower alkyl groups. Japanese products.  [10] A medicament comprising the compound represented by the general formula (I) according to claim 1, a salt thereof or a solvate thereof as an active ingredient.  [11] A pharmaceutical composition comprising a compound represented by the general formula (I) according to claim 1, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.  [12] Use of the compound represented by the general formula (I) according to claim 1, a salt thereof or a solvate thereof for the production of a medicine. [13] General formula (Π) [Chemical 2]

(In the above formula, R ⁷ represents a hydrogen atom or an unsubstituted lower alkyl group, R ^1QQ represents a methyl group or a methoxy group, R ² ° represents a hydrogen atom or a methyl group. )  Or a salt or a solvate thereof. [14] The ^{compound according} to [13], wherein R ^1QQ is a methyl group, and is a hydrogen atom or a methyl group. 15. The compound according to claim 13, wherein R ^1QQ is a methoxy group, and R ^2QQ is a hydrogen atom. [16] A medicament comprising the compound represented by the general formula (Π) according to claim 13, a salt thereof, or a solvate thereof.  [17] A pharmaceutical composition comprising a compound represented by the general formula (Π) according to claim 13, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. [18] The compound represented by the general formula (Π) according to claim 13, a salt thereof, or a solvate thereof Use for pharmaceutical manufacture. [19] An insulin resistance improving agent comprising the compound represented by the general formula (Π) according to claim 13, a salt thereof, or a solvate thereof. [20] A therapeutic agent for diabetes comprising the compound represented by the general formula (Π) according to claim 13, a salt thereof, or a solvate thereof.