WO2013182070A1

WO2013182070A1 - Drug for preventing or treating mycobacterial diseases

Info

Publication number: WO2013182070A1
Application number: PCT/CN2013/076872
Authority: WO
Inventors: 阙峰; 王莹
Original assignee: 四川贝力克生物技术有限责任公司
Priority date: 2012-06-08
Filing date: 2013-06-06
Publication date: 2013-12-12
Also published as: CN104364240B; CN104364240A

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 medicine for preventing or treating mycobacterial diseases

Technical field

The present invention pertains to the field of medicine and relates to a compound for preventing or treating mycobacterial diseases, and in particular, the compound of the present invention is useful for preventing or treating tuberculosis. Background technique

Mycobacteria are quite diverse, and they are pathogenic and non-pathogenic. Causes of human diseases are: (1) infections caused by human and Bovine Mycobacterium tuberculosis and several atypical mycobacteria; (2) leprosy. Most of these infections are chronic infections, long-term prolongation, and destructive tissue lesions.

Tuberculosis is a chronic infectious disease caused by the Mycobacterium tuberculosis complex (Mycobacterium tuberculosis complex, M. tuberculosis or tuberculosis), which can affect the multiple organ system of the whole body. The most common diseased part is the lung, which accounts for tuberculosis in various organs. 80-90% of the total; can also involve organs such as liver, kidney, brain, lymph nodes. The main transmission routes are the respiratory tract, the digestive tract, the skin and the uterus, but mainly through the respiratory tract. After the sputum of the sterilized tuberculosis patient is dried, the bacteria fly with the dust and are inhaled by others to cause infection. Whether the human body inhales the droplets containing M. tuberculosis is mainly affected by the amount of inhaled tuberculosis, the virulence, and the resistance of the human body. And so on a variety of factors. Tuberculosis is a chronic infectious disease that seriously endangers people's health. At present, about 2 billion people are infected worldwide, and the incidence of tuberculosis carriers can account for 80%. The number of new tuberculosis patients is about 8-10 million per year, and 3 million people are caused. death.

In recent years, non-governmental organizations such as the World Health Organization, the Global Tuberculosis Drug Research and Development Alliance, and related pharmaceutical companies have increased their investment in tuberculosis prevention, and governments have also strongly supported relevant research. The isoniazid, invented in 1952, and rifampin, which was invented in 1965, made a leap in the treatment of tuberculosis. However, with the use of these very good anti-tuberculosis drugs, the recovery of a large number of tuberculosis patients has also brought about the prevalence of MDR-TB. The current treatment of tuberculosis has a long course of treatment, and the method is complicated. Many patients cannot complete the treatment, and the drug resistance of the disease is increasing, which is an increasingly serious global health threat. There are more than 500,000 cases of new drug-resistant tuberculosis worldwide each year. The WHO anti-tuberculosis drug resistance report shows that drug resistance has reached the highest level in the general population, and MDR-TB is still spiraling upward. If this trend cannot be reversed in time, drug-resistant tuberculosis will lead to an incurable epidemic. Multidrug-resistant and XDR-TB are difficult to cure, causing major harm to the patient's physical and mental health. The harm is no less than cancer, and it is almost incurable. Even more frightening is that individuals infected by these patients, once ill, are multidrug-resistant and XDR-TB patients, which is extremely harmful to individuals, families and society. It also poses a great threat to tuberculosis prevention and has become a serious threat to human health. Major public health issues and social issues.

At present, most of the first-line drugs for treating tuberculosis in the world still rely on a few drugs that were invented four or fifty years ago. Second-line drugs are often more expensive and less effective than first-line drugs. The treatment is long, the curative effect is poor, and the adverse reactions are serious. . The limitations of existing therapeutic drugs make tuberculosis a "time bomb" that hangs over human heads. Once it is not effectively controlled, the consequences are unimaginable. Therefore, there is an urgent need for a drug that can effectively prevent mycobacterial infections, especially effective prevention and treatment of tuberculosis.

CN1155585 discloses that the compound represented by the following formula has potent anti-Gram-positive bacteria activity,

In the formula, R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom or a halogenated alkyl group, and the haloalkyl group is an alkyl group having 1 to 6 carbon atoms substituted by one or more halogen atoms; Represents morpholinyl, piperidinyl, 4-benzylpiperidinyl, 4-phenylpiperazinyl or 4-(4'-methoxy)phenylpiperazinyl; R3 represents diimide, five a heterocyclic heterocyclic group, wherein the five-membered heterocyclic group is an imidazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group or a benzotriazole group. However, this document does not mention that these compounds can be used to treat mycobacterial diseases, especially tuberculosis. Summary of the invention

In order to find a new effective drug, the inventors conducted long-term and arduous research, and finally completed the present invention.

The present invention provides the use of a compound represented by the following formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof for the preparation of a medicament for preventing or treating mycobacteria.

The present invention also provides a pharmaceutical composition for preventing or treating tuberculosis, which comprises, as an active ingredient, a compound represented by the above formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, a complex or prodrug, or any combination thereof, and a pharmaceutically acceptable adjuvant.

The invention also provides a method of preventing or treating tuberculosis comprising administering to a patient a therapeutically effective amount of a compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex thereof or Prodrug, or any combination thereof, or a pharmaceutical composition as described.

The compound represented by the formula I of the present invention has a remarkable effect in the treatment or prevention of mycobacterial infection, particularly Mycobacterium tuberculosis infection, particularly drug-resistant Mycobacterium tuberculosis. detailed description

The compound represented by the above formula I of the present invention represents a hydroxyl group, an amino group, or a substituted or unsubstituted group: a C1-C10 amine group, a di(C1-C10) an imido group, a C1-C10 amide group, and C1- a C10 acyl imido group, a di(C1-C10 acyl)imido group, a C1-C10 sulfonylamino group, a C1-C10 sulfonyloxy group, a C1-C10 alkanoyloxy group, a five- or six-membered heterocyclic group, a five- or six-membered heterocyclic fluorenyl group, a benzoheterocyclyl fluorenyl group, a benzoheterocyclic group; R ₂ represents a substituted or unsubstituted five- or six-membered heterocyclic group; a substituted or unsubstituted C1-C10 acyl group; or a group of the formula:

among them,

R ₃ and R ₅ each independently represent 11, a halogen atom or a halogenated alkyl group;

R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl, 5- or 6-membered heterocyclylamino, benzoheterocyclylamino.

In a preferred embodiment, the formula I represents a hydroxy group, an amino group, a C1-C10 alkylamino group, a C1-C10 arylalkylamino group, a C1-C10 arylamino group, a bis(C1-C10 alkyl)imide. Base, bis(C1-C10 aryl)imido, C1-C10 alkylarylimino, bis(C1-C10 arylalkyl)imide, C1-C10 alkylamido, C1-C10 aromatic Alkylamide, C1-C10 arylamide, halogenated C1-C10 alkylamido, halogenated C1-C10 aromatic alkyl amide, halogenated C1-C10 aryl amide, C1-C10 alkyl sulfonate Amido, C1-C10 arylalkylsulfonylamino, C1-C10 arylsulfonylamino, halogenated C1-C10 alkylsulfonylamino, halogenated C1-C10 aromatic alkylsulfonylamino, halogenated C1-C10 Aromatic sulfonamide, C1-C10 arylsulfonyloxy, C1-C10 alkylsulfonyloxy, C1-C10 arylalkylsulfonyloxy, halogenated C1-C10 arylsulfonyloxy, halogen a C1-C10 alkylsulfonyloxy group, a halogenated C1-C10 arylalkylsulfonyloxy group, a di(C1-C10 aryl acyl)imide group, a di(C1-C10 alkanoyl)imide group, two (C1-C10 arylalkyl acyl) imido group , a C1-C10 alkanoyloxy group, a halogenated C1-C10 alkanoyloxy group, a substituted or unsubstituted five- or six-membered heterocyclic group, a five- or six-membered heterocyclic fluorenyl group or a benzoheterocyclyl fluorenyl group . In a more preferred case, in the formula I, hydroxy, amino, methylamino, ethylamino, benzylamino, anilino, dimethylimino, diethylimino, diphenyl Iminoimine, benzhydryl imido, formamide, acetamido, propionamide, haloformamide, 1-haloacetamido, methanesulfonamide, ethanesulfonamide, A Sulfonyloxy, ethanesulfonyloxy, phenylmethylsulfonyloxy, phthalimido, dimethylimido, diethylimido, acetyloxy, succinyl Amino, p-toluenesulfonyloxy, 1,3,4-thiadiazolylhydrazino, 1,2,4-1H-triazolyl, 1H-tetrazolyl, tetrazolylhydrazino, benzo Imidazole 2-mercapto, benzotriazolyl, imidazolyl or camphorimide. For example, in the specific compounds provided by the present invention, the formula I represents a hydroxy group, an amino group, an acetamido group, a chloroacetamido group, a methanesulfonylamino group, a methanesulfonyloxy group, an ethylsulfonyloxy group, an o-phenylene group. Methylimido, diimide, succinylimido, p-toluenesulfonyloxy, 1,3,4-thiadiazolylhydrazino, 1,2,4-1H-triazole Base, 1H-tetrazolyl, tetrazolylhydrazino, benzimidazole 2-indolyl, benzotriazolyl, imidazolyl or camphorimide.

In the preferred case, R ₂ in the formula I represents a substituted or unsubstituted group: pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyridyl An oxazolidinyl, pyrazolinyl, 4-morpholinyl, piperazinyl, piperidinyl, pyrimidinyl, oxazolyl, pyridyl; or C1-C4 acyl; or a group of the formula:

among them,

R ₃ and R ₅ each independently represent 15, a halogen atom or a halogenated alkyl group;

R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl.

In a more preferred case, R ₂ in the formula I represents an acetyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted oxa substituted pyridyl group, or a formula below group:

among them,

In a preferred embodiment, R _{2 in} formula I represents acetyl, 2-phenylpiperidinyl, 2-hydroxypyrimidinyl, 6-chloro-4-cyano-2-pyridyl, 4-oxazolyl Or 2-acetoxypyrimidinyl.

In the preferred case, the compound represented by Π:

Where Ri is as defined above;

R ₃ and R ₅ each independently represent 11, F, C1 or CF ₃ ;

R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, an alkoxy group, an aralkyloxy group, a five- or six-membered heterocyclic fluorenyl group, Benzoheterocyclyl fluorenyl. In a preferred embodiment, the R4 represents a substituted or unsubstituted group: pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, dihydropyrrolyl, pyrrolinyl, imidazolidinyl, imidazole Polinyl, pyrazolidinyl, imidazolylhydrazino, pyrazolinyl, thiadiazolyl, thiadiazolylamino, thiadiazolylhydrazino, morpholinyl, piperazinyl, triazinyl, pyrimidinyl, six Hydropyrimidine, pyridyl, chromanyl, quinolyl, benzofuranyl, pyrazinyl, pyrazinyloxy or piperidinyl.

Specifically, R4 represents morpholinyl, 4-phenylpiperazinyl, 1-methyl-5,6-dihydro-1,2,4-triazin-4C1H)-yl, 2-chloromethyl -piperidinyl, 2-chloromethyl-4-methyl-piperidinyl, 4,6-dimethoxy-2-hexahydropyrimidinyl, 4,6-dimethoxy- ₅ -methyl 2-hexahydropyrimidinyl, ₆ -chloro-4-cyano-2-pyridyl, 6-chloro-4-cyano-5-methyl-2-pyridyl, 4-oxo-2- Chromatidine, 5-fluoro-4-oxo-1,2,3,4-tetrahydro-2-quinolyl, benzofuranyl, 3-chloropropionyl-1-piperazine, 5-(nitrogen Heterocyclobutane-1-carbonyl)-2-oxopyrazinyl, 1-methyl-1-H-2-imidazolium, 1-H-1-Bpyryl, 1-piperidinyl 1,3,4-thiadiazol-2-amino, 3-methyl-H-pyrazolyl, 2,5-dioxopyrrolidinyl, 2,5-dihydro-1-H- 1- Pyrrolyl, 1-pyrrolidinyl, 1,3,4-thiadiazole-2-thio, 4-methyl-1H-imidazolyl, 4-methoxyphenylpiperazinyl, 4-benzylpiper Pyridyl or 4-piperidinyl.

In the compound represented by the above formula II, the R ₄ may represent a group of the formula:

R4 can also:

In addition, the following formula is indicated:

R4 can also

Wherein R ₇ represents a hydrogen atom, a C1-10 alkyl group or a C1-C10 halogenated alkyl group; R ₈ represents a hydrogen atom, a C1-C10 alkyl group or a C1-C10 phenylalkyl group; preferably R ₇ represents a hydrogen atom, a methyl group or a chloro group. Methyl; R ₈ represents a hydrogen atom, a methyl group or a benzyl group.

Further, R _{4 of the} formula 可以 may represent a group of the formula:

Wherein R ₉ represents a hydrogen atom, a C1-C10 alkoxy group or a C1-C10 alkylthio group; The same or different from R _u represents a hydrogen atom or a C1-C10 alkyl group; preferably R ₉ represents a hydrogen atom, a methoxy group or a methyl group; Same or different from Ru, indicating a hydrogen atom or a methyl group.

Further preferably, the compound represented by the formula I is a compound represented by the following formula III:

Wherein, R ₃ , R _{5 are} as defined above;

The following groups are represented by a substituted or unsubstituted group: a phenyl group, an aralkyl group, an alkyl acyl group, a five- or six-membered heterocyclic group. Preferably, it represents a phenyl group, a substituted phenyl group, a phenylalkyl group, an alkyl acyl group, or a halogenated alkyl acyl group. For example, the substituted or unsubstituted group: phenyl, benzyl, C1-C10 alkyl acyl, five- or six-membered heterocyclic group; preferred represents phenyl, substituted phenyl, benzyl, C1-C10 An alkyl acyl group, or a halogenated C1-C10 alkyl acyl group. Specifically, it means a phenyl group, a p-methoxyphenyl group, a benzyl group, or a chloropropionyl group.

In the present invention, the description of "C1-C10" and the like means that the modified group has a number of carbon atoms, for example, a C1-C10 alkyl group means a linear alkyl group having 1 to 10 carbon atoms, A branched alkyl group or a cycloalkyl group includes, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a t-butyl group, a n-hexyl group, a cyclopropyl group and the like.

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

"Substituted" means that the hydrogen atom on the defined group is substituted by another atom or group, for example by one or more halogen atoms.

The five- or six-membered heterocyclic group in the present invention means a saturated, partially saturated or unsaturated five- or six-membered ring system in which at least one carbon atom is substituted by N, 0, S, SO, S0 ₂ , such as imidazole , thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, piperidinyl, pyrimidinyl, piperazinyl, morpholinyl, furyl, tetrahydrofuranyl, pyrazinyl, pyrrolyl, pyrrolidine A pyrazole group, a pyrazolyl group, an oxazolyl group, an oxazolidinyl group, a chromanyl group, a quinolyl group, a dihydropyrrolyl group, or a hexahydropyrimidinyl group.

The benzo five-membered heterocyclic ring or the benzo six-membered heterocyclic ring in the present invention means quinoline, benzofuran, benzimidazole, or benzotriazole or the like.

The sulfonyloxy group of the present invention includes, but is not limited to, a methylsulfonyloxy group, a benzenesulfonyloxy group, an ethylsulfonyloxy group, a p-toluenesulfonyloxy group, preferably a methanesulfonyloxy group or a p-toluenesulfonyloxy group. .

The mycobacterial disease referred to in the present invention refers to a bacterium of the genus Mycobacterium as a pathogen or any disease, disorder, pathology, symptom, clinical disease or syndrome associated with, detecting or designing a mycobacterial infection. The mycobacterial disease includes Mycobacterium tuberculosis, non-tuberculous mycobacterial infection or mycobacterial diseases associated therewith, such as various forms of tuberculosis, leprosy, and the like.

The compound represented by the above formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof can be used for preventing or treating tuberculosis or leprosy, preferably for preventing or treating tuberculosis .

The pharmaceutical composition for preventing or treating tuberculosis of the present invention contains, as an active ingredient, the compound represented by the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or any thereof Combinations, as well as medicinal adjuvants. In the pharmaceutical composition of the present invention, the active ingredient is usually administered in a dose of 0.01 to 2000 mg/day, preferably, the dose is 0.01 to 1800 mg, more preferably 0.1 to 1500 mg, still more preferably 1 to 1200 mg. Further, the active ingredient is from 0.05 to 100% by weight of the composition.

The method for preventing or treating tuberculosis of the present invention comprises applying a therapeutically effective amount of a compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof to a patient in need of treatment.

"Therapeutically effective amount" in the present invention means an effective amount, such as a human or a non-human, when administered to a subject in need thereof to alleviate symptoms or to prevent further mycobacterial infection.

The pharmaceutically acceptable salts of the compounds of the above formula I in the present invention include sodium, potassium, calcium, aluminum, magnesium, zinc or other metal salts and ammonium salts. Also a salt of an organic acid such as acetate, lactate, citrate, tartrate, maleate, malate, fumarate, benzoate, methanesulfonate, benzenesulfonic acid salt. It may also be an inorganic acid salt such as a hydrochloride, a sulfate, a hydrobromide, a phosphate or a sulfonate.

The hydrate of the compound represented by the formula I includes a hemihydrate, a 3/4 hydrate, a 2/7 hydrate, a 2/5 hydrate, and a 1/12 hydrate.

The pharmaceutically acceptable salts, hydrates, complexes, and solvates can also be used as intermediates or prodrugs. The "prodrug" as used in the present invention means a substance which can be converted into a compound represented by the formula I or a pharmaceutically acceptable salt thereof in vivo to have the same pharmacological action as the compound represented by the formula I.

In the present invention, if an isomeric form of the compound represented by the general formula I appears, all forms including an enantiomer or an isomer are included in the present invention. The compound of the formula I of the present invention containing a chiral center or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof can be used as a racemic mixture or separately by a known technique.

Preferably, the compound of the formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof is as follows:

Compound 1

(5S)-[N-3-(3 ',5 '-difluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Acetamide compound 2

(5S)-[N-3-(3 ',5,-Difluoro-4'-(1"-methyl-5",6"-dihydro-indole' (Η), 2", 4"- Triazin-4-yl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide

Compound 3

(5S)-[N-3-(3 '-Fluoro-4'-(2"-chloromethyl-1"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]A Acetamide compound 4

(5S)-[N-3-(3 '-Fluoro-4'-(2"-chloromethyl-4"-methyl-1"-piperidinyl)phenyl)-2-oxo-5- Oxazolidine]methylacetamide

Compound 5

(5R)- [ Ν-3-(3 '-fluoro -4'-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol

Compound 6 (5S)-[N-3-(3'-fluoro-4'-(4",6"-dimethoxy-2"-hexahydropyrimidinyl)phenyl)-2-oxo-5-oxazole Alkyl]methylacetamide

Compound 7

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

Compound 8

(5R)-[N-3-(3'-fluoro-4'-(4",6"-dimethoxy-2"-hexahydropyrimidinyl)phenyl)-2-oxo-5-oxazole Alkyl]methanol compound 9

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

Compound 10

(5S)-[N-3-(3,-fluoro-4'-(6"-chloro-4"-cyano-2"-pyridine)phenyl)-2-oxo-5-oxazolidinyl ]methylacetamide compound 11

(5S)-[N-3-(3'-fluoro-4'-(6"-chloro-4"-cyano-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 Acetamide compound 14

(5S)-[N-3-(3'-fluoro-4'-(5"-fluoro-4"-oxo-1",2",3",4"-tetrahydro-2"-quinoline Phenyl)-2-oxo-5-oxazolidinyl]methylacetamide

Compound 15

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

Compound 16

(5S)-[N-3-(3'-fluoro-4'-(4"-(3"'-chloropropionyl)-1"-piperazinyl)phenyl)-2-oxo-5- Oxazolidine]methylacetamide

Compound 17

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

Compound 18

(5S)-[N-3-(3'-fluoro-4'-(1"-methyl-Γ'(Η)-imidazolyl-2"-thio)phenyl)-2-oxo-5 -oxazolidinyl]methylacetamide

Compound 19

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl acetamide compound 20 (5R)-[N-3-'3'-fluoro-4'4"-methyl-1"(H)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Methanesulfonamide compound 21

(5S)-[N-3 3'Good 4', 2",5"-Dioxo-1"-pyrrolidinyl)-phenyl)-2-oxo-5-oxazolidinyl]methyl Acetamide compound 22

(5R)-[N-3-' 3'-fluoro-4' 2",5"-dioxo-1"-pyrrolidinyl)-phenyl)-2-oxo-5-oxazolidinyl Methyl methanesulfonyl compound 23

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

Compound 24

(5R)-[N-3-' 3'Good 4'-' Γ(Η)-Γ'-pyrrolyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonamide 25

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

Compound 26

(5R)-[N-3-' 3'good 4'-' Γ-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonamide

Compound 27

(5S)-[N-3- 3'-fluoro-4' Γ',3", 4"-thiadiazole-2"-amino)-phenyl)-2-oxo-5-oxazolidinyl ]Methylacetamide Compound 28

(5S)-[N-3- 3'-fluoro-4' Γ',3", 4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazolidinyl] Methyl chloroacetamide compound 29

(5S)-[N-3- 3'-fluoro-4' 3"-methyl-Γ'(Η)-pyrazolyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Acetamide compound 30

(5R)-[N-3-' 3'good 4'-' 3"-methyl-1 "(Η)-Βbazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl methanesulfonamide compound 31

(5S)-[N-3- 3'-fluoro-4' 3"-methyl-Γ'(Η)-pyrazolyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Chloroacetamide compound 32

(5S)-[N-3- 3'-fluoro-4' 2",5"-dioxo-1"-pyrrolidinyl)-phenyl)-2-oxo-5-oxazolidinyl] Methyl acetamide compound 33

(5S)-[N-3- 3'-fluoro-4' 2",5"-dihydro-1"(-pyrrolyl)-phenyl)-2-oxo-5-oxazolidinyl]A Acetamide compound 34

(5R)-[N-3-' 3'Good 4'-' 2",5"-Dihydro-indole' (Η)-pyrrolyl)-phenyl)-2-oxo-5-oxazolidine Methyl methanesulfonamide compound 35

(5S)-[N-3 (3'good 4 <2",5"-dihydro-indole' (Η)-pyrrolyl)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'Good4'-' Γ-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonamide Compound 38

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)phenyl)-2-oxo-5-oxa Azolidinyl]methylacetamide compound 39

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)phenyl)-2-oxo-5-oxa Azolidinyl]methyl chloroacetamide compound 40

(5R)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methanol compound 41

(5R)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl methanesulfonate compound 42

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methylphthalimide

Compound 43

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methylamine

Compound 44

(5RMN-3-(3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol compound 45

(5RMN-3- 3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)phenyl 2-oxo-5-oxazolidinyl]methyl methanesulfonic acid Ester

Compound 46

(5SMN-3-C3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl- Phthalimide

Compound 47

(5S)-[N-3-(3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidine Methylamine compound 48

(5S)-[N-3-(3'-fluoro-4'-(Γ'(Η)-pyrrolyl)phenyl)-2-oxo-5-oxazolidinyl]methylamine

Compound 49

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

Compound 50

(5R)-[N-3-(3'-fluoro-4'-(Γ'(Η)-Β-rhyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonate Acid ester compound 51

(5S)-[N-3-(3'-fluoro-4'-(Γ'(Η)-pyrrolyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthalate Imide compound 52

(5S)-[N-3-(3'-fluoro-4'-(3"-methyl-Γ'(Η)-pyrazolyl)phenyl)-2-oxo-5-oxazolidinyl Methylphthalimide

Compound 53

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

(5R)-[N-3-' 3 '-fluoro-4'-(3"-methyl-1"(H)-B-pyrazyl)phenyl)-2-oxo-5-oxazolidine Methanol

Compound 55

(5R)-[N-3-' 3'-fluoro-4'-(3"-methyl-Γ'(Η)-Βbazolyl)phenyl)-2-oxo-5-oxazolidine Methyl methanesulfonate compound 56

(5R)-[N-3-' 3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-pyrrolyl)-phenyl)-2-oxo-5-oxa Azoliyl]methanol compound 57

(5S)-[N-3 3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-pyrrolyl)-phenyl)-2-oxo-5-oxazolidine Methylamine compound 58

(5R)-[N-3-' 3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-pyrrolyl)-phenyl)-2-oxo-5-oxa Azolidinyl]methyl methanesulfonate compound 59

(5S)-[N-3 3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-Βpyryl)-phenyl)-2-oxo-5-oxine Azolidinyl]methylphthalimide

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

Compound 63

(5S)-[N-3 3'-fluoro-4'-(1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthalimide 64

(5R)-[N-3-' 3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)-phenyl)-2-oxo-5- Oxazolidinyl]methanol compound 65

(5S)-[N-3- 3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)-phenyl)-2-oxo-5-oxa Azolidinyl]methylamine compound 66

(5S)-[N-3- 3'-fluoro-4'-(1",3",4"-thiadiazole-2-"thio)-phenyl)-2-oxo-5-oxa Azolidinyl]methylphthalimide

Compound 67

(5R)-[N-3-' 3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)-phenyl)-2-oxo-5- Oxazolidinyl]methyl methanesulfonate compound 68

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

Compound 69

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

Compound 70

(5R)-[N-3-'3'-fluoro-4'-(1"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate Compound 71

(5S)-[N-3-(3'-fluoro-4'-(1"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthaloyl Amine compound 72

(5R)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazole Alkyl]methanol compound 73

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazole Alkyl]methylamine compound 74

(5R)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazole Alkyl]methyl methanesulfonate compound 75

(58)-^-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazolidine Methylphthalimide

Compound 76

(5SMN-3-acetyl-2-oxo-5-oxazolidinyl)methylacetamide

Compound 77

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

Compound 78

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

Compound 79

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

Compound 80

(5S)-[N-3-(2'-acetyloxy-4'-pyrimidinyl)-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-2'-pyridine)-2-oxo-5-oxazolidinyl]methylacetamide

Compound 83

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

Compound 84

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

Compound 85

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

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-thio-1,3,4 Thiadiazole compound 88 (5R)-[N-3-(3,-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methyl-1,2,4-1H-triazole Azoline compound 89

(5R)-[N-3-(3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methyl-1H-tetrazole Compound 90

(5R)-[N-3-(3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylcamphorimide Compound 91

(5R)-[N-3-(3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylthiotetrazole Compound 92

(5R)-[N-3-(3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylphthalimide Compound 93

(5R)-[N-3-(3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methyl-2-thiobenzimidazole Compound 94

(5R)-[N-3-(3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylsuccinimide Compound 95

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

Compound 98

(5R)-[N-3-(4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylphthalimide 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-1,2,4-1H-triazole Compound 101

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

Compound 102

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

Compound 103

5SMN-3-C3 '-Chloro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methanol

Compound 104

(5S)-[N-3-(3'-Chloro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylmethanesulfonate Compound 105

(5S)-[N-3-(3'-Chloro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylphthalimide 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-1,2,4-1H-triazole Azoline compound 108

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

Compound 109

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

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 Compound 112

(5S)-[N-3-(3'-trifluoromethyl-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylphthalimide 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-1,2,4-1H -triazole compound 115

(5S)-[N-3-(3'-trifluoromethyl-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylcamphorimide Compound 116

(5S)-[N-3-(3'-trifluoromethyl-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylsuccinimide Compound 117

(5RMN-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]methyl methanesulfonate compound 119

(5R)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthalate Imide compound 120

(5R)-[N-3-(3,-fluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl-1,2 , 4-1H-triazole compound 121

(5R)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl 2-oxo-5-oxazolidinyl]methylcamphorimide compound 122

(5R)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylsuccinimide Compound 123

(5SMN-3-C3'-fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol compound 124 (5S)-[N-3-(3'-fluoro-4'•(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazole Alkyl]methyl methanesulfonate

Compound 125

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

Compound 126

(5S)-[N-3-(3-fluoro-4'-(4"-(4'"-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazolidine Methyl-1,2,4- 1H-triazole

Compound 127

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

Compound 128

(5S)-[N-3-(3-fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazolidine Methyl succinimide

Compound 129

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

Compound 130

(5S)-[N-3-(3-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate compound 131

(5S)-[N-3-(3-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthaloyl Imine compound 132

(5S)-[N-3-(3-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl-1,2, 4-1H- Compound 133

(5S)-[N-3-(3-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylcamphorimide compound 134

(5S)-[N-3-(3-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylsuccinimide Compound 135

(5R)-[N-3-(3'-Fluoro-4'-piperidinylphenyl)-2-oxo-5-oxazolidinyl]methyl-1,2,4-1H- Compound 136

(5R)-[N-3-(3'-fluoro-4'-piperidinylphenyl 2-oxo-5-oxazolidinyl]methylcamphorimide

Compound 137

(5R)-[N-3-(3'-fluoro-4'-piperidinylphenyl)-2-oxo-5-oxazolidinyl]methylsuccinimide

Compound 138

(5S)-[N-3-(3'-fluoro-4(2",5"-dioxo-1"-pyrrolidinyl)-phenyl)-2-oxo-5-oxazolidinyl Methyl chloroacetamide

Compound 139 (5S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide hemihydrate 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.

The compound represented by the formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may be used singly or in any combination.

The mycobacterial disease in the present invention is an infectious disease caused by infection of the human or animal body by mycobacteria, including but not limited to tuberculosis and leprosy. The mycobacteria are Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium marinum, Mycobacterium lactis, Mycobacterium fulvum, Mycobacterium phlei, Mycobacterium tuberculosis, Mycobacterium lactis, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium tuberculosis, Mycobacterium phlei, Mycobacterium phlei, Mycobacterium faecalis, Mycobacterium erythropolis, Mycobacterium smegmatis, Mycobacterium faecalis, Mycobacterium phlei, or Mycobacterium tuberculosis.

The present invention provides the use of a compound represented by Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, for the manufacture of a medicament for preventing or treating tuberculosis. Tuberculosis bacteria inhibited by the compounds of the invention include, but are not limited to, human, bovine, avian, African-type Mycobacterium tuberculosis, and Mycobacterium tuberculosis. The compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof can also be used for the prevention or treatment of a mixed infection caused by different types of Mycobacterium tuberculosis.

Tuberculosis which is prevented or treated by the pharmaceutically active ingredient of the present invention includes primary pulmonary tuberculosis, hematogenous disseminated pulmonary nucleus, secondary pulmonary tuberculosis, tuberculous pleurisy, bone and joint tuberculosis, tuberculous meningitis, renal tuberculosis, and intestinal tuberculosis.

In the present invention, a method of treating an individual having a mycobacterial infection comprises administering to the individual a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex thereof, or Prodrug.

Additionally, a method of treating an individual having a mycobacterial infection comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or administration thereof. Any combination of the compounds.

In the present invention, a method of treating an individual having a mycobacterial infection comprises administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof. a pharmaceutical composition comprising:

a compound represented by Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or any combination of at least one compound, and a pharmaceutically acceptable adjuvant, such as at least one pharmaceutically acceptable excipient. The effective amount of the compound represented by Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, to achieve the desired biological effect may depend on a number of factors, such as the intended use, mode of administration. And the patient's clinical.

The medicament of the present invention may be any of oral or parenteral dosage forms such as injections, respiratory administration, dermal administration, mucosal administration and the like. The drug is an oral agent such as a tablet, a capsule, a dry suspension, or an injection, from the viewpoint of convenience for the patient.

When used for the prevention of tuberculosis, the medicament of the present invention is usually administered at a dose of 0.01 to 2000 mg/day; the daily dose may be divided into multiple administrations. For example, the daily dose may be 0.01-1800 mg, or 0.1-1500 mg, or 1-1200 mg, administered in two, three or four doses. When used to prevent tuberculosis, the dosage can be adjusted according to the patient's condition, gender, age, and weight.

In the present invention, the pharmaceutical composition of the compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof as an active ingredient can be prepared into a slow release, a controlled release, and a slow release. Release, pulse release and sustained release dosage forms.

In the present invention, for the treatment of tuberculosis, the compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may be used in the form of a compound, or may be combined with a pharmaceutically acceptable auxiliary agent, for example. A pharmaceutically acceptable carrier is used in the form of a pharmaceutical composition. The carrier should conform to the compatibility test with the other ingredients of the composition and be harmless to the health of the patient. The carrier may be a solid or a liquid or a combination of the two, and can be prepared as a single dosage form with the compound of the formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof. For example, a tablet may be prepared in an amount of from 0.05% to 100% by weight of the compound represented by the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.

The pharmaceutical composition should have at least one active ingredient comprising a compound of the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof, or any combination thereof. The pharmaceutical composition can be prepared by a known method such as mixing the active ingredient with a pharmaceutically acceptable carrier such as a carrier and/or an excipient.

In the present invention, the excipient includes, but is not limited to, microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, glycine, a disintegrant (such as starch, croscarmellose sodium, Composite silicates and high molecular weight polyethylene glycols), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants (such as magnesium stearate, glycerin and talc).

In the present invention, the at least one compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may also be used with a sweetener, a flavoring agent, a pigment, a dye. Or an emulsifier and a mixture thereof.

The compound of the formula I of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may also be used in combination with other anti-tuberculosis drugs such as isoniazid and rifampin.

The invention is further illustrated by experiments and examples below.

As an active ingredient of the pharmaceutical composition for preventing or treating tuberculosis of the present invention, a part of the compounds of the formula I represented by the present invention are listed in Table 1 below: Compound table

R R2 R: R4 R:

, F

twenty one



Example 1

(5S)-[N-3-(3'-fluoro-4'-(4",6"-dimethoxy-2"-hexahydropyrimidinyl)phenyl)-2-oxo-5-oxazole Preparation of alkyl]methylacetamide (compound 6):

1, the first step

At room temperature, 25.5 g of 4-(4',6'-dimethoxy-2'-hexahydropyrimidine)-3-fluoroaniline and 400 ml of tetrahydrofuran were added to the reaction flask, and 1 mol/L of sodium hydroxide was added thereto with stirring. 110ml of aqueous solution, adjust the pH between 7.5-8.5, add 15ml (8.77g) of benzyl chloroformate, stir the reaction for 20 minutes, after the reaction is completed, add 1000ml of water to precipitate the material, and filter it for the next step. .

2, the second step

600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and a solution of 2.5 M butyllithium in 37 ml of n-hexane was added dropwise, followed by dropwise addition of R-glycidyl butyrate 13.6 g. (98%), after the completion of the dropwise addition, keep the temperature at -70 ° C for 1 hour, then react at room temperature for 16 hours. After the reaction is completed, filter, distill the mother liquor to dry at -0.08 MPa, 60 ° C, and obtain the solid for the next step. reaction.

3, the third step

At room temperature, 200 ml of dichloromethane and 15 g of the second reaction product were added to the reaction flask, and the mixture was stirred, cooled to 0 ° C in an ice water bath, and 5 g of triethylamine and 5 g of methanesulfonyl chloride were successively added dropwise. Reaction for 2 hours. After suction filtration, the mother liquor was distilled to dryness at -0.08 MPa at 60 ° C, and the obtained solid was used in the next step.

4, the fourth step

10 g of the third step reaction product and 150 ml of DMF were added to the reaction flask, and the mixture was heated to 80 ° C, and 3.7 g of anhydrous potassium carbonate and 3 g of potassium phthalimide were added. After reacting for 16 hours, after completion, suction filtration, distillation of the mother liquor to dryness (-0.08 MPa, 80 ° C), and the obtained solid was used in the next step.

5, the fifth step

500 ml of absolute ethanol and 5 g of the fourth step reaction product were placed in a reaction flask, and stirred under reflux. Heat 500ml aqueous solution of methylamine (25%), pass the steam to the reaction flask for 5 hours, continue to stir for 1 hour after stopping the aeration, filter by suction, and dilute the mother liquor to a certain amount (-0.08MPa, 60 °C). ), freeze crystallization, and the solid obtained by suction filtration is used in the next step.

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. Cool down to 0 ° C, add 0.7 g of triethylamine and 0.6 g of acetic anhydride (98%) dropwise, keep at 0 ° C for 1 hour, then stir at room temperature for 2 hours, after completion, suction filtration, steaming The mother liquor was concentrated to a certain amount (-0.08 MPa, 60 ° C), frozen and crystallized, and filtered to obtain the final product lg, with a total yield of 2.5%. Example 2

(5S)-[N-3-(3 '-Fluoro-4'-(4"-oxo-2"-chromanyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Acetamide

Preparation of 13)

1, the first step

To the reaction flask, 26 g of 2-(4'-amino-2'-fluorophenyl)chroman-4-one and 400 ml of tetrahydrofuran were added to the reaction flask, and 110 ml of a 1 mol/L sodium hydroxide aqueous solution was added thereto with stirring to adjust the pH. Between 7.5 and 8.5, 15 ml (8.77 g) of benzyl chloroformate was added dropwise, and the reaction was stirred for 20 minutes. After the completion of the reaction, 1000 ml of water was added to precipitate the material, and suction filtration was used for the next step.

2, the second step

600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and a solution of 2.5 M butyllithium in 37 ml of n-hexane was added dropwise, followed by dropwise addition of 13.6 g of R-glycidyl butyrate. (98%), after the completion of the dropwise addition, keep the temperature at -70 ° C for 1 hour, then react at room temperature for 16 hours. After the reaction is completed, filter, distill the mother liquor to dry (-0.08 MPa, 60 ° C), and obtain the solid for use. Step reaction.

3, the third step

At room temperature, 200 ml of dichloromethane and 15 g of the second reaction product were added to the reaction flask, and the mixture was stirred, cooled to 0 ° C in an ice water bath, and 5 g of triethylamine and 5 g of methanesulfonyl chloride were successively added dropwise. Reaction for 2 hours. After suction filtration, the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step.

4, the fourth step

5, the fifth step

500 ml of absolute ethanol and 5 g of the fourth step reaction product were placed in a reaction flask, and stirred under reflux. Heat 500ml aqueous solution of methylamine (25%), pass the steam to the reaction flask for 5 hours, continue to stir for 1 hour after stopping the aeration, filter by suction, and distill the mother liquor to a certain amount (-0.08MPa, 60 °C). ), freeze crystallization, and the solid obtained by suction filtration is used in the next step.

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. The temperature was lowered to 0 ° C, 0.7 g of triethylamine and 0.6 g of acetic anhydride (98%) were added dropwise, and kept at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. After completion, suction filtration was carried out, and the mother liquor was concentrated by distillation to a certain amount. (-0.08 MPa, 60 °C), freeze crystallization, suction filtration to obtain the final product 0.8g, the total yield of 2.0%. Example 3 (5S)-[N-3-(3'-fluoro-4'-(5"-fluoro-4"-oxo-1",2",3",4"-tetrahydro-2"-quinoline Of phenyl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide (Compound 14)

1, the first step

Add 2-(4'-amino-2'-fluorophenyl)-5-fluoro-2,3-dihydroquinolin-4(1H)-one 28 g, 400 ml of tetrahydrofuran to the reaction flask at room temperature, stir Add 120 ml of 1 mol/L sodium hydroxide aqueous solution, adjust the pH between 7.5 and 8.5, add 16 ml (8.77 g) of benzyl chloroformate dropwise, and stir the reaction for 20 minutes. After the reaction is completed, add 1000 ml of water to precipitate the material. Filter drying is used for the next step of the reaction.

2, the second step

600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and a solution of 2.5 M butyllithium in 36 ml of n-hexane was added dropwise, followed by dropwise addition of 13.4 g of R-glycidyl butyrate ( 98%), after the completion of the dropwise addition, keep the temperature at -70 ° C for 1 hour, then react at room temperature for 16 hours. After the reaction is completed, filter and distill the mother liquor to dryness (- 0.08 MPa, 60 ° C). The obtained solid is used in the next step. reaction.

3, the third step

At room temperature, 200 ml of dichloromethane and 15 g of the second reaction product were added to the reaction flask, and the mixture was stirred, cooled to 0 ° C in an ice water bath, and 5 g of triethylamine and 4.5 g of methanesulfonyl chloride were successively added dropwise. Reaction for 2 hours. After suction filtration, the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step.

4, the fourth step

10 g of the third step reaction product and 150 ml of DMF were added to the reaction flask, and the mixture was heated to 80 ° C, and 3.5 g of anhydrous potassium carbonate and 3 g of potassium phthalimide were added. After reacting for 16 hours, after completion, suction filtration, distillation of the mother liquor to dryness (-0.08 MPa, 80 ° C), and the obtained solid was used in the next step.

5, the fifth step

500 ml of absolute ethanol and 5 g of the fourth step reaction product were placed in a reaction flask, and stirred under reflux. Heat 500ml aqueous solution of methylamine (25%), keep the steam speed stable, and then put it into the reaction bottle for 5 hours. After stirring, stop stirring for 1 hour, filter, and distill the mother liquor to a certain amount (-0.08MPa, 60 °). C), freeze crystallization, and the solid obtained by suction filtration is used in the next step.

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. The temperature was lowered to 0 ° C, 0.7 g of triethylamine and 0.6 g of acetic anhydride (98%) were added dropwise, and kept at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. After completion, suction filtration was carried out, and the mother liquor was concentrated by distillation to a certain amount. (-0.08 MPa, 60 °C), freeze crystallization, suction filtration to obtain the final product 1.2g, the total yield of 2.9%. Example 4

Preparation of (5S)-[N-3-(3'-fluoro-4'-(benzofuranyl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide (Compound 15)

1, the first step 23.0 g of 4-(benzofuran-2'-yl)-3-fluoroaniline and 400 ml of tetrahydrofuran were added to the reaction flask at room temperature, and 110 ml of a 1 mol/L sodium hydroxide aqueous solution was added thereto with stirring to adjust the pH to 7.5-8.5. Between 15 ml ( 18.7 g) of benzyl chloroformate was added dropwise, and the reaction was stirred for 20 minutes. After the completion of the reaction, 1000 ml of water was added to precipitate a material, which was suction-filtered and dried for the next reaction.

2, the second step

600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and a solution of 2.5 M butyl lithium in 40 ml of n-hexane was added dropwise, followed by dropwise addition of R-glycidyl butyrate 14.0 g. (98%), after the completion of the dropwise addition, keep the temperature at -70 ° C for 1 hour, then react at room temperature for 16 hours. After the reaction is completed, filter, distill the mother liquor to dry (-0.08 MPa, 60 ° C), and obtain the solid for use. Step reaction.

3, the third step

200 ml of dichloromethane and 15 g of the second reaction product were added to the reaction flask at room temperature, stirred, and cooled to 0 ° C in an ice water bath, followed by dropwise addition of 6 g of triethylamine and 5.5 g of methanesulfonyl chloride. Reaction for 2 hours. After suction filtration, the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step.

4, the fourth step

10 g of the third step reaction product and 150 ml of DMF were added to the reaction flask, and the mixture was heated to 80 ° C, and 4.0 g of anhydrous potassium carbonate and 3.6 g of potassium phthalimide were added. After reacting for 16 hours, after completion, suction filtration, distillation of the mother liquor to dryness (-0.08 MPa, 80 ° C), and the obtained solid was used in the next step.

5, the fifth step

500 ml of absolute ethanol and 5 g of the fourth step reaction product were placed in a reaction flask, and stirred under reflux. Heat 500 ml of methylamine aqueous solution (25%), keep the steam speed steady, and then put it into the reaction flask for 5 hours. After stirring, stop stirring for 1 hour, filter, and distill the mother liquor to a certain amount (-0.08MPa, 60 °). C), freeze crystallization, and the solid obtained by suction filtration is used in the next step.

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. The temperature was lowered to 0 ° C, and l.Og of triethylamine and 0.8 g of acetic anhydride (98%) were added dropwise, and kept at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. After completion, suction filtration was carried out, and the mother liquor was concentrated by distillation. The amount (-0.08 MPa, 60 ° C), freeze crystallization, suction filtration to obtain the final product 0.7g, the total yield of 1.9%. Example 5

(5S)-[N-3-(3 '-Fluoro-4'-(4"-(3"'-chloropropionyl)-1"-piperazinyl)phenyl)-2-oxo-5- Preparation of oxazolidinyl]methylacetamide (Compound 16)

1, the first step

To the reaction flask, 29 g of 1-(4'-(4"-amino-2"-fluorophenyl)-1 '-piperazinyl)-3-chloropropan-1-one and 400 ml of tetrahydrofuran were added to the reaction flask. After stirring, 110 ml of a 1 mol/L sodium hydroxide aqueous solution was added thereto, the pH was adjusted to be between 7.5 and 8.5, and 15 ml of benzyl chloroformate ( 18.7 g) was added dropwise thereto, and the reaction was stirred for 20 minutes. After the completion of the reaction, 1000 ml of water was added to precipitate a material. Filtering and drying is used for the next step of the reaction. 2, the second step

600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and 2.5 M of butyl lithium in 35 ml of n-hexane was added dropwise, followed by dropwise addition of 13.2 g of R-glycidyl butyrate ( 98%), after the completion of the dropwise addition, keep the temperature at -70 ° C for 1 hour, then react at room temperature for 16 hours. After the reaction is completed, filter and distill the mother liquor to dryness (- 0.08 MPa, 60 ° C). The obtained solid is used in the next step. reaction.

3, the third step

200 ml of dichloromethane and 15 g of the second reaction product were added to the reaction flask at room temperature, stirred, and cooled to 0 ° C in an ice water bath, followed by dropwise addition of 4.8 g of triethylamine and 4.5 g of methanesulfonyl chloride. Reaction for 2 hours. After suction filtration, the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step.

4, the fourth step

10 g of the third step reaction product and 150 ml of DMF were added to the reaction flask, and the mixture was heated to 80 ° C, and 3.4 g of anhydrous potassium carbonate and 2.8 g of potassium phthalimide were added. After reacting for 16 hours, after completion, suction filtration, distillation of the mother liquor to dryness (-0.08 MPa, 80 ° C), and the obtained solid was used in the next step.

5, the fifth step

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. The temperature was lowered to 0 ° C, 0.6 g of triethylamine and 0.5 g of acetic anhydride (98%) were added dropwise, and kept at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. After completion, suction filtration was carried out, and the mother liquor was concentrated by distillation to a certain amount. (-0.08MPa, 60 °C), freeze crystallization, suction filtration to obtain the final product 1.4g, the total yield of 3.2%. Example 6

(S)-[N-3-(3',5,-difluoro-4'-(1"-methyl-5",6"-dihydro-1",2",4"-triazine) Preparation of -4(1H)-yl)phenyl)-2-oxo-5oxazolidinyl]methylacetamide (Compound 2)

First step: Add 3,5-difluoro-4-(1 '-methyl-5',6'-dihydro-1 ',2',4'-triazine-4' (1H) to the reaction flask. )-based) cyclohexene-

2,4-dienamine 23 g, acetone 400 ml, stirred at room temperature, completely dissolved in solid solution, placed in a low temperature coolant circulating pump to cool to 0 ° C, stirred, add saturated NaHCO^ solution 100ml (containing NaHCO ₃ 10g ), 20 g of benzyl chloroformate was added dropwise at 0 ° C, and the mixture was dropped at 0.5 h, and kept at 0 ° C for 30 min, and taken out at room temperature and stirred overnight.

The next day, after completion of the reaction, suction filtration, the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile. The oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water. The solid is added to the reaction flask for secondary recrystallization: it is refined by acetonitrile, heated in an oil bath, and condensed and refluxed. After dissolving, a suitable amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize for 2 hours. After suction filtration, the solid was washed with water and dried under vacuum for the next step. Step 2: Add 500ml of THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas. The tail gas is bubbled with a conical flask filled with liquid paraffin. The oil bath is heated and the external temperature of the oil bath is 95 °C. Condensation reflux. 5 g of LiAlH4 powder was added, and the THF was collected after 1 hour of dehydration with timed stirring, and the former fraction was discarded (about 50 ml).

Under a nitrogen-substitution environment, 20 g of the dried first-step reaction product was added to the reaction flask, and 400 ml of treated anhydrous THF was added thereto, and the mixture was cooled to -70 ° C with a mixture of dry ice and acetone. When the internal temperature is as low as -68 °C, 26 ml of butyl lithium is added dropwise, the internal temperature is controlled below -65 °C, the reaction is completed, the low temperature (below -68 °C) is reacted for 1.5 h, and then R-glycidol is added dropwise. Butyl ester 9.5g, control internal temperature below -65 ° C, drop, low temperature (-68 ° C below) reaction 0.5h, take out, stir the reaction at room temperature overnight.

The next day, the reaction solution was washed once with 100 ml of a saturated aqueous NH ₄ C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time). The upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of solid was precipitated by adding an appropriate amount of water, poured into a beaker and placed in a freezer to cool and crystallize. Filter by suction and dry under vacuum. Used in the next step of the reaction.

The third step: 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred. When the internal temperature is 0 ° C, 7 g of triethylamine is added, and 6 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.

After completion of the reaction, it was washed once with 80 ml of a saturated NaHC0 ₃ solution, washed with water (100 ml) three times, and the mixture was separated, and the organic layer was added to a flask containing anhydrous MgS04 and dried for 2 hours, suction filtered, and the filtrate was evaporated to dryness under reduced pressure. -0.08MPa, 60 °C), the obtained solid matter was added to the reaction flask, and refined by adding 100 ml of acetonitrile: the oil bath was heated, condensed and refluxed, and after dissolving, an appropriate amount of water was added to precipitate at least a solid, and poured into a beaker and placed in a freezer. The medium was cooled and crystallized for 2 h. Filter by suction, wash the solid three times, and dry in vacuo. Used in the next step of the reaction.

Step 4: Add 10 g of the third step reaction product, 150 ml of DMF to the reaction flask, install the device, stir, add 3.6 g of phthalimide, 4 g of anhydrous K ₂ C0 _{3 in turn} , heat in oil bath, set oil The outside temperature of the bath was 82 ° C, and the reaction was stirred overnight.

The next day, suction filtration, vacuum distillation of the filtrate (-0.08MPa, 80 °C) to a certain amount, poured into a saturated NaCl aqueous solution

The white solid was stirred out in 300 ml, cooled in a freezer for 30 min, and suction filtered, and washed with solid water three times (100 ml).

The solid matter was added to the reaction flask, and refined by adding 150 ml of DMF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer for 2 hours, and suction filtered. The obtained solid was recrystallized twice by the same operation method. After suction filtration, the obtained solid was washed with water and dried in vacuo. Used in the next step of the reaction.

Step 5: Add 5 g of the fourth step reaction product, 500 ml of absolute ethanol to the reaction flask, secure the device, and stir. The oil bath is heated, and the oil bath is set to an external temperature of 82 ° C, and condensed and refluxed.

500 ml of 40% aqueous methylamine solution was added to a single-mouth reaction flask, and the apparatus was placed in a water bath with a water bath temperature of 48 °C. The methylamine gas was introduced into the reaction flask through a gas-washing bottle (concentrated sulfuric acid), and the reaction was timed for 5.5 hours.

The methylamine gas was stopped and the reaction was continued for 2 h. After the reaction, suction filtration, the filtrate was poured into a beaker and placed in a freezer to cool and crystallize overnight. The next day, suction filtration, the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of ethyl acetate: the oil bath was heated, condensed and refluxed, and the solid was completely dissolved by adding an appropriate amount of DMF, and then a small amount of water was added dropwise, and a small amount of solid was precipitated. When pouring the liquid into the beaker, put it into a freezer and cool it for 2 hours, and filter it by suction. The obtained solid was recrystallized twice by the same operation method. Filter by suction, wash with water and dry in vacuum. Used in the next step of the reaction.

Step 6: Add 2 g of the reaction product of the fifth step, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add lg triethylamine at an internal temperature of 0 ° C, add 0.7 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, react at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .

After the reaction, the mixture was filtered, and the solid was purified by a mixture of 40 ml of anhydrous ethanol and 60 ml of ethyl acetate. The mixture was heated in an oil bath, and condensed and refluxed. After the solution was dissolved, it was poured into a beaker and cooled in a freezer for 2 hours, and suction filtered. The same procedure was followed, two times recrystallization, and vacuum drying. The solid product lg was obtained. Yield 2.7% Example 7

N-[(S)-3-(3'-fluoro-4'-(2"-chloromethyl-1"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]- Preparation of acetamide (Compound 3)

First step: 24.2 g of 4-(2'-(chloromethylhydrazine-piperidinyl)-3-fluoroaniline and 400 ml of acetone were added to the reaction flask, and the mixture was stirred at room temperature. After the solid was completely dissolved, it was cooled at a low temperature. Cool down to o°c in the liquid circulation pump, stir, add saturation

100ml of NaHC0 ₃ aqueous solution (containing NaHCO ₃ 10g), add 20g of benzyl chloroformate at 0 °C, keep 0 °C reaction

At 30 min, take off at room temperature and stir overnight.

The next day, after completion of the reaction, suction filtration, the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of acetonitrile. The oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of water was added to precipitate at least a solid amount, and the liquid was poured into a beaker. Cooling and crystallization in the freezer for 2h. Filter by suction and wash the solids three times with water. The solid is added to the reaction flask for secondary recrystallization: it is refined by adding acetonitrile, heated in an oil bath, and condensed and refluxed. After dissolving, a suitable amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize for 2 hours. After suction filtration, the solid was washed with water and dried under vacuum for the next step.

Step 2: Add 500ml of THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas. The tail gas is bubbled with a conical flask filled with liquid paraffin. The oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux. Add 5g

LiAlH4 powder, dehydrated by timed stirring, collected THF after lh, and the former fraction was discarded (50 ml).

Under a nitrogen atmosphere, 20 g of the dried first step reaction product was added to the reaction flask, and 400 ml of treated anhydrous THF was added thereto, and the mixture was cooled to -70 ° C with a mixture of dry ice and acetone. When the internal temperature is as low as -68 °C, the addition of butyl lithium begins.

25ml of n-hexane solution, control internal temperature below -65 °C, drop, low temperature (-68 °C below) reaction 1.5h, then add R-glycidyl butyl ester 9.2g, control internal temperature at -65 °C After the dropwise addition, the reaction was carried out at a low temperature (-68 ° C or lower) for 0.5 h, taken out, and stirred at room temperature overnight.

The next day, the reaction solution was washed once with 100 ml of a saturated aqueous NH ₄ C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time). The upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of solid was precipitated by adding an appropriate amount of water, poured into a beaker and placed in a freezer to cool and crystallize. Filter by suction and dry under vacuum. Used in the next step of the reaction. The third step: 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred. When the internal temperature was 0 ° C, 7 g of triethylamine was added, and 5.8 g of methanesulfonyl chloride was added dropwise at an internal temperature of -5 ° C. The internal temperature was controlled at 0 ° C for 0.5 h, and the reaction was carried out for 2 h at room temperature.

The fourth step: 10g of the third step reaction product, 150ml of DMF into the reaction bottle, the device is installed, stirred, and then added 3.5g phthalimide, 3.8g anhydrous K ₂ C0 ₃ , heated in oil bath, set The external temperature of the oil bath was 82 ° C, and the reaction was stirred overnight.

The next day, suction filtration, vacuum distillation of the filtrate (-0.08MPa, 80 °C) to a certain amount, poured into 300ml of saturated NaCl aqueous solution, stirred and precipitated white solids, cooled in a freezer for 30min, removed by suction filtration, washed with solid water 3 times ( 100ml).

The methylamine gas was stopped and the reaction was continued for 2 h. After the reaction was completed, suction filtration was carried out, and the filtrate was poured into a beaker and placed in a freezer to be crystallized overnight.

The next day, suction filtration, the obtained solid matter was added to the reaction flask, and purified by adding 100 ml of ethyl acetate: the oil bath was heated, condensed and refluxed, and the solid was completely dissolved by adding an appropriate amount of DMF, and then a small amount of water was added dropwise, and a small amount of solid was precipitated. When pouring the liquid into the beaker, put it into a freezer and cool it for 2 hours, and filter it by suction. The obtained solid was recrystallized twice by the same operation method. Filter by suction, wash with water and dry in vacuum. Used in the next step of the reaction.

Step 6: Add 2 g of the reaction product of the fifth step, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add lg triethylamine at an internal temperature of 0 ° C, add 0.6 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, the reaction at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .

After the reaction, the mixture was filtered, and the solid was purified by a mixture of 40 ml of anhydrous ethanol and 60 ml of ethyl acetate. The mixture was heated in an oil bath, and condensed and refluxed. After the solution was dissolved, it was poured into a beaker and cooled in a freezer for 2 hours, and suction filtered. The same procedure was followed, two times recrystallization, and vacuum drying. The solid product lg was obtained. Yield 2.5%. Example 8

(5S)-[N-3-(3,-fluoro-4'-(6"-chloro-4"-cyano-2"-pyridine)phenyl)-2-oxo-5-oxazolidinyl Methyl acetamide Preparation of matter 10)

First step: 25 g of 4-(6'-chloro-4'-isocyano-2'-pyridyl)-3-fluoroaniline and 400 ml of acetone were added to the reaction flask, and the mixture was stirred at room temperature, and the solid was completely dissolved. placed in the low-temperature coolant circulation pump was cooled to 0 ° C, with stirring, a saturated NaHC0 ₃ aqueous solution was added 100ml (containing NaHCO ₃ 10g), 0 ° C dropwise benzyl chloroformate 20g, 0.5h dropwise, maintaining 0 ° C the reaction At 30 min, take off at room temperature and stir overnight.

Step 2: Add 500ml THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas. The tail gas is bubbled with a conical flask filled with liquid paraffin. The oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux. 5 g of LiAlH4 powder was added, and the mixture was dehydrated for 1 hour, and then THF was collected, and the former fraction was discarded (50 ml).

Under a nitrogen-substitution environment, 20 g of the dried first-step reaction product was added to the reaction flask, and 400 ml of treated anhydrous THF was added thereto, and the mixture was cooled to -70 ° C with a mixture of dry ice and acetone. When the internal temperature is as low as -68 °C, 25 ml of butyl lithium is added dropwise, the internal temperature is controlled below -65 °C, the reaction is completed, the low temperature (below -68 °C) is reacted for 1.5 h, and then R-glycidol is added dropwise. 9 g of butyl ester, controlled internal temperature below -65 ° C, drop, low temperature (below -68 ° C) for 0.5 h, taken out, and stirred at room temperature overnight.

The next day, the reaction solution was washed once with 100 ml of a saturated aqueous NH ₄ C1 solution, and the reaction mixture was washed three times with saturated aqueous NaCl solution (100 ml each time). The upper organic phase was separated and collected, distilled under reduced pressure (-0.08 MPa, 60 °C) to a certain amount, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. After suction filtration, the solid matter was added to the reaction flask, and purified by adding 100 ml of THF: the oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, at least a solid amount of the solid was precipitated by adding an appropriate amount of water, poured into a beaker and placed in a freezer to be cooled and crystallized. Filter by suction and dry under vacuum. Used in the next step of the reaction.

The third step: 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred. When the internal temperature is 0 ° C, 6.5 g of triethylamine is added, and 5.6 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.

The fourth step: 10 g of the third step reaction product, 150 ml of DMF was added to the reaction flask, the device was set up, stirred, and 3.4 g of phthalimide, 3.6 g of anhydrous K ₂ C0 ₃ were added in sequence, and heated in an oil bath. The oil bath was set to an external temperature of 82 ° C, and the reaction was stirred overnight.

The white solid was stirred out in 300 ml, cooled in a freezer for 30 min, and suction filtered, washed three times with solid water. (100ml).

Step 6: Add 2 g of the reaction product of the fifth step, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add 0.8g of triethylamine at an internal temperature of 0 ° C, add 0.6 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, react at -5 ° C for 0.5 h, take out, and react at room temperature. 2h.

After the reaction, the mixture was filtered, and the solid was purified by a mixture of 40 ml of anhydrous ethanol and 60 ml of ethyl acetate. The mixture was heated in an oil bath, and condensed and refluxed. After the solution was dissolved, it was poured into a beaker and cooled in a freezer for 2 hours, and suction filtered. The same procedure was followed, two times recrystallization, and vacuum drying. The solid product was obtained in an amount of 1.2 g, yield 3.1%. Example 9

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylacetamide (Compound 12 Preparation

(1) Preparation of 3-fluoro-4-(4'-phenylpiperazinyl)nitrobenzene

50 ml of ethyl acetate, 13.5 ml of 4-phenylpiperazine and 15.30 ml of diisopropylethylamine were placed in a 250 ml three-necked flask. Magnetic stirring was carried out at room temperature, and 9.0 ml of 3,4-difluoronitrobenzene was added. After reacting for 105 hours, the reaction mixture was poured into water, and extracted with ethyl acetate (150 ml×3) three times, the extract was washed three times with saturated sodium chloride solution (150 ml < 3), and dried over anhydrous magnesium sulfate (MgS0 ₄ ). Evaporate dry. It has an orange-yellow solid. Acetone: water (volume ratio of 9:1) was recrystallized to give orange-yellow crystals (23.66 g), yield 96.33%.

(2) Preparation of 3-fluoro-4-(4'-phenylpiperazinyl)aniline

6.69 g (119 mmol) of reduced iron powder, 23.57 ml of water and 1.11 ml of glacial acetic acid were added to a 500 ml three-necked flask for reflux for 80 minutes. 150 ml of a solution of 3-fluoro-4-C4'-phenylpiperazinyl)nitrobenzene (12.0 g, 39.82 mmol) obtained in the step C1) was slowly added dropwise. After completion of the dropwise addition, the reaction was further carried out for 10 minutes, suction filtration, evaporation of ethanol, and dissolution of ethyl acetate. The filter cake was washed 3 times with ethyl acetate. The combined organic phases were washed with water three times, washed with a saturated NaCl solution, dried over anhydrous magnesium sulfate (MgS0 _4), evaporated to dryness. A light white solid was obtained which was used directly in the next step. (3) Preparation of N-benzyloxycarbonyl-3-fluoro-4-(4'-phenylpiperazinyl)aniline

100 ml of dichloromethane and 13.0 g of crude 3-fluoro-4-(4'-phenylpiperazinyl)aniline obtained in the step (2) were added to a 250 ml four-necked flask, and 7.91 ml of diiso was added at 0 °C. Propylethylamine. Mechanically stirred, 5.34 ml of benzyl chloroformate was added dropwise. The resulting solution was stirred at room temperature for 16 hours, extracted twice with dichloromethane (100 ml×3), washed three times with saturated sodium chloride solution (100 ml×3), dried over anhydrous magnesium sulfate and evaporated. A light white solid. Acetone: water (volume ratio 7:3) recrystallized. 11.46 g of white crystals were obtained in a yield of 76.66 %.

(4) Preparation of (R)-[N-3-C3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol

N-benzyloxycarbonyl-3-fluoro-4-(4'-phenylpiperazinyl)aniline obtained in step (3) was added to a 100 ml three-necked flask (baked at 120 °C for more than 2 hours), 3.4 g, Water tetrahydrofuran 50 ml. 6.60 ml of a 1.6 M butyl lithium solution was added dropwise at -78 °C under N ₂ protection. Stir at -78 °C for 80 minutes and gradually turn into a yellow-green solution. The solution was added dropwise at 1.78 ml of CR)-butyl glycerol and 5 ml of anhydrous tetrahydrofuran, and the solution quickly became clear. After reacting for 1 hour, the acetone bath was removed, the temperature was raised to room temperature, and the mixture was stirred for 16 hours, and a small amount of precipitate appeared. A white solid was obtained. After recrystallization from silica gel column chromatography and ethyl acetate: petroleum ether (yield: 1:3), 2.34 g of white crystals, yield 77.21.

(5) (R)-[N-3-(3'-Fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methanol methanesulfonic acid Preparation of the ester 25 mol ml of anhydrous dichloromethane, CR obtained in the step (4)-[N-3-C3'-fluoro-4'-(;4"-phenylpiperazinyl)phenyl)-2 - Oxo-5-oxazolidinyl]methanol 1.74 g, 1.32 ml of triethylamine was added to a 100 ml three-necked flask. At 0. 0.52 ml of methanesulfonyl chloride was added dropwise under C for 65 minutes, and a large amount of white precipitate appeared. The mixture was extracted three times with dichloromethane (50 ml <<3>), and the extract was washed three times with saturated NaCl (50 m3), dried over anhydrous magnesium sulfate and evaporated. A white solid was obtained which was recrystallized from acetonitrile:water (1:1 by volume). It gave 1.6065 g of white crystals. The yield was 75.92%.

(6) (R)-[N-3-(3'-Fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methyl- Preparation of phthalimide

(R)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methanol methanesulfonate 0.686 g, 0.347 g of potassium phthalimide and 0.432 g of anhydrous potassium carbonate were added to a 100 ml three-necked flask. After 3 hours of reaction, ethyl acetate (50 ml×3) was extracted three times, and the extract was saturated with NaCl solution (50 ml×3). It was washed 3 times, dried over anhydrous magnesium sulfate and evaporated to dryness.

(7) (S)-[N-3-(3'-Fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methyl b (R)-[N-3- 3'-fluoro-4'-(4"-phenylpiperazinyl"phenyl-2-oxo-5-oxazolidinyl]methyl obtained by the amide preparation step A crude phthalimide, 100 ml of absolute ethanol and a 25 wt% aqueous solution of methylamine (3.38 ml, 15.63 mmol) were placed in a 250 ml three-necked flask, heated to reflux for 1 hour, and then steamed under the end of the reaction. 50 ml 0.1 The hydrochloric acid of M was extracted, and then extracted twice with ethyl acetate (30 ml×2). The aqueous phase was transferred to a 100 ml three-necked flask, and the pH was adjusted to be weakly alkaline (pH = 8-9) with an appropriate amount of NaOH. Add acetic anhydride (0.46 ml, 4.49 mmol), and react for 10 minutes. Extract the mixture with ethyl acetate (100 ml×3) for 3 times, and wash with saturated sodium chloride solution (100 ml><3) for 3 times. Magnesium was dried, evaporated to dryness, purified by flash chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc '-(4"-Phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide. Yield: 29.49%. Elemental analysis results: N%: 13.61, C%: 64.07, H%: 6.02. Theoretical values: N%: 13.58, C%: 64.06, H%: 6.1 1. The content was determined by high performance liquid chromatography: 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).

¹³ C NMR (400 Hz, 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. Example 10

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide hemihydrate Preparation of Compound (Compound 139)

1 g of the crude compound 12 was added to 2 ml of 6% hydrochloric acid, and a small amount of activated carbon was added thereto, and the mixture was stirred under heating at 50 ° C for 2 hours, followed by filtration. The filtrate was subjected to crystallization at room temperature, and the obtained crystal was vacuum dried at 40 ° C for 5 hours to obtain a compound 139, which was determined by HPLC: 99.0%, melting point: 210-215 ° C (capillary measurement), NMR and mass spectrometry 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).

1 ³ C NMR (400 Hz, 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. The peak of [M-V2H ₂ 0+H] in the mass spectrum was 413.1; the theoretical value was 413.2. Example 11

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

Preparation of (Compound 140)

10 g of crude compound 12 was dissolved in 200 ml of a mixed solvent of water and ethyl acetate (2:8 by volume) at 30 ° C to obtain (S)-[N-3-(3'-fluoro-4'- The solution of (4"-phenylpiperazinyl"phenyl-2-oxo-5-oxazolidinyl]methylacetamide was stirred for 8 h, filtered, and the filtrate was allowed to stand at room temperature to precipitate crystals. )-[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 2/7 The water content of the hydrate is about 1.20 ± 0.15% (measured by TGA).

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylacetamide 2/7 The X-ray powder diffraction pattern of the crystalline hydrate, measured by CuK ct ray, has a peak (2 Θ ) selected from the following values: 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, 43.86, 45.37, 45.87, 47.40 and 49.36 ± 0.02

Example 12

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

(S)-[N-3-(3'-Fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide crude 10 g, added to 200 ml of a mixed solvent of aqueous aluminatic acid and butanol (3:7 by volume) to prepare CSMN-3-C3'-fluoro-4'-(;4"-phenylpiperazinyl)benzene The aqueous solution of keto-2-oxo-5-oxazolidinyl]methylacetamide was stirred at 50 ° C for 7 h, filtered, and crystals were precipitated at room temperature. The 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 2/5 The water content of the hydrate is about 1.70 ± 0.15% (measured by TGA).

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylacetamide 2/5 An X-ray powder diffraction pattern of the crystalline hydrate, measured by CuK ct ray, having a peak (2 Θ ) selected from the following values: 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, 43.14, 43.88, 45.30, 45.87, 47.33 and 49.18 ± 0.02 degrees.

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

(S)-[N-3-(3'-Fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide crude 10 g, (S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl) was prepared by adding 200 ml of a mixed solvent of water and ethanol (volume ratio 4:6). Aqueous phenyl-2-oxo-5-oxazolidinyl]methylacetamide. Stir at 70 ° C for 4 h, filter, and precipitate crystals at room temperature to give (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 1/ The water content of the 12 hydrate was about 0.40 ± 0.15% (measured by TGA).

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide 1/ X-ray powder diffraction pattern of 12 crystalline hydrate, measured by CuKct ray, having a peak (2Θ) selected from the following values: 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, 37.82, 39.56, 41.35, 43.33 44.42, 45.32, 46.02 and 47.32 ± 0.02 degrees. Example 14

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylacetamide 3/4 Preparation of hydrate (compound 143)

(S)-[N-3-(3'-Fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylacetamide crude 10 g , (S)-[N-3-(3'-fluoro-4'-(4"-phenylperidazole) was prepared by adding to a mixture of 200 ml of water and dimethyl sulfoxide (1:1 by volume). Azyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide aqueous solution, the resulting solution was stirred at 75 ° C for 25 h, filtered, and crystals were precipitated at room temperature to give (S)-[N 3-(3'-Fluoro-4'-(4"-phenylpiperazinyl"phenyl-2-oxo-5-oxazolidinyl]methylacetamide 3/4 hydrate. 48%, purity: 98.5%.

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

(S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methylacetamide 3/4 An X-ray powder diffraction pattern of the crystalline hydrate, measured by CuK ct ray, having a peak selected from the following values (2 Θ 4.04, 8.55, 9.81, 11.04, 14.10, 16.09, 18.66, 20.12, 22.08, 23.64, 25.98, 27.00, 29.00, 30.26, 31.40, 33.25 34.59, 35.36, 37.83 39.55, 40.88, 41.89, 43.11, 44.72, 47.87 and 48.07 ± 0.02 degrees. Example 15

(5S)-[N-3-(3',5'-difluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Preparation of acetamide (Compound 1)

First step: To the reaction flask, 29 g of 3,5-difluoro-4-(4'-phenyl-indole-piperazinyl)cyclohexane-2,4-dienamine and 400 ml of acetone were added, and the mixture was stirred at room temperature. After the solid is completely dissolved, it is placed in a low-temperature coolant circulating pump and cooled to 0 ° C. Stir, add 100 ml of saturated NaHC0 ₃ aqueous solution (containing NaHC0 ₃ 10 g), add 20 g of benzyl chloroformate at 0 ° C, and drop 0.5 h. The reaction was kept at 0 ° C for 30 min, and taken out at room temperature and stirred overnight.

Step 2: Add 500ml of THF to the distillation reaction bottle, stir, pass nitrogen protection, and export the tail gas. The tail gas is bubbled with a conical flask filled with liquid paraffin. The oil bath is heated and the external temperature of the oil bath is 95 °C. , condensed reflux. 5 g of LiAlH4 powder was added, and the mixture was dehydrated for 1 hour, and then THF was collected, and the former fraction was discarded (50 ml).

Under a nitrogen-substitution environment, 20 g of the dried first-step reaction product was added to the reaction flask, and 400 ml of treated anhydrous THF was added thereto, and the mixture was cooled to -70 ° C with a mixture of dry ice and acetone. When the internal temperature is as low as -68 °C, 24 ml of butyl lithium is added dropwise, the internal temperature is controlled below -65 °C, the reaction is completed, the low temperature (below -68 °C) is reacted for 1.5 h, and then R-glycidol is added dropwise. Butyl ester 9.2g, control internal temperature below -65 °C, drop, low temperature (-68 °C below) reaction 0.5h, take out, stir at room temperature Night.

The third step: 15g of the second step reaction product and 200ml of dichloromethane were added to the reaction flask, and placed in a low temperature coolant circulation pump to cool down to -8 ° C, the device was installed, and stirred. When the internal temperature is 0 ° C, 6.5 g of triethylamine is added, and 5.5 g of methanesulfonyl chloride is added dropwise at an internal temperature of -5 ° C, and the internal temperature is controlled to be 0.5 ° or less for 0.5 h, and the reaction at room temperature is taken for 2 h.

The fourth step: 10g of the third step reaction product, 150ml of DMF into the reaction bottle, the device is installed, stirred, and then added 3.3g phthalimide, 3.6g anhydrous K ₂ C0 ₃ , heated in oil bath, set The external temperature of the oil bath was 82 ° C, and the reaction was stirred overnight.

500 ml of 40% aqueous methylamine solution was placed in a single-mouth reaction flask, and placed in a water bath with a water bath temperature of 48 °C. The methylamine gas was introduced into the reaction flask through a gas-washing bottle (concentrated sulfuric acid), and the reaction was timed for 5.5 hours.

Step 6: 2 g of the fifth step reaction product, 100 ml of THF was added to the reaction flask, and the device was placed in a low temperature coolant circulation pump, and the mixture was cooled to -8 ° C with stirring. Add lg triethylamine at an internal temperature of 0 ° C, add 0.6 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, the reaction at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. . After completion of the reaction, the mixture was filtered, and the solid was purified by a mixture of 40 ml of anhydrous ethanol and 60 ml of ethyl acetate. The mixture was heated in an oil bath, and condensed and refluxed. After the solution was dissolved, it was poured into a beaker and cooled in a freezer for 2 h, and suction filtered. Using the same procedure, secondary recrystallization, vacuum drying. The solid product lg was obtained. Yield 2.7% Example 16

(5S)-[N-3-(3'-fluoro-4'-(6"-chloro-4"-cyano-5"-methyl-2"-pyridine)phenyl)-2-oxo- Preparation of 5-oxazolidinyl]methylacetamide (Compound 11)

First step: To the reaction flask, 26 g of 4-(6'-chloro-4'-isocyanato-5'-methyl-2'-pyridyl)-3-fluoroaniline and 400 ml of acetone were added, and the mixture was stirred at room temperature. After the solid is completely dissolved, it is placed in a low-temperature coolant circulating pump and cooled to 0 ° C. Stir, add 100 ml of saturated NaHCO ₃ aqueous solution (containing NaHCO ₃ 10 g), add 20 g of benzyl chloroformate at 0 ° C, and drop 0.5 h. The reaction was kept at 0 ° C for 30 min, and taken out at room temperature and stirred overnight.

After completion of the reaction, it was washed once with 80 ml of a saturated NaHC0 ₃ solution, washed with water (100 ml) three times, and the mixture was separated, and the organic layer was added to a flask containing anhydrous MgS04 and dried for 2 hours, suction filtered, and the filtrate was evaporated to dryness under reduced pressure. -0.08MPa, 60 °C), the obtained solid matter was added to the reaction flask, and refined by adding 100 ml of acetonitrile: the oil bath was heated, condensed and refluxed, and after dissolving, an appropriate amount of water was added to precipitate at least a solid, and poured into a beaker and placed in a freezer. The medium was cooled and crystallized for 2 h. Filtered, solid Wash 3 times with water and dry in vacuum. Used in the next step of the reaction.

Step 6: Add 2 g of the fifth step reaction product, 100 ml of THF to the reaction flask, install in a low temperature coolant circulation pump, and stir to cool to -8 °C. Add lg triethylamine at an internal temperature of 0 ° C, add 0.7 g of acetic anhydride at an internal temperature of -5 ° C, and control the internal temperature to below -5 ° C. After the dropwise addition, react at -5 ° C for 0.5 h, take out, and react at room temperature for 2 h. .

After the reaction, the mixture was filtered, and the solid was purified by a mixture of 40 ml of anhydrous ethanol and 60 ml of ethyl acetate. The mixture was heated in an oil bath, and condensed and refluxed. After the solution was dissolved, it was poured into a beaker and cooled in a freezer for 2 hours, and suction filtered. The same procedure was followed, two times recrystallization, and vacuum drying. The solid product was obtained in lg, yield 2.7%. Example 17

(5S)-[N-3-(3'-fluoro-4'-(5"-(azetidin-1"-carbonyl)-pyrazinyl-2"-oxy)phenyl) Preparation of -2-oxo-5-oxazolidinyl]methylacetamide (Compound 17)

1, the first step

To the reaction flask, 29 g of (5-(4'-aamino-2'-fluorophenoxy)-2-pyrazinyl)-1-azetidinyl)one and 400 ml of tetrahydrofuran were added to the reaction flask, followed by stirring. Add 110ml of 1mol/L sodium hydroxide aqueous solution, adjust the pH between 7.5-8.5, add 15ml (8.77g) of benzyl chloroformate, stir the reaction for 20 minutes. After the reaction is completed, add 1000ml of water to precipitate the material and pump it. Filter drying is used for the next step of the reaction.

2, the second step 600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, and 36 ml of butyl lithium was added to the dropping port, followed by dropwise addition of 13.5 g of R-glycidyl butyrate (98%). After the completion of the dropwise addition, the mixture was kept at a low temperature - 70 ° C for 1 hour, and then reacted at room temperature for 16 hours. After the completion of the reaction, the mixture was filtered, and the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step.

3, the third step

4, the fourth step

5, the fifth step

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. The temperature was lowered to 0 ° C, 0.7 g of triethylamine and 0.6 g of acetic anhydride (98%) were added dropwise, and kept at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. After completion, suction filtration was carried out, and the mother liquor was concentrated by distillation to a certain amount. (-0.08MPa, 60 °C), freeze crystallization, suction filtration to obtain the final product lg, the total yield of 2.3%. Example 18

(5S)-[N-3-(3'-fluoro-4'-(1"-methyl-Γ'(Η)-imidazolyl-2"-thio)phenyl)-2-oxo-5 Of oxazolidinyl]methylacetamide (Compound 18)

1, the first step

To the reaction flask, 23 g of 3-fluoro-4-(1 '-methyl-1 Ή-2'-imidazolyl)thioaniline and 400 ml of tetrahydrofuran were added to the reaction flask, and a 1 mol/L sodium hydroxide aqueous solution was added thereto with stirring. 110 ml, adjust the pH between 7.5 and 8.5, add 15 ml (8.77 g) of benzyl chloroformate dropwise, stir the reaction for 20 minutes. After the reaction is completed, add 1000 ml of water to precipitate the material, and filter and dry for the next step.

2, the second step

600 ml of tetrahydrofuran and 30 g of the first reaction product were added to the reaction flask, and the temperature was lowered to -70 ° C using liquid nitrogen, 37 ml of 2.5 M butyllithium was added, and then R-glycidyl butyrate (13.6 g) was added dropwise (98%). After the completion of the dropwise addition, the mixture was kept at a low temperature - 70 ° C for 1 hour, and then reacted at room temperature for 16 hours. After the completion of the reaction, the mixture was filtered, and the mother liquid was distilled to dryness (-0.08 MPa, 60 ° C), and the obtained solid was used for the next step. 3, the third step

4, the fourth step

5, the fifth step

6, the sixth step

100 ml of tetrahydrofuran and 2 g of the reaction product of the fifth step were added to the reaction flask. The temperature was lowered to 0 ° C, 0.7 g of triethylamine and 0.6 g of acetic anhydride (98%) were added dropwise, and kept at 0 ° C for 1 hour, and then stirred at room temperature for 2 hours. After completion, suction filtration was carried out, and the mother liquor was concentrated by distillation to a certain amount. (-0.08MPa, 60 °C), freeze crystallization, suction filtration to obtain the final product lg, the total yield of 2.5%. Example 19

(5R)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Preparation of methanol (compound 40)

Step 1: Add 4-methylimidazole 41g and absolute ethanol 1000ml into the reaction flask, stir, add 40g of triethylamine and 80g of 3, 4-difluoronitrobenzene in turn, heat in oil bath, set the temperature of oil bath At 82 ° C, condensed reflux, timed reaction for 3 days.

After completion of the reaction, the reaction solution was frozen, and a large amount of a yellow solid was precipitated in the reaction mixture, and the mixture was directly cooled and crystallized for 2 hours.

After suction filtration, the solid was purified by using anhydrous ethanol (1000 ml): the oil bath was warmed and refluxed. After dissolving, pour into a beaker to cool and crystallize for 2-3 h, suction filtration, vacuum drying: 80 ° C, -0.08 Mpa. Used in the next step of the reaction.

Step 2: Add 22g of the first reaction product and 400ml of acetone to the reaction flask, stir, add 20g of formic acid amine, 10% Pb/C5g, heat in oil bath, set the external temperature of oil bath 82 °C, condense reflux, time Reaction for 5 h.

After the reaction, suction filtration, Pb/C recovery, and the filtrate was used.

The filtrate was placed in a low-temperature coolant circulating pump to cool, stirred, and 12 g of pyridine was added at 5 ° C. 19 g of benzyl chloroformate (mixed acetone solvent) was added dropwise at 0 ° C. After lh, the reaction was carried out for 30 min at low temperature, and the reaction was carried out overnight at room temperature. .

After the treatment, a red liquid is obtained, concentrated to a certain volume, poured into a saturated aqueous solution of NaCl, stirred, and a white solid is precipitated, suction filtration, 30 g of solid is added to the reaction flask, and 500 ml of acetonitrile is added for purification: the oil bath is heated, condensed and refluxed, and dissolved. After that, add a proper amount of water to precipitate at least a solid, pour it into a beaker and put it into a freezer to cool and crystallize. The mother liquor is distilled under reduced pressure. When a small amount of mother liquor remains, it is poured into a beaker and placed in a freezer for cooling and crystallization, suction filtration, water washing, and solid use. Mother liquor recovery The solid matter is added to the reaction flask, and refined by adding acetonitrile: the oil bath is heated, and the mixture is condensed and refluxed. After the solution is dissolved, at least a solid amount of the solid is precipitated by adding an appropriate amount of water, poured into a beaker, cooled in a freezer, filtered, and washed with water.

A total of 28 g of the solid recovered in the reserve solid and the mother liquor was added to the reaction flask for secondary recrystallization, and the operation was the same as above. Filtered, washed with water and vacuum dried: 110 ° C, -0.08 Mpa. Used in the next step of the reaction.

In the third step, 1000ml of THF is added to the distillation reactor, stirred, and protected by nitrogen gas. The tail gas is exported. The tail gas is bubbled with a conical flask containing liquid paraffin, heated in an oil bath, and the external temperature of the oil bath is 95 °C. Condensation reflux. Turn off the small nitrogen, add 5g of LiAlH ₄ powder, time the reaction for 1h, start collecting THF, and discard the previous part.

The collected second step of the reaction product was added to the collected 600 ml of THF, and the apparatus was set up, purged with nitrogen, and cooled with a mixture of dry ice and acetone.

When the internal temperature is -68 °C, 35 ml of butyl lithium is added dropwise. After l-1.5 h, the internal temperature is controlled below -65 °C, and the reaction is completed at low temperature (-68 °C) for 1.5 h. Add 14 g of R-glycidyl butyl acrylate, 0.5 h after completion, control the internal temperature below -65 °C, drop, and react at low temperature (below -68 °C) for 0.5 h, take out, and react at room temperature overnight.

The next day, it was washed once with a saturated aqueous solution of NH ₄ C1, layered, and washed three times with a saturated aqueous solution of NaCl, and layered.

The upper mother liquor is distilled under reduced pressure, and a small amount of the solution is poured into a beaker and placed in a freezer for cooling and crystallization for 2 hours. The upper mother liquor is filtered, and the solid is added to the reaction flask and refined by adding THF. The oil bath is heated, condensed and refluxed. After the solution is dissolved, an appropriate amount of water is added to precipitate at least a solid, which is poured into a beaker and cooled to crystallize. A large amount of white solids in the lower supernatant is precipitated, suction filtered, solids are added to the reaction flask, and refined by adding THF: the oil bath is heated, condensed and refluxed, and after dissolution, an appropriate amount of water is added to precipitate at least a solid, which is poured into a beaker and placed in a freezer. Medium cooling and crystallization.

Filtered separately and vacuum dried: 110 ° C, -0.08 Mpa. The compound was obtained in 14 g.

Product yield: 38% Example 20

(5R)-[3-(3'-fluoro-4'-(4"-methyl-indole-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate Preparation of (Compound 41)

(5R)-3-[3'-fluoro-4'-(4"-methyl-indole-imidazolium-1"-yl)phenyl]-5-(hydroxymethyl)-oxazolidin-2-one 32g, 500ml of dichloromethane was added to the reaction flask, placed in a low-temperature coolant circulating pump to cool to -8 °C, the device was installed, and stirred. 15g of triethylamine was added at 0 °C, and 20g of methanesulfonyl chloride (mixed CH ₂ C1 ₂ ) was added dropwise at an internal temperature of -5 °C. After 0.5h, the internal temperature was controlled below 0 °C, and the temperature was low. The reaction was carried out for 0.5 h, and the reaction was carried out at room temperature for 2 h.

After completion of the reaction, the mixture was washed once with a saturated aqueous solution of NaHC0 ₃ , layered, washed with water three times, layered, and then dried in a flask containing anhydrous MgS0 ₄ for 2 h, suction filtration, and the mother liquor was distilled to dryness (-0.08). MPa, 40 °C). The compound was obtained in 25 g. Examples 26, 32, 40, 47, 53, 59, 63, 65, 69, 71, and 75 The same preparation method as in Example 20 except that in the first step, (R)-3-[3'-fluoro-4'-(4"- in Example 20 was replaced with the materials listed in Table 3 below, respectively. Methyl-indole-imidazole-1"-yl)phenyl]-5-(hydroxymethyl)-oxazolidin-2-one, the corresponding compound was obtained.

table 3

Example 21

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Preparation of methylphthalimide (compound 42)

(R)-[3-(3-Fluoro-4-(4-methyl-1Η-imidazol-1-yl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate 20 g, DMF 500 ml was added to the reaction flask, the device was set up, stirred, and 10 g of phthalimide and 12 g of polyethylene glycol 400 were sequentially added thereto, and heated in an oil bath, and the external temperature of the oil bath was set to 82 ° C, and the reaction was continued overnight.

The next day, suction filtration, the filtrate was light yellow transparent liquid, distilled under reduced pressure (-0.08 MPa, 80 ° C), when a small amount of mother liquor remained Pour into saturated NaCl aqueous solution for crystallization, cool in a freezer for 30 min, remove the suction filtration, and wash the solids obtained by washing three times into the reaction flask, and add 200 ml of DMF to refine: heat up the oil bath, condense and reflux, dissolve, and add at least the right amount of water. The solid matter was precipitated, poured into a beaker and placed in a freezer for cooling and crystallization for 2 h, suction filtration, and washing with water. The same operation method was used for secondary recrystallization. Filtered, washed with water and vacuum dried: 110 ° C, -0.08 Mpa. Compound 42 was obtained.

Product yield and quality:

The product was a yellow powdery solid, mp: 220-222 ° C, and the three experimental yields were: 100,903 batches of 27.7%, 101,001 batches of 41.4%, and 101,101 batches of 12.5%.

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

The same preparation method as in Example 21 except that in the first step, the (R)-[3-(3-fluoro-4-(4-methyl) group of Example 21 was replaced with the materials listed in Table 4 below, respectively. -1H-imidazol-1-yl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate and phthalimide, the corresponding compound was obtained.

Table 4

Example 22 (5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Preparation of methylamine (compound 43)

(S)-2-[(3-(3-Fluoro-4-(4-methyl-1Η-imidazol-1-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl] 10 g of phthalimide and 600 ml of absolute ethanol were added to the reaction flask, the device was well placed, and stirred. The oil bath is heated, and the external temperature of the oil bath is set at 82 ° C, and the mixture is cooled and refluxed.

500 ml of 40% aqueous solution of methylamine was added to a single-mouth bottle, placed in a water bath, and the temperature of the water bath was set at 48 ° C to secure the device. When a stable methylamine gas is generated, the methylamine vapor is introduced into the reaction flask by an air-guiding tube, and the reaction is stirred for 5.5 hours. Stop the methylamine gas and continue to heat the reaction for 2 h. After the reaction, suction filtration, poured into a beaker and placed in a freezer to cool and crystallize overnight.

The next day, suction filtration, 6 g of solid matter was added to the reaction flask, and 100 ml of absolute ethanol and ethyl acetate were added for purification. The oil bath was heated, condensed and refluxed, and after dissolution, an appropriate amount of n-hexane was added to precipitate at least a solid, which was poured into a beaker. The crystallizer was cooled and liquefied in a freezer for 2 h, and suction filtered. The same operation method was used for secondary recrystallization. After suction filtration, washing with water and vacuum drying: 110 ° C, -0.08 Mpao gave compound 43.

Product yield and quality:

The product is a pale yellow powdery solid, mp: 171-172 ° C, the three experimental yields are: 100902 batches

.Inch

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

The same preparation method as in Example 22 except that in the first step, (S)-2-[(3-(3-fluoro-4-(4)))) was replaced with the materials listed in Table 5 below, respectively. -Methyl-1H-imidazol-1-yl)phenyl)-2-oxo-5-oxazolidinyl)methyl]phthalimide, the corresponding compound was obtained.

table 5

Real materialization

Shi

Example

28 (S)-2-[(3-(4-(2,5-Dioxy-1-pyrrolidinyl)-3-fluoro 47 pale yellow powder

Phenyl 2-oxo-5-oxazolidinyl)methyl]-phthalic acid

Formimide

34 (S)-2-[(3-(3-Fluoro-4-(3-methyl-1H-pyrazolyl) 53 15 white soft solid

Phenyl 2-oxo-5-oxazolidinyl)methyl]-o-phenylene mp: 175.3-175.6 °C

Formimide

42 (S)-2-[(3-(4-(2,5-Dihydro -1H- 1-pyrrolyl)-3- 57 41% white fluffy solid

Fluorophenyl) _-2 -oxo-5-oxazolidinyl)methyl]o-benzene mp: 142.7-144.1 °C

Diimide

49 (S)-2-[(3-(3-Fluoro-4-(1-pyrrolidinyl)phenyl)-2- 61 75% White fluffy solid

Oxo-5-oxazolidinyl]methylphthalimide

55 (S)-2-[(3-(4-(l,3,4-thiadiazole-2-thio)-3-fluoro 65 50% white fluffy solid

Phenyl 2-oxo-5-oxazolidinyl)methyl]-o-phenylene mp: 174.6-174.8 °C

Formimide

61 (S)-2-[(3-(3-Fluoro-4-(1Η-1-pyrrolyl)phenyl)-2- 48 30.6% white powder Oxo-5-oxazolidinyl)methyl]phthalimide 65.7% mp: 153-154°C

67 (S)-2-[ H3-fluoro-4-0 piperidinyl)phenyl)-2-oxo 69 30.3% white powder

-5-oxazolidinyl)methyl]phthalimide mp: 159-161 °C

73 (S)-2-[(3-(4-(l,3,4-thiadiazole-2-amino)-3-fluoro 73 40.5% white powder

Phenyl 2-oxo-5-oxazolidinyl)methyl]-o-phenylene mp: 162-163 °C

Formimide Example 23

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Preparation of methyl acetamide (compound 19)

(S)-5-(Aminomethyl)-3-[3-fluoro-4-(4-methyl-1Η-imidazol-1-yl)phenyl]oxazolidin-2-one 5 g, THF 100 ml Add to the reaction flask, place in a low temperature coolant circulation pump, install the device, and stir. The internal temperature of 0 ° C was added to the triethylamine lg, the internal temperature -5 ° C began to add 0.8 g of acetic anhydride, 0.5 h after the completion of the internal temperature control below -5 ° C, the completion of the low temperature reaction 0.5 h, then shift React to room temperature for 2 h.

After completion of the reaction, the mixture was filtered, and the solid was added to 100 ml of anhydrous ethanol and ethyl acetate. The mixture was heated and evaporated to reflux. After dissolved, the mixture was poured into a beaker and cooled to crystallize for 2 hours. The product is recrystallized twice, and the operation method is the same. After the final filtration, vacuum drying: 120 ° C, -0.08 Mpa. Compound 19.

Product yield and quality:

The product was a white powdery solid, mp: 181-182 ° C. The total yield of the two experiments was: 101101 batches +101102 batches 23.2%, content: 99.6% (HPLC). Examples 24, 29, 30, 35, 36, 37, 38, 43, 44, 45, 50, 51, 56, 57, 62, 68 and 74

In the same manner as in Example 23, the (S)-5-(aminomethyl)-3-[3-fluoro-4-(4-methyl) group of Example 23 was replaced with the starting materials listed in Table 6 below. -1H-imidazol-1-yl)phenyl]oxazolidin-2-one and acetic anhydride afforded the corresponding compound.

Table 6

Raw materialization yield physical and chemical data

Shi

Example

29 (S)-l-[4-(5-(Aminomethyl)-2-oxo-3-oxazole 21 62.0 white powder,

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

Acetic anhydride 11.4

69.1

35 (S)-5-(Aminomethyl)-3-[3-fluoro-4-(3-methyl- 29 38 white solid

1H- 1-pyrazolyl)phenyl]oxazolidin-2-one and ethyl mp: 171.8-171.9 ° C

Anhydride

43 (S)-5- (aminomethyl)-3-[4-(2,5-dihydro -1H- 1- 33 38% white solid

Pyrrolyl)-3-fluorophenyl]oxazolidin-2-one and ethyl mp: 177.8.8-177.8 ° C anhydride

50 (S)-5-(aminomethyl)-3-[3-fluoro-4-(1-pyrrolidine 36 32% white solid

Phenyl]oxazolidin-2-one and acetic anhydride 56 (S)-3-[4-(l,3,4-thiadiazol-2-thio)-3-fluorobenzene 38 40% white solid

-5-(aminomethyl)oxazolidin-2-one and acetic acid mp: 180.5.8-180.7 °C anhydride

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

1H-1-pyrrolyl)phenyl]oxazolidin-2-one and ethyl mp: 177-178 ° C

Anhydride

68 (S)-5-(Aminomethyl)-3-[3-fluoro-4-(1-piperidinyl) 25 13.1% White powder

Phenyl]oxazolidin-2-one and acetic anhydride mp: 175-176 ° C

74 (S)-3-[4-(l,3,4-thiadiazole-2-amino)-3-fluorobenzene 27 30.6% white powder

-5-(aminomethyl)oxazolidin-2-one and acetic acid mp: 178-179°C

Anhydride

24 (S)-5-(aminomethyl)-3-(3-fluoro-4-(4-methyl- 20 26.3% white powder

1H-imidazolium-1-yl)phenyl)oxazolidin-2-one and mp: 179-180 ° C

Methanesulfonyl chloride

30 (S)- 1 -(4-(5-(Aminomethyl)-2-oxo-3-oxazole 22 45.4 white powder,

Alkyl)-2-fluorophenyl)pyrrolidinyl-2,5-dione and mp: 258-259 ° C

Methanesulfonyl chloride

37 (S)-5-(Aminomethyl)-3-(3-fluoro-4-(3-methyl- 30 34% white solid)

1H- 1-pyrazolyl)phenyl)oxazolidin-2-one and A

Sulfonyl chloride

36 (S)-5-(aminomethyl)-3-(3-fluoro-4-(3-methyl- 31 37% white crystal

1H- 1-pyrazolyl)phenyl)oxazolidin-2-one and chlorine

Acetyl chloride

38 (S)- 1 -(4-(5-(Aminomethyl)-2-oxooxazolidine 138 34% white crystal

Benzyl-3-yl)-2-fluorophenyl)pyrrolidinyl-2,5-dione

Chloroacetyl chloride

44 (S)-5- (aminomethyl)-3-(4-(2,5-dihydro -1H- 1- 34 39% white solid)

Pyrrolyl)-3-fluorophenyl)oxazolidin-2-one and A

Sulfonyl chloride

45 (S)-5- (aminomethyl)-3-(4-(2,5-dihydro -1H- 1- 35 41% white solid)

Pyrrolyl)-3-fluorophenyl)oxazolidin-2-one and chlorine

Acetyl chloride

51 (S)-5-(Aminomethyl)-3-(3-fluoro-4-(1-pyrrolidine) 37 36% white solid

Phenyl) oxazolidinyl-2-one and methanesulfonyl chloride

57 (S)-3-(4-(l,3,4-thiadiazole-2-thio)-3-fluorobenzene 39 35% White solid

-5-(Aminomethyl)oxazolidin-2-one and chloroethyl mp: 181.2-181.6 ° C

Acid chloride Example 25

(5RMN-3- 3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol (compound) Preparation of 44)

Step 1: Add 10g of NaOH and 400ml of absolute ethanol to the reaction flask, install the device, heat in the oil bath, set the oil bath to an external temperature of 82 ° C, condense and reflux, stir for 30 min, and dissolve the NaOH, then add 19 g of succinimide. , all dissolved, began to add 3, 4-difluoronitrobenzene 16g, drip, timed reaction 24h. After the reaction, a large amount of yellow solid matter was precipitated in the red reaction solution, and the crystal was directly cooled and crystallized for 2 hours.

The mixture was suction filtered, and the solid was washed three times with water, and dried in vacuo: 80 ° C, -0.08 MPa, for the next step.

Product yield and quality:

The reaction product of the first step was a yellow powdery solid, mp: 81-83 ° C, and the yields of the three experiments were: 101201 batches 62.5%, 101202 batches 64.6%, 101203 batches 64.0%.

The second step: 30 g of the first reaction product and 400 ml of acetone were added to the reaction flask, stirred, and then 25 g of formic acid amine, 10% Pb/C 5 g were sequentially added, and heated in an oil bath, and the external temperature of the oil bath was set to 50 ° C, and condensed and refluxed. The internal temperature was 48 ° C, and the reaction time was 5 h.

The third step: the filtrate obtained in the second step is placed in a low temperature coolant circulating pump to cool, stir, add pyridine llg at 5 ° C, start adding 20 g of benzyl chloroformate at 0 ° C, lh drop, low temperature reaction for 30 min, take out normal temperature The reaction was overnight.

After completion of the reaction, suction filtration, while leaving a small amount of mother liquor, pour into saturated NaCl aqueous solution for crystallization, suction filtration, washing with water, add solids to the reaction flask, add 400 ml of acetonitrile, heat up, condense and reflux, dissolve, add appropriate amount of water. At least a solid amount of material is precipitated, poured into a beaker and placed in a freezer to cool and crystallize. Filter by suction and wash.

Recrystallization was repeated twice by the same procedure. After suction filtration, vacuum drying after washing: 85 ° C, -0.08 Mpa. Used for the next step.

Product yield and quality:

The reaction product of the third step was a white powdery solid, mp: 100-lOrC. The yields of the three experiments were: 101201 batches of 85.3%, 101,202 batches of 84.8%, and 101,203 batches of 86.1%.

In the fourth step, THF is added to the distillation reactor, stirred, and protected by nitrogen gas. The tail gas is led out. The tail gas is bubbled with a conical flask filled with liquid paraffin. The oil bath is heated, and the external temperature of the oil bath is 95 ° C. Reflux. Turn off the small nitrogen, add 5g of LiAlH^ij at the end, time the reaction for 1h, start collecting THF, and discard the previous part.

To the collected THF, 30 g of the third reaction product which had been dried for more than 2 days was added, and the apparatus was placed, protected by nitrogen gas, and cooled with a mixture of dry ice and acetone.

When the internal temperature is -68 °C, 38 ml of butyl lithium is added dropwise. After l-1.5 h, the internal temperature is controlled below -65 °C, and the reaction is completed at low temperature (below -68 °C) for 1.5 h. Add 14 g of R-glycidyl butyl ester, 0.5 h after completion, control the internal temperature below -65 ° C, drop, low temperature (-68 ° C or less) reaction for 0.5 h, take out, and react at room temperature overnight.

The next day, it was washed once with a saturated aqueous solution of NH ₄ C1 and a small amount of purified water, layered, and washed three times with a saturated aqueous solution of NaCl, and layered.

Distilled under reduced pressure. When a small amount of solution remained, it was poured into a beaker and placed in a freezer for cooling and crystallization for 2 h. Filtration, solid matter was added to the reaction flask, and 200 ml of ethyl acetate was added for purification. The oil bath was heated, and the mixture was condensed and refluxed. After the solution was dissolved, an appropriate amount of petroleum ether was added to precipitate at least a solid, which was poured into a beaker and cooled to crystallize.

Filter by suction, wash with petroleum ether once, vacuum dry: 100 ° C, -0.08 Mpa. Compound 44 was obtained.

Product yield and quality:

The product was a pale yellow powdery solid, mp: 120-122 ° C, and the experimental yield was: 110101 batches 73.0%. Examples 39, 46, 52, 58, 64, and 70 In the same manner as in Example 25, the 3,4-difluoronitrobenzene of Example 25 was replaced with the starting materials listed below, to obtain the corresponding compounds.

Table 7

For the synthesis of compounds 83-137 see: CN1355165A.

Compound of the invention CN1355165A compound

83 5

84 11

85 12

86 13

87 14

88 15

89 16

90 17

91 18

92 19

93 20

94 21

95 22

96 26

97 27

98 28

99 30

100 31

101 32

102 33

103 37

104 38

105 39

106 41

107 42

108 43

109 44 110 48

111 49

112 50

113 52

114 53

115 54

116 55

117 59

118 60

119 61

120 64

121 65

122 66

123 70

124 71

125 72

126 75

127 76

128 77

129 81

130 82

131 83

132 86

133 87

134 88

135 95

136 96

137 97 Effect of inhibition of standard strains of Mycobacterium tuberculosis

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

The experimental strain according to the present invention: Mycobacterium tuberculosis standard strain H37Rv, which is provided by the Beijing Institute of Tuberculosis and Thoracic Oncology.

Experimental strains involved in the present invention: Mycobacterium tuberculosis sensitive clinical isolates: 9102, 3215, 1105,

4201, 2170, 6177, 3232, 1103, 3206, 23120 are all provided by the Beijing Institute of Tuberculosis and Thoracic Oncology.

Experimental strains involved in the present invention: Mycobacterium tuberculosis drug-resistant clinical isolates: 20161, 6233, 16543, 5116, 3328, 3289, 3303, 7153, 31251, 30129 are all provided by the Beijing Tuberculosis Thoracic Tumor Institute. I. Experimental materials, methods and results for MIC90 determination of Mycobacterium tuberculosis standard strain H37Rv 1. Test compound:

Compound 1-143

2. Reference drugs: Isoniazid (INH) and rifampicin (RFP) are products of Sigma.

3. Experimental strain: Mycobacterium tuberculosis standard strain H37Rv, provided by Beijing Institute of Tuberculosis and Thoracic Oncology.

4. Medium: 7H9 liquid medium (product of Difco).

5. Method:

Isoniazid was dissolved in sterile distilled water, and rifampicin and the test compound were dissolved in dimethyl sulfoxide to prepare an initial solution having a concentration of 6.4 mg/ml.

Using a sterile 96-well plate (Falcon3072; Becton Dickinson, Lincoln Park, NJ), add the highest concentration well to the 198μ1 7Η9 medium, 2μ1 compound initial solution, mix well, and then dilute to the remaining wells twice, the final concentration of the compound is : 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 g/ml. The final concentrations of INH were: 0.2, 0.1, 0.05, 0.025, 0.0125 g/ml.

Mycobacterium tuberculosis H37RV was selected and cultured for 2 to 3 weeks to prepare a bacterial suspension, inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC, and cultured at 37 ° C for 1 to 2 weeks. When the turbidity is McFarland 1 (equivalent to 10 ⁷ CFU/ml), after diluting 1:20, 100 μl of each well is added, and the final concentration of the bacterial solution is 106 CFU/ml. Two anti-bacterial growth control wells were placed on each plate and 96-well plates were incubated at 37 °C. After 7 days, a growth control well of 20 μl 1 O Alamar Blue (product of Setotec) and 5% Tween 80 50 μl was added, and incubation was carried out for 24 hours for 37 hours. If the color changed from blue to pink, the above amount was added to the wells of each experimental drug. The mixture of Alamar Blue and Tween80 was incubated at 37 ° C for 24 hours to record the color of each well, and the fluorescence values at 530 nm and 590 nm were measured using a microplate reader to calculate the MIC90.

6, the experimental results

The minimum inhibitory concentration (MIC) determined by the MABA method is shown in Table 1.

Table 1: MIC of test compound against M. tuberculosis standard strain H37Rv

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

Compound 105 4.811

Compound 106 4.951

Compound 107 4.930

Compound 108 4.721

Compound 109 4.789

Compound 110 4.520

Compound 111 4.855

Compound 112 4.800

Compound 113 4.907

Compound 114 4.216

Compound 115 4.857

Compound 116 4.880

Compound 117 1.974

Compound 118 1.987

Compound 119 1.822

Compound 120 2.953

Compound 121 2.939

Compound 122 2.922

Compound 123 3.905

Compound 124 3.621

Compound 125 3.785

Compound 126 3.803

Compound 127 3.859

Compound 128 3.613

Compound 129 3.891

Compound 130 3.306

Compound 131 3.876

Compound 132 3.899

Compound 133 3.842

Compound 134 3.947

Compound 135 4.311

Compound 136 4.853

Compound 137 4.878

Compound 138 5.889

Compound 139 1.055

Compound 140 0.527

Compound 141 0.588

Compound 142 0.531

Compound 143 1.280

INH 0.055

RFP 0.038 Determination of Mycobacterium tuberculosis sensitivity and resistance using the Microplate Alamar Blue Assay (MABA) method Materials, methods and results of in vitro antibacterial activity of clinical isolates

1. Test compound: Compound 1-143; Control drug isoniazid (INH), rifampicin (RFP) are produced by Sigma

Π

Hey.

2. Experimental strain: Mycobacterium tuberculosis sensitive clinical isolates: 9102, 3215, 1105, 4201, 2170, 6177, 3232, 1103, 3206, 23120;

Clinical isolates of Mycobacterium tuberculosis resistance: 20161, 6233, 16543, 5116, 3328, 3289, 3303, 7153, 31251, 30129;

The above strains were all provided by the Beijing Institute of Tuberculosis and Thoracic Oncology.

3. Medium: 7H9 liquid medium (product of Difco).

4. Method: Sterile 96-well plate (Falcon3072; Becton Dickinson, Lincoln Park, NJ), INH was dissolved in sterile distilled water, rifampicin and test compound were dissolved in dimethyl sulfoxide to a concentration of 32 mg/ml. For the initial solution, add the highest concentration well to the 198μ17Η9 medium, 2μ1 drug dilution solution, mix well, and then dilute to the remaining wells twice, the final concentration of the test compound is: 16, 8, 4, 2, 1, 0.5, 0.25 , 0.125, 0.06, 0.03 g/ml. 10 strains of M. tuberculosis sensitive clinical isolates and 10 strains of drug-resistant clinical isolates were selected, and the cultures were cultured for 2~3 weeks to prepare bacterial suspensions, which were inoculated into 7H9 containing 0.05% Tween 80 and 10% ADC. In the medium, culture at 37 ° C for 1 to 2 weeks, grow to a turbidity of McFarland 1 (equivalent to 10 ⁷ CFU / ml), after 1: 20 dilution, add 100 μ1 of each well, the final concentration of the bacterial solution is 10 ⁶ CFU/ ml. Two growth control wells containing no antibacterial agents were placed on each plate, and 96-well plates were incubated at 37 °C. After 7 days, a mixture of growth control wells 20 μl lO Alamar Blue (product of Setotec) and 5% Tween 80 50 μl was added, and incubation was carried out for 24 hours for 37 hours. If the color changed from blue to pink, the above amount was added to the wells of each experimental drug. The mixture of Alamar Blue and Tween80 was incubated at 37 ° C for 24 hours to record the color of each well, and the fluorescence values at 530 nm and 590 nm were measured using a microplate reader to calculate the MIC90.

5, the experimental results

The minimum inhibitory concentration (MIC) determined by the MABA method is shown in Table 2.

Table 2: Sensitivity and resistance of test compounds to Mycobacterium tuberculosis 1 MIC of isolated strains

Drug-resistant clinical isolates MIC range Sensitive clinical isolates MIC range Samples

(10 strains) (10 strains)

Compound 1 3.290-9.210 3.188-8.586

Compound 2 3.241-16 3.258-8

Compound 3 7.891-20.852 7.712-18

Compound 4 7.0-24.915 6.860-24

Compound 5 12.0-46.327 11.0-38.539

Compound 6 6.0-20.356 5.0-18.433

Compound 7 7.258-26.866 7.041-24.824

Compound 8 14.188-33.743 12.177-33.300

Compound 9 16.0-36.111 15.0-32.511

Compound 10 10.456-38.320 10.0-32.426

Compound 11 10.341-36 9.0-34.420

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Compound 142 1.083-5.843 0.983-5.669

Compound 143 2.0-8.825 1.899-8.428

INH 0.625- > 40 0.025-0.588

RFP 0.625- > 40 0.05-0.573 After the advent of rifampicin and isoniazid, the success of short-course chemotherapy has revolutionized the treatment of tuberculosis, but in the past decade, with the large number of rifampicin and isoniazid Use, so that its resistance increases year by year, leading to the failure of anti-tuberculosis treatment. While the MIC range of most of the compounds of the present invention against sensitive M. tuberculosis clinical isolates is 1-32 μ _§ /ml, a considerable portion of the compounds are in 1-16 μ _§ /ml, and some compounds are in 1-8 μ _§ /ml. At the same time, the MIC range of most compounds for single isolates of isoniazid, rifampicin or isoniazid-resistant rifampicin (MDR-TB) is 1-32μ _§ /ml , a considerable part of the compound is in 1-16μ _§ /ml, and some compounds are in 1-8μ _§ /ml, so the compound of the present invention has in vitro antibacterial activity against sensitive and drug-resistant clinical isolates of Mycobacterium tuberculosis, especially It has a significant effect on drug-resistant Mycobacterium tuberculosis.

The compounds of the present invention are capable of shortening and simplifying the course of treatment, overcoming multidrug resistance, and treating tuberculosis and AIDS co-infections, particularly for the treatment of latent tuberculosis infections. At the same time, it has improved the efficacy of multi-drug resistant tuberculosis, and can be specially developed into a drug for the treatment of multidrug-resistant tuberculosis, which will provide a safe and effective drug for tuberculosis patients.

Claims

Claim

A compound represented by the following formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof for use in the preparation for prevention or treatment:

2. The use of claim 1 wherein:

The formula I represents a hydroxy group, an amino group and the following or substituted or unsubstituted groups: a C1-C10 amine group, a di(C1-C10) an imido group, a C1-C10 amide group, a C1-C10 acyl imine group, a C1-C10 acyl)imino, C1-C10 sulfonylamino, C1-C10 sulfonyloxy, C1-C10 alkanoyloxy, five- or six-membered heterocyclic group, five- or six-membered heterocyclic group Mercapto, benzoheterocyclyl fluorenyl;

R ₂ represents a substituted or unsubstituted five- or six-membered heterocyclic group; a substituted or unsubstituted C1-C10 acyl group; or a group of the formula:

among them,

R ₃ and R ₅ each independently represent 15, a halogen atom or a C1-C10 haloalkyl group;

R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group,

C1-C10 alkoxy, C1-C10 aralkyloxy, 5- or 6-membered heterocyclyl fluorenyl, benzo-5-membered heterocyclyl fluorenyl or benzohexa-heterocyclyl fluorenyl, 5- or 6-membered hetero A cyclic amino group, a benzo five-membered heterocyclic amino group, a benzo six-membered heterocyclic amino group.

3. The use according to claim 2, wherein in the formula I, a hydroxyl group, an amino group, a C1-C10 alkylamino group, a C1-C10 arylalkylamino group, a C1-C10 arylamino group, a di(C1) -C10 alkyl)imino, bis(C1-C10 aryl)imino, C1-C10 alkylarylimino, bis(C1-C10 arylalkyl)imide, C1-C10 alkyl Amido, C1-C10 aromatic alkyl amide, C1-C10 aryl amide, halogenated C1-C10 alkyl amide, halogenated C1-C10 arylalkyl amide, halogenated C1-C10 aryl amide , C1-C10 alkylsulfonylamino, C1-C10 aromatic alkylsulfonylamino, C1-C10 aromatic sulfonylamino, halogenated C1-C10 alkylsulfonylamino, halogenated C1-C10 aromatic alkylsulfonamide , halogenated C1-C10 arylsulfonylamino, C1-C10 arylsulfonyloxy, C1-C10 alkylsulfonyloxy, C1-C10 arylalkylsulfonyloxy, halogenated C1-C10 aromatic Sulfonyloxy, halogenated C1-C10 alkylsulfonyloxy, halogenated C1-C10 arylalkylsulfonyloxy, bis(C1-C10 arylacyl)imino, bis(C1-C10 alkane Acyl)imino, di(C1-C10 Aromatic alkyl acyl imino group, C1-C10 alkanoyloxy group, halogenated C1-C10 alkanoyloxy group, substituted or unsubstituted five- or six-membered heterocyclic group, five- or six-membered heterocyclic group Mercapto, benzoheterocyclyl fluorenyl.

4. The use according to claim 3, wherein in the formula I, a hydroxyl group, an amino group, a methylamino group, an ethylamino group, a benzylamino group, an anilino group, a dimethylimino group, a diethyl group Imino, diphenylimine, benzhydryl imine, formamide, acetamido, propionamide, haloformamido, 1-haloacetamido, methanesulfonamide Ethylsulfonylamino, methanesulfonyloxy, ethanesulfonyloxy, phenylmethylsulfonyloxy, phthalimido, diimide, diethylimido, acetyloxy Base, succinyl imido, p-toluenesulfonyloxy, 1,3,4-thiadiazolylhydrazino, 1,2,4-1H-triazolyl, 1H-tetrazolyl, tetrazinc Azyl fluorenyl, benzimidazole 2-indenyl, benzotriazolyl, imidazolyl, camphorimide.

The use according to claim 4, wherein in the formula I, a hydroxyl group, an amino group, an acetamide group, a chloroacetamido group, a methanesulfonylamino group, a methanesulfonyloxy group, an ethylsulfonyloxy group, or a neighboring group are used. Phthalimide, dimethylimido, succinylimido, p-toluenesulfonyloxy, 1,3,4-thiadiazolylhydrazino, 1,2,4-1H-tri Azazolyl, 1H-tetrazolyl, tetrazolylhydrazino, benzimidazole 2-indolyl, benzotriazolyl, imidazolyl, camphorimide.

The use according to any one of claims 1 to 5, wherein the following group represented by the formula I is substituted or unsubstituted: pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinyl , imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 4-morpholinyl, piperazinyl, piperidinyl, pyrimidinyl, oxazolyl, pyridyl; or C1-C4 acyl; Lower formula

among them,

R4 represents a substituted or unsubstituted group: a five- or six-membered heterocyclic ring, a five- or six-membered heterocyclic oxy group, a C1-C10 alkoxy group, a C1-C10 aralkyloxy group, a five-membered or six-membered group. a heterocyclic fluorenyl group, a benzo five-membered heterocyclic fluorenyl group or a benzohexa-membered heterocyclic fluorenyl group, a five- or six-membered heterocyclic amino group, a benzo five-membered heterocyclic amino group, a benzo six-membered hetero Acyclic amine group.

7. The use according to claim 6, wherein R ₂ in the formula I represents an acetyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted oxazolyl group, Substituted or unsubstituted pyridyl, or a group of the formula:

8. The use according to claim 7, wherein R ₂ in the formula I represents acetyl, 2-phenylpiperidinyl, 2-hydroxypyrimidinyl, 6-chloro-4-cyano-2-pyridine Base, 4-oxazolyl or 2-acetoxypyrimidinyl.

9. R ₂ in the formula I according to claim 7 represents a group of the formula:

Wherein R ₃ and R ₅ each independently represent 11, F, C1 or CF ₃ ;

10. The use according to claim 9, wherein R4 represents a substituted or unsubstituted group: pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolyl, dihydropyrrolyl, pyrroline Base, imidazolidinyl, imidazolinyl, pyrazolidinyl, imidazolylhydrazino, pyrazolinyl, thiadiazolyl, thiadiazolylamino, thiadiazolylhydrazino, morpholinyl, piperazinyl, tri Zinyl, pyrimidinyl, hexahydropyrimidine, pyridyl, chromanyl, quinolyl, benzofuranyl, pyrazinyl, pyrazinyloxy or piperidinyl.

11. The use of claim 10, wherein the group is:

Wherein, it represents a substituted or unsubstituted group: a phenyl group, a C1-C10 alkyl acyl group, a five- or six-membered heterocyclic group; preferably a phenyl group, a substituted phenyl group, a C1-C10 alkyl acyl group, a halogen group a C1-C10 alkyl acyl group.

The use according to claim 11, wherein R ₆ represents a phenyl group, a p-methoxyphenyl group, a benzyl group or a chloropropionyl group. The use according to claim 9, wherein R4 represents morpholinyl, 4-phenylpiperazinyl, 1-methyl-5,6-dihydro-1,2,4-triazine- 4(1H)-yl, 2-chloromethyl-piperidinyl, 2-chloromethyl-4-methyl-piperidinyl, 4,6-dimethoxy-2-hexahydropyrimidinyl, 4, 6-Dimethoxy-5-methyl-2-hexahydropyrimidinyl, 6-chloro-4-cyano-2-pyridyl, 6-chloro-4-cyano-5-methyl-2-pyridine , 4-oxo-2-chromanyl, 5-fluoro-4-oxo-1,2,3,4-tetrahydro-2-quinolinyl, benzofuranyl, 3-chloropropanoyl- 1-piperazine, 5-(azetidin-1-ylcarbonyl)-2-oxopyrazinyl, 1-methyl small H-2-imidazolium, 1-H-1-pyrrolyl, 1-piperidinyl, 1,3,4-thiadiazol-2-amino, 3-methyl-H-pyrazolyl, 2,5-dioxopyrrolidinyl, 2,5-dihydro-small H - 1-pyrrolyl, 1-pyrrolidinyl, 1,3,4-thiadiazole-2-thio, 4-methyl-1H-imidazolyl, 4-methoxyphenylpiperazinyl, 4- Benzylpiperidinyl or 4-piperidinyl.

14. The use according to claim 10, wherein said R4 represents a group of the formula:

15. The use of the claim, wherein the R4 represents a group of the formula:

, ,

16. The use according to claim 10, wherein said R4 represents a group of the formula:

17. The use according to claim 10, wherein said represents a group of the formula:

18. The use according to claim 10, wherein said R4 represents a group of the formula:

Wherein R ₉ represents a hydrogen atom, a C1-C10 alkoxy group or a C1-C10 alkylthio group; The same or different from R _u represents a hydrogen atom or a C1-C10 alkyl group; preferably R ₉ represents a hydrogen atom, a methoxy group or a methyl group; Heb Ru ffi is the same or different and represents a hydrogen atom or a methyl group.

The use according to claim 1, wherein the compound represented by the formula I is a compound or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof:

Compound 1

(5S)-[N-3-(3',5'-difluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl Acetamide compound 2

(5S)-[N-3-(3',5,-Difluoro-4'-(1"-methyl-5",6"-dihydro-indole' (Η), 2", 4"- Triazin-4-yl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide

Compound 3

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

(5S)-[N-3-(3'-fluoro-4'-(2"-chloromethyl-4"-methyl-1"-piperidinyl)phenyl)-2-oxo-5- Oxazolidine]methylacetamide

Compound 5

(5R)-[ indole-3-(3'-fluoro-4'-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol

Compound 6

(5S)-[N-3-(3'-fluoro-4'-(4",6"-dimethoxy-2"-hexahydropyrimidinyl)phenyl)-2-oxo-5-oxazole Alkyl]methylacetamide

Compound 7

Compound 8

Compound 10

( _5S) -[ _N -3-(3,-fluoro-4'-(6"-chloro-4"-cyano-2"-pyridine)phenyl)-2-oxo-5-oxazolidinyl ]methylacetamide compound 11

(5S)-[N-3-(3,-fluoro-4'-(6"-chloro-4"-cyano-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

Compound 15

Compound 16

(5SMN-3-C3'-fluoro-4'-(4"-(3"'-chloropropionyl)-1"-piperazinyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl acetamide

Compound 17

(5SMN-3-C3 '-Fluoro-4'-(5"-(azetidinylcarbonylbipyridinyl-2"-oxy)phenyl)-2-oxo-5-oxazolidinyl Methyl acetamide

Compound 18

Compound 19

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl acetamide compound 20

(5R)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl methanesulfonamide

Compound 21

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

Compound 22

(5R)-[N-3-(3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)-phenyl)-2-oxo-5-oxazole Alkyl]methyl methanesulfonamide

Compound 23

(5S)-[N-3-(3'-fluoro-4'-(Γ'(Η)-Γ'-pyrrolyl)phenyl)-2-oxo-5-oxazolidinyl]methyl b Amide compound 24

(5R)-[N-3-(3'-fluoro-4'-(Γ(Η)-Γ'-pyrrolyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonate Amide compound 25

(5S)-[N-3-(3'-fluoro-4'-(1"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylacetamide Compound 26

(5R)-[N-3- 3'-fluoro-4'-G"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonamide Compound 27

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)-phenyl)-2-oxo-5-oxa Azolidinyl]methylacetamide

Compound 28

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazole Alkyl]methyl chloroacetamide

Compound 29

(5S)-[N-3-(3'-fluoro-4'-(3"-methyl-Γ'(Η)-pyrazolyl)phenyl)-2-oxo-5-oxazolidinyl ]Methylacetamide compound 30

(5R)-[N-3-(3 '-fluoro-4'-(3"-methyl-Γ'(Η)-Βbazolyl)phenyl)-2-oxo-5-oxazolidine Methyl methanesulfonamide

Compound 31

(5S)-[N-3-(3'-fluoro-4'-(3"-methyl-Γ'(Η)-pyrazolyl)phenyl)-2-oxo-5-oxazolidinyl Methyl chloroacetamide

Compound 32

Compound 33

(5S)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-Βpyrrolyl)-phenyl)-2-oxo-5 -oxazolidinyl]methylacetamide

Compound 34

(5R)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-pyrrolyl)-phenyl)-2-oxo-5-oxa Azolidinyl]methylmethanesulfonamide

Compound 35

(5S)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-Βpyrrolyl)phenyl)-2-oxo-5- Oxazolidine]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'-G"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonamide 38 (5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)phenyl)-2-oxo-5-oxa Azolidinyl]methylacetamide

Compound 39

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)phenyl)-2-oxo-5-oxa Azolidinyl]methyl chloroacetamide

Compound 40

(5R)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methyl methanesulfonate

Compound 42

Compound 43

(5S)-[N-3-(3'-fluoro-4'-(4"-methyl-Γ'(Η)-imidazolyl)phenyl)-2-oxo-5-oxazolidinyl] Methylamine compound 44

(5RMN-3- 3'-fluoro-4'-(2",5"-dioxo-1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol compound 45

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

Compound 46

Compound 47

Compound 49

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

Compound 50

(5S)-[N-3-(3'-fluoro-4'-(Γ'(Η)-pyrrolyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthalate Imide compound 52 (5S)-[N-3-(3'-fluoro-4'-(3"-methyl-1"(H)-pyrazolyl)phenyl)-2-oxo-5-oxazolidinyl Methylphthalimide

Compound 53

(5S)-[N-3-(3'-fluoro-4'-(3"-methyl-Γ'(Η)-pyrazolyl)phenyl) 5-oxazolidinyl]methylamine

Compound 54

(5R)-[N-3-(3'-fluoro-4'-(3"-methyl-Γ'(Η)-Βbazolyl)phenyl)-2-oxo-5-oxazolidine Methyl]methanol compound 55

(5R)-[N-3-(3 '-fluoro-4'-(3"-methyl-Γ'(Η)-Βbazolyl)phenyl)-2-oxo-5-oxazolidine Methyl methanesulfonate

Compound 56

(5R)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-pyrrolyl)-phenyl)-2-oxo-5-oxa Azoliyl]methanol compound 57

(5S)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-Βpyrrolyl)-phenyl)-2-oxo-5 -oxazolidinyl]methylamine compound 58

(5R)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-pyrrolyl)-phenyl)-2-oxo-5-oxa Azolidinyl]methylmethanesulfonate

Compound 59

(5S)-[N-3-(3'-fluoro-4'-(2",5"-dihydro-indole'(Η)-Βpyrrolyl)-phenyl)-2-oxo-5 -oxazolidinyl]methylphthalimide

Compound 60

(5RMN-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]methyl methanesulfonate compound 63

(5S)-[N-3-(3'-fluoro-4'-(1"-pyrrolidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthaloyl Amine compound 64

(5R)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)-phenyl)-2-oxo-5- Oxazolidinyl]methanol compound 65

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)phenyl)-2-oxo-5- Oxazolidinyl]methylamine compound 66

(5S)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazol-2-"thio)phenyl)-2-oxo-5- Oxazolidinyl]methylphthalimide Compound 67

(5R)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-thio)-phenyl)-2-oxo-5- Oxazolidinyl]methyl methanesulfonate

Compound 68

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

Compound 69

(5S)-[N-3-(3'-fluoro-4'-(indolyl-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl)methylamine

Compound 70

(5RMN-3- 3'-fluoro-4'-(1"-piperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylmethanesulfonate Compound 71

(5R)-[N-3-(3'-fluoro-4'-(1",3",4"-thiadiazole-2"-amino)phenyl)-2-oxo-5-oxazole Alkyl]methyl methanesulfonate

Compound 75

Compound 76

(5SMN-3-acetyl-2-oxo-5-oxazolidinyl)methylacetamide

Compound 77

Compound 78

Compound 79

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

Compound 80

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

Compound 81

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

Compound 82 (5S)-[N-3- _l 6'-chloro-4'-cyano-2'-pyridine)-2-oxo-5-oxazolidinyl]methylacetamide

Compound 83

(5R)-[N-3- 3'-fluoro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methyl methanesulfonate i compound 84

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethyl-p-toluenesulfonate Compound 85

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethyl acetate

Compound 86

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethylimidazole

Compound 87

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethyl-2-thio-1,3,4 thiadiazole Compound 88

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethyl-1,2,4-1 H-triazole compound 89

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethyl-1H-tetrazole Compound 90

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethylcamphorimide Compound 91

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethylthiotetrazole Compound 92

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethylphthalimidoimide Compound 93

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethyl-2-thiobenzimidazole Compound 94

(5R)-[N-3- 3'-fluoro-4'-morpholinylphenyl-2-oxo-5-oxazolidinylmethylsuccinimide Compound 95

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

Compound 98

(5R)-[N-3- 4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylphthalimide 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-1,2,4-1H-triazole

Compound 101

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

Compound 102

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

Compound 103

(5S)-[N-3-C3'-chloro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methanol

Compound 104

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

Compound 105

(5S)-[N-3-(3'-Chloro-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylphthalimide Compound 106

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

Compound 107

Compound 109

Compound 110

Compound 111

(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]methylcamphorimide compound 116 (5S)-[N-3-(3'-trifluoromethyl-4'-morpholinyl)phenyl-2-oxo-5-oxazolidinyl]methylsuccinimide compound 117

Compound 118

(5R)-[N-3- 3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl-2-oxo-5-oxazolidinyl]methyl methanesulfonate compound 119

(5R)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthalate Imide

Compound 120

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

Compound 121

(5SMN-3-C3 '-Fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol compound 124

(5S)-[N-3-(3'-fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazole Alkyl]methyl methanesulfonate

Compound 125

(5S)-[N-3-(3'-fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazole Alkyl]methylphthalimide

Compound 126

(5S)-[N-3-(3'-fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazole Alkyl]methyl-

1,2,4-1 H-triazole

Compound 127

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

Compound 128

(5S)-[N-3-(3'-fluoro-4'-(4"-(4"'-methoxyphenyl) piperazinyl)phenyl)-2-oxo-5-oxazole Alkyl]methylsuccinimide

Compound 129

(5SMN-3-C3 '-Fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methanol Compound 130

(5S)-[N-3-C3 '-Fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl methanesulfonate 131

(5S)-[N-3-(3'-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylphthalate Imide

Compound 132

(5S)-[N-3-(3,-Fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methyl-1,2 , 4-1H-triazole

Compound 133

(5S)-[N-3-C3'-fluoro-4' 4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylcamphorimide Compound 134

(5S)-[N-3-(3'-fluoro-4'-(4"-benzylpiperidinyl)phenyl)-2-oxo-5-oxazolidinyl]methylsuccinyl Amine compound 135

(5R)-[N-3-(3,-fluoro-4'-piperidinylphenyl)-2-oxo-5-oxazolidinyl]methyl-1,2,4-1H-triazole Azo compound 136

(5R)-[N-3- 3'-fluoro-4'-piperidinylphenyl)-2-oxo-5-oxazolidinyl]methylcamphorimide

Compound 137

Compound 138

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

Compound 139

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

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.

The use according to any one of claims 1 to 19, wherein the compound represented by the formula I or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof may be used arbitrarily or Use alone.

The use according to any one of claims 1 to 20, wherein the medicament is any clinically acceptable dosage form including, but not limited to, an oral preparation and an injection preparation.

The use according to any one of claims 1 to 21, wherein the mycobacterial disease is an infectious disease caused by infection of a human or animal body by mycobacteria, including but not limited to tuberculosis and leprosy.

The use according to any one of claims 1 to 21, wherein the mycobacteria are Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium kawaii, Mycobacterium marinum, Mycobacterium lactis, Fu Mycobacterium fulvum, Mycobacterium phlei, Mycobacterium tuberculosis, Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium tuberculosis, Mycobacterium phlei, Mycobacterium phlei, Mycobacterium faecalis, Mycobacterium tuberculosis, Foreskin Mycobacterium smegmatis, Mycobacterium septicum, Mycobacterium skrjab or Mycobacterium tuberculosis.

24. The use according to claim 22, wherein the mycobacterial disease is tuberculosis.

25. The use according to claim 24, wherein said tuberculosis is primary pulmonary tuberculosis, disseminated pulmonary tuberculosis, secondary pulmonary tuberculosis, tuberculous pleurisy, bone and joint tuberculosis, tuberculous meningitis, renal tuberculosis or intestine tuberculosis.

A pharmaceutical composition for preventing or treating tuberculosis, which comprises, as an active ingredient, a compound represented by the formula I according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, a hydrate, solvate, complex or prodrug, or any combination thereof, and a pharmaceutically acceptable adjuvant.

The pharmaceutical composition according to claim 26, wherein the active ingredient is usually administered in a dose of 0.01 to 2000 mg/day, preferably, the dose is 0.01 to 1800 mg, more preferably 0.1 to 1500 mg, further preferably It is l~1200mg.

The pharmaceutical composition according to claim 26 or 27, wherein the active ingredient is 0.05 to 100% by weight in the composition.

A method for preventing or treating tuberculosis, which comprises administering to a patient a therapeutically effective amount of the compound of the formula I according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, hydrate thereof, A solvate, complex or prodrug, or any combination thereof, or a pharmaceutical composition according to any one of claims 26-28.