WO2007088895A1

WO2007088895A1 - 3-arylamino-1,2,4-triazole derivative

Info

Publication number: WO2007088895A1
Application number: PCT/JP2007/051611
Authority: WO
Inventors: Manabu Itoh; Masahiko Ohta; Yutaka Miyazaki; Yuka Sawama; Shigeki Matsumoto; Fumiaki Yamasaki
Original assignee: Mochida Pharmaceutical Co., Ltd.
Priority date: 2006-01-31
Filing date: 2007-01-31
Publication date: 2007-08-09

Abstract

Disclosed is a pharmaceutical composition which is intended to be administered to a patient who needs the inhibition of 11β-HSD1 or the control of 11β-HSD1 activity. The pharmaceutical composition comprises a 3-arylamino-1,2,4-triazole derivative represented by the formula (I), a pharmaceutically acceptable salt or prodrug of the derivative, or a solvate of the derivative, salt or prodrug as an active ingredient. The 3-arylamino-1,2,4-triazole derivative is remarkably stable in a human serum and is a highly promising pharmaceutical agent.

Description

Specification

3-Arylamino- 1, 2, 4 _triazole derivatives

Technical field

[0001] The present invention relates to the use of substituted 3-arylamino-1,1,4-triazole derivatives in the medical field and the activity of 1-β-hydroxysteroid dehydrogenase 'type 1 enzyme (hereinafter referred to as 11 β-HSDl). The present invention relates to a pharmaceutical composition comprising as an active ingredient the derivative used for the treatment of diseases caused by control, and a method for producing the derivative.

Background art

[0002] The important role of 11-HSDl, ie, regulating hepatic glucose production by regulating the effects of local darcocorticoids, has already been demonstrated today (see Non-Patent Document 1). In addition, the blood levels of darcos and the production of hepatic glucose were decreased in the mice knocked out of the 11 jS-HSDl gene. The data obtained from this model also indicate that basal levels of phosphoenolpyruvate (PEPCK) and glucose-6-phosphatase (G6Pase) are regulated independently of darcocorticoids, even if I l j8-HSD1 is suppressed. Therefore, it was confirmed that it did not cause hypoglycemia as expected (see Non-Patent Document 2).

[0003] Obesity is an important factor in syndrome X and most type 2 diabetes, and it is speculated that the network plays a central role. Abdominal obesity is closely related to factors such as glucose sensitivity, hyperinsulinism, hyperglyceridemia, and other so-called syndrome X (e.g., increased blood pressure, decreased HDL levels, and increased VLDL levels). (See Patent Document 3). It was found that inhibition of enzymes in preadipocytes (stromal cells) reduces the rate of differentiation into adipocytes. As a result, the degree of swelling of the greater omental adipose tissue is expected to decrease (probably decrease), that is, the central obesity is expected to decrease (see Non-Patent Document 4).

[0004] Inhibition of 11 β -HSDl in mature adipocytes is expected to dilute secretion of plasminogen activator inhibitor 1 (PAI-1) —a separate cardiovascular risk factor (See Non-Patent Document 5). In addition, darcocorticoid "activity" and cardiovascular There is a clear correlation between risk factors, which suggests that reducing the effects of darcocorticoids is beneficial for cardiovascular events (Non-Patent Documents 6-7). reference).

[0005] When the adrenal gland is removed, the effect of increasing both food intake and hypothalamic neuropeptide sputum expression due to fasting can be suppressed. This fact supports the role of darcocorticoids in increasing food intake, suggesting that suppression of 11β-HSD1 in the brain increases satiety and therefore decreases food intake. (See Non-Patent Document 8) Inhibition of 11 β-HSD1 in isolated murine spleen β-cells improves insulin secretion by glucose stimulation (see Non-Patent Document 9). It has been known for a long time that darcocorticoids decrease the amount of insulin released in the spleen in vivo (see Non-Patent Document 10). Therefore, due to the inhibitory effect of 11 | 8 -HSD1, it is expected that positive effects will appear in the treatment of diabetes in addition to the effects on liver and fat.

[0006] In addition, inhibition of 11 β -HSD1 activity may have a positive effect on recognition and dementia, possibility of using immunoregulatory function, possibility of intraocular pressure adjustment, application to osteoporosis (Patent Document 1). It is also suggested that 11 β -HSD1 inhibitory drugs can be applied to dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscle atrophy, and neurodegenerative diseases (patents) Reference 2).

For the triazole compound having 11i8-HSDl inhibitory activity, for example, a compound represented by the following formula has been reported!

[0007] Equation (1) (see Patent Document 3)

In the formula, IT represents an adamantyl group or an optionally substituted OCH, OCF, CH, CF,

3 3 3 3 represents a phenyl group, and X represents CH or a single bond. R ² is a hydrogen atom or substituted

2

C alkyl, C alkenyl, CH CO H, CH CO C alkyl, CH CO

1-10 2-10 2 2 2 2 1-6 2

NH alkyl, (CH) C cycloalkyl, (CH) C bicycloalkyl, (CH) Adamantyl, (CH 2) aryl, W represents N alkyl or a single bond; R ³ is water

2 0-2

Elemental or optionally substituted C alkyl, C alkyl, YC cycloal

1-10 2-10 3-9 represents kill, YC bicycloalkyl, Y adamantyl, Y aryl, Y is-(CH)-or

5-12 2 0-2 represents —CH═CH—.

[0008] Equation (2) (see Patent Documents 4 and 5)

[Chemical 2]

In the formula, R ¹ is a group for which a hydroxyl group and a halogen atom isotropic force are selected, A and B are groups for which a halogen atom and a C alkyl group isotropic force are selected, and R ² is an optionally substituted C alkyl group.

1-6 1-14 group, phenol group, etc. is a group selected, R ³ may be substituted, C alkyl

1-14

, C alkenyl, SC alkyl, C aryl, heteroalkyl, heteroaryl groups

2-10 1-6 6-10

Power is the group chosen.

[0009] Equation (3) (see Patent Documents 6, 7, and 8)

[Chemical 3]

In the formula, R ¹ is aryl reel, (CH) aryl, (CH) hetero reel (n is 0-2)

2 n 2 n

R ² is a group selected such as C alkyl group, C alkenyl group, etc.

1-8 2-6

Yes, R ³ is a group selected from C alkyl group, C alkenyl group, etc., R ⁴ is C

1-10 2-10 1-3 Alkyl group, c Acoxy group, etc. Force selected X is amide bond, sulfonamide bond

1-3

Is chosen.

[0010] Equation (4) (see Patent Document 9)

[Chemical 4]

In the formula, Arl and Ar2 represent an aryl group or a heteroaryl group, and R ¹ is a group selected from an alkyl or cycloalkyl force, which may be substituted with a halogen atom, an alkoxy group or the like. And the ring containing Y may be substituted with a halogen atom, an alkyl group, or the like, and represents a cycloalkyl group or a heterocycloalkyl group, and R ² and R ³ are groups selected from a halogen atom, an alkyl group, or the like. Ζ is-(CH (R ¹⁴ )) p,-(CH (R ¹⁴ )) p- N (R ¹⁶ )-(CH (R ¹⁵ )) q- (where p and q are 0-3) Represents a group selected from alicyclic hydrocarbons and heteroalicyclic hydrocarbons, wherein R ¹⁴ , R ¹⁵ , and R ¹⁶ represent groups selected from a halogen atom, a haloalkyl group, etc., and are adjacent to triazole. At the position, it has the feature of forming a cyclic group including Y.

[0012] Equation (5) (see Patent Document 10)

[Chemical 5]

In the formula, R ¹ is a hydrogen atom or an optionally substituted cyclic group, R ² is an optionally substituted cyclic group, and Ar is further substituted, optionally 5 or 6 membered An aromatic heterocycle, L ¹ and L ² are the same or different and may be a bond or a divalent hydrocarbon group which may be substituted;-(C) -X- (C)-(where m, n Is 0 or 1, X is an oxygen atom, sulfur atom, SO,

1-6 m 1-6 n

SO, NR, SO NR, NRSO, R ³ represents a hydrogen atom or an optionally substituted C

2 2 2 1-6 represents an alkyl group).

In addition, the following compounds are known as 3-amino-1,2,4-triazole derivatives, but any disclosure has been made regarding their usefulness!

[0013] Equation (6) (see Patent Document 11)

[Chemical 6]

[0014] In the formula, R ¹ is an optionally substituted cycloalkyl or heterocyclic group, and R ² and R ³ are the same or different from each other, and each optionally substituted lower alkyl, lower alkenyl, Nitrogen containing lower alkynyl, cycloalkyl, aryl or hetero ring group, etc., or R ² and R ³ are in the form of a nitro group and carbon atom to which they are bonded A and B, which may form a heterocycle, are the same or different from each other, and represent halogen, OH, NH, or the like.

2

So, they are bonded together and each substituted with a carbon atom! It may form an alkyl ring or a non-aromatic hetero ring.

(7) (Non-Patent Document 11)

[Chemical 7]

In the formula, R ¹ is a methyl group or a methoxy group, R ² is a phenol group, a benzyl group, or a butyl group, and R ³ is an aryl optionally substituted with a methoxy group, a nitro group, or the like. Represents a group.

[0017] Patent Document 1: International Publication No. 2001Z090090 Pamphlet

Patent Document 2: International Publication No. 2004Z089367 Pamphlet

Patent Document 3: International Publication No. 2003Z065983 Pamphlet

Patent Document 4: International Publication No. 2003Z104207 Pamphlet

Patent Document 5: Pamphlet of International Publication No. 2003Z104208

Patent Document 6: International Publication No. 2004Z058730 Pamphlet

Patent Document 7: International Publication No. 2004Z058741 Pamphlet

Patent Document 8: International Publication No. 2004Z106294 Pamphlet

Patent Document 9: Pamphlet of International Publication No. 2005Z044192

Patent Document 10: Published Patent Publication No. 2005Z170939 Pamphlet

Patent Document 11: International Publication No. 2006Z30805 Pamphlet

Non-Patent Literature l: Jamieson et al., J. Endocrinol, 2000, 165: p.685-692

Non-Patent Document 2: Kotelevtsev, Y. et al., Proc. Natl. Acad. Sci., USA, 1997, 94: 14924-14

929

Non-Patent Document 3: Montague & O'Rahilly, Diabetes, 2000, 49: 883-888

Non-Patent Document 4: Bujalska, I.J., S. Kumar and P.M.Stewart, Lancet, 1997, 349: 1210

-1213

Non-patent document 5: Halleux, C.M. et al., J. Clin. Endocrinol. Metab., 1999, 84: 4097-4105 Non-patent document 6: Walker, B.R. et al., Hypertension, 1998, 31: 891-895

Non-Patent Document 7: Fraser, R. et al., Hypertension, 1999, 33: 1364-1368

Non-Patent Document 8: Woods, SC et al., Science, 1998, 280: 1378-1383 Non-Patent Document 9: Davani, B. et al., J. Biol. Chem., November 10, 2000; 275 (45): 34841-4 Non-Patent Document 10: Billaudel, B. and BCJ Sutter, Horm. Metab Res., 1979, 11: 55 5-560

Non-Patent Document l l: Jun-Ke Wang et al., Tetrahedron Letters, 2005, 46, 5139-5141 Disclosure of Invention

Problems to be solved by the invention

[0018] Diabetes, obesity, glaucoma, osteoporosis, cognitive impairment, immune disorder, depression, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscular atrophy, neurodegenerative disease, And for Syndrome X, we have been searching for a wide variety of compounds in the past to find a therapeutic drug. Is anxious. Under these circumstances, recently, therapies for the above-mentioned diseases using compounds that suppress the activity of human 11 jS-HSDl have been attracting attention. However, it is difficult to find such a compound, and it is still under development.

Means for solving the problem

[0019] A 3-arylamino-1,2,4-triazole derivative represented by the formula (I) or a salt thereof, a prodrug or a solvate thereof, or a pharmaceutically acceptable salt or prodrug thereof A pharmaceutical composition comprising a drug or a solvate thereof as an active ingredient.

The invention's effect

[0020] The present inventors have intensively studied paying attention to the compound represented by the formula (I), a 3-arylamino-1,2,4-triazole derivative, and the compound group has an excellent 11 β -HSD1 inhibitory action. It was found that Furthermore, it has been found that the compound shown in (I) exhibits excellent pharmacokinetics and has high potential as a medicine.

BEST MODE FOR CARRYING OUT THE INVENTION

[Aspect of the present invention]

The present invention relates to a pharmaceutical composition shown in the following embodiment, a novel compound or a combination thereof. It is a pharmaceutical use and a method for producing the compound.

The present invention will be described in detail by the following embodiments.

[0022] <Aspect 1>

Formula (I)

[Chemical 8]

(Where

X is arbitrarily selected from the following substituent group,

The substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

R is chosen as Ra), Rb), Rc), Rd) force,

[0023] Ra)

[Chemical 9]

And

Y in Ra) is selected from the following substituent group:

The substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.

1-3 1-3

, C amino groups optionally substituted mono- or di-substituted by alkyl groups, halogen atoms

1-3

, Cyano group, nitro group, C alkylcarbonylamino group, C alkylsulfonyl group,

1-3 1-3

A C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group,

1-3

[0024] Z is selected from the following substituent group:

The substituent group is

Z1) [Chemical 10]

Or

[Chemical 11]

And

[0025] R ¹ is a group selected from the following substituent group,

The substituent group is

Consisting of a hydrogen atom, a C alkyl group, and a full group,

1-3

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

[0026] R ³ is a group selected from the following substituent group,

The substituent group is

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1 ~ 6 1 ~ 6 l ~ t) 1 ~ 6 group, hydroxy C alkyl group, phenol group, alicyclic hydrocarbon group, water on nitrogen atom

1-6

Elementary atoms are mono- or disubstituted with C alkyl groups! /, May! /, Amino C al

1 to 6 1 to 6 kill group, and aminocarbonyl C alkyl group,

1-6

Consists of

[0027] Alternatively, forming a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R ² and R ³ are bonded In addition, the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,

The substituent group is

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

1 ~! l ~ t) l ~ t) l ~ t) Killcarbonylamino group, including nitrogen atom, N, 0, S force An aminocarbonyl group that may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1-2 children,

[0028] Z2)

[Chemical 12]

o ₂

R ⁴ '° -N "

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

[0029] R ⁴ is a group selected from the following substituent group,

The substituent group is

C alkyl group, full group, alicyclic hydrocarbon group, torino, logenomethyl group, and C

1 to 6 1 to 6 substituted with 12 groups arbitrarily selected from an alkyl group or a phenyl group, may be an amino group, a group selected by force,

[0030] Z3) is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

A hydrogen atom on the atom may be mono- or di-substituted with a C alkyl group.

1-6

C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di

1-6 1-6

Optionally substituted aminocarbonyl C alkyl group, phenyl group, phenyl C

1-6 1-6 alkyl groups, and alicyclic hydrocarbon groups,

May be substituted with 1 or 2 groups arbitrarily selected from

Alternatively, it may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom of the amino group. The alicyclic heterohydrocarbon group may be substituted with 12 groups optionally selected from the following forces,

The substituent group is

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group The hydrogen atom on the mino group, hydroxyl group, or nitrogen atom is a c alkyl group that is mono- or di-substituted.

1-6

Is replaced! /, May! /, Amino group, C alkylsulfonyl group, C alkylsulfonyl group

1-6 1-6

Including mino group, C alkoxyaminocarbo group, aminocarbonyl group, nitrogen atom

1-6

A 5- to 7-membered alicyclic complex hydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S may be formed on the aminoamino group and the nitrogen atom. From an aminocarbol group optionally substituted mono- or di- with a C alkyl group

1-6

Become

[0031] Z4)

[Chemical 13]

0

H

R ⁵ is arbitrarily selected from the following substituent group:

The substituent group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

Selected from a non-carbonyl C alkyl group, a phenyl C alkyl group, N, 0, and S.

1-6 1-6

5 to 7-membered fat containing 1 to 2 heteroatoms arbitrarily selected from 5 to 7-membered alicyclic heterohydrocarbon groups, N, 0, and S C alkyl group substituted with a cyclic heterohydrocarbon group, C alkylcarboxoxy C alkyl group, phenol

1 ~ 6 1 ~ 6 1 ~

Groups, C alkoxy groups, and C alkoxy carbo C alkyl groups,

1 ~! 1 ~ 6 l ~ t)

[0032] Z5)

[Chemical 14]

^R7 Hayato

R ₆ H

R ⁶ and R ⁷ are each independently selected from the following substituent group, and the substituent group is:

Substituted with hydrogen atom, hydroxyl group, C alkoxy group, C alkoxy group or hydroxyl group V, may be substituted with benzyloxy group, C alkoxy group or hydroxyl group !, may! /!

1-6

Phenoxy group, C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al

1 to 6 1 to 6 l to 1 to 6 kill group, hydrogen atom on nitrogen atom is mono- or di-substituted with c alkyl group

1-6

Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono

1-6 1-6

Mono- or di-substituted! /, May! /, Aminocarbonyl C alkyl group, phenyl group,

1-6

And an alicyclic hydrocarbon group,

Or a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R ⁶ and R ⁷ are bonded, and The alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups or C alkoxy groups.

1-6

[0033] Z6)

[Chemical 15]

R ⁸ and R ⁹ are hydrogen atoms or C alkyl groups, or R ⁸ and R ⁹ are bonded.

1-3

It may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including nitrogen atoms to be combined

The alicyclic heterocycle is further a hydroxyl group, a C alkyl group, or a C alkoxy group.

1-3 1-3

Can be replaced

[0034] Z7) hydroxyl group,

Z8) C alkoxy group, C alkyl group, trihalogenomethyl group, halogen atom, cyano

1-6 1-6

Group, and nitro group,

Power is the group chosen,

However, when Z force 8), at least one of (X) n is XI) hydroxyl group,

[0035] Rb)

[Chemical 16]

Or

[Chemical 17]

And

[0036] R ^1Q in Rb) is arbitrarily selected from the following substituent group:

R ^1Q is bonded to either the 3rd or 4th position of the adamantyl group,

The substituent group is

Halogen atom, hydroxyl group, C alkyl group, C alkoxy group, C alkyl carbo-

1 6 1 6 1 6

Group, C alkoxycarbonyl group, C alkoxy C alkyl group, C alkyl

1 6 l t) 1 6 1

1 to 2 of sulfo group, C alkyl sulfole C alkyl group, C alkyl group

1 6 l t) l o

It consists of an optionally substituted aminoamino group, a hydrogen atom, and an amino group, and the hydrogen atom on the nitrogen atom of the amino group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, C

1 1 6 1 6 1 6 1 6 Alkoxy group, hydrogen atom on nitrogen atom is mono- or disubstituted with c alkyl group

1 6

Optionally on amino C alkyl group, hydroxyaminocarbonyl group, on nitrogen atom

1 6

Aminocarbons in which the hydrogen atom may be mono- or di-substituted with a c alkyl group

1 6

-Group, aminocarbole C alkyl group, hydrogen atom on nitrogen atom is C alkyl

1 6 1 6

An aminosulfol group, a phenyl group, a phenyl C alkyl group, and an alicyclic hydrocarbon group, which may be mono- or di-substituted by a group,

1 6

May be substituted with 1 or 2 groups arbitrarily selected from

Provided that when R is Rb), (X) n is at least XI) a hydroxyl group;

[0037] Rc)

[Chemical 18]

And

R ¹¹ in Rc) is arbitrarily selected from the following substituent group:

The substituent group is

A hydroxyl group, a C alkoxy group, a halogen atom, and a hydrogen atom,

1 6

m represents an integer of 1—2, Provided that when R is Rc), at least one of (X) n or (R ¹¹ ) !!! is a hydroxyl group;

[0038] Rd)

[Chemical 19]

[0039] Y in Rd) is the same as the definition of Y in Ra)

Provided that when R is Rd), at least one of (X) n is XI) a hydroxyl group,

(X) n-substituted phenyl group 4-hydroxyphenol group, 3-hydroxyphenol group

-Hydroxyl group, 2-hydroxyphenyl group, 4-fluoro-3 hydroxyphenyl group, 4-chlorophenol 3-hydroxyphenyl group, 3-chlorophenyl 4-hydroxyphenol group, 3-hydroxymonoyl

4 methylphenol group, 4-hydroxy 3-methylphenol group,

R is 2-methylphenyl, 2-chlorophenol, 2-methoxyphenyl, or 1 (4-fluorophenyl) 1 methylethyl, where “→” is a bond. Represents. )

[0040] Preferably, in formula (I):

n is 1 or 2, and X is bonded to the 3-position and / or 4-position of the phenyl group.

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

[0041] <Aspect 1 1>

In embodiment 1, when R is Ra, a compound defined in the same manner as in the above formula (I), except that Z defined in the above is selected from the substituent group of Z1 to Z6 Or a pharmaceutically acceptable salt, prodrug or solvate thereof. That is, in embodiment 1, only Z7 and Z8 are not included! /.

Examples not included in this embodiment 1-1 include the following compounds, or pharmaceutically acceptable salts, prodrugs or solvates thereof.

3— [N— (4-Fluorophenol) N-methylamino] — 5— (4-hydroxy-2-methoxyphenyl) 4-methyl 4H— 1, 2, 4 Triazole; 1 4 Hide Roxyphenyl) — 5— [N— (4-Fluorophenol) —N—Methylamino] —4-Methyl — 4H— 1, 2, 4 Triazole; 3— (4 Hydroxy-2-methoxyphenyl) — [N

— (4-Methoxyphenol) -N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole; 3— [N— (4-Fluoro-3-methylphenol) —N-Methylamino] — 5 — (4-Hydroxy-2-methoxyphenyl) 1-4-Methyl 4H—1, 2, 4 Triazole; 3— [N-(4-Fluoro-3-methoxyphenol) N-Methylamino] — 5— ( 4-Hydroxy-1-methoxyphenyl) -4-methyl-4H—1, 2, 4 Triazole; 3 -— (4 Fluoro-2-methoxyphenol) 5— [N— (4-hydroxyphenol) N-methylamino] -4 — Methyl 4H— 1, 2, 4 Triazole; 3— (4 Hydroxy 2-methoxyphenyl) 1 5

— [N— (4-Hydroxyphenol) -N-methylamino] — 4-Methyl 4H—1, 2, 4— Triazolene; 3— (2 Chloro-4-hydroxyphenol) 5— [N— (4-Hydroxyphenol) ) N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (2 Black mouth —4-Fluorophenol) — 5— [N— (4-Hydroxyphenol) —N-Methylamino] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol) N-Methylamino] — 5— (4 Fluoro-2-methoxyphenol) 4-Methyl-4H-1 , 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol) -N-Methylamino] — 5— (4-hydroxy-2-methoxyphenol) 4-Methyl 4H— 1, 2, 4 Triazolone 3— (2 Black mouth 4 Funoleo mouth Hue-Nore) One 5— [N— (4 Funore Oro 3 Hydroxy Hue Le) Single N- Mechiruamino] - 4-methyl-4H-1, 2, 4 tri Azoru.

[0042] <Aspect 1 2>

In embodiment 1, compounds excluding the structures shown in Example 1 to Example 73, or pharmaceutically acceptable salts, prodrugs or solvates thereof.

[0043] <Aspect 1 3>

In Embodiment 1, compounds excluding the structures shown in Example 1 to Example 87, or pharmaceutically acceptable salts, prodrugs or solvates thereof.

[0044] <Aspect 2>

Formula (Π) [Chemical 20]

(Where

χ is arbitrarily selected from the following substituent group force,

The substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom, l to t) 1 to 6

Consists of

n represents an integer from 1 to 3,

[0045] Y is selected from the following substituent group:

1-3 1-3

1-3

, Cyano group, nitro group, C alkylcarbonylamino group, C alkylsulfonyl group,

1-3 1-3

A C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group,

1-3

[0046] Z is selected from the following substituent group:

The substituent group is

Z1)

[Chemical 21] o

Or

[Chemical 22]

And

[0047] R ¹ is a group selected from the following substituent group,

The substituent group is Consisting of a hydrogen atom, a C alkyl group, and a full group,

13

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

13

R ³ is a group selected from the following substituent group,

The substituent group is

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1 6 1 6 l t) 1 6 group, hydroxy C alkyl group, phenol group, alicyclic hydrocarbon group, water on nitrogen atom

1 6

1 6 1 6 kill group, and aminocarbonyl C alkyl group,

1 6

Consists of

Alternatively, a 5 7-membered alicyclic heterohydrocarbon group containing a nitrogen atom to which R ² and R ³ are bonded and containing 12 heteroatoms arbitrarily selected from N 0 S is formed, The cyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,

The substituent group is

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

1 3 lt) lt) lt) Kill carbonylamino group, including nitrogen atom, N 0 S force Containing 1 to 2 hetero atoms of choice 5 to 7-membered alicyclic heterohydrocarbon group An aminocarbonyl group,

[0049] Z2)

[Chemical 23]

〇 2

R ^z

And

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group, R ⁴ is a group selected from the following substituent group,

The substituent group is

1 to 6 1 to 6 may be substituted with 1 or 2 groups arbitrarily selected from an alkyl group or a phenyl group, and may be an amino group,

Power is the group chosen,

[0050] Z3) is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di

1-6 1-6

Optionally substituted aminocarbonyl C alkyl group, phenyl group, phenyl C

1-6 1-6 alkyl groups, and alicyclic hydrocarbon groups,

May be substituted with 1 or 2 groups arbitrarily selected from

[0051] Alternatively, a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S is formed, including the nitrogen atom of the amino group. Moyugu The alicyclic heterohydrocarbon group may be substituted with 12 groups selected arbitrarily in the following force,

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group

1 ~ 6 1 ~ 6 1 ~ 6 Mino group, hydroxyl group, hydrogen atom on nitrogen atom is c alkyl group, mono- or di-substituted

1-6

1-6 1-6

Including mino group, C alkoxyamino carbo group, amino carbonyl group, nitrogen atom,

1-6

A 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S may form an aminocarbo group and hydrogen on the nitrogen atom Atom is C

1-6 mono- or di-substituted with an alkyl group, which may be an aminocarbol group

[0052] Z4)

[Chemical 24]

R ⁵ is arbitrarily selected from the following substituent group:

The substituent group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

1-6 1-6

C alkyl group substituted with 5- to 7-membered alicyclic heterohydrocarbon group containing 1-2 heteroatoms, N, 0, S force 1-2 containing optionally selected heteroatoms 5 ~

1-6

7-membered C alkyl carbo-loxy C alkyl group, phenyl group, C alkoxy group

1 ~! 1-6 1-6

, And a C alkoxy carbo C alkyl group,

1-6 1-6

[0053] Z5)

[Chemical 25]

0

R ⁷ , N people N,

R ^{e H}

Substituted with hydrogen atom, hydroxyl group, C alkoxy group, C alkoxy group or hydroxyl group

1-6 1-6

V, may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ヽ

1-6

Phenoxy group, C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al

1 ~! l to t) 1 to 6 丄 to a hydrogen atom on the kill group or nitrogen atom is mono- or disubstituted with a c alkyl group

1-6

Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono

1-6 1-6

Mono- or di-substituted! /, May! /, Aminocarbonyl C alkyl group, phenyl group,

1-6

And an alicyclic hydrocarbon group,

1-6

[0054] Z6)

[Chemical 26]

R ⁸ 0 R ⁸ and R ⁹ are hydrogen atoms or C alkyl groups, or R ⁸ and R ⁹ are bonded.

1-3

1-3 1-3

Can be replaced

[0055] Z7) hydroxyl group,

Z8) C alkoxy group, C alkyl group, trihalogenomethyl group, halogen atom, cyano

1-6 1-6

Group, and nitro group,

Power is the group chosen,

However, when Z force 8), at least one of (X) n is XI) hydroxyl group,

[0056] Alternatively,

Formula (ΙΠ)

[Chemical 27]

(Where

X, Y and n have the same definition as in formula (I),

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ³ is a group selected from the following substituent group,

The substituent group is

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1-6 l-t) 1-6 1-0 group, hydroxy C alkyl group, phenol group, alicyclic hydrocarbon group, water on nitrogen atom

1-6

1 to 6 1 to 6 kill group, and aminocarbonyl C alkyl group,

1-6

Consists of Or a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including a nitrogen atom to which R ² and R ³ are bonded, The alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,

[0057] The substituent group includes

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

1 to 6 1 to 6 1 to 6 1 to 6 may comprise a carbonyl group, and a nitrogen atom may be used to form an alicyclic heterocycle or an aminocarbo group)

Alternatively,

Formula (IV)

[Chemical 28]

(Where

X, Y and n have the same definition as in formula (I),

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ⁴ is a group selected from the following substituent group,

[0058] The substituent group includes

C alkyl group, phenyl group, alicyclic hydrocarbon group, torino, logenomethyl group, and C

Power is the group chosen. Or a pharmaceutically acceptable salt, prodrug or solvate thereof.

Preferably, in the definition of each compound of formula (11), formula (III) or formula (IV), n is 1 or 2, and (X) the phenyl group substituted with n is in the 3-position or X is mono-substituted at position 4 Or a phenyl group in which any X is di-substituted at the 3- or 4-position, and the definitions of other Y, 、, R ² , R ³ and R ⁴ are as described above. )

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

Formula (II-a)

[Chemical 29]

(In the formula (Π-a), the definitions of X, Υ, Z, and n are the same as those in the formula (II) of embodiment 2.

However, at least one of (X) n and Z is a hydroxyl group. ) And

Above all,

Formula (III-a)

[Chemical 30]

(Wherein R ² , R ³ , X, Y and n have the same definition as in formula (III) of embodiment 2,

(X) At least one of n is XI) a hydroxyl group. ) And

Alternatively,

Formula (IV-a)

[Chemical 31]

(Wherein R ² , R ⁴ , X, Y and n have the same definition as in formula (IV) of embodiment 2,

(X) At least one of n is XI) a hydroxyl group. Or a pharmaceutically acceptable salt, prodrug or solvate thereof. Preferably, in the definition of each compound of formula (Il-a), formula (ΠΙ-a), and formula (IV-a), n is 1 or 2, and a phenyl group substituted with (X) Are compounds in which X is mono-substituted on the 3- or 4-position, or any X is di-substituted on the 3, 4-position or a pharmaceutically acceptable compound thereof. Salt, prodrug or solvate thereof.

[0062] <Aspect 3-1>

In the formula (Π-a) of the embodiment 3, the compounds defined by the formula (Π-a) or the pharmaceutically acceptable compounds thereof are similarly defined except that the substituent group strengths of ∑7 and Z8 are selected. Salts, prodrugs or solvates thereof.

That is, this embodiment 3-1 has the same definition as the formula (II) of the formula (II) in the formula (II-a), and the Z,

Z7) hydroxyl group,

Z8) C alkoxy group, C alkyl group, trihalogenomethyl group, halogen atom, cyano

1-6 1-6

Group, and nitro group,

The substituent group force is the group that is selected,

However, when Z force 8), at least one of (X) n is a hydroxyl group,

Or a pharmaceutically acceptable salt, prodrug or solvate thereof defined by the formula (Π-a) defined as:

[0063] <Aspect 4>

Formula (I-a)

[Chemical 32]

(In the formula (a), the definitions of X and n are the same as those in the embodiment 1,

R is chosen as Rb), Rc), Rd) force, respectively

Rb)

[Chemical 33]

Or

[Chemical 34]

And

[0064] R ^1Q in Rb) is arbitrarily selected from the following substituent group:

R ^1Q is bonded to either the 3rd or 4th position of the adamantyl group,

The substituent group is

[0065] Halogen atom, hydroxyl group, C alkyl group, C alkoxy group, C alkyl carbonyl

1-6 1-6 1-6

Group, C alkoxycarbonyl group, C alkoxy C alkyl group, C alkyl

1 ~ 6 l ~ t) 1 ~ 6 1 ~

1 to 2 of sulfo group, C alkyl sulfole C alkyl group, C alkyl group

1 ~ 6 l ~ t) l ~ o

[0066] C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, C

1 ~! 1-6 1-6 1-6 1-6 alkoxy group, hydrogen atom on nitrogen atom is mono- or di-substituted with c alkyl group

1-6

Optionally on amino C alkyl group, hydroxyaminocarbonyl group, on nitrogen atom

1-6

-Group, aminocarbole C alkyl group, hydrogen atom on nitrogen atom is C alkyl

1-6 1-6

Aminosulfol groups, phenol groups, phenols which may be mono- or di-substituted by groups

1 to 2 groups selected from the group consisting of an alkyl group and an alicyclic hydrocarbon group.

1-6

It may be exchanged

Provided that when R is Rb), at least one of (X) is XI) a hydroxyl group;

Rc)

[Chemical 35]

And

R ¹¹ in Rc) is arbitrarily selected from the following substituent group:

[0067] The substituent group includes A hydroxyl group, c an alkoxy group, a halogen atom, and a hydrogen atom,

1 6

m represents an integer of 1 2

Provided that when R is Rc), at least one of (X) n or (R ¹¹ ) !!! is a hydroxyl group;

Rd)

[Chemical 36]

[0068] Y is selected from the following substituent group:

1 3 1 3

C amino group optionally substituted mono- or di-substituted by alkyl group, halogen atom

13

, Cyano group, nitro group, C alkyl carbolumino group, C alkyl sulfol group,

1 3 1 3

C consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbol group,

13

[0069] However, when R is Rd), at least one of (X) is XI) a hydroxyl group,

(X) The n-substituted phenyl group is a 4-hydroxyphenyl group, a 3-hydroxyphenyl group, a 2-hydroxyphenyl group, a 4-fluoro-3 hydroxyphenyl group, a 4-chloro-3-hydroxyphenyl group. Group, 3-chloro 4-hydroxyphenol group, 3-hydroxy mono-4-methylphenol group, 4-hydroxy 3-methylphenol group,

R is a 2-methylphenol group, a 2-chlorophenol group, a 2-methoxyphenyl group, or a 14-fluorophenyl group).

[0070] Preferably, the formula (I-a)! /

n is 1 or 2, and X is bonded to the 3-position and Z- or 4-position of the phenyl group. )

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

[0071] <Aspect 5>

Formula (Π— b)

[Chemical 37]

[0072] (where

X is arbitrarily selected from the following substituent group,

The substituent group is

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

Y is selected from the following substituent group:

The substituent group includes c alkoxy group, C alkyl group, trihalogenomethyl group, C

1 to 3 1 to 3 1 to 3 Amino group, halogen atom, cyano group, nitro group, C alkylcarbolumino group, C alkylsulfol group, C alkyl which may be mono- or di-substituted with an alkyl group

1 to 3 1 to 3 1 to 3 consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group,

Z is selected from the following substituent group:

The substituent group is

1)

[Chemical 38]

Or

[Chemical 39]

O

And

[0073] R ¹ is a group selected from the following substituent group,

The substituent group is

A hydrogen atom, a C alkyl group, and a phenyl group, or

1-3

R ² is a group selected from the following substituent group, The substituent group is

A hydrogen atom and a c alkyl group,

1-3

R ³ is a group selected from the following substituent group,

[0074] The substituent group includes

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1-6

1 to 6 1 to 6 kill group, and aminocarbonyl C alkyl group,

1-6

[0075] Alternatively, it forms a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R ² and R ³ are bonded. In addition, the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,

[0076] The substituent group includes

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

1 ~! l ~ t) l ~ t) l ~ t) Kill carbonylamino group, including nitrogen atom, N, 0, S force 1 to 2 heteroatoms selected arbitrarily 5 to 7-membered fat An aminocarbonyl group that may form a cyclic heterohydrocarbon group,

2)

[Chemical 40]

o ₂

R ⁴ ' ^S , I

R ^z

And

R ² is a group selected from the following substituent group,

[0077] The substituent group includes

A hydrogen atom, a C alkyl group,

1-3

R ⁴ is a group selected from the following substituent group,

The substituent group is

C alkyl group, full group, alicyclic hydrocarbon group, torino, logenomethyl group, and C An amino group, which may be substituted with 12 or more groups arbitrarily selected from an alkyl group or a phenyl group;

Power is the group chosen,

Z3) is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di

1-6 1-6

Optionally substituted aminocarbonyl C alkyl group, phenyl group, phenyl C

1-6 1-6 alkyl groups, and alicyclic hydrocarbon groups,

May be substituted with 1 or 2 groups arbitrarily selected from

[0078] Alternatively, a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S is formed, including the nitrogen atom of the amino group. Moyugu The alicyclic heterohydrocarbon group may be substituted with 12 groups selected arbitrarily in the following force,

[0079] The substituent group includes

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group

1-6

1-6 1-6

Mino group, C alkoxyamino carbo group, including nitrogen atom, optionally from N, 0, S

1-6

A 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 selected heteroatoms may be formed, and the hydrogen atom on the nitrogen atom is a C alkyl group.

1-6

Mono- or di-substituted, which may be an aminocarbonyl group,

Z4)

[Chemical 41]

0

H

R ⁵ is arbitrarily selected from the following substituent group:

The substituent group is [0080] C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

1-6 1-6

1 ~ 6 1 ~ 6 1 ~

Groups, C alkoxy groups, and C alkoxy carbo C alkyl groups,

1 ~! 1 ~ 6 l ~ t)

Z5)

[Chemical 42]

0

^R7 , N people

R ₆ H

[0081] substituted with a hydrogen atom, a hydroxyl group, a C alkoxy group, a C alkoxy group or a hydroxyl group

1-6 1-6

V, may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ヽ

1-6

Phenoxy group, C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al

1-6

Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono

1-6 1-6

Mono- or di-substituted! /, May! /, Aminocarbonyl C alkyl group, phenyl group,

1-6

And an alicyclic hydrocarbon group,

[0082] Alternatively, forming a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R ⁶ and R ⁷ are bonded The alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups or C alkoxy groups.

1-6

Z6)

[Chemical 43]

1-3

[0083] The alicyclic heterocycle is further substituted with a hydroxyl group, a C alkyl group, or a C alkoxy group.

1-3 1-3

Can be replaced

Z8) C alkoxy group, C alkyl group, trihalogenomethyl group, halogen atom, cyano

1-6 1-6

Group, and nitro group,

Power is the group chosen,

However, when Z force 8), at least one of (X) n is XI) hydroxyl group,

However, “→” in the formula represents a bond. )

[0084] Alternatively,

Formula (III-b)

[Chemical 44]

(Where

R ² , Y and n have the same definition as in formula (III) of embodiment 2,

X is X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen

1-6 1-6

An atom, a group arbitrarily selected from

Alternatively,

Formula (IV-b)

[Chemical 45]

[0085] (where

R ² , R ⁴ , Y and n have the same definition as in formula (IV) of embodiment 2, X is X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen

1-6 1-6

A group arbitrarily selected from atoms. Or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[0086] Preferably, in the definition of each compound of formula (11), formula (Ill-b), formula (IV-b):

n is 1 or 2, and (X) n-substituted phenyl group is a mono-substituted phenyl group at the 3- or 4-position, or any X-disubstituted at the 3- or 4-position This is a ferrule group.

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

[0087] <Aspect 6>

Formula (Π-c)

[Chem 46]

(Where

X is arbitrarily selected from the following substituent group,

The substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

[0088] n represents an integer of 1 3

Y is selected from the following substituent group:

1-3 1-3

1-3

, Cyano group, nitro group, C alkylcarbonylamino group, C alkylsulfonyl group,

1-3 1-3

A C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group,

1-3

[0089] Z is selected from the following substituent group:

The substituent group is

Z1) [Chemical 47]

And

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ³ is a group selected from the following substituent group,

[0090] The substituent group includes

Hydrogen atom, C alkoxy group, C alkyl group, hydroxy C alkyl group, and C

1-6 1-6 1-6 1 alkoxy C alkyl group,

6 1-6

C alkoxy C alkyl group, C alkyl group, and hydroxy C alkyl group,

1 ~ 6 1 ~ ο 1 ~ 6 1 ~ 6

May be substituted with 1 or 2 groups arbitrarily selected from

Alternatively, it may contain a nitrogen atom of the amino group to form a 2-oxoxazolidine 3-yl group.

Z4)

[Chemical 48]

And R5 is arbitrarily selected from the following substituent group forces:

[0091] The substituent group includes

C alkyl group, hydroxy C alkyl group, and C alkoxy C alkyl group

1 ~! 1-6 1-6 1-6

Consists of

Z5)

[Chemical 49]

Hydrogen atom, C alkoxy group, C alkyl group, hydroxy C alkyl group, and C

1-6 1-6 1-6] an alkoxy c alkyl group,

6 1-6

Z7) hydroxyl group,

Z8) C alkoxy group, C alkyl group, trifluoromethyl group, halogen atom, force

1-6 1-6

A group of choice,

However, when Z is Z8), at least one of (X) n is XI) a hydroxyl group.

However, “→” in the formula represents a bond. )

And again,

Formula (Π-1)

[Chemical 50]

(Where

The definitions of X, Y, Ζ, and η are the same as those in Formula (II) in Embodiment 2,

However, at least one of (、) η and Ζ is a hydroxyl group. )

Alternatively,

Formula (Π-2)

[Chemical 51]

(Where

X is arbitrarily selected from the following substituent group,

The substituent group is

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of [0093] n represents an integer of 1 3

Y is selected from the following substituent group:

1 to 3 1 to 3 1 to 3 alkylthio group, and aminocarbol group,

[0094] Z is selected from the substituent groups Zl), Z2), Z3), Z4), Z5), Z6), and Z7) in the formula (II) of Embodiment 2.

Preferably, in Formula (11), Formula (II-1), and Formula (Π-2),

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

[0095] <Aspect 7>

Formula (Il-d)

[Chemical 52]

(Where

X is arbitrarily selected from the following substituent group,

[0096] The substituent group includes

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

Y is selected from the following substituent group:

[0097] The substituent group includes a hydroxyl group, a C alkoxy group, a C alkyl group, and a trihalogenomethyl group.

1-3 1-3

1-3

, Cyano group, nitro group, C alkylcarbonylamino group, C alkylsulfonyl group, c consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbol group,

1-3

Z is selected from the following substituent group:

The substituent group is

Z1)

[Chemical 53]

^R V 0

Or

[Chemical 54]

And

R ¹ is a group selected from the following substituent group,

The substituent group is

Consisting of a hydrogen atom, a C alkyl group, and a full group,

1-3

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ³ is a group selected from the following substituent group,

[0098] The substituent group includes

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1-6

1-6 1-6 kill group and aminocarbonyl C alkyl group

1-6

Consists of

[0099] However,

3— (4-Carboxyl 2-methoxyphenol) 5— [N— (4 Fluorophenol) N-Methylamino] — 4-Methyl-4H— 1,2,4 Triazole, 3— (4 Aminocarbo- 2—Methoxyphenyl) 5— [N— (4-Fluorophenol) —N—Methylamino] —4-Methyl—4H— 1,2,4 Triazole, and 3— [N— (4 Fluorophenol) —N —Methylamino] — 5— {2-Methoxy-1 4 -— [(2-Methoxyethyl) aminocarbol] phenol} — 4-Methyl-4H— Not 1,2,4 Triazole

[0100] Alternatively, it forms a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, including the nitrogen atom to which R ² and R ³ are bonded. In addition, the alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,

The substituent group is

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

Z2)

[Chemical 55]

o ₂

R ⁴ ' ^S , I

R ^z

And

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ⁴ is a group selected from the following substituent group,

The substituent group is

Power is the group chosen,

[0101] Z3) is an amino group, and the hydrogen atom on the nitrogen atom of the amino group is C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

2-6 3-6 1-6 1-6

1-6

C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di

1-6 1-6

Optionally substituted aminocarbonyl C alkyl group, phenyl group, phenyl C

1-6 1-6 alkyl groups, and alicyclic hydrocarbon groups,

1 or 2 is substituted with an arbitrary group selected from

[0102] Alternatively, a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S including the nitrogen atom of the amino group may be formed Yogu

However, the alicyclic heterohydrocarbon group is a 2-oxoxazolidine 3-yl group, a morpholino group, a 4- (4-1 morpholinocarbo) piperidine-1-yl group, or a 4 Acetyl rubiperazine

The alicyclic heterohydrocarbon group may be substituted with 12 groups optionally selected as follows.

[0103] The substituent group includes

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group

1-6

1-6 1-6

1-6

Mono- or di-substituted, which may be an aminocarbonyl group,

Z4)

[Chemical 56]

0

H

R ⁵ is arbitrarily selected from the following substituent group:

[0104] The substituent group includes

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen A hydrogen atom on the atom may be mono- or di-substituted with a c alkyl group.

1-6

1-6 1-6

2 ~ 6 1 ~ 6 2 ~ 6

Groups, C alkoxy groups, and C alkoxy carbo C alkyl groups,

3-6 1-6 1-6

Z5)

[Chemical 57]

^R7 Hayato

R ₆ H

R ⁶ and R ⁷ are each independently selected arbitrarily from the following substituent groups:

[0105] The substituent group includes

1-6 1-6

V, may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ヽ

1-6

Phenoxy group, C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al

1-6

Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono

1-6 1-6

Mono- or di-substituted! /, May! /, Aminocarbonyl C alkyl group, phenyl group,

1-6

And an alicyclic heterohydrocarbon group,

[0106] Alternatively, a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R ⁶ and R ⁷ are bonded, is formed. The alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups and C alkoxy groups.

1-6

However, when R ⁶ , R ^7a — is a hydrogen atom, the other is not a hydrogen atom, methoxy group or ethoxy group.

Z6)

[Chemical 58]

R ⁸ 0 R ⁸ and R ⁹ are a hydrogen atom or a C alkyl group, or contain the nitrogen atom.

1-3

It may form a 5- to 7-membered alicyclic complex hydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0 and S, provided that the alicyclic heterohydrocarbon group Is not a morpholino group

The alicyclic heterohydrocarbon group further includes a hydroxyl group, a C alkyl group, and a C alkoxy group.

1 to 3 1 to 3 groups may be substituted with 1 or 2 groups,

Power is the group chosen,

Preferably, in formula (Π):

However, “→” in the formula represents a bond. )

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

[0107] <Aspect 8>

Formula (Π-e)

[Chemical 59]

(Where

X is arbitrarily selected from the following substituent group,

The substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

[0108] Y is selected from the following substituent group,

1-3 1-3

1-3

, Cyano group, nitro group, C alkyl carbolumino group, C alkyl sulfol group, c consisting of an alkylthio group, a trifluoromethoxy group, and an aminocarbol group,

1-3

Z is selected from the following substituent group:

The substituent group is

Z1)

[Chemical 60]

^R V 0

Or

[Chemical 61]

And

R ¹ is a group selected from the following substituent group,

The substituent group is

Consisting of a hydrogen atom, a C alkyl group, and a full group,

1-3

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ³ is a group selected from the following substituent group,

The substituent group is

Hydroxyl group, phenyl group, alicyclic hydrocarbon group, hydrogen atom on nitrogen atom is C alkyl

An amino-C alkyl group optionally mono- or di-substituted with 1 to 6 groups, and an amino

1-6

Bonyl C alkyl group,

1-6

Consists of

Alternatively, a 5-7 alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R ² and R ³ are bonded, is formed, and The cyclic heterohydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group, The substituent group is

[0110] Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

1 3 lt) lt) lt) Nylon atom and N 0 S force 1 or 2 Heterocyclic heterocyclic hydrocarbon group An aminocarbonyl group that may be formed,

Z2)

[Chemical 62]

〇 2

R N and

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

13

R ⁴ is a group selected from the following substituent group,

The substituent group is

1 6 1 6 Substituted by 1 or 2 groups arbitrarily selected from an alkyl group or a phenyl group, an amino group,

Power is the group chosen,

[0111] Z3) an amino group, and the hydrogen atom on the nitrogen atom of the amino group is

The hydrogen atom on the nitrogen atom may be mono- or disubstituted with a C alkyl group.

1 6

Iamino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group

1 6 1 6

Is di-substituted aminocarbonyl C alkyl group, phenyl group, phenyl

1 6

C alkyl group and alicyclic hydrocarbon group,

1 6

May be substituted with 1 or 2 groups arbitrarily selected from

[0112] Alternatively, a 5 7-membered alicyclic heterohydrocarbon group or alicyclic heterohydrocarbon group containing 12 heteroatoms arbitrarily selected from N 0 S including the nitrogen atom of the amino group is formed. You may, However, the alicyclic heterohydrocarbon group is removed with a 2-oxoxazolidine 3-yl group. The alicyclic heterohydrocarbon group may be substituted with 12 groups optionally selected as follows. Often,

The substituent group is

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group

1 ~ 6 l ~ 1 ~ ο

The hydrogen atom on the mino group, hydroxyl group, or nitrogen atom is a c alkyl group that is mono- or di-substituted.

1-6

The amino group which may be substituted, the hydrogen atom on the nitrogen atom is mono- or c-alkyl group

1-6

Or di-substituted aminocarbonyl group, C alkylsulfonyl group, C

1 to 6 1 to 6 containing an alkylsulfonylamino group, a C alkoxyaminocarbonyl group, and a nitrogen atom

1-6

A 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, or an aminoamino group,

Z4)

[Chemical 63]

R ⁵ is arbitrarily selected from the following substituent group:

The substituent group is

1-6

Iaminocarbonyl C alkyl group, phenyl C alkyl group, N, 0, S

1-6 1-6

5 to 7-membered alicyclic ring containing 1 to 2 heteroatoms arbitrarily selected from 5 to 7-membered alicyclic heterohydrocarbon group, N, 0, S containing 1 to 2 selected heteroatoms C alkyl group substituted by a heterohydrocarbon group, C alkylcarboxoxy C alkyl

1 ~!丄 ~ 1 ~ 6

Group, vinyl group, C alkoxy group, and C alkoxy carbo C alkyl group

1 ~ 6 1 ~ 6 1 ~

Consists of

Z5)

[Chemical 64]

[0114] The substituent group includes

Substituted with hydroxyl group, C alkoxy group or hydroxyl group !, may! /, Benzyloxy group, C

1-6

Substituted with alkoxy groups or hydroxyl groups, phenoxy groups, water on nitrogen atoms

1-6

1-6 1-6 Kill group, hydrogen atom on nitrogen atom is mono- or disubstituted with c alkyl group

1-6

An aminocarbonyl C alkyl group, a phenyl group, and an alicyclic hydrocarbon group,

1-6

Consists of

[0115] Alternatively, a 5- to 7-membered alicyclic heterohydrocarbon group including a nitrogen atom to which R ⁶ and R ⁷ are bonded, including 1 to 2 heteroatoms arbitrarily selected from N, 0, and S And the alicyclic complex hydrocarbon group may be substituted with 12 hydroxyl groups or C alkoxy groups.

1-6

Z6)

[Chemical 65]

R ⁸ and R ⁹ are a hydrogen atom or a C alkyl group,

1-3

[0116] Alternatively, a 5- to 7-membered heterocyclic hydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R ⁸ and R ⁹ are bonded The alicyclic heterocycle may be further formed with a hydroxyl group, a C alkyl group, or a C alkoxy group.

1-3 1-3

Can be replaced

Z8) cyano group and -tro group,

Power is the group chosen,

However, when Z force 8), at least one of (X) n is XI) hydroxyl group,

Preferably, in formula (Π):

[0117] However, “→” in the equation represents a bond. )

Or a pharmaceutically acceptable salt, prodrug or a solution thereof. Solvate.

[0118] <Aspect 9>

Formula (I-b)

[Chemical 66]

[0119] (where

X is arbitrarily selected from the following substituent group,

The substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

R is chosen as Rb), Rc), Rd) force, respectively

Rb)

[Chemical 67]

[Chemical 68]

And

R ^1Q in Rb) is arbitrarily selected from the following substituent group:

R ^1Q is bonded to either the 3rd or 4th position of the adamantyl group,

[0120] The substituent group includes

Halogen atom, hydroxyl group, amino group, C alkyl group, C alkoxy group, C alkyl

1 to 6 1 to 6 1 to carbo group, c alkoxy carbo group, C alkoxy C alkyl group, C

1 to 6 l to t) l to ol to o alkylsulfol group, C alkylsulfol C alkyl group, C alkyl group 1 or 2 may be substituted with an aminocarbo group and a hydrogen atom, and the hydrogen atom on the nitrogen atom of the amino group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, C

1 ~ 6 l ~ t) l ~ o l ~ o 丄 ~ t) Alkoxy group, hydrogen atom on nitrogen atom is mono- or di-substituted with c alkyl group

1-6

Optionally on amino C alkyl group, hydroxyaminocarbonyl group, on nitrogen atom

1-6

-Group, aminocarbole C alkyl group, hydrogen atom on nitrogen atom is C alkyl

1-6 1-6

1-6

May be substituted with 1 or 2 groups arbitrarily selected from

However, when R is Rb), at least one of all X is XI) hydroxyl group,

Rc)

[Chem 69]

And

R ¹¹ in Rc) is arbitrarily selected from the following substituent group:

The substituent group is

A hydroxyl group, a C alkoxy group, and a halogen atom,

1-6

m represents an integer of 0—2,

Provided that when R is Rc) at least one of all X or R ¹¹ is a hydroxyl group,

[Chemical 70]

And

Y in Rd) is the same as Y in Ra) of embodiment 1.

However, when R is Rd), at least one of all X is XI) hydroxyl group, (X) The n-substituted phenyl group is a 4-hydroxyphenyl group, a 3-hydroxyphenyl group, a 2-hydroxyphenyl group, a 4-fluoro-3-hydroxyphenyl group, a 4-chlorophenyl group, 3- When a hydroxyphenol group, 3-chlorophenol 4-hydroxyphenol group, 3-hydroxy-4-methylphenyl group, 4-hydroxy-3-methylphenol group,

R is not 2-methylphenol group, 2-chlorophenol group, 2-methoxyphenyl group, or 1 (4-fluorophenyl) 1 methylethyl group.

However, “→” in the formula represents a bond.

[0123] Preferably, in formula (I):

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.

[0124] <Aspect 9 1>

An embodiment wherein in formula (I-b) of embodiment 9, R is Rc. That is, a compound represented by the following formula (I-c) or a pharmaceutically acceptable salt, prodrug or solvate thereof.

[Chemical 71]

(In the formula, X is the following substituent group force is arbitrarily selected, and the substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

[0125] R is Rc)

[Chemical 72]

And

R ¹¹ in Rc) is arbitrarily selected from the following substituent group: The substituent group is

A hydroxyl group, a c alkoxy group, and a halogen atom,

1-6

m represents an integer of 0—2,

“→” in the chemical formula represents a bond,

Provided that at least one of all X or R ¹¹ is a hydroxyl group,

[0126] Preferably,

[0127] <Aspect 10>

Compound group consisting of:

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— (2—Methoxy—4 nitrophenol) mono 4—Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) — N-methylamino] — 4-methyl-5- [4-tro-2- (trifluoromethyl) phenol] —4Η-1, 2, 4 triazole; 3- [N— (4 fluoro-) 3 Methylphenol) —N-Methylamino] — 5— (2-Methoxy-4 -trophenyl) — 4-Methyl-4H—1, 2, 4 Triazole; 3— (4 Amino-2-methoxyphenol) 5— [N— (4 Fluorophenol) — N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (4—Dimethylamino 2-methoxyphenol) 5— [N— (4 —Fluorophenol) N-Methylolamino] 4-Methanole 4H— 1, 2, 4 Triazolene; 3— (4-Cethinoleamino-2-methoxyphenyl) 5— [N (4-Fluorophenol) N-methylamino] —4-methyl 4H—1, 2, 4 triazole; 3 -— [N— (4 fluorophenyl) N-methylamino] — 5— [2-methoxy 1 4 — (2-Methoxyacetyl) aminophenol] —4-Methyl 4 H- 1, 2, 4 Triazole; 3-— [4- (2-Acetoxyacetyl) amino-2-methoxyphenyl] — 5— [ N— (4-Fluorophenol) —N—Methylamino] — 4—Methyl—4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [

4- (2-hydroxyacetyl) amino-2-methoxyphenyl] — 4-methyl 4H—1, 2

, 4-Triazole; 3— [N— (4-Fluorophenyl) —N—Methylamino] — 5 [2-Methoxy-4- (2 Morpholine 4-Iracetyl) aminophenol] 4 Methyl 4H —1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N-Methylamino] — 5 — [4— (2 Hydroxyethyl) amino 2 methoxyphenol] 4 Methyl 4H— 1, 2, 4 Triazole;

3— (4-Ethoxycarbolamino 1-methoxyphenol) 5— [N— (4-Fluorophenol) — N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [ N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy— 4— (2-Oxosazolidine—3-yl) phenol] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [N-(4 Fluorophenol) N-Methylamino] — 5— (2-Methoxy-4-ureidophenol) 4-Methyl-4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol- ) — N-Methylamino] — 5— [2-Methoxy-1-phenol (3-methoxyureido) phenol] —4-Methyl-4H— 1, 2, 4 Triazole; 3-— (4-Amino 2- Methoxyphenyl) 1-5— [N— (4 Fluoro-3-methylphenol) N-Methylamino] — 4-Methyl 4H— 1, 2,

4 Triazole; 3— [N— (4-Fluoro-3-methylphenol) —N-methylamino] — 5— [4- (2 Hydroxyacetyl) amino 2 methoxyphenol] 4-methyl-4H-1, 2 , 4 Triazole; 3— [N— (4 Fluoro-3-methylphenol) —N—methylamino] 5— [4 (2-hydroxyethylamino) 2-methoxyphenyl] —4—methyl 4H—1 , 2, 4 Triazole; 3— [N— (4 Fluoro-3 methylphenol) —N —Methylamino] — 5— (2-Methoxy-4-ureidophenol) 1-4-methyl 4H—1, 2, 4-triazole 3— [N— (4-Fluoro-3-methylphenol) —N-methylamino] —5— [2-methoxy-1- (3-methoxyureido) phenol] — 4-methyl 4H—1, 2 , 4 Triazole; 3— (2 Ethoxy— 4 -Trophenyl) 5 — [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— (4 amino 2 ethoxyphenol) 5— [N— (4-Fluorophenol) —N-methylamino] —

4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy—4— (Ethoxycarboamino) phenol] —5— [N— (4-Fluorophenol) —N—Methylamino] — 4 —Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy 1 4- (3-Methoxyureido) phenol] 5— [N— (4 Fluorophenol) —N-Methylamino] 4-Methyl 4H— 1, 2, 4 Triazonole; 3— (2 Black mouth 4-Trophe-nore) One 5— [N— (4 Funoleo mouth phenol) — N-Methylamino] — 4—Methyl 4H— 1, 2 , 4 Triazole; 3— (2— Black mouth — ₄ — — Trophe) — 5— [N— (4—Black mouth) N—Methylamino] —4 —Methinore 4H— 1, 2, 4 Triazonole; 3— (2 Black mouth 4—Trophe-Nole) One 5— [N— (3-Fold Mouth-Fuel) One N-Methylamino] — Four-Methyl 4H—1, 2, 4 Triazole; — -Trophenyl) — 4—Methyl—5— {N—Methyl—N— [4 — (Trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 Triazole; 3— (2 Chloro Mouth 4— -Trophenyl) 1 4—Methyl 5— {N—Methyl N— [3— (Trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 Triazole; 3— (4 Amino 1 2 Black mouth) — 5— [N— (4 Fluorophenol) —N-Methylamino] 4-Methyl 4H— 1, 2, 4-triazole;

3— [2 Black mouth— 4 (Dimethylamino) phenol] — 5— [N— (4 Fluorophenol) N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (4 Acetylamino) 1 2 Black mouth Hue-Nole) 5— [N— (4 Funoleo mouth Hue-Nole) N—Methinoreamino] —4 —Methyl 1 4H— 1, 2, 4 Triazole; 3— [2 Black mouth 4— (2 Hydroxyacetyl) Amino file] — 5— [N— (4-Fluorophenyl) —N—Methylamino] —4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Single 4— (2 Hydroxyethyl) aminophenol] — 5— [N— (4-Fluorophenol) —N—Methylamino] — 4—Methyl—4H — 1, 2, 4 Triazole; 3— [2 Black mouth— 4— (Ethoxycarboamino) phenol] — 5— [N— (4 Fluorophenol) —N—Methylamino] — 4—Methyl 4H— 1, 2, 4-Triazonore; Lochiichi 4— (2-Oxoxazolidine 3-yl) phenyl] — 5— [N— (4 fluorophenol) — N-methylamino] — 4-methyl 4H— 1, 2, 4 — Triazonole; 3— (2 black mouths 4 ureidophenols) 5— [N— (4 funoleolophole) N-methylamino] — 4—methyl 4H— 1, 2, 4 Triazoles; 3— [2 black mouths —4 — (3-Methoxyureido) phenol] — 5— [N— (4-Fluorophenol) N-methylamino] 4-methyl-4H— 1, 2, 4 triazole; 3— (4 amino-1-cyclohexane 5) [N— (4 Black Mouth Fell)] — N—Methylamino] 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Black Mouth — 4— (Ethoxycarbolamino) Hue- ] — 5— [N— (4 Black Mole)] 1—N—Methylamino] — 4—Methyl 4H—1, 2, 4 Triazo Monool; 3— [2 Black Mouth 4— (3-Methoxyureido ) Hue -Nole] — 5— [N— (4 Chloroph ) — N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (4 amino 2—black mouth phenol) 5— [N— (3—black mouth moisture) N-Methinoreamino] —4—Methyl— 4H— 1, 2, 4 Triazole; 3— [2 Black mouth— 4— (Ethoxycarbolamino) phenol] — 5— [N— (3 black mouth hue) -L) N-Methylamino] 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Black 4- (3-Methoxyureido) phenol] — 5— [N — (3-Black mouth 1-N-methylamino] — 4—methyl 4H—1, 2, 4 triazole; 3— (4 amino-2 cyclohexane) 4-methyl 5— {N—methyl N— [4— (triflu) 4-methyl- (phenyl) amino] — 4H— 1, 2, 4 triazole; 3— [2 black mouth — 4-— (ethoxycarbo-amino) phenol] — 4-methyl-5- {N-methyl —N— [4— (Trifluoromethyl) [Ethyl] amino} — 4H— 1, 2, 4 Triazole; 3— [2 Black mouth— 4— (3-Methoxyureido) phenol] — 4—Methyl 5— {N—Methyl N— [4— (Trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 triazole; 3— (4 amino-2-chlorophenol) 4—methyl 5— {N—methyl N— [3— (trifluoro) Methyl) phenol] amino} — 4H— 1, 2, 4 triazole; 3— [2 black 4- (ethoxycarboamino) phenol] — 4—methyl— 5— {N methyl N— [3 -— (Trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 Triazole; 3-— [2 Black 4- (3-methoxyureido) phenol] 4 Methyl 5— {N Methyl N— [3- (trifluoromethyl) phenyl] amino} — 4H— 1, 2, 4 triazole;

3— [4 amino 2- (trifluoromethyl) phenol] — 5— [N— (4 fluorophenol) — N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole; 3— [4 ethoxyluminamine 2 (trifluoromethyl) phenol] 5— [N— (4 fluorophenol) —N-methylamino] — 4—methyl 4H— 1, 2, 4 triazole; 3— [ N— (4 —Fluorophenol) N—Methylamino] — 5— [4— (3-Methoxyureido) -2- (trifluoromethyl) phenol] 4-Methyl-4H—1, 2, 4 Triazole; 3— [ N— (4 —Black mouth) N—Methylamino] —4—Methyl 5— [4-Tro-2- (trifluoromethyl) phenol] — 4H— 1, 2, 4 Triazole; 3— [N — (3 Black Mole) — N-Methylamino] 4 Methyl 5— [4 Nitro 2 (Trifluoromethyl) Phenol] -4H- 1, 2, 4 Triazole; 4-Methyl -3-{N-methyl--N-[3- (Torifuruo (Romethyl) phenol] amino} 3— [4-tro 2 (trifluoromethyl) phenol] — 4H-1, 2, 4 triazole; 3— [4 amino 2— (trifluoromethyl) phenol ] — 5— [N— (4 black mouth) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [N— (4—black mouth) —N—Methylamino] — 5— [4—Ethoxycarbolamino 2- (trifluoromethyl) phenol] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [N— (4 —Black mouth ring) N-Methylamino] — 5— [4— (3-Methoxyureido) — 2— (Trifluoromethyl) phenol] —4-Methyl-4H—1, 2, 4 Triazole; 3— [4 Amino-2- (trifluoromethyl) phenol] — 5— [N— (3-clonal phenyl) — N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3 — [N— (3 black mouthpiece) —N-methyl Mino] — 5— [4 Ethoxycarboamino 2— (trifluoromethyl) phenol] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [N— (3-clonal phenol) N—Methylamino ] — 5— [4— (3-Methoxyureido)-2- (trifluoromethinole) phenenole] — 4—Methylole 4H—1, 2, 4 Triazolene; 3— [4 Amino 2— (trifluoromethyl) -L] 4 methyl 5— {N-methyl N— [3- (trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 triazole; 3— [4 ethoxycarbo-lamino 2- (trifluoro) Methyl) phenol] 4 methyl 5— {N methyl N— [3— (trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 triazole; 3— [4— (3-methoxyureido )-2- (Trifluoromethyl) phenol] -4-Methyl-5- {N-Methyl-N- [3- (Trifluoromethyl) phenol -Lu] amino} — 4H— 1, 2, 4 Triazole; 3— (4 —Bromo-2-methoxyphenyl) 5— [N— (4-Fluorophenyl) N-methylamino] — 4-Methylolone 4H— 1, 2, 4 Triazolole; 3— (4 Cyano 2-methoxyphenol) — 5— [N— (4 Fluorophenol) —N-Methylamino] 4-Methyl 4H— 1, 2, 4 Triazole; 3 — (4-Carboxyl-2-methoxyphenol) 5— [N— (4-Fluorophenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 2—Methoxyphenol) 5— [N— (4 Fluorophenol) N—Methylamino] —4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N—Methylamino] — 5— {2-Methoxy— 4 -— [(2-Methoxyethyl) aminocarbol] phenol} — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy—4— (morpholine—4—yl) phenol] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [4— (4 — acetyl piperazine 1-yl) 2-methoxyphenol] — 5— [N— (4-fluorophenol) — N-methylamino] — 4-methyl 4H — 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N—Methylamino] — 5— {2—Methoxy— 4— [4— (Morpholine—4-ylcarbol) piperidine 1 Yl] phenyl} 4 methyl 4H— 1, 2, 4 -triazole; 3— [N— (4-fluorophenyl) N methylamino] — 5— (4-hydroxy-2-methoxyphenyl) 4- Methyl 4H—1, 2, 4 Triazole; 3— (2 — Black mouth 1 4-Hydroxy phenol) 5— [N— (4 — Funoleo mouth Fu-Nole) N—Methinorea Mino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (4 Hydroxy-2-methoxyphenol) 5— [N— (4-Methoxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3 — [N— (4 Fluoro-3 methylphenol) N Methylamino] — 5— (4 Hydroxy-2-methoxyphenol) 1 4-methyl 4H—1, 2, 4 Triazole; 3— [N— (4 —Fluoro-3-methoxyphenyl) —N-methylamino] — 5— (4 —hydroxy-2-methoxyphenyl) 1-4-methyl 4H—1, 2, 4 triazole; 3-— (4-fluoro-2-methoxyphenyl) 5) [N— (4-hydroxyphenol) N-methylamino] 4-methyl-4H— 1, 2, 4 triazole; 3— (4 hydroxy-1-methoxysilane) 5— [N— (4-Hydroxyphenol) N-Methylamino] —4-Methyl-4H- 1, 2, 4 Triazole; 3— (2 1) —— N— (4—Hydroxyphenyl) —N—Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— (2 ) 5— [N— (4 Hydroxyphenol) N—Methylamino] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluoro 3 —hydroxyphenol) N-Methylamino] — 5 — (4-Fluoro-2-methoxyphenyl) — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyl) N-Methylamino] — 5— (4-Hydroxy mono) 2—Methoxyphenol) 4—Methylole 4H— 1, 2, 4 Triazonole; 3— (2 Black mouth 1 4 Funoleo mouth 1) 5— [N— (4-Fluoro 3-hydroxyphenol) N-methylamino] — 4-methyl 4H —1, 2, 4 triazole; 3— [4-acetylamino-2 (trifluoromethyl Hue - Le ] — 5— [N— (4 Fluorophenol) —N—Methylamino] 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4— (2 Acetoxyacetyl) amino 2-— (Trifluoromethyl) ) Phenol] — 5— [N— (4-Fluorophenol) —N—Methylamino] — 4—Methyl— 4H — 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N —Methylamino] — 5-[4—Methanesulfo-Luamino 1- (trifluoromethyl) phenol] 4—Methyl 4H — 1, 2, 4 Triazole; 3— [4 Benzenesulfo-Lamino 2- (trifluoromethyl) ) Fuel] — 5— [N— (4-Fluorophenol) —N-Methylamino] —4-Methyl-4H- 1, 2, 4 卜 riazole;

3— [4— (2 Dimethylaminoacetyl) amino-2- (trifluoromethyl) phenol] — 5 — [N— (4 Fluorophenyl) — N-methylamino] — 4-Methyl-4H—1, 2, 4-triazole; 3 -— [N— (4-fluorophenol) —N-methylamino] — 4-methyl-5- [4 mono (2 morpholine 4-alkylacetyl) amino-2 (trifluoromethyl) phenol ] — 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) — N-Methylamino] —5— {4— [2— (4 Hydroxypiperidine— 1-Ilacetyl) amino] — 2 ( Trifluoromethyl) phenol} 4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluorophenyl) —N—Methylamino] — 5— [4— (2-hydroxyacetyl) amino 2 — (Trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 ) -N-Methylamino] — 5— [4— (2 Hydroxyethyl) amino 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 Triazole; 3 — [N— (4 fluorophenol) —N-methylamino] —4—methyl-5— [4— (2-oxoxazolidin-3-yl) -2 (trifluoromethyl) phenol] —4Η —1, 2, 4 1 Triazole; 3— [4 1 (3-Benzyloxyureido) 1 2 (Trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) —N —Methylamino] — 4—Methyl— 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) — N—Methylamino] — 5— [4— (3-Hydroxyureido)-2- (Triflu 4-methyl 4H — 1, 2, 4 triazole; 3— [N— (4 fluorophenol) —N-methylamino] — 4 -methyl-5— [4 (morpholine) - 4 Irukarubo - Ruamino) - 2- (Torifuruoromechi Le) Hue - le] -4Η-1, 2, 4 Toriazoru; 3- [N-(4 Furuorofe - Le) N -Methylamino] -5- [4 (4-methoxypiperidine 1-ylcarbolamino) 2- (trifluoromethyl) phenol] -4-methyl-4H-1,2,4 triazole; 3- [N- (4 fluorophenol -L) N-Methylamino] — 5— [4— (4-hydroxypiperidine- 1 -ylcarbo-amino) -2- (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 Triazole; 3— [4 Aminosulfo-Lamino 1- (trifluoromethyl) phenol] 5— [N— (4 Fluorophenol) —N-Methylamino] 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4 — (Dimethylamino) sulfo-Luamino 2— (Trifluoromethyl) phenol] — 5— [N— (4-Fluorophenyl) —N-methylamino] —4-Methyl-4H-1, 2, 4 Triazole; 3 — (4 Acetylamino 2 ethoxyphenol) — 5 — [N— (4 Fluorophenol -L) —N-methylamino] —4-methyl-4H-1,2,4 triazole;

3— (2 Ethoxy-l 4-Methanesulfo-Laminophenol) 5— [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— (4 Benzensulfo -Luamino 2 ethoxyphenol) 5 [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3-— [2 Ethoxy—

4— (2 morpholine—4—ylacetyl) aminophenol] — 5— [N— (4 fluorophenol) —N—methylamino] — 4—methyl 4H— 1, 2, 4 triazole; 3— [2 etho 4- (2 Hydroxyacetyl) aminophenol] — 5— [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Etoxy 4- (2 hydroxyethyl) aminophenol] — 5— [N— (4 fluorophenol) N-methylamino] — 4—methyl 4H— 1, 2, 4 triazole; 3— [2 ethoxy— 4- (2-Oxoxazolidine-3-yl) phenol] — 5— [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3 — [4— (3 Benzyloxyureido) —2 Ethoxyphenol] — 5— [N— (4-Fluorophenol) N —Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy— 4— (3 -Hydroxyureido) phenol] — 5— [N— (4-Fluorophenol) N-methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy 4- (morpholine 4-ylcarboamino) phenol] -5— [N— (4-Fluorophenol) —N—Methyl [Luamino] — 4—Methyl 4H— 1, 2, 4 卜 Riazole; 3— (4 Aminosulfo-Luamino—2 Ethoxyphenol) 5— [N— (4 Fluorophenol) —N—Methylamino] —4 —Methyl— 4H— 1, 2, 4 Triazole; 3— [4— (Dimethylamino) sulfo-lumino-2 Ethoxyphenol] —5— [N— (4 Fluorophenol) —N—Methylamino] —4—Methyl-4H—1 , 2, 4 Triazole; 3— [N— (4-Methoxyphenol) N-Methylamino] —4-Methyl-5— [4-Toro2- (trifluoromethyl) phenol] 4H— 1, 2, 4 Triazole; 3— [4 Amino 2 (trifluoromethyl) phenol] 5— [N— (4-Methoxyphenol) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole ; 3— [4 Acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (4-Methoxyphenyl) — N-methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [4 —Ethoxycarbolamino 1- (trifluoromethyl) phenol] — 5— [N— (4-Methoxyphenyl) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [4-Methanesulfo-Laminomino 2- (trifluoromethyl) phenol] — 5— [N— (4-Methoxyphenyl) -L) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [4 Benzenesulfo-Lamino 2- (trifluoromethyl) phenol] — 5— [N— ( 4-Methoxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3 -— [N— (4-Methoxyphenyl) N-methylamino] —4-Methyl-5- [4 — (2 morpholine-4-ylacetyl) amino-2 (trifluoromethyl) phenol] —4Η-1,2, 4 triazole; 3— [4 one (2 hydroxyacetyl) ) Amino-2 (trifluoromethyl) phenol] 5— [N— (4-methoxyphenol) N-methylamino] 4-methyl 4H— 1, 2, 4 triazole; 3— [4— (2 hydroxy) Ethyl) 2-amino (trifluoromethyl) phenol] — 5— [N— (4-methoxyphenol) —N-methylamino] —4-methyl—4H-1, 2, 4 triazole;

3— [N— (4-Methoxyphenol) N-Methylamino] —4—Methyl 5— [4— (2-Oxoxazolidin-3-yl) -2 (trifluoromethyl) phenol 3] [N— (4-methoxyphenol) —N-methylamino] — 5— [4— (3-methoxyureido) 2 (trifluoromethyl) phenol -L] -4-methyl- 4H-1,2,4 triazole; 3- [4 (3-hydroxyureido) 2 (trifluoromethyl) phenol] 5— [N— (4-Methoxyphenol) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole; 3-— [N— (4-Methoxyphenol) N-methylamino] —4— Methyl 5— [4 (Morpholine-4-ylcarbolamino) 2 (Trifluoromethyl) phenol] -4 H— 1, 2, 4 Triazole; 3-— [4 Aminosulfo-lamino-2- (trifluoromethyl) ) Phenol] — 5— [N— (4-Methoxyphenol) —N—Methylamino] — 4-Methyl—4H —1, 2, 4 Triazole; 3-— [4 (Dimethylamino) sulfolamino-2 (Trifluoro) Romethyl) phenol] — 5— [N— (4-Methoxyphenyl) N-methylamino] —4-Methyl 4H—1, 2, 4 Triazole; 3 -— [N— (4 Fluoro-3-methylphenol) —N —Methylamino] —4—Methyl—5— [4-Toro 2- (trifluoromethyl) phenol] 4H- 1, 2, 4 Triazole 3— (2 ethoxy-4 ditrophyl) — 5— [N— (4 —fluoro-3-methylphenol) —N-methylamino] —4-methyl-4H-1,2,4-triazole; 3 — [4 amino 2 (trifluoromethyl) phenol] 5— [N— (4 fluoro 3—methyl phenol) — N-methylamino] — 4—methyl—4H—1, 2, 4 triazole; 3— [4 Acetylamino 2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 —Triazole; 3— [4-Ethoxycarboamino] 2 -— (trifluoromethyl) phenol] — 5— [N— (4-Fluoro-3-methylphenol) —N-methylamino] —4-methyl-4H—1 , 2, 4 Triazole; 3— [N— (4 Fluoro-3-methylphenol) N—Methylamino] — 5— [4-Methanesulfo-lamino 2— (tri 4-methyl 4H— 1, 2, 4 triazole; 3— [4 benzenesulfo-lamino 2- (trifluoromethyl) phenol] 5— [N— (4 fluoro-3-methylphenol) ) N-Methylamino] -4-Methyl-4H-1,2,4 Triazole; 3- [N- (4 Fluoro 3-methylmethyl) -N-Methylamino] -4-methyl-5- [4- (2 morpholine — 4— ilacetyl) amino-2 (trifluoromethyl) phenol] —4Η-1,2,4 triazole; 3— [N— (4 fluoro-3-methylphenol) —N-methylamino] — 5— [4— (2 —Hydroxyacetyl) amino-2- (trifluoromethyl) phenol] 4—Methyl 4H-1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-methylphenol) —N —Methylamino] 5— [4 (2-hydroxyethyl) amino-2- (trifluoromethyl) phenol ] 4-Methyl-4H-1,2,4 Triazole; 3- [N- (4 Fluoro-3-methylphenol) -N-Methylamino]-4-Methyl-5- [4- (2-Oxoxazo Lysine-3-yl) -2 (trifluoromethyl) phenol] —4Η-1,2,4 triazole;

3— [N— (4 Fluoro-3-methylphenol) N-Methylamino] — 5— [4-— (3-Methylureido) 2 (trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4-to-triazole; 3 -— [N— (4-Fluoro-3-methylphenol) —N-methylamino] — 5— [4 (3-hydroxyureido) 2 (trifluoromethyl) phenol] -4-methyl- 4H-1, 2, 4 Triazole; 3— [N— (4 Fluoro-3 methylphenol) —N—Methylamino] —4—Methyl-5— [4— (Morpholine—4-ylcarbolamino)-2- (Trifluoromethyl) phenol] —4Η-1,2,4 Triazole; 3— [4 Aminosulfol Amino-2- (Trifluoromethyl) phenol] — 5— [N— (4-Fluoro-3— Methylphenol) N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4— (Dimethylamino) sulfur -Luamino-2 (trifluoromethyl) phenol] 5— [N— (4-Fluoro-3-methylphenol) —N-methylamino] —4-methyl-4H-1,2,4 triazole; 3 — (4 amino 2-ethoxyphenol) 5— [N— (4 fluoro 3 methylphenol) — N-methylamino] — 4-methyl—4H—1, 2, 4 卜 riazole; 3-— (4-acetylamino) 2—Ethoxyphenol) 5— [N— (4 Fluoro 3 methylphenol) — N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy— 4— (Ethoxycarbo -Luamino) phenol] — 5— [N— (4-Fluoro-3-methylphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3-— (2-Ethoxy 4-Methanesulfo-Laminophenol) 5— [N— (4-Fluoro-3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3— (4-Benzenesulfo-Lamino 2-Ethoxyphenol) 5— [N— (4 Fluoro 3-Methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3— [2 Ethoxy— 4— (2 Morpholine — 4 — ylacetyl) aminophenol] — 5 — [N— (4 Fluoro-3-methylphenol) — N-methylamino] — 4 — Methyl — 4H— 1, 2, 4 -triazole; 3-[2 ethoxy 4- (2 hydroxyacetyl) aminomino] 5 — [N— (4-fluoro-3-methylphenol) —N-methylamino] — 4-methyl— 4H -1, 2, 4 Triazole; 3— [2 Ethoxy 1 4- (2 Hydroxyethyl) aminophenol] — 5— [N— (4-Fluoro-3-methylphenol) —N-Methylamino] —4— Methyl — 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy 1 4- (2-Oxoxazolidine 1-yl) phenol] — 5— [N— (4-Fluoro 3— Methylphenol) —N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy 4- (3-methoxyureido) phenol] — 5— [N— (4— Fluoro-3-methylphenol) N-methylamino] — 4-methylolene 4H— 1, 2, 4 Triazolene;

3— [4— (3 Benzyloxyureido) 2 Ethoxyphenyl] — 5— [N— (4 Fluoro 3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 -Triazole; 3-[2 ethoxy 4- (3 hydroxyureido) phenol] 5— [N— (4-fluoro 3-methylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4 Triazole; 3— [2—Ethoxy— 4— (Morpholine— 4-ylcarboamino) phenol] — 5— [N— (4-Fluoro-3-methylphenyl) N Methylamino] — 4-Methyl 4 H— 1, 2, 4 Triazole; 3— (4 Aminosulfo-Luamino-2-Ethoxyphenol) — 5— [N— (4-Fluoro-3-methylphenol) N Methylamino] — 4-Methyl 4 H— 1, 2, 4 Triazole; 3— [4— (Dimethylamino) sulfo-Luamino 2 ethoxyphenol] — 5— [N— (4-Fluoro 3—Methylphenol) —N—Methylamino] —4—Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-methoxyphenol) —N—Methylamino] —4—Methyl 5— [ 4-Tro-2- (trifluoromethyl) phenol] 4H— 1, 2, 4 Triazole; 3-— (2 Ethoxy— 4-trifluoro) — 5— [N-(4 Fluoro-3-methoxyphenol- N) -Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4 Amino 2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methoxyphenol) N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [4 Acetylamino 2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methoxyphenol) N—Methylamino ] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [4 Ethoxycarbolamino 2— (trifluoromethyl) E - Le - 5-[N-(4- Furuoro 3 Metokishifue - Le) N Mechiruamino] - 4-methyl-4H-1, 2, 4 Toriazoru; 3- [N- (4 Furuoro 3 Metokishifue - Le ) —N-Methylamino] — 5— [4-Methanesulfo-Laminomino 2- (trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole; 3 -— [4 Benzenesulfo-Lamino 1 2 (Trifluoromethyl) phenol] 5— [N— (4 Fluoro3 methoxyphenol) N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4— Fluoro 3-methoxyphenyl) N-methylamino] —4-methyl-5— [4 -— (2-morpholin-4-ylacetyl) amino-2 (trifluoromethyl) phenol] —4Η—1, 2, 4— Triazole; 3— [N— (4-Fluoro-3-methoxyphenyl) N-methylamino] 5— [4 (2-hydroxyacetyl) amino-2 (trifluoromethyl) phenol] 4 —Methyl-4-H 1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-methoxyphenol) N-Methylamine ] — 5— [4— (2 Hydroxyethyl) amino-2- (trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-methoxyphenyl) ) N-Methylamino] —4—Methyl 5— [4— (2-Oxosazolidine—3—yl) —2— (trifluoromethyl) phenol] —4H—1, 2, 4 Triazo monoure;

3— [N— (4 Fluoro-3-methoxyphenyl) N-methylamino] — 5— [4 -— (3-Methoxyureido) 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 Triazole; 3— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] — 5

[4- (3-hydroxyureido) 2 (trifluoromethyl) phenol]-4-methyl- 4 H— 1, 2, 4 triazole; 3— [N— (4 fluoro-1,3-methoxyphenol) 1 N— Methylamino] —4-methyl-5- [4— (morpholine-4-ylcarbolumino) -2 (trifluoromethyl) phenol] —4Η-1,2,4 triazole; 3— [4 aminosulfolamino 2 (Trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methoxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [4— (Di Methylamino) sulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methoxyphenol) 1 N-methylamino] — 4-methyl 4H-1,2,4 triazole; 3 — (4 amino-2-ethoxyphenyl) 5— [N— (4-fluoro-3-methoxyphenyl) — N— Ruamino] - 4-methyl -4H-1, 2, 4 Toriazoru; 3- (4 - Asechiruamino 2 Etokishifue - Le) 5-[N-(4 Furuoro 3-methoxy (Fe) — N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2—Ethoxy—4 -— (Ethoxycarboamino) phenol] — 5— [N— (4— Fluoro-3-methoxyphenyl) — N-methylamino] — 4-methyl-4H—1, 2, 4 triazole; 3-(2 ethoxyl 4-methanesulfo-laminophenol) 5— [N— (4 fluoro-3 — Methoxyphenol) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— (4-Benzenesulfo-Lamino 2 ethoxyphenol) 5— [N— (4-Fluoro —3—methoxyphenol- 1) N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [2-Ethoxy 4— (2 Morpholine 4-Iracetyl) aminophenol] 5-[N— (4-Fluoro-3— Methoxyphenol) —N-Methylamino] — 4-Methyl-4H — 1, 2, 4 Triazole; TOXI 4- (2 Hydroxyacetyl) aminophenol] — 5— [N— (4-Fluoro-3-methoxyphenol) N-methylamino] —4-methyl-4H— 1, 2, 4 Triazole; 3 — [2 Ethoxy— 4— (2 Hydroxyethyl) aminophenyl] — 5— [N— (4-Fluoro-3-methoxyphenyl) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy 4- (2-Oxosazolidine-3-yl) phenol] — 5— [N— (4-Fluoro-3-methoxyphenol) — N-methylamino] — 4-methyl-4H — 1, 2, 4 Triazole; 3— [2 Ethoxy— 4-(3-Methoxyureido) phenol] — 5— [N— (4-Fluoro-3-methoxyphenol) — N—Methylamino] — 4 —Methyl 4H— 1, 2, 4 Triazole; 3-— [2 Ethoxy— 4-— (3-hydroxyureido) phenol] — 5— [N— (4-Full 3-Methoxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3-— [2 Etoxy 4 (Morpholine-4-ylcarbo-amino))] 5— [N— (4 Fluoro-3-methoxyphenyl) 1 N-methylamino] — 4-methyl 4H—1, 2, 4 triazole; 3— (4 aminosulfo-lumino 2-ethoxyphenol) 5— [N— (4 Fluoro —3—Methoxyphenyl) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [4 (Dimethylamino) sulfolamino-2 ethoxyphenol] 5— [N— (4 —Fluoro- 3—Methoxyphenyl) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [4 Bromo 2 (trifluoromethyl) phenol] 5— [N— (4 Fluorophenol) ) — N-methylamino] — 4-methyl-4H-1, 2, 4 triazole; 3 -[4-Ciano 2— (trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) —N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N—Methylamino] —4—Methyl—5— [4— (Morpholine—4—yl) 2— (Trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole;

3— [4 4 Acetylbiperazine 1 yl) 2 (Trifluoromethyl) phenol] 5— [N— (4 Fluorophenol) — N-Methylamino] — 4—Methyl-4H—1, 2, 4— Triazole; 3— {4— [4— (Acetyllamino) piperidine— 1—yl] —2 (trifluoromethyl) phenol} — 5— [N— (4-Fluorophenol) — N-methylamino] — 4—methyl 4H—1, 2, 4 triazole; 3— [N— (4 fluorophenol) N—methylamino] — 4—methyl—5— {4— [4— (morpholine— 4-ylcarbol) piperidine-1-yl] -2 (trifluoromethyl) phenol} -411 1, 2, 4 triazole; 3-[N-(4-fluorophenol) N-methylamino] — 5— [4— (4-Hydroxypiperidine 1-yl) -2 (trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole; 3— [4 Carboxyl 2 (Trifluoromethyl) phenol] 5— [N— (4-Fluorophenol) —N-Methylamino] —4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N-methylamino] — 5— [4-methoxycarboluol 2 (trifluoromethyl) phenol] —4-methyl—4H—1, 2, 4 triazole; — (Trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluorophyl) — N-Methylamino] — 5— {4— [(2-Methoxyethyl) aminocarbol] -2 (Trifluoromethyl) phenol} 4-Methyl-4H-1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) —N—Methylamino] — 5— {4— [(2 Hydroxyethyl) aminocarbo] 2 (Trifluoromethi ) Phenyl} 4 methyl 4H— 1, 2, 4 triazole; 3— {4— [2— (dimethylamino) ethylaminocarboro] — 2— (trifluoromethyl) phenyl} -5— [N— (4-Fluorophenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— {4— [(Strength of rubermoylmethyl) aminocarboxyl] 2 (Trifluoromethyl) phenol} -5 [N— (4 fluorophenyl) — N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole; 3— [N— (4 full Orophylls) —N—methylamino] —4—methyl—5— [4— (morpholine—4-ylcarbol) —2— (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole; 3— [4-(4-acetylbiperazine— 1-ylcarbol) —2— (trifluoromethyl) phenol] — 5— [N— (4 fluorophenyl) —N— Methylamino] 4—Methyl 4H— 1, 2, 4—Triazole; 3— [N— (4-Fluorophenol) —N—Methylamino] — 5— [4— (4 Hydroxypiperidine—1—ylcarbol) 2— (Trifluoromethyl) phenol] — 4—Methyl 4H— 1, 2, 4— 卜!; Azole;

3— {4 [4 (Acetylamino) piperidine 1 yl] carboluol 2 (trifluoromethyl) phenol} — 5— [N— (4-Fluorophenol) —N-methylamino] —4—Methyl Luo 4H—1, 2, 4 Triazole; 3— [N— (4 Fluorophenol) N—Methylamino] — 4—Methyl—5— {4— [4— (Morpholine—4—ylcarbol) pipette Lysine— 1-ylcarbol] 2 (trifluoromethyl) phenol} 4H-1,2,4-triazole; 3— [N— (4-fluorophenol) N-methylamino] — 5— [4— Hydroxamino force Lupolulu 2 (Trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4-Fluorophenol) —N-Methylamino] — 5— [4-Methoxyamino-carboru 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4-triazole; 3— [N— (4-F Orophylls) N-methylamino] — 5— [4-hydroxy-2- (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 triazole; 3— [N— (4-fluorophenol) ) —N-Methylamino] — 5 [1— (4-Hydroxyphenol) — 1-Methylethyl] — 4-Methyl 4H— 1, 2, 4 Triazole; 3 -— [4 Hydroxy—2 (trifluoromethyl) Phenyl] 4 Methyl 5— {N Methyl N— [3 (Trifluoromethyl) phenol] Amino} — 4H— 1, 2, 4 Triazole; 3— (2 Chlorine 4 —Hydroxyphenol) 4 —Methyl 5— {N—Methyl N— [3— (Trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 Triazole; 3— [1— (4 Hydroxyphenol) 1 1 Methylethyl ] 4 Methyl 5— {N Methyl N— [3- (Trifluoromethyl) phenyl] amino} — 4H— 1, 2, 4 Triazole; 3— [N— (4 hydride) Roxyphenyl) —N—Methylamino] —4—Methyl—5— [4-Toro2 -— (trifluoromethyl) phenol] 4H- 1, 2, 4 Triazole; 3— (2 Ethoxy—4 Nitrophe -Le) — 5— [N— (4 —Hydroxyphenyl) — N—Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— (2 Black 4-trophe-norre) 5— [N— (4 Hydroxyphenol-nor) N-methylamino] -4-methyl-4H-1,2,4 triazole; 3- [N- (4 hydroxyphenol) -N-methylamino] -5- [2- (trifluoromethyl) phenol] —4—Methyl—4 H— 1, 2, 4 Triazole; 3— [2— (Dimethylamino) phenol] — 5— [N— (4 Hydroxyphenyl) — N—Methylamino] — 4—Methyl— 4H—1, 2, 4 Triazole; 3— [N— (4 Hydroxyphenol) N-Methylamino] — 4—Methyl 5— (1-Methyl 1—Phenol) —4H— 1, 2, 4 Triazole 3— [N— (4 hydroxyphenol) —N—methylamino] — 5— [1— (4 hydroxyphenol) —1-methylethyl] —4—methyl 4H— 1, 2, 4 tria; Lumpur; 3- (Adamantan one 1-I le) 5-[N- (4-hydroxy Hue - Le) Single N- Mechiruamino] - 4-methyl-4H-1, 2, 4 Toriazoru;

3— [4-Amino 2-] (Trifluoromethyl) phenol] — 5— [N— (4-Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole 3— [4— (dimethylamino) -2- (trifluoromethyl) phenol] — 5— [N— (4-hydroxyphenol) N-methylamino] — 4—methyl 4H— 1, 2 , 4 Triazole; 3— [4 Acetylamino 2- (trifluoromethyl) phenol] — 5— [N— (4-Hydroxyphenol) N-methylamino] 4-Methyl-4-H— 1, 2, 4 Triazole; 3— [4 Ethoxycarboroamino 2-(trifluoromethyl) phenol] — 5— [N— (4-hydroxyphenol) N —Methylamino] — 4—Methyl 4H— 1 , 2, 4 Triazole; 3— [4— (2 Dimethylaminoacetyl) amino 2— (Trifluoromethyl) phenol] — 5— [N— (4-hydroxyphenol) — N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4— (2 —Hydroxyacetyl) amino-2- (trifluoromethyl) phenol] — 5— [N— ( 4-Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3— [4 (2-hydroxyethyl) amino-2 (trifluoromethyl) phenol] 5 — [N— (4 —Hydroxyphenyl) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Hydroxyphenol) —N-Methylamino] —4 —Methyl-5— [4— (2—oxoxazolidine 3 yl) -2 (trifluoromethyl) phenol] —4H—1, 2,

4—Triazole; 3— [N— (4-Hydroxyphenol) —N—Methylamino] — 5— [4— ( 3-methoxyureido)-2- (trifluoromethyl) phenol] — 4-methyl 4H—1, 2, 4-triazole; 3— (4 amino 2-ethoxyphenol) 5— [N— (4 Hydroxyphenol) — N-methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4— (Dimethylamino) 2 ethoxyphenol] — 5— [N— (4-hydroxyphenol) N) -Methinoremino] 4-Methinore 4H— 1, 2, 4 Triazolole; 3 -— (4-acetylenamino 2-ethoxyphenol) 5— [N— (4-Hydroxyphenol) N-Methylamino ] —4—methyl 4H— 1, 2, 4 triazole; 3— [2 ethoxy—4— (ethoxycarboamino) phenol] —5— [N— (4-hydroxyphenol) N-methylamino ] — 4-Methyl 4H — 1, 2, 4 Triazole; 3— (2 Ethoxy 1-Methanesulfo-Laminophenol) 1 5— [N— (4 H Rokishifue - Le) Single N- Mechiruamino] - 4-methyl-4H-1, 2, 4 - Toriazoru; 3- (4-benzenesulfonyl - Ruamino 2 Etokishifue - Le) 5-[N

— (4 Hydroxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3-[2 Ethoxy 4— (2 Morpholine 1 4-alkylacetyl) aminophenol] — 5— [N — (4 Hydroxyphenol) N-Methylamino] 4-Methyl 4H— 1, 2,

4-triazole; 3-[2 ethoxy 4- (2 hydroxyacetyl) aminophenol] 5

— [N— (4 hydroxyphenyl) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4-triazole; 3-— [2-Ethoxy— 4- (2-hydroxyethyl) aminophenol] — 5— [N

— (4 hydroxyphenyl) 1 N-methylamino] — 4-methyl 4H—1, 2, 4 triazole; 3— [2 ethoxy-4- (2-oxoxazolidine-3-yl) phenol] -5

— [N— (4 hydroxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4— Triazole; 3— [2 Ethoxy 1 4- (3-methoxyureido) phenol] — 5 — [N— (4-Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3— [2 Ethoxy 4- (3 Hydroxyureido) phenol] — 5 — [N— (4 Hydroxyphenol) — N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (4—Aminosulfo-lamino-2-ethoxyphenol) 5 [N— (4 Hydroxy) (Fuel)

— N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [4— (Dimethylamino) sulfo-lumino 2 ethoxyphenol] — 5 [N— (4 Hydroxyphenol) — N— Methylamino] — 4-methyl 4H— 1, 2, 4 triazole; 3— (4 amino 2 —Black mouth ring) 5— [N— (4-Hydroxyphenol) N-methylamino] —4—methyl 4H— 1, 2, 4 triazole; 3— [2 black mouth— 4— (dimethylamino) Phenol] — 5— [N— (4 hydroxyphenol) 1 N-methylamino] — 4-methyl 4H—1, 2, 4-triazolene; 3— (4 acetylenoamino 2-chlorophenol) 5— [N— (4 hydroxyphenol) — N-methylamino] — 4—Methyl-4H—1, 2, 4 Triazole; 3— [2 Chloromethyl 4- (ethoxycarbolumino) phenol] — 5 — [N— (4 Hydroxyphenol) N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (2 Black —4—Methanesulfo-Laminophenol) 5— [N— (4 —Hydroxyphenol) N-methylamino] 4-methyl-4H— 1, 2, 4 Triazole; 3— (4 Benzenesulfoamino-2-chlorophenol) 5— [N- (4-Hydroxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Black mouth— 4— (2 Morpholine— 4-Ilylacetyl) aminophenol] — 5— [N— (4-Hydroxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Chloromethyl 4-(2 Hydroxyacetyl) aminophenol] — 5— [N— (4-Hydroxyphenol) —N—Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Chloromethyl 4 -— (2 Hydroxyethyl) aminophenol] — 5— [N— (4-Hydroxyphenol) N-Methylamino] —4— Methyl 4H— 1, 2, 4 Triazole; 3— [2 Black-and-white 4-— (2-Oxoxazolidin — 3—Fille)] — 5— [N— (4-Hydroxyphenol) —N—Methylamino] —4 —Methyl mono 4H— 1, 2, 4 Triazole; 3— [2 — (3 —Methoxyureido) Phenol] — 5— [N— (4-Hydroxy Phenol) N-Methylamino] — 4-Methyl 4H — 1, 2, 4 Triazole; 3— [2 Hydroxyureido) phenyl] — 5 — [N— (4 Hydroxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4—Triazole; 3— (4 Aminosulfo-Lamino) 2 (Fuel) 5— [N— (4 Hydroxyphenyl) — N—Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [2 Chloromethyl 4- (Dimethylamino) sulfo-Laminophenol -L] — 5— [N— (4-Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3-— [N— (4-Fluoro-3-hydroxyphenol) ) N-Methylamino] — 4—Methyl 5— [4-Troo 2 (trifluoromethyl) phenol] —4Η-1,2, 4 Triazole; 3— ( 2—Ethoxy 4 nitrophenol) 5— [N— (4 Fluoro 3 hydroxyphenol) — N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 5) [N— (4-Fluoro-3-hydroxyphenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3-— [N— (4 Fluoro-3-hydroxyl ヱ-L) —N-Methylamino] — 5— [2— (Trifluoromethyl) phenol] —4-Methyl- 4H—1, 2, 4 Triazole; 3 -— [N— (4 Fluoro-3 hydroxyphenol- ) —N—Methylamino] — 5— [4 Hydroxy-2- (trifluoromethyl) phenol] —4 —Methyl mono 4H— 1, 2, 4 Triazole; 3— (2 Monochrome 4-hydroxy phenol) 1) 5— [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] — 4—Methyl-4H- 1, 2, 4 Triazole; 3— [2— (Dimethylamino) phenol] — 5— [N— (4 fluoro 3-hydroxyphenyl) mono N-methylamino] — 4-methyl 4H—1, 2, 4 triazole; 3— [N— (4— Fluoro-3-hydroxyphenyl) —N-methylamino] —4-methyl-5- (1-methyl-1-phenylethyl) —4Η—1, 2, 4 triazole; 3 — [N— (4 fluoro-3 hydroxyphenol) ― N Methylamino] 5— [1— (4-Hydroxyphenol) 1 1-Methylethyl] —4-Methyl 4H-1, 2, 4 Triazole; 3— (Adamantane 1-yl) 5— [N- (4-Fluoro-3-hydroxyphenol) N-methinoleamino] 4-methinolei 4H—1, 2, 4 ria zonole; 3— [4 amino-2- (trifluoromethyl) phenol] — 5— [N— (4— Fluoro-3-hydroxyphenol) N-Methinoreamino] 4-Methinore 4H— 1, 2, 4 卜 Ryazono 3— [4 (Dimethylolamino) -2- (trifluoromethyl) phenol] — 5— [N— (4-Fluoro-3-hydroxyphenol) — N-methylamino] — 4-methyl 4H— 1 , 2, 4 Triazole; 3— [4 Acetylamino 2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro3 hydroxyphenyl) — N-Methylamino] — 4—Methyl—4H—1 , 2, 4 Triazole; 3— [4 —Ethoxycarbolamino 2- (trifluoromethyl) phenol] — 5— [N— (4-Fluoro 3-hydroxyphenyl) mono N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazole; 3— [N— (4-Fluoro-3-hydroxyphenol) —N—Methylamino] — 5-[4—Methanesulfo-lamino 2- (trifluoro) Methyl) phenol] 4-methyl 4H — 1, 2, 4 triazole; 3— [4 benzenesulfo-lamino 2- Romechi ) Fuel] — 5— [N— (4-Fluoro-3-hydroxyphenol) —N-methylamino] — 4-methyl 4H— 1, 2, 4-!! azole;

3— [4 (2-Dimethylaminoacetyl) amino-2 (trifluoromethyl) phenol] 5 — [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] —4-methyl-4 H— 1, 2, 4 Triazole; 3— [N— (4 Fluoro-3 hydroxyphenol) 1 N—Methylamino] — 4—Methyl—5— [4— (2—morpholine—4-yllucetyl) amino-2 (Triflu) Fluoromethyl) phenol] —4Η-1,2,4 Triazole; 3— [N— (4 Fluoro 3-hydroxyphenol) N-Methylamino] — 5— [4— (2-Hydroxy) Acetyl) amino 2— (trifluoromethyl) phenol] — 4—methyl 4H—1, 2, 4 triazole; 3— [N— (4-fluoro-3-hydroxyphenyl) N Methylamino] — 5— [4 mono (2 hydroxyethyl) amino-2 (trifluoromethyl) phenol] 4-methyl-4 H— 1, 2, 4 Riazole; 3— [N— (4 fluoro-3-hydroxyphenol) -N-methylamino] — 4-methyl-5- [4 -— (2-oxoxazolidine-3-yl) -2 ( (Trifluoromethyl) phenol] —4Η-1,2,4 Triazole; 3— [N— (4 Fluoro—3—hydroxyphenol) N—Methylamino] — 5— [4— (3-Methoxyureido)- 2- (Trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino] — 5— [4— ( 3-Hydroxysulfide) 2 (Trifluoromethyl) phenol] -4-Methyl-4H-1,2,4-Triazole; 3- [4 Aminosulfolamino-2 (trifluoromethyl) phenol] 5- [ N— (4-Fluoro-3-hydroxyphenol) N-Methylamino] — 4-Methyl 4H 1, 2, 4 Triazole; 3-— (4 amino 1-2-Ethoxyphenyl) 1-5— [N— (4-Fluoro-3-hydroxyphenyl) -1-N-methylamino] —4-methyl 4H—1, 2, 4 triazole; 3- [4 (dimethylamino)- 2-Ethoxyphenol] -5— [N— (4 Fluoro-3-hydroxyphenyl) -N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole; 3-— (4 Acetylamino 2-ethoxyphenol) ) 5— [N— (4 Fluoro-3 hydroxyphenol) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole; 3-[2 Ethoxy 4 (ethoxycarboamino) phenol 5] [N— (4-Fluoro-3-hydroxyphenol) 1 N-methylamino] — 4—methyl 4H—1, 2, 4 -Triazole; 3— [2-Ethoxy 4 (methanesulfo-lumino) phenol] 5— [N— (4-Fluoro 3 hydroxyphenol) N Methylamino] 4 Methyl 4H— 1, 2, 4 Triazole; 3— (4 Benzenesulfo-lumino 2 ethoxyphenol) —5 — [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] —4-methyl 4 H— 1, 2, 4 triazole; 3— [2 Ethoxy-4— (2 morpholine-4-ylacetyl) aminophenol] — 5— [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] — 4-methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxyl 4— (2 Hydroxycetyl) aminophenol] — 5— [N— (4-Fluoro3-hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Ethoxy— 4— (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Fluoro-3 hydroxyphenol) —N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole;

3— [2 Ethoxy— 4— (2-Oxoxazolidin— 3—yl) phenol] — 5— [N— (

4 Fluoro-3 hydroxyphenol) N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole; 3— [2 ethoxy 4- (3-methoxyureido) phenol] — 5— [N-( 4 Fluoro-3 hydroxyphenyl) N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole; 3— [4— (3 benzyloxyureido) 1-2 ethoxyphenol] — 5— [N— ( 4-Fluoro-3-hydroxyphenol) N-methylamino] — 4-methyl — 4H— 1, 2, 4 triazole; 3-— [2 ethoxy 4- (3-hydroxyureido) phenol] — 5— [N — (4-Fluoro-3-hydroxyphenol) N Methylamino] — 4— Methyl 4H— 1, 2, 4 Triazole; 3— (4 Aminosulfo-Lamino-2-ethoxyphenol) — 5— [N— (4 —Fluoro-3-hydroxyphenol) —N-methylamino]-4-methyl 4H— 1, 2, 4 Triazol 3— [4- (dimethylamino) sulfo-lumino-2-ethoxyphenyl] 5— [N— (4 fluoro-3-hydroxyphenol) N-methylamino] -4-methyl-4-H-1,2,4 triazole; 3 — (4 amino-2-chlorophenol) 5— [N— (4-fluoro-3-hydroxyphenol) N-methylamino] — 4 —methyl— 4H— 1, 2, 4 triazole; 3— [2 Mouth— 4— (Dimethylamino) phenol] — 5— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino] — 4-Methyl— 4H— 1, 2, 4 Triazole; 3— (4 Acetylamino 2 black mouth) — 5- [N- (4-Fluoro-3-hydroxyphenol) N-Methylamino] — 4—Methyl-4H- 1, 2, 4 Triazole; 3— [2 Black mouth — 4— (Ethoxycarbolamino) phenol ] — 5— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino] — 4—Methyloo 4H—1, 2, 4 Triazole; 3— (2 Chloro-4-methanesulfonylaminophenol) — 5— [N— (4-Fluoro-3-hydroxyphenol) —N-Methylamino] — 4— Methyl-4H—1, 2, 4 Triazole; 3— (4 Benzenesulfonylamino-2 black mouth) — 5— [N— (4-Fluoro-3-hydroxyphenol) —N-Methylamino]-4-Methyl 4H— 1, 2, 4 Triazole; 3— [2 Black mouth 4— (2 Morpholine 1 4 — Ylacetyl) aminophenol] — 5— [N— (4-Fluoro-3-hydroxyphenol) — N-methylamino] — 4— Methyl 4H— 1, 2, 4 Triazole; 3— [2 Black Mouth 4-(2-Hydroxyacetyl) aminophenol] — 5— [N— (4-Fluoro-3-hydroxyphenol) — N— Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [2— Black mouth 4— (2 Hydroxyenole) aminophenol-Nole 5— [N— (4 Funoleo mouth 3 Hydroxyl phenyl) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3 — [2 Black 4— (2-Oxoxazolidine 1-yl) phenol] — 5— [N— (4-Fluoro-3 hydroxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 —Triazole; 3— [2 Cross mouth 4— (3-Methoxyureido) phenol ] — 5— [N— (4 —Fluoro-3 hydroxyphenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4-Triazolene;

3— [2 Black mouth 4— (3 Hydroxyureido) phenol] 5— [N— (4 Fluoro 3 —hydroxyphenyl) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole: 3— (4 Aminosulfo-Luamino 2-Chroophthalate) 5— [N— (4 Fluoro 3-hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole ; 3— [2 Black 4-(Dimethylamino) sulfo-Luaminophenol] — 5— [N— (4 Fluoro 3 Hydroxyphenyl) 1 N-Methylamino] — 4 -Methyl 4H—1, 2, 4 Triazole; 3— [N— (3-Hydroxy—4-Methylphenol) —N—Methylamino] — 4—Methyl—5— [4-Tro-2- (trifluoromethyl) phenol] — 4H —1, 2, 4-Triazole; 3— [N— (3 Hydroxy-4-methylphenol) —N-Methylamino] — 5— [2 (Trifluoromethyl) phenol] -4-Methyl-4H-1, 2, 4 Triazole; 3- [N-(3-Hydroxyl 4-methylphenol) N-Methylamino] -5- [4 Hydroxyl 2 — (Trifluoromethyl) phenol] — 4—Methyl—4H—1, 2, 4 Triazole; 3— (2 —Black mouth 4-hydroxyphenol) 5— [N— (3-Hydroxy one 4-Methylenophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [2— (Dimethylamino) phenol] — 5— [N— (3-hydroxy 1 4— Methylphenol) N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [N— (3 Hydroxy-4-methylphenol) —N—Methylamino] — 4—Methyl-5— ( 1-Methyl-1-phenyl) 4H- 1, 2, 4 Triazole; 3-— [N— (3 Hydroxy 4-methylphenol) 1 N-methylamino] — 5 [1— (4 Hydroxyphenyl) — 1—Methylethyl] —4—Methyl—4H- 1, 2, 4 Triazole; 3— (Adamantane 1—yl) 5— [N- (3 Black 4 1 —Hydroxyphenyl) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole; 3— [4-Amino-2- (trifluoromethyl) phenol] — 5— [N— ( 3—Hydroxy mono 4 —methylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4 triazole; 3

[4 (Dimethylamino) 2 (Trifluoromethyl) phenol] -4-Methyl-5- [N — (3-Hydroxy-1 4-methylphenol) 1 N-Methylamino] — 4H—1, 2, 4 Triazole 3— [4 acetylamino-2 (trifluoromethyl) phenol] 5— [N— (3 —hydroxy 1-methylphenyl) 1 N-methylamino] — 4—methyl 4H—1, 2, 4 — Triazole; 3— [4— (Ethoxycarbol) amino-2- (trifluoromethyl) phenol] — 5— [N— (3-hydroxy-4-methylphenol) N-methylamino] —4— Methyl 4H— 1, 2, 4 Triazole; 3— [4— (2 Hydroxyacetyl) amino-2— (Trifluoromethyl) phenol] — 5— [N— (3-hydroxy-1,4-methylphenol) N-Methylolamino] 4-Methanole 4H— 1, 2, 4 Triazolene; 3— [4 1 (2 Dimethylolamino) Til) amino-2- (trifluoromethyl) phenol] — 5— [N— (3-hydroxy-4-methyl) -N-methylamino] — 4-methyl-4H—1, 2, 4 triazole 3

[4 (2-Hydroxyethyl) amino-2 (trifluoromethyl) phenol] 5— [N— (3 Hydroxy-4-methylphenol) N-methylamino] — 4-methyl-4H— 1, 2 , 4-triazonore; [0144] 3— [N— (3 Hydroxy 4-methylphenol) N-Methylamino] —4-Methyl 5 [4 (2-oxoxazolidine 3-yl) -2 (trifluoromethyl) Phenyl] 4H- 1, 2, 4 Triazole; 3— [N— (3 Hydroxy 4-methylphenol) 1 N-Methylamino] -5— [4 1 (3-Methoxyureido)-2- (Trifluoromethyl) phenol] -4-Methylenole 4H— 1, 2, 4 Triazolene; 3— [N— (3 Chloro-4-hydroxyphenol) —N-methylamino] —4-methyl-5— [2— (Trifluoromethyl) phenol] 4H —1, 2, 4 Triazolene; 3— [N— (3 Chloro-4-hydroxyphenenole) N—Methylamino] — 4—Methyl-5— [2— (Trifluoro) (Romethyl) phenol] — 4H—1, 2, 4 Triazole; 3— [N— (3-hydroxyphenol) N-methylamino] — 5— [4 Hydro 2— (Trifluoromethyl) phenol] — 4—Methyl 4H—1, 2, 4 Triazolone; 3— (2 x 1 4-hydroxyphenol) 5— [N— (3 x 1) 4-Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (3-Hydroxyphenol) N-Methylamino] — 5 — [2— (Dimethylamino) phenol] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— [N— (3 × 4 —hydroxyphenol) N Methylamino] 4 Methyl 5— ( 1 Methyl 1 phe-ruetyl) 4H— 1, 2, 4 Triazole; 3— [N— (3 chlorophenyl) 4-N-methylamino] — 5— [1— (4-Hydroxy phe- ) — 1-Methylethyl] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (Adamantane 1—yl) 5— [N- (3—Black 1 4-hydroxyphenol) 1 N— Chiruamino] - 4-methyl-4H-1, 2, 4 Toriazoru, and their pharmaceutically acceptable salts, prodrugs or solvates thereof.

Similarly, the claimed compound groups also include the compound groups listed in Table 5. The compound definition is the same as described in Table 5.

[0145] <Aspect 10— 1>

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4-hydroxy-1- (trifluoromethyl) phenol] 4-methyl-4H—1, 2, 4 triazole; Xyl-2-(trifluoromethyl) phenol] — 4-methyl-5- {N-methyl-N— [3-— (trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 Triazole; 3— (2 Black mouth— 4-hydroxyphenyl) 4-methyl 5— {N-methyl N— [3- (trifluoromethyl) phenol] amino} — 4H— 1, 2, 4 triazole; 3— [N— (4 hydroxyphenol) -L) —N—Methylamino] —4—Methyl 5— [4-Toro 2- (trifluoromethyl) phenol] 4H— 1, 2, 4 Triazole; 3— (2 Ethoxy—4-Trophe- ) — 5— [N — (4 Hydroxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Tria Zonole; 3— (2 Chloro 1-trophe-nore) 5— [ N— (4 Hydroxyphenol) -N—Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol-Nole) N Methylenoamino] — 4— Methinole 5— [4—-Toro 2— (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole; 3— (2 Ethoxy—4—Nitrophenol) 5— [N— (4 — 1-hydroxyphenol) N-methylamino] — 4—methyl 4H— 1, 2, 4 triazole; 3— (2-chlorophenol 4-trophenol) — 5— [N— (4-fluoro- 3—Hydroxyphenol) N-Methylamino] — 4—Methyl-4H- 1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol) -1 N-Methylamino] — 5— [4 Hydroxy-2- (trifluoromethyl) phenol] —4-Methyl-4-H-4, 1, 2, 4 Triazole; 3-— (2-Black 4-hydroxyphenol) 1-5— [N— (4 —Fluoro-3-hydroxyphenyl) N-methylamino] — 4-methyl-4H —1, 2, 4 triazole; 3— [N— (3 hydroxy-1-methylphenyl) -one N-methylamino] —4— Methyl 5— [4-Tro-2- (trifluoromethyl) phenol] 4H— 1, 2, 4 Triazole; 3— [N— (3 Hydroxy-4-methylphenol) N Methyl amino] — 5— [4 Hydroxy 2- (trifluoromethyl) phenol] 4—Methyl 4H —1, 2, 4 Triazole; 3— (2 Monochloro 4-hydroxy phenol) 1 5— [N— (3-hydroxy-1-4-methylphenol) -N-methylamino] — 4-methyl-4H—1, 2, 4-triazole; 3 -— [N— (3--monophenyl 4-hydroxyphenol) ) N-Methylamino] — 5— [4 Hydroxy-2- (trifluoromethyl) phenol] — 4-Methyl 4H—1, 2, 4 Triazonole; 3— (2 Monochloro 4-hydroxyphenol) ) 5— [N— (3 Hydroxyphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole, and their pharmaceutically acceptable salts and prodrugs Or a solvate thereof.

Embodiment 10-2> 3— [N— (4-Fluorophenol) N-methylamino] — 5— (4-hydroxy-2-methoxyphenol) 4-methyl 4H— 1, 2, 4 triazole; 4-Hydroxyphenyl) — 5— [N— (4-Fluorophenol) —N-Methylamino] —4-Methyl — 4H— 1, 2, 4 Triazole; 3-— (4 Hydroxy-2-methoxyphenyl) ) One 5— [N

— [N— (4-Hydroxyphenol) -N-methylamino] — 4-Methyl 4H—1, 2, 4— Triazolene; 3— (2 Chloro-4-hydroxyphenol) 5— [N— (4-Hydroxyphenol) ) N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole; 3— (2 Black mouth —4-Fluorophenol) — 5— [N— (4-Hydroxyphenol) —N-Methylamino] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol) N-Methylamino] — 5— (4 Fluoro-2-methoxyphenol) 4-Methyl-4H-1 , 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol) -N-Methylamino] — 5— (4-hydroxy-2-methoxyphenol) 4-Methyl 4H— 1, 2, 4 Triazolone 3— (2 Black mouth 4 Funoleo mouth Hue-Nore) One 5— [N— (4 Funore Oro 3 Hydroxy Hue Le) Single N- Mechiruamino] - 4-methyl-4H-1, 2, 4 tri Azoru, and their pharmaceutically acceptable salts, prodrugs or their solvate thereof.

3— [Ν— (4-Fluorophenol) Ν-Methylamino] — 5 [1— (4-Hydroxyphenol) 1-methylethyl] — 4-Methyl 4Η— 1, 2, 4 Triazole; 3— [1 — (4-Hydroxyphenol) 1 Methylethyl] 4 Methyl 5— {Ν Methyl Ν— [3 — (Trifluoromethyl) phenol] amino} — 4Η— 1, 2, 4 Triazole; 3— [Ν - (Four -Hydroxyphenol) N Methylamino] 4 Methyl 5— (1 Methyl 1 Phenylethyl) —4Η—1, 2, 4 Triazole; 3— [N— (4 Hydroxyphenol) N—Methylamino] — 5— [1— (4 Hydroxyphenol) — 1-Methylethyl] —4-Methyl-4H- 1, 2, 4 Triazole; 3— [N— (4 Fluoro-3-hydroxyphenol) -N-Methylamino] 4 Methyl 5— (1 Methyl 1 Phenol) 4H— 1, 2, 4—Triazole; 3— [N— (4-Fluoro-3-hydroxyphenol) N—Methylamino] — 5— [1— (4 Hydroxyphenyl) 1-methylethyl] 4-methyl 4H— 1, 2, 4 triazole; 3-— [N— (3-hydroxy-4-methylphenol) N-methylamino] — 4-methyl-5— (1— Methyl 1-phenol) -4H— 1, 2, 4 Triazole; 3— [N— (3 Hydroxy-4-methylphenol) —N-Methyla NO] — 5— [1— (4-Hydroxyphenol) -1 Methylethyl] -4-Methyl-4H—1, 2, 4 Triazole; 3— [N— (3--Dichlorophenol 4-hydroxyphenol) N —Methylamino] —4—Methyl 1-5— (1-Methyl-1-Fe-ruethyl) -411 1, 2, 4 Triazole; 3— [N— (3 —Kuroguchi 1-hydroxyphenol) N—Methylamino] — 5 — [1— (4 Hydroxyphenol) 1-methylethyl] — 4-methyl 4H— 1, 2, 4 triazole, and pharmaceutically acceptable salts, prodrugs or solvates thereof.

[0148] Each group in the above embodiments 1 to 10 will be described.

The substituent group in the above Ri～R ^u, tail or deviation, unless otherwise stated Te, the expression "Ariru" refers to monocyclic or fused cyclic 6 of: represents a LO-membered ring Ariru group, The expression “alicyclic hydrocarbon group” represents a saturated or partially unsaturated, saturated monocyclic, fused or bridged cyclic alicyclic hydrocarbon group having 3 to 10 carbon atoms, for example Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexyl group, a bicyclooctyl group, a noradamantyl group, and an adamantyl group.

[0149] Examples of the "C alkyl group" include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

1-6

Butyl group, isobutyl group, sec butyl group, tert butyl group, pentyl group, isopentyl group, neopentyl group, tert pentyl group, 1 methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group , Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2— Dimethylbutyl group, 2,2 Dimethylbutyl group, 1,3 Dimethylbutyl group, 2,3 Dimethylbutyl group, 3,3 Dimethylbutyl group, 1-Ethylbutyl group, 2 Ethylbutyl group, 1,1,2-Trimethylpropyl group 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like.

[0150] "Halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the “trihalogenomethyl group” include a trifluoromethyl group and a trichloromethyl group, and a trifluoromethyl group is preferable.

Examples of the “C alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropyl group.

1-6

Poxy group, butoxy group, sec butoxy group, tert butoxy group, pentyloxy group, 1,2 dimethylpropyloxy group, 1,1 dimethylpropyloxy group, 2,2-dimethylpropyloxy group, 2-ethylpropyloxy Xyl, Hexyloxy, 1,2-Dimethylbutoxy, 2,3 Dimethylbutoxy, 1,3 Dimethylbutoxy, 1-ethyl-2-methylpropyloxy, 1-methyl-2- And propylpropyloxy group.

[0151] "5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S" includes pyrrolidyl group, tetrahydrofuryl group, oxazolidinyl group Piperidyl group, tetrahydrovinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group and the like.

“C alkyl group substituted with a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, S” includes a morpholinomethyl group, piperi

1-6

Examples include a dinomethyl group.

[0152] "Hydroxy C alkyl group" includes hydroxymethyl group, hydroxyethyl group and the like.

1-6

I can get lost.

Examples of “c alkoxy C alkyl group” include methoxymethyl group, methoxyethyl group, and the like.

1-6 1-6

Can be mentioned.

"Even if the hydrogen atom on the nitrogen atom is mono- or disubstituted with a c alkyl group

1-6

YO! Camino alkyl group includes aminomethyl group, dimethylaminoethyl group, etc.

1-6

I can get lost. "Even if the hydrogen atom on the nitrogen atom is mono- or disubstituted with a c alkyl group

1-6

Examples of the “good amino group” include a methylamino group and a dimethylamino group.

“The hydrogen atom on the nitrogen atom is arbitrarily selected from the alkyl group or phenyl group.

1-6

Examples of the “amino group optionally substituted by 1 to 2 groups” include a methylamino group and a phenolamino group.

“Even if the hydrogen atom on the nitrogen atom is mono- or disubstituted with a C alkyl group

1-6

Yo! / Aminocarbonyl C alkyl group includes aminoaminomethyl group, dimethyl group

1-6

Examples thereof include an aminocarbo-ruethyl group.

“Aryl C alkyl group” includes benzyl group, phenethyl group, or j8-naphth

1-6

A tilmethyl group etc. are mentioned.

“Phenol c alkyl group” includes a acetyl group, propiol group, butyryl group,

1-6

Groups derived from aliphatic saturated carboxylic acids having 2 to 6 carbon atoms, such as ryl, isovaleryl, bivaloyl, and force-propyl groups, carbon numbers such as attalyloyl, propioroyl, methacryloyl, crotonol, and isocrotonol And groups derived from 3 to 6 aliphatic unsaturated carboxylic acids.

Examples of the “C alkoxy carbo group” include a methoxy carbo group and an ethoxy carbo group.

1-6

Groups and the like.

“C alkyl carbolumino group” includes methyl carbolumino group, butyl carboxy group

1-6

Bonylamino group and the like can be mentioned.

“The hydrogen atom on the nitrogen atom may be mono- or disubstituted with a c alkyl group.

1-6

Examples of the “aminocarbonyl group” include a dimethylaminocarbonyl group.

"If the hydrogen atom on the nitrogen atom is replaced by 12 alkyl groups, the amino force

1-6

“Luponyl group” includes methylaminocarbonyl group and the like.

1-6

Examples of the “aminosulfol group” include a dimethylaminosulfol group.

Examples of the morpholino include a nitrolino group which may form a 5- to 7-membered alicyclic heterocycle containing a nitrogen atom and 1 to 2 heteroatoms arbitrarily selected from N, 0 and S. Examples thereof include a carbo group and a piperidinocarbonyl group. Examples of the “c alkyl carbo-loxy c alkyl group” include a acetomethyl group and the like.

1-6 1-6

Can be mentioned.

“C alkoxycarbol C alkyl group” includes a methoxycarboromethyl group

1-6 1-6

Etc.

The “c alkoxyaminocarbol group” includes methoxyaminocarbol group, ethoxy

1-6

Examples thereof include an aminocarbonyl group.

“C alkylsulfol group” includes methanesulfol group, butanesulfol group, etc.

1-6

Can be mentioned.

The “c alkylsulfo-lumino group” includes methanesulfo-lumino group, butanesulfo group.

1-6

-Luamino group etc. are mentioned.

“C alkylsulfol C alkyl group” includes methanesulfolmethyl group,

1-6 1-6

And n-sulfonylbutyl group.

Examples of the “c alkylthio group” include a methylthio group and an ethylthio group.

1-6

The “aminocarbonyl C alkyl group” includes an aminocarbonylmethyl group, an aminocarbo

1-6

-Ruetyl group and the like.

“C substituted with an alkoxy group or a hydroxyl group, which may be a benzyloxy group”

1-6

Examples include 1-methoxybenzyloxy group, 1-hydroxybenzyloxy group and the like.

“C substituted with an alkoxy group or a hydroxyl group and may be a phenoxy group” includes 1-me

1-6

Examples thereof include a toxiphenoxy group and a 1-hydroxyphenoxy group.

Although Y is not limited to the argument, it is preferable that Y is of such a size that the free rotation of the 5-position phenyl group is limited by the steric repulsion between the triazole 4-position methyl group and the substituent Y.

A pharmaceutical composition comprising a compound according to any one of the embodiments 1 to 10, a pharmaceutically acceptable salt, a prodrug or a solvate thereof as an active ingredient.

Embodiment 12>

A compound according to any one of the embodiments 1 to 10, a pharmaceutically acceptable salt, a prodrug or a solvate thereof as an active ingredient,

I) ll j8-inhibition of HSD1 or 2) A pharmaceutical composition for administration to a patient in need of modulation of 11 β -HSD1 activity.

[0155] <Aspect 13>

Aspect 1 to: A compound according to any one of LOs, a pharmaceutically acceptable salt, prodrug or solvate thereof as an active ingredient, comprising diabetes, obesity, green Disorder, osteoporosis, cognitive impairment, immune disorder, depression, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscle atrophy, or neurodegenerative disease, or at least one of syndrome X A pharmaceutical composition for treating or preventing one. <Aspect 14>

A compound according to any one of embodiments 1 to 10, a pharmaceutically acceptable salt thereof, a prodrug, or a solvate thereof as an active ingredient, and the treatment or treatment of the following diseases: Is a pharmaceutical composition intended to prevent or reduce the side effects of glucocorticoid receptor agonist treatment when used in combination with a darcocorticoid receptor agonist. Allergic immune diseases · respiratory diseases; infectious visceral diseases; immunity, connective tissue and joint diseases; endocrine diseases; blood diseases; cancer, vomiting due to chemotherapy; muscle and neuromuscular cell diseases; Preoperative and postoperative treatment; brain tumor, vomiting, infection, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, medullary disease or saccular aneurysm . Examples of such side effects include osteoporosis, aseptic osteonecrosis, Cushing-like facial appearance, psychiatric symptoms, insulin resistance, hypertension, myopathy, cataract or glaucoma.

[0156] <Aspect 15>

A prophylactic or therapeutic treatment for the following diseases characterized by containing the compound according to any one of Embodiments 1 to 10, a pharmaceutically acceptable salt, prodrug or solvate thereof as an active ingredient. A pharmaceutical composition intended to be used in combination with a darcocorticoid receptor agonist for the purpose of Cushing disease, Cushing syndrome, asthma, atopic dermatitis, cystic fibrosis, emphysema, bronchi Inflammation, hypersensitivity, pneumonia, eosinophilic pneumonia, pulmonary fibrosis, Crohn's disease, ulcerative colitis, reactive arthritis, rheumatoid arthritis, Scherdalen syndrome, systemic lupus erythematosus, lupus nephritis, Hahn-Hossien line Purpura, ugener granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis , Dermatomyositis polymyositis, pemphigus vulgaris, hyperthyroidism, hypoaldosteronism, hypopituitarism, hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, spinal cord tumor compression, brain tumor Acute lymphoblastic leukemia, Hodgkin disease, chemotherapy nausea, myasthenia gravis, heriditary muscle disease, Duchenne muscular dystrophy, trauma, postoperative stress, surgical stress, kidney transplantation, liver transplantation, lung transplantation, spleen Islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal transplantation, tracheal transplantation (intestinal transplantation), corneal transplantation, skin transplantation, corneal transplantation, lens metastasis, nausea, infectious disease, hypercalcemia, adrenal hyperplasia Formation, self-immune hepatitis Power is the disease of choice.

[0157] <Aspect 16>

The pharmaceutical composition for the combination therapy according to embodiment 14 or 15, wherein the darcocorticoid receptor agonist is also selected from the following group of drugs

Betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butychicort, clobetasol, flu-zolide, flucatisone (and analogues thereof), mometasone, triamcinolone acetonide, triamcinolone hexose 698, GW 685 NXC-1015, NXC-1020, NXC-1021, NS-1226, P-4112, P-4114, RU-24858, and T-25.

[0158] <Aspect 17>

A compound according to any one of embodiments 1-10, a pharmaceutically acceptable salt, prodrug or solvate thereof, and a carrier, excipient, and diluent that are acceptable for use in a pharmaceutical product Included in the same container, the dalcocorticoid receptor agonist and the carriers, excipients, and diluents that are acceptable for use in the drug are collectively administered as the second dose. Kit.

[0159] <Aspect 18>

A prophylactic or therapeutic treatment for the following diseases characterized by containing the compound according to any one of Embodiments 1 to 10, a pharmaceutically acceptable salt, prodrug or solvate thereof as an active ingredient. A combination drug intended to be used in combination with an antihypertensive drug for the purpose of, wherein the disease is any of metabolic syndrome, insulin resistance, dyslipidemia, obesity or hypertension . [0160] <Aspect 19>

The combination pharmaceutical composition according to embodiment 18, wherein the antihypertensive drug is selected from the following intermediate forces:

Beta blocker, beta 2 blocker, ACE (angiotensin converting enzyme) inhibitor, calcium 'channel' blocker, alpha blocker, diuretic, loop diuretic, potassium-retaining diuretic, endothelin ΕΤ-Α antagost, endothelin antagost , Renin inhibitor, vasopressin VI antagonist, vasopressin V2 antagonist, Β type sodium excretion peptide agonist, angiotensin 11 antagonist, 5-ΗΤ2 agonist, adenosine A1 antagonist, thromboxane Α2 antagonist Endobeptidase inhibitor, nitric oxide agonist, dopamine D1 antagonist, dopamine D2 agonist, η-3 fatty acid, prostacyclinagost, PGE1 agonist, Na + / K + ATPase modulator, potassium 'channel activator, vacchi N.

[0161] <Aspect 20>

The combination pharmaceutical composition according to embodiment 19, wherein the antihypertensive drug is selected as follows: Alopreno Noronore, Atenoro Nore, Timoronore, Pindronore, Propranolo Nore, Metoprolonore, Bisprono Lefmelato, Esmolonore, Asetello Nore, Asetro Nore, Betaxolone, Seripro Ronore, Nebiboronore, Tenoretatro Nore, Oxprenolol, Amsoralol, Carvedilol, Labetalol, Satenolol, OPC-1085, Quinapril, Ishinopril, Capripril, Pripril, Pripril, Pripril, Pripril Fuocinopril, Ramipril, Cilazapril, Delapril, Imidapril, Moexipril, Spirapril.

[0162] <Aspect 21>

Formula (VI,)

[Chemical 73]

N-N

Person, (νι ')

RNL CH ₃

(Where

L is a halogen atom, a linear or branched alkyl sulfo group of C (eg methane

1-6

Sulfo group) or the same aralkyl sulfo group (for example, benzyl sulfo group). Group)) or a thiol group,

R is chosen as Ra), Rb), Rc), Rd) force,

Ra)

[Chemical 74]

And

Y in Ra) is selected from the following substituent group:

1-3 1-3

1-3

, Cyano group, nitro group, C alkylcarbonylamino group, C alkylsulfonyl group,

1-3 1-3

A C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group,

1-3

[0164] Z is selected from the following substituent group:

The substituent group is

Z1)

[Chemical 75]

Or

[Chemical 76]

And

[0165] R ¹ is a group selected from the following substituent group,

The substituent group is

A hydrogen atom, a C alkyl group, and a phenyl group, or

1-3

R ² is a group selected from the following substituent group,

The substituent group is A hydrogen atom and a c alkyl group,

1-3

[0166] R ³ is a group selected from the following substituent group,

The substituent group is

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1-6

1 to 6 1 to 6 kill group, and aminocarbonyl C alkyl group,

1-6

Consists of

Or a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S, including the nitrogen atom to which R ² and R ³ are bonded, and The alicyclic complex hydrocarbon group may be further substituted with 12 groups arbitrarily selected from the following substituent group,

The substituent group is

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

[0167] Z2)

[Chemical 77]

o ₂

R ⁴ ' ^S , I

R ^z

And

[0168] R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ⁴ is a group selected from the following substituent group,

The substituent group is

C alkyl group, full group, alicyclic hydrocarbon group, torino, logenomethyl group, and C Substituted with 12 or more groups selected from an alkyl group or a phenyl group, and may be an amino group or a force group;

[0169] Z3) an amino group, and the hydrogen atom on the nitrogen atom of the amino group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di

1-6 1-6

Optionally substituted aminocarbonyl C alkyl group, phenyl group, phenyl C

1-6 1-6 alkyl groups, and alicyclic hydrocarbon groups,

May be substituted with 1 or 2 groups arbitrarily selected from

The substituent group is

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group

1-6

Or di-substituted aminocarbonyl group, C alkylsulfonyl group, C

1-6 1-6 alkylsulfonylamino groups, C alkoxyaminocarbonyl groups, aminocarbonyl groups

1-6

Including a nitrogen atom, N, 0, S force may form a 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms selected arbitrarily, an aminocarbo group, And the hydrogen atom on the nitrogen atom may be mono- or di-substituted with a C alkyl group.

1-6

A rubonyl group,

[0170] Z4)

[Chemical 78]

0

H

R ⁵ is arbitrarily selected from the following substituent group: The substituent group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~! 1-6 1-6 1-6

1-6

1-6 1-6

1 ~ 6 1 ~ 6 1 ~

Groups, C alkoxy groups, and C alkoxy carbo C alkyl groups,

1 ~! 1 ~ 6 l ~ t)

[0171] Z5)

[Chemical 79]

0

R ⁷ , N people N,

R ^{e H}

[0172] The substituent group includes

1-6 1-6

V, may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ヽ

1-6

Phenoxy group, C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al

1-6

Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono

1-6 1-6

Mono- or di-substituted! /, May! /, Aminocarbonyl C alkyl group, phenyl group,

1-6

And an alicyclic hydrocarbon group,

1-6

[0173] Z6)

[Chemical 80]

R ⁸ and R ⁹ are hydrogen atoms or C alkyl groups, or R ⁸ and R ⁹ are bonded to each other.

1-3

A 5- to 7-membered alicyclic heterohydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S may be formed.

1-3 1-3

Can be replaced

[0174] Z7) hydroxyl group,

Z8) C alkoxy group, C alkyl group, trihalogenomethyl group, halogen atom, cyano

1-6 1-6

Group, and nitro group,

Power is the group chosen,

However, when Z force 8), at least one of (X) n is XI) hydroxyl group,

[0175] Rb)

[Chemical 81]

And

[0176] R ^1Q in Rb) is arbitrarily selected from the following substituent group,

R ^1Q is bonded to either the 3rd or 4th position of the adamantyl group,

The substituent group is

Halogen atom, hydroxyl group, C alkyl group, C alkoxy group, C alkyl carbo-

1-6 1-6 1-6

Group, C alkoxycarbonyl group, C alkoxy C alkyl group, C alkyl

1 ~ 6 l ~ t) 1 ~ 6 1 ~

1 to 2 of sulfo group, C alkyl sulfole C alkyl group, C alkyl group

1 ~ 6 l ~ t) l ~ o

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, C

1 ~! 1-6 1-6 1-6 1-6 alkoxy group, hydrogen atom on nitrogen atom is mono- or di-substituted with c alkyl group The amino amino group, hydroxyamino carbonyl group, on the nitrogen atom.

1 6

-Group, aminocarbole C alkyl group, hydrogen atom on nitrogen atom is C alkyl

An aminosulfol group, a phenyl group, a phenyl C alkyl group, and an alicyclic hydrocarbon group, which may be mono- or di-substituted by 1 6 1 6 groups,

1 6

May be substituted with 1 or 2 groups arbitrarily selected from

Provided that when R is Rb), at least one of (X) n is XI) a hydroxyl group,

[0177] Rc)

[Chemical 83]

And

R ¹¹ in Rc) is arbitrarily selected from the following substituent group:

The substituent group is

A hydroxyl group, a C alkoxy group, a halogen atom, and a hydrogen atom,

1 6

m represents an integer of 1 2

[0178] Rd)

[Chemical 84]

Y in Rd) is the same as the definition of Y in Ra)

Provided that when R is Rd), at least one of X) n is XI) a hydroxyl group,

(X) The n-substituted phenyl group is a 4-hydroxyphenyl group, a 3-hydroxyphenyl group, a 2-hydroxyphenyl group, a 4-fluoro-3 hydroxyphenyl group, or a 4-chloro-3 hydroxyphenyl group. group, 3-black port one 4-hydroxy Hue - group, 3-hydroxy-one 4- ^main; Rufue - group, 4-hydroxy 3-Mechirufue - when the group, R is not a 2-methylphenol group, a 2-chlorophenol group, a 2-methoxyphenyl group, or a 1 (4-fluorophenyl) 1 methylethyl group.

However, “→” in the formula represents a bond. )

Or a salt, prodrug or solvate thereof.

[0179] Aspects of the pharmaceutical composition according to aspects 1 to 17 of the present invention are also:

(1) Use of a compound of formula (I) or the like to produce a pharmaceutical composition of interest using the compound of formula (I) defined in each embodiment,

(2) A method for preventing or treating the target disease or symptom or a combination therapy, characterized by using a compound of formula (I) as defined in each embodiment, or the darco It is a method for reducing or preventing side effects in corticoid receptor agonist therapy.

[0180] The compound (I) of the present invention may form an acid addition salt. Depending on the type of substituent, a salt with a base may be formed. The salt is not particularly limited as long as it is a pharmaceutically acceptable salt, and specifically, a base such as an alkali metal such as sodium, potassium, magnesium, calcium, or aluminum or an alkaline earth metal. And salts; mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Organic carboxylic acids such as formic acid, malic acid, tartaric acid, citrate, and mandelic acid, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, aspartic acid, glutamic acid Acid addition salts with acidic amino acids such as methylamine, ethylamine, triethylamine, ethanolamine, pyridine, lysine, Ginin, and salts with organic bases such as Orunichi emissions, ammonium - © beam salts.

[0181] The salt of the compound of the present invention may include a mono salt, a di salt, or a tri salt. Alternatively, the compound of the present invention can simultaneously form both an acid addition salt and a base salt, depending on the side chain substituent. The compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various isomers such as geometric isomers, tautomers and optical isomers, and isolated isomers. Isolation and purification of such optical isomers can be achieved by those skilled in the art using conventional techniques through resolution or asymmetric synthesis using column chromatography once the preferential crystals are obtained. it can.

[0182] Furthermore, the present invention includes various pharmaceutically acceptable solvates and crystal polymorphs of Compound (I). Needless to say, the present invention is not limited to the compounds described in the examples below, but 3-allylamino 1,2,4 triazole compounds represented by the formula (I) or pharmaceutically acceptable. All salts are included. It also includes pharmacologically acceptable solvates. Although it does not specifically limit as a solvate, Specifically, a hydrate, alcohol hydrate (For example, methanol solvate, ethanol solvate, propanol solvate, etc.), ether solvate (ethyl ether hydrate) Product, THF solvate, etc.), ester solvate (ethyl acetate solvate, etc.), acetic acid solvate, etc.

[0183] The prodrug of compound (I) is not particularly limited, but under physiological conditions as described in “Drug Development” Section 7; Molecular Design of Prodrugs (pages 163 to 198). What changes to compound (I), that is, (1) is a derivative of a drug (parent compound) with known action and does not itself have a medicinal effect or is clearly weaker than the parent compound (2) Included are compounds that have been converted to the parent compound either physically or chemically, and (3) improved the physical properties and pharmacokinetics of the parent compound (gastrointestinal absorption, blood concentration, tissue distribution, etc.) and enhanced therapeutic value.

[0184] As a prodrug of compound (I), a compound in which the amino group of compound (I) is alkylated (for example, 2-tetrahydrofurylated), acylated (for example, acetylated), phosphorylated or sulfated A compound in which the hydroxyl group (alcoholic or phenolic) of compound (I) is acylated, alkylated, phosphorylated, sulfated, glocron oxidized, boric acid; carboxy of compound (I) Examples include compounds in which a group is esterified or amidated. These compounds can be produced from compound (I) by a known method.

Each compound shown as embodiment 110 is also explained in the same manner as the pharmaceutically acceptable salt, prodrug or solvate thereof for compound (I).

[Method for producing compound of the present invention]

In the following, the ability to explain the method for producing the 3-arylamino-1,2,4 triazole derivative (I) of the present invention The present invention is not limited to this method.

[0186] [Production Method 1]

The compound represented by the formula (I), a salt thereof or a solvate thereof can be represented by, for example, It can be produced by the method 1).

[Chemical 85]

CH ₃

(V) (VI) (I)

(Reaction formula 1)

(In the formula, RX and n represent the same meaning as described above, M represents an oxygen atom or a sulfur atom, and L represents a leaving group typified by a halogen atom, an alkylsulfol group or an aralkylsulfol group. )

That is, the compound represented by the formula (I) is converted into the compound represented by the formula (VII) after converting the compound represented by the formula (V) into the compound represented by the formula (VI). It can be manufactured by reacting with.

Conversion to the compound represented by the formula (V) and the compound represented by the formula (VI) can be carried out by the following methods depending on the type of M and salt.

[0188] [When M is an oxygen atom and L is a halogen atom]

A compound represented by the formula (V) in a solvent not involved in the reaction with a halogenating agent typified by sodium chloride, thiobromide, phosphorus oxychloride, phosphorus pentachloride, etc. at -20 ° C The compound represented by the formula (VI) can be produced by reacting for a time during which the reaction sufficiently proceeds within the temperature range where the reaction mixture is refluxed. Reaction solvents that are not involved in the reaction include aromatic hydrocarbon solvents such as toluene and benzene, halogenated solvents such as chloroform, methylene chloride, and 1,2-dichloroethane. The temperature at which the reaction mixture is refluxed from room temperature is preferred.

[0189] [When M is a sulfur atom and L is a halogen atom]

Halogenating agent typified by chlorine, bromine, sulfuryl chloride, sulfuryl bromide, etc. in a solvent that does not participate in the reaction of the compound represented by formula (V), and the temperature range at which the reaction mixture refluxes. Thus, the compound represented by the formula (VI) can be produced by reacting for a time for which the reaction proceeds sufficiently. Solvents that do not participate in the reaction include water, methanol, Preferred are polar solvents such as acetonitrile, aromatic hydrocarbon solvents such as toluene and benzene, halogenated solvents such as chloroform, methylene chloride and 1,2-dichloroethane. The reaction temperature is 0 ° C to 50 °. C is preferred. When using a sulfuryl halide, the reaction can be carried out in the presence of a nitrate such as potassium nitrate. In this case, toluene or acetonitrile is preferred as the solvent! /.

[When M is a sulfur atom and L is an alkylsulfol group or an aralkylsulfol group] A solvent that does not participate in the reaction with the compound represented by the formula (V), preferably Ν, Ν dimethylformamide, 1 , 3 In a polar solvent such as dimethyl-2-imidazolidinone, an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or triethylamine, pyridine, Ν, Ν dialkyla- The reaction proceeds sufficiently in the temperature range where the reaction mixture refluxes from 20 ° C with an alkylating agent represented by halogenated alkyl, alkyl sulfate, etc. in the presence of an organic base such as phosphorus or lithium diisopropylamide. After the reaction for a period of time, the resulting alkylthio form does not participate in the reaction !, a solvent, preferably a polar solvent such as water or alcohol, Acids such as hydrogen peroxide, peracetic acid and peroxyacids such as 3-chloroperbenzoic acid in halogenated solvents such as 1,2-dichloroethane. Thus, the compound represented by the formula (VI) can be produced.

[0191] The production of the compound represented by the formula (I) does not involve the compound represented by the formula (VI) in the reaction! It can be carried out by reacting with a compound represented by the formula (VII) in a solvent or without a solvent. It can also be carried out in the presence of a base or a metal catalyst. Solvents that do not participate in the reaction include aromatic hydrocarbon solvents such as toluene and benzene, polarities such as water, methanol, ethanol, Ν, Ν dimethylformamide, 1,3 dimethyl-2-imidazolidinone, and dimethyl sulfoxide. Solvents, basic solvents such as triethylamine, pyridine, halogenated solvents such as chloroform, methylene chloride, 1,2-dichloroethane, ether solvents such as jetyl ether, tetrahydrofuran, 1,4 dioxane, or mixtures thereof A solvent may be used, and the base may be an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or triethylamine, depending on the type of solvent and the respective reactivity. , Pyridine, Ν, Ν dialkyl aryl An organic base such as lithium diisopropylamide can be used. Examples of the metal catalyst that can be used include copper catalysts such as copper and copper iodide, and palladium catalysts such as palladium acetate and tetrakistriphenylphosphine palladium. The reaction can be carried out at a temperature ranging from 78 ° C. at which the reaction mixture is refluxed. However, if the reaction is difficult to proceed, it can also be carried out at a temperature higher than the boiling point in a sealed tube. The reaction temperature is preferably 100 to 200 ° C. without solvent. The reaction time is a time for which the reaction proceeds sufficiently.

[0192] The compound represented by the formula (I) is a compound represented by the formula (VII ') instead of the compound represented by the formula (VII) (wherein X and n are as defined above). )) And then methylated with a methylating agent such as methyl iodide or dimethyl sulfate.

[0193] [Chemical 86]

The compound represented by the formula (V), which is a raw material of the (Reaction Scheme 1), can be produced according to a method known in the literature or according thereto, for example, according to the following (Reaction Scheme 2).

[Chemical 87]

OH

o CH ₃ -N = C = M o NN

R people _N, NH ₂ _ ^ _R A丫₃ R's NM M- ^H

H

HM CH ₃

(XIII) (XII) 00

(Scheme 2)

(Wherein R and M represent the same meaning as described above.)

A compound represented by the formula (X) obtained by reacting a hydrazine represented by the formula (VIII) or a hydrate thereof with a compound represented by the formula (IX) is converted into a carboxylic acid represented by the formula (XI). It is possible to produce a compound represented by the formula (V) by reacting with an acid or a derivative thereof to obtain a compound represented by the formula (ΧΠ) and cyclizing it under a basic condition or an acidic condition. it can. [0194] The compound represented by formula (XII) is obtained by reacting hydrazine represented by formula (VIII) or a hydrate thereof with a carboxylic acid represented by formula (XI) or a derivative thereof. It can also be produced by reacting with a compound represented by the formula (IX) after preparing a compound represented by the formula (IX). Among the compounds represented by the formula (X), a compound represented by the formula (Χ ′) in which M is a sulfur atom is prepared according to a method known in the literature or according thereto, for example, according to the following (Scheme 3). I'll do it.

[Chemical 88]

(Scheme 3)

That is, a compound represented by the formula (XIV) is reacted with carbon dioxide and then alkylated with methyl iodide to obtain a compound represented by the formula (XV), and then represented by the formula (VIII). The compound represented by the formula (χ ′) can be produced by reacting with hydrazine or its hydrate.

[0195] [Production Method 2]

The compound represented by the formula (I), a salt thereof or a solvate thereof can be produced by the following method (Reaction Scheme 4).

[Chemical 89]

(Scheme 4)

(Wherein R X n represents the same meaning as described above.)

[0196] The compound represented by the formula (I) does not participate in the reaction with the compound represented by the formula (XVI) or a salt thereof, and the carboxylic acid represented by the formula (XI) or a derivative thereof in a solvent. It can be produced by reacting. This reaction can be performed in the presence or absence of a base or acid. Examples of solvents that do not participate in the reaction include toluene and benzene. Aromatic hydrocarbon solvent, water, methanol, ethanol, polar solvent such as Ν, アミド -dimethylformamide, 1,3 dimethyl-2-imidazolidinone, dimethylsulfoxide, basic solvent such as triethylamine, pyridine, formic acid, acetic acid, etc. Acidic solvents, chloroform-form, methyl chloride, halogen solvents such as 1,2-dichloroethane, ether solvents such as jetyl ether, tetrahydrofuran, 1,4 dioxane, or a mixture of these. As the base, an inorganic base such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or the like, or triethylamine, pyridine, Ν , Ν Dialkylaline, lithium diisopropylamide, sodium acetate As the organic base and acid such as sodium chloride, mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, or organic acids such as formic acid and acetic acid can be used. The reaction can be carried out at a temperature of -78 ° C at a temperature at which the reaction mixture is refluxed. However, if the reaction is difficult to proceed, it can also be carried out at a temperature above the boiling point in a sealed tube. The reaction time is the time for which the reaction proceeds sufficiently.

The compound represented by the formula (XVI) or a salt thereof used as a starting material for (Reaction Scheme 4) can be produced according to a method known in the literature or a modification thereof, for example, according to the following (Reaction Scheme 5).

[Chemical 90]

H ₃ CN = C = S

(Scheme 5)

(In the formula, X and n have the same meaning as described above.) The compound represented by the formula (IX ′) is alkylated with methyl iodide after reacting the compound represented by the formula (XV) with the hydrazine represented by the formula (VIII) or a hydrate thereof. Obtained C-Ί H,

Formula (X I)

A compound represented by the formula (XVI) or a salt thereof can be produced by reacting a compound represented by NH or a salt thereof with a compound represented by the formula (VI).

[0198] The compound represented by formula (XVI) or a salt thereof is represented by the compound represented by formula (IX ') or the compound represented by formula (XV) and formula (VII). Reacting a compound represented by the formula (XIX) or a salt thereof obtained by alkylating with methyl after reacting the compound with a hydrazine represented by the formula (VII I) or a hydrate thereof. Can also be manufactured by

[0199] Further, the compound represented by the formula (XVII) which is an intermediate of (Reaction Scheme 4) is represented by the formula (ΧΠΙ) instead of the compound represented by the Formula (VIII) in the Reaction Scheme 5. It can also be produced by using a compound to be prepared.

[0200] [Production method 3]

The compound represented by the formula (I), a salt thereof or a solvate thereof can also be produced by the following method (Reaction Scheme 6).

[Chemical 91]

CH ₃

CH

(I)

(Scheme 6)

(In the formula, R, M, X, and n represent the same meaning as described above, E represents a leaving group such as a hydroxyl group, a halogen atom, an alkyl sulfo-loxy group, or an aralkyl sulfo-loxy group, V represents a halogen atom, Represents a leaving group such as an alkylsulfol group or an aralkylsulfonyl group, or a thiol group.) [0201] The compound represented by the formula (I) was reacted with the compound represented by the formula (XX) in the presence of a base in a solvent without involving the compound represented by the formula (v) in the reaction. After that, by performing methylation

Can be manufactured. Examples of solvents that do not participate in the reaction include aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as water, methanol, ethanol, Ν, Ν dimethylformamide, 1,3 dimethyl-2-imidazolidinone, and dimethyl sulfoxide, Basic solvents such as triethylamine, pyridine, halogenated solvents such as chloroform, methylene chloride, 1,2-dichloroethane, ether solvents such as jetyl ether, tetrahydrofuran, 1,4-dioxane, Alternatively, a mixed solvent of these can be used. As the base, an inorganic substance such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or the like is used depending on the type of solvent and the reactivity of each. Base or triethylamine, pyridine, Ν, Ν dialkylaline, lithium It can be used organic bases such as isopropyl amides. The reaction can be carried out at a temperature ranging from 78 ° C to the temperature at which the reaction mixture is refluxed. However, if the reaction is difficult to proceed, it can also be carried out at a temperature above the boiling point in a sealed tube. The reaction time is a time for which the reaction proceeds sufficiently. This reaction can also be carried out using a copper catalyst such as copper and copper iodide, a palladium catalyst such as palladium acetate and tetrakistriphenylphosphine noradium. Methyl candy can be obtained using a methylating agent such as methyl iodide or dimethyl sulfate in the presence of a base such as sodium hydride or sodium hydroxide.

[0202] In this reaction, when M is an oxygen atom, E is a hydroxyl group and L is preferably a combination of a halogen atom or an alkylsulfonyl group. When M is a sulfur atom, E is a halogen atom and L ' Is preferably a combination of thiol groups. When M is an oxygen atom, the reaction proceeds even at room temperature. When M is a sulfur atom, reaction at room temperature yields an intermediate compound represented by the formula (XXI), which is isolated and then reacted under the above conditions to give a compound represented by the formula (I ) Can be produced.

The intermediate compound represented by the formula (XXI) can be produced according to the following (Scheme 7).

[Chem 92]

(Scheme 7)

(Wherein R, E, L ′, M, X, n represent the same meaning as described above, R ¹² represents a hydrogen atom, C alkyl

Represents 1 to 6 groups. )

That is, the compound represented by the formula (XXI) is a compound represented by the formula (ΧΧΙΠ) in the same manner as described above using the compound represented by the formula (v) and the compound represented by the formula (ΧΧΠ). It can also be produced by reacting with a compound represented by the formula (νπ ′) after conversion to.

[0203] When R ^{12 of the} compound represented by the formula (ΧΧΠΙ) is a hydrogen atom, the compound represented by the formula (ΧΧΠΙ) and the compound represented by the formula (νπ ') are not involved in the reaction. The compound represented by the formula (XXI) can be produced by reacting with a condensing agent. Examples of solvents that do not participate in the reaction include aromatic hydrocarbon solvents such as toluene and benzene, aprotic polar solvents such as Ν, Ν-dimethylformamide, 1,3 dimethyl-2-imidazolidinone, and dimethyl sulfoxide, triethylamine, Use basic solvents such as pyridine, halogen solvents such as chloroform, methylene chloride, 1,2-dichloroethane, ether solvents such as jetyl ether, tetrahydrofuran, 1,4 dioxane, or a mixture of these. As the condensing agent, 1-ethyl 3- (3 dimethylaminobutyryl) carbodiimide hydrochloride (WSC · HC1), dicyclohexylcarbodiimide (DCC), and the like can be used. The reaction can be carried out at a temperature ranging from 0 ° C to the temperature at which the reaction mixture is refluxed. The reaction time is a time for which the reaction proceeds sufficiently.

[0204] The compound represented by the formula (XXI) is a compound represented by the formula (VII ') after converting the compound represented by the formula (ΧΧΙΠ) into an acid chloride using a salt such as thiothionyl. It can also be produced by the use of a dehydrating agent such as oxyphosphorus chloride.

When R ^{12 of the} compound represented by the formula (ΧΧΠΙ) is a C alkyl group,

1-6

The condensation reaction can be carried out. Hydrolysis is carried out in a known manner, for example, in a solvent such as an alcohol solvent such as methanol or ethanol, at a temperature at which the reaction mixture is refluxed from room temperature in the presence of an aqueous solution such as lithium hydroxide or sodium hydroxide. Can do. In (Reaction Scheme 6) and (Reaction Scheme 7), when M of the compound represented by Formula (XXI) and Formula (ΧΧΙΠ) is a sulfur atom, hydrogen peroxide, peracetic acid, 3 —After conversion to a compound in which M in the compounds represented by formula (XXI) and (ΧΧΠΙ) is a sulfo group by acidification with a peroxy acid such as black perbenzoic acid. A compound represented by the formula (I) can also be produced.

[0205] In the above reaction, when R and X have a reactive substituent (for example, a hydroxyl group, an amino group, a carboxyl group, etc.), the reaction was carried out while appropriately protecting these groups. The protecting group can be removed later. Such protecting group introduction / removal methods can be performed according to the type of protecting group or protecting group. For example, [Protective Groups in Organic Synthesis, 3rd edition, 1999, The method described in the review by John Willie and Sons] can be used. In addition, the functional group present in the compound represented by the formula (I) can be converted to other functional groups according to a known method or a similar method.

[0206] For example, when the functional group has a primary or secondary amino group, alkylation with a halogen alkyl, reductive alkylation with an aldehyde, acylation with a carboxylic acid derivative, sulfone with sulfourel chloride. Amidation and urination with carbamoyl chloride can be performed.

[0207] In addition, when the functional group has a halogen atom, it can be aminated with a primary or secondary amine. This reaction can be carried out in the presence of a base or a metal catalyst. Bases include inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, or triethylenoamine, pyridine, Ν,有機 Use organic catalysts such as dianolenoquinodilin and lithium diisopropylamide, and metal catalysts such as copper catalysts such as copper and copper iodide, palladium catalysts such as palladium acetate and tetrakistriphenylphosphine palladium. It is out.

[0208] Further, when the functional group has a carboxyl group, it can be converted into an amide group by primary or secondary amine using a condensing agent. Condensation agents include 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC'HCl), dicyclohexylca Rubodiimide (DCC) can be used. Conversion to an amide group can also be performed by converting a carboxyl group to an acid halide using a salt such as thiothionyl or oxalyl chloride, and then reacting with a primary or secondary amine.

[0209] The ability to specifically explain the present invention by giving test examples below The present invention is not limited by these.

(Test Example 1) 11 β-HSD1 inhibitory activity test

The excellent 11 i8 -HSDl inhibitory activity of the 3-allylamino-1,2,4-triazole derivative which is the compound of the present invention is confirmed by the following test examples. Inhibitory activity against 11 | 8-HSD1 was measured by the following method using a 384 well plate.

[0210] In other words, the reaction was performed by adding a mixed solution of the test drug (specimen, compound of the present invention), cortisone, and NADPH to a well in which 11 β-HSD1 enzyme solution was previously added. Started. The enzyme used was a homogenate of Cos-1 cells in which human 11 j8-HSD1 was forcibly overexpressed using a vector for mammalian cells. The composition of the reaction solution (final concentration) is 0.01 ~ 0.03mgZml enzyme, 150nM cortisone, 2mM NADPH, 2% DMSO, 1 ~: L0,000nM specimen, 0.15mM EDTA, 20mM sodium phosphate Buffer, pH = 7.4. Of these wells, a well containing no specimen was used as a control group V, and neither specimen nor enzyme was used! / ヽ well was used as an enzyme blank.

After incubation at room temperature for 1 hour, the reaction solution in each well was diluted 30-fold with a reaction stop solution, and the cortisol concentration in the diluted solution was measured using a kit based on the HTRF method of Cisbio. As the reaction stop solution, 10 _i u M carbenoxolone-containing, 20 mM sodium phosphate buffer, pH = 7.4 was used. The inhibitory activity (%) was calculated by linear regression of the cortisol concentration of each well, assuming that the cortisol concentration of the control group was 0% inhibition and the cortisol concentration of the enzyme blank group was 100% inhibition. IC value is 5 for inhibitory activity

50

The calculation was performed by linear regression of the logarithmic value of the analyte concentration and the inhibitory activity value using data of 2 or 3 points showing a value around 0%.

The IC value for I l j8-HSD1 of the compounds of the present invention is usually between 1 and 10,000 ηΜ.

50

Exists. In order to explain the present invention, IC values of the following compounds of the present invention against human 11 jS-HSDl were measured. [0211] [Table 1]

table 1

[0212] (Test Example 2) Cortisol production inhibition test using cultured human hepatocytes

In 24-well cell culture plate, 1.5 X 10 ⁴ cellsZwell seeded human hepatoma derived cell line HepG2 cells after 24 hr or, using an expression vector for mammalian cells, forcibly overexpressing human 11 beta-HSDl, further two days Later, 150ηΜ cortisone and the test sample or DMSO were added to the medium. Four hours after the addition, a part of the medium was collected, diluted with 20 mM sodium phosphate buffer containing 10 M carbenoxolone, and the amount of cortisol in the medium was measured by the HTRF method. Inhibit cortisol production (%) using the cortisone-free group as a blank.

[0213] (Test Example 3) Cortisol production inhibition test using human adipocytes

24-well or 96-well cell culture plates were seeded with normal human preadipocytes HPRAD-SQ, and after confluence, the medium was changed to a differentiation medium and cultured for another week. Thereafter, as with cultured human hepatocytes, the inhibitory activity (%) on cortisol production is inhibited.

[0214] (Test Example 4) Cortisol production inhibition test using 3T3-L1 adipocytes

Inoculate mouse 3T3-L1 adipocytes in a 24-well cell culture plate, using a conventional method for 4 days in differentiation medium containing 0.3 μΜ rosiglitazone, and then for 4 days in media containing 0.3 μΜ rosiglitazone Cultured. After further culturing for 1 day in a maturation medium not containing rosiglitazone, the inhibitory activity (%) on cortisol production was measured in the same manner as in cultured human hepatocytes to determine the IC value.

50 (Table 2).

[0215] [Table 2] Table 2

[0216] As shown in Table 1, it is clear that the compound group of the present invention inhibits 1 1 β-HSD1 and suppresses cortisol production from the low concentration region by enzyme inhibition test.

In general, when considering the possibility of clinical application of low molecular weight compounds, stability in serum, cell membrane permeability, and effectiveness in target organs may be problematic. In this respect as well, the compound group of the present invention has a low concentration region potentiating effect in inhibiting cortisol production even when it is applied to hepatocytes and fat cells in a medium containing 10% serum. Therefore, its usefulness seems to be high.

This compound group inhibits 11 β-HSD1 in the target organs such as liver and fat, and spleen 8 cells, ocular tissue, bone tissue, immune cells, muscle cells, and peripheral blood vessels, resulting in glucose and lipid metabolism. Expected to improve diabetes, obesity, glaucoma, osteoporosis, immune disorders, dyslipidemia, hypertension, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, muscular atrophy, and syndrome X .

[0217] In vivo testing

(1) In vivo inhibition test of 11 β-HSD1 of the present invention in mammals is described in a known report, for example, ASSAY: MEASUREMENT OF IN VIVO IN HIBITION (p.29-30) of WO2004 / 058741. The following method can be carried out with reference to the following method. Generally, the test compound (compound A of the present invention) is administered orally to a mammal at a predetermined time within 1 to 24 hours. Tritium-labeled cortisone is administered intravenously, and blood is collected after several minutes. Steroids are extracted from the separated serum and measured by HPLC. —Measured in animals receiving cortisone and its metabolite ³ H-cortisol drug or in control animals receiving vehicle. The inhibition rate of these value changes is obtained.

[0218] More specifically, the test compound is an excipient (5% hydroxypropyl mono-β cyclodextrin). Phosphorus vZvH 2 O) for oral administration, typically at the desired concentration

A dose of 2 lOmgZkg is administered. After the animals are fasted, ICR mice (Charles Liver) are orally tested in groups of 3 animals with a dose of 0.5 mL per animal.

After the desired time has elapsed, between 4 and 16 hours, ³ μΜ of 3Η-cortisone is added to dPBS to make 0.2 mL, which is then injected through the tail vein. After restraining the animal in the CO room for 2 minutes,

2

Collect blood while reviving. Blood is serum separated in a separation tube within 30 minutes at room temperature. At the end of the incubation, the serum is centrifuged for 10 minutes at 3000 X g and 4 ° C.

[0219] For analysis of steroids, extraction with an organic solvent is first performed. Transfer 0.2 mL of serum to a clean microcentrifuge tube, add l.OmL of ethyl acetate, and shake vigorously for 1 minute. Centrifuge rapidly to precipitate the aqueous phase and obtain the supernatant of the organic layer. Transfer 0.85 mL of organic layer to a fresh microcentrifuge tube and dry. Suspend the dried sample in 0.250 mL DMSO containing high concentrations of cortisone and cortisol for HPLC.

Apply 0.200 mL of the test solution to a Metachem Inertsil C-18 chromato column or equivalent reversed-phase chromatographic column equilibrated with 30% methanol, and elute the desired steroids with a linear concentration gradient up to 50% methanol. . At the same time, measure the unlabeled internal standard at UV254nm. Tritium signals are collected using a radiochromatography detector and analyzed. ³ H- conversion to ³ H- cortisone cortisone, calculated as the ratio of AUC for cortisol with respect to the composite AUC between Col Chizon and cortisol.

[0220] (2) Or, test drugs are orally administered to a disease model for 3 to 28 days, blood is collected, blood glucose, serum lipids, serum insulin, etc. are measured, or after fasting overnight, orally Glucose tolerance is measured by taking blood over time after blood load and measuring blood glucose, or measuring body weight every day to measure body weight gain, or autopsy after the end of continuous injection, and whole body fat Experiments such as measuring tissue weight and lipid content in the liver can be conducted to examine anti-diabetic, anti-hypertensive, anti-hyperlipidemic, anti-obesity, and body fat reduction effects. Pathological models include, for example, spontaneously diabetic, obese or hypertensive mice and rats, such as db / db mice that are spontaneously type 2 obese diabetic model mice, obZo bMice or KK-Ay mice Drug-induced diabetes, obesity or hypertension mice and rats, special diet (high fat diet, high sucrose diet, etc.)-induced diabetes, obesity or hypertension mice and rats To do. Such a test can be carried out, for example, with reference to the method described in Endocrinology 144 (11): 4755-4762, 2003, in particular pages 4756-4758.

(Test Example 4) Spontaneous obesity type II diabetes The therapeutic effect on db / db mice can be tested, for example, as follows.

That is, 12-week-old male db / db mice are mixed with a powdered CE-2 diet (normal diet; Nippon Claire) at a final concentration of 0.1% for 7 days. Blood is collected on the 8th day, and the glucose concentration in serum can be measured with Glucose C-Test® Co (Wako Pure Chemical Industries), and the serum triglyceride can be measured with Triglyceride®-2 Test® Co (Wako Pure Chemical Industries).

The metabolic stability test in human liver microsomes can be tested, for example, as follows. Specifically, a phosphate buffer solution (PH7.4) containing the compound (final concentration 1 μΜ) and liver microsomes (final protein concentration 0.5 mgZmL) was preincubated for 5 minutes at 37 ° C, and after addition of the NADPH production system After 20 minutes of reaction, stop the reaction with acetonitrile and measure the concentration of unchanged product in the supernatant. The metabolic degradation rate is calculated as the rate of decrease of unchanged substance by comparing the unchanged substance concentration of the unreacted specimen and the specimen reacted for 20 minutes.

[0222] Furthermore, when considering the possibility of clinical application of low molecular weight compounds with the target organ in the periphery, (1) it acts specifically on the target organ, and (2) it does not show a central action, that is, it is translocated into the brain. Ideally, the compound should have very little.

In particular, here, (1) “remarkably low ability to enter the brain” is defined as satisfying one or more properties, more preferably two or more properties, of parameters 1) to 4) below. The

[0223] 1)

In vitro blood-brain barrier (BBB) permeability (a) is remarkably low. Specifically, it is performed according to the method of Wang et al. (Evaluation of the MDR—MD and K cell line as a permeability screen for the blood—brain barrier: International Journal of Pharmaceutics 288 (2005) 349-359). dividing, MDR in drug permeability test for CNS migration evaluation using MDCK model, Papp (A- B) value of a drug is less than 10 X 10- ⁶ cm / s, more preferably 5 X 1 0 less than ^_6 cm / s, more preferably, to exhibit a value of less than 1 X 10- ⁶ cmZs.

[0224] 2)

In vitro blood-brain barrier (BBB) permeability (b) is extremely low. Specifically, Stefan et al. (Prediction of Drug Transport through the Blood-Brain Barrier in Vivo: A Com parison between Two in Vitro Cell Models: Pharmaceutical Research, Vol. 19, No. 7, July (2002) 976- 981), the ln [Pe X MW] value is 7.5 cmZs in the pseudo-BBB model system based on the coculture of brain capillary end othelial cells and astrocytes. Below, more preferably -8 or less. Alternatively, Pe value is less than 2 X 10- ³ cm / min, more preferably takes a value less than ^{1 X 10 "3 cm / min} .

[0225] 3)

In vivo blood-brain barrier (BBB) permeability (c) is extremely low. Specifically, it must be less than the value of ln [BUI X MW] calculated according to the report by Stefan et al.

[0226] 4)

In vivo blood-brain barrier (BBB) permeability (d) is extremely low. Specifically, the ratio of the brain concentration to the plasma concentration of the drug in the test animal or human should be 10% or less, preferably 3% or less. The concentration ratio can be calculated using, for example, the method shown in Test Example 5 described later.

[0227] (Test Example 5) Brain migration test

That is, the compound is orally administered to mice, and after a certain period of time, blood and brain are collected under anesthesia. After blood is centrifuged, plasma is collected. After adding an organic solvent to the plasma and deproteinizing it, the concentration of the compound in the extract is measured by LCZMSZMS. After adding organic solvent to the brain, the tissue is homogenized, and after centrifugation, the concentration of the compound in the supernatant is measured by LCZMSZ MS. Evaluate brain migration from the calculated ratio of brain concentration / plasma concentration.

[0228] Next, the pharmaceutical composition of the present invention will be described below. As solid compositions for oral administration, capsules, pills, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances, at least one inert carrier and Made in combination. More specifically, excipients (eg lactose, sucrose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, metasilicate), binders (eg crystalline cellulose, saccharides, dextrin, hydroxypropylcellulose, hydroxypropyl). Mouth pyrmethylcellulose, polybulurpyrrolidone, macrogol), lubricants (eg, magnesium stearate, calcium stearate, talc), disintegrants (eg, corn starch, carboxymethylcellulose, calcium fibroglycolate), stabilizers ( Sugar alcohols and sugars such as ratatoses, etc.) soluble solubilizers or solubilizers (eg cholesterol, triethanolamine, glutamic acid, aspartic acid), colorants, flavoring agents, preservatives, isotonic agents, dispersing agents , Anti-oxidation agent (for example, For example, ascorbic acid, butyl hydroxyasol), buffering agents, preservatives (eg, parabens, benzyl alcohol).

[0229] Note that tablets, pills, granules, and the like may be provided with a gastric or enteric film coating such as sucrose, gelatin, hydroxypropylmethylcellulose phthalate or the like, if necessary.

Injections for parenteral administration include sterile aqueous or non-aqueous solubilizers, suspensions, and emulsions. Examples of carriers for aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of carriers for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethyl alcohol, and polysorbate 80 (TM).

[0230] Such a composition may further contain additives such as the above-mentioned isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers or solubilizers. These are sterilized by, for example, filtration through a membrane filter, blending of a bactericide, or ultraviolet irradiation. They can also be used as injectables which are prepared as sterile solid compositions and dissolved, emulsified or suspended when used. When the solubility of the compound of the present invention is low, solubilization treatment may be performed.

[0231] As the treatment, known methods applicable to pharmaceutical preparations, for example, a method of adding a surfactant (polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan higher fatty acid esters, sucrose fatty acid esters, etc.), Drugs and solubilizers such as polymers (polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), polybulu Intestines such as water-soluble polymers such as pyrrolidone (PVP), hydroxypropylmethylcellulose phthalate (HPMCP), methyl methacrylate-methacrylic acid copolymer (Eudragit L, S (TM); manufactured by Rohm and Haas) And a method of forming a solid dispersion with a soluble polymer). Furthermore, if necessary, a method of forming an inclusion complex using a-, β- or γ-cyclodextrin, hydroxypropyl cyclodextrin and the like can also be mentioned. In addition, “Pharmaceutical Monograph No. l, Biochemical Usability”, Tsuneji Nagai et al., Soft Science, 78-82 (1988) or “Recent formulation technology and its application”, Isami Utsumi, Pharmaceutical Journal 157-159 (1 983) can be used as a reference, and the solubilization method can be appropriately changed according to the target drug. Of these, a method of improving the solubility by preferably forming a solid dispersion of a drug and a solubilizer can be employed (Japanese Patent Laid-Open Nos. 56-49314 and FR2460667).

[0232] The desired dose may conveniently be expressed as a single dose, or as divided doses administered at appropriate intervals (eg, 2, 3, 4 or more sub-doses per day). This sub-dose itself can be further divided (eg, into a number of discretely spaced administrations; eg, by multiple inhalations of the injector force, or application of multiple drops to the eye). The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the patient's symptoms, body weight, age, sex, etc. to be applied, but usually 0.001 to 50 mgZ kg, preferably 0.01 to 25 mgZkg per day for an adult. More preferably, it is 0.05-5 mgZkg.

Example

The following are examples of the pharmaceutical composition of the present invention.

(a) Tablet (lmg)

Compound A l .Og which is the compound of this example

Lactose 90.0g

Sodium carboxymethylcellulose 7.0g

Corn starch paste (5% WZV paste) l .Og

Magnesium stearate l .Og

The above ingredients are weighed and compressed into tablets by conventional methods to make lOOmg tablets.

(b) Tablet (lOmg) Compound A which is a compound of this example 10 g

Lactose 140g

Croscanolemellose sodium 7.0g

Corn starch 37.5g

Polyvinylenorepyrrolidone 2.5g

Magnesium stearate

The above ingredients are weighed and tableted by a conventional method to give a 200 mg tablet, which is then coated with cellulose acetate phthalate to form an enteric solvent.

[0234] (c) Tablet (lOOmg)

Compound A lOOg which is the compound of this example

Lactose 180g

Croscarmellose sodium 13g

Corn starch (5% WZV paste) 4g

Magnesium stearate 3g

The above ingredients are weighed and compressed into a 300 mg tablet by a conventional method.

(d) Capsule (50mg)

Compound A lOOg which is the compound of this example

Rattan 395.5g

Magnesium stearate 4.5g

Weigh each of the above ingredients and mix evenly. Enclose the mixed powder in a No. 1 hard force capsule of 250 mg.

[0235] [Synthesis Examples]

Next, synthesis examples will be given to describe the present invention in more detail, but the present invention is not limited thereto.

(Example 1)

3— [N— (4-Fluorophenyl) —N-methylamino] — 5— (2-Methoxy—4-nitrophenyl) — 4-Methyl-4H— 1,2,4-Triazole

Step 1> N, N, —Dimethyl— N— (4-Fluorophenol) thiourea 4 Fluoro-N-methylaline (6.0 g) was dissolved in methylene chloride (60 ml), and a solution of methyl isothiocyanate (3.5 g) in methylene chloride (10 ml) was added dropwise with ice water cooling. After heating under reflux for 4 hours, the organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (elution solvent; methylene chloride to methanol: methylene chloride = 1: 100) to give the title compound (5.7 g). Obtained.

<Process 2> N— (4 Fluorophenol) Ν, Ν, S Trimethyl-isothiorea hydroiodide

The compound (5.7 g) obtained in Step 1 was dissolved in acetonitrile (60 ml), methyl iodide (2. Oml) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the title compound (lO.Og).

[0236] Step 3> 1-amino-2,3 dimethyl-2- (4 fluorophenyl) guanidine hydroiodide

The compound (5.9 g) obtained in Step 2 was dissolved in ethanol (30 ml), hydrazine monohydrate (0.8 ml) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the title compound (5.6 g).

Step 4> 3— [N— (4 Fluorophenol) —N-Methylamino] — 5— (2-Methoxy—4 Nitrophenol) 1-Methinore 4H— 1,2,4 Triazonore

The compound obtained in Step 3 (0.40 g) is suspended in methylene chloride (4.0 ml), and 2-methoxy-4-trobenzoic acid (0.20 g) and 1-ethyl-3- (3 dimethylaminopropyl) force rubodiimide. Hydrochloride (0.23g) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, pyridine (2.0 ml) was added to the resulting residue, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated Japanese brine, and dried over anhydrous sodium sulfate. The desiccant is removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure is purified by column chromatography (elution solvent; ethyl acetate: hexane = 1: 4 to ethyl acetate-methanol: ethyl acetate = 1: 50). This gave the title compound (0.17 g).

[Example 2] 3— [N— (4-Fluorophenol) —N—Methylamino] —4—Methyl—5— [4-Nitro-2- (trifluoromethyl) phenol] 4H— 1, 2,4 Triazole

Using the compound (0.64 g) obtained in Step 3 of Example 1 and 4-tro-2- (trifluoromethyl) benzoic acid (0.44 g) in the same manner as in Step 4 of Example 1. The title compound (0.27 g) was obtained.

[Example 3]

3— [N— (4 Fluoro-3-methylphenol) —N-Methylamino] — 5— (2-Methoxy

—4 Nitrophenol 2) 1—Metinore 1H— 1,2,4 Triazonore

Process 1> N, N, —Dimethyl— N— (4-Fluoro-3-methylphenol) thiorea

Using 4 fluoro 3-methyl N methylaniline (4.5 g) and methyl isothiocyanate (2.3 g), the title compound (5.6 g) was obtained in the same manner as in Step 1 of Example 1. Step 2> N— (4-Fluoro-3-methylphenol) N, N ,, S Trimethylisothia rare hydroiodide

Using the compound (5.6 g) obtained in Step 1 and methyl iodide (1.9 ml), the title compound (9.5 g) was obtained in the same manner as in Step 2 of Example 1.

<Step 3> 1-amino-2,3 dimethyl 2- (4 fluoro-3-methylphenol) guanidin hydroiodide

The title compound (8.8 g) was obtained in the same manner as in Step 3 of Example 1 using the compound (9.2 g) obtained in Step 2 and hydrazine monohydrate (1.3 ml).

Step 4> 3— [N— (4-Fluoro-3-methylphenol) —N—Methylamino] — 5— (

2-Methoxy-1 4 nitrophenyl) 1 4-methyl 4H— 1,2,4 triazole

Using the compound (4.2 g) obtained in Step 3 and 2-methoxy-4-trobenzoic acid (2.3 g), the title compound (2.4 g) was obtained in the same manner as in Step 4 of Example 1. It was.

[0240] (Example 4)

3— (4-Amino 2-methoxymethoxy) 5— [N— (4-Fluorophenol) N-methylamino] — 4-Methyl-4H— 1,2,4 Triazole

The compound (4.6 g) obtained in Step 4 of Example 1 was dissolved in methanol (46 ml), 10% palladium carbon (0.46 g) was added, and then at room temperature under a hydrogen atmosphere. Stir overnight. Reaction liquid After removing palladium on carbon using Celite, the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (3.9 g).

(Example 5)

3-(4-Dimethylamino 2-methoxyphenyl) 5- [N- (4-Fluorophenol) N-methylamino] -4-methyl-4H- 1, 2,4 triazole

A 36% aqueous formaldehyde solution (47 1) was dissolved in tetrahydrofuran (5. Oml), and 20% sulfuric acid (0.15ml) was added thereto. The mixture obtained in Example 4 was then cooled with ice water. (50 mg) and a suspension of sodium borohydride (17 mg) in tetrahydrofuran (3. Oml) were slowly charged. The mixture was stirred for 1 hour under cooling with ice water. The reaction mixture was made alkaline by adding 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (elution solvent; methylene chloride to methanol: methylene chloride = 1: 19) to give the title compound (33 mg). It was.

[0241] (Example 6)

3— (4-Acetylamino 2-methoxymethoxy) 5— [N— (4-Fluorophenol) — N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

The compound (0.10 g) obtained in Example 4 was dissolved in methylene chloride (1. Oml), and pyridine (2 5 1) and then acetyl chloride (0.22 ml) were added under ice water cooling. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was filtered with ether and filtered. The obtained solid was dissolved in methanol (0.50 ml), and 4N salt-hydrogen-ethyl acetate solution (1.0 ml) was added. Ether was added to the residue obtained by concentration under reduced pressure, and the resulting solid was collected by filtration to obtain the title compound (90 mg).

[0242] (Example 7)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy—4— (2—Methoxyacetyl) aminophenol] — 4—Methyl—4H— 1,2,4 Triazole Hydrochloride hydrochloride The title compound (99 mg) was obtained in the same manner as in Example 6 using the compound (0.10 g) obtained in Example 4 and 2-methoxyacetyl chloride (28 jul). (Example 8)

3— [4— (2acetoxyacetyl) amino-2-methoxyphenyl] — 5— [N— (4-fluorophenyl) N-methylamino] 4 methyl 4H— 1,2,4 triazole obtained in Example 4 The obtained compound (0.15 g) was dissolved in methylene chloride (1.5 ml), and pyridine (4 5 1) and then 2-acetoxyacetyl chloride (59 1) were added under ice-water cooling. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (0.16 g).

(Example 9)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [4— (2 Hydroxyacetyl) amino 2 Methoxyphenol] 4 Methyl 4H— 1, 2,4 Triazole

The compound (0.14 g) obtained in Example 8 was dissolved in methanol (0.64 ml) and tetrahydrofuran (0.64 ml), 1N aqueous sodium hydroxide solution (0.32 ml) was added, and the mixture was stirred at room temperature. Stir for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (0. llg).

(Example 10)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy—4— (2—Morpholine 4-Irylacetyl) aminophenol] 4 Methyl 4H— 1, 2,4 Triazole hydrochloride salt

The compound obtained in Example 4 (0.18 g) was dissolved in methylene chloride (1.8 ml), morpholine 4-yl acetate hydrochloride (0.12 g), and 1-ethyl 3- (3 dimethylaminopropyl). Carpositimide hydrochloride (0.13 g) was added and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (elution solvent; methylene chloride to methanol: methylene chloride = 1: 19). It was. The obtained solid was dissolved in methanol (0.50 ml), and 4N hydrogen chloride-ethyl acetate solution (1.0 ml) was added. Ether was added to the residue obtained by concentration under reduced pressure, and the obtained solid was collected by filtration to obtain the title compound (0.13 g).

[Example 11]

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [4— (2 Hydroxyethyl) amino 2 methoxyphenol] — 4 Methyl 4H— 1, 2,4 Triazole

The compound (0.24 g) obtained in Example 9 was suspended in tetrahydrofuran (3.4 ml), borane-methylsulfide complex (10M; 0.34 ml) was slowly added, and the mixture was heated to reflux for 2 hours. Under ice-water cooling, a 10% salt-hydrogen-hydrogen methanol solution was added, and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue to make it alkaline, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [Chromatolex NH ™; Chroma torex NH ™] (elution solvent; ethyl acetate to methanol: ethyl acetate = 1: 50) to obtain the title compound (0.15 g).

[Example 12]

3— (4-Ethoxycarbolamino 1-methoxyphenol) 5— [N— (4-Fluorophenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole hydrochloride Obtained in Example 4 The title compound (97 mg) was obtained in the same manner as in Example 6 using the above compound (0.10 g) and ethyl chloroformate (30 μ1).

[Example 13]

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy—4— (2-Oxoxazolidine 1-phenyl) phenol] 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

The compound (0.10 g) obtained in Example 4 was dissolved in methylene chloride (2.0 ml), and pyridine (2 5 1) was added, followed by cooling with iced water. After stirring, the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated Japanese brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in ethanol (2.0 ml), and 1N aqueous sodium hydroxide solution was added. The mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (elution solvent; methylene chloride to methanol: methylene chloride = 1: 19). The obtained solid was dissolved in methanol (0.50 ml), and 4N salt-hydrogen-ethyl acetate solution (1.0 ml) was added. Ether was added to the residue obtained by concentration under reduced pressure, and the resulting solid was collected by filtration to obtain the title compound (43 mg).

[Example 14]

3— [N— (4 Fluorophenyl) N-methylamino] — 5— (2-Methoxy-4-ureidophenyl) 4 Methyl 4H— 1, 2,4 Triazole

The compound (0.50 g) obtained in Example 4 was suspended in acetic acid (2.5 ml) and water (5. Oml), and an aqueous solution of sodium cyanate (0.20 g) (5. Oml) was added. And stirred at room temperature for 2 hours. Sodium silicate (0.20 g) aqueous solution (5. Oml) was added, and the mixture was further stirred at room temperature for 2 hours. Sodium silicate (0.20 g) aqueous solution (5. Oml) was added, and the mixture was further stirred at room temperature for 2 hours. A sodium silicate (0.20 g) aqueous solution (5. Oml) was added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture to make it alkaline, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [Chromatolex NH ™; Chromatorex NH ™] (elution solvent; methanol: methylene chloride = 1: 20 to 1:10) to obtain the title compound (0.26 g).

[Example 15]

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy—4— (3—Methoxyureido) phenol] 4—Methyl-4H— 1, 2,4 Triazole hydrochloride

The compound (0.30 g) obtained in Example 4 was dissolved in N, N dimethylacetamide (3. Oml), pyridine (89 μ1) was added, and then ice-water cooling was applied to crotuccinic acid. Ferrule (0.14 ml) was added and stirred at room temperature for 2 hours. To the reaction solution, O-methylhydroxyammonium chloride (84 mg) and triethylamine (0.42 ml) were added and heated at 50 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with water and saturated saline, and then anhydrous Dried with sodium acid. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Methylene chloride was added to the residue, and the resulting solid was collected by filtration. The obtained solid was dissolved in methanol (0.50 ml), and 4N hydrogen chloride solution in ethyl acetate (1.0 ml) was added. Ether was added to the residue obtained by concentration under reduced pressure, and the resulting solid was collected by filtration to obtain the title compound (43 mg).

[Example 16]

3- (4-Amino-2-methoxyphenyl) 5— [N— (4-Fluoro-3-methylphenol) —N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

Using the compound (2.3 g) obtained in Step 4 of Example 3, the title compound (2. Og) was obtained in the same manner as in Example 4.

(Example 17)

3— [N— (4 Fluoro-3-methylphenol) —N—Methylamino] — 5— [4— (2 Hydroxyacetyl) amino 2-methoxyphenyl] 4 Methyl 4H— 1, 2,4 Triazo Monore

The compound obtained in Example 16 (0.30 g) was dissolved in methylene chloride (3.0 ml), and pyridine (85 1) and then 2-acetoxycetyl chloride (0.11 ml) were added under ice-water cooling. . After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected by filtration. The obtained solid was dissolved in methanol (1.5 ml) and tetrahydrofuran (1.5 ml), 1N aqueous sodium hydroxide solution (0.77 ml) 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 was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the obtained solid was collected by filtration to obtain the title compound (0.29 g).

[0250] (Example 18)

3— [N— (4 Fluoro-3-methylphenol) —N-Methylamino] — 5— [4— (2 Hydroxychetilamino) —2-methoxyphenyl] —4-Methyl-4H— 1, 2,4 Triazole

Using the compound (0.21 g) obtained in Example 17, the title compound was prepared in the same manner as in Example 11. Product (0.15 g) was obtained.

(Example 19)

3— [N— (4 Fluoro-3-methylphenol) —N—Methylamino] — 5— (2-Methoxy—4 ureidophenol) 1—Methinore 4H— 1,2,4 Triazonore

Using the compound (0.30 g) obtained in Example 16, the title compound (95 mg) was obtained in the same manner as in Example 14.

[Example 20]

3— [N— (4-Fluoro-3-methylphenol) —N-methylamino] — 5— [2-methoxy —4-— (3-methoxyureido) phenol] — 4-methyl 4H— 1,2, 4 Triazole Dissolve the compound obtained in Example 16 (0.20 g) in N, N dimethylacetamide (2. Oml), add pyridine (59 1), and then ice-cool with a black mouth. The acid phenol (931) was removed and stirred at room temperature for 2 hours. To the reaction mixture, O-methylhydroxyammonium chloride (56 mg) and triethylamine (0.42 ml) were added and heated at 50 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was charged with methylene chloride and collected by filtration to give the title compound (0.16 g).

[0252] (Example 21)

3— (2 Ethoxy mono 4-trophenol) 5— [N— (4 Fluorophenol) N-methylamino] -4-methyl-4H— 1,2,4 triazole

Step 1> 3— (2-Ethoxy-4 -trophenyl) — 5—Mercapto— 4—Methyl—4 H— 1,2,4 Triazolene

2 Dissolve ethoxy-4-trobenzoic acid (5.4 g) and 4-methylthiosemicarbazide (2.8 g) in methylene chloride (50 ml), 1-ethyl 3- (3 dimethylaminopropyl) force rubodiimide hydrochloride (4.4 g) And stirred at room temperature for 6 hours. 1-Ethyl 3- (3 dimethylaminopropyl) carpositimide hydrochloride (0.97 g) was added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered. The obtained solid was washed with ice-cooled methylene chloride. A 10% aqueous sodium hydroxide solution (52 ml) was added to the obtained powder and stirred at 60 ° C. for 30 minutes. The reaction solution was cooled, 10% hydrochloric acid was added little by little, the precipitated solid was collected by filtration, washed with ethyl acetate, The title compound (4.6g) was obtained by drying.

[0253] Process 2> 3 Black mouth 5— (2 Ethoxy 1-to 4-phenol) 1 4-Methyl 4H— 1,2,4 Triazolene

Dissolve the compound obtained in step 1 (2.5 g) in toluene (100 ml), and add potassium nitrate (2.7 g). Under ice water cooling, add sulfuryl chloride (2.2 ml). Stir overnight at room temperature. Under ice water cooling, saturated aqueous sodium bicarbonate was added to the reaction solution to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.2 g).

Step 3> 3— (2 Ethoxyl 4-trophenol) 5— [N— (4 Fluorophenol) —N-Methylamino] — 4-Methyl-4H— 1,2,4 Triazole

4 Fluoro-N-methylaline (1.1 ml) was added to the compound obtained in Step 2 (2.2 g) and heated at 110 degrees for 1 hour 30 minutes. 4 Fluoro-N-methylaline (0.26 ml) was added, and the mixture was further heated at 110 ° C. for 2 hours. 4 Fluoro-N-methyl-line (0.18 ml) was added and heated at 110 ° C. for 30 minutes. The reaction mixture was purified by column chromatography [Chromatorex NH ™] (elution solvent; ethyl acetate: hexane = 1: 1 to 9: 1) to give the title compound (1.7 g). Obtained.

[Example 22]

3— (4 amino-2-ethoxyphenol) 5 [N— (4 fluorophenol) N-methylamino] -4-methyl-4H— 1,2,4 triazole

The compound (1.0 g) obtained in Example 21 was suspended in methanol (20 ml), acetic acid (1.1 ml) and iron (powder; 0.53 g) were added, and the mixture was heated to reflux for 45 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the mixture was stirred at room temperature for 15 minutes. Insoluble material was removed by filtration, saturated aqueous sodium hydrogen carbonate was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography [Chromatolex NH ™; Chromatorex NH ™] (elution solvent: ethyl acetate-methanol: ethyl acetate = 1: 19). As a result, the title compound (0.78 g) was obtained.

[0255] (Example 23)

3— [2 Ethoxy— 4— (Ethoxycarboamino) phenol] — 5— [N— (4 Fluoro Mouth phenyl) —N-methylamino] — 4-methyl-4H— 1,2,4 triazole Using the compound (0.10 g) obtained in Example 22 and ethyl chloroformate (34 1), In the same manner as in Example 8, the title compound (0.10 g) was obtained.

(Example 24)

3— [2 Ethoxy mono 4— (3-Methoxyureido) phenol] — 5— [N— (4 Fluorophenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

Using the compound (0.10 g) obtained in Example 22, the title compound (0.10 g) was obtained in the same manner as in Example 20.

[0256] (Example 25)

3— (2 Black mouth 4-Trophe-Nole) 5— [N— (4 Funoleo mouth Fu-Nole) N-Methylamino] — 4-Methyl-4H— 1,2,4 Triazole

Process 1> 3— (2—Black mouth 1-trophenol) 1 5-Mercapto 1-Methyl 4H 1,2,4 Triazole

The title compound (8.7 g) was obtained in the same manner as in Step 21 of Example 21 using 2 chloro-4-trobenzoic acid (13 g) and 4-methylthiosemicarbazide (7.4 g).

Process 2> 3 Black Mouth 5— (2 Black Mouth 4-Trophe) 1 4-Methyl 4H— 1,2,4-Triazole

Using the compound obtained in Step 1 (7.5 g), potassium nitrate (8.4 g) and sulfuryl chloride (6.7 ml), the title compound (2.9 g) was obtained in the same manner as in Step 2 of Example 21. It was. Step 3> 3— (2 Black mouth 4-Trophe-Nore) 5— [N— (4 Funoleo mouth Fu-Nore) —N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

Using the compound obtained in Step 2 (3.0 g) and 4 fluoro-N-methylaline (1.87 m 1), the title compound (0.34 g) was obtained in the same manner as Step 3 in Example 21. It was.

The following compound was synthesized in the same manner as in Step 3 of Example 21 using the compound obtained in Step 2 of Example 25 and the corresponding amine.

[0257] (Example 26)

3— (2 Black mouth 4-Trophe-Nole) 5— [N— (4 Black mouth Fu-Nore) N-Methinorea Mino] -4-Methyl-4H— 1,2,4 Triazole (Example 27)

3- (2 Black mouth 4-2 Trophe-Nole) 5— [N— (3 Black mouth Fu-Nore) N-Methinorea Mino] -4-Methyl-4H— 1,2,4 Triazole

(Example 28)

3— (2—Black mouth 4—-Trophe-Nole) 4—Methinore 5— {N—Metinole N— [4- (Trifluoromethyl) phenol] amino} 4H— 1,2,4 Triazole

(Example 29)

3— (2—Black mouth 4—-Trophe-Nole) 4—Methinore 5— {N—Metinole N— [3- (Trifluoromethyl) phenol] amino} 4H— 1,2,4 Triazole

[Example 30]

3— (4—Amino-2 Black-mouthed Hue-Nole) 5— [N— (4-Funoleo-Headed Fu-Nole) N-Methylamino] — 4-Methyl-4H— 1,2,4 Triazole

The title compound (0.23 g) was obtained in the same manner as in Example 22 using the compound (0.33 g) obtained in Step 3 of Example 25.

(Example 31)

3— [2 Black mouth— 4 (Dimethylamino) phenol] — 5— [N— (4 Fluorophenol) N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The title compound (27 mg) was obtained in the same manner as in Example 5 using the compound (45 mg) obtained in Example 30.

[0259] (Example 32)

3— (4 acetyleno amino 1 2 black mouth-nore) 5— [N— (4 funoleo mouth fu-nore)-N-methylamino] -4-methyl-4H— 1,2,4 triazole

The title compound (92 mg) was obtained in the same manner as in Example 8 using the compound (0.10 g) obtained in Example 30 and acetyl chloride (261).

(Example 33)

3— [2 Black 4-(2 Hydroxyacetyl) aminophenol] — 5— [N— (4 Fluorophenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

The compound obtained in Example 30 (0.30 g) and 2-acetoxyacetyl chloride (0.12 The title compound (0.28 g) was obtained in the same manner as in Example 17.

[0260] (Example 34)

3— [2 Black Mouth 4 -— (2 Hydroxyethyl) aminophenol] — 5— [N— (4-Fluorophenyl) — N-Methylamino] — 4-Methyl-4H— 1,2,4 Triazole

The title compound (0.14 g) was obtained in the same manner as in Example 11 using the compound (0.18 g) obtained in Example 33.

(Example 35)

3— [2 Black mouth— 4— (Ethoxycarboamino) phenol] — 5— [N— (4 fluorophenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

The title compound (77 mg) was obtained in the same manner as in Example 8 by using the compound (0.10 g) obtained in Example 30 and ethyl chloroformate (351).

[0261] (Example 36)

3— [2 Black 4-(2-Oxoxazolidine 1-Fill)]] — 5— [N— (4-Fluorophenyl) -N-methylamino] 4 Methyl 4H— 1, 2,4 Triazole The compound (0.20 g) obtained in Example 30 was dissolved in methylene chloride (2.0 ml), pyridine (61 1), and then ice-cooled under ice-cold formic acid 2 (78 1) was added and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated Japanese brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was dissolved in ethanol (2.0 ml), 1N aqueous sodium hydroxide solution (0.60 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by filtering off the desiccant and concentrating the filtrate under reduced pressure was purified by column chromatography (elution solvent; methanol: ethyl acetate- = 1: 50 to methanol: ethyl acetate = 1: 10). The title compound (0.17 g) was obtained.

[0262] (Example 37)

3- (2 Black mouth 4 Ureido-Fole) 5— [N— (4 Funoleo mouth-Fole) N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

Using the compound (0.20 g) obtained in Example 30, the title compound was prepared in the same manner as in Example 14. Product (42 mg) was obtained.

(Example 38)

3— [2 Black Mouth 4— (3-Methoxyureido) phenol] — 5— [N— (4 Funoleo mouth phenol) — N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

Using the compound (0.15 g) obtained in Example 30, the title compound (0.14 g) was obtained in the same manner as in Example 20.

[0263] (Example 39)

3— (4-Amino-2 Black-mouthed Hue-Nole) 5— [N— (4-Black-headed Hue-Nole) N-Methinorea Mino] -4-Methyl-4H— 1,2,4 Triazole

The title compound (36 mg) was obtained in the same manner as in Example 22 using the compound (50 mg) obtained in Example 26.

(Example 40)

3— [2 Black 4 (Ethoxycarboamino) phenol] 5— [N— (4 Black polyethylene) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

The title compound (47 mg) was obtained in the same manner as in Example 8 using the compound (50 mg) obtained in Example 39 and ethyl chromoformate (14 μ1).

(Example 41)

3— [2 Black Mouth 4— (3-Methoxyureido) Hue-Nole] — 5— [N— (4 Black Mouth Hue-Nole) —N-Methylamino] -4 Methyl 4H— 1,2,4 Triazole

The title compound (46 mg) was obtained in the same manner as in Example 20 using the compound (50 mg) obtained in Example 39.

[Example 42]

3— (4 Amino-2 Black-mouthed Hue-Nole) 5— [N— (3 Black-mouthed Hue-Nole) N-Methinorea Mino] -4-Methyl-4H— 1,2,4 Triazole

The title compound (0.13 g) was obtained in the same manner as in Example 22 using the compound (0.20 g) obtained in Example 27.

(Example 43)

3— [2 Black mouth 4 (Ethoxycarbolamino) feather] 5— [N— (3 Black mouth fue -L) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

The title compound (35 mg) was obtained in the same manner as in Example 8 using the compound (35 mg) obtained in Example 42 and ethyl chromoformate (11 μ1).

[0265] (Example 44)

3— [2 Black Mouth 4— (3-Methoxyureido) Hue-Nole] — 5— [N— (3 Black Mouth Hue-Nole) —N-Methylamino] -4 Methyl 4H— 1,2,4 Triazole

Using the compound (43 mg) obtained in Example 42, the title compound (44 mg) was obtained in the same manner as in Example 20.

(Example 45)

3— (4 amino 1-phenyl) 4-methyl 5— {N-methyl N— [4- (trifluoromethyl) phenol] amino} 4H— 1,2,4 triazole

Using the compound (0.10 g) obtained in Example 28, the title compound (54 mg) was obtained in the same manner as in Example 22.

[0266] (Example 46)

3— [2 Black 4 (Ethoxycarboamino) phenol]-4 Methyl 5— {N Methyl N— [4 (Trifluoromethyl) phenol] amino} -411 1,2,4 —Triazole The title compound (16 mg) was obtained in the same manner as in Example 8 using the compound (20 mg) obtained in Example 45 and ethyl chloroformate (5.21).

(Example 47)

3— [2 Black Mouth 4— (3-Methoxyureido) phenol] — 4—Methyl 5— {N—Methyl —N— [4— (Trifluoromethyl) phenol] Amine} —4Η— 1,2,4 Triazole The title compound (16 mg) was obtained in the same manner as in Example 20 using the compound (20 mg) obtained in Example 45.

[0267] (Example 48)

3— (4 amino 1 2 chlorophenol) 4—methyl 5— {N—methyl N— [3— (trifluoromethyl) phenol] amino} 4H— 1,2,4 triazole

The title compound (0.37 g) was obtained in the same manner as in Example 22 using the compound (0.94 g) obtained in Example 29. (Example 49)

3— [2 Black mouth 4 (Ethoxycarbolamino) phenol]-4 Methyl 5— {N Methylo N— [3 (Trifluoromethyl) phenol] Amine} —4Η— 1,2, 4 Triazole The title compound (90 mg) was obtained in the same manner as in Example 8 using the compound (0.10 g) obtained in Example 48 and ethyl chloroformate (261).

[0268] (Example 50)

3— [2 Black Mouth 4— (3-Methoxyureido) phenol] — 4—Methyl 5— {N—Methyl —N— [3— (Trifluoromethyl) phenol] Amine} —4Η— 1,2,4 Triazole The title compound (89 mg) was obtained in the same manner as in Example 20 using the compound (0.10 g) obtained in Example 48.

(Example 51)

3— [4-Amino 2- (trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) — N-methylamino] 4 Methyl 4H— 1, 2,4 Triazole

Using the compound (0.25 g) obtained in Example 2, the title compound (0.15 g) was obtained in the same manner as Example 22.

[0269] (Example 52)

3— [4 Ethoxycarbolamino 2 (trifluoromethyl) phenol] 5— [N— (

4-fluorophenyl) -N-methylamino] 4 methyl 4H— 1, 2,4 triazole Using Example 51 and the compound obtained in Example 51 (45 mg) and ethyl chloroformate (12 1), Example 8 and Similarly, the title compound (38 mg) was obtained.

(Example 53)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4— (3-Methoxyureido) -2- (trifluoromethyl) phenol] — 4—Methyl—4H— 1, 2,4 Triazole The title compound (40 mg) was obtained in the same manner as in Example 20 using the compound (47 mg) obtained in Example 51.

[0270] (Example 54)

3— [N— (4 Black Mole)] — N—Methylamino] —4—Methyl—5— [4-Toro 2 (trifluoromethyl) phenol] —4H— 1,2,4 Triazole Process 1> 3-Mercapto-4-methyl-5- [4-troo 2 (trifluoromethyl) phenyl] 4H— 1,2,4 Triazole

The title compound (l lg) was obtained in the same manner as in Step 21 of Example 21 using 4-troh 2 trifluoromethylbenzoic acid (15 g) and 4-methylthiosemicarbazide (6.6 g).

<Process 2> 3 Black mouth 4 Methyl 5— [4-Toro 2 (trifluoromethyl) phenol 4H— 1, 2,4 Triazonore

Using the compound (l lg) obtained in Step 1, potassium nitrate (l lg) and sulfuryl chloride (8.3 ml), the title compound (5.7 g) was obtained in the same manner as in Step 2 of Example 21. .

<Step 3> 3— [N— (4-Floam) N-methylamino] — 4-Methyl 5— [4-Tro-2- (trifluoromethyl) phenol] — 4H— 1,2, 4 Triazole Using the compound obtained in Step 2 (1.5 g) and 4 chloro-N-methylaline (0.72 ml) in the same manner as in Step 3 of Example 21, the title compound (1.4 g) was obtained. It was.

The following compounds were synthesized in the same manner as in Step 3 of Example 21, using the compound obtained in Step 2 of Example 54 and the corresponding amine.

[0271] (Example 55)

3— [N— (3-Chromium) N-Methylamino] —4-Methyl 5— [4-Toro 2 (trifluoromethyl) phenol] —4H— 1,2,4 Triazole

(Example 56)

4 -Methyl 3— {N Methyl N— [3— (Trifluoromethyl) phenol] amino} — 3— [4 -Toro 2 (trifluoromethyl) phenol] 4H— 1, 2, 4 Triazole

[0272] (Example 57)

3— [4-Amino 1- (Trifluoromethyl) phenol] — 5— [N— (4—Black Mole) —N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The title compound (0.74 g) was obtained in the same manner as in Example 22 using the compound (1.4 g) obtained in Step 3 of Example 54.

(Example 58)

3— [N— (4—Black mouth) —N—Methylamino] — 5— [4-Ethoxycarboxylamine 2 (trifluoromethyl) phenol] — 4 methyl 4H— 1, 2,4 triazole Using the compound (0.12 g) obtained in Example 57 and ethyl chloroformate (31 μ 1), In the same manner as in Example 8, the title compound (0.13 g) was obtained.

[0273] (Example 59)

3— [N— (4—Black mouth) N-Methylamino] — 5— [4— (3-Methoxyureido) 2 (trifluoromethyl) phenol] 4-Methyl-4H— 1, 2,4 Triazole Using the compound (0.20 g) obtained in Example 57, the title compound (0.16 g) was obtained in the same manner as in Example 20.

(Example 60)

3— [4-Amino 1- (Trifluoromethyl) phenol] — 5— [N— (3—Black Mole) —N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The title compound (0.60 g) was obtained in the same manner as in Example 22 using the compound (1.lg) obtained in Example 55.

[0274] (Example 61)

3— [N— (3—Black mouth ring) —N—Methylamino] — 5— [4-Ethoxycarboamino 2 (trifluoromethyl) phenol] — 4 Methyl 4H— 1, 2, 4 Triazole The title compound (0.1 g) was obtained in the same manner as in Example 8, using the compound (0.12 g) obtained in Example 60 and ethyl chloroformate (31 1).

(Example 62)

3— [N— (3- mouthpiece) N-methylamino] — 5— [4— (3-methoxyureido) 2 (trifluoromethyl) phenol] 4-methyl-4H— 1, 2,4 Triazole Using the compound (0.20 g) obtained in Example 60, the title compound (0.16 g) was obtained in the same manner as in Example 20.

[0275] (Example 63)

3— [4 amino-2- (trifluoromethyl) phenol] — 4-methyl-5— {N-methyl-N— [3 (trifluoromethyl) phenol] amino} 4H— 1, 2,4 Triazole

The title compound (0.40 g) was obtained in the same manner as in Example 4 using the compound (0.50 g) obtained in Example 56. (Example 64)

3— [4 Ethoxycarbolamino 1- (trifluoromethyl) phenol] —4—Methyl — 5— {N Methyl N— [3 (Trifluoromethyl) phenol] amino} 4H— 1 , 2,4-Triazole

Using the compound (0.12 g) obtained in Example 63 and ethyl ethyl chromate (29 μ1), the title compound (0.1 llg) was obtained in the same manner as in Example 8.

[0276] (Example 65)

3— [4 (3-Methoxyureido) -2- (trifluoromethyl) phenol] —4-Methyl-5 — {N-methyl-N— [3- (trifluoromethyl) phenol] Amino} —4H— 1,2,4 Triazole

Using the compound (0.12 g) obtained in Example 63, the title compound (0.1 llg) was obtained in the same manner as in Example 20.

The following compounds were synthesized in the same manner as in Step 4 of Example 1, using the compound obtained in Step 3 of Example 1 and the corresponding carboxylic acid.

(Example 66)

3— (4-Bromo 2-methoxyphenol-nore) 5— [N— (4-Funoleo-Fueno-ole) N-methylamino] -4-methyl-4H— 1,2,4 Triazole

(Example 67)

3— (4-Cyano-2-methoxyphenol) 5— [N— (4-Funoleolopheninole) N-methylamino] -4-methyl-4H— 1,2,4 Triazole

[0277] (Example 68)

3— (4-Carboxyl 2-methoxyphenol) 5— [N— (4 Fluorophenol) N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The compound (0.20 g) obtained in Example 67 was dissolved in ethanol (1. Oml) and water (1. Oml), sodium hydroxide (95 mg) was added, and the mixture was heated to reflux for 2 hours. 1N Hydrochloric acid was added to the reaction mixture to adjust the pH to about 7, and the precipitate was collected by filtration, washed with water and dried to give the title compound (0.20 g).

(Example 69) 3- (4—Strengthened Lubamoyl 2-methoxyphenol) 5— [N— (4 Fluorophenol) N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The compound obtained in Example 67 (0.20 g) was suspended in methanol (2. Oml), 10% aqueous sodium hydroxide solution (2. Oml) and 30% hydrogen peroxide solution (2. Oml). Was stirred and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (elution solvent; ethyl acetate--methanol: ethyl acetate = 1: 9) to give the title compound (0.17 g )was gotten.

(Example 70)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— {2—Methoxy—4— [(2—Methoxyethyl) aminocarbol] phenyl} 4 Methyl 4H— 1, 2,4 Triazole Examples The compound obtained in 68 (0.17 g) was suspended in methylene chloride (1.7 ml) and 2-methoxychetilamine (46 μ 1), 1 hydroxybenzotriazole (71 mg) and 1 ethyl 3- (3 dimethyl Aminopropyl) carbodiimide hydrochloride (0.10 g) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (0.17 g).

(Example 71)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [2—Methoxy—4— (morpholine—4-yl) phenol] — 4—Methyl—4H— 1,2, 4 Triazole

The compound (0.10 g) obtained in Example 66 was dissolved in toluene (2. Oml), and morpholine (6 7 1), 2- (dicyclohexylphosphino) biphenol (18 mg) and t-butoxycali were dissolved. UM (86 mg) was added, tris (dibenzylideneacetone) dipalladium (0) (23 mg) was added thereto, and the mixture was heated to reflux for 2 hours under an argon atmosphere. The reaction solution was purified by column chromatography (elution solvent; methylene chloride to methanol: methylene chloride = 1: 19) to obtain the title compound (52 mg).

Using the compound obtained in Example 66 and the corresponding amine, in the same manner as in Example 71 The following compounds were synthesized.

[Example 72]

3— [4— (4-acetylbiperazine 1-yl) 2-methoxyphenol] — 5— [N— (4-Fluorophenyl) -N-methylamino] 4 Methyl 4H— 1, 2, 4 Triazole (Example 73)

3— [N— (4 Fluorophenyl) N-methylamino] — 5— {2—Methoxy 4- [4 -— (Morpholine 4-vinyl) piperidine 1-yl] phenyl} 4 Methyl 4H 1,2 , 4 Triazole

[0280] (Example 74)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— (4-Hydroxy-1-methoxyphenol) 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

In the same manner as in Step 4 of Example 1, using the compound (0.20 g) obtained in Step 3 of Example 1 and 4 hydroxy-1-2-methoxybenzoic acid (0.1 g), The obtained solid was dissolved in methanol (0.5 ml), and 4N salt-hydrogen-ethyl acetate solution (1.0 ml) was added. Ether was added to the residue obtained by concentration under reduced pressure, and the obtained solid was collected by filtration to obtain the title compound (0.29 g).

(Example 75)

3— (2 Black mouth 4 hydroxy phenol-nore) 5— [N— (4 Funoleo mouth fu-nore) N-methylamino] -4-methyl-4H— 1,2,4 Triazole

The title compound was prepared in the same manner as in Step 4 of Example 1, using the compound (0.60 g) obtained in Step 3 of Example 1 and 2 hydroxybenzoic acid 4 hydroxybenzoic acid (0.29 g). was gotten.

[0281] (Example 76)

3— (4 Hydroxy-2-methoxyphenyl) 5— [N— (4-Methoxyphenol) N—Methylamino] -4-Methyl-4H— 1,2,4 Triazole hydrochloride

Step 1> N, N, —Dimethyl- N— (4-Methoxyphenol) thiourea

The title compound (5. Og) was obtained in the same manner as in Step 1 of Example 1 using 4-methoxy-N-methylaline (4.0 g) and methyl isothiocyanate (2. lg).

Process 2> N— (4-Methoxyphenol) N, N ,, S Trimethylisothrea urea iodide water Synthesis of borate

Using the compound (5.0 g) obtained in Step 1 and methyl iodide (1.9 ml), the title compound (8.7 g) was obtained in the same manner as in Step 2 of Example 1.

<Process 3> Synthesis of 1 amino 2, 3 dimethyl-2- (4 methoxyphenol) guanidine iodoiodide

Using the compound obtained in Step 2 (8.6 g) and hydrazine monohydrate (1.2 ml), the title compound (8.1 g) was obtained in the same manner as in Step 3 of Example 1.

Step 4> 3— (4 Hydroxy-2-methoxyphenyl) 5— [N— (4-Methoxyphenyl) — N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

The title compound (21 mg) was obtained in the same manner as in Example 74, using the compound (0.15 g) obtained in Step 3 and 4 hydroxy-2-methoxybenzoic acid (83 mg).

(Example 77)

3— [N— (4-Fluoro-3-methylphenol) N-Methylamino] — 5— (4-Hydroxy-2-methoxyphenol) 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

The title compound (25 mg) was obtained in the same manner as in Example 74, using the compound (0.15 g) obtained in Step 3 of Example 3 and 4 hydroxymono-2-methoxybenzoic acid (82 mg). It was. (Example 78)

3— [N— (4-Fluoro-3-methoxyphenyl) N-methylamino] — 5— (4-Hydroxy-2-methoxyphenyl) — 4-Methyl-4H— 1,2,4 Triazole hydrochloride Process 1> N, N, Monodimethyl Mono N— (4 Fluoro-3-methoxyphenol) thiourea

Using 4-fluoro-3-methoxy-1-N-methyl-line (3.2 g) and methyl isothiocyanate (1.5 g) in the same manner as in Step 1 of Example 1, the title compound (3.9 g) was obtained. It was.

<Step 2> Synthesis of N— (4 Fluoro 3-methoxyphenol) Ν, Ν, S S-trimethylisothiourea hydroiodide

Using the compound (3.9 g) obtained in Step 1 and methyl iodide (1.3 ml), the title compound (6. lg) was obtained in the same manner as in Step 2 of Example 1. <Process 3> Synthesis of 1 amino 2, 3 dimethyl 2- (4 fluoro 3 methoxyphenol) guanidine hydroiodide

Using the compound (6. Og) obtained in Step 2 and hydrazine monohydrate (0.79 ml), the title compound (5.8 g) was obtained in the same manner as in Step 3 of Example 1.

<Step 4> 3— [N— (4-Fluoro-3-methoxyphenyl) N-methylamino] — 5— (4 Hydroxy-2-methoxyphenol) 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

The title compound (34 mg) was obtained in the same manner as in Example 74, using the compound obtained in Step 3 (0.15 g) and 4 hydroxy-2-methoxybenzoic acid (78 mg).

(Example 79)

3— (4-Fluoro-2-methoxyphenyl) 5— [N— (4-Hydroxyphenol) N- Methylamino] -4-Methyl-4H— 1,2,4 Triazole hydrochloride

Step 1> N, N, —Dimethyl— N— (4 Hydroxyphenol) Thiourea Synthesis

The title compound (0.79 g) was obtained in the same manner as in Step 1 of Example 1 using 4 hydroxy-1-N-methylaline (0.60 g) and methyl isothiocyanate (0.36 g).

Process 2> N— (4 Hydroxyphenol) N, N ,, S Synthesis of trimethylisothiourea hydroiodide

The title compound (1.3 g) was obtained in the same manner as in Step 2 of Example 1, using the compound obtained in Step 1 (0.79 g) and methyl iodide (0.26 ml).

<Step 3> Synthesis of 1-amino-2,3 dimethyl 2- (4-hydroxyphenol) guazin hydrobromide

Using the compound (1.3 g) obtained in Step 2 and hydrazine monohydrate (0.19 ml), the title compound (1.3 g) was obtained in the same manner as in Step 3 of Example 1.

<Step 4> 3— (4 Fluoro 2 methoxyphenol) 5— [N— (4 Hydroxyphenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole hydrochloride

The title compound (17 mg) was obtained in the same manner as in Example 74, using the compound (0.15 g) obtained in Step 3 and 4 fluoro-2-methoxybenzoic acid (87 mg).

Using the compound obtained in Step 3 of Example 79 and the corresponding carboxylic acid, Example 7 The following compounds were synthesized as in 4.

[0284] (Example 80)

3- (4-Hydroxy-2-methoxyphenyl) 5- [N- (4-Hydroxyphenol) N-methylamino] -4-methyl-4H- 1,2,4 Triazole hydrochloride

(Example 81)

3— (2 Black and 4-hydroxyphenol) 5— [N— (4-hydroxyphenol) N- Methylamino] -4-Methyl-4H— 1,2,4 Triazole hydrochloride

[Example 82]

3— (2 Black mouth 4 Funoleo mouth Fuenore) 5— [N— (4 Hydroxyphenol-Nole) N-Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The compound (0.50 g) obtained in Step 3 of Example 79 was dissolved in pyridine (5.0 ml), and under cooling with ice water, 2 × 4 fluorobenzoyl chloride (0.36 g) was added, Heated to reflux for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methanol (5. Oml), and an aqueous sodium hydroxide solution was added. After stirring at room temperature for 1 hour, water was added to the reaction solution. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected by filtration to obtain the title compound (0.19 g).

[0286] (Example 83)

3— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino] — 5— (4-Fluoro-2-methoxyphenol) — 4-Methyl-4H— 1,2,4 Triazole hydrochloride Process 1> N, N, monodimethyl mono N— (4 fluoro-3 hydroxyphenol) thiourea

The title compound (2.7 g) was obtained in the same manner as in Step 1 of Example 1 using 4-fluoro-3hydroxy-N-methylaline (2.2 g) and methyl isothiocyanate (1.lg).

Process 2> N— (4 Fluoro-3 hydroxyphenol) N, N ,, S Trimethylisothiorea hydroiodide

Using the compound obtained in Step 1 (2.7 g) and methyl iodide (0.93 ml), Example 1 In the same manner as in Step 2, the title compound (4.5 g) was obtained.

<Step 3> 1-Amino-2,3 dimethyl 2- (4-Fluoro-3-hydroxyphenol) guanidine hydroiodide

Using the compound (4.3 g) obtained in Step 2 and hydrazine monohydrate (0.59 ml), the title compound (4.4 g) was obtained in the same manner as in Step 3 of Example 1.

<Step 4> 3— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino]-5-(4 Fluoro-2-methoxyphenol) —4-Methyl-4H— 1,2,4 Triazole hydrochloride salt

After using the compound obtained in Step 3 (0.20 g) and 4 fluoro 2-methoxybenzoyl chloride (0. l lg) in the same manner as in Example 82, 4N hydrogen chloride-ethyl acetate solution was used. To give the title compound (40 mg).

[0287] (Example 84)

3— [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] — 5— (4-Hydoxy-2-methoxyphenol) — 4 Methyl 4H— 1, 2,4 Triazole hydrochloride Example 83 The title compound (28 mg) was obtained in the same manner as in Example 74, using the compound (0.20 g) obtained in Step 3 of 4 and 4-hydroxymono-2-methoxybenzoic acid (0.1 g). It was.

(Example 85)

3— (2 Black mouth 4 Huneleo mouth Fuenore) 5— [N— (4 Funoleo mouth 3 hydroxyphenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

Using the compound (0.40 g) obtained in Step 3 of Example 83 and 2 chloro-4fluorobenzoyl chloride (0.27 g), the title compound (0.25 g) was obtained in the same manner as in Example 82. .

[0288] (Example 86)

3— [N— (3 hydroxyphenol) N-methylamino] — 5— (2-methoxyphenol) —4-methyl-4H— 1,2,4 triazole

Process 1> 3 Black mouth 5— (2-Methoxyphenol) 1—Methinore 4H— 1,2,4 Tria Zonole Process of Example 21 using 3- (2-methoxyphenyl) 5-mercapto 4-methyl 4H— 1,2,4 triazole (4.3 g), potassium nitrate (5.9 g) and sulfuryl chloride (4.7 ml) In the same manner as in 2, the title compound (0.90 g) was obtained.

Step 2> 3— [N— (3 hydroxyphenol) N-methylamino] — 5— (2-methoxyphenyl) — 4-methyl-4H— 1,2,4 triazole

The title compound (81 mg) was obtained in the same manner as in Step 3 of Example 21 using the compound obtained in Step 1 (0.20 g) and 3 hydroxy-N-methylaline (0.17 g). . (Example 87)

3— (2 Black Mole) 5— [N— (4 Hydroxyl) N-Methylamino] —4-Methyl-4H— 1,2,4 Triazole

Process 1> 3 Black mouth 5— (2 Black mouth) One 4-Methyl 4H— 1,2,4 Triazole synthesis

3- (2 Chlorophenyl) 5-Mercapto-4-methyl 4H— 1,2,4 Triazole (5.0 g), potassium nitrate (6.7 g) and sulfuryl chloride (8.5 ml), step 2 of Example 21 In the same manner as described above, the title compound (0.80 g) was obtained.

Step 2> 3— (2 Black Mole) 5— [N— (4 Hydroxyl) N-Methylamino] — 4-Methyl-4H— 1,2,4 Triazole

To the compound obtained in Step 1 (50 mg), add 4-hydroxymono-N-methylaline 1Z2 sulfate (0. l lg) and N-ethyldiisopropylamine (57 1), at 150 ° C. for 2 hours. Heated. Methanol and methylene chloride were added to the reaction solution, and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (developing solvent; methanol: ethyl acetate = 1: 9) to obtain the title compound (20 mg).

The following compounds were synthesized in the same manner as in Example ⁸ using the compound obtained in Example 51 and the corresponding acid chloride.

(Example 88)

3— [4-acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (4-fluoro oral) — N-methylamino] — 4-methyl-4H—1, 2, 4 Triazole

(Example 89) 3— [4 (2-acetoxycetyl) amino-2 (trifluoromethyl) phenol] 5— [N— (4 fluorophenol) —N-methylamino] — 4-methyl-4H—1, 2 , 4-Tria Zonole

[0290] (Example 90)

3— [N— (4-Fluorophenol) —N—Methylamino] — 5— [4—Methanesulfolamino 2— (trifluoromethyl) phenol] — 4—Methyl 4H—1, 2, 4 Triazole (Example 91)

3— [4 Benzenesulfolamino-2 (trifluoromethyl) phenol] 5— [N— (

4-fluorophenol) —N-methylamino] —4-methyl-4H—1, 2, 4 triazole

(Example 92)

3— [4— (2 Dimethylaminoacetyl) amino-2- (trifluoromethyl) phenol] — 5 — [N— (4 Fluorophenyl) — N-methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

The compound (50 mg) obtained in Example 51 was dissolved in methylene chloride (1.0 ml), and pyridine (9 7 1) was added, and then 2 chloroacetyl chloride (13 1) was added under ice water cooling. Stir at room temperature for 30 minutes. To the reaction solution was added 50% aqueous dimethylamine solution (0.10 ml), and the mixture was stirred at room temperature for 1 hour. Furthermore, 50% dimethylamine aqueous solution (501) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (elution solvent; methanol: methylene chloride = 1: 49 to 3:17) to give the title compound (39 mg). Obtained.

The following compound was synthesized in the same manner as in Example 92 using the compound obtained in Example 51, 2 chloroacetyl chloride and the corresponding amine.

[0291] (Example 93)

3— [N— (4 Fluorophenol) —N—Methylamino] —4—Methyl—5— [4— (2 Morpholine-4-ylacetyl) amino-2 (trifluoromethyl) phenol] —4Η—1, 2,4-triazole (Example 94)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— {4— [2- (4 Hydroxypiperidine— 1-Ilylacetyl) amino]-2- (Trifluoromethyl) phenol } —4—methyl 4H— 1, 2, 4 triazole

[0292] (Example 95)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [4— (2 Hydroxyacetyl) amino-2 (trifluoromethyl) phenol] 4-Methyl-4H—1, 2, 4-Tria Zonole

The title compound (0.25 g) was obtained in the same manner as in Example 9 using the compound (0.30 g) obtained in Example 89.

(Example 96)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— [4— (2 Hydroxyethyl) amino-2- (trifluoromethyl) phenol] — 4—Methyl 4H—1, 2, 4 Triazo Inore

Using the compound (0.15 g) obtained in Example 95, the title compound (62 mg) was obtained in the same manner as in Example 11.

[0293] (Example 97)

3— [N— (4 Fluorophenyl) —N—Methylamino] —4—Methyl—5— [4— (2-oxoxazolidin-3-yl) -2 (trifluoromethyl) -Le] —4Η—1, 2, 4-triazole

The title compound (94 mg) was obtained in the same manner as in Example 36 using the compound (0.10 g) obtained in Example 51.

(Example 98)

3— [4 (3-Benzyloxyureido) 2 (Trifluoromethyl) phenol] 5— [N — (4 Fluorophenol) —N-Methylamino] — 4-Methyl-4H—1, 2 , 4 Triazo Inore

The title compound (0.12 g) was obtained in the same manner as in Example 20 using the compound (0.10 g) obtained in Example 51 and O benzyloxy ammonium chloride. [0294] (Example 99)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4— (3-hydroxyureido) — 2— (trifluoromethyl) phenol] — 4—Methyl—4H—1 , 2, 4 Triazole The title compound (47 mg) was obtained in the same manner as in Example 4 using the compound (60 mg) obtained in Example 98.

(Example 100)

3— [N— (4-Fluorophenol) —N—Methylamino] —4—Methyl—5— [4— (Morpholine—4-ylcarbolumino) 2 (trifluoromethyl) phenol] —4H— 1, 2, 4-triazole

To a solution of triphosgene (14 mg) in methylene chloride (1. Oml) was slowly added the compound (50 mg) obtained in Example 51 and a solution of triethylamine (21 1) in methylene chloride (1. Oml) and stirred at room temperature for 1 hour. . To the reaction solution, morpholine (13 1) and triethylamine (42 1) were added and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (elution solvent; methanol: salt-methylene- = 1: 99 to methanol: methylene chloride = 1: 17). The title compound (39 mg) was obtained.

The following compounds were synthesized in the same manner as in Example 100 using the compound obtained in Example 51 and the corresponding amine.

[0295] (Example 101)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4— (4-Methoxypiperidine 1-ylcarbo-amino) 2 (trifluoromethyl) phenol] -4-methyl-4H-1, 2, 4 卜 riazole

(Example 102)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4— (4-hydroxypiperidine 1-ylcarboamino) 2 (trifluoromethyl) phenol] 4 Methyl-4H- 1, 2, 4 Triazonole

[0296] (Example 103) 3— [4 Aminosulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluorophenol) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole Chlorosulfol isocyanate (39 mg) was dissolved in methylene chloride (1. Oml), t-butanol (29 μ1) was added, and the mixture was stirred for 30 minutes. The compound (50 mg) obtained in Example 51 was dissolved in pyridine (1. Oml), and the solution prepared above was added thereto while cooling with ice water. Stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and methylene chloride (0.50 ml) and trifluoroacetic acid (0.50 ml) were added to the residue. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography [Chromatolex NH ™; Chromatorex NH ™] (elution solvent; ethyl acetate-methanol: ethyl acetate = 1: 4) to give the title compound (27 mg). Obtained.

[0297] (Example 104)

3— [4 (Dimethylamino) sulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluorophenol) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Tri Azol

The compound (50 mg) obtained in Example 51 was dissolved in pyridine (l ml), and dimethylaminosulfamoyl chloride (0.44 ml) was added. After heating to reflux for 1 hour, dimethylsulfamoyl chloride (0.42 ml) was added, and the mixture was further heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography [Chromatolex NH ™; Chromatorex NH ™] (elution solvent: ethyl acetate to methanol: ethyl acetate = 1: 4) to give the title compound ( 16 mg) was obtained.

Using the compound obtained in Example 22 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

[0298] (Example 105)

3— (4 Acetylamino 2-ethoxyphenol) 5— [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

(Example 106)

3— (2 Ethoxy-l 4-Methanesulfolaminophenol) 5— [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole (Example 107)

3- (4 Benzenesulfo-Lamino 2 ethoxyphenol) 5 [N— (4 Fluorophenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

[0299] (Example 108)

3— [2 Ethoxy— 4— (2 Morpholine— 4-ylacetyl) aminophenol] — 5— [N — (4 Fluorophenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazo One nore

The title compound (45 mg) was obtained in the same manner as in Example 92, using the compound (50 mg) obtained in Example 22, 2-chloroacetyl chloride (17 1) and morpholine (64 1). (Example 109)

3— [2 Ethoxy-1-4- (2 Hydroxyacetyl) aminophenol] — 5— [N— (4-Fluorophenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole Implementation The title compound (70 mg) was obtained in the same manner as in Example 17 using the compound (0.10 g) obtained in Example 22 and 2-acetoxyacetyl chloride (38 μ 1).

[0300] (Example 110)

3— [2 Ethoxy 1 4- (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Fluorophenol) —N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole

Using the compound (44 mg) obtained in Example 109, the title compound (33 mg) was obtained in the same manner as in Example 11.

(Example 111)

3— [2 Ethoxy— 4— (2-Oxoxazolidin— 3—yl) phenol] — 5— [N— (

4-fluorophenol) —N-methylamino] —4-methyl-4H—1, 2, 4 triazole

The title compound (46 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 22 and 2 chloroethyl phthalate (191).

[0301] (Example 112)

3— [4— (3 Benzyloxyureido) 2 Ethoxyphenol] — 5— [N— (4 Fluorophenol) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole In the same manner as in Example 20, using the compound obtained in Example 22 (0.10 g), chloroformate phenol (44 μ 1), and benzyloxymum chloride (56 mg), The compound (78 mg) was obtained.

(Example 113)

3— [2 Ethoxy mono 4— (3 Hydroxyureido) phenol] — 5— [N— (4 Fluorophenol) —N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole

Using the compound (50 mg) obtained in Example 112, the title compound (37 mg) was obtained in the same manner as in Example 4.

(Example 114)

3— [2 Ethoxy— 4— (Morpholine— 4-ylcarbolamino) phenol] — 5— [N — (4 Fluorophenol) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazo Ichinole

The title compound (33 mg) was obtained in the same manner as in Example 100 using the compound (50 mg), triphosgene (15 mg) and morpholine (38 mg) obtained in Example 22.

(Example 115)

3— (4 Aminosulfo-Luamino 2-Ethoxyphenol) 5— [N— (4 Fluorophenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (41 mg) was obtained in the same manner as in Example 103, using the compound (50 mg) obtained in Example 22, chlorosulfol isocyanate (41 mg) and t-butanol (31 1).

(Example 116)

3— [4 (Dimethylamino) sulfo-Luamino 2-Ethoxyphenol] 5— [N— (4-Fluorophenol) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole In Example 22 The obtained compound (50 mg) was dissolved in pyridine (l ml), and dimethylaminosulfamoyl chloride (0.44 ml) and 4- (N, N-dimethylamino) pyridine (5 mg) were added under ice cooling. After stirring overnight, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography [chromatography. The title compound (25 mg) was obtained by purification with Chloxatorex NH] (elution solvent; ethyl acetate-methanol: ethyl acetate = 1: 4).

[0303] (Example 117)

3— [N— (4-Methoxyphenol) N-Methylamino] —4—Methyl 5— [4-Nitro-2- (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole

Using the compound (3.6 g) obtained in Step 3 of Example 76 and 4-tro 2 trifluoromethylbenzoic acid (2.5 g) in the same manner as in Step 4 of Example 1, the title compound ( 1. 3g) was obtained.

(Example 118)

3— [4 amino 1- (trifluoromethyl) phenol] — 5— [N— (4-methoxyphenol) — N-methylamino] — 4—methyl 4H— 1, 2, 4 triazole

The title compound (1. lg) was obtained in the same manner as in Example 4 using the compound (1.3 g) obtained in Example 117.

Using the compound obtained in Example 118 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

[0304] (Example 119)

3— [4 Acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (4-Methoxyphenol) —N-methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole

(Example 120)

3— [4 Ethoxycarbolamino 2 (trifluoromethyl) phenol] 5— [N— (

4-methoxyphenyl) mono-N-methylamino] — 4-methyl 4H—1, 2, 4 triazole (Example 121)

3— [4 Methanesulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Methoxyphenol) -N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole [0305] ( (Example 122)

3— [4 Benzenesulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4-methoxyphenol) 1 N-methylamino] — 4-methyl 4H—1, 2, 4 Triazole (Example 123) 3— [N— (4-Methoxyphenol) —N-Methylamino] —4-Methyl-5— [4— (2-Morpholine-4-ylacetyl) amino-2 (trifluoromethyl) phenol] —4Η— 1, 2, 4-triazole

The title compound (15 mg) was obtained in the same manner as in Example 92 using the compound (50 mg) obtained in Example 118, 2-chloroacetyl chloride (121) and morpholine (701).

(Example 124)

3— [4 (2-Hydroxyacetyl) amino-2 (trifluoromethyl) phenol] 5— [N— (4-Methoxyphenyl) -1-N-methylamino] — 4-Methyl 4H—1, 2, 4-tria Zonole

The title compound (77 mg) was obtained in the same manner as in Example 17 using the compound (94 mg) obtained in Example 118 and 2-acetoxyacetyl chloride (0.1 2 ml).

(Example 125)

3— [4 (2-Hydroxyethyl) amino-2 (trifluoromethyl) phenol] 5— [N — (4-Methoxyphenyl) one N-methylamino] — 4-Methyl 4H-1,2, 4 Triazo Inore

The title compound (38 mg) was obtained in the same manner as in Example 11 using the compound (50 mg) obtained in Example 124.

[0307] (Example 126)

3— [N— (4-Methoxyphenol) —N—Methylamino] —4—Methyl—5— [4— (2-Oxoxazolidin-3-yl) -2 (Trifluoromethyl) [Fuel] —4Η-1,2,4-triazole

The title compound (27 mg) was obtained in the same manner as in Example 36, using the compound (38 mg) obtained in Example 118 and 2 kuroguchi fortilate (13 1).

The following compounds were synthesized in the same manner as in Example 20 using the compound obtained in Example 118, phenyl chloroformate and the corresponding amine.

(Example 127)

3— [N— (4-Methoxyphenol) N-Methylamino] — 5— [4— (3-Methoxyureido) —2— (Trifluoromethyl) phenol] — 4-Methyl 4H—1, 2, 4 Triazole

[0308] (Example 128)

3— [4 (3-Hydroxyureido) 2 (trifluoromethyl) phenol] 5— [N— (4-Methoxyphenyl) -1-N-methylamino] — 4-Methyl 4H-1,2, 4 Triazole (Example 129)

3— [N— (4-Methoxyphenol) —N—Methylamino] —4—Methyl-5— [4— (Morpholine-4-ylcarboamino) 2 (Trifluoromethyl) phenol] —4Η—1 , 2, 4-triazole

The title compound (19 mg) was obtained in the same manner as in Example 100 using the compound (50 mg), triphosgene (12 mg) and morpholine (131) obtained in Example 118.

[0309] (Example 130)

3— [4 Aminosulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Methoxyphenol) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole In Example 118 The title compound (37 mg) was obtained in the same manner as in Example 103, using the obtained compound (50 mg), chlorosulfuryl isocyanate (23 μ 1) and t-butanol (301).

(Example 131)

3— [4 (Dimethylamino) sulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4-Methoxyphenol) -N-methylamino] — 4-Methyl 4H-1,2,4-tria Zonole

The title compound (23 mg) was obtained in the same manner as in Example 104, using the compound (38 mg) obtained in Example 118 and dimethylsulfamoyl chloride (54 μ1).

The following compounds were synthesized in the same manner as in Step 4 of Example 1, using the compound obtained in Step 3 of Example 3 and the corresponding carboxylic acid.

[0310] (Example 132)

3— [N— (4-Fluoro-3 —methylphenol) N Methylamino] — 4—Methyl— 5— [4-Toro 2- (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole (Example 133) 3- (2 Ethoxy-4 ditrophyl) 5— [N— (4 Fluoro 3-methylphenol) 1 N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

[0311] (Example 134)

3— [4 amino 2 (trifluoromethyl) phenol] 5— [N— (4 fluoro 3 methyl phenol) —N-methylamino] -4-methyl-4H-1,2,4-triazole In Example 132 The title compound (4.5 g) was obtained in the same manner as Example 4 using the obtained compound (4.9 g).

Using the compound obtained in Example 134 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 135)

3— [4-acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (4-Fluoro-3-methylphenol) —N-methylamino] — 4—methyl—4H—1, 2, 4 Triazo Inore

(Example 136)

3— [4 Ethoxycarbolamino 2 (trifluoromethyl) phenol] 5— [N— (

4 Fluoro-3-methylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4-triazole

[0312] (Example 137)

3— [N— (4-Fluoro-3-methylphenol) N-methylamino] — 5— [4-Methanesulfonylamino-2 (trifluoromethyl) phenol] -4-methyl-4H-1, 2, 4 Thorazole

(Example 138)

3— [4 Benzenesulfolamino-2 (trifluoromethyl) phenol] 5— [N— (

4 Fluoro-3-methylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4-triazole

(Example 139)

3— [N— (4-Fluoro-3—methylphenol) N Methylamino] — 4—Methyl—5— [4 (2-morpholine 4-alkylacetyl) amino-2 (trifluoromethyl) phenol] -4H- 1, 2, 4 Triazonole

The title compound (37 mg) was obtained in the same manner as in Example 92 using the compound (50 mg) obtained in Example 134, 2 chloroacetyl chloride (131) and morpholine (69 1).

[0313] (Example 140)

3— [N— (4 Fluoro-3-methylphenol) —N—Methylamino] — 5— [4— (2 Hydroxycetyl) amino-2- (trifluoromethyl) phenol] 4—Methyl 4H— 1, 2, 4 Triazonole

The title compound (95 mg) was obtained in the same manner as in Example 17 using the compound (lOOmg) obtained in Example 134 and 2-acetoxyacetyl chloride (341).

(Example 141)

3— [N— (4 Fluoro-3-methylphenol) —N—Methylamino] — 5— [4— (2 Hydroxetyl) amino-2- (trifluoromethyl) phenol] — 4—Methyl—4H— 1, 2, 4-triazole

Using the compound (63 mg) obtained in Example 140, the title compound (56 mg) was obtained in the same manner as in Example 11.

[0314] (Example 142)

3— [N— (4-Fluoro-3 —methylphenol) N Methylamino] — 4—Methyl— 5— [4 (2-oxoxazolidine 3 yl) -2 (trifluoromethyl) phenol -Le] -4 H- 1, 2, 4 Triazonole

The title compound (33 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 134 and 2 cloguchiethyl acetate (17 ^ 1).

The following compounds were synthesized in the same manner as in Example 20 using the compound obtained in Example 134, phenyl chloroformate and the corresponding amine.

(Example 143)

3— [N— (4-Fluoro-3-methylphenol) —N-methylamino] — 5— [4 -— (3-Methylureido) 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 to riazole [0315] (Example 144)

3— [N— (4-Fluoro-3-methylphenol) —N-methylamino] — 5— [4 -— (3-hydroxyureido) 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 Triazole

(Example 145)

3— [N— (4-Fluoro-3 —methylphenol) N Methylamino] — 4—Methyl— 5— [4 (Morpholine—4-ylcarbolumino) 2 (Trifluoromethyl) phenol] 4H-1 , 2, 4 卜 riazole

The title compound (20 mg) was obtained in the same manner as in Example 100 using the compound (50 mg), triphosgene (12 mg) and morpholine (131) obtained in Example 134.

[0316] (Example 146)

3— [4 Aminosulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methylphenol) — N-methylamino] — 4-Methyl-4H—1, 2, 4 G Riazole

The title compound (25 mg) was obtained in the same manner as in Example 103, using the compound obtained in Example 134 (50 mg), chlorosulfuryl isocyanate (23 μ 1) and t-butanol (301).

(Example 147)

3— [4 (Dimethylamino) sulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methylphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (20 mg) was obtained in the same manner as in Example 104, using the compound (50 mg) obtained in Example 134 and dimethylsulfamoyl chloride (701).

[0317] (Example 148)

3— (4 amino 2-ethoxyphenyl) 5— [N— (4 fluoro 3-methylphenol) 1 N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole

The title compound (4.8 g) was obtained in the same manner as in Example 4 using the compound (6.2 g) obtained in Example 133. Using the compound obtained in Example 148 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 149)

3— (4 Acetylamino 2-Ethoxyphenol) 5— [N— (4 Fluoro-3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

[0318] (Example 150)

3— [2-Ethoxy 4- (ethoxycarboamino) phenol] 5— [N— (4-Fluoro 3-methylphenol) —N-Methylamino] — 4-Methyl-4H-1, 2, 4 Triazo Ichinole

(Example 151)

3— (2 Ethoxy 1- 4-Methanesulfo-Laminophenol) 5— [N— (4 Fluoro 3-Methylphenol) — N-Methylamino] — 4—Methyl-4H—1, 2, 4 Triazole (Examples) 152)

3— (4—Benzenesulfo-Lamino 2 ethoxyphenol) 5— [N— (4-Fluoro-3—methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

[0319] (Example 153)

3— [2 Ethoxy— 4— (2 Morpholine — 4-ylacetyl) aminophenol] — 5— [N-(4 Fluoro-3-methylphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 -Triazole

The title compound (55 mg) was obtained in the same manner as in Example 92, using the compound (50 mg) obtained in Example 148, 2 chloroacetyl chloride (151) and morpholine (231).

(Example 154)

3— [2 Ethoxy 1 4- (2 Hydroxyacetyl) aminophenol] — 5— [N— (4 Fluoro 3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

The compound obtained in Example 148 (150 mg) and 2-acetoxyacetyl chloride (54 The title compound (154 mg) was obtained in the same manner as in Example 17 using 1).

[0320] (Example 155)

3— [2 Ethoxyl 4- (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Fluoro 3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4-tria Zonole

Using the compound (50 mg) obtained in Example 154, the title compound (34 mg) was obtained in the same manner as in Example 11.

(Example 156)

3— [2 Ethoxy— 4— (2-Oxoxazolidin— 3—yl) phenol] — 5— [N— (

4 Fluoro-3-methylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4-triazole

The title compound (30 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 148 and 2 chromoethyl formic acid (18 1).

The following compounds were synthesized in the same manner as in Example 20 using the compound obtained in Example 148, phenyl chloroformate and the corresponding amine.

[0321] (Example 157)

3— [2 Ethoxy 1- 4— (3-Methoxyureido) phenol] — 5— [N— (4 Fluoro 1-methylphenol) — N-Methylamino] — 4—Methyl-4H—1, 2, 4 Triazole (Example 158)

3— [4— (3 Benzyloxyureido) 2 Ethoxyphenyl] — 5— [N— (4 Fluoro 3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 -Tria Zonole

[0322] (Example 159)

3— [2 Ethoxy mono 4— (3 hydroxyureido) phenol] — 5— [N— (4 Fluoro-3-methylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4 Triazole

The title compound (43 mg) was obtained in the same manner as in Example 4 using the compound (60 mg) obtained in Example 158. (Example 160)

3— [2 Ethoxy— 4— (Morpholine— 4-ylcarbolamino) phenol] — 5— [N-(4 Fluoro-3-methylphenol) N-methylamino] — 4-Methyl4H— 1, 2,, 4-triazole

The title compound (42 mg) was obtained in the same manner as in Example 100 using the compound (71 mg), triphosgene (20 mg) and morpholine (21 1) obtained in Example 148.

[0323] (Example 161)

3— (4 Aminosulfo-Luamino 2-Ethoxyphenol) 5— [N— (4 Fluoro 3-Methylphenol) —N-Methylamino] —4-Methyl-4H—1, 2, 4 Triazole Obtained in Example 148 The title compound (29 mg) was obtained in the same manner as in Example 103, using the obtained compound (50 mg), chlorosulfurol isocyanate (18 μ 1) and t-butanol (201).

(Example 162)

3— [4 (Dimethylamino) sulfo-Luamino 2-Ethoxyphenol] 5— [N— (4-Fluoro-3-methylphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

The title compound (32 mg) was obtained in the same manner as in Example 116, using the compound (50 mg) obtained in Example 148 and dimethylaminosulfamoyl chloride (0.23 ml).

Using the compound obtained in Step 3 of Example 78 and the corresponding carboxylic acid, the following compounds were synthesized in the same manner as in Step 4 of Example 1.

[0324] (Example 163)

3— [N— (4-Fluoro-3-methoxyphenol) —N—Methylamino] —4—Methyl—5 — [4-Tro-2- (trifluoromethyl) phenol] — 4H—1, 2 , 4 Triazole (Example 164)

3— (2 Ethoxy-4-methoxy) 5— [N— (4 Fluoro-3-methoxyphenol) -1-N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

[0325] (Example 165)

3— [4 amino 2 (trifluoromethyl) phenol] 5— [N— (4 fluoro 3 melo Toxipherol) —N-methylamino] —4-methyl-4H-1,2,4 triazole Using the compound (2. Og) obtained in Example 163, the title compound (1 7 g) was obtained.

Using the compound obtained in Example 165 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 166)

3— [4 Acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (4 Fluoro 3-methoxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazo Inore

[0326] (Example 167)

3— [4 Ethoxycarbolamino 2 (trifluoromethyl) phenol] 5— [N— (

4 Fluoro-3-methoxyphenyl) mono-N-methylamino] — 4-methyl 4H—1, 2, 4-triazole

(Example 168)

3— [N— (4-Fluoro-3-methoxyphenyl) N-methylamino] — 5— [4-Methane sulfo-lumino 2- (trifluoromethyl) phenol] — 4-Methyl-4H—1, 2, 4— Triazole

(Example 169)

3— [4 Benzenesulfolamino-2 (trifluoromethyl) phenol] 5— [N— (

[0327] (Example 170)

3— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] —4-methyl-5

[4 (2 morpholine 4-ylacetyl) amino-2 (trifluoromethyl) phenol] — 4H— 1, 2, 4 卜 riazole

The title compound (40 mg) was obtained in the same manner as in Example 92, using the compound (50 mg) obtained in Example 165, 2-chloroacetyl chloride (121) and morpholine (661). (Example 171)

3— [N— (4 Fluoro 3-methoxyphenol) —N—Methylamino] — 5— [4— (2 —Hydroxyacetyl) amino-2- (trifluoromethyl) phenol] 4 —Methyl 4H— 1, 2, 4 Triazole

The title compound (55 mg) was obtained in the same manner as in Example 17 using the compound (50 mg) obtained in Example 165 and 2-acetoxyacetyl chloride (33 μ1).

[0328] (Example 172)

3— [N— (4 Fluoro 3-methoxyphenyl) —N—Methylamino] — 5— [4— (2—Hydroxyethyl) amino-2- (trifluoromethyl) phenol] 4—Methyl 4H— 1, 2, 4 Triazonole

The title compound (22 mg) was obtained in the same manner as in Example 11 using the compound (30 mg) obtained in Example 171.

(Example 173)

3— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] —4-methyl-5

[4 (2-oxoxazolidine 3 yl) -2 (trifluoromethyl) phenol] 4H- 1, 2, 4 卜 riazole

The title compound (36 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 165 and 2 cloguchiethyl acetate (16 1).

[0329] The following compound was synthesized in the same manner as in Example 20 using the compound obtained in Example 165, phenyl chloroformate and the corresponding amine.

(Example 174)

3— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] — 5— [4 -— (3-methoxyureido) 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 Triazole

(Example 175)

3— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] — 5— [4-— (3-hydroxyureido) 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4-triazole (Example 176)

3— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] —4-methyl-5

[4 (Morpholine 4-ylcarboamino) 2 (trifluoromethyl) phenol] -4H- 1, 2, 4 Triazolone

The title compound (20 mg) was obtained in the same manner as in Example 8 using the compound (50 mg) obtained in Example 165 and morpholinyl carbochloride (17 μ1).

[0330] (Example 177)

3— [4 Aminosulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3-methoxyphenol) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole

The title compound (37 mg) was obtained in the same manner as in Example 103, using the compound (50 mg) obtained in Example 165, chlorosulfuryl isocyanate (22 μ 1) and t-butanol (291).

(Example 178)

3— [4 (Dimethylamino) sulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4-Fluoro-3-methoxyphenol) —N-methylamino] — 4-methyl—4H— 1, 2, 4 Triazole

The title compound (23 mg) was obtained in the same manner as in Example 104, using the compound (50 mg) obtained in Example 165 and dimethylaminosulfamoyl chloride (0.27 ml).

[0331] (Example 179)

3— (4 amino 2-ethoxyphenol) 5— [N— (4 fluoro 3 methoxyphenol) 1 N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole

The title compound (4.3 g) was obtained in the same manner as in Example 4 using the compound (5.3 g) obtained in Example 164.

Using the compound obtained in Example 179 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 180)

3— (4 Acetylamino 2-Ethoxyphenol) 5— [N— (4 Fluoro 3 Met Xylphenol) — N-methylamino] — 4-methyl-4H—1, 2, 4 triazole (Example 181)

3— [2-Ethoxy 4- (ethoxycarboamino) phenol] 5— [N— (4 Fluorophthalate 3-methoxyphenol) N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazo Ichinole

[0332] (Example 182)

3— (2 Ethoxy-1-4-methanesulfo-laminophenol) 5— [N— (4-Fluoro-3-methoxyphenyl) -1-N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole (Example 183) )

3— (4-Benzenesulfo-lumino 2 ethoxyphenol) 5— [N— (4-Fluoro-3 — methoxyphenol) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole

(Example 184)

3— [2 Ethoxy—4 -— (2 Morpholine—4-ylacetyl) aminophenol] — 5— [N-(4 Fluoro-3-methoxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazonole

The title compound (75 mg) was obtained in the same manner as in Example 92, using the compound (70 mg) obtained in Example 179, 2 chloroacetyl chloride (221) and morpholine (501).

[0333] (Example 185)

3— [2 Ethoxy 1 4- (2 Hydroxyacetyl) aminophenol] — 5— [N— (4 Fluoro 3-methoxyphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

The title compound (0.23 g) was obtained in the same manner as in Example 17 using the compound (0.28 g) obtained in Example 179 and 2-acetoxyacetyl chloride (0.12 ml).

(Example 186)

3— [2 Ethoxy 1- 4— (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Fluoro 3-methoxyphenol) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 -Tria Zonole

The title compound (89 mg) was obtained in the same manner as in Example 11 using the compound (0.1Og) obtained in Example 185.

[0334] (Example 187)

3— [2 Ethoxy— 4— (2-Oxoxazolidin— 3—yl) phenol] — 5— [N— (

The title compound (24 mg) was obtained in the same manner as in Example 36, using the compound (70 mg) obtained in Example 179 and 2 cloguchiethyl acetate (29 μ1).

The following compounds were synthesized in the same manner as in Example 20 using the compound obtained in Example 179, phenyl chloroformate and the corresponding amine.

(Example 188)

3— [2 Ethoxy 1- 4— (3-Methoxyureido) phenol] — 5— [N— (4 Fluoro 1-methoxyphenyl) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazole [0335] (Example 189)

3— [2 Ethoxy 1- 4— (3 Hydroxyureido) phenol] — 5— [N— (4 Fluoro-3-3-methoxyphenyl) 1 N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazol Le

(Example 190)

3— [2 Ethoxy— 4— (Morpholine— 4-ylcarbolumino) phenol] — 5— [N-(4 Fluoro-3-methoxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazonole

The title compound (46 mg) was obtained in the same manner as in Example 100 using the compound (70 mg), triphosgene (13 mg) and morpholine (371) obtained in Example 179.

(Example 191)

3— (4 Aminosulfo-Luamino 2-Ethoxyphenol) 5— [N— (4 Fluoro 3 —Methoxyphenol) 1 N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazole Obtained in Example 179 Compound (0.10 g), chlorosulfur isocyanate (35 μ 1) The title compound (25 mg) was obtained in the same manner as in Example 103, using t-butanol (391).

[0336] (Example 192)

3— [4 (Dimethylamino) sulfo-Luamino 2-Ethoxyphenol] 5— [N— (4-Fluoro-3-methoxyphenol) 1 N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazole

The title compound (14 mg) was obtained in the same manner as in Example 104, using the compound (0.10 g) obtained in Example 179 and dimethylaminosulfamoyl chloride (0.57 ml). (Example 193)

3— [4-Bromo 2— (trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) —N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

The compound (3. Og) obtained in Step 3 of Example 1 was dissolved in pyridine (60 ml), and 4-bromo-2 (trifluoromethyl) benzoyl chloride (4. Og) was added under ice water cooling. The mixture was stirred at room temperature for 2 hours and heated to reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the residue obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (elution solvent; ethyl acetate-methanol: ethyl acetate = 1: 19) to give the title compound (1.6 g )was gotten.

[0337] (Example 194)

3— [4-Ciano 2— (trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) —N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

The title compound (1) was prepared in the same manner as in Example 193 using the compound (3.2 g) obtained in Step 3 of Example 1 and 4 cyano 2- (trifluoromethyl) benzoyl chloride (3.6 g). 4 g) was obtained.

Using the compound obtained in Example 193 and the corresponding amine, the following compound was synthesized in the same manner as in Example 71.

(Example 195)

3— [N— (4-Fluorophenol) —N—Methylamino] —4—Methyl—5— [4— (mol Holin—4-yl) —2— (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole (Example 196)

3— [4 4 Acetylbiperazine 1 yl) 2 (Trifluoromethyl) phenol] 5— [N— (4 Fluorophenol) — N-Methylamino] — 4—Methyl-4H—1, 2, 4— Triazole

[0338] (Example 197)

3— {4 [4 (Acetylamino) piperidine 1-yl] 2 (Trifluoromethyl) phenol} 5— [N— (4 Fluorophenyl) —N-methylamino] 4-Methyl 4H— 1, 2 , 4 Triazole

(Example 198)

3— [N— (4-Fluorophenyl) —N—Methylamino] —4—Methyl—5— {4— [4— (Morpholine 4-ylcarbol) piperidine 1-yl] 2 (Trifluoromethyl) Feninore 4H—1, 2, 4 Triazonole

(Example 199)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4— (4-Hydroxypiperidine— 1—yl) —2— (trifluoromethyl) phenol] — 4 —Methyl—4H—1, 2, 4-triazole

[0339] (Example 200)

3— [4—Carboxyl-2— (trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) —N-methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole

The title compound (0.68 g) was obtained in the same manner as in Example 68, using the compound (1.3 g) obtained in Example 194.

(Example 201)

3— [N— (4-Fluorophenol) —N—Methylamino] — 5— [4-Methoxycarbole —2— (Trifluoromethyl) phenol] — 4—Methyl 4H—1, 2, 4 Triazole The compound (30 mg) obtained in Example 200 was suspended in methylene chloride (5 ml). Under ice cooling, oxalyl chloride (141) and N, N-dimethylformamide were prepared. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. Methanol (lml) was added to the precipitated solid and concentrated under reduced pressure. The mixture was shrunk, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, hexane and jetyl ether were added to the residue, and the obtained solid was collected by filtration to give the title compound (16 mg).

[0340] (Example 202)

3— [4 Strike Lumamoyl 2 (trifluoromethyl) phenol] 5— [N— (4 fluorophenol) —N-methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole

The title compound (18 mg) was obtained in the same manner as in Example 69 using the compound (50 mg) obtained in Example 194.

Using the compound obtained in Example 200 and the corresponding amine, the following compound was synthesized in the same manner as in Example 70.

(Example 203)

3— [N— (4 Fluorophenol) —N—Methylamino] — 5— {4— [(2-Methoxyethyl) aminocarbol] 2 (Trifluoromethyl) phenol} 4-Methyl-4H—1, 2,4-triazole

[0341] (Example 204)

3— [N— (4 Fluorophenyl) —N—Methylamino] — 5— {4— [(2 Hydroxyethyl) aminocarbonyl] 2 (Trifluoromethyl) phenyl} 4 Methyl 4H— 1, 2, 4 Triazonole

(Example 205)

3— {4 [2 (Dimethylamino) ethylaminocarbol] 2 (Trifluoromethyl) phenol} — 5— [N— (4-Fluorophenyl) —N-methylamino] — 4— Methyl— 4H— 1, 2, 4 Triazole

(Example 206)

3— {4 [(Strengthened ruberamoylmethyl) aminocarbol] 2 (Trifluoromethyl) phenyl} 5— [N— (4 Fluorophenyl) —N-methylamino] 4-Methyl 4H— 1, 2, 4 -Triazole

[0342] (Example 207) 3— [N— (4-Fluorophenol) —N—Methylamino] — 4—Methyl—5— [4— (Morpholine-4-ylcarbole) -2 (Trifluoromethyl) phenol] —4Η— 1, 2, 4 Triazole

(Example 208)

3— [4 (4-acetylbiperazine 1-ylcarbol) 2 (trifluoromethyl) phenol] — 5— [N— (4-Fluorophenol) —N-methylamino] — 4-methyl — 4H-1, 2, 4 Triazole

(Example 209)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4— (4-Hydroxypiperidine 1-ylcarbol) 2 (Trifluoromethyl) phenol] -4-Methyl-4H- 1, 2, 4 Triazole

[0343] (Example 210)

3- {4- [4- (Acetylamino) piperidine 1 yl] carboru 2 (trifluoromethyl) phenol} — 5— [N— (4-Fluorophenol) —N—methylamino] —4 —Methyl Lou 4H— 1, 2, 4 Triazole

(Example 211)

3— [N— (4-Fluorophenyl) —N—Methylamino] —4—Methyl—5— {4— [4— (Morpholine 4-ylcarbol) piperidine 1-ylcarbol] 2 (Trifluoromethyl) Fuel} -411 1, 2, 4-triazole

[0344] (Example 212)

3— [N— (4-Fluorophenol) N-methylamino] — 5— [4-hydroxyaminocarbole 2 (trifluoromethyl) phenol] -4-methyl-4H—1, 2, 4 Triazole

Using the compound obtained in Example 200 and O benzyloxymoum chloride, the compound was synthesized in the same manner as in Example 70, and then the title compound was obtained in the same manner as in Example 4.

(Example 213)

3— [N— (4-Fluorophenyl) N-methylamino] — 5— [4-Methoxyaminocarbo -Lu-2- (trifluoromethyl) phenol] — 4-Methyl-4H-1,2,4-triazole Example using the compound obtained in Example 200 and O-methylhydroxyammonium chloride In the same manner as in 70, the title compound was obtained.

[0345] (Example 214)

3— [N— (4-Fluorophenol) N-methylamino] — 5— [4-hydroxy-1- (trifluoromethyl) phenol] 4 Methyl 4H— 1, 2,4 Triazole

(Example 215)

3— [N— (4-Fluorophenol) N-methylamino] — 5— [1— (4-hydroxyphenol) 1-methylethyl] -4-methyl-4H— 1,2,4 triazole

[0346] (Example 216)

3 -— [4-Hydroxy-2 (trifluoromethyl) phenol] —4-Methyl-5— {N—methyl N— [3 -— (trifluoromethyl) phenol] amino} —4Η— 1,2, 4 Triazole Process 1> Ν, Ν, mono-dimethyl Ν— Synthesis of [3 (trifluoromethyl) phenol] thiourea

標記 -Methyl 3- (trifluoromethyl) aline (0.60 g) and methyl isothiocyanate (0.36 g) were used in the same manner as in Step 1 of Example 1 to obtain the title compound (0.79 g). was gotten.

<Step 2> N— [3 (Trifluoromethyl) phenol] Ν, Ν, S S Synthesis of trimethylisothiorea hydroiodide

<Step 3> Synthesis of 1 amino 2, 3 dimethyl 2- [3 (trifluoromethyl) phenol] guan dizine hydroiodide

<Process 4> 3— [4 Hydroxy-2- (trifluoromethyl) phenol] 4 Methyl 5 — {N—Methyl—N— [3— (Trifluoromethyl) phenol] amino} —4H— 1,2,4 Triazole

Using the compound obtained in Step 3 (0.20 g) and 4-hydroxy-1- (trifluoromethyl) benzoic acid (0.12 g) in the same manner as in Step 4 of Example 1, the title compound (7 mg) was gotten.

The following compounds were synthesized in the same manner as in Step 4 of Example 1, using the compound obtained in Step 3 of Example 216 and the corresponding carboxylic acid.

(Example 217)

3— (2—Black mouthpiece 4-Hydroxyphenol) 4—Methyl 5— {N—Methyl N— [3— (Trifluoromethyl) phenol] Amine} —4Η— 1,2,4 Triazole

[0347] (Example 218)

3— [1— (4 hydroxyphenyl) 1 1-methylethyl] —4—methyl 5— {Ν—methyl Ν— [3— (trifluoromethyl) phenol] amino} —4Η— 1, 2,4 Triazole The following compound was synthesized in the same manner as in Example 82 using the compound obtained in Step 3 of Example 79 and the corresponding acid chloride.

(Example 219)

3— [Ν— (4-Hydroxyphenol) Ν—Methylamino] —4—Methyl 5— [4-Nitro —2— (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole

(Example 220)

3— (2 Ethoxy mono 4-trophenyl) 5— [Ν— (4-hydroxyphenol) Ν—Methylamino] — 4-Methyl 4Η— 1, 2, 4 卜 riazole

(Example 221)

3— (2 Black mouth 4-Trophe-nore) 5— [Ν— (4-Hydroxyphenol-nore) Ν—Methylamino] — 4-Methyl 4Η— 1, 2, 4 卜 Riazole

The following compounds were synthesized in the same manner as in Step 4 of Example 1 using the compound obtained in Step 3 of Example 79 and the corresponding carboxylic acid.

[Example 222]

3— [Ν— (4-Hydroxyphenol) —Ν—Methylamino] — 5— [2— (Trifluoromethyl ) Fuel] — 4-Methyl-4H— 1,2,4 Triazole

(Example 223)

3— [2 (Dimethylamino) phenol] 5— [N— (4-Hydroxyphenol) -N-methylamino] — 4-Methyl-4H— 1,2,4 Triazole

(Example 224)

3— [N— (4 Hydroxyphenol) N-Methylamino] —4—Methyl 5— (1-Methyl-1 phenylethyl) —4H— 1,2,4 Triazole

[0349] (Example 225)

3— [N— (4-Hydroxyphenol) N-Methylamino] — 5— [1— (4-Hydroxyphenol) 1-methylethyl] -4-methyl-4H— 1,2,4 Triazole

(Example 226)

3— (adamantane 1-yl) 5— [N- (4-hydroxyphenol) N-methylamino] —4-methyl-4H— 1,2,4 triazole

The compound (0.50 g) obtained in Step 3 of Example 79 was dissolved in pyridine (5.0 ml), adamantane-1-ylcarbonyl chloride (0.36 g) was added with cooling with ice water, and at room temperature. The mixture was stirred for 2 hours and heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (elution solvent; hexane-ethyl acetate-methanol: ethyl acetate- = 1: 9) to give the title compound (0.18 g) was obtained.

[0350] (Example 227)

3— [4-Amino 2- (Trifluoromethyl) phenol] — 5— [N— (4-Hydroxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (0.26 g) was obtained in the same manner as in Example 4 using the compound (0.40 g) obtained in Example 219.

(Example 228)

3— [4 (Dimethylamino) 2 (Trifluoromethyl) phenol] 5— [N— (4-Hydroxyphenol) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole The title compound (18 mg) was obtained in the same manner as in Example 5 using the compound (20 mg) obtained in Example 227.

The following compounds were synthesized in the same manner as in Example ⁸ using the compound obtained in Example 227 and the corresponding acid chloride.

[Example 229]

3— [4-acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (4-hydroxyphenyl) —N-methylamino] — 4—methyl—4H—1, 2, 4 Triazole

(Example 230)

3— [4 Ethoxycarbolamino 2 (trifluoromethyl) phenol] 5— [N— (

4-Hydroxyphenol) N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazole

(Example 231)

3— [4— (2 Dimethylaminoacetyl) amino-2- (trifluoromethyl) phenol] — 5

— [N— (4-Hydroxyphenol) N-Methylamino] — 4-Methyl 4H—1, 2, 4— Triazole

Using the compound (25 mg) obtained in Example 227, 2 chloroacetyl chloride (111) and 50% aqueous dimethylamine solution (0.10 ml), the title compound (21 mg) was obtained in the same manner as in Example 92. It was.

[0352] (Example 232)

3— [4 (2-Hydroxyacetyl) amino-2 (trifluoromethyl) phenol] 5— [N— (4Hydroxyphenyl) -1-N-methylamino] — 4-Methyl 4H—1, 2, 4 Triazole

The title compound (45 mg) was obtained in the same manner as in Example 17 using the compound (60 mg) obtained in Example 227 and 2-acetoxyacetyl chloride (26 μ1).

(Example 233)

3— [4 (2-hydroxyethyl) amino-2 (trifluoromethyl) phenol] 5— [N

— (4 hydroxyphenol) 1 N-methylamino] — 4—methyl 4H—1, 2, 4 Tria Zonole The title compound (3.7 mg) was obtained in the same manner as in Example 11 using the compound (30 mg) obtained in Example 232.

[0353] (Example 234)

3— [N— (4 Hydroxyphenol) N—Methylamino] —4—Methyl 5— [4— (2—oxoxazolidine 3 yl) -2 (trifluoromethyl) phenol] —4H—1, 2, 4-triazole

The title compound (13 mg) was obtained in the same manner as in Example 36, using the compound (25 mg) obtained in Example 227 and 2 cloethyl octylate (8.9 ^ 1).

(Example 235)

3— [N— (4-Hydroxyphenol) N-Methylamino] — 5— [4— (3-Methoxyureido) -2 (trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4-Triazole In the same manner as in Example 20 using the compound (30 mg) obtained in Example 227, chloroformate phenol (131) and O-methylhydroxyammonium chloride (7.6 mg), The title compound (7.3 mg) was obtained.

[0354] (Example 236)

3— (4-Amino-2-ethoxyphenyl) 5— [N— (4-Hydroxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 卜 Riazole

The title compound (2.9 g) was obtained in the same manner as in Example 4 using the compound (5.6 g) obtained in Example 220.

(Example 237)

3— [4— (Dimethylamino) 2 ethoxyphenol] — 5— [N— (4 Hydroxyphenol) mono N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (23 mg) was obtained in the same manner as in Example 5 using the compound (50 mg) obtained in Example 236.

(Example 238)

3— (4 Acetylamino-2-ethoxyphenol) 5— [N— (4 Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The compound (50 mg) obtained in Example 236 was added to pyridine (0.12 ml) and acetic anhydride (0. 11ml). After stirring at room temperature for 30 minutes, acetyl chloride was calcined until there was no suspension. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The salt ammonia was added to adjust the pH to 7 and extracted with tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the resulting solid was collected by filtration and dried to give the title compound (53 mg).

[0355] (Example 239)

3— [2 Ethoxy— 4— (Ethoxycarboamino) phenol] — 5— [N— (4 Hydroxyphenol) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole Implementation The title compound (44 mg) was obtained in the same manner as in Example 238 using the compound (50 mg) obtained in Example 236 and ethyl chloroformate (31 1).

Using the compound obtained in Example 236 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 240)

3— (2 Ethoxy-l 4-Methanesulfo-Laminophenol) 5— [N— (4-Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

[0356] (Example 241)

3— (4-Benzenesulfo-Luamino-2-ethoxyphenol) 5— [N— (4-Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

(Example 242)

3— [2 Ethoxy— 4— (2 Morpholine — 4-ylacetyl) aminophenol] — 5— [N — (4 Hydroxyl) mono-N-methylamino] — 4-Methyl 4H—1, 2, 4 Tria Zonole

The title compound (40 mg) was obtained in the same manner as in Example 92, using the compound (50 mg) obtained in Example 236, 2 chloroacetyl chloride (120 μ1) and morpholine (0.26 ml).

[0357] (Example 243)

3— [2 Ethoxy mono 4— (2 Hydroxyacetyl) aminophenol] — 5— [N— (4 hydride Roxyphenyl) —N-methylamino] —4-methyl-4H-1,2,2,4 triazole Examples using the compound obtained in Example 236 (150 mg) and 2-acetoxyacetyl chloride (0.14 ml) In the same manner as in 17, the title compound (0.17 g) was obtained.

(Example 244)

3— [2Ethoxy 4- (2hydroxyethyl) aminophenol] — 5— [N— (4 Hydroxyphenol) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

The title compound (l 1 mg) was obtained in the same manner as in Example 11 using the compound (50 mg) obtained in Example 243.

[0358] (Example 245)

3— [2 Ethoxy— 4— (2-Oxoxazolidin— 3—yl) phenol] — 5— [N— (

4-hydroxyphenol) 1 N-methylamino] — 4-methyl 4H—1, 2, 4 triazole

The title compound (56 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 236 and 2 guchiuchiyl formic acid (46 μ1).

(Example 246)

3— [2 Ethoxy mono 4— (3-Methoxyureido) phenol] — 5— [N— (4 Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The compound (50 mg) obtained in Example 236 was dissolved in N, N dimethylacetamide (1. Oml), pyridine (301) was added, and then the black formic acid phenol ( 41 ju l) was added and stirred at room temperature for 1 hour. To the reaction solution, O-methylhydroxyammonium chloride (54 mg) and triethylamine (0.14 ml) were added and heated at 50 ° C. for 3 hours. 1N Aqueous sodium hydroxide solution (0.2 ml) was added at room temperature, and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was charged with methylene chloride and the resulting solid was collected by filtration to give the title compound (30 mg).

[0359] (Example 247)

3— [2 Ethoxy mono 4— (3 Hydroxyureido) phenol] — 5— [N— (4 Hydroxyphenol) —N—Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole The title compound (47 mg) was prepared in the same manner as in Example 246, using the compound (50 mg) obtained in Example 236, chloroformate phenol (41 μ 1), and hydroxymum chloride (45 mg). Obtained.

(Example 248)

3— (4 Aminosulfo-Lumino-2-Ethoxyphenol) 5 [N— (4-Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (17 mg) was obtained in the same manner as in Example 103, using the compound (50 mg) obtained in Example 236, chlorosulfol isocyanate (42 μ 1) and t-butanol (31 1).

[0360] (Example 249)

3— [4 (Dimethylamino) sulfo-Luamino 2-Ethoxyphenol] 5— [N— (4-Hydroxyphenol) —N-Methylamino] — 4-Methyl-4H-1,2,4 Triazole In Example 236 To the obtained compound (50 mg) were added pyridine (1. Oml) and dimethylaminosulfamoyl chloride (0.16 ml), and the mixture was stirred at 50 degrees for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by preparative thin layer chromatography (developing solvent; methanol: methylene chloride = 1: 9) to obtain the title compound (10 mg).

(Example 250)

3— (4—Amino-2 black mouth phenol) 5— [N— (4-hydroxyphenol-NO) N-methylamino] — 4-methyl 4H— 1, 2, 4 卜 riazole

Using the compound (6. Og) obtained in Example 221, the title compound (3.9 g) was obtained in the same manner as in Example 22.

[0361] (Example 251)

3— [2 Black 4 (Dimethylamino) phenol] — 5— [N— (4 Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (36 mg) was obtained in the same manner as in Example 5 using the compound (50 mg) obtained in Example 250.

(Example 252)

3— (4-acetinoleamino 1 2 kurofu-nore) 5— [N— (4-hydroxyphenol-nore)- N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

To the compound (50 mg) obtained in Example 250, methylene chloride (1.OmL) was added. Pyridine (24 μ 1) and acetyl chloride (22 μ 1) were added and stirred at room temperature for 2 hours. Methanol (1. Oml) and 3N sodium hydroxide aqueous solution (0.20 ml) were stirred at room temperature for 1 hour. Hydrochloric acid was added to adjust the pH to 7, and the mixture was extracted with methylene chloride. The residue was purified by thin layer chromatography (developing solvent; methanol: methylene chloride = 1: 14). Ether was added to the obtained residue, and the obtained solid was collected by filtration to give the title compound (15 mg). Using the compound obtained in Example 250 and the corresponding acid chloride, Example 252 was obtained. The following compounds were synthesized in the same manner as above.

[0362] (Example 253)

3— [2 Black 4— (Ethoxycarboamino) phenol] — 5— [N— (4 Hydroxyphenol) — N-Methylamino] — 4—Methyl 4H— 1, 2, 4 Triazole

Using the compound obtained in Example 250 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 254)

3— (2 Black 4-Methanesulfo-Luaminophenol) 5— [N— (4-Hydroxyphenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

(Example 255)

3— (4 Benzenesulfo-Luamino-2-chlorophage) 5— [N— (4-Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

[0363] (Example 256)

3— [2 Black mouth— 4— (2 Morpholine— 4-ylacetyl) aminophenol] — 5— [N— (4 Hydroxyl) mono-N-methylamino] — 4-methyl 4H—1, 2, 4 Triazo Ichinole

Using the compound (50 mg) obtained in Example 250, 2 chloroacetyl chloride (241) and morpholine (0.13 ml), the title compound (33 mg) was obtained in the same manner as in Example 92. (Example 257)

3— [2 Black Mouth 4 -— (2 Hydroxyacetyl) aminophenol] — 5— [N— (4 Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole The title compound (75 mg) was obtained in the same manner as in Example 17 using the compound (lOOmg) obtained in Example 250 and 2-acetoxyacetyl chloride (72 mg).

[0364] (Example 258)

3— [2 Black 4— (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Hydroxyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

The title compound (18 mg) was obtained in the same manner as in Example 11 using the compound (50 mg) obtained in Example 257.

(Example 259)

3— [2 Black mouth 4— (2—Oxoxazolidin 1—Fill)]] — 5— [N— (4 —Hydroxyphenyl) — N—Methylamino] — 4— Methyl-4H-1, 2, 4 triazole The title compound (27 mg) was prepared in the same manner as in Example 36, using the compound (70 mg) obtained in Example 250 and 2 chloroethyl phthalate (44 μ 1). )was gotten.

The following compounds were synthesized in the same manner as in Example 246 using the compound obtained in Example 250, phenyl chloroformate and the corresponding amine.

[0365] (Example 260)

3— [2 Black Mouth 4— (3-Methoxyureido) phenol] — 5— [N— (4 Hydroxyphenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

(Example 261)

3— [2 Black Mouth 4— (3 Hydroxyureido) phenol] — 5— [N— (4 Hydroxyphenol) — N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

(Example 262)

3— (4 Aminosulfo-Luamino 1-Black Mole) 5— [N— (4-Hydroxyphenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (3. Omg) was obtained in the same manner as in Example 103, using the compound obtained in Example 250 (70 mg), chlorosulfuryl isocyanate (27 μ 1) and t-butanol (31 1). was gotten.

[0366] (Example 263)

3— [2 Black mouth 4-(Dimethylamino) sulfo-Luaminophenol] — 5— [N— (4-Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole Implementation The title compound (12 mg) was obtained in the same manner as in Example 116, using the compound obtained in Example 250 (50 mg) and dimethylaminosulfamoyl chloride (0.16 ml).

The following compounds were synthesized in the same manner as in Example 82 using the compound obtained in Step 3 of Example 83 and the corresponding acid chloride.

(Example 264)

3— [N— (4-Fluoro-3-hydroxyphenyl) N-methylamino] — 4-Methyl-5— [4-Tro-2- (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole (Example 265)

3-(2 Ethoxy 4 -trophenyl) 5— [N— (4 Fluoro 3 hydroxyphenol) N-Methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

[0367] (Example 266)

3— (2 Black mouth 1-trophe-nore) 5— [N— (4 Funoleoro 3 hydroxyphenol) 1 N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The following compounds were synthesized in the same manner as in Step 4 of Example 1, using the compound obtained in Step 3 of Example 83 and the corresponding carboxylic acid.

(Example 267)

3— [N— (4 Fluoro-3 hydroxyphenol) N-Methylamino] — 5— (2-Methoxyphenyl) 4 Methyl 4H— 1, 2,4 Triazole

(Example 268)

3— [N— (4-Fluoro-3-hydroxyphenol) —N-methylamino] — 5 [2— (trifluoromethyl) phenol] 4 Methyl 4H— 1, 2,4 Triazole

(Example 269)

3— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino] — 5— [4-Hydroxy-2-(trifluoromethyl) phenol] — 4-Methyl-4H— 1, 2,4 Triazole [0368] (Example 270)

3— (2 Black and 4-hydroxyphenol) 5— [N— (4 Hydrophenol and 3-hydroxyphenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

(Example 271)

3— [2 (Dimethylamino) phenol] 5— [N— (4 Fluoro-3-hydroxyphenol) — N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

(Example 272)

3— [N— (4-Fluoro-3-hydroxyphenol) N-Methylamino] — 4-Methyl-5- (1 Methyl-1-phenolethyl) —4H— 1,2,4 Triazole

(Example 273)

3— [N— (4 Fluoro 3 hydroxyphenol) —N Methylamino] 5— [1— (4-Hydroxyphenol) 1—Methylethyl] 4 Methyl 4H— 1, 2,4 Triazole (Example 274)

3— (adadamantane 1-yl) 5— [N- (4 fluoro-3-hydroxyphenol) N-methylamino] -4-methyl-4H— 1,2,4 triazole

The title compound (12 mg) was obtained in the same manner as in Example 226, using the compound (200 mg) obtained in Step 3 of Example 83 and adamantane-1-ylcarbonyl chloride (129 mg).

[0369] (Example 275)

3— [4 amino 2 (trifluoromethyl) phenol] 5— [N— (4 fluoro 3 hydroxyphenyl) — N-methylamino] — 4—methyl—4H—1, 2, 4 triazole Examples Using the compound (0.88 g) obtained in 264, the title compound (0.60 g) was obtained in the same manner as in Example 4.

(Example 276)

3— [4 (Dimethylamino) 2 (Trifluoromethyl) phenol] 5— [N— (4 Fluoro 3 Hydroxyphenyl) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Tri Azol

The title compound was obtained in the same manner as in Example 5 using the compound (30 mg) obtained in Example 275. (29 mg) was obtained.

The following compounds were synthesized in the same manner as in Example 252 using the compound obtained in Example 275 and the corresponding acid chloride.

[0370] (Example 277)

3— [4 Acetylamino 1- (Trifluoromethyl) phenol] — 5— [N— (4 Fluoro3-hydroxyphenol) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4-tria Zonole

(Example 278)

3— [4 Ethoxycarbolamino 2 (trifluoromethyl) phenol] 5— [N— (

4 Fluoro-3 hydroxyphenyl) N-methylamino] — 4-methyl 4H— 1, 2, 4-triazole

The following compounds were synthesized in the same manner as in Example ⁸ using the compound obtained in Example 275 and the corresponding acid chloride.

(Example 279)

3— [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] — 5— [4-Methanesulfonylamino-2- (trifluoromethyl) phenol] — 4-Methyl-4H—1, 2, 4-triazole

[0371] (Example 280)

3— [4 Benzenesulfolamino-2 (trifluoromethyl) phenol] 5— [N— (

4 Fluoro-3 hydroxyphenyl) N-methylamino] — 4-methyl 4H— 1, 2, 4-triazole

(Example 281)

3— [4— (2 Dimethylaminoacetyl) amino-2- (trifluoromethyl) phenol] — 5 — [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] —4-methyl-4 H- 1, 2, 4 Triazonole

Using the compound (50 mg) obtained in Example 275, 2 chloroacetyl chloride (21 μ1) and 50% aqueous dimethylamine solution (0.20 ml), the title compound (47 mg) was obtained in the same manner as in Example 92. It was. (Example 282)

3— [N— (4-Fluoro-3-hydroxyphenol) N-Methylamino] — 4-Methyl-5— [4— (2 Morpholine-4-ylacetyl) amino-2- (trifluoromethyl) phenol] — 4H— 1, 2, 4 Triazole

The title compound (30 mg) was obtained in the same manner as in Example 92, using the compound (35 mg) obtained in Example 275, 2 chloroacetyl chloride (18 μ 1) and morpholine (40 1).

(Example 283)

3— [N— (4 Fluoro-3 hydroxyphenyl) N-methylamino] — 5— [4— (2 —hydroxyacetyl) amino-2- (trifluoromethyl) phenol] 4—Methyl 4H-1 , 2, 4 Triazole

The title compound (53 mg) was obtained in the same manner as in Example 17 using the compound (80 mg) obtained in Example 275 and 2-acetoxyacetyl chloride (36 μ1).

[0372] (Example 284)

3— [N— (4 Fluoro-3 hydroxyphenol) N—Methylamino] — 5— [4— (2 —Hydroxyethyl) amino-2- (trifluoromethyl) phenol] 4—Methyl 4H— 1 , 2, 4 Triazole

The title compound (23 mg) was obtained in the same manner as in Example 11 using the compound (30 mg) obtained in Example 283.

(Example 285)

3— [N— (4-Fluoro-3-hydroxyphenol) N-Methylamino] — 4-Methyl-5— [4 (2-oxoxazolidin-3-yl) -2 (trifluoromethyl) [Fuel] -4H- 1, 2, 4 Triazonole

The title compound (18 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 275 and 2 cloguchiethyl acetate (27 1).

Using the compound obtained in Example 275, phenyl chloroformate and the corresponding amine, the following compound was synthesized in the same manner as in Example 246.

[0373] (Example 286) 3— [N— (4-Fluoro-3-hydroxyphenol) N-methylamino] — 5— [4 -— (3-methoxyureido) 2 (trifluoromethyl) phenol] -4-methyl-4H-1 , 2, 4-triazole

(Example 287)

3— [N— (4-Fluoro-3-hydroxyphenyl) N-methylamino] — 5— [4— (3-hydroxyureido)-2- (trifluoromethyl) phenol] 4-methyl 4H— 1, 2, 4-triazole

(Example 288)

3— [4 Aminosulfolamino-2 (trifluoromethyl) phenol] 5— [N— (4 Fluoro-3 hydroxyphenol) 1 N-methylamino] — 4-Methyl 4H-1,2,4-triazole

The title compound (l lmg) was obtained in the same manner as in Example 103, using the compound (35 mg) obtained in Example 275, chlorosulfuryl isocyanate (12 μ 1) and t-butanol (131).

(Example 289)

3— (4 amino 2-ethoxyphenol) 5— [N— (4 fluoro 3 hydroxyphenol) N-methylamino] — 4-methyl 4H— 1, 2, 4 triazole

The title compound (2.6 g) was obtained in the same manner as in Example 4 using the compound (3.2 g) obtained in Example 265.

(Example 290)

3— [4 (Dimethylamino) -2-ethoxyphenyl] 5— [N— (4 Fluoro-3-hydroxyphenyl) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole In Example 289 The title compound (20 mg) was obtained in the same manner as in Example 5 using the obtained compound (50 mg).

The following compounds were synthesized in the same manner as in Example 252 using the compound obtained in Example 289 and the corresponding acid chloride.

(Example 291)

3— (4 Acetylamino 2-Ethoxyphenol) 5— [N— (4 Fluoro 3-hydride Roxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole

[0375] (Example 292)

3— [2-Ethoxy 4- (ethoxycarboamino) phenol] 5— [N— (4 Fluorophthalate 3 Hydroxyphenol) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 -Tria Zonole

Using the compound obtained in Example 289 and the corresponding acid chloride, the following compound was synthesized in the same manner as in Example ⁸ .

(Example 293)

3— [2 Ethoxy 4 (Methanesulfo-Luamino) phenol] 5— [N— (4 Fluoro-3 hydroxyphenol) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazo Inore

(Example 294)

3— (4-Benzenesulfo-Luamino 2 ethoxyphenol) 5— [N— (4-Fluoro-3 hydroxyphenol) 1 N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazo Inore

[0376] (Example 295)

3— [2 Ethoxy— 4— (2 Morpholine — 4-ylacetyl) aminophenol] — 5— [N-(4 Fluoro-3-hydroxyphenol) N-methylamino] — 4-Methyl 4H— 1, 2, 4 Triazole

The title compound (20 mg) was obtained in the same manner as in Example 92, using the compound (50 mg) obtained in Example 289, 2 chloroacetyl chloride (25 μ 1) and morpholine (50 1).

(Example 296)

3— [2 Ethoxy mono 4— (2 Hydroxyacetyl) aminophenol] — 5— [N— (4 fluoro 3-hydroxyphenyl) mono N-methylamino] — 4-methyl 4H—1, 2, 4 Triazole

The title compound (80 mg) was obtained in the same manner as in Example 17 using the compound (100111 ₈ ) obtained in Example 289 and 2-acetoxyacetyl chloride (601). (Example 297)

3— [2 Ethoxy 1- 4— (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Fluoro 3 Hydroxyphenyl) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazole

The title compound (40 mg) was obtained in the same manner as in Example 11 using the compound (57 mg) obtained in Example 296.

[0377] (Example 298)

3— [2 Ethoxy— 4— (2-Oxoxazolidin— 3—yl) phenol] — 5— [N— (

4 Fluoro-3 hydroxyphenyl) N-methylamino] — 4-methyl 4H— 1, 2, 4-triazole

The title compound (39 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 289 and 2 cloethyl octylate (29 μ1).

Using the compound obtained in Example 289, phenyl chloroformate and the corresponding amine, the following compounds were synthesized in the same manner as in Example 246.

(Example 299)

3— [2 Ethoxy 1 4- (3-Methoxyureido) phenol] — 5— [N— (4 Fluoro 3-hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2 , 4 Triazole [0378] (Example 300)

3— [4— (3 Benzyloxyureido) 2 Ethoxyphenyl] — 5— [N— (4 Fluoro 3 Hydroxyphenyl) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Tri Azol

(Example 301)

3— [2 Ethoxy 1- 4— (3 Hydroxyureido) phenol] — 5— [N— (4 Fluoro—3 Hydroxyphenol) 1 N-methylamino] — 4—Methyl 4H—1, 2, 4 Triazo One nore

Using the compound (49 mg) obtained in Example 300, the title compound (35 mg) was obtained in the same manner as in Example 4.

(Example 302) 3— (4 Aminosulfo-Luamino 2-Ethoxyphenol) 5— [N— (4 Fluoro 3 —Hydroxyphenyl) —N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole In Example 289 The title compound (28 mg) was obtained in the same manner as in Example 103, using the obtained compound (50 mg), chlorosulfol isocyanate (48 μ 1) and t-butanol (63 1).

[0379] (Example 303)

3— [4 (Dimethylamino) sulfo-Luamino 2-Ethoxyphenol] 5— [N— (4-Fluoro-3-hydroxyphenol) 1 N-Methylamino] — 4-Methyl 4H—1, 2, 4-triazole

The title compound (15 mg) was obtained in the same manner as in Example 116, using the compound (50 mg) obtained in Example 289 and dimethylaminosulfamoyl chloride (0.15 ml).

(Example 304)

3— (4 amino 2 black mouth phenol) 5— [N— (4 phenolic mouth 3 hydroxyphenol) 1 N-methylamino] — 4—methyl 4H— 1, 2, 4 triazole

Using the compound (2.9 g) obtained in Example 266, the title compound (2.4 g) was obtained in the same manner as in Example 22.

[0380] (Example 305)

3— [2 Black mouth 4 (Dimethylamino) phenol] 5— [N— (4 Fluoro 3 hydroxyphenyl) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole

Using the compound (50 mg) obtained in Example 304, the title compound (29 mg) was obtained in the same manner as in Example 5.

The following compound was synthesized in the same manner as in Example 252 using the compound obtained in Example 304 and the corresponding acid chloride.

(Example 306)

3— (4 acetyleno amino 2 black mouth phenol) 5— [N— (4 funoleo mouth 3 hydroxyl) — N-methylamino] — 4-methyl-4H—1, 2, 4 triazole

(Example 307)

3— [2 Black mouth — 4— (Ethoxycarboamino) phenol] — 5— [N— (4 Fluoro —3 Hydroxyphenol) One N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazo Inore

[0381] (Example 308)

3— (2 Black Mouth 4—Methanesenophoninoreaminophenol-Nole) 5— [N— (4 Funoleoro 3 —Hydroxyphenyl) — N-Methylamino] — 4-Methyl-4H—1, 2, 4 Triazole (Example 309)

3— (4 Benzenesulfo-Luamino-2-chlorophage) 5— [N— (4-Fluoro-3-Hydroxyphenol) 1 N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazole

[0382] (Example 310)

3— [2 Black mouth— 4— (2 Morpholine— 4-ylacetyl) aminophenol] — 5— [N— (4-Fluoro-3-hydroxyphenol) N Methylamino] 4 Methyl 4H— 1, 2, 4 Triazolone

The title compound (49 mg) was obtained in the same manner as in Example 92, using the compound (50 mg) obtained in Example 304, 2 chloroacetyl chloride (25 μ1) and morpholine (0.13 ml).

(Example 311)

3— [2 Black 4-(2 Hydroxyacetyl) aminophenol] — 5— [N— (4 Fluoro 3 Hydroxyphenyl) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazole

The title compound (0.11 lg) was obtained in the same manner as in Example 17, using the compound (0.13 g) obtained in Example 304 and 2-acetoxyacetyl chloride (681).

(Example 312)

3— [2 Black Mouth 4-— (2 Hydroxyethyl) aminophenol] — 5— [N— (4 Fluo Methyl 3-hydroxyphenol) One N-Methylamino] — 4-Methyl 4H—1, 2 , 4-Tria Zonole

The title compound (7 mg) was obtained in the same manner as in Example 11 using the compound (53 mg) obtained in Example 311. [0383] (Example 313)

3— [2 Black mouth 4— (2—Oxoxazolidin 1—Fill)]] — 5— [N— (4 —Fluoro-3 hydroxyphenol) N—Methylamino] — 4 —Methyl 4H— 1, 2, 4-triazole

The title compound (30 mg) was obtained in the same manner as in Example 36, using the compound (50 mg) obtained in Example 304 and 2 chloroethyl phthalate (33 μ1).

The following compound was synthesized in the same manner as in Example 246 using the compound obtained in Example 304, phenyl chloroformate and the corresponding amine.

(Example 314)

3— [2 Black Mouth 4— (3-Methoxyureido) phenol] — 5— [N— (4 Fluoro-3-hydroxyphenol) 1 N-Methylamino] — 4—Methyl 4H—1, 2 , 4 Triazole [0384] (Example 315)

3— [2 Black mouth 4— (3 Hydroxyureido) phenol] 5— [N— (4 Fluoro 3 —hydroxyphenyl) — N-Methylamino] — 4—Methyl—4H—1, 2, 4 Triazole (Example 316)

3— (4 Aminosulfo-Luamino 2-chlorophenyl) 5— [N— (4 Fluoro 3-hydroxyphenol) 1 N-Methylamino] — 4-Methyl 4H—1, 2, 4 Triazole Obtained in Example 304 The title compound (32 mg) was obtained in the same manner as in Example 103, using the obtained compound (50 mg), chlorosulfurol isocyanate (19 μ 1) and t-butanol (21 1).

[0385] (Example 317)

3— [2 Black 4— (Dimethylamino) sulfo-Luaminophenol] — 5— [N— (4 Fluoro 3 Hydroxyphenyl) 1 N-Methylamino] — 4—Methyl 4H—1, 2, 4 Triazole

The title compound (29 mg) was obtained in the same manner as in Example 116, using the compound (lOOmg) obtained in Example 304 and dimethylaminosulfamoyl chloride (0.62 ml). (Example 318)

3— [N— (3-Hydroxy— 4-methylphenol) —N-Methylamino] — 4-Methyl-5 — [4-Tro-2- (trifluoromethyl) phenol] — 4H—1, 2, 4 Triazole Step 1> N, N, monodimethyl mono N— (3 hydroxy mono 4-methylphenol) The title compound (7.4 g) was prepared in the same manner as in Step 1 of Example 1 using thiourea 3-hydroxy-l-methyl 4-methyl N-methylaline (5.5 g) and methyl isothiocyanate (2.9 g). Obtained.

Process 2> N— (3-hydroxy-1,4-methylphenol) N, N ,, S Trimethylisothiourea hydroiodide

The title compound (12 g) was obtained in the same manner as in Step 2 of Example 1 using the compound (7.4 g) obtained in Step 1 and methyl iodide (2.6 ml).

<Step 3> 1-Amino-1,2,3 dimethyl 2- (3 Hydroxy-4-methylphenol) guanidine hydroiodide

The title compound (12 g) was obtained in the same manner as in Step 3 of Example 1 using the compound (12 g) obtained in Step 2 and hydrazine monohydrate (1.7 ml).

Step 4> 3— [N— (3-hydroxy-1-methylphenol) N-methylamino] —4—methyl-5— [4-tro-2- (trifluoromethyl) phenol] — 4H— 1, 2, 4-Tria Zonole

Using the compound obtained in Step 3 (3.5 g) and 4-tro 2- (trifluoromethyl) benzoic acid (0.82 g) in the same manner as in Step 4 of Example 1, the title compound (1 lg) was obtained.

The following compounds were synthesized in the same manner as in Step 4 of Example 1, using the compound obtained in Step 3 of Example 318 and the corresponding carboxylic acid.

(Example 319)

3— [N— (3 Hydroxy 4-methylphenol) N-Methylamino] — 5— (2-Methoxyphenyl) — 4-Methyl-4H— 1,2,4 Triazole

(Example 320)

3— [N— (3 Hydroxy—4-methylphenol) —N—Methylamino] — 5— [2— (Trifluoromethyl) phenol] 4 Methyl 4H— 1, 2,4 Triazole

(Example 321) 3— [N— (3-Hydroxymono-4-methylphenol) N-Methylamino] — 5— [4-Hydroxy-2 (trifluoromethyl) phenyl] 4 Methyl 4H— 1, 2,4 Triazole (Example 322)

3— (2 Black 4-hydroxyphenol) 5— [N— (3-Hydroxy-4-methyl) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

(Example 323)

3— [2 (Dimethylamino) phenol] 5— [N— (3 Hydroxy-4-methylphenol) —N-methylamino] -4-methyl-4H— 1,2,4 Triazole

(Example 324)

3— [N— (3-Hydroxy—4-methylphenol) —N-methylamino] —4-Methyl-5 mono (1-methyl-1-phenolethyl) 4H— 1,2,4 Triazole

(Example 325)

3— [N— (3 Hydroxy 4-methylphenol) N-Methylamino] — 5— [1— (4-Hydroxyphenol) — 1-Methylethyl] —4—Methyl—4H— 1,2,4 Triazole [0387] (Example 326)

3— (Adamantane 1-yl) 5— [N— (3 Black 4-hydroxyphenol) N- Methylamino] -4-Methyl-4H— 1,2,4 Triazole

The title compound (20 mg) was obtained in the same manner as in Example 226, using the compound (0.20 g) obtained in Step 3 of Example 318 and adamantane 1-ylcarbonyl chloride (0.13 g).

(Example 327)

3— [4-Amino 2- (trifluoromethyl) phenol] — 5— [N— (3-hydroxy-1-methylphenol) — N-methylamino] — 4-methyl-4H—1, 2,4 Triazole The title compound (0.5 lg) was obtained in the same manner as in Example 4 using the compound (0.56 g) obtained in Example 318.

[0388] (Example 328)

3— [4 (Dimethylamino) 2 (Trifluoromethyl) phenol] -4-Methyl-5- [N — (3-Hydroxy-1-4-methylphenol) -N-Methylamino] — 4H—1, 2, 4 Thoria Zonole

The title compound (27 mg) was obtained in the same manner as in Example 5 using the compound (30 mg) obtained in Example 327.

The following compound was synthesized in the same manner as in Example 252 using the compound obtained in Example 327 and the corresponding acid chloride.

(Example 329)

3— [4—Acetylamino 1- (trifluoromethyl) phenol] — 5— [N— (3-hydroxy-4-methylphenol) —N-methylamino] — 4—methyl—4H—1 , 2, 4 Triazo Inore

(Example 330)

3— [4 (Ethoxycarbol) amino-2 (trifluoromethyl) phenol] 5— [N— (3 Hydroxy-4-methylphenol) N-methylamino] — 4-Methyl-4H— 1, 2, 4-triazole

(Example 331)

3— [4 (2-hydroxyacetyl) amino-2 (trifluoromethyl) phenol] 5— [N— (3-hydroxy-4-methylphenol) N-methylamino] — 4-methyl 4H— 1 , 2, 4 Triazole

The title compound (63 mg) was obtained in the same manner as in Example 17 using the compound (lOOmg) obtained in Example 327 and 2-acetoxyacetyl chloride (341).

(Example 332)

3— [4— (2 Dimethylaminoacetyl) amino-2- (trifluoromethyl) phenol] — 5-[N— (3-hydroxy-4-methylmethyl) —N-methylamino] — 4-methyl — 4H-1, 2, 4 Triazole

Using the compound obtained in Example 327 (25 mg), 2 chloroacetyl chloride (9.6 1) and 50% aqueous dimethylamine solution (0.10 ml), the title compound (25 mg) was prepared in the same manner as in Example 92. Obtained.

(Example 333)

3— [4 (2-hydroxyethyl) amino-2 (trifluoromethyl) phenol] 5— [N -(3-Hydroxy— 4-methylphenol) N-Methylamino 4-methyl 4H— 1, 2, 4 Triazol

The title compound (3 mg) was obtained in the same manner as in Example 11 using the compound (30 mg) obtained in Example 331.

[0390] (Example 334)

3— [N— (3-Hydroxy— 4-methylphenol) —N-Methylamino] — 4-Methyl-5

[4 (2-oxoxazolidine 3 yl) -2 (trifluoromethyl) phenol] 4H- 1, 2, 4 卜 riazole

The title compound (26 mg) was obtained in the same manner as in Example 36, using the compound (30 mg) obtained in Example 327 and 2 kuroguchi formate (9.9 ^ 1).

(Example 335)

3— [N— (3-Hydroxymono-4-methylphenol) N-Methylamino] — 5— [4- (3-Methoxyureido) 2 (trifluoromethyl) phenol] -4-Methyl-4H—1, 2, 4 Triazole

The title compound (15 mg) was obtained in the same manner as in Example 246 using the compound (50 mg) obtained in Example 327, phenyl chloroformate (201) and O-methylhydroxyammonium chloride (12 mg). It was.

[0391] (Example 336)

3— [N— (3 Chloro 4-hydroxyphenol) N-Methylamino 5-— (2-Methoxyphenyl) — 4-Methyl-4H— 1,2,4 Triazole

Process 1> N, N, Monodimethyl N— (3-Black, 4-Hydroxyphenol) thiourea

The title compound (l lg) was obtained in the same manner as in Step 1 of Example 1 using 3-chloro 4-hydroxy-1-N-methylaline (9. Og) and methyl isothiocyanate (4.2 g). . <Step 2> Synthesis of N— (3-chloro-4-hydroxyphenol) Ν, Ν S-trimethylisothiourea hydroiodide

The title compound (16 g) was obtained in the same manner as in Step 2 of Example 1 using the compound (10 g) obtained in Step 1 and methyl iodide (3.2 ml). <Step 3> Synthesis of 1-amino-1,2,3 dimethyl 2- (3 black mouth 4 hydroxyphenol) guanidin hydroiodide

The title compound (14g) was obtained in the same manner as in Step 3 of Example 1 using the compound (16g) obtained in Step 2 and hydrazine monohydrate (2.lml).

Process 4> 3— [N— (3—Black 1-hydroxyphenol) N-Methylamino] — 5— (

2 Methoxyphenol) 4 Methyl 4H— 1, 2,4 Triazole

Using the compound (0.20 g) obtained in Step 3 and 2-methoxybenzoic acid (94 mg), the title compound (26 mg) was obtained in the same manner as in Step 4 of Example 1.

The following compounds were synthesized in the same manner as in Step 4 of Example 1, using the compound obtained in Step 3 of Example 336 and the corresponding carboxylic acid.

[0392] (Example 337)

3— [N— (3-Dichloro 4-hydroxyphenol) N-Methylamino] —4-Methyl 5- [2- (trifluoromethyl) phenol] —4H— 1,2,4 Triazole

(Example 338)

3— [N— (3—Black 1-hydroxyphenol) N-Methylamino] — 5— [4-Hydroxyl 2 (trifluoromethyl) phenol]-4 Methyl 4H— 1, 2 , 4 Triazole

[0393] (Example 339)

3- (2 Black and 4-hydroxyphenol) 5— [N— (3 Black and 4-hydroxyphenol) N Methylamino] 4 Methyl 4H— 1, 2,4 Triazole

(Example 340)

3— [N— (3-hydroxyphenol) N-methylamino] — 5— [2— (dimethylamino) phenol] — 4—methyl—4H— 1,2,4 triazole

[0394] (Example 341)

3— [N— (3—Black 1-hydroxyphenol) N-Methylamino] —4-Methyl 5 1 (1-methyl-1 1-phenyl) 1 4H— 1,2,4 Triazole

(Example 342)

3— [N— (3 Hydroxenoyl) N-Methylamino] — 5— [1— (4 Hydroxyphenol) — 1-Methylethyl] —4-Methyl-4H— 1,2,4 Triazole [0395] (Example 343)

3- (adadamantane 1-yl) 5— [N— (3 black mouth 4 hydroxyphenol-N) N-methylamino] -4-methyl-4H— 1,2,4 triazole

Using the compound (0.20 g) obtained in Step 3 of Example 336 and adamantane 1-yl chloride (0.12 g), the title compound (7.3 mg) was obtained in the same manner as in Example 226. .

The structures of the compounds of the present invention obtained in the above examples are shown in Table 3. In addition, Table 4 shows physical property data of the Example compounds and intermediates thereof. In Table 4, “Example No. 1-1” means the compound obtained by “Step 1 of Example 1”. It should be noted that in each example, for example, step 1 and step 2, the product of step 1 is the raw material of step 2 and is not included in the compound of formula (I).

[0396] JEOL JNM—EX270 (manufactured by JEOL Ltd.) or ¾JEOL JNM—LA300 (manufactured by JEOL Ltd.) was used to measure the nuclear magnetic resonance spectrum (NMR), and TMS (tetramethylsilane) was used internally. It was displayed as δ (ppm) as a standard. In the NMR spectrum data, those marked with * are data measured with JEOL JNM—EX270 (manufactured by JEOL Ltd.). None, JEOL JNM—LA300 (manufactured by JEOL Ltd.) It is the data measured by. Liquid chromatography Z mass spectrometry (LCZMS) was measured using a FractionLynx—MS system (Waters), column: SunFire—C18 (4.6 X 50mm; Waters), temperature: room temperature, flow rate: 3.0 mlZ, elution Solvent: (A) 0.05% acetic acid aqueous solution, (B) acetonitrile, those marked with a ^{# in} the data are gradients: 0 minutes 90% AZB → 5 minutes 10% AZB → 7 minutes 10% AZB, none , Gradient: 0 min 90% AZB → 6 min 50% AZB → 9 min 10% AZ B

For physical properties data, mass spectral data was mainly described for the final compound, and some NMR data was omitted due to space limitations. In addition, "1" was attached to the omitted part.

[0397] Table 3

[Table 3] Example 1 Example 2 Example 3

, " Π

. .

Example 4

0

Example 7

. >> d

-. Or

Example 10 Example 11 Example 12

. fi 1 'or Example 15

n Second.

'Or

Example 18

, Ί

Example 19 Example 20 Example 21

^-01 '. ^F

. Or Λ 4]

Example a Example Example

₀ NN OB

Example 25 Example 26 Example

N-N 'N-N

. Or Λ. Λ. ¹

Example 34 Example 35 Example 36

Example ^ Example 41 Example

CI

-N ft

Or Λ ". Or _S A

Five]

Example 43 Example. Λ Λ ¹

Example 46 Example 47 Example 48

Example 58 Example 59 Example 60

6]

Example 70 Example _ρ Example 72 ヽ

Is it? To Example 73

ヽ_N - _N r

¾o or〗

Example 76 Example "Example 78

J-

Example 79 Example 80 Example

Example 82 Example 83 Example M l

F or "."

7]

Table 8]

Example 106 _f Example 107:;

Example 109 Example 110 Example 111

0 ", ^0. ⁰ Example 113 Example 114

"Or ₀ H?

Example 115 Example 116 ^ Example 117

. N-N Q

': H, I: H or JN ^ I \

9]

Example 129 ^ Example 132

. Ά

Example 135

⁰¹ Example 136 Example 137 Example 138 To ⁰ ,

Example 139 Example 140 Example 141

. ⁵ Example 1 «Example 144

'.

ί Fu

Example 1 Example ''

Ten]

Examples Example 149 Example 150

Example 1 Example Example

Example 163 Example 164 Example 165

. ^ ≠ ^ I ¹ Example Example 1 Example

Λ; F. '

Table 11]

Examples Example 185 Examples

¾. '' Example 18

Person

12]

Example 208 Example 209 Example 21D

Table 13]

Example

.

Example Example ^ Example

Table 14]

Examples Examples Examples Examples

t ""

™ A or Λ

Example

Table 15]

Example

C ^{1 1}

Example 256 Example 257 Example 258

Example 263 Example 264

⁰ .

Example 268 Example Example 270

(¾

Fruit

Table 16]

Example

H,. "

Examples Examples Examples Examples

- 〗 , " But .

Example

".

Example

„ ^Η

Examples Examples Examples Examples

. »-N fi. ™ -Ν

, ^ 0,. ^H Example Example Example

d _n ft ^ Λ. ^H Table 17]

Example Example Example

". But: ⁰ ^

Examples Examples Examples Examples

⁰ Λ. "

. Examples Examples Examples Examples

. θ ^N ,: Table 18]

Example 31 9 Example 320 Example 1

Example 334 Example 335 Example In Λ ^Ν '. F Λ. ^H r hi. ¹ ,

[Table 19]

Example 7 Example s Example 9 ¹ - 1 L ^Cl Example 340 Example Example 342

c Example ^ 3

Table 4 [Table 20]

[Table 21] 3 ― 41 4 4.1 # 4 ― 41 5 3.5 # -1 ― 271 3.5 # -2 ― 273 3.2 # -3 ― 362 4.1 # 6 ― 378 4.4 # 7 ― 378 4.5 # 8 ― 41 2 4.6 # 9 ― 41 2 4.6 # 0 ― 332 5.41 ― 360 4.3 # 2 ― 374 5.43 ― 390 4.94 ― 376 5.25 ― 404 6.66 ― 402 5.77 ― 375 4.98 ― 405 5.49 ― 348 3.8 # 0 ― 421 4.4 # 1 ― 422 3.7 # 2 ― 348 3.9 # 3 ― 420 4.5 # 4 ― 421 3.8 # 5 ― 382 4.1 # 6 ― 454 4.5 # 7 ― 455 3.9 # 8 ― 382 4.0 # 9 ― 454 4.4 # 0-455 3.9 # 22]

twenty three]

77 ― 343 5.5

78-1 ― 229 3.4

78-2 ― 243 0.5

78-3 ― 227 0.5

78-4 ― 359 3.3 #

DMSO-: 9.66 (1 H, S), 7.01 (2H, d,

79-1 J = 9Hz), 6.81 (2H, d, J = 9Hz), 6.88-6.69 (1 H, ― ― m), 3.42 (3H, s), 2.80 (3H, d, J = 4Hz)

DMSO-: 9.94 (1 H, S), 9.31 (1 H, S), 7.27

79-2 (2 H, d, J = 8Hz), 6.85 (2H, d, J = 8Hz), 3.48

(3 H, s), 3.07 (3H, s), 2.32 (3H, s)

DMSO—: 7.02 (2H, d J = 9 Hz), 6.79 (2H, d,

79-3 195 0.2 J = 9Hz), 3.1 7 (3H, s), 2.37 (3H, s)

79-4 ― 329 4.4

80 ― 327 3.2

81 ― 331 3.9

82 ― 333 3.3 #

DMSO: 10.1 8 (1 H, s), 7.20 (1 H, d, J = 9,

1 1 Hz), 7.08-6.90 (1 H, m), 6.75 (1 H, dd, J = 3,

83-1 ―-8Hz), 6.65 (1 H, ddd, J = 3, 4, 9 Hz), 3.42 (3H,

s), 2.81 (3H, d J = 4Hz)

DMSO-: 10.45 (1 H, s), 9.40 (1 H, br.s),

7.31 (1 H, dd, J = 9, 1 1 Hz), 7.04 (1 H, dd, J = 3,

83-2

8Hz), 7.00-6.85 (1 H, m), 3.49 (3H, s), 3.10

(3 H, br.s), 2.38 (3H, br.s)

DMSO-: 7.22 (1 H, dd, J = 9, 1 1 Hz), 6.77

83-3 (1 H, dd, J = 3, 8Hz), 6.70-6.60 (1 H, m), 4.37

(1 H, br.s), 3.23 (3H, s), 2.44 (3H, s) ― ―

83-4 ― 347 5.2

84 ― 345 4.0

85 ― 351 3.6 #

86-1 ― 224 3.5

86-2 ― 31 1 4.7

87-1 ― 228 4.0

87-2 ― 31 5 4.5

88 ― 408 3.6 #

89 ― 466 3.8 #

DMSO-: 10.51 (1 H, s), 7.76-7.58 (3H, m),

90 7.23-7.12 (2H, m), 6.91 -6.80 (2H, m), 3.34 444 3.8 # (3 H, s), 3.17 (3H, s), 2.95 (3H, s)

91 ― 506 4.3 #

92 ― 451 2.3 #

93 ― 493 3.0 #

94 ― 507 2.3 #

95-424 3.4 # 24]

96 ― 410 3.5 #

97 ― 436 3.8 #

98 ― 515 4.3 #

99 ― 425 3.3 #

100 ― 479 3.7 #

101 ― 507 3.9 #

102 ― 493 3.4 #

103 ― 445 3.6 #

104 ― 473 4.0 #

105 ― 384 3.4 #

106 ― 420 3.6 #

107 ― 482 4.2 #

108 ― 469 2.8 #

109 ― 400 3.2 #

110 ― 386 3.2 #

111 ― 412 3.7 #

112 ― 491 4.2 #

113 ― 401 3.2 #

114 ― 455 3.4 #

115 ― 421 3.4 #

116 ― 449 3.8 #

117 ― 408 4.1 #

118 ― 378 3.5 #

119 ― 420 3.5 #

120 ― 450 4.1 #

121 ― 456 3.6 #

122 ― 518 4.2 #

123 ― 505 2.9 #

124 ― 436 3.3 #

125 ― 422 3.4 #

[0419] [Table 25]

[0420] [Table 26] 156 ― 426 3.9 #

157 ― 429 3.7 #

158 ― 505 4.4 #

159 ― 415 3.4 #

160 ― 469 3.6 #

161 ― 435 3.6 #

162 ― 463 4.0 #

163 ― 426 4.2 #

164 ― 402 4.1 #

165 ― 396 3.7 #

166 ― 438 3.6 #

167 ― 468 4.2 #

168 ― 474 3.8 #

169 ― 536 4.3 #

170 ― 523 3.0 #

171 ― 454 3.4 #

172 ― 440 3.6 #

173 ― 466 3.8 #

174 ― 469 3.7 #

175 ― 455 3.4 #

176 ― 509 3.7 #

177 ― 475 3.6 #

178 ― 503 4.0 #

179 ― 372 3.3 #

180 ― 414 3.5 #

181 ― 444 4.0 #

182 ― 450 3.6 #

183 ― 512 4.1 #

184 ― 499 2.9 #

185-430 3.3 # 27]

186 ― 416 3.3 #

187 ― 442 3.7 #

188 ― 445 3.5 #

189 ― 431 3.2 #

190 ― 485 3.5 #

191 ― 451 3.4 #

192 ― 479 3.8 #

193 ― 429 4.5 #

194 ― 376 4.0 #

195 ― 436 4.1 #

196 ― 477 3.9 #

197 ― 491 3.7 #

198 ― 547 3.9 #

199 ― 450 3.8 #

200 ― 395 4.9 #

201 ― 409 4.2 #

202 ― 394 3.3 #

203 ― 452 3.6 #

204 ― 438 3.7 #

205 ― 465 2.3 #

206 ― 451 3.2 #

207 ― 464 3.6 #

208 ― 505 3.3 #

209 ― 478 3.3 #

210 ― 519 3.3 #

211 ― 575 3.4 #

212 ― 410 3.2 #

213 ― 424 3.4 #

214 ― 367 3.7 #

215-341 3.4 # [0422] [Table 28]

[0423] [Table 29]

243 ― 398 2.7 #

244 ― 384 2.5 #

245 ― 410 2.9 #

246 ― 413 2.7 #

247 ― 399 2.5 #

DMSO-: 9.80 (1H, s), 9.27 (1H, S), 7.44- 7.08 (2H, m), 7.31 (1H, d J = 8Hz), 6.88 (1H,

248 d 2Hz), 6.82 (1H, dd, J = 2, 8Hz), 6.78-6.68 419 2.7 # (4H, m), 3.98 (2H, q, J = 7Hz), 3.28 (3H, s),

2.83 (3H, s), 1.24 (3H, t J = 7Hz)

249 ― 447 3.0 #

250 ― 330 2.7 #

251 ― 358 3.4 #

252 ― 372 2.8 #

253 ― 402 3.3 #

254 ― 408 2.9 #

255 ― 470 3.5 #

256 ― 457 2.2 #

257 ― 388 2.5 #

258 ― 374 2.7 #

259 ― 400 3.0 #

260 ― 403 2.8 #

261 ― 389 2.5 #

262 ― 409 2.6 #

263 ― 437 3.1 #

264 ― 412 3.8 #

265 ― 388 3.6 #

266 ― 378 3.6 #

267 ― 329 3.2 #

268 ― 367 3.5 #

269 ― 383 3.3 #

270 ― 349 3.1 #

271 ― 342 3.5 #

272 ― 341 3.6 # 30]

273 ― 357 3.0 #

274 ― 357 3.8 #

275 ― 382 3.2 #

276 ― 410 3.9 #

277 ― 424 3.2 #

278 ― 454 3.7 #

279 ― 460 3.3 #

280 ― 522 3.9 #

281 ― 467 1.9 #

282 ― 509 2.9 #

283 ― 440 3.0 #

284 ― 426 3.1 #

285 ― 452 3.4 #

286 ― 455 3.2 #

287 ― 441 2.9 #

288 ― 461 3.1 #

289 ― 358 2.8 #

290 ― 386 3.5 #

291 ― 400 3.0 #

292 ― 430 3.5 #

293 ― 436 3.1 #

294 ― 498 3.7 #

295 ― 485 2.5 #

296 ― 416 2.8 #

297 ― 402 2.8 #

298 ― 428 3.3 #

299 ― 431 3.0 #

300 ― 507 3.7 #

301 ― 417 2.8 #

302 ― 437 3.0 # [0425] [Table 31]

[0426] [Table 32]

330 ― 450 3.9 #

331 ― 436 3.2 #

332 ― 463 2.3 #

333 ― 422 3.3 #

334 ― 448 3.6 #

335 ― 451

DMSO-: 10.41 (1 H, s), 7.28-7.19 (1 H, m),

336-1 7.1 0-6.90 (3H, m), 3.41 (3 H, s), 2.81 (3H, d,

J = 4Hz) ― ―

DMSO-: 10.75 (1 H, s), 9.39 (1 H, br.s),

336-2 7.67-7.52 (1 H, m), 7.36-7.20 (1 H, m), 7.05 ― ― (1 H d, J = 9 Hz), 3.48 (3H, s), 3.10 (3H, br.s ), 2.37 (3H, br.s)

DMSO-: 10.47 (1 H, s), 9.48 (1 H, br.s),

336-3 7.40-7.27 (1 H, m), 7.10-6.89 (2H, m), 4.87

(2 H, br.s), 3.21 (3H, s), 2.30 (3H, s) ― ―

336-4 ― 345 3.3 #

337 ― 383 3.5 #

338 ― 399 3.3 #

339 ― 365 3.1 #

340 ― 358 3.5 #

341 ― 357 3.6 #

342 ― 373 3.0 #

343-373 3.9 # [0427] Further, the compounds shown below are also synthesized in the same manner as in the above Examples. The compounds can be produced by arbitrarily combining the following U1 to U25 and Z1 to Z102 groups, and the combinations shown in Table 5 are particularly preferred. Here, for example, in the following notation:

[0428] [Chemical 93]

U1 represented as 4 represents a fluorophenyl group, and Z1 represented as R represents an adamantyl group. Specifically, Compound NO. 4 represents a compound represented by a combination of Z13 and U1, and NO. 395 represents a compound represented by a combination of Z13 and U2. Each Compound NO corresponds to each Example compound number.

[0429] [Chemical 94]

U24 U25 [0430] [Chemical 95]

R:

Z10 Z11 Z12

[0431] [Chem 96]

H ₃ C_〇 H ₃ C_〇〇 H ₃ C_〇〇

c \-\ ₂ ; ₂ H ₅

-NH, -NH-NH

Z13 Z14 Z15

H ₃ CO ○ H ₃ CO ○ H ₃ CO ○

DCH ₃ KDC ₂ H ₅ NH〇CH ₃ -NH -NH -NH

Z16 Z17 Z18

H3CO 〇 CI. CI. 〇

NH〇C ₂ H ₅ CH-,

-NH -NH, -NH

Z19 Z20 Z21

CI, 〇 CI. 〇 CI, 〇

^ C ₂ H ₅ OCH-, OC ₂ H ₅ -NH H -NH

Z22 Z23 Z24

CI, 〇〇 F ₃ C

NH〇CH ₃ to NH〇C ₂ H,

-NH -NH-NH ₂

Z25 Σ26 Z27

[0432] [Chemical 97]

Z28 Σ29 Z30

F ₃ CF ₃ C q

NC ₂ H ₅ NHOCH.NH C ₂ H,-NH -NH NH c

Z31 Z32 Z33

H ₃ CO H ₅ C ₂ -H ₅ C ₂ -0

-NH, -NH

Z34 Z35 Z36

H5C2O -1 ^ο¾Η5 H ₅ c ₂ -qq H ₅ C ₂ -O

NHOH ^{5 2} NHOCH ₃

Z37 Z38 Z39

H ₅ c _2- , ¾ ° NH ₂ ² — Sa-N (CH ₃ ) ₂

Σ40 Z41 Z42

Z49 Z50 Z51

[Chemical 98]

H ₅ C ₂ -OH ₅ C ₂ -〇, 〇

〇〇

Λ 飞.

ΗΝΌΗ HN-OCH ₃ '' H ₃

Z52 Z53 Z54

Z61 Z62 Z63

CI. CI, 〇 CI.

-NH OH-N ○ Z64 Z65 Z66

[Chemical 99]

[0435] [Chemical 100]

Z100 Z101 Z102

[0436] Table 5

[Table 33] compound

Ul U2 U3 U4 U5 U6 U7 U8 U9 No.

Z 13 4 395 485 575 665 749 833 923 1005

Z 14 6 396 486 576 666 750 834 924 1006

Z 15 344 397 487 577 667 751 835 925 1007

Z 16 345 398 488 578 668 752 836 926 1008

Z 17 12 399 489 579 669 753 837 927 1009

Z 18 15 400 490 580 670 754 838 928 1010

Z 19 346 401 491 581 671 755 839 929 101 1

Z20 30 402 492 582 39 42 840 930 1012

Z21 32 403 493 583 672 756 841 931 1013

Z22 347 404 494 584 673 757 842 932 1014

Z23 348 405 495 585 674 758 843 933 1015

Z24 35 406 496 586 40 43 844 934 1016

Z25 38 407 497 587 41 44 845 935 1017

Z26 349 408 498 588 675 759 846 936 1018

Z27 51 409 499 589 57 60 847 1 18 1019

Z28 88 410 500 590 676 760 848 1 19 1020

Z29 350 41 1 501 591 677 761 849 937 1021

Z30 351 412 502 592 678 762 850 938 1022

Z31 52 413 503 593 58 61 851 120 1023

Z32 53 414 504 594 59 62 852 127 1024

Z33 352 415 505 595 679 763 853 939 1025

Z34 353 416 506 596 680 764 854 940 1026

Z35 22 417 507 597 681 765 855 941 1027

Z36 105 418 508 598 682 766 856 942 1028

Z37 23 419 509 599 683 767 857 943 1029

Z38 113 420 510 600 684 768 858 944 1030

Z39 24 421 511 601 685 769 859 945 1031

Z40 106 422 512 602 686 770 860 946 1032

Z41 115 423 513 603 687 771 861 947 1033

Z42 116 424 514 604 688 772 862 948 1034

Z43 354 425 515 605 689 773 863 949 1035

Z44 355 426 516 606 690 774 864 950 1036

Z45 356 427 517 607 691 775 865 951 1037

Z46 357 428 518 608 692 776 866 952 1038

Z47 358 429 519 609 693 777 867 953 1039

Z48 359 430 520 610 694 778 868 954 1040

Z49 360 431 521 61 1 695 779 869 955 1041

Z50 361 432 522 612 696 780 870 956 1042

Z51 362 433 523 613 697 781 871 957 1043

Z52 363 434 524 614 698 782 872 958 1044

Z53 364 435 525 615 699 783 873 959 1045

Z54 365 436 526 616 700 784 874 960 1046

Z55 366 437 527 617 701 785 875 961 1047

Z56 367 438 528 618 702 786 876 962 1048

Z57 368 439 529 619 703 787 877 963 1049 Table 34]

[ss 挲] [8ε ^ ο]

Tl9lS0 / .00Zdf / X3d ZYZ S68880 / .00Z OAV compound

U10 Ull U12 U13 U14 U15 U16 U17 No.

Z13 1095 1185 1259 1349 1439 1529 1619 16

Z14 1096 1186 1260 1350 1440 1530 1620 1703

Z15 1097 1187 1261 1351 1441 1531 1621 1704

Z16 1098 1188 1262 1352 1442 1532 1622 1705

Z17 1099 1189 1263 1353 1443 1533 1623 1706

Z18 1100 1190 1264 1354 1444 1534 1624 20

Z19 1101 1191 1265 1355 1445 1535 1625 1707

Z20 1102 1192 1266 1356 1446 1536 48 1708

Z21 1103 1193 1267 1357 1447 1537 1626 1709

Z22 1104 1194 1268 1358 1448 1538 1627 1710

Z23 1105 1195 1269 1359 1449 1539 1628 1711

Z24 1106 1196 1270 1360 1450 1540 49 1712

Z25 1107 1197 1271 1361 1451 1541 50 1713

Z26 1108 1198 1272 1362 1452 1542 1629 1714

121 1109 165 1273 1363 1453 1543 63 134

Z28 1110 166 1274 1364 1454 1544 1630 135

Z29 1111 1199 1275 1365 1455 1545 1631 1715

Z30 1112 1200 1276 1366 1456 1546 1632 1716

Z31 1113 167 1277 1367 1457 1547 64 136

Z32 1114 174 1278 1368 1458 1548 65 143

Z33 1115 1201 1279 1369 1459 1549 1633 1717

Z34 1116 1202 1280 1370 1460 1550 1634 1718

Z35 1117 179 1281 1371 1461 1551 1635 148

Z36 1118 180 1282 1372 1462 1552 1636 149

Z37 1119 181 1283 1373 1463 1553 1637 150

Z38 1120 189 1284 1374 1464 1554 1638 159

Z39 1121 188 1285 1375 1465 1555 1639 157

Z 0 1122 182 1286 1376 1466 1556 1640 151

Z41 1123 191 1287 1377 1467 1557 1641 161

Z 2 1124 192 1288 1378 1468 1558 1642 162

Z 3 1125 1203 1289 1379 1469 1559 1643 1719

Z 4 1126 1204 1290 1380 1470 1560 1644 1720

Z 5 1127 1205 1291 1381 1471 1561 1645 1721

Z 6 1128 1206 1292 1382 1472 1562 1646 1722

Z 7 1129 1207 1293 1383 1473 1563 1647 1723

Z 8 1130 1208 1294 1384 1474 1564 1648 1724

Z 9 1131 1209 1295 1385 1475 1565 1649 1725

Z50 1132 1210 1296 1386 1476 1566 1650 1726

Z51 1133 1211 1297 1387 1477 1567 1651 1727

Z52 1134 1212 1298 1388 1478 1568 1652 1728

Z53 1135 1213 1299 1389 1479 1569 1653 1729

Z54 1136 1214 1300 1390 1480 1570 1654 1730

Z55 1137 1215 1301 1391 1481 1571 1655 1731

Z56 1138 1216 1302 1392 1482 1572 1656 1732

Z57 1139 1217 1303 1393 1483 1573 1657 1733 Table 36]

Tl9lSO / .OOZdf / X3d S68880 / .00Z OAV compound

U18 U19 U20 U21 U22 U23 U24 U25 No.

Z l 226 1849 1951 274 2124 343 326 2424

Z2 1775 1850 1952 2053 2125 2226 2327 2425

Z3 1776 1851 1953 2054 2126 2227 2328 2426

Z4 1777 1852 1954 2055 2127 2228 2329 2427

Z5 1778 1853 1955 2056 2128 2229 2330 2428

Z6 1779 1854 1956 2057 2129 2230 2331 2429

Z7 1780 1855 1957 2058 2130 2231 2332 2430

Z8 1781 1856 1958 2059 2131 2232 2333 2431

Z9 1782 1857 1959 2060 2132 2233 2334 2432

Z 10 1783 1858 1960 2061 2133 2234 2335 2433

Z l l 1784 1859 1961 2062 2134 2235 2336 2434

Z 12 1785 1860 1962 2063 2135 2236 2337 2435

Z 13 1786 1861 1963 2064 2136 2237 2338 2436

Z 14 1787 1862 1964 2065 2137 2238 2339 2437

Z 15 1788 1863 1965 2066 2138 2239 2340 2438

Z 16 1789 1864 1966 2067 2139 2240 2341 2439

Z 17 1790 1865 1967 2068 2140 2241 2342 2440

Z 18 1791 1866 1968 2069 2141 2242 2343 2441

Z 19 1792 1867 1969 2070 2142 2243 2344 2442

Z20 250 1868 1970 304 2143 2244 2345 2443

Z21 252 1869 1971 306 2144 2245 2346 2444

Z22 1793 1870 1972 2071 2145 2246 2347 2445

Z23 1794 1871 1973 2072 2146 2247 2348 2446

Z24 253 1872 1974 307 2147 2248 2349 2447

Z25 260 1873 1975 314 2148 2249 2350 2448

Z26 1795 1874 1976 2073 2149 2250 2351 2449

Z27 227 1875 1977 275 2150 2251 327 2450

Z28 229 1876 1978 277 2151 2252 329 2451

Z29 1796 1877 1979 2074 2152 2253 2352 2452

Z30 1797 1878 1980 2075 2153 2254 2353 2453

Z31 230 1879 1981 278 2154 2255 330 2454

Z32 235 1880 1982 286 2155 2256 335 2455

Z33 1798 1881 1983 2076 2156 2257 2354 2456

Z34 79 1882 1984 83 2157 2258 2355 2457

Z35 236 1883 1985 289 2158 2259 2356 2458

Z36 238 1884 1986 291 2159 2260 2357 2459

Z37 239 1885 1987 292 2160 2261 2358 2460

Z38 247 1886 1988 301 2161 2262 2359 2461

Z39 246 1887 1989 299 2162 2263 2360 2462

Z 0 240 1888 1990 293 2163 2264 2361 2463 Table 38]

Z ^ Z 9Z Z £ ZZZ Z \ Z zsoz 0961 8Ϊ-8Ϊ Z 1I

VZ9Z ZZ Z ZZZ 1206 6t6T Ϊ0ΪΖ

\ Z Z ZZZ \ z \ z 0S0 Sf6T 9fS \ 00ΪΖ

ZZ £ Z 7 Ζ 0 to f Z in \ s 66Z

\ Z ^ Z Q \ Z Z7 Z ewz Sf Z 9Ϊ6Ϊ s \ 86Z Z £ Z Sl Z \ 7 SllZ mz sm £ m Z6Z

6l Z Ll Z Z Z LUZ f6T zm 96Z

Sl ^ Z 9 \ Z SIZZ 9Π "in \ 36Z

L19Z LIZZ s noz on Ϊ6Ζ

9l £ Z n z LV0Z 91? .Z mi S6Z

\ ZZ 0f6T 8 ^ 81 Z6I f Z \ Z nzz zwz noz L S \ Ϊ6Ζ

?. \ £ Z WfZ \\\ z 9 £ Sl 06Z

7A £ Z \ Z ΫΛΫ, Ζ z \ zz ons 6SZ

\ l ^ Z wzz 60 to 8C0 9C6t s \ 88Z \ £ Z sots mz 01 Z8Z

L Z zz ss 98Z

S £ Z 90fS s zz 6LZ 38Z

LO Z Z LOZZ LSZ noz z dO ^ Z Z 9066 L0 \ Z 6 ^ 81 esz

Z 901 "οε6ϊ ZS ZSI £ Z ZO Z ZZ Z LZSl Ϊ8Ζ

n9lSO / .OOZdf / X3d 91-3 S68880 / .00Z OAV Industrial applicability

The compound of the present invention has an excellent 11-HSD1 inhibitory activity, and is useful as a pharmaceutical agent such as a prophylactic / therapeutic agent for diabetes, obesity, insulin resistance, hypertension, lipid metabolism abnormality and the like.

Claims

Claim Formula (I)

[Chemical 1]

(Where

X is arbitrarily selected from the following substituent group,

The substituent group is

XI) hydroxyl group,

X2) C alkoxy group, C alkyl group, trihalogenomethyl group, and halogen atom,

1-6 1-6

Consists of

n represents an integer of 1 3

R is chosen as Ra), Rb), Rc), Rd) force,

Ra)

[Chemical 2]

And

Y in Ra) is selected from the following substituent group:

1-3 1-3

1-3

, Cyano group, nitro group, C alkylcarbonylamino group, C alkylsulfonyl group,

1-3 1-3

A C alkylthio group, a trifluoromethoxy group, and an aminocarbonyl group,

1-3

z is selected from the following substituent group:

The substituent group is

Z1)

[Chemical 3] o

Or

[Chemical 4]

And

R ¹ is a group selected from the following substituent group,

The substituent group is

Consisting of a hydrogen atom, a C alkyl group, and a full group,

1-3

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ³ is a group selected from the following substituent group,

The substituent group is

Hydrogen atom, C alkoxy C alkyl group, hydroxyl group, C alkoxy group, C alkyl

1-6

1 to 6 1 to 6 kill group, and aminocarbonyl C alkyl group,

1-6

Consists of

The substituent group is

Hydroxyl group, C alkoxy group, C alkyl group, C alkylcarbonyl group, C alkyl

1 to 6 1 to 6 1 to 6 1 to 6 Kill carbonylamino group, including nitrogen atom, N, 0, S force 1 to 2 heteroatoms selected arbitrarily 5 to 7-membered fat An aminocar which may form a cyclic heterohydrocarbon group A bonyl group,

Z2)

[Chemical 5]

R ²

And

R ² is a group selected from the following substituent group,

The substituent group is

A hydrogen atom and a C alkyl group,

1-3

R ⁴ is a group selected from the following substituent group,

The substituent group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~ 6 l ~ t) l ~ o l ~ o

1-6

C alkyl group, hydrogen atom on nitrogen atom is C alkyl group, mono or di

1-6 1-6

Optionally substituted aminocarbonyl C alkyl group, phenyl group, phenyl C

1-6 1-6 alkyl groups, and alicyclic hydrocarbon groups,

May be substituted with 1 or 2 groups arbitrarily selected from

The substituent group is

Oxo group, C alkyl group, C alkyl carbo group, C alkyl carbo group

1 ~!丄 ~ t) 1 ~

The hydrogen atom on the mino group, hydroxyl group, or nitrogen atom is a c alkyl group that is mono- or di-substituted. Optionally substituted amino group, C alkylsulfol group, C alkylsulfuryl group

1-6 1-6

1-6

To form a 5- to 7-membered alicyclic complex hydrocarbon group containing 1 to 2 heteroatoms arbitrarily selected from N, 0, and S! /, An aminocarbonyl group, and a nitrogen atom The upper hydrogen atom is C

1 consisting of a mono- or di-substituted alkyl group, an aminocarbol group,

~ 6

Z4)

[Chemical 6]

0

H

R ⁵ is arbitrarily selected from the following substituent group:

The substituent group is

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, nitrogen

1 ~ 6 l ~ t) l ~ o l ~ o

1-6

1-6 1-6

1 ~! l ~ t) 1 ~ 6

Groups, C alkoxy groups, and C alkoxy carbo C alkyl groups,

1-6 1-6 1-6

The

Z5)

[Chemical 7]

R ° and R ⁷ are each independently selected from the following substituent group, and the substituent group is:

1-6 1-6

V, may! /, Substituted with benzyloxy, C alkoxy or hydroxyl! /, May! / ヽ

1-6

Phenoxy group, C alkyl group, Hydroxy C alkyl group, C Alkoxy C Al Kill group, hydrogen atom on nitrogen atom is mono- or disubstituted with c alkyl group

1-6

Amino C alkyl group, hydrogen atom on nitrogen atom is C alkyl group and mono

1 to 6 1 to 6 mono- or di-substituted! /, May! /, Aminocarbonyl C alkyl group, phenyl group,

1-6

And an alicyclic hydrocarbon group,

1-6

Z6)

[Chemical 8]

R ⁸ and R are hydrogen atoms or C alkyl groups, or the R ° and R ′ are bonded.

1-3

1-3 1-3

Can be replaced

Z7) hydroxyl group,

Z8) C alkoxy group, C alkyl group, trihalogenomethyl group, halogen atom, cyano

1-6 1-6

Group, and nitro group,

A group selected from

However, when Z force 8), at least one of (X) n is XI) hydroxyl group,

Rb)

[Chemical 9]

Or

[Chemical 10]

And

R ^1Q in Rb) is arbitrarily selected from the following substituent group:

R ^1Q is bonded to either the 3rd or 4th position of the adamantyl group,

The substituent group is

Halogen atom, hydroxyl group, C alkyl group, C alkoxy group, C alkyl carbo-l t) l o

Group, C alkoxycarbonyl group, C alkoxy C alkyl group, C alkyl

1 1 6 1 6 1 6 Sulfol group, C alkylsulfur C alkyl group, C alkyl group 1-2

1 1 6 1 6

C alkyl group, hydroxy C alkyl group, C alkoxy C alkyl group, C

1 6 l t) l o l o t) Alkoxy group, hydrogen atom on nitrogen atom is mono- or disubstituted with c alkyl group

1 6

Optionally on amino C alkyl group, hydroxyaminocarbonyl group, on nitrogen atom

1 6

-Group, aminocarbole C alkyl group, hydrogen atom on nitrogen atom is C alkyl

1 6 1 6

1 6

May be substituted with 1 or 2 groups arbitrarily selected from

Provided that when R is Rb), (X) n is at least XI) a hydroxyl group;

Rc)

[Chemical 11]

And

R ¹¹ in Rc) is arbitrarily selected from the following substituent group:

The substituent group is

A hydroxyl group, a C alkoxy group, a halogen atom, and a hydrogen atom,

1 6

m represents an integer of 1 2

Provided that when R is Rc), (X) n or (R ^u ) m is at least a hydroxyl group; Rd)

[Chemical 12]

Y in Rd) is the same as the definition of Y in Ra)

Provided that when R is Rd), at least one of (X) n is XI) a hydroxyl group,

(X) n-substituted phenyl group 4-hydroxyphenol group, 3-hydroxyphenol group

4 methylphenol group, 4-hydroxy 3-methylphenol group,

R is not a 2-methylphenol group, a 2-chlorophenol group, a 2-methoxyphenyl group, or a 1 (4-fluorophenyl) 1 methylethyl group.

However, “→” in the formula represents a bond. )

Or a pharmaceutically acceptable salt, prodrug or solvent thereof.