CN1938287A - Phenoxyacetic acid derivative and medicine containing the same - Google Patents

Abstract

A novel compound having excellent PPARalpha/gamma agonistic activity and having desirable properties required of medicines. It is a peroxisome proliferation-activated receptor alpha/gamma agonist represented by the following general formula (I) (wherein Q represents an optionally substituted benzene ring or pyridine ring; R¹ and R² each represents an optionally substituted, phenyl or 5- or 6-membered aromatic heterocyclic group; X, Y, and Z each independently represents carbon, oxygen, sulfur, or nitrogen; R³ to R⁹ each represents hydrogen, lower alkyl, etc.; and n is an integer of 0 to 3).

Description

Phenoxyacetic acid derivative and the medicine that comprises it

Technical field

The present invention relates to can be effectively as phenoxyacetic acid derivative, its salt and their solvate of the prophylactic agent/curative of diabetes.More specifically, the present invention relates to peroxisome proliferation activated receptor α/gamma agonist (PPAR α/gamma agonist).

Background technology

Diabetes are to cause various acute or the morbidity of chronic complicating diseases such as typical ischemic heart disease and cerebrovascular disorder and the diseases of development, thereby have seriously disturbed daily life.Therefore, be necessary to prevent the morbidity and the development of these complication by early detection and strict controlling blood sugar.

Diabetes are divided into type i diabetes and type ii diabetes, obstacle takes place in the generation and the secretion that are used for the Regular Insulin of glycemic control in type i diabetes, the generation of Regular Insulin and secretion are in normal range in high-level scope in type ii diabetes, but the insulin sensitivity of Target organ and tissue reduces (perhaps, that is to say that insulin resistance increases).

The Regular Insulin target organs mainly is muscle, fatty tissue and liver with organizing; At intramuscular, Regular Insulin promotes glucose uptake and glycogen to synthesize, and in fatty tissue, Regular Insulin promotes glucose uptake and consumption, and in liver, Regular Insulin suppresses gluconeogenesis and promotes glycogen to synthesize.In addition, Regular Insulin is not only controlled glucose metabolism as mentioned above, and participates in the metabolism of fat (promote lipogenesis and suppress steatolysis) in the fatty tissue.

Recently, thiazolidine diketone derivative, as the pioglitazone with following structure have been developed as the medicine (non-patent literature 1) that improves insulin resistance, and be widely used in treatment type ii diabetes patient, particularly relevant type ii diabetes patient with obesity.

Having disclosed these thiazolidine diketone derivatives is agonists (non-patent literature 2) of peroxisome proliferation activated receptor γ (PPAR γ).PPAR γ improves the mechanism of insulin resistance and does not illustrate fully as yet, but a kind of theory thinks that it promotes the program death of loose adipocyte, and loose adipocyte produces and the secretion free fatty acids, and free fatty acids causes insulin resistance; By promoting that Preadipocyte In Vitro is divided into picked-up and the storage that adipocyte promotes free fatty acids.

Pioglitazone, as the PPAR gamma agonist, by clearly to the patient medication relevant with type ii diabetes, realizing high treatment result, and in some patients, observe weight increase or fluid gathers (non-patent literature 3).As indicated above, because diabetes cause morbidity and development such as complication such as ischemic heart disease and cerebrovascular disorders, it is disadvantageous that this weight increase and fluid gather.Recently, be under the active research, in animal model, it is suggested that PPAR α/gamma agonist shows more excellent character as remedy for diabetes than PPAR gamma agonist by the PPAR α/gamma agonist that PPAR γ is increased the acquisition of PPAR alfa agonists effect.For example, in the test of using the db/db mouse, can show that PPAR α/gamma agonist KRP-297 is than the remarkable inhibition weight increase of pioglitazone (non-patent literature 4).In addition, can show that PPAR α/gamma agonist LY465608 dose-dependently increases high-density lipoprotein (HDL) (HDL) and reduces plasma triglyceride, thereby reduce the risk (non-patent literature 5) of ischemic heart disease.

Typical PPAR α/gamma agonist is following compound (non-patent literature 6 and 7, and patent documentation 1 and 2):

Non-patent literature 1:Chem.Pharm.Bull., 39,1440-1445 (1991),

Non-patent literature 2:J.Biol.Chem., 270,12953-12956 (1995),

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

Non-patent literature 4:Am.J.Physiol., 284, E966-E971 (2003),

Non-patent literature 5:Diabetes, 51,1083-1087 (2002),

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

Non-patent literature 7:Chem.Pharm.Bull., 51,138-151 (2003),

Patent documentation 1:WO2001-021602,

Patent documentation 2:WO2004-000785.

Summary of the invention

The technical problem to be solved in the present invention

The purpose of this invention is to provide the compound that has the chemical structure different with above-mentioned known PPAR α/gamma agonist and have excellent PPAR α/gamma agonist effect, this compound has the required favourable character of medicine.

The method of technical solution problem

The inventor carries out various researchs, and has therefore found to have the compound of following general formula (I), and this compound has excellent PPAR α/gamma agonist effect and can be used as the prophylactic agent/curative of diabetes, has therefore finished the present invention.

Especially, the invention provides the compound of general formula (I):

(wherein:

Q represents phenyl ring or pyridine ring, and it can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replacement or unsubstituted low alkyl group, replacement or unsubstituted amino, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, replacement or unsubstituted phenyl and replacement or unsubstituted pyridine base;

R ¹Expression phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base,  di azoly or triazolyl, it can be replaced by one or two identical or different following group that is selected from: halogen atom, low-grade alkenyl, lower alkoxy, phenoxy group, replacement or unsubstituted low alkyl group and replacement or unsubstituted amino;

R ²The expression pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base, the  di azoly, triazolyl, quinolyl, isoquinolyl, quinazolyl, 1, the 2-phthalazinyl, quinoxalinyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, indyl, benzimidazolyl-, indazolyl, benzothiazolyl, the benzoxazol base, the benzisothiazole base, benzisoxa  azoles base or benzotriazole base, it can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replace or unsubstituted low alkyl group, replace or unsubstituted amino, replace or unsubstituted phenyl and replacement or unsubstituted pyridine base, or expression can be by the formamyl of one or two identical or different low alkyl group replacement;

X, Y and Z represent C, O, S or N (condition is that any one is O, S or N at least among X, Y and the Z) independently of one another;

R ³To R ⁶Represent hydrogen atom or low alkyl group independently of one another, or R ³And R ⁴, or R ⁵And R ⁶Can combine with the carbon atom that they are replaced and form 3-to 6-unit saturated rings;

R ⁷, R ⁸And R ⁹Represent hydrogen atom or low alkyl group independently of one another;

N represents 0 to 3 integer),

Its salt, or its solvate.

The present invention also provides compound or its salt or its solvate of general formula (I), and 5 yuan of rings that wherein contain X, Y and Z are  azoles ring, thiazole ring or  diazole ring.

The present invention also provides compound or its salt or its solvate of general formula (I), wherein Q is a phenyl ring, and phenyl ring can be replaced by one or two identical or different following group that is selected from: halogen atom, low-grade alkenyl, lower alkoxy and replacement or unsubstituted low alkyl group.

The present invention also provides compound or its salt or its solvate, the wherein R of general formula (I) ¹Be phenyl, phenyl can be replaced by one or two identical or different following group that is selected from: halogen atom and replacement or unsubstituted low alkyl group.

The present invention also provides compound or its salt or its solvate, the wherein R of general formula (I) ²Be pyridyl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base,  di azoly, benzimidazolyl-, benzothiazolyl or benzoxazol base, they can be replaced by one or two identical or different following group that is selected from: halogen atom, lower alkoxy, replacement or unsubstituted low alkyl group and replacement or unsubstituted phenyl.

The present invention also provides compound or its salt or its solvate, the wherein R of general formula (I) ²Be the formamyl that can be replaced by one or two identical or different low alkyl group.

The present invention also provides its salt of compound of comprising general formula (I) or its solvate medicine as activeconstituents.

The present invention also provides its salt of compound that comprises general formula (I) or the pharmaceutical composition of its solvate and pharmaceutically acceptable carrier.

The present invention also provides its salt of compound or the application of its solvate in pharmacy of general formula (I).

The present invention also provides the method for the disease that treatment causes by insulin resistance, comprises to compound, its salt or its solvate with the general formula (I) of significant quantity.

The invention effect

The compound of general formula of the present invention (I) has excellent PPAR α/r agonist effect, and can act on the prophylactic agent/curative of diabetes.

Implement best mode of the present invention

Substituting group in the general formula (I) is as described below.

Halogen atom is meant fluorine atom, chlorine atom, bromine atoms and iodine atom.

For halogen atom, preferred fluorine atom and chlorine atom.

Unsubstituted low alkyl group is meant straight chain, side chain or the cyclic alkyl that contains 1-6 carbon atom, generally includes, for example, methyl, ethyl, propyl group, butyl, amyl group, hexyl, 1-methylethyl.1,1-dimethyl ethyl, 1-methyl-propyl, 2-methyl-propyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl.Wherein, preferable methyl, ethyl and propyl group.

The low alkyl group that replaces is meant by 1-3 the identical or different low alkyl group that is selected from following group replacement: hydroxyl, halogen atom, amino, alkylamino, dialkyl amido, lower alkoxy, carboxyl, lower alkoxycarbonyl, formamyl, alkyl-carbamoyl, dialkyl amido formyl radical, formamyl amino, alkyl-carbamoyl, dialkyl amido formyl radical, alkyl sulfonyl-amino, elementary alkoxy carbonyl amino and low-grade alkane acidyl amino; For example generally include: trifluoromethyl; hydroxymethyl; the 2-hydroxyethyl; the 3-hydroxypropyl; the 2-fluoro ethyl; the 2-chloroethyl; the 3-fluoropropyl; amino methyl; the 2-amino-ethyl; the 3-aminopropyl; the methylamino methyl; 2-methylamino ethyl; 3-methylamino propyl group; dimethylaminomethyl; the 2-dimethyl aminoethyl; the 3-dimethylaminopropyl; methoxymethyl; the 2-methoxy ethyl; the 3-methoxy-propyl; carboxymethyl; the 2-propyloic; 3-carboxylic propyl group; the methoxycarbonyl methyl; 2-methoxycarbonyl ethyl; 3-methoxycarbonyl propyl group; the carbamyl ylmethyl; 2-formamyl ethyl; 3-formamyl propyl group; methylamino formyl radical methyl; 2-methylamino formyl radical ethyl; 3-methylamino formyl radical propyl group; ethylamino formyl radical methyl; 2-ethylamino formyl radical ethyl; 3-ethylamino formyl radical propyl group; the formyl-dimethylamino methyl; 2-formyl-dimethylamino ethyl; 3-formyl-dimethylamino propyl group; diethylamino formyl radical methyl; 2-diethylamino formyl radical ethyl; 3-diethylamino formyl radical propyl group; the formamyl amino methyl; 2-formamyl amino-ethyl; 3-formamyl aminopropyl; methylamino formyl radical amino methyl; 2-methylamino formyl radical amino-ethyl; 3-methylamino formyl radical aminopropyl; ethylamino formyl radical amino methyl; 2-ethylamino formyl radical amino-ethyl; 3-ethylamino formyl radical aminopropyl; the formyl-dimethylamino amino methyl; 2-formyl-dimethylamino amino-ethyl; 3-formyl-dimethylamino aminopropyl; diethylacbamazine acyl amino methyl; 2-diethylacbamazine acyl amino ethyl; 3-diethylacbamazine acyl amino propyl group; the methyl sulphonyl amino methyl; 2-methyl sulphonyl amino-ethyl; 3-methyl sulphonyl aminopropyl; the methoxycarbonyl amino methyl; 2-methoxycarbonyl amino-ethyl; 3-methoxycarbonyl aminopropyl; the ethoxy carbonyl amino methyl; 2-ethoxy carbonyl amino-ethyl; 3-ethoxy carbonyl aminopropyl; the acetylamino methyl; 2-acetylamino ethyl and 3-acetylamino propyl group.Preferred trifluoromethyl, hydroxymethyl, the 2-hydroxyethyl, the 2-fluoro ethyl, the 2-chloroethyl, amino methyl, the 2-amino-ethyl, the methylamino methyl, 2-methylamino ethyl, dimethylaminomethyl, the 2-dimethyl aminoethyl, methoxymethyl, the 2-methoxy ethyl, carboxymethyl, the 2-propyloic, the methoxycarbonyl methyl, 2-methoxycarbonyl ethyl, the carbamyl ylmethyl, 2-formamyl ethyl, methylamino formyl radical methyl, 2-methylamino formyl radical methyl, ethylamino formyl radical methyl, 2-ethylamino formyl radical ethyl, the formyl-dimethylamino ethyl, 2-formyl-dimethylamino ethyl, diethylamino formyl radical methyl, 2-diethylamino formyl radical ethyl, the formamyl amino methyl, 2-formamyl amino-ethyl, methylamino formyl radical amino methyl, 2-methylamino formyl radical amino-ethyl, ethylamino formyl radical amino methyl, 2-ethylamino formyl radical amino-ethyl, the formyl-dimethylamino amino methyl, 2-formyl-dimethylamino amino-ethyl, diethylacbamazine acyl amino methyl, 2-diethylacbamazine acyl amino ethyl, the methyl sulphonyl amino methyl, 2-methyl sulphonyl amino-ethyl, the methoxycarbonyl amino methyl, 2-methoxycarbonyl amino-ethyl, the ethoxy carbonyl amino methyl, 2-ethoxy carbonyl amino-ethyl, acetylamino methyl and 2-acetylamino ethyl; More preferably trifluoromethyl, hydroxymethyl, the 2-hydroxyethyl, the 2-fluoro ethyl, amino methyl, the 2-amino-ethyl, the methylamino methyl, 2-methylamino ethyl, dimethylaminomethyl, the 2-dimethyl aminoethyl, methoxymethyl, the 2-methoxy ethyl, the carbamyl ylmethyl, 2-formamyl ethyl, methylamino formyl radical methyl, 2-methylamino formyl radical ethyl, the formyl-dimethylamino methyl, 2-formyl-dimethylamino ethyl, diethylamino formyl radical methyl, the formamyl amino methyl, methylamino formyl radical amino methyl, ethylamino formyl radical amino methyl, the formyl-dimethylamino amino methyl, diethylacbamazine acyl amino methyl and methyl sulphonyl amino methyl; Preferred especially trifluoromethyl, hydroxymethyl, 2-hydroxyethyl and 2-fluoro ethyl.

Low-grade alkenyl is meant the straight or branched thiazolinyl that contains 2-6 carbon atom, for example generally includes: vinyl, allyl group and butenyl.

Lower alkoxy is meant straight chain, side chain or the cyclic alkyl oxygen base that contains 1-6 carbon atom, for example generally includes: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, pentyloxy and cyclopentyloxy.Wherein, preferred methoxyl group and oxyethyl group; More preferably methoxyl group.

The amino that replaces is meant alkylamino; dialkyl amido; elementary alkoxy carbonyl amino; formamyl amino; alkyl-carbamoyl amino; dialkyl amido formyl radical amino; alkyl sulfonyl-amino and low-grade alkane acidyl amino; for example generally include: methylamino; ethylamino; propyl group amino; butyl amino; amyl group amino; hexyl amino; 1-methylethyl amino; 1,1-dimethyl ethyl amino; 1-methyl-propyl amino; dimethylamino; diethylamino; dipropyl amino; dibutylamino; diamyl amino; dihexyl amino; two (1-methylethyl) amino; methylethyl amino; methoxycarbonyl amino; ethoxy carbonyl amino; methylamino formyl radical amino; ethylamino formyl radical amino; formyl-dimethylamino amino; the diethylacbamazine acyl amino; methyl sulphonyl amino; ethylsulfonyl amino; acetylamino and propionyl amino.In above-mentioned group, preferable methyl amino, ethylamino, 1-methylethyl amino, dimethylamino, diethylamino, dipropyl amino, methylethyl amino, methoxycarbonyl amino, ethoxy carbonyl amino, methylamino formyl radical amino, ethylamino formyl radical amino, formyl-dimethylamino amino, diethylacbamazine acyl amino, methyl sulphonyl amino, ethylsulfonyl amino, acetylamino.

The phenyl that replaces is meant by one or two identical or different phenyl that is selected from following group replacement: alkyl, hydroxyl, halogen atom, amino, alkylamino, dialkyl amido, lower alkoxy, phenoxy group and replacement or unsubstituted amino.The example of monosubstituted phenyl comprises: aminomethyl phenyl, trifluoromethyl, ethylphenyl, hydroxy phenyl, fluorophenyl, chloro-phenyl-, bromophenyl, aminophenyl, methylamino phenyl, ethylamino phenyl, diethylamino phenyl, p-methoxy-phenyl, Phenoxyphenyl, methoxycarbonyl aminophenyl, formamyl aminophenyl, methylamino formyl radical aminophenyl, formyl-dimethylamino aminophenyl, methyl sulphonyl aminophenyl and acetylamino phenyl; The example of di-substituted-phenyl comprises: the fluoro-2-methyl-phenyl; the chloro-aminomethyl phenyl; the fluoro-hydroxy phenyl; the chloro-hydroxy phenyl; difluorophenyl; dichlorophenyl; the chloro-fluorophenyl; amino fluorophenyl; the amino-chloro-benzene base; the fluoro-2-methyl-aminophenyl; chloro-methylamino phenyl; dimethylamino-fluorophenyl; dimethylamino-chloro-phenyl-; diethylamino-fluorophenyl; chloro-diethylamino phenyl; the fluoro-p-methoxy-phenyl; the chloro-p-methoxy-phenyl; fluoro-methoxycarbonyl aminophenyl; chloro-methoxycarbonyl aminophenyl; formamyl amino-fluorophenyl; formamyl amino-chloro-phenyl-; fluoro-2-methyl-formamyl aminophenyl; chloro-methylamino formyl radical aminophenyl; formyl-dimethylamino amino-fluorophenyl; chloro-formyl-dimethylamino aminophenyl; fluoro-2-methyl-sulfuryl amino phenyl; chloro-methyl sulphonyl aminophenyl; acetylamino-fluorophenyl and acetylamino-chloro-phenyl-.For monosubstituted phenyl, preferable methyl phenyl, trifluoromethyl, p-methoxy-phenyl, Phenoxyphenyl, fluorophenyl, chloro-phenyl-and bromophenyl; More preferably aminomethyl phenyl, trifluoromethyl, p-methoxy-phenyl, Phenoxyphenyl, fluorophenyl and chloro-phenyl-.For di-substituted-phenyl, preferred fluoro-2-methyl-phenyl, chloro-aminomethyl phenyl, difluorophenyl, dichlorophenyl, chloro-fluorophenyl, fluoro-p-methoxy-phenyl and chloro-p-methoxy-phenyl; More preferably difluorophenyl, dichlorophenyl and chloro-fluorophenyl.

Substituted pyridinyl is meant by one or two identical or different pyridyl that is selected from following group replacement: alkyl, hydroxyl, halogen atom, amino, alkylamino, dialkyl amido, lower alkoxy, phenoxy group, replacement or unsubstituted amino.About the example of substituted pyridinyl, the example of single substituted pyridinyl comprises picolyl, the 5-flumethiazine base, ethyl pyridinyl, hydroxy-pyridyl, the fluorine pyridyl, the chloropyridine base, the bromopyridine base, the aminopyridine base, the methylamino pyridyl, the ethylamino pyridyl, the dimethyl aminopyridine base, the diethylamino pyridyl, the methoxypyridine base, the phenoxypyridines base, methoxycarbonyl aminopyridine base, formamyl aminopyridine base, methylamino formyl radical aminopyridine base, formyl-dimethylamino aminopyridine base, methyl sulphonyl aminopyridine base and acetylamino pyridyl; The example of disubstituted pyridines base comprises: the fluoro-2-methyl-pyridyl; the chloro-picolyl; the fluoro-hydroxy-pyridyl; the chloro-hydroxy-pyridyl; the difluoro pyridine base; the dichloropyridine base; chloro-fluorine pyridyl; amino fluorine pyridyl; amino chloropyridine base; fluoro-2-methyl-aminopyridine base; chloro-methylamino pyridyl; dimethylamino-fluorine pyridyl; dimethylamino-chloropyridine base; diethylamino-fluorine pyridyl; chloro-diethylamino pyridyl; fluoro-methoxypyridine base; chloro-methoxypyridine base; fluoro-methoxycarbonyl aminopyridine base; chloro-methoxycarbonyl aminopyridine base; formamyl amino-fluorine pyridyl; formamyl amino-chloropyridine base; fluoro-2-methyl-formamyl aminopyridine base; chloro-methylamino formyl radical aminopyridine base; formyl-dimethylamino amino-fluorine pyridyl; chloro-formyl-dimethylamino aminopyridine base; fluoro-2-methyl-sulfuryl amino pyridyl; chloro-methyl sulphonyl aminopyridine base; acetylamino-fluorine pyridyl and acetylamino-chloropyridine base.For single substituted pyridinyl, preferable methyl pyridyl, 5-flumethiazine base, methoxypyridine base, phenoxypyridines base, fluorine pyridyl, chloropyridine base and bromopyridine base; More preferably picolyl, 5-flumethiazine base, methoxypyridine base, phenoxypyridines base, fluorine pyridyl and chloropyridine base.For the disubstituted pyridines base, preferred fluoro-2-methyl-pyridyl, chloro-picolyl, difluoro pyridine base, dichloropyridine base, chloro-fluorine pyridyl, fluoro-methoxypyridine base and chloro-methoxypyridine base; More preferably difluoro pyridine base, dichloropyridine base and chloro-fluorine pyridyl.

R ¹And R ²As described below.

R ¹Be preferably phenyl, pyridyl or thienyl, they can be replaced by one or two identical or different following group that is selected from: halogen atom, low-grade alkenyl, lower alkoxy, phenoxy group, replacement or unsubstituted low alkyl group and replacement or unsubstituted amino.Particularly, R ¹Preferred example be phenyl, fluorophenyl, chloro-phenyl-, bromophenyl, trifluoromethyl, aminomethyl phenyl, p-methoxy-phenyl, Phenoxyphenyl and fluoro-2-methyl-phenyl and thiotolene base.

R ²Be preferably pyridyl, imidazolyl,  di azoly, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base, benzimidazolyl-, indazolyl, benzothiazolyl, benzoxazol base, benzisothiazole base or benzisoxa  azoles base, they can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replacement or unsubstituted low alkyl group, replacement or unsubstituted amino, replacement or unsubstituted phenyl and replacement or unsubstituted pyridine base; Or formamyl, it is optional by one or two identical or different low alkyl group replacement.Particularly, R ²Preferred example be pyridyl, imidazolyl, methylimidazolyl, pyrazolyl, the methylpyrazole base, thiazolyl, the methylthiazol base,  azoles base, methyl  azoles base, methoxyl group  azoles base, phenyl  azoles base, methyl-phenyl  azoles base, hydroxyl  di azoly, methyl  di azoly, isothiazolyl, the methyl isothiazolyl, the dimethyl isothiazolyl, different  azoles base, the different  azoles of methyl base, the different  azoles of dimethyl base, benzimidazolyl-, the tolimidazole base, indazolyl, the methylindazole base, benzothiazolyl, the benzoxazol base, the benzisothiazole base, benzisoxa  azoles base, formamyl, the methylamino formyl radical, the ethylamino formyl radical, the sec.-propyl formamyl, the butyl formamyl, the cyclopropyl formamyl, cyclopropyl methylamino formyl radical, formyl-dimethylamino, methyl-ethylamino formyl radical and diethylamino formyl radical; R ²Preferred example be pyridyl; imidazolyl; methylimidazolyl; thiazolyl; the methylthiazol base;  azoles base; methyl  azoles base; methoxyl group  azoles base; phenyl  azoles base; methyl-phenyl  azoles base; hydroxyl  di azoly; methyl  di azoly; different  azoles base; the different  azoles of methyl base; the different  azoles of dimethyl base; benzimidazolyl-; the tolimidazole base; formamyl; the methylamino formyl radical; the ethylamino formyl radical; the sec.-propyl formamyl; the butyl formamyl; the cyclopropyl formamyl; cyclopropyl methylamino formyl radical; formyl-dimethylamino; diethylamino formyl radical and methyl-ethylamino formyl radical.

Q is described below.

The example of Q is single-substituted ring, for example phenyl ring, hydroxyl phenyl ring, fluorobenzene ring, chlorobenzene ring, bromobenzene ring, vinyl phenyl ring, allyl group phenyl ring, methoxyl group phenyl ring, oxyethyl group phenyl ring, methyl phenyl ring, ethyl phenyl ring, methoxymethyl phenyl ring, amino phenyl ring, methylamino phenyl ring, dimethylamino phenyl ring, pyrrolidyl phenyl ring, piperidyl phenyl ring, piperazinyl phenyl ring, morpholinyl phenyl ring, phenyl phenyl ring, pyridyl phenyl ring; Dibasic phenyl ring, for example dimethyl phenyl ring, methyl-ethyl phenyl ring, methyl-methoxyl group phenyl ring, methoxyl group-fluorobenzene ring, difluoro phenyl ring, dimethoxy phenyl ring; With pyridine ring, pyridone ring, fluorine pyridine ring, chloropyridine ring, bromopyridine ring, vinyl pyridine ring, allyl pyridine ring, methoxypyridine ring, ethoxy pyridine ring, picoline ring, ethylpyridine ring, methoxymethyl pyridine ring, aminopyridine ring, methylamino pyridine ring, dimethyl aminopyridine ring, pyrrolidyl pyridine ring, piperidyl pyridine ring, piperazinyl pyridine ring, morpholinyl pyridine ring, phenylpyridine ring and pyridyl pyridine ring.Preferred example is phenyl ring, hydroxyl phenyl ring, fluorobenzene ring, chlorobenzene ring, allyl group phenyl ring, methoxyl group phenyl ring, methyl phenyl ring, phenyl phenyl ring, pyridyl phenyl ring, pyridine ring, pyridone ring, fluorine pyridine ring, chloropyridine ring, allyl pyridine ring, methoxypyridine ring and picoline ring.Wherein, preferred example is phenyl ring, fluorobenzene ring, chlorobenzene ring, bromobenzene ring, allyl group phenyl ring, methoxyl group phenyl ring, methyl phenyl ring, difluoro phenyl ring, dimethyl phenyl ring, methyl-ethyl phenyl ring, methyl-methoxyl group phenyl ring, methoxyl group-fluorobenzene ring, dimethoxy phenyl ring and pyridine ring.Wherein, preferred especially phenyl ring, allyl group phenyl ring, methoxyl group phenyl ring, methyl phenyl ring, dimethyl phenyl ring, methyl-ethyl phenyl ring, methyl-methoxyl group phenyl ring and dimethoxy phenyl ring.

R ³To R ⁹Be described below with n.

Preferably, R ³And R ⁴Respectively do for oneself hydrogen atom, methyl or ethyl, more preferably hydrogen atom or methyl, more preferably hydrogen atom.

Preferably, R ⁵And R ⁶Respectively do for oneself hydrogen atom, methyl or ethyl.Also preferably, they and R ⁵And R ⁶The hydrogen atom that is connected forms 3-together to 6-unit saturated rings, more preferably, and R ⁵And R ⁶Respectively do for oneself hydrogen atom or methyl, more preferably methyl.Particularly preferably, R ⁵And R ⁶It all is methyl.

R ⁷Be preferably hydrogen atom, methyl, ethyl or the tertiary butyl.

Preferably, R ⁸And R ⁹Respectively do for oneself hydrogen atom, methyl or ethyl, more preferably hydrogen atom or methyl.

N is 0 to 3 integer, is preferably 0 to 2 integer, more preferably 1 to 2 integer.

The ring that contains X, Y and Z in the general formula (I) is meant 5 yuan of heterocycles, and its example is thiphene ring, furan nucleus, pyrrole ring, imidazole ring, pyrazoles ring, thiazole ring,  azoles ring, isothiazole ring, different  azoles ring,  diazole ring and triazole ring.When 5 yuan of heterocycles were thiazole ring,  azoles ring, isothiazole ring, different  azoles ring or triazole ring, then this heterocycle was not by R ⁹Replace; When heterocycle was  diazole ring, it was not by R ⁸And R ⁹Replace.

By R ⁸And R ⁹The 5-unit heterocyclic preferred example that replaces is thiphene ring, furan nucleus, pyrrole ring, imidazole ring, pyrazoles ring, thiazole ring,  azoles ring, isothiazole ring, different  azoles ring and triazole ring, and they are replaced by a methyl or ethyl; With thiphene ring, furan nucleus, pyrrole ring, imidazole ring and pyrazoles ring, they are by two methyl substituted.Wherein, more preferably thiphene ring, furan nucleus, pyrrole ring, imidazole ring, pyrazoles ring, thiazole ring,  azoles ring, isothiazole ring, different  azoles ring and triazole ring, they are by a methyl substituted; Even more preferably thiazole ring and  azoles ring, they are by a methyl substituted.Preferably not by R ⁹That replace or not by R ⁸And R ⁹The 5-unit heterocycle that replaces is a  diazole ring.

The compound of general formula of the present invention (I) comprises by the optical isomer of steric isomer origin or the optical isomer of unsymmetrical carbon origin, and described steric isomer, optical isomer and composition thereof are all located within the scope of the invention.

The salt of the compound of general formula of the present invention (I) is specifically definition not, as long as they are pharmacologically acceptable salts.Particularly, pharmacologically acceptable salt comprises inorganic acid salt, as hydrogen chlorate, hydrobromate, hydriodate, phosphoric acid salt, nitrate and vitriol; Benzoate; Organic sulfonate is as mesylate, 2-isethionate and tosilate; And organic carboxylate, as acetate, propionic salt, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, oxysuccinic acid and amygdalate.

When the compound of general formula (I) had acidic-group, they can be the form of the salt that forms with alkalimetal ion or alkaline-earth metal ions.Specifically do not define solvate,, and comprise hydrate, ethylate especially as long as they are pharmaceutically useful solvates.

As indicated above, the known detrimental action of PPAR gamma agonist etc. with weight increase.On the other hand, compound of the present invention can prevent that excess weight from increasing.Reason may be because compound of the present invention all has strong agonist effect to PPAR α acceptor and PPAR γ acceptor, therefore improved because the insulin resistance due to the effect of PPAR γ receptor stimulant, and suppressed to increase by the excess weight due to the effect of PPAR α receptor stimulant.For this reason, compound of the present invention has the excellent character as remedy for diabetes.

When the compound oral administration that has low solubility in water is given the time spent, its by GI absorption usually owing to its low solubility and lower.Even compound is higher by GI specific absorption, its absorbability may have individual difference owing to the low solubility of compound in giving the animal and human of compound.About this point, compound of the present invention usually can be highly water-soluble under the neutrallty condition in acidity, so they have the excellent character as medicine.

Compound with fat-solubility may lack metabolic stability usually, may have undesirable influence to liver function.Yet medium fat-soluble because compound of the present invention has, they can have the excellent character as medicine.

The typical production method of The compounds of this invention is described below.

At first describe to produce Ia and Ib type compound (R wherein ²Be optional pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base,  di azoly, triazolyl, quinolyl, isoquinolyl, the quinazolyl, 1 that replaces, 2-phthalazinyl, quinoxalinyl, 2,3-phthalazinyl, naphthyridine base, indyl, benzimidazolyl-, indazolyl, benzothiazolyl, benzoxazol base, benzisothiazole base, benzisoxa  azoles base or benzotriazole base) method.

Production method 1-1

(in following formula, R ¹, R ², R ⁵To R ⁹, Q, X, Y, Z and n have definition same as described above.)

Compound 3 is by compound 1 and aldehyde 2 prepared in reaction in the presence of reductive agent.Exist or do not exist under the condition of acid as acetate, forming Schiff's base (Schiff base), with the reductive agent reaction, obtaining compound 3 then from compound 1 and aldehyde 2.In this case, compound 1 and aldehyde 2 dissolve in the solvent, can react with reductive agent then, need not to confirm the formation of Schiff's base, and obtain compound 3.Usually, use the aldehyde 2 of equimolar amount or molar excess with respect to compound 1.Reductive agent can be a metal hydride complexes, and as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, and it uses with equimolar amount or molar excess with respect to compound 1 usually.Preferably, use 3 moles to 5 moles reductive agent.Reaction solvent comprises: alcohols, as methyl alcohol, ethanol; Ether solvents is as tetrahydrofuran (THF); Halohydrocarbon is as methylene dichloride, chloroform.Temperature of reaction can be-20 ℃ of boiling temperatures to solvent for use, preferred 0 ℃ to 50 ℃; Reaction times can be 15 minutes to 24 hours, preferred 30 minutes to about 10 hours.

3 preparation Compound I a can react acquisition by compound 3 and aldehyde 4 in the presence of reductive agent from compound.Usually, use the aldehyde 4 of equimolar amount or molar excess with respect to compound 3.Reductive agent can be a metal hydride complexes, as sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, and preferred sodium triacetoxy borohydride, and it uses with equimolar amount or molar excess with respect to compound 3 usually.Preferably, use 2 moles to 3 moles reductive agent.Reaction solvent can be halohydrocarbon such as methylene dichloride or chloroform.Temperature of reaction can be 0 ℃ to 40 ℃, preferred 0 ℃ to 30 ℃; Reaction times can be 1 to 48 hour, preferred 1 to about 30 hours.

Although because the difference of ester type, different compounds ibs can according to the described method of document or its similar approach from Compound I a preparation [referring to Protective Groups in OrganicSynthesis), 2nd Ed., written by T.W.Green and P.G.M.Wuts, JohnWiley ﹠amp; Son publishes (1991)].Methods availalbe is to use the method for hydrolysis of acid or alkali, the method for hydrogenation in the presence of catalyzer such as palladium-carbon, or the method for use trifluoroacetic acid.For example, in the method for using basic hydrolysis, the metal hydroxides of equimolar amount or molar excess such as lithium hydroxide or sodium hydroxide, or carbonate such as yellow soda ash or salt of wormwood and Compound I a reaction.Solvent comprises alcohols such as methyl alcohol, ethanol; Ether solvents such as tetrahydrofuran (THF); Water; And mixed solvent.Temperature of reaction can be 0 ℃ to 100 ℃, preferred 0 ℃ to 60 ℃; Reaction times can be according to the difference of ester type and difference, but is generally 1 to 72 hour, preferred 1 to about 24 hours.R in Ia ⁷During for the tertiary butyl, this compound can obtain expecting compound with sour as trifluoroacetic acid or hydrochloric acid reaction.Can use the trifluoroacetic acid or the hydrochloric acid of molar excess.Solvent comprises methylene dichloride and dioxane; Temperature of reaction can be 0 ℃ of boiling temperature to solvent for use, preferred 0 ℃ to 30 ℃; Reaction times can be 1 to 48 hour, preferred 1 to 24 hour.

In production method 1-1, can be according to following production method 1-2 from compound 3 preparation Compound I a, compound 5 and compound 3 reactions in production method 1-2.

Production method 1-2

(in formula, R ¹, R ², R ⁵To R ⁹, Q, X, Y, Z and n have definition same as described above.)

For preparing Compound I a from compound 3, the compound 5 of compound 3 and equimolar amount or molar excess, preferably in the presence of alkali, react, if desired, can use reaction promotor such as tetrabutylammonium iodide or potassiumiodide with the compound 5 of equimolar amount to 2 molar weights.Alkali comprises tertiary amine such as triethylamine, carbonate such as salt of wormwood, cesium carbonate, and the amount of alkali can be equimolar amount or molar excess.Reaction solvent comprises alcohols such as methyl alcohol, ethanol; Ether solvents such as tetrahydrofuran (THF); N, dinethylformamide, acetonitrile.Temperature of reaction can be 20 ℃ of boiling temperatures to solvent for use, is preferably room temperature to 80 ℃; Reaction times can be 1 hour to 7 days, preferred 1 to about 48 hours.

For preparation Compound I a, preferred production process 1-1.

Describe below and produce Ic and Id type compound (R wherein ²Be the optional formamyl that is replaced by one or two low alkyl group) method.

Production method 2

(in following formula, R ¹, R ², R ⁵To R ⁹, X, Y, Z and n have definition same as described above; R ¹⁰And R ¹¹Represent hydrogen atom or low alkyl group separately.)

For preparing compounds 7 from compound 3, metal hydride complexes such as triethoxy sodium borohydride, sodium borohydride or sodium cyanoborohydride, preferred triethoxy sodium borohydride and compound 3 and oxoethanoic acid 6 reactions.Usually, use the oxoethanoic acid of equimolar amount or molar excess with respect to compound 3.Metal hydride complexes is used with equimolar amount or molar excess with respect to compound 3 usually, preferably uses with 2 to 3 moles amount with respect to compound 3.Reaction solvent can be inert solvent such as tetrahydrofuran (THF), methylene dichloride, chloroform; Temperature of reaction can be 0 ℃ to 40 ℃, preferred 0 ℃ to 30 ℃; Reaction times can be 1 to 48 hour, preferred 1 to about 10 hours.

For preparing Compound I c from compound 7, amine 8 reacts in the presence of condensing agent with compound 7.For example, the amine 8 of equimolar amount or molar excess and compound 7 in inert solvent ,-50 ℃ under the boiling temperature of solvent for use, preferably at 0 ℃ under 30 ℃, in the presence of condensing agent, react.Reaction times can be 10 minutes to 48 hours, preferred 30 minutes to 12 about hours.Condensing agent comprises N, N '-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, cyano group di(2-ethylhexyl)phosphate ethyl ester, benzotriazole base oxygen base-three [pyrrolidyl]-phosphorus  hexafluorophosphate, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea a tetrafluoro borate.Use equimolar amounts or molar excess, the condensing agent of preferred 1 to 5 molar weight with respect to compound 7.Inert solvent comprises methylene dichloride, N, dinethylformamide, tetrahydrofuran (THF), ethyl acetate or its mixture.If desired, reaction also can be carried out in the presence of alkali such as triethylamine, diisopropyl ethyl amine, N-methylmorpholine or 4-dimethylaminopyridine.In addition, N-oxy-compound such as I-hydroxybenzotriazole, N-hydroxy-succinamide, N-hydroxyphthalimide, or phenolic compound such as 4-nitrophenols, 2,2, 4-dinitrophenol, 2,4,5-Trichlorophenol, pentachlorophenol can be used as reaction promotor and are added in the reaction system.

Can prepare Compound I d from Compound I c from the described same method of production method 1-1 that Compound I a prepares compounds ib.

The compound 2 that uses in production method 1-1 can be according to 3 preparations of following production method.

Production method 3

(in following formula, R ⁵To R ⁷Has definition same as described above with Q.)

For preparation compound 2, compound 10 reacts in the presence of alkali with compound.Compound 10 and compound 9 react in the presence of the carbonate of molar excess such as cesium carbonate, salt of wormwood or tertiary amine such as triethylamine.Solvent can be inert solvent such as N, dinethylformamide, methylene dichloride.Temperature of reaction can be the boiling temperature of room temperature to solvent for use; Reaction times can be 1 hour to 3 days, preferred 1 hour to about 1 day.

For giving the compound of the present invention that is used as diabetes mellitus prevention medicine/curative, can use various route of administration such as oral administration approach.For oral administration, compound can be free form or its salt form.When preparation contains the pharmaceutical composition of compound of the present invention, select suitable composition forms according to the administering mode of pharmaceutical composition, normally used prepared in various methods during they can be produced according to pharmaceutical preparation.Be used for the situation of pharmaceutical compositions at compound, its salt and the solvate thereof of general formula of the present invention (I), the form of composition can be the per os preparation, comprises for example tablet, pill, powder agent, granule, capsule.Preferred tablet wherein.Solid preparation contains pharmaceutically useful additive and active substance.For example, additive can suitably be selected from: filler, extender, tackiness agent, disintegrating agent, dissolution accelerator, wetting agent and lubricant, they are blended in the pharmaceutical preparation.

Compound is preferably 0.1 milligram to 1500 milligrams/case/sky as the prophylactic agent of diabetes or the dosage of curative, more preferably 1 milligram to 500 milligrams/case/sky.Described dosage can give once a day, also can be divided into 2 or 3 parts and give usefulness respectively in one day.

Embodiment

The present invention describes by following examples.

[reference example 1]

(1) 4-azido methyl-2-(3-bromophenyl)-5-methyl  azoles

2-(3-bromophenyl)-4-chloromethyl-5-aminomethyl phenyl  azoles (5.0g) is dissolved in dimethyl formamide (30ml), at room temperature sodiumazide (1.71g) and potassiumiodide (2.17g) is added to wherein, and the solution that obtains heats and stirred 7 hours at 80 ℃.

After being cooled to 0 ℃, add in the reaction soln water and stirring, filter the solid of collecting precipitation, obtain title compound (5.3g), be light yellow solid.

¹H-NMR(400MHz，CDCl ₃)δ：2.43(3H，s)，4.28(2H，s)，7.32(1H，t，J＝7.8Hz)，7.54-7.58(1H，m)，7.94(1H，dd，J＝7.9Hz，1.3Hz)，8.16(1H，s)。

MS m/z：293(M+H) ⁺。

(2) [2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] carboxylamine tertiary butyl ester

The compound (5.3g) of reference example 1-(1) is dissolved in tetrahydrofuran (THF) (150ml), at 0 ℃ triphenylphosphine (6.0g) and water (1.0ml) is added to wherein, the solution that obtains at room temperature stirred one day.Solvent evaporated under reduced pressure, resistates is dissolved in methylene dichloride (100ml), di-tert-butyl dicarbonic acid ester (8.0ml) and saturated sodium bicarbonate aqueous solution (50ml) are added to wherein, the solution that obtains at room temperature stirs, behind dichloromethane extraction, organic layer washs with saturated brine, then with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, with resistates (6.0g), be colorless solid by silica gel column chromatography purifying (hexane-ethyl acetate).

¹H-NMR(400MHz，CDCl ₃)δ：1.48(9H，s)，2.41(3H，s)，4.19(2H，d，J＝5.4 Hz)，7.31(1H，t，J＝8.0Hz)，7.52-7.56(1H，m)，7.88-7.92(1H，m)，8.13(1H，s)。

MS m/z：369(M+H) ⁺。

(3) C-[2-(3-bromophenyl)-5-methyl  azoles-4-yl] methylamine

The compound (6.0g) of reference example 1-(2) is dissolved in methylene dichloride (100ml), (10ml) adds to wherein with trifluoroacetic acid, the solution that obtains at room temperature stirred one day, solvent evaporated under reduced pressure is added saturated sodium bicarbonate aqueous solution in the resistates to, uses ethyl acetate extraction then, organic layer washs with saturated brine, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, obtain title compound (4.12g) then, be light yellow solid.

MS m/z：296(M+H) ⁺。

[reference example 2]

2-(4-formyl radical phenoxy group)-2 Methylpropionic acid tertiary butyl ester

4-hydroxy benzaldehyde (20g) and 2 bromo 2 methyl propionic acid tertiary butyl ester (40ml) are dissolved in dimethyl formamide (10ml), cesium carbonate (100g) and triethylamine (50ml) are added to wherein, the solution that obtains stirred one day at 80 ℃, reaction soln dilutes with ethyl acetate, water and saturated brine wash in proper order then, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (hexane-ethyl acetate), obtain title compound (15.4g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.41(9H，s)，1.64(6H，s)，6.91(2H，d，J＝8.82 Hz)，7.78(2H，d，J＝8.82Hz)，9.88(1H，s)。

[reference example 3]

2-[4-[[[2-(3-bromophenyl-5-methyl  azoles-4-ylmethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The compound (2.0g) of reference example 1-(3) and the compound (2.4g) of reference example 2 are dissolved in chloroform (30ml), the vlil that obtains 5 hours, solvent evaporated under reduced pressure, resistates is dissolved in methyl alcohol (40ml), at 0 ℃ sodium borohydride (0.85g) is added to wherein then, solution stirring 1 hour, raise the temperature to room temperature, solvent evaporated under reduced pressure, water is added to wherein, the solution ethyl acetate extraction, organic layer washs in proper order with saturated sodium bicarbonate aqueous solution and saturated brine, then with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (chloroform-methanol), obtain title compound (4.21g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.44(9H，s)，1.56(6H，s)，2.32(3H，s)，3.66(2H，s)，3.75(2H，s)，6.82(2H，d，J＝8.55Hz)，7.20(2H，d，J＝8.79Hz)，7.30(1H，t，J＝7.81Hz)，7.52(1H，d，J＝8.06Hz)，7.91(1H，d，J＝7.81Hz)，8.15(1H，s)。

MS m/z：517(M+H) ⁺。

[reference example 4]

2-(4-formyl radical phenoxy group)-2 Methylpropionic acid ethyl ester

The method same with reference example 2 from 4-hydroxy benzaldehyde (10g) and 2 bromo 2 methyl propionic acid ethyl ester (18ml), obtains title compound (8.91g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.21(3H，t，J＝7.1Hz)，1.67(6H，s)，4.23(2H，q，J＝7.1Hz)，6.90(2H，d，J＝8.8Hz)，7.79(2H，d，J＝8.8Hz)，9.88(1H，s)。

[reference example 5]

2-4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The method same with reference example 3 from the compound (1.42g) of reference example 1-(3) and the compound (1.51g) of reference example 4, obtains title compound (3.02g), is yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.25(3H，t，J＝7.1Hz)，1.58(6H，s)，2.31(3H，s)，3.66(2H，s)，3.75(2H，s)，4.24(2H，q，J＝7.2Hz)，4.61(1H，s)，6.81(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.6Hz)，7.30(1H，t，J＝7.8Hz)，7.51-7.55(1H，m)，7.89-7.93(1H，m)，8.15(1H，s)。

MS m/z：489(M+H) ⁺。

[reference example 6]

2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] carboxymethylamino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The compound (3.0g) and the oxoethanoic acid (696mg) of reference example 3 are dissolved in tetrahydrofuran (THF) (30ml), (2.47g) adds to wherein with the triethoxy sodium borohydride, the solution stirring that obtains one day, solvent evaporated under reduced pressure, resistates is diluted with ethyl acetate, water and saturated brine wash in proper order then, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (chloroform-methanol), and from acetone-hexane crystallization, obtain title compound (2.1g), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.43(9H，s)，1.56(6H，s)，2.44(3H，s)，3.59(2H，s)，4.24(2H，s)，4.37(2H，s)，6.89(2H，d，J＝8.6Hz)，7.43(1H，t，J＝8.0Hz)，7.51(2H，d，J＝8.6Hz)，7.65(1H，d，J＝6.8Hz)，7.98(1H，d，J＝7.8Hz)，8.16(1H，s)。

MS m/z：575(M+H) ⁺。

[reference example 7]

2-(2-allyl group-4-formyl radical phenoxy group)-2 Methylpropionic acid tertiary butyl ester

The method same with reference example 2 from 3-allyl group-4-hydroxy benzaldehyde (5.0g) and 2 bromo 2 methyl propionic acid tertiary butyl ester (10ml), obtains title compound (3.6g), is oily matter.

¹H-NMR(400MHz，CDCl ₃)δ：1.39(9H，s)，1.68(6H，s)，3.43(2H，d，J＝6.6Hz)，5.05-5.13(2H，m)，5.93-6.05(1H，m)，6.76(1H，d，J＝8.3Hz)，7.64(1H，dd，J＝2.2，8.3Hz)，7.70(1H，d，J＝2.2Hz)，9.87(1H，s)。

[reference example 8]

2-[2-allyl group-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The method same with reference example 3, compound (304.4mg) and 5-methyl-2-phenyl  azoles-4-ylmethyl amine (188.2mg) from reference example 7 obtain title compound (420.1mg), are oily matter.

¹H-NMR(400MHz，CDCl ₃)δ：1.39(9H，s)，1.56(6H，s)，1.55-1.70(1H，brs)，2.30(3H，s)，3.35(2H，d，J＝6.6Hz)，3.62(2H，s)，3.75(2H，s)，4.97-5.01(2H，m)，5.85-6.00(1H，m)，6.65(1H，d，J＝8.5Hz)，7.02(1H，dd，J＝2.2，8.5Hz)，7.07(1H，d，J＝8.5Hz)，7.40-7.50(3H，m)，7.97-8.03(2H，m)。

[reference example 9]

2-[2-allyl group-4-[[carboxymethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The method same with reference example 6, compound (420.1mg) and oxoethanoic acid (81.0mg) from reference example 8 obtain title compound, and this compound is directly used in following reaction.

[reference example 10]

2-[2-allyl group-4-[[[5-methyl-2-(3-bromophenyl)  azoles-4-ylmethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The method same with reference example 3 from the compound (304.4m) of reference example 7 and the compound (267.1mg) of reference example 1-(3), obtains title compound (212.0mg), is oily matter.

¹H-NMR(400MHz，CDCl ₃)δ：1.39(9H，s)，1.56(6H，s)，1.55-1.70(1H，brs)，2.30(3H，s)，3.35(2H，d，J＝6.6 Hz)，3.62(2H，s)，3.75(2H，s)，4.97-5.01(2H，m)，5.85-6.00(1H，m)，6.65(1H，d，J＝8.5Hz)，7.02(1H，dd，J＝2.2，8.5Hz)，7.07(1H，d，J＝8.5Hz)，7.25-7.30(1H，m)，7.50-7.60(1H，m)，7.90-8.00(1H，m)，8.15-8.17(1H，m)。

[reference example 11]

2-[2-allyl group-4-[[carboxymethyl-[5-methyl-2-(3-bromophenyl)  azoles-4-ylmethyl] amino] methyl] phenoxy group-2 Methylpropionic acid tertiary butyl ester

The method same with reference example 6, compound and oxoethanoic acid (81.0mg) from reference example 10 obtain title compound, and it is directly used in following reaction.

[reference example 12]

2-(4-formyl radical-2,6-dimethyl phenoxy)-2 Methylpropionic acid ethyl ester

With 3,5-dimethyl-4-hydroxy benzaldehyde (5.0g) is dissolved in N, dinethylformamide (20ml), cesium carbonate (10g) and 2 bromo 2 methyl propionic acid ethyl ester (10ml) are added to wherein, the solution that obtains stirred 12 hours at 80 ℃, raise the temperature to room temperature, ethyl acetate (200ml) and water (40ml) are added in the solution.Collect isolating organic layer,, use anhydrous sodium sulfate drying, it is carried out concentrating under reduced pressure, resistates by silica gel column chromatography purifying (ethyl acetate/hexane=1/3), is obtained title compound (6.2g), be light yellow oil with the saturated brine washing.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.50(6H，s)，2.31(6H，s)，4.30(2H，q，J＝7.2Hz)，7.52(2H，s)，9.85(1H，s)。

[reference example 13]

(1)  azoles-2-formaldehyde

 azoles (3.0g) is dissolved in tetrahydrofuran (THF) (120ml), under-78 ℃ of cooling and stirring, will be just-(hexane solution of 1.6M 41ml) is added drop-wise to wherein butyllithium.Reaction soln stirred 10 minutes at-10 ℃, was cooled to-78 ℃ and stirred 6 hours once more.(22ml) is added drop-wise in the reaction soln with the 4-formyl morpholine; solution at room temperature stirred 15 hours; with ice-water cooling, add saturated aqueous ammonium chloride to reaction soln, dilute with ethyl acetate then; saturated sodium tartrate aqueous solutions of potassium is added to wherein; obtain organic layer, organic layer washs with saturated brine, uses anhydrous sodium sulfate drying then; obtain the ethyl acetate solution of title compound, it is directly used in following reaction.

(2) (5-methyl-2-phenyl  azoles-4-ylmethyl)  azoles-2-ylmethyl carboxylamine tertiary butyl ester

C-(5-methyl-2-phenyl  azoles-4-yl) methylamine (2.05g) is dissolved in tetrahydrofuran (THF) (30ml),  azoles-2-formaldehyde (ethyl acetate solution) that reference example 13-(1) is obtained adds to wherein, the vlil that obtains 6 hours, solvent evaporated under reduced pressure, then resistates is dissolved in methyl alcohol, under ice-water cooling, sodium borohydride (1.24g) is added to wherein, at room temperature stirred then 5 hours, add water to reaction soln, it carries out concentrating under reduced pressure, resistates is dissolved in ethyl acetate, wash in proper order with saturated sodium bicarbonate aqueous solution and saturated brine, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, resistates is dissolved in methylene dichloride (50ml), under ice-water cooling, two-tertiary butyl, two carbonic ethers (2.86g) and saturated sodium bicarbonate aqueous solution (50ml) are added to wherein, mixture at room temperature stirred 12 hours, the reaction soln ethyl acetate extraction, water and saturated brine wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates are passed through silica gel column chromatography purifying (hexane/ethyl acetate=1/2), obtain title compound (1.51g), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.56(9H，s)，2.35-2.39(3H，m)，4.45-4.49(2H，m)，4.64-4.73(2H，m)，7.06(1H，s)，7.41-7.44(3H，m)，7.59(1H，s)，7.96-7.98(2H，m)。

MS m/z：370(M+H) ⁺。

(3) (5-methyl-2-phenyl  azoles-4-ylmethyl)  azoles-2-ylmethyl amine

The compound (1.51g) of reference example 13-(2) is dissolved in methylene dichloride (20ml), under ice-water cooling, (10ml) adds to wherein with trifluoroacetic acid, and the solution that obtains at room temperature stirred 12 hours, under ice-water cooling, reaction soln is alkalized by adding 50% sodium hydroxide solution, use ether extraction then, organic layer water and saturated brine wash in proper order, then with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, obtain title compound (0.87g), be light yellow solid.

¹H-NMR(400MHz，CDCl ₃)δ：2.36(3H，s)，3.74(2H，s)，3.97(2H，s)，7.07(1H，s)，7.40-7.45(3H，m)，7.61(1H，d，J＝0.7Hz)，7.98-8.01(2H，m)。

MS m/z：270(M+H) ⁺。

[reference example 14]

(1) methyl 2-[4-[(tert-butoxycarbonyl methylamino)]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (15.8g) of reference example 12 is dissolved in tetrahydrofuran (THF) (300ml), glycine tertiary butyl ester (9ml) and sal epsom (50g) are added to wherein, the vlil that obtains 4 hours, reaction soln returns to room temperature, pass through diatomite filtration, filtrate is carried out concentrating under reduced pressure, resistates is dissolved in methyl alcohol (100ml), under ice-water cooling, (2.3g) adds to wherein with sodium borohydride, and solution at room temperature stirred 4 hours then, water is added in the reaction soln, it carries out concentrating under reduced pressure, and resistates is diluted with ethyl acetate, washs in proper order with saturated sodium bicarbonate aqueous solution and saturated brine then, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates by silica gel column chromatography purifying (chloroform/methanol=19/1), is obtained title compound (21.6g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.46(6H，s)，1.48(9H，s)，2.18(6H，s)，3.30(2H，s)，3.65(2H，s)，4.29(2H，q，J＝7.1Hz)，6.93(2H，s)。

MSm/z：380(M+H) ⁺。

(2) 2-[4-[[tert-butoxycarbonyl methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (3.9g) of 4-chloromethyl-5-methyl-2-phenyl  azoles (1.87g) and reference example 14-(1) is dissolved in acetonitrile (30ml), (2.5g) adds to wherein with salt of wormwood, the vlil that obtains 24 hours, the reaction soln concentrating under reduced pressure, resistates is diluted with ethyl acetate, water and saturated brine wash in proper order then, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (hexane/ethyl acetate=2/1), obtain title compound (4.0g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，1.48(9H，s)，2.17(6H，s)，2.30(3H，s)，3.30(2H，s)，3.71(2H，s)，3.75(2H，s)，4.28(2H，q，J＝7.1 Hz)，6.99(2H，s)，7.38-7.46(3H，m)，8.00-8.02(2H，m)。

MS m/z：551(M+H) ⁺。

(3) 2-[4-[[carboxymethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (4.0g) of reference example 14-(2) is dissolved in methylene dichloride (30ml), under ice-water cooling, 4N hydrochloric acid-dioxane solution (30ml) is added to wherein, the solution that obtains at room temperature stirred 14 hours, the reaction soln concentrating under reduced pressure, resistates from the hexane crystallization, is obtained the hydrochloride (3.17g) of title compound, be light yellow solid.

MS m/z：495(M+H) ⁺。

[reference example 15]

(5-methyl-2-phenyl  azoles-4-ylmethyl) thiazol-2-yl methylamine

C-(5-methyl-2-phenyl  azoles-4-yl) methylamine (5.17g) and thiazole-2-formaldehyde (3.11g) are dissolved in chloroform (50ml), the reaction soln concentrating under reduced pressure, resistates is dissolved in methyl alcohol (100ml), (1.5g) adds to wherein with sodium borohydride, reaction soln at room temperature stirred 10 hours, add ethyl acetate and water, isolate organic layer and use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, resistates is carried out silica gel column chromatography (ethanol/methylene=1/30), obtain title compound (4.8g), be light yellow oil.

[reference example 16]

(1) 2-[4-[[[2-(N '-tert-butoxycarbonyl diazanyl)-2-oxoethyl]-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (1.0g) of reference example 14-(3) is dissolved in N, dinethylformamide (3ml), with hydrazine carboxylic acid's tertiary butyl ester (400mg), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (776mg) and I-hydroxybenzotriazole (622mg) add to wherein, the solution that obtains at room temperature stirs and spends the night, the reaction soln concentrating under reduced pressure, dilute with ethyl acetate, water, 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated brine wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, obtain title compound, be yellow oil, it is directly used in following reaction.

MS m/z：609(M+H) ⁺。

(2) 2-[4-[[diazanyl carbonyl methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound of reference example 16-(1) is dissolved in methylene dichloride (5ml), (5ml) adds to wherein with trifluoroacetic acid, the solution that obtains at room temperature stirred 14 hours, solvent evaporated under reduced pressure, resistates is dissolved in ethyl acetate, washs with saturated brine then with saturated sodium bicarbonate aqueous solution, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, obtain title compound (1.14g), be yellow oil.

MS m/z：509(M+H) ⁺。

[reference example 17]

2-[4-[[[2-(N '-the ethanoyl diazanyl)-the 2-oxoethyl]-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 16-(1), from reference example 14-'s (3) with acethydrazide (77mg), obtain title compound (503mg), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.02(3H，s)，2.18(6H，s)，2.23(3H，s)，3.40(2H，s)，3.60(2H，s)，3.65(2H，s)，4.28(2H，q，J＝7.1Hz)，6.98(2H，s)，7.42-7.45(3H，m)，8.00-8.02(2H，m)。

MS m/z：551(M+H) ⁺。

[reference example 18]

2-(4-formyl radical phenoxy group) ethyl hexanoate

The method same with reference example 12 from 2-hydroxy benzaldehyde (1.22g) and 2-bromocaproic acid ethyl ester (2.23g), obtains title compound (2.24g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：0.93(3H，t，J＝7.2Hz)，1.23(3H，t，J＝7.1Hz)，1.25-1.60(6H，m)，4.24(2H，q，J＝7.1Hz)，4.50-4.42(1H，m)，6.70(2H，d，J＝8.1Hz)，7.65(2H，d，J＝8.1Hz)，9.85(1H，s)。

[reference example 19]

2-[2,6-dimethyl-4-[[2-(5-methyl-2-phenyl  azoles-4-yl) ethylamino] methyl] phenoxy group]-2-methyl-ethyl propionate

The compound (523mg) of 2-(5-methyl-2-phenyl  azoles-4-yl) ethylamine (400mg) and reference example 12 is dissolved in tetrahydrofuran (THF) (10ml), (5g) adds to wherein with sal epsom, the mixture that obtains at room temperature stirred 17 hours, it passes through diatomite filtration, filtrate decompression concentrates, resistates is dissolved in methyl alcohol (10ml), under ice-water cooling, (225mg) adds to wherein with sodium borohydride, and solution at room temperature stirred 3 hours, the reaction soln concentrating under reduced pressure, water is added in the resistates, use ethyl acetate extraction,, use anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution and saturated brine washing, solvent evaporated under reduced pressure, resistates is carried out silica gel column chromatography (methyl alcohol/chloroform=1/9), obtain title compound (1.0g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.17(6H，s)，2.33(3H，s)，2.71(2H，t，J＝6.9Hz)，2.95(2H，t，J＝6.9Hz)，3.70(2H，s)，4.28(2H，q，J＝7.2Hz)，6.91(2H，s)，7.40-7.44(3H，m)，7.96-7.99(2H，m)。

[reference example 20]

2-[2,6-dimethyl-4-[[(5-methyl-2-phenoxy group  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The method same with reference example 19, the compound (2.0g) from C-(5-methyl-2-phenyl  azoles-4-yl) methylamine (1.43g) and reference example 12 obtains title compound (2.9g), is yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.18(6H，s)，2.31(3H，s)，3.67(2H，s)，3.70(2H，s)，4.29(2H，q，J＝7.2Hz)，6.95(2H，s)，7.40-7.45(3H，m)，7.98-8.00(2H，m)。

MS m/z：437(M+H) ⁺。

[reference example 21]

(1) 2-(4-hydroxyl imide ylmethyl-2,6-dimethyl phenoxy)-2 Methylpropionic acid ethyl ester

Compound (3.0g), oxammonium hydrochloride (3.15g) and the N-methylmorpholine (5ml) of reference example 12 are dissolved in methyl alcohol (100ml), (20g) adds to wherein with sal epsom, the mixture heating up that obtains refluxed 5 hours, after the cooling, mixture passes through diatomite filtration, filtrate decompression concentrates, and resistates is dissolved in ethyl acetate, washs with saturated brine then with the 0.5N aqueous hydrochloric acid.

Use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure by silica gel column chromatography purifying (ethyl acetate/hexane=1/1), obtains title compound (2.8g) with resistates, is light yellow oil.

MS m/z：280(M+H) ⁺。

(2) 2-(4-amino methyl-2,6-dimethyl phenoxy)-2 Methylpropionic acid ethyl ester

The compound (2.8g) of reference example 21-(1) is dissolved in the mixture of ethanol (50ml) and tetrahydrofuran (THF) (10ml), palladium-carbon with 10% (2g) adds to wherein, mixture was at room temperature placed 12 hours under about 30 nitrogen atmosphere, remove by filter catalyzer, filtrate joins in the resistates solid collected by filtration with ethyl acetate and hexane then through concentrating under reduced pressure, obtain title compound (1.72g), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.26(3H，t，J＝7.2Hz)，1.38(6H，s)，2.13(6H，s)，3.88(2H，brs)，4.19(2H，q，J＝7.1Hz)，7.15(2H，s)，8.37(2H，brs)。

[reference example 22]

(1) methyl 2-[4-[[[(2-hydroxyl-1-methylethyl formamyl)] (5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (0.200g) and the 2-amino-1-propyl alcohol (0.063ml) that obtain among the reference example 14-(3) are dissolved in methyl alcohol (3ml), with 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine  muriate n-hydrate (0.224g) adds to wherein, the solution that obtains at room temperature stirred 24 hours, once more with 2-amino-1-propyl alcohol (0.063ml) and 4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methylmorpholine  muriate n-hydrate (0.224g) adds to wherein, solution restir 16 hours, reaction soln dilutes with ethyl acetate, with the saturated brine washing, uses anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (0.292g) by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.19(3H，d，J＝6.9Hz)，1.34(3H，t，J＝7.1Hz)，1.43(6H，s)，2.14(6H，s)，2.32(3H，s)，3.02-4.01(9H，m)，4.10(1H，s)，4.27(2H，q，J＝7.2Hz)，4.59(1H，s)，6.85(2H，s)，7.45-7.52(3H，m)，8.00-8.05(3H，m)。

MS m/z：552(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[[(1-methyl-2-oxoethyl formamyl) methyl] (5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

Methyl chloride (10ml) solution of oxalyl chloride (0.45ml) is cooled to-78 ℃ and-78 ℃ of stirrings, dropping contains the methylene dichloride (1ml) of dimethyl sulfoxide (DMSO) (0.52ml), after 10 minutes, the solution of compound (0.292g) in methylene dichloride (5ml) that obtains among the reference example 22-(1) is added to wherein, and stirred 1 hour, (1.7ml) adds to wherein with triethylamine, make the solution that the obtains room temperature of rising again then, and stirred 1 hour, add water to reaction soln, it uses ethyl acetate extraction, wash in proper order with saturated sodium bicarbonate aqueous solution and saturated brine, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/19), obtain title compound (0.247g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.31-1.36(6H，m)，1.44(6H，s)，2.17(6H，s)，2.29(3H，s)，3.29(2H，s)，3.54(1H，d，J＝13.9Hz)，3.59(1H，d，J＝13.9Hz)，3.61(2H，s)，4.27(2H，q，J＝7.1Hz)，4.43(1H，quin，J＝7.3Hz)，6.95(2H，s)，7.42-7.45(3H，m)，7.95-7.97(2H，m)，8.34(1H，d，J＝7.3Hz)，9.51(1H，s)。

MS m/z：550(M+H) ⁺。

[reference example 23]

2-[2,6-dimethyl-4-[[( azoles-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (2.70g) and the N-methylmorpholine (1.7ml) that obtain among the reference example 21-(2) are dissolved in the mixture of methyl alcohol (10ml) and tetrahydrofuran (THF) (20ml), ethyl acetate solution of  azoles-2-formaldehyde (itself and reference example 13-(1) same method from  azoles (1.73g) preparation) and sal epsom (30g) are added to wherein, the mixture heating up that obtains refluxed 14 hours, after the cooling, remove insoluble substance by diatomite filtration, filtrate decompression concentrates, resistates is dissolved in methyl alcohol (30ml), under ice-water cooling, sodium borohydride (2.84g) is added to wherein and at room temperature stirred 2 hours, the reaction soln concentrating under reduced pressure, resistates is dissolved in ethyl acetate, wash with saturated brine then with saturated sodium bicarbonate aqueous solution, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure.The resistates that obtains obtains title compound (2.35g) by silica gel column chromatography purifying (ethyl acetate), is yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.18(6H，s)，3.71(2H，s)，3.93(2H，s)，4.29(2H，q，J＝7.2Hz)，6.93(2H，s)，7.07(1H，s)，7.61(1H，d，J＝1.0Hz)。

MS m/z：347(M+H) ⁺。

[reference example 24]

(1) methyl 2-[4-[(carboxymethyl  azoles-2-ylmethyl amino)]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The method same with reference example 6, the compound (0.5g) and the oxoethanoic acid (0.2g) that obtain from reference example 23, obtain title compound, it is dissolved in a spot of methylene dichloride, excessive 4N hydrochloric acid-dioxane solution is added to wherein, and the solution decompression that obtains concentrates, with the mixed solvent crystallization of resistates from ether/ethyl acetate/hexane, obtain the hydrochloride (0.43g) of title compound, be yellow solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.32(3H，t，J＝7.1Hz)，1.47(6H，s)，2.23(6H，s)，4.27-4.21(4H，m)，4.43(2H，s)，4.60(2H，s)，7.24(2H，s)，7.33(1H，s)，8.07(1H，d，J＝0.7Hz)。

MS m/z：405(M+H) ⁺。

(2) 2-[4-[[[2-(N '-benzoyl diazanyl)-2-oxoethyl]  azoles-2-ylmethyl amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (0.15g) that reference example 24-(1) is obtained, benzoyl hydrazine (0.070g) and I-hydroxybenzotriazole (0.079g) are dissolved in N, dinethylformamide (2ml), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.098g) is added to wherein, the solution that obtains at room temperature stirred 5 hours, the reaction soln concentrating under reduced pressure, resistates is dissolved in ethyl acetate, water then, aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated brine wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound (0.115g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34(3H，t，J＝7.3Hz)，1.45(6H，s)，2.20(6H，s)，3.45(2H，s)，3.71(2H，s)，3.95(2H，s)，4.27(2H，q，J＝7.2Hz)，7.03(2H，s)，7.12(1H，s)，7.47(2H，t，J＝7.7Hz)，7.52-7.58(1H，m)，7.67(1H，s)，7.83(2H，d，J＝7.1Hz)，8.54(1H，br s)，10.00(1H，br s)。

MS m/z：523(M+H) ⁺。

[reference example 25]

2-[2,6-dimethyl-4-[[ azoles-2-ylmethyl-[(2-oxo-2-phenylethyl formamyl) methyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 24-(2), compound (0.15g), 2-aminoacetophenone hydrochloride (0.064g) and N-methylmorpholine (0.083ml) from reference example 24-(1) obtains obtain title compound (0.122g), are light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34(3H，t，J＝7.6Hz)，1.45(6H，s)，2.21(6H，s)，3.35(2H，s)，3.68(2H，s)，3.91(2H，s)，4.28(2H，q，J＝7.1Hz)，4.76(2H，d，J＝4.7Hz)，7.08(2H，s)，7.09(1H，s)，7.51(2H，t，J＝8.0Hz)，7.62(1H，t，J＝6.7Hz)，7.65(1H，s)，7.99(2H，d，J＝8.3Hz)。

MS m/z：522(M+H) ⁺。

[reference example 26]

2-[2,6-dimethyl-4-[[ azoles-2-ylmethyl-[[2-oxo-2-[N '-(thiophene-2-carbonyl) diazanyl] ethyl] amino] methyl] amino] methyl] phenoxy group-2 Methylpropionic acid ethyl ester

With the same method of reference example 24-(2), compound (0.15g) and 2-thiophene carboxylic hydrazides (0.053g) from reference example 24-(1) obtains obtain title compound (0.12g), are yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34(3H，t，J＝7.1Hz)，1.45(6H，s)，2.20(6H，s)，3.43(2H，s)，3.69(2H，s)，3.94(2H，s)，4.28(2H，q，J＝7.1Hz)，6.99(2H，s)，7.12-7.10(2H，m)，7.55(1H，d，J＝4.9Hz)，7.62(1H，d，J＝3.7Hz)，7.66(1H，s)，8.31(1H，s)，9.81(1H，s)。

MS m/z：529(M+H) ⁺。

[reference example 27]

(1) N-hydroxyl thiophene-2-amidine

2-nitrilthiophene (1.0g) is dissolved in ethanol (20ml), azanol with 50% (1.2ml) adds to wherein, the vlil that obtains 18 hours, after the cooling, the reaction soln concentrating under reduced pressure adds ether-hexane in the resistates to then, collects insoluble substance by filtering, obtain title compound (1.1g), be colorless solid.

¹H-NMR(400MHz，CD ₃OD)δ：7.05-7.02(1H，m)，7.37-7.40(2H，m)。

MS m/z：143(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-[2-oxo-2-[(thiophene-2-carboxamide groups imino-(carboximidoyl)) amino oxygen base (aminoxy)] ethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 24-(2), the compound (0.053g) that compound (0.15g) that obtains from reference example 24-(1) and reference example 27-(1) obtain obtains title compound, is brown oil, and it is directly used in following reaction.

MS m/z：529(M+H) ⁺。

[reference example 28]

2-(2-fluoro-4-formyl radical-6-methoxyl group phenoxy group)-2 Methylpropionic acid ethyl ester

The method same with reference example 12 from 3-fluoro-4-hydroxy-5-methyl oxygen benzaldehyde (0.50g) and 2 bromo 2 methyl propionic acid ethyl ester (1.8g), obtains title compound (0.78g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.32(3H，t，J＝7.1Hz)，1.55(6H，s)，3.86(3H，s)，4.26(2H，q，J＝7.1Hz)，7.22-7.26(2H，m)，9.85(1H，d，J＝1.2Hz)。

MS m/z：285(M+H) ⁺。

[reference example 29]

2-(4-formyl radical-2-methoxyl group-6-methylphenoxy)-2 Methylpropionic acid ethyl ester

The method same with reference example 12 from 4-hydroxyl-3-methoxyl group-5-tolyl aldehyde (11.5g) and 2 bromo 2 methyl propionic acid ethyl ester (30ml), obtains title compound (21.5g), is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.32(3H，t，J＝7.3Hz)，1.50(6H，s)，2.30(3H，s)，3.78(3H，s)，4.28(2H，q，J＝7.3Hz)，7.22(1H，s)，7.30(1H，s)，9.78(1H，s)。

MS m/z：281(M+H) ⁺。

[reference example 30]

(1) 2-[4-[[tert-butoxycarbonyl methyl-(9H-fluorenes-9-ylmethoxy carbonyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (3.5g) that reference example 14-(1) is obtained is dissolved in acetonitrile (30ml), under ice-water cooling, N-(9-fluorenyl methoxy ketonic oxygen base) succinimide (3.74g) is added to wherein, the solution that obtains at room temperature stirred 4 hours, the reaction soln concentrating under reduced pressure, then with the resistates ethyl acetate extraction, the organic layer water, saturated sodium bicarbonate aqueous solution, aqueous citric acid solution, saturated brine washs in proper order, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (5.24g) by silica gel column chromatography purifying (ethyl acetate/hexane=1/1), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34-1.38(3H，m)，1.43-1.54(15H，m)，2.17(3H，s)，2.18(3H，s)，3.78(1H，s)，3.84(1H，s)，4.26-4.30(3H，m)，4.44-4.49(4H，m)，6.77(1H，s)，6.85(1H，s)，7.25-7.31(2H，m)，7.41-7.35(2H，m)，7.53(1H，d，J＝7.4Hz)，7.59(1H，d，J＝7.4Hz)，7.73(1H，d，J＝7.6Hz)，7.76(1H，d，J＝7.6Hz)。

MS m/z：624(M+Na) ⁺。

(2) 2-[4-[[carboxymethyl-(9H-fluorenes-9-ylmethoxy carbonyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (5.24g) that reference example 30-(1) is obtained is dissolved in methylene dichloride (60ml), under ice-water cooling, (20ml) adds to wherein with trifluoroacetic acid, the solution that obtains at room temperature stirred 16 hours, the reaction soln concentrating under reduced pressure, with the resistates ethyl acetate extraction, organic layer water and saturated brine wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound (5.70g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.33-1.38(3H，m)，1.45(3H，s)，1.46(3H，s)，2.17(6H，s)，3.77(1H，s)，3.98(1H，s)，4.25-4.32(3H，m)，4.44(2H，s)，4.52-4.55(2H，m)，6.75(1H，s)，6.82(1H，s)，7.23-7.31(2H，m)，7.38(2H，t，J＝7.4Hz)，7.56-7.53(2H，m)，7.74(2H，d，J＝7.3Hz)。

MS m/z：568(M+H) ⁺。

(3) 2-[4-[[[2-(N '-ethanoyl diazanyl)-2-oxoethyl]-(9H-fluorenes-9-ylmethoxy carbonyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The method same with reference example 17, compound (1.5g) and acethydrazide (0.31g) from reference example 30-(2) obtains obtain title compound (1.1g), are colorless solid.

MS m/z：602(M+H) ⁺。

(4) amino 2-[4-[[(9H-fluorenes-9-ylmethoxy carbonyl)-(5-methyl-[1,3,4]  diazole-2-ylmethyl)] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 18-(1), the compound (1.1g) from reference example 30-(3) obtains obtains title compound (1.0g), is colorless solid.

¹H-NMR (400MHz, CDCl ₃) δ: 1.36 (3H, t, J=7.1Hz), 1.46 (6H, s), 2.16 (6H, s), 2.46,2.49 (3H, each is s), 4.26-4.31 (3H, m), 4.39-4.44 (3H, m), 4.55-4.59 (3H, m), 6.73,6.85 (2H, each is s), 7.36-7.40 (2H, m), and 7.46-7.49 (1H, m), 7.53-7.57 (3H, m), 7.65-7.70 (1H, m), 7.75-7.73 (2H, m).

MS m/z：584(M+H) ⁺。

(5) 2-[2,6-dimethyl-4-[[(5-methyl-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group-2 Methylpropionic acid ethyl ester

The compound (1.0g) that reference example 30-(4) is obtained is dissolved in tetrahydrofuran (THF) (50ml), under ice-water cooling, with 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (2% tetrahydrofuran solution, 42.2ml) add to wherein, the solution that obtains at room temperature stirred 2 hours, reaction soln concentrating under reduced pressure then, with the resistates ethyl acetate extraction, wash in proper order with saturated sodium bicarbonate aqueous solution and saturated brine then, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound (0.54g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.46(7H，s)，2.19(6H，s)，2.53(3H，s)，3.73(2H，s)，3.98(2H，s)，4.29(2H，q，J＝7.1Hz)，6.92(2H，s)。

MS m/z：362(M+H) ⁺。

[reference example 31]

2-[2,6-dimethyl-4-[[(thiazol-2-yl methyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

Compound (the hydrochloride that reference example 21-(2) is obtained, 1.0g), 2-thiazole carboxaldehyde (0.46g) and N-methylmorpholine (0.40ml) add tetrahydrofuran (THF) (20ml) to, the vlil that obtains 2 hours, after the cooling, solvent evaporated under reduced pressure, the resistates that obtains is dissolved in methyl alcohol (30ml), (0.38g) adds to wherein with sodium borohydride, solution at room temperature stirred 18 hours, the reaction soln concentrating under reduced pressure, with the resistates ethyl acetate extraction, water and saturated brine wash in proper order, and with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound (1.2g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.46(7H，s)，2.19(7H，s)，3.76(2H，s)，4.14(2H，s)，4.29(2H，q，J＝7.1Hz)，6.95(2H，s)，7.28(1H，d，J＝3.4Hz)，7.73(1H，d，J＝3.2Hz)。

MS m/z：363(M+H) ⁺。

[reference example 32]

4-chloromethyl-5-methyl-2-(5-thiotolene-2-yl)  azoles

With 5-methyl-2 thiophene carboxaldehyde (1.07ml) and 2,3-dimethyl diketone list oxide compound (2.0g) mixes, 4N hydrochloric acid-dioxane solution (10ml) is added to wherein, the solution that obtains at room temperature stirred 14 hours, 4N hydrochloric acid-dioxane solution (10ml) is added to wherein, solution restir 3 days, under ice-water cooling, ether is added to wherein, solid collected by filtration, obtain 4,5-dimethyl-2-(2-thiotolene-5-yl)  azoles 3-oxide hydrochloride (2.3g) is brown solid.It is dissolved in chloroform (30ml), (2ml) adds to wherein with phosphoryl chloride, the vlil that obtains 4 hours after the cooling, is diluted with chloroform, solution with water and saturated brine washing, use anhydrous sodium sulfate drying then, solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (ethyl acetate/hexane=1/4), obtain title compound (1.34g), be light yellow solid.

¹H-NMR(400MHz，CDCl ₃)δ：2.39(3H，s)，2.52(3H，s)，4.51(2H，s)，6.74(1H，d，J＝3.7Hz)，7.42(1H，d，J＝3.7Hz)。

MS m/z：228(M+H) ⁺。

[reference example 33]

(1) amino 2-[4-[[(9H-fluorenes-9-ylmethoxy carbonyl)-[(2-hydroxypropyl formamyl) methyl]] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (1.70g) that reference example 30-(2) is obtained is dissolved in methyl alcohol (30ml), with 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine  muriate n-hydrate (1.29g) and 1-amino-2-propyl alcohol (0.36m) add to wherein, the solution that obtains at room temperature stirred 20 hours, the reaction soln concentrating under reduced pressure, resistates is dissolved in ethyl acetate, solution with water, 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated brine wash in proper order, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (1.89g) by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), is light yellow oil.

MS m/z：603(M+H) ⁺。

(2) amino 2-[4-[[(9H-fluorenes-9-ylmethoxy carbonyl)-[(2-oxopropyl formamyl) methyl]] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 22-(2), the compound (1.89g) that obtains from reference example 33-(1) obtains title compound (1.1g), is light yellow solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.16-2.18(9H，m)，3.69-4.13(4H，m)，4.26-4.31(3H，m)，4.42(2H，s)，4.56(2H，d，J＝6.6Hz)，6.73(1H，s)，6.83(1H，s)，7.23-7.29(9H，m)，7.38(2H，t，J＝7.5Hz)，7.56-7.54(2H，m)，7.74(2H，d，J＝7.6Hz)。

MS m/z：601(M+H) ⁺。

(3) amino 2-[4-[[(9H-fluorenes-9-ylmethoxy carbonyl)-(5-methyl  azoles-2-ylmethyl)] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

Triphenylphosphine (1.01g) is dissolved in methylene dichloride (50ml), under ice-water cooling, hexachloroethane (0.78g) and triethylamine (0.51ml) are added to wherein, the compound (1.10g) that reference example 33-(2) is obtained adds to wherein then, the solution stirring that obtains 1 hour, restir 2 days at room temperature then, the reaction soln concentrating under reduced pressure, resistates is dissolved in ethyl acetate, solution with water, 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated brine wash in proper order, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (0.71g) by silica gel column chromatography purifying (ethyl acetate/hexane=3/1), is light yellow oil.

MS m/z：583(M+H) ⁺。

(4) 2-[2,6-dimethyl-4-[[(5-methyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (0.71g) that reference example 33-(3) is obtained is dissolved in tetrahydrofuran (THF) (10ml), under ice-water cooling, (1.26ml) adds to wherein with diethylamide, the solution that obtains at room temperature stirred 23 hours, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (0.44g) by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), is light yellow oil.

MS m/z：361(M+H) ⁺。

[reference example 34]

(1) 2-[4-[[tert-butoxycarbonyl methyl-5-(methyl-2-right-tolyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With 4-chloromethyl-5-methyl-2-right-compound (0.198g) that tolyl  azoles (0.127g) and reference example 14-(1) obtain is dissolved in acetonitrile (5ml), (0.087g) adds to wherein with salt of wormwood, the mixture that obtains is 50 ℃ of stirred overnight, stirred 4 days at 70 ℃ then, after the cooling, by removing by filter insoluble substance, filtrate decompression concentrates, resistates by silica gel column chromatography purifying (1.3% ethyl acetate-hexane), is obtained title compound (0.258g), be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，1.47(9H，s)，2.17(6H，s)，2.29(3H，s)，2.38(3H，s)，3.30(2H，s)，3.71(2H，brs)，3.74(2H，br s)，4.28(2H，q，J＝7.2Hz)，6.99(2H，s)，7.23(2H，d，J＝8.3Hz)，7.89(2H，d，J＝8.3Hz)。

MS m/z：565(M+H) ⁺。

(2) 2-[4-[[carboxymethyl-(5-methyl-2-right-tolyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (0.258g) that reference example 34-(1) is obtained is dissolved in methylene dichloride (5.2ml), 4N hydrochloric acid-dioxane solution (5.2ml) is added to wherein, the solution that obtains at room temperature stirred 2 days, and it obtains title compound (0.232g) through concentrating under reduced pressure, is colorless oil.

[reference example 35]

(1) 2-[4-[[tert-butoxycarbonyl methyl-[2-(4-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 34-(1), the compound (0.208g) that obtains from 4-chloromethyl-2-(4-chloro-phenyl-)-5-methyl  azoles (0.146g) and reference example 14-(1) obtains title compound (0.289g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34(3H，t，J＝7.1Hz)，1.44(6H，s)，1.47(9H，s)，2.17(6H，s)，2.29(3H，s)，3.29(2H，s)，3.71(2H，br s)，3.73(2H，br s)，4.27(2H，q，J＝7.1Hz)，6.98(2H，s)，7.36-7.42(2H，m)，7.90-7.96(2H，m)。

MS m/z：585(M+H) ⁺。

(2) 2-[4-[[carboxymethyl-[2-(4-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 34-(2), the compound (0.289g) that obtains from reference example 35-(1) obtains title compound (0.261g), is colorless oil.

[reference example 36]

(1) 2-[4-[[tert-butoxycarbonyl methyl-[2-(3-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 34-(1), the compound (0.190g) that obtains from 4-chloromethyl-2-(3-chloro-phenyl-)-5-methyl  azoles (0.134g) and reference example 14-(1) obtains title compound (0.236g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，1.48(9H，s)，2.18(6H，s)，2.30(3H，s)，3.30(2H，s)，3.71(2H，br s)，3.75(2H，br s)，4.28(2H，q，J＝7.2Hz)，6.99(2H，s)，7.34-7.38(2H，m)，7.85-7.91(1H，m)，8.00-8.02(1H，m)。

MS m/z：585(M+H) ⁺。

(2) 2-[4-[[carboxymethyl-[2-(3-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 34-(2), the compound (0.236g) that obtains from reference example 36-(1) obtains title compound (0.214g), is colorless oil.

[reference example 37]

(1) 2-(4-formyl radical-2-methoxyl group-6-methylphenoxy)-2 Methylpropionic acid tertiary butyl ester

4-hydroxy-3-methyl-5-methoxybenzaldehyde (7.0g) is dissolved in N, dinethylformamide (110ml), salt of wormwood (17.4g) and 2 bromo 2 methyl propionic acid tertiary butyl ester (23.5ml) are added to wherein, the mixture that obtains stirred 27 hours at 80 ℃, after the cooling, by diatomite filtration, filtrate is diluted with ethyl acetate, washes with water, the water layer ethyl acetate extraction, merge organic layer, use the saturated brine washed twice, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (4.25g) by silica gel column chromatography purifying (ethyl acetate/hexane=1/4), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.47(6H，s)，2.31(3H，s)，3.80(3H，s)，7.24-7.30(2H，m)，9.84(1H，s)。

MS m/z：309(M+H) ⁺。

(2) amino 2-[2-methoxyl group-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The method same with reference example 19 is from C-[5-methyl-2-phenyl  azoles-4-yl] compound (1.63g) that obtains of methylamine (1.0g) and reference example 37-(1) obtains title compound (2.3g), is brown oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.40(6H，s)，1.51(9H，s)，2.21(3H，s)，2.31(3H，s)，3.67(2H，s)，3.70(3H，s)，3.73(2H，s)，6.70-6.73(2H，m)，7.38-7.49(3H，m)，8.01-7.97(2H，m)。

MS m/z：481(M+H) ⁺。

(3) 2-[4-[[carboxymethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2-methoxyl group-6-methylphenoxy-2 Methylpropionic acid ester

The method same with reference example 6, the compound (0.20g) that obtains from reference example 37-(2) obtains title compound (0.12g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.40(6H，s)，1.50(9H，s)，2.21(3H，s)，2.27(3H，s)，3.44(2H，s)，3.67(2H，s)，3.68(3H，s)，3.76(2H，s)，6.67(1H，s)，6.69(1H，s)，7.43-7.47(3H，m)，7.97-8.01(2H，m)。

MS m/z：539(M+H) ⁺。

[reference example 38]

2-(2-fluoro-4-formyl radical phenoxy group)-2 Methylpropionic acid ethyl ester

The method same with reference example 2 obtains title compound (1.54g) from 3-fluoro-4-hydroxy benzaldehyde (2.5g) and 2 bromo 2 methyl propionic acid ethyl ester (7.0g), is colorless oil.

MS m/z：255(M+H) ⁺。

[reference example 39]

The different  azoles of 5-phenyl-3-ylmethyl methanesulfonates

The different  azoles of 3-hydroxymethyl-5-phenyl (0.101g) is dissolved in methylene dichloride (4ml), under ice-water cooling, methylsulfonyl chloride (0.048ml) and triethylamine (0.094ml) are added to wherein, the solution stirring that obtains 1 hour is added saturated sodium bicarbonate aqueous solution wherein to, uses dichloromethane extraction then three times, wash with saturated brine, obtain title compound with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, be oily matter, this title compound is directly used in following reaction.

[reference example 40]

2-(2-ethyl-4-formyl radical-6-methylphenoxy)-2 Methylpropionic acid ethyl ester

The method same with reference example 12 obtains title compound (2.46g) from 3-ethyl-4-hydroxy-5-methyl benzaldehyde (2.08g) and 2 bromo 2 methyl propionic acid ethyl ester (7.0g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.24(3H，t，J＝7.4Hz)，1.36(3H，t，J＝7.1Hz)，1.50(6H，s)，2.28(3H，s)，2.65(2H，q，J＝7.4Hz)，4.30(2H，q，J＝7.1Hz)，7.53(1H，d，J＝2.2Hz)，7.58(1H，d，J＝2.2Hz)，9.90(1H，s)。

MS m/z：279(M+H) ⁺。

[reference example 41]

(1) 2-(4-formyl radical-2,6-dimethyl phenoxy)-2 Methylpropionic acid tertiary butyl ester

With the same method of reference example 37-(1), from 3,5-dimethyl-4-hydroxy benzaldehyde (15.0g) and 2 bromo 2 methyl propionic acid tertiary butyl ester (56ml) obtained title compound (4.47g) in 2 days 80 ℃ of reactions in the presence of salt of wormwood (55.3g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.41(6H，s)，1.47(9H，s)，2.25(6H，s)，7.48(2H，s)，9.83(1H，s)。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The method same with reference example 19, the compound (3.0g) that obtains from C-(5-methyl-2-phenyl  azoles-4-yl) methylamine (1.94g) and reference example 41-(1) obtains title compound (5.8g), is light yellow oil.

MS m/z：465(M+H) ⁺。

(3) 2-[4-[[carboxymethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid tertiary butyl ester

The method same with reference example 6, the compound (1.00g) that obtains from reference example 41-(2) obtains title compound (0.90g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.42(6H，s)，1.51(9H，s)，2.21(6H，s)，2.25(3H，s)，3.45(2H，s)，3.67(2H，s)，3.74(2H，s)，6.92(2H，s)，7.44-7.47(3H，m)，8.01-7.98(2H，m)。

MS m/z：523(M+H) ⁺。

(4) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-[N '-(2,2, the 2-trifluoroacetyl group)-diazanyl carbonyl methyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of reference example 16-(1), compound (0.150g) the trifluoroacetyl hydrazine (0.046g) that obtains from reference example 41-(3) obtains title compound (0.135g), is light yellow oil.

MS m/z：633(M+H) ⁺。

[reference example 42]

(1) 2-[4-[[[2-[N '-(9H-fluorenes-9-ylmethoxy carbonyl) diazanyl]-the 2-oxoethyl]-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of reference example 16-(1), the compound (0.350g) and the 9H-fluorenes-9-ylmethyl hydrazine carboxylic acid (0.24g) that obtain from reference example 41-(3) obtain title compound (0.48g), are yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.26(3H，t，J＝7.2Hz)，1.40(6H，s)，1.50(9H，s)，2.04(2H，s)，2.18(6H，s)，2.23(3H，s)，3.40(2H，s)，3.57-3.65(4H，m)，4.12(2H，q，J＝7.2Hz)，4.43(2H，d，J＝7.3Hz)，6.90(2H，s)，7.26(2H，s)，7.42-7.40(5H，m)，7.56-7.58(2H，m)，7.72-7.75(2H，m)，7.97-7.99(2H，m)。

(2) 2-[4-[[diazanyl carbonyl methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid tertiary butyl ester

The compound (0.48g) that reference example 42-(1) is obtained is dissolved in tetrahydrofuran (THF) (20ml), under ice-water cooling, (0.98ml) adds to wherein with diethylamide, the solution that obtains at room temperature stirred 2 hours, solvent evaporated under reduced pressure, the resistates that obtains is dissolved in ethyl acetate, wash with saturated brine then with saturated sodium bicarbonate aqueous solution, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains obtains title compound (0.3g) by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), is yellow oil.

MS m/z：537(M+H) ⁺。

[reference example 43]

2-(2,6-two fluoro-4-formyl radical phenoxy groups)-2 Methylpropionic acid tertiary butyl ester

The method same with reference example 12, from 3,5-two fluoro-4-hydroxy benzaldehydes (3.8g) and 2 bromo 2 methyl propionic acid butyl ester (20g) obtained title compound (6.68g) in 3 days 80 ℃ of reactions in the presence of cesium carbonate (12.6g), be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.48(9H，s)，1.59(6H，s)，7.44(2H，d，J＝7.8Hz)，9.85(1H，t，J＝1.6Hz)。

MS m/z：323(M+H) ⁺。

[reference example 44]

2-(3-formyl radical-4-methoxyl group phenoxy group)-2 Methylpropionic acid tertiary butyl ester

The method same with reference example 12 obtains title compound (2.62g) from 5-hydroxyl-2-methoxybenzaldehyde (2.1g) and 2 bromo 2 methyl propionic acid tertiary butyl ester (9g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.48(9H，s)，1.53(6H，s)，3.89(3H，s)，6.89(1H，d，J＝9.1Hz)，7.16(1H，dd，J＝9.1，3.2Hz)，7.34(1H，d，J＝3.2Hz)，10.41(1H，s)。

MS m/z：295(M+H) ⁺。

[reference example 45]

(1) methyl 2-[4-[(benzyloxycarbonyl-tert-butoxycarbonyl methylamino)]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The solution of compound (1.0g) in methylene dichloride (20ml) that reference example 14-(1) is obtained mixes with saturated sodium bicarbonate aqueous solution (20ml), under ice-water cooling, (0.49ml) adds to wherein with Carbobenzoxy Chloride, the solution that obtains at room temperature stirred 18 hours, reaction soln dilutes with ethyl acetate, water washs with saturated brine then, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (ethyl acetate/hexane=1/2), obtain title compound (1.35g), be colorless oil.

MS m/z：536(M+Na) ⁺。

(2) methyl 2-[4-[(benzyloxycarbonyl-formamyl methylamino)]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (1.35g) that reference example 45-(1) is obtained is dissolved in methylene dichloride (20ml), under ice-water cooling, (5ml) adds to wherein with trifluoroacetic acid, the solution that obtains at room temperature stirred 18 hours, solvent evaporated under reduced pressure, the resistates that obtains obtains 2-[4-[(benzyloxycarbonyl-carboxymethylamino by silica gel column chromatography purifying (methyl alcohol/chloroform=1/19)) methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid ethyl ester (1.2g), be colorless oil.It is dissolved in the acetonitrile (20ml), with ammonium chloride (0.28 g), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.76g), I-hydroxybenzotriazole (0.61g) and N-methylmorpholine (0.58ml) add to wherein, the solution that obtains at room temperature stirred 4 hours, solvent evaporated under reduced pressure, the resistates that obtains is dissolved in ethyl acetate, water, 10% aqueous citric acid solution, saturated sodium bicarbonate aqueous solution and saturated brine wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound (1.1g), be colorless oil.

MS m/z：457(M+H) ⁺。

(3) 2-[4-[[benzyloxycarbonyl-(3-methyl [1,2,4]  diazole-5-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 19-(2), the compound (1.10g) that obtains from reference example 45-(2) obtains title compound (0.73g), is light yellow oil.

¹H-NMR (400MHz, CDCl ₃) δ: 1.35 (3H, t, J=7.2Hz), 1.45 (6H, s), 2.12,2.16 (6H, each is s), 2.35,2.38 (3H, each is s), 4.28 (2H, q, J=7.2Hz), 4.51 (2H, s), 4.55,4.60 (2H, each is s), 5.20,5.24 (2H, each is s), 6.75, (6.86 2H, each is s), and 7.36-7.29 (5H, m).

MS m/z：496(M+H) ⁺。

(4) 2-[2,6-dimethyl-4-[[(3-methyl-[1,2,4]  diazole-5-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (0.73g) that reference example 45-(3) is obtained is dissolved in methylene dichloride (5ml), and under ice-water cooling, (30% acetic acid solution 5ml) adds to wherein, and the solution that obtains at room temperature stirred 6 hours with hydrogen bromide.Its vacuum concentration to doing, is obtained the hydrobromate (0.345g) of title compound, be brown oil.It is directly used in following reaction.

¹H-NMR(400MHz，CD ₃OD)δ：1.23(3H，t，J＝7.1Hz)，1.36(6H，s)，2.13(6H，s)，2.32(3H，s)，4.15(2H，q，J＝7.1Hz)，4.22(2H，s)，4.77(2H，s)，7.10(2H，s)。

[reference example 46]

2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-[2-oxo-2-[N '-(pyridine-3-carbonyl) diazanyl] ethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 16-(1), the compound (0.200g) and the nicotinic acid hydrazide (0.078g) that obtain from reference example 14-(3) obtain title compound (0.170g), are yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.04(3H，t，J＝7.2Hz)，1.15(6H，s)，1.89(6H，s)，1.96(3H，s)，3.16(2H，s)，3.35(2H，s)，3.39(2H，s)，3.97(2H，q，J＝7.0Hz)，6.71(2H，s)，7.07-7.11(3H，m)，7.70-7.73(2H，m)，7.76-7.79(1H，m)，8.23-8.22(1H，m)，8.45-8.47(1H，m)，8.70(1H，s).

MS m/z：614(M+H) ⁺。

[embodiment 1]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] the thiazol-2-yl methylamino] methyl] phenoxy group-2 Methylpropionic acid tertiary butyl ester

The compound (75mg) and the 2-formyl thiazole (19 μ l) of reference example 3 are dissolved in methylene dichloride (1ml); (62mg) adds to wherein with the triethoxy sodium borohydride; the mixture that obtains stirred one day; reaction soln dilutes with methylene dichloride; wash in proper order with saturated sodium bicarbonate aqueous solution and saturated brine; then with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure; resistates is passed through preparative thin layer chromatography (hexane-ethyl acetate); obtain title compound (64mg), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.43(9H，s)，1.57(6H，s)，2.27(3H，s)，3.64(2H，s)，3.69(2H，s)，4.06(2H，s)，6.83(2H，d，J＝8.6Hz)，7.28-7.31(4H，m)，7.53(1H，d，J＝9.1Hz)，7.69(1H，d，J＝3.4Hz)，7.92(1H，d，J＝7.8Hz)，8.14(1H，s)。

MS m/z：614(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] the thiazol-2-yl methylamino] methyl] phenoxy group-2 Methylpropionic acid hydrochloride

The compound (64g) of embodiment 1-(1) is dissolved in methylene dichloride (1.0ml), 4N hydrochloric acid-dioxane solution (2ml) is added to wherein, the solution that obtains at room temperature stirred one day, solvent evaporated under reduced pressure, with resistates from acetone-hexane crystallization, obtain title compound (55mg), be light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.50(6H，s)，2.32(3H，s)，4.10(2H，s)，4.25(2H，s)，4.53(2H，s)，6.84(2H，d，J＝8.8Hz)，7.48-7.53(3H，m)，7.72-7.74(1H，m)，7.84-7.96(3H，m)，8.08(1H，s)。

MS m/z：556(M+H) ⁺。

[embodiment 2]

(1) 2-[4-[[[2-(3-bromine phenoxy group)-5-methyl  azoles-4-ylmethyl]-(1-methyl isophthalic acid H-imidazoles-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (95mg) and the 1-methyl-2-imidazole formaldehyde (32mg) of reference example 5 are dissolved in methylene dichloride (2.0ml), (83mg) adds to wherein with the triethoxy sodium borohydride, the mixture that obtains stirred one day, reaction soln dilutes with methylene dichloride, wash in proper order with sodium bicarbonate aqueous solution and saturated brine, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through preparative thin layer chromatography purifying (hexane-ethyl acetate), obtain title compound (76mg), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.25(3H，t，J＝7.2Hz)，1.57(6H，s)，2.21(3H，s)，3.50(2H，s)，3.53(3H，s)，3.59(2H，s)，3.74(2H，s)，4.23(2H，q，J＝7.1Hz)，6.77(1H，d，J＝1.2Hz)，6.79(2H，d，J＝7.0Hz)，6.89(1H，d，J＝1.0Hz)，7.19(12H，d，J＝8.6Hz)，7.30(1H，t，J＝8.0Hz)，7.53(1H，d，J＝9.1Hz)，7.91(1H，d，J＝7.8Hz)，8.14(1H，s)。

MS m/z：583(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromine phenoxy group)-5-methyl  azoles-4-ylmethyl]-(1-methyl isophthalic acid H-imidazoles-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (70mg) of embodiment 2-(1) is dissolved in ethanol (10ml), 1N aqueous sodium hydroxide solution (1ml) and 5N aqueous sodium hydroxide solution (0.2ml) are added to wherein, the vlil that obtains one day, solvent evaporated under reduced pressure, then resistates is neutralized with the 1N aqueous hydrochloric acid that adds wherein, use ethyl acetate extraction, the organic layer water and the saturated brine that obtain wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, with resistates by preparative thin layer chromatography purifying and from acetone-hexane crystallization, obtain title compound (29mg), be light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.46(6H，s)，2.25(3H，s)，3.33-3.39(5H，m)，3.43-3.46(2H，m)，3.63-3.66(2H，m)，6.76-6.78(3H，m)，7.04(1H，s)，7.19-7.22(2H，m)，7.48(1H，t，J＝8.1Hz)，7.69(1H，d，J＝7.8Hz)，7.92(1H，d，J＝7.8Hz)，8.03(1H，s)。

MS m/z：555(M+H) ⁺。

Ultimate analysis is C ₂₇H ₂₉BrN ₄O ₄H ₂O

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

Measured value: C, 57.01; H, 5.47; N, 9.30.

[embodiment 3]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 2-(1), obtain title compound (89mg), be colorless oil from the compound (95mg) and the 1-methyl-2-formyl radical benzoglyoxaline (47mg) of reference example 5.

1H-NMR(400MHz，CDCl3)δ：1.24(3H，t，J＝7.1Hz)，1.56(6H，s)，2.17(3H，s)，3.56(2H，s)，3.66，(2H，s)，3.73(3H，s)，3.99(2H，s)，4.23(2H，q，J＝7.1Hz)，6.79(2H，d，J＝8.6Hz)，7.20-7.32(6H，m)，7.53(1H，d，J＝6.0Hz)，7.70(1H，d，J＝5.8Hz)，7.89(1H，d，J＝8.1Hz)，8.11(1H，s)。

MS m/z：633(M+H)+。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 2-(2), obtain title compound (26mg) from the compound (85mg) of embodiment 3-(1), be light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.46(6H，s)，2.25(3H，s)，3.33-3.39(5H，m)，3.43-3.46(2H，m)，3.63-3.66(2H，m)，6.76-6.78(3H，m)，7.04(1H，s)，7.19-7.22(2H，m)，7.48(1H，t，J＝8.1Hz)，7.69(1H，d，J＝7.8Hz)，7.92(1H，d，J＝7.8Hz)，8.03(1H，s)。

MS m/z：605(M+H) ⁺。

Ultimate analysis is C ₃₃H ₃₁BrN ₄O ₅0.75H ₂O

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

Measured value: C, 60.74; H, 5.31; N, 8.63.

[embodiment 4]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] the pyridin-4-yl methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 2-(1), obtain title compound (69mg) from the compound (75mg) and the Pyridine-4-Carboxaldehyde of reference example 5, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.24(3H，t，J＝7.1Hz)，1.56(6H，s)，2.22(3H，s)，3.52(2H，s)，3.59，(2H，s)，3.59(2H，s)，3.67(2H，s)，4.23(2H，q，J＝7.1Hz)，6.81(2H，d，J＝8.6Hz)，7.24-7.35(5H，m)，7.53(1H，d，J＝9.8Hz)，7.91(1H，d，J＝7.8Hz)，8.14(1H，s)，8.53(2H，d，J＝5.9Hz)。

MS m/z：580(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] the pyridin-4-yl methylamino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 2-(2), obtain title compound (51mg) from the compound (67mg) of embodiment 4-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.47(6H，s)，2.24(3H，s)，3.48(2H，s)，3.56(2H，s)，3.64(2H，s)，6.79(2H，d，J＝8.6Hz)，7.29(2H，d，J＝8.1Hz)，7.40(2H，d，J＝5.4Hz)，7.49(1H，t，J＝7.8Hz)，7.70(1H，d，J＝9.1Hz)，7.92(1H，d，J＝7.8Hz)，8.03(1H，s)，8.49(2H，d，J＝4.9Hz).

MS m/z：550(M+H) ⁺。

Ultimate analysis is C ₂₈H ₂₈BrN ₃O ₄0.25H ₂O0.5EtOH

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

Measured value: C, 60.32; H, 5.55; N, 6.82.

[embodiment 5]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] thiazole-4-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The compound (300mg) and 4-(chloromethyl) thiazole hydrochloride (129mg) of reference example 3 are dissolved in tetrahydrofuran (THF) (5ml), tetrabutylammonium iodide (108mg) and triethylamine (3ml) are added to wherein, the vlil that obtains 5 days, reaction soln dilutes with ethyl acetate, wash in proper order with sodium bicarbonate aqueous solution, water, saturated brine, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (hexane-ethyl acetate), obtain title compound (140mg), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.43(9H，s)，1.45(6H，s)，2.26(3H，s)，3.59(2H，s)，3.64(2H，s)，3.95(2H，s)，6.81(2H，d，J＝8.3 Hz)，7.22-7.35(4H，m)，7.50-7.55(1H，m)，7.91-7.95(1H，m)，8.15(1H，s)，8.78(1H，s)。

MS m/z：614(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] thiazole-4-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid hydrochloride

The compound (141mg) of embodiment 5-(1) is dissolved in methylene dichloride (3.0ml), 4N hydrochloric acid-dioxane solution (5ml) is added to wherein, the solution that obtains at room temperature stirred one day, solvent evaporated under reduced pressure, resistates by silica gel column chromatography purifying (chloroform-methanol), is dissolved in 4N hydrochloric acid-dioxane solution then, and the solution decompression that obtains concentrates, resistates is obtained title compound (83mg) from crystallization acetone-ethyl acetate-hexane, be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.53(6H，s)，2.34(3H，s)，4.19(2H，s)，4.39(2H，s)，4.49(2H，s)，6.86(2H，d，J＝8.3Hz)，7.50-7.57(3H，m)，7.76(1H，d，J＝4.7Hz)，7.99(1H，d，J＝7.8Hz)，8.02(1H，s)，8.11(1H，s)，9.26(1H，s)。

MS m/z：558(M+H) ⁺。

[embodiment 6]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-(2-methylthiazol-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 5-(1), obtain title compound (212mg), be yellow oil from the compound (300mg) and the 4-chloromethyl-2-methylthiazol hydrochloride (140mg) of reference example 3.

¹H-NMR(400MHz，CDCl ₃)δ：1.43(9H，s)，1.53(6H，s)，2.26(3H，s)，2.70(3H，s)，3.59(2H，s)，3.64(2H，s)，3.85(2H，s)，6.81(2H，d，J＝8.3Hz)，7.10(1H，s)，7.24(2H，d，J＝6.9Hz)，7.30(1H，t，J＝7.8Hz)，7.50-7.54(1H，m)，7.91-7.95(1H，m)，8.15(1H，s)。

MS m/z：628(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-(2-methylthiazol-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid hydrochloride

With the same method of embodiment 5-(2), obtain title compound (148mg) from the compound (210mg) of embodiment 6-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.53(6H，s)，2.35(3H，s)，2.69(3H，s)，4.21(2H，s)，4.39(4H，bs)，6.87(2H，d，J＝8.8Hz)，7.50-7.56(3H，m)，7.77(2H，d，J＝7.4Hz)，7.99(1H，d，J＝7.8Hz)，8.11(1H，s)。

MS m/z：570(M+H) ⁺。

Ultimate analysis is C ₂₇H ₂₈BrN ₃O ₄S2H ₂OHCl

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

Measured value: C, 50.44; H, 5.28; N, 6.12.

[embodiment 7]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-(3, the different  azoles of 5-dimethyl-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 5-(1), from the compound (300mg) and the 4-chloromethyl-3 of reference example 3, the different  azoles of 5-dimethyl (111mg) obtains title compound (324mg), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.44(9H，s)，1.54(6H，s)，2.17(3H，s)，2.19(3H，s)，2.36(3H，s)，3.41(2H，s)，3.42(2H，s)，3.46(2H，s)，6.81(2H，d，J＝8.5Hz)，7.15(2H，d，J＝8.5Hz)，6.31(1H，t，J＝8.1Hz)，7.53(1H，d，J＝9.8Hz)，7.91(1H，d，J＝7.8Hz)，8.13(1H，s)。

MS m/z：626(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-(3, the different  azoles of 5-dimethyl-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid hydrochloride

With the same method of embodiment 1-(2), obtain title compound (237mg) from the compound (141mg) of embodiment 7-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.52(6H，s)，2.10(3H，s)，2.32-2.43(4H，m)，4.08-4.26(4H，m)，4.31-4.48(2H，m)，6.90(2H，bs)，7.54(3H，bs)，7.76(1H，bs)，7.98(1H，d，J＝5.4Hz)，8.12(1H，s)。

MS m/z：570(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₀BrN ₃O ₅HCl

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

Measured value: C, 55.53; H, 5.36; N, 6.52.

[embodiment 8]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-methylamino formyl radical methylamino] methylphenoxy]-the 2 Methylpropionic acid tertiary butyl ester

The compound (100mg) of reference example 6 is dissolved in dimethyl formamide (2ml), with methylamine hydrochloride (20mg), N-methylmorpholine (30 μ l), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (50mg) and I-hydroxybenzotriazole (35mg) add to wherein, the solution stirring that obtains one day, reaction soln dilutes with ethyl acetate, water and saturated brine wash in proper order, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, resistates is passed through preparative thin layer chromatography purifying (chloroform-methanol), obtain title compound (97mg), be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.43(9H，s)，1.58(6H，s)，2.29(3H，s)，2.79(3H，d，J＝4.9Hz)，3.18(2H，s)，3.51(2H，s)，3.63(2H，s)，6.81(2H，d，J＝8.3Hz)，7.15(2H，d，J＝8.3Hz)，7.33(1H，t，J＝7.8Hz)，7.56(1H，d，J＝7.8Hz)，7.63-7.69(1H，m)，7.92(1H，d，J＝7.8Hz)，8.15(1H，s)。

MS m/z：588(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]-methylamino formyl radical methylamino] methylphenoxy]-the 2 Methylpropionic acid hydrochloride

With the same method of embodiment 1-(2), the compound (95mg) by Processing Example 8-(1) obtains title compound (87mg) with products therefrom from acetone-hexane crystallization subsequently, is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.53(6H，s)，2.43(3H，s)，2.59(3H，d，J＝3.7Hz)，3.82(2H，s)，4.28-4.39(4H，m)，6.87(2H，d，J＝8.6Hz)，7.51-7.55(3H，m)，7.76(1H，d，J＝8.1Hz)，7.97(1H，d，J＝7.8Hz)，8.11(1H，s)。

MS m/z：532(M+H) ⁺。

Ultimate analysis is C ₂₅H ₂₈BrN ₃O ₅2H ₂OHCl

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

Measured value: C, 50.31; H, 5.23; N, 6.55.

[embodiment 9]

(1) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] the formyl-dimethylamino methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 8-(1), obtain title compound (75mg) from the compound (100mg) of reference example 6, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.44(9H，s)，1.58(6H，s)，2.29(3H，s)，2.89(6H，d，J＝5.9Hz)，3.36(2H，s)，3.66(2H，s)，3.71(2H，s)，6.81(2H，d，J＝6.9Hz)，7.23(2H，d，J＝8.3Hz)，7.29(1H，t，J＝7.8Hz)，7.53(1H，d，J＝7.4Hz)，7.89-7.94(1H，m)，8.15(1H，s)。

MS m/z：602(M+H) ⁺。

(2) 2-[4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl] the formyl-dimethylamino methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid hydrochloride

With the same method of embodiment 1-(2), obtain title compound (60mg) from the compound (70mg) of embodiment 9-(1), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.54(6H，s)，2.46(3H，s)，2.82(3H，s)，2.88(3H，s)，4.19-4.39(6H，m)，6.88(2H，d，J＝8.6Hz)，7.52-7.60(3H，m)，7.76(1H，d，J＝9.1Hz)，7.98(1H，d，J＝7.8Hz)，8.10(1H，s)。

MS m/z：546(M+H) ⁺。

[embodiment 10]

(1) 2-[2-allyl group-4-[[methylamino formyl radical methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 8-(1), the compound and the N-methylamine hydrochloride (100mg) that obtain from reference example 9 obtain title compound (120.5mg), are solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.39(9H，s)，1.56(6H，s)，2.30(3H，s)，2.77(3H，d，J＝6.6Hz)，3.20(2H，s)，3.35(2H，d，J＝6.6Hz)，3.50(2H，s)，3.61(2H，s)，4.97-5.01(2H，m)，5.85-6.00(1H，m)，6.65(1H，d，J＝8.5Hz)，6.98(1H，dd，J＝2.2，8.5Hz)，7.07(1H，d，J＝8.5Hz)，7.40-7.50(3H，m)，7.72-7.80(1H，m)，7.97-8.03(2H，m)。

(2) 2-[2-allyl group-4-[[methylamino formyl radical methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid trifluoroacetate

Trifluoroacetic acid (1ml) is added in methylene dichloride (3ml) solution of compound (125.0mg) of embodiment 10-(1), the solution stirring that obtains 4 hours, solvent evaporated under reduced pressure obtain title compound (122.0mg), are oily matter.

¹H-NMR(400MHz，CDCl ₃)δ：1.64(6H，s)，2.36(3H，s)，2.64(3H，s)，3.36(2H，d，J＝6.6Hz)，3.87(2H，s)，4.25(2H，s)，4.36(2H，s)，5.00-5.10(2H，m)，5.87-5.98(1H，m)，6.60-7.05(3H，m)，7.34(1H，s)，7.43-7.48(3H，m)，7.92-7.98(2H，m)，8.17-8.27(1H，m)。

[embodiment 11]

(1) 2-[2-allyl group-4-[[methylamino formyl radical methyl-[5-methyl-2-(3-bromophenyl)  azoles-4-ylmethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 8-(1), the compound and the N-methylamine hydrochloride (100mg) that obtain from reference example 11 obtain title compound (140.1mg), are oily matter.

¹H-NMR(400MHz，CDCl ₃)δ：1.39(9H，s)，1.56(6H，s)，2.30(3H，s)，2.77(3H，d，J＝6.6Hz)，3.20(2H，s)，3.35(2H，d，J＝6.6Hz)，3.50(2H，s)，3.61(2H，s)，4.95-5.05(2H，m)，5.85-6.00(1H，m)，6.65(1H，d，J＝8.5Hz)，6.98(1H，dd，J＝2.2，8.5Hz)，7.07(1H，d，J＝8.5Hz)，7.30-7.35(1H，m)，7.50-7.75(2H，m)，7.92-7.98(1H，m)，8.17-8.27(2H，m)。

(2) 2-[2-allyl group-4-[[methylamino formyl radical methyl-[5-methyl-2-(3-bromophenyl)  azoles-4-ylmethyl] amino] methyl] phenoxy group]-the 2 Methylpropionic acid trifluoroacetate

With the same method of embodiment 10-(2), trifluoroacetic acid (1ml) is added in methylene dichloride (3ml) solution of compound (141.0mg) of embodiment 11, it is oily matter that the solution stirring that obtains 4 hours, solvent evaporated under reduced pressure obtain title compound (122.0mg).

¹H-NMR(400MHz，CDCl ₃)δ：1.64(6H，s)，2.37(3H，s)，2.71(3H，s)，3.37(2H，d，J＝6.4Hz)，3.88(2H，s)，4.29(2H，s)，4.39(2H，s)，5.00-5.10(2H，m)，5.88-5.98(1H，m)，6.62-7.05(2H，m)，7.34(1H，s)，7.43-7.68(3H，m)，7.92-7.98(1H，m)，8.17-8.27(2H，m)。

[embodiment 12]

(1) 2-4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 1-(1), the compound (1.3g) and the  azoles-2-formaldehyde (244mg) that obtain from reference example 3 obtain title compound (193mg), are colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.45(9H，s)，1.56(6H，s)，2.30(3H，s)，3.65(2H，s)，3.68(2H，s)，3.88(2H，s)，6.82(1H，d，J＝8.6Hz)，6.85(2H，d，J＝8.6Hz)，7.24(2H，d，J＝8.3Hz)，7.30(1H，t，J＝7.9Hz)，7.53(1H，d，J＝6.8Hz)，7.64(1H，s)，7.93(1H，d，J＝7.8Hz)，8.16(1H，s).

MS m/z：598(M+H) ⁺。

2-4-[[[2-(3-bromophenyl)-5-methyl  azoles-4-ylmethyl]  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid hydrochloride

With the same method of embodiment 1-(2), obtain title compound (50mg) from the compound (190mg) of embodiment 12-(1), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.52(6H，s)，2.36(3H，s)，4.07-4.25(6H，s)，6.84(2H，d，J＝8.8Hz)，7.32(1H，bs)，7.44(2H，d，J＝9.0Hz)，7.94(1H，d，J＝8.1Hz)，8.07(1H，bs)，8.20(1H，s).

MS m/z：542(M+H) ⁺。

Ultimate analysis is C ₂₆H ₂₆BrN ₃O ₅0.75H ₂OHCl

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

Measured value: C, 52.91; H, 4.94; N, 6.77.

[embodiment 13]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (162mg) of reference example 12 and the compound (150mg) of reference example 13-(3) are dissolved in methylene dichloride (3ml), (180mg) adds to wherein with the triethoxy sodium borohydride, the mixture that obtains at room temperature stirs and spends the night, the reaction mixture ethyl acetate extraction, wash in proper order with sodium bicarbonate aqueous solution and saturated brine, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (hexane/ethyl acetate=1/1), obtain title compound (307mg), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.27(3H，s)，3.63(2H，s)，3.65(2H，s)，3.93(2H，s)，4.28(2H，q，J＝6.9Hz)，6.98(2H，s)，7.08(1H，s)，7.41-7.43(3H，m)，7.64(1H，s)，8.00-8.02(2H，m)。

MS m/z：518(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)  azoles-2-ylmethyl amino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (300mg) of embodiment 13-1 is dissolved in methyl alcohol (2ml), (1ml) adds to wherein with the 2N aqueous sodium hydroxide solution, the solution that obtains at room temperature stirred 3 days, the reaction soln concentrating under reduced pressure, the resistates that obtains neutralizes with the 1N aqueous hydrochloric acid that adds to wherein, it dilutes with ethyl acetate, wash with saturated brine, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, by silica gel column chromatography purifying (chloroform/methanol=9/1), the title compound that so obtains is dissolved in methylene dichloride, and 4N hydrochloric acid-dioxane solution (2ml) is added to wherein with resistates, the solution decompression that obtains concentrates, with the crystalline mixture of resistates from ethyl acetate and hexane, obtain the hydrochloride (201mg) of title compound, be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.14(6H，s)，2.32(3H，s)，4.11-4.35(6H，m)，7.14(2H，s)，7.30(1H，s)，7.51-7.55(3H，m)，7.93-7.95(2H，m)，8.19(1H，s)。

MS m/z：490(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₁N ₃O ₅HCl

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

Measured value: C, 63.63; H, 6.42; N, 7.58.

[embodiment 14]

(1) 2-[2,6-dimethyl-4-[[methylamino formyl radical methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (3.0g) of reference example 14-(3) is dissolved in N, dinethylformamide (10ml), with the methylamine (tetrahydrofuran solution of 2M, 4.5ml), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.27g) and I-hydroxybenzotriazole (1.82g) add to wherein, the solution that obtains at room temperature stirred 13 hours, the reaction soln concentrating under reduced pressure, resistates is dissolved in ethyl acetate, water, 10% aqueous citric acid solution, water, saturated sodium bicarbonate aqueous solution and saturated brine wash in proper order, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (using eluent ethyl acetate), obtain title compound (2.59g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.25(3H，s)，2.80(3H，d，J＝4.9Hz)，3.22(2H，s)，3.49(2H，s)，3.60(2H，s)，4.28(2H，q，J＝7.2Hz)，6.89(2H，s)，7.43-7.47(3H，m)，7.80(1H，s)，7.99-8.01(2H，m)。

MS m/z：508(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[methylamino formyl radical methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (2.59g) of embodiment 14-(1) is dissolved in methyl alcohol (2.0ml), 1N aqueous sodium hydroxide solution (5ml) and 5N aqueous sodium hydroxide solution (2ml) are added to wherein, the solution that obtains at room temperature stirred 13 hours, the reaction soln concentrating under reduced pressure, resistates is neutralized with the 1N aqueous hydrochloric acid that adds to wherein, it dilutes with ethyl acetate, water and saturated brine wash in proper order, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (chloroform/methanol=7/1) then from the crystalline mixture of ethyl acetate and hexane, obtain title compound (1.85g), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.31(6H，s)，2.12(6H，s)，2.22(3H，s)，2.60(3H，d，J＝4.6Hz)，3.09(2H，s)，3.50(2H，s)，3.56(2H，s)，6.99(2H，s)，7.48-7.53(3H，m)，7.74-7.78(1H，m)，7.91-7.93(2H，m)。

MS m/z：480(M+H) ⁺。

Ultimate analysis is C ₂₇H ₃₃N ₃O ₅

Calculated value: C, 67.62; H, 6.94; N, 8.76.

Measured value: C, 67.57; H, 7.09; N, 8.56.

[embodiment 15]

(1) 2-[4-[[formyl-dimethylamino methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 14-(1), (40% aqueous solution 0.76ml) obtains title compound (1.80g), is light yellow oil from the compound (2.37g) of reference example 14-(3) and dimethyl amine.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.26(3H，s)，2.89(6H，s)，3.39(2H，s)，3.66(4H，s)，4.29(2H，q，J＝7.1Hz)，6.97(2H，s)，7.40-7.46(3H，m)，7.98-8.01(2H，m)。

MS m/z：522(M+H) ⁺。

(2) 2-[4-[[formyl-dimethylamino methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 13-(2), compound (1.8g) by Processing Example 15-(1), with the product that obtains mixed solvent crystallization, obtain the hydrochloride of title compound (1.3g) subsequently, be colorless solid from methylene dichloride-ethyl acetate-hexane.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.36(6H，s)，2.18(6H，s)，2.42(3H，s)，2.84(3H，s)，2.89(3H，s)，4.11-4.40(6H，m)，7.31(2H，s)，7.54-7.59(3H，m)，7.97-7.99(2H，m)。

MS m/z：494(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₅N ₃O ₅H ₂OHCl0.2CH ₂Cl ₂

Calculated value: C, 59.94; H, 6.85; Cl, 8.78; N, 7.44.

Measured value: C, 60.15; H, 6.74; Cl, 9.12; N, 7.36.

[embodiment 16]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl) the thiazol-2-yl methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 13-(1), obtain title compound (499mg) from the compound (264mg) of reference example 12 and the compound (285mg) of reference example 15, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.20(3H，t，J＝7.1Hz)，1.45(6H，s)，2.22(6H，s)，2.28(3H，s)，3.63(2H，s)，3.65(2H，s)，4.10(2H，s)，4.24(2H，q，J＝7.1Hz)，7.05(2H，s)，7.28(1H，d，J＝3.4Hz)，7.35-7.45(3H，m)，7.70(1H，d，J＝3.4 Hz)，7.96-8.00(2H，m)。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl) the thiazol-2-yl methylamino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (499mg) of embodiment 16-(1) is dissolved in tetrahydrofuran (THF) (4ml), methyl alcohol (2ml) and 1N aqueous sodium hydroxide solution (2ml) are added to wherein, the solution that obtains at room temperature stirred 1 hour, it neutralizes with the 1N aqueous hydrochloric acid, use ethyl acetate extraction, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure obtains title compound (452mg), is light yellow solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.50(6H，s)，2.22(6H，s)，2.28(3H，s)，3.63(2H，s)，3.65-3.68(3H，br s)，4.10(2H，s)，7.05(2H，s)，7.28(1H，d，J＝3.4Hz)，7.40-7.45(3H，m)，7.78(1H，d，J＝3.4Hz)，7.98-8.02(2H，m)。

[embodiment 17]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-oxo-4,5-dihydro-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (200mg) of reference example 16-(2) is dissolved in the dioxane (5ml), (234mg) adds to wherein with triphosgene, the solution that obtains at room temperature stirs and spends the night, (234mg) adds to wherein with other triphosgene, solution stirred 4 hours at 60 ℃, reaction soln concentrating under reduced pressure then, resistates is dissolved in ethyl acetate, with saturated sodium bicarbonate aqueous solution and saturated brine washing, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, resistates by silica gel column chromatography purifying (ethyl acetate/hexane=1/2), is obtained title compound (176mg), be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.57(6H，s)，2.18(6H，s)，2.28(3H，s)，3.65(2H，s)，3.67(2H，s)，3.73(2H，s)，4.28(2H，q，J＝7.1Hz)，6.97(2H，s)，7.40-7.46(3H，m)，7.99-8.01(2H，m)，8.54(1H，s)。

MS m/z：535(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-oxo-4,5-dihydro-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 14-(2), obtain title compound (100mg) from the compound (170mg) of embodiment 17-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.12(6H，s)，2.26(3H，s)，3.57(2H，s)，3.59(2H，s)，3.62(2H，s)，6.95(2H，s)，7.46-7.53(3H，m)，7.90-7.92(2H，m)。

MS m/z：505(M-H) ^-。

[embodiment 18]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-[1,3,4]  diazole-2-ylmethyl)-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

Triphenylphosphine (675mg) is dissolved in methylene dichloride (15ml), under ice-water cooling and stirring, hexachloroethane (510mg) and triethylamine (716mg) are added to wherein, methylene dichloride (5ml) solution with the compound (0.5g) of reference example 17 adds to wherein then, the solution that obtains at room temperature stirred 13 hours, saturated sodium bicarbonate aqueous solution is joined wherein, and solution stirring 1 hour is used dichloromethane extraction three times then.It washs with saturated brine, uses anhydrous sodium sulfate drying then, and concentrating under reduced pressure by silica gel column chromatography purifying (ethyl acetate/hexane=2/1), obtains title compound (577mg) with resistates, is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.18(6H，s)，2.27(3H，s)，2.51(3H，s)，3.67(4H，br s)，3.99(2H，s)，4.28(2H，q，J＝7.1Hz)，6.98(2H，s)，7.40-7.45(3H，m)，8.00-8.02(2H，m)。

MS m/z：533(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-[1,3,4]  diazole-2-ylmethyl)-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 13-(2), obtain the hydrochloride (315mg) of title compound from the compound (0.57g) of embodiment 18-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.13(6H，s)，2.29(3H，s)，2.46(3H，s)，3.66-4.26(6H，m)，7.05(2H，s)，7.50-7.52(3H，m)，7.91-7.93(2H，m)。

MS m/z：505(M+H) ⁺。

[embodiment 19]

(1) 2-[4-[[carbamyl ylmethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of reference example 16-(1), obtain title compound (528mg) from the compound (400mg) and the ammonium chloride (55mg) of reference example 14-(3), it contains small amount of impurities, is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.25(3H，s)，3.24(2H，s)，3.54(2H，s)，3.60(2H，s)，4.28(2H，q，J＝7.1Hz)，6.91(2H，s)，7.44-7.45(3H，m)，7.98-8.02(2H，m)。

MS m/z：494(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(3-methyl-[1,2,4]  diazole-5-ylmethyl)-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-phenoxy group]-the 2 Methylpropionic acid ethyl ester

With N, N-dimethylacetamide dimethylacetal (5ml) is added in the compound (528mg) of embodiment 19-(1), the mixture that obtains was 120 ℃ of heating 2 hours, solvent evaporated under reduced pressure, 50% aqueous hydroxylamine (70ml) and 70% acetic acid aqueous solution (6ml) are added in the resistates, solution at room temperature stirs and spends the night, and solvent evaporated under reduced pressure is dissolved in ethyl acetate with resistates.It then with the saturated brine washing, uses anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution, and evaporating solvent by silica gel column chromatography purifying (ethyl acetate/hexane=1/3), obtains title compound (379mg) with resistates, is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.18(6H，s)，2.27(3H，s)，2.41(3H，s)，3.67(2H，s)，3.70(2H，s)，4.04(2H，s)，4.28(2H，q，J＝7.1Hz)，7.00(2H，s)，7.40-7.46(3H，m)，7.99-8.01(2H，m)。

MS m/z：533(M+H) ⁺。

(3) 2-[2,6-dimethyl-4-[[(3-methyl-[1,2,4]  diazole-5-ylmethyl)-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 13-(2), obtain the hydrochloride (273mg) of title compound from the compound (375mg) of embodiment 19-(2).

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.13(6H，s)，2.27(3H，s)，2.31(3H，s)，3.81(4H，br s)，4.15(2H，br s)，7.01(2H，s)，7.49-7.53(3H，m)，7.90-7.92(2H，m)。

MS m/z：505(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₃ClN ₄O ₅1.4H ₂O (HCl

Calculated value: C, 61.65; H, 6.19; N, 10.27.

Measured value: C, 62.02; H, 6.53; N, 9.87.

[embodiment 20]

(1) 2-[4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-and  azoles-2-ylmethyl amino] methyl] phenoxy group] ethyl hexanoate

With the same method of embodiment 13-(1), obtain title compound (96mg) from the compound (50mg) of reference example 13-(3) and the compound (54mg) of reference example 18, be colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：0.92(3H，t，J＝7.2Hz)，1.24(3H，t，J＝7.1Hz)，1.35-1.42(4H，m)，1.90-1.97(2H，m)，2.31(3H，s)，3.66(2H，s)，3.69(2H，s)，3.87(2H，s)，4.20(2H，q，J＝7.1Hz)，4.54-4.58(1H，m)，6.83(2H，d，J＝8.5Hz)，7.08(1H，d，J＝0.7Hz)，7.31(2H，d，J＝8.8Hz)，7.41-7.43(3H，m)，7.63(1H，d，J＝0.7Hz)，7.99-8.01(2H，m)。

MS m/z：518(M+H) ⁺。

(2) 2-[4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-and  azoles-2-ylmethyl amino] methyl] phenoxy group] caproic acid

With the same method of embodiment 13-(2), obtain the hydrochloride (51mg) of title compound from the compound (95mg) of embodiment 20-(1), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：0.87(3H，t，J＝7.1Hz)，1.14-1.45(4H，m)，1.74-1.93(3H，m)，2.34(3H，s)，4.03-4.23(6H，m)，4.67-4.70(1H，m)，6.90(2H，d，J＝8.3Hz)，7.30(1H，s)，7.43(2H，brs)，7.51-7.54(3H，m)，7.93-7.95(2H，m)，8.18(1H，s)。

MS m/z：488(M-H) ^-。

[embodiment 21]

(1) 2-[2,6-dimethyl-4-[[[2-(5-methyl-2-phenyl  azoles-4-yl) ethyl] the thiazol-2-yl methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound (200mg) and the 2-formyl thiazole (0.06ml) of reference example 19 are dissolved in methylene dichloride (5ml), and (188mg) adds to wherein with the triethoxy sodium borohydride, and the solution that obtains at room temperature stirred 23 hours, and it dilutes with ethyl acetate.Anhydrous sodium sulfate drying is used in water and saturated brine washing, and solvent evaporated under reduced pressure by silica gel column chromatography purifying (ethyl acetate/hexane=1/1), obtains title compound (223mg) with resistates, is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34(3H，t，J＝7.1Hz)，1.43(6H，s)，2.15(6H，s)，2.24(3H，s)，2.70(2H，t，J＝7.4Hz)，2.86(2H，t，J＝7.2Hz)，3.64(2H，s)，3.98(2H，s)，4.27(2H，q，J＝7.1Hz)，6.97(2H，s)，7.22(1H，d，J＝3.4Hz)，7.38-7.44(3H，m)，7.66(1H，d，J＝3.2Hz)，7.93-7.95(2H，m)。

MS m/z：548(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[[2-(5-methyl-2-phenyl  azoles-4-yl) ethyl] the thiazol-2-yl methylamino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 13-(2), obtain the hydrochloride (167mg) of title compound from the compound (220mg) of embodiment 21-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1 .35(6H，s)，2.15(6H，s)，2.34(3H，s)，3.06(2H，t，J＝7.6Hz)，3.34(2H，t，J＝7.8Hz)，4.41(2H，s)，4.82(2H，s)，7.28(2H，s)，7.50-7.54(3H，m)，7.88-7.90(2H，m)，7.94(1H，d，J＝3.4Hz)，8.02(1H，d，J＝3.2Hz)。

MS m/z：520(M+H) ⁺。

Ultimate analysis is C ₂₉H ₃₄ClN ₃O ₄S2HCl

Calculated value: C, 58.78; H, 5.95; N, 7.09.

Measured value: C, 58.75; H, 5.99; N, 7.01.

[embodiment 22]

(1) 2-[4-[[benzoxazol-2-ylmethyl-(methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (200mg) and the 2-chloromethyl benzo  azoles (77mg) of reference example 20 are dissolved in N, dinethylformamide (5ml), (300mg) adds to wherein with cesium carbonate, and the mixture that obtains stirred 20 hours at 70 ℃, and it dilutes with ethyl acetate, water and saturated brine washing, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure is passed through silica gel column chromatography purifying (ethyl acetate/hexane=1/1) with resistates, obtain title compound (100mg), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.43(6H，s)，2.17(6H，s)，2.26(3H，s)，3.74(2H，s)，3.76(2H，s)，4.11(2H，s)，4.28(2H，q，J＝7.2Hz)，7.02(2H，s)，7.31-7.33(2H，m)，7.40-7.43(3H，m)，7.52-7.54(1H，m)，7.70-7.73(1H，m)，7.98-8.00(2H，m)。

MS m/z：568(M+H) ⁺。

(2) 2-[4-[[benzoxazol-2-ylmethyl-(methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 13-(2), obtain the hydrochloride (49mg) of title compound from the compound (100mg) of embodiment 22-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.31(6H，s)，2.13(6H，s)，2.33(3H，s)，4.02-4.46(6H，m)，7.15(2H，s)，7.38-7.45(2H，m)，7.51-7.53(3H，m)，7.73-7.79(2H，m)，7.87-8.00(2H，m).

MS m/z：520(M+H) ⁺。

Ultimate analysis is C ₃₂H ₃₄ClN ₃O ₅3/4H ₂OHCl

Calculated value: C, 65.19; H, 6.07; N, 7.13.

Measured value: C, 65.31; H, 6.11; N, 7.00.

[embodiment 23]

(1) 2-[4-[[pair-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

The compound (50mg) and the 5-methyl-2-phenyl  azoles-4-formaldehyde (75mg) of reference example 21-(2) are dissolved in methylene dichloride (2ml), (120mg) adds to wherein with the triethoxy sodium borohydride, the solution that obtains at room temperature stirred 17 hours, it dilutes with ethyl acetate, water and saturated brine washing, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, resistates is passed through silica gel column chromatography purifying (ethyl acetate/hexane=1/3), obtain title compound (105mg), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.44(6H，s)，2.17(6H，s)，2.29(6H，s)，3.61(2H，s)，3.68(4H，s)，4.28(2H，q，J＝7.1Hz)，7.00(2H，s)，7.40-7.45(6H，m)，8.00-8.02(4H，m)。

MS m/z：608(M+H) ⁺。

(2) two (5-methyl-2-phenyl  azoles-4-ylmethyl) amino of 2-[4-[[] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 13-(2), obtain the hydrochloride (57mg) of title compound from the compound (100mg) of embodiment 23-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.34(6H，s)，2.15(6H，s)，2.38(6H，s)，4.32-4.51(6H，m)，7.29(2H，s)，7.53-7.57(6H，m)，7.96-7.98(4H，m)。

Ultimate analysis is C ₃₅H ₃₈ClN ₃O ₅5/4H ₂O (HCl

Calculated value: C, 65.82; H, 6.39; N, 6.58.

Measured value: C, 65.94; H, 6.44; N, 6.32.

[embodiment 24]

(1) 2-[2,6-dimethyl-4-[[(4-methyl  azoles-2-ylmethyl) (5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With triphenylphosphine (0.341g), hexachloroethane (0.260g) and triethylamine (0.361ml) add in the methylene dichloride (10ml), under ice-water cooling, stirred 15 minutes afterwards, the compound (0.242g) that reference example 22-(2) is obtained adds to wherein, the room temperature of then solution being risen again also stirs and spends the night, add water to reaction soln, use ethyl acetate extraction, water washs with saturated brine then, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (ethyl acetate/hexane=1/1), obtain title compound (0.085g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.16(3H，s)，2.17(6H，s)，2.26(3H，s)，3.62(2H，s)，3.63(2H，s)，3.88(2H，s)，4.28(2H，q，J＝7.2Hz)，6.99(2H，s)，7.34(1H，s)，7.40-7.44(3H，m)，8.02-7.99(2H，m)。

MS m/z：532(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(4-methyl  azoles-2-ylmethyl) (5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (0.080g) that embodiment 24-(1) is obtained is dissolved in methyl alcohol (5ml), (2ml) adds to wherein with the 1N aqueous sodium hydroxide solution, the vlil that obtains 3 hours, the reaction soln cooling, then with the 1N aqueous hydrochloric acid neutralization that joins wherein, concentrating under reduced pressure, with the resistates ethyl acetate extraction, water is then with the saturated brine washing, with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound, it is dissolved in 4N hydrochloric acid-dioxane (1ml), and drying under reduced pressure, obtain the hydrochloride (0.060g) of title compound, be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.35(6H，s)，2.09(3H，s)，2.16(6H，s)，2.33(3H，s)，3.54-3.60(4H，m)，4.07-4.32(3H，m)，7.14(2H，s)，7.52-7.55(3H，m)，7.86(1H，s)，7.96-7.92(2H，m)。

MS m/z：504(M+H) ⁺。

Ultimate analysis is C ₂₉H ₃₃N ₃O ₅HCl2H ₂O

Calculated value: C, 60.46; H, 6.65; N, 7.29.

Measured value: C, 60.94; H, 6.82; N, 6.76.

[embodiment 25]

(1) 2-[2,6-dimethyl-4-[[ azoles-2-ylmethyl-(5-phenyl [1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 24-(1), the compound (0.115g) that obtains by processing reference example 24-(2) obtains title compound (0.090g), is yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝6.6Hz)，1.45(6H.s)，2.18(6H，s)，3.75(2H，s)，4.02(2H，s)，4.11(2H，d，J＝4.4Hz)，4.28(2H，q，J＝7.2Hz)，7.00(2H，s)，7.08(1H，d，J＝1.0Hz)，7.49-7.55(3H，m)，7.64(1H，d，J＝1.0Hz)，8.07-8.05(2H，m)。

MS m/z：505(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[ azoles-2-ylmethyl-(5-phenyl [1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.090g) that obtains from embodiment 25-(1) obtains the hydrochloride (0.050g) of title compound, is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.30(6H，s)，2.11(6H，s)，3.71(2H，s)，3.98(2H，s)，4.08(2H，s)，6.96(2H，s)，7.17(1H，d，J＝0.7Hz)，7.65-7.59(3H，m)，7.96-7.98(2H，m)，8.08(1H，d，J＝1.0Hz)。

MS m/z：477(M+H) ⁺。

Ultimate analysis is C ₂₆H ₂₈N ₄O ₅1/4HCl3/4H ₂O

Calculated value: C, 62.56; H, 6.01; N, 11.22.

Measured value: C, 62.98; H, 5.87; N, 10.79.

[embodiment 26]

2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-(5-phenyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 24-(1), the compound (0.12g) that obtains by processing reference example 25 obtains title compound (0.06g), is yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.18(6H，s)，3.72(2H，s)，3.98(2H，s)，4.00(2H，s)，4.28(2H，q，J＝7.1Hz)，7.02(2H，s)，7.09(1H，s)，7.28(1H，s)，7.34(1H，d，J＝7.3Hz)，7.44-7.40(2H，m)，7.63-7.65(3H，m)。

MS m/z：504(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-(5-phenyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.06g) that obtains from embodiment 26-(1) obtains the hydrochloride (0.04g) of title compound, is light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.12(6H，s)，3.67(2H，s)，3.92(2H，s)，3.95(2H，s)，6.96(2H，s)，7.18(1H，s)，7.35-7.39(1H，m)，7.48(2H，t，J＝7.6Hz)，7.60(1H，s)，7.70-7.68(2H，m)，8.08(1H，d，J＝0.7Hz)。

MS m/z：476(M+H) ⁺。

Ultimate analysis is C ₂₇H ₂₉N ₃O ₅3/4HCl

Calculated value: C, 64.49; H, 5.96; N, 8.36.

Measured value: C, 64.33; H, 6.13; N, 7.94.

[embodiment 27]

(1) 2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-(5-thiophene-2-base-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 24-(1), the compound (0.12g) that obtains by processing reference example 26 obtains title compound (0.09g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.18(6H，s)，3.74(2H，s)，4.00(2H，s)，4.08(2H，s)，4.28(2H，q，J＝7.2Hz)，7.00(2H，s)，7.09(1H，s)，7.18(1H，dd，J＝4.9，3.9Hz)，7.56(1H，dd，J＝5.1，1.2Hz)，7.64(1H，s)，7.76(1H，dd，J＝3.8，1.1Hz)。

MS m/z：511(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-(5-thiophene-2-base-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.09g) that obtains from embodiment 27-(1) obtains the hydrochloride (0.06g) of title compound, is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.31(6H，s)，2.12(6H，s)，3.69(2H，s)，3.96(2H，s)，4.05(2H，s)，6.95(2H，s)，7.17(1H，d，J＝0.7Hz)，7.30(1H，dd，J＝4.9，3.7Hz)，7.78(1H，dd，J＝3.7，1.2Hz)，7.95(1H，dd，J＝5.1，1.2Hz)，8.07(1H，d，J＝0.7Hz)。

MS m/z：483(M+H) ⁺。

Ultimate analysis is C ₂₄H ₂₆N ₄O ₅S1/2HCl1/5C ₄H ₈O ₂

Calculated value: C, 57.46; H, 5.46; N, 10.81; S, 6.19.

Measured value: C, 57.45; H, 5.26; N, 10.44; S, 6.11.

[embodiment 28]

(1) 2-[2,6-dimethyl-4-[[ azoles-2-ylmethyl-(3-thiophene-2-base-[1,2,4]  diazole-5-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

The compound that reference example 27-(2) is obtained is dissolved in tetrahydrofuran (THF) (5ml), with the tetrabutyl ammonium fluoride (tetrahydrofuran solution of 1M, 0.034ml) add to wherein, the solution that obtains at room temperature stirred 3 days, solvent evaporated under reduced pressure, the resistates that obtains is dissolved in ethyl acetate, solution with water and saturated brine washing, use anhydrous sodium sulfate drying, concentrating under reduced pressure, resistates by silica gel column chromatography purifying (ethyl acetate/hexane=3/1), is obtained title compound (0.14g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.19(6H，s)，3.76(2H，s)，4.04(2H，s)，4.11(2H，s)，4.28(2H，q，J＝7.2Hz)，7.00(2H，s)，7.09(1H，d，J＝0.7Hz)，7.17-7.15(1H，m)，7.51(1H，dd，J＝5.0，1.1Hz)，7.64(1H，d，J＝0.7Hz)，7.82(1H，dd，J＝3.8，1.1Hz)。

MS m/z：511(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[ azoles-2-ylmethyl-(3-thiophene-2-base-[1,2,4]  diazole-5-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.14g) that obtains from embodiment 28-(1) obtains title compound (0.091g), is light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.13(6H，s)，3.72(2H，s)，3.97(2H，s)，4.14(2H，s)，6.96(2H，s)，7.17(1H，s)，7.27(1H，dd，J＝4.9，3.7Hz)，7.79(1H，dd，J＝3.7，1.2Hz)，7.88(1H，dd，J＝4.9，1.2Hz)，8.07(1H，d，J＝0.7Hz)。

MS m/z：483(M+H) ⁺。

Ultimate analysis is C ₂₄H ₂₆N ₄O ₅S

Calculated value: C, 59.74; H, 5.43; N, 11.61.

Measured value: C, 60.31; H, 5.79; N, 11.08.

(1)  azoles-2-ylmethyl amino 2-[2-fluoro-6-methoxyl group-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 13-(1), the compound (0.10g) that compound (0.11g) that obtains from reference example 28 and reference example 13-(3) obtain obtains title compound (0.14g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.32(3H，t，J＝7.2Hz)，1.49(6H，s)，2.31(3H，s)，3.68(2H，s)，3.70(2H，s)，3.78(3H，s)，3.91(2H，s)，4.25(2H，q，J＝7.1Hz)，6.76(1H，d，J＝9.8Hz)，7.09(1H，s)，7.23(1H，s)，7.40-7.44(3H，m)，7.64(1H，s)，7.98-8.02(2H，m)。

MS m/z：538(M+H) ⁺。

(2)  azoles-2-ylmethyl amino 2-[2-fluoro-6-methoxyl group-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.14g) that obtains from embodiment 29-(1) obtains the hydrochloride (0.04g) of title compound, is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.55(6H，s)，2.48(3H，s)，4.01(3H，s)，4.06-4.30(6H，m)，6.96(1H，d，J＝10.0Hz)，7.22(1H，s)，7.26(1H，s)，7.43-7.48(3H，m)，7.75(1H，s)，7.98-7.94(2H，m)。

MS m/z：510(M+H) ⁺。

Ultimate analysis is C ₂₇H ₂₈FN ₃O ₆HCl1/4C ₂H ₈O ₂1/2H ₂O

Calculated value: C, 58.28; H, 5.59; N, 7.28.

Measured value: C, 58.75; H, 5.66; N, 6.85.

[embodiment 30]

(1)  azoles-2-ylmethyl amino 2-[2-methoxyl group-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 13-(1), the compound (0.10g) that compound (0.093g) that obtains from reference example 29 and reference example 13-(3) obtain obtains title compound (0.16g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.34(3H，t，J＝7.4Hz)，1.43(6H，s)，2.20(3H，s)，2.29(3H，s)，3.66(2H，s)，3.67(2H，s)，3.70(3H，s)，3.91(2H，s)，4.28(2H，q，J＝7.4Hz)，6.74(1H，s)，6.82(1H，s)，7.08(1H，s)，7.39-7.45(3H，m)，7.63(1H，s)，8.02-7.98(2H，m)。

MS m/z：534(M+H) ⁺。

(2)  azoles-2-ylmethyl amino 2-[2-methoxyl group-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.154g) that obtains from embodiment 30-(1) obtains the hydrochloride (0.112g) of title compound, is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.51(6H，s)，2.26(3H，s)，2.48(3H，s)，3.93(3H，s)，4.08-4.66(6H，m)，6.93(1H，s)，7.23(1H，s)，7.26(1H，s)，7.43-7.47(3H，m)，7.76(1H，s)，7.98-7.93(2H，m)。

MS m/z：506(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₁N ₃O ₆HCl1/4C ₄H ₈O ₂1/2H ₂O

Calculated value: C, 60.78; H, 6.16; N, 7.33.

Measured value: C, 60.67; H, 6.26; N, 6.83.

[embodiment 31]

(1) amino 2-[2,6-dimethyl-4-[[(5-methyl-[1,3,4]  diazole-2-ylmethyl)-(5-methyl-2-right-tolyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

Compound (0.147g) and the 4-chloromethyl-5-methyl-2-that reference example 30-(5) is obtained be right-and tolyl  azoles (0.09g) is dissolved in N, N-2 methylformamide (3ml), cesium carbonate (0.198g) and potassiumiodide (0.02g) are added to wherein, the mixture that obtains stirred 3 days at 60 ℃, reaction mixture dilutes with ethyl acetate, water and saturated brine wash in proper order, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure then, the resistates that obtains is by silica gel column chromatography purifying (ethyl acetate/hexane=3/1), obtain title compound (0.15g), be yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.18(6H，s)，2.26(3H，s)，2.39(4H，s)，2.51(3H，s)，3.66(4H，br s)，3.99(2H，s)，4.28(2H，q，J＝7.2Hz)，6.98(2H，s)，7.24(2H，d，J＝8.1Hz)，7.89(2H，d，J＝8.1Hz)。

MS m/z：547(M+H) ⁺。

(2) amino 2-[2,6-dimethyl-4-[[(5-methyl-[1,3,4]  diazole-2-ylmethyl)-(5-methyl-2-right-tolyl  azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

The compound (0.15g) that embodiment 31-(1) is obtained is dissolved in methyl alcohol (10ml), (2ml) adds to wherein with the 1N aqueous sodium hydroxide solution, the solution that obtains at room temperature stirred 19 hours, reflux is 5 hours then, after the cooling, (2ml) adds to wherein with the 1N aqueous hydrochloric acid, concentrating under reduced pressure, with the resistates ethyl acetate extraction, water and saturated brine wash in proper order, and with anhydrous sodium sulfate drying and solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/9), obtain title compound (0.082g), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.14(6H，s)，2.25(3H，s)，2.36(3H，s)，2.45(3H，s)，3.57(2H，s)，3.61(2H，s)，3.91(2H，s)，6.96(2H，s)，7.32(2H，d，J＝8.1Hz)，7.81(2H，d，J＝8.1Hz)。

MS m/z：519(M+H) ⁺

Ultimate analysis is C ₂₉H ₃₄N ₄O ₅3/5H ₂O

Calculated value: C, 65.79; H, 6.70; N, 10.58.

Measured value: C, 66.10; H, 6.75; N, 10.10.

[embodiment 32]

(1) 2-[4-[[[2-(4-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl]-(5-methyl-[1,3,4]  diazole-2-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.147g) and 4-chloromethyl-2-(4-the chloro-phenyl-)-5-methyl  azoles (0.098g) that obtain from reference example 30-(5) obtain title compound (0.18g), are light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(5H，s)，2.18(5H，s)，2.27(2H，s)，2.51(3H，d，J＝0.7Hz)，3.66(1H，s)，3.66(2H，s)，3.98(2H，s)，4.28(2H，q，J＝7.1Hz)，6.97(2H，s)，7.41(2H，d，J＝8.1Hz)，7.94(2H，d，J＝8.3Hz)。

MS m/z：567(M+H) ⁺。

(2) 2-[4-[[[2-(4-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl]-(5-methyl-[1,3,4]  diazole-2-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.18g) that obtains from embodiment 32-(1) obtains title compound (0.094g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.13(6H，s)，2.26(3H，s)，2.46(3H，s)，3.59(2H，s)，3.61(2H，s)，3.91(2H，s)，6.96(2H，s)，7.58(2H，d，J＝8.6Hz)，7.92(2H，d，J＝8.6Hz).

MS m/z：540(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₁ClN ₄O ₅3/4H ₂O

Calculated value: C, 60.87; H, 5.93; N, 10.14.

Measured value: C, 61.36; H, 5.92; N, 9.64.

[embodiment 33]

(1) 2-[2,6-dimethyl-4-[[(3-phenyl [1,2,4]  diazole-5-ylmethyl) the thiazol-2-yl methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.13g) that obtains from 5-chloromethyl-3-phenyl [1,2,4]  diazole (0.070g) and reference example 31 obtains title compound (0.080g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.20(5H，s)，3.78(2H，s)，4.10(2H，s)，4.22(2H，s)，4.28(2H，q，J＝7.1Hz)，7.05(2H，s)，7.33(1H，d，J＝3.4Hz)，7.49-7.52(4H，m)，7.72(1H，d，J＝3.2Hz)，8.12-8.10(2H，m)。

MS m/z：521(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(3-phenyl [1,2,4]  diazole-5-ylmethyl) the thiazol-2-yl methylamino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.080g) that obtains from embodiment 33-(1) obtains title compound (0.038g), is light yellow oil.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.31(6H，s)，2.14(6H，s)，3.74(2H，s)，4.15(2H，s)，4.17(2H，s)，7.03(2H，s)，7.61-7.57(3H，m)，7.69(1H，d，J＝3.2Hz)，7.74(1H，d，J＝3.4Hz)，8.01-8.03(2H，m)。

MS m/z：493(M+H) ⁺。

[embodiment 34]

(1) 2-[2,6-dimethyl-4-[[(5-phenyl  azoles-2-ylmethyl) the thiazol-2-yl methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.084g) that obtains from 2-chloromethyl-5-phenyl  azoles (0.045g) and reference example 31 obtains title compound (0.053g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(4H，t，J＝7.1Hz)，1.45(7H，s)，2.19(6H，s)，3.73(2H，s)，3.96(2H，s)，4.16(2H，s)，4.28(2H，q，J＝7.2Hz)，7.07(2H，s)，7.27-7.36(4H，m)，7.43(2H，t，J＝7.6Hz)，7.66-7.64(2H，m)，7.71(1H，d，J＝3.4Hz)。

MS m/z：520(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-phenyl  azoles-2-ylmethyl) the thiazol-2-yl methylamino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.050g) that obtains from embodiment 34-(1) obtains title compound (0.034g), is light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.14(6H，s)，3.66(2H，s)，3.91(2H，s)，4.10(2H，s)，7.04(2H，s)，7.40-7.36(1H，m)，7.49(2H，t，J＝7.7Hz)，7.62(1H，s)，7.67-7.73(4H，m)。

MS m/z：492(M+H) ⁺。

[embodiment 35]

(1) 2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl] the thiazol-2-yl methylamino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.090g) that compound (0.143g) that obtains from reference example 31 and reference example 32 obtain obtains title compound (0.155g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(7H，s)，2.19(7H，s)，2.21(3H，s)，2.51(3H，s)，3.60(2H，s)，3.63(2H，s)，4.06(2H，s)，4.28(2H，q，J＝7.0Hz)，6.73(1H，d，J＝3.2Hz)，7.03(2H，s)，7.27(1H，d，J＝2.9Hz)，7.38(1H，d，J＝3.4Hz)，7.68(1H，d，J＝3.2Hz)。

MS m/z：554(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl] the thiazol-2-yl methylamino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.15g) that obtains from embodiment 35-(1) obtains title compound (0.114g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.15(6H，s)，2.19(3H，s)，3.29(2H，s)，3.53(2H，s)，3.57(3H，s)，3.99(2H，s)，6.88(1H，dd，J＝3.6，1.1Hz)，7.03(2H，s)，7.40(1H，d，J＝3.4Hz)，7.64(1H，d，J＝3.2Hz)，7.71(1H，d，J＝3.4Hz)。

MS m/z：526(M+H) ⁺。

Ultimate analysis is C ₂₇H ₃₁N ₃O ₄S ₂1/2H ₂O

Calculated value: C, 60.65; H, 6.03; N, 7.86; S, 11.99.

Measured value: C, 60.70; H, 5.90; N, 7.66; S, 11.68.

[embodiment 36]

(1) 2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl]  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.15g) that compound (0.23g) that obtains from reference example 23 and reference example 32 obtain obtains title compound (0.296g), is yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.23(3H，s)，2.51(3H，s)，3.61(4H，s)，3.90(2H，s)，4.28(2H，q，J＝7.1Hz)，6.73(1H，d，J＝2.7Hz)，6.98(2H，s)，7.07(1H，s)，7.39(1H，d，J＝3.7Hz)，7.63(1H，s)。

MS m/z：538(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl]  azoles-2-ylmethyl amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.296g) that obtains from embodiment 36-(1) obtains title compound (0.150g), is light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.13(6H，s)，2.21(3H，s)，3.51(2H，s)，3.56(2H，s)，3.57(3H，s)，3.79(2H，s)，6.88(1H，dd，J＝3.7，1.0Hz)，6.95(2H，s)，7.18(1H，d，J＝0.7Hz)，7.39(1H，d，J＝3.7Hz)，8.07(1H，d，J＝0.7Hz)。

MS m/z：510(M+H) ⁺。

Ultimate analysis is C ₂₇H ₃₁N ₃O ₅S1/2H ₂O

Calculated value: C, 62.53; H, 6.22; N, 8.10; S, 6.18.

Measured value: C, 62.73; H, 6.15; N, 7.77; S, 6.00.

[embodiment 37]

(1) 2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl]-(5-methyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.142g) that compound (0.090g) that obtains from reference example 32 and reference example 33-(4) obtain obtains title compound (0.16g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.18(6H，s)，2.24(3H，s)，2.30(3H，s)，2.51(3H，s)，3.61(2H，s)，3.61(2H，s)，3.82(2H，s)，4.28(2H，q，J＝7.2Hz)，6.65(1H，d，J＝1.2Hz)，6.73(1H，dd，J＝3.7，1.0Hz)，6.98(2H，s)，7.39(1H，d，J＝3.7Hz)。

MS m/z：552(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl]-(5-methyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.16g) that obtains from embodiment 37-(1) obtains title compound, then 4N hydrochloric acid-dioxane added to wherein, and drying under reduced pressure, obtain the hydrochloride (0.11g) of title compound, be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.35(6H，s)，2.16(6H，s)，2.27-2.28(6H，m)，2.49-2.51(3H，m)，4.21-4.01(6H，m)，6.89-6.92(2H，m)，7.12(2H，s)，7.45(1H，d，J＝3.7Hz)。

MS m/z：524(M+H) ⁺。

Ultimate analysis: be C ₂₈H ₃₃N ₃O ₅SHCl1/2H ₂O

Calculated value: C, 59.09; H, 6.20; N, 7.38; S, 5.63.

Measured value: C, 59.20; H, 6.04; N, 7.13; S, 5.65.

[embodiment 38]

(1) 2-[2,6-dimethyl-4-[[(5-methyl  azoles-2-ylmethyl)-(3-phenyl [1,2,4]  diazole-5-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.13g) that obtains from 5-chloromethyl-3-phenyl [1,2,4]- diazole (0.070g) and reference example 33-(4) obtains title compound (0.12g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.19(6H，s)，2.29(3H，d，J＝1.2Hz)，3.77(2H，s)，3.98(2H，s)，4.12(2H，s)，4.28(2H，q，J＝7.2Hz)，6.66(1H，d，J＝1.2Hz)，7.01(2H，s)，7.52-7.48(3H，m)，8.09-8.12(2H，m)。

MS m/z：519(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl  azoles-2-ylmethyl)-(3-phenyl [1,2,4]  diazole-5-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.12g) that obtains from embodiment 38-(1) obtains title compound, then 4N hydrochloric acid-dioxane added to wherein, and drying under reduced pressure, obtain the hydrochloride (0.082g) of title compound, be light yellow oil.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.14(6H，s)，2.22(3H，s)，3.76(2H，s)，3.91(2H，s)，4.17(2H，s)，6.73(1H，d，J＝1.2Hz)，6.98(2H，s)，7.56-7.61(3H，m)，7.99-8.01(2H，m).

MS m/z：491(M+H) ⁺。

[embodiment 39]

(1) 2-[2,6-dimethyl-4-[[(5-methyl  azoles-2-ylmethyl)-(5-phenyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.084g) that obtains from 2-chloromethyl-5-phenyl  azoles (0.045g) and embodiment 33-(4) obtains title compound (0.11g), is light yellow oil.

MS m/z：518(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl  azoles-2-ylmethyl)-(5-phenyl  azoles-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.11g) that obtains from embodiment 39-(1) obtains title compound, then 4N hydrochloric acid-dioxane is added to wherein and drying under reduced pressure, obtain the hydrochloride (0.033g) of title compound, be light yellow solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.13(6H，s)，2.25(3H，s)，3.76(2H，s)，3.95(2H，s)，4.00(2H，s)，6.78(1H，d，J＝1.2Hz)，6.99(2H，s)，7.37-7.40(1H，m)，7.46-7.50(2H，m)，7.62(1H，s)，7.68-7.72(2H，m)。

MS m/z：490(M+H) ⁺。

[embodiment 40]

(1) 2-[2,6-dimethyl-4-[[methylamino formyl radical methyl-(5-methyl-2-right-tolyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 14-(1), compound (0.232g) that obtains from reference example 34-(2) and methylamine hydrochloride (0.037g) and triethylamine (0.172ml) obtain title compound (0.084g), are colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.17(6H，s)，2.25(3H，s)，2.41(3H，s)，2.79(3H，d，J＝4.9Hz)，3.26(2H，s)，3.55(2H，s)，3.66(2H，s)，4.28(2H，q，J＝7.2Hz)，6.92(2H，s)，7.26(2H，d，J＝7.8Hz)，7.80-7.94(3H，m)。

MS m/z：522(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[methylamino formyl radical methyl-(5-methyl-2-right-tolyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 16-(2), the compound (0.084g) that Processing Example 40-(1) obtains, by silica gel column chromatography purifying (11% methyl alcohol-chloroform), obtain title compound (0.072g) then, be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.49(6H，s)，2.20(6H，s)，2.27(3H，s)，2.40(3H，s)，2.78(3H，d，J＝4.9Hz)，3.24(2H，br s)，3.53(2H，br s)，3.63(2H，br s)，6.92(2H，s)，7.22-7.29(2H，m)，7.85-8.01(3H，m)。

MS m/z：494(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₅N ₃O ₅1/2H ₂O

Calculated value: C, 66.91; H, 7.22; N, 8.36.

Measured value: C, 67.10; H, 7.28; N, 8.09.

[embodiment 41]

(1) 2-[4-[[[2-(4-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] methylamino formyl radical methylamino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

[0519]

With the same method of embodiment 40-(1), the compound (0.261g) that obtains from reference example 35-(2) obtains title compound (0.220g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.17(6H，s)，2.24(3H，s)，2.79(3H，d，J＝5.1Hz)，3.22(2H，s)，3.50(2H，s)，3.59(2H，s)，4.28(2H，q，J＝7.2Hz)，6.88(2H，s)，7.40-7.46(2H，m)，7.64-7.75(1H，m)，7.90-7.96(2H，m)。

MS m/z：542(M+H) ⁺。

(2) 2-[4-[[[2-(4-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] methylamino formyl radical methylamino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 40-(2), the compound (0.220g) that obtains from embodiment 41-(1) obtains title compound (0.180g), is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.49(6H，s)，2.20(6H，s)，2.28(3H，s)，2.79(3H，d，J＝4.9Hz)，3.24(2H，br s)，3.53(2H，br s)，3.63(2H，br s)，6.92(2H，br s)，7.40-7.47(2H，m)，7.76-7.89(1H，m)，7.90-7.97(2H，m)。

MS m/z：514(M+H) ⁺。

Ultimate analysis is C ₂₇H ₃₂ClN ₃O ₅

Calculated value: C, 63.09; H, 6.27; Cl, 6.90; N, 8.17.

Measured value: C, 63.02; H, 6.30; Cl, 6.97; N, 8.10.

[embodiment 42]

(1) 2-[4-[[[2-(3-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] methylamino formyl radical methylamino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 40-(1), the compound (0.214g) that obtains from reference example 36-(2) obtains title compound (0.194g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.17(6H，s)，2.25(3H，s)，2.81(3H，d，J＝4.9Hz)，3.22(2H，s)，3.50(2H，s)，3.59(2H，s)，4.28(2H，q，J＝7.2Hz)，6.89(2H，br s)，7.36-7.43(2H，m)，7.65-7.75(1H，m)，7.84-7.91(1H，m)，7.97-8.00(1H，m)。

MS m/z：542(M+H) ⁺。

(2) 2-[4-[[[2-(3-chloro-phenyl-)-5-methyl  azoles-4-ylmethyl] methylamino formyl radical methylamino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 40-(2), the compound (0.194g) that obtains from embodiment 42-(1) obtains title compound (0.156g), is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.49(6H，s)，2.20(6H，s)，2.29(3H，s)，2.80(3H，d，J＝4.9Hz)，3.24(2H，s)，3.53(2H，s)，3.62(2H，s)，6.92(2H，s)，7.36-7.44(2H，m)，7.76-7.92(2H，m)，7.97-8.01(1H，m)。

MS m/z：514(M+H) ⁺。

Ultimate analysis is C ₂₇H ₃₂ClN ₃O ₅1/4H ₂O

Calculated value: C, 62.54; H, 6.32; Cl, 6.84; N, 8.10.

Measured value: C, 62.45; H, 6.36; Cl, 6.71; N, 7.80.

[embodiment 43]

(1) 2-[2-methoxyl group-6-methyl-4-[[methylamino formyl radical methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 14-(1), the compound (0.118g) that obtains from reference example 37-(3) obtains title compound (0.109g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.40(6H，s)，1.50(9H，s)，2.20(3H，s)，2.28(3H，s)，2.79(3H，d，J＝4.9Hz)，3.22(2H，s)，3.52(2H，s)，3.62(2H，s)，3.68(3H，s)，6.65(1H，d，J＝1.7Hz)，6.68(1H，d，J＝1.7Hz)，7.41-7.48(3H，m)，7.85(1H，q，J＝4.9Hz)，7.97-8.02(2H，m)。

MS m/z：552(M+H) ⁺。

(2) 2-[2-methoxyl group-6-methyl-4-[[methylamino formyl radical methyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 1-(2), the compound (0.109g) that Processing Example 43-(1) obtains, by silica gel column chromatography purifying (methyl alcohol/chloroform=8/92), obtain title compound (0.087g) then, be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.48(6H，s)，2.24(3H，s)，2.31(3H，s)，2.81(3H，d，J＝4.9Hz)，3.21(2H，s)，3.55(2H，s)，3.65(2H，s)，3.77(3H，s)，6.73(1H，d，J＝1.7Hz)，6.76(1H，d，J＝1.7Hz)，7.44-7.48(3H，m)，7.90(1H，q，J＝4.6 Hz)，8.01-7.96(2H，m)。

MS m/z：496(M+H) ⁺。

Ultimate analysis is C ₂₇H ₃₃N ₃O ₆1/2H ₂O

Calculated value: C, 64.27; H, 6.79; N, 8.33.

Measured value: C, 64.34; H, 6.71; N, 8.16.

[embodiment 44]

(1) thiazol-2-yl methylamino 2-[2-methoxyl group-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 1-(1), the compound (0.100g) that obtains from reference example 37-(2) obtains title compound (0.058g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.40(6H，s)，1.51(9H，s)，2.22(3H，s)，2.28(3H，s)，3.66(2H，s)，3.68(2H，s)，3.76(3H，s)，4.08(2H，s)，6.77(1H，d，J＝1.7Hz)，6.90(1H，d，J＝1.7Hz)，7.28(1H，d，J＝3.2Hz)，7.38-7.45(3H，m)，7.69(1H，d，J＝3.4Hz)，7.97-8.02(2H，m)。

MS m/z：578(M+H) ⁺。

(2) thiazol-2-yl methylamino 2-[2-methoxyl group-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 1-(2), the compound (0.058g) that obtains from embodiment 44-(1) obtains title compound (0.041g), is colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.49(6H，s)，2.27(3H，s)，2.31(3H，s)，3.69(2H，s)，3.74(2H，s)，3.87(3H，s)，4.07(2H，s)，6.85(1H，s)，7.01(1H，s)，7.29(1H，d，J＝3.2Hz)，7.40-7.47(3H，m)，7.70(1H，d，J＝3.2Hz)，8.01-7.97(2H，m)。

MS m/z：522(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₁N ₃O ₅S1/4H ₂O

Calculated value: C, 63.92; H, 6.03; N, 7.99; S, 6.09.

Measured value: C, 63.92; H, 5.97; N, 7.63; S, 5.93.

[embodiment 45]

(1)  azoles-2-ylmethyl amino 2-[2-fluoro-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 13-(1), the compound that compound (0.094g) that obtains from reference example 38 and reference example 13-(3) obtain obtains title compound (0.082g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.28(3H，t，J＝7.1Hz)，1.56(6H，s)，2.31(3H，s)，3.67(2H，s)，3.70(2H，s)，3.89(2H，s)，4.24(2H，q，J＝7.1Hz)，6.92(1H，t，J＝8.4Hz)，7.03(1H，d，J＝8.3Hz)，7.08(1H，s)，7.19(1H，dd，J＝11.8，1.7Hz)，7.38-7.46(3H，m)，7.64(1H，s)，8.03-7.98(2H，m).

MS m/z：508(M+H) ⁺。

(2)  azoles-2-ylmethyl amino 2-[2-fluoro-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 24-(2), the compound (0.082g) that obtains from embodiment 45-(1) obtains the hydrochloride (0.059g) of title compound, is colorless solid.

MS m/z：450(M+H) ⁺。

Ultimate analysis is C ₂₆H ₂₆FN ₃O ₅HCl

Calculated value: C, 60.52; H, 5.27; N, 8.14.

Measured value: C, 60.38; H, 5.23; N, 7.98.

[embodiment 46]

(1) 2-[2,6-dimethyl-4-[[[2-(5-methyl-2-phenyl  azoles-4-yl) ethyl]  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.100g) and 2-(5-methyl-2-phenyl  azoles-4-yl) ethyltoluene-4-sulphonate (0.206g) that obtain from reference example 23 obtain title compound (0.069g), are colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.44(6H，s)，2.15(6H，s)，2.28(3H，s)，2.67-2.74(2H，m)，2.81-2.87(2H，m)，3.64(2H，s)，3.86(2H，s)，4.28(2H，q，J＝7.1Hz)，6.93(2H，s)，7.06(1H，d，J＝0.7Hz)，7.37-7.44(3H，m)，7.61(1H，d，J＝0.7Hz)，7.99-7.93(2H，m).

MS m/z：532(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[[2-(5-methyl-2-phenyl  azoles-4-yl) ethyl]  azoles-2-ylmethyl amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.069g) that obtains from embodiment 46-(1) obtains title compound (0.026g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.46(6H，s)，2.16(6H，s)，2.30(3H，s)，2.66(2H，t，J＝7.2Hz)，2.83(2H，t，J＝7.2Hz)，3.63(2H，s)，3.88(2H，s)，6.93(2H，s)，7.08(1H，s)，7.44-7.38(3H，m)，7.63(1H，d，J＝0.7Hz)，7.95-7.90(2H，m)。

MS m/z：504(M+H) ⁺。

[embodiment 47]

(1) 2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-(the different  azoles of 5-phenyl-3-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), but be to use salt of wormwood to replace cesium carbonate, the compound that compound (0.166g) that obtains from reference example 23 and reference example 39 obtain obtains title compound (0.142g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.19(6H，s)，3.64(2H，s)，3.81(2H，s)，3.85(2H，s)，4.28(2H，q，J＝7.1Hz)，6.59(1H，s)，6.99(2H，s)，7.09(1H，s)，7.41-7.48(3H，m)，7.65(1H，s)，7.79(2H，d，J＝8.3Hz)。

MS m/z：504(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[ diazole-2-ylmethyl-(the different  azoles of 5-phenyl-3-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.138g) that obtains from embodiment 47-(1) obtains title compound (0.083g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.15(6H，s)，3.59(2H，s)，3.80(2H，s)，3.81(2H，s)，6.98(2H，s)，7.01(1H，s)，7.19(1H，s)，7.48-7.57(3H，m)，7.88(2H，d，J＝7.3Hz)，8.08(1H，s)。

MS m/z：476(M+H) ⁺。

Ultimate analysis is C ₂₇H ₂₉N ₃O ₅1/4C ₄H ₈O ₂3/4H ₂O

Calculated value: C, 66.98; H, 6.32; N, 8.37.

Measured value: C, 67.15; H, 6.31; N, 8.01.

[embodiment 48]

(1) 2-[2-ethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-and  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 13-(1), the compound (0.100g) and 2-(2-ethyl-4-formyl radical the phenoxy group)-2 Methylpropionic acid ethyl ester (0.099g) that obtain from reference example 13-(3) obtain title compound (0.107g), are colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.19(3H，t，J＝7.6Hz)，1.23(3H，t，J＝7.1Hz)，1.58(6H，s)，2.30(3H，s)，2.63(2H，q，J＝7.4Hz)，3.66(2H，s)，3.67(2H，s)，3.89(2H，s)，4.22(2H，q，J＝7.1Hz)，6.59(1H，d，J＝8.1Hz)，7.09-7.04(2H，m)，7.19(1H，d，J＝1.7Hz)，7.45-7.36(3H，m)，7.63(1H，s)，8.02-7.97(2H，m)。

MS m/z：518(M+H) ⁺。

(2) 2-[2-ethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-and  azoles-2-ylmethyl amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.107g) that obtains from embodiment 48-(1) obtains title compound, then 4 N hydrochloric acid-dioxanes are added to wherein and concentrating under reduced pressure, obtain the hydrochloride (0.075g) of title compound, be colorless solid.

MS m/z：490(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₁N ₃O ₅HCl

Calculated value: C, 63.93; H, 6.13; Cl, 6.74; N, 7.99.

Measured value: C, 63.74; H, 6.19; Cl, 6.46; N, 7.64.

[embodiment 49]

(1)  azoles-2-ylmethyl amino 2-[2-ethyl-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 13-(1), the compound (0.124g) that compound (0.120g) that obtains from reference example 13-(3) and reference example 40 obtain obtains title compound (0.156g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.18(3H，t，J＝7.6Hz)，1.35(3H，t，J＝7.4 Hz)，1.44(6H，s)，2.18(3H，s)，2.28(3H，s)，2.56(2H，q，J＝7.5Hz)，3.66(2H，s)，3.66(2H，s)，3.93(2H，s)，4.28(2H，q，J＝7.1Hz)，7.00(1H，s)，7.04(1H，s)，7.08(1H，s)，7.39-7.45(3H，m)，7.64(1H，s)，8.03-7.98(2H，m)。

MS m/z：532(M+H) ⁺。

(2)  azoles-2-ylmethyl amino 2-[2-ethyl-6-methyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.154g) that obtains from embodiment 49-(1) obtains title compound, then 4N hydrochloric acid-dioxane is added to wherein and be concentrated into dried, from ethyl acetate-hexane crystallization, obtain the hydrochloride (0.094g) of title compound, be colorless solid.

MS m/z：504(M+H) ⁺。

Ultimate analysis is C ₂₉H ₃₃N ₃O ₅0.85HCl0.5H ₂O

Calculated value: C, 64.08; H, 6.46; Cl, 5.54; N, 7.70.

Measured value: C, 64.33; H, 6.64; Cl, 5.56; N, 7.28.

[embodiment 50]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-trifluoromethyl-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

Method similarly to Example 18, the compound (0.135g) that obtains from reference example 41-(4) obtains title compound (0.036g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.41(6H，s)，1.51(9H，s)，2.21(6H，s)，2.28(3H，s)，3.70(2H，s)，3.72(2H，s)，4.12(2H，s)，6.96(2H，s)，7.42-7.44(3H，m)，8.00-7.98(2H，m)。

MS m/z：615(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-trifluoromethyl-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (0.035g) that embodiment 50-(1) is obtained is dissolved in methylene dichloride (5ml), under ice-water cooling, (1ml) adds to wherein with trifluoroacetic acid, and the solution that obtains at room temperature stirred 15 hours, evaporating solvent, the resistates that obtains is by preparative thin layer chromatography purifying (methyl alcohol/chloroform=1/19), obtain title compound, it is dissolved in 4N hydrochloric acid-dioxane solution, be concentrated into dried then, obtain the hydrochloride (0.030g) of title compound, be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.33(6H，s)，2.13(6H，s)，2.29(3H，s)，3.72(4H，s)，4.13(2H，s)，6.98(2H，s)，7.49-7.53(3H，m)，7.92-7.89(2H，m)。

MS m/z：559(M+H) ⁺。

[embodiment 51]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-oxo-4,5-dihydro-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 17-(1), the compound (0.100g) that obtains from reference example 41-(2) obtains title compound (0.052g), is light yellow oil.

MS m/z：563(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(4-methyl-5-oxo-4,5-dihydro-[1,3,4]  diazole-2-ylmethyl)-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

The compound (0.052g) that embodiment 51-(1) is obtained, methyl alcohol (0.50ml) and triphenylphosphine (0.038g) are dissolved in tetrahydrofuran (THF) (5ml), at-78 ℃, (0.03ml) is added drop-wise to wherein with azo-2-carboxylic acid's diisopropyl ester, the room temperature of then solution that obtains being risen again also stirred 19 hours, reaction soln dilutes with ethyl acetate, water washs with saturated brine then, use anhydrous sodium sulfate drying, solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (ethyl acetate/hexane=2/1), obtain title compound (0.055g), be light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.41(6H，s)，1.51(9H，s)，2.21(6H，s)，2.28(3H，s)，3.37(3H，s)，3.64(2H，s)，3.65(2H，s)，3.72(2H，s)，6.97(2H，s)，7.42-7.45(3H，m)，8.01-7.98(2H，m).

MS m/z：577(M+H) ⁺。

(3) 2-[2,6-dimethyl-4-[[(4-methyl-5-oxo-4,5-dihydro-[1,3,4]  diazole-2-ylmethyl)-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 50-(2), the compound (0.052g) that obtains from embodiment 51-(2) obtains the hydrochloride (0.036g) of title compound, is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.34(6H，s)，2.15(6H，s)，2.30(3H，s)，3.27(3H，s)，3.56-3.71(4H，m)，3.87-3.95(2H，m)，7.07(2H，s)，7.52-7.54(3H，m)，7.95-7.92(2H，m)。

MS m/z：521(M+H) ⁺。

Ultimate analysis is C ₂₈H ₃₂N ₄O ₆HCl1/2H ₂O

Calculated value: C, 59.41; H, 6.05; N, 9.90.

Measured value: C, 59.60; H, 6.15; N, 9.69.

[embodiment 52]

(1) 2-[2,6-two fluoro-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)- azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 13-(1), the compound (0.100g) that compound (0.223g) that obtains from reference example 43 and reference example 13-(3) obtain obtains title compound (0.201g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.48(9H，s)，1.49(6H，s)，2.32(3H，s)，3.68(2H，s)，3.71(2H，s)，3.90(2H，s)，7.00(2H，d，J＝8.6Hz)，7.09(1H，s)，7.38-7.46(3H，m)，7.65(1H，d，J＝0.5Hz)，8.03-7.98(2H，m)。

MS m/z：554(M+H) ⁺。

(2) 2-[2,6-two fluoro-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)- azoles-2-ylmethyl amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 5-(2), the compound (0.201g) that obtains from embodiment 52-(1) obtains the hydrochloride (0.150g) of title compound, is colorless solid.

MS m/z：498(M+H) ⁺。

Ultimate analysis is C ₂₆H ₂₅F ₂N ₃O ₅HCl

Calculated value: C, 58.49; H, 4.91; N, 7.87.

Measured value: C, 58.38; H, 4.87; N, 7.69.

[embodiment 53]

(1) 2-[4-methoxyl group-3-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-and  azoles-2-ylmethyl amino] methyl] phenoxy group]-the 2 Methylpropionic acid tertiary butyl ester

With the same method of embodiment 13-(1), the compound (0.100g) that compound (0.219g) that obtains from reference example 44 and reference example 13-(3) obtain obtains title compound (0.183g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.44(9H，s)，1.50(6H，s)，2.31(3H，s)，3.69(2H，s)，3.71(3H，s)，3.75(2H，s)，3.92(2H，s)，6.69(1H，d，J＝8.8Hz)，6.77(1H，dd，J＝8.8，2.9Hz)，7.06(1H，s)，7.17(1H，d，J＝2.9Hz)，7.45-7.36(3H，m)，7.62(1H，s)，8.02-7.98(2H，m)。

MS m/z：548(M+H) ⁺。

(2) 2-[4-methoxyl group-3-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-and  azoles-2-ylmethyl amino] methyl] phenoxy group]-2 Methylpropionic acid

The compound (0.181g) that embodiment 53-(1) is obtained is dissolved in methylene dichloride (3ml), 4N hydrochloric acid-dioxane solution (5ml) is added to wherein, the solution that obtains at room temperature stirred one day, solvent evaporated under reduced pressure, the resistates that obtains is by silica gel column chromatography purifying (methyl alcohol/chloroform=1/19), obtain title compound (0.090g), be colorless solid.

¹H-NMR(400MHz，CDCl ₃)δ：1.58(6H，s)，2.35(3H，s)，3.57(2H，s)，3.75(3H，s)，3.81(2H，s)，3.86(2H，s)，6.74(1H，d，J＝8.6Hz)，6.86(1H，d，J＝7.6Hz)，7.11(1H，s)，7.49-7.43(3H，m)，7.64(1H，s)，7.72(1H，d，J＝2.7Hz)，8.05-7.99(2H，m)。

MS m/z：492(M+H) ⁺。

Ultimate analysis is C ₂₇H ₂₉N ₃O ₆1/2H ₂O

Calculated value: C, 64.79; H, 6.04; N, 8.39.

Measured value: C, 64.66; H, 6.03; N, 8.09.

[embodiment 54]

(1) amino 2-[2,6-dimethyl-4-[[(3-methyl-[1,2,4]  diazole-5-ylmethyl)-(5-methyl-2-right-tolyl- azoles-4-ylmethyl)] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), compound (0.150g) and the 4-chloromethyl-5-methyl-2-that obtains from reference example 45-(4) be right-and tolyl  azoles (0.075g) obtains title compound (0.090g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.26(3H，s)，2.39(6H，br s)，3.66(2H，s)，3.69(2H，s)，4.02(2H，s)，4.28(2H，q，J＝7.1Hz)，6.99(2H，s)，7.23(2H，d，J＝8.5Hz)，7.88(2H，d，J＝8.1Hz)。

MS m/z：547(M+H) ⁺。

(2) amino 2-[2,6-dimethyl-4-[[(3-methyl-[1,2,4]  diazole-5-ylmethyl)-(5-methyl-2-right-tolyl- azoles-4-ylmethyl)] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.090g) that obtains from embodiment 45-(1) obtains title compound (0.047g), is colorless oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.50(6H，s)，2.22(6H，s)，2.28(3H，s)，2.39(3H，s)，2.41(3H，s)，3.69(2H，s)，3.71(2H，s)，4.03(2H，s)，7.04(2H，s)，7.22-7.24(2H，m)，7.87-7.90(2H，m).

MS m/z：519(M+H) ⁺。

[embodiment 55]

2-[2,6-dimethyl-4-[[[5-methyl-2-(5-thiotolene-2-yl)  azoles-4-ylmethyl]-(3-methyl-[1,2,4]  diazole-5-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 31-(1), the compound (0.077g) that compound (0.150g) that obtains from embodiment 45-(4) and reference example 32 obtain obtains title compound (0.055g), is light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.18(6H，s)，2.23(3H，s)，2.41(3H，s)，2.51(3H，s)，3.64(2H，s)，3.66(2H，s)，4.01(2H，s)，4.28(2H，q，J＝7.2Hz)，6.73(1H，dd，J＝3.7，1.2Hz)，6.99(2H，s)，7.39(1H，d，J＝3.7Hz)。

MS m/z：553(M+H) ⁺。

[embodiment 56]

(1) 2-[4-[[cyclopropyl carbamyl ylmethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 14-(1), the compound (0.150g) and the cyclopropylamine (0.030ml) that obtain from reference example 14-(3) obtain title compound (0.110g), are light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：0.48-0.52(2H，m)，0.71-0.76(2H，m)，1.26(1H，br s)，1.35(3H，t，J＝7.1Hz)，1.44(6H，s)，2.16(6H，s)，2.26(3H，s)，3.18(2H，s)，3.48(2H，s)，3.57(2H，s)，4.28(2H，q，J＝7.1Hz)，6.86(2H，s)，7.44-7.48(3H，m)，7.89(1H，br s)，8.00-8.02(2H，m)。

MS m/z：534(M+H) ⁺。

(2) 2-[4-[[cyclopropyl carbamyl ylmethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.110g) that obtains from embodiment 56-(1) obtains title compound (0.076g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：0.36-0.40(2H，m)，0.59-0.63(2H，m)，1.32(6H，s)，2.11(6H，s)，2.25(3H，s)，2.66-2.68(1H，m)，3.06(2H，s)，3.53(2H，s)，3.57(2H，s)，6.94(2H，s)，7.50-7.55(3H，m)，7.83(1H，d，J＝4.2Hz)，7.95-7.92(2H，m)。

MS m/z：506(M+H) ⁺。

Ultimate analysis is C ₂₉H ₃₅N ₃O ₅3/4H ₂O

Calculated value: C, 67.10; H, 7.09; N, 8.09.

Measured value: C, 67.21; H, 6.60; N, 7.93.

[embodiment 57]

(1) methyl 2-[4-[[[(cyclopropyl methylamino formyl radical)]-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 14-(1), the compound (0.150g) and the cyclopropyl methylamine (0.040ml) that obtain from reference example 14-(3) obtain title compound (0.075g), are light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：0.19-0.21(2H，m)，0.44-0.48(2H，m)，0.92-0.97(1H，m)，1.35(3H，t，J＝7.1Hz)，1.45(6H，s)，2.17(6H，s)，2.27(3H，s)，3.10-3.13(2H，m)，3.22(2H，s)，3.53(2H，s)，3.60(2H，s)，4.28(2H，q，J＝7.1Hz)，6.93(2H，s)，7.42-7.46(3H，m)，7.81(1H，br s)，8.01-7.98(2H，m)。

MS m/z：548(M+H) ⁺。

(2) methyl 2-[4-[[[(cyclopropyl methylamino formyl radical)]-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.075g) that obtains from embodiment 57-(1) obtains title compound (0.058g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：0.12-0.16(2H，m)，0.34-0.39(2H，m)，1.32(6H，s)，2.13(6H，s)，2.26(3H，s)，2.66-2.68(1H，m)，2.97(2H，t，J＝6.3Hz)，3.10(2H，s)，3.54(2H，s)，3.58(2H，s)，7.00(2H，s)，7.49-7.55(3H，m)，7.85(1H，t，J＝5.6Hz)，7.95-7.92(2H，m)。

MS m/z：520(M+H) ⁺。

Ultimate analysis is C ₃₀H ₃₇N ₃O ₅1/2H ₂O

Calculated value: C, 68.16; H, 7.25; N, 7.95.

Measured value: C, 68.22; H, 6.93; N, 7.86.

[embodiment 58]

(1) 2-[4-[[butyl carbamyl ylmethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-the 2 Methylpropionic acid ethyl ester

With the same method of embodiment 14-(1), the compound (0.150g) and the butylamine (0.042ml) that obtain from reference example 14-(3) obtain title compound (0.120g), are light yellow oil.

¹H-NMR(400MHz，CDCl ₃)δ：0.88(3H，t，J＝7.4Hz)，1.30-1.36(5H，m)，1.44(6H，s)，1.47-1.53(2H，m)，2.17(6H，s)，2.27(3H，s)，3.19-3.25(4H，m)，3.51(2H，s)，3.59(2H，s)，4.28(2H，q，J＝7.1Hz)，6.90(2H，s)，7.43-7.46(3H，m)，7.78(1H，br s)，8.01-7.99(2H，m)。

MS m/z：550(M+H) ⁺。

(2) 2-[4-[[butyl carbamyl ylmethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the compound (0.120g) that obtains from embodiment 58-(1) obtains title compound (0.069g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：0.81(3H，t，J＝7.2Hz)，1.19-1.28(2H，m)，1.32(6H，s)，1.33-1.41(2H，m)，2.12(6H，s)，2.26(3H，s)，3.04-3.09(4H，m)，3.54(2H，s)，3.58(2H，s)，6.98(2H，s)，7.50-7.55(3H，m)，7.79(1H，t，J＝6.1Hz)，7.92-7.95(2H，m)。

MS m/z：522(M+H) ⁺。

Ultimate analysis is C ₃₀H ₃₉N ₃O ₅1/2H ₂O

Calculated value: C, 67.90; H, 7.60; N, 7.92.

Measured value: C, 68.09; H, 7.23; N, 7.87.

[embodiment 59]

(1) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-pyridin-3-yl-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-the 2 Methylpropionic acid ethyl ester

Method similarly to Example 18, the compound (0.170g) that obtains from reference example 46 obtains title compound, and it is the mixture with triphenyl phosphorus oxide (0.62g).

¹H-NMR(400MHz，CDCl ₃)δ：1.35(3H，t，J＝7.2Hz)，1.45(6H，s)，2.18(6H，s)，2.31(3H，s)，3.75(6H，br s)，4.28(2H，q J＝7.1Hz)，7.03(2H，s)，7.40-7.42(3H，m)，7.96-7.99(2H，m)，8.33-8.30(1H，m)，8.76(1H，dd，J＝4.7，1.7Hz)，9.26(1H，d，J＝1.5Hz)。

MS m/z：596(M+H) ⁺。

(2) 2-[2,6-dimethyl-4-[[(5-methyl-2-phenyl  azoles-4-ylmethyl)-(5-pyridin-3-yl-[1,3,4]  diazole-2-ylmethyl) amino] methyl] phenoxy group]-2 Methylpropionic acid

With the same method of embodiment 31-(2), the mixture that obtains from embodiment 59-(1) obtains title compound (0.065g), is colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.28(6H，s)，2.10(6H，s)，2.29(3H，s)，3.69(2H，s)，3.71(2H，s)，4.06(2H，s)，7.00(2H，s)，7.44-7.46(3H，m)，7.59(1H，dd，J＝8.0，4.8Hz)，7.86-7.84(2H，m)，8.28(1H，d，J＝7.8Hz)，8.76(1H，d，J＝3.2Hz)，9.09(1H，s)。

MS m/z：568(M+H) ⁺。

[embodiment 60]

2-[4-[[carbamyl ylmethyl-(5-methyl-2-phenyl  azoles-4-ylmethyl) amino] methyl]-2, the 6-dimethyl phenoxy]-2 Methylpropionic acid

With the same method of embodiment 31-(2), obtain title compound (0.080g) from the compound (0.119g) of embodiment 19-(1), be colorless solid.

¹H-NMR(400MHz，DMSO-d ₆)δ：1.32(6H，s)，2.13(6H，s)，2.24(3H，s)，3.07(2H，s)，3.53(2H，s)，3.57(2H，s)，7.15(1H，br s)，7.31(1H，br s)，7.49-8.53(3H，m)，7.94-7.91(2H，m)。

MS m/z：466(M+H) ⁺。

[experimental example 1]

The test of GAL4-hPPAR trans-activation

(a) plasmid:

The structure that is used for the plasmid pFA-hPPAR α/GAL4 of expressing fusion protein of GAL4 DNA calmodulin binding domain CaM-PPAR ligand binding region and pFA-hPPAR γ/GAL4 is undertaken by under the CMV promotor LBD cDNA of hPPAR α and hPPAR γ being inserted in the commercially available expression vector (pFA trans-activatorplasmid derives from STRATAGENE) with zymic GAL4 DNA calmodulin binding domain CaM (GAL4 DBD) respectively.For the proteic expression of report, use commercially available cDNA upstream to have the plasmid (pFR-SEAP derives from STRATAGENE) that GAL4 replys zone (GAL4 UAS) at secretor type alkaline phosphatase (SEAP).

(b) cell cultures and trans-activation test:

The HEK293T cell suspension is in the Dulbecco of high concentration glucose modification Eagle's medium (DMEM), and this substratum contains 10% foetal calf serum (deriving from Hyclone), 100U/mL penicillin G and 100mg/mL Vetstrep, and with 8 * 10 ⁴The density of individual cells/well is seeded in the 24 porocyte culture plates.Cell is being contained 5%CO ₂Moistening atmosphere under cultivated 24 hours at 37 ℃, under serum-free condition, use Lipofectamine (deriving from Invitrogen) and Plus reagent (deriving from Invirogen) to carry out transfection according to manufacturer's teachings then.Particularly, with cell cultures (OPTI-MEM in the transfection medium of 225 μ L, derive from Invitrogen), this transfection medium contains the pFA-PPAR/GAL4 expression plasmid of Lipofectamine, 0.030 μ g of 0.48 μ L and the pFR-SEAP of 0.13 μ g, at 5%CO ₂Cultivated 5 hours at 37 ℃ under the atmosphere.Then, the fresh high concentration glucose DMEM (contain 10% foetal calf serum, 100U/mL penicillin G, 100mg/mL Vetstrep and be the test compound of prescribed concentration twice) of equal volume is added to wherein, about 48 hours of cell cultures, after being dissolved in compound among the DMSO, DMSO with equal concentrations cultivates with control cells, final DMSO concentration is maximum 0.1%, and known this concentration does not have any influence to transactivation activity.After cultivation, collect culture supernatant, use test kit (reporter assay test kit-SEAP derives from TOYOBO), measure the SEAP activity according to manufacturer's teachings.Particularly, the intrinsic alkaline phosphatase enzyme inhibitors of same amount is added in the medium supernatant of 5 μ L, and 37 ℃ of cultivations 30 minutes, then with chemoluminescence matrix (the Lumiphos PLUS of 100 μ L, derive from Lumigen) add to wherein and cultivated 15 minutes at 37 ℃, use multiple labeling counter (ARVOsx derives from Perkin Elmer) to measure luminous level then.The value of aforesaid operations gained and the concentration of test compound are drawn, obtain EC ₅₀Value.

＜test-results 〉

As shown in the table, compound of the present invention has strong GAL4-hPPAR transactivation activity.

Table 1

The embodiment numbering	GAL4-hPPAR transactivation activity (μ M)
			PPARα	PPARγ
	Embodiment 1-(2)	0.013			0.59
Embodiment 4-(2)			0.0048	0.18
	Embodiment 5-(2)	0.0026			0.22
Embodiment 13-(2)			0.0037	0.0055
	Embodiment 16-(2)	0.0024			0.0088
Embodiment 18-(2)			0.0029	0.033
	Embodiment 19-(3)	0.0027			0.0069
SKB-compd			0.044	0.048

[experimental example 2] determination of dissolution rate

＜test method 〉

1 milligram test compound is placed test tube, first liquid (the simulated gastric fluid with 1 milliliter JapanesePharmacopoeia Disintegration Test Method, pH1.2: hereinafter to be referred as JP-liquid 1) or second liquid of Japanese Pharmacopoeia Disintegration TestMethod (simulated intestinal fluid pH6.8: hereinafter to be referred as JP-liquid 2) adds to wherein and jolting, at room temperature left standstill then 12 hours or the longer time, after leaving standstill, filter by 0.45-μ m membrane filter, filtrate is suitably used the mixture diluted of DMSO-pure water (1/1), with preparation dissolution determination solution.

Except that above-mentioned, the 1mg test compound placed 20 milliliters of measuring bottles, and be dissolved in the mixture of DMSO-pure water (1/1), to prepare the standardized solution of 50 μ g/mL, standardized solution obtains the serial dilution thing through stepwise dilution, uses described dilution to draw working curve.

The above-mentioned dissolution determination that contains JP-liquid 1 or JP-liquid 2 uses HPLC to analyze with solution, based on the working curve of above formation, calculates the dissolution rate of test compound.

The HPLC condition is as follows:

Alliance analyze with the HPLC system (derive from Waters, USA),

Fresh feed pump: 2795 separation modules

UV detector: 2996 photodiode array detectors

Post: ODS-type C18 post (3.5 μ m, 3.0mm ID * 30mm),

Column temperature: 60 ℃,

Mobile phase A: pH4.5, the 10mM acetate buffer,

Mobile phase B: 50% acetate-acetonitrile mixture (1/999),

The ratio of gradient condition: mobile phase A/B, 95/5 to 10/90,

Flow velocity: 1.5mL/min,

Sample temperature: 25 ℃,

Sample size: 5 μ L,

Detect wavelength: the maximum absorption wavelength in 220 to 420 nanometer range.

＜test-results 〉

As shown in the table, compound of the present invention has good dissolution rate in JP-liquid 1 and JP-liquid 2.

Table 2

The embodiment numbering	Dissolution rate (μ g/mL)
			JP-liquid 1	JP-liquid 2
	Embodiment 1-(2)	490			＞1000
Embodiment 4-(2)			930	＜3
	Embodiment 5-(2)	520			680
Embodiment 13-(2)			＞870	＞870
	Embodiment 16-(2)	＞490			480
Embodiment 18-(2)			＞710	＞710
	Embodiment 19-(3)	650			＞710
SKB-compd			240	10

[experimental example 3] is fat-soluble

＜test method 〉

Isopyknic mixture jolting in proper container with the isotonic phosphate buffer liquid (hereinafter to be referred as water) of octanol (hereinafter to be referred as octanol) and pH7.4, left standstill then 24 hours or the longer time, collect upper strata (water-saturated octanol) and lower floor's (octanol-saturation water) respectively.

1 milligram test compound is placed test tube, 5 milliliters water-saturated octanol is added to wherein, supersound process 10 minutes, stir about is 30 seconds then.When observing insoluble substance, with the membrane filter of liquid filtering by 0.45 μ m.Water-saturated the octanol solution of 2 milliliters test compounds is placed test tube, add wherein octanol-saturation waters of 2 milliliters to also jolting 30 minutes.Then, it is carried out centrifugal treating to be separated into upper strata (octanol phase) and lower floor's (water), collect each phase then respectively.

Octanol phase and water suitably dilute with DMSO, detect the concentration of HPLC or MS-detection HPLC mensuration test compound wherein by UV-.

From each concentration of measuring mutually and each thinning ratio mutually, by calculating partition ratio.

When the solvability of test compound in water is higher according to estimates, then test compound is dissolved in octanol-saturation water, to wherein adding entry-saturated octanol, jolting and centrifugal, collect upper strata (octanol phase) and lower floor's (water) respectively, the determination test compound concentrations then.

Details are as follows for HPLC instrument and running status thereof:

＜UV detects the HPLC system 〉

Alliance analysis HPLC system (by Waters, USA),

Fresh feed pump: 2795 separation modules,

UV detector: 2996 photodiode array detectors

＜MS detects the HPLC system 〉

High-throughput LC/MS system (derive from Agilent, USA),

Fresh feed pump: 1100 series/binary pump

MS detector: 1100 serial LC/MSD SL.

＜experiment condition 〉

Post: ODS-type C18 post (3.5 μ m, 3.0mm ID * 30mm),

Column temperature: 60 ℃,

Mobile phase A: pH4.5, the 10mM acetate buffer,

Mobile phase B: 50% acetate-acetonitrile mixture (1/999),

The ratio of gradient condition: mobile phase A/B, 95/5 to 10/90,

Flow velocity: 1.5mL/min,

Sample temperature: 25 ℃,

Sample size: 5 μ L,

Detect wavelength: the maximum absorption wavelength in 220 to 420 nanometer range

The MS testing conditions is as follows:

Pattern: SIM,

Dry gas flow velocity: 12L/min,

Atomizer pressure: 55psig.,

Capillary voltage: 3000V,

The dry gas temperature: 350 ℃,

Fragment voltage: 100V.

＜experimental result 〉

As shown in the table, compound of the present invention has required good fat-soluble of medicine.

Table 3

The embodiment numbering	logD(pH7.4)
		Embodiment 1-(2)	2.7
Embodiment 4-(2)	2.5
		Embodiment 5-(2)	2.3
Embodiment 13-(2)	1.8
		Embodiment 16-(2)	2.6
Embodiment 18-(2)	1.1
		Embodiment 19-(3)	1.8
SKB-compd	4.4

Describe the present invention in detail with reference to concrete scheme of the present invention, those skilled in the art obviously can carry out various changes and modifications and not break away from the spirit and scope of the present invention.

The application is based on the Japanese patent application (Tokugan2005-15954) of Japanese patent application of submitting on March 30th, 2004 (Tokugan2004-99201) and submission on January 24th, 2005, and it all incorporates this paper into as a reference.

Industrial applicibility

Compound of the present invention, its salt and solvate thereof have excellent PPAR α/gamma agonist effect, can be used as the preventive medicine/curative of diabetes.

Claims (12)

1. by the compound of general formula (I) expression:

(wherein:

Q represents phenyl ring or pyridine ring, and it can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replacement or unsubstituted low alkyl group, replacement or unsubstituted amino, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, replacement or unsubstituted phenyl and replacement or unsubstituted pyridine base;

R ¹Expression phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base,  di azoly or triazolyl, it can be replaced by one or two identical or different following group that is selected from: halogen atom, low-grade alkenyl, lower alkoxy, phenoxy group, replacement or unsubstituted low alkyl group and replacement or unsubstituted amino;

R ²The expression pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base, the  di azoly, triazolyl, quinolyl, isoquinolyl, quinazolyl, 1, the 2-phthalazinyl, quinoxalinyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, indyl, benzimidazolyl-, indazolyl, benzothiazolyl, the benzoxazol base, the benzisothiazole base, benzisoxa  azoles base or benzotriazole base, it can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replace or unsubstituted low alkyl group, replace or unsubstituted amino, replace or unsubstituted phenyl and replacement or unsubstituted pyridine base, or expression can be by the formamyl of one or two identical or different low alkyl group replacement;

X, Y and Z represent C, O, S or N (condition is that any one is O, S or N at least among X, Y and the Z) independently of one another;

R ³To R ⁶Represent hydrogen atom or low alkyl group independently of one another, or R ³And R ⁴, or R ⁵And R ⁶Can combine with the carbon atom that they are replaced and form 3-to 6-unit saturated rings;

R ⁷, R ⁸And R ⁹Represent hydrogen atom or low alkyl group independently of one another;

N represents 0 to 3 integer),

Its salt, or its solvate.

2. compound, its salt or its solvate of general formula (I) expression, the 5-unit ring that wherein contains X, Y and Z is  azoles ring, thiazole ring or  diazole ring.

3. claim 1 or 2 described compounds, its salt or its solvate, wherein Q is a phenyl ring, and phenyl ring can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replacement or unsubstituted low alkyl group, replacement or unsubstituted amino, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, replacement or unsubstituted phenyl and replacement or unsubstituted pyridine base.

4. claim 1 or 2 described compounds, its salt or its solvate, wherein Q is a phenyl ring, and phenyl ring can be replaced by one or two identical or different following group that is selected from: halogen atom, low-grade alkenyl, lower alkoxy and replacement or unsubstituted low alkyl group.

5. each described compound, its salt or its solvate, wherein R in the claim 1 to 4 ¹Be phenyl, phenyl can be replaced by one or two identical or different following group that is selected from: halogen atom, low-grade alkenyl, lower alkoxy, phenoxy group, replacement or unsubstituted low alkyl group and replacement or unsubstituted amino.

6. each described compound, its salt or its solvate, wherein R in the claim 1 to 4 ¹Be phenyl, phenyl can be replaced by one or two identical or different following group that is selected from: halogen atom and replacement or unsubstituted low alkyl group.

7. each described compound, its salt or its solvate, wherein R in the claim 1 to 6 ²Be pyridyl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base,  di azoly, benzimidazolyl-, indazolyl, benzothiazolyl, benzoxazol base, benzisothiazole base or benzisoxa  azoles base, they can be replaced by one or two identical or different following group that is selected from: hydroxyl, halogen atom, low-grade alkenyl, lower alkoxy, replacement or unsubstituted low alkyl group, replacement or unsubstituted amino, replacement or unsubstituted phenyl and replacement or unsubstituted pyridine base.

8. each described compound, its salt or its solvate, wherein R in the claim 1 to 6 ²Be pyridyl, imidazolyl, pyrazolyl, thiazolyl,  azoles base, isothiazolyl, different  azoles base,  di azoly, benzimidazolyl-, benzothiazolyl or benzoxazol base, they can be replaced by one or two identical or different following group that is selected from: halogen atom, lower alkoxy, replacement or unsubstituted low alkyl group and replacement or unsubstituted phenyl.

9. each described compound, its salt or its solvate, wherein R in the claim 1 to 6 ²Be the formamyl that can be replaced by one or two identical or different low alkyl group.

10. comprise the medicine of described compound, its salt or its solvate by general formula (I) expression of claim 1 as activeconstituents.

11. comprise the pharmaceutical composition of described compound, its salt or its solvate and the pharmaceutically acceptable carrier by general formula (I) expression of claim 1.

12. claim 1 described compound, its salt or the application of its solvate in pharmacy by general formula (I) expression.