Biaryl oxazolidinone compound and application thereof

Abstract

The invention relates to the field of medicinal chemistry, in particular to a biaryl oxazolidinone compound and application thereof. The invention relates to a biaryl oxazolidinone compound, which is a compound as shown in a general formula I, and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof. The compound provided by the invention has better antibacterial activity than linezolid, and has remarkable antibacterial activity on drug-resistant bacteria. Meanwhile, compared with linezolid, the compound has lower MAO inhibition and better safety.

Description

Technical field:

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

[0002] Through continuous evolution and mutation, bacteria render drugs used to treat bacterial infections ineffective, leading to the development of antimicrobial resistance. In recent years, with the overuse and even abuse of antimicrobial drugs, an increasing number of bacteria have evolved from drug-sensitive bacteria to superbugs resistant to multiple antimicrobials, posing a significant threat to clinical treatment. By addressing the mechanisms and transmission pathways of bacterial resistance, the development of new drugs targeting multidrug-resistant (MDR) bacteria is urgently needed.

[0003] Oxazolidinone antibiotics are a novel class of fully synthetic antimicrobial drugs, following the sulfonamide and quinolone classes. They are clinically used primarily to treat drug-resistant Gram-positive bacterial infections, exhibiting excellent antimicrobial activity against resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), and multidrug-resistant Mycobacterium tuberculosis (MDR-TB). Compared to other antimicrobial drugs, oxazolidinone antibiotics exert their antimicrobial effects by specifically binding to the 50S large ribosome subunit near the 30S small subunit, hindering the formation of the 70S initiation complex and thereby inhibiting protein synthesis. Due to their unique chemical structure and mechanism of action, these drugs are less likely to induce bacterial resistance and exhibit no cross-resistance to other clinically used antimicrobial drugs.

[0004]

[0005] Linezolid was approved by the FDA in April 2000 for the treatment of Gram-positive bacteria. Despite its significant antibacterial activity, long-term clinical use has inevitably led to the emergence of linezolid-resistant strains. Its use is also limited by its toxicity, primarily manifested by bone marrow suppression and monoamine oxidase (MAO) inhibition. Bone marrow suppression is directly related to linezolid's mode of action, with symptoms primarily including thrombocytopenia, leukopenia, pancytopenia, and anemia. MAO inhibition may lead to serotonin syndrome, characterized by altered mental status (irritability, hallucinations), increased autonomic excitability (rapid heart rate, elevated blood pressure, elevated body temperature, nausea, vomiting, diarrhea, hyperreflexia), and neuromuscular abnormalities.

[0006] Tedizolid phosphate was approved by the US FDA in June 2014, becoming the second oxazolidinone antibiotic to be marketed after linezolid. It is used to treat acute bacterial skin and soft tissue infections in adults caused by susceptible bacteria. Tedizolid phosphate does not significantly improve toxicity compared to linezolid.

[0007] In the patent application for biarylhydrazone oxazolidinone compounds (CN107721943A) filed by the inventors in the early stage, the compounds involved had significant antibacterial activity against a variety of drug-resistant bacteria. However, in later studies, it was found that some compounds had low bioavailability. For example, in Example 35, its AUC in rats was 0-t The drugability is only 379 ng·h / mL, which is poor. Further modification of this will yield a series of compounds that not only improve bioavailability but also reduce the inhibitory effect of the compound on MAO, thereby reducing toxicity. Summary of the invention:

[0008] The primary purpose of the present invention is to provide novel compounds of formula I that can be used as antibacterial agents. In particular, the present invention also relates to methods for preparing such compounds, compositions containing such compounds, and their use as antibacterial agents in the preparation and treatment of infectious diseases.

[0009] To achieve the above purpose, the present invention adopts the following technical solutions:

[0010] A biaryl oxazolidinone compound, which is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs,

[0011]

[0012] I

[0013] in,

[0014] 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;

[0015] X is CH or N;

[0016] 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;

[0017] R 7is 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;

[0018] 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;

[0019] 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;

[0020] 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;

[0021] 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.

[0022] Preferably, the compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0023] 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;

[0024] X is CH or N;

[0025] 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;

[0026] 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;

[0027] 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;

[0028] 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;

[0029] 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;

[0030] R 9 、R 10 、R 11 、R 12 and R 13Independently 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.

[0031] More preferably, the compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0032] 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;

[0033] X is CH or N;

[0034] 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;

[0035] 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;

[0036] 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;

[0037] R 5 and R 6 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl;

[0038] 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 R6 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;

[0039] 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.

[0040] Still further preferably, the compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0041] R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine;

[0042] X is N;

[0043] 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;

[0044] 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;

[0045] 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;

[0046] R 5 and R6 are the same or different and are independently selected from hydrogen, (C1-C4) alkyl;

[0047] 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;

[0048] 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.

[0049] More preferably, the compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0050] R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine;

[0051] X is N;

[0052] 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;

[0053] R 7 is hydrogen, (C1-C4) alkylsulfonyl, 5-membered heteroaryl, the heteroaryl being optionally substituted by 0-3 identical or different R 10 replace;

[0054] R 8 is hydrogen, (C3-C5) cycloalkylsulfonyl, 5-membered heteroaryl, the heteroaryl being optionally substituted by 0-3 identical or different R11 replace;

[0055] R 5 and R 6 The same or different, each independently selected from (C1-C4) alkyl;

[0056] 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;

[0057] 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.

[0058] Still further preferably, the compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0059] R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine;

[0060] X is N;

[0061] R 4 For-OR 7 、-NHR 8 or triazole;

[0062] R 7 is hydrogen, (C1-C4)alkylsulfonyl, isoxazol-3-yl;

[0063] R 8 is hydrogen, (C3-C5)cycloalkylsulfonyl, isoxazol-3-yl;

[0064] R 5 and R 6 The same or different, each independently selected from (C1-C4) alkyl;

[0065] or R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form

[0066] Still further preferably, the compound is a compound of formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0067] R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine;

[0068] X is N;

[0069] R 4 is a triazole group;

[0070] R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form

[0071] The compound is a compound of general formula I and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs, wherein:

[0072] R 1 is fluorine, R 2 and R 3 are independently selected from hydrogen and fluorine;

[0073] X is N;

[0074] R 4 is a triazole group;

[0075] R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form

[0076] The compound of general formula I according to claim 1 and its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof:

[0077] (R,E)-3-[3-Fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0078] (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0079] (R,E)-3-[3-Fluorophenyl-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3-yl)]-5-(hydroxymethyl)oxazolidin-2-one

[0080] (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0081] (R,E)-3-(3-Fluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0082] (R,E)-3-(3-Fluoro-4-{6-[(thiomorpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0083] (R,E)-3-{3-fluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0084] (R,E)-3-{3-fluoro-4-[6-({[4-(aminoacyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0085] (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

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

[0087] (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

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

[0089] (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

[0090] (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

[0091] (R,E)-3-{3-fluoro-4-[6-({[4-(1,4'-bipiperidinyl)-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

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

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

[0094] (S,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(aminomethyl)oxazolidin-2-one

[0095] (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methanesulfonamidomethyl)oxazolidin-2-one

[0096] (R,E)-3-(3-Fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(cyclopropanesulfonamidomethyl)oxazolidin-2-one

[0097] (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

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

[0099] (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

[0100] (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

[0101] (R,E)-3-(3-Fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(isoxazol-3-yl)oxy]methyl}oxazolidin-2-one

[0102] (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

[0103] (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

[0104] (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

[0105] (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

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

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

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

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

[0110] (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

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

[0112] (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

[0113] (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0114] (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

[0115] (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

[0116] (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

[0117] (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

[0118] (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

[0119] (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

[0120] (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

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

[0122] (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

[0123] (S,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

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

[0125] (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

[0126] (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

[0127] The present invention also includes solvates of the compound of formula I, such as ethanol, water, etc., which may contain different amounts of water, such as monohydrate, hemihydrate, dihydrate or trihydrate.

[0128] According to some common methods in the field of the present invention, the compound of formula I of the present invention can be reacted with an acid to form a pharmaceutically acceptable salt thereof. The acid can include an inorganic acid or an organic acid, and 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.

[0129] The present invention also includes prodrugs of the compounds of formula I. According to the present invention, prodrugs are derivatives of the compounds of formula I, which themselves may have weak activity or even no activity, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0130] The present invention also includes racemates, optically active isomers, polymorphs, or mixtures thereof of compounds of Formula I, which possess the useful properties described herein. Compounds of Formula I of the present invention contain a chiral center (C-5 position of the oxazolidinone ring) and thus exist as two enantiomers or racemic mixtures thereof. The present invention also encompasses both enantiomers and mixtures containing both enantiomers that possess useful properties.

[0131] Unless otherwise indicated, the term "alkyl" as used in the present invention refers to a straight-chain or branched alkyl group; "alkoxy" refers to a straight-chain or branched alkoxy group; "alkenyl" refers to a straight-chain or branched alkenyl group; "alkynyl" refers to a straight-chain or branched alkynyl group; 5-10 membered heteroaryl includes one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, and the ring system is aromatic, containing 5-10 atoms in total, and examples thereof include pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolinyl, indolyl, naphthyl and the like.

[0132] The present invention also includes pharmaceutical compositions comprising compounds of formula I and their pharmaceutically acceptable salts and / or solvates as active ingredients and pharmaceutically acceptable carriers; the compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0133] The carriers used in the pharmaceutical compositions of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0134] The present invention also includes its use in the preparation of a medicament for treating microbial, particularly bacterial, infections in mammals. The method of use comprises administering an effective amount of a compound of formula I to a mammal in a pharmaceutical composition, which can be administered orally, parenterally, transdermally, or topically.

[0135] The oxazolidinone compounds of the general formula I of the present invention have antimicrobial activity, particularly antibacterial activity. Further, the oxazolidinone compounds of the general formula I of the present invention can exhibit potent antibacterial activity against human and animal pathogens, including Gram-positive bacteria such as Staphylococcus, Enterococcus, and Streptococcus, and anaerobic bacteria such as Bacteroides fragilis and Mycobacterium tuberculosis. Therefore, they can be used to prepare medicaments for treating bacterial infections in mammals. The compounds according to the present invention can be used as active ingredients in preparing methods for treating bacterial infections in mammals, comprising administering a therapeutically effective amount of the compounds according to the present invention to a patient suffering from or susceptible to the disease.

[0136] The exact amount of the compound of the present invention required to treat microbial, particularly bacterial, infections will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the disease being treated, the specific compound used and the mode of administration, such as the route and frequency of administration, etc. An appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

[0137] The compound can be administered in an amount of 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 dosage may vary depending on the patient's needs, the severity of the bacterial infection being treated, and the specific compound being used. Furthermore, it will be appreciated that the initial dose administered may be increased beyond the upper limit in order to quickly reach the desired blood level, or the initial dose may be less than the optimal value, and the daily dose may be gradually increased during treatment, depending on the specific circumstances. If desired, the daily dose may also be administered in multiple doses, for example 2-4 times per day.

[0138] Mammal means a human or an animal.

[0139] The amount of active ingredient, i.e., the compound according to the present invention, in the pharmaceutical composition and its unit dosage form can vary depending on the specific application, the potency of the specific compound and the desired concentration. Generally speaking, the active ingredient content will be between 0.5% and 90% by weight of the total weight of the composition.

[0140] In combination therapy, the compound of the present invention and the other compound may be administered simultaneously or intermittently. When administered simultaneously, the compound of the present invention and the other compound may be combined in a single pharmaceutical composition or in separate compositions.

[0141] The following synthetic routes A, B, C, D, and E describe the preparation of the general formula I of the present invention. All starting materials are prepared by the methods described in these synthetic routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these synthetic routes or by methods similar thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these synthetic routes are as defined below or as defined in the claims.

[0142] According to the compound of formula I of the present invention, in route A, route B, route C, route D and route E, the following compound is exemplified: 1 、R 2 、R 3 、R 5 、R 6 、R 8 、R 9 、R 10 、R 11 The definition is the same as that in the claims.

[0143] When R 3 is hydrogen, R 4 For-OR 7 , R 7 When H is present, some compounds represented by the general formula I are synthesized according to route A.

[0144]

[0145] Route A, take R 1 、R 2 Substituted aniline is used as a starting material, and intermediate A4 is prepared through acylation, cyclization, and iodination. 5-Bromo-2-pyridinecarboxaldehyde, another starting material, is reacted with biboronic acid pinacol ester via a Miyaura reaction to prepare intermediate A6. Intermediate A4 and intermediate A6 undergo a Suzuki reaction to prepare intermediate A7. Intermediate A7 is then reacted with various substituted amines to prepare some compounds (Ii) represented by general formula I.

[0146] When R 2 is hydrogen, R 4 For-OR 7 , R 7 H, R 2 and R 3 When fluorine is present, some compounds represented by the general formula I are synthesized according to route B.

[0147]

[0148] In Route B, 2,3-difluoroaniline is used as the starting material, and intermediate B4 is prepared through bromination, acylation, and cyclization. Intermediate B4 and intermediate A6 are then reacted with Suzuki reaction to produce intermediate B6. Intermediate B6 is then reacted with various substituted amines to produce some compounds (I-ii) represented by general formula I.

[0149] When R 4 For-OR 7 , R 7 H, R 1 、R 2 and R 3 When fluorine is present, some compounds represented by the general formula I are synthesized according to route C.

[0150]

[0151] In Route C, 2,3,5-trifluoroaniline is used as the starting material to obtain intermediate C7 through acylation, iodination, Suzuki reaction, condensation, cyclization, and deprotection. Intermediate C7 is then reacted with various substituted amines to produce some compounds (I-iii) represented by Formula I.

[0152] When R 4 NHR 8 When the compound of formula I is synthesized according to route D

[0153]

[0154] In Route D, starting from D1, intermediate D4 is obtained through sulfonation, substitution, reduction, and acylation. Intermediate D4 is reacted with various substituted sulfonyl chlorides to obtain some compounds (I-iv) of Formula I.

[0155] When R 4 When it is 1,2,3-triazole-1-yl, some compounds represented by the general formula I are synthesized according to route E.

[0156]

[0157] In Route E, D3 is used as the starting material to obtain a partial compound (Iv) represented by Formula I through cyclization reaction and deprotection reaction.

[0158] When R 4 NHR 8 When the compound of formula I is synthesized according to route F

[0159]

[0160] In route F, intermediate D2 undergoes substitution reaction and deprotection reaction to produce a partial compound (I-vi) represented by general formula I. Specific implementation method:

[0161] The following examples describe methods for preparing some of the compounds described. It should be understood that the following methods, as well as other methods known to those skilled in the art, are applicable to the preparation of all compounds described herein. The examples are intended to illustrate, not to limit, the scope of the invention. H NMR spectra of the compounds were measured using a Bruker ARX-300, and mass spectra were measured using an Agilent 1100 LC / MSD. All reagents used were of analytical or chemical grade.

[0162] 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

[0163] 1.1 Preparation of benzyl (3-fluorophenyl)carbamate (A2)

[0164] Under an ice bath, add 45.0 g (0.40 mol) of m-fluoroaniline and 68.1 g (0.80 mol) of sodium bicarbonate to 200 mL of tetrahydrofuran. Control the temperature at 0-5°C. Add 68.5 mL (0.48 mol) of benzyl chloroformate dropwise to the reaction solution. Allow to react at room temperature for 2 h. After the reaction, add the reaction solution to 200 mL of ice water and stir for 0.5 h. Extract with ethyl acetate (150 mL x 2). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 75.7 g of a light red solid (76.2% yield).

[0165] 1. Preparation of 2(R)-3-(3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (A3)

[0166] At room temperature, 75.0 g (0.31 mol) of intermediate A2 was added to 400 mL of dry tetrahydrofuran. At -78°C, under nitrogen protection, 135 mL (0.34 mol) of 2.5 M n-butyl lithium was slowly added dropwise to the reaction solution. The mixture was stirred for 0.5 h. 47 mL (0.34 mol) of (R)-(-)-glycidyl butyrate was slowly added dropwise to the reaction solution. The mixture was stirred for 2 h and then heated to room temperature for 12 h. After the reaction, the reaction solution was cooled to 0-5°C, and 200 mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction solution, and the dropping rate was controlled to keep the temperature below 10°C. After the dropwise addition, the mixture was stirred at 0-5°C for 1 h, extracted with ethyl acetate (200 mL × 2), and the organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 51.4 g of a white solid with a yield of 79.5%.

[0167] 1. Preparation of 3(R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)oxazolidin-2-one (A4)

[0168] 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 elemental iodine were added sequentially to 250 mL of acetonitrile. The reaction was allowed to proceed in the dark for 12 h at room temperature. After completion of the reaction, 100 mL of 5% sodium thiosulfate solution was added to precipitate a white solid. The solid was filtered with suction, and the filter cake was rinsed with ethyl acetate. The filtrate was collected and extracted with ethyl acetate (150 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain 68.1 g of a white solid (85.3% yield).

[0169] 1.4 Preparation of 2-Formylpyridine-5-boronic acid pinacol ester (A6)

[0170] At room temperature, 10.0 g (53.8 mmol) of 5-bromopyridine-2-carboxaldehyde, 20.5 g (80.7 mmol) of pinacol diboronate, and 15.8 g (161 mmol) of potassium acetate were added sequentially to 150 mL of dry tetrahydrofuran. After addition, the mixture was degassed and, under nitrogen, 2.5 g (2.7 mmol) of Pd2(dba)3 and 2.6 g (5.4 mmol) of X-Phos were added to the reaction mixture. After addition, the mixture was heated to reflux and reacted for 4 h. After the reaction, the mixture was filtered through a pad of celite. The filter cake was rinsed with 50 mL of ethyl acetate and the filtrate was evaporated to dryness under reduced pressure to obtain a yellow oil, which was used directly in the next step without purification.

[0171] 1. Preparation of 5-(R)-5-{2-fluoro-4-[5-(hydroxymethyl)-2-oxooxazolidin-3-yl]phenyl}pyridinecarboxaldehyde (A7)

[0172] At room temperature, 15.0 g (44.5 mmol) of Intermediate A4, Intermediate A6, and 15.0 g (109 mmol) of potassium carbonate were added sequentially to 100 mL of 1,4-dioxane and 25 mL of water. After the addition was complete, the mixture was degassed and, under nitrogen, 2.0 g (2.7 mmol) of Pd(dppf)Cl2 was added to the reaction solution. The temperature was raised to 80°C and the reaction was allowed to react for 4 h. After the reaction, 100 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (100 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain a yellow oil, which was purified by column chromatography to yield 9.8 g of a yellow solid (69.8% yield).

[0173] 1. Preparation of 6(R,E)-3-[3-fluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0174] At room temperature, 0.06 g (0.19 mmol) of intermediate A7 and 0.03 g (0.26 mmol) of 1-amino-4-methylpiperazine were added to 1.0 mL of ethanol. The mixture was heated to reflux and reacted for 0.5 h. A solid precipitated, which was filtered and dried in an oven at 40°C for 24 h to yield 0.06 g of a white solid (80.2% yield).

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

[0176] (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using N-aminomorpholine as the starting material according to the synthesis method of 1.6 in Example 1. The yield was 76.3%.

[0177] Example 3 Preparation of (R,E)-3-[3-fluorophenyl-4-(6-{[(1,1-dioxythiomorpholin-4-yl)imino]methyl}pyridin-3-yl)]-5-(hydroxymethyl)oxazolidin-2-one

[0178] (R,E)-3-[3-fluorophenyl-4-(6-{[(1,1-dioxythiomorpholin-4-yl)imino]methyl}pyridin-3-yl)]-5-(hydroxymethyl)oxazolidin-2-one was synthesized using 4-aminothiomorpholine-1,1-dioxide as the starting material according to the method described in step 1.6 of Example 1. The yield was 77.6%.

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

[0180] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using N-aminopiperidine according to the synthesis method of 1.6 in Example 1. The yield was 63.4%.

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

[0182] (R,E)-3-(3-fluoro-4-{6-[(2-isopropylhydrazine)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using isopropylhydrazine hydrochloride as the starting material according to the synthesis method of 1.6 in Example 1. The yield was 69.1%.

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

[0184] (R,E)-3-(3-fluoro-4-{6-[(thiomorpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using 4-thiomorpholinamine according to the method described in step 1.6 of Example 1. The yield was 57.2%.

[0185] 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

[0186] (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 using 4-(methylsulfonyl)-1-piperazinamine according to the method described in Step 1.6 of Example 1. The yield was 62.1%.

[0187] 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

[0188] (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 using 4-aminopiperazine-1-carboxamide according to the method described in Step 1.6 of Example 1. The yield was 46.3%.

[0189] Example 9 Preparation of (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

[0190] (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 was synthesized using 4-amino-N,N-dimethylpiperazine-1-carboxamide according to the method described in Step 1.6 of Example 1. The yield was 76.3%.

[0191] 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

[0192] (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 using 1-(4-aminopiperazin-1-yl)-2-hydroxyethane-1-one according to the method described in Section 1.6 of Example 1. The yield was 72.4%.

[0193] 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

[0194] (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 was synthesized using 4-(pyrrolidin-1-yl)piperidin-1-amine according to the method described in Section 1.6 of Example 1. The yield was 56.9%.

[0195] 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

[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 using 4-(dimethylamino)piperidin-1-amine according to the method described in step 1.6 of Example 1. The yield was 63.7%.

[0197] 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

[0198] (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 was synthesized using 4-(morpholin-1-yl)piperidin-1-amine according to the method described in Step 1.6 of Example 1. The yield was 54.8%.

[0199] 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

[0200] (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 was synthesized using 4-(4-methylpiperazin-1-yl)piperidin-1-amine according to the method described in Step 1.6 of Example 1. The yield was 76.1%.

[0201] Example 15 Preparation of (R,E)-3-{3-fluoro-4-[6-({[4-(1,4'-bipiperidinyl)-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0202] (R,E)-3-{3-fluoro-4-[6-({[4-(1,4'-bipiperidin-1-yl)piperidin-1-amine]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one was synthesized using 4-(4-piperidin-1-yl)piperidin-1-amine according to the method described in step 1.6 of Example 1. The yield was 71.2%.

[0203] Example 16 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5-(methanesulfonatemethyl)oxazolidin-2-one

[0204] At room temperature, 0.1 g (0.25 mmol) of Example 4 and 0.05 g (0.50 mmol) of triethylamine were added to 2 mL of dichloromethane. In an ice bath, 0.04 g (0.38 mmol) of methanesulfonyl chloride was added dropwise to the reaction solution, maintaining the temperature below 5°C, and the reaction was continued for 2 h. After completion, 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 obtain (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylamino)methyl]pyridin-3-yl}phenyl)-5-(mesylatemethyl)oxazolidin-2-one. The yield was 56.7%.

[0205] Example 17 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methoxymethyl)oxazolidin-2-one

[0206] In an ice bath, 0.08 g (0.17 mmol) of Example 16 and 0.006 g (0.30 mmol) of sodium lumps were added to 3 mL of methanol, maintained below 5°C, and the reaction continued for 2 hours. After completion, 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 obtain (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methoxymethyl)oxazolidin-2-one. The yield was 63.7%.

[0207] Example 18 Preparation of (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(aminomethyl)oxazolidin-2-one

[0208] 18.1 Preparation of (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(azido)oxazolidin-2-one (D3)

[0209] 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 the reaction was allowed to proceed for 6 h. After the reaction, the reaction solution was poured into 90 mL of water. A solid precipitated, which was 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%.

[0210] 18.2 Preparation of (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(aminomethyl)oxazolidin-2-one

[0211] 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 completion of the reaction, the mixture was filtered through a pad of celite, and the filter cake was rinsed with 3 mL of ethyl acetate. The filtrate was evaporated to dryness under reduced pressure and purified by column chromatography to obtain (S,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(aminomethyl)oxazolidin-2-one in a yield of 61.2%.

[0212] Example 19 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methanesulfonamidomethyl)oxazolidin-2-one

[0213] 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. In an ice bath, 0.04 g (0.35 mmol) of methanesulfonyl chloride was added dropwise to the reaction solution, maintaining the temperature below 5°C, and the reaction was continued for 2 h. After completion, 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 obtain (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(methylsulfonamidomethyl)oxazolidin-2-one. The yield was 45.6%.

[0214] Example 20 Preparation of (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(cyclopropanesulfonamidomethyl)oxazolidin-2-one

[0215] (R,E)-3-(3-fluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(cyclopropylsulfonamidomethyl)oxazolidin-2-one was synthesized using cyclopropylsulfonyl chloride as the starting material according to the method of Example 19. The yield was 78.3%.

[0216] Example 21 Preparation of (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

[0217] Using Example 2 as the raw material, the key intermediate D3 was synthesized according to the synthesis method in Example 18.

[0218] 21.1 Preparation of (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]methyl}oxazolidin-2-one (E1)

[0219] At room temperature, 1.0 g (2.35 mmol) of intermediate D3 and 1.2 g (11.8 mmol) of trimethylsilyl acetylene were added to 10 mL of DMF. After addition, the temperature was raised to 90°C and the reaction was continued for 12 h. After completion of the reaction, the reaction solution was added to 30 mL of ice water and stirred for 0.5 h. A solid precipitated, which was filtered and dried in an oven at 40°C for 24 h to yield 1.0 g of a white solid (81.3% yield).

[0220] 21.2 Preparation of (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

[0221] At room temperature, 0.1 g (69.0 mmol) of intermediate E1 and 1 mL of glacial acetic acid were added to a solution of 5 mL (69.0 mmol) of 1M TBAF in tetrahydrofuran. The reaction was continued at room temperature for 3 h. After the reaction, the solvent was evaporated, and 5 mL of water was added to the residue. Stirring was continued at room temperature for 0.5 h. Filtration afforded a yellow solid, which was purified by column chromatography to afford (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. The yield was 67.7%.

[0222] Example 22 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] Using Example 2 as the raw material, the key intermediate D2 was synthesized according to the synthesis method in Example 19.

[0224] 22.1 Preparation of (S,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(3-tert-butylcarbamate-isoxazol-3-yl)methyl]oxazolidin-2-one (F1)

[0225] 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-cooling. After the addition, the temperature was raised to 35°C and stirring was continued for 0.5 h. Then, a solution of 0.1 g (0.42 mmol) of tert-butyl N-3-isoxazolecarbamate in N,N-dimethylformamide was slowly added dropwise to the reaction solution. After the addition, the temperature was raised to 50°C and the reaction was continued for 5 h. After the reaction, the reaction solution was added to 5 mL of ice water and stirred for 0.5 h. Solid precipitated, which was filtered and 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%.

[0226] 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

[0227] At room temperature, 0.2 g (0.35 mmol) of intermediate F1 was added to dichloromethane. 1 mL of trifluoroacetic acid was slowly added dropwise to the reaction mixture under an ice bath. After addition, the mixture was warmed to room temperature and the reaction continued for 2 h. After completion of the reaction, the solvent was evaporated, and 3 mL of water was added to the residue. The pH was adjusted to 12 with 4 M aqueous sodium hydroxide. A solid precipitated and was filtered to obtain a white solid. This solid was purified by column chromatography to afford (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%.

[0228] 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

[0229] (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 according to the methods described in 22.1-22.2 of Example 22. The yield was 51.9%.

[0230] Example 24 Preparation of (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

[0231] Using Example 2 as the raw material, the key intermediate D3 was synthesized according to the synthesis method in Example 18.

[0232] At room temperature, 0.15 g (0.35 mmol) of intermediate D3 and 0.06 g (0.70 mmol) of 2-chloroacrylonitrile were added to 2 mL of N,N-dimethylformamide. After addition, the mixture was heated to 95°C and allowed to react for 9 h. After completion of the reaction, the reaction solution 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 obtain (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 in a yield of 40.7%.

[0233] 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

[0234] At room temperature, 0.13 g (0.50 mmol) of triphenylphosphine and 0.10 g (0.50 mmol) of diisopropyl azodicarboxylate were added sequentially to 2 mL of dry tetrahydrofuran and stirred at room temperature for 5 minutes. Then, 0.04 g (0.50 mmol) of 2-hydroxyisoxazole was added to the reaction solution. Stirring was continued for 5 minutes, followed by 0.15 g (0.37 mmol) of Example 2. The reaction was continued at room temperature for 12 hours. After completion of the reaction, the reaction solution 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 obtain (R,E)-3-(3-fluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-{[(isoxazol-3-yl)oxy]methyl}oxazolidin-2-one. The yield was 32.8%.

[0235] 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

[0236] Using Example 1 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, and key intermediate D3 was synthesized according to the synthesis method of 18.1 in Example 18. Then, (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 synthesis methods of 21.1-21.2 in Example 21. The yield was 60.4%.

[0237] 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

[0238] Using Example 4 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method of 18.1 in Example 18 to synthesize key intermediate D3, and then followed the synthesis methods of 21.1-21.2 in Example 21 to synthesize (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. The yield was 56.3%.

[0239] 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

[0240] Using Example 7 as starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16. Key intermediate D3 was then synthesized according to the synthesis method of 18.1 in Example 18. (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 then synthesized according to the synthesis methods of 21.1-21.2 in Example 21. The yield was 47.8%.

[0241] Example 29 Preparation of (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

[0242] Using Example 5 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, and key intermediate D3 was synthesized according to the synthesis method of 18.1 in Example 18. Then, (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 was synthesized according to the synthesis methods of 21.1-21.2 in Example 21. The yield was 67.3%.

[0243] 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

[0244] (R,E)-3-(3,5-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using 3,5-difluoroaniline as the starting material according to the synthesis methods of 1.1-1.6 in Example 1. The yield was 43.7%.

[0245] 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

[0246] 31.1 Preparation of 2,3-difluoro-4-bromoaniline (B2)

[0247] At room temperature, 50.0 g (0.39 mol) of 2,3-difluoroaniline was added to 250 mL of N,N-dimethylformamide. In an ice bath, 69.0 g (0.39 mol) of N-bromosuccinimide was added to the reaction solution in five portions. The temperature was maintained below 5°C and the reaction was continued for 2 hours. After completion, the reaction solution was poured into 250 mL of water and extracted with ethyl acetate (200 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 64.3 g of a yellow solid, with a yield of 80.2%.

[0248] 31.2 Preparation of Benzyl (2,3-Difluoro-4-bromophenyl)carbamate (B3)

[0249] Under an ice bath, 60.0 g (0.29 mol) of intermediate B2 and 23.2 g (0.58 mol) of sodium hydroxide were added to 500 mL of tetrahydrofuran. The temperature was controlled at 0-5°C, and 61 mL (0.44 mol) of benzyl chloroformate was added dropwise to the reaction solution. The reaction was allowed to react at room temperature for 2 h. After the reaction, the reaction solution was added to 500 mL of ice water and stirred for 0.5 h. The mixture was extracted with ethyl acetate (300 mL x 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 88.8 g of a white solid with a yield of 89.8%.

[0250] 31. Preparation of 3(R)-3-(2,3-difluoro-4-bromophenyl)-5-(hydroxymethyl)oxazolidin-2-one (B4)

[0251] At room temperature, 70.0 g (0.21 mol) of intermediate B3 was added to 500 mL of dry tetrahydrofuran. At -78°C, under nitrogen protection, 38 mL (0.27 mol) of 2.5 M n-butyl lithium was slowly added dropwise to the reaction solution. The mixture was stirred for 0.5 h. 108 mL (0.27 mol) of (R)-(-)-glycidyl butyrate was slowly added dropwise to the reaction solution. The mixture was stirred for 2 h and then heated to room temperature for 12 h. After the reaction, the reaction solution was cooled to 0-5°C, 300 mL of saturated aqueous ammonium chloride solution was added dropwise to the reaction solution, and the addition rate was controlled to keep the temperature below 10°C. After the addition was completed, the solution was stirred at 0-5°C for 1 h, extracted with ethyl acetate (300 mL × 2), and the organic phases were combined, washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 52.0 g of a white solid with a yield of 82.5%.

[0252] 31. Preparation of 4(R)-5-{2,3-difluoro-4-[5-(hydroxymethyl)-2-oxooxazolidin-3-yl]phenyl}pyridinecarboxaldehyde (B6)

[0253] 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 added sequentially to 200 mL of 1,4-dioxane and 50 mL of water. After the addition was complete, the mixture was degassed and, under nitrogen, 6.9 g (9.5 mmol) of Pd(dppf)Cl2 and 9.0 g (18.9 mmol) of X-Phos were added to the reaction solution. After the addition was complete, the temperature was raised to 80°C and the reaction was allowed to react for 4 h. After the reaction was completed, 100 mL of water was added to the reaction solution, which was extracted with ethyl acetate (200 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain a yellow oil, which was purified by column chromatography to obtain 31.5 g of a yellow solid in a yield of 72.4%.

[0254] 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

[0255] At room temperature, 0.1 g (0.30 mmol) of intermediate B6 and 0.04 g (0.33 mmol) of N-aminomorpholine were added to 1.0 mL of ethanol. The mixture was heated to reflux and reacted for 0.5 h. A solid precipitated, which was filtered and dried in an oven at 40°C for 24 h to yield 0.09 g of a white solid (75.4% yield).

[0256] 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

[0257] 32.1 Preparation of Benzyl (2,3,5-Trifluorophenyl)carbamate (C2)

[0258] Under an ice bath, add 5.0 g (34.0 mmol) of 2,3,5-trifluoroaniline and 5.8 g (69.0 mmol) of sodium bicarbonate to 50 mL of tetrahydrofuran. Control the temperature between 0 and 5°C. Add 5.8 mL (41.2 mmol) of benzyl chloroformate dropwise to the reaction solution. Allow to react at room temperature for 2 h. After the reaction, add 50 mL of ice water and stir for 0.5 h. Extract with ethyl acetate (25 mL x 2). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain 8.2 g of a white solid (85.5% yield).

[0259] 32.2 Preparation of Benzyl (2,3,5-Trifluoro-4-iodophenyl)carbamate (C3)

[0260] 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 added sequentially to 50 mL of acetonitrile. The reaction was allowed to proceed in the dark for 12 h at room temperature. After completion of the reaction, 50 mL of 5% sodium thiosulfate solution was added to precipitate a white solid. The solid was filtered and the filter cake was rinsed with ethyl acetate. The filtrate was collected and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 7.7 g of a white solid (70.4% yield).

[0261] 32.3 Preparation of Benzyl [2,3,5-Trifluoro-4-(6-formylpyridin-3-yl)phenyl]carbamate (C4)

[0262] 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 sequentially to 60 mL of 1,4-dioxane and 15 mL of water. After the addition was complete, the mixture was degassed and, under nitrogen, 0.78 g (1.1 mmol) of Pd(dppf)Cl2 was added to the reaction solution. After the addition was complete, the temperature was raised to 80°C and the reaction was allowed to react for 4 h. After the reaction was complete, 20 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (50 mL x 2). The organic phases were combined and concentrated under reduced pressure to obtain a yellow oil, which was purified by column chromatography to obtain 4.4 g of a white solid in a 69.7% yield.

[0263] 32.4 Preparation of Benzyl {2,3,5-trifluoro-4-[6-(1,3-dioxolan-2-yl)pyridin-3-yl]phenyl}carbamate (C5)

[0264] 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 sequentially to 40 mL of toluene. After the addition was complete, the temperature was raised to 110°C and the reaction was allowed to proceed for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 50 mL of ethyl acetate was added to the residue. The organic phase was washed with saturated sodium bicarbonate solution (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 3.2 g of a yellow solid (yield 72.7%).

[0265] 32.5 Preparation of (R)-3-{2,3,5-trifluoro-4-[6-(1,3-dioxolane-2-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one (C6)

[0266] At room temperature, 3.2 g (7.4 mmol) of intermediate C5 was added to 30 mL of dry tetrahydrofuran. At -78°C, under nitrogen, 3.3 mL (8.2 mmol) of 2.5 M n-butyl lithium was slowly added dropwise to the reaction solution. The mixture was stirred for 0.5 h. 1.2 mL (8.2 mmol) of (R)-(-)-glycidyl butyrate was slowly added dropwise to the reaction solution. Stirring was continued for 2 h after the addition, and the temperature was raised to room temperature for 12 h. After the reaction, the reaction solution was cooled to 0-5°C and 30 mL of saturated aqueous ammonium chloride was added dropwise to the reaction solution at a controlled rate to keep the temperature below 10°C. After the addition, the solution was stirred at 0-5°C for 1 h and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The solution was purified by column chromatography to obtain 1.7 g of a white solid in a yield of 57.1%.

[0267] 32.6 Preparation of (R)-5-{2,3,5-trifluoro-4-[5-(hydroxymethyl)-2-oxooxazolidin-3-yl]phenyl}pyridinecarboxaldehyde (C7)

[0268] At room temperature, 0.20 g (0.50 mmol) of intermediate C6 and 2.0 mL of 2M hydrochloric acid were added to 2.0 mL of tetrahydrofuran. After addition, the temperature was raised to 50°C and the reaction was allowed to proceed for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 10 mL of ethyl acetate was added to the residue. The organic phases were washed with saturated sodium bicarbonate solution (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 0.13 g of a yellow solid (yield 73.5%).

[0269] 32.7 Preparation of (R,E)-3-(2,3,5-trifluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0270] At room temperature, 0.1 g (0.28 mmol) of intermediate C7 and 0.03 g (0.34 mmol) of N-aminomorpholine were added to 1.0 mL of ethanol. The mixture was heated to reflux and allowed to react for 0.5 h. A solid precipitated, which was filtered and dried in an oven at 40°C for 24 h to yield 0.09 g of a white solid (69.7% yield).

[0271] Example 33 Preparation of (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxidothiomorpholin-4-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0272] (R,E)-3-[2,3-difluoro-4-(6-{[(1,1-dioxythiomorpholin-4-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one was synthesized using 4-aminothiomorpholine-1,1-dioxide as the starting material according to the method described in 31.5 of Example 31. The yield was 47.5%.

[0273] Example 34 Preparation of (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one

[0274] (R,E)-3-[2,3-difluoro-4-(6-{[(4-methylpiperazin-1-yl)imino]methyl}pyridin-3-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one was synthesized from 1-amino-4-methylpiperazine according to the method described in 31.5 of Example 31. The yield was 48.0%.

[0275] Example 35 Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0276] (R,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using N-aminopiperidine according to the method described in 31.5 of Example 31. The yield was 71.2%.

[0277] Example 36 Preparation of (R)-3-{2,3-difluoro-4-[6-({[4-(4-methylsulfonyl)piperazin-1-yl]imino}methyl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)oxazolidin-2-one

[0278] (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 was synthesized using 4-(methylsulfonyl)-1-piperazinamine according to the method described in 31.5 of Example 31. The yield was 67.2%.

[0279] Example 37 Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazine)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one

[0280] (R,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazine)methyl]pyridin-3-yl}phenyl)-5-(hydroxymethyl)oxazolidin-2-one was synthesized using isopropylhydrazine hydrochloride according to the method described in 31.5 of Example 31. The yield was 50.6%.

[0281] Example 38 Preparation of (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

[0282] Using Example 31 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method of 18.1 in Example 18 to synthesize key intermediate D3, and then followed the synthesis methods of 21.1-21.2 in Example 21 to synthesize (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. Yield: 49.5%.

[0283] 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

[0284] Using Example 33 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method of 18.1 in Example 18 to synthesize key intermediate D3, and then by the synthesis methods of 21.1-21.2 in Example 21 to synthesize (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. The yield was 43.8%.

[0285] Example 40 Preparation of (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

[0286] Using Example 34 as starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method of 18.1 in Example 18 to synthesize key intermediate D3, and then followed the synthesis methods of 21.1-21.2 in Example 21 to synthesize (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. Yield: 58.6%.

[0287] 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

[0288] Using Example 35 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method of 18.1 in Example 18 to synthesize key intermediate D3, and then followed the synthesis methods of 21.1-21.2 in Example 21 to synthesize (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. The yield was 60.7%.

[0289] Example 42 Preparation of (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

[0290] Using Example 36 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method in 18.1 of Example 18 to synthesize key intermediate D3, and then (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 according to the synthesis methods in 21.1-21.2 of Example 21. The yield was 64.8%.

[0291] Example 43 Preparation of (R,E)-3-(2,3-fluoro-4-{6-[(2-isopropylhydrazine)methyl]pyridin-3-yl}phenyl)-5-[(1H-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one

[0292] Using Example 37 as the starting material, key intermediate D2 was synthesized according to the synthesis method in Example 16, followed by the synthesis method of 18.1 in Example 18 to synthesize key intermediate D3, and then followed the synthesis methods of 21.1-21.2 in Example 21 to synthesize (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. The yield was 57.2%.

[0293] Example 44 Preparation of (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

[0294] Using Example 34 as the starting material, key intermediate D2 was synthesized according to the synthesis method of Example 16. Then, (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 was synthesized according to the synthesis methods of 22.1-22.2 of Example 22. The yield was 67.4%.

[0295] 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

[0296] Using Example 35 as the starting material, key intermediate D2 was synthesized according to the synthesis method of Example 16, and then (S,E)-3-(2,3-difluoro-4-{6-[(piperidin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one was synthesized according to the synthesis methods of 22.1-22.2 of Example 22. The yield was 53.9%.

[0297] 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

[0298] Using Example 36 as the starting material, key intermediate D2 was synthesized according to the synthesis method of Example 16. Then, (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 was synthesized according to the synthesis methods of 22.1-22.2 of Example 22. The yield was 57.3%.

[0299] Example 47 Preparation of (S,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0300] Using Example 37 as the starting material, key intermediate D2 was synthesized according to the synthesis method of Example 16. Then, (S,E)-3-(2,3-difluoro-4-{6-[(2-isopropylhydrazonoyl)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one was synthesized according to the synthesis methods of 22.1-22.2 of Example 22. The yield was 50.6%.

[0301] Example 48 Preparation of (R,E)-3-(2,3-difluoro-4-{6-[(morpholin-1-ylimino)methyl]pyridin-3-yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]oxazolidin-2-one

[0302] Using Example 31 as the starting material, key intermediate D2 was synthesized according to the synthesis method of Example 16. 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 synthesis methods of 22.1-22.2 of Example 22. The yield was 52.7%.

[0303] 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

[0304] Using Example 31 as the starting material, (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 according to the synthesis method of Example 23. The yield was 48.2%.

[0305] 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

[0306] Using Example 31 as the starting material, (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 according to the synthesis method of Example 24. The yield was 52.9%.

[0307] Example 51 Preparation of Tablets (250 mg / Tablet) of the Compound of Example 1

[0308] Take 250 g of the compound of Example 1, 30 g of starch, 80 mL of a 2% HPMC aqueous solution, 15 g of sodium carboxymethyl starch, and 2 g of magnesium stearate, and follow the steps below:

[0309] a. Prepare an appropriate amount of 2% HPMC solution and set aside;

[0310] b. Dry the raw materials and auxiliary materials appropriately, pass them through 100 mesh sieves respectively, and set aside;

[0311] c. Weigh the raw materials and excipients according to the prescribed amount. Mix the compound of Example 1, starch, and sodium starch glycolate evenly, add 2% HPMC solution to form a soft material, and sieve through a 20-mesh sieve to prepare wet granules.

[0312] d. Dry the wet granules at 55°C for about 3 hours, let them cool slightly after drying, add magnesium stearate, and sieve through a 20-mesh sieve; determine the content and calculate the tablet weight;

[0313] e. Use a 10 mm shallow concave punch to press tablets and make 1000 tablets;

[0314] f. Finished products are inspected and packaged for storage after passing the inspection.

[0315] Example 52 Preparation of capsules (125 mg / capsule) of the compound of Example 3

[0316] Take the following components: 125 g of the compound of Example 3, 15 g of starch, 15 g of lactose, approximately 40 mL of a 2% HPMC aqueous solution, 7.5 g of sodium carboxymethyl starch, and 1 g of magnesium stearate. Proceed as follows:

[0317] a. Prepare an appropriate amount of 2% HPMC solution and set aside.

[0318] b. Dry the raw and auxiliary materials appropriately, sieve them through 100 mesh sieves respectively and set aside.

[0319] c. Weigh the raw materials and auxiliary materials according to the prescribed amount: Mix the compound of Example 2, starch, lactose, and sodium carboxymethyl starch uniformly, add 2% HPMC solution to prepare a soft material, and sieve through a 20-mesh sieve to prepare wet granules.

[0320] d. Dry the wet granules at 55°C for about 3 hours. After drying, let them cool slightly, add magnesium stearate, and sieve through a 20-mesh sieve. Determine the content and calculate the filling amount.

[0321] e. Use 2# capsule shells to fill the granules and obtain 1000 capsules.

[0322] f. Polish and remove dust from the capsules.

[0323] g. Finished products are inspected and packaged for storage after passing the inspection.

[0324] Example 53 Preparation of Dispersible Tablets (250 mg / Tablet) of the Compound of Example 7

[0325] The following components were taken: 250 g of the compound of Example 7, 50 g of pregelatinized starch, 50 g of microcrystalline cellulose, 20 g of sodium carboxymethyl starch, approximately 90 ml of a 2% HPMC aqueous solution, 20 g of micropowdered silica gel, 18 g of stevia glycosides, and 2 g of magnesium stearate, and prepared according to the following steps:

[0326] a. Prepare an appropriate amount of 2% HPMC solution and set aside.

[0327] b. Dry the raw and auxiliary materials appropriately, sieve them through 100 mesh sieves respectively and set aside.

[0328] c. Weigh the raw materials and excipients according to the prescribed amount. Mix the compound of Example 4, pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, and stevia glycosides evenly, add 2% HPMC solution to prepare a soft material, and sieve through a 20-mesh sieve to prepare wet granules.

[0329] d. Dry the wet granules at 55°C for 3 hours. After drying, let them cool slightly. Add micro-powdered silica gel and magnesium stearate. Sieve through a 20-mesh sieve. Determine the content and calculate the tablet weight.

[0330] e. Use an 11mm shallow concave punch to press tablets and obtain 1000 tablets.

[0331] f. Finished products are inspected and packaged for storage after passing the inspection.

[0332] Example 54 Preparation of Sodium Chloride Injection (100 mL: 250 mg) of the Compound of Example 8

[0333] Take the following components: 250 g of the compound of Example 8, 825 g of sodium chloride, 6.5 g of citric acid, and add water for injection to 100 L, and proceed as follows:

[0334] a. Weigh the prescribed amounts of the compound of Example 4, sodium chloride, and citric acid.

[0335] b. Dissolve the main and auxiliary materials in about 90% of the total amount of water for injection (about 80°C), and stir until completely dissolved.

[0336] c. Add 0.05% needle-grade activated carbon that has been activated at 120°C for 2 hours, stir, and let stand for 15 minutes.

[0337] d. After filtering and removing carbon with a 0.6μm titanium rod filter, add water for injection to the full amount.

[0338] The structures of the compounds of the examples and 1 H-NMR and MS data are shown in the table below.

[0339] Table 1 Structure of the compounds in the examples 1 H-NMR and MS data

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352] The compounds of the present invention were studied for their in vitro antibacterial activity, and the results are as follows:

[0353] After sterilization, the test samples were diluted in Mueller-Hinton (MH) broth to form a series of concentrations, with the lowest concentration being 0.06 mg / L and the highest concentration being 128 mg / L, with a concentration gradient of 2. 100 μL of M-H broth was added to the 12th well of each row of a 96-well dilution plate as a blank control, 50 μL of MH broth was added to the 11th well, and 50 μL of the sample test solution was added sequentially from the 10th well to the 1st well in descending order.

[0354] Inoculate an appropriate amount of the test bacteria and standard strain into MH nutrient broth suitable for their growth and incubate at 37°C for 16-18 hours. After growth, calibrate the solution with physiological saline to a 0.5 McFarland turbidimetric standard and dilute it 1:100 (v / v) with MH broth. This solution serves as the test solution. Then, inoculate 50 μL of the test solution into wells 1-11, shake to mix, and place in a covered square dish lined with wet gauze. Incubate at 37°C for 18-20 hours.

[0355] When observed under a light source with a black background, wells with bacterial growth will show diffuse turbidity or a button-like precipitate at the bottom of the well, while wells without bacterial growth will not show this phenomenon. The lowest drug concentration in the wells without bacterial growth is the minimum inhibitory concentration (MIC). The test results are shown in Table 2.

[0356] Table 2 Activity of some of the compounds in the examples against Gram-positive bacteria (MIC: μg / mL)

[0357]

[0358]

[0359]

[0360] 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, and LREF is linezolid-resistant Enterococcus faecalis; “-” means not detected.

[0361] Then, some of the compounds obtained in the present invention were further tested for their MAO inhibitory effects (see Table 3).

[0362] Table 3 MAO inhibitory effects of some compounds (IC 50 :nM)

[0363]

[0364] The preliminary in vitro antibacterial activity test results in Tables 2 and 3 above indicate that the compounds of the present invention have better antibacterial activity than linezolid, and have significant antibacterial activity against drug-resistant bacteria. Furthermore, they have lower MAO inhibition than linezolid 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 any one of claims 1 to 8, 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.

10. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 8, and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof.

11. Use of a compound of formula I according to any one of claims 1 to 8, its stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, or the composition according to claim 10 in the preparation of a medicament for treating microbial infection.

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