WO2006013939A1 - Pyrazole derivatives - Google Patents

Abstract

A compound represented by the general formula (I), which is useful as a peroxisome proliferator-activated receptor α/Ϝ agonist, a salt of the compound, and a solvate of either. (In the formula, X, Y, and Z each represents nitrogen or carbon; m is an integer of 0 to 3; n is an integer of 1 to 3; Q represents a benzene ring optionally substituted by hydroxy, halogeno, lower alkenyl, lower alkoxy, lower alkyl, and amino; R1 represents a phenyl, naphthyl, or 5- or 6-membered aromatic heterocyclic group optionally substituted by hydroxy, halogeno, lower alkenyl, lower alkoxy, phenoxy, phenyl, lower alkyl, and amino; R2 represents lower alkyl, carbamoyl, phenyl, or a 5- or 6-membered aromatic heterocyclic group; R3 and R4 each represents hydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, or benzyl; and R6 represents hydrogen, hydroxy, halogeno, lower alkenyl, lower alkoxy, phenoxy, phenyl, lower alkyl, or amino

Description

 Specification

 Pyrazole derivative

 Technical field

 [0001] The present invention relates to a preventive / therapeutic agent for diabetes. More specifically, the present invention relates to a peroxisome proliferator-activated receptor a ligand (PPAR / y agonist: Peroxisome proliferator-activated a / y receptor 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.

 In recent years, thiazolidinedione derivatives such as pioglitazone (pioglitazone) (Non-Patent Document 1) have been developed as drugs that improve insulin resistance, and are widely used for the treatment of type 2 diabetics, especially type 2 diabetics with obesity. RU

[0003] [Chemical 1]

 Pi ogl i tazone

[0004] These thiazolidinedione derivatives have been shown to be pergosomes of 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.

 [0005] PPAR γ-agonist, pioglitazone, is especially high when administered to type 2 diabetic patients with obesity and has improved therapeutic effects, 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).

[0006] [Chemical 2]

[0007] 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

[0008] The object of the present invention is to have a chemical structure that is different from the above-mentioned known PPAR a / y agonist, has an excellent PPAR a / y agonist action, and has desirable properties as a pharmaceutical product. Is to provide a compound.

 Means for solving the problem

[0009] Thus, 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)

[0010] [Chemical 3]

R

 0

 (In the above formula, the following partial structural formula represents a 5-membered aromatic heterocyclic ring,

[0012] [Chemical 4]

[In the above structure, X, Y, and 各 々 each independently represent a nitrogen atom or a carbon atom.]

 m represents an integer of 0 to 3,

 n represents an integer of 1 to 3,

 Q may be substituted with one or two groups selected from among hydroxyl group, halogen atom, lower alkenyl group, lower alkoxy group, substituted or unsubstituted lower alkyl group, and substituted or unsubstituted amino group. !, Indicates a benzene ring,

R ¹ is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. And a substituted or unsubstituted amino group, a phenyl group, a naphthyl group, or a 5- or 6-membered aromatic heterocyclic group, which may be substituted with 1 or 2 groups selected,

R ² represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group,

R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group, R ⁵ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted benzyl group.

R ⁶ is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted Provided is a compound represented by an unsubstituted amino group (provided that when m is 2 or more, two or more R ^{6 s} may be the same or different from each other), a salt thereof, and a solvate thereof To do.

[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.

 The invention's effect

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

 BEST MODE FOR CARRYING OUT THE INVENTION

 [0016] The substituent will be described below.

 The hydrogen atom and the rogen atom mean a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the halogen atom, a fluorine atom or a chlorine atom is preferable.

An unsubstituted lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, tert-pentyl group, 1,2-dimethylpropyl group, neopentyl group, sec-pentyl group, 2-methylbutyl group, isopentyl group, tert —Hexyl group, 1,2-dimethylbutyl group, 1,3-di Methylbutyl group, neohexyl group, 2, 3-dimethylbutyl group, 3,3-dimethylbutyl group, sec-hexyl group, 2-methylpentyl group, 3-methylpentyl group, isohexyl group, cyclopropyl group , Cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclobutylmethyl group, and cyclopentylmethyl group can be given as representative examples, and a methyl group, an ethyl group, and a propyl group are preferable.

 [0017] The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, and a buyl group, an allyl group, and a butenyl group can be given as typical examples. An unsubstituted lower alkoxy group means an alkoxy group having a linear, branched and cyclic lower alkyl group having 1 to 6 carbon atoms, and includes a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Typical examples include butoxy, isobutoxy, pentoxy, and cyclopentyloxy. Of these, a methoxy group is preferred, with a methoxy group and an ethoxy group being preferred.

 [0018] Examples of the substituted lower alkoxy group include a lower alkoxy group substituted with 1 to 3 groups selected from the group consisting of a hydroxyl group, a halogen atom, and a lower alkoxy group. Specific examples include trifluoromethoxy group, 2, 2, 2-trifluoroethoxy group, 2-hydroxyethoxy group, 3-hydroxypropoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, 3-fluoro group. Typical examples include fluoropropoxy, methoxymethoxy, 2-methoxyethoxy, and 3-methoxypropoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy. Groups, 2-fluoroethoxy group, 2-chloroethoxy group, methoxymethoxy group, and 2-methoxyethoxy group are preferred trifluoromethoxy group, 2, 2, 2-trifluoroethoxy group, 2-hydroxy group Trifluoromethoxy is more preferred, with ethoxy, 2-fluoroethoxy, methoxymethoxy, and 2-methoxyethoxy. Group, 2, 2, 2-triflate Ruo b ethoxy group, 2-Furuoroetokishi group, and 2-Metokishieto alkoxy group is particularly preferred.

[0019] The substituted lower alkyl group includes a hydroxyl group, a halogen atom, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkoxy group, a carboxy group, a lower alkoxy group, a rubamoyl group, and a lower alkyl group rubamoyl. Group, di-lower alkylcarbamoyl group, force ruberamoylamino group, lower alkyl force ruberamoylamino group, di-lower alkyl Kill power ruberamoylamino group, lower alkyl sulfo-ramino group, lower alkoxycarbo

-Lumino group and lower alkyl group substituted with 1 to 3 groups selected from the medium strength of lower alkanoylamino group. Here, the lower alkanoylamino group means an amino group substituted by an alkanoyl group having 2 to 6 carbon atoms, and specifically includes an acetylamino group, a propio-lamino group, a butyrylamino group, an isobutyryl group. Mention may be made of amino groups and valeryl amino groups. Specific examples of the substituted lower alkyl group include trifluoromethyl group, 2, 2, 2-trifluoroethyl group, hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-fluoroethyl group, 2-chloro group. Oral ethyl group, 3-fluoropropyl group, aminomethyl group, 2-aminoethyl group, 3-aminoamino group, methylaminomethyl group, 2-methylaminoethyl group, 3-methylaminopropyl 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, methoxycarboromethyl group , 2-methoxycarbo-ruethyl group, 3-methoxycarbopropyl group, rubamoyl A methyl group, a 2-carbamoylethyl group, a 3-carbamoylpropyl group, a methylcarbamoylmethyl group, a 2-methylcarbamoylethyl group, a 3-methylcarbamoylpropyl group, an ethylcarbamoylmethyl group, a 2-ethylcarbamoylethyl group, 3-Ethylcarbamoylpropyl group, Dimethylcarbamoylmethyl group, 2-Dimethylcarbamoylethyl group, 3-Dimethylcarbamoylpropyl group, Detylcarbamoylmethyl group, 2-Detylcarbamoylpropyl group, 3-Dethylcarbamoylpropyl group, Power Luba Molyaminomethyl group, 2-force rubamoylaminoethyl group, 3-force rubamoylaminopropyl group, methylcarbamoylaminomethyl group, 2-methylcarbamoylaminoethyl group, 3-methylcarbamoylaminopropyl group, ethylcarba Iraminomethyl group, 2-ethylcarbamoylaminoethyl group, 3-ethylcarbamoylaminopropyl group, dimethylcarbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, 3-dimethylcarbamoylaminopropyl group, jeti Rucarbamoylaminomethyl group, 2-Dethylcarbamoylaminoethyl group, 3-Dethylcarbamoylaminopropyl group, Methylsulfo-luminomethyl group, 2-Methylsulfoaminoamino group, 3-Methylsulfo-laminopropyl group, Methoxy Carbo-aminoamino group, 2-methoxycarboaminoamino group, 3-methoxycarbo-aminoamino group, ethoxycarboaminomethyl group, 2-ethoxycarboaminoethyl group, 3-ethoxycarboaminopropyl group, acetylaminoamino group , 2-acetylaminoethyl group, and 3-acetylaminopropyl group can be given as representative examples, such as trifluoromethyl group, 2,2,2-trifluoroethyl 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-carbo Shetyl group, methoxycarbolmethyl group, 2-methoxycarboleethyl group, strong rubamoylmethyl group, 2-strong rubamoylethyl group, methylcarbamoylmethyl group, 2-methylcarbamoylethyl group, ethylcarbamoylmethyl group, 2-ethylcarbamoyl group Ethyl group, Dimethylcarbamoylmethyl group, 2-Dimethyl strong rubamoylethyl group, Jetylcarbamoylmethyl group, 2-Dethylcarbamoylethyl group, Strong rubamoylaminomethyl group, 2-Strong rubamoylaminoethyl group, Methylcarbamoyl Aminomethyl group, 2-methylcarbamoylaminoethyl group, ethylcarbamoylaminomethyl group, 2-ethylcarbamoylaminoethyl group, dimethylcarbamoylaminomethyl group, 2-dimethylcarbamoylaminoethyl group, jetylcarbamoyla Minomethyl group, 2-Dethylcarbamoylaminoethyl group, Methylsulfolaminomethyl group, 2-Methylsulfolaminoethyl group, Methoxycarboaminomethyl group, 2-Methoxycarbolaminoethyl group, Ethoxycarboaminoamino group, 2-Ethoxycarbo- Triaminomethyl group, 2,2,2-trifluoroethyl group, hydroxymethyl group, 2-hydroxyethyl group are preferred, which is preferably aminoethyl group, acetylaminoamino group, and 2-acetylaminoamino group. 2-fluoroethyl group, aminomethyl group, 2-aminoethyl group, methylaminomethyl group, 2-methylaminoethyl group, dimethylaminomethyl group, 2-dimethylaminoethyl group, methoxymethyl group, 2-methoxyethyl group, Rubamoylmethyl group, 2 rubamoylethyl group, Carbamoylmethyl group, 2-methylcarbamoyl E methyl group, dimethylcarbamoylmethyl group, 2-dimethylcarbamoyl E methyl group, Jefferies Chi carbamoylmethyl group, a force Luba Moyle § amino methyl, methylcarbamoylamino main A trifluoromethyl group, 2, 2, 2-triflul, more preferably a til group, an ethylcarbamoylaminomethyl group, a dimethylcarbamoylaminomethyl group, a dimethylcarbamoylaminomethyl group, and a methylsulfo-luminaminomethyl group Particularly preferred are oloethyl, hydroxymethyl, 2-methoxyethyl and 2-fluorethyl groups.

 [0020] The substituted phenoxy group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a phenoxy substituted with 1 or 2 groups selected from the central forces of a substituted or unsubstituted amino group. Groups such as fluorophenoxy, chlorophenoxy, bromophenoxy, methoxyphenoxy, ethoxyphenoxy, methylphenoxy, ethylphenoxy, trifluoromethylphenoxy, dimethylphenol Representative examples include an enoxy group, a fluoromethylphenoxy group, a chloromethylphenoxy group, a difluorophenoxy group, a dichlorophenoxy group, and a black chlorophenoxy group. Of these, a fluorophenoxy group, a chlorophenoxy group, a bromophenoxy group, a methylphenoxy group, and a trifluoromethylphenoxy group are preferable.

[0021] The substituted phenol group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group. Examples include phenyl groups substituted with 1 or 2 groups selected, such as hydroxyphenyl group, fluorophenol group, black-opened phenyl group, bromophenol group, methoxyphenyl group, and ethoxyphenol group. Group, butylphenol group, methylsulfophenyl group, methylphenol group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group Typical examples of mono-substituted phenyl groups are ethylaminophenol, dimethylaminophenol, dimethylaminophenol, and methylsulfophenol. Dimethylphenol group, methyl-trifluoromethylphenol group, fluoromethylphenyl group, chloromethylphenol group, fluorohydroxyphenyl group, chlorohydroxyphenyl group Group, difluorophenol group, dichlorophenol group, black-and-fluorophenol group, amino-fluorophenol group, amino-chlorophenol group, fluoromethylaminophenol group and chloromethyl Aminophenol group, dimethylamino-fluorophenol group, dimethylaminochlorophenol group, jetylamino-fluorophenol group, chloro-jetyl Aminophenyl group, fluoromethoxyphenyl group, chloromethoxyphenyl group, ethylenediphenyl group and the like can be given as typical examples of disubstituted phenyl groups. Among them, hydroxyphenyl group, black-faced phenyl group, fluorophenol group, bromophenol group, methoxyphenyl group, methylphenol group, trifluoromethylphenol group, methylsulfur group. -Luxoxyphenyl groups and methylsulfo-aminophenol groups are preferred.

 [0022] The substituted amino group includes a lower alkylamino group, a di-lower alkylamino group, a lower alkoxycarbolamino group, a strong ruberamoylamino group, a lower alkyl force ruberamoylamino group, a di-lower alkyl force ruberamoylamino group, and a lower alkylsulfo-amino group. , And lower alkanoylamino groups, such as methylamino group, ethylamino group, propylamino group, butyramino group, pentylamino group, hexylamino group, isopropylamino group, tert-butylamino group, sec-butylamino group, dimethylamino group, Jetylamino group, dipropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, diisopropylamino group, methylethylamino group, methoxycarbolamino group, ethoxycarboamino group, force rubamoi Typical examples are amino group, methylcarbamoylamino group, ethylcarbamoylamino group, dimethylcarbamoylamino group, jetylcarbamoylamino group, methylsulfolumino group, ethylsulfo-lumino group, acetylamino group, and propio-ramino group. Methylamino group, ethylamino group, isopropylamino group, dimethylamino group, jetylamino group, dipropylamino group, methylethylamino group, methoxycarbolamamino group, ethoxycarbolamamino group, strong ruberamoylamino group. A methylcarbamoylamino group, an ethylcarbamoylamino group, a dimethylcarbamoylamino group, a jetylcarbamoylamino group, a methylsulfo-lumino group, an ethylsulfo-amino group, and an acetylamino group are preferred.

[0023] Hereinafter, Q will be described.

Q may be substituted with one or two groups selected from the group consisting of a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group. A benzene ring, which may be substituted with one or two groups selected from among halogen atoms, lower alkenyl groups, lower alkoxy groups, and substituted or unsubstituted lower alkyl groups; Preferred lower alkoxy group And a benzene ring is more preferred, when substituted with one or two groups selected from among a substituted or unsubstituted lower alkyl group.

 [0024] Specifically, a hydroxybenzene ring, a fluorobenzene ring, a black benzene ring, a bromobenzene ring, a butylbenzene ring, an arylbenzene, a methoxybenzene ring, an ethoxybenzene ring, a methylbenzene ring, an ethylbenzene ring, and tert-butylbenzene The ring, trifluoromethylbenzene ring, aminobenzene ring, methylaminobenzene ring, ethylaminobenzene ring, dimethylaminobenzene ring, and jetylaminobenzene ring can be listed as typical examples of mono-substituted benzene rings. Benzene ring, methyl-trifluoromethylbenzene ring, fluoro-methylbenzene ring, chloro-methylbenzene ring, fluoro-hydroxybenzene ring, black-hydroxybenzene ring, difluorobenzene ring, dichlorobenzene ring, Chlorofluoro Ring, amino-fluorobenzene ring, amino-chlorobenzene ring, fluoro-methylaminominobenzene ring, chloromethylaminoaminobenzene ring, dimethylaminofluorobenzene ring, dimethylamino-chlorobenzene ring, Typical examples of the di-substituted benzene ring include a jetylamino-fluorobenzene ring, a chloro-jetylaminobenzene ring, a fluoro-methoxybenzene ring, a chloro-methoxybenzene ring, and an ethylenedioxybenzene ring. Among them, a methylbenzene ring, a dimethylbenzene ring, and a methoxybenzene ring are more preferable, with a methylbenzene ring, a dimethylbenzene ring, a methoxybenzene ring, a fluorobenzene ring, a trifluoromethylbenzene ring, and an arylbenzene ring being preferred. .

[0025] R ¹ will be described below.

R ¹ is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. And a substituted or unsubstituted amino group, in the case of a phenyl group which may be substituted with one or two selected groups, in addition to the unsubstituted phenol group, a hydroxyphenol group, Fluorophenol group, Chlorophenol group, Bromophenol group, Buhlphenol group, Methoxyphenol group, Ethoxyphenyl group, 2-Methoxyethoxyphenyl group, Phenoxyphenyl group, Fluorophenyl group Group, chlorophenol group, biphenyl group, fluoro-furol group, methylphenol Group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group, ethylaminophenol group, dimethylaminophenol group, jetyl The aminophenyl group can be cited as a typical example of a mono-substituted phenyl group, such as a dimethylphenol group, a methyl-trifluoromethylphenol group, a fluoromethylphenol group, a black mouth. 1-methylphenol group, fluoro-hydroxyphenyl group, black-hydroxyl group, difluorophenol group, dichloro-phenol group, black-fluorophenol group, amino-fluorophenol group, Amino-black mouth phenyl group, fluoro-methylamino phenol group, chloro-methyl amino-phenol group, dimethylamino-fluorophenol group, dimethylamino-chlorophenol group, jetylamino Fluorophenol group, chloro-diethylaminophenol group, fluoro-methoxyphenyl group, chloro-methoxyphenyl group, ethylenediphenyl group, etc. can be mentioned as typical examples of disubstituted phenol groups. it can. Among these, a phenol group, a fluorophenol group, a chlorophenol group, a bromophenol group, a methoxyphenol group, a methylphenol group, a trifluoromethylphenol group, a dimethylphenol group, And 2-methoxyphenyl groups are preferred, chlorophenyl, fluorophenyl, methoxyphenol, methylphenol, dimethylphenol, and 2-methoxyethoxy. A phenol group is more preferred.

R ¹ is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. In the case of a naphthyl group that may be substituted with one or two selected groups, hydroxy naphthyl group, fluoronaphthyl group, chloronaphthyl Group, bromonaphthyl group, vinyl naphthyl group, methoxy naphthyl group, ethoxy naphthyl group, methyl naphthyl group, ethyl naphthyl group, tert-butyl naphthyl group, trifluoromethyl naphthyl group, amino naphthyl group, methylamino naphthyl group, ethyl Aminonaphthyl group, dimethylaminonaphthyl group, jetylaminonaphthyl group Typical examples of the non-substituted naphthyl group include dimethyl naphthyl group, methyl monotrifluoromethyl naphthyl group, fluoromethyl naphthyl group, chloro-methyl naphthyl group, fluoro-hydroxy naphthyl group, chloro-hydroxy naphthyl group, Difluoronaphthyl group, dichloronaphthyl group, chloro Low fluoronaphthyl, amino-fluoronaphthyl, amino-chloronaphthyl, fluoromethylaminonaphthyl, chloromethylaminonaphthyl, dimethylamino-fluoronaphthyl, dimethylamino-chloronaphthyl, A typical example of a disubstituted naphthyl group is a jetylamino-fluoronaphthyl group, a chloro-jetylaminonaphthyl group, a fluoro-methoxynaphthyl group, or a chloro-methoxynaphthyl group. Of these, naphthyl, chloronaphthyl, chloronaphthyl, bromonaphthyl, trifluoronaphthyl, naphthyl, chloronaphthyl, and trifluoronaphthyl are more preferred.

[0027] R ¹ is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted group. The case of a lower alkyl group and a 5- or 6-membered aromatic heterocyclic group which may be substituted with 1 or 2 groups selected from substituted or unsubstituted amino groups will be described.

 A 5- or 6-membered aromatic heterocycle means a 5- or 6-membered aromatic ring containing one or more nitrogen, oxygen or sulfur atoms as a constituent of the ring structure. Specific examples include pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, thiophene ring, furan ring, pyrrole ring, imidazole ring, pyrazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring. , Triazole rings, and thiadiazol rings. Among them, a pyridine ring, a furan ring, a thiazole ring, and an oxazole ring are preferred, and a pyridine ring, a pyrimidine ring, a furan ring, a thiazole ring, and an oxazole ring are preferred.

[0028] A specific example will be described below.

When the aromatic heterocycle is a pyridine ring, R ¹ is preferably a pyridyl group, a fluoropyridyl group, a cyclopyridyl group, a bromopyridyl group, a trifluoromethylpyridyl group, a ferrobiridyl group, or a methoxypyridyl group. Pyridyl group, black-and-white pyridyl group, trifluoromethyl pyridyl group, and methoxypyridyl group are more preferred.

When the aromatic heterocycle is a pyrimidine ring, R ¹ represents a pyrimidyl group, a fluoropyrimidyl group, a black-opened pyrimidyl group, a bromopyrimidyl group, a trifluoromethylpyrimidyl group, Pyrimidyl, chloropyrimidyl, trifluoromethylpyrimidyl, and methoxypyrimidyl groups are more preferred, as are phenylpyrimidinyl and methoxypyrimidinyl groups.

[0029] When the aromatic heterocycle is a pyridazine ring, R ¹ represents a pyridazyl group, a fluoropyridazil group, a chloropyridazyl group, a bromopyridazyl group, a trifluoromethylpyridazil group, and A methoxypyridazinyl group is preferred, a pyridazinyl group, a chloropyridazinyl group, a trifluoromethylpyridazyl group, and a methoxypyridazyl group are more preferred. When the aromatic heterocyclic ring is a pyrazine ring, R ¹ is preferably a birazinyl group, a fluorobirazinyl group, a chlorobirazyl group, a bromopyrazuryl group, a trifluoromethylpyrazuryl group, or a methoxypyrazinyl group. More preferred are a pyrajur group, a chlorovirazyl group, a trifluoromethyl pyrajur group, and a methoxypyradur group.

[0030] When the aromatic heterocycle is a thiophene ring, R ¹ represents a chael group, a fluorchael group, a black-eye chaer group, a bromochael group, a trifluoromethyl chaer group, and More preferred are a methoxy group, a chloro group, a trifluoromethyl group, and a methoxy group.

When the aromatic heterocycle is a furan ring, R ¹ is preferably a furyl group, a fluorofuryl group, a chlorofuryl group, a bromofuryl group, a trifluoromethylfuryl group, or a methoxyfuryl group, and a furyl group, a chlorofuryl group , Trifluoromethylfuryl group, and methoxyfuryl group are more preferred.

When the aromatic heterocyclic ring is a pyrrole ring, R ¹ is a pyrrolyl group, a chloropyrrolyl group, a chloropyrrolyl group, a bromopyrrolyl group, a trifluoromethylpyrrolyl group, or a methoxypyrrolyl group, and a chloropyrrole group. Pyrrolyl, trifluoromethylpyrrolyl, and methoxypyrrolyl groups are more preferred.

[0031] Aromatic heterocyclic ring In the case of an S imidazole ring, R ¹ is preferably an imidazolyl group, a fluorloyimidazolyl group, a chloroimidazolyl group, a bromoimidazolyl group, a trifluoromethylimidazolyl group, or a methoxyimidazolyl group. More preferred are groups, chloroimidazolyl, trifluoromethylimidazolyl, and methoxyimidazolyl.

When the aromatic heterocycle is a pyrazole ring, R ¹ is a pyrazolyl group, fluorovirazolyl Groups, chlorovirazolyl, bromopyrazolyl, trifluoromethylpyrazolyl, and methoxypyrazolyl are preferred, pyrazolyl, chlorovirazolyl, trifluoromethylpyrazolyl, and methoxypyrazolyl are more preferred.

When the aromatic heterocyclic ring is a thiazole ring, R ¹ is preferably a thiazolyl group, a fluorothiazolyl group, a black thiazolyl group, a bromothiazolyl group, a trifluoromethylthiazolyl group, or a methoxythiazolyl group. More preferred are thiazolyl, black thiazolyl, trifluoromethylthiazolyl, and methoxythiazolyl! / ,.

[0032] In the case of an aromatic heterocyclic force S isothiazole ring, R ¹ is an isothiazolyl group, a fluoroloy thiazolyl group, a black isothiazolyl group, a bromoisothiazolyl group, a trifluoromethylisothiazolyl group, and a methoxyisothiazolyl An isothiazolyl group, a chloroisothiazolyl group, a trifluoromethylisothiazolyl group, and a methoxyisothiazolyl group, which are preferable to a ryl group, are more preferable.

When the aromatic heterocycle is an oxazole ring, R ¹ represents an oxazolyl group, a fluoroxazolyl group, a chlorooxazolyl group, a bromooxazolyl group, a trifluoromethyloxazolyl group, and a methoxyoxaxyl group. Of these, oxazolyl, chlorooxazolyl, trifluoromethyloxazolyl, and methoxyoxazolyl are preferred. Aromatic heterocyclic force In the case of S isoxazole ring, R ¹ is an isoxazolyl group, a fluoroisoxazolyl group, a chloroisoxazolyl group, a bromoisoxazolyl group, a trifluoromethylisooxazol group. Izoxazolyl, chloroisoxazolyl, trifluoromethylisoxazolyl, and methoxyisoxazolyl are more preferred than zolyl and methoxyisoxazolyl ,.

[0033] When the aromatic heterocyclic ring is an oxadiazole ring, R ¹ represents an oxadiazolyl group, a fluoroxadiazolyl group, a clooxadiazolyl group, a bromooxadiazolyl group, a methyloxazia Zolyl, ethyloxadiazolyl, trifluoromethyloxadiazolyl, and methoxyoxadiazolyl are preferred. Oxadiazolyl, chloroxadiazolyl, methyloxadi U, more preferred are azolyl, ethyloxadiazolyl, trifluoromethyloxadiazolyl, and methoxyoxadiazolyl.

When the aromatic heterocycle is a triazole ring, R ¹ is a triazolyl group, a fluorotriazolyl. Group, chlorotriazolyl group, bromotriazolyl group, trifluoromethyltriazolyl group, and methoxytriazolyl group are preferred triazolyl group, chlorotriazolyl group, trifluoromethyltriazolyl group , And methoxytriazolyl groups are more preferred!

In the above description of R ¹ , a phenyl group, a black-opened phenyl group, a fluorophenol group, a methoxyphenyl group, a methylphenol group, and a dimethylphenol group are particularly preferable.

[0034] R ² will be described below.

 The substituted or unsubstituted lower alkyl group means the above-mentioned alkyl group, and particularly preferable examples include trifluoromethyl group, 2, 2, 2-trifluoroethyl group, methoxymethyl group, and 2 -Methoxyethyl group can be mentioned.

 Examples of the substituted or unsubstituted force rubamoyl group include force rubamoyl groups which may be substituted with one or two lower alkyl groups. Specific examples include force rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, Examples include butyl carbamoyl group, jetyl carbamoyl group, propyl carbamoyl group, isopropyl carbamoyl group, butyl carbamoyl group, pentyl carbamoyl group, carbamoyl group, methyl carbamoyl group, dimethyl carbamoyl group, ethyl carbamoyl group. And a jetylcarbamoyl group are preferred.

[0035] The substituted or unsubstituted phenyl group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfoxy group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted amino group, and a substituted group. Alternatively, an unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, and a substituted or unsubstituted pyridyl group may be substituted with one or two selected phenyl groups. Can be mentioned. Specific examples include hydroxyphenol groups, fluorophenol groups, black-and-white phenyl groups, bromophenol groups, methoxyphenol groups, ethoxyphenol groups, butylphenol groups, arylphenol groups, and methylsulfol groups. Xylophyl group, methylphenol group, ethylphenol group, tert-butylphenol group, trifluoromethylphenol group, aminophenol group, methylaminophenol group, ethylaminophenol group, dimethylamino Phenyl group, jetylaminophenyl group, methylsulfoaminophenol group, phenoxyphenyl group, fluorophenol group, chlorophenol group, biphenyl group, and fluorophenol -Mono-substituted fue Typical examples of the benzene group include: dimethylphenol group, methyl trifluoromethyl group, fluoromethylphenol group, chloromethylphenol group, fluoro-hydroxyphenol group, Mouth hydroxyphenol group, difluorophenol group, diclonal phenyl group, black monofluorophenol group, amino-fluorophenol group, amino-chlorophenol group, fluoromethylaminophenol -Group, chloromethylaminophenol group, dimethylamino-fluorophenol group, dimethylamino-chlorophenol group, jetylaminofluorophenol group, chloro-demethylaminophenol group, Fluoromethoxyphenyl group, chloromethoxyphenyl group, ethylenedioxyphenyl group and the like can be mentioned as typical examples of disubstituted phenol groups. Among these, hydroxyphenyl group, black-faced phenol group, fluorophenol group, bromophenol group, methoxyphenol group, methylphenol group, trifluoromethylphenol group, methylsulfoxyphenyl group. -Methyl group, and methylsulfolaminophenol group are preferred.

[0036] The substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group includes a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a methylsulfo-oxy group, a substituted or unsubstituted lower alkyl group, and a substituted group. Alternatively, an unsubstituted amino group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenoxy group, and a substituted or unsubstituted pyridyl group may also be substituted with one or two groups that are also selected 5 or 6 Member aromatic heterocyclic group. Here, the 5- or 6-membered aromatic heterocycle is the same as the 5- or 6-membered aromatic heterocycle described in R ¹ , and preferred examples are the same, but among them, the 5-membered aromatic heterocycle is the same. Rings are preferred, and a furan ring, a thiazole ring, an oxazole ring, an isoxazole ring, and an oxaziazole ring are particularly preferred. As specific substituents, a furyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, and a methyloxazazolyl group are particularly preferable.

Among the groups described above for R ² , particularly preferred groups include rubamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, methoxymethyl group, 2-methoxyethyl group, oxazolyl group, and methyloxadiazolyl group. Can be mentioned.

[0037] R ^{3 to} R ⁵ will be described below.

When R ³ and R ⁴ are a lower alkyl group, it means the aforementioned alkyl group, specifically The methyl group, ethyl group, propyl group, butyl group, pentyl group and hexyl group can be mentioned as representative examples, and each independently preferred is a methyl group in which a methyl group or an ethyl group is preferred.

[0038] When R ⁵ is a lower alkyl group means an alkyl group described above include a methyl group, E Ji group, a propyl group, a tert- butyl group Preferred examples.

When R ⁵ is a substituted or unsubstituted benzyl group, a hydroxyl group, a halogen atom, a lower alkoxy group, a lower alkenyl group, a nitro group, a substituted or unsubstituted lower alkyl group, and a substituted or unsubstituted amino group are selected. Examples thereof include a benzyl group which may be substituted with 1 or 2 groups. Specific examples include a benzyl group, a hydroxybenzyl group, a fluorbenzyl group, a black benzyl group, a bromobenzyl group, a methoxybenzyl group, an ethoxybenzyl group, a burbenzil group, a arrylbenzyl group, and a nitrobenzyl group. , Methyl benzyl group, ethyl benzyl group, tert-butyl benzyl group, trifluoromethyl benzyl group, amamino benzyl group, methylamino benzyl group, ethylamino benzyl group, dimethylamino benzyl group, jetylamino benzyl group, and methyl sulfo-laminobenzyl group As typical examples of mono-substituted benzyl groups, dimethylbenzyl group, methyl-trifluoromethylbenzyl group, fluoro-methylbenzyl group, chloromethylbenzyl group, fluoro-hydroxybenzyl group, black-and-hydroxy group Ben Group, difluorine benzyl group, dichlorobenzil group, chlorofluorine benzyl group, amino-fluorobenzil group, amino-chloro benzyl group, fluoro-methylaminobenzil group, chloromethylaminobenzyl group, Dimethylamino-fluoro-benzyl group, dimethylamino-chloro-benzyl group, jetylamino-fluoro-benzyl group, chloro-jetylaminobenzyl group, fluoro-methoxybenzyl group, chloro-methoxybenzyl group An ethylenedioxybenzyl group can be given as a typical example of a di-substituted benzyl group. Of these, benzyl, hydroxybenzyl, black benzyl, fluorbenzyl, bromobenzyl, methoxybenzyl, methylbenzyl, trifluoromethylbenzyl, and -trobenzyl are preferred. ,.

[0039] Preferred examples of R ⁵ include a hydrogen atom, a methyl group, an ethyl group, a propyl group, a tert-butyl group, a benzyl group, a 4-methoxybenzyl group, or a 4-trobenzyl group. It can be done.

[0040] R ⁶ will be described below.

R ⁶ is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted Although it is an unsubstituted amino group, each of those substituents is the same as described above. Among them, a hydrogen atom, a chlorine atom, a methyl group, or an ethyl group, preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methoxy group, or an ethoxy group. An isopropyl group, a trifluoromethyl group, and a methoxy group are more preferable.

 m is an integer of 0 to 3, preferably 1 or 2.

 n is an integer of 1 to 3, preferably 1 or 2.

 The following 5-membered aromatic heterocycle is described below.

[0041] [Chemical 5]

(R.) m

(In the above formula, X, Y and Z each independently represent a nitrogen atom or a carbon atom, m represents an integer of 0 to 3, R ⁶ represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, A lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted amino group (where m is 2 In these cases, two or more R ^{6 s} may be the same or different.

 [0043] Specific examples of the 5-membered aromatic heterocycle include a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, and a tetrazole ring.

R ⁶ substituted on the 5-membered aromatic heterocyclic ring is preferably a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, and a substituted amino group, preferably 1 or 2 The 5-membered aromatic heterocycle substituted with R ⁶ includes methylpyrrole ring, trifluoromethylpyrrole ring, methylbiazole ring, trifluoromethylpyrazo ring. Preferable examples are a diol ring, a methyl imidazole ring, a trifluoromethyl imidazole ring, a methyl triazole ring, a trifluoromethyl triazole ring, a fluoro ferrobiazole ring, a dimethyl pyrrole ring, a dimethyl virazole ring, and a dimethyl imidazole ring. It can be mentioned as.

 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, optical isomers and Deviations of these and mixtures thereof are also included in the present invention.

 [0045] 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. Specifically, hydrochloride, hydrobromide, iodine Examples thereof include hydrous acid salts and mineral acid salts such as sulfates, methanesulfonic acid salts, and organic sulfonic acid salts such as 2-hydroxyethanesulfonic acid salts and p-toluenesulfonic acid salts.

 [0046] When the compound represented by the general formula (I) has an acidic group, an alkali metal such as sodium or potassium, an alkaline earth metal such as magnesium or calcium, or methylamine, dimethylamine, or trimethylamine. It may be a salt of an organic base such as ethylamine, jetylamine, triethylamine, isopropylamine, diisopropylamine, butylamine, isobutylamine, sec-butylamine, tert-butylamine. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include hydrates and ethanol solvates.

 [0047] A typical synthesis method of the compound of the present invention will be described below.

First, a compound represented by general formula (I) of the present invention (hereinafter referred to as compound (I). Here, when R ⁵ represents a group other than a hydrogen atom, compound (la), R ⁵ represents a hydrogen atom. The method of synthesizing the compound (lb) is described below.

[0048] [Chemical 6] Synthesis method 1 1 1

(In the above formula, ¹ to! ^ ⁶ , Q, X, Y, Ζ, m, and η represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.) Compound ( 3) can be synthesized by reacting aldehyde (1) and amine (2) in the presence of a reducing agent. Compound (3) is obtained by producing a Schiff base from aldehyde (1) and amine (2) in the presence or absence of an acid such as acetic acid and then reacting with a reducing agent. In this case, compound (3) can also be synthesized by dissolving aldehyde (1) and amine (2) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, 1 equivalent to an excess of amine (2) is used with respect to aldehyde (1). Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and the like. Use 5 equivalents of reducing agent. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogen alkanes such as dichloromethane and chloroform. The reaction temperature is up to the boiling point of the solvent that also uses 20 ° C force, preferably 0-50 ° C, and the reaction time is 15 minutes-24 hours, preferably 30 About minutes to 10 hours.

 [0050] Synthesis of compound (la) from compound (3) can be carried out by allowing compound (4) to act on compound (3). 1 equivalent to excess, preferably 1 to 2 equivalents, of compound (4) is allowed to act on compound (3) in the presence of a base, and if necessary, such as tetrabutylammonium iodide and potassium iodide. A reaction accelerator can be used. As the base, 1 equivalent to an excess amount of tertiary amine such as triethylamine, potassium carbonate, carbonate such as cesium carbonate, or the like is used. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and 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 100 ° C, and the reaction time is from 1 hour to 7 days, preferably from about 1 to 48 hours.

[0051] The synthesis of compound (lb) from compound (la) differs depending on the type of ester, but the method described in the literature [Protective Groups in Organic Synthesis, 2nd] Edition, TW Green, by 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, 1 equivalent to an excess amount of 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). By doing. Examples of the solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, water, and a mixed solvent thereof. The reaction temperature is 0 to 100 ° C, preferably 0 to 60 ° C. The reaction time varies depending on the type of ester, usually 1 to 72 hours, preferably about 1 to 24 hours. In the case of the R ⁵ force tert butyl group of the compound (la), it can be carried out by a method of reacting an acid such as trifluoroacetic acid or hydrochloric acid. Use excess amounts of trifluoroacetic acid and hydrochloric acid. Examples of the solvent include solvents such as dichloromethane and dioxane. The reaction temperature is from 0 ° C to the boiling point of the solvent used, preferably 0 to 30 ° C, and the reaction time is 1 to 48 hours, preferably 1 to 24 hours.

[0052] The compound (la) described in the above synthesis method 11 is a compound (la) as shown in the following synthesis method 12 It can also be produced by reaction of 3) with compound (5).

[0053] [Chemical 7]

 Synthesis method 1 1 2

(In the above formula, ¹ to! ^ ⁶ , Q, X, Y, Z, m, and n represent the above-mentioned ones.)

[0054] Compound (la) can be synthesized by reacting amine (3) with aldehyde (5) in the presence of a reducing agent. In the presence or absence of an acid such as acetic acid, a Schiff base is formed from amine (3) and aldehyde (5), and then a reducing agent is allowed to act to give compound (la). In this case, compound (la) can also be synthesized by dissolving ammine (3) and aldehyde (5) in a solvent and allowing a reducing agent to act without confirming the formation of a Schiff base. Usually, 1 equivalent to excess of aldehyde (5) is used with respect to amine (3). Examples of the reducing agent include metal hydride complexes such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc. Among them, 1 equivalent is usually equivalent to aldehyde (5) in which sodium triacetoxyborohydride is preferred. An excess of, preferably 15 equivalents of reducing agent is used. Examples of the reaction solvent include alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, and halogenated alkanes such as dichloromethane and chloroform. The reaction temperature is up to the boiling point of the solvent which also uses 20 ° C force, preferably 050 ° C, and the reaction time is about 15 minutes to 24 hours, preferably about 30 minutes to 10 hours.

 [0055] The compound (la) described in the synthesis method 11 can also be synthesized by the synthesis method 2 via the compound (7) as shown below.

[0056] [Chemical 8] Synthesis method 2

(In the above formula, the scales ¹ to! ^ ⁶ , Q, X, Y, Ζ, m, and η are as described above.)

Compound (7) is synthesized from compound (1) and compound (6) in the same manner as compound (3) is synthesized from compound (1) and compound (2) in Synthesis Method 1-1. It can be carried out. The synthesis of compound (la) from compound (7) and compound (8) is the same as the synthesis of compound (la) from compound (3) and compound (5) in synthesis method 1-2. It can be done by the method.

 [0058] The compound (la) described in the above synthesis method 11 can also be synthesized by the synthesis method 3-1 via the compound (9) as shown below.

[0059] [Chemical 9]

Synthesis method 3 1

 (l a)

(In the above formula,! ^ To Shaku ⁶ , Q, X, Y, Ζ, m, and η represent the aforementioned ones.)

[0060] The synthesis of compound (9) from compound (5) and compound (2) and the synthesis of compound (9) from compound (6) and compound (8) are carried out by using compound (1) and compound ( It can be carried out by the same method as in the synthesis of compound (3) from 2).

 The synthesis of compound (la) from compound (9) and compound (1) is the same as the synthesis of compound (la) from compound (3) and compound (5) in synthesis method 1-2. It can be done by the method.

 [0061] Compound (9) described in Synthesis Method 3-1 can also be synthesized by Synthesis Method 3-2 shown below.

[0062] [Chemical 10] Synthesis Method 3— 2

 (11)

(In the above formula, RR ² , R ⁶ , X, Y, Z, m, and n represent the above, R ³⁰ represents a hydrogen atom or a nitro group, LG represents a hydroxyl group, a halogen atom, an alkylsulfo group. It represents a diloxy group or an arylsulfonyloxy group.)

[0063] Compound (9) was prepared by the method described in the literature using compound (2) and compound (12) [T. Fuk uyama et al, Tetrahedron Letters, 36th, No. 36, 637 3-6374, 1995].

 Compound (11) is synthesized from compound (2) by reacting compound (2) with 2 equivalents of compound (10) in the presence of a base. As the base, tertiary amines such as triethylamine, pyridine, or carbonates such as sodium hydrogen carbonate are used. Examples of the solvent include halogenated alkanes such as dichloromethane, ether solvents such as jetyl ether, N, N-dimethylformamide, acetonitrile, water and the like, or a mixed solvent thereof. The reaction is up to the boiling point of the solvent that also uses 0 ° C. force, preferably about 0 to 30 ° C., and the reaction time is 30 minutes to 24 hours, preferably about 30 minutes to 5 hours.

[0064] Compound (11) and Compound (12) Strength The synthesis of compound (13) varies depending on the type of substituent LG of compound (12) as described below. When the substituent LG is a hydroxyl group, a method described in the literature in which an azodicarboxylate ester and triphenylphosphine are allowed to act on the compound (11) and the compound (12) [Mitsunobu (0. Mitsunobu), Synthesis, 1 Page, 1981], can be synthesized by the so-called Mitsunobu reaction. For example, compound (11) and compound (12) are allowed to act on azodicarboxylic acid diester and triphenylphosphine in an amount of 1 equivalent to excess, preferably 1 to 2 equivalents. Examples of the solvent include halogenated alkanes such as dichloromethane, ether solvents such as jetyl ether and tetrahydrofuran, solvents such as N, N-dimethylformamide, toluene and benzene, or a mixed solvent thereof. The reaction is carried out from 0 ° C. to the boiling point of the solvent used, preferably about 0 to 30 ° C., and the reaction time is usually 10 minutes to 48 hours, preferably about 20 minutes to 10 hours.

 [0065] When the substituent LG is a halogen atom, 1 equivalent to an excess amount of the compound (12) is added to an excess amount of the chloride group (11) in which a chlorine atom, a bromine atom or an iodine atom is preferred as the halogen atom. It can be synthesized by reacting in the presence. Examples of the base include carbonates such as potassium carbonate, and examples of the solvent include N, N-dimethylformamide, acetonitrile, and dichloromethane. The reaction temperature is up to the boiling point of the solvent that also uses 0 ° C force, preferably about 0 to 30 ° C, and the reaction time is usually about 10 minutes to 24 hours, preferably about 30 minutes to 8 hours. When the substituent LG is an alkylsulfo-loxy group or an arylsulfo-loxy group, the compound (13) can be produced under the same reaction conditions as when the substituent LG is a halogen atom. A typical example of the alkylsulfo-oxy group is a methanesulfo-oxy group, and examples of the aryl sulfo-oxy group include a benzene sulfo-oxy group and a p-toluenesulfonyloxy group.

[0066] Compound (13) and compound (9) were synthesized in the presence of an excess amount of potassium carbonate, a carbonate such as cesium carbonate, a tertiary amine such as triethylamine, or a base such as lithium hydroxide. It can be synthesized by reacting thiophenol or thioglycolic acid. Of these, the combination of triethylamine and thioglycolic acid is preferred. Examples of the solvent include alkyl halides such as dichloromethane, N, N-dimethylformamide and the like. The reaction temperature is 0 ° C force, up to the boiling point of the solvent used, preferably about 0 to 30 ° C, and the reaction time is usually 30 minutes to 24 hours, preferably about 30 minutes to 8 hours. [0067] The compound (13) described in the above synthesis method 3-2 can also be synthesized by the synthesis method 3-3 shown below by the synthesis method described in the synthesis method 3-2 or a synthesis method analogous thereto. Is possible.

 [0068] [Chemical Formula 11] Synthesis Method 3— 3

(In the above formula, R ¹ R ² , R ⁶ , X, Y, Z, m, and η represent the above, R ³⁰ represents a hydrogen atom or a nitro group, LG represents a hydroxyl group, a halogen atom, Represents an alkylsulfonoxy group or an arylsulfonyloxy group.)

[0069] The compound (14) can be synthesized from the compound (6) according to the synthesis method of the compound (11) from the compound (2) in Synthesis Method 3-2. In addition, the synthesis of compound (13) from compound (14) can be performed according to the synthesis method of compound (13) from compound (11) in synthesis method 3-2.

 [0070] The compound (la) described in the above synthesis method 11 can also be synthesized by a synthesis route via the compound (17) as shown in the following synthesis method 4.

[0071] [Chemical 12] Synthesis method 4

(In the above formula,! ^ To ⁶ , Q, X, Y, Ζ, m, and η represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.) Compound (3 ) And compound (16) can be synthesized from compound (17) by a method similar to that for synthesizing compound (la) from compound (3) and compound (5) in synthesis method 12. ) Force Compound (la) can be synthesized by methods described in the literature, such as the Ullman reaction or the Goldberg coupling reaction [HJ. Crisau et al. 'Ob' Organic 'Chemistry (European Journal of Organic Chemistry), 695-709, 2004], or a similar method. Compound (17) and compound (18) are reacted with copper iodide or acid copper salt in the presence of a base. The halogen atom of compound (18) is preferably a bromine atom or an iodine atom. Usually, compound (18) is used in an amount of 1 equivalent to an excess amount relative to compound (17). Copper iodide or copper oxide is 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, and a palladium complex such as tetrakis (triphosphine) palladium is used instead of copper iodide or copper oxide. be able to. As the base, 2 equivalent to excess amounts of metal carbonates such as cesium carbonate and potassium carbonate, metal phosphates such as tripotassium phosphate, and metal alkoxides such as sodium tert butoxide are used. As the solvent, an inert solvent such as dioxane, toluene, acetonitrile, pyridine, N, N dimethylformamide, tetrahydrofuran, etc. is used, the reaction temperature is up to the boiling point of the solvent using 10 ° C force, and the reaction time is 30. Min to 48 hours, preferably 2 to 24 hours. Furthermore, diamines such as 1,2-diaminocyclohexane and oximes such as salicylaldoxime dimethyldarioxime as reaction accelerators. XX

 6 can be added, and it is about 0.01 to 0.5 equivalent, preferably about 0.1 equivalent.

 [0073] The compounds (4), (5), (6), and (12) used in the above synthesis differ in the length of the methylene chain depending on the number of n. Can be easily synthesized. Although the synthesis method used varies depending on the type of 5-membered heterocycle and the desired methylene chain, for example, the methylene chain can be easily extended as shown in Synthesis Method 5 below.

 X ¾ 士

 6)

 S 6

 [0074] [Chemical 13]

 Synthesis method 5

NaCN 還

'Ha l, Les ^Γ CN

 (18) (19) (20) Hydrolysis

, Les ^Γ 0 ₂ H

 (21) (22) (24)

 Oxidation

, 1-CH0

 (twenty three)

(In the above formula, R ⁶ , X, Y, Ζ, and m represent the above, and H a 1 represents a chlorine atom, a bromine atom, or an iodine atom.)

[0075] A cyano derivative (19) was synthesized by reacting the compound (18) contained in the compound (4) with cyanide sodium or cyanate potassium, followed by a reduction reaction in which an amine (20) ) Can be synthesized. On the other hand, the cyano derivative (19) is acid or Carboxylic acid (21) can be obtained by alkaline hydrolysis, and hydroxy derivative (22) can be obtained by subsequent reduction reaction. By acidifying the hydroxy derivative (22), an aldehyde (23) having one extended methylene chain can be obtained. Further, a compound having a longer methylene chain can be obtained by halogenating the hydroxy derivative (22) to lead to the compound (24) and further extending the carbon chain in the same manner as described above. In addition to the above method, for example, a compound in which carbon is extended by an aldehyde (23) force Wittig reaction to extend one methylene chain can be synthesized.

[0076] In the synthesis of the cyano derivative (19) from the compound (18), 1 equivalent to excess, preferably 1 to 2 equivalents, of sodium cyanide or potassium cyanide is allowed to act on the compound (18). . In an inert solvent such as N, N-dimethylformamide, the reaction is usually performed at a temperature of 0 ° C up to the boiling point of the solvent used for the reaction, preferably about 0 to 80 ° C. The reaction time is usually 1 to 16 hours, preferably 1 to 5 hours. In the compound (18), when Hal is a chlorine atom or a bromine atom, sodium iodide or potassium iodide is used if necessary. Reaction can be promoted.

 Amine (20) is capable of catalytic reduction of compound (19) in the presence of a catalyst such as palladium-carbon or can be synthesized by reduction using lithium aluminum hydride or the like. In catalytic reduction, palladium hydroxide, platinum oxide, etc. may be used in addition to palladium-carbon as a catalyst. Examples of the solvent include water, alcohol solvents such as ethanol, ether solvents such as jetyl ether, and ethyl acetate. The reaction time is usually about 3 hours to 5 days, preferably about 10 hours to 2 days. In the case of reduction with lithium aluminum hydride, lithium aluminum hydride is usually used in an amount of 1 to 5 equivalents, preferably about 1 to 3 equivalents, relative to compound (19). As the solvent, ether solvents such as jetyl ether and tetrahydrofuran are used. The reaction time is usually about 1 to 10 hours, preferably about 1 to 3 hours, and the reaction temperature is usually about 0 ° C to the boiling point of the solvent used, preferably about 0 to 60 ° C.

[0078] Cyan derivative (19) force Hydrolysis to carboxylic acid (21) uses an acid such as sulfuric acid or hydrochloric acid, or an alkali such as sodium hydroxide, potassium hydroxide, or lithium hydroxide. An excess of acid relative to the Cyan derivative (19), and usually 3 to 20 equivalents in the case of alkali, preferably 3-15 equivalents are used. As the solvent, water, an alcohol solvent such as ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide, or a mixed solvent thereof is used. The reaction time is usually 1 to 24 hours, preferably about 1 to 8 hours, and the reaction temperature is usually from 50 ° C to the boiling point of the solvent used, preferably about 50 to 100 ° C.

 [0079] Carboxylic acid (21) force The reduction reaction to the compound (22) can be carried out by using a borane complex such as lithium aluminum hydride or a borane-dimethylsulfide complex for the carboxylic acid (21). it can. The lithium aluminum hydride or borane complex is usually used in an excess amount, preferably about 2 to 3 equivalents, relative to the carboxylic acid (21). As the solvent, an ether solvent such as tetrahydrofuran is used. The reaction time is usually 1 to 24 hours, preferably about 1 to 8 hours, and the reaction temperature is usually 0 ° C. to the boiling point of the solvent used, preferably about 30 to 80 ° C.

 [0080] For the synthesis of the aldehyde (23), the compound (22) force can be used in the usual acid-acid reaction. For example, Swern oxidation using oxalyl chloride and dimethyl sulfoxide (SL Huang, K. Omura and D. Swern, Tetrahedron, 34, 1651 (1978)), oxidation reaction using Dess-Martin periodinane (DB Dess and JC Martin, Journal of America n Chemical Society, 113, 7277 (1991)), oxidation reaction using tetra-n-propylammonium perruthemate and 4-methylmorpholine-4-oxide (WP Griffith, SL Ley, u P. Whitcombe, and AD White, Journal Chemical Society Chemical, omm unication, 1625 (1987).

 [0081] The synthesis of the halogen derivative (24) from the compound (22) can be carried out by a normal halogen reaction. For example, chlorination with sodium chloride, bromination using boron tribromide, dibuccyl trifluorophosphine or N-bromosuccinimide and triphenylphosphine, iodination using sodium iodide and trimethylchlorosilane, etc. .

 The compound (18) in the above synthesis method is the method described in Heterocycles, 60s, pp. 167-175, 2003, the method described in Reference Examples, or a method according to them. Can be manufactured.

[0082] Among the compounds represented by the general formula (I) of the present invention, a compound in which R ² is a substituted or unsubstituted carbamoyl group (where R ² is a substituted or unsubstituted force rubamoyl group) And When R ⁵ is other than a hydrogen atom (Ic), when R ² is a substituted or unsubstituted force rubermoyl group and R ⁵ is a hydrogen atom, the compound (Id) To do. ) Can also be synthesized by the following method.

 [0083] [Chemical 14] Synthesis method 6

[0084] (In the above formula,

R ^{3 to} R ⁶ , Q, X, Y, Z, m and n represent the above, and R ⁷ and R ⁸ each independently represent a hydrogen atom or a lower alkyl group. )

 [0085] The compound (26) is synthesized from the compound (7) by compounding a metal hydride complex such as sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, etc. into the compound (7) and darioxylic acid (25). Preferably, it is carried out by the action of sodium triacetoxyborohydride. Usually, 1 equivalent or excess of darioxylic acid (25) is used relative to compound (7). The metal hydride complex is usually used in an amount of 1 equivalent or excess, preferably 2 to 3 equivalents, relative to compound (7). Examples of the reaction solvent include inert solvents such as tetrahydrofuran, dichloromethane, chloroform, etc., the reaction temperature is 0 ° C. force up to 40 ° C., preferably about 0 to 30 ° C., and the reaction time is 1 to 48 hours. It is preferably about 1 to 10 hours.

[0086] Synthesis of compound (Ic) from compound (26) can be carried out by a general amide bond forming reaction. For example, compound (26) is reacted with ammine (27) in the presence of a condensing agent. Can be done. For example, 1 equivalent or excess of ammine (27) to compound (26) Is carried out in an inert solvent at −50 ° C. until the boiling point of the solvent used in the reaction, preferably 0 to 30 ° C., in the presence of a condensing agent. The reaction time is 10 minutes at 48 hours, preferably 30 minutes to 12 hours. Condensation agents include N, N'-dicyclohexylcarbodiimide, 1-ethyl 3- (3 dimethylaminopropyl) carbodiimide, cyanoethyl ethylate, benzotriazolyloxy-tris [pyrrolidino] -phospho-um hexa Fluorophosphate, 2- (1H benzotriazole 1-yl) 1, 1, 3, 3-tetramethyluronium tetrafluoroborate, etc. An equivalent to excess amount, preferably 1 to 5 equivalents is used. Examples of the inert solvent include solvents such as dichloromethane, N, N dimethylformamide, tetrahydrofuran, and ethyl acetate, or mixtures thereof. If necessary, it can be carried out in the presence of a base such as triethylamine, di-sodium pyrethylamine, N-methylmorpholine or 4-dimethylaminopyridine. In addition, N-hydroxy compounds such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide, 4-nitrophenol, 2,4 dinitrophenol, 2,4,5 triclonal phenol, pentachlorophenol Phenolic compounds such as ru can be added as a reaction accelerator.

 [0087] The compound (Id) can be synthesized from the compound (Ic) by the same method as in the synthesis of the compound (lb) from the compound (la) in Synthesis Method 11.

[0088] Further, among the compounds represented by the general formula (I) of the present invention, a compound in which R ² is a substituted or unsubstituted 1,3,4-oxadiazolyl group (wherein R ² is substituted or unsubstituted A substituted 1, 3, 4-oxadiazolyl group, wherein R ⁵ is other than a hydrogen atom (Ie), R ² is a substituted or unsubstituted 1, 3, 4 oxadiazolyl group The case where R ⁵ is a hydrogen atom is referred to as a compound (If)) can also be synthesized by the following method.

[0089] [Chemical 15] Synthesis method 7

[0090] (In the above formula,

R ^{3 to} R ⁶ , Q, X, Y, Ζ, m and η are as defined above, and R, a hydrogen atom, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted phenyl group. )

 [0091] Compound (29) can be synthesized from compound (26) and compound (28) by the same method as in the synthesis of compound (Ic) from compound (26) in synthesis method 6.

 Compound (29) Strength Compound (Ie) can be synthesized by a conventional method, for example, a heat treatment in the presence of polyphosphoric acid or phosphorus oxychloride, or triphenylamine in the presence of a base such as triethylamine. It can be carried out by a known method such as a method in which ruphorphine and tetrasalt carbon are reacted in dichloromethane [for example, US Patent Publication No. 2004019215].

 [0093] Synthesis of compound (If) from compound (Ie) is carried out by compound from compound (la) in synthesis method 11

 It can be carried out by the same method as in the synthesis of (lb).

[0094] Further, among the compounds (I) of the present invention represented by the general formula (I), R ² is a substituted or unsubstituted pyrazole ring, thiazole ring, oxazole ring, isoxazole ring, 1, 2, 4 — A compound having an oxaziazole ring or a 1,2,4-triazole ring may be obtained by referring to the carboxy group of the above compound (26) in the literature [for example, W. Roger Tully et al., Journal of Medicinal Chemistry, 34, 2060-2067, (1991 ) And the like. Can be synthesized by converting to a 5-membered heterocyclic ring. [0095] Compound (I) of the present invention can be administered orally using various preparations. The compound (I) of the present invention used for the preparation may be any of a free form, a salt, and a hydrate or solvate thereof. Examples of the oral preparation containing the compound (I) of the present invention include tablets, fine granules, powders, granules, and capsules, and tablets and capsules are preferred. These oral preparations contain pharmaceutically acceptable additives such as fillers, extenders, binders, disintegrants, dissolution promoters, wetting agents, lubricants and the like. It can be selected and used as needed.

 [0096] The dosage is preferably 0.1 mg to 1500 mg per person per day, particularly 1 mg to 500 mg. This dose may be once a day or divided into 2 to 3 times. Example

 [0097] The present invention will be described below with reference to examples.

[0098] [Reference Example 1]

 4 Chloromethyl 1- (4-chlorophenyl) 3-methyl 1H pyrazole

[0099] [Chemical 16]

[0100] 1- (4 Black Mole) 1-Methyl 1H Pyrazole (1.25 g) is dissolved in 4N hydrochloric acid-dioxane solution (10 ml), and paraformaldehyde (292 mg) is added at 80 ° C. And stirred for 10 hours. The reaction mixture was allowed to return to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer 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 = 1: 9) to give the title compound (1.30 g) as a pale yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.38 (3Η, s), 4.60 (2Η, s), 7.39 (2H, d

 Three

 , J = 8.8Hz), 7.57 (2H, d, J = 8.8Hz), 7.84 (1H, s).

[0101] [Reference Example 2]

 (1) 2— (4 Formylphenoxy) 2 Methylpropionic acid ethyl ester

[0102] [Chemical 17]

[0103] 4-Hydroxybenzaldehyde (lOg) and 2-bromo-2-methylpropionic acid ethyl ester (18 ml) were dissolved in N, N dimethylformamide (50 ml), cesium carbonate (53 g) was added, and the mixture was heated to 80 ° C. And stirred for 4 days. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (8.91 g) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.21 (3Η, t, J = 7.1 Hz), 1.67 (6H, s), 4

 Three

 23 (2H, q, J = 7.1 Hz), 6. 90 (2H, d, J = 8.8 Hz), 7. 79 (2H, d, J = 8.8 Hz), 9. 88 (1H, s).

 [0104] (2) 2— [4— [[(Furan-2-ylmethyl) amino] methyl] phenoxy] —2-methylpropionic acid ethyl ester

[0105] [Chemical 18]

Reference Example 2—The compound (10 g) obtained in (1) and furfurylamine (4.1 ml) were added to tetrahydrofuran.

 (100 ml) and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (2.4 g) was added, and the mixture was stirred at 0 ° C. for 2 hr. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 96: 4) to give the title compound (12.9 g) as a yellow oil.

iH—NMR (400MHz, CDC1) δ: 1.25 (3Η, t, J = 7.4Hz), 1.58 (6H, s), 3.71 (2H, s), 3.79 (2H, s), 4.23 (2H, q, J = 7.4Hz), 6.1

7 (1H, d, J = 2.9Hz), 6.31 (1H, dd, J = 2.0, 2.9Hz), 6.80 (2H, d, J = 8.

8Hz), 7.19 (2H, d, J = 8.8Hz), 7.37 (1H, d, J = 2. OHz).

 MS m / z: 318 (M + H) +.

[0107] [Reference Example 3]

 (1) 3-Methyl-1 (4 trifluoromethyl phenol) 1H pyrazole

[0108] [Chemical 19]

[0109] (4 Trifluoromethylphenol) hydrazine (2. Og) was dissolved in a mixed solvent of ethanol (15 ml) and water (15 ml), and 1,1-dimethoxy-1-butanone (1.5 ml) was dissolved in It was heated at 100 ° C for 14 hours. The reaction mixture was cooled to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer 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 = 1: 19) to give the title compound (718 mg) as a yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.38 (3Η, s), 6.29 (1Η, d, J = 2.5Hz), 7

 Three

 .68 (2H, d, J = 8.6Hz), 7.78 (2H, d, J = 8.6Hz), 7.87 (1H, d, J = 2.5Hz).

MS m / z: 227 (M + H) ⁺ .

[0110] (2) 4 Chloromethyl mono 1— (4 trifluoromethyl phenol) 3-Methyl 1H—Villa Zonole

[0111] [Chemical 20]

In the same manner as in Reference Example 1, the compound (715 mg) obtained in Reference Example 3- (1) and paraformaldehyde (142 mg) also gave the title compound (597 mg) as a yellow oil. NMR-NMR (400MHz, CDC1) δ: 2.39 (3H, s), 4.57 (2H, s), 7.69 (2H, d

 Three

 , J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz), 7.94 (1H, s).

[0113] [Reference Example 4]

 4-chloromethyl 3 methyl 1 phenyl 1 H pyrazole

[0114] [Chemical 21]

[0115] In the same manner as in Reference Example 1, the title compound (3.04 g) was also obtained in terms of 3-methyl-1phenol 1H pyrazole (7.87 g) and paraformaldehyde (2. Og).

 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 4.59 (2Η, s), 7.25 (1H, t,

 Three

 J = 8.6Hz), 7.43 (2H, t, J = 8.6Hz), 7.62 (2H, d, J = 8.6Hz), 7.87 (1H, s).

 [0116] [Reference Example 5]

 (1) 2- (4-Formyl-2-methoxyphenoxy) -2-ethyl propionate

[0117] [Chemical 22]

[0118] 4 Hydroxy-3-methoxybenzaldehyde (5. Og) was dissolved in N, N dimethylformamide (20 ml), cesium carbonate (10 g), 2 bromo-2-methylpropionic acid ethyl ester (10 ml) ) Was stirred at 80 ° C for 12 hours. After returning to room temperature, ethyl acetate (200 ml) and water (40 ml) were added for liquid separation. 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 (6.3 g) as a solid. Ή-NMR (400MHz, CDC1): 1.23 (3H, t, J = 7.1 Hz), 1.66 (6H, s), 3.

 Three

 90 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.85 (1H, d, J = 8.3Hz), 7.35 (1H, dd, J = 8.3, 1.9Hz), 7.42 (1H, d , J = l.9Hz), 9.85 (1H, s).

 [0119] (2) 2- [4 [[(Furan-2-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2 methyl propionic acid ethyl ester

 [0120] [Chemical 23]

 [0121] In the same manner as in Reference Example 2, the compound (850 mg) obtained in (5) (1) and the furfurylamine (310 1) strength were also obtained from the title compound (1.1 lg) as a colorless oil. Obtained.

 iH—NMR (400MHz, CDC1) δ: 1.28 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 3

 Three

 .72 (2H, s), 3.78 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = 2.0, 3.2Hz), 6.74 (1H, dd, J = 2.0, 8.1Hz), 6.82 (1H, d, J = 8.1Hz), 6.88 (1H, d, J = 2. OHz) , 7.37 (1H, d, J = 2. OHz).

 MS m / z: 348 (M + H) +.

[0122] [Reference Example 6]

 (1) 2- (4 Formylphenoxy) 2 Methylpropionic acid tert butyl ester [0123] [Chemical formula 24]

In the same manner as in Reference Example 2- (1), the title compound (15.4 g) was obtained as a pale yellow oil from 4-hydroxybenzaldehyde (20 g) and 2 bromo-2-methylpropionic acid tert butyl ester (40 ml). NMR-NMR (400MHz, CDC1) δ: 1.41 (9H, s), 1.64 (6H, s), 6. 91 (2H, d

 Three

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

[0125] (2) Azidomethyl mono 1— (4 black mouth) 3-methyl 1H pyrazole

[0126] [Chemical 25]

[0127] 4 Chloromethyl mono 1- (4 black mouth phenol) 3-Methyl 1H Pyrazole (634 mg) was dissolved in N, N dimethylformamide (8 ml), and sodium azide (205 mg) was added to prepare 70 The mixture was stirred at ° C for 2 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 15) to give the title compound (576 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 2.36 (3Η, s), 4.27 (2Η, s), 7.40 (2H, d

 Three

 , J = 8.8Hz), 7.59 (2H, d, J = 8.8Hz), 7.83 (1H, s).

[0128] (3) [1— (4 Black Mole) —3-Methyl-1H-pyrazole-4-ylmethyl] carbamic acid tert-Butinole Estenole

[0129] [Chemical 26]

Reference Example 6— The compound (570 mg) obtained in (2) and trif-phosphine (785 mg) were dissolved in tetrahydrofuran (10 ml), and water (0.5 ml) was added in an ice bath. The mixture was gradually warmed to room temperature and stirred for 1 day. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, and anhydrous sodium sulfate. After drying with hum, concentrated under reduced pressure. The residue was dissolved in dichloromethane (8 ml), ditert-butyl dicarbonate (5811) was added, and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with dichloromethane. The organic layer 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 = 1: 4) to give the title compound (689 mg) as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.46 (9Η, s), 2.32 (3Η, s), 4.20 (2H, d

 Three

 , J = 5.7Hz), 4.67 (1H, brs), 7.38 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9

0Hz), 7.76 (1H, s).

MS m / z: 322 (M + H) ⁺ .

[0131] (4) 2— [4— [[[1 (4-Chromium) 3 Methyl 1 H Pyrazole 4-Methyl] amino] Methyl] phenoxy] -2-Methylpropionic acid tert-butyl ester [ 0132] [Chemical 27]

Reference Example 6— The compound (322 mg) obtained in (3) was dissolved in dichloromethane (4 ml), trifluoroacetic acid (lml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 ml), and the compound (317 mg) obtained in Reference Example 6- (1) was collected and stirred at 70 ° C. for 3.5 hours. The reaction solution was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in methanol (8 ml), sodium borohydride (57 mg) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 97: 3) to give the title compound (428 mg) as a pale brown oil. NMR-NMR (400MHz, CDC1) δ: 1.44 (9H, s), 1.56 (6H, s), 2.28 (3H, s)

 Three

 , 3.68 (2H, s), 3.78 (2H, s), 6.85 (2H, d, J = 8.8Hz), 7.23 (2H, d, J = 8.8Hz), 7.37 (2H, d, J = 9. 1Hz), 7.56 (2H, d, J = 9.1Hz), 7.78 (1H, s).

 [0134] [Reference Example 7]

 (1) N-furan-2-ylmethyl-1,2,4-di-trobenzenesulfonamide

[0135] [Chemical 28]

[0136] Furfurylamine (3 ml) and 2,4-dinitrobenzenesulfuryl chloride (8.65 g) were dissolved in dichloromethane (50 ml), triethylamine (5.4 ml) was added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Jetyl ether was added to the residue and the insoluble material was collected by filtration to give the title compound (8.49 g).

 'H-NMR (400MHz, CDC1) δ: 4.43 (2Η, d, J = 6.1Hz), 5.98 (1H, t, J =

 Three

 6.1Hz), 6.13 (1H, dd, J = 2.0, 3.2Hz), 6.15 (1H, d, J = 3.2Hz), 7.02

(1H, d, J = 2.0Hz), 8.19 (1H, d, J = 8.8Hz), 8.42 (1H, dd, J = 2.2, 8.8

Hz), 8.64 (1H, d, J = 2.2Hz).

[0137] (2) 4-Methyl—1— (4-Trifluoromethylphenol) — 1H—Pyrrole— 3-Carbonic acid Ethenole Estenole

[0138] [Chemical 29]

[0139] 3-Methyl- 1H-Pyrro-Lu 4 Strong Eruvyl Ethyl Bonate (lg), 4 Trifluoromethyl Benzene (1.06 ml), Yowi Copper (124 mg), Potassium Phosphate (2. 77 g), Trans-cyclohexanediamine (75 mg) was dissolved in dioxane (30 ml) and stirred at 120 ° C. for 4 hours. The reaction solution was cooled to room temperature, water was added to the reaction solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 1: 19) to give the title compound (1.75 g).

 'H-NMR (400MHz, CDC1) δ: 1.37 (3Η, t, J = 7.1 Hz), 2.34 (3H, s), 4

 Three

 31 (2H, q, J = 7.1 Hz), 6. 87 (1H, d, J = 2.5 Hz), 7. 49 (2H, d, J = 8.3 Hz)

), 7.68 (1H, s), 7.70 (2H, d, J = 8.3Hz).

MS m / z: 297 (M + H) ⁺ .

[0140] (3) N—Furan 2-methylmethyl N— [4 Methyl 1 4 Trifluoromethylphenol

-L) —1H pyrrole—3-ylmethyl] —2, 4 di-trobenzenesulfonamide [0141] [Chemical 30]

[0142] Reference Example 7— Dissolving the compound (500 mg) obtained in (2) in anhydrous tetrahydrofuran (7 ml), adding lithium aluminum hydride (96 mg) with cooling with ice water and stirring at the same temperature for 2 hours. did. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted three times with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [4-methyl-1- (4-trifluoromethyl) -1- 1H-pyrrole-1-yl] methanol. It was. This compound was dissolved in tetrahydrofuran (15 ml), and the compound obtained in Reference Example 7- (1) (550 mg), triphenol-norephosphine (529 mg), azodi force norlevonic acid diisopropinole esterol (397 μ 1) And stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9 to 1: 5) to give the title compound (603 mg). Obtained as a yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.05 (3Η, s), 4.49 (2Η, s), 4.52 (2H, s)

 Three

 , 6.17 (1H, d, J = 3.2Hz), 6.25 (1H, dd, J = 2.0, 3.2Hz), 6.85 (1H, d, J = 2.5Hz), 7.03 (1H, d, J = 2.5Hz) , 7.21 (1H, d, J = 2.0Hz), 7.39 (2H, d, J = 8.3Hz), 7.67 (2H, d, J = 8.3Hz), 8.05 (1H, d, J = 8.6Hz), 8.32 (1H, dd, J = 2.2, 8.6Hz), 8.44 (1H, d, J = 2.2Hz).

 MS m / z: 565 (M + H) +.

 [0143] (4) Furan 2-ylmethyl- [4-methyl-1 4 trifluoromethylphenol) 1 H pyrrole-3-ylmethylamine

 [0144] [Chemical 31]

[0145] Reference Example 7— The compound (600 mg) obtained in (3) was dissolved in dichloromethane (8 ml), and tritylamine (442 1) and thiodaricholic acid (222 1) were added in this order in an ice bath, The mixture was stirred for 1.5 hours while gradually raising the temperature. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness to give the title compound as an oil. This was used in the next reaction without purification.

 [0146] [Reference Example 8]

 2- [4 -— [[Furan-2-ylmethyl- (1H-imidazole-4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid ethyl ester

[0147] [Chemical 32]

Example 7— In the same manner as in (1), from the compound (677 mg) obtained in 1H-imidazole-3-carbaldehyde (215 mg) and Reference Example 2- (2), the title compound (771 mg) Was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 3

 Three

 .54 (2H, s), 3.61 (2H, s), 3.63 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6 Hz), 6.95 (1H, s), 7.20 (2H, d, J = 8.6Hz), 7.40 (1H, d, J = 2 OHz), 7 .58 (1H, s).

 MS m / z: 398 (M + H) +.

[0149] [Reference Example 9]

 (1) 4 Azidomethyl 3 Methyl 1 Phenyl 1 H Pyrazole

[0150] [Chemical 33]

Reference Example 6—The title compound (6.0 7 g) was obtained as a colorless oil from the compound (6. lg) obtained in Reference Example 4 in the same manner as (2).

 'H-NMR (400MHz, CDC1) δ: 2.37 (3Η, s), 4.27 (2Η, s), 7.25— 7.29

 Three

 (1Η, m), 7.40-7.46 (2H, m), 7.63—7.65 (2H, m), 7.86 (1H, s).

MS m / z: 214 (M + H) ⁺ .

[0152] (2) (3-Methyl-1-phenol-H 1H pyrazole-4-ylmethyl) rubamic acid te rt-butyl ester

[0153] [Chemical 34]

[0154] Reference Example 6— In the same manner as in (3), from the compound (6. Og) obtained in Reference Example 9— (1), the title compound (5.85 g) was obtained as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.47 (9Η, s), 2.33 (3Η, s), 3.49 (2H, s)

 Three

 , 4.21 (2H, d, J = 5.6Hz), 4.67 (1H, br s), 7.22— 7.26 (1H, m), 7.42

(2H, t, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 7.79 (1H, s).

 MS m / z: 288 (M + H) +.

[0155] (3) 2- [2-Methoxy-1-4-[[(3-Methyl 1-phenol-1 1H Pyrazole-1-4-methyl) amino] methyl] phenoxy] -2-Methylpropionic acid ethyl ester [0156] ] [Chemical 35]

 [0157] Reference Example 6— In the same manner as (4), Reference Example 9— From the compound (1. Og) obtained in (2) and Reference Example 5- (1) from the compound (1.18 g) The title compound (1.43 g) was obtained as a colorless oil.

 MS m / z: 438 (M + H) +.

[0158] [Reference Example 10]

 (1) 1 Ferru 3 Trifluoromethyl 1H Pyrazole 4 Strenuous rubonic acid ester

 [0159] [Chemical 36]

[0160] 3 Trifluoromethyl— 1H pyrazole — 4-carboxylic acid ethyl ester (1.

Og), benzene iodide (803 μ 1), salicylaldoxime (132 mg), cuprous oxide (34 mg) and cesium carbonate (3.13 g) were suspended in acetonitrile (6 ml) at 80 ° C. -Stirred. The reaction mixture was cooled to room temperature, aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. It was. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (1.5 lg) as a colorless solid.

 MS m / z: 285 (M + H) +.

[0161] (2) (1—Ferule 3 Trifluoromethyl 1 1H Pyrazole 1-yl) Methanol [0162] [Chemical Formula 37]

[0163] Reference Example 10— The compound (1.5 g) obtained in (1) was dissolved in anhydrous tetrahydrofuran (15 ml) and lithium aluminum hydride (200 mg) was added and stirred at 0 ° C for 30 minutes. did. Water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. To the mother liquor was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer 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 = 1: 1) to give the title compound (603 mg) as a colorless oil.

 — NMR (400 MHz, CDC1) δ: 1. 83 (1Η, t, J = 5. 9Hz), 4. 77 (2Η, d, J

 Three

 = 5. 9Hz), 7. 34— 7. 38 (1H, m), 7. 45— 7. 50 (2H, m), 7. 67— 7. 70 (2H

, m), 8.00 (1H, s).

MS m / z: 243 (M + H) ⁺ .

[0164] (3) N furan-2-ylmethyl-1,2,4 dinitro-N— (1-Ferru 3 trifluoromethyl-1H pyrazole-4-ylmethyl) benzenesulfonamide

[0165] [Chemical 38]

Reference Example 7—In the same manner as (3), Reference Example 10—Compound (242 mg) obtained in (2), Reference Example 7

-The compound (327 mg) obtained in (1) also gave the title compound (586 mg) as a yellow oil. NMR-NMR (400MHz, CDCl) δ: 4.54 (2H, s), 4.61 (2H, s), 6.24— 6.25

 Three

 (2H, m), 7.19 (1H, d, J = l.7Hz), 7.37—7.41 (1H, m), 7.47—7.52 (2

H, m), 7.65-7.69 (2H, m), 8.05 (1H, s), 8.12 (1H, d, J = 8.8Hz), 8.

42 (1H, dd, J = 2.2, 8.8Hz), 8.50 (1H, d, J = 2.2Hz).

 MS m / z: 551 (M + H) +.

[0167] [Reference Example 11]

 (1) 2- (2, 6 dimethylphenoxy) 2-methylpropionic acid ethyl ester [0168] [Chemical 39]

[0169] In the same manner as in Reference Example 5— (1), 3,5 dimethyl-4-hydroxybenzaldehyde (5.0 g) and 2-bromo-2-methylpropionic acid ethyl ester (10 ml) force the title compound (6.2 g) as a solid Got as.

 iH—NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.2Hz), 1.50 (6H, s), 2

 Three

 .31 (6H, s), 4.30 (2H, q, J = 7.2Hz), 7.52 (2H, s), 9.85 (1H, s).

[0170] (2) 2— [4— [[(Furan-2-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy]

 2-Methylpropionic acid ethyl ester

[0171] [Chemical 40]

Reference Example 5— In the same manner as in (2), the compound (2. Og) and furfurylamine (700 μ 1) force obtained in Reference Example 11 (1) were also applied to the title compound (2.13 g) in a colorless manner. Obtained as an oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

18 (6H, s), 3.66 (2H, s), 3.79 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = l.7, 3.2Hz), 6.92 (2H, s), 7.37 ( (1H, d, J = l.7Hz).

 MS m / z: 346 (M + H) +.

[0173] [Reference Example 12]

 (5-Methyl-2-Ferru 2H- [1, 2, 3] Triazol-4-yl) methanol

[0174] [Chemical 41]

[0175] (5-Methyl-2-phenol-2H— [1, 2, 3] triazole-4-yl) carboxylic acid (3 OOmg) was dissolved in anhydrous tetrahydrofuran (5ml) to give a borane-dimethylsulfide complex (28 0 1) was added, and the mixture was stirred overnight at room temperature and then stirred at 60 ° C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (259 mg) as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.85 (1Η, t, J = 6.1Hz), 2.42 (3H, s), 4

 Three

 .81 (2H, d, J = 6.1Hz), 7.29— 7.33 (1H, m), 7.46 (2H, t, J = 8.6Hz) 7

.99 (2H, d, J = 8.6Hz).

 MS m / z: 190 (M + H) +.

[0176] [Reference Example 13]

 (1) (3-Methyl 1-phenol 1 H-pyrazole 4-yl) acetonitrile

[0177] [Chemical 42]

[0178] The compound (1. Og) obtained in Reference Example 4 was dissolved in N, N dimethylformamide (10 ml), cyano sodium (237 mg) was added, and the mixture was stirred at 80 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel force on the residue Purification by ram chromatography (ethyl acetate: hexane = 1: 6) gave the title compound (931 mg

) Was obtained as a colorless oil.

[0179] (2) 2- (3-Methyl 1-Ferru 1H pyrazole-4-yl) ethanol

[0180] [Chemical 43]

Reference Example 13— The compound (93 lmg) obtained in (1) was dissolved in concentrated hydrochloric acid (20 ml) and stirred at 80 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in anhydrous tetrahydrofuran (10 ml), and borane-dimethylsulfide complex (885 1) was added in an ice bath and stirred for 1.5 hours. A 10% aqueous citrate solution was added to the reaction mixture, and the mixture was stirred for 10 minutes, and then extracted three times with ethyl acetate. The organic layer 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 = 1: 1) to give the title compound (481 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 2.32 (3Η, s), 2.74 (2Η, t, J = 6.6Hz), 3

 Three

 .82 (2H, br s), 7.20— 7.24 (1H, m), 7.40— 7.44 (2H, m), 7.61— 7.6

4 (2H, m), 7.74 (1H, s).

MS m / z: 203 (M + H) ⁺ .

[0182] (3) N furan-2-ylmethyl-1-N- [2- (3-methyl-1-phenyl-1H pyrazo-lru 4-yl) ethyl] -2, 4 dinitrobenzenesulfonamide

[0183] [Chemical 44]

Reference Example 7—In the same manner as (3), Reference Example 13—The compound (470 mg) obtained in (2) and Reference Example 7-Compound (761 mg) obtained in (1). Gave the title compound (1.19 g) as a yellow solid. 'H-NMR (400MHz, CDCl) δ: 2.25 (3Η, s), 2.74 (2Η, t, J = 6.9Hz), 3

 Three

 .51 (2H, t, J = 6.9Hz), 4.63 (2H, s), 6.30—6.34 (2H, m), 7.21—7.2 5 (1H, m), 7.33 (1H, d, J = l.7Hz ), 7.37—7.42 (2H, m), 7.49—7.52 (2H, m), 7.63 (1H, s), 8.01 (1H, d, J = 8.6Hz), 8.24 (1H, d, J = 2.2Hz) , 8.32 (1H, dd, J = 2.2, 8.6Hz).

MS m / z: 512 (M + H) ⁺ .

 [0185] [Reference Example 14]

 (1) N— [3— (4 Fluorophenol) —1—Fueru 1H Pyrazole-4-ylmethyl] —N Furan-2-ylmethyl-1,2,4 dinitrobenzenesulfonamide

 [0186] [Chemical 45]

 [0187] In the same manner as in Reference Example 7- (3), in [3— (4 Fluoro-Fel) 1 Ferru 1H-pyrazole-4-yl] methanol (lOOmg) and Reference Example 7- (1) The title compound (207 mg) was obtained as a yellow solid from the obtained compound.

MS m / z: 578 (M + H) ⁺ .

[0188] (2) [3— (4 Fluorophenol) —1—Fueru 1H Pyrazole-4-ylmethyl

] Fran 1-ylmethylamine

[0189] [Chem 46]

Reference Example 7—In the same manner as in (4), the title compound was obtained as an oil from the compound (200 mg) obtained in Reference Example 14- (1). Used for reaction.

[0191] [Reference Example 15]

 (1) 4-Bromomethyl-5-methyl-2-ferro- 2H— [1, 2, 3] triazole

[0192] [Chemical 47]

[0193] The compound (4.2 g) obtained in Reference Example 12 was dissolved in dichloromethane (60 ml), and after cooling with ice water, phosphorus tribromide (2.3 ml) was added and kept at the same temperature for 1 hour. Stir. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was 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 (ethyl acetate: hexane = 1: 19) to give the title compound (5.2 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 4.58 (2Η, s), 7.32 (IH, t,

 Three

 J = 7.4Hz), 7.45 (2H, t, J = 7.8Hz), 7.98 (2H, d, J = 8.6Hz).

[0194] (2) 4-Azidomethyl-5-methyl-2-ferro- 2H— [1, 2, 3] triazole

[0195] [Chemical 48]

Reference Example 6—Similar to (2), the compound (3.5 g) obtained in Reference Example 15- (1) and the aziana sodium (0.993 g) force were also applied to the title compound (2 86 g) was obtained as a colorless oil.

'H-NMR (400MHz, CDCl) δ: 2. 42 (3Η, s), 4. 46 (2Η, s), 7. 33 (IH, t, J = 7.4Hz), 7.47 (2H, t, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz).

[0197] (3) (5-Methyl-2-Fel-Lo 2H- [1, 2, 3] Triazol-4-ylmethyl) carbamic acid tert-Butinole Estenole

[0198] [Chemical 49]

Reference Example 6- In the same manner as in (3), the title compound (3.06 g) was obtained as a colorless solid from the compound (2.85 g) obtained in Reference Example 15- (2).

 'H-NMR (400MHz, CDCl) δ: 1.47 (9Η, s), 2.38 (3Η, s), 4.44 (2H, d

 Three

 , J = 5.6Hz), 5.00 (1H, br s), 7.30 (1H, t, J = 7.4Hz), 7.45 (2H, t, J =

7.6Hz), 7.97 (2H, d, J = 7.6Hz).

[0200] (4) 2— [2, 6 Dimethyl 4-— [[(5-Methyl-2 Ferrule 2H— [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] -2 Methylpropion Acid ethyl ester

[0201] [Chemical 50]

Reference Example 6—In the same manner as (4), Reference Example 15—Compound (2. Og) obtained in (3) and Reference Example 11—Compound obtained in (1) (1.83 g) To give the title compound (3.03 g) as a pale yellow oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 19 (6H, s), 2.34 (3H, s), 3.74 (2H, s), 3.88 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.95 (2H, s), 7.29 (1H, t, J = 7.4Hz), 7.43 (2H, t, J = 7.8Hz), 7.99 (2H, d, J = 8.6Hz).

[0203] [Reference Example 16] (1) 2— (4-Formyl-2,6 dimethylphenoxy) -2-methylpropionic acid tert-butyl ester

 [0204] [Chemical 51]

[0205] In the same manner as Reference Example 6- (1) except that potassium carbonate was used in place of cesium carbonate, 3, 5 dimethyl-4-hydroxybenzaldehyde (15. Og) and 2 bromo-2-methylpropionic acid tert butyl ester ( 56 ml) was treated in the presence of potassium carbonate (55.3 g) to give the title compound (4.47 g) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.47 (9Η, s), 2.25 (6H, s)

 Three

 , 7. 48 (2H, s), 9. 83 (1H, s).

[0206] (2) 2- [2, 6 Dimethyl-4 [(Methylcarbamoylmethylamino) methyl] phenoxy

] —2-Methylpropionic acid tert-butyl ester

[0207] [Chemical 52]

[0208] Reference Example 16- Compound (2.92g) obtained in (1) and 2-amino-1-N-methylacetamide hydrochloride (

2. 49 g) was dissolved in methanol (200 ml), and sodium cyanoborohydride (1N tetrahydrofuran solution, 15 ml) was added under ice water cooling. After returning to room temperature and stirring overnight, the solvent was distilled off under reduced pressure, and the residue was diluted with dichloromethane and 1N aqueous sodium hydroxide solution. 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 column chromatography (dichloromethane: methanol = 9: 1) to give the title compound (

3.6 lg) was obtained as a yellow oil. NMR-NMR (400MHz, CDC1) δ: 1.42 (3H, s), 1.52 (9H, s), 2.22 (6H, s)

 Three

 , 2.83 (3H, d, J = 5.1Hz), 3.31 (2H, s), 3.66 (2H, s), 6.89 (2H, s), 7.23 (1H, br s).

MS m / z: 364 (M + H) ⁺ .

[0209] [Reference Example 17]

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

[0210] [Chemical 53]

[0211] Reference Example 11— The compound (15.8 g) obtained in (1) 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. did. The reaction solution was returned to room temperature, filtered through celite, and the filtrate was evaporated 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, 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. The residue was purified by silica gel column chromatography (black mouth form: methanol = 19: 1) to give the title compound (21.6 g) as a pale yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .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) +.

[0212] (2) 2— [4 [[tert Butoxycarbamoylmethyl- (5-methyl-2-phenol 2 H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 Enoki 2] 2-Methylpropionic acid ethyl ester

[0213] [Chemical 54]

[0214] Reference Example 17— Combine the compound (0.301 g) obtained in (1) with the compound (0.20 g) obtained in Reference Example 15 (1) into N, N dimethylformamide (5 ml). After dissolution, potassium carbonate (0.132 g) was added and stirred at 80 ° C. for 3 days. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 1: 4) to give the title compound (0.42 lg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .47 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 3.24 (2H, s), 3.69 (2H, s), 3.87 (2H, s), 4.28 (2H, q , J = 7.1Hz), 6.98 (2H, s), 7.28 (1H, t, J = 7.6H z), 7.44 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz) .

 MS m / z: 551 (M + H) +.

 [0215] (3) 2— [4 — [[Carboxymethyl— (5-methyl-2 phenol—2H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2,6 dimethyl Phenoxy] —2-methyl propionate ethenore estenore

 [0216] [Chemical 55]

Reference Example 17— Dissolving the compound (0.437 g) obtained in (2) in dichloromethane (2 ml) Oroacetic acid (lml) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (black form: methanol = 94: 6) to give the title compound (0.236 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 19 (6H, s), 2.25 (3H, s), 3.43 (2H, s), 3.72 (2H, s), 3.85 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.94 (2H, s), 7.32 (1H, t, J = 7.8Hz), 7.46 (2H, t, J = 7.8Hz), 7.99 (2H, d, J = 7.8Hz).

 MS m / z: 509 (M + H) +.

[0218] [Reference Example 18]

 2- [4-[[[2- (Ν'-acetyl-hydrazino) 2-oxoethyl]-(5-methyl-2-phenol-2Η- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] 2, 6-dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0219] [Chem 56]

[0220] Reference Example 17—Compound obtained in (3) (0.230 g), acetohydrazide (0.038 g), 1-ethyl — 3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.107 g) ), 1-hydroxybenzotriazole hydrate (0.085 g) was dissolved in N, N dimethylformamide (4 ml) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate) to give the title compound (0.163 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

.05 (3H, s), 2.21 (6H, s), 2.24 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3. 77 (2H, s), 4.29 (2H, q, J = 7.1Hz), 7.02 (2H, s), 7.30 (1H, t, J = 7.6H z), 7.45 (2H, t, J = 7.6Hz) , 8.00 (2H, d, J = 7.6Hz), 8.12 (1H, br s),

9.56 (1H, br s).

 MS m / z: 551 (M + H) +.

[0221] [Reference Example 19]

 2- [4 -— [(3-Methoxypropylamino) methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethyl ester

[0222] [Chemical 57]

[0223] Reference Example 2—In the same manner as (2), the compound (0.800 g) obtained in Reference Example 11- (1) and 3-methoxypropylamine (0.339 ml) were also used in the title compound. (1.02 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .79 (2H, quint, J = 6.4Hz), 2. 18 (6H, s), 2.72 (2H, t, J = 6.9Hz), 3.33

(3H, s), 3.45 (2H, t, J = 6.4Hz), 3.66 (2H, s), 4.28 (2H, q, J = 7.1 Hz)

, 6.91 (2H, s).

MS m / z: 437 (M + H) ⁺ .

[0224] [Reference Example 20]

 2- [4 -— [(2-Methoxyethylamino) methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid tert butyl ester

[0225] [Chemical 58]

[0226] Reference Example 16— The compound (3. lg) obtained in (1) and 2-methoxyethylamine (1. The product was dissolved in anol (30 ml) and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled with ice water, sodium borohydride (0.40 g) was added, and the mixture was stirred overnight while gradually warming to room temperature. Saturated saline was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 = 97: 3) to obtain the title compound (3.73 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s)

 Three

 , 2.80 (2H, t, J = 5.1Hz), 3.35 (3H, s), 3.51 (2H, t, J = 5.1Hz), 3.68 (2H, s), 6.91 (2H, s).

MS m / z: 352 (M + H) ⁺ .

[0227] [Reference Example 21]

 The compound of Reference Example 21- (3) was synthesized according to a method described in the literature (E. Klingsberg, Synthesis, 475-477 (1972)).

 (1) 2- (Hydroxyimino) 3-oxo-N-butylbutyramide

[0228] [Chemical 59]

Acetoxyacetolide (10 g) was dissolved in acetic acid (100 ml), and an aqueous solution (50 ml) of sodium nitrite (4.67 g) was added dropwise with cooling with ice water. After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Jetyl ether was added to the residue, and insolubles were collected by filtration. The mother liquor was concentrated under reduced pressure, to the residue was added diethyl ether monohexane, and the insoluble material was collected by filtration to give the title compound (1 0.9 g) as a yellow solid.

 [0230] (2) 2- (Hydroxyimino) N Hue-Lou 3— (p-tolylhydrazono) butyramide

[0231] [Chemical 60]

 Reference Example 21— The compound (1.16 g) obtained in (1) was dissolved in ethanol (20 ml), and p-trinolehydrazine hydrochloride (0.985 g) and triethinoreamine (0 865ml) free from calo, 80. I carried it with C for 30 minutes. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the title compound (1.75 g).

MS m / z: 311 (M + H) +.

[0233] (3) 5-Methyl-2-p-tolyl-2H— [1, 2, 3] triazole-4-carboxylic acid

[0234] [Chemical 61]

[0235] Reference Example 21— The compound (1.75 g) obtained in (2) was dissolved in methoxyethanol (15 ml), and potassium hydroxide (3.4 g) was added at 140 ° C. Stir overnight. The reaction mixture was poured into concentrated hydrochloric acid-ice and extracted three times 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 a crude product of the title compound.

 [0236] (4) (5-Methyl-2-p-tolyl-2H— [1, 2, 3] triazole-4-yl) methanol

[0237] [Chemical 62]

[0238] Reference Example 21— The compound (1.22 g) obtained in (3) was dissolved in tetrahydrofuran (10 ml). N-dimethylsulfide complex (1.08 ml) was added and stirred at 60 ° C for 45 minutes. Water was added to the reaction solution, and the mixture was stirred at 60 ° C for 10 minutes. The reaction mixture was poured into saturated brine and extracted three times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 1: 3) to give the title compound (0.80 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.39 (3Η, s), 2.41 (3Η, s), 4.80 (2H, s)

 Three

 , 7. 25 (2H, d, J = 8.6 Hz), 7. 86 (2H, d, J = 8.6 Hz).

MS m / z: 204 (M + H) ⁺ .

[0239] (5) 4-Bromomethyl-5-methyl-2-p-tolyl-2H- [1, 2, 3] triazole

[0240] [Chemical 63]

[0241] In the same manner as in Reference Example 15- (1), the title compound (0.665 g) was obtained as a colorless solid from the compound (0.80 g) obtained in Reference Example 21- (4).

 'H-NMR (400MHz, CDCl) δ: 2.39 (3Η, s), 2.41 (3Η, s), 4.58 (2H, s)

 Three

 , 7. 25 (2H, d, J = 8.6 Hz), 7. 86 (2H, d, J = 8.6 Hz).

[0242] [Reference Example 22]

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

 [0243] [Chemical 64]

[0244] Reference Example 17— The compound (3.5 g) obtained in (1) was dissolved in acetonitrile (30 ml), and N— (9-fluoromethoxycarbo-loxy) succinimide (3.74) was cooled with ice water. g) was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium bicarbonate, aqueous citrate solution 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 (ethyl acetate: hexane = 1: 1) to give the title compound (5.24 g) as pale yellow Obtained as an 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), 7.35—7.41 (2H, m), 7.53 (1H, d, J = 7.4Hz), 7.59 (1H, d, J = 7.4Hz), 7.73 (1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 7.6Hz).

MS m / z: 624 (M + Na) ⁺ .

[0245] (2) 2— [4 [[Carboxymethyl- (9H-fluorene-9-ylmethoxycarbol) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionate Ethyl ester

[0246] [Chemical 65]

Reference Example 22— The compound (5.24 g) obtained in (1) was dissolved in dichloromethane (60 ml), and trifluoroacetic acid (20 ml) was added while cooling with ice water, followed by stirring at room temperature for 16 hours. . 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 residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (5.70 g) Yellow oil Obtained as a product.

 '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 (2 H, d, J = 7.3 Hz).

 MS m / z: 568 (M + H) +.

 [0248] (3) 2— [4— [[[2- (N, -Acetylhydrazino) 2-oxoethyl] (9H-fluorene-9-ylmethoxycarbol) amino] methyl] — 2,6 Dimethylphenoxy] —2-Methylpropionic acid ethyl ester

 [0249]

[0250] In the same manner as in Reference Example 18, the title compound (1. lg) was colorless from the compound (1.5 g) obtained in Reference Example 22- (2) and acetohydrazide (0.31 g). Obtained as a solid.

MS m / z: 602 (M + H) ⁺ .

 [0251] (4) 2— [4— [[(9H Fluorene-9-ylmethoxycarbol) mono (5-methyl- [1, 3, 4] oxadiazo-ru 2-ylmethyl) amino] methyl] — 2, 6-Dimethylphenoxy] 1 2-methylpropionic acid ethyl ester

[0252] [Chemical 67]

In the same manner as in Example 26- (1), the title compound (1. Og) was obtained as a colorless solid from the compound (1. lg) obtained in Reference Example 22- (3). It was.

 'H-NMR (400MHz, CDC1) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 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).

MS m / z: 584 (M + H) ⁺ .

[0254] (5) 2- [2,6 Dimethyl 4-[[((5-Methyl [1, 3, 4] oxadiazol 2-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid Ethyl ester [0255] [Chemical formula 68]

[0256] Reference Example 22— 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, and the solvent was evaporated under reduced pressure. Acetic acid residue The mixture 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 residue was purified by silica gel column chromatography (methanol: chloroform = 1: 9) to give the title compound (0.54 g) as a yellow oil. Got as.

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

MS m / z: 362 (M + H) ⁺ .

[0257] [Reference Example 23]

 (1) (5-Methyl-2- m-tolyl-2H- [1, 2, 3] triazol-4-yl) methanol [0258] [Chemical 69]

Reference Example 21 In the same manner as (2) to (4), m-tolylhydrazine hydrochloride (0.846 g) was also obtained as the title compound (0.944 g) as a pale yellow solid.

 'H-NMR (400MHz, CDC1) δ: 2.41 (3Η, s), 2.42 (3Η, s), 4.80 (2H, s)

 Three

 , 7.12 (1H, d, J = 8.1Hz), 7.33 (1H, t, J = 8.1Hz), 7.78 (1H, d, J = 8.1)

Hz), 7.82 (1H, s).

MS m / z: 204 (M + H) ⁺ .

[0260] (2) 4-Bromomethyl-5-methyl-2-m-tolyl-2H— [1, 2, 3] triazole [0261] [Chemical 70]

[0262] In the same manner as in Reference Example 15- (1), the title compound (0.805 g) was obtained as a colorless solid from the compound (0.940 g) obtained in Reference Example 23- (1).

 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 2.43 (3Η, s), 4.58 (2H, s)

 Three

 , 7.13 (1H, d, J = 8.1Hz), 7.33 (1H, t, J = 8.1Hz), 7.80 (1H, d, J = 8.1 Hz), 7.82 (1H, s).

[0263] [Reference Example 24]

 (1) 2— [4— [[tert-Butoxycarboromethyl (5 methyl 2-m tolyl-2H — [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 dimethylphenol ] 2-Methylpropionic acid ethyl ester

[0264] [Chemical 71]

In the same manner as Reference Example 17- (2), the compound (0.210 g) obtained in Reference Example 23- (2) and the compound (0.299 g) obtained in Reference Example 17- (1) were also used. The title compound (0.398 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .47 (9H, s), 2.18 (6H, s), 2.31 (3H, s), 2.42 (3H, s), 3.23 (2H, s), 3.69 (2H, s), 3.86 (2H, s ), 4.28 (2H, q, J = 7.1Hz), 6.98 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.32 (1H, t, J = 7.8Hz), 7.79 (1H, d , J = 7.8Hz), 7. 83 (1H, s).

 MS m / z: 565 (M + H) +.

[0266] (2) 2— [4 — [[Carboxymethyl— (5-methyl-2-m-tolyl-2H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 Dimethylphenoxy] -2-ethyl propionate [0267] [Chemical 72]

Reference Example 17- In the same manner as in (3), the compound (0.446 g) force obtained in Reference Example 24- (1) was also used to give the title compound (0.235 g) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 .20 (6H, s), 2.24 (3H, s), 2.44 (3H, s), 3.44 (2H, s), 3.72 (2H, s), 3.85 (2H, s), 4.29 (2H, q , J = 7.1Hz), 6.94 (2H, s), 7.14 (1H, d, J = 7.8 Hz), 7.34 (1H, t, J = 7.8Hz), 7.79 (1H, d, J = 7.8Hz), 7.82 (1H, s) .MS m / z: 509 (M + H) +.

 [0269] (3) 2— [4— [[[2— (N, -acetyl-hydrazino) 2-oxoethyl]-(5-methyl-2-m-tolyl— 2H— [1, 2, 3] triazole — 4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0270] [Chemical 73]

In the same manner as in Reference Example 18, the compound (0.230 g) obtained in Reference Example 24- (2) and acetohydrazide (0.037 g) also gave the title compound (0.196 g) as a colorless oil. .

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

.21 (6H, s), 2.23 (3H, s), 2.43 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q , J = 7.1Hz), 7.02 (2H, s), 7.12 (1H, d, J = 7.6 Hz), 7.33 (1H, t, J = 8.1Hz), 7.79 (1H, d, J = 8.1 Hz), 7.83 (1H, s), 8. 16 (1H, br s), 9.56 (1H, br s).

 MS m / z: 565 (M + H) +.

[0272] [Reference Example 25]

 (1) [2— (4 Chlorophenyl) 1-5-methyl 2H— [1, 2, 3] triazole- 4 yl] methanol

[0273] [Chemical 74]

Reference Example 21 In the same manner as in (2) to (4), the title compound (0.926 g) was obtained as a colorless solid in the same manner as in (4), with the strength of hydrochloric acid (4 black mouth) hydrazine (0.955 g).

 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 4.80 (2Η, s), 7.42 (2H, d

 Three

 , J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz).

MS m / z: 224 (M + H) ⁺ .

[0275] (2) 4 Bromomethyl 2— (4 Black Mole) 1-Methyl 2H— [1, 2, 3] Tria Zonole

[0276] [Chemical 75]

Reference Example 15—In the same manner as in (1), the compound (0.920 g) force obtained in Reference Example 25- (1) also gave the title compound (0.772 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 4.57 (2Η, s), 7.42 (2H, d

 Three

 , J = 8.8Hz), 7.94 (2H, d, J = 8.8Hz).

[0278] [Reference Example 26] (1) 2— [4— [[tert-Butoxycarbolmethyl- [2— (4 Chlorophthalyl-tilu 2H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, Ruphenoxy] 2— Methyl propionic acid ethyl ester

 [0279] [Chem 76]

[0280] In the same manner as Reference Example 17- (2), the compound (0.130 g) obtained in Reference Example 25- (2) and the compound (0.172 g) force obtained in Reference Example 17- (1) were also used. The title compound (0.21 lg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .47 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.23 (2H, s), 3.68 (2H, s), 3.86 (2H, s), 4.28 (2H, q , J = 7.1Hz), 6.96 (2H, s), 7.40 (2H, d, J = 9.1 Hz), 7.94 (2H, d, J = 9.1Hz).

 [0281] (2) 2— [4 [[Carboxymethyl— [2— (4 Chlorophenyl) 5-Methyl 2H— [1, 2, 3] Triazol-4-ylmethyl] amino] methyl] —2, 6 Dimethyl Phenoxy] 2-methylpropionic acid ethyl ester

 [0282] [Chemical 77]

Reference Example 17—In the same manner as in (3), the compound (0.205 g) force obtained in Reference Example 26- (1) was also used to give the title compound (0.185 g) as a colorless solid.

MS m / z: 529 (M + H) +. [0284] (3) 2- [4-[[[2- (N, -acetyl-hydrazino) 2-oxoethyl] [2 -— (4-cylinder)-5-methyl 2H— [1, 2 , 3] Triazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0285] [Chemical 78]

[0286] In the same manner as in Reference Example 18, the compound (0.185 g) obtained in Reference Example 26- (2) and the acetohydrazide (0.03 lg) force were also obtained from the title compound (0.183 g) as a colorless oil. Got as.

 'H-NMR (400MHz, CDC1) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 .05 (3H, s), 2.20 (6H, s), 2.23 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q , J = 7.1Hz), 7.01 (2H, s), 7.42 (2H, d, J = 8.8 Hz), 7.95 (2H, d, J = 8.8Hz), 8.08 (1H, br s), 9.55 (1H, br s).

MS m / z: 584 (M + H) ⁺ .

 [0287] [Reference Example 27]

 (1) [2— (3 black mouth) 1-5-methyl 2H— [1, 2, 3] triazole- 4 yl] methanol

 [0288] [Chemical 79]

Reference Example 21—In the same manner as (2) to (4), the title compound (0.815 g) was also obtained as a colorless solid with the strength of hydrochloric acid (3 black mouth) hydrazine (0.955 g). NMR-NMR (400MHz, CDCl) δ: 2.42 (3H, s), 4.81 (2H, s), 7.26— 7.29

 Three

 (1H, m), 7.38 (1H, t, J = 8.1Hz), 7.90 (1H, d, J = 8.1 Hz), 8.04 (1H, t

, J = 2.0Hz).

MS m / z: 224 (M + H) ⁺ .

 [0290] (2) 4 Bromomethyl 2— (3 Black Mole) 1-Methyl 2H— [1, 2, 3] Tria Zonole

 Reference Example 15—In the same manner as in (1), the compound (0.810 g) force obtained in Reference Example 27- (1) was also used to obtain the title compound (0.761 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.42 (3Η, s), 4.56 (2Η, s), 7.28 (1H, d

 Three

 , J = 2. OHz), 7.38 (1H, t, J = 8.1Hz), 7.88— 7.91 (1H, m), 8.04 (1H, t, J = 2. OHz).

 [0293] [Reference Example 28]

 (1) 2— [4— [[tert-Butoxycarboromethyl] [2— (3—Black mouth phenyl) -5-methyl-2H— [1, 2, 3] triazole-4-ylmethyl] amino] methyl] —2, 6-dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0294] [Chemical 81]

[0295] In the same manner as in Reference Example 17- (2), the compound (0.130 g) obtained in Reference Example 27- (2) and Reference Example 17- Compound (0.172 g) force obtained in (1) The title compound (0.265 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .48 (9H, s), 2.18 (6H, s), 2.30 (3H, s), 3.23 (2H, s), 3.68 (2H, s), 3.86 (2H, s), 4.29 (2H, q , J = 7.1Hz), 6.97 (2H, s), 7.24— 7.26 (1H, m), 7.36 (1H, d, J = 7.8Hz), 7.88— 7.90 (1H, m), 8.04 (1H, d, J = 2.OHz).

 [0296] (2) 2— [4— [[Carboxymethyl mono [2— (3 throat) phenol] 5-Methyl 2H— [1, 2, 3] Triazol-4-ylmethyl] amino] methyl] —2 , 6 Dimethylphenoxy] 2-Methylpropionic acid ethyl ester

 [0297] [Chemical 82]

Reference Example 17—In the same manner as in (3), the compound (0.260 g) force obtained in Reference Example 28- (1) was also used to give the title compound (0.235 g) as a colorless solid.

 MS m / z: 529 (M + H) +.

[0299] (3) 2- [4-[[[2- (Ν'-Acetylhydrazino) 2-oxoethyl] [2-— (3-Circle Phenyl) — 5-Methyl 2Η— [1, 2 , 3] Triazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0300] [Chemical 83]

[0301] In the same manner as in Reference Example 18, the compound (0.233 g) obtained in Reference Example 28- (2) and acetohydrazide (0.039 g) were also used to obtain the title compound (0.206 g) as a colorless oil. .

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 .05 (3H, s), 2.20 (6H, s), 2.23 (3H, s), 3.37 (2H, s), 3.63 (2H, s), 3.

76 (2H, s), 4.28 (2H, q, J = 7.1Hz), 7.01 (2H, s), 7.26— 7.28 (1H, m)

, 7.38 (1H, d, J = 8.1Hz), 7.89— 7.92 (1H, m), 8.02 (1H, d, J = 2. OHz

), 8.27 (1H, br s), 9.57 (1H, br s).

 MS m / z: 585 (M + H) +.

[0302] [Reference Example 29]

 (1) [2— (4-Methoxyphenol) —5-Methyl 2H— [1, 2, 3] Triazole—4-yl] methanol

[0303] [Chemical 84]

Reference Example 21 In the same manner as in (2) to (4), the title compound (0.468 g) was obtained as a yellow solid in the same manner as in (4), with the strength of hydrochloric acid (4-methoxyphenol) hydrazine (0.9 32 g).

 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.85 (3Η, s), 4.80 (2H, s)

 Three

 , 6.97 (2H, d, J = 9.1Hz), 7.89 (2H, d, J = 9.1Hz).

MS m / z: 220 (M + H) ⁺ .

[0305] (2) 4 Bromomethyl 2- (4-methoxyphenyl) 1 5-methyl 2H— [1, 2, 3] tri Azol

[0306] [Chemical 85]

Reference Example 15 In the same manner as in (1), the compound (0.460 g) force obtained in Reference Example 29- (1) also gave the title compound (0.458 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.85 (3Η, s), 4.58 (2H, s)

 Three

 , 6.96 (2H, d, J = 9.1Hz), 7.90 (2H, d, J = 9.1Hz).

MS m / z: 282 (M + H) ⁺ .

[0308] [Reference Example 30]

 (1) 2- [4 [[tert Butoxycarboromethyl- [2- (4-methoxyphenyl) -5-methyl 2H- [1, 2, 3] triazol-4-ylmethyl] amino] methyl] -2, 6 dimethyl Tylphenoxy] 2-methylpropionic acid ethyl ester

[0309] [Chemical 86]

Reference Example 17—In the same manner as (2), the compound (0.190 g) obtained in Reference Example 29— (2) and the compound (0.256 g) obtained in Reference Example 17— (1) The compound (0.391 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

.47 (9H, s), 2.18 (6H, s), 2.29 (3H, s), 3.23 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 3.84 (3H, s ), 3.85 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.95 (2H, d, J = 9.1Hz), 6.97 (2H, s), 7.90 (2H, d, J = 9.1 Hz). MS m / z: 581 (M + H) +.

[0311] (2) 2— [4 [[Carboxymethyl mono [2— (4-methoxyphenyl) 5-methyl 2H—

 [1, 2, 3] triazol-4-ylmethyl] amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0312] [Chemical 87]

Reference Example 17— In the same manner as in (3), the title compound (0.318 g) was obtained as a colorless solid from the compound (0.391 g) obtained in Reference Example 30— (1).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 19 (6H, s), 2.26 (3H, s), 3.60 (2H, s), 3.85 (3H, s), 3.99 (2H, s), 4.

11 (2H, s), 4.28 (2H, q, J = 7.1Hz), 6.97 (2H, d, J = 9.1Hz), 7.04 (2H

, s), 7.91 (2H, d, J = 9.1Hz).

MS m / z: 525 (M + H) ⁺ .

[0314] (3) 2- [4-[[[2- (N, acetohydrazino) -2-oxoethyl] [2- (4-methoxyethyl) -5-methyl-2-H- [1, 2, 3] triazole 4 [Ilmethyl] amino] methyl]

—2, 6-Dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0315] [Chemical 88]

[0316] Reference Example 30—Compound (0.150 g) obtained in (2) and acetohydrazine in the same manner as Reference Example 18. The title compound (0.145 g) was also obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 .05 (3H, s), 2.21 (6H, s), 2.23 (3H, s), 3.38 (2H, s), 3.63 (2H, s), 3.75 (2H, s), 3.85 (3H, s ), 4.29 (2H, q, J = 7.1Hz), 6.96 (2H, d, J = 9.1 Hz), 7.02 (2H, s), 7.91 (2H, d, J = 9.1 Hz), 8.09 (1H, br s), 9.58 (1H, br s).

 MS m / z: 581 (M + H) +.

[0317] [Reference Example 31]

 (l) [2- (3,4-dimethylphenol) -5-methyl-2H— [1,2,3] triazole-4-yl] methanol

[0318] [Chemical 89]

 [0319] Reference Example 21—Similarly to (2) to (4), the strength of hydrochloric acid (3,4 dimethylphenol) hydrazine (0.392 g) was reduced to the title compound (0.195 g) as a pale yellow solid. Obtained.

 'H-NMR (400MHz, CDCl) δ: 2.29 (3Η, s), 2.33 (3Η, s), 2.42 (3H, s)

 Three

 , 4.80 (2H, s), 7.20 (1H, d, J = 8.1 Hz), 7.68 (1H, dd, J = 2.2, 8.1 Hz)

, 7.77 (1H, d, J = 2.2Hz).

MS m / z: 218 (M + H) ⁺ .

[0320] (2) 4 Bromomethyl-2- (3,4 dimethylphenol)-5-methyl-2H- [1, 2, 3

] Triazole

[0321] [Chemical 90]

[0322] Reference Example 15—Similar to (1), Reference Example 31—Compound (0.190 g) force obtained in (1) The compound (0.177 g) was obtained as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.29 (3Η, s), 2.33 (3Η, s), 2.41 (3H, s)

 Three

 , 4.58 (2H, s), 7.19 (1H, d, J = 8.1 Hz), 7.69 (1H, dd, J = 2.2, 8.1 Hz)

, 7.77 (1H, d, J = 2.2Hz).

 MS m / z: 280 (M + H) +.

[0323] [Reference Example 32]

 (1) 3 — [(4-Fluorophenyl) hydrazono] —2— (Hydroxyimino) N-phenol butyramide

[0324] [Chemical 91]

[0325] In the same manner as in Reference Example 21- (2), the compound (0.958 g) obtained in Reference Example 21- (1) and hydrochloric acid (p-fluorophenyl) hydrazine (0.83 lg) force were also measured. A crude crude product was obtained.

 [0326] (2) 2- [4- (2-Methoxyethoxy) phenol] -5-Methyl-211— [1, 2, 3] triazo

 [0327] [Chem 92]

Reference Example 21—In the same manner as (3), the compound obtained in Reference Example 32— (1) was treated with methoxyethanol (15 ml) by adding potassium hydroxide (2. Og), A crude product of the title compound was obtained. [0329] (3) [2- [4- (2-Methoxyethoxy) phenol] -5-methyl-211— [1, 2, 3] triazole 4-yl] methanol

[0330] [Chemical 93]

[0331] In the same manner as in Reference Example 21- (4), the compound strength obtained in Reference Example 32- (2) was also the same as that of the title compound (0.

 928 g) was obtained as a brown solid.

 'H-NMR (400MHz, CDCl) δ: 2.41 (3Η, s), 3.47 (3Η, s), 3.77 (2H, t,

 Three

 J = 4.7Hz), 4.16 (2H, t, J = 4.7Hz), 4.79 (2H, s), 7.00 (2H, d, J = 8.8

Hz), 7.88 (2H, d, J = 8.8Hz).

MS m / z: 264 (M + H) ⁺ .

[0332] (4) 4-Bromomethyl-2- [4 (2-methoxyethoxy) phenol] -5-Methyl-2H

 [1, 2, 3] triazole

[0333] [Chemical 94]

Reference Example 15—In the same manner as in (1), the compound (0.924 g) force obtained in Reference Example 32- (3) also gave the title compound (0.558 g) as a colorless solid.

 'H-NMR (400MHz, CDCl) δ: 2.40 (3Η, s), 3.47 (3Η, s), 3.76— 3.79

 Three

 (2H, m), 4.15-4.17 (2H, m), 4.57 (2H, s), 7.00 (2H, d, J = 9.1Hz), 7.89 (2H, d, J = 9.1Hz).

MS m / z: 326 (M + H) ⁺ .

[0335] [Reference Example 33]

(1) 4- (2 Azidoethyl) -5-Methyl-2 Phenol-2H— [1, 2, 3] Triazol Le

 [0336] [Chemical 95]

[0337] 2— (5-Methyl-2-phenol-2H— [1, 2, 3] triazol-4-yl) ethanol (1.02 g) was dissolved in acetonitrile (10 ml) and cooled with ice water to triethylamine. (1.05 ml) and methanesulfonyl chloride (0.47 ml) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the oily residue was dissolved in N, N dimethylformamide (6 ml). Azimuth sodium (0.39 g) was added and stirred at room temperature for 18 hours. The reaction mixture was poured into about 200 ml of ice water, extracted with ethyl acetate, washed twice with saturated aqueous sodium bicarbonate, and then once with saturated brine. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (5% ethyl acetate-hexane) to obtain the title compound (0.58 g) as a colorless oil. .

 'H-NMR (400MHz, CDC1) δ: 2.36 (3Η, s), 2.96 (2Η, t, J = 7.1 Hz), 3

 Three

 67 (2H, t, J = 7.1 Hz), 7. 27— 7. 31 (1H, m), 7. 41— 7. 46 (2H, m), 7. 9 6- 7. 99 (2H , m).

 [0338] (2) [2— (5-Methyl-2-Ferrule 2H— [1, 2, 3] Triazol-4-yl) ethyl] strength rubamic acid tert butyl ester

[0339] [Chemical 96]

[0340] Reference Example 33— The compound (0.58 g) obtained in (1) was dissolved in ethyl acetate (15 ml), and 10% Radium monocarbon (0.10 g) and di-tert-butyl dicarbonate (0.999 g) were added, and the mixture was stirred under a hydrogen atmosphere for 24 hours. 10% palladium-carbon was filtered off and washed with ethyl acetate. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure. The residue was crystallized from hexane to give the title compound (0.6 lg) as a colorless solid.

 'H-NMR (400MHz, CDC1) δ: 1.44 (9Η, s), 2.34 (3Η, s), 2.87 (2H, t,

 Three

 J = 6.4Hz), 3.50-3.54 (2H, m), 4.91 (1H, br), 7.27—7.30 (1H, m),

7. 42- 7. 46 (2H, m), 7. 97 (2H, d, J = 7.6 Hz)

[0341] (3) 2— [2, 6 Dimethyl 4-— [[2— (5-Methyl-2 Fe-Lu 2H— [1, 2, 3] Triazol-4-yl) ethylamino] methyl] phenoxy] 2 Methylpropionic acid te rt-butyl ester

[0342] [Chemical 97]

Reference Example 33— The compound (0.60 g) obtained in (2) was dissolved in dichloromethane (2 ml), 4N hydrochloric acid-dioxane solution (10 ml) was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and 0.1N sodium hydroxide aqueous solution (20 ml) was added to the residue, followed by extraction with dichloromethane. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 2- (5-methyl-2phenol-2H— [1, 2, 3] triazol-4-yl) ethylamine (0.38 g) was dissolved as a yellow oil. I got it. This was dissolved in ethanol (10 ml), the compound (0.55 g) obtained in Reference Example 16- (1) was added, and the mixture was stirred at 85 ° C. for 2 hours. After cooling, sodium borohydride (0.092 g) was collected under cooling with ice water and stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate 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 (4% methanol / dichloromethane) to obtain the title compound (0.66 g) as a pale yellow oil. NMR-NMR (400MHz, CDC1) δ: 1.41 (6H, s), 1.51 (9H, s), 2.20 (6H, s)

 Three

 , 2.32 (3H, s), 2.87-2.91 (2H, m), 2.97—3.01 (2H, m), 3.72 (2H, s), 6.91 (2H, s), 7.27-7.29 (1H, m), 7.41 -7.48 (2H, m), 7.95—7.9 7 (2H, m).

 [0344] (4) 2— [4— [[Carboxymethyl- [2— (5-Methyl-2-Ferrule 2H— [1, 2, 3] Triazol-4-yl) -ethyl] amino] methyl] — 2, 6-Dimethylphenoxy] —2 Methylpropionic acid tert butyl ester

 [0345] [Chemical 98]

[0346] Reference Example 33—The compound (0.66 g) obtained in (3) was dissolved in a mixture of tetrahydrofuran (3 ml) and methanol (3 ml), and darioxylic acid (0.254 g) and triacetoxyborohydride. Sodium (0.585 g) was added and stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol: chloroform = 3: 7) to give the title compound (0.64 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.36 (6Η, s), 1.49 (9Η, s), 2.05 (6H, s)

 Three

 , 2.19 (3H, s), 2.86-2.91 (4H, m), 3.38 (2H, s), 3, 67 (2H, s), 6.71 (2H, s), 7.29 (1H, d, J = 7.5Hz ), 7.44 (2H, t, J = 7.8Hz), 7.98 (2H, d, J = 8.1 Hz).

MS m / z: 537 (M + H) ⁺ .

[0347] [Reference Example 34]

2- [4-[[[2- (Ν'-Acetylhydrazino) 2-oxoethyl] [2- (5 Methyl — 2 -Fu-Lu 2Η— [1, 2, 3] Triazol-4-yl) ethyl ] Amino] methyl] —2 , 6-Dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

[0348] [Chemical 99]

In the same manner as in Reference Example 18, the title compound (0.29 g) was obtained as a colorless oil from the compound (0.24 g) obtained in Reference Example 33- (4).

 'H-NMR (400MHz, CDC1) δ: 1.39 (6Η, s), 1.51 (9Η, s), 1.91 (3H, s)

 Three

 , 2.14 (6H, s), 2.17 (3H, s), 2.85 (4H, s), 3.31 (2H, s), 3.56 (2H, s), 6.82 (2H, s), 7.27-7.30 (1H, m ), 7.43 (2H, dd, J = 8.3, 7.5Hz), 7.9 6 (2H, d, J = 7.5Hz), 8.04 (1H, br s), 9.60 (1H, br).

[0350] [Reference Example 35]

 2- [2,6dimethyl 4-[[((3-methyl 1H pyrazole 4-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid tert butyl ester

[0351] [Chemical 100]

Reference Example 9— The compound (1.6 g) obtained in (2) was dissolved in dichloromethane (15 ml), trifluoroacetic acid (3 ml) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Residue The compound (1.63 g) obtained in Reference Example 16- (1) was added to the residue dissolved in ethanol (20 ml), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was cooled with ice water, sodium borohydride (0.316 g) was added, and the mixture was stirred for 4.5 hours. Brine was added to the reaction solution, and the mixture was extracted 3 times with acetyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black mouth form: methanol = 97: 3) to give the title compound (2.16 g) as a colorless oil.

[0353] 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.22 (6H, s)

 Three

 , 2.30 (3H, s), 3.68 (2H, s), 3.72 (2H, s), 6.93 (2H, s), 7.22 (1H, t, J = 8.3Hz), 7.41 (2H, t, J = 8.3 Hz), 7.63 (2H, d, J = 8.3Hz), 7.81 (1H, s).

MS m / z: 464 (M + H) ⁺ .

[0354] [Reference Example 36]

 (1) 2— [4 — [[tert-Butoxycarboromethyl- (3-Methyl-1-Ferru 1H

—Pyrazol-4-ylmethyl) amino] methyl] —2, 6-dimethylphenoxy] —2-methylpropionic acid ethyl ester

[0355] [Chemical 101]

In the same manner as in Reference Example 17- (2), the compound (0.759 g) obtained in Reference Example 17- (1) and the compound (0.455 g) obtained in Reference Example 4 were also treated with the title compound (0.770 g). g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (9H, s), 1

 Three

.47 (9H, s), 2.19 (6H, s), 2.28 (3H, s), 3.17 (2H, s), 3.66 (2H, s), 3.68 (2H, s), 4.28 (2H , q, J = 7.1Hz), 6.96 (2H, s), 7.20— 7.24 (1H, m), 7.39-7.43 (2H, m), 7.61— 7.64 (2H, m), 7.79 (1H, s). MS m / z: 550 (M + H) +.

[0357] (2) 2— [4 [[Carboxymethyl- (3-methyl-1-phenol 1H pyrazole-

4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionate ethinole ester

[0358] [Chemical 102]

Reference Example 17- In the same manner as in (3), the compound (0.765 g) force obtained in Reference Example 36- (1) also gave a crude product of the title compound (0.690 g).

[0360] [Reference Example 37]

 (1) Isoxazole 5 carboxylic acid (3-methyl 1-phenyl-1H-pyrazole 4-ylmethyl) amide

[0361] [Chemical 103]

Reference Example 9— The compound (0.710 g) obtained in (2) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10 ml), and isoxazole-5-carboxylic acid (0. 279 g), 1-ethyl-3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.568 g) and 1 -Hydroxybenzotriazole hydrate (0.454 g) was added and stirred at room temperature. reaction The solution was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 2) to give the title compound (0.573 g) as a colorless solid.

[0363] 'H-NMR (400MHz, CDC1) δ: 2.37 (3Η, s), 4.54 (2Η, d, J = 5.6Hz), 6

 Three

 .78 (1H, br s), 6.95 (1H, d, J = l.7Hz), 7.24— 7.28 (1H, m), 7.40— 7.45 (2H, m), 7.61— 7.64 (2H, m) , 7.89 (1H, s), 8.34 (1H, d, J = l.7H z).

MS m / z: 283 (M + H) ⁺ .

[0364] (2) Isoxazo One-Lou 5-ylmethyl- (3-Methyl-1 Hueru 1H Pyrazole

—4—Ilmethyl) amine

[0365] [Chemical 104]

[0366] Reference Example 37— The compound (0.276 g) obtained in (1) was dissolved in tetrahydrofuran (7 ml), and borane-dimethylsulfide complex (0.278 ml) was added thereto at 50 ° C. Stir for 3 hours. Water was added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours. Then, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and extracted three times with ethyl acetate. The organic layer was 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 (ethyl acetate: methanol = 99: 1) to give the title compound (0.068 g) as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 2.33 (3Η, s), 3.73 (2Η, s), 4.00 (2H, s)

 Three

 , 6.19 (1H, d, J = l.7Hz), 7.24 (1H, d, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.63 (2H, d, J = 7.6Hz), 7.81 (1H, s), 8.21 (1H, d, J = l.7Hz) .MS m / z: 269 (M + H) +.

[0367] [Reference Example 38]

2— [2, 6 Dimethyl-4 [(Methylcarbamoylmethylamino) methyl] phenoxy] 2-Methylpropionic acid ethyl ester

[0368] [Chemical 105]

Reference Example 16—In the same manner as (2), 2-amino-N-methylacetamide hydrochloride (1.12 g) and triethylamine (1.5 ml) were combined with the compound (2.38) obtained in Reference Example 11- (1). The title compound (1.89 g) was obtained as a colorless oil from g).

MS m / z: 337 (M + H) ⁺ .

 [0370] [Reference Example 39]

 (1) 2— [4 [[tert Butoxycarboromethyl] [2— (3, 4 Dimethylphenol) 5—Methyl 2H— [1, 2, 3] Triazol 4-ylmethyl] amino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0371] [Chem 106]

[0372] In the same manner as Reference Example 17- (2), the compound (0.207 g) obtained in Reference Example 31- (2) and the compound obtained in Reference Example 17- (1) (0.280 g) The title compound (0.359 g) was obtained as a colorless oil from g).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

.47 (9H, s), 2.18 (6H, s), 2.28 (3H, s), 2.30 (3H, s), 2.32 (3H, s), 3. 23 (2H, s), 3.68 (2H, s ), 3.86 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.98 ( 2H, s), 7.18 (1H, d, J = 8.3Hz), 7.69 (1H, dd, J = 2.2, 8.3Hz), 7.77 (

(1H, d, J = 2.2Hz).

MS m / z: 579 (M + H) ⁺ .

[0373] (2) 2— [4 [[Carboxymethyl- [2— (3,4-dimethylphenol) -5-Methyl-2

H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0374] [Chemical 107]

Reference Example 17 In the same manner as in (3), the compound (0.352 g) force obtained in Reference Example 39- (1) was also used to give the title compound (0.359 g) as a colorless solid.

 [0376] (3) 2— [4— [[[2— (N, -Acetylhydrazino) 2-oxoethyl] [2— (3,4 Dimethylphenol) -5-methyl-2H— [1, 2 , 3] Triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] —2-methylpropionic acid ethyl ester

[0377] [Chemical 108]

[0378] In the same manner as in Reference Example 18, the compound (0.318 g) obtained in Reference Example 39- (2) and acetohydrazide (0.054 g) were also mixed with the title compound (0.262 g) as a colorless oil. Got as.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

.05 (6H, s), 2.21 (3H, s), 2.23 (3H, s), 2.29 (3H, s), 2.33 (3H, s), 3. 38 (2H, s), 3.63 (2H, s), 3.76 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 7.02 (2H, s), 7.19 (1H, d, J = 8.3Hz), 7.69 (1H, dd, J = 2.2, 8.3Hz), 7.78 (1H, d, J = 2.2Hz), 8.13 (1H, br s), 9.57 (1H, br s).

MS m / z: 579 (M + H) ⁺ .

 [0379] [Reference Example 40]

 2- [4 -— [(2-Methoxyethylamino) methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0380] [Chem 109]

[0381] In the same manner as in Reference Example 20, the compound (2. Og) obtained in Reference Example 11- (1) (2-Og) and 2-methoxyethylamine (0.568 g) also had the same force as the title compound (2.53 g). Obtained as a colorless oil.

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

 Three

 18 (6H, s), 2.81 (2H, t, J = 4.9Hz), 3.35 (3H, s), 3.52 (2H, t, J = 4.9

Hz), 3.69 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.93 (2H, s).

MS m / z: 324 (M + H) ⁺ .

[0382] [Reference Example 41]

 2- [4 — [(2 Hydroxyethylamino) methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid tert butyl ester

[0383] [Chem 110]

[0384] In the same manner as in Reference Example 20, the compound (1.02 g) obtained in Reference Example 16- (1) and ethanolamine (0.230 ml) were mixed with the title compound (1.08 g) as a yellow oil. Obtained as a thing.

 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.82 (2H, t, J = 5.1Hz), 3.69 (2H, t, J = 5.1Hz), 3.73 (2H, s), 6.95 (2H, s).

 MS m / z: 338 (M + H) +.

[0385] [Reference Example 42]

 (1) (1— p-Tolyl— 1H— [1, 2, 3] triazol-4-yl) methanol

[0386] [Chem 111]

[0387] 1—p-Tolyl— 1H— [1, 2, 3] triazole-4-carboxylic acid ethyl ester (0.575 g) was dissolved in tetrahydrofuran (7 ml), and lithium aluminum hydride was cooled with ice water. (0.094 g) was added and stirred for 1.5 hours. Water was added to the reaction solution and filtered using Celite. The filtrate was extracted 3 times with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4 to ethyl acetate) to give the title compound (0.404 g) as a pale yellow solid.

 [0388] 'H-NMR (400MHz, CDC1) δ: 2.43 (3Η, s), 4.89 (2Η, s), 7.32 (2H, d

 Three

 , J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.94 (1H, s).

 MS m / z: 190 (M + H) +.

[0389] (2) 4-Bromomethyl- 1- p-tolyl- 1H- [1, 2, 3] triazole

[0390] [Chem 112]

Reference Example 15—In the same manner as in (1), the compound (0.400 g) force obtained in Reference Example 42— (1) was also used to obtain the title compound (0.205 g) as a pale yellow solid.

 'H-NMR (400MHz, CDCl) δ: 2.43 (3Η, s), 4.65 (2Η, s), 7.32 (2H, d

 Three

 , J = 8.6Hz), 7.60 (2H, d, J = 8.6Hz), 7.98 (1H, s).

[0392] [Reference Example 43]

 (1) 2- [4 -— [[tert-Butoxycarboromethyl- (1-p-tolyl-1H- [1,2,3] triazole-4-ylmethyl) amino] methyl] -2,6-dimethyl Phenoxy] —2-methyl propionate ethenore estenore

[0393] [Chem 113]

Reference Example 17—In the same manner as (2), Reference Example 42—Compound (0. lOOg) obtained in (2) and Reference Example 17—Compound obtained in (1) (0.166 g) The title compound (0.240 g) was also obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 1

 Three

 .47 (9H, s), 2.19 (6H, s), 2.42 (3H, s), 3.26 (2H, s), 3.72 (2H, s), 4.00 (2H, s), 4.28 (2H, q , J = 7.1Hz), 7.00 (2H, s), 7.31 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.6Hz), 7.89 (1H, br s).

 MS m / z: 551 (M + H) +.

[0395] (2) 2— [4— [[Carboxymethyl— (1— p-tolyl— 1H— [1, 2, 3] triazole 4 —Ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid ethynole ester

 [0396] [Chemical 114]

[0397] In the same manner as Reference Example 17- (3), the title compound (0.240g) containing impurities was removed from the compound (0.218g) obtained in Reference Example 43- (1) as a colorless oil. Got as.

 [0398] (3) 2- [4-[[[2- (Ν'—Acetylhydrazino) —2-Oxoethyl] — (1— ρ Tolyl — 1H— [1, 2, 3] triazol-4-ylmethyl ) Amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0399] [Chemical 115]

[0400] In the same manner as in Reference Example 18, the compound (0.196 g) obtained in Reference Example 43- (2) and acetohydrazide (0.059 g) were also mixed with the title compound (0.202 g) as a colorless oil. Got as.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 .06 (3H, s), 2.19 (6H, s), 2.42 (3H, s), 3.31 (2H, s), 3.69 (2H, s), 3.94 (2H, s), 4.28 (2H, q , J = 7.1Hz), 6.97 (2H, s), 7.32 (2H, d, J = 8.3 Hz), 7.65 (2H, d, J = 8.3Hz), 8.14 (1H, s), 8.26 (1H, br s), 9.60 (1H, br s).

MS m / z: 551 (M + H) +. [0401] [Reference Example 44]

 (1) 2, 2 Difluoro-N— (5-Methyl 2 phenol— 2H— [1, 2, 3] triazol 4-ylmethyl) acetamide

[0402] [Chem 116]

Reference Example 15— The compound (0.250 g) obtained in (3) was dissolved in dichloromethane (4 ml), 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 15 hours. Concentrate under reduced pressure, dissolve the residue in N, N dimethylformamide (6 ml), difluoroacetic acid (0.083 ml), 1 ethyl 3- (3 dimethylaminopropyl) carbodiimide hydrochloride (0.199 g), 1-hydroxybenzo Triazole hydrate (0.159 g) and N-methylmorpholine (0.286 ml) were added and stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and the residue was charged with aqueous sodium hydrogen carbonate and extracted three times with ethyl acetate. The extract was 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 (ethyl acetate: hexane = 1: 4-4: 1) to give the title compound (0.128 g) as a colorless solid.

[0404] 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 4.64 (2Η, d, J = 5.4Hz), 5

 Three

 .96 (1H, t, J = 54.2Hz), 6.82 (1H, br s), 7.33 (1H, t, J = 7.8Hz), 7.4

7 (2H, t, J = 7.8Hz), 7.98 (2H, d, J = 7.8Hz).

MS m / z: 267 (M + H) ⁺ .

[0405] (2) (2, 2 Difluoroethyl) mono (5-methyl-2 ferrue 2H— [1, 2, 3] triazole 4-ylmethyl) amine

[0406] [Chemical 117]

[0407] Reference Example 44— The compound (0.124 g) obtained in (1) was dissolved in tetrahydrofuran (4 ml), and borane-dimethylsulfide complex (0.133 ml) was added thereto at 50 ° C. Stir for 23 hours. Water was added to the reaction mixture, and the mixture was stirred at 60 ° C for 1 hour, saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. Further, the compound (0.066 g) obtained in Reference Example 44- (1) was reacted and treated in the same manner as above and extracted with ethyl acetate. The obtained two organic layers were combined, 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 (ethyl acetate: hexane = 1: 9 to 1: 1) to obtain the title compound (0.113 g) as a brown solid.

 [0408] 'H-NMR (400MHz, CDC1) δ: 2.39 (3Η, s), 3.06 (2Η, dt, J = 4, 2, 15.

 Three

 OHz), 3.98 (2H, s), 5.90 (1H, tt, J = 4, 2, 56.4Hz), 7.30 (1H, t, J = 7.6Hz), 7.45 ( 2H, t, J = 7.6Hz), 7.98—8.00 (2H, m).

MS m / z: 253 (M + H) ⁺ .

[0409] [Example 1]

 (1) 2— [4— [[[1— (4 Black Mole) 1-Methyl 1H Pyrazole 1-yl Methyl] furan 2-ylmethylamino] Methyl] phenoxy] —2-Methylpropionic acid Echinore Esther

 [0410] [Chemical 118]

[0411] The compound (362 mg) obtained in Reference Example 1 and the compound (317 mg) obtained in Reference Example 2- (2) were dissolved in N, N-dimethylformamide (8 ml), and cesium carbonate (489 mg) was added. Potassium (catalyst amount) was added, and the mixture was stirred at 80 ° C for 15 hours. Cool the reaction solution to room temperature and evaporate the solvent After adding an aqueous sodium hydrogen carbonate solution, the mixture was extracted 3 times with ethyl acetate. The organic layer 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 = 1: 6) to give the title compound (39 7 mg) as a colorless oil.

 iH—NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.3Hz), 1.58 (6H, s), 2

 Three

 26 (3H, s), 3.46 (2H, s), 3.54 (2H, s), 3.61 (2H, s), 4.22 (2H, q, J = 7.3 Hz), 6.16 ( 1H, d, J = 2.9Hz), 6.34 (1H, dd, J = 2.0, 2.9Hz), 6.80 (2H, d, J = 8.3Hz), 7.22 (2H, d, J = 8. 3Hz), 7.37 (2H, d, J = 8.8Hz), 7.40 (1H, d, J = 2.0Hz), 7.57 (2H, d, J = 8.8Hz), 7. 77 (1H, s).

MS m / z: 522 (M + H) ⁺ .

 [0412] (2) 2— [4 [[[1- (4-Chromium-Fuel) 3 Methyl 1H Pyrazole 4-yl Methyl] furan 2-ylmethylamino] methyl] phenoxy] —2-Methylpropionic acid

[0413] [Chemical 119]

[0414] Example 1— The compound (394 mg) obtained in (1) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and ethanol (4 ml), and 5N aqueous sodium hydroxide solution (453 μ 1) was added at room temperature. Stir for 20 hours. The reaction mixture was neutralized with concentrated hydrochloric acid (0.3 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 95: 5) and then purified again by preparative thin phase chromatography (20x20xlmm, developed in dichloromethane: methanol = 96: 4). Compound (269 mg) was obtained as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.46 (6Η, s), 2.13 (3Η, s), 3.40 (2

 6

H, s), 3.47 (2H, s), 3.55 (2H, s), 6.34 (1H, d, J = 2.9Hz), 6.42 (1H, dd, J = l. 7, 2. 9Hz), 6.79 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 7.49 (2H, d, J = 9.1Hz), 7.62 ( 1H, d, J = l. 7Hz), 7. 81 (2H, d, J = 9.1Hz), 8. 34 (1H, s). MS m / z: 494 (M + H) ⁺ .

 Elemental analysis value C H C1N O · 1 / 2H O

 27 28 3 4 2

 Calculated values: C, 64.47; H, 5.81; C1, 7.05; N, 8.35.

 measured value:. 64.46; H, 5.62; CI, 7.43; N, 8.28.

[0415] [Example 2]

 (1) 2— [4 [[Furan-2-ylmethylamino] [3-Methyl 1- (4 Trifluoromethyl)-1H Pyrazole-4-ylmethyl] amino] methyl] phenoxy] — 2 Methylpropionic acid ethyl ester

[0416] [Chemical 120]

 [0417] Example 1— In the same manner as (1), Reference Example 3—The compound obtained in (2) (275 mg) and Reference Example 2

 -The compound (317 mg) obtained in (2) also gave the title compound (503 mg) as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2

 Three

 .27 (3H, s), 3.47 (2H, s), 3.55 (2H, s), 3.62 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 6.17 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 1.7, 3.2Hz), 6.8 1 (2H, d, J = 8.8Hz), 7.22 (2H, d, J = 8.8Hz), 7.40 (1H, d, J = l.7Hz), 7.67 (2H, d, J = 8.6Hz), 7.76 (2H, d, J = 8.6Hz), 7.85 (1H, s).

 MS m / z: 556 (M + H) +.

 [0418] (2) 2— [4 — [[Furan-2-ylmethylamino] [3-Methyl 1- (4 trifluoromethyl)-1H pyrazole-4-ylmethyl] amino] methyl] phenoxy] — 2 methylpropionic acid

 [0419] [Chemical 121]

[0420] Example 2— The compound obtained in (1) (500 mg) was dissolved in a mixed solvent of tetrahydrofuran (4 ml) and methanol (4 ml), and 5N aqueous sodium hydroxide solution (360 μ1) was added at room temperature. Stir for 14 hours. The reaction mixture was neutralized with concentrated hydrochloric acid (0.15 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 94: 6), and then the aqueous ethanol was crystallized to obtain the title compound (158 mg) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.48 (6Η, s), 2.15 (3Η, s), 3.42 (2

 6

 H, s), 3.48 (2H, s), 3.56 (2H, s), 6.35 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz), 6.79 (2H, d , J = 8.6Hz), 7.23 (2H, d, J = 8.6Hz), 7

.63 (1H, d, J = 2.0Hz), 7.81 (2H, d, J = 8.6Hz), 8.01 (2H, d, J = 8.6Hz)

), 8.47 (1H, s).

MS m / z: 528 (M + H) ⁺ .

 Elemental analysis value C H FNO 1 / 4H O

 27 28 3 3 4 2

 Calculated values: C, 63.21; H, 5.40; F, 10.71; N, 7.90.

 measured value:. 63.21; H, 5.50; F, 10.42; N, 7.93.

[0421] [Example 3]

 (1) 2- [4 -— [[Furan-2-ylmethyl-((3-methyl-l-phenyl) 1 H-pyrazole-l-ylmethyl) amino] methyl] phenoxy] —2-methylpropionate

[0422] [Chemical 122]

In the same manner as in Example 1- (1), the compound (207 mg) obtained in Reference Example 4 and the compound (317 mg) obtained in Reference Example 2- (2) were also mixed with the title compound (424 mg). Obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2

 Three

.27 (3H, s), 3.47 (2H, s), 3.54 (2H, s), 3.61 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.16 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = l.7, 3.2Hz), 6.81 (2H, d, J = 8.3Hz), 7.20— 7.26 (3H, m), 7.39— 7.43 (3H, m), 7.63 (2

H, d, J = 7.6Hz), 7.81 (IH, s).

 MS m / z: 488 (M + H) +.

[0424] (2) 2— [4— [[Furan-2-ylmethyl- (3 methyl 1-phenol 1 H-pyrazol 4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid

[0425] [Chemical 123]

In the same manner as in Example 2- (2), the title compound (335 mg) was obtained as a colorless solid from the compound (420 mg) obtained in Example 3- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.48 (6Η, s), 2.14 (3Η, s), 3.41 (2

 6

 H, s), 3.47 (2H, s), 3.55 (2H, s), 6.34 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz), 6.79 (2H, d , J = 8.6Hz), 7.23 (IH, s), 7.23 (2H, d

, J = 8.6Hz), 7.42-7.46 (2H, m), 7.63 (1H, d, J = 2.0Hz), 7.76—7.7

9 (2H, m), 8.31 (IH, s).

 MS m / z: 458 (M-H) +.

 Elemental analysis value as C H NO '1Z4HO

 27 29 3 4 2

 Calculated value: C, 69.88; H, 6.41; N, 9.06.

 measured value:. 70.13; H, 6.38; N, 9.04.

[0427] [Example 4]

 (1) 2- [4-[[Furan-2-ylmethyl-((3-methyl-1-phenol) 1 H-pyrazole-l-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2-methylpropionate Ester

[0428] [Chemical 124]

In the same manner as in Example 1- (1), the compound (207 mg) obtained in Reference Example 4 and the compound (347 mg) obtained in Reference Example 5- (2) were also treated with the title compound (347 mg). 182 mg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2

 Three

 .28 (3H, s), 3.49 (2H, s), 3.55 (2H, s), 3.63 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 2.0, 3.2Hz), 6.79 (1H, ABq, J = 8.3Hz), 6.82 (1H, ABq, J = 8.3Hz) , 6.95 (1 H, s), 7.24 (1H, t, J = 7.4Hz), 7.39—7.43 (3H, m), 7.63 (2H, d, J = 8.3Hz), 7.81 (1H, s).

 MS m / z: 518 (M + H) +.

[0430] (2) 2— [4— [[Furan-2-ylmethyl-1- (3-methyl-1-phenol-1H 1-pyrazolu 4-ylmethyl) amino] methyl] -2-methoxyphenoxy] -2 —Methylpropionic acid

 [0431] [Chemical 125]

Example 2- In the same manner as in (2), the title compound (125 mg) was obtained as a colorless solid from the compound (178 mg) obtained in Example 4- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.41 (6Η, s), 2.15 (3Η, s), 3.43 (2

 6

H, s), 3.49 (2H, s), 3.58 (2H, s), 3.73 (3H, s), 6.35 (1H, d, J = 2.9Hz), 6.43 (1H, dd, J = l.7, 2.9Hz), 6.79 (2H, s), 6.95 (1H, s), 7.44 (1H, t, J = 8.6Hz), 7.63 (1H, d, J = l.7Hz), 7.77 (2H, d, J = 8.8Hz), 8.31 ( 1H, s).

 MS m / z: 488 (M-H) +.

 Elemental analysis value as C H NO '1Z4HO

 28 31 3 5 2

 Calculated values: C, 68.07; H, 6.43; N, 8.50.

 measured value:. 67.90; H, 6.44; N, 8.33.

 [0433] [Example 5]

 (1) 2— [4— [[[1— (4 Phylogen) 1-Methyl 1H Pyrazole 1-yl Methyl] Furan 2-ylmethylamino] Methyl] -2-Methoxyphenoxy] —2—Methylpropionate Ethenole Estenore

[0434] [Chemical 126]

In the same manner as in Example 1- (1), the compound (241 mg) obtained in Reference Example 1 and the compound (347 mg) obtained in Reference Example 5- (2) were also used in the title compound ( 255 mg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2

 Three

 .27 (3H, s), 3.48 (2H, s), 3.54 (2H, s), 3.62 (2H, s), 3.90 (3H, s), 4.

25 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 2.9Hz), 6.34 (1H, dd, J = l.7, 2

.9Hz), 6.79 (1H, ABq, J = 8.6Hz), 6.82 (1H, ABq, J = 8.6Hz), 6.94 (1

H, s), 7.37 (2H, d, J = 8.8Hz), 7.41 (1H, d, J = l.7Hz), 7.57 (2H, d, J

= 8.8Hz), 7.76 (1H, s).

 MS m / z: 551 (M + H) +.

[0436] (2) 2— [4— [[[1- (4-Cylphlophthal) 3 methyl 1H pyrazole 4-yl methyl] furan 2-ylmethylamino] methyl] —2-methoxyphenoxy ] —2-Methylpropionic acid

[0437] [Chemical 127]

In the same manner as in Example 2- (2), the title compound (151 mg) was obtained as a colorless solid from the compound (250 mg) obtained in Example 5- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.41 (6Η, s), 2.14 (3Η, s), 3.42 (2

 6

 H, s), 3.49 (2H, s), 3.58 (2H, s), 3.72 (3H, s), 6.35 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz ), 6.79 (2H, s), 6.95 (1H, s), 7.50 (2H, d, J = 9.1Hz), 7.63 (1H, d, J = 2.0Hz), 7.80 (2H, d, J = 9.1Hz) ), 8.35 (1H, s).

MS m / z: 522 (MH) ⁺ .

 Elemental analysis value C H C1N O · 1 / 4H O

 28 30 3 5 2

 Calculated values: C, 63.63; H, 5.82; CI, 6.71; N, 7.95.

 measured value:. 63.53; H, 5.90; CI, 6.53; N, 7.70.

[0439] [Example 6]

 (1) 2- [4 -— [[(3,5 Dimethyl 1-phenol-1H-pyrazole 4-methyl) furan-2-ylmethylamino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

[0440] [Chemical 128]

3, 5 Dimethyl 1-phenol -1H-pyrazole 4 Carbaldehyde (173 mg) and Reference Example 2-—Compound obtained in (2) (250 mg) was dissolved in dichloromethane (5 ml) and triacetoxyborohydride Sodium (334 mg) was added and stirred at room temperature for 15 hours. Saturated with reaction solution An aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with dichloromethane. The organic layer 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 = ₃ : 7) to give the title compound (323 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2

 Three

 .23 (3H, s), 3.26 (3H, s), 3.42 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 4.

23 (2H, q, J = 7.1Hz), 6.15 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = 2.0, 3

.2Hz), 6.79 (2H, d, J = 8.6Hz), 7.21 (2H, d, J = 8.6Hz), 7.30—7.34 (

1H, m), 7.38-7.45 (5H, m).

MS m / z: 502 (M + H) ⁺ .

[0442] (2) 2- [4-[[(3,5-Dimethyl-1-phenol- 1H-pyrazole-4-ylmethyl) furan 2-ylmethylamino] methyl] phenoxy] —2-methylpropionic acid

[0443] [Chemical 129]

Example 2- In the same manner as (2), the title compound (206 mg) was obtained as a colorless solid from the compound (320 mg) obtained in Example 6- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.45 (6Η, s), 2. 11 (3Η, s), 2.20 (3

 6

H, s), 3.35 (2H, s), 3.42 (2H, s), 3.51 (2H, s), 6.28 (1H, d, J = 2.9Hz), 6.40 (1H, dd, J = l.7, 2.9Hz), 6.77 (2H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz), 7.32-7.36 (1H, m), 7.43— 7.48 (4H, m), 7.60 (1H, s) .MS m / z: 472 (MH) ⁺ .

 Elemental analysis value as C H NO '1Z4HO

 28 31 3 4 2

 Calculated values: C, 70.35; H, 6.64; N, 8.79.

 measured value:. , 70.13; H, 6.69; N, 8.51.

[0445] [Example 7] (1) 2- [4 -— [[(3,5 Dimethyl 1-phenol-1H-pyrazole 4-methyl) furan-2-ylmethylamino] methyl] -2-methoxyphenoxy] -2-methylpropionate Ethenole Estenole

 [0446] [Chemical 130]

[0447] In the same manner as in Example 6- (1), the title compound was prepared from 3,5 dimethyl-1 ferlue 1H pyrazole-4-carbaldehyde (252 mg) and the compound obtained in Reference Example 5-(2) (437 mg). (304 mg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2

 Three

 .24 (3H, s), 2.27 (3H, s), 3.44 (2H, s), 3.50 (2H, s), 3.58 (2H, s), 3.80 (3H, s), 4.24 (2H, q , J = 7.1Hz), 6. 15 (1H, d, J = 2.9Hz), 6.33 (1H, dd, J = 2.0, 2.9Hz), 6.76— 6.82 (2H, m), 6.95 (1H, s) , 7.30- 7.34 (1H, m), 7.38-7.45 (5H, m).

 MS m / z: 532 (M + H) +.

 [0448] (2) 2— [4— [[(3, 5 Dimethyl 1-Fell 1H Pyrazole 4-Yrmethyl) Furan-2-ylmethylamino] Methyl] -2-Methoxyphenoxy] -2-Methylpropionic acid

 [0449] [Chemical 131]

 Example 2- In the same manner as (2), the title compound (238 mg) was obtained as a colorless solid from the compound (300 mg) obtained in Example 7- (1).

'H-NMR (400MHz, DMSO-d) δ: 1.40 (6Η, s), 2.12 (3Η, s), 2.20 (3 H, s), 3.37 (2H, s), 3.44 (2H, s), 3.54 (2H, s), 3.71 (3H, s), 6.29 (1H, d, J = 3.2Hz), 6.41 (1H, dd , J = 2.0, 3.2Hz), 6.76 (2H, s), 6.93 (2H, s), 7.32-7.36 (1H, m), 7.42— 7.48 (4H, m), 7.61 (1H, d, J = 2 OHz).

MS m / z: 502 (MH) ⁺ .

 Elemental analysis value as C H NO '1Z4HO

 29 33 3 4 2

 Calculated values: C, 68.55; H, 6.65; N, 8.27.

 measured value:. 68.35; H, 6.74; N, 7.93.

 [0451] [Example 8]

 (1) 2— [4 — [[[1— (4 Black Mole) 1-Methyl 1H Pyrazole 1-yl Methyl] thiazole-2-ylmethylamino] methyl] phenoxy] -2-Methylpropionic acid tert Butyl ester

[0452] [Chemical 132]

[0453] Reference Example 6-The compound (420 mg) obtained in (4) was dissolved in dichloromethane (8 ml), and 2-formylthiazole (931) and sodium triacetoxyborohydride (379 mg) were added to the room temperature. And stirred for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer 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 = 1: 2) to give the title compound (363 mg) as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.45 (9Η, s), 1.56 (6Η, s), 2.27 (3H, s)

 Three

 , 3.53 (2H, s), 3.62 (2H, s), 3.92 (2H, s), 6.86 (2H, d, J = 8.8Hz), 7. 24 (2H, d, J = 8.8Hz), 7.27 ( 1H, d, J = 3.4Hz), 7.37 (2H, d, J = 9.1Hz), 7.56 (2H, d, J = 9.1Hz), 7.68 (1H, d, J = 3.4Hz), 7.80 (1H, s).

MS m / z: 567 (M + H) ⁺ . (2) 2— [4— [[[1- (4 Chlorophthalate) 3 Methyl 1H Pyrazole 4 Yil Methyl] thiazole-2-yl Methylamino] Methyl] phenoxy] -2-Methylpropion

Example 8— The compound (360 mg) obtained in (1) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (lml) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 95: 5) and crystallized from ethanol-ether carbonate to give the title compound trifluoroacetate (15 lmg) as colorless. Obtained as a solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.50 (6Η, s), 2.14 (3Η, s), 6.83 (2

 6

 H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.3 Hz), 7. 53 (2H, d, J = 8.8 Hz), 7. 7 8- 7. 81 ( 4H, m), 8.45 (1H, br s).

 MS m / z: 511 (M + H) +.

[Example 9]

 (1) 2— [4 [[Furan 2-ylmethyl- [4-methyl-11] (1 trifluoromethyl-3-aminomethyl] amino] methyl] phenoxy] -2-methylpropionic acid ethynole Estenore

[0458] [Chemical 134]

Reference Example 7— Dissolve the compound obtained in (4) in dichloromethane (8 ml), add the compound (250 mg) obtained in Reference Example 2- (1) and sodium triacetoxyborohydride (449 mg), and add room temperature. so Stir for 19 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer 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 = 1: 19-1: 6) to give the title compound (494 mg) as a yellow oil.

 'H-NMR (400MHz, CDC1) δ: 1.24 (3Η, t, J = 7.1Hz), 1.58 (6H, s), 2

 Three

 .06 (3H, s), 3.46 (2H, s), 3.55 (2H, s), 3.62 (2H, s), 4.23 (2H, q, J = 7.1 Hz), 6.17 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6Hz), 6.87 (1H, s), 7.04 (1H, d, J = 2.0Hz), 7.24 (2H, d, J = 8.6Hz), 7.40 (2H, d, J = 8.6Hz), 7.40 (1H, s), 7.63 (2H, d, J = 8.6Hz).

MS m / z: 554 (M + H) ⁺ .

[0460] (2) 2— [4 [[Furan 2-ylmethyl- [4-methyl-11] (1 trifluoromethyl-3-ylmethyl] amino] methyl] phenoxy] —2-methylpropyl Lopionic acid

[0461] [Chemical 135]

Example 2- In the same manner as (2), the title compound (362 mg) was obtained as a yellow solid from the compound (490 mg) obtained in Example 9- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.45 (6Η, s), 1.97 (3Η, s), 3.37 (2

 6

 H, s), 3.46 (2H, s), 3.55 (2H, s), 6.32 (1H, d, J = 3.2Hz), 6.42 (1H, dd, J = 2.0, 3.2Hz), 6.78 (2H, d , J = 8.6Hz), 7.20 (2H, d, J = 8.6Hz), 7.25 (1H, s), 7.38 (1H, d, J = 2.5Hz), 7.62 (1H, d, J = 2.0Hz ), 7.74 (4 H, s).

MS m / z: 525 (MH) ⁺ .

Elemental analysis value CH FNO · 1 / 4H O Calculated values: C, 65. 59; H, 5. 60; N, 5. 28.

 measured value:. , 65.44; H, 5.45; N, 5.02.

[Example 10]

 (1) 2— [4 -— [[Furan-2-ylmethyl mono [1— (4 trifluoromethyl phenol) -mono 1H imidazole-4-ylmethyl] amino] methyl] phenoxy] -2 methyl propionic acid ethinole ester

 [0464] [Chemical 136]

[0465] Reference Example 7—In the same manner as (2), the force of 4 trifluoromethyl iodide benzene (109 μ 1) and the compound (267 mg) obtained in Reference Example 8 was also the same as that of the title compound ( 113 mg) was obtained as a yellow oil. MS m / z: 542 (M + H) ⁺ .

 [0466] (2) 2— [4— [[Furan-2-ylmethyl] [1— (4 trifluoromethylphenol) — 1H imidazole-4-ylmethyl] amino] methyl] phenoxy] -2 methylpropionic acid

[0467] [Chemical 137]

Example 2- In the same manner as (2), the title compound (31 mg) was obtained as a colorless solid from the compound (llOmg) obtained in Example 10- (1).

 iH—NMR (400MHz, DMSO d) δ: 1.44 (6H, s), 3.51 (4H, s), 3.60 (2

 6

H, s), 6.34 (1H, d, J = 3.2 Hz), 6.39 (1H, dd, J = 2.0, 3.2 Hz), 6.75 (2 H, d, J = 8.6 Hz ), 7.23 (2H, d, J = 8.6Hz), 7.58 (1H, d, J = 2.0Hz), 7. 7 2 (1H, s), 7. 85 (2H, d, J = 8.6Hz), 7.90 (2H, d, J = 8.6Hz), 8. 34 (1H, s MS m / z: 514 (M + H) ⁺ .

 Elemental analysis value C H FNO 1 / 2H O

 27 26 3 3 4 2

 Calculated values: C, 62.06; H, 5.21; F, 10.91; N, 8.04.

 measured value:. 62.21; H, 5. 16; F, 10.77; N, 7.83.

[Example 11]

 (1) 2- [2-Methoxy-1-4-[[((3-Methylenol 1-Phenol-1-H1Pyrazonole 4-Hydrmethyl) oxazole- 2-ylmethylamino] methyl] phenoxy]-2-methylpropionic acid ethyl Ester

[0470] [Chemical 138]

Example 8— Similar to (1), the compound (335 mg) obtained in Reference Example 9 (3) and oxazole-2-carbaldehyde (85 mg) were combined with the title compound (64 mg) in brown color. Obtained as an oil. 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2

 Three

 .28 (3H, s), 3.56 (2H, s), 3.64 (2H, s), 3.78 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.82 (2H, s), 6.96 (1H, s), 7.09 (1H, s), 7.20— 7.24 (1H, m), 7.39— 7.44 (2H, m), 7.61— 7.64 (3H, m), 7.86 ( 1H, s)

MS m / z: 519 (M + H) +.

[0472] (2) 2- [2-Methoxy-1-4-[[(3-Methyl-1-Phenol-1H-Pyrazole-1-4-Methyl) oxazole-2-ylmethylamino] methyl] phenoxy]-2-Methylpropionic acid

[0473] [Chemical 139]

In the same manner as in Example 2- (2), the title compound (56 mg) was obtained as a colorless solid from the compound (62 mg) obtained in Example 11- (1).

 'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 2.16 (3Η, s), 3.51 (2H, s)

 Three

 , 3.56 (2H, s), 3.70 (2H, s), 3.71 (3H, s), 6.75— 6.81 (2H, m), 6.94 (1H, s), 7. 19-7.24 (2H, m), 7.43 (2H, t, J = 8.6Hz), 7.74 (2H, d, J = 8.6Hz), 8.08 (1H, s), 8.29 (1H, s).

 MS m / z: 491 (M + H) +.

[0475] [Example 12]

 (1) 2- [4 -— [[furan-2-ylmethyl-1- (1-phenol 3 trifluoromethyl-1H —pyrazole-4-ylmethyl) amino] methyl] —2-methoxyphenoxy] -2-methyl Propionate Etenore Estenore

[0476] [Chemical 140]

 Reference Example 7—Similar to (4), from the compound (551 mg) obtained in Reference Example 10 (3), furan-2-ylmethyl mono (1-phenol 3 trifluoromethyl-1H-pyrazole 4 A crude product of ilmethyl) amine was obtained. From this and the compound (268 mg) obtained in Reference Example 5- (1), the title compound (603 mg) was obtained as a yellow oil in the same manner as in Example 7- (1).

 iH—NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 3

 Three

.59 (2H, s), 3.65 (2H, s), 3.67 (2H, s), 3.81 (3H, s), 4.23 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0, 3.2Hz), 6.80 -6.81 (2H, m), 6.97 (1H, s), 7.34— 7.37 (1H, m), 7.40- 7.42 (1H, m), 7.46-7.50 (2H, m), 7.67-7.70 (2H, m), 7.99 (1H, s).

MS: m / z: 572 (M + H) ⁺ .

 [0478] (2) 2— [4— [[Furan-2-ylmethyl-1- (1-phenol-3 Trifluoromethyl-1- 1H-pyrazole-4-ylmethyl) amino] methyl] -2-methoxyphenoxy] —2—Methyl propionic acid

 [0479] [Chemical 141]

 Example 2— In the same manner as in (2), the title compound (449 mg) was obtained as a yellow solid from the compound (571 mg) obtained in Example 12 (1).

 'H-NMR (400MHz, CDCl) δ: 1.39 (6Η, s), 3.51 (2Η, s), 3.59 (2H, s)

 Three

 , 3.61 (2H, s), 3.71 (3H, s), 6.32 (1H, d, J = 3.2Hz), 6.41 (1H, dd, J =

2.0, 3.2Hz), 6.75 (1H, d, J = 8.1Hz), 6.80 (1H, d, J = 8.1Hz), 6.96 (

1H, s), 7.39 (1H, t, J = 7.4Hz), 7.53 (2H, t, J = 7.4Hz), 7.61 (1H, d, J

= 2.OHz), 7.85 (2H, d, J = 7.4Hz), 8.64 (1H, s).

MS m / z: 544 (M + H) ⁺ .

 Elemental analysis value C H FNO 1 / 2H O

 28 28 3 3 5 2

 Calculated C: 60.86, H: 5.29, N: 7.60, F: 10.31.

 Actual value C: 60.78, H: 5.22, N: 7.61, F: 10.21.

 [0481] [Example 13]

(1) 2- [4 -— [[Furan-2-ylmethyl mono (3 methyl 1-phenol 1 H pyrazol 4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] -2-methylpropionic acid Echinore Estenore [0482] [Chemical 142]

[0483] In the same manner as in Example 1- (1), the title compound (312mg) was obtained from the compound (345mg) obtained in Reference Example 11- (2) and the compound (207mg) obtained in Reference Example 4. Obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 19 (6H, s), 2.26 (3H, s), 3.45 (2H, s), 3.50 (2H, s), 3.63 (2H, s), 4.

28 (2H, q, J = 7.1Hz), 6.17 (1H, d, J = 3.2Hz), 6.34 (1H, dd, J = 2.0,

3.2Hz), 6.96 (2H, s), 7.22 (1H, t, J = 7.6Hz), 7.38—7.43 (3H, m), 7

.63 (2H, d, J = 8.6Hz), 7.82 (1H, s).

 MS m / z: 516 (M + H) +.

[0484] (2) 2— [4— [[Furan-2-ylmethyl- (3 methyl 1-phenol 1 H-pyrazole-l-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] —2— Methyl propionic acid

[0485] [Chemical 143]

Example 2- In the same manner as (2), the title compound (224 mg) was obtained as a colorless solid from the compound (310 mg) obtained in Example 13- (1).

 'H-NMR (400MHz, CDCl) δ: 1.33 (6Η, s), 2.12 (3Η, s), 2.15 (6Η, s)

 Three

, 3.39 (2H, s), 3.43 (2H, s), 3.57 (2H, s), 6.34 (1H, d, J = 3.2Hz), 6.43 (1H, dd, J = 2.0, 3.2Hz), 6.95 (2H, s), 7.23 (1H, t, J = 7.4Hz), 7.44 (2H, t, J = 7.4Hz), 7.63 (1H, d, J = 2. OHz), 7.77 (2H, d, J = 8.6Hz) , 8.31 (1H, s).

 MS m / z: 488 (M + H) +.

 Elemental analysis value as C H NO 1/2 H O

 29 33 3 4 2

 Calculated C: 70.14, H: 6.90, N: 8.46.

 Found C: 70.34, H: 6.84, N: 8.56.

 [Example 14]

 (1) 2- [4-[[Furan-2-ylmethyl-1- (5-methyl-2-phenol-1H- [1, 2, 3] triazole 4-ylmethyl) amino] methyl] -2-Methoxyphenoxy ] —2-Methyl propionate Estenole Estenore

[0488] [Chemical 144]

[0489] The compound (125 mg) obtained in Reference Example 12 was dissolved in dichloromethane (4 ml), triethylamine (110 1) and methanesulfuryl chloride (56 μ 1) were added, and the mixture was stirred for 3 hours in an ice bath. did. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Ν, Ν dimethylformamide (4 ml), the compound of Reference Example 5- (2) (230 mg) and cesium carbonate (258 mg) were added, and the mixture was stirred at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer 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 = 1: 6) to give the title compound (149 mg) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.27 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2

 Three

.30 (3H, s), 3.58 (2H, s), 3.67 (2H, s), 3.72 (2H, s), 3.81 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.26 (1H, d, J = 3.2Hz), 6.35 (1H, dd, J = 2.0, 3 [9fl ^ [6 0] d ^ d ci ci l / ^ —

[^ [^ (^ / — — / —, (H [ε 'ζ' ΐ] — HS— / é — ^ — s) — ^ / — Be έ]] —] —

• ₊ (H + PV) I6 ^: ^Z / ^RA SPV

 • (ZHS '8 = Γ

'Ρ' HS) S6 'L' ( ^Ζ Η0 2 = Γ'Ρ 'Ηΐ) 9' L '( ^Z HS 8 = Γ' HS) S9 'L' (^ 'HI

) ζε ζ-εε 'L' ( ^S 'ΗΙ) 96 9' ( ^s ' HS) 8 9 '( ^z HS Έ' Ο 2 = Γ'ΡΡ ¾ΐ) ε

• 9 '( ^Ζ Η2 Έ = Γ'Ρ' HI) 9S 9 '( ^s ' U £) ZL Έ '( ^s ' Η2) 89 Έ '( ^s ΉΖ) £ 9 Έ'

( ^S 'Η2) ε9 · ε' ( ^s ¾ε) ζ 'ζ' ( ^s ¾9) ΐ · ΐ: 9 (\ οαο 'ZH OO ^) H NH _T

 . : (SraiOI) i¾J ^

[^ [i6 o] 邈 ΰ 1 ^ — S—

S— [^ [^ (^ / — — / —, (H [S 'Ζ' ΐ] — HS— / é — ^ — S) — ^ / — Be έ]] —] — [06W)]

• ₊ (H + PV) 6I9: ^z / ^ra SPV • (ZHS · 8 = ΓΡ 'Η2) 66' L '( ^Z HS · 8 = Γ' UZ) 'L' ( ^Ζ Η0 'Ζ = ί' Ρ ' ΗΙ)

0 'L' ^ 'ΗΙ) θε Ί- Ζ' L '( ^s ' ΗΙ) 96 9 '(^' HS) S8 '9-8Ζ 9' ( ^Ζ Η2

ZCCM0 / S00Zdf / X3d ε 6C6CT0 / 900Z OAV

In the same manner as in Example 14-1 (1), the title compound (236 mg) was obtained from the compound (125 mg) obtained in Reference Example 12 and the compound (230 mg) obtained in Reference Example 11- (2). Obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.26 (3H, s), 3.52 (2H, s), 3.68 (2H, s), 3.69 (2H, s), 4.

28 (2H, q, J = 7.1Hz), 6.26 (1H, d, J = 3.2Hz), 6.35 (1H, dd, J = 2.0,

3.2Hz), 6.96 (2H, s), 7.29 (1H, t, J = 8.3Hz), 7.41— 7.46 (3H, m), 7

.99 (2H, d, J = 8.3Hz).

MS m / z: 517 (M + H) ⁺ .

[0496] (2) 2— [4— [[Furan-2-ylmethyl- (5-methyl-2-phenyl) 2H— [1, 2, 3

] Triazole-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

[0497] [Chemical 147]

Example 2- In the same manner as (2), the title compound (192 mg) was obtained as a colorless solid from the compound (230 mg) obtained in Example 15- (1).

 'H-NMR (400MHz, CDCl) δ: 1.32 (6 Η, s), 2. 12 (6 Η, s), 2.19 (3 Η, s)

 Three

, 3.48 (2H, s), 3.645 (2H, s), 3.652 (2H, s), 6.36 (1H, d, J = 2.9Hz), 6.44 (1H, dd, J = l.7.2.9Hz), 6.92 (2H, s), 6.96 (1H, s), 7.33—7.3 7 (1H, m), 7.52 (2H, t, J = 8.3Hz), 7.64 (1H, d, J = l.7Hz), 7.93 ( (2H, d, J = 8.3Hz). MS m / z: 489 (M + H) +.

[0499] [Example 16]

 (1) 2— [4 — [[Furan-2-ylmethyl-1- [2- (3-Methyl-1-phenyl-1H-virazol-4-yl) ethyl] amino] methyl] -2,6 dimethylphenol 2] 2 methyl propionate ethenore estenore

[0500] [Chemical 148]

 [0501] Example 12- Reference Example 13- Compound (593mg) obtained in (3) in the same manner as (1) and Reference Example 11

 -The title compound (516 mg) was obtained as a yellow oil from the compound (264 mg) obtained in (1).

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

 Three

 16 (6H, s), 2.20 (3H, s), 2.64 (4H, s), 3.54 (2H, s), 3.71 (2H, s), 4.

28 (2H, q, J = 7.1Hz), 6.18 (1H, d, J = 3.2Hz), 6.33 (1H, dd, J = 2.0,

3.2Hz), 6.92 (2H, s), 7.20 (1H, t, J = 7.4Hz), 7.38—7.42 (3H, m), 7

.60 (2H, d, J = 8.8Hz), 7.65 (1H, s).

MS m / z: 529 (M + H) ⁺ .

[0502] (2) 2— [4 [[furan-2-ylmethyl-1- [2- (3-methyl-1-phenyl-1H-virazol-4-yl) ethyl] amino] methyl] —2, 6 dimethyl Phenoxy] 2-methyl propionic acid

[0503] [Chemical 149]

 Example 2- In the same manner as in (2), the title compound (441 mg) was obtained as a pale yellow solid from the compound (510 mg) obtained in Example 16- (1).

 'H-NMR (400MHz, CDCl) δ: 1.32 (6 Η, s), 2.07 (3 Η, s), 2.10 (6H, s)

 Three

 , 2.53-2.58 (4H, m), 3.50 (2H, s), 3.70 (2H, s), 6.32 (1H, d, J = 3.2 Hz), 6.42 (1H, dd, J = l.7, 3.2Hz ), 6.89 (2H, s), 7.21 (IH, t, J = 7.4 Hz), 7.41-7.45 (2H, m), 7.62 (1H, d, J = l.7Hz), 7.70 (2H, d, J = 8. 6Hz), 8.11 (IH, s).

MS m / z: 504 (M + H) ⁺ .

[0505] [Example 17]

 (1) 2- [4 -— [[Furan-2-ylmethyl-1- [2- (3-Methyl-1-phenyl-1H-virazol-4-yl) ethyl] amino] methyl] 2-methoxyphenoxy] 2 Methylpropionic acid ethyl ester

[0506] [Chemical 150]

Example 12- Reference Example 13- In the same manner as (1), the title compound (617 mg) was obtained from the compound (593 mg) obtained in (3) and the compound (264 mg) obtained in Reference Example 5- (1). Was obtained as a yellow oil.

'H-NMR (400MHz, CDCl) δ: 1.23 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2

 Three

.22 (3H, s), 2.65-2.68 (4H, m), 3.60 (2H, s), 3.71 (2H, s), 3.72 (3 [23ΐ ^] [2 ISO]

 / É ^ e 邈 be — — / — ½ — Ηΐ— / é— ΐ— ^ — ε)]] — — ^^ — S] —

 ismm ^ [π so]

• ₊ (H + V) SOS: ^z Z ^ra SPV • ( ^s ΉΙ) ΖΙ · 8 '( ^Ζ Η9' 8 = Γ 'Ρ ΉΖ) 69' L '( ^Ζ ΗΖ · Ι = Γ'Ρ' ΗΙ) 29 'L' ΉΖ) ^ 'L- \ V' L '( ^Ζ Η Ί =

Γ 'ΐ ΉΙ) ΙΖ' L '( ^s ' ΗΙ) Ι6 9 '( ^s ' Η2) 9Ζ9 '( ^Ζ Η6' Ζ ΊΊ = ΓΡΡ Ήΐ) Ζ ^

• 9 '( ^Ζ Η6' Ζ = ΓΡ ΉΙ) Ζ £ 9 '( ^s ' UZ) OL Έ' ( ^s ¾ε) 9 Έ '( ^s ' UZ) L Έ' ( ^s ' Η ^) 69 'Ζ' ( ^s ¾ε) 60 'Ζ' ( ^s 'Η9) ΐ · ΐ: 9 (\ θαθ' ZH 00 ^) H NH _T

 . : (^ I)

[ΐ3ΐ¾] [60S0]

 ΰ l ^ [^ :, é ^ ー S— [^ [^ [^ é (/ — one / —, 6c¾-HI— / é — ΐ / —ε) -Ζ-/ ^ ^ -Ζ- ^ Δ ^ -^-Ζ (Ζ) [80S0]

(U + W) Z £ 9- ^Z / ^ SPV

• ( ^s ' HI)

99 'L' ( ^Ζ Η9 8 = ΓΡ 'HS) 69' L '(^' U £) Z 'LS £' L '( ^Ζ Η · Ζ = Γ' HI

) 02 'L' ( ^Ζ ΗΖ · Ι = Γ'Ρ 'ΗΙ) 06 9' (^ 'Η2) Ι8' 9-9Ζ 9 '( ^Ζ Η6' Ζ Ί Ί =

Γ 'ΡΡ' ΗΙ) εε 9 '( ^Ζ Η6' Ζ = ΓΡ 'ΗΙ) ΖΙ 9' ( ^Ζ ΗΙ · = Γ '¾ ΉΖ) £ Ζ''( ^S ' Η

ZCCM0 / S00Zdf / X3d III 6C6CT0 / 900Z OAV

[0513] In the same manner as in Example 8- (1), the compound (250 mg) obtained in Reference Example 9- (3) and 2- (trifluoromethyl) benzaldehyde (83 μ 1) force were combined. (167 mg) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.25 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2

 Three

 .26 (3H, s), 3.46 (2H, s), 3.51 (2H, s), 3.74 (2H, s), 3.80 (3H, s), 4.

23 (2H, q, J = 7.1Hz), 6.82 (2H, s), 6.89 (1H, s), 7.22 (1H, t, J = 7.4H z), 7.31 (IH, t, J = 7.6Hz) , 7.41 (2H, t, J = 7.4Hz), 7.52 (1H, t, J = 7.

4Hz), 7.58-7.66 (3H, m), 7.76 (IH, s), 7.90 (1H, d, J = 7.6Hz).

MS m / z: 596 (M + H) +.

[0514] (2) 2 -— [2-Methoxy-1-4-[[(3-Methyl-1-phenol-1 IH-Pyrazole-1-4-methyl)-(2-trifluoromethylbenzyl) amino] methyl] phenoxy ] —2-Methylpropionic acid

[0515] [Chemical 153]

Example 2- In the same manner as in (2), the title compound (63 mg) was obtained as a colorless solid from the compound (163 mg) obtained in Example 18- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.39 (6Η, s), 2.13 (3Η, s), 3.43 (2

 6

H, s), 3.47 (2H, s), 3.68 (2H, s), 3.71 (3H, s), 6.78 (IH, d, J = 8.3Hz ), 6.83 (1H, d, J = 8.3Hz), 6.92 (1H, s), 7.22 (1H, t, J = 7.6Hz), 7.41

-7.45 (3H, m), 7.65— 7.70 (2H, m), 7.74 (2H, dd, J = l.2, 8.8Hz), 7

.96 (1H, d, J = 7.6Hz), 8.35 (1H, s).

 MS m / z: 568 (M + H) +.

 Elemental analysis value C H FNO 1 / 4H O

 31 32 3 3 4 2

 Calculated values: C, 65.08; H, 5.73; N, 7.34.

 Found: C, 64.97; H, 5.75; N, 7.10.

[0517] [Example 19]

 (1) 2- [2-Methoxy-1-4-[[(2-Methoxybenzyl)-(3-methyl-1-phenyl-

1H Pyrazole 4-methyl) amino] methyl] phenoxy] 2 methylpropionate ethinole ester

[0518] [Chemical 154]

 [0519] In the same manner as in Example 8- (1), the compound (250 mg) obtained in Reference Example 9- (3) and o-anisaldehyde (83 1) force, title compound (109 mg) Was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.1Hz), 1.54 (6H, s), 2

 Three

 .24 (3H, s), 3.47 (2H, s), 3.53 (2H, s), 3.61 (2H, s), 3.79 (3H, s), 3. 87 (3H, s), 4.23 (2H, q , J = 7.1Hz), 6.79— 7.28 (7H, m), 7.40 (2H, t, J = 7.6Hz), 7.49 (1H, d, J = 7.4Hz), 7.61 (2H, d, J = 7.6Hz ), 7.78 (1 H, s).

 MS m / z: 558 (M + H) +.

[0520] (2) 2- [2-Methoxy-1-4-[[(2-Methoxybenzyl)-((3-Methyl-11-Ferru 1H-Pyrazole-4-ylmethyl) amino] methyl] phenoxy] 2 Methylpropionic acid

[0521] [Chemical 155]

 Example 2- In the same manner as in (2), the title compound (59 mg) was obtained as a colorless oil from the compound (105 mg) obtained in Example 19- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.39 (6Η, s), 2.12 (3Η, s), 3.41 (2

 6

 Η, s), 3.46 (2Η, s), 3.51 (2H, s), 3.70 (3H, s), 3.73 (3H, s), 6.77 (1H, d, J = 8.1Hz), 6.82 (1H, d , J = 8.1Hz), 6.92— 6.95 (3H, m), 7.21 (1 H, t, J = 7.6Hz), 7.41-7.48 (3H, m), 7.74 (2H, d, J = 7.8Hz), 8.31 (1H, s).

 MS m / z: 530 (M + H) +.

 Elemental analysis value as C H NO -3 / 4HO

 31 35 3 5 2

 Calculated values: C, 68.55; H, 6.77; N, 7.74.

 Found: C, 68.59; H, 6.70; N, 7.53.

 [0523] [Example 20]

 (1) 2— [4 — [[(5 Black Mouth 3—Metinole 1—Phenol 1 1H Pyrazolone 1—4-Inole Methyl) Furan 2—Yylmethylamino] Methyl] Phenoxy] —2-Methylpropionic acid Ester

 [0524] [Chemical 156]

[0525] Example 6— In the same manner as (1), the compound (250 mg) obtained in Reference Example 2 (2) and 5 × 3 methyl 1-phenol 1H pyrazole 4 carbaldehyde (174 mg) ) The title compound (371 mg) was obtained as a colorless oil.

 iH—NMR (400MHz, DMSO d) δ: 1.24 (3H, t, J = 7.1Hz), 1.58 (6H,

 6

 s), 2.27 (3H, s), 3.47 (2H, s), 3.50 (2H, s), 3.59 (2H, s), 4.23 (2H, q, J = 7.1Hz), 6.19 (1H, d, J = 3.2Hz), 6.32 (1H, dd, J = 2.0, 3.2Hz), 6.80 (2H, d, J = 8.6Hz), 7.22 (2H, d, J = 8.6Hz), 7.34— 7.46 (4H , m), 7.50-7.53 (2H, m).

MS m / z: 521 (M + H) ⁺ .

 [0526] (2) 2— [4 — [[(5 Mouth 3-Methyl 1-Fel 1H 1 Pyrazole 1-Fil Methyl) Furan 2-ylmethylamino] Methyl] Phenoxy] —2-Methyl Propionic acid

[0527] [Chemical 157]

 Example 2- In the same manner as in (2), the title compound (268 mg) was obtained as a colorless solid from the compound (365 mg) obtained in Example 20- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.46 (6Η, s), 2.16 (3Η, s), 3.42 (2

 6

H, s), 3.45 (2H, s), 3.55 (2H, s), 6.31 (1H, d, J = 3.2Hz), 6.40 (1H, dd, J = 2.0, 3.2Hz), 6.77 (2H, d , J = 8.6Hz), 7.19 (2H, d, J = 8.6Hz), 7.40-7.45 (1H, m), 7.48—7.53 (4H, m), 7.61 (1H, d, J = 2.0 Hz) .MS m / z: 494 (M + H) ⁺ .

 Elemental analysis value C H C1N O · 1 / 4H O

 27 28 3 4 2

 Calculated values: C, 65.06; H, 5.76; CI, 7.11; N, 8.43.

 Found: C, 64.86; H, 5.69; CI, 7.10; N, 8.21.

[0529] [Example 21]

(1) 2- [2-Methoxy-1-4-[[((3-Methyl-1-phenol-1 1H-pyrazole-1-4-methyl)] ((3, 3, 3 trifluoropropyl) amino] methyl] phenoxy] —2—Methyl propionate [0530] [Chemical 158]

 [0531] In the same manner as in Example 8- (1), from the compound (120 mg) obtained in Reference Example 9- (3) and 3, 3, 3 trifluoropropionaldehyde (34 mg), the title was obtained. Compound (80 mg) was obtained as a colorless oil.

 iH—NMR (400MHz, CDCl) δ: 1.26 (3Η, t, J = 7.1Hz), 1.55 (6H, s), 2

 Three

 .22-2.28 (2H, m), 2.29 (3H, s), 2.73 (2H, t, J = 7.4Hz), 3.47 (2H, s), 3.52 (2H, s), 3.80 (3H, s), 4.24 (2H, q, J = 7.1Hz), 6.75 (1H, dd, J = 2.0, 8.1Hz), 6.82 (1H, d, J = 8.1Hz), 6.88 (1H, d, J = 2. OHz) , 7.23 (1H, t, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.60—7.63 (2H, m), 7.75 (1H, s).

MS m / z: 534 (M + H) ⁺ .

[0532] (2) 2— [2-Methoxy-1-4- [[(3-Methyl 1-phenol 1H 1-Pyrazole 4- 4-methyl)] (3, 3, 3 trifluoropropyl) amino] methyl] Phenoxy] -2-methylpropionic acid

[0533] [Chemical 159]

 Example 2- In the same manner as (2), the title compound (45 mg) was obtained as a colorless solid from the compound (75 mg) obtained in Example 21- (1).

H-NMR (400MHz, DMSO d) δ: 1.41 (6Η, s), 2. 19 (3H, s), 2.49— 2.54 (2H, m), 2.56— 2.67 (2H, m), 3.46 (2H, s), 3.51 (2H, s), 3.72 (3H, s), 6.79 (2H, s), 6.95 (1H, s) , 7.21— 7.25 (1H, m), 7.45 (2H, t, J = 8.6Hz), 7.75 (2H, d, J = 8.6Hz), 8.33 (1H, s).

 MS m / z: 506 (M + H) +.

[0535] [Example 22]

 (l) 2- [4-[[[3- (4-Fluorophenyl) 1 Phyl 1H Pyrazole 4-ylmethyl] furan-2-ylmethylamino] methyl] —2-methoxyphenoxy] —2-methyl Propionic acid ethyl ester

[0536] [Chemical 160]

In the same manner as in Example 9- (1), the title compound (207 mg) was obtained from the compound obtained in Reference Example 14- (2) and the compound obtained in Reference Example 5- (1) (92 mg) from yellow. Obtained as an oil.

 MS m / z: 598 (M + H) +.

[0538] (2) 2— [4 [[[3- (4 Fluorophenol) 1 Phenol 1H Pyrazole 4-ylmethyl] furan 2-ylmethylamino] methyl] -2-Methoxyphenoxy] -2-Meth Lupropionic acid

[0539] [Chemical 161]

Example 2- In the same manner as in (2), the title compound (164 mg) was obtained as a pale yellow solid from the compound (204 mg) obtained in Example 22- (1).

 iH—NMR (400MHz, DMSO—d) δ: 1.39 (6H, s), 3.53 (2H, s), 3.59 (3

 6

 H, s), 3.61 (2H, s), 3.63 (2H, s), 6.33 (1H, d, J = 2.9Hz), 6.42 (1H, dd, J = l.7, 2.9Hz), 6.73 (2H , s), 6.83 (1H, s), 7.20 (2H, t, J = 8.8Hz), 7.31 (1H, t, J = 7.6Hz), 7.51 (2H, d, J = 7.6Hz), 7.69 (1H , d, J = l.7 Hz), 7.88 (2H, d, J = 8.8Hz), 7.95—7.99 (2H, m), 8.56 (1H, s).

MS m / z: 570 (M + H) ⁺ .

 Elemental analysis value as C H FNO '3Z4HO

 33 32 3 5 2

 Calculated values: C, 67.97; H, 5.79; N, 7.21.

 Found: C, 68.14; H, 5.70; N, 7.19.

 [0541] [Example 23]

 (1) 2— [4 — [[Strengthened rubermoylmethyl- (5-methyl-2-ferro- 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2,6-dimethyl Phenoxy] —2-methyl propionate ethenore estenore

[0542] [Chemical 162]

[0543] Reference Example 15—Dissolve the compound (0.20 g) obtained in (4) and 2-bromoacetamide (0.095 g) in N, N —dimethylformamide (5 ml), and add potassium carbonate (0.095 g). And stirred at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 = 97: 3) to give the title compound (0.226 g) as a pale yellow oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 19 (6H, s), 2.24 (3H, s), 3.26 (2H, s), 3.60 (2H, s), 3.72 (2H, s), 4.29 (2H, q, J = 7.1Hz), 5.42 (1H, br s), 6.93 (2H, s), 7.14 (1H, br s), 7.31 (1H, t, J = 7.4Hz), 7.46 (2H, t, J = 7.4Hz), 7.99 (2H , t, J = 7.6H z).

MS m / z: 494 (M + H) ⁺ .

 [0544] (2) 2— [4— [[Strengthened rubermoylmethyl- (5-methyl-2-phenol—2H— [1, 2, 3] triazole-4-ylmethyl) amino] methyl] —2, 6-Dimethylphenoxy] —2-methylpropionic acid

 [0545] [Chemical 163]

In the same manner as in Example 1- (2), the compound (0.226 g) force obtained in Example 23- (1) was also used to give the title compound (0.143 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 13 (6H, s), 2.22 (3

 6

 H, s), 3.06 (2H, s), 3.57 (2H, s), 3.73 (2H, s), 6.99 (2H, s), 7.09 (1H, br s), 7.16 (1H, br s), 7.36 (1H, t, J = 7.4Hz), 7.53 (2H, t, J = 7.8Hz), 7.93 (2H, t, J = 7.8Hz).

 MS m / z: 466 (M + H) +.

 [0547] [Example 24]

 (1) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-phenol-2H- [1,2,3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 methylpropion Acid ethyl ester

[0548] [Chemical 164]

[0549] The compound (0.13 g) obtained in Reference Example 12 was dissolved in dichloromethane (4 ml). Stir for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Dissolve the residue in N, N-dimethylformamide (4 ml), add the compound (0.175 g) obtained in Reference Example 16- (2) and potassium carbonate (0.095 g), and stir at 70 ° C overnight. did. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 3: 2) to give the title compound (0.262 g) as a colorless oil.

 [0550] 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.24 (3H, s), 2.80 (3H, d, J = 5.1 Hz), 3.25 (2H, s), 3.58 (2H, s), 3.

69 (2H, s), 6.90 (2H, s), 7.23— 7.26 (1H, m), 7.31 (1H, t, J = 7.6Hz)

, 7.46 (2H, t, J = 7.6Hz), 7.99 (2H, d, J = 7.6Hz).

 MS m / z: 536 (M + H) +.

[0551] (2) 2— [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-phenol

-Lu-2H— [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] —2 methylpropionic acid

[0552] [Chemical 165]

Example 24— The compound (0.257 g) obtained in (1) was dissolved in dichloromethane (3 ml), 4N hydrochloric acid-dioxane solution (2 ml) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 92: 8) to give the title compound (0.186 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.13 (6Η, s), 2.21 (3

 6

 H, s), 2.57 (3H, d, J = 4.7Hz), 3.08 (2H, s), 3.56 (2H, s), 3.70 (2H, s

), 6.99 (2H, s), 7.35 (1H, t, J = 7.6Hz), 7.52 (2H, t, J = 7.6Hz), 7.58

(1H, q, J = 4.7Hz), 7.92 (2H, t, J = 7.6Hz).

MS m / z: 480 (M + H) ⁺ .

[0554] [Example 25]

 (1) 2— [4 — [[Dimethylcarbamoylmethyl- (5-methyl-2-phenol-2H— [1

, 2, 3] triazol-4-ylmethyl) amino] methyl] —2,6-dimethylphenoxy] —

2-Methylpropionic acid ethyl ester

[0555] [Chemical 166]

Reference Example 17—Compound obtained in (3) (0.250 g), dimethylamine hydrochloride (0.062 g), 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.116 g), 1-hydride Roxybenzotriazole hydrate (0.093g) and N-methylmorpholine (0.083ml) , N-dimethylformamide (4 ml) and stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 3: 2) to give the title compound (0.202 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.25 (3H, s), 2.82 (3H, s), 2.91 (3H, s), 3.33 (2H, s), 3.

62 (3H, s), 3.80 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.94 (2H, s), 7.29 (

1H, t, J = 7.5Hz), 7.45 (2H, t, J = 7.5Hz), 7.99 (2H, d, J = 7.5Hz).

MS m / z: 522 (M + H) ⁺ .

[0557] (2) 2— [4— [[Dimethylcarbamoylmethyl- (5-methyl-2-phenol-2H— [1

, 2, 3] triazol-4-ylmethyl) amino] methyl] —2,6-dimethylphenoxy] —

2-Methylpropionic acid

[0558] [Chemical 167]

In the same manner as in Example 1- (2), the compound (0.197 g) force obtained in Example 25- (1) was also used to give the title compound (0.167 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6 Η, s), 2. 11 (6 Η, s), 2.19 (3

 6

 H, s), 2.79 (3H, s), 2.83 (3H, s), 3.32 (2H, s), 3.58 (3H, s), 3.77 (2H, s), 6.90 (2H, s), 7.35 (1H , t, J = 7.6Hz), 7.52 (2H, d, J = 7.6Hz), 7. 92 (2H, d, J = 7.6Hz).

MS m / z: 494 (M + H) ⁺ .

[0560] [Example 26]

(1) 2— [2, 6-Dimethyl- 4 -— [[[5-Methyl- [1, 3, 4] Oxadiazo 2-L Rumethyl] — (5-Methyl-2-Fe-Lu 2H— [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] —2-methylpropionic acid ethyl ester

[0561] [Chemical 168]

Triphenylphosphine (0.244 g) was dissolved in tetrahydrofuran (5 ml), and hexachloroethane (0.186 g) was added with cooling with ice water, followed by stirring for 15 minutes. To this, triethylamine (0.259 ml) and the compound obtained in Reference Example 18 (0.160 g) were added, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 3: 2) to give the title compound (0.141 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 18 (6H, s), 2.28 (3H, s), 2.52 (3H, s), 3.64 (2H, s), 3.82 (2H, s), 3.

93 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.95 (2H, s), 7.29 (1H, t, J = 7.6H z), 7.45 (2H, t, J = 7.6Hz) , 7.99 (2H, d, J = 7.6Hz).

 MS m / z: 533 (M + H) +.

[0563] (2) 2- [2, 6-Dimethyl-4-[[[[5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl]-(5-Methyl-2-Fe-Lu 2H- [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid

[0564] [Chemical 169]

In the same manner as in Example 1- (2), the compound (0.135 g) force obtained in Example 26- (1) also gave the title compound (0.112 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3

 6

 H, s), 2.45 (3H, s), 3.60 (2H, s), 3.80 (2H, s), 3.90 (2H, s), 6.93 (2H, s), 7.36 (1H, t, J = 7.6Hz ), 7.53 (2H, t, J = 7.6Hz), 7.92 (2H, d, J = 7.6Hz).

 MS m / z: 505 (M + H) +.

[0566] [Example 27]

 (1) 2- [4-[[(3-Methoxypropyl) mono (5-methyl-2-phenyl) 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 Dimethylphenoxy] -2-methylpropionic acid ethyl ester

[0567] [Chemical 170]

Reference Example 15— The compound (0.10 g) obtained in (1) and the compound (0.134 g) obtained in Reference Example 19 were dissolved in N 2, N-dimethylformamide (4 ml), and potassium carbonate (0.066 g) was added. The mixture was stirred at 70 ° C for 3.5 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated saline and anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (0.202 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1

 Three

 .79 (2H, quint, J = 6.9Hz), 2.17 (6H, s), 2.26 (3H, s), 2.56 (2H, t, J = 6.9Hz), 3.25 (3H, s), 3.36 ( 2H, t, J = 6.6Hz), 3.48 (2H, s), 3.64 (2

H, s), 4.28 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.27 (1H, t, J = 6.4Hz), 7

.44 (2H, t, J = 7.6Hz), 7.98 (2H, t, J = 7.6Hz).

 MS m / z: 509 (M + H) +.

[0569] (2) 2— [4— [[(3-Methoxypropyl) -one (5-methyl-2-phenyl) 2H— [1, 2, 3

] Triazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid

[0570] [Chemical 171]

In the same manner as in Example 1- (2), the compound (0.202 g) force obtained in Example 27- (1) also gave the title compound (0.114 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.31 (6H, s), 1.70 (2H, quint, J = 6

 6

 1Hz), 2.12 (6H, s), 2.23 (3H, s), 2.47 (2H, t, J = 6.1Hz), 3.11 (3H, s), 3.29 (2H, t, J = 6.1Hz), 3.44 (2H, s), 3.62 (2H, s), 6.91 (2H, s), 7.35 (1H, t, J = 7.4Hz), 7.52 (2H, t, J = 7.6Hz), 7.92 (2H, t, J = 7.6Hz) Elemental analysis CH NO '1Z4HO

 27 36 4 4 2

Calculated value: C, 66.85; H, 7.58; N, 11.55. Found: C, 66.77; H, 7.63; N, 11.32.

[0572] [Example 28]

 (1) 2- [4-[[(2-Methoxyethyl)-(5-Methyl-2-Flu-Lu 211- [1, 2, 3] Triazol-4-ylmethyl) amino] methyl] -2, 6- Dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

[0573] [Chemical 172]

[0574] The compound (0.130 g) obtained in Reference Example 12 was dissolved in dichloromethane (4 ml). Stir for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (4 ml), the compound (0.169 g) obtained in Reference Example 20 and potassium carbonate (0.095 g) were added, and the mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 1: 4) to give the title compound (0.263 g) as a colorless oil.

 [0575] 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.20 (6Η, s)

 Three

 , 2.29 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (2H, s), 3.50 (3H, t, J = 5.9Hz), 3.56 (2H, s), 3.74 (2H , s), 6.93 (2H, s), 7.26— 7.29 (1H, m), 7.44 (2H, t, J = 8.6Hz), 7.99 (2H, d, J = 8. Hz).

MS m / z: 522 (M + H) ⁺ .

[0576] (2) 2— [4— [[(2-Methoxyethyl) mono (5-methyl-2-phenol-2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6-dimethylphenoxy] -2-methyl Lupropionic acid

[0577] [Chemical 173]

Example 24-—In the same manner as (2), the compound (0.258 g) force obtained in Example 28- (1) was also used to give the title compound (0.175 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.30 (6Η, s), 2. 11 (6Η, s), 2.23 (3

 6

 H, s), 2.62 (2H, t, J = 5.9Hz), 3.18 (3H, s), 3.44 (2H, t, J = 5.9Hz), 3.49 (2H, s), 3.69 (2H, s ), 6.91 (2H, s), 7.34 (1H, t, J = 7.6Hz), 7.51 (2H, t, J = 7.6Hz), 7.91 (2H, t, J = 7.6Hz).

 Elemental analysis value as C H NO '1Z4HO

 26 34 4 4 2

 Calculated value: C, 66.29; H, 7.38; N, 11.89.

 Found: C, 66.37; H, 7.44; N, 11.45.

 [0579] [Example 29]

 (1) 2- [4 -— [[(2-Methoxymethyl)-(5-methyl-2-p-tolyl-2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2 6-Dimethylphenoxy] -2-methylpropionic acid tert-butyl ester

 [0580] [Chemical 174]

Reference Example 21— The compound (0.12 g) obtained in (5) and the compound (0.174 g) obtained in Reference Example 20 were dissolved in N 2, N-dimethylformamide (4 ml), and potassium carbonate ( 0.075g), 70 ° C For 3 days. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 1: 6) to give the title compound (0.242 g) as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.20 (6H, s)

 Three

 , 2.29 (3H, s), 2.38 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.29 (3H, s), 3.

50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.73 (2H, s), 6.93 (2H, s), 7.23 (2

H, d, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz).

MS m / z: 537 (M + H) ⁺ .

[0582] (2) 2 -— [4 -— [[(2-Methoxymethyl)-(5-methyl-2-p-tolyl-2H— [1, 2, 3] triazole-4-ylmethyl) amino] methyl] — 2, 6-Dimethylphenoxy] —2-methylpropionic acid

[0583] [Chemical 175]

Example 24—In the same manner as in (2), the compound (0.242 g) strength obtained in Example 29- (1) was also used to obtain the title compound (0.217 g) as a light brown solid.

 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3

 6

 H, s), 2.34 (3H, s), 2.63 (2H, t, J = 5.9Hz), 3.19 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3.50 (2H, s), 3.68 (2H, s), 6.92 (2H, s), 7.32 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz).

 MS m / z: 481 (M + H) +.

[0585] [Example 30]

(1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl (5 Methyl 2- p-Tolyl-2H— [1, 2, 3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 Methylpropionic acid tert butyl ester

[0586] [Chemical 176]

[0587] Reference Example 21- Compound (0.120 g) obtained in (5) and Reference Example 16- (2) (0.18 lg) were dissolved in N, N dimethylformamide (4 ml), and potassium carbonate ( 0.075 g) was added and stirred at 70 ° C for 3 days. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 3: 2) to give the title compound (0.248 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.24 (3H, s), 2.39 (3H, s), 2.80 (3H, d, J = 5.1Hz), 3.25 (3H, s), 3.

57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.26 (2H, d, J = 8.3Hz), 7.87 (

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

 MS m / z: 550 (M + H) +.

[0588] (2) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2-p-tolyl-2H- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] phenoxy]- 2 Methylpropionic acid

[0589] [Chemical 177]

Example 24—In the same manner as in (2), the title compound (0.209 g) was obtained as a colorless solid from the compound (0.248 g) obtained in Example 30- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.21 (3

 6

 H, s), 2.35 (3H, s), 2.58 (3H, d, J = 4.7Hz), 3.08 (3H, s), 3.56 (2H, s), 3.57 (2H, s), 3.69 (2H, s ), 7.00 (2H, s), 7.33 (2H, d, J = 8.3Hz), 7.58 (1H, q, J = 4.7Hz), 7.81 (2H, d, J = 8.3Hz).

MS m / z: 494 (M + H) ⁺ .

 [0591] [Example 31]

 (1) 2— [2, 6-Dimethyl-4-[[((5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(5-Methyl-2-p-tolyl-2H- [1 , 2, 3] triazole—4-methyl) amino] methyl] phenoxy] —2-methylpropionic acid ethyl ester

 [0592] [Chemical 178]

[0593] Reference Example 21— Compound (0.120 g) obtained in (5) and Reference Example 22— Compound (0.120 g) obtained in (5) were dissolved in N, N-dimethylformamide (4 ml), and potassium carbonate was dissolved. (0.055 g) was added and stirred at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was 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 (ethyl acetate: hexane = 2: 3) to give the title compound (0.149 g) as a colorless oil.

 [0594] 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

18 (6H, s), 2.27 (3H, s), 2.38 (3H, s), 2.52 (3H, s), 3.65 (2H, s), 3.82 (2H, s), 3.93 (2H, s ), 4.29 (2H, q, J = 7.1Hz), 6.96 (2H, s), 7.24 ( 2H, d, J = 8.6Hz), 7.86 (2H, d, J = 8.6Hz).

MS m / z: 547 (M + H) ⁺ .

[0595] (2) 2- [2, 6 Dimethyl 4 -— [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(5-Methyl-2-p-tolyl-2H- [1 , 2, 3] triazole-4-methyl) amino] methyl] phenoxy] -2-methylpropionic acid

[0596] [Chemical 179]

In the same manner as in Example 1- (2), the compound (0.145 g) force obtained in Example 31- (1) was also used to obtain the title compound (0.134 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.13 (6Η, s), 2.21 (3

 6

 H, s), 2.35 (3H, s), 2.45 (3H, s), 3.59 (2H, s), 3.78 (2H, s), 3.89 (2H, s), 6.93 (2H, s), 7.32 (2H , d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz) .MS m / z: 519 (M + H) +.

[0598] [Example 32]

 (1) 2- [4-[[(3-Methoxypropyl) mono (5-methyl-2-p-tolyl 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 dimethyl Phenoxy] -2-methylpropionic acid ethyl ester

[0599] [Chemical 180]

Example 27— In the same manner as (1), the force of the compound (0.138 g) obtained in Reference Example 21- (5) and the compound (0.176 g) obtained in Reference Example 19 Compound (0.218 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1

 Three

 .79 (2H, quint, J = 6.9Hz), 2. 18 (6H, s), 2.26 (3H, s), 2.38 (3H, s), 2

.55 (2H, t, J = 6.9Hz), 3.25 (3H, s), 3.35 (2H, t, J = 6.9Hz), 3.47 (2H

, s), 3.63 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.23 (2H, d, J

= 8.6Hz), 7.85 (2H, d, J = 8.6Hz).

MS m / z: 523 (M + H) ⁺ .

[0601] (2) 2— [4— [[(3-Methoxypropyl) mono (5-methyl-2-p-tolyl) 2H— [1, 2, 3

] Triazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid

[0602] [Chemical 181]

[0603] In the same manner as in Example 1- (2), the title compound (0.163 g) was obtained as a colorless solid from the compound (0.213 g) obtained in Example 32- (1). This was dissolved in 4N hydrochloric acid-dioxane solution and concentrated to dryness under reduced pressure to obtain the hydrochloride of the title compound as a colorless solid. 'H-NMR (400MHz, DMSO-d) δ: 1.36 (6Η, s), 2.17 (6Η, s), 2.28 (3

 6

 Η, s), 2.37 (3Η, s), 3.10—3.21 (5H, m), 3.35—3.40 (6H, m), 4.30—4.34 (2H, m), 4.40—4.44 (2H, m), 7.25 ( 2H, s), 7.39 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6 Hz).

 Elemental analysis value as C H NO 'HC1'3 / 4H O

 28 38 4 4 2

 Calculated values: C, 61.75; H, 7.50; CI, 6.51; N, 10.29.

 Found: C, 61.96; H, 7.57; CI, 6.29; N, 10.09.

MS m / z: 495 (M + H) +. [0604] [Example 33]

 (1) 2- [4-[[(2-Methoxyethyl)-(5-methyl-2-m-tolyl-2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 Dimethylphenoxy] -2-methylpropionic acid tert butyl ester

 [0605] [Chemical 182]

[0606] In the same manner as in Example 29- (1), the compound (0.1Og) obtained in Reference Example 23- (2) and the compound (0.132g) obtained in Reference Example 20 were also subjected to the same effect. The compound (0.116 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s)

 Three

 , 2.33 (3H, s), 2.42 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 (2H, t, J = 5.9Hz), 3.55 ( 2H, s), 3.74 (2H, s), 6.93 (2H, s), 7.09 (1 H, d, J = 8.1Hz), 7.31 (1H, t, J = 8.1Hz), 7.78 (1H, d, J = 8.1Hz), 7.8 2 (1H, s).

MS m / z: 537 (M + H) ⁺ .

[0607] (2) 2— [4 — [[(2-Methoxyethyl) mono (5-methyl-2-m-tolyl) 2H— [1, 2, 3

] Triazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid

[0608] [Chemical 183]

Example 24—Similar to (2), Example 33—Compound (0. llOg) force obtained in (1) The compound (0.071 g) was obtained as a colorless solid. This was dissolved in 4N hydrochloric acid-dioxane solution and concentrated to dryness under reduced pressure to obtain the hydrochloride of the title compound as a colorless solid. Elemental analysis value as CH NO 'HC1'5 / 4H O

 27 36 4 4 2

 Calculated values: C, 59.42; H, 7. 19; C1, 6.75; N, 10.66.

 Found: C, 59.59; H, 7.09; CI, 6.92; N, 10.39.

MS m / z: 537 (M + H) ⁺ .

[0610] [Example 34]

 (1) 2- [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2m-tolyl-2H- [1,2,3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 methylpropionic acid tert butyl ester

[0611] [Chemical 184]

[0612] In the same manner as in Example 30- (1), the compound (0.100g) obtained in Reference Example 23- (2) and the compound (0.137g) obtained in Reference Example 16- (2) were also subjected to the same effect. The compound (0.180 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.24 (3H, s), 2.43 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.25 (3H, s), 3.57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.13 (1H, d, J = 8.1 Hz), 7.22 (1H, d, J = 4.9 Hz), 7.34 (1H, t, J = 8.1 Hz), 7.79 (1H, d, J = 8.1Hz), 7.82 (1H, s).

 MS m / z: 550 (M + H) +.

[0613] (2) 2— [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (5-methyl-2 m-tolyl-2H- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] phenoxy] -2 Methyl propionic acid [0614] [Chemical 185]

Example 24—In the same manner as in (2), the compound (0.175 g) force obtained in Example 34- (1) was also used to give the title compound (0.132 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.21 (3

 6

 H, s), 2.40 (3H, s), 2.58 (3H, d, J = 4.7Hz), 3.09 (2H, s), 3.56 (2H, s), 3.70 (2H, s), 7.00 (2H, s ), 7.17 (1H, d, J = 7.8Hz), 7.40 (1H, t, J = 7.8Hz), 7.60 (1H, q, J = 4.7Hz), 7.72 (1H, d, J = 7.8Hz), 7.76 (IH, s).

MS m / z: 494 (M + H) ⁺ .

 [0616] [Example 35]

 (1) 2— [2, 6 Dimethyl 4 -— [[[5-Methyl- [1, 3, 4] Oxadiazo 2-ylmethyl] — (5-Methyl 2- m-Tolyl— 2H— [1, 2 , 3] Triazol-4-ylmethyl) amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

 [0617] [Chemical 186]

Example 26- In the same manner as in (1), the title compound (0.173 g) was obtained as a colorless oil from the compound (0.192 g) obtained in Reference Example 24- (3).

'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 [88ΐ ^] [S290] d ^ d ci ci ci l / ^ ー [^ :, — ^ — 9 's— [^ [^ (^ ^ — — / —, (Η [ε

'Ζ Ί] -Η2- ίί4-^-2- ^ -9)-(^ ΰ ₀ ^ ^: 4 ^ -ε)]]-^]-2 (Ι)

[9S zone number] [2290] • ₊ (H + PV) 8I9: ^z / ^ra SPV • ( ^s 'ΗΙ) 9Ζ' L '( ^Ζ Η8' Ζ = Γ 'Ρ' ΗΙ) ΙΖ

'L' ( ^Ζ Η8 · = Γ'ΐ 'Ηΐ) 0 Ί' ( ^Ζ Η8 · Ζ = ΓΡ 'ΗΙ) ΖΙ' L '( ^s ' HS) S6 9' ( ^s ' HS) 06 Έ '( ^s 'Η2) 6Ζ Έ' ( ^s ' Η2) 69 Έ '( ^s ' HS) S' Ζ '( ^s ' HS) 6S' Ζ '( ^s ' Η

£) ΙΖ 'Ζ' ( ^s ' Η9) 2Ι 'Ζ' ( ^s ' H9) SS · ΐ: 9 (P-OSWa 'zH OO ^) H NH _T

oM ^ m ^ ^ ( ^§ χοχ Ό) 呦

[Ζ8ΐ ^] [0290] 邈 S [^ :, ye [^ [^ (^

 / — — / —, ΊΗ [ε 'z' x] -HS- fi4-ra-2- ^ -g)-[^

S— / —,

[6Ϊ90]

• ₊ (H + S: ^z Z ^ra SPV

• ^(s' HI) S8

'L' ( ^Z HI 8 = ΓΡ 'ΗΙ) 8 ^Ζ ' L '( ^Ζ ΗΙ 8 = Γ' HI) SS 'L' ( ^Ζ ΗΙ 8 = ΓΡ 'HI

) 11 'L' ( ^s ' HS) 96 9 '( ^Ζ ΗΙ · Ζ = Γ¾' HS) 6S '( ^s ' HS) 6 Έ' ( ^s ' HS) S8

Έ '( ^s ' HS) 99 Έ '( ^s ' HS) S9 '( ^s ' HS) S '( ^s ' HS) 8S '( ^s ' H9) 8I

ZCCM0 / S00Zdf / X3d 6C6CT0 / 900Z OAV

[0624] In the same manner as in Example 27- (1), the compound (0.138 g) obtained in Reference Example 23- (2) and the compound (0.176 g) obtained in Reference Example 19 were also combined with the title compound. Product (0.239 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 1

 Three

 .79 (2H, quint, J = 6.6Hz), 2.17 (6H, s), 2.26 (3H, s), 2.42 (3H, s), 2.55 (2H, t, J = 6.6Hz), 3.25 (3H, s), 3.36 (2H, t, J = 6.6Hz), 3.47 (2H, s), 3.63 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s ), 7.09 (1H, d, J = 7.8Hz), 7.31 (1H, d, J = 7.8Hz), 7.78 (1H, d, J = 7.8Hz), 7.81 (1H, s).

MS m / z: 523 (M + H) ⁺ .

[0625] (2) 2 -— [4 -— [[(3-Methoxypropyl) -one (5-methyl-2-m-tolyl-one 2H— [1, 2,

3] Triazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid

[0626] [Chemical 189]

In the same manner as in Example 1- (2), the compound (0.234 g) force obtained in Example 36- (1) also gave the title compound (0.20 lg) as a colorless solid. This was dissolved in 4N hydrochloric acid-dioxane solution and concentrated to dryness under reduced pressure to obtain the hydrochloride of the title compound as a colorless solid. NMR-NMR (400MHz, DMSO d) δ: 1.36 (6H, s), 2.17 (6H, s), 2.29 (3

 6

 H, s), 2.42 (3H, s), 3.15—3.23 (5H, m), 3.35—3.41 (6H, m), 4.32 (2H, br s), 4.43 (2H, d, J = 3.9Hz), 7.26 (2H, s), 7.26 (1H, d, J = 7.8 Hz), 7.47 (1H, t, J = 7.8Hz), 7.79 (1H, d, J = 7.8Hz), 7.83 (1H, s). Elemental analysis value as CH NO 'HC1'3 / 4H O

 28 38 4 4 2

 Calculated values: C, 61.75; H, 7.50; CI, 6.51; N, 10.29.

 Found: C, 61.90; H, 7.59; CI, 6.40; N, 10.13.

 MS m / z: 495 (M + H) +.

[0628] [Example 37]

 (1) 2— [4— [[[2— (4 Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole —4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] — 2-Methylpropionic acid tert-butyl ester

[0629] [Chemical 190]

 [0630] In the same manner as in Example 30- (1), the compound (0.120 g) obtained in Reference Example 25- (2) and the compound (0.153 g) obtained in Reference Example 16- (2) were also subjected to the same effect. The compound (0.151 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.22 (6H, s)

 Three

 , 2.23 (3H, s), 2.80 (3H, d, J = 5.1 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.89 (2H, s) , 7.18 (1H, br s), 7.43 (2H, d, J = 8.8Hz), 7.9 4 (2H, d, J = 8.8Hz).

MS m / z: 570 (M + H) ⁺ .

[0631] (2) 2— [4— [[[2— (4 Chlorophenyl) -5-methyl-2H— [1, 2, 3] triazole —4-ylmethyl] methylcarbamoylmethylamino] methyl] — 2, 6 Dimethylphenol 2] 2-Methylpropionic acid

[0632] [Chemical 191]

Example 24— In the same manner as (2), the title compound (0. llOg) was obtained as a colorless solid from the compound (0.145 g) obtained in Example 37 (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (6Η, s), 2.21 (3

 6

 H, s), 2.58 (3H, d, J = 5.1Hz), 3.09 (2H, s), 3.57 (2H, s), 3.71 (2H, s), 6.99 (2H, s), 7.58-7.59 (1H , m), 7.59 (2H, d, J = 8.8Hz), 7.93 (2 H, d, J = 8.8Hz).

MS m / z: 514 (M + H) ⁺ .

[0634] [Example 38]

 (1) 2— [4 — [[[2— (4 Chlorophenol) 1 5-methyl 2H— [1, 2, 3] triazole 4-ylmethyl] 1 (5-methyl- [1, 3, 4] oxazolazo 1 Ru-2-ylmethyl) amino] methyl] —2,6 dimethylphenoxy] —2-methylpropionic acid ethyl ester [0635] [Chemical 192]

Example 26- In the same manner as in (1), the compound (0.180 g) strength obtained in Reference Example 26- (3) also gave the title compound (0.142 g) as a colorless oil.

'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2 18 (6H, s), 2.27 (3H, s), 2.52 (3H, s), 3.65 (2H, s), 3.81 (2H, s), 3.

93 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6. 95 (2H, s), 7.41 (2H, d, J = 8.8

Hz), 7.93 (2H, d, J = 8.8Hz).

MS m / z: 567 (M + H) ⁺ .

[0637] (2) 2— [4— [[[2— (4 Chlorophenyl) -5-methyl-2H— [1, 2, 3] triazole

 4-methyl] mono (5-methyl- [1, 3, 4] oxadiazo 2-ylmethyl) amino] methyl] 2,6 dimethylphenoxy] -2-methylpropionic acid

[0638] [Chemical 193]

[0639] In the same manner as in Example 1- (2), the compound (0.138 g) force obtained in Example 38- (1) was also obtained as the title compound (0.118 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3

 6

 H, s), 2.45 (3H, s), 3.60 (2H, s), 3.80 (2H, s), 3. 91 (2H, s), 6. 92 (2H, s), 7. 59 (2H, d, J = 8.8Hz), 7. 92 (2H, d, J = 8.8Hz).

 MS m / z: 539 (M + H) +.

[0640] [Example 39]

 (1) 2— [4— [[[2— (3 Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole —4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] — 2-Methylpropionic acid tert-butyl ester

[0641] [Chemical 194]

Example 30— Reference Example 27—Compound (0.120 g) obtained in (2) and Reference Example 16— (2)) (0.153 g) The compound (0.151 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.23 (6H, s)

 Three

 , 2.24 (3H, s), 2.81 (3H, d, J = 4.9Hz), 3.25 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.89 (2H, s), 7.20 (1H, q, J = 4.9Hz), 7.26— 7.30 (1H, m), 7.39 (1H, t, J = 8.1Hz), 7.89 (1H, dd, J = 2.0, 8.1Hz), 8.03 (1H , t, J = 2. OHz).

MS m / z: 570 (M + H) ⁺ .

[0643] (2) 2— [4— [[[2— (3 Chlorophenol)] 5-Methyl 2H— [1, 2, 3] triazole

—4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid

[0644] [Chemical 195]

Example 24- In the same manner as in (2), the title compound (0.115 g) was obtained as a colorless solid from the compound (0.155 g) obtained in Example 39- (1).

 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2. 13 (6H, s), 2.22 (3

 6

H, s), 2.58 (3H, d, J = 4.7Hz), 3.10 (2H, s), 3.57 (2H, s), 3.72 (2H, s ), 7.00 (2H, s), 7.42-7.45 (1H, m), 7.56 (1H, t, J = 8.1Hz), 7.61 (1 H, q, J = 4.7Hz), 7.88—7.90 (1H, m ), 7.92 (1H, t, J = 2.0Hz).

 Elemental analysis value as C H NO '1Z2HO

 27 35 5 4 2

 Calculated values: C, 59.71; H, 6.36; CI, 6.78; N, 13.39.

 Found: C, 59.71; H, 6.43; CI, 6.92; N, 12.98.

MS m / z: 514 (M + H) ⁺ .

[0646] [Example 40]

 (1) 2- [4 -— [[[[2- (3 Chlorophenol)] 5-Methyl 2H— [1, 2, 3] triazole 4-ylmethyl] -one (5-Methyl- [1, 3, 4] oxazodiazo [Ru-2-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] —2-methylpropionic acid ethyl ester [0647] [Chemical 196]

In the same manner as in Example 26- (1), the title compound (0.194 g) was obtained as a colorless oil from the compound (0.200 g) obtained in Reference Example 28- (3).

 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 19 (6H, s), 2.27 (3H, s), 2.53 (3H, s), 3.65 (2H, s), 3.81 (2H, s), 3.93 (2H, s), 4.29 (2H, q , J = 7.1Hz), 6.95 (2H, s), 7.25— 7.26 (1H, m), 7.37 (1H, d, J = 8.3Hz), 7.89 (1H, dd, J = 2.0, 8.3Hz), 8.03 (1H, t, J = 2.0Hz).

MS m / z: 567 (M + H) ⁺ .

 [0649] (2) 2— [4— [[[2— (3 Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole

 4-ylmethyl] mono (5-methyl- [1, 3, 4] oxadiazo 2-ylmethyl) amino] methyl] 2,6-dimethylphenoxy] -2-methylpropionic acid

[0650] [Chemical 197] HS) 96 9 '( ^Z HS 6 = ΓΡ ΉΖ) 6 9' ( ^Ζ ΗΙ ΗΙ Ζ = Γ¾ ΉΖ) 6 Ζ '' ( ^s ' HS) S6

Έ '( ^s ' Η2) 98 Έ' ( ^s ' HS) 9 Έ '( ^s ' HS) S9' Ζ '( ^s ' U £) LZ' Z '( ^s ' H9) 8I z' ( ^S ¾9) 9 · χ '( ^Ζ ΗΙ · = Γ' ^ 'Ηε) 9ε · χ: 9 (\ οαο' ZH OO ^) H NH _T

[86ΐ ^] [SS90] D ^ D

 [^ (^ ^ ー s— / —, fH ['ε' I]--9)-→ -Λ (

 —, (Η [ε 'Ζ Ί] (/-^ Δ ^^ →)-2]]]-¾ -2 (I)

[lH} «] [2S90] • ₊ (H + PV) 6S9: ^z / ^ra SPV

 · (

^ ΉΖ) 16 · Ζ— 98 'L' ( ^Ζ ΗΙ · 8 = Γ 'ΗΙ) 99' L '' Ηΐ) 'L-ZV' L '( ^s '

HS) S6 9 '( ^s ' HS) S6 Έ '( ^s ' Η2) 08 Έ '( ^s ' Η2) 09 Έ '( ^s ¾ε) 9' Ζ '( ^s ' Η

£) ΖΖ 'Ζ' ( ^s ' Η9) 2Ι 'Ζ' ( ^s ' H9) SS · ΐ: 9 (P-OSWa 'ZH 00 ^) H NH _T

oM ^ m ^ ^ ( ^§ s9i Ό) 呦

ZCCM0 / S00Zdf / X3d 6 6C6CT0 / 900Z OAV , s), 7.89 (2H, d, J = 9.3Hz).

 MS m / z: 563 (M + H) +.

[0655] (2) 2— [4— [[[2— (4-Methoxyphenol) 5-methyl-2H— [1, 2, 3] triazol 4-ylmethyl] one (5-methyl- [1, 3, 4] Triazol-2-ylmethyl) amino] methyl] 2, 6 dimethylphenoxy] 2 methylpropionic acid

[0656] [Chemical 199]

In the same manner as in Example 1- (2), the compound (0.130 g) force obtained in Example 41- (1) was also used to obtain the title compound (0.105 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2. 13 (6H, s), 2.20 (3

 6

 H, s), 2.45 (3H, s), 3.59 (2H, s), 3.77 (2H, s), 3.80 (3H, s), 3.89 (2H, s), 6.93 (2H, s), 7.07 (2H , d, J = 9.1Hz), 7.83 (2H, d, J = 9.1Hz) .MS m / z: 535 (M + H) +.

 [0658] [Example 42]

 (1) 2— [4 — [[[2— (4-Methoxyphenyl) 5-methyl-2H— [1, 2, 3] triazol 4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropionic acid ethyl ester

 [0659] [Chemical 200]

Example 25—In the same manner as in (1), the compound (0.160 g) obtained in Reference Example 30— (2) and methylamine hydrochloride (0.023 g) were also mixed with the title compound (0.096 g). Obtained as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.36 (3Η, t, J = 7.1Hz), 1.46 (6H, s), 2

 Three

 19 (6H, s), 2.23 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.25 (2H, s), 3.57 (2H, s), 3.67 (2H, s), 3.86 ( 3H, s), 4.29 (2H, q, J = 7.1 Hz), 6.90 (2H, s), 6.97 (2H, d, J = 9.1Hz), 7.23— 7.26 (1H, m), 7.90 (2H, d, J = 9.1 Hz).

 MS m / z: 538 (M + H) +.

[0661] (2) 2— [4— [[[2— (4-Methoxyphenol) 5-methyl-2H— [1, 2, 3] triazol 4-ylmethyl] methylcarbamoylmethylamino] methyl] — 2, 6-Dimethylphenoxy] 2-methylpropionic acid

[0662] [Chemical 201]

Example 1— In the same manner as in (2), the title compound (0.076 g) was obtained as a colorless solid from the compound (0.090 g) obtained in Example 42 (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.20 (3

 6

 H, s), 2.58 (3H, d, J = 4.7Hz), 3.08 (2H, s), 3.56 (2H, s), 3.67 (2H, s), 3.80 (3H, s), 7.00 (2H, s ), 7.07 (2H, d, J = 9.1Hz), 7.59 (1H, q, J = 4.7Hz), 7.84 (2H, d, J = 9.1Hz).

MS m / z: 510 (M + H) ⁺ .

[0664] [Example 43]

(l) 2- [4-[[[2- (3,4-Dimethylphenol) -5-methyl-2H- [1, 2, 3] triazol-4-ylmethyl] methylcarbamoylmethylamino] methyl] -2, 6-Dimethylphenoxy] -2-methylpropionic acid tert butyl ester [0665] [Chemical 202]

Example 30— Reference Example 31—Compound (0.090 g) obtained in (2) and Reference Example 16—Compound (0.117 g) obtained in (2) in the same manner as (1). The compound (0.117 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.24 (3H, s), 2.30 (3H, s), 2.34 (3H, s), 2.80 (3H, d, J = 5.1Hz), 3.

25 (2H, s), 3.57 (2H, s), 3.68 (2H, s), 6.90 (2H, s), 7.20 (1H, d, J = 8

1Hz), 7.23-7.26 (1H, m), 7.69 (1H, dd, J = 2.2, 8.1Hz), 7.77 (1H

, d, J = 2.2Hz).

MS m / z: 564 (M + H) ⁺ .

[0667] (2) 2- [4-[[[2- (3,4-Dimethylphenol) -5-methyl-2H- [1, 2, 3] triazole-4-ylmethyl] methylcarbamoylmethylamino] methyl] —2, 6-dimethylphenoxy] 2-methylpropionic acid

[0668] [Chemical 203]

Example 24- In the same manner as in (2), the title compound (0.031 g) was obtained as a colorless solid from the compound (0.112 g) obtained in Example 43- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.21 (3

 6

H, s), 2.25 (3H, s), 2.30 (3H, s), 2.58 (3H, d, J = 4.7Hz), 3.08 (2H, s ), 3.56 (2H, s), 3.69 (2H, s), 7.00 (2H, s), 7.27 (1H, d, J = 8.3Hz), 7.58-7.64 (2H, m), 7.72 (1H, d, J = 2.0Hz).

 MS m / z: 508 (M + H) +.

[0670] [Example 44]

 (l) 2- [4-[[[2- [4 (2-Methoxyethoxy) phenol] 5-Methyl-2H- [1,2,3] Triazol-4-ylmethyl] methylcarbamoylmethylamino] methyl] 2, 6-dimethylphenoxy] 2-methylpropionic acid tert butyl ester

[0671] [Chemical 204]

Example 30— In the same manner as in (1), the compound (0.120 g) obtained in Reference Example 32— (4) and the compound (0.134 g) obtained in Reference Example 16— (2) were also used. The title compound (0.147 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.23 (3H, s), 2.80 (3H, d, J = 4.9Hz), 3.24 (2H, s), 3.47 (3H, s), 3.57 (2H, s), 3.78 (2H, t, J = 4.9Hz), 4.16 (2H, t, J = 4.9Hz), 6.89 (2H, s), 7.20 (2H, d, J = 9.1Hz), 7.22 (1H, q, J = 4.9Hz), 7.89 ( 2H, d, J = 9.1 Hz).

MS m / z: 610 (M + H) ⁺ .

[0673] (2) 2— [4— [[[2— [4— (2-Methoxyethoxy) phenol] -5-methyl-2-H— [1, 2

, 3] Triazol-4-ylmethyl] methylcarbamoylmethylamino] methyl] 2,6-dimethylphenoxy] 2-methylpropionic acid

[0674] [Chemical 205]

Example 24—In the same manner as in (2), the compound (0.142 g) force obtained in Example 44 (1) was also used to obtain the title compound (0.091 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (6Η, s), 2.20 (3

 6

 H, s), 2.58 (3H, d, J = 4.9Hz), 3.08 (2H, s), 3.57 (2H, s), 3.67 (2H, s

), 4.14 (2H, dd, J = 2.9, 6.1 Hz), 7.00 (2H, s), 7.08 (2H, d, J = 9.3 Hz)

, 7.59 (1H, q, J = 4.9Hz), 7.82 (2H, d, J = 9.3Hz).

MS m / z: 554 (M + H) ⁺ .

[0676] [Example 45]

 (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl [2— (5 Methyl 2

—Fe-Lu 2H— [1, 2, 3] triazol-4-yl) ethyl] amino] methyl] phenoxy] — 2-methylpropionic acid tert-butyl ester

[0677] [Chemical 206]

Example 25—In the same manner as (1), the title compound (0.064 g) was prepared using the compound (0.20 g) obtained in Reference Example 33- (4) and methylamine (2M-tetrahydrofuran solution). ) Was obtained as a colorless oil.

'H-NMR (400MHz, CDCl) δ: 1.40 (6Η, s), 1.51 (9Η, s), 2.13 (6H, s) [802 ^] [S890]

 / D

ζ-

[^ [^ [^ D (^ — — / —, (Η [ε '

 Ζ Ί] -Η2- / Ζ -Ζ- -9) -2]-^ / ¾]]-^]-2 (1)

[9, No. 2] [2890] • ₊ (H + V) 6: ^z Z ^ra SPV • (ra 'UZ) Z · 8— 66' L '(m' HS) 6 · 'L' (m 'ΗΙ) εε Ί-6Ζ 'L' ( ^s 'UZ) LL 9' ( ^s 'HS) S 9 Έ' ( ^s 'HS) 9 IS S (m' HS) 88 'Z →' Z '(m' UZ) Z 'Z-LL' Ζ '( ^Ζ Η6 · = ΓΡ' HS) S9 'Z' ( ^s ' U £) IZ 'Z' ( ^s ' H9) SI 'Ζ' ( ^s ' Η9) 8 · ΐ: 9 (\ θαθ 'zH OO ^) H NH _T

[0890] l l ^ S [,

 ^ P, e [^ [^ [^ e (^ — — / —, (Η [ε 'ζ' ΐ] — — / -e —

 -Ζ — ^ / ¾ ^]] — — ^ — 9 'Ζ -Ζ {Ζ) [6 90]

• ₊ (H + V) OSS: ^z Z ^ra SPV

 · (

^ 'HS) SO 8—66' L '(m' HS) 8 'L →' L '(^' HI) SS Ί-6Ζ 'L' (^ 'H l) £ Z Ί- Ζ' L ' ( ^s 'UZ) L 9' ( ^s 'HS) S 9 Έ' ( ^s 'UZ) l Έ' (^ 'HS) 98 · Z- £ S' Z '(m' HS) 6Z 'Z-9L' Ζ '( ^Ζ ΗΙ 9 = ΓΡ' HS) S9 '( ^s ' HS) IS'

ZCCM0 / S00Zdf / X3d 991- 6C6CT0 / 900Z OAV

[0684] Reference Example 33— The compound (0.20 g) obtained in (4) was dissolved in dichloromethane (5 ml), and 1-ethyl-3- (3 aminopropyl) carbodiimide hydrochloride (0.075 g), trie Tyramine (0.055 ml) and 1-hydroxybenzotriazole hydrate (0.060 g) were added, and the mixture was stirred at room temperature for 15 minutes. Ammonium chloride (0.060 g) and triethylamine (0.156 ml) were added, and the mixture was further stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with 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 (1% methanol / chloroform form) to give the title compound (0.156 g) as a colorless oil. I got it.

 [0685] 'H-NMR (400MHz, CDC1) δ: 1.40 (6Η, s), 1.51 (9Η, s), 2.12 (6H, s)

 Three

 , 2.19 (3H, s), 2.75-2.88 (4H, m), 3.17 (2H, s), 3.53 (2H, s), 5.27 (

1H, br), 6.72 (2H, s), 7.26— 7.30 (1H, m), 7.43— 7.47 (2H, m), 7.9

5-7.98 (2H, m).

 MS m / z: 536 (M + H) +.

[0686] (2) 2— [4 [[Strengthened Lubamoylmethyl- [2— (5-Methyl-2 Ferro-Lu 2H— [1, 2

, 3] Triazol-4-yl) ethyl] amino] methyl] -2, 6 dimethylphenoxy] -2 methylpropionic acid

[0687] [Chemical 209]

Example 24-—In the same manner as in (2), the title compound (0.104 g) was obtained as a colorless solid from the compound (0.153 g) obtained in Example 46- (1).

 iH—NMR (400MHz, CD OD) δ: 1.39 (6H, s), 2.08 (6H, s), 2. 16 (3H, s

 Three

 ), 2. 79-2.82 (2H, m), 2.86— 2. 91 (2H, m), 3. 18 (2H, s), 3. 54 (2H, s), 6. 78 (2H, s) , 7. 29— 7. 34 (1H, m), 7.45— 7. 50 (2H, m), 7. 94— 7. 97 (2H, m).

MS m / z: 480 (M + H) ⁺ .

 [0689] [Example 47]

 (1) 2— [2, 6 Dimethyl 4 -— [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl) [2-— (5-Methyl-2-Ferru 2H— [1, 2 , 3] Triazol-4-yl) ethyl] amino] methyl] phenoxy] —2-methylpropionic acid tert-butyl ester

 [0690] [Chemical 210]

[0691] In the same manner as in Example 26- (1), from the compound (0.29 g) obtained in Reference Example 34, the title compound ( [ZIZ ^ [9690] d Λ (-^-^^

^ / — —

]]-¾ -2 (I)

[8H} «] [S690] • ₊ (H + PV) 6I9: ^z / ^ra SPV • (ra ΉΖ) 96 Ί- £ 6 'L' (^ 'HS) S' L- \ V 'L' (^ 'HI) OS' L-LZ 'L

'( ^s ' HS) 06 9 '( ^s ' HS) S6 Έ '( ^s ' HS) 99 Έ '( ^s ' Η) ΐ6 '( ^s ' HS) 09 'Z' ( ^s 'HS) 9S' Z '( ^s ' H9) 9I 'Z' ( ^s 'Η9) 8 Ί-9 (\ OaO' zH OO ^) H NH _T

⁰ -M ^ Ww ^ ( ^§ 990 -o) ^

[ΠΖ ^ [S690]? , ^ Λί ^ -Ζ-i ^-^ [^ ["^ é (— One / —, (Η [ε 'Ζ' I]-HS--Ζ--9)-S]-(/ ^ / yZ -— ^ 'Ε' ΐ] — / ^ ー S)]] — — ^ ー 9 'Ζ -Ζ {Ζ) [S690]

• ₊ (H + PV) 9Z9: ^z / ^ra SPV

) Z6 'Z-96' L '(m' HS) S Ί-I 'L' (^ 'HI) 6S' L '( ^s ' HS) 88 9

'( ^s ' HS) S6 Έ '( ^s ' HS) 99 Έ '( ^s ' H) 06 'Z' ( ^s ¾ε) 8 'Ζ' ( ^s 'U £) Z' Z '( ^s ' H9) 8I 'Z' ( ^s 'H6) I9 Ί' ( ^s 'Η9) Ι ^ Ί- 9 (\ OaO' zH OO ^) H NH _T

ZCCM0 / S00Zdf / X3d 891- 6C6CT0 / 900Z OAV

[0697] The compound (0.463 g) obtained in Reference Example 35 was dissolved in dichloromethane (7 ml), and methoxyacetaldehyde (0.170 g) and sodium triacetoxyborohydride (0.424 g) were added at room temperature. Stir overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was 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 (ethyl acetate: hexane = 1: 2) to give the title compound (0.390 g) as a colorless oil.

 [0698] 'H-NMR (400MHz, CDC1) δ: 1.41 (6Η, s), 1.51 (9Η, s), 2.21 (6H, s)

 Three

, 2.27 (3H, s), 2.66 (2H, t, J = 6.1Hz), 3.29 (3H, s), 3.47 (2H, t, J = 6.1 Hz), 3.50 (2H, s), 3.51 (2H , s), 6.92 (2H, s), 7.22 (1H, t, J = 7.6H z), 7.41 (2H, t, J = 7.6Hz), 7.63 (2H, d, J = 7.6Hz), 7.78 ( 1H, s) .MS m / z: 522 (M + H) ⁺ .

 [0699] (2) 2— [4— [[(2-Methoxyethyl) mono (3-methyl-11-phenol 1H pyrazole-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] -2 —Methylpropionic acid

 [0700] [Chemical 213]

Example 48— The compound (0.385 g) obtained in (1) was dissolved in dichloromethane (5 ml), 4N hydrochloric acid dioxane solution (l ml) was added, and the mixture was stirred overnight at room temperature. Concentrate the reaction under reduced pressure The residue was purified by silica gel column chromatography (chloroform: methanol = 93: 7) to give the title compound (0.334 g) as a colorless solid.

[0702] 'H-NMR (400MHz, DMSO— d) δ: 1.32 (6H, s), 2. 14 (6H, s), 2.16 (3

 6

 H, s), 2.56 (2H, t, J = 6.1Hz), 3.18 (3H, s), 3.41—3.46 (6H, m), 6.9

4 (2H, s), 7.22 (1H, t, J = 7.6Hz), 7.44 (2H, t, J = 8.6Hz), 7.76 (2H, d

, J = 8.6Hz), 8.29 (1H, s).

 MS m / z: 466 (M + H) +.

[0703] [Example 49]

 (1) 2- [2, 6-Dimethyl- 4-[[(3-Methyl-1-Fuelue 1H-pyrazole- 4

—Ylmethyl) mono (3,3,3-trifluoropropyl) amino] methyl] phenoxy] —2-methylpropionic acid tert-butyl ester

[0704] [Chemical 214]

Example 48—Similarly to (1), the compound (0.463 g) obtained in Reference Example 35 and 3, 3, 3-trifluoropropionaldehyde (0.224 g) force were The compound (0.432 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.22 (6H, s)

 Three

 , 2.24-2.28 (2H, m), 2.26 (3H, s), 2.71 (2H, t, J = 7.8Hz), 3.44 (2H, s), 3.47 (2H, s), 6.91 (2H, s), 7.23 (1H, t, J = 7.8Hz), 7.42 (2H, t, J = 7.8Hz), 7.62 (2H, d, J = 7.8Hz), 7.75 (1H, s).

 MS m / z: 560 (M + H) +.

[0706] (2) 2— [2, 6-Dimethyl-4-] [[(3-Methyl-1-Ferru 1H-Pyrazole-4-Ilmethyl) (3,3,3-Trifluoropropyl) amino] Methyl] phenoxy] -2-methylpropionic acid [0707] [Chemical 215]

Example 48— In the same manner as (2), the title compound (0.379 g) was obtained as a colorless solid from the compound (0.425 g) obtained in Example 49 (1). This was dissolved in dichloromethane (2 ml), 4N hydrochloric acid dioxane solution (0.376 ml) was added, and the solvent was distilled off under reduced pressure to obtain hydrochloride.

 'H-NMR (400MHz, DMSO-d) δ: 1.35 (6Η, s), 2.17 (6Η, s), 2.19 (3

 6

 Η, s), 2.95-3.12 (2Η, m), 3.60—3.80 (4Η, m), 4.18—4.29 (2H, m)

, 7.32-7.34 (3H, m), 7.52 (2H, t, J = 7.6Hz), 7.76 (2H, d, J = 7.6Hz

), 8.74 (1H, s).

MS m / z: 504 (M + H) ⁺ .

[0709] [Example 50]

 (1) 2— [2, 6 Dimethyl 4 [[Methylcarbamoylmethyl (3 Methyl 1 Hue

-Le 1H pyrazole 4-methyl) amino] methyl] phenoxy] -2-methylpropionic acid ethyl ester

[0710] [Chemical 216]

 Example 25— In the same manner as in (1), using the compound (0.345 g) obtained in Reference Example 36- (2) and methylamine (2M tetrahydrofuran solution, 1 ml), the title compound ( 0.341 g) was obtained as a colorless oil.

'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (9H, s), 2 17 (6H, s), 2.23 (3H, s), 2.76 (3H, d, J = 4.9Hz), 3.24 (2H, s), 3.62

(2H, s), 3.64 (2H, s), 4.29 (2H, q, J = 7.1Hz), 6.90 (2H, s), 7.21— 7.

24 (1H, m), 7.33 (1H, d, J = 7.6Hz), 7.40 (2H, t, J = 7.6Hz), 7.58 (2H

, d, J = 7.6Hz), 7.80 (1H, s).

MS m / z: 507 (M + H) ⁺ .

[0712] (2) 2— [2, 6 Dimethyl-4 [[Methylcarbamoylmethyl- (3-methyl-1-phenol

-Le 1H pyrazole 4-methyl) amino] methyl] phenoxy] -2-methylpropionic acid

[0713] [Chemical 217]

[0714] In the same manner as in Example 1- (2), the compound (0.335g) force obtained in Example 50- (1) also gave the title compound (0.266g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.14 (3Η, s), 2.16 (6

 6

 H, s), 2.59 (3H, d, J = 4.7Hz), 2.97 (2H, s), 3.43 (2H, s), 3.50 (2H, s), 7.01 (2H, s), 7.24 (1H, t , J = 7.8Hz), 7.46 (2H, d, J = 7.8Hz), 7.55 (1H, q, J = 4.7Hz), 7.76 (2H, d, J = 7.8Hz), 8.37 (1H, s).

 Elemental analysis value as C H NO · Η O

 27 34 4 4 2

 Calculated value: C, 65.30; H, 7.31; N, 11.28.

 Found: C, 65.45; H, 7.22; N, 10.92.

MS m / z: 479 (M + H) ⁺ .

[0715] [Example 51]

(1) 2- [4 [[Dimethylcarbamoylmethyl- (3-methyl-1 phenol- 1H pyrazole-4-ylmethyl) amino] methyl] -2, 6 dimethylphenoxy] 2 methyl Propionate Etenore Estenore

 [0716] [Chemical 218]

Example 25— In the same manner as in (1), using the compound (0.345 g) obtained in Reference Example 36- (2) and dimethylamine (2M tetrahydrofuran solution, 1 ml), the title compound ( 0.195 g) was obtained as a colorless oil.

 'H-NMR (400MHz, CDCl) δ: 1.36 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.25 (3H, s), 2.81 (3H, s), 2.87 (3H, s), 3.22 (2H, s), 3.55 (2H, s), 3.61 (2H, s ), 4.29 (2H, q, J = 7.1Hz), 6.92 (2H, s), 7.23 (1H, t, J = 7.6Hz), 7.42 (2H, t, J = 7.6Hz), 7.64 (2H, d , J = 7.6Hz), 7. 83 (1H, s).

MS m / z: 521 (M + H) ⁺ .

 [0718] (2) 2— [4 [[Dimethylcarbamoylmethyl- (3-methyl-1 phenol- 1H pyrazole-4-ylmethyl) amino] methyl] —2, 6 dimethylphenoxy] 2 methyl propionic acid

 [0719] [Chemical 219]

In the same manner as in Example 1- (2), the compound (0.190 g) force obtained in Example 51- (1) was also used to obtain the title compound (0.087 g) as a colorless solid. NMR-NMR (400MHz, DMSO— d) δ: 1.32 (6H, s), 2.11 (3H, s), 2.14 (6

 6

 H, s), 2.75 (3H, s), 2.79 (3H, s), 3.18 (2H, s), 3.49 (2H, s), 3.50 (2H, s), 6.92 (2H, s), 7.23 (1H , t, J = 7.6Hz), 7.44 (2H, t, J = 7.6Hz), 7.75 (2H, d, J = 7.6Hz), 8.29 (1H, s).

 Elemental analysis value as C H NO 3Ζ4ΗΟ

 28 36 4 4 2

 Calculated values: C, 66.45; H, 7.47; N, 11.07.

 Found: C, 66.33; H, 7.41; N, 10.74.

 MS m / z: 493 (M + H) +.

[0721] [Example 52]

 (1) 2— [4— [[Isoxazole-5-ylmethyl- (3-methyl-1-phenol- 1 H-pyrazole-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] — 2-Methylpropionic acid tert-butyl ester

[0722] [Chemical 220]

Reference Example 37— Compound (0.073 g) obtained in (2) and Reference Example 16— Compound (0.08 8 g) obtained in (1) were dissolved in dichloromethane (4 ml), and sodium triacetoxyborohydride (0.086 g) was added and stirred at room temperature overnight. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was 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 (ethyl acetate: hexane = 1: 4) to give the title compound (0.110 g) as a colorless oil.

 'H-NMR (400MHz, CDC1) δ: 1.42 (6Η, s), 1.51 (9Η, s), 2.23 (6H, s)

 Three

, 2.28 (3H, s), 3.50 (2H, s), 3.53 (2H, s), 3.78 (2H, s), 6.12 (1H, d, J = 1.7Hz), 6.96 (2H, s), 7.23 ( 1H, d, J = 7.4Hz), 7.42 (2H, t, J = 8.6H z), 7.64 (2H, d, J = 8.6Hz), 7.83 (1H, s), 8.21 (1H, d, J = l.7Hz) MS m / z: 545 (M + H) +.

 [0724] (2) 2— [4 [[Isoxazole 5ylmethyl (3methyl-1phenol-1H-pyrazole-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2-methylpropionic acid

 [0725] [Chem 221]

Example 24-—In the same manner as (2), the title compound (0.081 g) was obtained as a colorless solid from the compound (0.105 g) obtained in Example 52- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (3Η, s), 2.15 (6

 6

 H, s), 3.43 (2H, s), 3.47 (2H, s), 3.77 (2H, s), 6.46 (1H, d, J = l.7Hz), 6.97 (2H, s), 7.23 (1H, d, J = 7.6Hz), 7.45 (2H, t, J = 7.6Hz), 7.77 (2H, d, J = 7.6Hz), 8.34 (1H, s), 8.52 (1H, d, J = l.7Hz ).

 MS m / z: 545 (M + H) +.

 [0727] [Example 53]

 (1) 2— [4— [[[1— (4 Black Mouth Phenol) 1 3-Methyl 1H Pyrazole 1- 4-Methyl] methylcarbamoylmethylamino] methyl] —2, 6 Dimethylphenoxy ] —2— Methylpropionic acid ethyl ester

 [0728] [Chemical 222]

Example 30— In the same manner as (1), the compound (0.143 g) obtained in Reference Example 1 and Reference Example 38 were obtained. The title compound (0.305 g) was obtained as a colorless oil from the compound (0.200 g).

MS m / z: 540 (M + H) ⁺ .

[0730] (2) 2— [4— [[[1— (4 Black Mouth Phenol) 3 Methyl 1H Pyrazole 4 Methyl] Methylcarbamoylmethylamino] Methyl] -2, 6-Dimethylphenoxy ] —2— Methylpropionic acid

 [0731] [Chemical 223]

[0732] In the same manner as in Example 1- (2), the title compound (0.091g) was obtained as a colorless solid from the compound (0.300g) obtained in Example 53- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.33 (6Η, s), 2.13 (3Η, s), 2.16 (6

 6

 H, s), 2.58 (3H, d, J = 4.9Hz), 2.97 (2H, s), 3.42 (2H, s), 3.50 (2H, s), 7.00 (2H, s), 7.50-7.55 (3H , m), 7.79 (2H, t, J = 8.8Hz), 8.39 (1 H, s).

MS m / z: 512 (M + H) ⁺ .

 [0733] [Example 54]

 (l) 2- [4-[[[2- (3,4-Dimethylphenol) -5-methyl-2H— [1, 2, 3] triazole 4-methylmethyl] (5 Methyl— [1, 3, 4] Oxadiazole 2-dimethyl) amino] methyl] 2,6 dimethylphenoxy] 2 methyl propionic acid ethyl ester

[0734] [Chemical 224] PP ΉΙ) ^Ζ 9 'L' ( ^Ζ · 9 8 = Γ Ρ 'ΗΙ) 92' L '( ^S ' HS) S6 9 '( ^S ' HS) 68 Έ '( ^S ' UZ) SL Έ '( ^S ' HS ) 69 Έ '( ^S ' HS) S 'Z' ( ^S 'HS) OS' Z '( ^S ' HS) 9S 'Z' ( ^S 'H

£) IZ 'Z' ( ^S 'H9) SI' Ζ '( ^S ' H9) SS Ί-9 (P-OSWa 'ZH 00 ^) H NH _T

^ m ^ ^ ^ ^ ( ^§ oox -o) ^

 -Z- / —,; ^ ^ 'ε' χ]--9)-→-/ —, (Η [ε 'Ζ Ί] -Η2- -έ ^ -9- (/ — ^ Δ / ^^ → 'ε) -2]]]-¾-2 (2) [9SZ0]

• ₊ (H + PV) I99: ^Z / ^RA SPV

 • (ZHS '2 = Γ' Ρ 'ΗΙ

) 91 Ί '( ^ζ Ηε 8' Ζ 'Ζ = ί'νν' ΗΙ) 69 'L' ( ^Z HS 8 = ΓΡ 'ΗΙ) 6 Ι L' ( ^s ' ΗΖ

) 96 · 9 '( ^Ζ ΗΙ · = Γ' ¾ 'Η2) 62' ( ^S 'HS) 6 Έ' ( ^S 'HS) S8 Έ' ( ^S 'HS) 99

Ε '( ^s Ή £) Ζ' ζ '( ^s Ήε) εε' ζ '( ^S ' HS) 8S 'Ζ' ( ^S Ή £) ιζ 'Ζ' ( ^S 'Η9) 8 Ι z' ( ^S ¾9 ) 9 χ '( ^Ζ ΗΙ · = Γ' ^ 'Ηε) 9ε χ: 9 (' ιοαο 'ZH OO ^) H NH _T

ZCCM0 / S00Zdf / X3d 19 V 6C6CT0 / 900Z OAV , J = 2.2, 8.6Hz), 7.70 (1H, d, J = 2.2Hz).

 MS m / z: 533 (M + H) +.

[0739] [Example 55]

 (1) 2- [4 -— [[[2- (4-Chlorophenyl)] 5-methyl 2H— [1, 2, 3] triazole 4-methyl]-(2-methoxyethyl) amino] methyl] —2, 6 Dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0740] [Chemical 226]

[0741] In the same manner as in Example 29- (1), the compound (0.113g) obtained in Reference Example 25- (2) and the compound (0.141g) obtained in Reference Example 40 were also combined with the title compound. Product (0.226 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 17 (6H, s), 2.27 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.72 (2H, s), 4.29 (2H, q, J = 7.1 Hz), 6.93 (2H, s), 7.40 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz).

 MS m / z: 529 (M + H) +.

 [0742] (2) 2— [4— [[[2— (4 Chlorophenyl) -5-methyl-2H— [1, 2, 3] triazole

 4-ylmethyl]-(2-methoxyethyl) amino] methyl] -2,6 dimethylphenoxy] 2-methylpropionic acid

 [0743] [Chemical 227]

In the same manner as in Example 1- (2), the compound (0.210 g) force obtained in Example 55- (1) was also used to obtain the title compound (0.200 g) as a colorless solid.

 'H-NMR (400MHz, DMSO-d) δ: 1.31 (6Η, s), 2.11 (6Η, s), 2.23 (3

 6

 H, s), 2.63 (2H, t, J = 5.9Hz), 3.20 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3.50 (2H, s), 3.70 (2H, s ), 6.91 (2H, s), 7.58 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz).

 Elemental analysis value C H C1NO · 0.25HO

 26 33 4 4 2

 Calculated values: C, 61.77; H, 6.68; CI, 7.01; N, 11.08.

 Found: C, 61.52; H, 6.67; CI, 6.73; N, 10.94.

[0745] [Example 56]

 (1) 2— [4 [[((2-Methoxyethyl) [2- (4-methoxyphenyl) 5-methyl-2]

H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid ethyl ester

[0746] [Chemical 228]

[0747] In the same manner as in Example 29- (1), the compound (0.120g) obtained in Reference Example 29- (2) and the compound (0.138g) obtained in Reference Example 40 had the same strength. Product (0.130 g) was obtained as a colorless oil. 'H-NMR (400MHz, CDC1) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 18 (6H, s), 2.28 (3H, s), 2.73 (2H, t, J = 5.9Hz), 3.30 (3H, s), 3.50 (2H, t, J = 5.9Hz), 3.55 (2H, s), 3.72 (2H, s), 3.84 (3H, s), 4.29 (2H, q, J = 7.1 Hz), 6.94 (2H, s), 6.95 (2H, d, J = 9.1 Hz), 7.89 (2H, d, J = 9.1 Hz).

 MS m / z: 525 (M + H) +.

[0748] (2) 2— [4— [[(2-Methoxyethyl) [2- (4-methoxyphenyl) 5-methyl-2] H— [1, 2, 3] triazol-4-ylmethyl] amino] methyl] —2, 6 dimethylphenoxy] 2-methylpropionic acid

 [Chemical 229]

 In the same manner as in Example 1- (2), the compound (0.125 g) force obtained in Example 56- (1) was also used to obtain the title compound (0.117 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.32 (6H, s), 2. 12 (6H, s), 2.22 (3

 6

 H, s), 2.62 (2H, t, J = 5.9Hz), 3.19 (3H, s), 3.45 (2H, t, J = 5.9Hz), 3.49 (2H, s), 3.68 (2H, s ), 3.80 (3H, s), 6.92 (2H, s), 7.07 (2H, d, J = 9.1Hz), 7.83 (2H, d, J = 9.1Hz).

 Elemental analysis value as C H NO · 0.25HO

 27 36 4 5 2

 Calculated value: C, 64.72; H, 7.34; N, 11.18.

 Found: C, 64.51; H, 7.38; N, 11.06.

[0751] [Example 57]

 (1) 2- [4 -— [[(2 Hydroxyethyl) mono (5-methyl-2 furo-lu 2H- [1, 2, 3] triazole-4-ylmethyl) amino] methyl] -2, 6 dimethyl Phenoxy] -2-methylpropionic acid tert butyl ester

[0752] [Chemical 230]

[0753] Example 29—In the same manner as (1), Reference Example 15—Compound (0.108 g) obtained in (1) and Reference Example The title compound (0.228 g) was obtained as a colorless oil from the compound (0.145 g) obtained in 41. 'H-NMR (400MHz, CDCl) δ: 1.42 (6Η, s), 1.52 (9Η, s), 2.21 (6H, s)

 Three

 , 2.22 (3H, s), 2.79 (2H, br s), 3.59 (2H, br s), 3.65 (2H, br s), 3.7

3 (2H, br s), 6.93 (2H, s), 7.30 (1H, t, J = 7.6Hz), 7.45 (2H, t, J = 7.6

Hz), 7.99 (2H, d, J = 7.6Hz).

 MS m / z: 509 (M + H) +.

[0754] (2) 2— [4— [[(2-Hydroxyethyl) mono (5-methyl-2-ferrue) 2H— [1, 2, 3

] Triazole-4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy] -2-methylpropionic acid

[0755] [Chemical 231]

Example 24- In the same manner as in (2), the title compound (0.184 g) was obtained as a colorless solid from the compound (0.219 g) obtained in Example 57- (1).

 'H-NMR (400MHz, DMSO-d) δ: 1.32 (6Η, s), 2.12 (6Η, s,), 2.24 (

 6

 3Η, s), 2.55 (2Η, t, J = 6.4Hz), 3.51 (2H, s), 3.52 (2H, t, J = 6.4Hz), 3.68 (2H, s), 4.39 (1H, br s) , 6.93 (2H, s), 7.35 (1H, t, J = 7.6Hz), 7.52 (2H, t, J = 7.6Hz), 7.92 (2H, d, J = 7.6Hz).

 Elemental analysis value as C H NO · 0.25HO

 25 32 4 4 2

 Calculated values: C, 65.70; H, 7. 17; N, 12.26.

 Found: C, 65.81; H, 7.25; N, 12.04.

[0757] [Example 58]

(1) 2- [4-[[(2-Methoxyethyl)-(1-p-tolyl- 1H- [1, 2, 3] triazole —4-ylmethyl) amino] methyl] -2,6-dimethylphenoxy 2] -Methylpropioate Ethenole Estenole [0758] [Chemical 232]

Example 29— In the same manner as (1), Reference Example 42—Compound (0. lOOg) obtained in (2) and the compound (0.128 g) force obtained in Reference Example 40 were The compound (0.182g) was obtained as a colorless oil. 'H-NMR (400MHz, CDCl) δ: 1.35 (3Η, t, J = 7.1Hz), 1.45 (6H, s), 2

 Three

 19 (6H, s), 2.42 (3H, s), 2.73 (2H, t, J = 5.4Hz), 3.31 (3H, s), 3.53 (2H, t, J = 5.4Hz), 3.60 (2H, s), 3.92 (2H, s), 4.28 (2H, q, J = 7.1 Hz), 6.97 (2H, s), 7.31 (2H, d, J = 8.6Hz), 7.61 (2H, d, J = 8.6Hz), 7.87 (1 H, s).

 MS m / z: 495 (M + H) +.

[0760] (2) 2— [4 — [[(2-Methoxyethyl) — (1—p-tolyl—1H— [1, 2, 3] triazole

—4-ylmethyl) amino] methyl] —2,6-dimethylphenoxy] —2-methylpropionic acid

[0761] [Chemical 233]

In the same manner as in Example 1- (2), the compound (0.178 g) force obtained in Example 58- (1) was also used to obtain the title compound (0.164 g) as a colorless solid.

 iH-NMR (400MHz, DMSO- d) δ: 1.33 (6H, s), 2. 15 (6H, s), 2.38 (3

 6

H, s), 2.59 (2H, t, J = 6.1Hz), 3.20 (3H, s), 3.45 (2H, t, J = 6.1Hz), 3.52 (2H, s), 3.78 (2H, s ), 6.99 (2H, s), 7.40 (2H, d, J = 8.6Hz), 7.80 (2H, d, J = 8.6Hz), 8.64 (1H, s).

 Elemental analysis value as C H NO 0.5 HO

 26 34 4 4 2

 Calculated values: C, 65.66; H, 7.42; N, 11.78.

 Found: C, 65.95; H, 7.41; N, 11.86.

 [0763] [Example 59]

 (1) 2- [2, 6 Dimethyl-4-[[((5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(1-p-tolyl- 1H- [1, 2, 3] triazole- 4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid ethyl ester

 [0764] [Chemical 234]

Example 26—In the same manner as (1), the title compound (0.467 g) containing triphenylphosphine oxide was obtained from the compound (0.200 g) obtained in Reference Example 43- (3). Was obtained as a colorless solid.

MS m / z: 533 (M + H) +.

[0766] (2) 2— [2, 6 Dimethyl-4 [[(5-Methyl- [1, 3, 4] oxadiazol 2-ylmethyl)-(1-p-tolyl- 1H— [1, 2, 3 ] Triazol-4-ylmethyl) amino] methyl] phenoxy] 2-methylpropionic acid

[0767] [Chemical 235]

In the same manner as in Example 1- (2), the mixture (0.467 g) obtained in Example 59- (1) also gave the title compound (0.124 g) as a colorless solid.

 iH—NMR (400MHz, DMSO d) δ: 1.33 (6H, s), 2. 15 (6H, s), 2.39 (3

 6

 H, s), 2.46 (3H, s), 3.61 (2H, s), 3.86 (4H, s), 6.98 (2H, s), 7.40 (2H, d, J = 8.6Hz), 7.79 (2H, d , J = 8.6Hz), 8.65 (1H, s).

 Elemental analysis value as C H NO 0.5 HO

 27 32 6 4 2

 Calculated values: C, 63.14; H, 6.48; N, 16.36.

 Found: C, 63.16; H, 6.47; N, 15.99.

[0769] [Example 60]

 (l) 2- [4-[[(2, 2 Difluoroethyl) mono (5-methyl-2-ferule 2H- [1,

2,3] Triazol-4-ylmethyl) amino] methyl] -2,6 dimethylphenoxy] -2 methyl propionate ethyl ester

[0770] [Chemical 236]

[0771] Reference Example 44— The compound (0.105 g) obtained in (2) and the reference compound 11- (1) (1) were dissolved in dichloromethane (5 ml) and triacetoxy was added. Sodium borohydride (0.106 g) was added and stirred at room temperature for 21 hours. Aqueous sodium hydrogen carbonate was added and extracted three times with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give a mixture (0.105 g) of the compound of Reference Example 11— (1) and the title compound as a colorless oil.

 MS m / z: 501 (M + H) +.

[0772] (2) 2— [4— [[(2, 2 Difluoroethyl)-(5-methyl-2 ferro- 2H- [1, 2, 3] triazol-4-ylmethyl) amino] methyl] —2, 6 Dimethylphenoxy] —2 Methyl propionic acid

 [0773] [Chemical 237]

Example 60— After treating the mixture obtained in (1) in the same manner as in Example 1— (2), the mixture was purified by thin layer silica gel chromatography ( ₇ % methanol-chloroform form). A compound was obtained. To this was added a 4N hydrochloric acid-dioxane solution (0.063 ml), and the mixture was concentrated to dryness under reduced pressure to give the title compound hydrochloride (0.060 g) as a colorless solid.

[0775] 'H-NMR (400MHz, DMSO d) δ: 1.31 (6H, s), 2. 12 (6H, s), 2. 21 (3

 6

 H, s), 2. 92 (2H, dt, J = 4, 2, 15.4Hz), 3.60 (2H, s), 3. 79 (2H, s), 6. 1 0 (1H, tt, J = 4. 2, 55.9Hz), 6.93 (2H, s), 7.36 (1H, t, J = 7.6Hz), 7.5 3 (2H, t, J = 7.6Hz), 7.93 (2H, d, J = 7.6Hz).

 Elemental analysis value C H FNO · 0.6HC1-0.75H O

 25 30 2 4 3 2

 Calculated values: C, 59. 12; H, 6. 37; CI, 4. 19; F, 7.48; N, 11.03.

 Found: C, 59. 30; H, 6. 36; C1; 4. 39; F, 7.41; N, 10.87.

[0776] [Test Example 1]

 GAL4— hPPAR transactivation assembly

 (a) Plasmid

GAL4 DNA binding region PPAR ligand binding region fusion protein expression plasmids pFA -hPPAR a / GAL4 and pFA— hPPAR y / GAL4 are the hPPAR a and hPPARy LBD cDNAs respectively, and the yeast GAL4 DNA binding region under the CMV promoter (GAL4 DBD) was obtained by incorporating into a commercially available expression vector (pFA trans-Activator plasmids, STRATAGENE). As a reporter protein expression plasmid, a commercially available plasmid (pFR—SEAP, STRATAGENE) having a GAL4 response region (GA L4 UAS) upstream of the secretory alkaline phosphatase (SEAP) cDNA is used. It was.

 [0777] (b) Cell culture and transactivation assembly

Suspend HEK293T cells in high glucose Dulbecco's conditioned Eagle's medium (DM EM) containing 10% urine fetal serum (Hyclone), 100 units ZmL penicillin G and lOOmgZm L streptomycin sulfate, and add 8 X 10 ⁴ seeded at a density of Zwell. After 24 hours of incubation at 37 ° C in a humidified atmosphere of 5% CO, the manufacturer's

 2

 According to the description, transfection was performed under serum-free conditions using Lipofectamine (Lipofectamine, Invitrogen) and Plus Reagent (Invitrogen). In other words, 0.48 μL of lipofectamine, 030 μg of pFA—PPAR / GAL4 expression plasmid, 0.030 μg, and pFR-SEAPO. 13 μg (OPT I—MEM, Invitrogen Incubate the cells for 5 hours at 37 ° C in a 5% CO atmosphere.

 2

 I started. Next, add an equal volume of 10% urine fetal serum, 100 units ZmL penicillin G and lOOmgZm L streptomycin sulfate and the specified 2X concentration of test compound, and incubate the cells for approximately 48 hours. did. Since the compounds were soluble in DMS O, control cells were incubated with an equivalent concentration 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. 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, 5 L of the culture supernatant was mixed with an equal volume of endogenous alkaline phosphatase inhibitor, incubated at 37 ° C for 30 minutes, and then added with 100 L of chemiluminescent substrate (Lumiphos PLUS, Lumigen). After incubation for 15 minutes at ° C, luminescence was measured using a multilabel counter (ARVOsx, PerkinElmer). The EC value was obtained by plotting the relationship between the value obtained by the above operation and the concentration of the test compound.

 50

 [0778] <Test results>

 As shown in the table below, the compounds of the present invention showed potent GAL4-hPPAR transactivation activity.

[0779] [Table 1] GA I.4-h PP AR 卜 Lance activation activity (μ Μ) Example number

 P PAR a P PAR γ

 Example 2— (2) 0. O il 0. 3 2 Example ^ 5— (2) 0. Oil 0. 2 3 Example 1 5— (2) 0.00 2 8 0. 00 8 9 Example 4 8— (2) 0. 0 8 0 0. 06 9 Example 5 2— (2) 0. 0 0 7 1 0. 0 1 5

[0780] Although the present invention has been described in detail and with reference to certain 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.

 This application is based on a Japanese patent application filed on August 5, 2004 (Japanese Patent Application No. 2004-229445), the contents of which are incorporated herein by reference.

 Industrial applicability

[0781] The compound represented by the general formula (I) of the present invention is useful as a preventive or therapeutic agent for diabetes.

Claims

Claim [1] General formula (I)

 [Chemical 1]

 0

 (In the above formula, the following partial structural formula represents a 5-membered aromatic heterocyclic ring,

 [Chemical 2]

(In the above structure, X, Y and Z each independently represent a nitrogen atom or a carbon atom.

. )

 m represents an integer of 0 to 3,

 n represents an integer of 1 to 3,

 Q may be substituted with one or two groups selected from among hydroxyl group, halogen atom, lower alkenyl group, lower alkoxy group, substituted or unsubstituted lower alkyl group, and substituted or unsubstituted amino group. !, Indicates a benzene ring,

R ¹ is a hydroxyl group, a halogen atom, a lower alkenyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group. And a substituted or unsubstituted amino group, a phenyl group, a naphthyl group or a 5- or 6-membered aromatic heterocyclic group, which may be substituted with 1 or 2 groups selected,

R ² represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted force rubamoyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group, R ³ and R ⁴ each independently represent a hydrogen atom or a lower alkyl group,

R ⁵ represents a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted benzyl group.

R ⁶ is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkenyl group, a lower alkoxy group, a substituted or unsubstituted phenoxy group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted A compound represented by an unsubstituted amino group (provided that when m is 2 or more, two or more R ^{6 s} may be the same or different from each other), salts thereof, and solvates thereof.

[2] The compound according to claim 1, wherein X, Y and Z are all carbon atoms, salts thereof, and solvates thereof.

 [3] The compound according to claim 1, wherein X is a nitrogen atom, and Y and Z are carbon atoms, a salt thereof, and a solvate thereof.

[4] The compound according to claim 1, wherein X and Z are nitrogen atoms and Y is a carbon atom, salts thereof, and solvates thereof.

[5] Q force A compound according to any one of claims 1 to 4, which is a benzene ring which may be substituted with one or two groups selected from among the lower alkoxy group and the substituted or unsubstituted lower alkyl group. , Its salts, and their solvates.

[6] R ¹ is hydroxyl group, halogen atom, lower alkenyl group, substituted or unsubstituted lower alkoxy group, substituted or unsubstituted ring phenoxy group, substituted or unsubstituted phenyl group, substituted or unsubstituted lower alkyl 6. A compound according to any one of claims 1 to 5, a salt thereof, and a salt thereof, which is a phenyl group which may be substituted with one or two groups selected from a group and a substituted or unsubstituted amino group Solvate.

[7] The compound according to any one of claims 1 to 6, wherein R ² is a substituted or unsubstituted lower alkyl group, a salt thereof, and a solvate thereof.

[8] The compound according to any one of claims 1 to 6, a salt thereof, and a solvate thereof, wherein R ² is a substituted or unsubstituted force rubamoyl group.

[9] The compound according to any one of claims 1 to 6, wherein R ² is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted 5- or 6-membered aromatic heterocyclic group. ,and Their solvates.

[10] The compound according to any one of claims 1 to 6, a salt thereof, and a solvate thereof, wherein R ² is a substituted or unsubstituted 5-membered aromatic heterocyclic group.

[11] R ³ and compounds of the mounting serial to any of claims 1 to 10 in the R ⁴ force each independently a lower alkyl group, a salt thereof, and a solvate thereof.

[12] R ⁵ is, claim 1 is a hydrogen atom: a compound according to any one of L 1, its salts, and their solvates.

[13] The compound according to any one of claims 1 to 12, wherein R ⁶ is a hydrogen atom, a halogen atom, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted lower alkyl group. And their solvates.

[14] R ² is a furyl group, a thiazolyl group, an oxazolyl group, an isoxazolyl group, and a methyloxadiazolyl group,

The compound according to any one of claims 1 to 13, a salt thereof, and a solvate thereof, wherein each of R ⁴ and R ⁶ forces is a methyl group.

[15] 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.

 16. A pharmaceutical composition comprising the compound represented by the general formula (I) according to claim 1, a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

[17] Use of the compound represented by the general formula (I) according to claim 1, a salt thereof, or a solvate thereof for the manufacture of a medicine.