CN1226555A

CN1226555A - Antifungal agent and preparation method thereof and intermediate

Info

Publication number: CN1226555A
Application number: CN97126356.6A
Authority: CN
Inventors: 内藤俊彦; 畑桂; 加耒由美子; 鹤冈明彦; 塚田格; 柳泽学; 丰泽逸生; 奈良一诚
Original assignee: Eisai Co Ltd
Current assignee: Eisai Co Ltd
Priority date: 1994-02-07
Filing date: 1995-02-06
Publication date: 1999-08-25
Anticipated expiration: 2015-02-06

Abstract

The salt of compound or its salt shown in below general formula, its intermediate or intermediate, with and preparation method thereof and be adapted as the pharmaceutical composition of antifungal agent:Wherein R¹And R²Represent halogen atom or hydrogen atom;R³Represent hydrogen atom or low alkyl group;1st, r and m is 0 or 1;A is N or CH;W represents aromatic rings or its condensed ring;X represents another aromatic rings, alkane 2 basis, olefin 2 base or alkyne diyl;Y is-S- etc.;Z represents hydrogen atom etc..

Description

Antifungal agent and preparation method thereof and intermediate

The present invention relates to a kind of antifungal agent, especially, the present invention relates to the antifungal agent for treating dermatomycosis, internal organ nosomycosis etc..In particular it relates to derivative and its acid-addition salts containing 5 circle heterocycles or its condensed ring, they are used as antifungal agent.Moreover, the present invention relates to the method for preparing this derivative and acid-addition salts, and the pharmaceutical composition containing the derivative and its officinal salt.

Further, the present invention relates to synthetic intermediate of azole compounds as antifungal agent and preparation method thereof.Particularly, the present invention relates to for preparing to treatment dermatomycosis, the fine synthetic intermediate for infecting the effective antifungal agent such as (Visceral micotic infection) of internal organ, and preparation method thereof.

In antifungal agent field, amphotericin B (amphoterin B) or its analog are used for as treated depth fungi before this.However, the antifungal agent of azole synthesis is developed recently.Develop a kind of fabulous epiphyte pharmaceutical even in the antifungal agent of these azoles, also craving for from the viewpoint of its suppression patient's immunity function.

For example, Japanese patent application, which discloses (KOKAI) number 70885/1982, discloses triazole (tirazole) compound as azole synthesis of antifungal agents.In addition, Japanese patent application, which discloses (KOKAI) number 224689/1985, discloses (1,2,4- triazol-1-yl)-methyl-carbinol derivatives.

It is intended that providing a kind of more more effective than traditional antifungal agent antifungal agent and its intermediate.

The present inventor has been carried out widely grinding peace.As a result, following invention is completed.

I. the compound or its salt represented by general formula：

Wherein R¹And R²It is same to each other or different to each other, and each represents halogen atom or hydrogen atom；R³For hydrogen atom or low alkyl group；1st, r and m may be the same or different, and each represent 0 or 1；A is N or CH；W is represented to have one or more hetero atoms and can be had the aromatic rings or its condensed ring of one or more substituents, or W represents aromatic rings or its condensed ring, it is partly or entirely saturation that can wherein have one or more hetero atoms or can have the aromatic rings or its condensed ring of one or more substituents, X is represented to have one or more substituents and can be selected from N comprising one or more, S and O heteroatomic aromatic rings, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or can have the alkyne diyl of one or more substituents；Y serves as reasons-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- the group represented, wherein R⁶For hydrogen atom or low alkyl group, and j is 1-4 integer, and Z represents hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, there can be the phenyl of one or more substituents, there can be the phenoxy group of one or more substituents, there can be the imidazole radicals of one or more substituents, there can be the triazolyl of one or more substituents, there can be the tetrazole radical of one or more substituents or there can be the amino of one or more substituents, unless as 1=1 and r=m=0, W is thiazole ring, R³For methyl and Z is hydrogen atom.

II. optically active (2S is prepared, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazol-1-yls) butyronitrile method, including by optically active (2R, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxiranes and diethyl cyaniding reactive aluminum.

III. optically active (2S is prepared, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazole-l- bases) butyronitrile method, including by optically active (2R, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxiranes and cyaniding ytterbium react.

IV. Stereoselective prepares optically active (2S, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazol-1-yls) butyronitrile method, including by optically active (2R, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxiranes and acetone cyanohydrin react.

V. compound shown in following formula or the method for its acid-addition salts are prepared：

Wherein W refers to substituted thiazole ring, and A, R¹、R²、R³, X, Y, Z, r and m be defined as above, this method is included compound shown in following formula：

Wherein A, R¹、R²And R³It is defined as above, is reacted with compound shown in following formula：

Wherein Hal is Br or Cl, and X, Y, Z, r and m be defined as above.

VI. compound shown in following formula or the method for its acid-addition salts are prepared：

Wherein A, R¹、R²、R³, X, Y, Z, r and m be defined as above, and W represents substituted or unsubstituted, nitrogenous 5 circle heterocycles or its condensed ring, and this method is included compound shown in following formula：

Wherein A, R¹And R²It is defined as above, is reacted with compound shown in following formula：

Wherein D is substituted or unsubstituted, nitrogenous 5 circle heterocycles or its condensed ring, and Z is H or CH₃。

VII. compound shown in following formula or the method for its acid-addition salts are prepared：

Wherein W means substituted or unsubstituted 5 circle heterocycles or its condensed ring, and A, R¹、R²、R³, X, Y, Z, r and m be defined as above, this method is included compound shown in following formula：

Reacted with compound shown in following formula：

Wherein R³, X, Y, Z, r and m be defined as above.

VIII. compound shown in following formula or the method for its acid-addition salts are prepared：

Wherein A, R¹、R²、R³, W, X, Y, Z, r and m be defined as above, this method is included compound shown in following formula：

Wherein A, R¹、R²、R³, W, X, Y, Z, r and m be defined as above, reacted with metachloroperbenzoic acid, then again with 1,2,4. 1-Sodium-1,2,4-Triazoles or 1,3- imidazole natrium are reacted.

IX. compound or the pharmaceutical composition of its acid-addition salts and officinal salt shown in formula (1) are contained：

Wherein R¹And R²It is identical or different, and each represent halogen atom or hydrogen atom, R³Mean hydrogen atom or low alkyl group；R and m can be with identical or different, and represents 0 or 1 respectively；A is N or CH；W is represented to have one or more substituents and can be contained one or more heteroatomic aromatic rings or its condensed ring selected from N, S and O；X means to have one or more substituents and can contain one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y is-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- shown group, wherein R⁶Refer to hydrogen atom or low alkyl group, and j is 1-4 integer；And Z represents hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, rudimentary a heatable brick bed epoxide, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, the phenyl can with one or more substituents, the phenoxy group can with one or more substituents, the imidazole radicals can with one or more substituents, the triazolyl can with one or more substituents, the tetrazole radical can with one or more substituents; or can have the amino of one or more substituents; unless as r=m=0, W is thiazole ring, R³For methyl, and Z is hydrogen atom.

X. derivative shown in following formula or the method for its acid-addition salts are prepared：

Wherein A is=CH- or=N-,

L and M are identical or different, and each represent hydrogen atom or halogen atom, and

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；And there is the aromatic rings that can contain one or more hetero atoms and can have a substituent；Or part thereof or whole condensed ring for being saturated, this method includes, when derivative or its acid-addition salts is prepared, in the presence of alkyl lithium, 2- halos-acetophenone shown in general formula is added in the compound containing 5 circle heterocycles or its condensed ring or part thereof or whole condensed ring being saturated and reacted, then 1,2,4- triazole and sodium hydride are added in the reaction product of gained again and reacted：

Wherein U represents halogen atom, and L and M are defined as above.

XI. the logical shown derivative of following formula or the method for its acid-addition salts are prepared：

Wherein A is-CH- or=N-,

L and M are same to each other or different to each other, and each represent hydrogen atom or halogen atom, and

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more its hetero atom in addition to sulphur atom and with a substituent, and with can contain the aromatic rings of one or more hetero atoms and a substituent；Or part thereof or whole condensed ring for being saturated, this method includes：When preparing derivative or its acid-addition salts, it is reacted containing 5 circle heterocycles that cyano-phenyl replaces with sodium azide and triethylamine hydrochloride accordingly.

XII prepares derivative shown in general formula or the method for its acid-addition salts：

Wherein A is=CH=or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent, and with can contain one or more hetero atoms and can the aromatic rings with a substituent；Or part thereof or whole condensed ring for being saturated, the derivative is replaced on 3- or 4- of tetrazole ring by alkyl, this method includes two when preparing derivative or its acid-addition salts, and the derivative of its 5 circle heterocycles replaced accordingly containing tetrazolium phenyl is reacted with alkyl halide.

XIII. derivative shown in general formula or the method for its acid-addition salts are prepared：

Wherein A is=CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；And there is the aromatic rings that can contain one or more hetero atoms and can have a substituent；Or part thereof or whole condensed ring for being saturated, this method includes：When preparing derivative or its acid-addition salts, its corresponding 5 circle heterocycles replaced containing halogenophenyl and 1,2,4- triazoles and sodium hydride are reacted.

XIV. derivative shown in general formula or the method for its acid-addition salts are prepared：

Wherein A is=CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；And there is the aromatic rings that can contain one or more hetero atoms and can have a substituent；Or part thereof or whole condensed ring for being saturated, this method includes：When preparing derivative or its acid-addition salts, its corresponding derivative containing (1,2,4- triazol-1-yl) ethanol is reacted.

XV. the method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and Pr represents hydroxyl protecting group, and L is leaving group, and this method includes protecting the hydroxyl of compound shown in general formula with protection group：

Wherein R is defined as above, and R¹The protection group of hydrogen atom or hydroxyl is represented, compound shown in below formula is formed：

Wherein R, R¹With Pr definition ibid, then it is deprotected the protection group of the carboxyl of compound shown in formula (2), forms the compound shown in below formula：

Wherein R and Pr are defined as above, and are further reacted compound shown in formula (3) with compound shown in formula LH, wherein L is as defined above.

XVI. the method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other, and each represents hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method is included the compound shown in below formula：

Wherein R and Pr are defined as above, and L represents leaving group, with compound shown in below formula or

Its reactive derivative is reacted：

Two of which X is defined as above, and Y refers to chlorine, bromine or iodine atom.

XVII. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group; two X are same to each other or different to each other; and hydrogen or halogen atom are each represented, and Pr is hydroxyl protecting group, this method is included the compound shown in below formula and the triphenyl as derived from methyl triphenyl chlorination , methyltriphenylphospbromide bromide  or methyltriphenylphosphonium iodide .Methylene  (triphenyl-phosphonium methylide) reacts, or is reacted with trimethylsilyl methyl magnesium chloride, trimethylsilyl methyl magnesium bromide or trimethylsilyl lithium methide,

Wherein R, two X and Pr are defined as above.

XVIII. the method for preparing the compound or its salt as shown in following formula is logical：

Wherein R means low alkyl group, and two X are same to each other or different to each other, and each represents hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method includes being reacted the compound shown in below formula and peroxy acid,

Wherein R, two X and Pr are defined as above.

XIX. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group; two X are same to each other or different to each other; and each represent hydrogen or halogen atom; and Pr is hydroxyl protecting group; the chloromethyl lithium that this method includes by the compound shown in below formula with being formed by chloroiodomethane or bromochloromethane is reacted, or is reacted with dimethyl-sulfoxonium methide, dimethyl sulfonium methide, diethyl-sulfoxonium methide or diethyl sulfonium methide：

Wherein R, two X and Pr are defined as above.

XX. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other, and each represents hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method includes being reacted in the compound shown in below formula and oxidant：

Wherein R, two X and Pr are defined as above.

XXI. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, R²Refer to low alkyl group, and R³Methyl or lower alkoxy are represented, this method includes being reacted the compound shown in below formula with alkoxy dimetylsilyl methylmagnesium halide or dialkoxymethyl silyl methyl magnesium halide：

Wherein R, two X and Pr are defined as above.

XXII. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and this method includes in the presence of a base being reacted compound shown in below formula with peroxy acid：

Wherein R, two X and Pr are defined as above, R²For low alkyl group, and R³Represent methyl or lower alkoxy.

XXIII. the method for preparing the compound or its salt as shown in following formula formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and A refers to CH or nitrogen-atoms, and this method includes being reacted compound shown in below formula and l, 2,4- triazoles or imidazoles, or its salt：

Wherein R, two X and Pr are defined as above.

XXIV. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and L refers to leaving group, and it is included halogenations shown in below formula, alkyl sulfonation or aryl sulfonation：

Wherein R, two X and Pr are defined as above.

XXV. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are mutually the same or differ and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and A is CH or nitrogen-atoms, and it includes being reacted the compound shown in below formula and 1,2,4- triazoles or imidazoles or its salt：

Wherein R, two X and Pr are defined as above, and L represents leaving group.

XXVI. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and A refers to CH or nitrogen-atoms, and it includes the Pr (hydroxyl protecting group) in compound shown in deblocking below formula：

Wherein R, two X and A are defined as above, and Pr is hydroxyl protecting group.

XXVII. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and A is CH or nitrogen-atoms, and it is included compound shown in below formula and oxidant reaction：

Wherein R, two X and A are defined as above.

XXVIII. the method for preparing compound or its salt shown in below formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and A is CH or nitrogen-atoms, and it includes being reacted compound shown in below formula and hydroxylamine derivative：

Wherein R, two X and A are defined as above.

XXIX. the pharmaceutical composition containing compound or its salt shown in general formula and officinal salt：

Wherein R¹And R²It is same to each other or different to each other, and each represents halogen atom or hydrogen atom；R3 means hydrogen atom or low alkyl group；L, r and m may be the same or different, and each represent 0 or 1；A is N or CH；W is represented to have one or more hetero atoms and can be used the aromatic rings or its condensed ring of one or more substituents, or W represents aromatic rings or its condensed ring, wherein it is saturation that can have one or more hetero atoms and can have the aromatic rings or part or all of its condensed ring of one or more substituents；X is represented to have one or more substituents and can be included one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y is-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- the group represented, wherein R⁶For hydrogen atom or low alkyl group, and j is 1-4 integer, and Z represents hydrogen atom, halogen atom, low alkyl group, halo paper level a heatable brick bed base, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, there can be the phenyl of one or more substituents, there can be the phenoxy group of one or more substituents, there can be the imidazole radicals of one or more substituents, there can be the triazolyl of one or more substituents, there can be the tetrazole radical of one or more substituents or there can be the amino of one or more substituents, unless during l=1 and r=m=0, W is thiazole ring, R³For methyl, and Z is hydrogen atom.

The present invention provides compound or its acid-addition salts shown in a kind of logical formula (I) with fabulous antifungal property：

Wherein A is=CH- or=N-,

L and M are same to each other or different to each other and each represent hydrogen atom or halogen atom, and

R¹Mean 5 circle heterocycles, it can contain one or more other hetero atoms in addition to sulphur atom, and with a substituent；Or with can contain one or more hetero atoms and can have substituent aromatic rings 5 circle heterocycles condensed ring, it can contain one or more other hetero atoms in addition to sulphur atom, and with a substituent；Or part thereof or whole condensed ring for being saturated.

The derivative of the present invention can be prepared by various route of synthesis.Some of which method is enumerated as follows：

Method A：

In the presence of positive fourth lithium, chloro- 2 ', the 4 '-difluoro acetophenones of 2- are added to 4- (2,4- difluorophenyls) in thiazole, after reaction product is post-processed, 1,2 is added, 4- triazoles and sodium hydride, obtain 1- (2,4- difluorophenyl) -1- (4- (2,4- difluorophenyl) thiazol-2-yl) -2- (1H-1,2,4- triazol-1-yls)-ethanol.

Method B：

(1) in the presence of n-BuLi, chloro- 2 ', the 4 '-difluoro acetophenones of 2- are added in 6- cyanobenzothiazoles, 1- (2,4- difluorophenyl) -1- (6- cyanobenzothiazole -2- bases)-ethylene chlorhydrin is formed.

(2) by 1,2,4- triazoles are added in the sodium hydride suspension in dimethylformamide, the 1- (2 that will be formed in step (1), 4- difluorophenyls) -1- (6- cyanobenzothiazole -2- bases)-ethylene chlorhydrin is added in the suspension and reacted, and is derived from 1- (2,4- difluorophenyl) -1- (6- benzonitriles and thiazol-2-yl) -2- (1H-1,2,4- triazol-1-yls) ethanol.

Method C：

By 1- (2,4- difluorophenyls) -1- (4- (4- cyano-phenyls) thiazol-2-yl) -2- (1H-1,2,4- triazol-1-yls)-ethanol reacted with sodium azide and triethylamine hydrochloride, obtain 1- (2,4- difluorophenyls) -1- 4- [(4- (5- tetrazoliums) phenyl) thiazole] -2- bases) -2- (1H-1,2,4- triazol-1-yls)-ethanol.

Method D：

The 1- (2 that will be obtained in Methyl iodide and above method C, 4- difluorophenyls) -1- { 4- [(4- (5- tetrazoliums)-phenyl)-thiazole] -2- bases } -2- (1H-1,2,4- triazol-1-yls) ethanol reacted, two isomers are obtained, 3- or 4- in the isomers tetrazole ring are replaced by methyl.

Method E：

By 1- (2,4- difluorophenyls) -1- (2- (4- fluorophenyls) thiazole -5- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol and 1,2,4- triazoles and sodium hydride reaction, obtain 1- (2,4- difluorophenyl) -1- { 2 [(4- (1-1H-1,2,4- triazoles) phenyl)-thiazole] -5- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol.

Method F：

By 1- (2,4- difluorophenyls) -1- (6- thiocarbamoyls-benzothiazole -2- bases) -2- (1H-1,2,4- triazoles-yl) ethanol reacted with sodium acid carbonate and bromacetone, obtain 1- (2,4- difluorophenyls) -1- (6- (3- methylthiazol -1- bases)-benzothiazole -2- bases) -2- (1H-1,2,4- triazole-l- bases) ethanol.

Method G：

By 1- (2,4- difluorophenyl) -1- (6- cyanobenzothiazole -2- bases), (1H-1, the ethanol of 2,4- triazol-1-yl 1 and triethylamine are dissolved in dimethylformamide -2-.Lead in resulting solution and put hydrogen sulfide gas and reacted, be derived from 1- (2,4- difluorophenyl) -1- (6- thiocarbamoyls-benzothiazole -2- bases) -2- (1H-1,2,4- triazole-l- bases) ethanol.

Method H：

By 1- (2,4- difluorophenyls) -1- (the 2- yls of 6- thiocarbamoyls-benzothiazole one) -2- (1H-1,2,4- triazol-1-yls) ethanol and bromoacetaldehyde dimethyl acetal reacted to obtain 1- (2,4- difluorophenyls) -1- (6- thiazole -1- bases)-benzothiazole -2- base -2- (1H-1,2,4- triazol-1-yls) ethanol.

Method I：

(1) by 1- (2,4- difluorophenyls) -1- (4- thiocarbamoyls-benzene sulphur -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol and -2- bromoethyl acetone acid reactions, form 1- (2,4- difluorophenyls -1- (4- (4- carbethoxyl groups thiazol-2-yl)-benzene sulphur -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol (A).

(2) thus obtained compound (A) is dissolved in the methanol solution of ammonia saturation; and stand resulting solution; therefore compound is reacted with ammonia and obtains 1- (2; 4- difluorophenyls) -1- (4- (4- carbamoyls thiazol-2-yl)-benzene sulphur -2- bases) -2- (1H-1; 2,4- triazole-l- bases) ethanol (B).

Method J：

The compound (B) obtained in above method I steps (2) is dissolved in pyridine and reacted with phosphoryl chloride phosphorus oxychloride, obtain 1- (2,4- difluorophenyls) -1- (4- (4- cyano thiazole -2- bases)-benzene sulphur -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol.

Be used as the example of solvent workable for the present invention, it may be mentioned that have lower alcohol such as methanol, ethanol, propyl alcohol and butanol；Polyalcohol such as 1,2- ethylene glycol；Ketone such as acetone, methyl ethyl ketone, metacetone and cyclohexanone；Ether such as ether, isopropyl ether, tetrahydrofuran, two  alkane, 2-methyl cellosolve and 1,2- dimethoxy-ethane；Nitrile such as acetonitrile and propionitrile；Ester such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl phthalate；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, trichloro ethylene and tetrachloro-ethylene；Aromatic such as benzene,toluene,xylene, monochlorobenzene, nitrobenzene, indenes, pyridine, quinoline, collidine and phenol；Hydrocarbon such as pentane, hexamethylene, hexane, heptane, octane, isooctane and petroleum ether；Amine such as monoethanolamine, diethylamine, triethylamine, pyrrolidines, piperidines, piperazine, morpholine, aniline, dimethylaniline, benzene methanamine and toluidines；Acid amides such as formamide, 1-METHYLPYRROLIDONE, N, N- dimethyl-imidazolinones, DMA and DMF；Phosphamide such as HMPA and the sub- phosphoric triamide of hexamethyl；Organic acid such as formic acid, acetic acid, difluoroacetic acid, trifluoroacetic acid and monoxone；Sulfoxide such as dimethyl sulfoxide (DMSO)；The sulfide of carbon such as carbon disulfide；Water；With other general solvents.These solvents can be single or the solvent of its two or more mixing.To not being particularly limited to forcibly in the mixed proportion of intermixture.

The derivative of the present invention or the officinal salt of its acid-addition salts that can be mentioned that are as follows.

That is, the example for the inorganic salts that can be mentioned that has alkali metal salt such as sodium salt and sylvite；Ammonium salt；Tetraethyl ammonium salt；Quaternary ammonium salt such as betaine；Alkali salt such as calcium salt and magnesium salts；With inorganic acid salt such as hydrochloride, hydrobromate, hydriodate, sulfate, carbonate and bicarbonate.

In addition, the example that can be mentioned that organic salt is organic carboxylate such as acetate, maleate, lactate and tartrate；Organic sulfonate such as mesylate, hydroxymethane sulfonic acid salt, isethionate, taurate, benzene sulfonate and toluene fulfonate；Amino-acid salt such as arginine salt, lysine salt, serine salt, aspartate, glutamate and glycinate；Amine salt such as front three amine salt, triethylamine salt, pyridiniujm, procaine salt, picoline salt, dicyclohexyl amine salt, N, N- dibenzyl ethylenediamine salts, N-METHYL-ALPHA-L-GLUCOSAMINE salt, diethanolamine salt, triethanolamine salt, three (methylol) methane salt and ethoxyphenyl benzylamine salts.

Moreover, the present invention provides the compound or its acid-addition salts shown in a kind of logical formula (I) with fabulous antifungal property：

Wherein R¹And R²It is same to each other or different to each other and each represents halogen atom or hydrogen atom；R³Mean hydrogen atom or low alkyl group；R and m can be same to each other or different to each other and respectively 0 or 1；A is N or CH；W represents aromatic rings (it can have one or more substituents and can contain one or more hetero atoms selected from N, S and O) or its condensed ring；X means to have one or more substituents and can contain one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y is-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- shown group, wherein R6 is hydrogen atom or low alkyl group, and j is 1-4 integer；Hydrogen atom, halogen atom, low alkyl group, junior alkyl halides are represented with Z; lower alkoxy; halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, the phenyl can with one or more substituents, the phenoxy group can with one or more substituents, the imidazole radicals can with one or more substituents, the triazolyl can with one or more substituents, the tetrazole radical can with one or more substituents or the amino can with one or more substituents; unless as r=m=0; W is thiazole ring, R³For methyl, and Z is hydrogen atom.

The compound of the present invention can be prepared by various route of synthesis, and some of which approach enumerates as follows：

Approach I：

By following formula: compound：

Wherein A, R¹、R²And R³It is defined as above, is reacted with following formula: compound：

Wherein Hal is Br or Cl, and X, Y, Z, r and m be defined as above, and obtains compound shown in following formula：

Wherein W is the group that is made up of the azole replaced, and A, R¹、R²、R³, X, Y, Z, r and m be defined as above.

Approach II.

By following formula: compound：

Wherein A, R¹And R²It is defined as above, is reacted with following formula: compound：

Wherein D is the group being made up of substituted or unsubstituted, nitrogenous 5 circle heterocycles or its condensed ring, and Z is H or CH₃；It is derived from the compound shown in following formula：

Wherein W is substituted or unsubstituted, nitrogenous 5 circle heterocycles or condensed ring, and A, R¹、R²、R³, X, Y, Z, r and m be defined as above.

Approach III：

By following formula: compound：

Wherein R³, X, Y, Z, r and m be defined as above, be derived from the compound shown in following formula：

Wherein W is the group that is made up of substituted or unsubstituted 5 circle heterocycles or condensed ring, and A, R¹、R²、R³, X, Y, Z, r and m be defined as above.

Approach IV：

By following formula: compound：

Wherein R¹、R²、R³, X, Y, Z, r and m be defined as above, reacted with metachloroperbenzoic acid, then again with 1,2,4. 1-Sodium-1,2,4-Triazoles or the reaction of 1,3- imidazole natrium are derived from compound shown in following formula：

Wherein A, R¹、R²、R³, W, X, Y, Z, r and m be defined as above.

As the acid for the acid-addition salts for forming the compounds of this invention, conventional inorganic acid such as hydrochloric acid and sulfuric acid, and organic acid such as acetic acid and citric acid can be used.It is preferred that acid be hydrochloric acid and acetic acid.

As the example of the workable solvent of the present invention, lower alcohol such as methanol, ethanol, propyl alcohol and butanol there can be mentioned；Polyalcohol such as 1,2- ethylene glycol；Ketone such as acetone, MEK, metacetone and cyclohexanone；Ether such as ether, isopropyl ether, tetrahydrofuran, two  alkane, 2-methyl cellosolve and 1,2- dimethoxy-ethane；Nitrile such as acetonitrile and propionitrile；Ester such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl phthalate；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, trichloro ethylene and tetrachloro-ethylene；Aromatic such as benzene,toluene,xylene, monochloro-benzene, nitrobenzene, indenes, pyridine, quinoline, collidine and phenol；Hydrocarbon such as pentane, hexamethylene, hexane, heptane, octane, isooctane and petroleum ether；Amine such as monoethanolamine, diethylamine, triethylamine, pyrrolidines, piperidines.Piperazine, morpholine, aniline, dimethylaniline, benzene methanamine and toluidines；Acid amides such as formamide, 1-METHYLPYRROLIDONE, N, N- dimethyl-imidazolinones, DMA and DMF；Phosphamide such as HMPA and the sub- phosphoric triamide of pregnancy；Organic acid such as formic acid, acetic acid, difluoroacetic acid, trifluoroacetic acid and monoxone；Sulfoxide such as dimethyl sulfoxide (DMSO)；The sulfide and carbon disulfide of carbon；Water；With other common solvents.These solvents can be single solvent or the mixed solvent of its two or more solvent.Mixed proportion to mixed solvent is not particularly limited to forcibly.

As the compounds of this invention or the pharmaceutically useful salt of its acid-addition salts, it can enumerate as follows.

That is, as the example of inorganic salts, alkali metal salt such as sodium salt and sylvite be can be mentioned that；Ammonium salt；Tetraethyl ammonium salt；Quaternary ammonium salt such as betaine；Alkali salt such as calcium salt and magnesium salts；With inorganic acid salt such as hydrochloride；Hydrobromate, hydriodate, sulfate, carbonate and bicarbonate.

In addition, as the example of organic salt, organic carboxylate such as acetate, maleate, lactate and succinate be can be mentioned that；Organic sulfonate such as mesylate, hydroxymethane sulfonic acid salt, isethionate, taurate, benzene sulfonate and toluene fulfonate, hydroxymethane sulfonic acid salt, isethionate, taurate, benzene sulfonate and toluene fulfonate；Amino-acid salt such as arginine salt, lysine salt, serine salt, aspartate, glutamate and glycinate；With amine salt such as front three amine salt, triethylamine salt, pyridiniujm, procaine salt, picoline salt, dicyclohexyl amine salt, N, N- dibenzyl ethylenediamine salts, N- methyl glucamine salts, diethanolamine salt, triethanolamine salt, three (methylol) methane salt and ethoxyphenyl benzylamine salts.

Moreover, the present invention provides a kind of preparation method of compound or its salt shown in general formula：

Wherein R means low alkyl group, and Pr represents hydroxyl protecting group and L is leaving group, and it includes protecting the hydroxyl of compound shown in general formula with protection group：

Wherein R is defined as above, and R¹Hydrogen atom or carboxyl-protecting group are represented, to form compound shown in general formula：

Wherein R, R¹It is defined as above with Pr, is deprotected the carboxyl-protecting group of formula (2), forms compound shown in following formula：

Wherein R and Pr are defined as above, then by the reaction of formula (3) compound and compound shown in formula LH (wherein L represents leaving group)；

A kind of method for preparing compound or its salt shown in below general formula：

Wherein R means that low alkyl group, two X are same to each other or different to each other and each represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and it is included compound shown in general formula：

Wherein R and Pr are defined as above, and L represents leaving group, are reacted with compound shown in general formula or its reactive derivative：

Two of which X is defined as above, and Y represents chlorine atom, bromine atoms or iodine atom；

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and it is included compound shown in general formula：

Wherein R, X and Pr are defined as above, react, or reacted with trimethylsilyl methyl magnesium chloride, trimethylsilyl methyl magnesium bromide or trimethylsilyl methyl lithium with the triphen methylene  as derived from methyl triphenyl chlorination , methyltriphenylphospbromide bromide  or methyltriphenylphosphonium iodide ：

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and it is included compound shown in a row formula：

Wherein R, X and Pr are defined as above, and are reacted with peroxy acid；

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr represents hydroxyl protecting group, and it is included compound shown in general formula：

Wherein R, X and Pr are defined as above, and are reacted with the chloromethyl lithium that is formed by chloroiodomethane or bromoiodomethane, or reacted with dimethylated methylene base oxygen sulfonium or dimethylated methylene base sulfonium；

It is a kind of to prepare compound shown in general formula and its method for salt：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr represents hydroxyl protecting group, including compound shown in general formula and oxidant are reacted：

Wherein R, X and Pr are defined as above；

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, R²Represent low alkyl group and R³Methyl or lower alkoxy are represented, it includes being reacted compound shown in general formula with alkoxy dimetylsilyl methylmagnesium halide or dialkoxymethyl silyl methyl magnesium halide：

Wherein R, X and Pr are defined as above；

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr represents hydroxyl protecting group, and it includes with peroxy acid being reacted compound shown in general formula in the presence of a base：

Wherein R, X and Pr are defined as above, and R2 represents low alkyl group, and R3 represents methyl or lower alkoxy；

It is a kind of to prepare compound shown in following formula and its method for salt：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr refers to hydroxyl protecting group and A is CH or nitrogen-atoms, and it includes being reacted compound shown in general formula and 1,2,4- triazoles or imidazoles or its salt：

Wherein R, X and Pr are defined as above；

It is a kind of to prepare general formula compound and its method for salt：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent that hydrogen atom or halogen atom, Pr hydroxyl protecting groups, and L are leaving group, and it includes halogenation, alkyl sulfonation warp or compound shown in aryl sulfonation general formula：

Wherein R, X and Pr are defined as above；

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and A is CH or nitrogen-atoms, and it includes being reacted compound shown in following formula and 1,2,4- triazoles or imidazoles or its salt：

Wherein R, X and Pr are defined as above and L is leaving group；

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and A is CH or nitrogen-atoms, and it includes the hydroxyl protecting group Pr of compound or its salt shown in following formula being deprotected：

Wherein R, X, Pr and A are defined as above；

A kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and A is CH or nitrogen-atoms, and it is reacted including compound shown in general formula with oxidant：

Wherein R, X and A are defined as above；With

A kind of method for preparing general formula compound or its salt：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent atom or halogen atom, and A is CH or nitrogen-atoms, and it includes being reacted compound shown in following formula and hydroxylamine-o-sulfonic acid：

Wherein R, X and A are defined as above.

These methods are related to the method for preparing the synthetic intermediate for being used to prepare antifungal agent.

The present invention further to as the following compounds of synthetic intermediate or its salt.That is,

The present invention relates to compound or its salt shown in general formula；

Wherein R means low alkyl group, and Pr represents hydroxyl protecting group, and L represents leaving group；

Compound or its salt shown in general formula；

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and Q represents oxygen atom or CH₂；

Compound or its salt shown in general formula；

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group；

Compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and M represents hydroxyl or leaving group：With

Compound shown in general formula and its salt；

Wherein R means low alkyl group, and two X are same to each other or different to each other and represent hydrogen atom or halogen atom, and Pr is hydroxyl protecting group, and A represents CH or nitrogen-atoms.

Term of the invention and used herein is explained in detail below.

R means low alkyl group.The low alkyl group refers to the straight or branched alkyl containing 1-6 carbon atom, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, sec-amyl, tertiary pentyl, neopentyl, 1- methyl butyls, 2- methyl butyls, 1, 1- dimethyl propyls, 1, 2- dimethyl propyls, n-hexyl, isohesyl, 1- methyl amyls, 2- methyl amyls, 3- methyl amyls, l, 1- dimethylbutyls, l, 2- dimethylbutyls, 2, 2- dimethylbutyls, 1, 3- dimethylbutyls, 2, 3- dimethylbutyls, 3, 3- dimethylbutyls, 1- ethyl-butyls, 2- ethyl-butyls, 1, 1, 2- thmethylpropyls, 1, 2, 2- thmethylpropyls, 1- ethyl -1- methyl-propyls, 1- Ethyl-2-Methyl propyl group etc..It is preferred that group include methyl, ethyl, propyl group etc..

R¹Represent hydrogen atom or carboxyl-protecting group.

Carboxyl-protecting group used herein can be any known groups generally in organic synthesis field as carboxyl-protecting group, and not make special restriction.The carboxyl-protecting group that can be enumerated is included for example, the straight or branched low alkyl group containing 1-6 carbon atom, such as methyl, ethyl, isopropyl and the tert-butyl group；Junior alkyl halides, such as 2- iodoethyls and 2,2,2- trichloroethyls；Low-grade alkoxy alkyl；Such as methoxy, ethoxyl methyl and isobutoxymethyl；Lower aliphatic acidic group alkyl such as acetoxymethyl, propionic acid ylmethyl, butyric acid ylmethyl and neopentanoic acid ylmethyl；Elementary alkoxy carbonyl oxyalkyl, such as methoxycarbonyl oxygen methyl, 1- methoxycarbonyl oxygen ethyl, ethoxycarbonyloxymethyl, 1- ethoxy carbonyl oxygen ethyls and 2- methoxycarbonyl oxygen ethyls；Aralkyl, such as benzyl, p- methoxy-benzyl, adjacent nitro benzyl and to nitrobenzyl；Benzhydryl and 2- benzos [c] furanonyl；(5- methyl -2- oxo -1,3- dioxolane -4- bases)-methyl etc..

The deprotection of these carbonyl-protection bases can be completed by conventional method, such as be hydrolyzed, reduction etc., and this depends on the type for using protection group.

Pr represents hydroxyl protecting group.

Hydroxy-protective group used herein can be any known groups for being used as hydroxyl protecting group in organic synthesis field, and not particularly limited.The example of hydroxyl protecting group includes, for example, low alkyl group silicyl, such as trimethyl silyl, t-butyldimethylsilyl；Low-grade alkylaryl silicyl, such as t-butyldiphenylsilyl；Lower alkoxymethyl, such as methoxy, 2- methoxvethoxvmethvls etc., for example, THP trtrahydropyranyl；Aralkyl, such as benzyl, to methoxy-benzyl, 2,4- dimethoxy-benzyls, adjacent nitro benzyl, to nitrobenzyl, trityl, Methoxytrityl, dimethoxytrityl etc.；Acyl group, such as formoxyl, acetyl group；Elementary alkoxy carbonyl, such as t-butoxy carbonyl, 2- iodoethoxycarbonyls, 2,2,2- tri-chloroethoxy base carbonyls etc.；Alkenyl oxygen carbonyl, such as 2- acrylic oxygen carbonyl, 2- chloro-2-propene bases oxygen carbonyl, 3- methoxycarbonyl -2- acrylic oxygen carbonyl, 2- methyl -2- acrylic oxygen carbonyl, 2- cyclobutenyls oxygen carbonyl, cinnamyl oxygen carbonyl；Aryl alkyl carbonyl oxygen, such as Benzyloxycarbonyl, to methoxy-benzyl oxygen carbonyl, adjacent nitro Benzyloxycarbonyl, to nitrobenzyl oxygen carbonyl.

The deprotection of these hydroxyl protecting groups can be completed by conventional method, such as hydrolyzed, reduced, and it depends on using the type of protection group.

L is leaving group.

Leaving group used herein can be any known groups as leaving group in organic synthesis field, and be not particularly limited.The example of leaving group includes, for example, halogen atom, such as chlorine atom, bromine atoms, iodine atom；Alkylthio group, such as methyl mercapto, ethylmercapto group, rosickyite base；Arylthio, such as thiophenyl, Tolylsulfanvl, 2- pyridine thios；Alkylsulfonyloxy, such as mesyloxy, trifluoro-methanesulfonyl oxy, ethanesulfonyloxy group, third sulfonyloxy etc.；Aryl-sulfonyl oxygen, e.g., phenylsulfonyloxy, tosyloxy etc.；Alkanoyloxy, such as acetoxyl group, trifluoroacetyl epoxide；Alkoxy, such as methoxyl group, ethyoxyl, propoxyl group；Alkylamino, such as methylamino, ethylamino, the third amino, fourth amino；Dialkylamino, such as dimethylamino, lignocaine, dipropyl amino, methylethylamine, ethylpropylamino, methylpropylamino；With substituted phosphinylidyne epoxide, such as diphenyl phosphoryl epoxide.Therefore, the activator used in present invention reaction includes, for example, acid anhydrides, such as trifluoroacetyl acid anhydride, methanesulfonic acid acid anhydride, trifluoromethanesulfanhydride anhydride, p-toluenesulfonic anhydride；Acyl chlorides, such as mesyl chloride, paratoluensulfonyl chloride, chlorinated diphenyl phosphate, also including 2- mercaptopyridines, oxalyl chloride, thionyl chloride, thionyl bromide etc..

Two X are same to each other or different to each other and represent hydrogen atom or halogen atom.The example of halogen atom includes fluorine atom, chlorine atom, bromine atoms, iodine atom etc..

Y means chlorine atom, bromine atoms or iodine atom.For example by using metal as Mg activation Y shapes can obtain the reactive derivative of compound shown in general formula into magnesium halide (- MgY) and form Grignard reagent：

Two of which X is same to each other or different to each other and represents hydrogen atom or halogen atom, and Y represents chlorine atom, bromine atoms or iodine atom.

Peroxy acid used herein can be any peroxy acid commonly used in organic synthesis, and not be particularly limited.The example of peroxy acid includes, for example organic peroxide acid, such as metachloroperbenzoic acid (metha chloroperbenzoic acid) (mCPBA), peracetic acid, and aqueous hydrogen peroxide solution.Metachloroperbenzoic acid is preferred.

Oxidant used herein can be those that oxidant is commonly used in any organic synthesis, and not be particularly limited.The example of oxidant can include, for example, osmium tetroxide, potassium permanganate etc..

Alkoxy dimetylsilyl methylmagnesium halide means the dimetylsilyl methylmagnesium halide replaced with alkoxy corresponding with above-mentioned low alkyl group, and specifically includes methoxyl group dimetylsilyl methyl-magnesium-chloride,

Methoxyl group dimetylsilyl methyl-magnesium-bromide,

Ethyoxyl dimetylsilyl methyl-magnesium-chloride,

Ethyoxyl dimetylsilyl methyl-magnesium-bromide,

Propoxyl group dimetylsilyl methyl-magnesium-chloride,

Isopropoxy dimetylsilyl methyl-magnesium-chloride,

Propoxyl group dimetylsilyl methyl-magnesium-bromide,

Isopropoxy dimetylsilyl methyl-magnesium-bromide etc..

Dialkoxymethyl silyl methyl magnesium halide means the methyl silicane ylmethyl magnesium halide replaced with alkoxy corresponding with above-mentioned low alkyl group, specifically includes：

Dimethoxy-methyl silyl methyl magnesium chloride,

Dimethoxy-methyl silyl methyl magnesium bromide,

Diethoxymethyl silyl methyl magnesium chloride,

Diethoxymethyl silyl methyl magnesium bromide,

Dipropoxy methyl silicane ylmethyl magnesium chloride,

Dipropoxy methyl silicane ylmethyl magnesium bromide,

Dibutoxymethyl silyl methyl magnesium chloride,

Dibutoxymethyl silyl methyl magnesium bromide etc..

Alkali used herein can be that organic synthesis field is commonly used for any conventional base of alkali, and not be particularly limited.The example of alkali includes, for example, sodium carbonate, sodium acid carbonate, potassium carbonate, sodium hydride, hydrofining, potassium tert-butoxide, pyridine, dimethyl aminopyridine base, trimethylamine, triethylamine, N, N- diisopropyl ethyl amines, N-methylmorpholine, N- crassitudes, N- methyl piperidines, N, accelerine, carbon -7- the alkene (DBU) of 1,8- diazabicylo [5.4.0] 11, pyridine, 4-dimethylaminopyridine, picoline, lutidines, quinoline, isoquinolin, sodium hydroxide, potassium hydroxide, lithium hydroxide, butyl lithium etc..

A is CH or nitrogen-atoms.

R²Low alkyl group is represented, the low alkyl group is defined as above.

R³Represent methyl or lower alkoxy.Lower alkoxy is corresponding to above-mentioned rudimentary base, straight or branched alkoxyl specially containing 1-6 carbon atom, and including, for example, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, secondary amoxy, tertiary amoxy, neopentyl oxygen, 1- methylbutoxy groups, 2- methylbutoxy groups.1,1- dimethyl propylenes epoxide, 1,2- dimethyl propylenes epoxide, positive hexyloxy, dissident's epoxide, 1- methyl amoxy, 2- methyl amoxy, 3- methyl amoxy, 1,1- dimethyl butyrates epoxide, 1,2- dimethyl butyrates epoxide, 2,2- dimethyl butyrates epoxide, 1,3- dimethyl butyrates epoxide, 2,3- dimethyl butyrates epoxide, 3,3- dimethyl butyrates epoxide, 1- ethyl-butoxies, 2- ethyl-butoxies, 1,1,2- trimethyl propoxyl group, l, 2,2- trimethyl propoxyl group, l- ethyl -1- methyl propoxyl group, 1- Ethyl-2-Methyl propoxyl group etc..

Q represents oxygen atom or CH₂。

M represents hydroxyl or leaving group.The leaving group is defined as above.

Used salt is not limited by its type, and including for example, the addition salts of inorganic acid, such as hydrofluoride, hydrochloride, sulfate, nitrate, high hydrohalogenic acid salt, phosphate, carbonate, bicarbonate, hydrobromate, hydriodate；The addition salts of organic carboxyl acid, such as acetate, maleate, fumarate, oxalates, lactate, citrate, trifluoroacetate；The addition salts of organic sulfonic acid, such as mesylate, fluoroform sulphonate, esilate, hydroxymethane sulfonic acid salt, isethionate, benzene sulfonate, toluene fulfonate, taurate；The addition salts of amine, such as front three amine salt, triethylamine salt, pyridiniujm, procaine salt, picoline salt, dicyclohexyl amine salt, N, N- '-benzhydryl ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, diethanolamine salt, triethanolamine salt, three (methylol) methyls, ethoxyphenyl benzylamine salts etc.；The addition salts of alkali metal, such as sodium salt, sylvite；The addition salts of alkaline-earth metal, such as magnesium salts, calcium salt；The addition salts of amino acid, such as arginine salt, lysine salt, serine salt, glycinate, aspartate, glutamate.

Pharmaceutically useful salt means to prepare the conventional conventional salt of medicine.

Hydroxylamine derivative used herein can generally can derive any compound of cyano group from formoxyl in organic synthesis, and be not particularly limited, and it includes, for example, hydroxylamine-o-sulfonic acid etc..

The preparation method of the application below shown in net reaction explained below.

Approach A-1 is approach [wherein R and the R of compound hydroxyl shown in protection formula (101)¹It is defined as above.Similarly hereinafter].Hydroxyl is protected according to method known in the art, can compound shown in formula (102) [wherein Pr is defined as above.Similarly hereinafter], its hydroxyl is protected in such a way.According to such as Green " Protective Groups in Organic Synthesis (A Wiley-Interscience Publication CO.) " methods described can prepare the hydroxyl protected with various protection groups.

Approach A-2 is the approach of the carboxyl-protecting group of compound shown in desealed (102).Similar to approach A-1, in the approach, conventionally, for example, being reduced with acid or basic hydrolysis or catalysis, the protection group of carboxylic acid is unsealed, can compound shown in formula (103).More specifically, by the way that in the solvent for not suppressing reaction, formula (102) compound and hydrochloric acid, trifluoroacetic acid, acetic acid, hydrobromic acid, formic acid, tosic acid, hydrogen peroxide, trimethylsilyl chloride, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine, potassium carbonate, sodium carbonate, boron trifluoride, Boron tribromide, aluminum halide, tetrabutyl ammonium fluoride or the like are carried out into reaction can complete deblocking.

Approach A-3 is that leaving group (L) is added to the process shown in formula (103) in compound.By by compound and activator shown in formula (103), for example, acid anhydrides such as TFAA, methylsulfonyl acid anhydride, trifluoromethanesulfanhydride anhydride or p-toluenesulfonic anhydride；Acyl chlorides, for example, mesyl chloride, paratoluensulfonyl chloride, chlorine di-phosphate ester, oxalyl chloride or thionyl chloride；Or 2- sulfenyl pyridines are reacted, formula (104) compound can be obtained.If desired, condensing agent such as dicyclohexyl carbodiimide (DCC) can be used according to the activity of used reagent.

In approach B-1, by by compound shown in formula (104) and compound shown in following formula：

[wherein X and Y are defined as above, similarly hereinafter] or its reactive derivative (for example, wherein Y is-the MgCl ,-MgBr or-MgI Grignard reagent activated by magnesium metal) reacted, can leaving group L is replaced by dibasic phenyl in formula (104) formula (105) compound.

In approach C-1, by by compound shown in formula (105), (it is to handle methyl triphenyl chlorination  by using alkali such as butyl lithium with triphen methylene , methyltriphenylphospbromide bromide  or methyltriphenylphosphonium iodide  and produce) reaction (be referred to as witig reaction), or by with trimethylsilyl methyl magnesium chloride, trimethylsilyl methyl magnesium bromide or trimethylsilyl methyl lithium react and form silicyl alcohol intermediate, silicyl alcohol intermediate desilylation is refined with boron trifluoride ether compound or the like again, olefin(e) compound that can be shown in formula (106).

Approach D-1 is the approach of olefin(e) compound shown in epoxidation formula (106).Epoxidizing agent used is not particularly limited, as long as it is the reagent of energy epoxidation double bond.However, as its example, can be mentioned that organic peroxide acid such as metachloroperbenzoic acid (mCPBA) and peracetic acid, and aqueous hydrogen peroxide solution.Preferably, can be by being reacted with metachloroperbenzoic acid come the epoxides shown in formula (107).

Also the epoxides shown in formula (107) can be obtained by following approach E-1.I.e., epoxides can be prepared by formula (105) compound and chloromethyl lithium (adding alkali as butyl lithium is formed by chloroiodomethane or bromoiodomethane) reaction, or with the reaction of dimethylated methylene base sulfonium oxygen, dimethylated methylene base sulfonium, diethyl methylene sulfonium oxygen or diethyl methylene sulfonium.

Approach F-1 is the direct open loop of epoxides shown in formula (107) and imidazole ring or 1, the reaction that 2,4- triazole rings are combined.Epoxides shown in formula (107) and imidazoles or 1 can be passed through, 2, (it is by alkali metal hydride such as sodium hydride, lithium hydride or hydrofining and imidazoles or 1 to the alkali metal salt of 4- triazoles, 2,4- triazoles are mixed and obtained in a solvent) [wherein A is nitrogen-atoms or CH to the reaction compound that obtains shown in formula (108).Similarly hereinafter].

Approach G-1 is the approach of deblocking hydroxyl protecting group.The hydroxyl protecting group can be unsealed by method well known in the prior art.For example, it can be carried out by being given above the method described in Green document.

Approach H-1 is that olefin(e) compound is oxidized into l, the approach of 2- ethylene glycol with oxidant.Can compound shown in formula (110) with oxidant compound as shown in osmium tetroxide or potassium permanganate processing formula (106).

Approach I-1 is the approach that compound shown in formula (105) is converted into compound shown in (110).In the approach, compound shown in formula (110) can react to form compound shown in general formula by compound shown in formula (105) and alkoxy dimetylsilyl methylmagnesium halide or dialkoxymethyl silyl methyl magnesium halide：

[wherein R²For low alkyl group, and R³Methyl or lower alkoxy are represented, similarly hereinafter], then again thus obtained compound is reacted to prepare in the presence of a base with peroxy acid.

Approach J-1 is the approach that the primary hydroxyl of compound shown in formula (110) is replaced by leaving group L.This method can be carried out by approach A-3.Compound shown in formula (111) can react to prepare by formula (110) compound with (preferably) acyl chlorides such as mesyl chloride, paratoluensulfonyl chloride, diphenyl phosphate chloride, oxalyl chloride or thionyl chloride.

In approach J-2, by being reacted by approach F-1, imidazole radicals or 1, the leaving group L of compound shown in 2,4- triazolyl displaced types (111) can be used.

Approach k-1 is by approach that the primary hydroxy group of compound shown in formula (109) is formoxyl.The oxidation of the primary hydroxyl can be carried out by method known in the art.By using, for example, the salt or oxide of metal such as chromium, manganese or silver, or the organic oxidizing agent of dimethyl sulfoxide (DMSO) (DMSO) type is come to carry out the reaction be easy.As reagent, it can be used, for example, chromic acid pyridine complex, pyridine chlorochromate or Pyridinium dichromate.In addition, the use of the DMSO oxidizing process of oxalic acid chlorine being conventional.

Approach L-1 is the approach that the formoxyl of compound shown in formula (112) is replaced by cyano group.Compound shown in formula (113) can react to prepare by compound shown in formula (112) with hydroxylamine derivative such as hydroxylamine acid.

Approach M-1 and N-1 are the process for preparing antifungal agent, and the antifungal agent is the final compound shown in formula (115).In these approach, show compound shown in formula (114) can be formed by hydrogen sulfide being added in the compound shown in formula (113) by the compound shown in formula (115) and then again being prepared the compound obtained and the reaction of 2- bromo- 4 '-methyl thio acetophenones for fabulous antifungal activity.

Workable solvent is not particularly limited in the present invention, as long as their without prejudice tos are reacted and are commonly used in organic synthesis.However, as its example, can be mentioned that lower alcohol such as methanol, ethanol, propyl alcohol and butanol；Polyalcohol such as 1,2- ethylene glycol and glycerine；Ketone such as acetone, methyl ethyl ketone, metacetone and cyclohexanone；Ether such as ether, isopropyl ether, tetrahydrofuran, two  alkane, 2-methyl cellosolve and 1,2- dimethoxy-ethane；Nitrile such as acetonitrile and propionitrile；Ester such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate and diethyl phthalate；Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, trichloro ethylene and tetrachloro-ethylene；Aromatic such as benzene,toluene,xylene, monochloro-benzene, nitrobenzene, indenes, pyridine, quinoline, collidine and phenol；Hydrocarbon such as pentane, hexamethylene, hexane, heptane, octane, isooctane and petroleum ether；Amine such as monoethanolamine, diethylamine, triethylamine, pyrrolidines, piperidines, piperazine, morpholine, aniline, dimethylaniline, benzene methanamine and toluidines；Acid amides such as formamide, N- methylpyrrolidones, N, N- dimethyl-imidazolinones, DMA and DMF；Phosphamide such as HMPA and the sub- phosphoric triamide of hexamethyl；Organic acid such as formic acid, acetic acid, difluoroacetic acid, trifluoroacetic acid and monoxone；Sulfoxide such as dimethyl sulfoxide (DMSO)；The sulfide of carbon such as carbon disulfide；Water；With other common solvents.These solvents can be single solvent or the mixed solvent of its two or more solvent.The mixed proportion of mixed solvent is not particularly limited.

In above approach, if it is desired, the product formed can be purified by the column chromatography of method well known in the prior art such as silica gel or the like, and if desired, it can carry out unsealing the reaction of its protection group.The deblocking of protection group can be carried out by the way that product to be reduced to (as catalysis is reduced) or solvolysis.

In addition, compound or its salt shown in following formula：

Compound or its salt shown in general formula；

Compound or its salt shown in general formula；

With compound or its salt shown in general formula；

[wherein formula (116) is arrived in (120), and R, Pr, L, X, Q, M and A are defined ibid] is useful in the application preparation method and in the synthesis with fabulous Antifungal Compounds.

Here, the present invention compound and preparation method in, in the molecule thereof with the presence of asymmetric carbon atom stereoisomer with S configurations or R configurations.In addition, due to double bond, there is E or Z-type geometric isomer.For convenience, a kind of configuration is described in this manual.However, its two kinds of compounds and its mixture are included in the present invention.For convenience's sake, compound of the invention is not limited by compound shown in the chemical formula.Optical isomer can split technology by normal optical and separate, meanwhile, diastereomer can be separated using conventional separation method such as chromatogram.

When intending to prepare individual isomer, according to the corresponding preparation method of the application, it can be prepared Stereoselective or enantioselectivity.

In view of the viewpoint of antifungal activity, spatially it is preferably used using optically active hydroxy-2-methyl propionic acid (S) methyl esters as formula (101) compound or the preparation method of raw material to complete process made above, to form the compound of formula (113) while its stereochemical structure is kept, it is derived from optically active (2S, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazol-1-yls) butyronitrile, as the compound of formula (113), and obtains the intermediate for being synthesized with this stereochemical structure.

According to the application, for example, the new compound or its salt shown in general formula can be prepared：

Two of which X is same to each other or different to each other and respectively halogen atom or hydrogen atom；R⁴Represent hydrogen atom or low alkyl group, r and m are same to each other or different to each other and respectively 0 or 1；A is N or CH；W is represented to have one or more substituents and can be contained one or more heteroatomic aromatic rings selected from N, S and oxygen, or its condensed ring；E is can have one or more substituents and can contain one or more heteroatomic aromatic rings selected from N, S and O, can have the alkane 2 basis of one or more substituents, can have the olefin 2 base of one or more substituents, can the alkyne diyl with one or more substituents；G is formula-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C-O ,-O-, ＞ N-R⁵, ＞ C=N-OR⁵Or-(CH₂)_j- shown group, the integer that wherein R5 is hydrogen atom or low alkyl group and j is 1-4；And Z represent hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, can have one or more substituents phenoxy group, can have one or more substituents imidazole radicals, can have one or more substituents triazolyl, can have one or more tetrazole radicals being substituted in or the amino with one or more substituents.

Certain embodiments of the present invention is described in more detail.However, the present invention is not restricted by the embodiments.In the examples below that, 1HNMR spectrums are that the FTNMR (400MHz) manufactured with Varian Company is measured.

In addition, Tr, Ms, MOM, TBDPS and Bn hereinafter represents trityl, mesyl, methoxy, t-butyldiphenylsilyl and benzyl respectively.

Embodiment

Hereafter the present invention will more specifically be described by embodiment, EXPERIMENTAL EXAMPLE and preparation embodiment.But the present invention is not only limited to these embodiments, EXPERIMENTAL EXAMPLE and prepares embodiment.

Embodiment 1

The synthesis of 1- (2,4- difluorophenyl) -1- (4- (2,4- difluorophenyl) thiazol-2-yl) -2- (1H-1,2,4- triazol-1-yls) ethanol.

By 4- (2,4- difluorophenyls) thiazole (330mg) is dissolved in after ether (3ml), the solution is cooled to -78 DEG C under nitrogen atmosphere, the hexane solution (1.06ml) of 1.6M n-BuLis is added, and by resulting mixture stir about 10 minutes.After the tetrahydrofuran solution of chloro- 2 ', the 4 '-difluoro acetophenones of 2- (306mg) is added dropwise into the mixture, the liquid reaction mixture is heated to -20 DEG C, aqueous ammonium chloride solution is added.The reactant mixture is extracted with ethyl acetate.Dried with magnesium sulfate after organic layer, remove solvent under reduced pressure.The residue is dissolved in generation solution (A) in dimethylformamide (3ml).On the other hand, the dimethyl formamide solution (3ml) (B) for containing 1,2,4- triazoles (350ml) and 60% sodium hydride (135mg) is prepared.Then solution (B) is added in solution (A), and the mixture is heated 6 hours in 60 DEG C.Ethyl acetate and water are added in the liquid reaction mixture, and organic layer is washed with water for several times, the solvent is evaporated off.Then the residue is contained the cut of purposeful compound with Diethyl ether recrystallization, thus obtain title compound (390mg) in carrying out chromatogram on silicagel column.Then described table 1 shows its physical property.

Embodiment 2

(1) synthesis of 1- (2,4- difluorophenyl) -1- (6- cyano-benzothiazol -2- bases)-ethylene chlorhydrin

6- cyanobenzothiazoles (1.60g) are dissolved in after tetrahydrofuran (80ml), the solution is set to be cooled to -98 DEG C under nitrogen atmosphere, the hexane solution (5.9ml) of 1.6M n-BuLis is added drop-wise in the solution with 10 minutes, and by the mixing 5 minutes of gained.Tetrahydrofuran (20ml) solution of chloro- 2 ', the 4 '-difluoro acetophenones of 2- (2.85g) is added dropwise into the mixture.The liquid reaction mixture is heated to after -10 DEG C, ammonium chloride solution is charged with.The mixture is heated to after room temperature, organic layer is taken out and removes solvent under reduced pressure.Water layer is extracted with ethyl acetate, the extract merges with the residue of organic layer.The organic layer is washed with water, then is washed with saturated brine, is dried with magnesium sulfate, and vacuum distillation.The residue is then subjected to chromatogram (solvent on a silica gel column：Hexane/ethyl acetate=20/1, then, hexane/ethyl acetate=5/1), thus obtain purpose compound (1.49g).

(2) synthesis of 1- (2,4- difluorophenyl) -1- (6- cyano-benzothiazol -2- bases) -2- (1H-1,2,4- triazol-1-yls)-ethanol

Sodium hydride (440mg) is suspended in dimethylformamide (10ml), and by 1,2,4- triazoles (948mg) are added in the suspension, dimethylformamide (10ml) solution of 1- (2,4- difluorophenyl) -1- (6- cyanobenzothiazole -2- bases)-ethylene chlorhydrin (1.49g) is charged with again.The mixture is heated 4 hours in 60 DEG C.The liquid reaction mixture is cooled to after room temperature, and ethyl acetate and water are added thereto.The organic layer of separation is washed with water 3 times, then dried with magnesium sulfate, solvent is evaporated off again afterwards.The residue is recrystallized in dichloromethane-Di Iso Propyl Ether, obtains purpose compound (1.17g) fusing point：170-172℃.

Embodiment 3

The synthesis of 1- (2,4- difluorophenyl) -1- { 4- [4- (5- tetrazoliums)-phenyl) thiazole] -2- bases } -2- (1H-1,2,4- triazol-1-yls) ethanol

By 1- (2,4- difluorophenyl) -1- (4- (4- cyano-phenyls)-thiazol-2-yl) -2- (1H-1,2,4- triazol-1-yls) ethanol (fusing point：195-198 DEG C) (400mg) be dissolved in dimethylformamide (1.2ml).Sodium azide (191mg) and triethylamine hydrochloride (404mg) are added into the solution.Gained mixture is heated overnight (12 hours) in 100 DEG C.It is filtered to remove after insoluble matter, solvent is evaporated off, the residue is dissolved in the acetoneand ethyl acetate of (respectively about 2ml) on a small quantity.Add water in the solution, the pH to about 4 of the solution is adjusted with concentrated hydrochloric acid.The precipitation of the generation is collected by filtration, is washed with water, then dries, title compound (380mg) is thus obtained.Fusing point：252-254℃.The subsequent table 2 shows its physical characteristic.

Embodiment 4

1- (2,4- difluorophenyls) and -1- { 4- [4- (5- (3- methyl) tetrazolium)-phenyl) thiazole] -2- bases } -2- (1H-1,2,4- triazol-1-yls) ethanol [structural formula A] and 1- (2,4- difluorophenyls) and -1- { 4- [4- (5- (4- methyl) tetrazolium)-phenyl) thiazole] -2- bases } -2- (1H-1,2,4- triazol-1-yls) ethanol [structural formula B] synthesis

Structural formula A：

Structural formula B：

The 1- (2 that embodiment 3 is obtained, 4- difluorophenyls) -1- 4- [(4- (5- tetrazoliums)-phenyl)-thiazole] -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol (320mg) is dissolved in dimethylformamide (3ml).Cesium carbonate (231mg) is added into the solution and stirs the mixture 30 minutes in 60 DEG C, room temperature is subsequently cooled to.Add methyl iodide (O.048ml), then being stirred overnight at room temperature by gained mixture.Water is added in the mixture and is extracted with ethyl acetate.The extract is evaporated off after solvent under reduced pressure, and silicagel column on residue is carried out into chromatogram, from there through the compound [fusing point that structural formula A is afforded with 1% methanol chloroform：188-191 DEG C], structural formula B compound [double fusing points are then afforded with 2% methanol chloroform：110-115 DEG C and 185-187 DEG C] (60mg).The subsequent table 2 shows their physical characteristic.

Embodiment 5

The synthesis of 1- (2,4- difluorophenyl) -1- [2- (4-1H-1,2,4- triazol-1-yls)-phenyl)-thiazole -5- bases)] -2- (1H-1,2,4- triazol-1-yls) ethanol

By 1- (2,4- difluorophenyls) -1- (2- (4- fluorophenyls)-thiazole -5- bases) -2- (1H-1,2,4- triazol-1-yls) dimethylformamide (3ml) solution of ethanol is added drop-wise to by 1H-1, in dimethylformamide (3ml) solution prepared by 2,4- triazoles (168mg) and 60% sodium hydride (81mg).Gained mixture is heated 30 hours in 100 DEG C.The liquid reaction mixture is cooled to after room temperature, is added water and is extracted with ethyl acetate.The solvent of the extract is evaporated off, silicagel column on gained residue is then subjected to chromatogram (being eluted with 3% methanol ethyl acetate), the title compound (60mg) is thus obtained.

Then described table 2 shows its physical characteristic.

Embodiment 6

The synthesis of 1- (2,4- difluorophenyl) -1- (6- thio-carbamoyl benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol

By 1- (2,4- difluorophenyls) -1- (6- cyanobenzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol (418mg) and triethylamine (500ml) be dissolved in dimethylformamide (4ml).While being cooled down with frozen water, hydrogen sulfide gas is passed through into resulting solution 5 minutes.After room temperature is placed 6 hours, into the solution, addition water and ethyl acetate are layered it.Organic layer is washed twice with water, then is dried with salt water washing and with magnesium sulfate.Solvent is evaporated off, purpose compound (437mg) is obtained.Its physical characteristic is shown in the subsequent table 2.

Embodiment 7

The synthesis of 1- (2,4- difluorophenyl) -1- (6- (3- methYl-thiazol -1- bases)-benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol

By 1- (2; 4- difluorophenyls) -1- (6- thiocarbamoyls-benzothiazole -2- bases) -2- (1H-1; 2; 4- triazol-1-yls) ethanol (219mg) is dissolved in ethanol (2ml), and sodium acid carbonate (42mg) and bromo acetone (46 μ l) are added in the solution.Obtained mixture is heated 3 hours in 60 DEG C.Water and ethyl acetate are added into the liquid reaction mixture is layered it.Organic layer is washed and dried with salt, and solvent is then evaporated off.Silicagel column on the residue is then subjected to chromatogram (eluting solvent：Chloroform: methanol=100: 1), purpose compound (114mg) is thus obtained.Fusing point：213-215℃.

Embodiment 8

1- (2,4- difluorophenyl) -1- (6- thiazole -1- bases)-benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol synthesis

By 1- (2; 4- difluorophenyls) -1- (6- thiocarbamoyl benzothiazole -2- bases) -2- (1H-1; 2,4- triazole -1-) ethanol (181mg) and bromoacetaldehyde dimethyl acetal (256 μ l) be dissolved in ethanol (2ml).3 are added into the solution to drip the concentrated sulfuric acid and it is flowed back 2.5 hours.Cool down after the liquid reaction mixture, be charged with water and the sodium bicarbonate aqueous solution of saturation, gained mixture is extracted with ethyl acetate again.Organic layer is washed with water, then uses salt water washing, and is dried with magnesium sulfate.Solvent is evaporated off.Hexane is added in the residue with curing reaction product, reaction product is then collected by filtration and is washed with hexane, purpose compound (168mg) is thus obtained.162-166 DEG C of molten point.

Embodiment 9

(1) synthesis of 1- (2,4- difluorophenyl) -1- (4- (4- carbethoxyl groups thiazol-2-yl)-thiophene -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol

By 1- (2; 4- difluorophenyls) -1- (4- thiocarbamoyl thiophene -2- bases) -2- (1H-1; 2; 4- triazol-1-yls) ethanol (1.6g) is dissolved in dimethylformamide (10ml), and it is charged with α-bromoethyl pyruvic acid (O.67ml).Resulting mixture is stirred 4 hours in 60 DEG C.After reaction, add water and the reactant mixture is extracted with ethyl acetate.Organic layer is washed with saturated brine.Silicagel column on residue is then subjected to chromatogram and (chloroform: methanol=80: 1), thus obtains oily mater (1.78g).

(2) synthesis of 1- (2,4- difluorophenyl) -1- (4- (4- carbamoyls thiazol-2-yl)-thiophene -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol

The 1- (2 that step (1) is obtained, 4- difluorophenyls) -1- (4- (4- carbethoxyl groups thiazol-2-yl)-thiophene -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol (1.7g) is dissolved in the methanol solution of the ammonia of saturation (35ml), and resulting solution is placed 23 hours in room temperature.Remove under reduced pressure after solvent, crystallized from dichloromethane-ether (1.2g).112-115 DEG C of fusing point.

Embodiment 10：

The synthesis of 1- (2,4- difluorophenyl) -1- (4- (4- cyano thiazole -2- bases)-thiophene -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol

By 1- (2; 4- difluorophenyls) -1- (4- (4- carbamoyls thiazol-2-yl)-thiophene -2- bases) -2- (1H-1; 2,4- triazol-1-yls) ethanol (1.2g) is dissolved in pyridine (7.1ml).The solution is cooled down in ice bath, and is charged with phosphoryl chloride phosphorus oxychloride (O.29ml).Obtained mixture is stirred 30 minutes.After reaction, salt solution is added into the reactant mixture and is extracted with ethyl acetate.Organic layer is washed once with 6N hydrochloric acid (20ml).Respectively it washed once with water, saturated sodium bicarbonate aqueous solution and saturated brine again.Solvent is evaporated off after being dried with magnesium sulfate in such washed organic layer.Residue is purified on silica gel through chromatogram.Recrystallized from the diethyl ether solution of dichloromethane, obtain solid (800mg).Fusing point：172-173℃.

Embodiment 11-17

Compound represented by logical formula (II) is prepared using method same as Example 1：

In Formula II, A, M and L are substituted as shown in table 1.

Table 1

Apply example	AML	Physical characteristic
Apply example	AML	Physical characteristic	1	NFF	mp：148~150 DEG C¹HN.M.R.(CDCl₃) 65.23 (1H.d.J=14.1Hz) .5.28 (1H.d.J=14.1Hz) .5.97 (1H.s) .6.8~7.0 (4H.m) .7.66 (1H.d.J=2.2Hz) .7.69 (1H.td.J=9.5.6.4Hz) .7.86 (1H.s) .8.10 (1H.s) .8.14 (1H.td.J=9.5.6.6Hz)
11	CHFF	mp：191~192 DEG C¹HN.M.R.(DMSO-d₆) 64.98 (2H.brs) .6.67 (1H.brs) .6.81 (1H.brs) .7.0~7.08 (1H.m) .7.18~7.26 (2H.m) .7.30 (1H.brs) .7.35~70.42 (1H.m) .7.39 (1H.s) .7.55~7.62 (1H.m) .7.91 (1H.d.J=2.5Hz) .8.12~8.2 (1H.m)	1	NFF
11	CHFF		12	NFH	mp：158~160 DEG C¹HN.M.R.(DMSO-d₆) 65.08 (2H.brs) .7.1~7.18 (2H.m) .7.22~7.28 (1H.m) .7.35~7.42 (1H.m) .7.37 (1H.s) .7.6~7.66 (2H.m) .7.75 (1H.s) .7.86 (1H.d.J=2.8Hz) .8.22 (1H.s) .8.24~8.3 (1H.m)
13	CHFH	mp：184~186 DEG C¹HN.M.R.(DMSO-d₆) 64.79 (1H.d.J=14.5Hz) .4.87 (1H.d.J=14.5Hz) .6.66 (1H.brs) .6.8l (1H.brs) .7.1~7.18 (2H.m) .7.22~7.28 (1H.m) .7.30 (1H.brs) .7.32 (1H.s) .7.35~7.42 (1H.m) .7.86 (1H.d.J=2.5Hz) .8.25~8.32 (1H.m)	12	NFH
13	CHFH		14	NClCl	mp：188~189 DEG C¹HN.M.R.(DMSO-d₆) 65.35 (1H.d.J=14.4Hz) .5.50 (1H.d.J=14.4Hz) .7.2~7.26 (1H.m) .7.35~7.44 (3H.m) .7.54~7.58 (2H.m) .7.68 (1H.s) .8.00 (1H.d.J=2.5Hz) .8.15~8.22 (1H.m) .8.31 (1H.s)
15	CHClCl	mp：238~239 DEG C¹HN.M.R.(DMSO-d₆) 65.05 (1H.d.J=14.4Hz) .5.26 (1H.d.J=14.4Hz) .6.67 (1H.brs) .6.73 (1H.brs) .7.2~7.25 (1H.m) .7.23 (1H.s) .7.37 (1H.s) .7.37~7.42 (2H.m) .7.57 (1H.d.J=2.5Hz) .7.64 (1H.d.J=8.8Hz) .7.98 (1H.d.J=2.5Hz) .8.14~8.2 (1H.m)	14	NClCl
15	CHClCl		16	NClH	mp：167~168 DEG C¹HN.M.R.(DMSO-d₆) 65.09 (2H.brs) .7.22~7.28 (1H.m) .7.35~7.40 (2H.m) .7.42 (1H.s) .7.6~7.64 (2H.m) .7.76 (1H.s) .7.87 (1H.d.J=2.8Hz) .8.24 (1H.s) .8.24~8.3 (1H.m)
17	CHClH	mp：201~203 DEG C¹HN.M.R.(DMSO-d₆) 64.81 (1H.d.J=14.5Hz) .4.86 (1H.d.J=14.5Hz) .6.67 (1H.s) .6.83 (1H.s) .7.22~7.23 (1H.m) .7.31 (1H.s) .7.35~7.42 (4H.m) 7.62~7.66 (2H.m) .7.87 (1H.d.J=2.5Hz) .8.25~8.32 (1H.m)	16	NClH

Embodiment 18-87

Table 2 is summarized using the purpose compound prepared with embodiment 1-10 identicals method.

Table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

The (Continued) of table 2

[0070]

EXPERIMENTAL EXAMPLE 1

The ICR mouse of every group five inject Candida albicans MCY8622 bacterial strains (2 × 106cfu/ mouse) by its tail vein and are infected.After 1 hour, the mouse to each group orally administers [logical to show the compound that (III) is represented] compound shown in table 3, and dosage is per Kg mouse 2.5mg or 10mg.Observation calculates every group of average Survival number of days over 7 days.It regard the average as an index for representing internal antifungal activity.Additionally, formula (III) compound is led to as follows：

Table 3

The (Continued) of table 3

Prepare embodiment 1：

Preparing raw material 1：

(2S, 3R) -3- (2,4- difluorophenyl) -3- hydroxy-2-methyls -4- (1H-1,2,4- triazol-1-yls) butyronitrile

Structural formula：

Under nitrogen atmosphere, to 5g (20.0ml) optically active (2R being dissolved in 40ml toluene, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) 80ml diethyl cyanidings aluminium (1.0M toluene solutions) is added in methyl oxirane solution.The mixture is heated in 50 DEG C 12 hours, and 10ml water and 120ml1NHCl are gradually added dropwise thereto.Obtained mixture is stirred at room temperature 2 hours, through florisil filter plates, then extracted again with ethyl acetate.The liquid scrubbing of water and saturated brine that resulting organic layer is mixed with 1: 1 ratio 4 times, is finally washed with saturated brine again.Remove under reduced pressure after solvent, the residue is washed with Di Iso Propyl Ether, thus obtain 3.15g (56.6%) optically active (2S, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyls -4- (1H-1,2,4- triazol-1-yls) butyronitrile.The physical characteristic of the product is as described below.

mp.181-182℃

NMR：δ solvents (CDCl₃)

1.17 (3H, d, J=7.2Hz), 3.29 (1H, q, J=7.2Hz),

4.82 (1H, d, J=14.0Hz), 4.97 (1H, d, J=14.0Hz),

5.44 (1H, d, J=0.8Hz), 6.74-6.82 (2H, m), 7.39-7.46 (1H, m),

7.83 (1H, s), 7.84 (1H, s)

MS：MH⁺=279.

Prepare embodiment 2：

Pass through another method preparing raw material 1：

Six hydrous ytterbium chlorides that 388mg (1mmol) is measured are in 120 DEG C, and decompression is lower to place more than 6 hours.By the compound in blanket of nitrogen low suspension in 10ml tetrahydrofurans, and the suspension is cooled to -78 DEG C.1.9ml n-BuLis (1.63M hexane solutions) are added dropwise into the suspension, the gained mixture is stirred 5 minutes at room temperature, -78 DEG C are subsequently cooled to.0.8ml trimethyl silyls cyanogen is slowly added drop-wise in the mixture.Resulting mixture is stirred 10 minutes in -78 DEG C, then then at being stirred at room temperature 5 minutes, -78 DEG C are cooled to afterwards.128mg (0.5mmol) optically active (2R of 1ml tetrahydrofurans will be dissolved in, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxirane is added drop-wise in the mixture, while being warmed to room temperature the temperature of resulting mixture.Saturated aqueous ammonium chloride is added in the mixture, the organic layer obtained by is then extracted with ethyl acetate and is washed with water and saturated brine.Remove under reduced pressure after the solvent, the residue Diethyl ether recrystallization, thus obtain 81mg (58.2%) optically active (2s, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyls -4- (1H-1,2,4- triazol-1-yls) butyronitrile.

Prepare embodiment 3：

Pass through another method preparing raw material 1：

By 478mg) 60.Ommol) lithium hydride of amount is added in the tetrahydrofuran solution of ice cooling (50ml) and it is suspended completely.After 10 minutes, by 5.4g (63.5mmo1) acetone cyanohydrins [(CH₃)₂C (OH) CN] it is added drop-wise in suspension, room temperature is continued at afterwards to be stirred for 1.5 hours.5g (20.0mmol) optically active (2R, 3S) -2- (2,4- difluorophenyl) -3- methyl -2- (1H.1,2,4- triazol-1-yls) methyl oxirane is added into the mixture.The whole is flowed back 7 hours.100ml ethyl acetate is added into the reactant mixture of gained, is then gradually washed with 100ml water and 50ml sodium chloride solutions.Then, it is dried with magnesium sulfate.Then refilter resulting solution.Be concentrated under reduced pressure filtrate.50ml Di Iso Propyl Ethers are added into the concentrate.Then resulting solution is filtered, optically active (2S, 3R) -3- (2,4- the difluorophenyl) -3- hydroxy-2-methyls -4- of 4.2g (76.0%) (1H-1,2,4- azoles -1- bases) butyl is obtained.

Prepare embodiment 4

Preparing raw material 2：

Prepare 2- (2,4- difluorophenyl) -3- thioamides -1- (1H-1,2,4- triazol-1-yl -2- butanol

Structural formula：

Toward the racemic modification for preparing the raw material 1 that embodiment 1 or 2 is obtained, i.e. add 14mlH in 3- (2,4- difluorophenyl) -3- hydroxy-2-methyls -4- (1H-1,2,4- triazol-1-yls) butyronitrile (14g)₂0 and O, 0- phosphordithiic acid diethylester (73ml), gained mixture is heated to reflux 30 minutes.The liquid reaction mixture is cooled to room temperature, adds water, is then extracted with AcOEt.AcOEt layers of gained uses H₂O and the washing of the saturation NaCl aqueous solution, and use MgSO₄Dry.Hereafter, solvent is evaporated off.Gained residue is through silica gel chromatography (SiO₂：300g, uses CH₂Cl₂Elution, then gradually with 1%, 2% and 3%MeOH CH₂Cl₂Solution is eluted), then use CH₂Cl₂- IPE is recrystallized, and thus obtains purpose compound (8.1g).Additionally, when with the racemic modifications of the optically active substance alternative materials 1 of raw material 1, optically active raw material 2 can be similarly obtained.

The physical characteristic of the product is as described below.

mp：164-167℃

NMR：δ solvents (CDCl₃)

1.11 (3H, d, J=7.1Hz), 3.69-3.72 (1H, m),

4.55 (1H, d, J=14-3Hz), 5.08 (1H, d, J=14.3Hz),

6.71-6.08 (2H, m), 7,42-7.48 (1H, m),

7.80 (1H, brs), 7.94 (1H, s), 8.41 (1H, brs)

MS：MH⁺=313.

Prepare embodiment 5：

Preparing raw material 3：

Prepare the bromo- 4 '-cyano-acetophenones of 2-

Structural formula：

4 '-cyano-acetophenone (10g) is dissolved in 100mlCHCl₃, and toward adding 1m148%HBr in resulting solution.At room temperature, toward Br is added dropwise in the mixture₂The CHCl of (3.7ml)₃(10ml) solution.It is stirred at room temperature after 2 hours, by saturation NaHCO₃The aqueous solution, which is added in the liquid reaction mixture, neutralizes it.The CHCl₃Layer is washed with water, and is then washed with saturation NaCl solution, then use MgSO₄Dry.Afterwards, chloroform is evaporated off.Gained solid matter is recrystallized in AcOEt-nHex, purpose compound (3.49g) is thus obtained.The physical characteristic of the product is as described below.

mp.82-84℃

NMR：δ solvents (CDCl₃)

4.44 (2H, s), 7.81-7.84 (2H, m), 8.09 (1H, d, J=8Hz),

8.23 (1H, d, J=8Hz)

Prepare embodiment 6：

Preparing raw material 4：

Prepare 2- ethyl -6- chloro benzothiazoles

Structural formula：

2- amino -5- thiophenols (2.618g) are dissolved in 1-METHYLPYRROLIDONE (6ml), and toward adding propionyl chloride (1.57ml) in the solution, heated 1.5 hours after 130 DEG C.Ethyl acetate and sodium bicarbonate aqueous solution are added into the liquid reaction mixture so that the demixing.Gained organic layer is washed with water, and the residues are dried and concentrated and (hexane: ethyl acetate=20: 1) purifies through silicagel column, obtains 2- ethyl -6- chloro benzothiazoles (2.3g).The product physical characteristic is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.47 (3H, t, J=7.4Hz), 3.14 (2H, q, J=7.4Hz),

7.40 (1H, dd, J=2.0m, 8.8Hz), 7.81 (1H, d, J=2.OHz),

7.86 (1H, d, J=8.8Hz)

Prepare embodiment 7：

Preparing raw material 5：

Prepare 2- ethyls -6- (1,2,3-triazoles -2- bases)-benzothiazole

Structural formula：

By 1H-1,2,3- triazoles (10.Og) are dissolved in dimethylformamide (280ml), and dispersion liquid of 60% sodium hydride (5.79g) in mineral oil was added in the solution bit by bit in 10 minutes.At room temperature, toward dimethylformamide (40ml) solution that 4- fluoronitrobenzenes (18.6g) are added dropwise in the mixture, then by gained mixture in 50 DEG C of heating stirrings 9 hours.The reactant mixture is poured into 400ml saturated aqueous ammonium chlorides, then is charged with 200ml water.Then mixture be extracted with ethyl acetate to (400ml × 1,200ml × 2), the ethyl acetate washed with water and then is washed with saturated brine, then is dried with anhydrous magnesium sulfate.Organic layer is concentrated under reduced pressure and (hexane: ethyl acetate=2: 1 → 1: 1) purifies through silicagel column, obtain 4- (1,2,3-triazoles -2- bases)-nitrobenzene (11.5g).

4- (1,2,3-triazoles -2- bases)-nitrobenzene (5.75g) is dissolved in 300ml ethanol, and is charged with 10% palladium-carbon (O.58g) and hydrazine hydrate (15.0g).Then it is heated to reflux 5 hours.The reactant mixture is cooled to room temperature and filtered through diatomite.The filtrate concentrates once under reduced pressure, adds 500ml water, then with ethyl acetate (200ml, 100ml × 2) extracted.So obtained organic layer is washed with water and then saturated brine, then with anhydrous sodium sulfate drying, is then concentrated under reduced pressure, and obtains 4- (1,2,3-triazoles -2- bases)-aniline (5.Og).The product can be used for next step reaction without purifying.

Obtained 4- (1,2,3-triazoles -2- bases)-aniline (5.Og) will be reacted above and is dissolved in 55ml acetic acid, and ammonium thiocyanate (6.Og) is added in the solution.While frozen water is cooled down, the mixture obtained by stirring.The 20ml acetic acid solutions of bromine (1.62ml) were added drop-wise in the mixture with 30 minutes.Hereafter, the mixture is heated to room temperature and stirred 4 hours in the temperature underground.

The reactant mixture frozen water is cooled down and concentrated ammonia liquor is added dropwise to, pH6 is then adjusted to.The precipitation of generation is recovered by filtration, the precipitation is washed with water and then with cold ethanol, and is dried under reduced pressure, obtains 2- amino -6- (1,2,3-triazoles -2- bases) benzothiazole (5.6g).

By 2- amino -6- (1,2,3- triazole -2- bases) benzothiazole (2.8g) is dissolved in DMF (60ml), isoamyl nitrate (8.66ml) is added in the solution again, then stirred 20 minutes in 65 DEG C.The reactant mixture is poured into 100ml water, then (100ml × 3) are extracted with ethyl acetate.Gained organic layer is washed with water and then with saturated brine, is dried with anhydrous magnesium sulfate, is then concentrated under reduced pressure.Gained grease is purified through silica gel column chromatography (dichloromethane), obtains 6- (1,2,3-triazoles -2- bases) benzothiazole (1.1g).

6- (1,2,3-triazoles -2- bases) benzothiazole (1.1g) is suspended in ethanol (90ml), and the hydrazine hydrates of 12ml mono- are added in the suspension.Gained mixture is heated to reflux 2 hours.It is concentrated under reduced pressure after the reactant mixture, is charged with 20ml water, and its pH is adjusted to about 7 with acetic acid.The mixture become reconciled in this is extracted 3 times with ashamed acetoacetic ester, gained organic layer is washed with saturated brine, is dried with anhydrous magnesium sulfate, is then concentrated under reduced pressure, and obtains 2- amino -5- (1,2,3-triazoles -2- bases) thiophenol (2.3g).The product can be reacted without purifying with next step.

2- amino -5- (1,2,3-triazoles -2- bases) thiophenol (2.3g) is dissolved in 1-METHYLPYRROLIDONE (8ml), and propionyl chloride (0.472ml) is added in the solution, then in 70 DEG C of heating stirrings 5 hours.The reactant mixture is poured into saturated sodium bicarbonate aqueous solution, extracted afterwards with dichloromethane.Gained organic layer is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and then (isohexane ethyl acetate=4: 1-1 → 1: 1) is purified through silicagel column, obtain purpose compound, that is 2- ethyls -6- (1,2,3-triazoles -2- bases)-benzothiazole (940mg).The physical characteristic of the product is as described below.

State：Solid

NMR：δ solvents (CDCl₃)

1.49 (3H, t, J=7.7Hz), 3.17 (2H, q, J=7.7Hz)

7.83 (2H, s), 8.03 (1H, d, J=8.8Hz),

8.20 (1H, dd, J=8.8,3.2Hz), 8.55 (1H, d, J=8.8Hz)

Embodiment 88：

Prepare the compound of following structural formula：

By 2- (2,4- difluorophenyls) -3- thioamides -1- (1H, 1,2,4- triazol-1-yls) -2- butanol (raw material 2) (156mg) is dissolved in EtOH (2ml), and the bromo- 4 '-cyano-acetophenones of 2- (raw material 3) (224mg) are added in the solution, 1 hour saturation NaHCO is heated to reflux afterwards₃The aqueous solution neutralizes the liquid reaction mixture, is then extracted with AcOEt.Extract H₂O and then after being washed with the saturation NaCl aqueous solution, uses MgSO₄Dry, AcOEt is evaporated off.Gained residue is through silica gel chromatograph (SiO₂：20g, uses CH₂Cl₂And then with 1%MeOH CH₂Cl₂Solution is eluted) purifying, then recrystallized with IPE, obtain purpose compound (109mg).The physical characteristic of the compound is as described below.

mp：196-197℃

NMR：δ solvents (CDCl₂)

1.23 (3H, d, J=8.0Hz), 4.09 (1H, q, J=8.OHz),

4.26 (1H, d, J=14.3Hz), 4.92 (1H, d, J=14.3Hz)

5.74 (1H, s), 6.78-6.85 (2H, m), 7.48-7.54 (1H, m),

7.64 (1H, s), 7.69 (1H, s), 7.75 (1H, d, J=8.1Hz),

7.85 (1H, s), 8.03 (1H, d, J=8.1Hz)

MS：MH⁺=438

Embodiment 89：

Prepare the compound that following structural is represented：

In addition to substituting the bromo- 4 '-cyano-acetophenones of 2- with the bromo- 4 '-methyl thio acetophenones of 2-, according to same procedure described in embodiment 88, the purpose compound is obtained.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₂)

1.23 (3H, d, J=7.2Hz), 2.54 (3H, s) 4.05 (1H, q, J=7.2Hz),

4.28 (1H, d, J=14.4Hz), 4.88 (1H, d, J=14-4Hz), 6.13 (1H, s),

6.75-6.85 (2H, m), 7.33 (2H, br-d, J=8.4Hz), 742 (1H, s),

7.46-7.54 (1H, m), 7.66 (1H, s), 7.82 (2H, br-d, J=8-4Hz),

7.92 (1H, s))

MS∶MH⁺=459.

Embodiment 90：

[0081]

Prepare the compound that following structural is represented：

Except being replaced with bromo- 2 ', the 4 '-difluoro acetophenones of 2- outside the bromo- 4 '-cyano-acetophenones of 2-, the same procedure as described in embodiment 88, and obtain the purpose compound.The physical characteristic of the compound is for example following.

State：Solid.

NMR：δ solvents (CDCl₂)

1.23 (3H, d, J7=1Hz), 4.07 (1H, q, J=7.1Hz),

4.26 (1H, d, J=144Hz), 4.89 (1H, d, J=144Hz), 5.93 (1H, s),

6.92-6.98 (1H, m), 7.00-7.05 (1H, m), 7.47-7.54 (1H, m),

7.67 (1H, s), 7.68 (1H, s), 7.88 (1H, s), 8.13-8.19 (1H, m)

MS∶MH⁺=449

Embodiment 91：

Prepare the compound that following structural is represented：

In addition to substituting the bromo- 4 '-cyano-acetophenones of 2- with the bromo- 4 '-methyl acetophenones of 2-, according to the same procedure of embodiment 88, purpose compound is obtained.The physical characteristic of the compound is for example following.

State：Solid.

NM is limited：δ solvents (CDCl₃)

1.23 (3H, d, J=7.1Hz), 241 (3H, s), 4.04 (1H, q, J=7.1Hz),

4.28 (1H, d, J=14.3Hz), 4.88 (1H, d, J=14.3Hz), 6.24 (1H, s),

6.76-6.84 (1H, s), 7.27 (1H, d, J=8.3Hz), 740 (1H, s),

7.47-7.53 (1H, m), 7.65 (1H, s), 7.80 (2H, d, J=8.3Hz),

7.94 (1H, s)

MS∶MH⁺=427.

Embodiment 92：

Prepare the compound that following structural is represented：

State：Solid.

NMR：δ solvents (CDCl₃)

1.23 (3H, d, J=7.1Hz), 3.88 (3H, s), 4.04 (1H, q, J=7.1 Hz),

4.28 (1H, d, J=14.3Hz), 4.87 (1H, d, J=14.3Hz), 6.24 (1H, s),

6.76-6.84 (2H, m), 7.00 (2H, d, J=8.2Hz), 732 (1H, s),

7.47-7.53 (1H, m), 7.65 (1H, s), 7.84 (2H, d, J=8.2Hz),

7.94 (1H, s)

MS：MH⁺=443.

Embodiment 93：

Prepare the compound that following structural is represented：

In addition to substituting the bromo- 4 '-cyano-acetophenones of 2- with the bromo- 4 '-nitro-acetophenones of 2-, according to the same procedure of embodiment 88, purpose compound is obtained.The physical characteristic of the compound is for example following.

mp：180-182℃

NMR：δ solvents (CDCl₃)

1.25 (3H, d, J=7.1Hz), 4.11 (1H, d, J=7.1Hz),

4.27 (1H, d, J=14.2Hz), 4.94 (1H, d, J=14.2Hz), 5.70 (1H, s),

6.79-6.85 (2H, m), 743-7.55 (1H, m), 7.70 (1H, s),

7.71 (1H, s), 7.85 (1H, s), 8.08 (2H, d, J=9.OHz),

8.32 (2H, d, J=9.0Hz)

MS∶MH⁺=458.

Embodiment 94：

Prepare the compound that following structural is represented：

5g-4 fluorine thiophenols are added into the suspension of the 1.570g60% sodium hydrides in 30mlDMD, gained mixture is stirred at room temperature 5 minutes.Again toward 4.9g4 '-fluoro acetophenone is added in the mixture, then stirred 3.5 hours in 80 DEG C.Add water in the reactant mixture, then be extracted with ethyl acetate.Extract is washed with water and then with saturated brine, removes solvent under reduced pressure, obtains the fluoro- 4'- acetyl diphenyl sulfides of 10.008g4-.

Hereafter, the midbody compound that following structural is represented is prepared according to same procedure described in preparation embodiment 4：

Then in addition to substituting the bromo- 4 '-cyano-acetophenones of 2- with the compound, purpose compound is obtained according to the same procedure described in embodiment 88.The physical characteristic of this compound is for example following.

State：Solid.

NMR：δ solvents (CDCl₃)

1.22 (3H, d, J=7.0Hz), 4.05 (1H, q, J=7.0Hz),

4.26 (1H, d, J=14.6Hz), 4.88 (1H, d, J=14.6Hz), 6.04 (1H, s),

6.76-6.85 (2H, m), 7.07 (2H, br-dd, J=8.4,8.4Hz),

7.32 (2H, br-d, J=8.4Hz), 7.44 (1H, br-s),

7.44 (2H, br-dd, J=8.4,8.4Hz), 7.45-7.54 (1H, m),

7.66 (1H, s), 7.82 (2H, br-dd, J=84Hz), 7.89 (1H, s)

MS：MH⁺=539.

Embodiment 95：

Prepare the compound that following structural is represented：

Compound made from 400mg embodiments 88 is dissolved in 4ml- methyl pyrrolidones, and toward adding 123mgNaN in the solution₃And 260mgEt₃N·HCl.Gained mixture is heated 6.5 hours in external temperature is 100 DEG C of oil bath, and adds 31mgNaN₃And 65mgEt₃NHCl, makes it be reacted 20 hours in 90 DEG C.CH is added into the reactant mixture₂Cl₂, the salt of generation is filtered out, then the liquid reaction mixture is evaporated.EtOH, acetone, H are added in the residue₂O and 1N Hcl, gained mixture is placed, and is settled out solid matter.The solid matter is collected by filtration, the compound of 390mg mesh is obtained.The physical characteristic of this compound is as described below.

mp：166-169℃.

NMR：δ solvents (CDCl₃)

1.14 (3H, d, J=73Hz), 4.11 (1H, q, J=7.3Hz),

4.37 (1H, d, J=14.6Hz), 4.87 (1H, d, J=14.6Hz), 6.08 (1H, s),

6.91-6.96 (1H, m), 7.18-7.25 (1H, m), 7.27-7.34 (1H, m),

7.62 (1H, s), 8.11 (2H, d, J=8.5Hz), 8.20 (2H, d, J=8.5Hz),

8.22 (1H, s), 8.29 (1H, s)

MS∶MH⁺=481.

Embodiment 96：

Prepare the compound that following structural is represented：

The compound that 800mg embodiments 88 are obtained is suspended in 4ml water, and toward adding the compound that 2.6ml (16.479mmol) following formula is represented in the suspension：

Then it is heated to reflux 30 minutes.By H₂O is added in the liquid reaction mixture, and the mixture is then extracted with AcOEt.Extract H₂O, washed again with the saturation NaCl aqueous solution after, use MgSO₄Dry, AcOEt is evaporated off.Without purifying will gained residue be dissolved in 10ml acetone, added O.45mlCH into the solution₃I, is then stirred 40 minutes in 40 DEG C.Water is added into gained liquid reaction mixture, is then extracted with AcOEt.Extract is washed with water, again with the saturation NaCl aqueous solution, uses MgSO₄After drying, AcOEt is evaporated off.Gained residue is dissolved in 10mlEtOH without purifying, and by 220mgNH₂NHCHO、0.26mlEt₃The drops of N and 1 H₂SO₄It is added in the solution, is heated to reflux afterwards 1 hour.Water is added in gained liquid reaction mixture, then gained extracts are extracted with AcOEt and is washed with water, again with the saturation NaCl aqueous solution, MgSO is used₄AcOEt is evaporated off after drying.Gained residue is through column chromatography (SiO₂：50g, uses CH₂Cl₂, again use 1%MeOH CH₂Cl₂The CH of solution, 2%MeOH₂Cl₂Solution is eluted) purifying, thus obtain the compound of 369mg mesh.The physical characteristic of this compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.24 (3H, d, J=7.1Hz), 4.08 (1H, q, J=7.1Hz),

434 (1H, d, J=14.4Hz), 4.91 (1H, d, J=14.4Hz), 6.15 (1H, s),

6.79-6.85 (1H, s), 7.52-7.56 (2H, m), 7.69 (1Hs),

7.97-7.99 (3H, m), 8.14 (2H, d, J=8.2Hz), 8.25 (1H, s)

MS∶MH⁺=480.

Embodiment 97：

Prepare the compound that following structural is represented：

The compound that 250mg embodiments 95 are obtained is dissolved in 3mlDMF, and by 174mgCsCO₃It is added in the solution.Gained mixture is heated 30 minutes in external temperature is 60 DEG C of oil bath and 0.05mlCH is added₃I, is then stirred at room temperature 30 minutes.Add water in the liquid reaction mixture and extracted with AcOEt.Extract H₂O, washed again with the saturation NaCl aqueous solution, and use MgSO₄After drying, AcOEt is steamed.Gained residue is through column chromatography (SiO₂：30g CH₂Cl₂, again use 1%MeOH CH₂Cl₂The CH of solution and 2%MeOH₂Cl₂Solution is eluted) purifying, obtain the compound of 125mg mesh.The physical characteristic of this compound is for example following.

mp：191-193℃

NMR：δ solvents (CDCl₃)

1.25 (3H, d, J=7.0Hz), 4.09 (1H, q, J=7.0Hz),

4.29 (1H, d, J=14Hz), 433 (3H, s), 4.92 (1H, d, J=14Hz),

6.01 (1H, s), 6.77-6.85 (2H, m), 7.49-7.55 (1H, m),

7.58 (1H, s), 7.67 (1H, s), 7.91 (1H, s),

8.04 (2H, d, J=8.2, Hz), 8.24 (2H, d, J=8.2Hz)

MS∶MH⁺=495.

Embodiment 98：

Prepare the compound that following structural is represented：

The compound that 200mg embodiments 96 are obtained is dissolved in 5ml acetone, and by 60.6mgK₂CO₃And 0.03mlCH₃I is added thereto.Gained mixture is stirred at room temperature 19 hours.Add water in the liquid reaction mixture and extracted with AcOEt.The extract with water, washed again with the saturation NaCl aqueous solution and use MgSO₄After drying, AcOEt is steamed.Gained residue is through column chromatography (SiO₂：40g, uses CH₂Cl₂And then with 0.5%MeOH CH₂Cl₂The CH of solution and 1%MeOH₂Cl₂Solution is eluted) purifying, obtain the compound of 142mg mesh.The physical characteristic of the compound is for example following.

State：Solid.

NMR：δ solvents (CDCl₃)

1.13 (1H, d, J=6.0Hz), 1.25 (2H, d, J=7.1Hz),

4.01-4.13 (4H, m), 4.27 (2/3H, d, J=14Hz),

4.29 (1/3H, d, J=14Hz), 4.91 (1H, d, J=14Hz),

5.45 (1/3H, s), 6.08 (2/3H, s), 6.70-6.84 (2H, m),

7.50-7.55 (2H, m), 7.67-7.68 (4/3H, m), 7.79-7.81 (2/3H, m)

7.93 (1H, s), 7.96 (1H, s), 7.98 (1H, s), 8.10 (1H, s),

8.19 (2H, d, H=8.4Hz)

Embodiment 99：

Prepare the compound that following structural is represented：

215mg metachloroperbenzoic acids are added in the compound solution that the 138mg embodiments 89 being dissolved in 3ml chloroforms are obtained, be then stirred at room temperature.After raw material disappears, add water in the liquid reactions compound, then be extracted with ethyl acetate.Gained organic layer is with 50% saturation NaHCO₃The aqueous solution is washed, then is washed with water and saturated brine.Decompression is steamed after solvent, and residue obtains the compound of 98.5mg mesh through silica gel chromatography and with difluoromethane-crystallizing from diisopropylether.The physical characteristic of the product is as described below.

NMR：δ solvents (CDCl₃)

1.24 (3H, d, J=7.2Hz), 3.09 (3H, s), 4.09 (1H, q, J=7.2Hz),

4.27 (1H, d, J=14.4Hz), 4.9l (1H, d, J=14.4Hz),

5.78 (1H, s), 6.78-6.85 (2H, m), 747-7.55 (1H, m),

7.67 (1H, s), 7.69 (1H, s), 7.87 (1H, s),

8.02 (2H, br-d, J=8.4Hz), 8.1O (2H, br-d, J=8.4Hz)

MS∶MH⁺=491.

Embodiment 100：

Prepare the compound that following structural is represented：

According to the same procedure of embodiment 99, the compound obtained by embodiment 7 can obtain the purpose compound.The physical characteristic of the product is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.22 (3H, d, J=7.2Hz), 4.07 (1H, q, J=7.2Hz),

4.23 (1H, d, J=144Hz), 4.90 (1H, d, J=14.4Hz), 5.73 (1H, s),

6.77-6.84 (2H, m), 7.20 (2H, br-dd, J=8.4,8.4Hz),

7.46-7.53 (1H, m), 7.63 (1H, s), 7.68 (1H, s), 7.83 (1H, s),

7.97-8.07 (6H, m)

MS∶MH⁺=571.

Embodiment 101：

Prepare the compound that following structural is represented：

In addition to the 4- cyano-phenyls part in raw material 3 to be changed into compound I, II pyridine radicals different with corresponding coupling position to each other in III, compound I, II and III of the embodiment can be obtained according to the same procedure of embodiment 88.The physical characteristic of these compounds is as described below.

(I)

mp：149-151℃

NMR：δ solvents (DMSO-d⁶)

1.13 (3H, d, J=7.1Hz), 4.07 (1H, q, J=7.1Hz),

4-36 (1H, d, J=14.3Hz), 4.86 (1H, d, J=14-3Hz), 6.07 (1H, s),

6.91-6.96 (1H, m), 7.18-7.24 (1H, m), 7.27-7.36 (2H, m),

7.61 (1H, s), 7.88 (1H, t, J=8Hz), 8.11 (1H, d, J=8Hz),

8.22 (1H, s), 8.28 (1H, s), 8.60-8.62 (1H, m)

MS∶MH⁺=414

(II)

mp：148-149℃

NMR：δ solvents (DMSO-d⁶)

1.24 (3H, d, J=7.1Hz), 4.09 (1H, q, J=7.1Hz),

4.27 (1H, d, J=14.3Hz), 4.92 (1H, d, J=14.3Hz),

5.84 (1H, brs), 6.77-6.85 (2H, m),

7.40 (1H, ddd, J=7.8,4.8, O.92Hz), 7.48-7.56 (1H, m),

7.58 (1H, s), 7.68 (1H, s), 7.88 (1H, s),

8.21 (1H, ddd, J=7.8,2.2,1.6Hz),

8.6l (1H, dd, J=4.8,1.6Hz), 9.15 (1H, dd, J=2.2, O.92Hz)

MS∶MH⁺=414.

(III)

State：Solid.

NMR：δ solvents (CDCl₃)

1.24 (3H) (4/5, d, J=7.1Hz), 1.68 (3Hx1/5, d, J=6.2Hz),

4.08-4.15 (1H, m), 4.25 (4/5H, q, J=14.5Hz),

4.73 (1/5H, d, J=13.9Hz), 4.92 (1/5H, d, J=13.9Hz),

4.95 (4/5H, d, J=14.5Hz), 5.77 (4/5H, brs), 5.88 (1/5H, brs),

6.49-6.55 (1/5H, m), 6.66-6.72 (1/5H, m), 6.76-6.85 (1H, m),

7.07-7.14 (4/5H, and m) 7.26 (1/5H, s), 7.44 (1/5Hs),

7.47-7.55 (4/5H, m), 7.61-7.64 (1/5H, m) 7.69 (4/5H, s),

7.73 (4/5H, s), 7.78-7.81 (4/5H, m), 7.87 (4/5H, s),

8.03 (1/5H, s), 8.64-8.66 (4/5H, m), 8.69-8.72 (1/5H, m)

MS∶MH⁺=414.

Embodiment 102：

Prepare the compound that following structural is represented：

The compound (I) that 700mg embodiments 101 are obtained is dissolved in 7mlAcOEt and 5mlTHF, and is charged with 500mg mCPBA, is stirred at room temperature afterwards 1 hour, then adds 227mg (0.882mmo1) mCPBA.Gained mixture is stirred 1 hour.Sodium sulfite aqueous solution is added into the liquid reaction mixture, stirs 5 minutes, is then extracted with AcOEt.Extract sodium sulfite aqueous solution, the NaHCO₃After the aqueous solution, water washing, then washed with the NaCl aqueous solution, and use MgSO₄After drying, solvent is steamed.Residue CH₂Cl₂- IPE is crystallized, and obtains 510mgN- oxide intermediates.The compound is dissolved in 5mlCH₂Cl₂, and 0.49mlTMS-CN is charged with room temperature.After 5 minutes, 0.34mlMe is added₂NCOCl, and the mixture is heated to reflux 1.5 hours adds 0.25mlTMS-CN and 0.17Me₂NCOCl, then gained mixture is heated to reflux 2.5 hours.NaHCO is added into the liquid reaction mixture₃The aqueous solution, then extracted with AcOEt.The extract is washed with water and the saturation NaCl aqueous solution and uses MgSO₄After drying, solvent is evaporated off.Gained residue is through silica gel chromatograph (SiO₂：40g, uses CH₂Cl₂And then with 1%MeOH CH₂Cl₂The CH of solution and 2%MeOH₂Cl₂Solution is eluted) purifying, obtain the compound of 198mg mesh.The physical characteristic of the compound is as described below.

mp：197-200℃

NMR：δ solvents (DMSO-d⁶)

1.14 (3H, d, J=7.0Hz), 4.07-4.11 (1H, m),

4.47 (1H, q, H=143Hz), 4.84 (1H, d, J=143Hz), 6.10 (1H, s),

6.91-6.96 (1H, m), 7.17-7.22 (1H, m), 7.23-7.33 (2H, m)),

7.61 (1H, s), 7.98 (1H, d, J=7.7Hz), 8.14 (1H, t, J=7.7Hz),

8.21 (1H, s), 8.40 (1H, d, J=7.7Hz), 8.44 (1H, s)

MS∶MH⁺=439.

Embodiment 103：

Prepare the compound (I) that following structural is represented：

The compound (II) represented with following structural：

1.6g2- (2,4- difluorophenyl) -3- sulphamides -1- (1H, 1,2,4- triazol-1-yl) -2- butanol (156mg) is dissolved in 16mlEtOH, and toward adding 0.71ml ethyl bromide acetones in the solution.Gained mixture is heated to reflux 5 hours.The liquid reaction mixture is cooled to room temperature, use saturation NaHCO₃The aqueous solution is neutralized, and is then extracted with AcOEt.The extract is with water and then is washed with the saturation NaCL aqueous solution and uses MgSO₄After drying, solvent is evaporated off.The residue is through chromatogram (SiO₂：150g, uses CH₂Cl₂, again use 1%MeOH CH₂Cl₂The CH of solution and 2%MeOH₂Cl₂Solution is eluted) purifying, obtain 435mg2- (2,4- difluorophenyl) -3- (4- carbethoxyl groups thiazol-2-yl) -1- (1H-1,2,4- triazol-1-yls) butyl- 2- alcohol.By 1.9g, the compound is dissolved in 20mlTHF, and -78 DEG C of toluene solutions by 5.1ml1MDIBAL are slowly added in the solution.After 40 minutes, 2.3ml1M DIBAL toluene solution is added at identical temperature.After 1 hour, in -78 DEG C, by NH₄The Cl aqueous solution is added in the liquid reaction mixture.The reactant mixture is heated to room temperature, water is added, then extracted with AcOEt.Extract H₂O is washed and is used MgSO₄After drying, solvent is steamed, 989mg2- (2,4- difluorophenyl) -3- (4- formyl thiazole -2- bases) -1- (1H-1,2,4- triazol-1-yls) butyl- 2- alcohol crude products are obtained.

While frozen water is cooled down, 60%NaH (109mg) is added in 5mlTHF, and (Et2O) is added dropwise toward in the mixture₂P (=0) CH₂CN (0.44ml) 5mlTHF solution.After the mixture is stirred 1 hour, the solution of the above-mentioned products therefroms of the 989mg for being dissolved in 10mlTHF is slowly added in the mixture.Gained mixture was stirred at room temperature after 30 minutes, is added water into the liquid reaction mixture, is then extracted with AcOEt.Extract H₂O is washed, and is then washed with the saturation NaCl aqueous solution and is used MgSO₄After drying, AcOEt is evaporated off.Gained residue is through silica gel chromatograph (SiO₂：60g, uses CHCl₃Elution, then with 1%MOH CHCl₃The CHCl of solution and 2%MeOH₃Solution is eluted) purifying, obtain the 115mg compounds I as the first eluate and 220mg geometric isomer compounds II as the second eluate.The physical characteristic of these compounds is as described below.

(I)

State：Solid

mp：175-177℃

NMR：δ solvents (CDCl₃)

1.19 (3H, d, J=7.1Hz), 4.02 (1H, q, J=7.1Hz),

4.16 (1H, d, J=14.3Hz), 4.91 (1H, d, J=14.3Hz),

5.47 (1H, s), 633 (1H, d, J=16.0Hz), 6.77-6.84 (2H, m),

733 (1H, d, J=16.0Hz), 746 (1H, s), 7.47-7.51 (1H, m),

7.72 (1H, s), 7.82 (1H, s)

MS∶MH⁺=388.

(II)

State：Solid.

NMR：δ solvents (CDCl₃)

1.20 (3H, d, J=7.0Hz), 4.05 (1H, q, J=7.OHz),

4.45 (1H, d, J=14.0Hz), 4.89 (1H, d, J=14.OHz),

5.56 (1H, d, J=11.9Hz), 5.78 (1H, s), 6.75-6.82 (2H, m),

7.17 (1H, d, J=11.9Hz), 7.50-7.59 (1H, m), 7.60 (1H, s),

7.75 (1H, s), 8.10 (1H, s)

MS∶MH⁺=388.

Embodiment 104：

Prepare the compound that following structural is represented：

Except with 2- (2,4- difluorophenyls) -3- thioamides -1- (1H-1,2,4- triazol-1-yls) propan-2-ol replace 2- (2,4- difluorophenyls) -3- thioamides -1- (1H-1,2,4- triazol-1-yls) outside butyl- 2- alcohol, the purpose compound can be obtained according to the same procedure of embodiment 88.The physical characteristic of this compound is as described below.

mp：148-149℃

NMR：δ solvents (CDCl₃)

3.38 (1H, d, J=15.2Hz), 3.87 (1H, d, J=15.2Hz),

4.65 (1H, d, J=14.0Hz), 4.71 (1H, d, J=14.0Hz), 5.97 (1H, s),

6.70-6.76 (1H, m), 6.77-6.83 (1H, m), 7.42 (1H, m),

7.47-7.41 (1H, m), 7.69-7.72 (2H, m), 7.86 (1H, s),

7.86-7.90 (2H, m), 8.18 (1H, s),

MS∶MH⁺=424.

Embodiment 105：

Prepare the compound that following structural is represented：

In addition to replacing the bromo- 4 '-cyano-acetophenones of 2- with the bromo- 4 '-fluoro acetophenones of 2-, according to the same procedure described in embodiment 104, the purpose compound is obtained.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

3.34 (1H, d, J=15.4Hz), 3.84 (1H, d, J=15.4Hz),

4.62 (1H, d, J=14.0Hz), 4.71 (1H, d, J=14.0Hz), 6.25 (1H, s),

6.82-6.69 (2H, m), 7.13-7.08 (2H, m), 7.17 (1H, s),

7.47-740 (1H, m), 7.76-7.72 (2H, m), 7.85 (1H, s),

8.12 (1H, s)

MS∶MH⁺=417.

Embodiment 106：

Prepare the compound I that following structural is represented：

With another compound II, compound II is compound I diastereomer

In at -65 DEG C by n-BuLi (1.6M hexane solutions；After 313ml) being added drop-wise in the diisopropylamine in 15ml tetrahydrofurans (840 μ l), the mixture is risen to 4 DEG C, makes it react 15 minutes to prepare lithium diisopropylamide solution.The solution is cooled to after -63 DEG C, at a temperature of no more than -60 DEG C, the tetrahydrofuran solution (10ml) and 1- (1H-1 of the chloro- benzothiazoles of 2- ethyls -6- (988mg) prepared by embodiment 5,2,4- triazol-1-yls) -2 ', the tetrahydrofuran solution (12ml) of 4 '-difluoro acetophenone (1.227g) is gradually added in the amide solution.After it reacts 15 minutes, the reactant mixture is heated to 0 DEG C and aqueous ammonium chloride solution is added.Then obtained mixture is extracted with ethyl acetate.Gained organic layer is washed with water, and then uses salt water washing, re-dry and evaporated under reduced pressure.The residue (dichloromethane: methanol=100: 1) is purified through silicagel column.So obtained non-enantiomer mixture further passes through silicagel column (dichloromethane: ethyl acetate=10: 1 → 5: 1), thus low polarity fraction, i.e. 442mg compounds I and highly polar fraction, i.e. 66mg compounds II are obtained, the latter is compound I diastereomer.The physical characteristic of these compounds is for example following.

I

mp：187℃.

NMR：δ solvents (CDCl₃)

1.25 (3H, d, J=7.OHz), 4.09 (1H, q, J=7.0Hz),

4.27 (1H, d, J=14.4Hz), 4.93 (1H, d, J=14.4Hz), 5.80 (1H, s),

6.85-6.78 (2H, m), 7.48 (1H, dd, J=8.8Hz, 2.4Hz),

7.49-7.55 (1H, m), 7.67 (1H, s), 7.87 (1H, s),

7.90 (1H, d, J=2.4Hz) 7.94 (1H, d, J=8.8Hz)

MS∶MH⁺=421.

II

mp：127-130℃.

NMR：δ solvents (CDCl₃)

1.68 (3H, d, J=6.8Hz), 4.13 (1H, q, J=6.8Hz),

4.71 (1H, d, J=14Hz), 4.94 (1H, d, J=14Hz), 5.87 (1H, s),

6.46-6.50 (1H, m), 6.43-6.69 (1H, m), 7.09-7.16 (1H, m),

(7.38 1H, dd, J=2.OHz, 8.8Hz), 7.69 (1H, s),

7.72 (1H, d, J=2.0Hz), 7.80 (1H, d, J=8.8Hz), 8.04 (1H, s)

MS∶MH⁺=421.

Embodiment 107：

Prepare the compound that following structural is represented：

By 2- ethyl -6- cyanobenzothiazoles (1.78g), the mixture of sodium azide (1.22g) and triethylamine hydrochloride (2.59g) is heated 3 hours in 300mlN- methyl pyrrolidones, in 100 DEG C.The mixture is cooled to after room temperature, 150ml water is added, pH3 is adjusted to dense HCl, then be extracted with ethyl acetate 2 times.Gained organic layer is washed and dried with saturated brine.Solvent is evaporated off, and residual solvent is further removed with toluene by azeotropic distillation, 2- ethyls -6- (tetrazolium -5- bases) benzothiazole (1.86g) is obtained.The compound is dissolved in dimethylformamide (20ml), and is charged with cesium carbonate (3.06g), is then heated 1.5 hours in 80 DEG C.Again under ice-cooling, 1.17ml iodomethane is added in the reactant mixture.The mixture is returned to be warmed to room temperature and stir 7 hours.Adding water and ethyl acetate makes the demixing, and gained organic layer is washed with water and dried.The residue (hexane: ethyl acetate=4: 1) purifies through silicagel column, obtains 2- ethyls -6- (2- methyl-tetrazole -5- bases) benzothiazole (930mg).With such obtained compound, purpose compound is obtained with the same procedure of embodiment 106.The physical characteristic of this compound is as described below.

mp：184-185℃.

NMR：δ solvents (CDCl₃)

1.28 (3H, d, J=7.2Hz), 4.13 (1H, q, J=7.2Hz),

4.31 (1H, d, J=14.2Hz), 4.44 (3H, s), 4.96 (1H, d, J=14.2HZ),

5.89 (1H, s), 6.78-6.86 (2H, m), 7.50-7.58 (1H, m),

7.67 (1H, s), 7.89 (1H, s), 8.13 (1H, dd, J=0.4Hz, 8.8Hz),

8.30 (1H, dd, J=1.6Hz, 8.8HZ), 8.74 (1H, dd, J=0.4Hz, 16Hz)

Embodiment 108：

Prepare the compound that following structural is represented：

In addition to the chloro- benzothiazoles of 2- ethyls -6- are replaced with the fluoro- benzothiazoles of 2- ethyls -6-, the purpose compound is made with the same procedure of embodiment 106.The physical characteristic of the compound is as described below.

mp：151-153℃.

NMR：δ solvents (CDCl₃)

1.25 (3H, d, J=7.1Hz), 4.08 (1H, q, J=7.1Hz),

4.28 (1H, d, J=144Hz), 4.93 (1H, d, J=144Hz), 5.83 (1H, s),

6.77-6.85 (2H, m), 7.23-7.29 (1H, m), 749-7.56 (1H, m),

7.58-7.62 (1H, m), 7.67 (1H, s), 7.87 (1H, s),

7.96-8.00 (1H, m)

MS∶MH⁺=405.

Embodiment 109：

Prepare the compound that following structural is represented：

In addition to the chloro- benzothiazoles of 2- ethyls -6- are replaced with 2- ethyl -6- cyano-benzothiazols, the purpose compound is prepared in the identical mode of embodiment 106.The physical characteristic of the compound is as described below.

mp：186-188℃.

NMR：δ solvents (CDCl₃)

1.27 (3H, d, J=7.2Hz), 4.16 (1H, q, J=7.2Hz),

4.24 (1H, d, J=14.0Hz), 4.96 (1H, d, J=14.0Hz), 5.67 (1H, s),

6.79-6.86 (2H, m), 7.49-7.56 (1H, m), 7.69 (1H, s),

7.77 (1H, dd, J=1.6Hz, 8.4Hz), 7.83 (1H, s),

8.11 (1H, d, J=8.4Hz), 8.27 (1H, d, J=1.6Hz)

MS∶MH⁺=412.

Embodiment 110：

Prepare the compound that following structural is represented：

The compound (506mg) that embodiment 109 is obtained is suspended in methanol (10ml), and 0.37ml1N sodium hydrate aqueous solutions and 30% aqueous hydrogen peroxide solution (0.42ml) is sequentially added in the suspension.Gained mixture is stirred at room temperature 2 hours.Add water and ethyl acetate is extracted.Gained organic layer is washed, dried, is then distilled again.The residue (dichloromethane: methanol=50: 1 → 20: 1) purifies through silicagel column, obtains the purpose compound (311mg).The physical characteristic of the compound is as described below.

mp：112-117℃.

NMR：δ solvents (CDCl₃)

1.25 (3H, d, J=7.0Hz), 4.13 (1H, q, J=7.0Hz),

4.29 (1H, d, J=144Hz), 4.94 (1H, d, J=14.4Hz), 5.82 (1H, s),

5.60-6.25 (2H, br), 6.78-6.86 (2H, m), 7.50-7.56 (1H, m),

7.67 (1H, s), 7.87 (1H, s), 7.09 (1H, dd, J=1.6Hz, 8.4Hz),

8.08 (1H, dd, J=1.6Hz, 8.4Hz), 8.48 (1H, dd, J=O.6Hz, 1.6Hz)

MS∶MH⁺=430.

Embodiment 111：

Prepare the compound that following structural is represented：

The compound (507mg) that embodiment 109 is obtained and a drop triethylamine are dissolved in dimethylformamide (5ml), at room temperature, are made the solution saturation with hydrogen sulfide gas and are placed 6 hours in room temperature.Sodium bicarbonate aqueous solution and ethyl acetate, which are added in the liquid reaction mixture, is layered it.Gained organic layer is washed with water, is dried and concentrated.Residue silicagel column (eluant, eluent：Dichloromethane: methanol=50: 1) purify, obtain the purpose compound (538mg).The physical characteristic of the compound is as described below.

mp：157-160℃.

NMR：δ solvents (CDCl₃)

1.23 (3H, d, J=7.2Hz), 4.13 (1H, q, J=7.2Hz),

4.27 (1H, d, J=14.0Hz), 4.94 (1H, d, J=14.0Hz), 5.81 (1H, s),

6.78-6.85 (2H, m), 7.24-730 (1H, br-s), 7.39-7.56 (1H, m),

7.67 (1H, s), 7.66-7.72 (1H, brs), 7.86 (1H, s),

7.95 (1H, dd, J=2.0Hz, 8.8Hz), 8.02 (1H, d, J=8.8Hz),

8.59 (1H, d, J=2.0Hz)

MS∶MH⁺=446.

Embodiment 112：

Prepare the compound (1: l non-enantiomer mixture) that following structural is represented：

The compound (2.67g) that embodiment 111 is obtained is suspended in 130ml acetone, then toward addition 1.12ml iodomethane in the suspension, and gained mixture is heated to reflux 8 hours in 40 DEG C.Solvent is evaporated off, the midbody compound that following structural is represented is obtained：

The midbody compound (584mg) is dissolved in ethanol (5.8ml), and aminoacetaldehyde diethyl base acetal (174 μ l) is added in the solution, the gained mixture is heated to reflux 5 hours.Then, plus 6N hydrochloric acid (5ml) is into the mixture, backflow 1 hour is reheated.Sodium bicarbonate aqueous solution and ethyl acetate, which are added in the liquid reaction mixture, is layered it.Gained organic layer is washed with water, dries and be evaporated to dryness.The residue (dichloromethane: methanol=100: 1-10: 1) purifies through silicagel column, obtains the purpose compound of 1: 1 non-enantiomer mixture form.

State：Solid.

NMR：δ solvents (CDCl₃)

1.27 (3H, d, J=7.2Hz), 1.73 (1H, d, J=7.2Hz),

4.10 (1H, q, J=7.2Hz), 4.15 (1H, q, J=7.2Hz),

4.32 (1H, d, J=14.0Hz), 4.73 (1H, d, J=14.0H),

4.94 (1H, d, J=14.0Hz), 4.95 (1H, d, J=14.0Hz), 5.92 (1H, s),

5.98 (1H, s), 6.44-6.50 (1H, m), 6.63-6.70 (1H, m),

6.77-6.84 (2H, m), 7.12-7.17 (1H, m), 7.17 (1H, br-s),

7.22 (1H, br-s), 7.50-7.57 (1H, m), 7.66 (1H, s),

7.69 (1H, s), 7.84 (1H, dd, J=1.6Hz, 8.4Hz), 7.89 (1H, s),

7.91 (1H, d, J=8.4Hz), 7.93 (H, dd, J=1.6Hz, 8.4Hz),

8.05 (1H, d, J=8.4Hz), 8.06 (1H, s), 8.27 (1H, d, J=1.6Hz),

8.46 (1H, d, J=1.6Hz)

Embodiment 113：

Prepare the compound that following structural is represented：

Midbody compound (1.17g) in embodiment 112 is dissolved in ethanol (12ml), and formylhydrazine (240mg), triethylamine (250 μ l) and a drop concentrated sulfuric acid are sequentially added in the solution, make it in room temperature reaction 40 minutes, be then again heated to reflux the reactant mixture 1.5 hours.After after reactant mixture cooling, add ethyl acetate and water is extracted.Gained organic layer is washed with water, is dried and concentrated.The residue (dichloromethane: methanol=20: 1) purifies through silica gel column chromatography, obtains purpose compound (742mg).The physical characteristic of the compound is as described below.

mp：138-140℃.

NMR：δ solvents (CDCl₃)

1.27 (3H, d, J=7.2Hz), 4.13 (1H, q, J=7.2Hz),

4.33 (1H, d, J=14.2Hz), 4.95 (1H, d, J=14.2Hz), 5.96 (1H, s),

6.78-6.86 (2H, m), 7.51-7.57 (1H, m), 7.67 (1H, s),

7.91 (1H, s), 8.10 (1H, d, J=84Hz), 8.25 (1H, d'J=84Hz),

8.32 (1H, s), 8.69 (1H, s)

MS∶MH⁺=472.

Embodiment 114：

Prepare the compound that following structural is represented：

Compound (264mg), bromoacetaldehyde dimethyl acetal (390 μ l) and the 1 drop concentrated sulfuric acid that embodiment 111 is obtained are heated to reflux 1 hour in ethanol (2.5ml).Add after bromoacetaldehyde dimethyl acetal (390 μ l), then the mixture is heated to reflux 1 hour, ethyl acetate and water are added into the liquid reaction mixture is layered it.Gained organic layer is washed with water and dried, and solvent is evaporated off.Hexane is added in the residue, the precipitation of generation is collected by filtration, purpose compound (180mg) is obtained.The physical characteristic of the compound is as described below.

mp：153-158℃.

NMR：δ solvents (CDCl₃)

1.28 (3H, d, J=7.2Hz), 4.12 (1H, q, J=7.2Hz),

4.31 (1H, d, J=14.2Hz), 4.96 (1H, d, J=14.2Hz), 5.89 (1H, s),

6.78-6.25 (2H, m), 7.40 (1H, d, J=3.4Hz), 7.66 (1H, s),

7.89 (1H, s), 7.92 (1H, d, J=3.4Hz), 8.09 (1H, d, J=0.4Hz),

8.10 (1H, d, J=1.6Hz), 8.75 (1H, dd, J=0.4Hz, 1.6Hz)

MS∶MH⁺=470.

Embodiment 115：

Prepare the compound that following structural A is represented：

The compound represented with following structural B：

The compound (453mg) obtained in embodiment 113 is dissolved in acetone (4.5ml), and is charged with potassium carbonate powder (138mg) and iodomethane (62 μ l).Gained mixture is stirred at room temperature overnight.Then the mixture is extracted with ethyl acetate-water.Gained organic layer is washed with water and dried, and solvent is evaporated off.The residue (dichloromethane: methanol=50: 1 → 30: 1) is purified through silicagel column, then (methanol: water=60: 40 → 65: 35) separate and purify, obtain structural formula A compound (192mg) and structural formula B compound (52mg) through ODS posts again.The physical characteristic of these compounds is as described below.

A

mp：180-190℃.

NMR：δ solvents (CDCl₃)

1.27 (3H, d, J=7.0Hz), 4.10 (3H, s), 4.11 (1HJ, q, J=7.0Hz),

4.32 (1H, d, J=14.0Hz), 4.94 (1H, d, J=14.0Hz), 5.99 (1H, s),

6.77-6.86 (2H, m), 7.50-7.57 (1H, s), 7.65 (1H, s),

7.91 (1H, s), 8.08 (1H, d, J=8.4Hz), 8.10 (1H, s),

8.27 (1H, dd, J=8.4Hz, 1.6Hz), 8.67 (1H, d, J=1.6Hz)

MS∶MH⁺=454.

B

mp：196-197℃.

NMR：δ solvents (CDCl₃)

1..29 (3H, d, J=7.2Hz), 4.07 (1H, s), 4.15 (1H, q, J=7.2Hz),

4.30 (1H, d, J=14.2Hz), 4.97 (1H, d, J=14.2Hz), 5.82 (1H, s),

6.79-6.86 (2H, m), 7.50-7.58 (1H, m), 7.68 (1H, s),

7.82 (1H, dd, J=1.8Hz, 8.4Hz), 7.87 (1H, s), 7.99 (1H, s)

8.16 (1H, d, J=8.4Hz), 8.28 (1H, d, J=1.8Hz)

Embodiment 116：

Prepare the compound that following structural is represented：

Except with 2- ethyls -6- (1,2,3- triazole -2- bases)-benzothiazole (529mg) (compound be prepare embodiment 7 preparation raw material 5) replace 2- ethyl -6- chloro benzothiazoles outside, obtain the purpose compound according to same procedure described in embodiment 106.The physical characteristic of the compound is descended described.

State：Oily.

NMR：δ solvents (CDCl₃)

1.29 (3H, d, J=71Hz), 4.12 (1H, q, J=7.1Hz),

4.32 (1H, d, J=14.2Hz), 4.97 (1H, d, J=14.2Hz),

5.87 (1H, brs), 6.79-6.83 (2H, m), 7.50-7.58 (1H, m),

7.67 (1H, s), 7.87 (2H, s), 7.89 (1H, s),

8.12 (1H, d, J=9.0Hz), 8.30 (1H, dd, J=8.8,2.2Hz),

8.65 (1H, d, J=2.2Hz)

Embodiment 117：

Prepare the compound (1: 1 non-enantiomer mixture) that following structural is represented：

Same procedure according to embodiment 7 is prepared prepares 2- ethyl -6- methoxycarbonyl group benzo thiazoles.The compound is dissolved in 1ml ether, and in 0 DEG C toward adding methylpyridinium iodide magnesium (2.0M diethyl ether solutions, 1.2ml) in the solution.It is stirred at room temperature after the mixture, adds saturated aqueous ammonium chloride, be then extracted with ethyl acetate.The organic layer that must be taken is washed with water and then with saturated brine, and removes solvent under reduced pressure.So obtained crude on silica gel column chromatography purifying is obtained (2- methyl -2- (2- ethyl-benzothiazole -6- bases) ethanol) (138mg).In addition to the consumption that 2- ethyl -6- chloro benzothiazoles and n-BuLi are replaced with this product is 2 times of embodiment 116, the same procedure as described in embodiment 19 obtains purpose compound (1: 1 non-enantiomer mixture).The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.25 (1.5H, d, J=7.2Hz), 1.60 (3H, s), 1.67 (3H, s),

(1.80 1.5H, d, J=8.4Hz), 4.05-4.17 (1H, m),

4.27 (0.5H, d, J=14.4Hz), 4.71 (0.5H, d, J=14.0Hz),

4.90-4.95 (1H, n), 6.02 (0.5H, s), 6.13 (0.5H, d, J=1.6Hz),

6.44-6.51 (0.5H, m), 6.63-6.70 (0.5H, m),

6.63-6.70 (0.5H, m), 6.76-6.85 (1H, m), 7.10-7.17 (0.5H, m)

7.50-7.56 (1H, m), 7.61-7.65 (0.5H, m), 7.64 (0.5H, s),

7.66 (0.5H, s), 7.84 (0.5H, d, J=8.8Hz), 7.89 (0.5H, s),

7.91 (0.5H, d, J=1.6Hz), 8.00 (0.5H, d, J=8.8Hz),

8.06 (0.5H, s) 8.10 (0.5H, d, J=1.6Hz)

MS∶MH⁺=445.

Embodiment 118：

In water and methanol solvate (20ml) that the identical 2- ethyl -6- methoxycarbonyl group benzo thiazoles (699mg) used in embodiment 117 are dissolved in 1: 1 mixing, and toward the addition 1NNaOH aqueous solution (8ml) in the solution, be then heated and refluxed for 4.5 hours.8ml1N HCl are added into the reactant mixture, salt are then added, then extracted with ethyl acetate.After the extract is washed with saturated brine, solvent is evaporated off under reduced pressure, 6- carboxyl -2- ethyl-benzothiazoles (642mg) are obtained.The product (1.957g) is dissolved in dimethylbenzene (50ml) without purifying, and 2-amino-2-methyl-1-propanol (6ml) is added in the solution.Then gained mixture is heated to reflux 3 days by dean stark trap.Solvent is evaporated off in decompression from the liquid reaction mixture, and gained residue obtains the midbody compound that following structural is represented through silica gel chromatography：

Using the midbody compound, purpose compound is obtained according to the same procedure of such as embodiment 106.The physical characteristic of the compound is as described below.

mp：

State：Solid.

NMR：δ solvents (CDCl₃)

1.27 (1.5H, d, J=6.8Hz), 1.38 (3H, s), 1.42 (3H, s),

1.70 (1.5H, d, J=6.8Hz), 4.08-4.18 (1H, m), 4.12 (1H, s),

4.18 (1H, s), 4.29 (0.5H, d, J=14.4Hz),

4.74 (0.5H, d, J=14Hz), 4.94 (0.5H, d, J=14.4Hz),

4.95 (0.5H, d, J=14Hz), 5.90 (0.5H, s),

5.94 (0.5H, d, J=1.6Hz), 6.43-6.49 (0.5H, m)

6.62-6.69 (0.5H, m), 6.77-6.85 (1H, m), 7.07-7.14 (0.5H, m),

7.49-7.57 (0.5H, m), 7.66 (0.5H, s), 7.68 (0.5H, s),

7.89 (0.5H, d, J=8.4Hz), 7.89 (0.5H, s),

8.00 (0.5H, dd, J=1.6,8.4Hz), 8.03 (0.5H, d, J=8.4Hz),

8.05 (0.5H, s), 8.10 (0.5H, dd, J=1.68,84Hz),

8.35 (0.5H, d, J=1.6Hz), 8.53 (0.5H, d, J=1.6Hz).

MS∶MH⁺=484.

Embodiment 119：

Prepare the compound (I) that following structural is represented：

With another compound (II) of its diastereomer：

2- ethyl -6- methyl-thio-benzothiazoles are prepared according to preparing same procedure described in embodiment 7, therefore in addition to using the product, according to the non-enantiomer mixture that purpose compound is can obtain with the identical method of embodiment 106.Then the mixture is subjected to silica gel chromatograph, isolates compound (I) and compound (II), the two is respectively another diastereomer.

State：Solid.

NMR：δ solvents (CDCl₃)

1.24 (3H, d, J=7.0Hz), 2.57 (3H, s), 4.06 (1H, q, J=7.0Hz),

4.27 (1H, d, J=14.2Hz), 4.92 (1H, d, J=14.2Hz), 5.93 (1H, s),

6.76-6.84 (2H, m), 7.42 (1H, dd, J=2.08,8.4Hz),

7.47-7.55 (1H, m), 7.65 (1H, s), 7.76 (1H, d, J=2.O),

7.88 (1H, s), 7.92 (1H, d, J=8.4Hz)

MS∶MH⁺=433.

State：Solid.

NMR：δ solvents (CDCl₃)

1.24 (3H, d, J=7.0Hz), 2.57 (3H, s), 4.06 (1H, q, J=7.0Hz),

4.27 (1H, d, J=14.2Hz), 4.92 (1H, d, J=14.2Hz), 5.93 (1H, s),

6.76-6.84 (2H, m), 7.42 (1H, dd, J=2.0,8.4Hz),

7.47-7.55 (1H, m), 7.65 (1H, s), 7.76 (1H, d, J=2.0),

7.88 (1H, s), 7.92 (1H, d, J=8.4Hz)

MS∶MH⁺=433.

Embodiment 120：

Prepare the compound (I) that following structural is represented：

And its another compound (II) of diastereomer：

The compound that is obtained respectively by embodiment 119 and its it is non-reflect body, respectively obtain above-claimed cpd (I) and its diastereomer compound (II) according to the identical method as described in embodiment 99.The physical characteristic of these compounds is as described below.

(I)

State：Solid.

NMR：δ solvents (CDCl₃)

1.29 (3H, d, J=7.2Hz), 3.13 (3H, s), 4.18 (1H, q, J=7.2Hz),

4.24 (1H, d, J=14.12Hz), 4.98 (1H, d, J=14.2Hz), 5.68 (1H, s),

6.79-6.86 (2H, m), 7.49-7.56 (1H, m), 7.70 (1H, s),

7.84 (1H, s), 8.06 (1H, dd, J=2.0,8.8Hz),

(8.19 1H, d, J=8.8Hz), 8.58 (1H, d, J=2.0Hz)

MS∶MH⁺=465.

(II)

State：Solid.

NMR：δ solvents (CDCl₃)

1.71 (3H, d, J=6.8Hz), 3.08 (3H, s), 4.22 (1H, q, J=6.8Hz),

4.73 (1H, d, J=14.0Hz), 4.98 (1H, d, J=14.0Hz), 5.72 (1H, s),

6.47-6.54 (1H, m), 6.64-6.71 (1H, m), 7.12-7.19 (1H, m),

7.72 (1H, s), 7.96 (1H, dd, J=1.7,8.8Hz), 8.02 (1H, s),

8.04 (1H, d, J=8.8Hz), 8.41 (1H, brd, J=1.7Hz)

MS∶MH⁺=465.

Embodiment 121：

Prepare the compound that following structural is represented：

Except in addition to replacing 2- ethyl -6- chloro benzothiazoles, the purpose compound is prepared according to same procedure described in embodiment 106 using 2- ethyls -6- (the 4- fluorophenyls sulphur) benzothiazoles prepared with identical method described in preparation embodiment 6.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.24 (3H, d, J=7.2Hz), 4.07 (1H, q, J=7.2Hz),

4.26 (1H, d, J=144Hz), 4.92 (1H, d, J=14.4Hz), 5.84 (1H, s),

6.76-6.84 (2H, m), 7.06 (2H, br-dd, J=8.6,8.6Hz),

7.39-7.44 (3H, m), 7.47-7.55 (1H, m), 7.66 (1H, s),

7.77 (1H, d, J=1.6Hz), 7.86 (1H, s), 7.93 (1H, d, J=8.8Hz)

MS∶MH⁺=513.

Embodiment 122：

Prepare the compound (I) that following structural is represented：

Another compound (II) represented with following structural：

By the compound prepared by embodiment 121, the mixture of above-claimed cpd is made according to the same procedure described in embodiment 99.Then the mixture is subjected to silica gel chromatograph, two compounds is separated each other, obtain single compound.The physical characteristic of these compounds is as described below.

(I)

State: solid.

NMR：δ solvents (CDCl₃)

1.27 (3H, d, J=7.2Hz), 4.22 (1H, d, J=14.4Hz),

4.63 (1H, q, J=7.2Hz), 5.11 (1H, d, J=14.4Hz), 6.56 (1H, brs),

6.76-6.87 (2H, m), 7.23 (2H, br-dd, J=8.4,8.4Hz),

7.46-7.54 (1H, m), 7.68 (1H, s), 7.92 (1H, s),

7.99-8.04 (2H, m), 8.12 (1H, dd, J=1.6,8.4Hz),

8.32 (1H, d, J=8.4Hz), 8.51 (1H, br-d, J=1.6Hz)

MS∶MH⁺=561.

(II)

State：Solid.

NMR：δ solvents (CDCl₃)

1.26 (3H, d, J=7.2Hz), 4.14 (1H, q, J=7.2Hz),

4.19 (1H, d, J=144Hz), 4.94 (1H, d, J=14.4Hz),

5.64 (1H, s), 6.78-6.85 (2H, m),

7.20 (2H, br-dd, J=8.6,8.6Hz), 7.47-7.54 (1H, m),

7.68 (1H, s), 7.81 (1H, s), 7.98-8.03 (3H, m),

8.12 (1H, d, J=8.8Hz), 8.58 (1H, d, J=2.0Hz)

MS∶MH⁺=545.

Embodiment 123：

Prepare the compound that following structural is represented：

In addition to replacing the chloro- benzothiazoles of 2- ethyls -6- using 2- ethyl -4- chloro benzothiazoles, the purpose compound is obtained according to the same procedure described in embodiment 106.The physical characteristic of the compound is as described below.

State：Oily.

NMR：δ solvents (CDCl₃)

1.26 (3H, d, J=8.0Hz), 4.19 (1H, q, J=8.0Hz),

4.34 (1H, d, J=15.2Hz), 4.96 (1H, d, J=15.2Hz),

5.92 (1H, brs), 6.78-6.84 (2H, m), 734-7.40 (1H, m),

7.50-7.58 (2H, m), 7.68 (1H, s), 7.78-7.58 (2H, m),

7.68 (1H, s), 7.78-7.85 (1H, m), 7.92 (1H, s)

Embodiment 124：

Prepare the compound that following structural is represented：

In addition to 2- ethyl -6- cyanobenzothiazoles are replaced using 2- ethyl -4- cyanobenzothiazoles, the same procedure as described in embodiment 109 obtains the purpose compound.The physical characteristic of the compound is for example following.

NMR：δ solvents (CDCl₃)

1.26 (3H, d, J=7.1Hz), 4.15 (1H, q, J=7.1Hz),

4.22 (1H, d, J=14.2Hz), 4.98 (1H, d, J=14.2Hz),

5.63 (1H, brs), 6.78-6.86 (2H, m), 7.48-7.56 (1H, m),

7.67 (1H, dd, J=8.2,1.5Hz), 7.70 (1H, s), 7.84 (1H, s),

8.03 (1H, d, J=8.2Hz), 8.33 (1H, d, J=1.5Hz)

Embodiment 125：

Prepare the compound that following structural is represented：

At 90 DEG C, the chloro- 7- azepines benzothiazoles (3.16g) of 2- ethyls -6- and Sodium thiomethoxide (1.67g) are reacted 1 hour in 1-METHYLPYRROLIDONE (9ml).Cool down after the reactant mixture, being charged with water and ethyl acetate is layered it.Gained organic layer is washed with water and dried, then solvent is evaporated off.The residue (hexane: ethyl acetate=10: 1) purifies through silicagel column, obtains midbody compound, i.e. 2- ethyls -6- thiornethoxy groups -7- azepines benzothiazole (2.25g).Using the midbody compound, according to the same method of embodiment 106, purpose compound is obtained.The physics physical property of the compound is as described below.

mp：185-186℃

NMR：δ solvents (CDCl₃)

1.25 (3H, d, J=7.2Hz), 2.65 (3H, s), 4.03 (1H, q, J=7.2Hz),

4.30 (1H, d, J=14.2Hz), 4.94 (1H, d, J=14.2Hz), 5.75 (1H, s),

6.77-6.85 (2H, m), 7.31 (1H, d, J=8.4Hz), 7.48-7.55 (1H, m),

7.68 (1H, s), 7.86 (1H, s), 8.02 (1H, d, J=8.4)

Embodiment 126：

Prepare the compound that following structural is represented：

The change obtained in embodiment 125 house thing (400mg) is dissolved in dichloromethane (4ml), and metachloroperbenzoic acid (476mg) is added in the solution, is then stirred at room temperature 1.5 hours.The reactant mixture is dried successively with the sodium bicarbonate aqueous solution and water washing added with dichloromethane.Solvent is steamed, purpose compound (425mg) is obtained.The physics physical property of the compound is as described below.

mp：211-214℃.

NMR：δ solvents (CDCl₃)

1.30 (3H, d, J=7.0Hz), 3.32 (3H, s), 4.14 (1H, q, J=7.0Hz),

4.23 (1H, d, J=14.4Hz), 5.01 (1H, d, J=14.4Hz), 5.59 (1H, s),

6.80-6.86 (2H, m), 7.48-7.56 (1H, m), 7.72 (1H, s),

7.82 (1H, s), 8.25 (1H, d, J=8.4Hz), 8.47 (1H, d, J=8.4Hz)

MS∶MH⁺=466.

Embodiment 127：

Prepare the compound that following structural is represented：

Except using the chloro- 7- azepines benzothiazoles of 2- ethyls -6- as intermediate compound beyond the region of objective existence, the same procedure as described in embodiment 125 obtains the purpose compound.The physical characteristic of the compound is as described below.

mp：177-178℃

NMR：δ solvents (CDCl₃)

1.27 (3H, d, J=7.2Hz), 4.07 (1H, q, J=7.2Hz),

4.27 (1H, d, J=14.0Hz), 4.96 (1H, d, J=14.0Hz),

5.63 (1H, s), 6.78-6.85 (2H, m), 7.47 (1H, d, J=8.4Hz),

7.48-7.55 (1H, m), 7.70 (1H, s), 7.83 (1H, s),

8.19 (1H, d, J=8.4Hz)

Embodiment 128：

Prepare the compound that following structural is represented：

2- ethyl -7- azepines benzothiazoles (2.95g) are dissolved in dichloromethane (30ml), and metachloroperbenzoic acid (4.7g) is added in the solution at room temperature.After 3.5 hours, metachloroperbenzoic acid (2.3g) is added.After the completion of question response, the reactant mixture is handled with sodium sulfite aqueous solution under frozen water cooling.So obtained reactant mixture dchloromethane, and gained organic layer is evaporated off solvent and is obtained 2- ethyl -7- azepine benzothiazole -7- oxides (2.69g) with sodium bicarbonate aqueous solution, water and salt water washing and dry in order.The compound is added in dichloromethane (27ml), sequentially add dimethylamino carbamyl chloride (4.16g), trimethylsilyl cyanide (5.69ml) and triethylamine (63ml), and be allowed in room temperature reaction 8 hours.Add trimethyl base silicyl cyanide (2.5ml) and dimethylamino carbamyl chloride (2.5ml).After this reacts on room temperature progress 2 days, sodium bicarbonate aqueous solution is added into the reactant mixture, is then stirred 1 hour.Then the reactant mixture is extracted with ethyl acetate, gained organic layer is washed with water, dries and evaporate.The residue footpath silicagel column (using dichloromethane: methanol=200: 1 elution) after purification, is recrystallized with dichloromethane-isopropyl ether, obtains 2- ethyl -6- cyano group -7- azepines benzothiazoles (1.37g).In addition to 2- ethyl -6- chloro benzo thiazoles are replaced using above-claimed cpd, the purpose compound is obtained by the same procedure of embodiment 106.The physical characteristic of the compound is as described below.

mp：170-173℃

NMR：δ solvents (CDCl₃)

1.30 (3H, d, J=7.0Hz), 4.13 (1H, qd, J=7.0Hz, 0.8Hz),

4.25 (1H, d, J=14.OHz), 4.98 (1H, d, J=14.0Hz),

5.59 (1H, d, J=0.8Hz), 5.59 (1H, d, J=0.8Hz),

6.79-6.86 (2H, m), 7.49-7.56 (1H, m), 7.72 (1H, s),

7.81 (1H, s), 7.84 (1H, d, J=8.4Hz), 8.35 (1H, d, J=8.4Hz)

MS∶MH⁺=413.

Embodiment 129：

Prepare the compound that following structural is represented：

The compound prepared by embodiment 128, the purpose compound is prepared according to same procedure described in embodiment 111.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.30 (3H, d, J=7.2Hz), 4.12 (1H, q, J=7.2Hz),

4.28 (1H, d, J=14.4Hz), 5.00 (1H, d, J=14.4Hz), 5.65 (1H, s),

6.80-6.87 (2H, m), 7.49-7.56 (1H, m), 7.70 (1H, s),

7.70-7.76 (1H, brs), 7.80 (1H, s), 8.33 (1H, d, J=8.8Hz),

8.91 (1H, d, J=8.8Hz), 9.32-8.38 (1H, br-s)

Embodiment 130：

Prepare the compound that following structural is represented：

Except being replaced using 1- (1H-1,2,4- triazol-1-yls) -2 '-chloro-acetophenone outside 1- (1H-1,2,4- triazol-1-yls) -2 ', 4 '-difluoro acetophenone, purpose compound is obtained according to same procedure described in embodiment 127.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

1.22 (3H, d, J=7.2Hz), 4.22 (1H, d, J=14.4Hz),

4.67 (1H, q, J=7.2Hz), 5.55 (1H, s), 5.60 (1H, d, J=14.4Hz),

7.18-7.22 (2H, m), 7.34-7.38 (1H, m), 7.46 (1H, d, J=8.8Hz),

7.68 (1H, s), 7.69-7.73 (1H, 2), 7.81 (1H, s),

8.20 (1H, d, J=8.8Hz)

Embodiment 131：

Prepare the compound that following structural is represented：

In addition to replacing 2- ethyl -6- chloro benzo thiazoles using 2- methyl -6- chloro benzos thiazole, the physical characteristic for preparing the purpose compound compounds according to same procedure described in embodiment 106 is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

3.43 (1H, d, J=15.2 Hz), 3.88 (1H, d, J=15.2Hz),

4.65 (1H, d, J=14.2Hz), 4.70 (1H, d, J=14.2Hz), 6.03 (1H, s),

6.69-6.74 (1H, m), 6.76-6.81 (1H, m),

7.40 (1H, dd, J=8.8Hz, 2.0Hz), 7.42-7.50 (1H, m),

7.75 (1H, d, J=2.0Hz), 7.82 (1H, d, H=8.8H), 7.85 (1H, s)

8.18 (1H, s)

Embodiment 132：

Prepare the compound that following structural is represented：

In addition to replacing 2- methyl -6- chloro benzo thiazoles using 2- methyl -6- cyanobenzothiazoles, the purpose compound is prepared according to same procedure described in embodiment 131.The physical characteristic of the compound is as described below.

mp：176-178℃.

NMR：δ solvents (CDCl₃)

3.52 (1H, d, J=15.4Hz), 3.95 (1H, d, J=15.4Hz), 4.69 (2H, s)

5.87 (1H, s), 6.71-6.82 (1H, m), 7.51-7.45 (1H, m),

7.69 (1H, dd, J=1.6Hz, 8.6Hz), 7.86 (1H, s),

7.99 (1H, dd, J=0.4Hz, 8.6Hz), 8.13 (1H, dd, J=0.4Hz, 1.6Hz),

8.15 (1H, s)

Embodiment 133：

Prepare the compound that following structural formula is represented：

In addition to replacing the chloro- 7- azepines benzothiazoles of 2- ethyls -6- using the chloro- 7- azepines benzothiazoles of 2- methyl -6-, the same procedure as described in embodiment 127 prepares the purpose compound.The physical characteristic of the purpose compound is as described below.

mp：145-147℃(MeOH).

NMR：δ solvents (CDCl₃)

3.47 (1H, d, J=15.2Hz), 3.90 (1H, d, J=15.2Hz),

4.69 (2H, S), 5.76 (1H, S), 6.70-6.83 (2H, m),

7.39 (1H, d, J=8.4Hz), 7.42-7.49 (1H, m),

7.86 (1H, S), 8.08 (1H, d, J=8.4Hz), 8.13 (1H, S).

Embodiment 134：

Prepare the compound that following structural is represented：

3- nitro -4- pyridinium chloride hydrochlorides (2038mg) are dissolved in ethanol (42ml), then sodium hydrogensulfite (2148mg) is added in the solution, are then stirred at room temperature 40 minutes.Add sodium hydrogensulfite (6.67g) aqueous solution into the reactant mixture, and by gained mixture in 80 DEG C of heating stirrings 12 hours.It is filtered to remove after insoluble matter, concentrates the solution.The concentrate is dissolved in methanol-water, and the solution is mixed and is dried under reduced pressure with silica gel.Hereafter, eluted with 5: 1 chloroform-methanols and then with 1: 1 chloroform-methanol, obtain 3- amino -4- mercaptopyridines (892mg).7ml ethyl acetate and 4 molecular sieves are added in the product, and by gained mixture in being heated to reflux under blanket of nitrogen 20 minutes.The reactant mixture is dissolved in methanol in the lower drying of decompression.The solution is set to be adsorbed on silica gel.The solution is eluted with 50: 1 chloroform-methanols, 590mg2- methyl -5- azepine benzothiazoles are obtained.In addition to replacing 2- methyl -6- chloro benzo thiazoles using above-mentioned 2- methyl -5- azepines benzothiazole, purpose compound is obtained according to same procedure described in embodiment 131.The physical characteristic of the compound is as described.

mp：137-148℃

NMR：δ solvents (CD₃OD)

3.69 (1H, d, J=14.8Hz), 4.08 (1H, d, J=14.8Hz),

4.77 (1H, d, J=14.4Hz), 4.87 (1H, d, J=14.4Hz),

6.71-6.84 (1H, m), 6.92-7.04 (1H, m), 7.32-7.46 (1H, m),

7.83 (1H, s), 7.97 (1H, d, J=5.2Hz), 8.37 (1H, d, J=5.2Hz),

8.37 (1H, s), 9.06 (1H, s)

Embodiment 135：

Prepare the compound that following structural is represented：

Sodium azide (2301mg) is dissolved in dimethyl sulfoxide (DMSO) (60ml), the bromo- 4 '-sulfidomethyl acetophenones (3000mg) of 2- are added into the solution, are then stirred at room temperature 20 minutes.The reactant mixture is poured into 200ml frozen water, then extracted with ethyl acetate (200ml × 5).The extract is dried with anhydrous magnesium sulfate, and is concentrated under reduced pressure, and then (hexane → hexane-ethylacetate=8: 1) is purified through silica gel column chromatography, is obtained 2- azidos (azide) -4'- sulfidomethyls acetophenone (2155mg).The N-Lithiodiisopropylamide solution that will be generated by the hexane solution (7.8ml) of diisopropylamine (1.75ml) and 1.6M n-BuLis in 47ml tetrahydrofurans, under frozen water cooling, it is cooled to -78 DEG C, the tetrahydrofuran solution (19ml) of 2- azido (azide) -4 '-sulfidomethyl acetophenones (2155mg) was added dropwise thereto with 5 minutes, is then stirred 1 hour in -78 DEG C.Then propionyl chloride (1.81ml) is added dropwise again, and the gained mixture is placed lO minutes in -78 DEG C, is again heated to room temperature and is stirred at room temperature 10 minutes.The reactant mixture is poured into frozen water, then extracted with ethyl acetate (300ml × 3).Extract is dried with anhydrous magnesium sulfate, then is concentrated under reduced pressure.Gained oily mater (hexane → hexane: ethyl acetate=10: 1) purifies through silica gel column chromatography, obtains propionic acid 2- azidos (azide) -1- (4 '-sulfidomethyl phenyl) vinyl acetate (1.98g).The product is dissolved in hexamethylene (38ml), and toward adding phosphate in the solution.Gained mixture under blanket of nitrogen, be stirred at room temperature 1 hour, then heated 20 hours in 90 DEG C.The reactant mixture (hexane → hexane: ethyl acetate=30: 1) purifies through silica gel column chromatography, obtains 2- ethyls -5- (4- sulfidomethyls phenyl)  azoles (630mg).2- ethyl -6- chloro benzo thiazoles are replaced using the compound, the same procedure as described in embodiment 106 obtains purpose compound.The physical characteristic of the compound is as described below.

State：Oily.

NMR：δ solvents (CDCl₃)

1.55 (3H, d, J=8.0Hz), 2.50 (3H, s), 3.88 (1H, d, J=8.0Hz),

4.69 (1H, d, J=13.3Hz), 4.98 (1H, d, J=13.3Hz),

5.56 (1H, brs), 6.60-6.72 (2H, In), 7.20-7.26 (2H, m),

7.22-7.34 (1H, m), 7.27 (2H, s), 7.33-7.38 (2H, m),

7.70 (1H, s), 8.30 (1H, s)

Embodiment 136：

Prepare the compound that following structural is represented：

The product (77mg) of embodiment 135 is dissolved in dichloromethane (6.0ml), under frozen water cooling, benzylhydroperoxide (156mg) between being added into the solution.Heat after the mixture to room temperature, stir 1 hour.Saturated aqueous sodium thiosulfate and saturated sodium bicarbonate aqueous solution are added into the reactant mixture.Make the demixing toward addition 10ml dichloromethane in gained mixture again.Then gained water layer is further extracted with dichloromethane (10ml × 2).Organic layer merges, and is washed, is dried with anhydrous magnesium sulfate with saturated brine, is then concentrated under reduced pressure.So obtained grease (hexane-ethylacetate=4: 1 → methylene chloride-methanol=10: 1) purifies through silica gel column chromatography, obtains purpose compound (54mg).The physical characteristic of the compound is as described below.

State：Oily.

NMR：δ solvents (CDCl₃)

1.60 (3H, d, J=7.2Hz), 3.07 (3H, s), 3.91 (1H, q, J=7.1Hz),

4.71 (1H, d, J=14.1Hz), 5.00 (1H, d, J=14.1Hz),

5.40-5.50 (1H, brs), 6.62-6.72 (2H, m), 7.26-7.33 (1H, m),

7-31 (1H, s), 7.6-7.64 (2H, m), 7.73 (1H, s),

7.92-7.97 (2H, m), 8.05 (1H, s)

MS：m/eFAB475(MH⁺)。

Embodiment 137：

Prepare the compound that following structural is represented：

And its diastereomer：

In -65 DEG C, in the tetrahydrofuran solution that the 10ml tetrahydrofuran solutions of 2- ethyl -4- cyano group -5- trimethyl silyls thiazoles (1.58g) are added drop-wise to 20ml lithium diisopropylamides (being prepared by 1.40 blood diisopropylamines and 3.2ml butyl lithiums (1.6M hexane solutions)).Then in -65 DEG C, then the tetrahydrofuran solution of 10ml (1H-1,2,4- triazol-1-yls) -2,4- difluorophenyl acetophenones is added dropwise.After the mixture is stirred 1.5 hours, aqueous ammonium chloride solution is charged with, and add ethyl acetate and the separating obtained mixture of water.Gained organic layer is washed with water and dried, and solvent is evaporated off.The residue is dissolved in 20ml tetrahydrofurans, and toward the tetrahydrofuran solution (20ml) of addition 1.0M tetrabutyl ammonium fluorides in the solution, is then stirred at room temperature 1 hour.After the reactant mixture ethyl acetate and water stratification, gained organic layer is washed with water, and is dried and concentrated to dry.The residue (dichloromethane: methanol=200: 1) purifies through silica gel column chromatography, obtains single diastereomer compound (I) (464mg).Contain another diastereomer and (1H-1 with the methanol solution processing of sodium borohydride, 2,4- triazol-1-yls) -2,4- difluoro acetophenones fraction, then by silica gel post separation, obtaining (564mg), another non-reflects body compound (II).The physical characteristic of these compounds is as described below.

(I)

mp：198-205℃

NMR：δ solvents (CDCl₃)

(1.20 3H, d, J=7.1Hz), 4.06 (1H, q, J=14.4Hz),

4.08 (1H, q, J=7.1Hz), 4.96 (1H, d, J=14.4Hz), 5.41 (1H, s),

6.77-6.83 (2H, m), 7.42-7.49 (1H, m), 7.75 (1H, s),

7.80 (1H, s), 8.05 (1H, s)

MS：MH⁺=362.

(II)

mp：191-194℃.

NMR：δ solvents (CDCl₃)

(1.6l 3H, d, J=7.1Hz), 4.08 (1H, q, J=7.1Hz),

4.66 (1H, d, J=14.0Hz), 4.98 (1H, d, J=14.0Hz), 5.37 (1H, s),

6.58-6.70 (2H, m), 7.12-7.18 (1H, m), 7.75 (1H, s),

7.79 (1H, s), 7.97 (1H, s)

MS∶MH⁺=362.

Embodiment 138：

Prepare the compound shown in following structural：

Dissolve compound prepared by 150mg embodiments 137 in 2mlN- methyl-pyrrolidons, and by 54mg NaN₃And 115mgEt₃NHCl is added in the solution, is then heated 5 hours in external temperature is 100 DEG C of oil bath.Water is added into the liquid reaction mixture, is then extracted 3 times with AcOEt.The extract is washed with water, and is then washed with the saturation NaCl aqueous solution and uses MgSO₄Dry, ACOEt is evaporated off.Acetone, 4mlEtOH and 10mlH are added into residue₂O.Gained mixture is adjusted to pH3 with the 1NHCl aqueous solution, is then placed.As a result, solid deposits come out.Solid matter is recovered by filtration, the compound of 82mg mesh is obtained.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (DMSO-d⁶)。

1.13 (3H, d, J=7.0Hz), 4.11-4.14 (1H, m),

4.34 (1H, d, J=14.2Hz), 4.80 (1H, d, J=14.2Hz), 6.16 (1H, s),

6.93-6.98 (1H, m), 7.18-7.24 (1H, m), 7.28-7.33 (1H, m),

7.61 (1H, s), 8.22 (1H, s), 8.45 (1H, br-s)

MS∶MH⁺=405.

Embodiment 139：

Prepare the compound that following structural is represented：

The compound that 80mg embodiments 138 are obtained is dissolved in 1mlDMF, and by 65mgCSCO₃It is added in the solution, is then heated 30 minutes in external temperature is 60 DEG C of oil bath.Again by 0.02mlCH₃I is added in the reactant mixture, is stirred at room temperature afterwards 30 minutes.By H₂O is added in the liquid reaction mixture and extracted with AcOEt.Extract H₂O is washed, and after then being washed with the saturation NaCl aqueous solution, uses MgSO₄Dry, AcOEt is evaporated off.Gained residue is through column chromatography (SiO₂：20g, is eluted with CH2Cl2, then with 1%MeOH CH₂Cl₂The CH of solution and 2%MeOH₂Cl₂Solution is eluted) purifying, obtain the compound of 58mg mesh.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)。

1.22 (0.9H, d, J=7.1Hz), 1.25 (2.1H, d, J=7.1Hz),

4.08-4.21 (2H, m), 4.45 (0.9H, s), 449 (2.1H, s),

4.95 (O.7H, d, J=14.2Hz), 5.00 (0.3H, d, J=14.8Hz),

5.40 (0.7H, s), 5.53 (0.3H, s), 6.76-6.84 (2H, m),

7.45-7.52 (1H, m), 7.72 (0.3H, s), 7.75 (0.7H, s),

7.78 (0.7H, s), 7.81 (0.3H, s), 8.14 (O.3H, s), 8.35 (0.7H, s)

MS∶MH⁺=419.

Embodiment 140：

Prepare the compound (I) that following structural is represented：

And its diastereomer compound (II)：

In addition to replacing 2- ethyl -4- cyano group -5- trimethyl silyls-thiazole using 2- ethyls -4- (4 '-fluorophenyl) -5- trimethyl silyls-thiazole, corresponding purpose compound is obtained according to identical method described in embodiment 137.The physical characteristic of these compounds is as described below.

(I)

mp：122-124℃

NMR：δ solvents (CDCl₃)

1.67 (3H, d, J=7.0Hz), 4.09 (1H, q, J=7.0Hz),

4.73 (1H, d, J=13.8Hz), 4.93 (1H, d, J=13.8Hz),

6.14 (1H, d, J=1.7Hz), 6.48-6.54 (1H, m), 6.66-6.73 (1H, m),

7.06-7.12 (3H, m), 7.67 (1H, s), 7.71-7.74 (1H, m),

8.05 (1H, s)

(II)

mp：87-89℃.

NMR：δ solvents (CDCl₃)

1.23 (3H, d, J=7.1Hz), 4.06 (1H, q, J=7.1Hz),

4.28 (1H, d, J=14.4Hz), 4.89 (1H, d, J=14.4Hz), 6.04 (1H, s),

6.77-6.85 (2H, m), 7.13-7.17 (1H, m), 741 (1H, s),

7.47-7.55 (1H, m), 7.67 (1H, s), 7.85-7.92 (2H, m),

7.90 (1H, s)

Embodiment 141：

Prepare the compound (I) that following structural is represented：

And its diastereomer compound (II)：

In addition to replacing 2- ethyl -4- cyano group -5- trimethyl silyl thiazoles using 2- ethyls -4- (4 '-chlorphenyl) -5- trimethyl silyls thiazole, corresponding purpose compound is obtained according to identical method described in embodiment 137.The physical characteristic of these compounds is as described below.

(I)

mp：132-133℃

NMR：δ solvents (CDCl₃)

1.67 (3H, d, J=7.0Hz), 4.10 (1H, q, J=7.0Hz),

4.73 (1H, d, J=13.9Hz), 4.93 (1H, d, J=13.9Hz),

6.09 (1H, m), 6.46-6.55 (2H, m), 7.65-6.73 (1H, m),

7.05-7.13 (1H, m), 7.17 (1H, s), 7.35-7.40 (2H, m),

7.65-7.70 (2H, m), 8.04 (1H, s)

(II)

mp：162-164℃.

NMR：δ solvents (CDCl₃)

1.23 (3H, d, J=7.1Hz), 4.06 (1H, q, J=7.1Hz),

4.27 (1H, d, J=14.4Hz), 4.89 (1H, d, J=14.4Hz), 5.97 (1H, s),

6.76-6.85 (2H, m), 7.40-7.55 (4H, m), 7.67 (1H, s),

7.72-7.77 (2H, s), 7.89 (1H, s)

Embodiment 142：

Prepare the compound that following structural is represented：

In addition to replacing 2- ethyl -4- cyano group -5- trimethyl silyl thiazoles using 2- methyl -4- cyano group -5- trimethyl silyls thiazole, purpose compound is obtained according to identical method described in embodiment 137.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

3.44 (3H, d, J=15.0Hz), 3.81 (1H, d, J=15.0Hz),

4.58 (1H, d, J=14.2Hz), 4.74 (1H, d, J=14.2Hz),

5.48 (1H, s), 6.74-6.82 (2H, m), 7.40-7.46 (1H, m),

7.85 (1H, s), 7.87 (1H, s), 8.07 (1H, s)

MS∶MH⁺=348.

Embodiment 143：

Prepare the compound that following structural is represented：

In addition to replacing 2- ethyl -4- cyano group -5- trimethyl silyl thiazoles using 2- methyl -4- (4 '-chlorphenyl) -5- trimethyl silyls thiazole, purpose compound is obtained according to identical method described in embodiment 137.The physical characteristic of the compound is as described below.

State：Solid.

NMR：δ solvents (CDCl₃)

3.34 (1H, d, J=15.3Hz), 3.85 (1H, d, J=15.3Hz),

4.62 (1H, d, J=14.2Hz), 4.71 (1H, d, J=14.2Hz),

6.21 (1H, s), 6.69-6.83 (2H, m), 7.27 (1H, s),

7.36-7.46 (3H, m), 7.68-7.73 (2H, m),

7.85 (1H, s), 8.20 (1H, s)

Embodiment 144：

Prepare the compound that following structural is represented：

5.77g difluorobenzenes are added to AlCl₃(5.88g) is in CH₂Cl₂In suspension in (50ml), and by the CH of 2- (4- cyano-phenyls) chloroacetic chlorides (5.28g)₂Cl₂(30ml) solution is added drop-wise in gained mixture, and the mixture was heated to reflux after 6 hours, frozen water is charged with.CHCl will be used₃The product of extraction carries out column chromatography (SiO₂), use CH₂Cl₂- hexane (1: 1) is eluted, and obtains 4- (2- (2,4- difluorophenyl) -2- oxos) ethyl benzonitrile (2.45g).

Into EtOH (12ml) solution of the compound, 50%NaOH (0.67g) is added, MeI (0.46ml) is then added dropwise.Gained mixture is stirred at room temperature 4 hours.Add after ethyl acetate, be washed with water into the mixture, by evaporating residue that the organic layer obtains through column chromatography (SiO₂；Hexane-CH₂Cl₂=3: 1 → 1: 1) purify, obtain 0.5g compounds, i.e. 4- (2- (2,4- difluorophenyl) -1- methyl -2- oxos) ethyl benzonitrile.

By 1.0M TMSCH₂MgCl diethyl ether solutions (3.9ml) are cooled to -78 DEG C, and the diethyl ether solution (5ml) of above-claimed cpd (0.5g) is added dropwise thereto.Afterwards, the mixture is heated to 0 DEG C and stirred 10 minutes.Saturated aqueous ammonium chloride is added into the mixture, is then evaporated to dryness gained organic layer with AcOEt extractions, and CH is added in 0 DEG C₂Cl₂(10ml) and BF₃-OEt₂(0.24ml), then after AcOEt is added in the mixture by 1.5 hours of stirring at this temperature, uses saturation NaHCO₃The aqueous solution and then washed with saturated brine, solvent is evaporated off.Gained residue is through column chromatography (SiO₂；Hexane-CH₂Cl₂=3: 1 → 1: 1) purify, obtain compound, i.e. 4- (2- (2,4- difluorophenyl) -1- methyl -2- acrylic benzonitriles (0.2g).

Under frozen water cooling, it will ask in chloroform (4ml) solution that chlorine benzylhydroperoxide (490mg) is added to the compound (200mg), and the gained mixture is stood overnight.The dilute Na of the liquid reaction mixture₂CO₃Washing, is then washed with water, and 5mlDMF is added in the residue obtained afterwards toward the organic layer as obtained by evaporation.So obtained mixture is added in DMF (3ml) solution of 1,2,4- 1-Sodium-1,2,4-Triazoles, the solution of the latter is obtained by 1,2,4- triazole (272mg) and 60%NaOH (141mg).After 90 DEG C make the reaction carry out 2 hours, ethyl acetate is added into the reactant mixture, is then washed with water.Solvent is evaporated off, resulting residue is subjected to column chromatography (SiO₂；Hexane-ethylacetate=1: 1 → 1: 2), obtain the compound of 50mg mesh.The physical characteristic of the compound is as described below.

mp：208-209℃.

NMR：δ solvents (CDCl₃)

1.13 (3H, t, J=7.1Hz), 338 (1H, q, J=7.1Hz),

3.79 (1H, d, J=14.5Hz), 4.79 (1H, d, J=14.5Hz),

4.98 (1H, d, J=1.5Hz), 6.74-6.81 (2H, m),

7.44-7.51 (1H, m), 7.64 (2H, d, J=8.4Hz),

7.67 (2H, d, J=8.4Hz), 7.72 (1H, s), 7.75 (1H, s)

Embodiment 145：

Prepare the compound that following structural A is represented：

And the compound that following structural B is represented：

I) compound (625mg) obtained embodiment 144 is dissolved in DMF (2ml), and in 100 DEG C by the solution and NaN₃(345mg) and Et₃NHcl (731mg) is heated 7 hours together.It is filtered to remove after insoluble matter, removes solvent under reduced pressure, and a small amount of second alcohol and water is added in obtained residue.Afterwards, gained mixture is adjusted to pH2 with HCl.The solid matter of precipitation is recovered by filtration, is washed with water, then dries.Yield：539mg.

Ii) above-mentioned solid matter (514mg) is dissolved in DMF (5ml), by Cs₂CO₃(422mg) and MeI (0.089ml) are added in the solution, are then stirred at room temperature 4 hours.Ethyl acetate is added, gained organic layer is washed with water 3 times.Afterwards, solvent is evaporated off, gained residue is through column chromatography (SiO₂；CH₂Cl₂→CH₂Cl₂: EtOAc=4: 1) purify, obtain structural formula A compound (333mg) and structural formula B compound (93mg).The physical characteristic of the compound is as described below.

A

mp：216-218℃.

NMR：δ solvents (CDCl₃)

1.17 (3H, t, J=7.0 Hz), 3.39 (1H, q, J=7.0Hz),

3.89 (1H, d, J=143Hz), 4.41 (3H, s), 4.83 (1H, d, J=143Hz),

4.83 (1H, d, J=1.5Hz), 6.74-6.81 (2H, m), 7.44-7.54 (1H, m),

7.64 (2H, d, J=8.4Hz), 7.71 (1H, s), 7.75 (1H, s),

8.14 (2H, d, J=84Hz)

B

mp：169-171℃.

NMR：δ solvents (CDCl₃)

1.17 (3H, d, J=7.1Hz), 3.42 (1H, q, J=7.1Hz),

3.88 (1H, d, J=14.1Hz), 4.22 (3H, s), 4.83 (1H, d, J=14.1Hz),

4.95 (1H, d, J=1.5Hz), 6.75-6.82 (2H, m), 7.44-7.55 (1H, m),

7.70-7.78 (6H, m)

Embodiment 146：

Prepare the compound A that following structural is represented：

And its diastereomer compound B：

Except using 2- (4- (1,2,3- triazole -2- bases) phenyl) chloroacetic chloride replaced beyond 2- (4- cyano-phenyls) chloroacetic chloride, and the physical characteristic for obtaining purpose compound these compounds according to the same procedure of embodiment 144 is as described below.

A

mp：198-199℃.

NMR：δ solvents (CDCl₃)

1.16 (3H, d, J=7.1Hz), 3.39 (1H, q, J=7.1Hz),

3.89 (1H, d, J=14.1Hz), 4.83 (1H, d, J=14.1Hz),

4.85 (1H, s), 6.72-6.80 (2H, m), 7.44-7.55 (1H, m),

7.64 (2H, d, J=8.6Hz), 7.72 (1H, s), 7.76 (1H, s)

7.83 (2H, s), 8.08 (2H, d, J=8.6Hz)

B

State：Solid.

NMR：δ solvents (CDCl₃)

1.58 (3H, d, J=7.0Hz), 3.46 (1H, q, J=7.0Hz),

4.67 (1H, d, J=13.9Hz), 4.85 (1H, d, J=1.3Hz),

5.03 (1H, d, J=13.9Hz), 6.42-6.48 (1H, m), 6.61-6.67 (1H, m),

6.93-6.99 (1H, m), 7.14 ((2H, brd, J=8.6Hz) .7.75 (2H, s),

7.76 (1H, s), 7.80 (2H, brd, J=8.6Hz), 7.86 (1H, s)

EXPERIMENTAL EXAMPLE 2：

The ICR mouse of every group five inject Candida albicans MCY8622 bacterial strains (2 × 10 by its tail vein⁶Cfu/ mouse) and be infected.After 1 hour, compound shown in table 4 is applied to each group Mouse oral, dosage is per kg mouse 2.5mg or 10mg.Observation calculates every group of average Survival number of days over 7 days.It regard the average as the index for representing internal antifungal activity.

Table 4

The (Continued) of table 4

The (Continued) of table 4

Embodiment 147：

6.6ml (60mmol) (S)-hydroxy-2-methyl methyl propionate is dissolved in 33ml pyridines.18.1g (1.5 equivalent) triphenylchloromethane is added into resulting solution, is then heated 1 hour in 80 DEG C.The reactant mixture is cooled to room temperature, is then added to bit by bit in 350ml water.The crystallization of precipitation is collected by filtration, is washed with water and dries the so obtained product ethyl alcohol recrystallizations of, obtain 18.3g (yields：85%) purpose compound (203).

C₂₄H₂₄O₃ MH⁺=360

H C N

The O of calculated value % 6.71 79.97

Measured value % 6.76 79.77 0.05

Crystalline melt point： 84-85℃

¹H-NMR (δ, CDCl₃)：

1.15 (3H, d；J=7.1Hz), 2.69-2.77 (1H, m),

3.17 (1H, dd, J=5.6Hz, 8.8Hz), 3.29 (1H, dd；J=5.6Hz, 8.8Hz),

3.70 (3H, s), 7.20-7.44 (15H, m)

10.8g (30.0mmol) compound (203) is dissolved in the liquid mixture of 108ml tetrahydrofurans and 54ml methanol.While frozen water is cooled down, with 15 minutes under agitation toward the 54ml aqueous solution of dropwise addition 2.52g (2 equivalent) lithium hydroxide monohydrate in the resulting solution.Gained mixture is heated to room temperature and stirred 4 hours, 3.6ml glacial acetic acids is added and removes organic solvent under reduced pressure.After the residue is extracted with ethyl acetate, extract is washed with water, and is dried and concentrated, and obtains the compound (204) of 10.4g mesh.By being recrystallized from dichloromethane/hexane, (quantitative) analysis sample is obtained.

C₂₃H₂₂O₃ MH⁺=347

C H N

The O of calculated value % 79.74 6.47

Measured value % 79.59 6.47 is O.07

Crystalline melt point： 99-102℃

¹H-NMR (δ, CDCl₃)：

1.18 (3H, d；J=7.2Hz), 2.69-2.78 (1H, m),

3.25 (1H, dd, J=5.6Hz, 8.8Hz), 3.32 (1H, dd；J=5.6Hz, 8.8Hz),

7.15-7.45 (15H, m)

103g (29.8mmol) compound (204) is dissolved in 50ml dichloromethane.Under frozen water cooling, successively toward addition 3.64g (1.1 equivalent) 2- mercaptopyridines, 3.64g (0.1 equivalent) DMAPs and 6.76g (1.1 equivalent) dicyclohexyl carbodiimide in resulting solution.After gained mixture is stirred 3.5 hours under frozen water cooling, then at being stirred at room temperature 2 hours, the precipitation of generation is separated by filtration.After filtrate is diluted with ethyl acetate, it is washed twice with water, then is washed and dried with magnesium sulfate with saturated brine, removes solvent under reduced pressure.

The residue obtains 11.9g (yields through silicagel column (using hexane: ethyl acetate=9: 1 elution) purifying：91%) yellow oily purpose compound (205).

¹H-NMR (δ, CDCl₃)：

1.21 (3H, d；J=7.2Hz), 2.99-3.09 (1H, m),

3.21 (1H, dd, J=5.6Hz, 9.2Hz), 3.44 (1H, dd；J=7.6Hz, 9.2Hz),

7.21-7.33 (10H, m), 7.43-7.47 (6H, m), 7.63 (1H, d；J=8.0Hz),

7.73 (1H, t；J=8.0Hz), 8.63 (1H, d；J=4.8Hz)

Embodiment 148：

Suspension 780mg [equivalent to 1.2 equivalents of compound (205)] passes through the magnesium powder staying overnight and be activated in 120 DEG C of stirred under nitrogen flow in 7.8ml tetrahydrofurans.2 are dripped by 1,4- difluoro bromobenzenes and an iodine crystallization are added in the suspension, are stirred, internally temperature is maintained at 40-60 DEG C, 3.67ml [equivalent to 1.2 equivalents of compound (205)] 2, the 4- difluoro bromobenzene solution being dissolved in 17ml tetrahydrofurans is added dropwise thereto again.Add after 20ml tetrahydrofurans, the internal temperature of the mixture is cooled to -30 DEG C.When keeping its internal temperature in -25~-30 DEG C, the solution for 11.9g (27.1mmol) compound (205) being dissolved in 90ml tetrahydrofurans is added drop-wise in the mixture.Gained mixture is in after -30 DEG C of stirrings 15 minutes, then at being stirred at room temperature 2 hours, then toward drink and aqueous ammonium chloride solution is added in the reactant mixture, then stirs 15 minutes.Ethyl acetate and water are added in the mixture, organic layer is reclaimed.The organic layer is washed twice with water and washed once with saturated brine, is then dried with anhydrous magnesium sulfate, and solvent is evaporated off under reduced pressure.Gained residue further uses recrystallizing methanol through silicagel column (using hexane: ethyl acetate=9: l is eluted) purifying, obtains 7.46g (yield 62%) purpose compounds (206).

C₂₉H₂₄F₂O₂ MH⁺=442

H C N

Calculated value % 5.47 78.7 0

Measured value % 5.48 78.73 0

Crystalline melt point： 94-97℃

¹H-NMR (δ, CDCl₃)：

1.21 (3H, d, J=6.8Hz), 3.21 (1H, dd, J=5.2Hz, 8.8Hz),

3.42 (1H, dd, J=6.4Hz, 8.8Hz), 3.56 (1H, m), 6.80 (1H, m),

6.94 (1H, m), 7.17-7.31 (15H, m), 7.77-7.83 (6H, m)

Embodiment 149：

Under nitrogen flowing, suspension 6.43g [equivalent to 1.2 equivalents of compound (206)] the methyl triphen brominations  in 64ml tetrahydrofurans.Under frozen water cooling, 11.2ml [equivalent to 1.2 equivalents of compound (206)] butyl lithium (1.6mol hexane solutions) is added dropwise into the suspension.Gained mixture is heated to room temperature, then stirred 2 hours, the 30ml tetrahydrofuran solutions of 6.63g (15.0mmol) compound (206) are added dropwise, is then stirred 30 minutes.500ml hexanes and 300ml water are added into the liquid reaction mixture, and is filtered to remove insoluble matter.

Reclaim organic layer and be washed with water 3 times, washed once with saturated brine, dried with anhydrous magnesium sulfate and solvent is evaporated off under reduced pressure.The residue obtains 5.4g (yield 85%) oil product (207) through silicagel column (using hexane: ethyl acetate=50: 1 elution) purifying.

¹H-NMR (δ, CDCl₃)：

1.16 (3H, d, J=7.0Hz), 2.81-2.89 (1H, m),

2.97-3.01 (1H, dd, J=6.0Hz, 9.2Hz),

3.04-3.08 (1H, dd, J=6.0Hz, 9.2Hz), 5.11 (1H, S), 5.21 (1H, s),

6.68-6.75 (2H, m), 7.00-7.06 (1H, m), 7.18-7.28 (9H, m),

735-7.39 (6H, m)

Embodiment 150：

2.70g (6.14mmol) compound (207) is dissolved in 25ml dichloromethane.Under frozen water cooling, by 1.46 (1.1 equivalent) metachloroperbenzoic acid (purity：80%) be added in the solution, after 4 DEG C stir 12 hours.By 290mg) 0.34 equivalent) metachloroperbenzoic acid is added in the reactant mixture, mixed again 5 hours after room temperature.10% aqueous solution of sodium bisulfite is added in the mixture, is then extracted with ethyl acetate.Gained organic layer is washed with water, saturated sodium bicarbonate aqueous solution, water and saturated brine successively, then is dried with magnesium sulfate, and solvent is evaporated off under reduced pressure, obtains 2.813g oily compounds (208).The result of Proton NMR analysis finds that the compound is 2: 1 mixtures of required isomers (208a) and its diastereomer (208b).¹H-NMR (δ, CDCl₃)：

0.93 (3H, d；J=8.8Hz),<a>, 0.98 (3H, d；J=8.8Hz),

2.04-2.12 (1H, m), 2.20-2.28 (1H, m)<a>,

2.76 (1H, d；J=5.2Hz),<a>, 2.76 (1H, d；J=5.2Hz),,

2.88 (1H, dd；J=7.2Hz, 9.2.Hz)<a>,

2.96 (1H, dd；J=7.2Hz, 9.2Hz), 3.00-3.06 (1H, m)<a+b>,

3.02 (1H, d；J=5.2Hz)<a>, 3.11 (1H, d；J=5.2Hz),

6.61-6.73 (2H, m)<a+b>, 7.12-7.50 (16H, m)<a+b>.

Embodiment 151：

Under -70 DEG C, logical condition of nitrogen gas, in tetrahydrofuran (2.2ml) solution that the hexane solution of 1.6M butyl lithiums is added drop-wise to 221mg compounds (206) and 44 μ l (1.2 equivalent) chloroiodomethane.Gained mixture is stirred 5 minutes at such a temperature, its internal temperature is then heated to up to room temperature, stirs 1 hour.Aqueous ammonium chloride solution and ethyl acetate, which are sequentially added in the mixture, is layered it.Gained organic layer is washed with water and saturated brine, and dried with magnesium sulfate, solvent is removed under reduced pressure.Gained residue obtains 219mg (yields through silicagel column (using hexane: ethyl acetate=9: 1 elution) purifying：96%) compound (208).The result of Proton NMR analysis finds that the compound is the non-enantiomer mixture containing 1: 2.5 compound (208a) and (208b).

Embodiment 152：

In 85ml dimethylformamides, suspension 370mg [equivalent to 1.5 equivalents of compound (208)] sodium hydride (60% dispersion oil), and 851mg [equivalent to 2 equivalents of compound (208)] 1,2,4- triazoles are added in the suspension.Be stirred at room temperature after 15 minutes, into the suspension add be dissolved in 22ml dimethylformamides 2.813g (6.17mmol) compound (208) (<a>∶=2: 1 non-enantiomer mixture) solution, and gained mixture is stirred 7.5 hours in 80 DEG C.The mixture is cooled to after room temperature, and being charged with water and ethyl acetate is layered it.Gained organic layer salt water washing, then magnesium sulfate drying, removes solvent under reduced pressure.The residue is through silicagel column (using dichloromethane: methanol=200: 1 elution) purifying, respectively obtain the compound (209a) of 860mg mesh, the mixture of both compounds of its highly polar diastereomer (209b) of 99mg and 867mg, is white solid.

¹H-NMR (δ, CDCl₃)：

0.87 (3H, d；J=7.6Hz), 2.37-2.45 (1H, m),

3.40 (1H, dd；J=3.2Hz, 10.0Hz),

3.55 (1H, dd；J=5.6Hz, 10.0Hz), 4.19 (1H, d；J=14.4Hz),

4.65 (1H, d；J=14-4Hz), 4.88 (1H, s), 6.64-6.72 (2H, m),

7.22-7.3O (6H, m), 7.32-7.37 (6H, m), 7.46-7.50 (6H, m),

7.64 (1H, s), 7.84 (1H, s)

Referring to the description solids of compound (209a).

¹H-NMR (δ, CDCl₃)：

1.48 (3H, d；J=7.6HZ), 2.47-2.56 (1H, m),

2.92 (1H, dd；J=3.2Hz, 9.6Hz), 3.19 (1H, dd；J=3.2Hz, 9.6Hz),

4.56 (1H, d；J=14.0Hz), 4.69 (1H, d；J=14.0Hz), 4.78 (1H, s),

6.49-6.61 (2H, m), 7.01-7.09 (1H, m), 7.16-7.37 (15H, m),

7.63 (1H, s), 7.88 (1H, s)

Embodiment 153：

740mg (1.41mmol) compound (209a) is dissolved in 7.4ml methanol, and is charged with 295mg (1.1 equivalent) toluenesulfonic acid monohydrate, is then stirred at room temperature 1 hour.Again toward in obtained mixture, 295mg (1.1 equivalent) toluenesulfonic acid monohydrate is added, is stirred for 3 hours with after room temperature.Saturated sodium bicarbonate aqueous solution and ethyl acetate, which are added in the mixture, makes liquid layered.Gained organic layer is washed with water, is then washed and is dried with magnesium sulfate with saturated brine, remove solvent under reduced pressure.The residue (successively with mixture (ratio is 100: 1,50: 1 and 25: 1) is eluted) purifying of dichloromethane and methanol, obtains 246mg crude products through silicagel column.The mixed solvent recrystallization of the crude product dichloromethane and isopropyl ether, obtains 190mg (yields：48%) purpose compound (210), are pure products.

C₁₃H₁₅F₂N₃O₂ MH⁺+284

H C N

Calculated value % 5.34 55.12 14.83

Measured value % 5.33 55.09 14.93

Crystalline melt point：134.135 DEG C

¹H-NMR (δ, CDCl₃)：

0.84 (3H, d, J=7.2Hz), 2.30-2.39 (1H, m),

2.67-2.77 (1H, br, s), 3.83 (1H, dd；J=5.4Hz, 11,2Hz),

3.99 (1H, dd；J=3.2Hz, 11.2Hz), 4.76 (1H, d, J=14.0Hz),

4.97 (1H, d, J=14.0Hz), 5.28 (1H, s), 6.69-6.79 (2H, m),

7.36-7.43 (1H, m), 7.75 (1H, s), 7.91 (1H, s)

Embodiment 154：

In the mixed solution of 5ml water and 2.5ml acetone, 144mgN- methylmorpholineoxides (50% aqueous solution) are dissolved, and the 2.54ml acetone solns of 36 μ l osmium tetroxides (4% aqueous solution) and 247mg compounds (207) are sequentially added in resulting solution.After being stirred at room temperature overnight, 100 μ l osmium tetroxides (4% aqueous solution) are added in the mixture, then then at being stirred at room temperature 24 hours.Again toward 10% aqueous solution of sodium bisulfite is added in the mixture, then extracted with ethyl acetate.Gained organic layer is dried with salt water washing and with magnesium sulfate, and solvent is then evaporated off under reduced pressure.The residue (elutes) purifying with 10: 1 hexane: ethyl acetate and 4: 1 hexane: ethyl acetate mixture successively through silicagel column, obtains the principal product (211a) and 23g of 153mg solid forms its highly polar diastereomer (211b).

¹H-NMR (δ, CDCl₃)：

0.75 (3H, d, J=8.8Hz), 1.80 (1H, dd；J=5.2Hz, 8.4Hz),

2.44-2.53 (1H, m), 2.77 (1H, dd；J=5.6Hz, 8.4Hz),

3.21 (1H, dd；J=8.4Hz, 14.0Hz),

3.32 (1H, dd；J=2.8Hz, 14.0Hz),

3.63 (1H, dd；J=8.4Hz, 11.2Hz),

3.96 (1H, ddd；2.8Hz, 5.6Hz, 11.2Hz), 4.39 (1H, s),

6.69-6.76 (1H, m), 6.79-6.84 (1H, m), 7.22-7.30 (3H, m),

7.32-7.37 (6H, m), 7.43-747 (6H, n1), 7.52-7.58 (1H, m)

Referring to the description solids of compound (211a).

¹H-NMR (δ, CDCl₃)：

1.35 (3H, d, J=7.2Hz), 2.34-2.44 (1H, m),

2.93 (1H, dd；J=3.6Hz, 9.6Hz), 3.19 (1H, dd；J=3.6Hz, 9.6Hz),

3.82 (1H, dd；J=6.8Hz, 10.6Hz),

3.96 (1H, dd；J=5.2Hz, 10.6Hz), 4.50 (1H, s),

6.57-6.64 (1H, m), 6.70-6.75 (1H, m), 7.18-7.31 (15H, m),

7.39-7.45 (1H, m)

Embodiment 155：

96 μ l (2.2 equivalents of substrate) oxalyl chloride is dissolved in 3.3ml dichloromethane, and -60 DEG C of dichloromethane (0.9ml) solution by 185 μ l (4.8 equivalents of substrate) dimethyl sulfoxide (DMSO) is neutralized in nitrogen stream and is added drop-wise in resulting solution.After stirring 5 minutes, dichloromethane (4.2ml) solution of 142mg (0.500mmol) compound (210a) is added dropwise.After stirring 30 minutes, 350 μ l triethylamines (5 equivalents of substrate) are added.Gained mixture is heated to room temperature.Add water in the mixture, be then extracted twice with dichloromethane.Gained organic layer is washed twice with water, and washed once and is dried with magnesium sulfate with saturated brine, removes solvent under reduced pressure.Gained residue obtains 106mg (yields through silicagel column (using dichloromethane: methanol=50: 1 elution) purifying：75%) purpose compound (212).

C₁₃H₁₃F₂N₃O₂ MH⁺=262

H C N

Calculated value % 4.66 55.52 14.96

Measured value % 4.68 55.44 14.96

Crystalline melt point： 140-144℃

¹H-NMR (δ, CDCl₃)：

1.01 (3H, d；J=7.2Hz), 2.96-3.03 (1H, m),

4.62 (1H, d；J=14.0Hz), 4.90 (1H, d, J=14.0Hz), 5.16 (1H, s),

6.73-6.81 (2H, m), 7.37-7.44 (1H, m), 7.79 (1H, s),

7.86 (1H, s), 9.85 (1H, d；J=3.2Hz)

Embodiment 156：

36mg (0.128mmol) compound (212) is suspended in 0.36ml water, and toward addition 17mg (1.2 equivalent) hydroxylamine acid in the suspension, then heated 1.5 hours in 50 DEG C.Again toward addition 21mg hydroxylamine acids in gained mixture, reheat 40 minutes afterwards.Ethyl acetate and sodium bicarbonate aqueous solution are added into the liquid reaction mixture makes liquid layered.Gained organic layer is washed with water and saturated brine and dried with magnesium sulfate, and the solvent residues are then evaporated off under reduced pressure through silicagel column (using dichloromethane: methanol=100: 1 elution) purifying, 12mg purpose products (202) are obtained.

C₁₃H₁₂F₂N₄O₁ MH⁺=279

Fusing point：181-182℃.

¹H-NMR (δ, CDCl₃)：

1.17 (3H, d；J=7.2Hz), 3.29 (1H, q；J=7.2Hz),

4.82 (1H, d；J=14.0Hz), 4.97 (1H, d；J=14.0Hz),

5.44 (1H, d；J=0.8Hz), 6.74-6.82 (2H, m), 7.39-7.46 (1H, m),

7.83 (1H, s), 7.84 (1H, s)

Embodiment 157：

110mg compounds (206) are dissolved in 1.1ml methanol, and toward addition 53mg (1.1 equivalent) p-methyl benzenesulfonic acid monohydrate in the solution, then heated 20 minutes in 40 DEG C.Water and ethyl acetate are added in the mixture and extracted.Gained organic layer is washed with saturated brine, is dried with magnesium sulfate, and solvent is then evaporated off under reduced pressure.The residue obtains 32mg (yields through silicagel column purifying：58%) oily purpose compound.By high performance liquid chromatography, the optical purity of the compound is determined using chiral column.The optical purity is 90.0%ee..The analysis condition is as described below.

Post：Chiral Cell OB (internal diameters：4mm, length：250mm)

Mobile phase：Hexane: isopropanol=9: 1.

Flow velocity：0.5ml/min

¹H-NMR (δ, CDCl₃)：

118 (3H, d；J=6.8Hz), 2.50 (1H, t；J=6.0Hz),

3.45-3.54 (1H, m), 3.72-3.79 (1H, m), 3.84-3.94 (1H, m),

6.82-6.88 (1H, m), 6.92-6.98 (1H, m), 7.83-7.90 (1H, m)

Embodiment 158：

472mg (2.36mmol) compound (213) is dissolved in 5ml dichloromethane, and toward adding 448 μ l (2.5 equivalent) Chloromethyl methyl ether in the solution, the 4-dimethylaminopyridine of 822 μ l (2 equivalent) diethyl isopropyl amines and catalytic amount, is then stirred at room temperature overnight.Dichloromethane and water are added in the mixture and extracted.Gained organic layer is washed with water and saturated brine, and is dried with magnesium sulfate, then removes solvent under reduced pressure.The residue obtains 485mg (yields through silicagel column (using hexane: acetoacetic ester=10: 1 elution) purifying：84%) oily purpose compound) 214).

¹H-NMR (δ, CDCl₃)：

1.22 (3H, d；J=6.8Hz), 3.29 (1H, s), 3.85-3.68 (2H, m),

3.87-3.94 (1H, m), 4.56 (1H, d；J=84Hz),

4.59 (1H, d；J=8.4Hz), 6.84-6.91 (1H, m), 6.94-6.99 (1H, m),

7.85-7.92 (1H, m)

Embodiment 159：

According to alternative method of synthesis compound (208), purpose compound (215) that obtain oily, 1: 1 non-enantiomer mixture.

¹H-NMR (δ, CDCl₃)：

0.99 (3H, d；J=6.8Hz),<a>, 1.20 (3H, d；J=6.8Hz),

2.08-2.22 (1H, m)<a+b>, 2.78 (1H, d；J=5.2Hz)<a+b>,

3.09 (1H, d；J=5.2Hz), 3.33 (1H, s)<a>, 3.36 (1H, s),,

3.19-3.38 (1H, m),<a+b>, 3.45-3.54 (1H, m)<a+b>,

4.57 (2H, s)<a>, 4.61 (1H, s), 6.75-6.88 (2H, m)<a+b>,

7.32-7.45 (1H, m)<a+b>.

Embodiment 160：

500mg compounds (213) are dissolved in 2.5ml dimethylformamides, and are then stirred at room temperature 2.5 hours toward addition 715mg imidazoles and 715 μ l tert-butyl diphenyl silyl chlorides in the solution successively.Ethyl acetate and water are added into the reactant mixture makes liquid layered.Gained organic layer is washed with water and saturated brine and dried with magnesium sulfate.The product obtains the purpose compound (216) of 939mg cured forms through silicagel column (using hexane: ethyl acetate=9: 1 elution) purifying.

¹H-NMR (δ, CDCl₃)：

0.94 (9H, s), 1.19 (3H, d；J=10.0Hz), 3.58 (1H, m),

3.75 (1H, ddd；J=10.0Hz, 5.2Hz, 0.8Hz),

3.94 (1H, ddd；J=10.0Hz, 6.8Hz, 1.6Hz), 6.82-6.87 (1H, m),

6.92-6.98 (1H, m), 7.29-7.44 (6H, m), 7.49-7.52 (2H, m),

7.57-7.61 (2H, m), 7.79-7.85 (1H, m)

Embodiment 161：

In under room temperature and nitrogen stream, the 4.4ml diethyl ether solutions of 438mg (1.00mmol) compound (216) are added drop-wise in the diethyl ether solution of 3.0ml1.0M trimethyl ammonia chloride magnesium, are stirred at room temperature afterwards 2.5 hours.After aqueous ammonium chloride solution is added in gained mixture, extracted with ethyl acetate.The extract is washed with water and saturated brine, is then dried with magnesium sulfate.524mg solid products are obtained with toluene azeotropic distillation.

By 262mg, the product is dissolved in 2.5ml dichloromethane, and toward 69 μ l Eorontrifluoride etherate compounds are added dropwise in the solution under frozen water cooling.After stirring 10 minutes, sodium bicarbonate aqueous solution is added in the reactant mixture.Then extracted with dichloromethane.The extract is washed with water and saturated brine, and is dried with magnesium sulfate, then removes solvent under reduced pressure.The residue obtains 174mg oily purpose compounds (217) through silicagel column (using hexane: ethyl acetate=20: 1 elution) purifying.

¹H-NMR (δ, CDCl₃)：

1.02 (9H, s), 1.17 (3H, d；J=6.8Hz), 2.72-2.80 (1H, m),

3.50 (1H, dd；J=6.4Hz, 10.0Hz),

3.64 (1H, dd；J=5.2Hz, 10.0Hz), 5.13 (1H, s), 5.23 (1H, s),

6.71-6.78 (2H, m), 7.04-7.11 (1H, m), 7.31-7.43 (6H, m),

7.58-7.63(4H’m).

Embodiment 162：

Here is that the method for synthesizing compound (208) finds that the diastereomer ratio of oil product (218) is 1: 2 by the result of Proton NMR analysis.

¹H-NMR (δ, CDCl₃)：

0.92 (3H, d；J=8.8Hz)<a>, 0.97 (3H, d；J=8.8Hz),

1.03 (9H, s), 1.06 (9H, s)<a>, 1.96-2.05 (1H, m),

2.14-2.22 (1H, m)<a>, 2.78 (1H, d；J=5.2Hz),,

2.79 (1H, d；J=5.2Hz)<a>, 3.08 (1H, d；J=5.2Hz),

3.17 (1H, d；J=5.2Hz)<a>, 3.45-3.66 (2H, m)<a+b>,

6.70-6.82 (2H, m)<a+b>, 7.3O-7.45 (6H, m)<a+b>,

7.59-7.68 (4H, m)<a+b>.

Embodiment 163：

72mg (0.16mmol) compound (216) and 3.2 μ l (0.18mmol) chloroiodomethanes are dissolved in 2ml tetrahydrofurans.Make resulting solution in being cooled to -78 DEG C under nitrogen stream.The diethyl ether solution of 0.12ml (0.17mmol) 1.5M lithium methide lithium bromide compounds is added drop-wise in the solution.The gained mixture is heated to room temperature, while stirring 1 hour.Saturated aqueous ammonium chloride is added into the reactant mixture, is then extracted with ethyl acetate.Gained organic layer is washed and dried with saturated brine, is then concentrated under reduced pressure, and obtains 86mg oily compounds (218).The diastereomer ratio that the product is found by the result of Proton NMR analysis is l: l.

Embodiment 164：

By compound (213) (223mg；0.507mmol) it is dissolved in 5.0ml toluene, and toward addition 141mg (0.609mmol) silver oxides and 84 μ l (0.710mmol) benzyl bromide a-bromotoluenes in the solution, is then stirred at room temperature 7 days.The reactant mixture is filtered through diatomite, gained filtrate washed with diethylether.The filtrate is concentrated, then through silica gel column chromatography (Hex being used, then with hexane: ethyl acetate=12: 1 elution) purifying, obtains 66mg (yields：44%) colorless oil as product：That is compound (219).

¹H-NMR (δ, CDCl₃)：

1.21 (3H, d；J=7.0Hz), 3.54 (1H, dd；J=8.8Hz, 5.5Hz),

3.60-3.70 (1H, m), 3.82 (1H, dd；J=8.8Hz, 3.6Hz),

4.47 (1H, d；J=11.9Hz), 4.54 (1H, d；J=11.9Hz),

6.80-6.98 (2H, m), 7.20-7.40 (5H, m), 7.82-7.88 (1H, m)

Embodiment 165：

66mg (0.23mmol) compound (219) and 18 μ l (0.25mmol) chloroiodomethanes are dissolved in 2ml anhydrous tetrahydro furans.Resulting solution is cooled to -78 DEG C.The diethyl ether solution of 0.16ml (0.24mmol) 1.5M lithium methide lithium bromide compounds is added dropwise into the solution.Then gained mixture is heated to room temperature and stirred 2.5 hours.Saturated aqueous ammonium chloride is added in the reactant mixture, is then extracted with ethyl acetate.Gained organic layer is washed with saturated brine, is dried with anhydrous magnesium sulfate, is then concentrated under reduced pressure, and obtains 60mg (yields：86%) oil product：That is compound (220).

Incidentally, the compound (220) is 1: 1 non-enantiomer mixture.

¹H-NMR (δ, CDCl₃)：

0.97 (3H, d；J=7.2Hz)<a>, 1.01 (3H, d；J=7.5Hz),

2.14-2.18 (1H, m)<a>, 2.20-2.28 (1H, m),

2.77-2.80 (2H, m)<a+b>, 3.07-3.10 (2H, m),<a+b>,

3.24-3.32 (2H, m)<a+b>, 3.38-3.46 (2H, m),<a+b>,

4.40-4.52 (4H, m)<a+b>, 6.75-6.84 (2H, m),<a+b>,

7.26-7.40 (12H, m)<a+b>.

Prepare embodiment：

The preparation embodiment that thing is given up by compound (202) to finalization is described below.

Prepare embodiment 8：

By 33m1H₂O and 172ml phosphordithiic acid diethyl esters are added in 33g compounds (202), and the mixture is heated to reflux 30 minutes.Reactant mixture is cooled to room temperature, water is added, is then extracted with ethyl acetate.Gained ethyl acetate washed with water and saturated brine washing and all magnesium sulfate dryings.Solvent is evaporated off.70ml ether is added in gained residue and forms crystal.The crystallization so generated is collected by filtration, crude product purpose compound (35g) is obtained.The crude product (13.9g) is dissolved in ethyl acetate, the solution is washed with 5% aqueous sodium carbonate, solvent is then evaporated off.The gained residue ether and diisopropyl ether recrystallization, obtain the compound (221) of 7.8g mesh.

MH⁺=313

Fusing point：132-134℃

¹H-NMR (δ, CDCl₃)：

1.11 (3H, d；J=7.1Hz), 3.71 (1H, q；J=7.1Hz),

4.55 (1H, d；J=14.3Hz), 5.08 (1H, d；J=14.3Hz),

6.71-6.80 (2H, m), 7.42-7.48 (1H, m), 7.80 (1H, brs),

7.94 (1H, s), 8.41 (1H, brs)

Prepare embodiment 9

Compound (221) (15.02g) is dissolved in ethanol (150ml), and adds the bromo- 4 '-methyl thio acetophenones (14.97mg) of 2-, is then heated to reflux 4 hours.The liquid reaction mixture is cooled to 0 DEG C, then neutralized with sodium bicarbonate aqueous solution, then extracted with ethyl acetate.The extract is washed with water, and is then washed and is dried with magnesium sulfate with saturated brine, ethyl acetate is evaporated off.The residue is through silica gel chromatograph (SiO₂, with dichloromethane eluent, then with the dichloromethane of 1% methanol) and purifying, purpose compound (222) (10.19g) is obtained, is solid product.

MH⁺=459

¹H-NMR (δ, CDCl₃)：

1.23 (3H, d；J=7.2Hz), 2.54 (1H, s), 4.05 (1H, q；J=7.2Hz),

4.28 (1H, d；J=14.4Hz), 4.88 (1H, d；J=14.4Hz), 6.13 (H, s),

6.75-6.85 (2H, m), 7.33 (2H, br-d：J=8.4Hz), 7.42 (1H, s),

7.46-7.54 (1H, m), 7.66 (1H, s), 7.82 (2H, br-d：J=8.4Hz),

7.92 (1H, s)

Prepare embodiment 10：

Toward being dissolved in the solution of compound (222) (10.19g) of 150ml chloroforms, 18.35g metachloroperbenzoic acids are added, are then stirred at room temperature.After after raw material disappearance, add water in the liquid reaction mixture, then extracted with chloroform.Gained organic layer is washed with 50% saturated sodium bicarbonate aqueous solution, is washed with water, and is then washed again with saturated brine, and is dried with magnesium sulfate.Remove under reduced pressure after solvent, the residue obtains purpose compound (223) (8.2g), be solid product through silica gel chromatography.

MH⁺=491

¹H-NMR (δ, CDCl₃)：

1.24 (3H, d；J=7.2Hz), 3.09 (3H, s), 4.09 (1H, q；J=7.2Hz),

4.27 (1H, d；J=14.4Hz), 4.91 (1H, d；J=14.4Hz), 5.78 (1H, s),

6.78-6.85 (2H, m), 7.47-7.55 (1H, m), 7.67 (1H, s),

7.69 (1H, s), 7.87 (1H, s), 8.02 (2H, br-d：J=8.4Hz),

8.10 (2H, br-d：J=8.4Hz)

EXPERIMENTAL EXAMPLE 3：

The ICR mouse of every group five pass through past its tail vein injection Candida albicans MCY8622 mattresses strain (2 × 10⁶Cfu/ is only) and infect.After 1 hour, the Mouse oral to each group applies the compound (223) of the present invention, and application dosage is 2.5mg or 10mg/kg mouse.Observation calculates the average Survival number of days of every group of mouse over 7 days.The average is used as the index for representing internal antifungal activity.

[result]

Table 5 below shows the experimental result.

Table 5

Average Survival number of days (my god)

Compound 2.5mg/kg 10mg/kg

By the result, it is evident that the compound prepared with synthetic intermediate by the preparation method of the present invention shows significant antifungal activity, therefore it can be used for preventing and treating various fungal infection diseases.

Claims

1. a kind of prepare compound shown in following formula or the method for its acid-addition salts：

Wherein W is the thiazole ring of substitution；R¹And R²It is same to each other or different to each other and each represents a halogen atom or hydrogen atom；R³For a hydrogen atom or low alkyl group；R and m may be the same or different and each expression 0 or 1；A is N or CH；X is represented to have one or more substituents and can be included one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y serves as reasons-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- the group represented, wherein R₆For hydrogen atom or low alkyl group, j is 1-4 integer, and Z represents hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, there can be the phenyl of one or more substituents, there can be the phenoxy group of one or more substituents, there can be the imidazole radicals of one or more substituents, there can be the triazolyl of one or more substituents, there can be the tetrazole radical of one or more substituents or there can be the amino of one or more substituents, unless as r=m=0, R³For methyl and Z is hydrogen atom.It is included compound shown in following formula：

Wherein Hal is Br or Cl, and X, Y, Z, r and m be defined as above.

2. a kind of prepare compound shown in following formula or the method for its acid-addition salts：

Wherein R¹And R²It is same to each other or different to each other and each represents a halogen atom or hydrogen atom；R³For a hydrogen atom or low alkyl group；R and m may be the same or different and each expression 0 or 1；A is N or CH；X is represented to have one or more substituents and can be included one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y serves as reasons-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- the group represented, wherein R₆For hydrogen atom or low alkyl group, j is 1-4 integer, and Z represents hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, there can be the phenyl of one or more substituents, there can be the phenoxy group of one or more substituents, there can be the imidazole radicals of one or more substituents, there can be the triazolyl of one or more substituents, there can be the tetrazole radical of one or more substituents or there can be the amino of one or more substituents, unless as r=m=O, W is thiazole ring,

R³It is hydrogen atom two for methyl and Z and wherein W is substituted or unsubstituted, nitrogenous 5 circle heterocycles or its condensed ring, it is included compound shown in following formula：

Wherein D is substituted or unsubstituted nitrogenous 5 circle heterocycles or its condensed ring, and Z is H or CH₃。

3. a kind of prepare following formula shownization house thing or the method for its acid-addition salts：

Wherein W means substituted or unsubstituted 5 circle heterocycles or its condensed ring, and R¹And R²It is same to each other or different to each other and each represents a halogen atom or hydrogen atom；R³For a hydrogen atom or low alkyl group；R and m may be the same or different and each expression 0 or 1；A is N or CH；X is represented to have one or more substituents and can be included one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y serves as reasons-S-, ＞ SO, ＞ S0₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- the group represented, wherein R₆For hydrogen atom or low alkyl group, j is 1-4 integer, and Z represents hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, there can be the phenyl of one or more substituents, there can be the phenoxy group of one or more substituents, there can be the imidazole radicals of one or more substituents, there can be the triazolyl of one or more substituents, there can be the tetrazole radical of one or more substituents or there can be the amino of one or more substituents, unless as r=m=0, W is thiazole ring, R³For methyl and Z is hydrogen atom, it is included compound shown in following formula：

Reacted with compound shown in following formula：

Wherein R³, X, Y, Z, r and m be defined as above.

4. a kind of prepare compound shown in following formula or the method for its acid-addition salts：

Wherein R¹And R²It is same to each other or different to each other and each represents a halogen atom or hydrogen atom；R³For a hydrogen atom or low alkyl group；R and m may be the same or different and each expression 0 or 1；A is N or CH；W is represented to have one or more hetero atoms and can be had the aromatic rings or its condensed ring of one or more substituents, or W represents an aromatic rings or its condensed ring, wherein can have one or more hetero atoms and can have the aromatic rings of one or more substituents or being partly or entirely saturated for its condensed ring；X is represented to have one or more substituents and can be included one or more heteroatomic aromatic rings selected from N, S and O, there can be the alkane 2 basis of one or more substituents, there can be the olefin 2 base of one or more substituents, or there can be the alkyne diyl of one or more substituents；Y serves as reasons-S-, ＞ SO, ＞ SO₂, ＞ C=S, ＞ C=O ,-O-, ＞ N-R⁶, ＞ C=N-OR⁶Or-(CH₂)_j- the group represented, wherein R₆For hydrogen atom or low alkyl group, j is 1-4 integer, and Z represents hydrogen atom, halogen atom, low alkyl group, junior alkyl halides, lower alkoxy, halogenated lower alkoxy, hydroxyl, thiol base, nitro, cyano group, lower alkanol, there can be the phenyl of one or more substituents, there can be the phenoxy group of one or more substituents, there can be the imidazole radicals of one or more substituents, there can be the triazolyl of one or more substituents, there can be the tetrazole radical of one or more substituents or there can be the amino of one or more substituents, unless as r=m=0, W is thiazole ring, R³For methyl and Z is hydrogen atom, it is included compound shown in following formula：

Wherein A, R¹、R²、R³, W, X, Y, Z, r and m be defined as above, reacted with metachloroperbenzoic acid, then again with 1,2,4- 1-Sodium-1,2,4-Triazoles or the reaction of 1,3- imidazole natrium.

5. one kind prepares optically active (2S, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazol-1-yls) butyronitrile method, it is included optically active (2R3S) -2- (2,4- difluorophenyl) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxirane reacted with diethyl cyaniding aluminium.

6. one kind prepares optically active (2S, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazol-1-yls) butyronitrile method, it is included optically active (2R, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxiranes and cyaniding ytterbium react.

7. a kind of Stereoselective prepares optically active (2S, 3R) -3- (2,4- difluorophenyls) -3- hydroxy-2-methyl -4- (1H-1,2,4- triazole -1- tombs) butyronitrile method, it is included optically active (2R, 3S) -2- (2,4- difluorophenyls) -3- methyl -2- (1H-1,2,4- triazol-1-yls) methyl oxiranes and acetone cyanohydrin react.

8. a kind of prepare derivative shown in general formula or the method for its acid-addition salts：

Wherein

A is=CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent, and with can contain one or more hetero atoms and can the aromatic rings with a substituent；Or part thereof or whole condensed ring for being saturated, this method includes, when preparing the derivative or its acid-addition salts, 2- halogenated acetophenones shown in general formula are added in the presence of alkyl lithium in the compound of the condensed ring containing 5 circle heterocycles or condensed ring or part thereof or whole saturations and reacted, then again by 1,2,4- triazoles and sodium hydride, which are added in gained reaction product, to be reacted：

Wherein U represents halogen atom, and L and M are defined as above.

9. a kind of prepare derivative shown in general formula or the method for its acid-addition salts：

Wherein A is CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent, and with can contain the aromatic rings of one or more hetero atoms and a substituent；Or part thereof or whole condensed ring for being saturated, this method includes, when preparing derivative or its acid-addition salts, and the derivative of its 5 circle heterocycles replaced accordingly containing benzonitrile base is reacted with sodium azide and triethylamine hydrochloride.

10. a kind of prepare derivative shown in general formula or the method for its acid-addition salts：

Wherein A is=CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent, and with can contain the aromatic rings of one or more hetero atoms and a substituent；Or part thereof or whole condensed ring for being saturated, the derivative is replaced on 3- or 4- of tetrazole ring by alkyl, this method includes, when preparing the derivative or its acid-addition salts, and the derivative of its 5 circle heterocycles replaced accordingly containing tetrazolium phenyl is reacted with alkyl halide.

11. a kind of prepare derivative shown in general formula or the method for its acid-addition salts：

Wherein A is=CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent, and with can contain the aromatic rings of one or more hetero atoms and a substituent；Or part thereof or whole condensed ring for being saturated, this method includes, when preparing the derivative or its acid-addition salts, and by 5 membered heterocycle derivatives and 1 that it replaces containing halogenophenyl accordingly, 2,4- triazoles and sodium hydride are reacted.

12. a kind of prepare derivative shown in general formula or the method for its acid-addition salts：

Wherein A is=CH- or=N-,

R¹Mean 5 circle heterocycles, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent；Or 5 circle heterocycles condensed ring, it can be containing one or more other hetero atoms in addition to sulphur atom and with a substituent, and with can contain the aromatic rings of one or more hetero atoms and a substituent；Or part thereof or whole condensed ring for being saturated, this method includes, when preparing the derivative or its acid-addition salts, it is contained to 1 accordingly, the derivative and 1 for 5 circle heterocycles that 2,4- triazoles-phenyl replaces, 2,4- triazoles and sodium hydride react.

13. the method for the prepare compound according to claim 8, wherein the compound containing 5 circle heterocycles is 4- (2,4- difluorophenyl) thiazole, and 2- halos-acetophenone is chloro- 2 ', the 4 '-difluoro acetophenones of 2-.

14. the method for the prepare compound according to claim 8, wherein the compound of the condensed ring containing 5 circle heterocycles is 6- cyanobenzothiazoles, and 2- halos-acetophenone is chloro- 2 ', the 4 '-difluoro acetophenones of 2-.

15. one kind prepares 1- (2,4- difluorophenyls) -1- (6- thiocarbamoyl benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol method, it is included hydrogen sulfide gas and 1- (2,4- difluorophenyls) -1- (6- cyanobenzothiazole -2- bases) -2- (- 1H-1,2,4- triazol-1-yls) ethanol and triethylamine reacted.

16. one kind prepares 1- (2,4- difluorophenyls) -1- (6- (4- methylthiazol -2- bases)-benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol method, it is included sodium acid carbonate and bromacetone and 1- (2,4- difluorophenyls) -1- (6- thiocarbamoyl benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol reacted.

17. one kind prepares 1- (2,4- difluorophenyls) -1-6- (thiazole -1- bases)-benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol method, it is included 1- (2,4- difluorophenyls) -1- (6- thiocarbamoyl benzothiazole -2- bases) -2- (1H-1,2,4- triazol-1-yls) ethanol reacted with bromoacetaldehyde dimethyl acetal.

18. one kind prepares 1- (2, bis--fluorophenyls of 4-) -1- (4- (4- carbamoyls thiazol-2-yl)-thiophene -2- bases) -2- (1H-1, 2, 4- triazol-1-yls) ethanol method, it is included 1- (2, 4- difluorophenyls) -1- (4- thiocarbamoyl thiophene -2- bases) -2- (1H-1, 2, 4- triazol-1-yls) ethanol and α-bromoethyl acetone acid reaction formation 1- (2, 4- difluorophenyls) -1- (4- (4- carbethoxyl groups thiazol-2-yl)-thiophene -2- bases) -2- (1H-1, 2, 4- triazol-1-yls) ethanol, then this compound and ammonia are reacted again.

19. one kind prepares 1- (2; 4- difluorophenyls) -1- (4- (4- cyano thiazole -2- bases)-thiophene -2- bases) -2- (1H-1; 2; 4- triazol-1-yls) ethanol method; it is included 1- (2; 4- difluorophenyls) (4- (4- carbamoyls thiazol-2-yl)-thiophene -2- bases -2- (1H-1,2,4- triazol-1-yls) ethanol is reacted -1- with phosphoryl chloride phosphorus oxychloride.

20. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is defined as above, and R¹Hydrogen atom or carboxyl-protecting group are represented, compound shown in general formula is formed：

Wherein R, R¹It is defined as above with Pr, then the carboxyl-protecting group of compound shown in desealed (2), forms compound shown in general formula：

Wherein R and Pr are defined as above, and are further reacted compound shown in formula (3) with compound shown in formula LH, and wherein L is defined as above.

21. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method includes, by compound shown in general formula：

Wherein R and Pr are defined as above, and L represents leaving group, with compound shown in general formula or

Its reactive derivative is reacted：

Two of which X is defined as above, and Y is chlorine, bromine or iodine atom.

22. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two x are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method is included compound shown in general formula：

Wherein R, two X and Pr are defined as above, and are reacted with the triphen methylene  as derived from methyl triphenyl chlorination , methyltriphenylphospbromide bromide  or methyltriphenylphosphonium iodide , or with trimethylsilyl methyl magnesium chloride.Trimethylsilyl methyl magnesium bromide or trimethylsilyl methyl lithium are reacted.

23. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method includes being reacted compound shown in general formula and peroxy acid：

Wherein R, two X and Pr are defined as above.

24. a kind of method for preparing compound or its salt shown in general formula：

Wherein R, two X and Pr are synonymous ibid, are reacted with the chloromethyl lithium that is formed by chloroiodomethane or bromochloromethane, or reacted with dimethylated methylene base sulfonium oxygen, dimethylated methylene base sulfonium, diethyl methylene sulfonium oxygen or diethyl methylene sulfonium.

25. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method includes being reacted in compound shown in general formula and oxidant：

Wherein R, two X and Pr are defined as above.

26. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, R²For low alkyl group, and R³Methyl or lower alkoxy are represented, this method includes being reacted compound shown in general formula with alkoxy dimetylsilyl methylmagnesium halide or dialkoxy silyl methyl magnesium halogen compound：

Wherein R, two X and Pr are defined as above.

27. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and this method includes in the presence of a base being reacted compound shown in general formula with peroxy acid：

28. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and A is CH or nitrogen-atoms, and this method includes being reacted compound shown in general formula and 1,2,4- triazoles or imidazoles or its salt：

Wherein R, two X and Pr are defined as above.

29. a kind of method for preparing compound or its salt shown in general formula：

Wherein R means low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and L is leaving group, and this method is included halogenations shown in general formula, alkyl sulfonation or aryl sulfonation：

Wherein R, two X and Pr are defined as above.

30. a kind of method for preparing compound or its salt shown in general formula：

Wherein R, two X and Pr are defined as above, and L represents leaving group.

31. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and A is CH or nitrogen-atoms, and this method includes the hydroxyl protecting group Pr in compound shown in deblocking general formula：

32. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and A is CH or nitrogen-atoms, and this method includes being reacted in compound shown in general formula and oxidant：

Wherein R, two X and A are defined as above.

33. a kind of method for preparing compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and A is CH or nitrogen-atoms, and this method includes being reacted compound shown in general formula and hydroxylamine derivative：

Wherein R, two X and A are defined as above.

34. compound or its salt shown in general formula：

Wherein R is low alkyl group, and Pr represents hydroxyl protecting group, and L is leaving group.

35. compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr represents hydroxyl protecting group, and Q is oxygen atom or CH₂。

36. compound or its salt shown in general formula：

Wherein R is low alkyl group, and two x are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr represents hydroxyl protecting group.

37. compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr is hydroxyl protecting group, and M is hydroxyl or leaving group.

38. compound or its salt shown in general formula：

Wherein R is low alkyl group, and two X are same to each other or different to each other and each represent hydrogen or halogen atom, and Pr represents hydroxyl protecting group, and A is CH or nitrogen-atoms.