CN104364240A

CN104364240A - Drug for preventing or treating mycobacterial diseases

Info

Publication number: CN104364240A
Application number: CN201380029863.5A
Authority: CN
Inventors: 阙峰; 王莹
Original assignee: Sichuan Beilike Biotechnology LLC
Current assignee: Sichuan Beilike Biotechnology LLC
Priority date: 2012-06-08
Filing date: 2013-06-06
Publication date: 2015-02-18
Anticipated expiration: 2033-06-06
Also published as: WO2013182070A1; CN104364240B

Abstract

Disclosed in the present invention is a drug for preventing or treating mycobacterial diseases. In particular, disclosed is the use of a compound represented by the following general formula (I) or pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs thereof in preparing drugs for preventing or treating mycobacterial diseases, providing a new way for the prevention and treatment of tuberculosis and the like.

Description

Drug for preventing or treating mycobacterial diseases

A kind of medicine for being used to preventing or treating micobacterial conditions

Technical field

The invention belongs to field of medicaments, it is related to the compound for preventing or treating micobacterial conditions, specifically, compound of the present invention is used to prevent or treat tuberculosis.Background technology

Mycobacterium species is a lot of, there is the pathogenic and major class of non-pathogenic two.Cause human diseases has：（1) infection caused by human-like and bacillus tuberculosis bovis and several anonymous mycobacterias；（2) leprosy.These most infection are chronic infection process, long-term delay, and damaging lesion tissue.

Tuberculosis is by mycobacterium tuberculosis complex (Mycobacterium tuberculosis complex, abbreviation mycobacterium tuberculosis or tulase) caused by chronic infectious disease, whole body multiple organ system can be involved, most common disease sites are lungs, account for the 80-90% of each organ tuberculosis sum;The organs such as liver, kidney, brain, lymph node can also be involved.There are respiratory tract, alimentary canal, skin and uterus in main route of transmission, but mainly passes through respiratory infectious.After the pulmonary tuberculosis patient sputum of discharge of bacteria is dried, bacterium is with stirring up a cloud of dust, sucked by other people and cause infection, whether ill many factors such as the spittle of the human body suction containing mycobacterium tuberculosis quantity, virulence, resistance of human body mainly with sucking tulase are relevant.Tuberculosis is a kind of chronic infectious disease for seriously endangering people's health, and the current whole world has about 2,000,000,000 people to be infected, and the tulase carrier incidence of disease can account for 80%, newly occurs tuberculosis patient about 800-1000 ten thousand every year, and cause 3,000,000 people dead.

In recent years, the non-government organization such as the World Health Organization, global tubercular drugs development alliances, related pharmaceutical factory both increases the input in terms of tuberculosis prevention and treatment, and national governments also all support correlative study energetically.Invention was leaped treatment lungy in the isoniazid of nineteen fifty-two, invention in the rifampin of 1965.But, with the use of these good antituberculotics, while a large amount of tuberculosis patient rehabilitations, also bring the popular problem of multi-drug resistance tuberculosis.The course for the treatment of of Current therapeutic pulmonary tuberculosis is long, and method is complicated, and many patients can not complete treatment, so that the sick drug resistance constantly strengthens, is threatened as an increasingly serious global health.The annual whole world occurs more than 50 million new drug-tolerant pulmonary tuberculosis examples.The report display of WHO antituberculosis resistance：Resistance situation has reached highest level in population, and multi-drug resistance tuberculosis is still in helically ascendant trend.Such as the trend can not be reversed in time, and drug-tolerant pulmonary tuberculosis will trigger the epidemic situation that can not be cured.Multi-drug resistant and extensive resistant tuberculosis is difficult to cure, and the physical and mental health to patient causes great bodily injury, and it, which endangers, is no less than cancer, almost incurable disease.More frighteningly by the individual of these patient infections, once morbidity is exactly multi-drug resistant and extensive resistant tuberculosis patient, this is very big to personal, family and social danger, also grave danger is constituted to tuberculosis prevention and treatment, it has also become the great public health problem and social concern of serious threat human health.

The current whole world treats first-line drug lungy and still relies on a few four, medicine for being invented before 50 years mostly, and the often expensive and relative first-line drug effect of Second line Drug is not satisfactory, and course for the treatment of length, weak curative effect, adverse reaction are serious. The limitation of existing medicine, makes tuberculosis be tantamount to be suspended in " time bomb " on human tau, once can not effectively control, consequence is hardly imaginable.Therefore, in the urgent need to one kind can effectively prevent and treat mycobacteria infections, tuberculosis is especially effectively prevented and treated.

CN1155585, which discloses the compound that following formula represents, has potent resisting gram-positive bacteria activity,

In formula, R1 represents alkyl, halogen atom or the haloalkyl that hydrogen atom, carbon number are 16, and the haloalkyl is the alkyl that the carbon number that one or more halogen atoms replace is 16；R2 represents morpholinyl, piperidyl, 4- benzyl piepridines base, 4- Phenylpiperazinyls or 4- (4'- methoxyl groups) Phenylpiperazinyl；R3 represents imidodicarbonic diamide base, five-ring heterocycles group, and described five-ring heterocycles group is imidazole radicals, thiadiazolyl group, triazol radical, tetrazole base or BTA base.But the document does not refer to that these compounds can be used to treat micobacterial conditions, especially tuberculosis.The content of the invention

To find new active drug, present inventor has performed long-term and arduous research, the present invention has been finally completed.

The purposes in being used to prevent or treat micobacterial conditions is being prepared the invention provides the below formula I compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug.

It is used to prevent present invention also offers one kind or treats tuberculosis composition, the pharmaceutical composition contains as the formula I of the active component compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug, or its any combination, and medicinal adjuvant.

Prevent present invention also offers one kind or treat method lungy, this method is included to the formula I of the patient therapeuticallv's effective dose compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug, or its any combination, or described pharmaceutical composition.

The compound that formula I of the present invention is represented has remarkable result in terms of mycobacterial infections, especially mycobacterium tuberculosis infection, particularly resistance tubercle bacillus is treated or prevented.Embodiment

Hydroxyl, amino or substituted or unsubstituted following groups are represented in the compound that the above-mentioned formula I of the present invention is represented：C1-C10 amidos, two (C1-C10) imido grpups, C1-C10 amide groups, C1-C10 acyl imines base, two (C1-C10 acyl groups) imido grpups, C1-C10 sulfoamidos, C1-C10 sulfonyloxies, C1-C10 alkanoyls epoxide, five yuan or hexa-member heterocycle group, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl, benzheterocycle base； R₂Represent substituted or unsubstituted five yuan or hexa-member heterocycle group；Substituted or unsubstituted C1-C10 acyl groups；Or following formula group：

Wherein,

R₃And R₅11, halogen atom or haloalkyl are represented independently of one another；

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, alkoxy, aralkyl oxy, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl, five yuan or hexa-member heterocycle base amido, benzheterocycle base amido.

In the preferred case,Expression hydroxyl in formula I,Amino,C1-C10 alkylamino radicals,C1-C10 aromatic alkyl amidos,C1-C10 aromatic radical amidos,Two (C1-C10 alkyl) imido grpups,Two (C1-C10 aromatic radicals) imido grpups,C1- C10 alkylaryl imido grpups,Two (C1-C10 aromatic alkyls) imido grpups,C1-C10 alkylamidoalkyls,C1-C10 aromatic alkyl amide groups,C1-C10 aromatic radical amide groups,Halo C1-C10 alkylamidoalkyls,Halo C1-C10 aromatic alkyl amide groups,Halo C1-C10 aromatic radical amide groups,C1-C10 alkylsulfonamidos,C1-C10 aromatic alkyl sulfoamidos,C1-C10 aromatic radical sulfoamidos,Halo C1-C10 alkylsulfonamidos,Halo C1-C10 aromatic alkyl sulfoamidos,Halo C1-C10 aromatic radical sulfoamidos,C1-C10 aromatic radical sulfonyloxies,C1-C10 alkylsulfonyloxies,C1-C10 aromatic alkyl sulfonyloxies,Halo C1-C10 aromatic radical sulfonyloxies,Halo C1-C10 alkylsulfonyloxies,Halo C1-C10 aromatic alkyl sulfonyloxies,Two (C1-C10 aromatic radicals acyl group) imido grpups,Two (C1-C10 alkanoyls) imido grpups,Two (C1-C10 aromatic alkyls acyl group) imido grpups,C1-C10 alkanoyl epoxides,Halo C1-C10 alkanoyl epoxides,Substituted or unsubstituted five yuan or hexa-member heterocycle group,Five yuan or hexa-member heterocycle base sulfydryl or benzheterocycle base sulfydryl.In a more preferred case, expression hydroxyl in formula I, amino, methylamino, ethylamino-, benzylamino, anilino-, dimethyliminio, diethyl imido grpup, diphenyl imine base, benzhydryl imido grpup, formamido, acetamido, propionamido-, halo formamido, 1- haloacetyl amidos, methylsulfonyl amido, ethanesulfonamide group, mesyloxy, ethanesulfonyloxy group, benzyl sulfonyloxy, phthalimide-based, dicarboximide base, diethyl imide, acetyl group epoxide, succinyl base imido grpup, p-toluenesulfonyl epoxide, 1, 3, 4- thiadiazolyl group sulfydryls, 1, 2, 4-1H- triazol radicals, 1H- tetrazole bases, tetrazole base sulfydryl, benzimidazole 2- sulfydryls, BTA base, imidazole radicals or camphorimide base.For example; in the particular compound that the present invention is provided; expression hydroxyl, amino, acetamido, chloracetyl amido, methylsulfonyl amido, mesyloxy, ethanesulfonyloxy group, phthalimide-based, dicarboximide base, succinyl base imido grpup, p-toluenesulfonyl epoxide in formula I, 1; 3; 4- thiadiazolyl groups sulfydryl, 1; 2,4-1H- triazol radicals, 1H- tetrazoles base, tetrazole base sulfydryl, benzimidazole 2- sulfydryls, BTA base, imidazole radicals or camphorimide base.

In situations where it is preferred, the R in formula I₂Represent substituted or unsubstituted following groups：Pyrrole radicals, imidazole radicals, pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 4- morpholinyls, piperazinyl, piperidyl, pyrimidine radicals, oxazolyls, pyridine radicals；Or C1-C4 acyl groups；Or following formula group：

Wherein,

R₃And R₅15, halogen atom or haloalkyl are represented independently of one another；

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, alkoxy, aralkyl oxy, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl.

In a more preferred case, the R in formula I₂Represent acetyl group, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrimidine radicals, Qu generations or the pyridine radicals or following formula group for not replacing Evil to replace：

Wherein,

In situations where it is preferred, the R in formula I₂Represent acetyl group, 2- Phenylpiperidines base, 2- hydroxy pyrimidines base, the chloro- 4- cyano group -2- pyridine radicals of 6-, 4- oxazolyls or 2- acetoxyl group pyrimidine radicals.

In situations where it is preferred, the compound that Π is represented：

Wherein, Ri is as defined above；

R₃And R₅11, F, C1 or CF are represented independently of one another₃;

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, alkoxy, aralkyl oxy, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl.In situations where it is preferred, the R4 represents substituted or unsubstituted following groups：Pyrrole radicals, imidazole radicals, pyrazolyl, pyrrolidinyl, pyrrole radicals, pyrrolin base, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, imidazole radicals sulfydryl, pyrazolinyl, thiadiazolyl group, thiadiazolyl group amino, thiadiazolyl group sulfydryl, morpholinyl, piperazinyl, triazine radical, pyrimidine radicals, hexahydropyrimidine, pyridine radicals, Chromanyl, quinolyl, benzofuranyl, pyrazinyl, pyrazinyl epoxide or piperidyl.

Specifically, the R4 represents morpholinyl, 4- Phenylpiperazinyls, 1- methyl -5,6- dihydro -1,2,4- triazine -4C1H)-base, 2- chloromethyls-piperidyl, 2- chloromethyl -4- methyl-piperidyls, 4,6- dimethoxy -2- hexahydropyrimidines base, 4,6- dimethoxys -₅- methyl -2- hexahydropyrimidines base,₆- chloro- 4- cyano group -2- pyridine radicals, the chloro- 4- cyano group -5- methyl -2- pyridine radicals of 6-, 4- oxos -2- Chromanyl, 5- fluorin-4-oxygens generation -1, 2, 3, 4- tetrahydrochysene -2- quinolyls, benzofuranyl, 3- chlorine propiono -1- piperazines, 5- (azetidinyl -1- carbonyls) -2- Oxopyrazine bases, 1- methyl isophthalic acid-H-2- imidazoles sulfenyls, 1-H-1-B ratios cough up base, 1- piperidyls, 1, 3, 4- thiadiazoles -2- amino, the small pyrazolyls of the small H of 3- methyl, 2, the small pyrrolidinyl of 5- dioxies, 2, 5- dihydro -1-H- 1- pyrrole radicals, 1- pyrrolidinyls, 1, 3, 4- thiadiazoles -2- sulfenyls, 4- methyl isophthalic acid H- imidazole radicals, 4- methoxyphenylpiperazderivatives bases, 4- benzyl piepridines base or 4- piperidyls.

In the compound that above-mentioned formula II is represented, the R₄Following formula group can be represented：

R4 can also:

In addition, logical show following formula group:

R4 can also

Wherein R₇Represent hydrogen atom, C1-10 alkyl or C1-C10 haloalkyls； R₈Represent hydrogen atom, C1-C10 alkyl or C1-C10 benzene alkyls；It is preferred that R₇Represent hydrogen atom, methyl or chloromethyl； R₈Represent hydrogen atom, methyl or benzyl.

In addition, formula Π R₄Following formula group can be represented：

Wherein, R₉Represent hydrogen atom, C1-C10 alkoxies or C1-C10 alkylthio groups；.And R_uIt is identical or different, represent hydrogen atom or C1-C10 alkyl；It is preferred that R₉Represent hydrogen atom, methoxyl group or methyl；.It is identical or different with Ru, represent hydrogen atom or methyl.

It is further preferred that the compound that formula I is represented is the compound that general formula III is represented：

Wherein, R₃, R₅As defined above；

Represent substituted or unsubstituted following groups：Phenyl, aralkyl, alkyl acyl, five yuan or hexa-member heterocycle group.It is preferred that, represent the alkyl acyl of phenyl, substituted-phenyl, phenylalkyl, alkyl acyl or halo.For example represent substituted or unsubstituted following groups：Phenyl, benzyl, C1-C10 alkyl acyls, five yuan or hexa-member heterocycle group；Preferably represent the C1-C10 alkyl acyls of phenyl, substituted-phenyl, benzyl, C1-C10 alkyl acyls or halo.Specifically, phenyl, p-methoxyphenyl, benzyl or chlorine propiono are represented.

In the present invention, the description of similar fashions such as " C1-C10 " refers to the carbon atom number that modified group has, for example, C1-C10 alkyl refers to the straight chained alkyl with 1-10 carbon atom, branched alkyl or cycloalkyl, such as including methyl, ethyl, n-propyl, isopropyl, the tert-butyl group, n-hexyl, cyclopropyl.

In the present invention, " halogen " refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

" substitution " refer to defined in hydrogen atom on group by other atoms or substituent group, be for example optionally substituted with one or more halogen atoms.

Five yuan or hexa-member heterocycle group refer to saturation, fractional saturation or undersaturated five yuan or hexa-atomic member ring systems in the present invention, and wherein at least one carbon atom is by N, 0, S, SO, S0₂Substitution, such as imidazole radicals, thiazolyl, thiadiazolyl group, triazol radical, tetrazole base, piperidyl, pyrimidine radicals, piperazinyl, morpholinyl, furyl, tetrahydrofuran base, pyrazinyl, pyrrole radicals, pyrrolidinyl, pyrazolyl, pyrazolidinyl, oxazolyl, oxazole alkyl, Chromanyl, quinolyl, pyrrolin base or hexahydropyrimidine base.

Benzo five-membered heterocycle or benzo hexa-member heterocycle refers to quinoline, benzofuran, benzimidazole or BTA etc. in the present invention.

Sulfonyl epoxide of the present invention includes but is not limited to mesyl epoxide, benzenesulfonyl epoxide, ethylsulfonyl epoxide, p-toluenesulfonyl epoxide, preferably mesyl epoxide or p-toluenesulfonyl epoxide.

Meaning micobacterial conditions of the invention refer to the bacterium of mycobacterium as pathogen or any disease, illness, pathology, symptom, clinical disease or syndrome of its association, detection or design mycobacteria infections.The micobacterial conditions include Mycobacterium tuberculosis, non-tuberculous mycobacteria infection or associated micobacterial conditions, such as various forms of tuberculosis, leprosy.

The compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that the formula I of the present invention is represented can be used for preventing or treating tuberculosis or leprosy, it is preferred that for preventing or treating tuberculosis.

Being used for of the present invention prevents or treats tuberculosis composition to contain as the formula I of the active component compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug, or its any combination, and medicinal adjuvant. In the pharmaceutical composition of the present invention, wherein the common dosage of the active component is 0.01 2000mg/ days, it is preferred that the dosage is 0.01 1800mg, more preferably 0.1 1500mg, further preferably for l 1200mg.This sunset is foretold, and the active component is 0.05-100% by weight in the composition.

The prevention of the present invention or treatment method lungy include being applied to the formula I of the therapeutically effective amount compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug into the patient for needing to treat.

" therapeutically effective amount " in the present invention refers to the effective dose when being administered to the individual of needs, such as mankind or non-human, to mitigate symptom or avoid further mycobacteria infections.

The pharmaceutically acceptable salt for the compound that heretofore described formula I is represented includes sodium, potassium, calcium, aluminium, magnesium, zinc or other metal salts and ammonium salt.It may also be the salt of organic acid, such as acetate, lactate, citrate, tartrate, maleate, malate, fumarate, benzoate, mesylate, benzene sulfonate.It may also be inorganic acid salt, such as hydrochloride, sulfate, hydrobromate, phosphate and sulfonate.

The hydrate for the compound that formula I is represented includes its semihydrate, 3/4 hydrate, 2/7 hydrate, 2/5 hydrate, 1/12 hydrate.

It can also be used as the salt pharmaceutically received, hydrate, complex, solvate as intermediate or prodrug." prodrug " of the present invention refers to that compound or its pharmaceutically acceptable salt that formula I is represented can be converted into vivo, so as to have the material of identical pharmacological action with the formula I compounds represented.

In the present invention, if there is the isomeric form for the compound that formula I is represented, it includes enantiomter or the form of ownership of isomers is included in the present invention.The compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that formula I of the present invention containing chiral centre is represented can carry out separation exclusive use with racemic mixture using or using known technology.

It is preferred that, the compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that formula I of the invention is represented are following compound：

Compound 1

(5S)-[N-3- (3 ', the 5 fluoro- 4'- of '-two (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 2

(5S)-[N-3- (3 ', 5,-two fluoro- 4'- (1 "-methyl -5 ", 6 "-dihydro-Γ ' (Η), 2 ", 4 "-triazine -4- bases) phenyl) -2- oxo -5- Evil oxazolidinyls] methylacetamide

Compound 3

(5S)-[N-3- (3 '-fluoro- 4'- (2 "-chloromethyl -1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 4

(5S)-[N-3- (3 '-fluoro- 4'- (2 "-chloromethyl -4 "-methyl isophthalic acids "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 5

(5R)-[Ν -3- (3 '-fluoro- 4'- morpholino phenyls）- 2- oxo -5- oxazoles alkyl] methanol

Compound 6 (5S)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -2 "-hexahydropyrimidines) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 7

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -5 "-methyl -2 "-hexahydropyrimidine) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 8

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -2 "-hexahydropyrimidines) phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 9

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -5 "-methyl -2 "-hexahydropyrimidine) phenyl）- 2- oxo -5- oxazoles alkyl] methanol

Compound 10

(5S)-[N-3- (3,-fluoro- 4'- (6 "-chloro- 4 "-cyano group -2 "-pyridine) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 11

(5S)-[N-3- (the fluoro- 4'- of 3'- (6 "-chloro- 4 "-cyano group -5 "-methyl -2 "-pyridine) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 12

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 13

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-oxo -2 "-Chromanyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 14

(5S)-[N-3- (the fluoro- 4'- of 3'- (5 "-fluoro- 4 "-oxo -1 ", 2 ", 3 ", 4 "-tetrahydrochysene -2 "-quinolyls) and phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 15

(5S)-[N-3-C3'- fluoro- 4'- (benzofuranyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 16

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-(3 " '-chlorine propiono) -1 "-piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 17

(5S)-[N-3- (the fluoro- 4'- of 3'- (5 "-(azetidinyl carbonyl)-pyrazinyl -2 "-epoxide) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 18

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-methyl-Γ ' (Η)-imidazole radicals -2 "-sulfenyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 19

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 20 (5R)-[the fluoro- 4'4 of N-3-'3'- "-methyl -1 " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 21

(5S)-[N-3 3' are apt to 4', 2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 22

(5R)-[N-3-'3'- fluoro- 4'2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methyl mesyl compound 23

(5S)-[fluoro- 4' Γ ' (Η)-the Γ '-pyrrole radicals of N-3- 3'-) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 24

(5R)-[N-3-'3' is apt to 4'-' Γ (Η)-Γ '-pyrrole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 25

(5S)-[N-3 3'- fluoro- 4'1 "-piperidyls) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 26

(5R)-[N-3-'3' is apt to 4'-' Γ-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide

Compound 27

(5S)-[N-3- 3'- fluoro- 4' Γ ', 3 ", 4 "-thiadiazoles -2 "-amino)-phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 28

(5S)-[N-3- 3'- fluoro- 4' Γ ', 3 ", 4 "-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazoles alkyl] methyl chloride acetamide compound 29

(5S)-[N-3- 3'- fluoro- 4'3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 30

(5R)-[N-3-'3' is apt to 4'-'3 "-methyl -1 " (Η)-Β than oxazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 31

(5S)-[N-3- 3'- fluoro- 4'3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl）- 2- oxo -5- oxazoles alkyl] methyl chloride acetamide compound 32

(5S)-[N-3- 3'- fluoro- 4'2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 33

(5S)-[N-3- 3'- fluoro- 4'2 ", 5 "-dihydro -1 " (- pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 34

(5R)-[N-3-'3' is apt to 4'-'2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 35

(5S)-[N-3 (3' kind 4<2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl chloride acetamide compound 36

(5S)-[N-3 3'- fluoro- 4'1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 37

(5R)-[N-3-'3' is apt to 4'-' Γ-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide Compound 38

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 39

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and phenyl) -2- oxo -5- oxazoles alkyl] methyl chloride acetamide compound 40

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl）- 2- oxo -5- oxazoles alkyl] carbinol compound 41

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 42

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 43

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylamine

Compound 44

(5RMN-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 45

(the fluoro- 4'- of 5RMN-3- 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl 2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 46

(the fluoro- 4'- of 5SMN-3-C3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 47

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl）- 2- oxo -5- oxazoles alkyl] methylamine compound 48

(5S)-[N-3- (the fluoro- 4'- of 3'- (Γ ' (Η)-pyrrole radicals) phenyl）- 2- oxo -5- oxazoles alkyl] methylamine

Compound 49

(5R)-[N-3- (the fluoro- 4'- of 3'- (Γ (Η)-mouth ratio coughs up base) phenyl）- 2- oxo -5- oxazoles alkyl] methanol

Compound 50

(5R)-[N-3- (the fluoro- 4'- of 3'- (Γ ' (Η)-Β ratios cough up base) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 51

(5S)-[N-3- (the fluoro- 4'- of 3'- (Γ ' (Η)-pyrrole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 52

(5S)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 53

(5S)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl）5- oxazoles alkyl] methylamine Compound 54

(5R)-[N-3-'3 '-fluoro- 4'- (3 "-methyl -1 " (H)-B are than oxazolyl) phenyl）- 2- oxo -5- oxazoles alkyl] methanol

Compound 55

(5R)-[the fluoro- 4'- of N-3-'3'- (3 "-methyl-Γ ' (Η)-Β is than oxazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 56

(5R)-[the fluoro- 4'- of N-3-'3'- (2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 57

(5S)-[the fluoro- 4'- of N-3 3'- (2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] methylamine compound 58

(5R)-[the fluoro- 4'- of N-3-'3'- (2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 59

(5S)-[the fluoro- 4'- of N-3 3'- (2 ", 5 "-dihydro-Γ ' (Η)-Β ratios cough up base)-phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 60

(5R)-[the fluoro- 4'- of N-3-'3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methanol

Compound 61

(5S)-[the fluoro- 4'- of N-3 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylamine

Compound 62

(5R)-[the fluoro- 4'- of N-3-'3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 63

(5S)-[the fluoro- 4'- of N-3 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 64

(5R)-[the fluoro- 4'- of N-3-'3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and-phenyl）- 2- oxo -5- oxazoles alkyl] carbinol compound 65

(5S)-[the fluoro- 4'- of N-3- 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and-phenyl）- 2- oxo -5- oxazoles alkyl] methylamine compound 66

(5S)-[the fluoro- 4'- of N-3- 3'- (1 ", 3 ", 4 "-thiadiazoles -2- " sulfenyls) and-phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 67

(5R)-[the fluoro- 4'- of N-3-'3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 68

(5R)-[N-3-'3'- fluoro- 4'-G "-piperidyls) phenyl) -2- oxo -5- oxazoles alkyl] methanol

Compound 69

(5S)-[the fluoro- 4'- of N-3 3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl) methylamine

Compound 70

(5R)-[the fluoro- 4'- of N-3-'3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester Compound 71

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 72

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 73

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] methylamine compound 74

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 75

(58)-^-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 76

(5SMN-3- acetyl group -2- oxo -5- oxazoles alkyl) methylacetamide

Compound 77

(5S, 2'R)-[N-3- (2'- phenyl-Γ-piperidyl) 2- oxo -5- oxazoles alkyl] methylacetamide

Compound 78

(5S, 2'S)-[N-3- (2'- phenyl-Γ-piperidyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 79

(5S)-[N-3- (2'- hydroxyl -4'- pyrimidine radicals) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 80

(5S)-[N-3- (2'- acetyl group epoxide -4'- pyrimidine radicals) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 81

(5S)-[N-3- (4'- oxazolyls) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 82

(_5S)-[_N- 3- (the chloro- 4'- cyano group -2'- pyridines of 6'-) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 83

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 84

(5R)-[the fluoro- 4'- morpholinyls of N-3- 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl p-methyl benzenesulfonic acid ester

Compound 85

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl acetic acid ester

Compound 86

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylimidazole

Compound 87

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl -2- sulfenyls -1,3,4 thiadiazole compounds 88 (5R)-[N-3- (3,-fluoro- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 89

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid H- tetrazotized zole compounds 90

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide compound 91

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylsulfany tetrazotized zole compound 92

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalyl base group with imine moiety 93

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl -2- sulfenyls benzimidazole compound 94

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide compound 95

(5R)-[N-3- (the fluoro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl benzotriazazole compound 96

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methanol

Compound 97

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 98

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 99

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 100

(5R)-[N-3- (4,-morpholinyl) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 101

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide

Compound 102

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 103

5SMN-3-C3 '-chloro- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methanol

Compound 104

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 105

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 106 (5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl vinyl amines 107

(5S)-[N-3- (3,-chloro- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 108

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide

Compound 109

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 110

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methanol

Compound 111

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 112

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 113

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 114

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 115

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide compound 116

(5S)-[N-3- (3'_ trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide compound 117

(the fluoro- 4'- of 5RMN-3- 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methanol

Compound 118

(5R)-[N-3- 3 '-fluoro- 4'- (4 "-Phenylpiperazinyl) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 119

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 120

(5R)-[N-3- (3,-fluoro- 4'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 121

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl 2- oxo -5- oxazoles alkyl] methyl camphorimide compound 122

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide compound 123

(the fluoro- 4'- of 5SMN-3-C3'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 124 (5S)-[N-3- (the fluoro- 4'(4 of 3'- "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate is cruel

Compound 125

(5S)-[N-3- (3-fluoro- 4'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl)-2- oxo-5- oxazoles alkyl] methyl phthalimide

Compound 126

(5S)-[N-3- (3-fluorine-4'- (4 "-(4' "-methoxyphenyl) piperazinyl) phenyl)-2- oxo-5- oxazoles alkyl] methyl isophthalic acid, 2,4- 1H- triazoles

Compound 127

(5S)-[N-3- (3-fluoro- 4'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl)-2- oxo-5- oxazoles alkyl] methyl camphorimide

Compound 128

(5S)-[N-3- (3-fluoro- 4'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl)-2- oxo-5- oxazoles alkyl] methyl succimide

Compound 129

(5S)-[N-3- (3-fluoro- 4'- (4 "-benzyl piepridine base) phenyl)-2- oxo-5- oxazoles alkyl] methanol

Compound 130

(5S)-[N-3- (3-fluoro- 4'- (4 "-benzyl piepridine base) phenyl)-2- oxo-5- oxazoles alkyl] methylmethanesulfonate ester compounds 131

(5S)-[N-3- (3-fluoro- 4'- (4 "-benzyl piepridine base) phenyl)-2- oxo-5- oxazoles alkyl] methyl phthalimide compound 132

(5S)-[N-3- (3-fluoro- 4'- (4 "-benzyl piepridine base) phenyl)-2- oxo-5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- compounds 133

(5S)-[N-3- (3-fluoro- 4'- (4 "-benzyl piepridine base) phenyl)-2- oxo-5- oxazoles alkyl] methyl camphorimide compound 134

(5S)-[N-3- (3-fluoro- 4'- (4 "-benzyl piepridine base) phenyl)-2- oxo-5- oxazoles alkyl] methyl succimide compound 135

(5R)-[N-3- (the fluoro- 4'- piperidinophenyls of 3'-) -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- compounds 136

(5R)-[N-3- (the fluoro- 4'- piperidinophenyls 2- oxos -5- oxazoles alkyl of 3'-] methyl camphorimide

Compound 137

(5R)-[N-3- (the fluoro- 4'- piperidinophenyls of 3'-) -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 138

(5S)-[N-3- (3'- fluoro- 4 (2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methyl chloroacetamide

Compound 139 (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide semihydrate compound 140

The hydrate compound 141 of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 2/7

The hydrate compound 142 of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 2/5

The hydrate compound 143 of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 1/12

The hydrate of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 3/4.

Compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that formula I of the present invention is represented, can be used alone or be used in any combination.

Heretofore described micobacterial conditions are the infectious diseases caused by mycobacteria infections human body or animal body, including but not limited to tuberculosis, leprosy.The mycobacterium is bird type Mycobacterium tuberculosis, Mycobacterium tuberculosis var.bovis, Mycobacterium butyricum, mycobacterium chelonei, Mycobacterium lacticola, mycobacterium friedmannii, mycobacterium graminis, johne's bacillus, Mycobacterium lacticola, hansen's bacillus, mycobacterium marinum, johne's bacillus, mycobacterium graminis, bacillus tuberculosis piscium, mycobacterium ranae, mycobacterium rhusiopathiae, smegma bacillus, mycobacterium stercoris, mycobacterium thamnopheos or Mycobacterium tuberculosis.

The invention provides the purposes of the formula I compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug in preparing prevention or treating medicament lungy.With the compound of the present invention suppress tuberculosis bacterium is including but not limited to human-like, ox type, bird type, African type tubercle bacillus and paratuberculosis bacillus.The compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that described formula I is represented can also be used to prevent or treat to include mixed infection caused by different types of tubercle bacillus.

Include primary pulmonary tuberculosis, hematogenous pulmonary tuberculosis, secondary tuberculosis of lung, tuberculous pleurisy, tuberculous osteoarthropathy, tubercular meningitis, nephrophthisis, intestinal tuberculosis with the tuberculosis of active constituents of medicine prevention or the treatment of the present invention.

In the present invention, method of the treatment with mycobacteria infections individual is included at least one formula I that the individual applies therapeutically effective amount compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug.

In addition, method of the treatment with mycobacteria infections individual is included to the formula I for the patient therapeuticallv's effective dose for needing the to treat compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug or any combination for applying the compound.

In the present invention, method of the treatment with mycobacteria infections individual includes the pharmaceutical composition that the compounds that represent of formula I or its pharmaceutically acceptable salt, hydrate, solvate, complex or the prodrug of therapeutically effective amount are applied to the individual, and the pharmaceutical composition includes：

Compound or any combination of its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug or at least one compound that formula I is represented, and medicinal adjuvant, for example, at least a kind of pharmaceutically acceptable excipient. The compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that described formula I is represented reach that the effective dose of expected biological effect is likely to be dependent on multinomial factor, as expected purposes, mode of administration and the clinic of patient.

The medicine of the present invention can be by oral administration or parenteral any formulation such as injection, respiratory tract administration, percutaneous drug delivery, mucosa delivery etc..From the point of view of patient's use is facilitated, the medicine is oral agents, such as tablet, capsule, dry suspensoid agent, or injection.

When for preventing tuberculosis, the common dosage of medicine of the invention is 0.01-2000mg/ days；Daily dosage is divided into multiple dosing.Such as daily dosage can be 0.01-1800mg, or 0.1-1500mg, or l-1200mg, and in two times, three times or four administrations.Dosage can be adjusted according to concrete conditions such as the state of an illness of patient, sex, age and body weight when for preventing tuberculosis.

In the present invention, the compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that described formula I is represented can be prepared into slow release, controlled release, sustained release, pulse release and sustained release forms for the pharmaceutical composition of active component.

In the present invention, for treatment lungy, the compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that the formula I is represented can be used with compound form, can also be used with the form of medicinal adjuvant such as pharmaceutically acceptable carrier composition pharmaceutical composition.The carrier should meet compatibility test and harmless to patient health with the other compositions of composition.The carrier can be the combination of solid or liquid or both, and single formulation can be prepared into the described formula I compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug, for example, the tablet that 0.05 % to 100% is calculated as with the formula I compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug weight can be prepared into.

Described pharmaceutical composition should have at least one active component, including the described formula I compounds represented or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug or its any combination.Described pharmaceutical composition can be prepared by known method, such as mix active component with pharmaceutically acceptable carrier and/or excipient medicinal adjuvant.

In the present invention, the excipient includes but is not limited to：Microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium monohydrogen phosphate, glycine, disintegrant (such as starch, Ac-Di-Sol, composition silicate and macromolecule polyethylene glycol), Granulating Bonding Agent (such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum) and lubricant (such as magnesium stearate, glycerine and talcum powder).

In the present invention, the compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that described at least one formula I is represented can be also combined with sweetener, flavouring, pigment, dyestuff or emulsifying agent and its mixture.

The compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that the formula I of the present invention is represented can also be applied in combination with other antituberculotics such as isoniazid, rifampin.

The present invention is further illustrated below by experiment and embodiment.

As the active component for being used to preventing or treating tuberculosis composition of the present invention, the part of compounds in the compound that formula I of the present invention is represented is listed in following table 1： Compound table

R R2 R: R4 R:

、 F

21

 

Embodiment 1

The preparation of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -2 "-hexahydropyrimidines) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide (compound 6)：

1st, the first step

At room temperature, 4- (4' are added into reaction bulb, 6'- dimethoxy -2'- hexahydropyrimidines) -3- fluoroanilines 25.5g, tetrahydrofuran 400ml, stirring addition lmol/L sodium hydrate aqueous solution 110ml, pH is between 7.5-8.5 for regulation, benzyl chloroformate 15ml (18.7g) is added dropwise, stirring reaction 20 minutes, after completion of the reaction, adds 1000ml water, separate out material, suction filtration is dried for the next step.

2nd, second step

Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, power mouthful 2.5M butyl lithium 37ml hexane solutions are dripped, R- Shrink water glycerol butyrate 13.6g (98%) are then added dropwise, drop keeps -70 °C of low temperature to stir 1 hour after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, in -0.08MPa, 60 °C of evaporated mother liquors are to doing, and obtained solid is used for the next step.

3rd, the 3rd step

At room temperature, dichloromethane 200ml and second step reaction product 15g is added into reaction bulb, stirring, ice-water bath is cooled to 0 °C, and 5g triethylamines and 5g methylsufonyl chlorides are added dropwise successively.Reaction 2 hours.Suction filtration, mother liquor is in -0.08MPa, and 60 °C of distillations are to doing, and obtained solid is used for the next step.

4th, the 4th step

10g three-step reactions product and 150ml DMF are added in reaction bulb, 80 °C are warming up to, 3.7g Anhydrous potassium carbonates and 3g potassium phthalimides is added.Reaction 16 hours, after the completion of, suction filtration, evaporated mother liquor is to dry（- 0.08MPa, 80 °C), obtained solid is used for the next step.

5th, the 5th step

500ml absolute ethyl alcohols and 5g four-step reaction products are added in reaction bulb, is stirred at reflux.500ml methylamine water solutions (25%) are heated, are passed through after vapor (steam) velocity is stable in reaction bulb, are kept for 5 hours, stop continuing to stir 1 hour after ventilation, suction filtration, dense Shrink mother liquors are distilled to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, the solid that suction filtration is obtained is used for the next step.

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, 0.7g triethylamines and 0.6g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, steam Liu Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product lg, total recovery 2.5%.Embodiment 2

(5S)-[N-3- (3 '-fluoro- 4'- (4 "-oxo -2 "-Chromanyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound

13) preparation

1st, the first step

At room temperature, 2- (4'- amino -2'- fluorophenyls) chroman-4-on 26g, tetrahydrofuran 400ml is added into reaction bulb, stirring adds lmol/L sodium hydrate aqueous solution 110ml, pH is adjusted between 7.5-8.5, benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes is added dropwise, after completion of the reaction, 1000ml water is added, separates out material, suction filtration is dried for the next step.

2nd, second step

Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, drip power mouthful 2.5M butyl lithium 37ml hexane solutions, then R- Shrink water glycerol butyrate 13.6g (98%) are added dropwise, drop keeps the stirring 1 hour of -70 °C of low temperature after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, evaporated mother liquor is to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

3rd, the 3rd step

At room temperature, dichloromethane 200ml and second step reaction product 15g is added into reaction bulb, stirring, ice-water bath is cooled to 0 °C, and 5g triethylamines and 5g methylsufonyl chlorides are added dropwise successively.Reaction 2 hours.Suction filtration, mother liquor is distilled to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

4th, the 4th step

5th, the 5th step

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, 0.7g triethylamines and 0.6g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, distillation Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product 0.8g, total recovery 2.0%.Embodiment 3 (5S)-[N-3- (the fluoro- 4'- of 3'- (5 "-fluoro- 4 "-oxo -1 ", 2 ", 3 ", 4 "-tetrahydrochysene -2 "-quinolyls) and phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 14) preparation

1st, the first step

At room temperature, 2- (4'- amino -2'- fluorophenyls) -5- fluoro- 2 is added into reaction bulb, (1H) -one of 3- EEDQs -4 28g, tetrahydrofuran 400ml, stirring add lmol/L sodium hydrate aqueous solution 120ml, and pH is between 7.5-8.5 for regulation, benzyl chloroformate 16ml (18.7g) is added dropwise, stirring reaction 20 minutes, after completion of the reaction, adds 1000ml water, separate out material, suction filtration is dried for the next step.

2nd, second step

Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, 2.5M butyl lithium 36ml hexane solutions are added dropwise, then R- Shrink water glycerol butyrate 13.4g (98%) are added dropwise, drop keeps the stirring 1 hour of -70 °C of low temperature after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, evaporated mother liquor is to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

3rd, the 3rd step

At room temperature, dichloromethane 200ml and second step reaction product 15g is added into reaction bulb, stirring, ice-water bath is cooled to 0 °C, and 5g triethylamines and 4.5g methylsufonyl chlorides are added dropwise successively.Reaction 2 hours.Suction filtration, mother liquor is distilled to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

4th, the 4th step

10g three-step reactions product and 150ml DMF are added in reaction bulb, 80 °C are warming up to, 3.5g Anhydrous potassium carbonates and 3g potassium phthalimides is added.Reaction 16 hours, after the completion of, suction filtration, evaporated mother liquor is to dry（- 0.08MPa, 80 °C), obtained solid is used for the next step.

5th, the 5th step

500ml absolute ethyl alcohols and 5g four-step reaction products are added in reaction bulb, is stirred at reflux.Heat in 500ml methylamine water solutions (25%), the reaction bulb being passed through after vapor (steam) velocity is stable, kept for 5 hours, stop continuing to stir 1 hour after ventilation, suction filtration, distill dense Shrink mother liquors to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, the solid that suction filtration is obtained is used for the next step.

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, 0.7g triethylamines and 0.6g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, distillation Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product 1.2g, total recovery 2.9%.Embodiment 4

(5S)-[N-3- (3'- fluoro- 4'- (benzofuranyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 15) preparation

1st, the first step At room temperature, 4- (benzofuran -2'- bases) -3- fluoroanilines 23.0g, tetrahydrofuran 400ml is added into reaction bulb, stirring adds lmol/L sodium hydrate aqueous solution 110ml, pH is adjusted between 7.5-8.5, benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes is added dropwise, after completion of the reaction, 1000ml water is added, separates out material, suction filtration is dried for the next step.

2nd, second step

Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, drip power mouthful 2.5M butyl lithium 40ml hexane solutions, then R- Shrink water glycerol butyrate 14.0g (98%) are added dropwise, drop keeps the stirring 1 hour of -70 °C of low temperature after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, evaporated mother liquor is to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

3rd, the 3rd step

At room temperature, dichloromethane 200ml and second step reaction product 15g is added into reaction bulb, stirring, ice-water bath is cooled to 0 °C, and 6g triethylamines and 5.5g methylsufonyl chlorides are added dropwise successively.Reaction 2 hours.Suction filtration, mother liquor is distilled to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

4th, the 4th step

10g three-step reactions product and 150ml DMF are added in reaction bulb, 80 °C are warming up to, 4.0g Anhydrous potassium carbonates and 3.6g potassium phthalimides is added.Reaction 16 hours, after the completion of, suction filtration, evaporated mother liquor is to dry（- 0.08MPa, 80 °C), obtained solid is used for the next step.

5th, the 5th step

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, l .Og triethylamines and 0.8g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, distillation Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product 0.7g, total recovery 1.9%.Embodiment 5

(5S)-[N-3- (3 ' _ fluoro- 4'- (4 "-(3 " '-chlorine propiono) -1 "-piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 16) preparation

1st, the first step

At room temperature, 1- (4'- (4 "-amino -2 "-fluorophenyl) -1 '-piperazinyl) -3- chlorine propyl- 1- ketone 29g, tetrahydrofuran 400ml is added into reaction bulb, stirring adds lmol/L sodium hydrate aqueous solution 110ml, pH is adjusted between 7.5-8.5, benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes is added dropwise, after completion of the reaction, 1000ml water is added, separates out material, suction filtration is dried for the next step. 2nd, second step

Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, 2.5M butyl lithium 35ml hexane solutions are added dropwise, then R- Shrink water glycerol butyrate 13.2g (98%) are added dropwise, drop keeps the stirring 1 hour of -70 °C of low temperature after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, evaporated mother liquor is to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

3rd, the 3rd step

At room temperature, dichloromethane 200ml and second step reaction product 15g is added into reaction bulb, stirring, ice-water bath is cooled to 0 °C, and 4.8g triethylamines and 4.5g methylsufonyl chlorides are added dropwise successively.Reaction 2 hours.Suction filtration, mother liquor is distilled to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

4th, the 4th step

10g three-step reactions product and 150ml DMF are added in reaction bulb, 80 °C are warming up to, 3.4g Anhydrous potassium carbonates and 2.8g potassium phthalimides is added.Reaction 16 hours, after the completion of, suction filtration, evaporated mother liquor is to dry（- 0.08MPa, 80 °C), obtained solid is used for the next step.

5th, the 5th step

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, 0.6g triethylamines and 0.5g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, distillation Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product 1.4g, total recovery 3.2%.Embodiment 6

(S)-[N-3- (3', 5,-two fluoro- 4'- (1 "-methyl -5 ", 6 "-dihydros -1 ", 2 ", 4 "-triazine) -4 (1H)-yls) phenyl) -5 Evil oxazolidinyls of -2- oxos] methylacetamide (compound 2) preparation

The first step：The fluoro- 4- of 3,5- bis- (1 '-methyl -5', 6'- dihydro -1 ', 2', 4'- triazines -4'(1H)-yl is added into reaction bulb) hexamethylene -

Stirred under the g of 2,4- bis- enamine 23, acetone 400ml, normal temperature, after solids is completely dissolved, is placed in low-temperature cooling fluid circulating pump and is cooled to 0 °C, stirring adds saturation NaHCO^ solution 100ml and (contains NaHCO₃10g), 0 °C is added dropwise benzyl chloroformate 20g, and 0.5h is dripped off, and keeps 0 °C of reaction 30min, takes out stirring at normal temperature and stay overnight.

Next day, reaction is finished, suction filtration, and obtained solids is added in reaction bulb, add 100ml acetonitrile refinings, oil bath heating, condensing reflux, after dissolved clarification, add suitable quantity of water to a small amount of solids and separate out, liquid is poured into beaker is put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solids is washed with water 3 times.Solid is added in reaction bulb, carries out secondary recrystallization：Add after acetonitrile refining, oil bath heating, condensing reflux, dissolved clarification, add suitable quantity of water to a small amount of solids and separate out, pour into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, is dried in vacuo after solid washing, for the next step. Second step：500mlTHF is added in distillation reaction bottle, stirring, be passed through nitrogen protection, export tail gas, tail gas does bubbling with the conical flask equipped with atoleine and shown, oil bath heating, if outer 95 °C of the temperature of oil bath, condensing reflux.THF is collected after adding 5g LiAlH4 powder, timing stirring dehydration lh, front-end volatiles are discarded about（50ml) .

Under nitrogen replacement environment, dried first step reaction product 20g is added in reaction bulb, the treated anhydrous THF of 400ml is added, -70 °C is cooled to the mixture of dry ice and acetone.When as little as -68 °C of interior temperature start that butyl lithium 26ml is added dropwise, temperature is below -65 °C in control, drop finishes, (less than -68 °C) reaction 1.5h of low temperature, then be added dropwise warm below -65 °C in R- Shrink water glycerine butyl ester 9.5g, control, drop finishes, (less than -68 °C) reaction 0.5h of low temperature, take out, stirring at normal temperature reaction is stayed overnight.

Next day, use saturation NH₄C1 aqueous solution 100ml washing reaction liquids 1 time, saturation NaCl aqueous solution washing reaction liquid 3 times（Each 100ml).Separate and collect upper organic phase, vacuum distillation（- 0.08MPa, 60 °C) to a certain amount of, pour into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solids is added in reaction bulb, is added lOOmlTHF and is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization in refrigerator-freezer.Suction filtration, solid vacuum drying.For the next step.

3rd step：15g second steps reaction product and 200ml dichloromethane are added in reaction bulb, is placed in low-temperature cooling fluid circulating pump and is cooled to -8 °C, good and sound device, stirring.Triethylamine 7g is added during 0 °C of interior temperature, Nei Wen -5 °C of dropwise addition 6g methane sulfonyl chlorides, interior temperature control system reacts 0.5h, taking-up normal-temperature reaction 2h less than 0 °C.

Reaction is finished, and uses saturation NaHC0₃Solution 80ml is washed 1 time, water（100ml) wash 3 times, point liquid, organic layer adds and 2h is dried in the conical flask equipped with anhydrous MgS04, suction filtration, vacuum distillation filtrate is to dry（- 0.08MPa, 60 °C), obtained solids is added in reaction bulb, 100ml acetonitrile refinings are added：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solid is washed 3 times, vacuum drying.For the next step.

4th step：10g three-step reactions product, 150mlDMF are added in reaction bulb, good and sound device, stirring sequentially adds 3.6g phthalimides, 4g anhydrous Ks₂C0₃, oil bath heating, if outer 82 °C of the temperature of oil bath, stirring reaction is stayed overnight.

Next day, suction filtration, vacuum distillation filtrate（- 0.08MPa, 80 °C) to a certain amount of, pour into the saturation NaCl aqueous solution

Stirring, which is separated out, in 300ml cools down 30min in white solid thing, refrigerator-freezer, take out suction filtration, solid washes 3 times (100ml).

Solids is added in reaction bulb, is added 150mlDMF and is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization 2h in refrigerator-freezer, suction filtration.By obtained solid same operation method secondary recrystallization.Suction filtration, is dried in vacuo after the washing of gained solid.For the next step.

5th step：5g four-step reactions product, 500ml absolute ethyl alcohols are added in reaction bulb, good and sound device, stirring.Oil bath heating, if outer 82 °C of the temperature of oil bath, condensing reflux.

The methylamine water solutions of 500ml 40% are added in stand up reaction bottle, are installed in water-bath, if 48 °C of bath temperature.Methylamine gas is produced through Drexel bottle（The concentrated sulfuric acid）It is passed through in reaction bulb, clock reaction 5.5h.

Stop logical methylamine gas, continue stirring reaction 2h.Reaction is finished, suction filtration, and filtrate, which is poured into beaker, to be put into cooling crystallization in refrigerator-freezer and stay overnight. Next day suction filtration, obtained solids is added in reaction bulb, is added 100ml ethyl acetate and is refined：Oil bath heats up, condensing reflux, and adding appropriate DMF makes after the complete dissolved clarification of solid, is then added dropwise to a small amount of water, when having a small amount of solid to separate out, liquid is poured into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.By obtained solid same operation method secondary recrystallization.Suction filtration, is dried in vacuo after washing.For the next step.

6th step：The step reaction products of 2g the 5th, 100ml THF are added in reaction bulb, are installed in low-temperature cooling fluid circulating pump, stirring is cooled to -8 °C.Interior 0 °C of addition lg triethylamine of temperature, Nei Wen -5 °C of dropwise addition 0.7g acetic anhydrides, interior temperature control system is below -5 °C, and drop finishes, -5 °C of reaction 0.5h, takes out, normal-temperature reaction 2h.

Reaction is finished, suction filtration, and solids is refined with 40ml absolute ethyl alcohols and 60ml ethyl acetate mixtures：Oil bath heats up, condensing reflux, after dissolved clarification, pours into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Use same operation method, secondary recrystallization, vacuum drying.Obtain solid product lg.The embodiment 7 of yield 2.7%

N- [(S) -3- (the fluoro- 4'- of 3'- (2 "-chloromethyl -1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 3) preparation

The first step：4- (2'- (chloromethyl Γ-piperidyl) -3- fluoroanilines 24.2g, acetone 400ml is added into reaction bulb, stirred under normal temperature, after solids is completely dissolved, is placed in low-temperature cooling fluid circulating pump and is cooled to o ° of c, stirring, adds saturation

NaHC0₃Aqueous solution 100ml (contains NaHCO₃10g), 0 °C of dropwise addition benzyl chloroformate 20g, keeps 0 °C of reaction

30min, takes out stirring at normal temperature and stays overnight.

Next day, reaction is finished, suction filtration, and obtained solids is added in reaction bulb, add 100ml acetonitrile refinings, oil bath heating, condensing reflux, after dissolved clarification, add suitable quantity of water to a small amount of solids and separate out, liquid is poured into beaker is put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solids is washed with water 3 times.Solid is added in reaction bulb, carries out secondary recrystallization：Add after acetonitrile refining, oil bath heating, condensing reflux, dissolved clarification, add suitable quantity of water to a small amount of solids and separate out, pour into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, is dried in vacuo after solid washing, for the next step.

Second step：500ml THF are added in distillation reaction bottle, stirring, be passed through nitrogen protection, export tail gas, tail gas does bubbling with the conical flask equipped with atoleine and shown, oil bath heating, if outer 95 °C of the temperature of oil bath, condensing reflux.Add 5g

THF is collected after LiAlH4 powder, timing stirring dehydration lh, front-end volatiles are discarded about（50ml) .

Under nitrogen replacement environment, dried first step reaction product 20g is added in reaction bulb, the treated anhydrous THF of 400ml is added, -70 °C is cooled to the mixture of dry ice and acetone.When as little as -68 °C of interior temperature start that butyl lithium is added dropwise

25ml hexane solutions, temperature is below -65 °C in control, drop finishes, (less than -68 °C) reaction 1.5h of low temperature, then be added dropwise warm below -65 °C in R- Shrink water glycerine butyl ester 9.2g, control, drop finishes, (less than -68 °C) reaction 0.5h of low temperature, take out, stirring at normal temperature reaction is stayed overnight.

Next day, use saturation NH₄C1 aqueous solution 100ml washing reaction liquids 1 time, saturation NaCl aqueous solution washing reaction liquid 3 times（Each 100ml).Separate and collect upper organic phase, vacuum distillation（- 0.08MPa, 60 °C) to a certain amount of, pour into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solids is added in reaction bulb, is added lOOmlTHF and is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization in refrigerator-freezer.Suction filtration, solid vacuum drying.For the next step. 3rd step：15g second steps reaction product and 200ml dichloromethane are added in reaction bulb, is placed in low-temperature cooling fluid circulating pump and is cooled to -8 °C, good and sound device, stirring.Triethylamine 7g is added during 0 °C of interior temperature, Nei Wen -5 °C of dropwise addition 5.8g methane sulfonyl chlorides, interior temperature control system reacts 0.5h, taking-up normal-temperature reaction 2h less than 0 °C.

4th step：10g three-step reactions product, 150mlDMF are added in reaction bulb, good and sound device, stirring sequentially adds 3.5g phthalimides, 3.8g anhydrous Ks₂C0₃, oil bath heating, if outer 82 °C of the temperature of oil bath, stirring reaction is stayed overnight.

Next day, suction filtration, vacuum distillation filtrate（- 0.08MPa, 80 °C) to a certain amount of, pour into saturation NaCl aqueous solution 300ml and cool down 30min in stirring precipitation white solid thing, refrigerator-freezer, take out suction filtration, solid washes 3 times (100ml).

Solids is added in reaction bulb, is added 150ml DMF and is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization 2h in refrigerator-freezer, suction filtration.By obtained solid same operation method secondary recrystallization.Suction filtration, is dried in vacuo after the washing of gained solid.For the next step.

Stop logical methylamine gas, continue stirring reaction 2h.Reaction is finished, suction filtration, and filtrate, which is poured into beaker, to be put into cooling crystallization in refrigerator-freezer and stay overnight.

Next day suction filtration, obtained solids is added in reaction bulb, is added 100ml ethyl acetate and is refined：Oil bath heats up, condensing reflux, and adding appropriate DMF makes after the complete dissolved clarification of solid, is then added dropwise to a small amount of water, when having a small amount of solid to separate out, liquid is poured into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.By obtained solid same operation method secondary recrystallization.Suction filtration, is dried in vacuo after washing.For the next step.

6th step：The step reaction products of 2g the 5th, 100ml THF are added in reaction bulb, are installed in low-temperature cooling fluid circulating pump, stirring is cooled to -8 °C.Interior 0 °C of addition lg triethylamine of temperature, Nei Wen -5 °C of dropwise addition 0.6g acetic anhydrides, interior temperature control system is below -5 °C, and drop finishes, -5 °C of reaction 0.5h, takes out, normal-temperature reaction 2h.

Reaction is finished, suction filtration, and solids is refined with 40ml absolute ethyl alcohols and 60ml ethyl acetate mixtures：Oil bath heats up, condensing reflux, after dissolved clarification, pours into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Use same operation method, secondary recrystallization, vacuum drying.Obtain solid product lg.Yield 2.5%.Embodiment 8

(5S)-[N-3- (3,-fluoro- 4'- (6 "-chloro- 4 "-cyano group -2 "-pyridine) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Chemical combination Thing 10) preparation

The first step：4- (the chloro- 4'- isocyano groups -2'- pyridine radicals of 6'-) -3- fluoroanilines 25g, acetone 400ml is added into reaction bulb, stirred under normal temperature, after solids is completely dissolved, is placed in low-temperature cooling fluid circulating pump and is cooled to 0 °C, stirring, adds saturation NaHC0₃Aqueous solution 100ml (contains NaHCO₃10g), 0 °C is added dropwise benzyl chloroformate 20g, and 0.5h is dripped off, and keeps 0 °C of reaction 30min, takes out stirring at normal temperature and stay overnight.

Second step：500ml THF are added in distillation reaction bottle, stirring, be passed through nitrogen protection, export tail gas, tail gas does bubbling with the conical flask equipped with atoleine and shown, oil bath heating, if outer 95 °C of the temperature of oil bath, condensing reflux.THF is collected after adding 5g LiAlH4 powder, timing stirring dehydration lh, front-end volatiles are discarded about（50ml) .

Under nitrogen replacement environment, dried first step reaction product 20g is added in reaction bulb, the treated anhydrous THF of 400ml is added, -70 °C is cooled to the mixture of dry ice and acetone.When as little as -68 °C of interior temperature start that butyl lithium 25ml is added dropwise, temperature is below -65 °C in control, drop finishes, (less than -68 °C) reaction 1.5h of low temperature, then be added dropwise warm below -65 °C in the g of R- Shrink water glycerine butyl ester 9, control, drop finishes, (less than -68 °C) reaction 0.5h of low temperature, take out, stirring at normal temperature reaction is stayed overnight.

Next day, use saturation NH₄C1 aqueous solution 100ml washing reaction liquids 1 time, saturation NaCl aqueous solution washing reaction liquid 3 times（Each 100ml).Separate and collect upper organic phase, vacuum distillation（- 0.08MPa, 60 °C) to a certain amount of, pour into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solids is added in reaction bulb, is added 100ml THF and is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization in refrigerator-freezer.Suction filtration, solid vacuum drying.For the next step.

3rd step：15g second steps reaction product and 200ml dichloromethane are added in reaction bulb, is placed in low-temperature cooling fluid circulating pump and is cooled to -8 °C, good and sound device, stirring.Triethylamine 6.5g is added during 0 °C of interior temperature, Nei Wen -5 °C of dropwise addition 5.6g methane sulfonyl chlorides, interior temperature control system reacts 0.5h, taking-up normal-temperature reaction 2h less than 0 °C.

4th step：10g three-step reactions product, 150ml DMF are added in reaction bulb, good and sound device, stirring sequentially adds 3.4g phthalimides, 3.6g anhydrous Ks₂C0₃, oil bath heating, if outer 82 °C of the temperature of oil bath, stirring reaction is stayed overnight.

Stirring, which is separated out, in 300ml cools down 30min in white solid thing, refrigerator-freezer, take out suction filtration, solid is washed 3 times ( 100ml) 。

6th step：The step reaction products of 2g the 5th, 100ml THF are added in reaction bulb, are installed in low-temperature cooling fluid circulating pump, stirring is cooled to -8 °C.Interior 0 °C of addition 0.8g triethylamine of temperature, Nei Wen -5 °C of dropwise addition 0.6g acetic anhydrides, interior temperature control system is below -5 °C, and drop finishes, -5 °C of reaction 0.5h, takes out, normal-temperature reaction 2h.

Reaction is finished, suction filtration, and solids is refined with 40ml absolute ethyl alcohols and 60ml ethyl acetate mixtures：Oil bath heats up, condensing reflux, after dissolved clarification, pours into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Use same operation method, secondary recrystallization, vacuum drying.Obtain solid product 1.2g, yield 3.1%.Embodiment 9

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide (compound 12) preparation

(1) preparation of the fluoro- 4- of 3- (4'- Phenylpiperazinyls) nitrobenzene

50ml ethyl acetate, 13.5ml 4- phenylpiperazines and 15.30ml diisopropyl ethyl amines are added in 250ml there-necked flasks.Magnetic agitation, adds 9.0ml 3,4- difluoro nitrobenzenes at room temperature.Reaction solution is poured into water by reaction after 105 hours, after ethyl acetate (150mlx3) is extracted 3 times, extract saturated nacl aqueous solution (150ml><3) wash 3 times, anhydrous magnesium sulfate (MgS0₄) dry, it is evaporated.Obtain orange/yellow solid.Acetone:Water (volume ratio 9:1) recrystallize, obtain orange-yellow crystal (23.66g), the % of yield 96.33.

(2) preparation of the fluoro- 4- of 3- (4'- Phenylpiperazinyls) aniline

6.69 g (119 mmol) reduced iron powder, 23.57 ml water and 1.11 ml glacial acetic acid are added in 500 ml there-necked flasks and flowed back 80 minutes.Step C1 is slowly added dropwise) obtained fluoro- 4-C4'- Phenylpiperazinyls of 3-) nitrobenzene (12.0 g, 39.82 mmol) the ml of ethanol solution 150.Completion of dropping, then react 10 minutes, suction filtration, boil off ethanol, ethyl acetate dissolving.Filter cake is washed with ethyl acetate 3 times.Merge organic phase, wash 3 times, saturation NaCl solution is washed 1 time, anhydrous magnesium sulfate (MgS0₄) dry, it is evaporated.Shallow white solid is obtained, the next step is directly used in. (3) preparation of the fluoro- 4- of N- benzyloxycarbonyl groups -3- (4'- Phenylpiperazinyls) aniline

The fluoro- 4- of 3- (4'- Phenylpiperazinyls) the aniline crude products 13.0g that 100 ml dichloromethane and step (2) are obtained is added in 250 ml four-hole bottles, and 7.91ml diisopropyl ethyl amines are added under 0 °C.Mechanical agitation, is added dropwise 5.34ml benzyl chloroformates.Resulting solution is stirred at room temperature 16 hours, and dichloromethane (100 mlx3) is extracted 3 times, and saturated nacl aqueous solution (100 mlx3) is washed 3 times, and anhydrous magnesium sulfate is dried, and is evaporated.Obtain shallow white solid.Acetone:Water（Volume ratio 7:3) recrystallize.Obtain 11.46g white crystals, the % of yield 76.66.

(4) preparation of (R)-[the fluoro- 4'- of N-3-C3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methanol

The g of N- benzyloxycarbonyl groups -3- fluoro- 4- (4'- Phenylpiperazinyls) aniline 3.4, the ml of anhydrous tetrahydro furan 50 that step (3) is obtained are added in 100 ml there-necked flask (120 °C are toasted more than 2 hours). -78 °C、 N₂Protection is lower to be added dropwise the ml of 1.6 M butyl lithium solutions 6.60.Stirred 80 minutes under -78 °C, gradually become yellow-green soln.1.21 mlCR are added dropwise under -78 °C)-Shrink glycerine butyl ester and 5 ml anhydrous tetrahydro furans, solution becomes clarification quickly.Reaction 1 hour, removes acetone bath, is warmed to room temperature, and stirs 16 hours, a small amount of precipitation occurs.Obtain white solid.Pass through silica gel column chromatography and ethyl acetate:Petroleum ether (volume ratio 1:3) after recrystallizing, 2.34 g white crystals, the % of yield 77.21 are obtained.

(5) (R)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methanol methanesulfonate the preparation CR that obtains 25 molml anhydrous methylene chlorides, step (4))-[the fluoro- 4'- of N-3-C3'- (；4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] 1.74 g of methanol, 1.32 ml triethylamines are added in 100 ml there-necked flask.0.0.52 ml mesyl chlorides are added dropwise under C, react 65 minutes, a large amount of white precipitates occur.Mixture dichloromethane (50 ml><3) extract 3 times, extract is washed 3 times with saturation NaCl solution (50 m 3), anhydrous magnesium sulfate is dried, and is evaporated.Obtain white solid, acetonitrile:Water (volume ratio 1:1) recrystallize.Obtain 1.6065g white crystals.Yield is 75.92 %.

(6) preparation of (R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimides

(R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] g of methanol methanesulfonate 0.686,0.347 g potassium phthalimides and 0.432 g Anhydrous potassium carbonates are added in 100 ml there-necked flasks.After reaction 3 hours, ethyl acetate (50 mlx3) is extracted three times, and extract is washed 3 times with saturation NaCl solution (50 mlx3), and anhydrous magnesium sulfate is dried, and is evaporated to dryness.White solid is obtained, next step reaction is directly used in without purifying.

(7) (R) that the preparation process of (S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] methylacetamides is obtained-[the fluoro- 4'- of N-3- 3'- (and 4 "-Phenylpiperazinyl》Phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide crude product, 100 ml absolute ethyl alcohols and 25 wt% methylamine water solutions (3.38ml, 15.63 mmol) add in 250 ml there-necked flasks, it is heated to reflux 1 hour, reaction is rotated after terminating.With the M of 50 ml 0.1 salt acid extraction, then extracted 2 times with ethyl acetate (30 mlx2).Aqueous phase is transferred in 100 ml there-necked flask, and its pH value is adjusted into alkalescent (pH value=8-9) with appropriate NaOH.Acetic anhydride (0.46 ml, 4.49 mmol) is added, is reacted 10 minutes.Gained mixture is extracted 3 times with ethyl acetate (100 mlx3), saturated nacl aqueous solution (100 ml><3) wash 3 times, anhydrous magnesium sulfate is dried, and is evaporated, column chromatography purifying, and be 3 with volume ratio:1 recrystallization from ethyl acetate/petroleum ether.The mg of white solid 183.5, be (S)-[the fluoro- 4'- of N-3- 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide.Yield is 29.49 %. Elementary analysis result： N%: 13.61 , C%: 64.07, H%: 6.02.Theoretical value： N%: 13.58, C%:64.06, H%: 6.1 1.Pass through high effective liquid chromatography for measuring content： 98.6 %.

Its nuclear magnetic data is as follows：

1H NMR (400Hz, DMSO-d6) δ:8.24 (t, 1H), 7.51 (dd, 1H), 7.26-7.18 (m, 3H), 7.12 (t, 1H)_:6.95 (d, 2H), 6.81 (t, 1H), 4.74-4.68 (m, 1H), 4.09 (t, 1H), 3.70 (q, 1H), 3.41 (t, 2H), 3.29-3.27 (m, 4H), 3.13-3.10 (m, 4H), 1.83 (s, 3H)

¹³C NMR (400Hz, DMSO-d6) δ:170.1,157.2,154.2,152.4,151.0,135.7,133.5,128.1,118.6,118.3,115.8,114.2,107.1,106.5,71.7,50.5,48.6,47.5,22.5. embodiments 10

(S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] preparation of methylacetamide semihydrate (compound 139)

The g of 12 crude product of compound 1 is added in 2 ml 6 ^ % hydrochloric acid, and adds a small amount of activated carbon, in 50 °C of heating stirrings 2 hours, is then filtered.Filtrate is placed into crystallization at room temperature, gained crystal is dried in vacuo 5 hours under 40 °C, obtain compound 139, HPLC measures content：99.0 %, fusing point： 210-215° C (；Capillary is measured), its nuclear-magnetism and mass spectrometric data are as follows.

1H NMR (400Hz, DMSO-d6) δ:8.25 (t, 1H), 7.51 (dd, 1H), 7.26-7.18 (m, 3H), 7.12 (t, 1H)_:6.99 (d, 2H), 6.81 (t, 1H), 4.74-4.70 (m, 1H), 4.10 (t, 1H), 3.71 (q, 1H), 3.41 (t, 2H), 3.30-3.27 (m, 4H), 3.13-3.11 (m, 4H), 1.84 (s, 3H)

1³C NMR (400Hz, DMSO-d6) δ:170.2,157.2,154.2,152.4,151.1,135.7,133.5,128.1,

118.6,118.3,115.8,114.2,107.1,106.5,71.7,50.5,48.6,47.5,22.6.[M-V2H in mass spectrum₂0+H] peak be 413.1;Theoretical value is 413.2.Embodiment 11

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] 2/7 hydrate of methylacetamide

The preparation of (compound 140)

By the g of 12 crude product of compound 10, with water and ethyl acetate（Volume ratio 2:8) the ml of mixed solvent 200 is in 30 °C of dissolvings, by gained (S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide solution stirring reaction 8h, filtering, filtrate is placed to precipitation crystal at room temperature.Obtain product (S)-hydrate of [N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 2/7.Yield：51%, purity： 98.8%.

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 2/7 the water content of hydrate be about 1.20 ± 0.15% (TGA measurements).

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 2/7 crystalline hydrate X ray powder diffraction patterns, using CuK ct radionetric surveys, with the peak (2 Θ) selected from values below: 4.21、 7.06、 8.19、 10.02、 12.25、 13.53 14.23、 16.29、 17.33 18.09、 18.77、 20.29、 21.25、 23.06、 25.13、 27.06、 27.89、 30.12、 33.39、 37.23 37.81 39.02nd, 39.58,41.48,41.84,43.22,43.86,45.37,45.87,47.40 and 49.36 ± 0.02

Embodiment 12

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 2/5 hydrate (compound 141) preparation

(S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] g of methylacetamide crude product 10, is added to the aluminic acid aqueous solution and butanol（Volume ratio 3:7) be made in the ml of mixed solvent 200 CSMN-3-C3'- fluoro- 4'- (；4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] methyl vinyl amine aqueous solution, resulting solution is selected at 50 °C stirs 7h, and filtering is placed separate out crystal at room temperature.Obtain product (S)-[N-3- 3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- Evil oxazolidinyls] 2/5 hydrate of methylacetamide.Yield：59%, purity 99%.

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 2/5 the water content of hydrate be about 1.70 ± 0.15% (TGA measurements).

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 2/5 crystalline hydrate X ray powder diffraction patterns, using CuK ct radionetric surveys, with the peak (2 Θ) selected from values below:4.13rd, 49.18 ± 0.02 degree of 7.07,8.16,9.97,12.20,13.50,14.13,16.27,17.25,18.03,18.72,20.24,21.19,22.16,23.04,25.10,26.90,27.89,30.08,33.45,37.16,38.94,39.62,40.96,41.42,41.84,43.14,43.88,45.30,45.87,47.33 standing grain mouthful.Embodiment 13

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 1/12 hydrate (compound 142) preparation

(S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] g of methylacetamide crude product 10, is added to water and ethanol（Volume ratio 4:6) (S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls are made in the ml of mixed solvent 200》Phenyl -2- oxo -5- oxazoles alkyl] methyl vinyl amine aqueous solution.4h is stirred under 70 °C, is filtered, places separate out crystal at room temperature, obtain (S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] 1/12 hydrate of methylacetamide.Yield：46%, purity： 99.2%.

(S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] water content of the hydrate of methylacetamide 1/12 is that about 0.40 ± 0.15% (TGA is measured）.

(S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] X-ray powder diffraction figure of the crystalline hydrate of methylacetamide 1/12; CuKct radionetric surveys are used, with the peak (2 Θ) selected from values below:4.16th, 4.44,7.09,8.76,10.02,12.15,13.07,13.57,16.21,17.77 18.14,18.74,19.53,20.23,21.18,21.85,23.06,23.77 25.33 26.89,28.54,30.21,31.41,33.19,33.94,36.89,37.82,39.56,41.35,43.33 44.42,45.32,46.02 and 47.32 ± 0.02 degree. Embodiment 14

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 3/4 hydrate (compound 143) preparation

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] 10 g of methylacetamide crude product, it is added to containing water and dimethyl sulfoxide（Volume ratio 1:1) 200 ml in the mixed solvents obtained (S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazoles alkyl] methyl vinyl amine aqueous solution; resulting solution stirs 25h under 75 °C; filtering, places separate out crystal at room temperature.Obtain (S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] 3/4 hydrate of methylacetamide.Yield：48%, purity： 98.5%.

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 3/4 the water content of hydrate be about 3.30 ± 0.15% (TGA measurements).

(S)-[N-3- (3'- fluoro- 4'- (4 "-Phenylpiperazinyls》Phenyl -2- oxo -5- oxazoles alkyl] methylacetamide 3/4 crystalline hydrate X-ray powder diffraction figure, with CuK ct radionetric surveys, with peak (2 Θ 4.04,8.55,9.81,11.04,14.10,16.09,18.66,20.12,22.08,23.64,25.98,27.00,29.00,30.26,31.40,33.25 34.59,35.36,37.83 39.55,40.88,41.89,43.11,44.72,47.87 and 48.07 ± 0.02 degree selected from values below.Embodiment 15

(5S)-[N-3- (the fluoro- 4'- of 3', 5'- bis- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 1) preparation

The first step：The enamine 29g of the fluoro- 4- of 3,5- bis- (4'- phenyl-Γ-piperazinyl) hexamethylene -2,4- bis-, acetone 400ml are added into reaction bulb, stirred under normal temperature, after solids is completely dissolved, is placed in low-temperature cooling fluid circulating pump and is cooled to 0 °C, stirring, adds saturation NaHC0₃Aqueous solution 100ml (contains NaHC0₃10g), 0 °C is added dropwise benzyl chloroformate 20g, and 0.5h is dripped off, and keeps 0 °C of reaction 30min, takes out stirring at normal temperature and stay overnight.

Under nitrogen replacement environment, dried first step reaction product 20g is added in reaction bulb, the treated anhydrous THF of 400ml is added, -70 °C is cooled to the mixture of dry ice and acetone.When as little as -68 °C of interior temperature start that butyl lithium 24ml is added dropwise, temperature is below -65 °C in control, drop finishes, (less than -68 °C) reaction 1.5h of low temperature, then be added dropwise warm below -65 °C in R- Shrink water glycerine butyl ester 9.2g, control, drop finishes, (less than -68 °C) reaction 0.5h of low temperature, take out, stirring at normal temperature was reacted Night.

3rd step：15g second steps reaction product and 200ml dichloromethane are added in reaction bulb, is placed in low-temperature cooling fluid circulating pump and is cooled to -8 °C, good and sound device, stirring.Triethylamine 6.5g is added during 0 °C of interior temperature, Nei Wen -5 °C of dropwise addition 5.5g methane sulfonyl chlorides, interior temperature control system reacts 0.5h, taking-up normal-temperature reaction 2h less than 0 °C.

4th step：10g three-step reactions product, 150mlDMF are added in reaction bulb, good and sound device, stirring sequentially adds 3.3g phthalimides, 3.6g anhydrous Ks₂C0₃, oil bath heating, if outer 82 °C of the temperature of oil bath, stirring reaction is stayed overnight.

500ml40% methylamine water solutions are added in stand up reaction bottle, are installed in water-bath, if 48 °C of bath temperature.Methylamine gas is produced through Drexel bottle（The concentrated sulfuric acid）It is passed through in reaction bulb, clock reaction 5.5h.

6th step：The step reaction products of 2g the 5th, lOOmlTHF are added in reaction bulb, are installed in low-temperature cooling fluid circulating pump, stirring is cooled to -8 °C.Interior 0 °C of addition lg triethylamine of temperature, Nei Wen -5 °C of dropwise addition 0.6g acetic anhydrides, interior temperature control system is below -5 °C, and drop finishes, -5 °C of reaction 0.5h, takes out, normal-temperature reaction 2h. Reaction is finished, suction filtration, and solids is refined with 40ml absolute ethyl alcohols and 60ml ethyl acetate mixtures：Oil bath heats up, condensing reflux, after dissolved clarification, pours into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Use same operation method, secondary recrystallization, vacuum drying.Obtain solid product lg.The embodiment 16 of yield 2.7%

(5S)-[N-3- (the fluoro- 4'- of 3'- (6 "-chloro- 4 "-cyano group -5 "-methyl -2 "-pyridine) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 11) preparation

The first step：4- (the chloro- 4'- isocyano groups -5'- methyl -2'- pyridine radicals of 6'-) -3- fluoroanilines 26g, acetone 400ml is added into reaction bulb, stirred under normal temperature, after solids is completely dissolved, is placed in low-temperature cooling fluid circulating pump and is cooled to 0 °C, stirring, adds saturation NaHC0₃Aqueous solution 100ml (contains NaHCO₃10g), 0 °C is added dropwise benzyl chloroformate 20g, and 0.5h is dripped off, and keeps 0 °C of reaction 30min, takes out stirring at normal temperature and stay overnight.

Reaction is finished, and uses saturation NaHC0₃Solution 80ml is washed 1 time, water（100ml) wash 3 times, point liquid, organic layer adds and 2h is dried in the conical flask equipped with anhydrous MgS04, suction filtration, vacuum distillation filtrate is to dry（- 0.08MPa, 60 °C), obtained solids is added in reaction bulb, 100ml acetonitrile refinings are added：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solid Washing 3 times, vacuum drying.For the next step.

6th step：The step reaction products of 2g the 5th, lOOmlTHF are added in reaction bulb, are installed in low-temperature cooling fluid circulating pump, stirring is cooled to -8 °C.Interior 0 °C of addition lg triethylamine of temperature, Nei Wen -5 °C of dropwise addition 0.7g acetic anhydrides, interior temperature control system is below -5 °C, and drop finishes, -5 °C of reaction 0.5h, takes out, normal-temperature reaction 2h.

Reaction is finished, suction filtration, and solids is refined with 40ml absolute ethyl alcohols and 60ml ethyl acetate mixtures：Oil bath heats up, condensing reflux, after dissolved clarification, pours into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Use same operation method, secondary recrystallization, vacuum drying.Obtain solid product lg, yield 2.7%.Embodiment 17

(5S)-[N-3- (the fluoro- 4'- of 3'- (5 "-(azetidinyl -1 " '-carbonyl)-pyrazinyl -2 "-epoxide) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 17) preparation

1st, the first step

At room temperature, (5- (4'-a amino -2'- fluorophenoxies are added into reaction bulb）- 2- pyrazinyls）- 1- azelidinyls）Ketone 29g, tetrahydrofuran 400ml, stirring adds lmol/L sodium hydrate aqueous solution 110ml, pH is adjusted between 7.5-8.5, benzyl chloroformate 15ml (18.7g) is added dropwise, stirring reaction 20 minutes, after completion of the reaction, adds 1000ml water, separate out material, suction filtration is dried for the next step.

2nd, second step Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, drip power mouthful 2.5M butyl lithiums 36ml, then R- Shrink water glycerol butyrate 13.5g (98%) are added dropwise, drop keeps the stirring 1 hour of -70 °C of low temperature after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, evaporated mother liquor is to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step.

3rd, the 3rd step

4th, the 4th step

5th, the 5th step

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, 0.7g triethylamines and 0.6g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, distillation Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product lg, total recovery 2.3%.Embodiment 18

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-methyl-Γ ' (Η)-imidazole radicals -2 "-sulfenyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide（Compound 18) preparation

1st, the first step

At room temperature, 3- fluoro- 4- (1 '-methyl isophthalic acid -2'- imidazole radicals) thio g of aniline 23, tetrahydrofuran 400ml are added into reaction bulb, stirring adds lmol/L sodium hydrate aqueous solution 110ml, pH is adjusted between 7.5-8.5, benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes is added dropwise, after completion of the reaction, 1000ml water is added, separates out material, suction filtration is dried for the next step.

2nd, second step

Tetrahydrofuran 600ml and first step reaction product 30g is added in reaction bulb, using liquid nitrogen cooling to -70 °C, drip power mouthful 2.5M butyl lithiums 37ml, then R- Shrink water glycerol butyrate 13.6g (98%) are added dropwise, drop keeps the stirring 1 hour of -70 °C of low temperature after finishing, then normal-temperature reaction 16 hours, after the completion of reaction, filtering, evaporated mother liquor is to dry（- 0.08MPa, 60 °C), obtained solid is used for the next step. 3rd, the 3rd step

4th, the 4th step

5th, the 5th step

6th, the 6th step

100ml tetrahydrofurans and the 5th step reaction product 2g are added in reaction bulb.0 °C is cooled to, 0.7g triethylamines and 0.6g acetic anhydrides is added dropwise（98%), keep under 0 °C 1 hour, then stirred 2 hours under normal temperature, after the completion of suction filtration, distillation Nong Shrink mother liquors are to a certain amount of（- 0.08MPa, 60 °C), crystallization is freezed, suction filtration dries to obtain final product lg, total recovery 2.5%.Embodiment 19

The preparation of (5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methanol (compound 40)

The first step：4-methylimidazole 41g, absolute ethyl alcohol 1000ml are added in reaction bulb, stirring, sequentially add triethylamine 60g, 3,4- difluoro nitrobenzene 80g, oil bath heating, if outer 82 °C of the temperature of oil bath, condensing reflux, clock reaction 3 days.

After the completion of reaction, freeze in reaction solution, reaction solution and separate out a large amount of yellow solids, direct cooling crystallization 2h.

Suction filtration, solids is refined with absolute ethyl alcohol 1000ml：Oil bath heats up, condensing reflux.Beaker cooling crystallization 2-3h, suction filtration, vacuum drying are poured into after dissolved clarification： 80°C、 -0.08Mpa.For the next step.

Second step：First step reaction product 22g, acetone 400ml are added in reaction bulb, stirring, sequentially add ammonium formate 20g, 10%Pb/C5g, oil bath heating, if outer 82 °C of the temperature of oil bath, condensing reflux, clock reaction 5h.

Reaction is finished, suction filtration, and Pb/C is reclaimed, and filtrate is standby.

Above-mentioned filtrate, which is placed in low-temperature cooling fluid circulating pump, to be cooled, stirring, and 5 °C add pyridine 12g, and 0 °C starts that benzyl chloroformate 19g (mixing acetone solvent) is added dropwise, and lh is dripped off, low-temp reaction 30min, takes out normal-temperature reaction and stays overnight.

Red liquid , Nong Shrink are obtained after processing to certain volume, are poured into the saturation Nacl aqueous solution, are stirred, white solid is separated out, suction filtration, solids 30g is added in reaction bulb, acetonitrile 500ml is added and refines：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization in refrigerator-freezer.Mother liquor vacuum distillation, during remaining a small amount of mother liquor, pours into beaker and is put into cooling crystallization in refrigerator-freezer, and suction filtration, washing, solid is standby.Disposing mother liquor Solids is added in reaction bulb, adds acetonitrile refining：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, and pours into beaker and is put into cooling crystallization in refrigerator-freezer, suction filtration, washing.

Reclaimed in standby solid and mother liquor in the common 28g of an obtained solid-addition reaction bulb, carry out secondary recrystallization, operating method is ibid.Suction filtration, is dried in vacuo after washing： 110°C、 -0.08Mpa.For the next step.

3rd step, 1000ml THF are added in distillation reactor, stirring, are passed through nitrogen protection, export tail gas, and tail gas does bubbling with the conical flask equipped with atoleine and shown, oil bath heating, if outer 95 °C of the temperature of oil bath, condensing reflux.Nitrogen is turned down, 5g LiAlH are added₄Powder, clock reaction lh starts to collect THF, preceding part discards.

The second step reaction product of drying is added in the 600ml THF gathered, good and sound device is passed through nitrogen protection, cooled with the mixture of dry ice and acetone.

Interior temperature starts that butyl lithium 35ml is added dropwise when being -68 °C, l-1.5h is dripped off, and temperature is below -65 °C in control, and drop finishes, (less than -68 °C) reaction 1.5h of low temperature, R- Shrink water glycerine butyl esters 14g is added dropwise again, 0.5h is dripped off, warm below -65 °C in control, drop finishes, (less than -68 °C) reaction 0.5h of low temperature, take out, normal-temperature reaction is stayed overnight.

Next day, use saturation NH₄The C1 aqueous solution is washed 1 time, layering, then is washed 3 times with the saturation NaCl aqueous solution, is layered.

Upper strata mother liquor vacuum distillation, pours into beaker during remaining a small amount of solution and is put into cooling crystallization 2h in refrigerator-freezer.Upper strata mother liquor suction filtration, solids is added in reaction bulb, is added THF and is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization in refrigerator-freezer.A large amount of white solid things are separated out in subnatant, suction filtration, and solids is added in reaction bulb, are added THF and are refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, pours into beaker and be put into cooling crystallization in refrigerator-freezer.

Suction filtration, is dried in vacuo respectively： 110°C、 -0.08Mpa.Obtain compound 14g.

Product yield：38% embodiment 20

The preparation of (5R)-[3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester (compound 41)

Oxazolidine -2- ketone the 32g of (5R) -3- [the fluoro- 4'- of 3'- (4 "-methyl-Γ-imidazoles -1 "-yl) phenyl] -5- (methylol) -, dichloromethane 500ml are added in reaction bulb, it is placed in low-temperature cooling fluid circulating pump and is cooled to -8 °C, good and sound device, stirring.Interior 0 °C of temperature adds triethylamine 15g, and Nei Wen -5 °C start that methane sulfonyl chloride 20g (mixing CH are added dropwise₂C1₂), 0.5h is dripped off, and interior temperature control system is below 0 °C, and drop finishes, low-temp reaction 0.5h, takes out normal-temperature reaction 2h.

Reaction is finished, and uses saturation NaHC0₃The aqueous solution is washed 1 time, layering, is washed with water 3 times, is layered, and adds and anhydrous MgS0 is housed₄Conical flask in dry 2h, suction filtration, vacuum distillation mother liquor is to dry（- 0.08MPa, 40 °C).Obtain compound 25g.Embodiment 26,32,40,47,53,59,63,65,69,71 and 75 With the identical preparation method of embodiment 20, simply in the first step, oxazolidine -2- the ketone of (R) -3- [the fluoro- 4'- of 3'- (4 "-methyl-Γ-imidazoles -1 "-yl) phenyl] -5- (methylol)-in the raw material alternative embodiment 20 listed respectively with following table 3, obtains corresponding compound.

Table 3

Embodiment 21

The preparation of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide (compound 42)

(R)-[3- (the fluoro- 4- of 3- (4- methyl isophthalic acids Η-imidazoles -1- bases) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester 20g, DMF 500ml are added in reaction bulb, good and sound device, stirring, sequentially add phthalimide 10g, 12g polyethylene glycol 400, oil bath heating, if outer 82 °C of the temperature of oil bath, reaction is stayed overnight.

Next day, suction filtration, filtrate is light yellow transparent liquid, vacuum distillation（- 0.08MPa, 80 °C), when remaining a small amount of mother liquor Pour into and 30min is cooled down in crystallization in the saturation NaCl aqueous solution, refrigerator-freezer, take out suction filtration, wash in the solids addition reaction bulb that 3 times obtain, add DMF 200ml and refine：Oil bath heats up, condensing reflux, after dissolved clarification, adds suitable quantity of water to a small amount of solids and separates out, and pours into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration, washing.Same operation method secondary recrystallization.Suction filtration, is dried in vacuo after washing： 110°C、 -0.08Mpa.Obtain compound 42.

Product yield and quality：

The product is yellow powdery solid, mp:220-222 °C, 3 times experiment yield is respectively：100903 batches 27.7%, 101001 batches 41.4%, 101101 batches 12.5%.

Embodiment 27,33,41,48,54,60,66 and 72

With the identical preparation method of embodiment 21, simply in the first step, (R)-[3- (the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-groups) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester and phthalimide in the raw material alternative embodiment 21 listed respectively with following table 4, obtain corresponding compound.

Table 4

Embodiment 22 The preparation of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylamine (compound 43)

(S) -2- [(3- (the fluoro- 4- of 3- (4- methyl isophthalic acids Η-imidazoles -1- bases) phenyl) -2- oxo -5- oxazoles alkyl) methyl] phthalimide 10g, absolute ethyl alcohol 600ml is added in reaction bulb, good and sound device, stirring.Oil bath heating, if outer 82 °C of the temperature of oil bath, condensing reflux.

The methylamine water solutions of 500ml 40% are added in single port bottle, are placed in water-bath, if 48 °C of bath temperature, good and sound device.When producing stable methylamine gas, methylamine steam is passed through in reaction bulb with airway tube, timing stirring reaction 5.5h.Stop logical methylamine gas, continue heating response 2h.Reaction is finished, suction filtration, is poured into beaker and is put into cooling crystallization in refrigerator-freezer and stays overnight.

Next day suction filtration, solids 6g is added in reaction bulb, adds 100ml absolute ethyl alcohols and ethyl acetate is refined：Oil bath heats up, condensing reflux, after dissolved clarification, adds appropriate n-hexane and is separated out to a small amount of solids, pours into beaker and be put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Same operation method secondary recrystallization.Suction filtration, is dried in vacuo after washing：110 °C, -0.08Mpao obtain compound 43.

Product yield and quality：

The product is pale yellow powder shape solid, mp:171-172 °C, 3 times experiment yield is respectively：100902 batches

It is very little

19.7%th, 101001 batches 3.6%, 101101 batches 20.1%.Embodiment 28,34,42,49,55,61,67 and 73

With the identical preparation method of embodiment 22, simply in the first step, (S) -2- [(3- (the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-groups) phenyl) -2- oxo -5- oxazoles alkyl) methyl] phthalimide in the raw material alternative embodiment 22 listed respectively with following table 5, obtains corresponding compound.

Table 5

Real raw material physicochemical data

Apply

Example thing

28 (S) -2- [(3- (pale yellow powders of 4- (2,5- dioxy -1- pyrrolidinyls) -3- fluorine 47

Phenyl 2- oxo -5- oxazoles alkyl) methyl] adjacent benzene two

Carboximide

34 (S) -2- [(3- (the fluoro- 4- of 3- (small pyrazolyls of 3- methyl isophthalic acids H）53 15 white, fluffy shape solids

Phenyl 2- oxo -5- oxazoles alkyl) methyl] the adjacent mp of benzene two: 175.3-175.6°C

Carboximide

42 (S) -2- [(3- (white, fluffy shape solids of 4- (2,5- dihydro -1H- 1- pyrrole radicals) -3- 57 41%

Fluorophenyl)-₂- oxo-5-oxazole alkyl) methyl] adjacent benzene mp: 142.7-144.1 °C

Dicarboximide

49 (S) -2- [(3- (the fluoro- 4- of 3- (1- pyrrolidinyls) phenyl）The white, fluffy shape solids of -2- 61 75%

Oxo -5- oxazoles alkyl] methyl phthalimide

55 (S) -2- [(3- (white, fluffy shape solids of 4- (l, 3,4- thiadiazoles -2- sulfenyls) -3- fluorine 65 50%

Phenyl 2- oxo -5- oxazoles alkyl) methyl] the adjacent mp of benzene two: 174.6-174.8 °C

Carboximide

61 (S) -2- [(white powders of 3- (the fluoro- 4- of 3- (1 Η -1- pyrrole radicals) phenyl) -2- 48 30.6% Oxo -5- oxazoles alkyl) methyl] 65.7% mp of phthalimide: 153-154°C

67 (S) -2- [the fluoro- 4-0 piperidyls of H3-) phenyl) 69 30.3% white powder of -2- oxygen

Generation -5- oxazoles alkyl) methyl] phthalimide mp: 159-161 °C

73 (S) -2- [(3- (white powders of 4- (l, 3,4- thiadiazoles -2- amino) -3- fluorine 73 40.5%

Phenyl 2- oxo -5- oxazoles alkyl) methyl] the adjacent mp of benzene two: 162-163 °C

Carboximide embodiment 23

The preparation of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide (compound 19)

(S) -5- (amino methyl) -3- [the fluoro- 4- of 3- (4- methyl isophthalic acids Η-imidazoles -1- bases) phenyl] oxazole alkyl -2- ketone 5g, THF 100ml is added in reaction bulb, it is placed in low-temperature cooling fluid circulating pump, good and sound device, stirring.0 °C of interior temperature adds triethylamine lg, and Nei Wen -5 °C start to be added dropwise acetic anhydride 0.8 g, and 0.5h is dripped off, and interior temperature control system is less than -5 °C, and drop is complete, and then low-temp reaction 0.5h moves to normal-temperature reaction 2h.

Reaction is finished, suction filtration, and solids adds 100ml absolute ethyl alcohols and ethyl acetate is refined, oil bath heating, condensing reflux, after dissolved clarification, is poured into beaker and is put into cooling crystallization 2h in refrigerator-freezer, suction filtration.Product secondary recrystallization, operating method is identical, after last suction filtration, vacuum drying： 120°C、 -0.08Mpa.Obtain compound 19.

Product yield and quality：

The product is white powdery solids, mp:181-182 °C, 2 times the total yield of experiment is：101101 batches+101102 batches 23.2%, content： 99.6%(HPLC).Embodiment 24,29,30,35,36,37,38,43,44,45,50,51,56,57,62,68 and 74

With the identical preparation method of embodiment 23, (S) -5- (amino methyl) -3- [the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-groups) phenyl] oxazole alkyl -2- ketone and acetic anhydride in the raw material alternative embodiment 23 listed respectively with following table 6, obtain corresponding compound.

Table 6

Real raw material yield physicochemical data

Apply

Example thing

29 (S)-l- [4- (white powder of 5- (amino methyl) -2- oxo -3- oxazoles 21 62.0,

Alkyl) -2- fluorophenyls] pyrrolidinyl -2,5- diketone and 32 42.4 mp: 164-165 °C

Acetic anhydride 11.4

69.1

35 (S) -5- (amino methyl) -3- [the fluoro- 4- of 3- (white solids of 3- methyl -29 38

1H- 1- pyrazolyls) phenyl] oxazole alkyl -2- ketone and second mp: 171.8-171.9°C

Acid anhydrides

43 (S) -5- (amino methyl) -3- [4- (white solids of 2,5- dihydro -1H- 1- 33 38%

Pyrrole radicals) -3- fluorophenyls] oxazole alkyl -2- ketone and second mp:177.8.8-177.8 °C acid anhydrides

50 (S) -5- (amino methyl) -3- [the fluoro- 4- of 3- (white solids of 1- pyrrolidines 36 32%

Base) phenyl] oxazole alkyl -2- ketone and acetic anhydride 56 (S) -3- [white solids of 4- (l, 3,4- thiadiazoles -2- sulfenyls) -3- fluorobenzene 38 40%

Base] -5- (amino methyl) oxazole alkyl -2- ketone and acetic acid mp:180.5.8-180.7 °C acid anhydride

62 (S) -5- (amino methyl) -3- [the fluoro- 4- of 3- (3- methyl -23 45.9%, white powder

1H-1- pyrrole radicals) phenyl] oxazole alkyl -2- ketone and second mp: 177-178°C

Acid anhydrides

68 (S) -5- (amino methyl) -3- [3- fluoro- 4- (1- piperidyls）25 13.1% white powders

Phenyl] oxazole alkyl -2- ketone and acetic anhydride mp: 175-176°C

74 (S) -3- [white powders of 4- (l, 3,4- thiadiazoles -2- amino) -3- fluorobenzene 27 30.6%

Base] -5- (amino methyl) oxazole alkyl -2- ketone and acetic acid mp: 178-179°C

Acid anhydride

24 (S) -5- (amino methyl) -3- (the fluoro- 4- of 3- (white powders of 4- methyl -20 26.3%

- 1-yl of 1H- imidazoles) phenyl) oxazole alkyl-2- ketone and mp: 179-180°C

Methane sulfonyl chloride

30 (S)-1-(4- (white powder of 5- (amino methyl)-2- oxo-3- oxazoles 22 45.4,

Alkyl) -2- fluorophenyls) pyrrolidinyl -2,5- diketone and mp: 258-259°C

Methane sulfonyl chloride

37 (S) -5- (amino methyl) -3- (the fluoro- 4- of 3- (white solids of 3- methyl -30 34%

1H- 1- pyrazolyls) phenyl) oxazole alkyl -2- ketone and first

Sulfonic acid chloride

36 (S) -5- (amino methyl) -3- (the fluoro- 4- of 3- (white crystals of 3- methyl -31 37%

1H- 1- pyrazolyls) phenyl) oxazole alkyl -2- ketone and chlorine

Chloroacetic chloride

38 (S)-1-(4- (white crystals of 5- (amino methyl)-2- oxooxazolidines 138 34%

Base -3- bases) -2- fluorophenyls) pyrrolidinyl -2,5- diketone

And chloracetyl chloride

44 (S) -5- (amino methyl) -3- (4- (white solids of 2,5- dihydro -1H- 1- 34 39%

Pyrrole radicals) -3- fluorophenyls) oxazole alkyl -2- ketone and first

Sulfonic acid chloride

45 (S) -5- (amino methyl) -3- (4- (white solids of 2,5- dihydro -1H- 1- 35 41%

Pyrrole radicals) -3- fluorophenyls) oxazole alkyl -2- ketone and chlorine

Chloroacetic chloride

51 (S) -5- (amino methyl) -3- (the fluoro- 4- of 3- (white solids of 1- pyrrolidines 37 36%

Base) phenyl) oxazole alkyl -2- ketone and mesyl chloride

57 (S) -3- (white solids of 4- (l, 3,4- thiadiazoles -2- sulfenyls) -3- fluorobenzene 39 35%

Base) -5- (amino methyl) oxazole alkyl -2- ketone and chloroethene mp:181.2-181.6°C

Acid chloride Example 25

(the fluoro- 4'- of 5RMN-3- 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] methanol (compound 44) preparation

The first step：10gNaOH, absolute ethyl alcohol 400ml are added in reaction bulb, good and sound device, oil bath heating, if outer 82 °C of the temperature of oil bath, condensing reflux, stirs 30min, after NaOH dissolvings, add 19g succimides, all dissolving, starts dropwise addition 3,4- difluoro nitrobenzenes 16g, drop finishes, clock reaction 24h. Reaction is finished, and a large amount of yellow solids, direct cooling crystallization 2h are separated out in red reaction solution.

Suction filtration, 3 refined, vacuum drying of solids washed with water:80 °C, -0.08Mpa, for the next step.

Product yield and quality：

First step reaction product is yellow powdery solid, mp:81-83 °C, 3 times experiment yield is respectively：101201 batches 62.5%, 101202 batches 64.6%, 101203 batches 64.0%.

Second step：First step reaction product 30g, acetone 400ml are added in reaction bulb, stirring, sequentially add ammonium formate 25g, 10%Pb/C5g, oil bath heating, if outer 50 °C of the temperature of oil bath, condensing reflux.Interior 48 °C of temperature, clock reaction 5h.

3rd step：Filtrate obtained by second step, which is placed in low-temperature cooling fluid circulating pump, to be cooled, stirring, and 5 °C add pyridine llg, and 0 °C starts to be added dropwise benzyl chloroformate 20g, and lh is dripped off, and low-temp reaction 30min takes out normal-temperature reaction and stayed overnight.

Reaction is finished, suction filtration, crystallization, suction filtration in the saturation NaCl aqueous solution are poured into during remaining a small amount of mother liquor, washing, solids is added in reaction bulb, is added acetonitrile 400ml and is refined, oil bath heating, condensing reflux, after dissolved clarification, add suitable quantity of water to a small amount of solids and separate out, pour into beaker and be put into cooling crystallization in refrigerator-freezer.Suction filtration, washing.

With same operation method secondary recrystallization.Suction filtration, is dried in vacuo after washing： 85°C、 -0.08Mpa.For the next step.

Product yield and quality：

Three-step reaction product is white powdery solids, mp:100-lOrC, 3 times experiment yield is respectively：101201 batches 85.3%, 101202 batches 84.8%, 101203 batches 86.1%.

4th step, THF are added in distillation reactor, stirring, are passed through nitrogen protection, export tail gas, and tail gas does bubbling with the conical flask equipped with atoleine and shown, oil bath heating, if outer 95 °C of the temperature of oil bath, condensing reflux.Nitrogen is turned down, 5gLiAlH^ij ends are added, clock reaction lh starts to collect THF, preceding part discards.

The drying three-step reaction product 30g of more than 2 days, good and sound device are added in the THF gathered, nitrogen protection is passed through, is cooled with the mixture of dry ice and acetone.

Interior temperature starts that butyl lithium 38ml is added dropwise when being -68 °C, l-1.5h is dripped off, and temperature is below -65 °C in control, and drop finishes, (less than -68 °C) reaction 1.5h of low temperature, R- Shrink water glycerine butyl esters 14g is added dropwise again, 0.5h is dripped off, warm below -65 °C in control, drop finishes, (less than -68 °C) reaction 0.5h of low temperature, take out, normal-temperature reaction is stayed overnight.

Next day, use saturation NH₄The C1 aqueous solution, a small amount of purifying water washing 1 time, layering, then washed 3 times with the saturation NaCl aqueous solution, it is layered.

Vacuum distillation, pours into beaker during remaining a small amount of solution and is put into cooling crystallization 2h in refrigerator-freezer.Suction filtration, solids is added in reaction bulb, is added 200ml ethyl acetate and is refined, oil bath heating, condensing reflux, after dissolved clarification, is added appropriate petroleum ether and is separated out to a small amount of solids, pour into beaker and be put into cooling crystallization in refrigerator-freezer.

Suction filtration, petroleum ether 1 time, vacuum drying： 100°C、 -0.08Mpa.Obtain compound 44.

Product yield and quality：

The product is pale yellow powder shape solid, mp:120-122 °C, testing yield is：110101 batches 73.0%.Embodiment 39,46,52,58,64 and 70 With the identical preparation method of embodiment 25,3, the 4- difluoro nitrobenzenes in the raw material alternative embodiment 25 listed respectively with following table obtain corresponding compound.

Table 7

Compound 83-137 synthesis referring to： CN1355165A.

The compounds of this invention CN1355165A compounds

83 5

84 11

85 12

86 13

87 14

88 15

89 16

90 17

91 18

92 19

93 20

94 21

95 22

96 26

97 27

98 28

99 30

100 31

101 32

102 33

103 37

104 38

105 39

106 41

107 42

108 43

109 44 110 48

111 49

112 50

113 52

114 53

115 54

116 55

117 59

118 60

119 61

120 64

121 65

122 66

123 70

124 71

125 72

126 75

127 76

128 77

129 81

130 82

131 83

132 86

133 87

134 88

135 95

136 96

137 97 suppress the effect experiment of tubercle bacillus reference culture

Minimum inhibitory concentration (MIC) of the compound to mycobacterium tuberculosis type strain H37Rv is determined using Microplate Alamar Blue Assay (MABA) method.[Collins L A, the system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial Agents Chemother of Franzblau S G. Microplate alamar blue assay versus BACTEC 460,1997,1004-1009.]

Experimental strain involved in the present invention：Mycobacterium tuberculosis type strain H37Rv, is provided by Beijing Tuberculosis and Thoracic Tumor Research Institute.

Experimental strain involved in the present invention：Mycobacterium tuberculosis sensitivity Clinical isolation： 9102、 3215、 1105、

4201st, 2170,6177,3232,1103,3206,23120 provided by Beijing Tuberculosis and Thoracic Tumor Research Institute.

Experimental strain involved in the present invention：Drug resistance of Mycobacterium tuberculosis Clinical isolation：20161st, 6233,16543,5116,3328,3289,3303,7153,31251,30129 provided by Beijing Tuberculosis and Thoracic Tumor Research Institute.First, experiment material, method and the result determined to mycobacterium tuberculosis type strain H37Rv MIC90 1st, test-compound：

Compound 1-143

2nd, comparison medicine：Isoniazid (INH), rifampin (RFP) are Sigma Products.

3rd, experimental strain：Mycobacterium tuberculosis type strain H37Rv, is provided by Beijing Tuberculosis and Thoracic Tumor Research Institute.

4th, culture medium：7H9 fluid nutrient mediums (Difco Products).

5th, method：

Isoniazid is dissolved with sterile purified water, and the first solution that concentration is 6.4mg/ml is made with dmso solution in rifampin and test-compound.

With sterile 96 orifice plate (Falcon3072;Becton Dickinson, Lincoln Park, N.J.), maximum concentration hole adds 198 μ 1 culture mediums of 7 Η 9, and the first solution of the compounds of 2 μ 1 after being well mixed, dilutes for 2 times, final compound concentration is successively to remaining each hole： 16、 8、 4、 2、 1、 0.5、 0.25、 0.125、 0.06、 0.03 g/ml.INH is final concentration of： 0.2、 0.1、 0.05、 0.025、 0.0125 g/ml.

Choose mycobacterium tuberculosis H37RV, bacteria suspension is made in the culture for cultivating 23 weeks, it is inoculated into containing in 0.05% Tween 80,10%ADC 7H9 culture mediums, 37 °C of static gas wave refrigerators 12 weeks, it is McFarland 1 (equivalent to 10 to grow to turbidity⁷When CFU/ml), with 1:After 20 dilutions, each μ 1 of hole 100, the final concentration of 106CFU/ ml of bacterium solution are added.2 growth control holes for being free of antimicrobial are all provided with per plate, 96 orifice plates are in 37 °C of incubations.The O Alamar Blue (Setotec Products) and the μ 1 of 5 %Tween80 50 of growth control 20 μ of hole 11 mixed liquor is added after 7 days, 37 are incubated 24 hours, if color is changed into pink colour from blueness, Alamar Blue and the Tween80 mixed liquors of above-mentioned amount are then added in the hole of each Experimental agents, the color in 37 °C of each holes of 24 hour records of incubation, and application ELIASA determines 530nm and 590nm fluorescent values, calculates MIC90.

6th, experimental result

The minimal inhibitory concentration (MIC) determined with MABA methods is shown in Table one.

Table one：MIC of the test-compound to mycobacterium tuberculosis type strain H37Rv

Compound, 14, 6.896, compound, 15, 6.992, compound, 16, 7.758, compound, 17, 7.833, compound, 18, 2.879, compound, 19, 2.836, compound, 20, 2.790, compound, 21, 5.899, compound, 22, 5.274, compound, 23, 5.860, compound, 24, 5.699, compound, 25, 5.731, compound, 26, 5.292, compound, 27, 5.938, compound, 28, 5.619, compound, 29, 5.771, compound, 30, 5.685, compound, 31, 5.735, compound, 32, 5.890, compound, 33, 5.874, compound, 34, 5.794, compound, 35, 5.791, compound, 36, 5.860, compound, 37, 5.811, compound, 38, 5.701, compound, 39, 5.788, compound, 40, 5.455, compound, 41, 5.818, compound, 42, 64.020, compound, 43, 5.955, compound, 44, 5.698, compound, 45, 5.790, compound, 46, 5.900, compound, 47, 5.020, compound, 48, 5.740, compound, 49, 5.875, compound, 50, 5.001, compound, 51, 62.452, compound, 52, 5.958, compound, 53, 5.808, compound, 54, 5.123, compound, 55, 5.890, compound, 56, 5.444, compound, 57, 5.696, compound, 58, 5.701 Compound, 59, 32.455, compound, 60, 5.765, compound, 61, 5.819, compound, 62, 5.905, compound, 63, 38.851, compound, 64, 5.822, compound, 65, 5.333, compound, 66, 64.003, compound, 67, 5.844, compound, 68, 5.600, compound, 69, 5.796, compound, 70, 5.321, compound, 71, 62.450, compound, 72, 5.923, compound, 73, 5.988, compound, 74, 5.003, compound, 75, 64.001, compound, 76, 5.757, compound, 77, 5.290, compound, 78, 5.780, compound, 79, 5.465, compound, 80, 5.745, compound, 81, 5.984, compound, 82, 5.452, compound, 83, 3.804, compound, 84, 3.877, compound, 85, 3.304, compound, 86, 3.940, compound, 87, 3.721, compound, 88, 3.907, compound, 89, 3.801, compound, 90, 3.232, compound, 91, 3.808, compound, 92, 3.861, compound, 93, 3.804, compound, 94, 3.924, compound, 95, 3.980, compound, 96, 3.915, compound, 97, 3.505, compound, 98, 3.799, compound, 99, 3.950, compound, 100, 3.815, compound, 101, 3.714, compound, 102, 3.271, compound, 103, 4.825 Compound 104 4.720

Compound 105 4.811

Compound 106 4.951

Compound 107 4.930

Compound 108 4.721

Compound 109 4.789

Compound 110 4.520

Compound 111 4.855

Compound 112 4.800

Compound 113 4.907

Compound 114 4.216

Compound 115 4.857

Compound 116 4.880

Compound 117 1.974

Compound 118 1.987

Compound 119 1.822

Compound 120 2.953

Compound 121 2.939

Compound 122 2.922

Compound 123 3.905

Compound 124 3.621

Compound 125 3.785

Compound 126 3.803

Compound 127 3.859

Compound 128 3.613

Compound 129 3.891

Compound 130 3.306

Compound 131 3.876

Compound 132 3.899

Compound 133 3.842

Compound 134 3.947

Compound 135 4.311

Compound 136 4.853

Compound 137 4.878

Compound 138 5.889

Compound 139 1.055

Compound 140 0.527

Compound 141 0.588

Compound 142 0.531

Compound 143 1.280

INH 0.055

Application Microplate Alamar Blue Assay (MABA) methods of RFP 0.038 determine and resistance sensitive to mycobacterium tuberculosis Material, method and the result of the antibacterial activity in vitro of Clinical isolation

1. test-compound：Compound 1-143;Control drug isoniazid (INH), rifampin (RFP) are the production of Sigma companies

Π

ΡΠ。

2. experimental strain：Mycobacterium tuberculosis sensitivity Clinical isolation： 9102、 3215、 1105、 4201、 2170、 6177、 3232、 1103、 3206、 23120；

Drug resistance of Mycobacterium tuberculosis Clinical isolation： 20161、 6233、 16543、 5116、 3328、 3289、 3303、 7153、 31251、 30129；

Above bacterial strain is provided by from Beijing Tuberculosis and Thoracic Tumor Research Institute.

3. culture medium：7H9 fluid nutrient mediums (Difco Products).

4. method：Sterile 96 orifice plate (Falcon3072;Becton Dickinson, Lincoln Park, N.J.), INH is dissolved with sterile purified water, and rifampin and test-compound are with dmso solution, the first solution that concentration is 32mg/ml is made, maximum concentration hole adds the culture mediums of 198 μ, 17 Η 9, the pharmaceutical diluted solutions of 2 μ 1, after being well mixed, to remaining each hole successively 2 times of dilutions, test-compound is final concentration of： 16、 8、 4、 2、 1、 0.5、 0.25、 0.125、 0.06、 0.03 g/ml.The sensitive Clinical isolation of 10 plants of mycobacterium tuberculosis and 10 plants of resistant clinical isolated strains are chosen respectively, bacteria suspension is made in the culture cultivated 23 weeks, it is inoculated into containing in 0.05% Tween 80,10%ADC 7H9 culture mediums, 37 °C of static gas wave refrigerators 12 weeks, it is McFarland 1 (equivalent to 10 to grow to turbidity⁷When CFU/ml), 1:After 20 dilutions, each μ 1 of hole 100, final concentration of the 10 of bacterium solution are added⁶CFU/ ml.2 growth control holes for being free of antimicrobial are all provided with per plate, 96 orifice plates are in 37 °C of incubations.The lO Alamar Blue (Setotec Products) and the μ 1 of 5 % Tween80 50 of growth control 20 μ of hole 1 mixed liquor is added after 7 days, 37 are incubated 24 hours, if color is changed into pink colour from blueness, Alamar Blue and the Tween80 mixed liquors of above-mentioned amount are then added in the hole of each Experimental agents, the color in 37 °C of each holes of 24 hour records of incubation, and application ELIASA determines 530nm and 590nm fluorescent values, calculates MIC90.

5th, experimental result

The minimal inhibitory concentration (MIC) determined with MABA methods is shown in Table two.

Table two：Test-compound is to mycobacterium tuberculosis sensitivity and the MIC of 1 isolated strains of resistance

Resistant clinical isolated strains MIC range-sensitive Clinical isolation MIC scope samples

(10 plants）(10 plants）

The 3.290-9.210 3.188-8.586 of compound 1

The 3.241-16 3.258-8 of compound 2

The 7.891-20.852 7.712-18 of compound 3

The 7.0-24.915 6.860-24 of compound 4

The 12.0-46.327 11.0-38.539 of compound 5

The 6.0-20.356 5.0-18.433 of compound 6

The 7.258-26.866 7.041-24.824 of compound 7

The 14.188-33.743 12.177-33.300 of compound 8

The 16.0-36.111 15.0-32.511 of compound 9

The 10.456-38.320 10.0-32.426 of compound 10

The 10.341-36 9.0-34.420 of compound 11

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The 2.0-8.825 1.899-8.428 of compound 143

INH 0.625- > 40 0.025-0.588

RFP 0.625- >After 40 0.05-0.573 Rimactazids come out, the success of short-term chemotherapy makes treatment lungy there occurs revolutionary change, still, nearly ten years, a large amount of with Rimactazid use, and its resistance is increased year by year, so as to cause antituberculosis therapy to fail.And most compounds of the present invention to the MIC scopes of sensitive mycobacterium tuberculosis clinical separation strain in 1-32 μ_§/ ml, wherein having considerable part compound in 1-16 μ_§/ ml, also part of compounds are in 1-8 μ_§/ml;Simultaneously most compounds to single resistance to isoniazid, single resistance to rifampin or simultaneously the MIC scopes of the mycobacterium tuberculosis clinical separation strain of resistance to rifampicin isoniazid (MDR-TB) in 1-32 μ_§/ ml, wherein having considerable part compound in 1-16 μ_§/ ml, also part of compounds are in 1-8 μ_§/ ml, therefore compound of the present invention has antibacterial activity in vitro to sensitive and Drug-Resistant Mycobacterium tuberculosis clinical separation strain, especially has remarkable result to Drug-Resistant Mycobacterium tuberculosis.

Compound energy Shrink of the present invention is short and simplifies the course for the treatment of, overcomes anti-many property of medicine, and treats tuberculosis and AIDS co-infection, especially provides tuberculosis latent infection more effective treatment.The curative effect to many resistant tuberculosis is improved simultaneously, the medicine for treating multi-drug resistant tuberculosis can be specially developed into, and a kind of safely and effectively medicine will be provided for tuberculosis patient at that time.

Claims

Claims

1st, the compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that general formula I is represented are preparing the application for preventing or treating：

2nd, application as claimed in claim 1, wherein：

Hydroxyl, amino and substituted or unsubstituted following groups are represented in formula I：C1-C10 amidos, two (C1-C10) imido grpups, C1-C10 amide groups, C1-C10 acyl imines base, two (C1-C10 acyl groups) imido grpups, C1-C10 sulfoamidos, C1-C10 sulfonyloxies, C1-C10 alkanoyls epoxide, five yuan or hexa-member heterocycle group, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl；

R₂Represent substituted or unsubstituted five yuan or hexa-member heterocycle group；Substituted or unsubstituted C1-C10 acyl groups；Or following formula group：

Wherein,

R₃And R₅15, halogen atom or C1-C10 haloalkyls are represented independently of one another；

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide,

C1-C10 alkoxies, C1-C10 aralkyl oxies, five yuan or hexa-member heterocycle base sulfydryl, benzo five-membered heterocyclic radical sulfydryl or benzo hexa-member heterocycle base sulfydryl, five yuan or hexa-member heterocycle base amido, benzo five-membered heterocyclic radical amido, benzo hexa-member heterocycle base amido.

3, application as claimed in claim 2, wherein, the expression hydroxyl in formula I, amino, C1-C10 alkylamino radicals, C1-C10 aromatic alkyl amidos, C1-C10 aromatic radical amidos, two (C1-C10 alkyl) imido grpups, two (C1-C10 aromatic radicals) imido grpups, C1-C10 alkylaryl imido grpups, two (C1-C10 aromatic alkyls) imido grpups, C1-C10 alkylamidoalkyls, C1-C10 aromatic alkyl amide groups, C1-C10 aromatic radical amide groups, halo C1- C10 alkylamidoalkyls, halo C1-C10 aromatic alkyl amide groups, halo C1-C10 aromatic radical amide groups, C1- C10 alkylsulfonamidos, C1-C10 aromatic alkyl sulfoamidos, C1-C10 aromatic radical sulfoamidos, halo C1- C10 alkylsulfonamidos, halo C1-C10 aromatic alkyl sulfoamidos, halo C1-C10 aromatic radical sulfoamidos, C1-C10 aromatic radical sulfonyloxies, C1-C10 alkylsulfonyloxies, C1-C10 aromatic alkyl sulfonyloxies, halo C1-C10 aromatic radical sulfonyloxies, halo C1-C10 alkylsulfonyloxies, halo C1-C10 aromatic alkyl sulfonyloxies, two (C1-C10 aromatic radicals acyl group) imido grpups, two (C1-C10 alkanoyls) imido grpups, two (C1-C10 Aromatic alkyl acyl group) imido grpup, C1-C10 alkanoyls epoxide, halo C1-C10 alkanoyls epoxide, substituted or unsubstituted five yuan or hexa-member heterocycle group, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl.

4, application as claimed in claim 3, wherein, expression hydroxyl in formula I, amino, methylamino, ethylamino-, benzylamino, anilino-, dimethyliminio, diethyl imido grpup, diphenyl imine base, benzhydryl imido grpup, formamido, acetamido, propionamido-, halo formamido, 1- haloacetyl amidos, methylsulfonyl amido, ethanesulfonamide group, mesyloxy, ethanesulfonyloxy group, benzyl sulfonyloxy, phthalimide-based, dicarboximide base, diethyl imide, acetyl group epoxide, succinyl base imido grpup, p-toluenesulfonyl epoxide, 1, 3, 4- thiadiazolyl group sulfydryls, 1, 2, 4-1H- triazol radicals, 1H- tetrazole bases, tetrazole base sulfydryl, benzimidazole 2- sulfydryls, BTA base, imidazole radicals, camphorimide base.

5th, application as claimed in claim 4; wherein; expression hydroxyl, amino, acetamido, chloracetyl amido, methylsulfonyl amido, mesyloxy, ethanesulfonyloxy group, phthalimide-based, dicarboximide base, succinyl base imido grpup, p-toluenesulfonyl epoxide in formula I, 1; 3; 4- thiadiazolyl groups sulfydryl, 1; 2,4-1H- triazol radicals, 1H- tetrazoles base, tetrazole base sulfydryl, benzimidazole 2- sulfydryls, BTA base, imidazole radicals, camphorimide base.

6th, the application as described in claim 1-5 any one, wherein, the substituted or unsubstituted following groups of expression in formula I：Pyrrole radicals, imidazole radicals, pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 4- morpholinyls, piperazinyl, piperidyl, pyrimidine radicals, oxazolyls, pyridine radicals；Or C1-C4 acyl groups；Or following formula base

Wherein,

R₃And R₅15, halogen atom or C1-C10 haloalkyls are represented independently of one another；

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, C1-C10 alkoxies, C1-C10 aralkyl oxies, five yuan or hexa-member heterocycle base sulfydryl, benzo five-membered heterocyclic radical sulfydryl or benzo hexa-member heterocycle base sulfydryl, five yuan or hexa-member heterocycle base amido, benzo five-membered heterocyclic radical amido, benzo hexa-member heterocycle base amido.

7th, application as claimed in claim 6, wherein, the R in formula I₂Represent acetyl group, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrimidine radicals, Qu generations or do not replace oxazolyls, substituted or unsubstituted pyridine radicals or following formula group：

R₃And R₅15, halogen atom or C1-C10 haloalkyls are represented independently of one another；

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide,

C1-C10 alkoxies, C1-C10 aralkyl oxies, five yuan or hexa-member heterocycle base sulfydryl, benzo five-membered heterocyclic radical sulfydryl or benzo hexa-member heterocycle base sulfydryl, five yuan or hexa-member heterocycle base amido, benzo five-membered heterocyclic radical amido, benzo hexa-member heterocycle base amido.

8th, application as claimed in claim 7, wherein, the R in formula I₂Represent acetyl group, 2- Phenylpiperidines base, 2- hydroxy pyrimidines base, the chloro- 4- cyano group -2- pyridine radicals of 6-, 4- oxazolyls or 2- acetoxyl group pyrimidine radicals.

9th, the R in formula I as claimed in claim 7₂Represent following formula group：

Wherein, R₃And R₅11, F, C1 or CF are represented independently of one another₃;

R4 represents substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, C1-C10 alkoxies, C1-C10 aralkyl oxies, five yuan or hexa-member heterocycle base sulfydryl, benzo five-membered heterocyclic radical sulfydryl or benzo hexa-member heterocycle base sulfydryl, five yuan or hexa-member heterocycle base amido, benzo five-membered heterocyclic radical amido, benzo hexa-member heterocycle base amido.

10th, application as claimed in claim 9, wherein, the R4 represents substituted or unsubstituted following groups：Pyrrole radicals, imidazole radicals, pyrazolyl, pyrrolidinyl, pyrrole radicals, pyrrolin base, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, imidazole radicals sulfydryl, pyrazolinyl, thiadiazolyl group, thiadiazolyl group amino, thiadiazolyl group sulfydryl, morpholinyl, piperazinyl, triazine radical, pyrimidine radicals, hexahydropyrimidine, pyridine radicals, Chromanyl, quinolyl, benzofuranyl, pyrazinyl, pyrazinyl epoxide or piperidyl.

11st, application as claimed in claim 10, shows following formula group：

Wherein, substituted or unsubstituted following groups are represented：Phenyl, C1-C10 alkyl acyls, five yuan or hexa-member heterocycle group；Preferably represent phenyl, substituted-phenyl, C1-C10 alkyl acyls, the C1-C10 alkyl acyls of halo.

12nd, application as claimed in claim 11, wherein, the R₆Represent phenyl, p-methoxyphenyl, benzyl, chlorine propiono. 13, application as claimed in claim 9, wherein, the R4 represents morpholinyl, 4- Phenylpiperazinyls, 1- methyl -5,6- dihydros -1,2,4- triazines -4 (1H)-base, 2- chloromethyls-piperidyl, 2- chloromethyl -4- methyl-piperidyls, 4,6- dimethoxy -2- hexahydropyrimidine bases, 4,6- dimethoxy -5- methyl -2- hexahydropyrimidine bases, the chloro- 4- cyano group -2- pyridine radicals of 6-, the chloro- 4- cyano group -5- methyl -2- pyridine radicals of 6-, 4- oxo -2- Chromanyls, 5- fluorin-4-oxygens -1,2,3,4- tetrahydrochysene -2- quinolyls of generation, benzofuranyl, 3- chlorine propiono -1- piperazines, 5- (azetidinyl -1- carbonyls) -2- Oxopyrazine bases, the small H-2- imidazoles sulfenyl of 1- methyl, 1-H-1- pyrrole radicals, 1- piperidyls, 1,3,4- thiadiazoles -2- amino, the small pyrazolyls of the small H of 3- methyl, the small pyrrolidinyl of 2,5- dioxies, the small H- 1- pyrrole radicals of 2,5- dihydros, 1- pyrrolidinyls, 1,3,4- thiadiazoles -2- sulfenyls, 4- methyl isophthalic acid H- imidazole radicals, 4- methoxyphenylpiperazderivatives bases, 4- benzyl piepridines base or 4- piperidyls.

14th, application as claimed in claim 10, wherein, the R4 represents following formula group：

15th, the application stated such as is weighed, wherein, the R4 represents following formula group:

、、

16th, application as claimed in claim 10, wherein, the R4 represents following formula group：

17th, application as claimed in claim 10, wherein, the expression following formula group:

Wherein R₇Represent hydrogen atom, C1-10 alkyl or C1-C10 haloalkyls； R₈Represent hydrogen atom, C1-C10 alkyl or C1-C10 benzene alkyls；It is preferred that R₇Represent hydrogen atom, methyl or chloromethyl； R₈Represent hydrogen atom, methyl or benzyl.

18th, application as claimed in claim 10, wherein, the R4 represents following formula group：

Wherein, R₉Represent hydrogen atom, C1-C10 alkoxies or C1-C10 alkylthio groups；.And R_uIt is identical or different, represent hydrogen atom or C1-C10 alkyl；It is preferred that R₉Represent hydrogen atom, methoxyl group or methyl；.Standing grain B Ru ffi are same or different, represent hydrogen atom or methyl.

19th, application as claimed in claim 1, the compound that its formula of I is represented is following compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug：

Compound 1

(5S)-[N-3- (the fluoro- 4'- of 3', 5'- bis- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 2

(5S)-[N-3- (3', 5,-two fluoro- 4'- (1 "-methyl -5 ", 6 "-dihydro-Γ ' (Η), 2 ", 4 "-triazine -4- bases) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 3

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 "-chloromethyl -1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 4

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 "-chloromethyl -4 "-methyl isophthalic acids "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 5

(5R)-[Ν -3- (fluoro- 4'- morpholino phenyls of 3'-）- 2- oxo -5- oxazoles alkyl] methanol

Compound 6

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -2 "-hexahydropyrimidines) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 7

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -5 "-methyl -2 "-hexahydropyrimidine) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 8

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 ", 6 "-dimethoxy -2 "-hexahydropyrimidines) phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 9

(5R)-[N-3- (the fluoro- 4'- of 3'_ (4 ", 6 "-dimethoxy -5 "-methyl -2 "-hexahydropyrimidine) phenyl）- 2- oxo -5- oxazoles alkyl] methanol

Compound 10

(_5S)-[_N- 3- (3,-fluoro- 4'- (6 "-chloro- 4 "-cyano group -2 "-pyridine) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 11

(5S)-[N-3- (3,-fluoro- 4'- (6 "-chloro- 4 "-cyano group -5 "-methyl -2 "-pyridine) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 12 (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 13

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-oxo -2 "-Chromanyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 14

(5S)-[N-3- (the fluoro- 4'- of 3'- (5 "-fluoro- 4 "-oxo -1 ", 2 ", 3 ", 4 "-tetrahydrochysene -2 "-quinolyls) and phenyl) -2- oxo -5- Evil oxazolidinyls] methylacetamide

Compound 15

(5S)-[N-3-C3'- fluoro- 4'- (benzofuranyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 16

(the fluoro- 4'- of 5SMN-3-C3'- (4 "-(3 " '-chlorine propiono) -1 "-piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 17

(5SMN-3-C3 '-fluoro- 4'- (5 "-(azetidinyl carbonyl is than piperazine base -2 "-epoxide) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 18

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-methyl-Γ ' (Η)-imidazole radicals -2 "-sulfenyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 19

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 20

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide

Compound 21

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 22

(5R)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide

Compound 23

(5S)-[N-3- (the fluoro- 4'- of 3'- (Γ ' (Η)-Γ '-pyrrole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 24

(5R)-[N-3- (the fluoro- 4'- of 3'- (Γ (Η)-Γ '-pyrrole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 25

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide Compound 26

(5R)-[N-3- 3'- fluoro- 4'-G "-piperidyls) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 27

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and-phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 28

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] methyl chloroacetamide

Compound 29

(5S)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 30

(5R)-[N-3- (3 '-fluoro- 4'- (3 "-methyl-Γ ' (Η)-Β is than oxazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide

Compound 31

(5S)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl）- 2- oxo -5- oxazoles alkyl] methyl chloroacetamide

Compound 32

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 33

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-Β ratios cough up base)-phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 34

(5R)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide

Compound 35

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-Β ratios cough up base) phenyl) -2- oxo -5- oxazoles alkyl] methyl chloroacetamide

Compound 36

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl vinyl amines 37

(5R)-[N-3- 3'- fluoro- 4'-G "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonamide compound 38 (5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and phenyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 39

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and phenyl) -2- oxo -5- oxazoles alkyl] methyl chloroacetamide

Compound 40

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl）- 2- oxo -5- oxazoles alkyl] carbinol compound 41

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 42

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 43

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-methyl-Γ ' (Η)-imidazole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methylamine compound 44

(the fluoro- 4'- of 5RMN-3- 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 45

(5R)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 46

(the fluoro- 4'- of 5SMN-3-C3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 47

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls) phenyl）- 2- oxo -5- oxazoles alkyl] methylamine compound 48

(5S)-[N-3- (the fluoro- 4'- of 3'- (Γ ' (Η)-pyrrole radicals) phenyl）- 2- oxo -5- oxazoles alkyl] methylamine

Compound 49

(5R)-[N-3- (the fluoro- 4'- of 3'- (Γ (Η)-mouth ratio coughs up base) phenyl）- 2- oxo -5- oxazoles alkyl] methanol

Compound 50

(5R)-[N-3- (the fluoro- 4'- of 3'- (Γ ' (Η)-Β ratios cough up base) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 51

(5S)-[N-3- (the fluoro- 4'- of 3'_ (Γ ' (Η)-pyrrole radicals) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 52 (5S)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 53

(5S)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl-Γ ' (Η)-pyrazolyl) phenyl）5- oxazoles alkyl] methylamine

Compound 54

(5R)-[N-3- (the fluoro- 4'- of 3'- (3 "-methyl-Γ ' (Η)-Β is than oxazolyl) phenyl）- 2- oxo -5- oxazoles alkyl] carbinol compound 55

(5R)-[N-3- (3 '-fluoro- 4'- (3 "-methyl-Γ ' (Η)-Β is than oxazolyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 56

(5R)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 57

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-Β ratios cough up base)-phenyl) -2- oxo -5- oxazoles alkyl] methylamine compound 58

(5R)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-pyrrole radicals)-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 59

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dihydro-Γ ' (Η)-Β ratios cough up base)-phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 60

(the fluoro- 4'- of 5RMN-3- 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methanol

Compound 61

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylamine

Compound 62

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 63

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 64

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and-phenyl）- 2- oxo -5- oxazoles alkyl] carbinol compound 65

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and-phenyl）- 2- oxo -5- oxazoles alkyl] methylamine compound 66

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2- " sulfenyls) and-phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide Compound 67

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-sulfenyls) and-phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 68

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methanol

Compound 69

(5S)-[N-3- (the fluoro- 4'- of 3'- (Γ-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl) methylamine

Compound 70

(the fluoro- 4'- of 5RMN-3- 3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 71

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 "-piperidyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 72

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 73

(5S)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] methylamine compound 74

(5R)-[N-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) and phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 75

(58)-^-3- (the fluoro- 4'- of 3'- (1 ", 3 ", 4 "-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 76

(5SMN-3- acetyl group -2- oxo -5- oxazoles alkyl) methylacetamide

Compound 77

(5S, 2'R)-[N-3- (2'- phenyl-Γ-piperidyl) 2- oxo -5- oxazoles alkyl] methylacetamide

Compound 78

(5S, 2'S)-[N-3- (2'- phenyl-Γ-piperidyl) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 79

(5S)-[N-3- (2'- hydroxyl -4'- pyrimidine radicals) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 80

(5S)-[N-3- (2'- acetyl group epoxide -4'- pyrimidine radicals) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 81

(5S)-[N-3- (4'- oxazolyls) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 82 (5S)-[N-3-_lThe chloro- 4'- cyano group -2'- pyridines of 6'-) -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 83

(5R)-[the fluoro- 4'- morpholinyls of N-3- 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate tenth of the twelve Earthly Branches i compounds 84

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl p-methyl benzenesulfonic acid ester compounds 85 of N-3- 3'-

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazolidines ethyl methyl acetic acid esters of N-3- 3'-

Compound 86

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl imidazoles of N-3- 3'-

Compound 87

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl -2- sulfenyls -1,3 of N-3- 3'-, 4 thiadiazole compounds 88

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazole alkyl methyls -1,2 of N-3- 3'-, 4-1 H- 3-triazole compounds 89

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl -1H- tetrazotized zole compounds 90 of N-3- 3'-

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl camphorimide compounds 91 of N-3- 3'-

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl sulfenyl tetrazotized zole compounds 92 of N-3- 3'-

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl phthalyl group with imine moiety 93 of N-3- 3'-

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl -2- sulfenyls benzimidazole compounds 94 of N-3- 3'-

(5R)-[fluoro- 4'- morpholino phenyls -2- oxos -5- oxazoles alkyl methyl succimide compounds 95 of N-3- 3'-

(5R)-[the fluoro- 4'- morpholinyls of N-3- 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl benzotriazazole compound 96

(5R)-[N-3- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methanol

Compound 97

(5R)-[N-3- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 98

(5R)-[N-3- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 99 (5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 100

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- triazoles

Compound 101

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide

Compound 102

(5R)-[N-3- (4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 103

(5S)-[the chloro- 4'- morpholinyls of N-3-C3'-) phenyl -2- oxo -5- oxazoles alkyl] methanol

Compound 104

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 105

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'_) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 106

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methylacetamide

Compound 107

(5S)-[N-3- (3,-chloro- 4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 108

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide

Compound 109

(5S)-[N-3- (the chloro- 4'- morpholinyls of 3'-) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 110

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methanol

Compound 111

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 112

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl phthalimide compound 113

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl vinyl amines 114

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 115

(5S)-[N-3- (3'- trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl camphorimide compound 116 (5S)-[N-3- (3'_ trifluoromethyl -4'- morpholinyls) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide compound 117

(the fluoro- 4'- of 5RMN-3- 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methanol

Compound 118

(5R)-[the fluoro- 4'- of N-3- 3'- (4 "-Phenylpiperazinyl) phenyl -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 119

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 120

(5R)-[N-3- (3,-fluoro- 4'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- triazoles

Compound 121

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl 2- oxo -5- oxazoles alkyl] methyl camphorimide compound 122

(5R)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl -2- oxo -5- oxazoles alkyl] methyl succimide compound 123

(5SMN-3-C3 '-fluoro- 4'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] carbinol compound 124

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester

Compound 125

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 126

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl -

1,2,4-1 H- triazoles

Compound 127

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl camphorimide

Compound 128

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 129

(5SMN-3-C3 '-fluoro- 4'- (4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazoles alkyl] methanol Compound 130

(5S)-[N-3-C3 '-fluoro- 4'- (4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazoles alkyl] methylmethanesulfonate ester compounds 131

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazoles alkyl] methyl phthalimide

Compound 132

(5S)-[N-3- (3,-fluoro- 4'- (4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- triazoles

Compound 133

(5S)-[N-3-C3'- fluoro- 4'4 "-benzyl piepridines base) phenyl) -2- oxo -5- oxazoles alkyl] methyl camphorimide compound 134

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazoles alkyl] methyl succimide compound 135

(5R)-[N-3- (3,-fluoro- 4'- piperidinophenyls) -2- oxo -5- oxazoles alkyl] methyl isophthalic acid, 2,4-1H- 3-triazole compounds 136

(5R)-[the fluoro- 4'- piperidinophenyls of N-3- 3'-) -2- oxo -5- oxazoles alkyl] methyl camphorimide

Compound 137

(5R)-[N-3- (the fluoro- 4'- piperidinophenyls of 3'-) -2- oxo -5- oxazoles alkyl] methyl succimide

Compound 138

(5S)-[N-3- (the fluoro- 4'- of 3'- (2 ", 5 "-dioxo -1 "-pyrrolidinyls)-phenyl) -2- oxo -5- oxazoles alkyl] methyl chloroacetamide

Compound 139

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide semihydrate

Compound 140

The hydrate of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 2/7

Compound 141

The hydrate of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 2/5

Compound 142

The hydrate of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 1/12

Compound 143 The hydrate of (5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl)-2--5-oxazoles of oxo alkyl] methylacetamide 3/4.

20th, the application as described in claim 1-19 any one, wherein compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that the formula I is represented can be used in any combination or be used alone.

21st, the application as described in claim 1-20 any one, wherein the medicine is clinically acceptable any formulation, including but not limited to oral formulations and ejection preparation.

22nd, the application as described in claim 1-21 any one, wherein, described micobacterial conditions are the infectious diseases caused by mycobacteria infections human body or animal body, including but not limited to tuberculosis and leprosy.

23, application as described in claim 1-21 any one, wherein, the mycobacterium is bird type Mycobacterium tuberculosis, ox [type] Mycobacterium tuberculosis, Mycobacterium butyricum, mycobacterium chelonei, Mycobacterium lacticola, mycobacterium friedmannii, mycobacterium graminis, johne's bacillus, Mycobacterium lacticola, hansen's bacillus, mycobacterium marinum, johne's bacillus, mycobacterium graminis, bacillus tuberculosis piscium, mycobacterium ranae, mycobacterium rhusiopathiae, smegma bacillus, mycobacterium stercoris, mycobacterium thamnopheos or Mycobacterium tuberculosis.

24th, application as claimed in claim 22, wherein the micobacterial conditions are tuberculosis.

25th, application as claimed in claim 24, wherein described tuberculosis is primary pulmonary tuberculosis, hematogenous pulmonary tuberculosis, secondary tuberculosis of lung, tuberculous pleurisy, tuberculous osteoarthropathy, tubercular meningitis, nephrophthisis or intestinal tuberculosis.

26th, it is a kind of to be used to prevent or treat tuberculosis composition, the pharmaceutical composition contains the compound or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug that formula I is represented described in claim 1 to 19 any one as active component, or its any combination, and pharmaceutically useful assistant agent.

27th, pharmaceutical composition as claimed in claim 26, the wherein described common dosage of active component is 0.01 2000mg/ days, it is preferred that the dosage is 0.01 1800mg, more preferably 0.1 1500mg, it is further preferred for l 1200mg.

28th, the pharmaceutical composition as described in claim 26 or 27, wherein the active component is 0.05-100% by weight in the composition.

29th, it is a kind of to prevent or treat method lungy, this method includes the compound that formula I is represented described in claim 1 to 19 any one to patient therapeuticallv's effective dose or its pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug, or its any combination, or the pharmaceutical composition described in claim 26-28 any one.