Biaryloxazolidinone compound and use thereof

Abstract

Provided is a biaryloxazolidinone compound, wherein the compound is a compound of general formula I and a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof. The present invention relates to the field of pharmaceutical chemistry, and in particular to a bbiaryloxazolidinone compound and a use thereof. The compound has better antibacterial activity than linezolid and has significant antibacterial activity against drug-resistant bacteria. In addition, the compound exhibits lower MAO inhibition and better safety compared to linezolid.

Description

Biaryl oxazolidinone compounds and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry, in particular to a biaryl oxazolidinone compound, or an optical isomer, a pharmaceutically acceptable salt and / or a solvate thereof, a preparation method and uses thereof. BACKGROUND

[0002] Bacteria force the drugs for treating bacterial infections to become ineffective by constantly evolving and mutating, and thus antibiotic resistance occurs. In recent years, with the overuse and even abuse of antibiotics, more and more bacteria gradually develop from drug-sensitive bacteria to superbugs that are resistant to multiple antibiotics, thus posing a great threat to clinical treatment. In view of the bacterial resistance mechanisms and transmission routes, it is urgent to develop new drugs targeting multidrug-resistant (MDR) bacteria.

[0003] Oxazolidinone antibacterial drugs are another kind of chemically fully synthetic antibacterial drugs with a completely new structure after sulfonamides and quinolone antibacterial drugs. They are mainly used for the treatment of drug-resistant gram-positive bacterial infections in clinical practice, and have excellent antibacterial activity against drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP) and multidrug-resistant Mycobacterium tuberculosis (MDR-TB). Compared with other antibacterial drugs, oxazolidinone antibacterial drugs specifically bind to the 50S large subunit near the 30S small subunit of the ribosome, hinder the formation of the 70S initiation complex, and thus block protein synthesis, thereby playing an antibacterial role. Due to its unique chemical structure and mechanism of action, this class of drugs is less likely to induce bacterial resistance, and there is no cross-resistance to other antibacterial drugs in clinical practice.

[0004] In April 2000, linezolid was approved for marketing by the FDA, and is mainly used for the treatment of gram-positive bacteria. Although linezolid has a significant antibacterial effect, drug-resistant strains of linezolid inevitably appear with long-term use in clinical practice. The application of linezolid is also limited by its toxicity, mainly bone marrow suppression and monoamine oxidase (MAO) inhibition. Bone marrow suppression is directly related to the inhibition mode of linezolid, and the symptoms mainly include thrombocytopenia, leukopenia, pancytopenia and anemia. MAO inhibition may cause 5-hydroxytryptamine syndrome, which is manifested as a change in mental status (restlessness, hallucinations), increased autonomic nervous excitability (rapid heartbeat, elevated blood pressure, elevated body temperature, nausea, vomiting, diarrhea, hyperreflexia) and neuromuscular abnormalities.

[0005] Sivdomide phosphate has been approved by FDA in June 2014 as the second oxazolidinone antibacterial drug after linezolid for the treatment of acute bacterial skin and soft tissue infections caused by sensitive bacteria in adults. Compared with linezolid, the toxicity of sivdomide phosphate has not been significantly improved.

[0006] The inventors of the present application found in the previous application of the biaryl hydrazone oxazolidinone compound patent (CN107721943A) that the compounds involved have significant antibacterial activity against multiple drug-resistant bacteria, but in the later research, it was found that the bioavailability of some compounds is low, such as Example 35, the AUC of which in rats is only 379 ng·h / mL, and the drugability is poor. Further modification of it will obtain a series of compounds, which not only improve the bioavailability, but also reduce the inhibition of the compounds on MAO, thereby reducing the toxicity. 0-t Further modification of it will obtain a series of compounds, which not only improve the bioavailability, but also reduce the inhibition of the compounds on MAO, thereby reducing the toxicity. SUMMARY

[0007] The main purpose of the present application is to provide a novel compound with the structure of general formula I which can be used as an antibacterial drug. In particular, the present application also relates to the preparation method of the compound and the composition comprising the compound, and the use of the compound as an antibacterial drug in the preparation of the treatment of infectious diseases.

[0008] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0009] A biaryl oxazolidinone compound, the compound is a compound of general formula I and its stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof,

[0010] wherein,

[0011] R 1 , R 2 and R 3 are the same or different, and are independently selected from hydrogen, fluorine, chlorine or trifluoromethyl, R 1 and R 2 at least one of which is fluorine;

[0012] X is CH or N;

[0013] R 4 is halogen, -OR 7 , -NHR 8 , 6-10 membered aryl or 5-10 membered heteroaryl, and the aryl and heteroaryl are optionally substituted with 0-3 R 9 which are the same or different;

[0014] R 7hydrogen, (C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, 6-10 membered aryl, 5-10 membered heteroaryl, which aryl and heteroaryl are optionally substituted with 0-3 of the same or different R 10 substituted;

[0015] R 8 hydrogen, (C1-C6)alkylsulfonyl, (C3-C7)cycloalkylsulfonyl, 6-10 membered aryl, 5-10 membered heteroaryl, which aryl and heteroaryl are optionally substituted with 0-3 of the same or different R 11 substituted;

[0016] R 5 and R 6 are the same or different, each independently selected from hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C6)heterocyclyl, which cycloalkyl and heterocyclyl are optionally substituted with 0-3 of the same or different R 12 substituted;

[0017] or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl, which heterocyclyl optionally contains 0-4 heteroatoms selected from N, O and / or S, optionally includes 0-3 carbon carbon double or triple bonds, which heterocyclyl is optionally substituted with 0-3 oxo and / or optionally substituted with 0-3 of the same or different R 5 substituted; 6 or R 13 substituted;

[0018] R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from hydrogen, hydroxyl, halogen, carboxyl, cyano, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonamide, (C1-C6)alkylsulfonyl, free, salted, esterified or amidated carboxyl, (C3-C6)heterocyclyl unsubstituted or substituted with at least one C1-C6 alkyl, amino unsubstituted or substituted with at least one C1-C6 alkyl, carbamoyl, (C1-C6)alkylacyl unsubstituted or substituted with at least one same or different hydroxyl, amino or halogen, 6-10 membered arylacyl unsubstituted or substituted with at least one same or different (C1-C6)alkyl or halogen.

[0019] Preferably, the compounds are of the general formula I and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,

[0020] R 1 、R 2 and R 3 are the same or different, independently selected from hydrogen, fluorine, chlorine or trifluoromethyl, R 1 and R 2 At least one of them is fluorine;

[0021] X is CH or N;

[0022] R 4 Halogen, -OR 7 、-NHR 8 , 6-10 membered aryl or 5-6 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 0-3 identical or different R 9 replace;

[0023] R 7 is hydrogen, (C1-C4) alkyl, (C1-C4) alkylsulfonyl, (C3-C5) cycloalkylsulfonyl, 6-10 membered aryl, 5-6 membered heteroaryl, said aryl and heteroaryl are optionally substituted by 0-3 identical or different R 10 replace;

[0024] R 8 is hydrogen, (C1-C4) alkylsulfonyl, (C3-C5) cycloalkylsulfonyl, 6-10 membered aryl, 5-6 membered heteroaryl, said aryl and heteroaryl are optionally substituted by 0-3 identical or different R 11 replace;

[0025] R 5 and R 6 The same or different, each independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclyl, the cycloalkyl and heterocyclyl are optionally substituted by 0-3 identical or different R 12 replace;

[0026] or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group. 5 and R 6 In addition to the nitrogen atom to which it is attached, it optionally contains 0-4 heteroatoms selected from N, O and / or S, optionally includes 0-3 carbon-carbon double bonds or triple bonds, and the heterocyclic group is optionally substituted by 0-3 oxo groups and / or optionally substituted by 0-3 identical or different R 13 replace;

[0027] R 9 、R 10 、R 11 、R 12 and R 13independently selected from the group consisting of hydrogen, hydroxyl, halogen, carboxyl, cyano, (Ci-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (Ci-C4)alkoxy, (Ci-C4)alkylamido, (Ci-C4)alkylsulfonyl, free, salted, esterified or amidated carboxyl, (C3-C6)heterocyclyl unsubstituted or substituted by at least one Ci-C6alkyl, amino unsubstituted or substituted by at least one (Ci-C4alkyl), aminocarbonyl, (Ci-C4)alkylcarbonyl unsubstituted or substituted by at least one hydroxyl, amino or halogen, 6-10 membered arylcarbonyl unsubstituted or substituted by at least one (Ci-C4)alkyl or halogen.

[0028] Further preferred, the compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,

[0029] R 1 , R 2 and R 3 are the same or different and are each independently selected from the group consisting of hydrogen, fluorine, R 1 and R 2 at least one of R 4 and R 7 is fluorine;

[0030] X is CH or N;

[0031] R 8 is -OR 9 , -NHR 7 or 5-6 membered heteroaryl optionally substituted by 0-3 R 10 ;

[0032] R 8 is hydrogen, (Ci-C4)alkylsulfonyl, (C3-C5)cycloalkylsulfonyl, 5-6 membered heteroaryl optionally substituted by 0-3 R 11 ;

[0033] R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl;

[0034] or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl, said heterocyclyl being unsubstituted or substituted by 0-3 R 5 and R 6 are the same or different and are each independently selected from the group consisting of hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylsulfonyl, 5-6 membered heteroaryl optionally substituted by 0-3 R 13 ;6 optionally containing 0-4 heteroatoms selected from N, O and / or S, optionally including 0-3 carbon-carbon double bonds or triple bonds, said heterocyclyl being optionally substituted with 0-3 oxo and / or optionally substituted with 0-3 R 13 substituted;

[0036] R 9 , R 10 , R 11 and R 13 are independently selected from the group consisting of hydrogen, hydroxy, halogen, carboxyl, cyano, (Ci-C4)alkyl, (Ci-C4)alkylamido, (Ci-C4)alkylsulfonyl, free, salted, esterified or amidated carboxyl, (C3-C6)heterocyclyl unsubstituted or substituted with at least one Ci-C6alkyl, amino unsubstituted or substituted with at least one (Ci-C4alkyl), (Ci-C4)alkylacyl unsubstituted or substituted with at least one (Ci-C4alkyl), amino unsubstituted or substituted with at least one (Ci-C4alkyl), 6-10 membered arylacyl unsubstituted or substituted with at least one (Ci-C4alkyl) or halogen.

[0037] Still further preferred, the compound is a compound of the general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,

[0038] R 1 is fluorine, R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine;

[0039] X is N;

[0040] R 4 is -OR 7 , -NHR 8 or 5-6 membered heteroaryl, said heteroaryl being optionally substituted with 0-3 R 9 identical or different;

[0041] R 7 is hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylsulfonyl, 5-6 membered heteroaryl, said heteroaryl being optionally substituted with 0-3 R 10 identical or different;

[0042] R 8 is hydrogen, (Ci-C4)alkylsulfonyl, (C3-C5)cycloalkylsulfonyl, 5-6 membered heteroaryl, said heteroaryl being optionally substituted with 0-3 R 11 identical or different;

[0043] R 5 and R6 the same or different, are independently selected from the group consisting of hydrogen, (Ci-C4)alkyl;

[0044] or R 5 and R 6 form, together with the nitrogen atom to which they are attached, a 4-7 membered heterocyclyl, optionally containing 0-4 heteroatoms selected from N, O and / or S, optionally comprising 0-3 carbon-carbon double or triple bonds, said heterocyclyl being optionally substituted with 0-3 oxo and / or optionally substituted with 0-3 R 5 and R 6 , are independently selected from the group consisting of hydrogen, halogen, cyano, (Ci-C4)alkyl, (Ci-C4)alkylsulfonyl, (C3-C6)heterocyclyl unsubstituted or substituted with at least one Ci-C6alkyl, amino substituted with at least one (Ci-C4alkyl), (Ci-C4)alkylcarbonyl substituted with at least one hydroxy, amino or halogen, (Ci-C4)alkylcarbonyl unsubstituted or substituted with at least one (Ci-C4alkyl), 6-10 membered arylcarbonyl substituted with at least one (Ci-C4alkyl) or halogen. 13

[0045] R 9 , R 10 , R 11 and R 13 are independently selected from the group consisting of hydrogen, halogen, cyano, (Ci-C4)alkyl, (Ci-C4)alkylsulfonyl, (C3-C6)heterocyclyl unsubstituted or substituted with at least one Ci-C6alkyl, amino substituted with at least one (Ci-C4alkyl), (Ci-C4)alkylcarbonyl substituted with at least one hydroxy, amino or halogen, (Ci-C4)alkylcarbonyl unsubstituted or substituted with at least one (Ci-C4alkyl), 6-10 membered arylcarbonyl substituted with at least one (Ci-C4alkyl) or halogen.

[0046] It is further preferred that the compounds are compounds of general formula I and the stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein

[0047] R 1 is fluorine, R 2 and R 3 are independently selected from the group consisting of hydrogen, fluorine;

[0048] X is N;

[0049] R 4 is -OR 7 , -NHR 8 or 5 membered heteroaryl, optionally substituted with 0-3 R 9 , which are the same or different;

[0050] R 7 is hydrogen, (Ci-C4)alkylsulfonyl, 5 membered heteroaryl, optionally substituted with 0-3 R 10 , which are the same or different;

[0051] R 8 is hydrogen, (C3-C5)cycloalkylsulfonyl, 5 membered heteroaryl, optionally substituted with 0-3 R​11 substituted;

[0052] R 5 and R 6 are each independently selected from the group consisting of (Ci-C4)alkyl;

[0053] or R 5 and R 6 form together with the nitrogen atom to which they are attached a 6-membered heterocyclyl, which optionally contains, in addition to the nitrogen atom to which R 5 and R 6 are attached, 0-1 heteroatoms selected from the group consisting of N, O and / or S, which is optionally substituted with 0-2 oxo and / or optionally with 0-1 R 13 identical or different;

[0054] R 9 , R 10 , R 11 and R 13 are independently selected from the group consisting of hydrogen, halogen, cyano, (Ci-C4)alkyl, amino substituted with at least one (Ci-C4alkyl), (Ci-C4)alkylsulfonyl, (Ci-C4)alkylcarbonyl substituted with at least one identical or different hydroxy, amino or halogen, unsubstituted or substituted with at least one (Ci-C4alkyl)carbamoyl, (C3-C6)heterocyclyl unsubstituted or substituted with at least one Ci-C6alkyl.

[0055] Still more preferred, the compounds are compounds of general formula I and the stereoisomers, the pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein,

[0056] R 1 is fluorine, R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine;

[0057] X is N;

[0058] R 4 is -OR 7 , -NHR 8 or triazolyl;

[0059] R 7 is hydrogen, (Ci-C4)alkylsulfonyl, isoxazol-3-yl;

[0060] R 8 is hydrogen, (C3-C5)cycloalkylsulfonyl, isoxazol-3-yl;

[0061] R 5 and R 6 are each independently selected from the group consisting of (Ci-C4)alkyl;

[0062] or R 5 and R 6 together with the nitrogen atom to which they are attached form

[0063] Still further preferred, the compound is a compound of the general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein

[0064] R 1 is fluoro, R 2 and R 3 are each independently selected from hydrogen, fluoro;

[0065] X is N;

[0066] R 4 is triazolyl;

[0067] R 5 and R 6 together with the nitrogen atom to which they are attached form

[0068] the compound is a compound of the general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein

[0069] R 1 is fluoro, R 2 and R 3 are each independently selected from hydrogen, fluoro;

[0070] X is N;

[0071] R 4 is triazolyl;

[0072] R 5 and R 6 together with the nitrogen atom to which they are attached form

[0073] the compound is a compound of the general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein

[0074] (R,E)-3-[3-fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5- (hydroxymethyl)oxazolidin-2-one

[0075] (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0076] (R,E)-3-[3-fluorophenyl-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3-yl)]-5- (hydroxymethyl)oxazolidin-2-one

[0077] (R,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0078] (R,E)-3-(3-fluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0079] (R,E)-3-(3-fluoro-4-{6-[(thiomorpholin-l-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0080] (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-l-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0081] (R,E)-3-{3-fluoro-4-[6-({[4-(aminoacyl)piperazin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0082] (R,E)-3-{3-fluoro-4-[6-({[4-(N,N-diformyl)piperazin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0083] (R,E)-3-{3-fluoro-4-[6-({[4-(2-hydroxyacetyl)piperazin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0084] (R,E)-3-{3-fluoro-4-[6-({[4-(pyrrolidin-l-yl)piperidin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0085] (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0086] (R,E)-3-{3-fluoro-4-[6-({[4-(morpholin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0087] (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]imino}methyl)pyridin- 3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0088] (R,E)-3-{3-fluoro-4-[6-({[4-(1,4'-bipiperidinyl)-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0089] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5- (methanesulfonatomethyl)oxazolidin-2-one

[0090] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5- (methoxymethyl)oxazolidin-2-one

[0091] (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5- (aminomethyl)oxazolidin-2-one

[0092] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5- (methanesulfonamidomethyl)oxazolidin-2-one

[0093] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5- (cyclopropylsulfonamidomethyl)oxazolidin-2-one

[0094] (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3- triazol-1-yl)methyl]oxazolidin-2-one

[0095] (S,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol- 3-ylamino)methyl]oxazolidin-2-one

[0096] (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5-{[(5- methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one

[0097] (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4- methoxyphenyl)hydroxy-methyl]oxazolidin-2-one

[0098] (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(isoxazol- 3-yl)oxy]methyl}oxazolidin-2-one

[0099] (R,E)-3-[3-Fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0100] (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3- triazol-1-yl)methyl]oxazolidin-2-one

[0101] (R,E)-3-{3-Fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0102] (R,E)-3-(3-Fluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3- triazol-1-yl)methyl]oxazolidin-2-one

[0103] (R,E)-3-(3,5-Difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0104] (R,E)-3-(2,3-Difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0105] (R,E)-3-(2,3,5-Trifluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0106] (R,E)-3-[2,3-Difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3- yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0107] (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3- yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0108] (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0109] (R,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin- 3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0110] (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one

[0111] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0112] (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3- yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0113] (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3- yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0114] (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0115] (R,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin- 3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0116] (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0117] (S,E)-3-[2,3-fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0118] (S,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0119] (S,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0120] (S,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0121] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0122] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(5-methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one

[0123] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

[0124] (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0125] (R,E)-3-[3,5-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0126] (R,E)-3-(3,5-difluoro-4-{6-[(piperidin-l-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one

[0127] (R,E)-3-{3,5-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-l-yl]imino}methyl)pyridin- 3-yl]phenyl}-5-[(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one

[0128] (R,E)-3-(3,5-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- [(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one.

[0129] The present application also includes solvates of the compounds of general formula I, such as ethanol, water and the like, wherein different amounts of water can be contained, such as monohydrate, hemihydrate, one and a half hydrate, dihydrate or trihydrate.

[0130] The compounds of general formula I according to the present application can form pharmaceutically acceptable salts with acids according to some usual methods in the field of the present application. The acids can include inorganic or organic acids, and the salts formed with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid and aspartic acid.

[0131] The present application also includes prodrugs of the compounds of general formula I. According to the present application, prodrugs are derivatives of the compounds of general formula I, which can have less or even no activity themselves, but which are converted into the corresponding biologically active form after administration, for example by metabolism, solvolysis or another means.

[0132] The present application also includes racemates, optically active isomers, polymorphic forms or mixtures thereof of the compounds of general formula I, which possess the useful properties described in the present application. The compounds of general formula I according to the present application contain a chiral center (C-5 position of the oxazolidinone ring), thus two enantiomers or a racemic mixture of the two exist. The present application relates to both enantiomers and mixtures containing both isomers, which possess the useful properties.

[0133] Unless otherwise indicated, the term "alkyl" as used herein refers to straight or branched chain alkyl groups; "alkoxy" refers to straight or branched chain alkoxy groups; "alkenyl" refers to straight or branched chain alkenyl groups; "alkynyl" refers to straight or branched chain alkynyl groups; 5-10 membered heteroaryl groups include heteroaromatic rings containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group can be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5-10 atoms, and can be exemplified by pyridyl, furanyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl, indolyl, naphthyl, and the like.

[0134] The present application also includes pharmaceutical compositions comprising the compounds of the general formula I and their pharmaceutically acceptable salts and / or solvates as active ingredients together with a pharmaceutically acceptable carrier; the compounds of the present application can be used in combination with other active ingredients, provided that they do not produce adverse effects, such as allergic reactions.

[0135] The carriers used in the pharmaceutical compositions of the present application are of the type commonly available in the pharmaceutical art, and include: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, colorless pigments, flavoring agents, and the like for oral preparations; preservatives, solubilizers, stabilizers, and the like for injectable preparations; bases, diluents, lubricants, preservatives, and the like for topical preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are not stable in the stomach, they can be formulated as enteric-coated tablets.

[0136] The present application also includes its use in the manufacture of a medicament for the treatment of microbial, particularly bacterial, infections in mammals. The method of use comprises administering to a mammal an effective amount of a compound of the general formula I, which can be administered orally, parenterally, transdermally, or topically to the mammal in a pharmaceutical composition.

[0137] The oxazolidinone compounds of the general formula I of the present application have antimicrobial, particularly antibacterial, activity. Further, the oxazolidinone compounds of the general formula I of the present application can exhibit potent antibacterial activity against human and animal pathogenic bacteria, including gram-positive bacteria such as Staphylococci, Enterococci, and Streptococci, anaerobic bacteria such as Bacteroides fragilis, and Mycobacterium tuberculosis. Thus, it can be used as a medicament for the treatment of bacterial infections in mammals, and the compounds according to the present application can be used as active ingredients in a method for the treatment of bacterial infections in mammals, which comprises administering to a patient suffering from or susceptible to such a disease a therapeutically effective amount of a compound according to the present application.

[0138] The exact amount of a compound according to the application required to treat a microbial, particularly bacterial, infection will vary depending on the subject, the nature, age and general condition of the subject, the severity of the disease treated, the particular compound used and the mode of administration, e.g. the route and frequency of administration. The appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

[0139] The compounds can be administered in an amount of from about 0.1 to 100 mg / kg body weight per day, preferably 1 to 50 mg / kg body weight per day. It will be appreciated that the dose will vary from patient to patient, depending on the severity of the bacterial infection treated and the particular compound used. Furthermore, it will be appreciated that the initial dose can be increased beyond the upper limit to rapidly achieve the desired blood level, or the initial dose can be less than optimal and the daily dose increased gradually during the course of treatment, depending on the circumstances. If desired, the daily dose can also be divided into multiple doses for administration, e.g. 2-4 times per day.

[0140] Mammal means a human or an animal.

[0141] The amount of active ingredient, i.e. the compound according to the application, in a pharmaceutical composition and in a unit dose form thereof can vary widely, depending on the particular application, the potency and the desired concentration of the particular compound. In general, the active ingredient will comprise between 0.5% and 90% by weight of the total composition.

[0142] In combination therapy, the compound according to the application and the other compound can be administered simultaneously or sequentially, in which case the compound according to the application and the other compound can be combined in a single pharmaceutical composition or in separate compositions.

[0143] The following synthetic routes A, B, C, D, E describe the preparation of the compounds of general formula I according to the application, all starting materials being prepared by the methods described in these synthetic routes, by methods well known to the person of ordinary skill in the art of organic chemistry or being commercially available. All final compounds according to the application are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to the person of ordinary skill in the art of organic chemistry. All variable factors used in these synthetic routes are defined below or as defined in the claims.

[0144] The compounds according to the application of general formula I, in route A, route B, route C, route D and route E, are exemplified by the following compounds: R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , R 9R 10 R 11 The definitions are the same as in the claims.

[0145] When R 3 is hydrogen, R 4 is -OR 7 , and R 7 is H, the compounds of partial structure of general formula I are synthesized according to Route A

[0146] In Route A, the aniline substituted with R 1 , R 2 is used as the starting material, and the intermediate A4 is prepared through acylation reaction, cyclization reaction, and iodination reaction. The intermediate A6 is prepared through Miyaura reaction of 5-bromo-2-pyridinecarboxaldehyde with pinacol diborane. The intermediate A7 is prepared through Suzuki reaction of the intermediate A4 and the intermediate A6. The compounds of partial structure of general formula I (I-i) are prepared through reaction of the intermediate A7 with amines substituted with different groups.

[0147] When R 2 is hydrogen, R 4 is -OR 7 , R 7 is H, R 2 and R 3 are fluorine, the compounds of partial structure of general formula I are synthesized according to Route B

[0148] In Route B, the 2,3-difluoroaniline is used as the starting material, and the intermediate B4 is prepared through bromination reaction, acylation reaction, and cyclization reaction. The intermediate B6 is prepared through Suzuki reaction of the intermediate B4 and the intermediate A6. The compounds of partial structure of general formula I (I-ii) are prepared through reaction of the intermediate B6 with amines substituted with different groups.

[0149] When R 4 is -OR 7 , R 7 is H, R 1 , R 2 and R 3 are fluorine, the compounds of partial structure of general formula I are synthesized according to Route C

[0150] In Route C, the 2,3,5-trifluoroaniline is used as the starting material, and the intermediate C7 is prepared through acylation reaction, iodination reaction, Suzuki reaction, condensation reaction, cyclization reaction, and deprotection reaction. The compounds of partial structure of general formula I (I-iii) are prepared through reaction of the intermediate C7 with amines substituted with different groups.

[0151] When R 4 is -NHR8 When R1is 1,2,3-triazol-1-yl, the partial compounds of general formula I are synthesized according to Route E

[0152] In Route D, intermediate D4 is prepared from D1 via sulfonylation, substitution, reduction and acylation. Intermediate D4 is reacted with different substituted sulfonyl chlorides to give the partial compounds of general formula I (I-iv).

[0153] When R1is -NHR 4 When R1is 1,2,3-triazol-1-yl, the partial compounds of general formula I are synthesized according to Route E

[0154] In Route E, the partial compounds of general formula I (I-v) are prepared from D3 via cyclization and deprotection.

[0155] When R1is -NHR 4 When R1is -NHR 8 When R1is -NHR

[0156] In Route F, intermediate D2 is reacted via substitution and deprotection to give the partial compounds of general formula I (I-vi). DETAILED DESCRIPTION

[0157] In the following examples, methods for preparing some of the compounds are described. It should be appreciated that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described in the present application. The examples are intended to be illustrative and not limiting of the scope of the present application. The nuclear magnetic resonance hydrogen spectra of the compounds were determined using a Bruker ARX-300, and the mass spectra were determined using an Agilent 1100 LC / MSD; all reagents used were of analytical or chemical purity.

[0158] Example 1. Preparation of (R,E)-3-[3-fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0159] 1.1 Preparation of benzyl (3-fluorophenyl)carbamate (A2)

[0160] Under ice-bath, 45.0 g (0.40 mol) of m-fluoroaniline, 68.1 g (0.80 mol) of sodium bicarbonate were added into 200 mL of tetrahydrofuran, and the temperature was controlled at 0-5 °C. 68.5 mL (0.48 mol) of benzyl chloroformate was added dropwise into the reaction solution, and after the dropping was completed, the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was added into 200 mL of ice water, and stirred for 0.5 h. Ethyl acetate (150 mL x 2) was used for extraction, and the organic layer was dried over anhydrous sodium sulfate. Filtration was performed under suction, and the filtrate was concentrated to dryness under reduced pressure to obtain 75.7 g of a light red solid with a yield of 76.2%.

[0161] 1.2 Preparation of (R)-3-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (A3)

[0162] At room temperature, 75.0 g (0.31 mol) of intermediate A2 was added into 400 mL of dry tetrahydrofuran. At -78 °C, 135 mL (0.34 mol) of 2.5 M n-butyllithium was slowly added dropwise into the reaction solution under nitrogen protection. After the dropping was completed, the reaction was stirred for 0.5 h. 47 mL (0.34 mol) of (R)-(-)-glycidyl butyrate was slowly added dropwise into the reaction solution. After the dropping was completed, the reaction was continuously stirred for 2 h, and then the temperature was increased to room temperature and the reaction was carried out for 12 h. After the reaction was completed, the reaction solution was cooled to 0-5 °C. 200 mL of saturated ammonium chloride aqueous solution was added dropwise into the reaction solution, and the dropping speed was controlled so that the temperature was lower than 10 °C. After the dropping was completed, the reaction was stirred at 0-5 °C for 1 h. Ethyl acetate (200 mL x 2) was used for extraction, and the combined organic phase was washed with saturated brine (150 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and then filtration was performed under suction. The filtrate was evaporated to dryness to obtain 51.4 g of a white solid with a yield of 79.5%.

[0163] 1.3 Preparation of (R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)oxazolidin-2-one (A4)

[0164] At room temperature, 50.0 g (0.24 mol) of intermediate A3, 78.4 g (0.36 mol) of silver trifluoroacetate, and 72.1 g (0.29 mol) of iodine were sequentially added into 250 mL of acetonitrile. After the addition was completed, the reaction was carried out at room temperature for 12 h in the dark. After the reaction was completed, 100 mL of 5% sodium thiosulfate solution was added, and a white solid was precipitated. Filtration was performed under suction, and the filter cake was washed with ethyl acetate. The filtrate was collected, and extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with saturated brine (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and then filtration was performed under suction. The filtrate was evaporated to dryness to obtain 68.1 g of a white solid with a yield of 85.3%.

[0165] 1.4 Preparation of 2-formylpyridine-5-boronic acid pinacol ester (A6)

[0166] Into 150 mL of dry tetrahydrofuran, 10.0 g (53.8 mmol) of 5-bromopyridine-2- carboxaldehyde, 20.5 g (80.7 mmol) of pinacol diboronic acid and 15.8 g (161 mmol) of potassium acetate were added successively at room temperature. After addition, the reaction solution was degassed and 2.5 g (2.7 mmol) of Pd2(dba)3 and 2.6 g (5.4 mmol) of X-Phos were added under nitrogen protection. After addition, the reaction solution was warmed to reflux for 4 h. After the reaction was completed, the reaction solution was filtered through celite and the filter cake was washed with 50 mL of ethyl acetate. The filtrate was evaporated under reduced pressure to obtain a yellow oil. The product was used in the next step without purification.

[0167] 1.5 Preparation of (R)-5-{2-fluoro-4-[5-(hydroxymethyl)-2-oxooxazolidin-3-yl]phenyl}pyridine carboxaldehyde (A7)

[0168] Into 100 mL of 1,4-dioxane and 25 mL of water, 15.0 g (44.5 mmol) of intermediate A4, intermediate A6 and 15.0 g (109 mmol) of potassium carbonate were added successively at room temperature. After addition, the reaction solution was degassed and 2.0 g (2.7 mmol) of Pd(dppf)Cl2 was added under nitrogen protection. After addition, the reaction solution was warmed to 80°C for 4 h. After the reaction was completed, 100 mL of water was added to the reaction solution and the reaction solution was extracted with ethyl acetate (100 mL x 2). The combined organic phase was concentrated under reduced pressure to obtain a yellow oil. The yellow oil was purified by column chromatography to obtain 9.8 g of a yellow solid with a yield of 69.8%.

[0169] 1.6 Preparation of (R,E)-3-[3-fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0170] Into 1.0 mL of ethanol, 0.06 g (0.19 mmol) of intermediate A7 and 0.03 g (0.26 mmol) of 1-amino-4-methylpiperazine were added successively at room temperature. After addition, the reaction solution was warmed to reflux for 0.5 h. After the reaction was completed, a solid was precipitated. The solid was filtered and dried in an oven at 40°C for 24 h to obtain 0.06 g of a white solid with a yield of 80.2%.

[0171] Example 2 Preparation of (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0172] (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic method of 1.6 in Example 1 using N-amino morpholine as a raw material. The yield was 76.3%.

[0173] Example 3 Preparation of (R,E)-3-[3-fluorophenyl-4-(6-{[(1,1-dioxidothiomorpholin-4- yl)imino]methyl}pyridin-3-yl)]-5-(hydroxymethyl)oxazolidin-2-one

[0174] (R,E)-3-[3-fluorophenyl-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin- 3-yl)]-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 4-aminothiomorpholine- 1,1-dioxide according to the synthesis of 1.6 in Example 1. Yield 77.6%.

[0175] Example 4 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0176] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one was synthesized from N-amino piperidine according to the synthesis of 1.6 in Example 1. Yield 63.4%.

[0177] Example 5 Preparation of (R,E)-3-(3-fluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin- 3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0178] (R,E)-3-(3-fluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one was synthesized from isopropylhydrazine hydrochloride according to the synthesis of 1.6 in Example 1. Yield 69.1%.

[0179] Example 6 Preparation of (R,E)-3-(3-fluoro-4-{6-[(thiomorpholin-1-ylimino)methyl]pyridin- 3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0180] (R,E)-3-(3-fluoro-4-{6-[(thiomorpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one was synthesized from 4-thiomorpholinamine according to the synthesis of 1.6 in Example 1. Yield 57.2%.

[0181] Example 7 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1- yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0182] (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 4-(methylsulfonyl)-1- piperazinamine following the synthetic procedure of 1.6 in Example 1. Yield 62.1%.

[0183] Example 8 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(aminoacyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0184] (R,E)-3-{3-fluoro-4-[6-({[4-(aminoacyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 4-aminopiperazine-1- carboxamide following the synthetic procedure of 1.6 in Example 1. Yield 46.3%.

[0185] Example 9 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(N,N-dicarboxy)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0186] (R,E)-3-{3-fluoro-4-[6-({[4-(N,N-dicarboxy)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 4-amino-N,N- dimethylpiperazine-1-carboxamide following the synthetic procedure of 1.6 in Example 1. Yield 76.3%.

[0187] Example 10 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(2-hydroxyacetyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0188] (R,E)-3-{3-fluoro-4-[6-({[4-(2-hydroxyacetyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 1-(4-aminopiperazin-1- yl)-2-hydroxyethan-1-one following the synthetic procedure of 1.6 in Example 1. Yield 72.4%.

[0189] Example 11 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(pyrrolidin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0190] (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic procedure of Example 1, 1.6, using 4-(dimethylamino)piperidin-1 -amine as starting material. Yield 63.7%.

[0191] Example 12 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0192] (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic procedure of Example 1, 1.6, using 4-(dimethylamino)piperidin-1 -amine as starting material. Yield 63.7%.

[0193] Example 13 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(morpholin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0194] (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic procedure of Example 1, 1.6, using 4-(dimethylamino)piperidin-1 -amine as starting material. Yield 63.7%.

[0195] Example 14 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0196] (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic procedure of Example 1, 1.6, using 4-(dimethylamino)piperidin-1 -amine as starting material. Yield 63.7%.

[0197] Example 15 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(1,4'-bipiperidin)-1 -yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0198] (R,E)-3-{3-fluoro-4-[6-({[4-(l,4'-bipiperidinyl)-l-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic procedure of Example 1.1.6 using 4-(4-piperidin-l-yl)piperidin-l-amine as the starting material. Yield 71.2%.

[0199] Example 16 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylamino)methyl]pyridin-3- yl}phenyl)-5-(methanesulfonatomethyl)oxazolidin-2-one

[0200] To 0.1 g (0.25 mmol) of Example 4 and 0.05 g (0.50 mmol) of triethylamine in 2 mL of dichloromethane was added 0.04 g (0.38 mmol) of methanesulfonyl chloride dropwise at ice bath under 5°C. The reaction was continued for 2 h. After the reaction was completed, the reaction solution was poured into 10 mL of water and extracted with dichloromethane (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to give (R,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylamino)methyl]pyridin-3-yl}phenyl)-5- (methanesulfonatomethyl)oxazolidin-2-one. Yield 56.7%.

[0201] Example 17 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylamino)methyl]pyridin-3- yl}phenyl)-5-(methoxymethyl)oxazolidin-2-one

[0202] To 0.08 g (0.17 mmol) of Example 16 and 0.006 g (0.30 mmol) of sodium in 3 mL of methanol was added at ice bath under 5°C. The reaction was continued for 2 h. After the reaction was completed, the reaction solution was poured into 10 mL of water and extracted with ethyl acetate (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to give (R,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylamino)methyl]pyridin-3-yl}phenyl)-5- (methoxymethyl)oxazolidin-2-one. Yield 63.7%.

[0203] Example 18 Preparation of (S,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylamino)methyl]pyridin-3- yl}phenyl)-5-(aminomethyl)oxazolidin-2-one

[0204] 18.1 Preparation of (S,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylamino)methyl]pyridin-3-yl}phenyl)-5- (azidomethyl)oxazolidin-2-one (D3)

[0205] At room temperature, 3.0 g (6.30 mmol) of Example 16 and 1.2 g (18.9 mmol) of sodium azide were added to 30 mL of N,N-dimethylformamide, after addition, the temperature was raised to 90 °C and reacted for 6 h. After the reaction was completed, the reaction solution was poured into 90 mL of water, and a solid was precipitated, which was suction filtered and dried in an oven at 40 °C for 24 h to obtain 2.4 g of a white solid, with a yield of 89.3%.

[0206] 18. Preparation of (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-(aminomethyl)oxazolidin-2-one

[0207] At room temperature, 0.2 g (6.30 mmol) of Intermediate D3 and 0.02 g of palladium on carbon were added to 3 mL of methanol, after addition, the reaction was continued under hydrogen for 5 h. After the reaction was completed, the reaction solution was suction filtered through celite, the filter cake was washed with 3 mL of ethyl acetate, and the filtrate was evaporated under reduced pressure, and (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (aminomethyl)oxazolidin-2-one was obtained by column chromatography purification. The yield was 61.2%.

[0208] Example 19. Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-(methanesulfonamidomethyl)oxazolidin-2-one

[0209] At room temperature, 0.09 g (0.23 mmol) of Example 18 and 0.06 g (0.69 mmol) of triethylamine were added to 2 mL of dichloromethane, and 0.04 g (0.35 mmol) of methanesulfonyl chloride was added dropwise to the reaction solution under ice bath, keeping the temperature below 5 °C, and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was poured into 10 mL of water, extracted with dichloromethane (20 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to dryness under reduced pressure, and (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (methanesulfonamidomethyl)oxazolidin-2-one was obtained by column chromatography purification. The yield was 45.6%.

[0210] Example 20. Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-(cyclopropylsulfonamidomethyl)oxazolidin-2-one

[0211] (R,E)-3-(3-fluoro-4-{6-[(piperidin-l-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic procedure in Example 19 using cyclopropylsulfonyl chloride as starting material. Yield 78.3%.

[0212] Example 21 Preparation of (R,E)-3-(3-fluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one

[0213] Key intermediate D3 was synthesized according to the synthetic procedure in Example 18 using Example 2 as starting material.

[0214] 21.1 Preparation of (R,E)-3-(3-fluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin-3- yl}phenyl)-5-{[4-(trimethylsilyl)-lH-l,2,3-triazol-l-yl]methyl}oxazolidin-2-one (E1)

[0215] To 10 mL DMF was added 1.0 g (2.35 mmol) of intermediate D3 and 1.2 g (11.8 mmol) of trimethylsilyl acetylene at room temperature. After addition, the reaction was heated to 90 °C for 12 h. After the reaction was completed, the reaction solution was added to 30 mL of ice water and stirred for 0.5 h. A solid was precipitated, which was filtered and dried in an oven at 40 °C for 24 h to give 1.0 g of white solid in 81.3% yield.

[0216] 21.2 Preparation of (R,E)-3-(3-fluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one

[0217] To 5 mL (69.0 mmol) of 1 M TBAF in tetrahydrofuran was added 0.1 g (69.0 mmol) of intermediate E1 and 1 mL of glacial acetic acid at room temperature. After addition, the reaction was continued at room temperature for 3 h. After the reaction was completed, the solvent was evaporated and 5 mL of water was added to the residue. The mixture was stirred at room temperature for 0.5 h and filtered to give a yellow solid. Purification by column chromatography gave (R,E)-3-(3-fluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one in 67.7% yield.

[0218] Example 22 Preparation of (S,E)-3-(3-fluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0219] Using Example 2 as the starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 19.

[0220] 22.1 Preparation of (S,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(3-t-butylcarbamate-isoxazol-3-yl)methyl]oxazolidin-2-one (F1)

[0221] At room temperature, 0.2 g (0.42 mmol) of intermediate D2 was added to 2 mL of N,N- dimethylformamide, 0.02 g (0.84 mmol) of sodium hydride was slowly added to the reaction solution under ice bath, after addition, the temperature was raised to 35 °C and the stirring was continued for 0.5 h, then 0.1 g (0.42 mmol) of N-3-isoxazolyl t-butyl carbamate in N,N-dimethylformamide was slowly added to the reaction solution, after addition, the temperature was raised to 50 °C and the reaction was continued for 5 h. After the reaction was completed, the reaction solution was added to 5 mL of ice water and stirred for 0.5 h, a solid was precipitated, suction filtration was performed, and the white solid was dried in an oven at 40 °C for 24 h to obtain 0.15 g of a white solid with a yield of 60.1%.

[0222] 22.2 Preparation of (S,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0223] At room temperature, 0.2 g (0.35 mmol) of intermediate F1 was added to dichloromethane, 1 mL of trifluoroacetic acid was slowly added to the reaction solution under ice bath, after addition, the temperature was raised to room temperature and the reaction was continued for 2 h. After the reaction was completed, the solvent was evaporated, 3 mL of water was added to the residue, and the pH value was adjusted to 12 using 4 M aqueous sodium hydroxide solution, a solid was precipitated, suction filtration was performed, and column chromatography was used to purify to obtain (S,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one. The yield was 58.7%.

[0224] Example 23 Preparation of (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-{[(5-methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one

[0225] (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(5- methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one was synthesized from tert-butyl 5- methylisoxazole-3-carbamate as the starting material following the synthetic procedures of 22.1- 22.2 in Example 22. Yield 51.9%.

[0226] Example 24 Preparation of (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(4-carbonyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

[0227] The key intermediate D3 was synthesized from Example 2 following the synthetic procedures in Example 18.

[0228] To 2 mL of N,N-dimethylformamide was added 0.15 g (0.35 mmol) of intermediate D3 and 0.06 g (0.70 mmol) of 2-chloropropenoyl chloride at room temperature. After the addition, the reaction mixture was warmed to 95 °C and stirred for 9 h. After the reaction was completed, the reaction mixture was added to 10 mL of water and extracted with ethyl acetate (10 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to give (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4- carbonyl)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one. Yield 40.7%.

[0229] Example 25 Preparation of (R)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(isoxazol-3-yl)oxy]methyl}oxazolidin-2-one

[0230] To 2 mL of dry tetrahydrofuran was added 0.13 g (0.50 mmol) of triphenylphosphine, 0.10 g (0.50 mmol) of diisopropyl azodicarboxylate at room temperature. After stirring for 5 min at room temperature, 0.04 g (0.50 mmol) of 2-hydroxyisoxazole was added to the reaction mixture. After stirring for another 5 min, 0.15 g (0.37 mmol) of Example 2 was added to the reaction mixture. After the addition, the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was added to 10 mL of water and extracted with ethyl acetate (10 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and purified by column chromatography to give (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(isoxazol-3- yl)oxy]methyl}oxazolidin-2-one. Yield 32.8%.

[0231] Example 26 Preparation of (R,E)-3-[3-fluoro-4-(6-{[(4-methylpiperazin-1- yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2- one

[0232] Using Example 1 as starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, then the key intermediate D3 was synthesized according to the synthetic procedure in Example 18, 18.1, and finally (R,E)-3-[3-fluoro-4-(6-{[(4-methylpiperazin-1- yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2- one was synthesized according to the synthetic procedure in Example 21, 21.1-21.2. Yield 60.4%.

[0233] Example 27 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0234] Using Example 4 as starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, then the key intermediate D3 was synthesized according to the synthetic procedure in Example 18, 18.1, and finally (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic procedure in Example 21, 21.1-21.2. Yield 56.3%.

[0235] Example 28 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1- yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2- one

[0236] Using Example 7 as starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, then the key intermediate D3 was synthesized according to the synthetic procedure in Example 18, 18.1, and finally (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1- yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2- one was synthesized according to the synthetic procedure in Example 21, 21.1-21.2. Yield 47.8%.

[0237] Example 29. Preparation of (R,E)-3-(3-fluoro-4-{6-[(2-isopropylantilazyl)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0238] Using Example 5 as the starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, and then the key intermediate D3 was synthesized according to the synthetic method of 18.1 in Example 18, and finally (R,E)-3-(3-fluoro-4-{6-[(2-isopropylantilazyl)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method of 21.1-21.2 in Example 21. The yield was 67.3%.

[0239] Example 30. Preparation of (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0240] Using 3,5-difluoroaniline as the starting material, (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic method of 1.1-1.6 in Example 1. The yield was 43.7%.

[0241] Example 31. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0242] 31.1 Preparation of 2,3-difluoro-4-bromoaniline (B2)

[0243] At room temperature, 50.0 g (0.39 mol) of 2,3-difluoroaniline was added to 250 mL of N,N-dimethylformamide, and 69.0 g (0.39 mol) of N-bromosuccinimide was added to the reaction solution in five batches under ice bath, keeping the temperature below 5°C, and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was poured into 250 mL of water, extracted with ethyl acetate (200 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow solid 64.3 g, with a yield of 80.2%.

[0244] 31.2 Preparation of benzyl (2,3-difluoro-4-bromophenyl)carbamate (B3)

[0245] Under ice-bath, 60.0 g (0.29 mol) of intermediate B2, 23.2 g (0.58 mol) of sodium hydroxide were added into 500 mL of tetrahydrofuran, and the temperature was controlled at 0-5 °C. 61 mL (0.44 mol) of benzyl chloroformate was added dropwise into the reaction solution, and after the dropping was completed, the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was added into 500 mL of ice water, stirred for 0.5 h, extracted with ethyl acetate (300 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 88.8 g of white solid with a yield of 89.8%.

[0246] 31.3 Preparation of (R)-3-(2,3-difluoro-4-bromophenyl)-5-(hydroxymethyl)oxazolidin-2-one (B4)

[0247] At room temperature, 70.0 g (0.21 mol) of intermediate B3 was added into 500 mL of dry tetrahydrofuran, and at -78 °C, 38 mL (0.27 mol) of 2.5 M n-butyllithium was slowly added dropwise into the reaction solution under nitrogen protection. After the dropping was completed, the reaction was stirred for 0.5 h, and then 108 mL (0.27 mol) of (R)-(-)-glycidyl butyrate was slowly added dropwise into the reaction solution. After the dropping was completed, the reaction was continuously stirred for 2 h, and then the temperature was increased to room temperature and the reaction was carried out for 12 h. After the reaction was completed, the reaction solution was cooled to 0-5 °C, 300 mL of saturated ammonium chloride aqueous solution was added dropwise into the reaction solution, and the dropping speed was controlled so that the temperature was lower than 10 °C. After the dropping was completed, the reaction was stirred at 0-5 °C for 1 h, extracted with ethyl acetate (300 mL x 2), and the organic phases were combined, washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to obtain 52.0 g of white solid with a yield of 82.5%.

[0248] 31.4 Preparation of (R)-5-{2,3-difluoro-4-[5-(hydroxymethyl)-2-oxooxazolidin-3-yl]phenyl}pyridinecarboxaldehyde (B6)

[0249] At room temperature, 40.0 g (0.13 mol) of intermediate B4, 44.0 g (0.19 mol) of intermediate A6, and 53.0 g (0.38 mol) of potassium carbonate were sequentially added into 200 mL of 1,4-dioxane and 50 mL of water, degassed, and 6.9 g (9.5 mmol) of Pd(dppf)Cl2 and 9.0 g (18.9 mmol) of X-Phos were added into the reaction solution under nitrogen protection. After the addition was completed, the reaction was carried out at 80 °C for 4 h. After the reaction was completed, 100 mL of water was added into the reaction solution, extracted with ethyl acetate (200 mL x 2), and the organic phases were combined and concentrated under reduced pressure to obtain yellow oil. Purification was performed by column chromatography to obtain 31.5 g of yellow solid with a yield of 72.4%.

[0250] 31.5 Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0251] At room temperature, 0.1 g (0.30 mmol) of intermediate B6 and 0.04 g (0.33 mmol) of N-amino morpholine were added into 1.0 mL of ethanol, after addition, the temperature was raised to reflux for 0.5 h. After the reaction was completed, a solid was precipitated, and was extracted by filtration, and was dried in an oven at 40 °C for 24 h to obtain a white solid 0.09 g with a yield of 75.4%.

[0252] Example 32 Preparation of (R,E)-3-(2,3,5-trifluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0253] 32.1 Preparation of benzyl (2,3,5-trifluorophenyl)carbamate (C2)

[0254] Under ice-bath, 5.0 g (34.0 mmol) of 2,3,5-trifluoroaniline, 5.8 g (69.0 mmol) of sodium bicarbonate were added into 50 mL of tetrahydrofuran, and the temperature was controlled at 0-5 °C, 5.8 mL (41.2 mmol) of benzyl chloroformate was added dropwise into the reaction solution, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the reaction solution was added into 50 mL of ice water, and was stirred for 0.5 h, and was extracted with ethyl acetate (25 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, and was extracted by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain a white solid 8.2 g with a yield of 85.5%.

[0255] 32.2 Preparation of benzyl (2,3,5-trifluoro-4-iodophenyl)carbamate (C3)

[0256] At room temperature, 7.6 g (27.0 mmol) of intermediate C2, 12.0 g (54.0 mmol) of silver trifluoroacetate and 10.4 g (40.5 mmol) of iodine were sequentially added into 50 mL of acetonitrile, and after addition, the reaction was carried out at room temperature for 12 h in the dark. After the reaction was completed, 50 mL of 5% sodium thiosulfate solution was added, and a white solid was precipitated, and was extracted by filtration, and the filter cake was washed with ethyl acetate, and the filtrate was extracted with ethyl acetate (50 mL x 2), and the combined organic phase was washed with saturated brine (50 mL x 2), and was dried over anhydrous sodium sulfate, and was extracted by filtration, and the filtrate was evaporated to dryness to obtain a white solid 7.7 g with a yield of 70.4%.

[0257] 32.3 Preparation of benzyl [2,3,5-trifluoro-4-(6-formylpyridin-3-yl)phenyl]carbamate (C4)

[0258] At room temperature, 6.6 g (16.2 mmol) of intermediate C3, 4.8 g (20.6 mmol) of intermediate A6, and 5.7 g (41.2 mmol) of potassium carbonate were added successively into 60 mL of 1,4-dioxane and 15 mL of water. After completion of the addition, 0.78 g (1.1 mmol) of Pd(dppf)Cl2 was added into the reaction solution. After completion of the addition, the reaction solution was heated to 80°C and reacted for 4 hours. After completion of the reaction, 20 mL of water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate (50 mL x 2). The organic layers were combined and concentrated under reduced pressure to obtain a yellow oily substance. The yellow oily substance was purified by column chromatography to obtain 4.4 g of a white solid, with a yield of 69.7%.

[0259] 32.4 Preparation of benzyl {2,3,5-trifluoro-4-[6-(1,3-dioxolan-2-yl)pyridin-3- yl]phenyl}carbamate (C5)

[0260] At room temperature, 4.0 g (10.4 mmol) of intermediate C4, 1.3 g (20.8 mmol) of ethylene glycol, and 0.12 g (0.7 mmol) of p-toluenesulfonic acid were added successively into 40 mL of toluene. After completion of the addition, the reaction solution was heated to 110°C and reacted for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. To the residue, 50 mL of ethyl acetate was added, and the organic layer was washed with saturated sodium bicarbonate solution (20 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.2 g of a yellow solid, with a yield of 72.7%.

[0261] 32.5 Preparation of (R)-3-{2,3,5-trifluoro-4-[6-(1,3-dioxolan-2-yl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one (C6)

[0262] At room temperature, 3.2 g (7.4 mmol) of intermediate C5 was added into 30 mL of dry tetrahydrofuran. At -78°C, 3.3 mL (8.2 mmol) of 2.5 M n-butyllithium was slowly added into the reaction solution under nitrogen atmosphere. After completion of the dropwise addition, the reaction solution was stirred for 0.5 hours. To the reaction solution, 1.2 mL (8.2 mmol) of (R)-(-)-glycidyl butyrate was slowly added dropwise. After completion of the dropwise addition, the reaction solution was continuously stirred for 2 hours, and then the temperature was increased to room temperature and reacted for 12 hours. After completion of the reaction, the reaction solution was cooled to 0-5°C. To the reaction solution, 30 mL of saturated ammonium chloride aqueous solution was added dropwise, and the temperature was controlled to be lower than 10°C. After completion of the dropwise addition, the reaction solution was stirred for 1 hour at 0-5°C. The reaction solution was extracted with ethyl acetate (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.7 g of a white solid, with a yield of 57.1%.

[0263] 32.6 Preparation of (R)-5-{2,3,5-trifluoro-4-[5-(hydroxymethyl)-2-oxo- oxazolidin-3-yl]phenyl}pyridinecarboxaldehyde (C7)

[0264] To 0.20 g (0.50 mmol) of intermediate C6 and 2.0 mL of 2M hydrochloric acid in 2.0 mL of tetrahydrofuran at room temperature, after addition, the temperature was raised to 50°C for 3h. After the reaction, the reaction solution was concentrated under reduced pressure, 10 mL of ethyl acetate was added to the residue, the organic phase was washed with saturated sodium bicarbonate solution (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 0.13 g of yellow solid, with a yield of 73.5%.

[0265] 32.7 Preparation of (R,E)-3-(2,3,5-trifluoro-4-{6-[(morpholin-1- ylidene)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0266] To 0.1 g (0.28 mmol) of intermediate C7 and 0.03 g (0.34 mmol) of N- aminomorpholine in 1.0 mL of ethanol at room temperature, after addition, the temperature was raised to reflux for 0.5h. After the reaction, a solid was precipitated, filtered, and dried in an oven at 40°C for 24h to give 0.09 g of white solid, with a yield of 69.7%.

[0267] Example 33 Preparation of (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4- yl)imidino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0268] (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4- yl)imidino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic method of 31.5 in Example 31, using 4- aminothiomorpholine 1,1-dioxide as the starting material. Yield 47.5%.

[0269] Example 34 Preparation of (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1- yl)imidino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0270] (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1- yl)imidino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one was synthesized according to the synthetic method of 31.5 in Example 31, using 1-amino-4-methylpiperazine as the starting material. Yield 48.0%.

[0271] Example 35. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-l- ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0272] (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-l-ylimino)methyl]pyridin-3- yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized from N- aminopiperidine following the synthetic procedure of Example 31, 31.5. Yield 71.2%.

[0273] Example 36. Preparation of (R)-3-{2,3-difluoro-4-[6-({[4-(4- methylsulfonyl)piperazin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5- (hydroxymethyl)oxazolidin-2-one

[0274] (R)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-l- yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 4-(methylsulfonyl)-l-piperazinamine following the synthetic procedure of Example 31, 31.5. Yield 67.2%.

[0275] Example 37. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(2- isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin- 2-one

[0276] (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3- yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized from isopropylhydrazine hydrochloride following the synthetic procedure of Example 31, 31.5. Yield 50.6%.

[0277] Example 38. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin- 1 -ylimino)methyl]pyridin-3-yl}phenyl)-5-[(lH-l,2,3-triazol-l-yl)methyl]oxazolidin- 2-one

[0278] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(lH-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one was synthesized from Example 31 following the synthetic procedure of Example 16, the synthesis of key intermediate D2, the synthetic procedure of Example 18, the synthesis of key intermediate D3, and the synthetic procedure of Example 21, 21.1-21.2. Yield 49.5%.

[0279] Example 39. Preparation of (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4- yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0280] Using Example 33 as starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, then the key intermediate D3 was synthesized according to the synthetic method in Example 18.1, and finally (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4- yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method in Example 21.1-21.2. Yield 43.8%.

[0281] Example 40. Preparation of (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1- yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0282] Using Example 34 as starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, then the key intermediate D3 was synthesized according to the synthetic method in Example 18.1, and finally (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1- yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method in Example 21.1-21.2. Yield 58.6%.

[0283] Example 41. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0284] Using Example 35 as starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, then the key intermediate D3 was synthesized according to the synthetic method in Example 18.1, and finally (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method in Example 21.1-21.2. Yield 60.7%.

[0285] Example 42 Preparation of (R,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1- yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0286] Using Example 36 as the starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, then the key intermediate D3 was synthesized according to the synthetic method of 18.1 in Example 18, and finally (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method of 21.1-21.2 in Example 21. The yield was 64.8%.

[0287] Example 43 Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0288] Using Example 37 as the starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, then the key intermediate D3 was synthesized according to the synthetic method of 18.1 in Example 18, and finally (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3- yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method of 21.1-21.2 in Example 21. The yield was 57.2%.

[0289] Example 44 Preparation of (S,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3- yl)phenyl]-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0290] Using Example 34 as the starting material, the key intermediate D2 was synthesized according to the synthetic method in Example 16, then (S,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3- yl)phenyl]-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one was synthesized according to the synthetic method of 22.1-22.2 in Example 22. The yield was 67.4%.

[0291] Example 45 Preparation of (S,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0292] Using Example 35 as the starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, and then (S,E)-3-(2,3-difluoro-4-{6-[(piperidin-l- ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one was synthesized according to the synthetic procedure of 22.1-22.2 in Example 22. Yield 53.9%.

[0293] Example 46 Preparation of (S,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin- 1 -yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2- one

[0294] Using Example 36 as the starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, and then (S,E)-3-{2,3-difluoro-4-[6-({[4-(4- methylsulfonyl)piperazin-l-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(isoxazol-3- ylamino)methyl]oxazolidin-2-one was synthesized according to the synthetic procedure of 22.1-22.2 in Example 22. Yield 57.3%.

[0295] Example 47 Preparation of (S,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin- 3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0296] Using Example 37 as the starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, and then (S,E)-3-(2,3-difluoro-4-{6-[(2- isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin- 2-one was synthesized according to the synthetic procedure of 22.1-22.2 in Example 22. Yield 50.6%.

[0297] Example 48 Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-l-ylimino)methyl]pyridin- 3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0298] Using Example 31 as the starting material, the key intermediate D2 was synthesized according to the synthetic procedure in Example 16, and then (R,E)-3-(2,3-difluoro-4-{6-[(morpholin- 1 -ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one was synthesized according to the synthetic procedure of 22.1-22.2 in Example 22. Yield 52.7%.

[0299] Example 49. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(5-methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one

[0300] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(5-methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one was synthesized from Example 31 following the synthetic procedure in Example 23. Yield 48.2%.

[0301] Example 50. Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one

[0302] (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one was synthesized from Example 31 following the synthetic procedure in Example 24. Yield 52.9%.

[0303] Example 51. (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0304] (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized from Example 30 following the synthetic procedure in Example 16 for key intermediate D2, then following the synthetic procedure in Example 18.1 for key intermediate D3, then following the synthetic procedure in Example 21.1-21.2. Yield 43.8%.

[0305] Example 52. (R,E)-3-[3,5-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0306] (R,E)-3-[3,5-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3- yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized from 3,5- difluoroaniline as the starting material following the synthetic procedures of 1.1-1.5 in Example 1, (R,E)-3-(3,5-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one following the synthetic procedure of 1.6 in Example 1, key intermediate D2 following the synthetic procedure in Example 16, key intermediate D3 following the synthetic procedure of 18.1 in Example 18, and (R,E)-3-{3,5-difluoro-4-[6-({[4-(4- methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1- yl)methyl]oxazolidin-2-one following the synthetic procedures of 21.1-21.2 in Example 21. Yield 58.1%.

[0307] Example 53 (R,E)-3-(3,5-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0308] (R,E)-3-(3,5-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized from 3,5-difluoroaniline as the starting material following the synthetic procedures of 1.1-1.5 in Example 1, (R,E)-3-(3,5-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one following the synthetic procedure of 1.6 in Example 1, key intermediate D2 following the synthetic procedure in Example 16, key intermediate D3 following the synthetic procedure of 18.1 in Example 18, and (R,E)-3-{3,5-difluoro-4-[6-({[4-(4- methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1- yl)methyl]oxazolidin-2-one following the synthetic procedures of 21.1-21.2 in Example 21. Yield 46.9%.

[0309] Example 54 (R,E)-3-{3,5-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin- 3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0310] (R,E)-3-{3,5-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method of 21.1-21.2 in Example 21, using 3,5-difluoroaniline as the starting material to synthesize the key intermediate A7 according to the synthetic method of 1.1-1.5 in Example 1, and using 4-(methylsulfonyl)-1-piperazinamine as the starting material to synthesize (R,E)-3-{3,5-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3- yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one according to the synthetic method of 1.6 in Example 1. Yield 47.3%.

[0311] Example 55 (R,E)-3-(3,5-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- [(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0312] (R,E)-3-(3,5-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3- triazol-1-yl)methyl]oxazolidin-2-one was synthesized according to the synthetic method of 21.1-21.2 in Example 21, using 3,5-difluoroaniline as the starting material to synthesize the key intermediate A7 according to the synthetic method of 1.1-1.5 in Example 1, and using isopropylhydrazine hydrochloride as the starting material to synthesize (R,E)-3-(3,5-difluoro-4-{6-[(2-isopropylhydrazono)methyl]pyridin-3-yl}phenyl)-5- (hydroxymethyl)oxazolidin-2-one according to the synthetic method of 1.6 in Example 1. Yield 40.6%.

[0313] Example 56 Preparation of tablets of the compound of Example 1 (250 mg / tablet)

[0314] Take 250 g of the compound of Example 1, 30 g of starch, 80 mL of 2% HPMC aqueous solution, 15 g of sodium carboxymethyl starch, and 2 g of magnesium stearate, and follow the steps below:

[0315] a. Prepare an appropriate amount of 2% HPMC solution and reserve;

[0316] b. Dry the raw and auxiliary materials properly, pass them through a 100-mesh sieve respectively, and reserve;

[0317] c. Weigh the ingredients according to the prescription. Mix the compound of Example 1, starch, sodium carboxymethyl starch, and then add 2% HPMC solution to make soft material, and use a 20 mesh sieve to make wet granules;

[0318] d. Dry the wet granules at 55°C for about 3 hours, and then add magnesium stearate after slightly cooling. Use a 20 mesh sieve to granulate. Determine the content and calculate the tablet weight;

[0319] e. Select 10 mm shallow concave punch to make tablets, and make 1000 tablets;

[0320] f. Test the finished product, and package and store in the warehouse after passing the test.

[0321] Preparation of capsules (125 mg / grain) of the compound of Example 3

[0322] Take the following components: 125 g of the compound of Example 3, 15 g of starch, 15 g of lactose, about 40 mL of 2% HPMC aqueous solution, 7.5 g of sodium carboxymethyl starch, and 1 g of magnesium stearate. Follow the steps below:

[0323] a. Prepare 2% HPMC solution in an appropriate amount and reserve.

[0324] b. Dry the ingredients appropriately, pass them through a 100 mesh sieve, and reserve.

[0325] c. Weigh the ingredients according to the prescription. Mix the compound of Example 2, starch, lactose, and sodium carboxymethyl starch, and then add 2% HPMC solution to make soft material, and use a 20 mesh sieve to make wet granules.

[0326] d. Dry the wet granules at 55°C for about 3 hours, and then add magnesium stearate after slightly cooling. Use a 20 mesh sieve to granulate. Determine the content and calculate the loading.

[0327] e. Select 2# capsule shells to fill the granules, and get 1000 capsules.

[0328] f. Polish and dust the capsules.

[0329] g. Test the finished product, and package and store in the warehouse after passing the test.

[0330] Preparation of dispersible tablets (250 mg / grain) of the compound of Example 7

[0331] Take the following components: 250 g of the compound of Example 7, 50 g of pregelatinized starch, 50 g of microcrystalline cellulose, 20 g of sodium carboxymethyl starch, about 90 mL of 2% HPMC aqueous solution, 20 g of silicon dioxide, 18 g of steviol glycoside, and 2 g of magnesium stearate. Follow the steps below to prepare:

[0332] a. Prepare 2% HPMC solution as needed.

[0333] b. Dry the raw and auxiliary materials properly, and pass them through a 100-mesh sieve, respectively, and reserve them for use.

[0334] c. Weigh the raw and auxiliary materials according to the prescription. Mix the compound of Example 4, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, and rebaudioside uniformly, and then add the 2% HPMC solution to make soft material, and then use a 20-mesh sieve to make wet granules.

[0335] d. Dry the wet granules at 55°C for 3 hours, and then slightly cool them after drying, add colloidal silicon dioxide and magnesium stearate, and then use a 20-mesh sieve to make granules. Determine the content and calculate the tablet weight.

[0336] e. Select 11 mm shallow concave punches to make tablets, and obtain 1000 tablets.

[0337] f. Perform product inspection, and after passing the inspection, package and store them in the warehouse.

[0338] Preparation of Example 59: Compound of Example 8 Sodium Chloride Injection (100 mL: 250 mg)

[0339] Take the following components: 250 g of the compound of Example 8, 825 g of sodium chloride, 6.5 g of citric acid, and water for injection to 100 L, and perform the following steps:

[0340] a. Weigh the compound of Example 4, sodium chloride, and citric acid according to the prescription.

[0341] b. Dissolve the main and auxiliary materials in about 90% of the total amount of water for injection (about 80°C), and stir to completely dissolve.

[0342] c. Add 0.05% of needle activated carbon activated at 120°C for 2 hours, stir, and stand for 15 minutes.

[0343] d. After decarbonization, filter with a 0.6 μm titanium rod filter, and then add water for injection to the full amount.

[0344] Structure and 1 H-NMR and MS data are shown in the following table.

[0345] Table 1 Structure and 1 H-NMR and MS data

[0346] The in-vitro antibacterial activity of the compounds of the present application was investigated, and the results are as follows:

[0347] After sterilization, the test sample was diluted in Mueller-Hinton (M-H) broth to a series of concentrations, with the lowest concentration being 0.06 mg / L and the highest concentration being 128 mg / L, and the concentration gradient being 2. In the 12th hole of each row of a 96-well dilution plate, 100 μL of M-H broth medium was added as a blank control, 50 μL of M-H broth was added to the 11th hole, and 50 μL of the sample test solution was added to the 10th hole to the 1st hole in order from low to high.

[0348] An appropriate amount of the test bacteria and standard strains was inoculated in M-H nutrient broth medium suitable for their growth, and incubated at 37°C for 16-18 h. The grown bacterial solution was corrected to a concentration of 0.5 McFarland turbidity standard using normal saline, and then diluted 1:100 (v / v) using M-H broth, and this solution was used as the test bacterial solution. Then, 50 μL of the test bacterial solution was inoculated in the 1st to 11th holes, mixed by shaking, and then placed in a covered square dish lined with wet gauze, and incubated at 37°C for 18-20 h.

[0349] The results were observed under a light source with a black background. The holes with bacterial growth had diffuse turbidity or a button-like precipitate at the bottom of the hole, and the holes without bacterial growth did not have such phenomena. The lowest drug concentration contained in the holes without bacterial growth was the minimum inhibitory concentration (MIC). The test results are shown in Table 2.

[0350] Table 2 Activity of some of the compounds of the examples on Gram-positive bacteria (MIC: μg / mL)

[0351] Note: S. aureus is standard Staphylococcus aureus (29213), MSSA is methicillin-sensitive Staphylococcus aureus, MRSA is methicillin-resistant Staphylococcus aureus, LRSA is linezolid-sensitive Enterococcus faecalis, LREF is linezolid-resistant Enterococcus faecalis; "-" means not detected.

[0352] Then, the MAO inhibitory effect of some of the compounds obtained in the present application was further detected (see Table 3)

[0353] Table 3 MAO inhibitory effect (IC50 : nM)

[0354] The preliminary in vitro antibacterial activity test results of the above Tables 2 and 3 show that the compounds in the present application have better antibacterial activity than linazamide, and have significant antibacterial activity against drug-resistant bacteria. At the same time, they have lower MAO inhibition than linazamide, and better safety.

Claims

1. A biaryl oxazolidinone compound, characterized in that: The compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, in, R 1 、R 2 and R 3 are the same or different, independently selected from hydrogen, fluorine, chlorine or trifluoromethyl, R 1 and R 2 At least one of them is fluorine; X is CH or N; R 4 Halogen, -OR 7 、-NHR 8 , 6-10 membered aryl or 5-10 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 0-3 identical or different R 9 replace; R 7 is hydrogen, (C1-C6) alkyl, (C1-C6) alkylsulfonyl, (C3-C7) cycloalkylsulfonyl, 6-10 membered aryl, 5-10 membered heteroaryl, said aryl and heteroaryl are optionally substituted by 0-3 identical or different R 10 replace; R 8 is hydrogen, (C1-C6) alkylsulfonyl, (C3-C7) cycloalkylsulfonyl, 6-10 membered aryl, 5-10 membered heteroaryl, said aryl and heteroaryl are optionally substituted by 0-3 identical or different R 11 replace; R 5 and R 6 The same or different, each independently selected from hydrogen, (C1-C6) alkyl, (C3-C7) cycloalkyl, (C3-C6) heterocyclyl, the cycloalkyl and heterocyclyl are optionally substituted by 0-3 identical or different R 12 replace; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 4-10 membered heterocyclic group. 5 and R 6 In addition to the nitrogen atom to which it is attached, it optionally contains 0-4 heteroatoms selected from N, O and / or S, optionally includes 0-3 carbon-carbon double bonds or triple bonds, and the heterocyclic group is optionally substituted by 0-3 oxo groups and / or optionally substituted by 0-3 identical or different R 13 replace; R 9 、R 10 、R 11 、R 12 and R 13 Independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkylamido, (C1-C6) alkylsulfonyl, free, salified, esterified or amidated carboxyl, (C3-C6) heterocyclyl which is unsubstituted or substituted by at least one C1-C6 alkyl, amino which is unsubstituted or substituted by at least one C1-C6 alkyl, carbamoyl, (C1-C6) alkylacyl which is unsubstituted or substituted by at least one identical or different hydroxyl, amino or halogen, 6-10 membered arylacyl which is unsubstituted or substituted by at least one identical or different (C1-C6) alkyl or halogen.

2. The biaryl oxazolidinone compound according to claim 1, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 、R 2 and R 3 are the same or different, independently selected from hydrogen, fluorine, chlorine or trifluoromethyl, R 1 and R 2 At least one of them is fluorine; X is CH or N; R 4 Halogen, -OR 7 、-NHR 8 , 6-10 membered aryl or 5-6 membered heteroaryl, wherein the aryl and heteroaryl are optionally substituted by 0-3 identical or different R 9 replace; R 7 is hydrogen, (C1-C4) alkyl, (C1-C4) alkylsulfonyl, (C3-C5) cycloalkylsulfonyl, 6-10 membered aryl, 5-6 membered heteroaryl, said aryl and heteroaryl are optionally substituted by 0-3 identical or different R 10 replace; R 8 is hydrogen, (C1-C4) alkylsulfonyl, (C3-C5) cycloalkylsulfonyl, 6-10 membered aryl, 5-6 membered heteroaryl, said aryl and heteroaryl are optionally substituted by 0-3 identical or different R 11 replace; R 5 and R 6 The same or different, each independently selected from hydrogen, (C1-C4) alkyl, (C3-C6) cycloalkyl, (C3-C6) heterocyclyl, the cycloalkyl and heterocyclyl are optionally substituted by 0-3 identical or different R 12 replace; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group. 5 and R 6 In addition to the nitrogen atom to which it is attached, it optionally contains 0-4 heteroatoms selected from N, O and / or S, optionally includes 0-3 carbon-carbon double bonds or triple bonds, and the heterocyclic group is optionally substituted by 0-3 oxo groups and / or optionally substituted by 0-3 identical or different R 13 replace; R 9 、R 10 、R 11 、R 12 and R 13 Independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkoxy, (C1-C4) alkylamido, (C1-C4) alkylsulfonyl, free, salified, esterified or amidated carboxyl, (C3-C6) heterocyclyl which is unsubstituted or substituted by at least one C1-C6 alkyl, amino which is unsubstituted or substituted by at least one (C1-C4 alkyl), carbamoyl, (C1-C4) alkylacyl which is unsubstituted or substituted by at least one identical or different hydroxyl, amino or halogen, 6-10 membered arylacyl which is unsubstituted or substituted by at least one identical or different (C1-C4) alkyl or halogen.

3. The biaryl oxazolidinone compound according to claim 2, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 、R 2 and R 3 are the same or different, independently selected from hydrogen, fluorine, R 1 and R 2 At least one of them is fluorine; X is CH or N; R 4 For-OR 7 、-NHR 8 or 5-6 membered heteroaryl, said heteroaryl being optionally substituted by 0-3 identical or different R 9 replace; R 7 is hydrogen, (C1-C4) alkyl, (C1-C4) alkylsulfonyl, 5-6 membered heteroaryl, said heteroaryl being optionally substituted by 0-3 identical or different R 10 replace; R 8 is hydrogen, (C1-C4)alkylsulfonyl, (C3-C5)cycloalkylsulfonyl, 5-6 membered heteroaryl, said heteroaryl being optionally substituted by 0-3 identical or different R 11 replace; R 5 and R 6 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group. 5 and R 6 In addition to the nitrogen atom to which it is attached, it optionally contains 0-4 heteroatoms selected from N, O and / or S, optionally includes 0-3 carbon-carbon double bonds or triple bonds, and the heterocyclic group is optionally substituted by 0-3 oxo groups and / or optionally substituted by 0-3 identical or different R 13 replace; R 9 、R 10 、R 11 and R 13 independently selected from hydrogen, hydroxy, halogen, carboxyl, cyano, (C1-C4) alkyl, (C1-C4) alkylamido, (C1-C4) alkylsulfonyl, free, salified, esterified or amidated carboxyl, (C3-C6) heterocyclyl which is unsubstituted or substituted by at least one C1-C6 alkyl, amino which is unsubstituted or substituted by at least one (C1-C4 alkyl), (C1-C4) alkylacyl which is unsubstituted or substituted by at least one identical or different hydroxyl, amino or halogen, carbamoyl which is unsubstituted or substituted by at least one (C1-C4 alkyl), 6-10 membered arylacyl which is unsubstituted or substituted by at least one identical or different (C1-C4) alkyl or halogen.

4. The biaryl oxazolidinone compound according to claim 3, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine; X is N; R 4 For-OR 7 、-NHR 8 or 5-6 membered heteroaryl, said heteroaryl being optionally substituted by 0-3 identical or different R 9 replace; R 7 is hydrogen, (C1-C4) alkyl, (C1-C4) alkylsulfonyl, 5-6 membered heteroaryl, said heteroaryl being optionally substituted by 0-3 identical or different R 10 replace; R 8 is hydrogen, (C1-C4)alkylsulfonyl, (C3-C5)cycloalkylsulfonyl, 5-6 membered heteroaryl, said heteroaryl being optionally substituted by 0-3 identical or different R 11 replace; R 5 and R 6 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 4-7 membered heterocyclic group. 5 and R 6 In addition to the nitrogen atom to which it is attached, it optionally contains 0-4 heteroatoms selected from N, O and / or S, optionally includes 0-3 carbon-carbon double bonds or triple bonds, and the heterocyclic group is optionally substituted by 0-3 oxo groups and / or optionally substituted by 0-3 identical or different R 13 replace; R 9 、R 10 、R 11 and R 13 Independently selected from hydrogen, halogen, cyano, (C1-C4) alkyl, (C1-C4) alkylsulfonyl, (C3-C6) heterocyclyl which is unsubstituted or substituted by at least one C1-C6 alkyl, amino which is substituted by at least one (C1-C4 alkyl), (C1-C4) alkylacyl which is substituted by at least one same or different hydroxyl, amino or halogen, carbamoyl which is unsubstituted or substituted by at least one (C1-C4 alkyl), 6-10 membered arylacyl which is substituted by at least one same or different (C1-C4) alkyl or halogen.

5. The biaryl oxazolidinone compound according to claim 3, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine; X is N; R 4 For-OR 7 、-NHR 8 or 5-membered heteroaryl, the heteroaryl being optionally substituted by 0-3 identical or different R 9 replace; R 7 is hydrogen, (C1-C4) alkylsulfonyl, 5-membered heteroaryl, the heteroaryl being optionally substituted by 0-3 identical or different R 10 replace; R 8 is hydrogen, (C3-C5) cycloalkylsulfonyl, 5-membered heteroaryl, the heteroaryl being optionally substituted by 0-3 identical or different R 11 replace; R 5 and R 6 The same or different, each independently selected from (C1-C4) alkyl; or R 5 and R 6 Together with the nitrogen atom to which they are attached, they form a 6-membered heterocyclic group. 5 and R 6 In addition to the nitrogen atom to which it is attached, it optionally contains 0-1 heteroatoms selected from N, O and / or S, and the heterocyclic group is optionally substituted with 0-2 oxo groups and / or 0-1 identical or different R 13 replace; R 9 、R 10 、R 11 and R 13 Independently selected from hydrogen, halogen, cyano, (C1-C4) alkyl, amino substituted by at least one (C1-C4 alkyl), (C1-C4) alkylsulfonyl, (C1-C4) alkylacyl substituted by at least one same or different hydroxyl, amino or halogen, carbamoyl unsubstituted or substituted by at least one (C1-C4 alkyl), (C3-C6) heterocyclyl unsubstituted or substituted by at least one C1-C6 alkyl.

6. The biaryl oxazolidinone compound according to claim 5, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine; X is N; R 4 For-OR 7 、-NHR 8 or triazole; R 7 is hydrogen, (C1-C4)alkylsulfonyl, isoxazol-3-yl; R 8 is hydrogen, (C3-C5)cycloalkylsulfonyl, isoxazol-3-yl; R 5 and R 6 The same or different, each independently selected from (C1-C4) alkyl; or R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form 7. The biaryl oxazolidinone compound according to claim 6, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine; X is N; R 4 is a triazole group; R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form 8. The biaryl oxazolidinone compound according to claim 7, characterized in that: The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein: R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine; X is N; R 4 is a triazole group; R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form 9. The biaryl oxazolidinone compound according to claim 1, wherein the compound is selected from the following compounds and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof: (R,E)-3-[3-Fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-[3-Fluorophenyl-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3-yl)]-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(thiomorpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(aminoacyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(N,N-diformyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(2-hydroxyacetyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(pyrrolidin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(dimethylamino)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(morpholin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{3-fluoro-4-[6-({[4-(1,4'-bipiperidinyl)-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5-(mesylatemethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methoxymethyl)oxazolidin-2-one (S,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(aminomethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methanesulfonamidomethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(cyclopropanesulfonamidomethyl)oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (S,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(5-methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(isoxazol-3-yl)oxy]methyl}oxazolidin-2-one (R,E)-3-[3-Fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-{3-Fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(3-Fluoro-4-{6-[(2-isopropylhydrazinyl)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(2,3,5-trifluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one (R,E)-3-(2,3-Difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-[2,3-Fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-{2,3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(2,3-fluoro-4-{6-[(2-isopropylhydrazinyl)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (S,E)-3-[2,3-Fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one (S,E)-3-(2,3-Difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one (S,E)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one (S,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one (R,E)-3-(2,3-Difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(5-methylisoxazol-3-yl)amino]methyl}oxazolidin-2-one (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(4-carbonitrile)-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-[3,5-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(3,5-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-{3,5-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (R,E)-3-(3,5-difluoro-4-{6-[(2-isopropylhydrazinyl)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one.

10. The biaryl oxazolidinone compound according to any one of claims 1 to 9, characterized in that: The pharmaceutically acceptable salt of the compound is a salt formed by the compound of the general formula and an acid, wherein the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid or aspartic acid.

11. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 10, and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

12. Use of a compound of formula I according to any one of claims 1 to 10, its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, or the composition according to claim 11 in the preparation of a medicament for treating microbial infection.

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