CN104364240B

CN104364240B - Drug for preventing or treating mycobacterial diseases

Info

Publication number: CN104364240B
Application number: CN201380029863.5A
Authority: CN
Inventors: 阙峰; 王莹
Original assignee: SICHUAN BEILIKE BIOTECHNIC CO Ltd
Current assignee: SICHUAN BEILIKE BIOTECHNIC CO Ltd
Priority date: 2012-06-08
Filing date: 2013-06-06
Publication date: 2017-02-22
Anticipated expiration: 2033-06-06
Also published as: CN104364240A; WO2013182070A1

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

A kind of medicine for preventing or treating micobacterial conditions

Technical field

The invention belongs to field of medicaments, relate to prevent or treat the compound of micobacterial conditions, specifically, this Invent described compound to be used for preventing or treat tuberculosis.

Background technology

Mycobacterium species is a lot of, has pathogenic and non-pathogenic two big class.Cause human diseasess has：(1) human-like With the infection caused by bacillus tuberculosis bovis and several anonymous mycobacteria；(2) leprosy.These infection are most to be chronic infection Process, long-term delay, and damaging lesion tissue.

Tuberculosis be by mycobacterium tuberculosis complex (Mycobacterium tuberculosis complex, referred to as Mycobacterium tuberculosis or tulase) chronic infectious disease that causes, can involve whole body multiple organ system, modal illness portion Position is lungs, accounts for the 80-90% of each organ tuberculosis sum；The organs such as liver, kidney, brain, lymph node can also be involved.Main biography The approach of broadcasting has respiratory tract, digestive tract, skin and uterus, but mainly passes through respiratory infectious.The pulmonary tuberculosis patient sputum of discharge of bacteria After drying, antibacterial, with stirring up a cloud of dust, is sucked by other people and causes infection, and whether human body sucks the spittle containing mycobacterium tuberculosis Ill main relevant with many factors such as the quantity sucking tulase, virulence, the resistances of human body.Tuberculosis are a kind of serious danger Do harm to the chronic infectious disease of people's health, the whole world has about 2,000,000,000 people infected at present, and tulase carrier sickness rate can account for 80%, often Newly tuberculosis patient about 800-1000 ten thousand in year, and leads to 3,000,000 people dead.

In recent years, the non-government organization such as World Health Organization (WHO), global tubercular drugs development alliances, related pharmaceutical factory all increases The input of tuberculosis prevention and treatment aspect, national governments also all support correlational study energetically.Invent isoniazid in nineteen fifty-two, invention Rifampicin in nineteen sixty-five makes treatment lungy there occurs leap.But, with the use of these good antituberculotics, While a large amount of tuberculosis patient rehabilitation, also bring the popular problem of multi-drug resistance tuberculosis.The treatment of Current therapeutic pulmonary tuberculosis Journey is long, and method is complicated, and many patients can not complete to treat so that this sick drug resistance constantly strengthens, become one increasingly serious Global health threaten.The whole world occurs more than 50 million new drug-tolerant pulmonary tuberculosis examples every year.WHO antituberculosis drug resistance is reported Display：In population, drug resistance situation has reached top level, and multi-drug resistance tuberculosis are still in helically ascendant trend.As This trend cannot be reversed in time, and drug-tolerant pulmonary tuberculosis will cause the epidemic situation that cannot cure.Multi-drug resistant and extensive resistant tuberculosis It is difficult to cure, great bodily injury is caused to the physical and mental health of patient, its harm is no less than cancer, almost incurable disease.More fearful Be by the individuality of these patient infection, once morbidity be exactly multi-drug resistant and extensive resistant tuberculosis patient, this to individual, family With social danger greatly, also grave danger is constituted to tuberculosis prevention and treatment, it has also become seriously threaten the great public of human health Hygienic issues and social problem.

The whole world is treated first-line drug lungy and is mostly still relied on what a few was invented before four, 50 years at present Medicine, and Second line Drug is often expensive and first-line drug effect relatively is not satisfactory, course for the treatment of length, weak curative effect, untoward reaction Seriously.

The limitation of existing medicine, makes tuberculosis be tantamount to " time bomb " being suspended on human tau, once can not Effective control, consequence is hardly imaginable.Therefore, mycobacteria infections can effectively be prevented and treated in the urgent need to one kind, especially effectively anti- Control tuberculosis.

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

In formula, R1 represents the alkyl, halogen atom or haloalkyl that hydrogen atom, carbon number are 1～6, described alkyl halide Base is the alkyl that the carbon number that one or more halogen atoms replace is 1～6；R2 represents morpholinyl, piperidyl, 4- benzyl Phenylpiperidines base, 4- Phenylpiperazinyl or 4- (4 '-methoxyl group) Phenylpiperazinyl；R3 represents imidodicarbonic diamide base, five-ring heterocycles group, Described five-ring heterocycles group is imidazole radicals, thiadiazolyl group, triazol radical, tetrazole base or BTA base.But this article Offer and do not refer to that these compounds can be used to treat micobacterial conditions, especially tuberculosis.

Content of the invention

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

The invention provides the compound that represents of below formula I or its pharmaceutically acceptable salt, hydrate, solvation Thing, coordination compound or prodrug are in preparation for preventing or treating the purposes in micobacterial conditions.

Present invention also offers one kind is used for preventing or treat tuberculosis compositionss, this pharmaceutical composition contains work The compound representing for the described formula I of active component or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound Or prodrug, or its combination in any, and medicinal adjuvant.

Present invention also offers a kind of prevention or treatment method lungy, the method includes effective to patient therapeuticallv Compound or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug that the described formula I of amount represents, or Its combination in any, or described pharmaceutical composition.

The compound that formula I of the present invention represents is being treated or is being prevented mycobacterial infectionses, especially tubercule bacillus sense Dye, particularly drug resistance tubercule bacillus aspect has remarkable result.

Specific embodiment

R in the compound that the above-mentioned formula I of the present invention represents₁Represent hydroxyl, amino or substituted or unsubstituted following base Group：C1-C10 amido, two (C1-C10) imido grpup, C1-C10 amide groups, C1-C10 acyl imine base, two (C1-C10 acyl group) are sub- Amido, C1-C10 sulfoamido, C1-C10 sulfonyloxy, C1-C10 alkanoyl 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 group；Or under Formula group：

Wherein,

R₃And R₅Represent H, halogen atom or haloalkyl independently of one another；

R₄Represent substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, alcoxyl Base, aralkyl oxy, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl, five yuan or hexa-member heterocycle base amido, benzo are miscellaneous Ring group amido.

In situations where it is preferred, the R in formula I₁Represent hydroxyl, amino, C1-C10 alkylamino radical, C1-C10 aromatic alkyl amine Base, C1-C10 aromatic radical amido, two (C1-C10 alkyl) imido grpup, two (C1-C10 aromatic radical) imido grpup, C1-C10 alkyl virtue Perfume base imido grpup, two (C1-C10 aromatic alkyl) imido grpup, C1-C10 alkylamidoalkyl, C1-C10 aromatic alkyl amide groups, C1- C10 aromatic radical amide groups, halo C1-C10 alkylamidoalkyl, halo C1-C10 aromatic alkyl amide groups, halo C1-C10 fragrance Base amide groups, C1-C10 alkylsulfonamido, C1-C10 aromatic alkyl sulfoamido, C1-C10 aromatic radical sulfoamido, halo C1-C10 alkylsulfonamido, halo C1-C10 aromatic alkyl sulfoamido, halo C1-C10 aromatic radical sulfoamido, C1-C10 Aromatic radical sulfonyloxy, C1-C10 alkylsulfonyloxy, C1-C10 aromatic alkyl sulfonyloxy, halo C1-C10 aromatic radical sulphonyl Epoxide, halo C1-C10 alkylsulfonyloxy, halo C1-C10 aromatic alkyl sulfonyloxy, two (C1-C10 aromatic radical acyl group) are sub- Amido, two (C1-C10 alkanoyl) imido grpup, two (C1-C10 aromatic alkyl acyl group) imido grpup, C1-C10 alkanoyl epoxide, halogen For C1-C10 alkanoyl epoxide, substituted or unsubstituted five yuan or hexa-member heterocycle group, five yuan or hexa-member heterocycle base sulfydryl or benzene And heterocyclic radical sulfydryl.In a more preferred case, the R in formula I₁Represent hydroxyl, amino, methylamino, ethylamino-, benzyl amine Base, anilino-, dimethyliminio, diethyl imido grpup, diphenyl imine base, benzhydryl imido grpup, formamido, acetyl Amido, propionamido-, halo formamido, 1- haloacetyl amido, methylsulfonyl amido, ethanesulfonamide group, mesyloxy, second Sulfonyloxy, benzyl sulfonyloxy, phthalimide-based, dicarboximide base, diethyl imide, acetyl group oxygen Base, succinyl imido grpup, p-toluenesulfonyl epoxide, 1,3,4- thiadiazolyl group sulfydryls, 1,2,4-1H- triazol radicals, 1H- tetra- Nitrogen oxazolyl, tetrazole base sulfydryl, benzimidazole 2- sulfydryl, BTA base, imidazole radicals or camphorimide base.For example, exist R in the particular compound that the present invention provides, in formula I₁Represent hydroxyl, amino, acetamido, chloracetyl amido, methylsulfonyl Amido, mesyloxy, ethanesulfonyloxy group, phthalimide-based, dicarboximide base, succinyl imido grpup, to first Benzenesulfonyl epoxide, 1,3,4- thiadiazolyl group sulfydryls, 1,2,4-1H- triazol radicals, 1H- tetrazole base, tetrazole base sulfydryl, benzene And imidazoles 2- sulfydryl, 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, pyrrole Oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 4- morpholinyl, piperazinyl, piperazine Piperidinyl, pyrimidine radicals, oxazolyl, pyridine radicals；Or C1-C4 acyl group；Or following formula group：

Wherein,

R₄Represent substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, alcoxyl Base, 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, replacement or not Pyrimidine radicals, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridine radicals or the following formula group replacing：

Wherein,

In situations where it is preferred, the R in formula I₂Represent that acetyl group, 2- Phenylpiperidine base, 2- hydroxy pyrimidine base, 6- are chloro- 4- cyano group -2- pyridine radicals, 4- oxazolyl or 2- acetoxyl group pyrimidine radicals.

In situations where it is preferred, the compound that the compound that formula I represents represents for general formula II：

Wherein, R₁As defined above；

R₃And R₅Represent H, F, Cl or CF independently of one another₃；

R₄Represent substituted or unsubstituted following groups：Five yuan or hexa-member heterocycle, five yuan or hexa-member heterocycle base epoxide, alcoxyl Base, aralkyl oxy, five yuan or hexa-member heterocycle base sulfydryl, benzheterocycle base sulfydryl.In situations where it is preferred, described R₄Expression takes Generation or unsubstituted following groups：Pyrrole radicals, imidazole radicals, pyrazolyl, pyrrolidinyl, pyrrole radicals, pyrrolin base, pyrrolin Base, imidazolidinyl, imidazolinyl, pyrazolidinyl, imidazole radicals sulfydryl, pyrazolinyl, thiadiazolyl group, thiadiazolyl group amino, thiophene two Oxazolyl sulfydryl, morpholinyl, piperazinyl, triazine radical, pyrimidine radicals, hexahydropyrimidine, pyridine radicals, Chromanyl, quinolyl, benzofuran Base, pyrazinyl, pyrazinyl epoxide or piperidyl.

Specifically, described R₄Represent morpholinyl, 4- Phenylpiperazinyl, 1- methyl -5,6- dihydro -1,2,4- triazines -4 (1H)-base, 2- chloromethyl-piperidyl, 2- chloromethyl -4- methyl-piperidyl, 4,6- dimethoxy -2- hexahydropyrimidine base, 4,6- Dimethoxy -5- methyl -2- hexahydropyrimidine base, 6- chloro- 4- cyano group -2- pyridine radicals, 6- chloro- 4- cyano group -5- methyl -2- pyridine Base, 4- oxo -2- Chromanyl, 5- fluorin-4-oxygen generation -1,2,3,4- tetrahydrochysene -2- quinolyls, benzofuranyl, 3- chlorine propiono -1- Piperazine, 5- (azetidinyl -1- carbonyl) -2- Oxopyrazine base, 1- methyl isophthalic acid-H-2- imidazoles sulfenyl, 1-H-1- pyrrole radicals, Piperidino, 1,3,4- thiadiazoles -2- amino, 3- methyl isophthalic acid-H-1- pyrazolyl, 2,5- dioxy -1- pyrrolidinyl, 2,5- bis- Hydrogen -1-H-1- pyrrole radicals, 1- pyrrolidinyl, 1,3,4- thiadiazoles -2- sulfenyls, 4- methyl isophthalic acid H- imidazole radicals, 4- methoxyphenyl Piperazinyl, 4- benzyl piepridine base or 4- piperidyl.

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

R₄Following formula group can also be represented：

In addition, the R in the compound that represents of formula II₄Following formula group can be represented：

R₄Following formula group can also be represented：

Wherein R₇Represent hydrogen atom, C1-10 alkyl or C1-C10 haloalkyl；R₈Represent hydrogen atom, C1-C10 alkyl or C1-C10 benzene alkyl；Preferably R₇Represent hydrogen atom, methyl or chloromethyl；R₈Represent hydrogen atom, methyl or benzyl.

Additionally, the R in the compound that represents of formula II₄Following formula group can be represented：

Wherein, R₉Represent hydrogen atom, C1-C10 alkoxyl or C1-C10 alkylthio group；R₁₀And R₁₁Identical or different, represent hydrogen Atom or C1-C10 alkyl；Preferably R₉Represent hydrogen atom, methoxyl group or methyl；R₁₀And R₁₁Identical or different, represent hydrogen atom or Methyl.

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

Wherein, R₁、R₃, R₅As defined above；

R₆Represent substituted or unsubstituted following groups：Phenyl, aralkyl, alkyl acyl, five yuan or hexa-member heterocycle group. Preferably, R₆Represent phenyl, substituted-phenyl, the alkyl acyl of phenylalkyl, alkyl acyl or halo.Such as R₆Represent replace or Unsubstituted following groups：Phenyl, benzyl, C1-C10 alkyl acyl, five yuan or hexa-member heterocycle group；Preferably R₆Represent benzene Base, substituted-phenyl, the C1-C10 alkyl acyl of benzyl, C1-C10 alkyl acyl or halo.Specifically, R₆Represent phenyl, right Methoxyphenyl, benzyl or chlorine propiono.

In the present invention, the description of the similar fashion such as " C1-C10 " refers to the carbon atom number that modified group has, example As C1-C10 alkyl refers to straight chained alkyl, branched alkyl or the cycloalkyl with 1-10 carbon atom, such as include methyl, second Base, n-pro-pyl, isopropyl, the tert-butyl group, n-hexyl, cyclopropyl etc..

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

" substituted " refers to hydrogen atom on defined group by other atoms or substituent group, such as by one or many Individual halogen atom replaces.

In the present invention, five yuan or hexa-member heterocycle group refer to saturation, fractional saturation or undersaturated five yuan or hexa-atomic ring body System, wherein at least one carbon atom is by N, O, S, SO, SO₂Replace, such as imidazole radicals, thiazolyl, thiadiazolyl group, triazol radical, four Nitrogen oxazolyl, piperidyl, pyrimidine radicals, piperazinyl, morpholinyl, furyl, tetrahydrofuran base, pyrazinyl, pyrrole radicals, pyrrolidinyl, Pyrazolyl, pyrazolidinyl, oxazolyl, oxazolidinyl, Chromanyl, quinolyl, pyrrolin base or hexahydropyrimidine base etc..

In the present invention, benzo five-membered heterocycle or benzo hexa-member heterocycle refer to quinoline, benzofuran, benzimidazole or benzo three Nitrogen azoles etc..

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

Indication micobacterial conditions of the present invention refer to the antibacterial of mycobacterium as pathogen or its association, detect or set Any disease of meter mycobacteria infections, disease, pathology, symptom, clinical disease or syndrome.Described micobacterial conditions bag Include Mycobacterium tuberculosiss, non-tuberculous mycobacteria infection or associated micobacterial conditions, such as various forms of tuberculosis, Leprosy etc..

Compound that the described formula I of the present invention represents or its pharmaceutically acceptable salt, hydrate, solvate, join Compound or prodrug can be used for preventing or treat tuberculosis or leprosy it is preferred that being used for preventing or treating tuberculosis.

The present invention's contains the described formula I table as active component for preventing or treating tuberculosis compositionss The compound showing or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug, or its combination in any, and Medicinal adjuvant.

In the pharmaceutical composition of the present invention, the common dosage of wherein said active component is 0.01～2000mg/ days, preferably , described dosage is 0.01～1800mg, more preferably 0.1～1500mg, further preferred for 1～1200mg.Additionally, Described active component is 0.05-100% in the composition by weight.

The prevention of the present invention or treat method lungy include compound that the formula I of therapeutically effective amount is represented or its Pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug are applied to patient in need for the treatment of.

" therapeutically effective amount " in the present invention refers to effective dose when to the individual administration needing, the such as mankind or inhuman Class, with mitigation symptoms or avoid further mycobacteria infections.

The pharmaceutically acceptable salt of the compound that heretofore described formula I represents includes sodium, potassium, calcium, aluminum, magnesium, zinc Or other slaines and ammonium salt.May also be the salt of organic acid, such as acetate, lactate, citrate, tartrate, Malaysia Hydrochlorate, malate, fumarate, benzoate, mesylate, benzene sulfonate.May also be inorganic acid salt, example hydrochloric acid salt, sulfur Hydrochlorate, hydrobromate, phosphate and sulfonate etc..

The hydrate of the compound that formula I represents includes its semihydrate, 3/4 hydrate, 2/7 hydrate, 2/5 hydration Thing, 1/12 hydrate.

Can also use as intermediate or prodrug as the salt pharmaceutically accepting, hydrate, coordination compound, solvate.

" prodrug " of the present invention refers to be converted in vivo the compound that formula I represents or it is pharmaceutically acceptable Salt, thus have the material of identical pharmacological action with the compound that formula I represents.

In the present invention, if the isomeric form of the compound that formula I represents, it includes enantiomer or isomer Form of ownership is all included in the present invention.Compound that formula I of the present invention containing chiral centre represents or its pharmaceutically may be used Salt, hydrate, solvate, coordination compound or the prodrug accepting can be used with racemic mixture or be carried out using known technology Separate and be used alone.

Preferably, the formula I of the present invention represents compound or its pharmaceutically acceptable salt, hydrate, solvate, Coordination compound or prodrug are following compound：

Compound 1

(5S)-[N-3- (3 ', 5 '-two fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl Acetamide

Compound 2

(5S)-[N-3- (3 ', 5 '-two fluoro- 4 '-(1 "-methyl -5 ", 6 " and-dihydro -1 " (H), and 2 ", 4 "-triazine -4- base) benzene Base) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 3

(5S)-[N-3- (3 '-fluoro- 4 '-(2 "-chloromethyl -1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methyl Acetamide

Compound 4

(5S)-[N-3- (3 '-fluoro- 4 '-(2 "-chloromethyl -4 "-methyl isophthalic acid "-piperidyl) phenyl) -2- oxo -5- azoles Alkyl] methylacetamide

Compound 5

(5R)-[N-3- (3 '-fluoro- 4 '-morpholino phenyl) -2- oxo -5- oxazolidinyl] methanol

Compound 6

(5S)-[N-3- (3 '-fluoro- 4 '-(4 ", 6 "-dimethoxy -2 "-hexahydropyrimidine) phenyl) -2- oxo -5- oxazolidine Base] methylacetamide

Compound 7

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

Compound 8

(5R)-[N-3- (3 '-fluoro- 4 '-(4 ", 6 "-dimethoxy -2 "-hexahydropyrimidine) phenyl) -2- oxo -5- oxazolidine Base] methanol

Compound 9

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

Compound 10

(5S)-[N-3- (3 '-fluoro- 4 '-(6 "-chloro- 4 "-cyano group -2 "-pyridine) phenyl) -2- oxo -5- oxazolidinyl] first Yl acetamide

Compound 11

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

Compound 12

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 13

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-oxo -2 "-Chromanyl) phenyl) -2- oxo -5- oxazolidinyl] methyl second Amide

Compound 14

(5S)-[N-3- (3 '-fluoro- 4 '-(5 "-fluoro- 4 "-oxo -1 ", 2 " and, 3 ", 4 " and-tetrahydrochysene -2 "-quinolyl) phenyl) - 2- oxo -5- oxazolidinyl] methylacetamide

Compound 15

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

Compound 16

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-(3 " '-chlorine propiono) -1 "-piperazinyl) phenyl) -2- oxo -5- azoles Alkyl] methylacetamide

Compound 17

(5S)-[N-3- (3 '-fluoro- 4 '-(5 "-(azetidinyl -1 " '-carbonyl)-pyrazinyl -2 "-epoxide) phenyl) - 2- oxo -5- oxazolidinyl] methylacetamide

Compound 18

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-methyl isophthalic acid " (H)-imidazole radicals -2 "-sulfenyl) phenyl) -2- oxo -5- azoles Alkyl] methylacetamide

Compound 19

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first Yl acetamide

Compound 20

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first Base Methanesulfomide

Compound 21

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl)-phenyl) -2- oxo -5- oxazolidine Base] methylacetamide

Compound 22

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl)-phenyl) -2- oxo -5- oxazolidine Base] methylmethanesulfonamide

Compound 23

(5S)-[N-3- (3 '-fluoro- 4 '-(1 " (H) -1 "-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] methyl vinyl Amine

Compound 24

(5R)-[N-3- (3 '-fluoro- 4 '-(1 " (H) -1 "-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] methyl first sulphur Amide

Compound 25

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 26

(5R)-[N-3- (3 '-fluoro- 4 '-(1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methylmethanesulfonamide

Compound 27

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-amino)-phenyl) -2- oxo -5- oxazolidine Base] methylacetamide

Compound 28

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazolidinyl] Methyl chloroacetamide

Compound 29

(5S)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazolidinyl] first Yl acetamide

Compound 30

(5R)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazolidinyl] first Base Methanesulfomide

Compound 31

(5S)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazolidinyl] first Base chloroacetamide

Compound 32

Compound 33

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals)-phenyl) -2- oxo -5- oxazolidine Base] methylacetamide

Compound 34

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals)-phenyl) -2- oxo -5- oxazolidine Base] methylmethanesulfonamide

Compound 35

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] Methyl chloroacetamide

Compound 36

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 37

(5R)-[N-3- (3 '-fluoro- 4 '-(1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidinyl] methylmethanesulfonamide

Compound 38

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-sulfenyl) phenyl) -2- oxo -5- oxazolidinyl] Methylacetamide

Compound 39

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-sulfenyl) phenyl) -2- oxo -5- oxazolidinyl] Methyl chloroacetamide

Compound 40

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first Alcohol

Compound 41

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first Base methanesulfonates

Compound 42

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first Base phthalimide

Compound 43

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first Amine

Compound 44

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidine Base] methanol

Compound 45

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidine Base] methylmethanesulfonate ester

Compound 46

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidine Base] methyl phthalimide

Compound 47

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidine Base] methylamine

Compound 48

(5S)-[N-3- (3 '-fluoro- 4 '-(1 " (H)-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] methylamine

Compound 49

(5R)-[N-3- (3 '-fluoro- 4 '-(1 " (H)-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] methanol

Compound 50

(5R)-[N-3- (3 '-fluoro- 4 '-(1 " (H)-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] methylmethanesulfonate Ester

Compound 51

(5S)-[N-3- (3 '-fluoro- 4 '-(1 " (H)-pyrrole radicals) phenyl) -2- oxo -5- oxazolidinyl] methyl neighbour's benzene two Carboximide

Compound 52

(5S)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazolidinyl] first Base phthalimide

Compound 53

(5S)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) 5- oxazolidinyl] methylamine

Compound 54

(5R)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazolidinyl] first Alcohol

Compound 55

(5R)-[N-3- (3 '-fluoro- 4 '-(3 "-methyl isophthalic acid " (H)-pyrazolyl) phenyl) -2- oxo -5- oxazolidinyl] first Base methanesulfonates

Compound 56

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals)-phenyl) -2- oxo -5- oxazolidine Base] methanol

Compound 57

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals)-phenyl) -2- oxo -5- oxazolidine Base] methylamine

Compound 58

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals)-phenyl) -2- oxo -5- oxazolidine Base] methylmethanesulfonate ester

Compound 59

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dihydro -1 " (H)-pyrrole radicals)-phenyl) -2- oxo -5- oxazolidine Base] methyl phthalimide

Compound 60

(5R)-[N-3- (3 '-fluoro- 4 '-(1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidinyl] methanol

Compound 61

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidinyl] methylamine

Compound 62

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

Compound 63

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl O-phthalic Acid imide

Compound 64

(5R)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-sulfenyl)-phenyl) -2- oxo -5- oxazolidine Base] methanol

Compound 65

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-sulfenyl)-phenyl) -2- oxo -5- oxazolidine Base] methylamine

Compound 66

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2- " sulfenyl)-phenyl) -2- oxo -5- oxazolidine Base] methyl phthalimide

Compound 67

(5R)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-sulfenyl)-phenyl) -2- oxo -5- oxazolidine Base] methylmethanesulfonate ester

Compound 68

(5R)-[N-3- (3 '-fluoro- 4 '-(1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methanol

Compound 69

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl) methylamine

Compound 70

(5R)-[N-3- (3 '-fluoro- 4 '-(1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methylmethanesulfonate ester

Compound 71

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methyl phthalyl Imines

Compound 72

(5R)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazolidinyl] Methanol

Compound 73

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazolidinyl] Methylamine

Compound 74

(5R)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazolidinyl] Methylmethanesulfonate ester

Compound 75

(5S)-[N-3- (3 '-fluoro- 4 '-(1 ", 3 ", 4 " and-thiadiazoles -2 "-amino) phenyl) -2- oxo -5- oxazolidinyl] Methyl phthalimide

Compound 76

(5S)-(N-3- acetyl group -2- oxo -5- oxazolidinyl) methylacetamide

Compound 77

(5S, 2 ' R)-[N-3- (2 '-phenyl -1 '-piperidyl) 2- oxo -5- oxazolidinyl] methylacetamide

Compound 78

(5S, 2 ' S)-[N-3- (2 '-phenyl -1 '-piperidyl) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 79

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

Compound 80

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

Compound 81

(5S)-[N-3- (4 '-oxazolyl) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 82

(5S)-[N-3- (6 '-chloro- 4 '-cyano group -2 '-pyridine) -2- oxo -5- oxazolidinyl] methylacetamide

Compound 83

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylmethanesulfonate ester

Compound 84

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl p-toluenesulfonic esters

Compound 85

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl acetic acid ester

Compound 86

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] Methylimidazole.

Compound 87

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl -2- sulfenyl -1,3,4 thiophenes Diazole

Compound 88

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl isophthalic acid, 2,4-1H- tri- nitrogen Azoles

Compound 89

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl isophthalic acid H- tetrazole

Compound 90

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl camphorimide

Compound 91

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylsulfany tetrazole

Compound 92

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl phthalyl base is sub- Amine

Compound 93

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl -2- sulfenyl benzimidazole

Compound 94

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl succimide

Compound 95

(5R)-[N-3- (3 '-fluoro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl benzotriazazole

Compound 96

(5R)-[N-3- (4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methanol

Compound 97

(5R)-[N-3- (4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylmethanesulfonate ester

Compound 98

(5R)-[N-3- (4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl phthalimide

Compound 99

(5R)-[N-3- (4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylacetamide

Compound 100

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

Compound 101

(5R)-[N-3- (4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl camphorimide

Compound 102

(5R)-[N-3- (4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl succimide

Compound 103

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methanol

Compound 104

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylmethanesulfonate ester

Compound 105

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl phthalimide

Compound 106

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylacetamide

Compound 107

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl isophthalic acid, 2,4-1H- tri- nitrogen Azoles

Compound 108

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl camphorimide

Compound 109

(5S)-[N-3- (3 '-chloro- 4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl succimide

Compound 110

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methanol

Compound 111

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylmethanesulfonate ester

Compound 112

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl O-phthalic Acid imide

Compound 113

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methylacetamide

Compound 114

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl isophthalic acid, 2,4- 1H- triazole

Compound 115

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl camphoroyl Asia Amine

Compound 116

(5S)-[N-3- (3 '-trifluoromethyl -4 '-morpholinyl) phenyl -2- oxo -5- oxazolidinyl] methyl succinyl Asia Amine

Compound 117

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methanol

Compound 118

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl -2- oxo -5- oxazolidinyl] methylmethanesulfonate Ester

Compound 119

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl neighbour's benzene two Carboximide

Compound 120

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

Compound 121

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl camphoroyl Imines

Compound 122

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl -2- oxo -5- oxazolidinyl] methyl succinyl Imines

Compound 123

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazolidine Base] methanol

Compound 124

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-(4 " '-methoxyphenyl) piperazinyl) phenyl) -2- oxo -5- oxazolidine Base] methylmethanesulfonate ester

Compound 125

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

Compound 126

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

Compound 127

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

Compound 128

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

Compound 129

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

Compound 130

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazolidinyl] methylmethanesulfonate Ester

Compound 131

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazolidinyl] methyl neighbour's benzene two Carboximide

Compound 132

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

Compound 133

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazolidinyl] methyl camphoroyl Imines

Compound 134

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-benzyl piepridine base) phenyl) -2- oxo -5- oxazolidinyl] methyl succinyl Imines

Compound 135

(5R)-[N-3- (3 '-fluoro- 4 '-piperidinophenyl) -2- oxo -5- oxazolidinyl] methyl isophthalic acid, 2,4-1H- tri- nitrogen Azoles

Compound 136

(5R)-[N-3- (3 '-fluoro- 4 '-piperidinophenyl) -2- oxo -5- oxazolidinyl] methyl camphorimide

Compound 137

(5R)-[N-3- (3 '-fluoro- 4 '-piperidinophenyl) -2- oxo -5- oxazolidinyl] methyl succimide

Compound 138

(5S)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl)-phenyl) -2- oxo -5- oxazolidine Base] methyl chloroacetamide

Compound 139

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide Semihydrate

Compound 140

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 2/7 hydrate

Compound 141

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 2/5 hydrate

Compound 142

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 1/12 hydrate

Compound 143

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 3/4 hydrate.

Compound that formula I of the present invention represents or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or Prodrug, can be used alone or be used in any combination.

Heretofore described micobacterial conditions are the infection being led to by mycobacteria infections human body or animal body Property disease, including but not limited to tuberculosis, leprosy.Described mycobacterium is bird type Mycobacterium tuberculosis, bovine tuberculosis branch Bacillus, Mycobacterium butyricum, mycobacterium chelonei, Mycobacterium lacticola, mycobacterium friedmannii, mycobacterium graminises, paratuberculosis Mycobacterium, Mycobacterium lacticola, Mycobacterium leprae, mycobacterium marinum, johne's bacillus, mycobacterium graminises, fish are divided Prop up bacillus, mycobacterium ranae, mycobacterium rhusiopathiae, smegma bacillus, mycobacterium stercoris, mycobacterium thamnopheos or tuberculosis to divide Prop up bacillus.

The invention provides the compound that represents of formula I or its pharmaceutically acceptable salt, hydrate, solvate, joining Compound or prodrug in preparation prevention or treat the purposes in medicament lungy.Tuberculosis pathogenic bacteria with the compound suppression of the present invention Including but not limited to human-like, cattle type, bird type, African type tubercule bacillus and paratuberculosiss bacillus.The compound that described formula I represents Or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug can be additionally used in preventing or treating including inhomogeneity The mixed infection that the tubercule bacillus of type lead to.

Include primary pulmonary tuberculosis, hematogenous spread type lung with the active constituents of medicine prevention of the present invention or the tuberculosis for the treatment of Tuberculosis, secondary pulmonary tuberculosis, tuberculous pleuritiss, tuberculosis of bone and joint, tuberculous meningitis, renal tuberculosis, tuberculosis of intestine.

In the present invention, treatment includes to described individual administration therapeutically effective amount with the individual method of mycobacteria infections Compound or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug that at least one formula I represents.

In addition, treatment includes to patient therapeuticallv's effective dose in need for the treatment of with the individual method of mycobacteria infections The compound that represents of formula I or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug or apply institute State the combination in any of compound.

In the present invention, treatment includes to described individual administration therapeutically effective amount with the individual method of mycobacteria infections Compound or the drug regimen of its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug that formula I represents Thing, this pharmaceutical composition includes：

Compound that formula I represents or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug or The combination in any of at least one compound, and medicinal adjuvant, for example, at least a kind of pharmaceutically acceptable excipient.

Compound that described formula I represents or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or The effective dose that prodrug reaches expected biological effect is likely to be dependent on multinomial factor, as expected the facing of purposes, mode of administration and patient Bed.

The medicine of the present invention can be by oral administration or parenteral any dosage form, such as injection, respiratory tract administration, and skin is given Medicine, mucosa delivery etc..From the point of view of facilitating patient to use, this medicine is oral agents, such as tablet, capsule, dry suspension, or Injection.

When for preventing tuberculosis, the common dosage of medicine of the present invention is 0.01-2000mg/ days；Daily dosage can It is divided into multiple dosing.Such as daily dosage can be 0.01-1800mg, or 0.1-1500mg, or 1-1200mg, and at twice, three Secondary or four times administration.For can be according to concrete conditions such as the state of an illness of patient, sex, age and body weight when preventing tuberculosis Adjust dosage.

In the present invention, compound that described formula I represents or its pharmaceutically acceptable salt, hydrate, solvate, Coordination compound or the pharmaceutical composition that prodrug is active component can be prepared into slow release, controlled release, slow release, pulse release and sustained release agent Type.

In the present invention, the compound that treatment lungy, described formula I are represented or its pharmaceutically acceptable salt, Hydrate, solvate, coordination compound or prodrug can be used with compound form, also can be for example pharmaceutically acceptable with medicinal adjuvant Vehicle group become the form of pharmaceutical composition to use.Described carrier should meet compatibility test and right with the other compositions of compositionss Patient health is harmless.This carrier can be solid or liquid or both combinations, and the compound that can represent with described formula I Or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug are prepared into single formulation, for example, can be prepared into The compound being represented with described formula I or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug weight It is calculated as 0.05% to 100% tablet.

Described pharmaceutical composition should have at least one active component, the compound representing including described formula I or Its pharmaceutically acceptable salt, hydrate, solvate, coordination compound or prodrug or its combination in any.Described pharmaceutical composition Can be prepared by known method, such as active component be mixed with medicinal adjuvants such as pharmaceutically acceptable carriers and/or excipient.

In the present invention, described excipient includes but is not limited to：Microcrystalline Cellulose, Lactose, sodium citrate, Calcium Carbonate, phosphoric acid Hydrogen calcium, glycine, disintegrating agent (as starch, cross-linking sodium carboxymethyl cellulose, composition silicate and macromolecule polyethylene glycol), pelletize Binding agent (as Polyvinylpyrrolidone, sucrose, gelatin and arabic gum) and lubricant are (as magnesium stearate, glycerol and Talcum Powder).

In the present invention, compound that described at least one formula I represents or its pharmaceutically acceptable salt, hydrate, Solvate, coordination compound or prodrug also can be combined with sweeting agent, correctivess, pigment, dyestuff or emulsifying agent and its mixture.

Compound or its pharmaceutically acceptable salt, hydrate, solvate, coordination compound that the formula I of the present invention represents Or prodrug can also be applied in combination with other antituberculotics such as isoniazid, rifampicin etc..

Further illustrate the present invention below by experiment and embodiment.

As the present invention for preventing or treating the active component of tuberculosis compositionss, list in following table 1 Part of compounds in the compound that formula I of the present invention represents：

Table 1

Embodiment 1

(5S)-[N-3- (3 '-fluoro- 4 '-(4 ", 6 "-dimethoxy -2 "-hexahydropyrimidine) phenyl) -2- oxo -5- oxazolidine Base] methylacetamide (compound 6) preparation：

1st, the first step

At room temperature, add in reaction bulb 4- (4 ', 6 '-dimethoxy -2 '-hexahydropyrimidine) -3- fluoroaniline 25.5g, Oxolane 400ml, stirring adds the sodium hydrate aqueous solution 110ml of 1mol/L, adjusts pH between 7.5-8.5, Deca chlorine Benzyl formate 15ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is separated out, sucking filtration dries Do for the next step.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 37ml hexane solution, then Deca R- Glycidyl Butyrate 13.6g (98%), drip and keep low after finishing - 70 DEG C of temperature stirs 1 hour, then normal-temperature reaction 16 hours, after the completion of reaction, filters, in -0.08MPa, 60 DEG C of evaporated mother liquor are extremely Dry, the solid obtaining is used for the next step.

3rd, the 3rd step

Under room temperature, add dichloromethane 200ml and second step product 15g, stirring in reaction bulb, ice-water bath is lowered the temperature To 0 DEG C, Deca 5g triethylamine and 5g methylsufonyl chloride successively.Reaction 2 hours.Sucking filtration, mother solution in -0.08MPa, 60 DEG C distill to Dry, the solid obtaining is used for the next step.

4th, the 4th step

Add 10g three-step reaction product and 150ml DMF in reaction bulb, be warming up to 80 DEG C, add the anhydrous carbon of 3.7g Sour potassium and 3g potassium phthalimide.Reaction 16 hours, after the completion of, sucking filtration, evaporated mother liquor to dry (- 0.08MPa, 80 DEG C), the solid obtaining is used for the next step.

5th, the 5th step

Add 500ml dehydrated alcohol and 5g four-step reaction product in reaction bulb, be stirred at reflux.Heating 500ml methylamine Aqueous solution (25%), is passed through in reaction bulb after vapor (steam) velocity is stable, keeps 5 hours, continues stirring 1 hour, take out after stopping ventilation Filter, distillation and concentration mother solution to a certain amount of (- 0.08MPa, 60 DEG C), freeze crystallize, the solid that sucking filtration obtains is used for the next step.

6th, the 6th step

100ml oxolane and the 5th step product 2g is added in reaction bulb.It is cooled to 0 DEG C, Deca 0.7g tri- second Amine and 0.6g acetic anhydride (98%), keep at 0 DEG C 1 hour, then stir 2 hours under room temperature, after the completion of sucking filtration, distillation and concentration is female Liquid, to a certain amount of (- 0.08MPa, 60 DEG C), freezes crystallize, and sucking filtration dries to obtain final product 1g, total recovery 2.5%.

Embodiment 2

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-oxo -2 "-Chromanyl) phenyl) -2- oxo -5- oxazolidinyl] methyl second The preparation of amide (compound 13)

1st, the first step

At room temperature, 2- (4 '-amino -2 '-fluorophenyl) chroman-4-on 26g, oxolane are added in reaction bulb 400ml, stirring adds the sodium hydrate aqueous solution 110ml of 1mol/L, adjusts pH between 7.5-8.5, Deca benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is separated out, sucking filtration is dried under being used for Step reaction.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 37ml hexane solution, then Deca R- Glycidyl Butyrate 13.6g (98%), drip and keep low after finishing - 70 DEG C of temperature stirs 1 hour, then normal-temperature reaction 16 hours, after the completion of reaction, filters, evaporated mother liquor to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

3rd, the 3rd step

Under room temperature, add dichloromethane 200ml and second step product 15g, stirring in reaction bulb, ice-water bath is lowered the temperature To 0 DEG C, Deca 5g triethylamine and 5g methylsufonyl chloride successively.Reaction 2 hours.Sucking filtration, mother solution distill to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

4th, the 4th step

5th, the 5th step

6th, the 6th step

100ml oxolane and the 5th step product 2g is added in reaction bulb.It is cooled to 0 DEG C, Deca 0.7g tri- second Amine and 0.6g acetic anhydride (98%), keep at 0 DEG C 1 hour, then stir 2 hours under room temperature, after the completion of sucking filtration, distillation and concentration is female Liquid, to a certain amount of (- 0.08MPa, 60 DEG C), freezes crystallize, and sucking filtration dries to obtain final product 0.8g, total recovery 2.0%.

Embodiment 3

(5S)-[N-3- (3 '-fluoro- 4 '-(5 "-fluoro- 4 "-oxo -1 ", 2 " and, 3 ", 4 " and-tetrahydrochysene -2 "-quinolyl) phenyl) - 2- oxo -5- oxazolidinyl] methylacetamide (compound 14) preparation

1st, the first step

At room temperature, add in reaction bulb 2- (4 '-amino -2 '-fluorophenyl) -5- fluoro- 2,3- dihydroquinoline -4 (1H) - Ketone 28g, oxolane 400ml, stirring adds the sodium hydrate aqueous solution 120ml of 1mol/L, adjusts pH between 7.5-8.5, Deca benzyl chloroformate 16ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is separated out, Sucking filtration is dried for the next step.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 36ml hexane solution, then Deca R- Glycidyl Butyrate 13.4g (98%), drip and keep low after finishing - 70 DEG C of temperature stirs 1 hour, then normal-temperature reaction 16 hours, after the completion of reaction, filters, evaporated mother liquor to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

3rd, the 3rd step

Under room temperature, add dichloromethane 200ml and second step product 15g, stirring in reaction bulb, ice-water bath is lowered the temperature To 0 DEG C, Deca 5g triethylamine and 4.5g methylsufonyl chloride successively.Reaction 2 hours.Sucking filtration, mother solution distill to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

4th, the 4th step

Add 10g three-step reaction product and 150ml DMF in reaction bulb, be warming up to 80 DEG C, add the anhydrous carbon of 3.5g Sour potassium and 3g potassium phthalimide.Reaction 16 hours, after the completion of, sucking filtration, evaporated mother liquor to dry (- 0.08MPa, 80 DEG C), the solid obtaining is used for the next step.

5th, the 5th step

Add 500ml dehydrated alcohol and 5g four-step reaction product in reaction bulb, be stirred at reflux.Heating 500ml methylamine Aqueous solution (25%), in the reaction bulb being passed through, keeps 5 hours after vapor (steam) velocity is stable, continues stirring 1 hour after stopping ventilation, Sucking filtration, distillation and concentration mother solution to a certain amount of (- 0.08MPa, 60 DEG C), freeze crystallize, the solid that sucking filtration obtains is used for the next step.

6th, the 6th step

100ml oxolane and the 5th step product 2g is added in reaction bulb.It is cooled to 0 DEG C, Deca 0.7g tri- second Amine and 0.6g acetic anhydride (98%), keep at 0 DEG C 1 hour, then stir 2 hours under room temperature, after the completion of sucking filtration, distillation and concentration is female Liquid, to a certain amount of (- 0.08MPa, 60 DEG C), freezes crystallize, and sucking 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- oxazolidinyl] methylacetamide (is changed Compound 15) preparation

1st, the first step

At room temperature, 4- (benzofuran -2 '-yl) -3- fluoroaniline 23.0g, oxolane are added in reaction bulb 400ml, stirring adds the sodium hydrate aqueous solution 110ml of 1mol/L, adjusts pH between 7.5-8.5, Deca benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is separated out, sucking filtration is dried under being used for Step reaction.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 40ml hexane solution, then Deca R- Glycidyl Butyrate 14.0g (98%), drip and keep low after finishing - 70 DEG C of temperature stirs 1 hour, then normal-temperature reaction 16 hours, after the completion of reaction, filters, evaporated mother liquor to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

3rd, the 3rd step

Under room temperature, add dichloromethane 200ml and second step product 15g, stirring in reaction bulb, ice-water bath is lowered the temperature To 0 DEG C, Deca 6g triethylamine and 5.5g methylsufonyl chloride successively.Reaction 2 hours.Sucking filtration, mother solution distill to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

4th, the 4th step

Add 10g three-step reaction product and 150ml DMF in reaction bulb, be warming up to 80 DEG C, add the anhydrous carbon of 4.0g Sour potassium and 3.6g potassium phthalimide.Reaction 16 hours, after the completion of, sucking filtration, evaporated mother liquor to dry (- 0.08MPa, 80 DEG C), the solid obtaining is used for the next step.

5th, the 5th step

6th, the 6th step

100ml oxolane and the 5th step product 2g is added in reaction bulb.It is cooled to 0 DEG C, Deca 1.0g tri- second Amine and 0.8g acetic anhydride (98%), keep at 0 DEG C 1 hour, then stir 2 hours under room temperature, after the completion of sucking filtration, distillation and concentration is female Liquid, to a certain amount of (- 0.08MPa, 60 DEG C), freezes crystallize, and sucking 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- azoles Alkyl] methylacetamide (compound 16) preparation

1st, the first step

At room temperature, add 1- (4 '-(4 "-amino -2 "-fluorophenyl) -1 '-piperazinyl) -3- chlorine propyl- 1- in reaction bulb Ketone 29g, oxolane 400ml, stirring adds the sodium hydrate aqueous solution 110ml of 1mol/L, adjusts pH between 7.5-8.5, Deca benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is separated out, Sucking filtration is dried for the next step.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 35ml hexane solution, then Deca R- Glycidyl Butyrate 13.2g (98%), drip and keep low after finishing - 70 DEG C of temperature stirs 1 hour, then normal-temperature reaction 16 hours, after the completion of reaction, filters, evaporated mother liquor to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

3rd, the 3rd step

Under room temperature, add dichloromethane 200ml and second step product 15g, stirring in reaction bulb, ice-water bath is lowered the temperature To 0 DEG C, Deca 4.8g triethylamine and 4.5g methylsufonyl chloride successively.Reaction 2 hours.Sucking filtration, mother solution distill to dry (- 0.08MPa, 60 DEG C), the solid obtaining is used for the next step.

4th, the 4th step

Add 10g three-step reaction product and 150ml DMF in reaction bulb, be warming up to 80 DEG C, add the anhydrous carbon of 3.4g Sour potassium and 2.8g potassium phthalimide.Reaction 16 hours, after the completion of, sucking filtration, evaporated mother liquor to dry (- 0.08MPa, 80 DEG C), the solid obtaining is used for the next step.

5th, the 5th step

6th, the 6th step

100ml oxolane and the 5th step product 2g is added in reaction bulb.It is cooled to 0 DEG C, Deca 0.6g tri- second Amine and 0.5g acetic anhydride (98%), keep at 0 DEG C 1 hour, then stir 2 hours under room temperature, after the completion of sucking filtration, distillation and concentration is female Liquid, to a certain amount of (- 0.08MPa, 60 DEG C), freezes crystallize, and sucking 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 " and-dihydro -1 ", 2 " and, 4 "-triazine) -4 (1H)-yls) Phenyl) -2- oxo -5 oxazolidinyl] methylacetamide (compound 2) preparation

The first step：Add in reaction bulb the fluoro- 4- of 3,5- bis- (1 '-methyl -5 ', 6 '-dihydro -1 ', 2 ', 4 '-triazine -4 ' (1H)-yl) hexamethylene -2,4- bis- enamine 23g, acetone 400ml, stir under room temperature, after solidss are completely dissolved, are placed in sub-cooled It is cooled to 0 DEG C in liquid circulating pump, stirring, add saturation NaHCO₃Aqueous solution 100ml is (containing NaHCO₃10g), 0 DEG C of Deca chloro-carbonic acid Benzyl ester 20g, 0.5h drips off, and keeps 0 DEG C of reaction 30min, takes out stirring at normal temperature overnight.

Next day, reaction is finished, sucking filtration, the solidss obtaining is added in reaction bulb, adds 100ml acetonitrile refining, oil bath liter Temperature, condensing reflux, molten clear after, add suitable quantity of water to separate out to a small amount of solidss, liquid is poured into beaker put into cooling in refrigerator-freezer and analyse Brilliant 2h.Sucking filtration, solidss wash 3 times with water.Solid adds in reaction bulb, carries out secondary recrystallization：Add acetonitrile refining, oil bath liter Temperature, condensing reflux, molten clear after, add suitable quantity of water to separate out to a small amount of solidss, pour beaker into and put into cooling crystallization 2h in refrigerator-freezer.Take out Filter, is vacuum dried, for the next step after solid washing.

Second step：500mlTHF is added in distillation reaction bottle, stirring, it is passed through nitrogen protection, derives tail gas, tail gas fills The conical flask having liquid paraffin is done bubbling and is shown, oil bath heating, if 95 DEG C of the outer temperature of oil bath, condensing reflux.Add 5gLiAlH4 powder End, collects THF after timing stirring dehydration 1h, front-end volatiles discard about (50ml).

Under nitrogen replacement environment, reaction bulb adds dried first step product 20g, adds 400ml process The anhydrous THF crossing, is cooled to -70 DEG C with the mixture of dry ice and acetone.Start Deca butyl lithium when as little as -68 DEG C of interior temperature 26ml, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 1.5h of low temperature, then Deca R- (+)-2,3-Epoxy-1-propanol butyl ester 9.5g, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 0.5h of low temperature, takes out, stirring at normal temperature is reacted overnight.

Next day, use saturation NH₄Cl aqueous solution 100ml washing reaction liquid 1 time, saturation NaCl solution washing reactant liquor 3 times (each 100ml).Separate and collect upper organic phase, vacuum distillation (- 0.08MPa, 60 DEG C), to a certain amount of, poured beaker into and put into ice Cooling crystallization 2h in cabinet.Sucking filtration, solidss are added in reaction bulb, add 100mlTHF to refine：Oil bath heats up, condensing reflux, Molten clear after, add suitable quantity of water to separate out to a small amount of solidss, pour beaker into and put into cooling crystallization in refrigerator-freezer.Sucking filtration, solid vacuum is done Dry.For the next step.

3rd step：15g second step product and 200ml dichloromethane are added in reaction bulb, is placed in cryogenic liquid It is cooled to -8 DEG C in circulating pump, good and sound device, stirring.Triethylamine 7g, -5 DEG C of Deca 6g sulfonyl methanes of interior temperature are added during 0 DEG C of interior temperature Chlorine, interior temperature controls reaction 0.5h below 0 DEG C, takes out normal-temperature reaction 2h.

Reaction is finished, and uses saturation NaHCO₃Solution 80ml washs 1 time, and water (100ml) washs 3 times, point liquid, and organic layer adds dress 2h, sucking filtration are dried, vacuum distillation filtrate is extremely dry (- 0.08MPa, 60 DEG C), by the solid obtaining in the conical flask having anhydrous MgSO4 Thing adds in reaction bulb, adds 100ml acetonitrile refining：Oil bath heats up, condensing reflux, molten clear after, add suitable quantity of water to solid on a small quantity Body thing separates out, and pours beaker into and puts into cooling crystallization 2h in refrigerator-freezer.Sucking filtration, solid is washed 3 times, vacuum drying.For the next step.

4th step：By 10g three-step reaction product, 150mlDMF add reaction bulb in, good and sound device, stirring, successively plus Enter 3.6g phthalimide, 4g anhydrous K₂CO₃, oil bath heating, if 82 DEG C of the outer temperature of oil bath, stirring reaction is overnight.

Next day, sucking filtration, vacuum distillation filtrate (- 0.08MPa, 80 DEG C), to a certain amount of, pours saturation NaCl aqueous solution 300ml into Middle stirring separates out white solid thing, cools down 30min in refrigerator-freezer, takes out sucking filtration, and 3 times (100ml) washed by solid.

Solidss add in reaction bulb, add 150mlDMF to refine：Oil bath heats up, condensing reflux, molten clear after, add appropriate Water separates out to a small amount of solidss, pours beaker into and puts into cooling crystallization 2h in refrigerator-freezer, sucking filtration.By the solid obtaining same operation side Method secondary recrystallization.Sucking filtration, is vacuum dried after the washing of gained solid.For the next step.

5th step：5g four-step reaction product, 500ml dehydrated alcohol are added in reaction bulb, good and sound device, stirring.Oil Bath heating, if 82 DEG C of the outer temperature of oil bath, condensing reflux.

500ml 40% methylamine water solution is added in stand up reaction bottle, is installed in water-bath, if 48 DEG C of bath temperature. Produce methylamine gas to be passed through in reaction bulb through Drexel bottle (concentrated sulphuric acid), clock reaction 5.5h.

Stop logical methylamine gas, continue stirring reaction 2h.Reaction finish, sucking filtration, filtrate pour into put in beaker cold in refrigerator-freezer But crystallize is overnight.

Next day sucking filtration, the solidss obtaining are added in reaction bulb, add 100ml ethyl acetate to refine：Oil bath heats up, cold Solidifying backflow, add appropriate DMF make solid completely molten clear after, be then added dropwise to a small amount of water, when having a small amount of solid to separate out, by liquid Pour beaker into and put into cooling crystallization 2h in refrigerator-freezer, sucking filtration.By the solid obtaining same operation method secondary recrystallization.Sucking filtration, It is vacuum dried after washing.For the next step.

6th step：2g the 5th step product, 100ml THF are added in reaction bulb, is installed on cryogenic liquid circulation In pump, stirring is cooled to -8 DEG C.0 DEG C of addition 1g triethylamine of interior temperature, -5 DEG C of Deca 0.7g acetic anhydrides of interior temperature, interior temperature controls at -5 DEG C Hereinafter, drip and finish, -5 DEG C of reaction 0.5h, take out, normal-temperature reaction 2h.

Reaction is finished, sucking filtration, and solidss are refined with 40ml dehydrated alcohol and 60ml ethyl acetate mixture：Oil bath heats up, Condensing reflux, molten clear after, pour beaker into and put into cooling crystallization 2h in refrigerator-freezer, sucking filtration.Use same operation method, secondary recrystallization, Vacuum drying.Obtain solid product 1g.Yield 2.7%

Embodiment 7

N- [(S) -3- (3 '-fluoro- 4 '-(2 "-chloromethyl -1 "-piperidyl) phenyl) -2- oxo -5- oxazolidinyl] methyl The preparation of acetamide (compound 3)

The first step：4- (2 '-(chloromethyl) -1 '-piperidyl) -3- fluoroaniline 24.2g, acetone is added in reaction bulb 400ml, stirs under room temperature, after solidss are completely dissolved, are placed in low-temperature cooling fluid circulating pump and are cooled to 0 DEG C, stirring, adds full And NaHCO₃Aqueous solution 100ml is (containing NaHCO₃10g), 0 DEG C of Deca benzyl chloroformate 20g, keeps 0 DEG C of reaction 30min, often takes out Temperature is stirred overnight.

Second step：500ml THF is added in distillation reaction bottle, stirring, it is passed through nitrogen protection, derives tail gas, tail gas is used Conical flask equipped with liquid paraffin is done bubbling and is shown, oil bath heating, if 95 DEG C of the outer temperature of oil bath, condensing reflux.Add 5gLiAlH4 Powder, collects THF after timing stirring dehydration 1h, front-end volatiles discard about (50ml).

Under nitrogen replacement environment, reaction bulb adds dried first step product 20g, adds at 400ml The anhydrous THF managing, is cooled to -70 DEG C with the mixture of dry ice and acetone.Start Deca butyl lithium when as little as -68 DEG C of interior temperature 25ml hexane solution, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 1.5h of low temperature, then Deca R- is shunk Glycerol butyl ester 9.2g, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 0.5h of low temperature, takes out, stirring at normal temperature is anti- Should overnight.

3rd step：15g second step product and 200ml dichloromethane are added in reaction bulb, is placed in cryogenic liquid It is cooled to -8 DEG C in circulating pump, good and sound device, stirring.Triethylamine 7g, -5 DEG C of Deca 5.8g methane sulphurs of interior temperature are added during 0 DEG C of interior temperature Acyl chlorides, interior temperature controls reaction 0.5h below 0 DEG C, takes out normal-temperature reaction 2h.

4th step：By 10g three-step reaction product, 150mlDMF add reaction bulb in, good and sound device, stirring, successively plus Enter 3.5g phthalimide, 3.8g anhydrous K₂CO₃, oil bath heating, if 82 DEG C of the outer temperature of oil bath, stirring reaction is overnight.

Solidss add in reaction bulb, add 150ml DMF to refine：Oil bath heats up, condensing reflux, molten clear after, add suitable Amount water separates out to a small amount of solidss, pours beaker into and puts into cooling crystallization 2h in refrigerator-freezer, sucking filtration.By the solid obtaining same operation Method secondary recrystallization.Sucking filtration, is vacuum dried after the washing of gained solid.For the next step.

6th step：2g the 5th step product, 100ml THF are added in reaction bulb, is installed on cryogenic liquid circulation In pump, stirring is cooled to -8 DEG C.0 DEG C of addition 1g triethylamine of interior temperature, -5 DEG C of Deca 0.6g acetic anhydrides of interior temperature, interior temperature controls at -5 DEG C Hereinafter, drip and finish, -5 DEG C of reaction 0.5h, take out, normal-temperature reaction 2h.

Reaction is finished, sucking filtration, and solidss are refined with 40ml dehydrated alcohol and 60ml ethyl acetate mixture：Oil bath heats up, Condensing reflux, molten clear after, pour beaker into and put into cooling crystallization 2h in refrigerator-freezer, sucking filtration.Use same operation method, secondary recrystallization, Vacuum drying.Obtain solid product 1g.Yield 2.5%.

Embodiment 8

(5S)-[N-3- (3 '-fluoro- 4 '-(6 "-chloro- 4 "-cyano group -2 "-pyridine) phenyl) -2- oxo -5- oxazolidinyl] first The preparation of yl acetamide (compound 10)

The first step：4- (6 '-chloro- 4 '-isocyano group -2 '-pyridine radicals) -3- fluoroaniline 25g, acetone is added in reaction bulb 400ml, stirs under room temperature, after solidss are completely dissolved, are placed in low-temperature cooling fluid circulating pump and are cooled to 0 DEG C, stirring, adds full And NaHCO₃Aqueous solution 100ml is (containing NaHCO₃10g), 0 DEG C of Deca benzyl chloroformate 20g, 0.5h drip off, and keep 0 DEG C of reaction 30min, takes out stirring at normal temperature overnight.

Under nitrogen replacement environment, reaction bulb adds dried first step product 20g, adds 400ml process The anhydrous THF crossing, is cooled to -70 DEG C with the mixture of dry ice and acetone.Start Deca butyl lithium when as little as -68 DEG C of interior temperature 25ml, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 1.5h of low temperature, then Deca R- (+)-2,3-Epoxy-1-propanol butyl ester 9g, Control interior temperature below -65 DEG C, drip and finish, (less than -68 DEG C) reaction 0.5h of low temperature, take out, stirring at normal temperature is reacted overnight.

Next day, use saturation NH₄Cl aqueous solution 100ml washing reaction liquid 1 time, saturation NaCl solution washing reactant liquor 3 times (each 100ml).Separate and collect upper organic phase, vacuum distillation (- 0.08MPa, 60 DEG C), to a certain amount of, poured beaker into and put into ice Cooling crystallization 2h in cabinet.Sucking filtration, solidss are added in reaction bulb, add 100ml THF to refine：Oil bath heats up, condensing reflux, Molten clear after, add suitable quantity of water to separate out to a small amount of solidss, pour beaker into and put into cooling crystallization in refrigerator-freezer.Sucking filtration, solid vacuum is done Dry.For the next step.

3rd step：15g second step product and 200ml dichloromethane are added in reaction bulb, is placed in cryogenic liquid It is cooled to -8 DEG C in circulating pump, good and sound device, stirring.Triethylamine 6.5g, -5 DEG C of Deca 5.6g methane of interior temperature are added during 0 DEG C of interior temperature Sulfonic acid chloride, interior temperature controls reaction 0.5h below 0 DEG C, takes out normal-temperature reaction 2h.

4th step：By 10g three-step reaction product, 150ml DMF add reaction bulb in, good and sound device, stirring, successively plus Enter 3.4g phthalimide, 3.6g anhydrous K₂CO₃, oil bath heating, if 82 DEG C of the outer temperature of oil bath, stirring reaction is overnight.

6th step：2g the 5th step product, 100ml THF are added in reaction bulb, is installed on cryogenic liquid circulation In pump, stirring is cooled to -8 DEG C.0 DEG C of addition 0.8g triethylamine of interior temperature, -5 DEG C of Deca 0.6g acetic anhydrides of interior temperature, interior temperature controls -5 Below DEG C, drip and finish, -5 DEG C of reaction 0.5h, take out, normal-temperature reaction 2h.

Reaction is finished, sucking filtration, and solidss are refined with 40ml dehydrated alcohol and 60ml ethyl acetate mixture：Oil bath heats up, Condensing reflux, molten clear after, pour beaker into and put into cooling crystallization 2h in refrigerator-freezer, sucking 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 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The preparation of (compound 12)

(1) preparation of the fluoro- 4- of 3- (4 '-Phenylpiperazinyl) Nitrobenzol

50ml ethyl acetate, 13.5ml 4- phenylpiperazine and 15.30ml diisopropyl ethyl amine are added tri- mouthfuls of 250ml In bottle.Magnetic agitation under room temperature, adds 9.0ml 3,4- difluoro nitrobenzene.Reactant liquor was poured into water after 105 hours by reaction, second After acetoacetic ester (150ml × 3) extracts 3 times, extract washs 3 times with saturated nacl aqueous solution (150ml × 3), anhydrous magnesium sulfate (MgSO₄) be dried, it is evaporated.Obtain orange/yellow solid.Acetone: water (volume ratio 9: 1) recrystallization, obtain orange-yellow crystal (23.66g), Yield 96.33%.

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

6.69g (119mmol) reduced iron powder, 23.57ml water and 1.11ml glacial acetic acid are added in 500ml there-necked flask and flows back 80 minutes.The nothing of the 3- fluoro- 4- (4 '-Phenylpiperazinyl) Nitrobenzol (12.0g, 39.82mmol) that slowly Deca step (1) obtains Hydrous ethanol solution 150ml.Completion of dropping, then react 10 minutes, sucking filtration, boil off ethanol, ethyl acetate dissolves.Washed with ethyl acetate Wash filter cake 3 times.Merge organic faciess, wash 3 times, saturation NaCl solution is washed 1 time, anhydrous magnesium sulfate (MgSO₄) be dried, it is evaporated. Obtain shallow white solid, be directly used in the next step.

(3) preparation of the fluoro- 4- of N- benzyloxycarbonyl group -3- (4 '-Phenylpiperazinyl) aniline

3- fluoro- 4- (4 '-Phenylpiperazinyl) the aniline crude product 13.0g that 100ml dichloromethane and step (2) are obtained adds In 250ml four-hole bottle, at 0 DEG C, add 7.91ml diisopropyl ethyl amine.Mechanical agitation, Deca 5.34ml benzyl chloroformate.Institute Obtain solution to be stirred at room temperature 16 hours, dichloromethane (100ml × 3) extracts 3 times, saturated nacl aqueous solution (100ml × 3) washing 3 Secondary, anhydrous magnesium sulfate is dried, and is evaporated.Obtain shallow white solid.Acetone: water (volume ratio 7: 3) recrystallization.Obtain 11.46g white brilliant Body, yield 76.66%.

(4) system of (R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methanol Standby

Add the N- benzyloxycarbonyl group -3- that step (3) obtains fluoro- in the there-necked flask (120 DEG C are toasted more than 2 hours) of 100ml 4- (4 '-Phenylpiperazinyl) aniline 3.4g, anhydrous tetrahydro furan 50ml.-78℃、N₂The lower Deca 1.6M butyl lithium solution of protection 6.60ml.Stir 80 minutes at -78 DEG C, gradually become yellow-green soln.Deca 1.21ml (R)-contracting glycerol butyl ester at -78 DEG C With 5ml anhydrous tetrahydro furan, solution quickly become clarify.Reaction 1 hour, removes acetone bath, is warmed to room temperature, and stirs 16 hours, A small amount of precipitation occurs.Obtain white solid.By silica gel column chromatography and ethyl acetate: after petroleum ether (volume ratio 1: 3) recrystallization, obtain 2.34g white crystal, yield 77.21%.

(5) (R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methanol first sulphur The preparation of acid esters

(R) that 25molml anhydrous methylene chloride, step (4) are obtained-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) Phenyl) -2- oxo -5- oxazolidinyl] methanol 1.74g, 1.32ml triethylamine add 100ml there-necked flask in.Deca at 0 DEG C 0.52ml mesyl chloride, reacts 65 minutes, a large amount of white precipitates.Mixture is extracted 3 times with dichloromethane (50ml × 3), Extract is washed 3 times with saturation NaCl solution (50ml × 3), and anhydrous magnesium sulfate is dried, and is evaporated.Obtain white solid, acetonitrile: water (volume ratio 1: 1) recrystallization.Obtain 1.6065g white crystal.Yield is 75.92%.

(6) (R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methyl neighbour's benzene The preparation of dicarboximide

(R)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methanol methanesulfonic acid Ester 0.686g, 0.347g potassium phthalimide and 0.432g Anhydrous potassium carbonate add in 100ml there-necked flask.Reaction 3 hours Afterwards, ethyl acetate (50ml × 3) extracts three times, and extract washs 3 times with saturation NaCl solution (50ml × 3), anhydrous magnesium sulfate It is dried, and be evaporated to dryness.Obtain white solid, be directly used in next step reaction without purification.

(7) (S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methyl vinyl The preparation of amine

(R) that step (6) obtains-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidine Base] methyl phthalimide crude product, 100ml dehydrated alcohol and 25wt% methylamine water solution (3.38ml, 15.63mmol) plus Enter in 250ml there-necked flask, be heated to reflux 1 hour, reaction terminates rear revolving.With the salt acid extraction of 50ml 0.1M, then use acetic acid Ethyl ester (30ml × 2) extracts 2 times.Aqueous phase is transferred in the there-necked flask of 100ml, and with appropriate NaOH, its pH value is adjusted to weak base Property (pH value=8-9).Add acetic anhydride (0.46ml, 4.49mmol), react 10 minutes.By gained mixture ethyl acetate (100ml × 3) extract 3 times, and saturated nacl aqueous solution (100ml × 3) washs 3 times, and anhydrous magnesium sulfate is dried, and is evaporated, column chromatography Purification, and be 3: 1 recrystallization from ethyl acetate/petroleum ether with volume ratio.White solid 183.5mg, for (S)-[N-3- (3 '- Fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide.Yield is 2949%.

Elementary analysiss result：N%：13.61, C%：64.07, H%：6.02.Theoretical value：N%：13.58, C%：64.06, H%：6.11.By 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.

Embodiment 10

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

Compound 12 crude product 1g is added in the 6wt% hydrochloric acid of 2ml, and adds a small amount of activated carbon, stir in 50 DEG C of heating Mix 2 hours, then filter.Filtrate is placed at room temperature crystallize, gained crystal is vacuum dried 5 hours at 40 DEG C, acquisitionization Compound 139, HPLC records content：99.0%, fusing point：210-215 DEG C (capillary tube measurement), 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 in mass spectrum^-1/ 2H₂O+H] peak be 413.1；Theoretical value is 413.2.

Embodiment 11

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The preparation of 2/7 hydrate (compound 140)

By compound 12 crude product 10g, dissolved at 30 DEG C with the mixed solvent 200ml of water and ethyl acetate (volume ratio 2: 8), By gained (S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide Solution stirring reacts 8h, filters, filtrate is placed at room temperature precipitation crystal.Obtain product (S)-[N-3- (3 '-fluoro- 4 '- (4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide 2/7 hydrate.Yield：51%, purity： 98.8%.

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The water content of 2/7 hydrate is about 1.20 ± 0.15% (TGA measurements).

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The X-ray powder diffraction figure of 2/7 crystalline hydrate, using the measurement of CuK alpha ray, has 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、39.02、39.58、41.48、41.84、43.22、 43.86th, 45.37,45.87,47.40 and 49.36 ± 0.02 degree.

Embodiment 12

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

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide Crude product 10g, be added in aluminic acid aqueous solution and the mixed solvent 200ml of butanol (volume ratio 3: 7) be obtained (S)-[N-3- (3 '- Fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methyl vinyl amine aqueous solution, resulting solution is at 50 DEG C Choosing stirring 7h, filters, places and separate out crystal under room temperature.Obtain product (S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) Phenyl -2- oxo -5- oxazolidinyl] methylacetamide 2/5 hydrate.Yield：59%, purity 99%.

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The water content of 2/5 hydrate is about 1.70 ± 0.15% (TGA measurements).

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The X-ray powder diffraction figure of 2/5 crystalline hydrate, using the measurement of CuK alpha ray, has the peak (2 θ) selected from values below：4.13、 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、 43.14th, 43.88,45.30,45.87,47.33 and 49.18 ± 0.02 degree.

Embodiment 13

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The preparation of 1/12 hydrate (compound 142)

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide Crude product 10g, be added in water and the mixed solvent 200ml of ethanol (volume ratio 4: 6) be obtained (S)-[N-3- (3 '-fluoro- 4 '-(4 "- Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methyl vinyl amine aqueous solution.Stir 4h at 70 DEG C, filter, room temperature Lower placement separates out crystal, obtains (S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] Methylacetamide 1/12 hydrate.Yield：46%, purity：99.2%.

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

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The X-ray powder diffraction figure of 1/12 crystalline hydrate, using the measurement of CuK alpha ray, has the peak (2 θ) selected from values below：4.16、 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、 37.82nd, 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 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The preparation of 3/4 hydrate (compound 143)

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide Crude product 10g, be added in the 200ml mixed solvent containing water and dimethyl sulfoxide (volume ratio 1: 1) be obtained (S)-[N-3- (3 '- Fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methyl vinyl amine aqueous solution, resulting solution is at 75 DEG C Lower stirring 25h, filters, and places and separate out crystal under room temperature.Obtain (S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) benzene Base -2- oxo -5- oxazolidinyl] methylacetamide 3/4 hydrate.Yield：48%, purity：98.5%.

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The water content of 3/4 hydrate is about 3.30 ± 0.15% (TGA measurements).

(S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl)) phenyl -2- oxo -5- oxazolidinyl] methylacetamide The X-ray powder diffraction figure of 3/4 crystalline hydrate, with the measurement of CuK alpha ray, has the peak (2 θ) selected from values below：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、 31.40th, 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.

Embodiment 15

(5S)-[N-3- (3 ', 5 '-two fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methyl The preparation of acetamide (compound 1)

The first step：The fluoro- 4- of 3,5- bis- (4 '-phenyl -1 '-piperazinyl) hexamethylene -2,4- bis- enamine is added in reaction bulb 29g, acetone 400ml, stir under room temperature, after solidss are completely dissolved, are placed in low-temperature cooling fluid circulating pump and are cooled to 0 DEG C, stir Mix, add saturation NaHCO₃Aqueous solution 100ml is (containing NaHCO₃10g), 0 DEG C of Deca benzyl chloroformate 20g, 0.5h drip off, and keep 0 DEG C reaction 30min, take out stirring at normal temperature overnight.

Second step：500ml THF is added in distillation reaction bottle, stirring, it is passed through nitrogen protection, derives tail gas, tail gas is used Conical flask equipped with liquid paraffin is done bubbling and is shown, oil bath heating, if 95 DEG C of the outer temperature of oil bath, condensing reflux.Add 5g LiAlH4 Powder, collects THF after timing stirring dehydration 1h, front-end volatiles discard about (50ml).

Under nitrogen replacement environment, reaction bulb adds dried first step product 20g, adds 400ml process The anhydrous THF crossing, is cooled to -70 DEG C with the mixture of dry ice and acetone.Start Deca butyl lithium when as little as -68 DEG C of interior temperature 24ml, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 1.5h of low temperature, then Deca R- (+)-2,3-Epoxy-1-propanol butyl ester 9.2g, controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 0.5h of low temperature, takes out, stirring at normal temperature is reacted overnight.

3rd step：15g second step product and 200ml dichloromethane are added in reaction bulb, is placed in cryogenic liquid It is cooled to -8 DEG C in circulating pump, good and sound device, stirring.Triethylamine 6.5g, -5 DEG C of Deca 5.5g methane of interior temperature are added during 0 DEG C of interior temperature Sulfonic acid chloride, interior temperature controls reaction 0.5h below 0 DEG C, takes out normal-temperature reaction 2h.

4th step：By 10g three-step reaction product, 150mlDMF add reaction bulb in, good and sound device, stirring, successively plus Enter 3.3g phthalimide, 3.6g anhydrous K₂CO₃, oil bath heating, if 82 DEG C of the outer temperature of oil bath, stirring reaction is overnight.

500ml40% methylamine water solution is added in stand up reaction bottle, is installed in water-bath, if 48 DEG C of bath temperature. Produce methylamine gas to be passed through in reaction bulb through Drexel bottle (concentrated sulphuric acid), clock reaction 5.5h.

6th step：2g the 5th step product, 100mlTHF are added in reaction bulb, is installed on low-temperature cooling fluid circulating pump In, stirring is cooled to -8 DEG C.0 DEG C of interior temperature addition 1g triethylamine, -5 DEG C of Deca 0.6g acetic anhydrides of interior temperature, interior temperature control -5 DEG C with Under, drip and finish, -5 DEG C of reaction 0.5h, take out, normal-temperature reaction 2h.

Embodiment 16

(5S)-[N-3- (3 '-fluoro- 4 '-(6 "-chloro- 4 "-cyano group -5 "-methyl -2 "-pyridine) phenyl) -2- oxo -5- Oxazolidinyl] methylacetamide (compound 11) preparation

The first step：4- (6 '-chloro- 4 '-isocyano group -5 '-methyl -2 '-pyridine radicals) -3- fluoroaniline is added in reaction bulb 26g, acetone 400ml, stir under room temperature, after solidss are completely dissolved, are placed in low-temperature cooling fluid circulating pump and are cooled to 0 DEG C, stir Mix, add saturation NaHCO₃Aqueous solution 100ml is (containing NaHCO₃10g), 0 DEG C of Deca benzyl chloroformate 20g, 0.5h drip off, and keep 0 DEG C reaction 30min, take out stirring at normal temperature overnight.

6th step：2g the 5th step product, 100mlTHF are added in reaction bulb, is installed on low-temperature cooling fluid circulating pump In, stirring is cooled to -8 DEG C.0 DEG C of interior temperature addition 1g triethylamine, -5 DEG C of Deca 0.7g acetic anhydrides of interior temperature, interior temperature control -5 DEG C with Under, drip and finish, -5 DEG C of reaction 0.5h, take out, normal-temperature reaction 2h.

Reaction is finished, sucking filtration, and solidss are refined with 40ml dehydrated alcohol and 60ml ethyl acetate mixture：Oil bath heats up, Condensing reflux, molten clear after, pour beaker into and put into cooling crystallization 2h in refrigerator-freezer, sucking filtration.Use same operation method, secondary recrystallization, Vacuum drying.Obtain solid product 1g, yield 2.7%.

Embodiment 17

(5S)-[N-3- (3 '-fluoro- 4 '-(5 "-(azetidinyl -1 " '-carbonyl)-pyrazinyl -2 "-epoxide) phenyl) - 2- oxo -5- oxazolidinyl] methylacetamide (compound 17) preparation

1st, the first step

At room temperature, add (5- (4 '-a amino -2 '-fluorophenoxy) -2- pyrazinyl) -1- azetidin in reaction bulb Base) ketone 29g, oxolane 400ml, stirring add 1mol/L sodium hydrate aqueous solution 110ml, adjust pH 7.5-8.5 it Between, Deca benzyl chloroformate 15ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is analysed Go out, sucking filtration is dried for the next step.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 36ml, then Deca R- Glycidyl Butyrate 13.5g (98%), drip and after finishing, keep -70 DEG C of stirrings 1 of low temperature Hour, then normal-temperature reaction 16 hours, after the completion of reaction, filter, to dry (- 0.08MPa, 60 DEG C), obtain consolidates evaporated mother liquor Body is used for the next step.

3rd, the 3rd step

4th, the 4th step

5th, the 5th step

6th, the 6th step

100ml oxolane and the 5th step product 2g is added in reaction bulb.It is cooled to 0 DEG C, Deca 0.7g tri- second Amine and 0.6g acetic anhydride (98%), keep at 0 DEG C 1 hour, then stir 2 hours under room temperature, after the completion of sucking filtration, distillation and concentration is female Liquid, to a certain amount of (- 0.08MPa, 60 DEG C), freezes crystallize, and sucking filtration dries to obtain final product 1g, total recovery 2.3%.

Embodiment 18

(5S)-[N-3- (3 '-fluoro- 4 '-(1 "-methyl isophthalic acid " (H)-imidazole radicals -2 "-sulfenyl) phenyl) -2- oxo -5- azoles Alkyl] methylacetamide (compound 18) preparation

1st, the first step

At room temperature, the fluoro- 4- of 3- (1 '-methyl isophthalic acid ' H-2 '-imidazole radicals) thio aniline 23g, tetrahydrochysene are added in reaction bulb Furan 400ml, stirring adds the sodium hydrate aqueous solution 110ml of 1mol/L, adjusts pH between 7.5-8.5, Deca chloro-carbonic acid Benzyl ester 15ml (18.7g), stirring reaction 20 minutes, after completion of the reaction, add 1000ml water, so that material is separated out, sucking filtration is dried and used In the next step.

2nd, second step

Add oxolane 600ml and first step product 30g in reaction bulb, using liquid nitrogen cooling to -70 DEG C, drip Plus 2.5M butyl lithium 37ml, then Deca R- Glycidyl Butyrate 13.6g (98%), drip and after finishing, keep -70 DEG C of stirrings 1 of low temperature Hour, then normal-temperature reaction 16 hours, after the completion of reaction, filter, to dry (- 0.08MPa, 60 DEG C), obtain consolidates evaporated mother liquor Body is used for the next step.

3rd, the 3rd step

4th, the 4th step

5th, the 5th step

6th, the 6th step

Embodiment 19

(5R)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first The preparation of alcohol (compound 40)

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

After the completion of reaction, freeze reactant liquor, in reactant liquor, separate out a large amount of yellow solid, direct cooling crystallization 2h.

Sucking filtration, solidss are refined with dehydrated alcohol 1000ml：Oil bath heats up, condensing reflux.Molten clear after pour beaker cooling into Crystallize 2-3h, sucking filtration, vacuum drying：80℃、-0.08Mpa.For the next step.

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

Reaction is finished, sucking filtration, and Pb/C reclaims, and filtrate is standby.

Above-mentioned filtrate is placed in cooling in low-temperature cooling fluid circulating pump, stirring, 5 DEG C of addition pyridine 12g, 0 DEG C of beginning Deca chlorine Benzyl formate 19g (mixing acetone solvent), 1h drips off, low-temp reaction 30min, takes out normal-temperature reaction overnight.

Obtain red liquid after process, be concentrated into certain volume, pour in saturation Nacl aqueous solution, stirring, separate out white Solid, sucking filtration, solidss 30g adds in reaction bulb, adds acetonitrile 500ml to refine：Oil bath heats up, condensing reflux, molten clear after, plus Enter suitable quantity of water to separate out to a small amount of solidss, pour beaker into and put into cooling crystallization in refrigerator-freezer.Mother solution vacuum distillation, remaining a small amount of mother solution When, pour into and in beaker, put into cooling crystallization in refrigerator-freezer, sucking filtration, washing, solid is standby.Disposing mother liquor solidss add reaction bulb In, add acetonitrile refining：Oil bath heats up, condensing reflux, molten clear after, add suitable quantity of water to separate out to a small amount of solidss, pour beaker into Put into cooling crystallization in refrigerator-freezer, sucking filtration, washing.

Standby solid adds in reaction bulb together with reclaiming the common 28g of the solid obtaining in mother solution, carries out secondary recrystallization, Operational approach is ibid.Sucking filtration, is vacuum dried after washing：110℃、-0.08Mpa.For the next step.

3rd step, 1000ml THF add in distillation reactor, stirring, are passed through nitrogen protection, derive tail gas, tail gas fills The conical flask having liquid paraffin is done bubbling and is shown, oil bath heating, if 95 DEG C of the outer temperature of oil bath, condensing reflux.Turn down nitrogen, add 5g LiAlH₄Powder, clock reaction 1h, start to collect THF, front part discards.

Add the second step product of drying, good and sound device in the 600ml THF gathering, be passed through nitrogen and protect Shield, with the mixture cooling of dry ice and acetone.

Interior temperature is to start Deca butyl lithium 35ml when -68 DEG C, and 1-1.5h drips off, and controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 1.5h of low temperature, then Deca R- (+)-2,3-Epoxy-1-propanol butyl ester 14g, 0.5h drips off, and controls interior temperature below -65 DEG C, Drip and finish, (less than -68 DEG C) reaction 0.5h of low temperature, take out, normal-temperature reaction is overnight.

Next day, use saturation NH₄Cl solution washing 1 time, layering, then with saturation NaCl solution washing 3 times, be layered.

Upper strata mother solution vacuum distillation, pours beaker into during remaining a small amount of solution and puts into cooling crystallization 2h in refrigerator-freezer.Upper strata mother solution Sucking filtration, solidss add in reaction bulb, add THF to refine：Oil bath heats up, condensing reflux, molten clear after, add suitable quantity of water to a small amount of Solidss separate out, and pour beaker into and put into cooling crystallization in refrigerator-freezer.In subnatant, a large amount of white solid things separate out, sucking filtration, solid Thing adds in reaction bulb, adds THF to refine：Oil bath heats up, condensing reflux, molten clear after, add suitable quantity of water to analyse to a small amount of solidss Go out, pour beaker into and put into cooling crystallization in refrigerator-freezer.

Sucking filtration respectively, vacuum drying：110℃、-0.08Mpa.Obtain compound 14g.

Product yield：38%

Embodiment 20

(5R)-[3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " H- imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] methyl first The preparation of sulphonic acid ester (compound 41)

(5R) -3- [3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " H- imidazoles -1 "-yl) phenyl] -5- (methylol)-oxazolidine -2- ketone 32g, dichloromethane 500ml add in reaction bulb, are placed in low-temperature cooling fluid circulating pump and are cooled to -8 DEG C, good and sound device, stirring. Interior temperature O DEG C adds triethylamine 15g, and -5 DEG C of interior temperature starts Deca methane sulfonyl chloride 20g (mixing CH₂Cl₂), 0.5h drips off, interior temperature control System, below O DEG C, is dripped and is finished, and low-temp reaction 0.5h takes out normal-temperature reaction 2h.

Reaction is finished, and uses saturation NaHCO₃Solution washing 1 time, layering, wash with water 3 times, layering, add equipped with anhydrous MgSO₄Conical flask in 2h be dried, sucking filtration, vacuum distillation mother solution to dry (- 0.08MPa, 40 DEG C).Obtain compound 25g.

Embodiment 26,32,40,47,53,59,63,65,69,71 and 75

With embodiment 20 identical preparation method, simply in the first step, replaced real respectively with the raw material that following table 3 is listed Apply (R) -3- in example 20 [3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " H- imidazoles -1 "-yl) phenyl] -5- (methylol)-oxazolidine -2- Ketone, obtains corresponding compound.

Table 3

Embodiment 21

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first The preparation of base phthalimide (compound 42)

(R)-[3- (the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-group) phenyl) -2- oxo -5- oxazolidinyl] methyl first sulphur Acid esters 20g, DMF 500ml adds in reaction bulb, good and sound device, and stirring sequentially adds the poly- second of phthalimide 10g, 12g Glycol 400, oil bath heating, if 82 DEG C of the outer temperature of oil bath, reaction is overnight.

Next day, sucking filtration, filtrate is light yellow transparent liquid, and vacuum distillation (- 0.08MPa, 80 DEG C) is fallen when remaining a small amount of mother solution Enter crystallize in saturation NaCl aqueous solution, in refrigerator-freezer, cool down 30min, take out sucking filtration, wash the solidss obtaining for 3 times and add reaction bulb In, add DMF 200ml to refine：Oil bath heats up, condensing reflux, molten clear after, add suitable quantity of water to separate out to a small amount of solidss, pour into Beaker puts into cooling crystallization 2h in refrigerator-freezer, sucking filtration, washing.Same operation method secondary recrystallization.Sucking filtration, after washing, vacuum is done Dry：110℃、-0.08Mpa.Obtain compound 42.

Product yield and quality：

This product is yellow powdery solid, mp：220-222 DEG 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 embodiment 21 identical preparation method, simply in the first step, replaced real respectively with the raw material that following table 4 is listed Apply (R)-[3- (the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-group) phenyl) -2- oxo -5- oxazolidinyl] the methyl first in example 21 Sulphonic acid ester and phthalimide, obtain corresponding compound.

Table 4

Embodiment 22

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first The preparation of amine (compound 43)

(S) -2- [(3- (the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-group) phenyl) -2- oxo -5- oxazolidinyl) methyl] Phthalimide 10g, dehydrated alcohol 600ml add in reaction bulb, good and sound device, stirring.Oil bath heating, if the outer temperature of oil bath 82 DEG C, condensing reflux.

500ml 40% methylamine water solution is added in single port bottle, is placed in water-bath, if 48 DEG C of bath temperature, good and sound dress Put.When methylamine gas are stablized in generation, with airway, methylamine steam is passed through in reaction bulb, timing stirring reaction 5.5h.Stop logical Methylamine gas, continue reacting by heating 2h.Reaction is finished, sucking filtration, pours into and puts in refrigerator-freezer cooling crystallization in beaker overnight.

Next day sucking filtration, solidss 6g adds in reaction bulb, adds 100ml dehydrated alcohol and ethyl acetate to refine：Oil bath liter Temperature, condensing reflux, molten clear after, add appropriate normal hexane to separate out to a small amount of solidss, pour beaker into and put into cooling crystallization in refrigerator-freezer 2h, sucking filtration.Same operation method secondary recrystallization.Sucking filtration, is vacuum dried after washing：110℃、-0.08Mpa.Obtain compound 43.

Product yield and quality：

This product is pale yellow powder shape solid, mp：171-172 DEG C, 3 times experiment yield is respectively：100902 batches 19.7%th, 101001 batches 3.6%, 101101 batches 20.1%.

Embodiment 28,34,42,49,55,61,67 and 73

With embodiment 22 identical preparation method, simply in the first step, replaced real respectively with the raw material that following table 5 is listed Apply (S) -2- [(3- (the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-group) the phenyl) -2- oxo -5- oxazolidinyl) first in example 22 Base] phthalimide, obtain corresponding compound.

Table 5

Embodiment 23

(5S)-[N-3- (3 '-fluoro- 4 '-(4 "-methyl isophthalic acid " (H)-imidazole radicals) phenyl) -2- oxo -5- oxazolidinyl] first The preparation of yl acetamide (compound 19)

(S) -5- (amino methyl) -3- [the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-group) phenyl] oxazolidinyl -2- ketone 5g, THF 100ml adds in reaction bulb, is placed in low-temperature cooling fluid circulating pump, good and sound device, stirring.0 DEG C of addition triethylamine of interior temperature 1g, -5 DEG C of beginning Deca acetic anhydride 0.8g of interior temperature, 0.5h drip off, and interior temperature controls below -5 DEG C, drips and finishes, low-temp reaction 0.5h, Then move to normal-temperature reaction 2h.

Reaction is finished, sucking filtration, and solidss add 100ml dehydrated alcohol and ethyl acetate to refine, and oil bath heats up, condensing reflux, Molten clear after, pour beaker into and put into cooling crystallization 2h in refrigerator-freezer, sucking filtration.Product secondary recrystallization, operational approach is identical, last sucking filtration Afterwards, it is vacuum dried：120℃、-0.08Mpa.Obtain compound 19.

Product yield and quality：

This product is white powdery solids, mp：181-182 DEG C, testing total yield for 2 times is：101101 batches+101102 Criticize 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 embodiment 23 identical preparation method, (S) in the raw material alternative embodiment 23 listed with following table 6 respectively- 5- (amino methyl) -3- [the fluoro- 4- of 3- (4- methyl-1 H-imidazole-1-group) phenyl] oxazolidinyl -2- ketone and acetic anhydride, it is right to obtain The compound answered.

Table 6

Embodiment 25

(5R)-[N-3- (3 '-fluoro- 4 '-(2 ", 5 "-dioxo -1 "-pyrrolidinyl) phenyl) -2- oxo -5- oxazolidine Base] methanol (compound 44) preparation

The first step：10gNaOH, dehydrated alcohol 400ml are added in reaction bulb, good and sound device, oil bath heating, if outside oil bath 82 DEG C of temperature, condensing reflux, stirs 30min, after NaOH dissolving, adds 19g succimide, all dissolve, start Deca 3,4- Difluoro nitrobenzene 16g, drips and finishes, clock reaction 24h.

Reaction is finished, and separates out a large amount of yellow solid, direct cooling crystallization 2h in red reactant liquor.

Sucking filtration, solids washed with water refines for 3 times, vacuum drying：80 DEG C, -0.08Mpa, for the next step.

Product yield and quality：

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

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

3rd step：Second step gained filtrate is placed in cooling in low-temperature cooling fluid circulating pump, stirring, and 5 DEG C add pyridine 11g, O DEG C start Deca benzyl chloroformate 20g, 1h drips off, low-temp reaction 30min, takes out normal-temperature reaction overnight.

Reaction is finished, sucking filtration, pours crystallize in saturation NaCl aqueous solution, sucking filtration, washing into, solidss add during remaining a small amount of mother solution Enter in reaction bulb, add acetonitrile 400ml to refine, oil bath heats up, condensing reflux, molten clear after, add suitable quantity of water to a small amount of solidss Separate out, pour beaker into and put into cooling crystallization in refrigerator-freezer.Sucking filtration, washing.

With same operation method secondary recrystallization.Sucking filtration, is vacuum dried after washing：85℃、-0.08Mpa.Anti- for lower step Should.

Product yield and quality：

Three-step reaction product is white powdery solids, mp：100-101 DEG C, 3 times experiment yield is respectively：101201 Criticize 85.3%, 101202 batches 84.8%, 101203 batches 86.1%.

4th step, THF add in distillation reactor, stirring, are passed through nitrogen protection, derive tail gas, tail gas is with equipped with liquid The conical flask of paraffin is done bubbling and is shown, oil bath heating, if 95 DEG C of the outer temperature of oil bath, condensing reflux.Turn down nitrogen, add 5gLiAlH4 Powder, clock reaction 1h, start to collect THF, front part discards.

Add the three-step reaction product 30g having dried more than 2 days, good and sound device in the THF gathering, be passed through nitrogen Protection, with the mixture cooling of dry ice and acetone.

Interior temperature is to start Deca butyl lithium 38ml when -68 DEG C, and 1-1.5h drips off, and controls interior temperature below -65 DEG C, drips and finish, (less than -68 DEG C) reaction 1.5h of low temperature, then Deca R- (+)-2,3-Epoxy-1-propanol butyl ester 14g, 0.5h drips off, and controls interior temperature below -65 DEG C, Drip and finish, (less than -68 DEG C) reaction 0.5h of low temperature, take out, normal-temperature reaction is overnight.

Next day, use saturation NH₄Cl aqueous solution, a small amount of purification water washing 1 time, layering, then with saturation NaCl solution washing 3 Secondary, layering.

Vacuum distillation, pours beaker into during remaining a small amount of solution and puts into cooling crystallization 2h in refrigerator-freezer.Sucking filtration, solidss add anti- Answer in bottle, add 200ml ethyl acetate to refine, oil bath heats up, condensing reflux, molten clear after, add appropriate petroleum ether to solid on a small quantity Body thing separates out, and pours beaker into and puts into cooling crystallization in refrigerator-freezer.

Sucking filtration, petroleum ether 1 time, vacuum drying：100℃、-0.08Mpa.Obtain compound 44.

Product yield and quality：

This product is pale yellow powder shape solid, mp：120-122 DEG C, testing yield is：110101 batches 73.0%.

Embodiment 39,46,52,58,64 and 70

With embodiment 25 identical preparation method, 3,4- in the raw material alternative embodiment 25 listed with following table 7 respectively Difluoro nitrobenzene, obtains corresponding compound.

Table 7

The synthesis of compound 83-137 referring to：CN1355165A.

The effect experimental of suppression tubercule bacillus reference culture

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

Experimental strain involved in the present invention：Mycobacterium tuberculosis type strain H37Rv, by Beijing's tuberculosis breast tumor Institute provides.

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：20161、6233、16543、 5116th, 3328,3289,3303,7153,31251,30129 provided by Beijing Tuberculosis and Thoracic Tumor Research Institute.

First, experiment material, method and the result that the MIC90 of mycobacterium tuberculosis type strain H37Rv is measured

1st, test-compound：

Compound 1-143

2nd, comparison medicine：Isoniazid (INH), rifampicin (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 medium (Difco Products).

5th, method：

With aseptic distillation water dissolution, with dmso solution, make concentration is isoniazid for rifampicin and test-compound The first solution of 6.4mg/ml.

With aseptic 96 orifice plate (Falcon3072；Becton Dickinson, Lincoln Park, N.J.), maximum concentration Hole adds the 7H9 culture medium of 198 μ l, 2 μ l compounds just solution, after mix homogeneously, to remaining each hole successively 2 times of dilutions, chemical combination Thing is final concentration of：16、8、4、2、1、0.5、0.25、0.125、0.06、0.03μg/ml.INH is final concentration of：0.2、0.1、0.05、 0.025、0.0125μg/ml.

Choose mycobacterium tuberculosis H37RV, the culture culture of 2～3 weeks is made bacteria suspension, is inoculated into containing 0.05% tween 80th, in the 7H9 culture medium of 10%ADC, 37 DEG C of static gas wave refrigerator 1～2 week, grow to turbidity and (be equivalent to for McFarland 1 10⁷When CFU/ml), after 1: 20 dilution, add each hole 100 μ l, the final concentration of 106CFU/ml of bacterium solution.It is all provided with 2 on every plate Growth control hole without antimicrobial drug, 96 orifice plates are incubated in 37 DEG C.Growth control hole 20 μ l 10 × Alamar is added after 7 days The mixed liquor of Blue (Setotec Products) and 5%Tween8050 μ l, 37 incubations 24 hours, if color is changed into from blueness Pink colour, then in Alamar Blue and the Tween80 mixed liquor of the in the hole above-mentioned amount of addition of each Experimental agents, 37 DEG C of incubations 24 are little The color in each hole of Shi Jilu, and apply microplate reader to measure 530nm and 590nm fluorescent value, calculate MIC90.

6th, experimental result

It is shown in Table one with the minimal inhibitory concentration (MIC) that MABA method measures.

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

2nd, application Microplate Alamar Blue Assay (MABA) method mensure is sensitive to mycobacterium tuberculosis and resistance to The material of the antibacterial activity in vitro of medicine Clinical isolation, method and result

1. test-compound：Compound 1-143；Comparison drug isoniazid (INH), rifampicin (RFP) are Sigma company and produce Product.

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 medium (Difco Products).

4. method：Aseptic 96 orifice plate (Falcon3072；Becton Dickinson, Lincoln Park, N.J.), INH With aseptic distillation water dissolution, with dmso solution, making concentration is the first molten of 32mg/ml for rifampicin and test-compound Liquid, maximum concentration hole adds 198 μ l7H9 culture medium, and 2 μ l pharmaceutical diluted solution, after mix homogeneously, to 2 times successively of remaining each hole Dilution, test-compound is final concentration of：16、8、4、2、1、0.5、0.25、0.125、0.06、0.03μg/ml.Choose 10 plants respectively Mycobacterium tuberculosis sensitivity Clinical isolation and 10 plants of resistant clinical isolated strains, the culture culture of 2～3 weeks is made bacterium Suspension, is inoculated into containing in 0.05% Tween 80, the 7H9 culture medium of 10%ADC, 37 DEG C of static gas wave refrigerator 1～2 week, grows to turbidity (be equivalent to 10 for McFarland 1⁷When CFU/ml), 1: 20 dilution after, add each hole 100 μ l, bacterium solution final concentration of 10⁶CFU/ml.2 growth control holes not containing antimicrobial drug are all provided with every plate, 96 orifice plates are incubated in 37 DEG C.Growth is added after 7 days The mixed liquor of control wells 20 μ l 10 × Alamar Blue (Setotec Products) and 5%Tween8050 μ l, 37 incubations 24 Hour, if color is changed into pink colour from blueness, each Experimental agents in the hole add above-mentioned amount Alamar Blue and Tween80 mixed liquor, the color in 37 DEG C of incubation each holes of 24 hour records, and apply microplate reader to measure 530nm and 590nm fluorescence Value, calculates MIC90.

5th, experimental result

It is shown in Table two with the minimal inhibitory concentration (MIC) that MABA method measures.

Table two：The MIC to mycobacterium tuberculosis sensitivity and resistant clinical isolated strains for the test-compound

After Rimactazid comes out, the success of short-course chemotherapy makes treatment lungy there occurs revolutionary change, but It is that nearly ten years, a large amount of with Rimactazid use so as to drug resistance increases year by year, thus leading to antituberculosis therapy to be lost Lose.And most compounds of the present invention to the MIC scope of sensitive mycobacterium tuberculosis clinical separation strain in 1-32 μ g/ml, wherein There is considerable part compound in 1-16 μ g/ml, also part of compounds is in 1-8 μ g/ml；Most compounds are to single resistance to simultaneously The MIC model of isoniazid, singly resistance to rifampicin or simultaneously the mycobacterium tuberculosis clinical separation strain of resistance to rifampicin isoniazid (MDR-TB) It is trapped among 1-32 μ g/ml, wherein have considerable part compound in 1-16 μ g/ml, also part of compounds is in 1-8 μ g/ml, therefore basis Invent described compound, to sensitive and Drug-Resistant Mycobacterium tuberculosis clinical separation strain, there is antibacterial activity in vitro, especially drug resistance is tied Core mycobacteria has remarkable result.

Compound of the present invention can shorten and simplify the course for the treatment of, overcome anti-many property of medicine, and treats tuberculosis and acquired immune deficiency syndrome (AIDS) altogether With infecting, especially tuberculosis latent infection is provided and more effectively treat.Improve the curative effect to many resistant tuberculosis simultaneously, permissible Specially develop into the medicine treating multi-drug resistant tuberculosis, one kind safely and effectively medicine will be provided for tuberculosis patient when the time comes.

Claims

1. (5S)-[N-3- (3 '-fluoro- 4 '-(4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide or Its pharmaceutically acceptable salt or hydrate preparation for prevent or treat micobacterial conditions medicine in application, wherein Described micobacterial conditions are tuberculosis.

2. apply as claimed in claim 1, the hydrate of wherein said compound is：

Compound 139

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide half water Compound

Compound 140

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 2/7 Hydrate

Compound 141

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

Compound 142

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 1/12 Hydrate

Compound 143

(5S)-[N-3- (the fluoro- 4'- of 3'- (4 "-Phenylpiperazinyl) phenyl) -2- oxo -5- oxazolidinyl] methylacetamide 3/4 Hydrate.

3. apply as claimed in claim 1 or 2, wherein said compound or its pharmaceutically acceptable salt or hydrate can be appointed Meaning is applied in combination or is used alone.

4. apply as claimed in claim 1 or 2, wherein said medicine is oral formulations or ejection preparation.

5. apply as claimed in claim 1, wherein said tuberculosis are primary pulmonary tuberculosis, hematogenous disseminated pulmonary tuberculosises, Secondary pulmonary tuberculosis, tuberculous pleuritiss, tuberculosis of bone and joint, tuberculous meningitis, renal tuberculosis or tuberculosis of intestine.