Pyridino-oxazolidinone compounds, methods of synthesis and uses thereof

Abstract

The application discloses pyridine-containing oxazolidinone compounds, a synthesis method and application thereof. A structural general formula of the pyridine-containing oxazolidinone compounds is shown in general formula I. In the application, a B ring phenyl ring of linezolid is replaced by a pyridine heterocycle, the introduction of the pyridine ring changes the distribution of the electron cloud, increases the basicity of the molecule, and further transforms a C ring. In order to further improve the antibacterial activity, fluorine is connected to the pyridine ring of part of the products, and the antibacterial activity is obviously improved. In-vitro antibacterial activity tests show that the pyridine-containing oxazolidinone compounds provided by the application all have definite antibacterial activity, and are expected to become substitutes of linezolid for clinical use.

Description

Technical Field

[0001] This invention relates to an oxazolidinone compound containing a pyridine structure, or its optical isomer, pharmaceutically acceptable salt and / or solvate, and further relates to a method for synthesizing the compound and its use as an antibacterial agent, belonging to the class of pyridine-containing oxazolidinone compounds and their applications. Background Technology

[0002] For many years, the discovery of numerous drug-resistant, multidrug-resistant, and cross-resistant bacteria in clinical practice has led to a sharp increase in the mortality rate of infectious diseases. Since the emergence of multidrug-resistant bacteria, only three drugs—quinupristin, linezolid, and daptomycin—have been marketed in Europe. Among them, linezolid, as a lead compound in the oxazolidinone class, has been approved by the FDA since 2000 for the clinical treatment of multidrug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) infections. Its mechanism of action involves binding to the 50S methylene group of the ribosome, thereby inhibiting the action of the 70S subunit of the initiation complex, ultimately inhibiting bacterial protein synthesis. This unique mechanism of action allows it to treat infections caused by drug-resistant bacteria and is less prone to cross-resistance with other drugs. In recent years, some linezolid-resistant strains have also been reported. These cases are caused by mutations in the 50S large subunit ribosomal immune region protein or by the expulsion of the drug by the endogenous ribosomal methyltransferase efflux pump. With the emergence of drug resistance issues, it is necessary to further optimize its structure and design more novel compounds to overcome drug resistance.

[0003] To rationally modify the structure of linezolid, it can be done according to the nomenclature of oxazolidinone drugs, such as... Figure 1 The molecular structure of linezolid is divided into four components: 1) A ring, a five-membered heterocycle composed of an oxazolidinone structure; 2) B ring, an aromatic ring attached to the N atom of the oxazolidinone ring; 3) C ring, a morpholine ring attached to the benzene ring, a flexible ring that is not a planar rigid structure; 4) C-5 side chain, composed of functional groups attached to the C-5 position of the oxazolidinone, generally in an isobathed position with the A ring.

[0004] Currently, numerous modifications to the C-5 side chain have been made, and there are many reports on the introduction of heterocyclic modifications into the A and C rings of linezolid. For example, the morpholine ring (C ring) has been replaced with a pyridine ring and a 1,2,4-dioxazole heterocycle has been introduced distally. There are also reports on replacing the oxazolidinone ring (A ring) with a five-membered aromatic heterocyclic isoxazole to maintain biological activity. Figure 2 To date, there have been few attempts and inventions to modify the benzene ring (B-ring), and no drugs with particularly good antibacterial effects have been found. Linezolid has been on the market for a long time, and bacterial resistance to it is quite common in clinical practice. There is an urgent need to provide a novel antibacterial compound that can replace linezolid. Summary of the Invention

[0005] One objective of this invention is to provide a pyridine-containing bioxazolidinone compound with antibacterial activity;

[0006] A second objective of this invention is to provide a method for synthesizing the aforementioned pyridine-containing bioxazolidinone compounds;

[0007] A third objective of this invention is to apply the aforementioned pyridine-containing bioxazolidinone compounds to the preparation of drugs for treating bacterial infectious diseases.

[0008] The above-mentioned objective of the present invention is achieved through the following technical solution:

[0009] This invention first provides a pyridine-containing bioxazolidinone compound, the structural formula of which is shown in general formula I:

[0010]

[0011] Among them, X1 and X2 are independently selected from O or N;

[0012] R1 and R3 are substituents of different types, including but not limited to any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-pyridineformyl, 2-furanoyl, 2-tetrahydrofuranoyl, 3-pyridineformyl, 6-chloropyridine-3-formyl, 2-furanoyl, 3-pyridineacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino, or 4-chlorophenylamino; R2 is hydrogen or F.

[0013] R4 is selected from any one of acetyl, propionyl, isovaleryl, cyclohexylcarboxyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-pyridinecarboxyl, 2-furancarboxyl, 2-tetrahydrofurancarboxyl, 3-pyridinecarboxyl, 6-chloropyridine-3-carboxyl, 2-furanacryloyl, 3-pyridineacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino, or 4-chlorophenylamino.

[0014] The compounds of general formula I of this invention contain a chiral center, and therefore exist as enantiomers and racemates. Accordingly, this invention also includes racemates, luminescent isomers, polymorphic forms, or mixtures thereof of the compounds of general formula I, all of which possess the useful properties described in this invention. This invention also relates to two enantiomers with useful properties and mixtures containing two isomers.

[0015] The present invention also includes solvates of compounds of general formula I, wherein the solvent of the solvate may be ethanol, water, etc., and may contain different amounts of water, such as monohydrate, hemihydrate, monihydrate, dihydrate, or trihydrate.

[0016] The compounds of general formula I of this invention can form pharmaceutically acceptable salts with acids. The acids may include inorganic or organic acids, 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.

[0017] The present invention also includes prodrugs of compounds of general formula I. According to the present invention, prodrugs are derivatives of compounds of general formula I, which may themselves have weak or no activity, but are converted into the corresponding biologically active form under physiological conditions (e.g., through metabolism, solvation, or other means) after administration.

[0018] As a specific embodiment of the present invention, the compound of general formula I can be any of the following specific compounds, but the following specific compounds do not imply any limitation on the present invention:

[0019] (S)-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide;

[0020] (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}-3-phenylpropionamide;

[0021] (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}cyclohexylcarboxamide;

[0022] (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}nicotinamide;

[0023] (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}furan-2-carboxamide;

[0024] (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}-4-(trifluoromethyl)benzamide;

[0025] N-{[(S)-3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}tetrahydrofuran-2-carboxamide;

[0026] (R)-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}methanesulfonamide;

[0027] (R)-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}benzenesulfonamide;

[0028] (S)-1-Cyclohexyl-3-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}urea;

[0029] (S)-3-methyl-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}butyramide;

[0030] (S)-1-(4-chlorophenyl)-3-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}urea;

[0031] (S)-N-{3-[6-(4-propionylpiperazin-1-yl)pyridin-3-yl-2-oxazolidinone-5-yl]methyl}acetamide;

[0032] (S)-N-[({3-[6-(4-cyclohexylcarbonyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide;

[0033] (S)-N-[(3-(6-{4-[4-[4-(trifluoromethyl)benzoyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide;

[0034] (S)-N-[(3-{6-[4-(6-chloronicotinamide)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide;

[0035] (S)-N-[(3-{6-[4-(furan-2-carbonyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-)methyl]acetamide;

[0036] (S)-N-[(3-{6-[4-(3-phenylpropionyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide;

[0037] (S,E)-N-[(3-(6-{4-[3-(furan-2-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide;

[0038] (S)-N-[(3-(6-(4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide;

[0039] (S)-N-{[3-(6-{4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide;

[0040] (S)-N-{[3-(6-{4-[(4-nitrophenyl)sulfonyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide;

[0041] (S)-4-{5-[5-(acetamidomethyl)-2-oxazolidinone-3-yl]pyridin-2-yl}-N-cyclohexylpiperazine-1-carboxamide;

[0042] (S)-4-{5-[5-(acetamidomethyl)-2-oxazolidinone-3-yl]pyridin-2-yl}-N-(4-chlorophenyl)piperazine-1-carboxamide;

[0043] (S)-N-({3-[5-fluoro-6-(4-propionylpiperazin-1-yl)pyridin-3-yl]-2-oxazolidinone-5-yl}methyl)acetamide;

[0044] (S)-N-[(3-{6-[4-(cyclohexanecarbonyl)piperazin-1-yl]-5-fluoropyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide;

[0045] (S)-N-[(3-{5-fluoro-6-[4-(3-phenylpropionyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide;

[0046] (S,E)-N-{[3-(5-fluoro-6-{4-[3-(furan-2-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide;

[0047] (S,E)-N-{[3-(5-fluoro-6-{4-[3-(pyridin-3-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide;

[0048] (S)-4-{5-[5-(acetaminomethyl)-2-oxazolidinone-3-yl]-3-fluoropyridin-2-yl}-N-(4-chlorophenyl)piperazine-1-carboxamide;

[0049] (S)-N-((3-(6-(4-(2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0050] (S)-N-((3-(6-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0051] (S)-N-((3-(6-(4-(2-(benzylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0052] (S)-N-((3-(6-(4-(2-morpholinidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0053] (S)-N-((3-(6-(4-(2-(methylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0054] (S)-N-((3-(5-fluoro-6-(4-(2-(isopropylamino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0055] (S)-N-((3-(5-fluoro-6-(4-(2-(((3-morpholinopropyl)amino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0056] (S)-N-((3-(6-(4-(4-methylpiperidin-1-yl)pyrimidin)4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0057] (S)-N-((3-(6-(4-(2-(naphth-1-ylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl-2-oxazolidinone-5-yl)methyl)acetamide;

[0058] (S)-N-((3-(6-(4-(2-((2,2-difluoroethyl)amino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0059] (S)-N-((3-(6-(4-(2-(quinolin-5-ylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0060] (S)-N-((3-(6-(4-(2-(phenylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0061] (S)-N-((3-(6-(4-(2-(allylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0062] (S)-N-((-3-(6-(4-(2-(propyrylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0063] (S)-N-((3-(6-(4-(2-(((6-chloropyridin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0064] (S)-N-((3-(6-(4-(6-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0065] (S)-4-(4-(5-(5-(acetamidomethyl)-2-oxazolidinone-3-yl)-3-fluoropyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidine-5-ethyl acetate;

[0066] (S)-N-((3-(5-fluoro-6-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0067] (S)-N-((3-(6-(4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0068] (S)-N-((3-(6-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0069] (S)-N-((3-(6-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0070] (S)-N-((3-(6-(4-(2,5-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0071] (S)-N-((3-(6-(4-(5-bromo-2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0072] (S)-N-((3-(5-fluoro-6-(4-(2,5,6-trichloropyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0073] (S)-N-((3-(6-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0074] (S)-N-((3-(6-(4-(2-chloro-5-fluoropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0075] (S)-N-((3-(6-(4-(2-aminopyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0076] (S)-N-((3-(6-(4-(4-aminopyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0077] (S)-2,2-dichloro-N-(3-(6-(4-(2,5-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0078] (S)-N-((3-(6-(4-(5-bromo-2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)-2,2-dichloroacetamide;

[0079] (S)-2,2-Dichloro-N-((3-(6-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide;

[0080] (S)-2,2-dichloro-N-((3-(6-(4-(2-chloro-5-fluoropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide.

[0081] The present invention further provides a method for synthesizing compounds of general formula I, wherein the method includes, but is not limited to, any one of the following methods (I), (II) or (III).

[0082] (I) A method for synthesizing a compound of general formula I, the method comprising:

[0083] (1) 2-chloro-5-nitropyridine reacts with morpholine to prepare intermediate A-1; (2) intermediate A-1 is reduced with palladium on carbon and hydrogen to generate intermediate A-2; (3) a Cbz protecting group is introduced into the amino group of intermediate A-2 to obtain intermediate A-3; (4) intermediate A-3 and (R)-(-)-glycidyl ester are cyclized to generate product A-4 with an oxazolidinone ring; (5) methanesulfonyl group is introduced into product A-4 to generate A-5; (6) A-5 reacts with potassium phthalimide to generate A-6; (7) A-6 is de-phthalimide group in methanethiol solution to obtain A-7; (8) different substituents are attached to the amino group of intermediate A-7 to obtain the final product.

[0084]

[0085] As a preferred embodiment of the above-mentioned synthesis method of the present invention, in step (4), intermediate A-3 and (R)-(-)-glycidyl butyl ester are cyclized at low temperature in a reaction solution of n-butyllithium and tetrahydrofuran at 78°C to generate product A-4 with an oxazolidinone ring.

[0086] In step (7), A-6 is dephthalimide group removed from it in a methyl alcohol solution to obtain A-7;

[0087] The substituents mentioned in step (8) are selected from any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-pyridineformyl, 2-furanoyl, 2-tetrahydrofuranoyl, 3-pyridineformyl, 6-chloropyridine-3-formyl, 2-furanoyl, 3-pyridineacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chlorophenylamino.

[0088] (II) Another method for synthesizing compounds of general formula I provided by the present invention, the method comprising:

[0089] (1) 2-Chloro-5-nitropyridine reacts with 1-Boc-piperazine to prepare intermediate B-1; (2) intermediate B-1 is reduced to generate intermediate B-2; (3) a Cbz protecting group is introduced into intermediate B-2 to obtain intermediate B-3; (4) 1-amino-3-chloropropane-2-ol is refluxed with acetic anhydride to obtain cyclization intermediate B-4; (5) intermediate B-3 and intermediate B-4 are cyclized to generate product B-5 with an oxazolidinone ring. (6) B-5 is de-Boc to obtain intermediate B-6; (7) Intermediate B-6 is further connected with different substituents to obtain the product; the substituents include, but are not limited to, any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-pyridineformyl, 2-furancaryl, 2-tetrahydrofurancaryl, 3-pyridineformyl, 6-chloropyridine-3-formyl, 2-furanacryloyl, 3-pyridineacryloyl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino or 4-chlorophenylamino.

[0090]

[0091] As a preferred embodiment of the above-mentioned legal method (II) of the present invention, in step (2), intermediate B-1 is reduced with palladium on carbon and ammonium formate to generate intermediate B-2; in step (4), 1-amino-3-chloropropane-2-ol and acetic anhydride are refluxed under triethylamine catalysis to obtain cyclization intermediate B-4; in step (6), B-5 ​​is de-Boced with trifluoroacetic acid to obtain intermediate B-6.

[0092] (III) A third synthetic method for a compound of general formula I provided by the present invention, the synthetic method comprising:

[0093] (1) 3-fluoro-2-hydroxypyridine is attached to a nitro group to obtain intermediate C-1; (2) intermediate C-1 is refluxed and chlorinated to obtain intermediate C-2; (3) intermediate C-2 is reacted with 1-Boc-piperazine to obtain intermediate C-3; (4) intermediate C-3 is reduced to generate intermediate C-4; (5) intermediate C-4 is introduced with a Cbz protecting group to obtain intermediate C-5; (6) 1-amino-3-chloropropane-2-ol is refluxed with acetic anhydride under triethylamine catalysis to obtain cyclization intermediate B-4; (7) intermediate C-5 and cyclization intermediate B-4 are cyclized to generate product C-6 with an oxazolidinone ring; (8) C-6 is de-Boc to obtain intermediate C-7; (9) intermediate C-7 is further attached with different substituents to obtain the final product.

[0094]

[0095] As a preferred embodiment of the above-mentioned (III) legal method of the present invention, in step (1), 3-fluoro-2-hydroxypyridine is prepared by nitro grouping with concentrated nitric acid to obtain intermediate C-1; in step (2), intermediate C-1 is refluxed with POCl3 and PCl5 to obtain intermediate C-2; in step (4), intermediate C-3 is reduced with palladium on carbon and ammonium formate to generate intermediate C-4; in step (8), under ice bath conditions, C-6 is deBoced with trifluoroacetic acid to obtain intermediate C-7; in step (9), the removal of... The substituents include, but are not limited to, any one of acetyl, propionyl, isovaleryl, cyclohexylformyl, phenylpropionyl, 4-trifluoromethylbenzoyl, 3-pyridineformyl, 2-furancaryl, 2-tetrahydrofurancaryl, 3-pyridineformyl, 6-chloropyridine-3-caryl, 2-furanacryl, 3-pyridineacryl, methanesulfonyl, benzenesulfonyl, 4-trifluoromethylbenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-methoxybenzenesulfonyl, cyclohexylamino, or 4-chlorophenylamino.

[0096] Another object of the present invention is to provide a pharmaceutical composition for inhibiting bacterial infection, comprising a pharmaceutically acceptable amount of the compound of general formula I as claimed in claim 1, or an enantiomer, racemate, solvate, or a pharmaceutically acceptable salt or prodrug formed with an acid, combined with a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable amount of the compound of general formula I is combined with a pharmaceutically acceptable carrier or excipient and prepared into any suitable pharmaceutical composition according to conventional formulation methods in the art. The composition is generally suitable for oral and injectable administration, and is also suitable for other methods of administration. The composition may be in liquid formulations such as tablets, capsules, powders, granules, lozenges, suppositories, or oral solutions. Depending on the method of administration, the pharmaceutical composition of the present invention may contain 0.1%-99% by weight, preferably 10-60% by weight, of the compound of general formula I. The excipients may be antioxidant complexing agents, fillers, matrix materials, etc.; the pharmaceutically acceptable carriers are one or more of xylitol, mannitol, lactose, fructose, dextran, glucose, polyvinylpyrrolidone, low molecular weight dextran, sodium chloride, calcium gluconate or calcium phosphate, preferably mannitol or lactose.

[0097] There are many reports on the modification of linezolid, most of which focus on modifications to the A ring, C ring, or the 5-position side chain of the A ring, or the introduction of other heterocycles into the molecule. Modifications to the B ring benzene ring are very rare, and most methods leave the B ring benzene ring unchanged. This invention replaces the B ring benzene ring of linezolid with a pyridine heterocycle. The introduction of the pyridine ring changes the electron cloud distribution and increases the basicity of the molecule.

[0098] As seen in Examples 1-12 of the present invention, when the B ring is replaced with a pyrimidine ring while the C ring remains unchanged, amide, sulfonamide, and urea compounds are formed in the side chains. The resulting compounds show some activity against Staphylococcus aureus ATCC25923, with little or no activity against other bacteria. Later, the C ring was modified, and the resulting compounds (Examples 13-24) showed some improvement in antibacterial spectrum, exhibiting activity against a variety of bacteria, but the effects were generally weak. The products obtained by adding fluorine to the pyrimidine ring (Examples 25-30) showed further improvement in antibacterial activity, with the MIC values ​​of some compounds approaching those of linezolid. Although the antibacterial effect is slightly weaker than linezolid, linezolid has been on the market for a long time, and bacterial resistance is quite common in clinical practice. In this context, given the novel structure of the above compounds, they are expected to become alternatives to linezolid in clinical applications.

[0099] In vitro antibacterial activity tests showed that the pyridine-containing bioxazolidinone compounds provided by this invention all have definite antibacterial activity. Attached Figure Description

[0100] Figure 1 A schematic diagram of the four components of the molecular structure of linezolid.

[0101] Figure 2 Examples of existing techniques for modifying the C-5 side chain of linezolid.

[0102] Figure 3 This invention provides a synthetic route for compounds containing pyridine bioxazolidinones.

[0103] Figure 4 This invention provides another synthetic route for compounds containing pyridine bioxazolidinones.

[0104] Figure 5 The present invention provides a third synthetic route for compounds containing pyridine bioxazolidinones.

[0105] Figure 6 Synthetic routes of the compounds prepared in Examples 31-58 provided by the present invention.

[0106] Figure 7 Synthetic routes of the compounds prepared in Examples 59-62 of this invention.

[0107] Figure 8 The present invention provides the molecular structural formula of a pyridine-containing bioxazolidinone compound. Detailed Implementation

[0108] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer as a result. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the present invention can be made without departing from the spirit and scope of the invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0109] Table 1. Structural formulas and chemical names of the compounds synthesized in Examples 1-30

[0110]

[0111]

[0112]

[0113] Preparation of intermediates A-1 to A-8 in Preliminary Example 1

[0114] 1. Preparation of intermediate A-1

[0115] At room temperature, 3.11 mL of morpholine (35.7 mmol) and 5 mL of triethylamine (35.7 mmol) were added to 80 mL of dichloromethane containing 4.79 g of 2-chloro-5-nitropyridine (29.7 mmol), and the mixture was stirred overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with dichloromethane and water (3 × 100 mL), and the combined organic phases were evaporated to dryness to give the crude product. Separation by silica gel column chromatography [V(PE):V(EA) = 1:1] yielded the target product intermediate A-1. The product was a yellow solid with a yield of 66.1% and a melting point of 144.2–144.9 °C. 1 H-NMR (400MHz, CDCl3) δ9.04 (d, J=2.8Hz, 1H), 8.23 ​​(dd, J=9.6, 2.8Hz, 1H), 6.57 (d, J=9.6Hz, 1H), 3.88–3.79 (m, 4H), 3.79–3.70 (m, 4H). 13 C-NMR (75MHz, DMSO-d6) δ160.2, 145.9, 134.5, 132.8, 105.6, 65.8, 44.7.

[0116] 2. Preparation of intermediate A-2

[0117] 6.73 g of compound A-1 (32.2 mmol) was dissolved in 300 mL of dichloromethane. Under nitrogen protection, 1.01 g of palladium on carbon (15%) and 6.09 g of ammonium formate (96.6 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC until complete. The palladium on carbon was removed by diatomaceous earth filtration. The diatomaceous earth was then washed with dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation. The solution was then rinsed with dichloromethane and water (3 × 200 mL).

[0118] Extracted by (mL), the organic phases were combined, washed with saturated brine, and distilled under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target product intermediate A-2. The product was a bronze-colored solid with a yield of 86% and a melting point of 146.3–149.6 °C. 1 H-NMR (400MHz, CDCl3) δ7.80 (d, J=2.8Hz, 1H), 7.01 (dd, J=8.8, 2.8Hz, 1H), 6.57(d,J=8.8Hz,1H),3.95–3.69(m,4H),3.43–3.23(m,4H),3.22–3.05(s,2H). 13 C-NMR (75 MHz, DMSO-d6) δ152.8, 138.0, 124.9, 108.7, 66.5, 47.3.

[0119] 3. Preparation of intermediate A-3

[0120] 0.179 g of compound A-2 (1 mmol) was dissolved in 4.5 mL of [V(acetone):V(water) = 2:1], followed by the addition of 0.17 mL of benzyl chloroformate (1.2 mmol) and 0.127 g of sodium carbonate (1.2 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate and water (3 × 20 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure to obtain the target intermediate A-3. The product was a brown solid with a yield of 97.3% and a melting point of 163.1–166.0 °C. 1 H-NMR (400MHz, CDCl3) δ8.08(d,J=2.8Hz,1H),7.77(s,1H),7.45–7.29(m,5H),6.62(d,J=9.2Hz, 1H),5.19(s,2H),3.98–3.63(m,4H),3.56–3.30(m,4H). 13C-NMR (75MHz, DMSO-d6) δ155.7, 153.7, 138.4, 136.6, 129.2, 128.4, 128.0, 127.0, 126.4, 107.0, 65.9, 65.8, 45.7.

[0121] 4. Preparation of intermediate A-4

[0122] 1.64 g of compound A-3 (5.24 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran at -78 °C under nitrogen protection. 4.2 mL of n-butyllithium (2 mmol) was added to the flask at -78 °C, and the mixture was stirred for 50 min. Then, 0.88 mL of (R)-(-)-glycidyl butyl ester (6.288 mmol) dissolved in 5 mL of anhydrous tetrahydrofuran was added. The mixture was reacted at -78 °C for 1 h, then allowed to rise naturally to room temperature and stirred for 16 h. The reaction was monitored by TLC until complete. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate and water (3 × 40 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure to obtain the target intermediate A-4. The product was a yellow solid with a yield of 68.5% and a melting point of 160.2–162.9 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.24(d,J=2.8Hz,1H),7.86(dd,J=9.2,2.8Hz,1H), 6.89(d,J=9.2Hz,1H),5.20(t,J=5.6Hz,1H),4.71–4.66(m,1H),4.06–4.01(m,1H),3.80– 3.77(m,1H),3.71–3.69(m,4H),3.65–3.64(m,1H),3.59–3.53(m,1H),3.40–3.38(m,4H). 13 C-NMR (75MHz, DMSO-d6) δ156.0, 154.0, 138.1, 128.9, 126.7, 107.0, 73.5, 65.9, 61.7, 46.1, 45.5.

[0123] 5. Preparation of intermediate A-5

[0124] 279 mg of compound A-4 (1 mmol) was dissolved in 10 mL of dichloromethane, and 0.12 mL of methanesulfonyl chloride (1.5 mmol) and 0.28 mL of triethylamine (2 mmol) were added. The reaction was carried out overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with ethyl acetate and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 5:1] to obtain the target product intermediate A-5. The product was a pale yellow solid with a yield of 99.4% and a melting point of 254.0–254.4 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.23(d,J=2.8Hz,1H),7.82(dd,J=9.2, 2.8Hz,1H),6.90(d,J=9.2Hz,1H),5.02–4.96(m,1H),4.53–4.44(m,2H),4.17–4. 12(m,1H),3.80–3.76(m,1H),3.71–3.69(m,4H),3.41–3.39(m,4H),3.26(s,3H). 13 C-NMR (100MHz, DMSO-d6) δ156.8,154.7,139.3,130.1,126.6,107.5,70.8,70.3,66.4,46.6,45.9,37.3.

[0125] 6. Preparation of intermediate A-6

[0126] 840 mg of compound A-5 (2.35 mmol) was dissolved in N,N-dimethylformamide (20 mL), and 522.35 mg of potassium phthalimide (2.82 mmol) and 498.2 mg of anhydrous sodium carbonate (4.7 mmol) were added. The mixture was placed in an oil bath and stirred at 80 °C for 2 h. The reaction was monitored by TLC until complete. The N,N-dimethylformamide was removed by extraction with ethyl acetate and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the target product intermediate A-6. The product was a pale yellow solid with a yield of 96.4% and a melting point of 206.0–208.1 °C. 1H-NMR(400MHz,DMSO-d6)δ8.19(d,J=2.8Hz,1H),7.93–7.86(m, 4H),7.77(dd,J=9.2,2.8Hz,1H),6.88(d,J=9.2Hz,1H),4.97–4.90(m,1H),4.18–4.1 4(m,1H),4.04–3.98(m,1H),3.94–3.85(m,2H),3.71–3.68(m,4H),3.40–3.38(m,4H). 13 C-NMR (100 MHz, DMSO-d6) δ168.3,156.8,154.7,139.3,135.1,132.0,130.0,126.7,123.7,107.4,70.8,66.4, 48.5,45.9,40.1.

[0127] 7. Preparation of intermediate A-7

[0128] 0.98 g of compound A-6 (2.4 mmol) was dissolved in 25 mL of methylamine alcohol solution and placed in a reaction vessel. The mixture was stirred at 80 °C for 4 h in an oil bath. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with ethyl acetate and water (3 × 5 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the target product intermediate A-7. The product was a white solid with a yield of 34.3% and a melting point of 185.4–187.7 °C. 1 H-NMR (400MHz, DMSO-d6) δ8.24(d,J=2.8Hz,1H),7.85(dd,J=9.2,2.8Hz,1H),6.89(d,J=9.2Hz, 1H),4.67–4.60(m,1H),4.05–4.00(m,1H),3.83–3.80(m,1H),3.71–3.69(m,4H),3.40–3.38(m,4H),3.01(s,2H),2.92–2.82(m,2H). 13 C-NMR (75MHz, DMSO-d6) δ156.1,154.7,138.4, 129.2,126.6,106.9,73.7,65.9,47.2,45.5,43.9.

[0129] Preparation of intermediates B-1 to B-6 in Preliminary Example 2

[0130] 1. Preparation of intermediate B-1

[0131] At room temperature, 6.65 g of N-Boc-piperazine (35.7 mmol) and 5 mL of triethylamine (35.7 mmol) were added to 80 mL of dichloromethane containing 4.79 g of 2-chloro-5-nitropyridine (29.7 mmol), and the mixture was stirred overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with dichloromethane and water (3 × 100 mL), and the combined organic phases were evaporated to dryness to give the crude product. Separation by silica gel column chromatography [V(PE):V(EA) = 1:1] yielded the target product intermediate B-1. The product was a yellow solid with a yield of 67.0% and a melting point of 160.5–163.3 °C.

[0132] 2. Preparation of intermediate B-2

[0133] 9.93 g of compound B-1 (32.2 mmol) was dissolved in 300 mL of dichloromethane. Under nitrogen protection, 1.01 g of palladium on carbon (15%) and 6.09 g of ammonium formate (96.6 mmol) were added and stirred at room temperature overnight. The reaction was monitored by TLC until complete. The palladium on carbon was removed by diatomaceous earth filtration. After filtration, the diatomaceous earth was washed with dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation. The mixture was extracted with dichloromethane and water (3 × 200 mL). The organic phases were combined, washed with saturated brine, and the crude product was obtained by vacuum distillation. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target product intermediate B-2, which was a bronze-colored oil.

[0134] 3. Preparation of intermediate B-3

[0135] 0.278 g of compound B-2 (1 mmol) was dissolved in 4.5 mL of [V(acetone):V(water) = 2:1], followed by the addition of 0.17 mL of benzyl chloroformate (1.2 mmol) and 0.127 g of sodium carbonate (1.2 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was removed by vacuum distillation, and the mixture was extracted with ethyl acetate and water (3 × 20 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give intermediate B-3, the target product. The product was a brown solid with a yield of 92.7% and a melting point of 125.8–128.8 °C.

[0136] 4. Preparation of intermediate B-4

[0137] 7.0 g of (S)-1-amino-3-chloro-2-propanol hydrochloride (47.9 mmol) was dissolved in 200 mL of dichloromethane, and 20 mL of triethylamine (143.7 mmol) was added. Under reflux at 35 °C, 11.32 mL of acetic anhydride (119.86 mmol) was added to the flask. After stirring for 2 h, the reaction was complete. The mixture was extracted with dichloromethane and water (3 × 200 mL), and the organic phases were combined. The mixture was washed with saturated brine, and the solvent was removed by vacuum distillation to obtain a yellow oily mixture. Recrystallization with petroleum ether yielded the target product intermediate B-4. The product was a white solid with a yield of 86.5% and a melting point of 31.4–31.9 °C.

[0138] 5. Preparation of intermediate B-5

[0139] 466 mg of compound B-3 (1.13 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran. One drop of N,N-dimethylformamide and 0.1 mL of methanol (2.49 mmol) were added to the reaction mixture. Under nitrogen protection, 1.55 mL of lithium tert-butoxide tetrahydrofuran solution (2.2 M, 3.39 mmol) was added to the flask at 0 °C. After stirring for 30 min, 437 mg of B-4 (6.288 mmol) dissolved in 1 mL of anhydrous tetrahydrofuran was added at room temperature. The mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC until complete. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate and water (3 × 40 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure to obtain the crude product. Separation by silica gel column chromatography [V(PE):V(EA) = 1:3] yielded the target product intermediate B-5. The product was a brown solid with a yield of 66.0% and a melting point of 160.1–161.3 °C. 1 H NMR (600MHz, DMSO-d6) δ8.31(t,J=6.0Hz,1H),8.21(d,J=3.0Hz,1H),7.80(dd,J=9.0,3.0 Hz,1H),6.91(d,J=9.0Hz,1H),4.74–4.67(m,1H),4.08–4.05(m,1H),3.73–3.70(m,1H),3.45–3.38(m,8H),1.84(s,3H),1.42(s,9H).

[0140] 6. Preparation of intermediate B-6

[0141] 474 mg (1.13 mmol) of compound B-5 was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added to the solution at 0 °C, and the mixture was stirred for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added until alkaline, and the solvent was evaporated under reduced pressure to obtain the target product intermediate B-5. The product was a brown oil.

[0142] Preparation of intermediates C-1 to C-6 in Preliminary Example 3

[0143] Preparation of intermediate C-1

[0144] Under ice-water bath conditions, 10 g of 3-fluoropyridine-2-ol (88.5 mmol) was dissolved in 66 mL of concentrated sulfuric acid (1062 mmol) in portions over 30 min. Then, 12 mL of concentrated nitric acid (177 mmol) was slowly added dropwise at 0 °C with stirring overnight, allowing the mixture to rise naturally to room temperature. After the reaction was complete, ice water was added, and the mixture was stirred for 30 min, after which intermediate C-1 precipitated. The product was a yellow solid with a yield of 58.5%. Melting point: 221.1–221.8 °C. 1 H-NMR (400MHz, CDCl3) δ9.13 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 7.2, 2.4 Hz, 1H).

[0145] Preparation of intermediate C-2

[0146] 7.4 g of intermediate C-1 (46.8 mmol) was dissolved in 150 mL of phosphorus oxychloride. 14.6 g of phosphorus pentachloride (70.3 mmol) was added slowly in portions over 50 min. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete, the solvent was evaporated, and the reaction mixture was extracted with 40 mL of ice water using ethyl acetate (3 × 50 mL). The organic phase was washed with saturated sodium carbonate and evaporated to dryness to give intermediate C-2. The product was a yellow solid with a yield of 52.1% and a melting point of 38.5–39.7 °C. 1 H-NMR (400MHz, CDCl3) δ9.13 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 7.2, 2.4 Hz, 1H).

[0147] 3. Preparation of intermediate C-3

[0148] At room temperature, 6.65 g of N-Boc-piperazine (35.7 mmol) and 5 mL of triethylamine (35.7 mmol) were added to 80 mL of dichloromethane containing 5.24 g of C-2 (29.7 mmol), and the mixture was stirred overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was extracted with dichloromethane and water (3 × 100 mL), and the organic phases were combined and evaporated to dryness to give the crude product. Separation by silica gel column chromatography [V(PE):V(EA) = 1:1] yielded the target product intermediate C-3. The product was a yellow solid with a yield of 67.1% and a melting point of 160.6–163.3 °C. 1 H NMR (300MHz, CDCl3) δ 8.89 (dd, J=2.4, 1.2Hz, 1H), 8.00 (dd, J=13.2, 2.4Hz, 1H), 3.89–3.79 (m, 4H), 3.62–3.53 (m, 4H), 1.50 (s, 9H).13 C NMR(150MHz,DMSO-d6)δ154.3,151.6,145.9(d,J C-F =259.4Hz),141.1, 139.9,119.5,79.4,46.8,43.0,28.5.

[0149] 4. Preparation of intermediate C-4

[0150] 10.51 g of compound C-3 (32.2 mmol) was dissolved in 300 mL of dichloromethane. Under nitrogen protection, 1.01 g of palladium on carbon (15%) and 6.09 g of ammonium formate (96.6 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was monitored by TLC until complete. The palladium on carbon was removed by diatomaceous earth filtration. The diatomaceous earth was washed with dichloromethane after filtration. The organic phases were combined, and the solvent was removed by vacuum distillation. Extraction was performed with dichloromethane and water (3 × 200 mL). The combined organic phases were washed with saturated brine, and the crude product was obtained by vacuum distillation. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target intermediate C-4. The product was a brown oil. 1 H NMR (600MHz, DMSO-d6) δ7.46 (d,J=2.4Hz,1H),6.81(dd,J=14.4,2.4Hz,1H),5.11(s,2H),3.43–3.41(m,4H),3.07–2.98(m, 4H),1.40(s,9H). 13 C NMR(150MHz,DMSO-d6)δ154.4,151.3(d,J C-F =254.1Hz),142.3,140.9, 128.6,110.6,79.4,49.1,45.7,28.5.

[0151] 5. Preparation of intermediate C-5

[0152] 0.296 g of compound C-4 (1 mmol) was dissolved in 4.5 mL of [V(acetone):V(water) = 2:1], followed by the addition of 0.17 mL of benzyl chloroformate (1.2 mmol) and 0.127 g of sodium carbonate (1.2 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate and water (3 × 20 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure to obtain the target intermediate C-5. The product was a brown solid with a yield of 93.3% and a melting point of 163.3–165.5 °C. 1H NMR (600 MHz, DMSO-d6) δ9.93 (s, 1H), 8.12 (d, J = 2.4Hz, 1H), 7.70 (dd, J = 14.4, 2.4Hz, 1H), 7.43–7.34 (m,5H),5.16(s,2H),3.45–3.43(m,4H),3.24–3.20(m,4H),1.42(s,9H). 13 C NMR(150MHz, DMSO-d6)δ154.4,154.0,149.41(d,J=257.1Hz),145.3,145.2,136.8,133.0,129.0,128.6,128.5, 126.3,79.5,66.6,48.1,48.1,28.5.

[0153] 6. Preparation of intermediate C-6

[0154] 486 mg of compound C-5 (1.13 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran. One drop of N,N-dimethylformamide and 0.1 mL of methanol (2.49 mmol) were added to the reaction mixture. Under nitrogen protection, 1.55 mL of lithium tert-butoxide tetrahydrofuran solution (2.2 M, 3.39 mmol) was added to the flask at 0 °C. After stirring for 30 min, 437 mg of B-4 (6.288 mmol) dissolved in 1 mL of anhydrous tetrahydrofuran was added at room temperature. The mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC until complete. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate and water (3 × 40 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure to obtain the crude product. Separation by silica gel column chromatography [V(PE):V(EA) = 1:3] yielded the target product intermediate C-6. The product was a brown solid with a yield of 61.0% and a melting point of 161.1–163.3 °C. 1 H NMR (600MHz, DMSO-d6) δ8.24(t,J=6.0Hz,1H),8.12(d,J=2.4Hz,1H),7.92(dd,J=14.4, 2.4Hz,1H),4.78–4.71(m,1H),4.12–4.10(m,1H),3.74–3.71(m,1H),3.47–3 .45(m,4H),3.42–3.41(m,2H),3.31–3.26(m,4H),1.84(s,3H),1.42(s,9H).

[0155] Example 1: Preparation of (S)-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide

[0156] 100 mg of compound A-7 (0.36 mmol) was dissolved in 5 mL of dichloromethane, and 0.04 mL of acetyl chloride (0.54 mmol), 0.064 mL of triethylamine (0.432 mmol), and 1 drop of N,N-dimethylformamide were added. The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was evaporated to obtain the target product (S)-N-{[3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide. The product was a light yellow-brown solid with a yield of 20% and a melting point of 148.8–152.6 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.24–8.21(m, 2H),7.80(dd,J=9.2,2.8Hz,1H),6.89(d,J=9.2Hz,1H),4.74–4.63(m,1H ),4.09–4.05(m,1H),3.71–3.67(m,5H),3.42–3.38(m,5H),1.84(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ169.9, 156.2, 154.5, 138.7, 129.4, 126.4, 106.9, 71.8, 65.9, 47.5, 45.5, 41.5, 22.4.

[0157] Example 2: Preparation of (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}-3-phenylpropionamide

[0158] 100 mg of compound A-7 (0.36 mmol) was dissolved in 10 mL of dichloromethane. 65 mg of phenylpropionic acid (0.432 mmol), 22 mg of 4-dimethylaminopyridine (0.18 mmol), and 103.4 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.54 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product (S)-N-{(3-(6-morpholinopyridin-3-yl-2-oxazolidinone-5-yl]methyl}-3-phenylpropionamide. The product was a white solid with a yield of 33.4% and a melting point of 213.5–214.4 °C. IR Vmax (cm) -1 ; KBr pellets): 3332(-NH), 2963(-CH), 1735(C=O), 1656(C=N), 1429(CN), 1230(CO). 1H-NMR (400MHz, DMSO-d6) δ8.24(t,J=5.6Hz,1H),8.21(d,J=2.8Hz,1H),7.79(dd,J=9.2, 2.8Hz,1H),7.19(m,5H),6.89(d,J=9.2Hz,1H),4.71–4.65(m,1H),4.04–3.99(m,1H),3.70(m, 4H),3.67–3.30(m,1H),3.47–3.20(m,6H),3.10–2.76(m,2H),2.43–2.40(m,2H). 13 C-NMR (75 MHz, DMSO-d6) δ172.2,156.2,154.5,141.1,138.5,129.2,128.2,128.1,126.4,125.8,106.9, 71.8,65.9,47.3,45.5,41.3,36.8,31.0.

[0159] Example 3: Preparation of (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}cyclohexaneformamide

[0160] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane. 0.06 mL of cyclohexanecarboxylic acid (0.48 mmol), 24.4 mg of 4-dimethylaminopyridine (0.2 mmol), and 115 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product (S)-N-{(3-(6-morpholinopyridin-3-yl-2-oxazolidinone-5-yl]methyl}cyclohexanecarboxamide. The product was a white solid, with a yield of 56.2% and a melting point of 183.3–184.9 °C. 1 H-NMR (400MHz, DMSO-d6) δ8.20(d,J=2.8Hz,1H),8.07(t,J=5.6Hz,1H),7.79(dd,J=9.2, 2.8Hz,1H),6.89(d,J=9.2Hz,1H),4.74–4.68(m,1H),4.08–4.03(m,1H),3.74–3.66(m,5H) ,3.48–3.41(m,1H),3.40–3.38(m,4H),3.36–3.33(m,1H),2.17–2.10(m,1H),1.66–1.58(m, 5H),1.38–0.94(m,5H).13 C-NMR (75MHz, DMSO-d6) δ176.6,156.6,155.0,138.9,129.7,126.9, 107.4,72.3,66.4,47.8,46.0,44.3,41.7,29.6,25.9,25.7.

[0161] Example 4: Preparation of (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}nicotinamide

[0162] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane, and 73.8 mg of nicotinic acid (0.6 mmol), 24.4 mg of 4-dimethylaminopyridine (0.2 mmol), and 115 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol) were added. The mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product (S)-N-{(3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}nicotinamide. The product was a yellow solid with a yield of 43.6% and a melting point of 178.1–180.2 °C. 1 H-NMR (400 MHz, DMSO-d6) δ9.04(t,J=5.6Hz,1H),9.00(s,1H),8.71(d,J=4.8Hz,1H),8.22(d,J=2.8Hz, 1H),8.20–8.17(m,1H),7.81(dd,J=9.2,2.8Hz,1H),7.53–7.50(m,1H),6.88(d,J=9.2Hz,1H ),4.90–4.84(m,1H),4.17–4.12(m,1H),3.87–3.83(m,1H),3.71–3.64(m,6H),3.48–3.34(m, 4H). 13 C-NMR (75MHz, DMSO-d6) δ165.6,156.2,154.5,152.0,148.4,138.6,135.0,129.5,129.3, 126.4,123.4,106.9,71.5,65.9,47.7,45.5,42.3.

[0163] Example 5: Preparation of (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}furan-2-carboxamide

[0164] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane. 67.2 mg of 2-furanic acid (0.6 mmol), 24.4 mg of 4-dimethylaminopyridine (0.2 mmol), and 115 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product (S)-N-{[(3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}furan-2-carboxamide. The product was a white solid, in 53.5% yield, with a melting point of 173.0–173.4 °C. 1 H-NMR (400MHz, DMSO-d6) δ8.69(t,J=6.0Hz,1H),8.21(d,J=2.8Hz,1H),7.85(d,J=1.6 Hz,1H),7.79(dd,J=9.2,2.8Hz,1H),7.15(d,J=3.6Hz,1H),6.88(d,J=9.2Hz,1H),6.64–6.62 (m,1H),4.81(m,1H),4.14–4.10(m,1H),3.83–3.80(m,1H),3.75–3.64(m,4H),3.62–3.53(m, 2H),3.45–3.32(m,4H). 13 C-NMR (75MHz, DMSO-d6) δ158.8,156.7,155.0,148.0,145.7,139.2, 129.9,126.9,114.3,112.4,107.4,72.0,66.4,48.2,46.0,42.1.

[0165] Example 6: Preparation of (S)-N-{[(3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}-4-(trifluoromethyl)benzamide

[0166] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane. 114.12 mg of 4-(trifluoromethyl)benzoic acid (0.6 mmol), 24.4 mg of 4-dimethylaminopyridine (0.2 mmol), and 115 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product (S)-N-{[(3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}-4-(trifluoromethyl)benzamide. The product was a white solid, with a yield of 37.8% and a melting point of 226.1–227.7 °C. 1 H-NMR(400MHz,DMSO-d6)δ9.07(t,J=5.6Hz,1H),8.22(d,J=2.4Hz,1H), 8.05(d,J=8.0Hz,2H),7.86(d,J=8.0Hz,2H),7.81(dd,J=9.2,2.4Hz,1H),6.88(d,J=9.2Hz, 1H),4.91–4.84(m,1H),4.17–4.12(m,1H),3.86–3.82(m,1H),3.73–3.67(m,4H),3.65–3.62 (m,1H),3.42–3.36(m,4H). 13 C-NMR(75MHz,DMSO-d6)δ165.8,156.2,154.5,138.6,137.8, 131.5,129.3(q,J C-F =216.8Hz),128.2,126.4,125.5,106.9,71.5,65.9,47.7,45.5,42.5.

[0167] Example 7 Preparation of N-{[(S)-3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}tetrahydrofuran-2-carboxamide

[0168] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane. 69.6 mg of tetrahydrofuran-2-carboxylic acid (0.6 mmol), 24.4 mg of 4-dimethylaminopyridine (0.2 mmol), and 115 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol) were added. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product N-{[(S)-3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}tetrahydrofuran-2-carboxamide. The product was a gray solid, with a yield of 36.9% and a melting point of 130.0–132.2 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.21(d,J=2.8Hz,1H),8.08(t,J=5.6Hz,1H),7.80 (dd,J=9.2,2.8,1.3Hz,1H),6.89(d,J=9.2Hz,1H),4.78–4.71(m,1H),4.25–4.21(m,1H),4. 09–4.04(m,1H),3.91–3.72(m,3H),3.72–3.65(m,4H),3.53–3.42(m,2H),3.42–3.36(m,4H), 2.14–2.06(m,1H),1.87–1.68(m,3H). 13 C-NMR (75MHz, DMSO-d6) δ173.4,156.2,154.5, 138.5,129.2,126.4,106.9,77.6,71.5,68.5,65.9,47.4,45.5,41.2,30.0,24.8.

[0169] Example 8: Preparation of (R)-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}methanesulfonamide

[0170] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane. 0.0325 mL of methanesulfonyl chloride (0.42 mmol), 0.11 mL of triethylamine (0.8 mmol), and 9.76 mg of 4-dimethylaminopyridine (0.08 mmol) were added. The reaction was carried out overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to give the target product (R)-N-{[3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}methanesulfonamide. The product was a white solid with a yield of 60.0% and a melting point of 248.7–249.8 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.23(d,J=2.8Hz,1H),7.82(dd,J=9.2, 2.8Hz,1H),7.48(t,J=6.4Hz,1H),6.90(d,J=9.2Hz,1H),4.79–4.72(m,1H),4.12–4.08(m ,1H),3.79–3.75(m,1H),3.74–3.62(m,4H),3.46–3.33(m,4H),3.35–3.25(m,2H),2.95(s, 3H). 13 C-NMR (75MHz, DMSO-d6) δ156.2,154.5,138.7,129.5,126.4,107.0,71.7,65.9,47.2, 45.5,45.1,39.9.

[0171] Example 9: Preparation of (R)-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}benzenesulfonamide

[0172] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane. 0.0325 mL of benzenesulfonyl chloride (0.42 mmol), 0.11 mL of triethylamine (0.8 mmol), and 9.76 mg of 4-dimethylaminopyridine (0.08 mmol) were added. The reaction was carried out overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target product (R)-N-{[3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}benzenesulfonamide. The product is a yellow solid with a melting point of 121.3–123.8 °C. 1H-NMR(400MHz,DMSO-d6)δ8.27–8.11(m,2H),7.93–7.74(m,3H),7.70–7.50(m, 3H),6.90(d,J=9.2Hz,1H),4.75–4.67(m,1H),4.10–4.03(m,1H),3.78 –3.73(m,1H),3.79–3.62(m,4H),3.41–3.38(m,4H),3.13–3.10(m,2H). 13 C-NMR(75MHz,DMSO-d6)δ156.7, 154.8,140.9,139.1,133.0,129.9,129.8,126.9,126.8,107.5,72.0,66.4,47.6,46.0,45.8.

[0173] Example 10: Preparation of (S)-1-cyclohexyl-3-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}urea

[0174] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane, and 0.1 mL of cyclohexyl isocyanate (0.8 mmol) and 0.083 mL of triethylamine (0.6 mmol) were added. The reaction was carried out overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to give the target product (S)-1-cyclohexyl-3-{[3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}urea. The product was a white solid with a yield of 47.1% and a melting point of 181.4–185.3 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.22(d,J=2.8Hz,1H),7.80(dd,J=9.2,2.8Hz, 1H),6.88(d,J=9.2Hz,1H),6.07(t,J=6.0Hz,1H),5.90(d,J=8.0Hz,1H),4.71–4.65(m,1H) ,4.07–4.03(m,1H),3.76–3.61(m,5H),3.44–3.35(m,4H),3.37–3.31(m,3H),1.81–1.37(m, 5H),1.30–0.90(m,5H). 13C-NMR (75MHz, DMSO-d6) δ157.4,156.2,154.6,138.7,129.3,126.5, 106.9,72.6,65.9,47.7,47.3,45.5,42.1,33.1,25.3,24.3.

[0175] Example 11 Preparation of (S)-3-methyl-N-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}butyramide

[0176] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane, and 0.066 mL of 3-methylbutyric acid (0.6 mmol), 24.4 mg of 4-dimethylaminopyridine (0.2 mmol), and 115 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol) were added. The mixture was stirred overnight at room temperature and the reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 120:1] to obtain the target product (S)-3-methyl-N-{[3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}butyramide. The product is a white solid with a yield of 39.6% and a melting point of 184.4–187.9 °C. 1 H-NMR(400MHz,DMSO-d6)δ 8.21(d,J=2.8Hz,1H),8.17(t,J=5.6Hz,1H),7.80(dd,J=9.2,2.8Hz,1H),6.89(d,J=9.2Hz, 1H),4.75–4.69(m,1H),4.10–4.05(m,1H),3.75–3.61(m,5H),3.51–3.40( m,2H),3.43–3.35(m,4H),2.05–1.85(m,2H),0.83(dd,J=8.4,6.4Hz,6H). 13 C-NMR (75MHz, DMSO-d6) δ172.3, 156.2, 154.5, 138.5, 129.3, 126.4, 106.9, 71.8, 65.9, 47.4, 45.5, 44.5, 41.2, 25.5, 22.2.

[0177] Example 12 Preparation of (S)-1-(4-chlorophenyl)-3-{[3-(6-morpholinpyridin-3-yl)-2-oxazolidinone-5-yl]methyl}urea

[0178] 111 mg of compound A-7 (0.4 mmol) was dissolved in 10 mL of dichloromethane, and 122.88 mg of 1-chloro-4-phenyl isocyanate (0.8 mmol) and 0.83 mL of triethylamine (0.6 mmol) were added. The reaction was carried out overnight in an ice bath. The reaction was monitored by TLC until complete. The solvent was evaporated, and the mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to give the target product (S)-1-(4-chlorophenyl)-3-{[3-(6-morpholinopyridin-3-yl)-2-oxazolidinone-5-yl]methyl}urea. The product was a white solid with a yield of 57.4% and a melting point of 229.1–229.5 °C. 1 H-NMR (400MHz, DMSO-d6)δ8.81(s,1H),8.24(d,J=2.0Hz,1H),7.82(dd,J=9.2,2.0Hz,1H),7.65(s, 1H),7.31–7.09(m,2H),6.96–6.87(m,2H),6.59(t,J=5.6Hz,2H),4.81–4.75(m,1H),4.13 –4.08(m,1H),3.80–3.72(m,1H),3.72–3.67(m,4H),3.49–3.46(m,2H),3.42–3.35(m,4H). 13 C-NMR (75MHz, DMSO-d6) δ155.2,152.2,141.0,138.6,133.2,130.3,121.7,120.9,117.7,116.8, 106.9,72.2,65.9,47.3,45.5,42.0.

[0179] Example 13 Preparation of (S)-N-{3-[6-(4-propionylpiperazin-1-yl)pyridin-3-yl-2-oxazolidinone-5-yl]methyl}acetamide

[0180] 159.5 mg of compound B-6 (0.5 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of 57 μL of acetyl chloride (0.65 mmol), 48 μL of triethylamine (0.65 mmol), and 2 mL of dichloromethane. The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from PE / EA yielded the target product (S)-N-{3-[6-(4-propionylpiperazin-1-yl)pyridin-3-yl-2-oxazolidinone-5-yl]methyl}acetamide. The product is a brown solid with a melting point of 105.4–108.5 °C. 1H-NMR(400MHz,DMSO-d6)δ8.25(t,J=6.0Hz, 1H),8.22(d,J=2.8Hz,1H),7.81(dd,J=9.2,2.8Hz,1H),6.92(d,J=9.2Hz,1H),4.73–4.69(m ,1H),4.09–4.06(m,1H),3.71–3.68(m,1H),3.60–3.50(m,4H),3.50–3.49(m,2H),3.44–3.40 (m, 4H), 2.36 (q, J = 7.2Hz, 2H), 1.01 (t, J = 7.2Hz, 3H). 13 C-NMR (75MHz, DMSO-d6) δ170.6, 155.6, 150.6, 139.0, 129.6, 127.0, 125.2, 108.0, 72.3, 47.9, 45.8, 44.9, 42.0, 22.9.

[0181] Example 14 Preparation of (S)-N-[({3-[6-(4-cyclohexylcarbonyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide

[0182] 159.5 mg of compound B-6 (0.5 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of 128 mg of cyclohexanecarboxylic acid (1 mmol), 12.2 mg of 4-dimethylaminopyridine (0.1 mmol), and 143.6 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.75 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from PE / EA yielded the target product (S)-N-[({3-[6-(4-cyclohexylcarbonyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide. The product is a brown solid with a melting point of 164.7–165.3 °C. 1H-NMR(400MHz,DMSO-d6)δ8.25(t,J=6.0Hz,1H),8.22(d,J=2.8Hz,1H), 7.81(dd,J=9.2,2.8Hz,1H),6.92(d,J=9.2Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3. 71–3.68(m,1H),3.65–3.51(m,5H),3.49–3.48(m,2H),3.42–3.38(m,4H),1.84(s,3H),1.74– 1.53(m,5H),1.35–1.29(m,5H). 13 C-NMR (75MHz, DMSO-d6) δ170.6,156.2,155.1,141.8, 139.2,128.9,128.7,107.7,72.3,48.0,45.6,45.4,44.9,42.0,41.1,34.4,31.2,22.9.

[0183] Example 15 Preparation of (S)-N-[(3-(6-{4-[4-(trifluoromethyl)benzoyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide

[0184] 475 mg of p-trifluoromethylbenzoic acid (2.5 mmol) was reacted with 5 mL of thionyl chloride and 1 drop of N,N-dimethylformamide for 30 min. After distilling off the thionyl chloride, 5 mL of dichloromethane was added to dissolve the thionyl chloride. 159.5 mg of compound B-6 (0.5 mmol) was added under ice bath conditions, and the mixture was stirred overnight under ice bath conditions. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from PE / EA yielded the target product (S)-N-[(3-(6-{4-[4-(trifluoromethyl)benzoyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide. The product is a white solid with a melting point of 167.3–169.1 °C. 1H-NMR(400MHz,DMSO-d6)δ8.24(t,J=5.6Hz,1H),8.23(d,J=2.8 Hz,1H),7.84(d,J=8.0Hz,2H),7.82(dd,J=9.2,2.8Hz,1H),7.68(d,J=8.0Hz,2H),6.92(d,J= 9.2Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.78–3.72(m,2H),3.71–3.68(m,1H),3.56 –3.52(m,4H),3.42–3.40(m,4H),1.84(s,3H). 13 C-NMR(75MHz,DMSO-d6)δ170.6,158.6, 155.7,155.0,139.4,138.9,133.5,129.9(q,J C-F =251.2Hz),129.0,127.2,108.0,72.3,46.2,45.9, 44.9,42.0,22.9.

[0185] Example 16: Preparation of (S)-N-[(3-{6-[4-(6-chloronicotinamide)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide

[0186] 472.5 mg of 6-chloronicotinic acid (3 mmol) was first reacted with 5 mL of thionyl chloride and 1 drop of N,N-dimethylformamide for 30 min. After distilling off the thionyl chloride, 5 mL of dichloromethane was added to dissolve it. 159.5 mg of compound B-6 (0.5 mmol) was added under ice bath conditions, and the mixture was stirred overnight under ice bath conditions. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target product (S)-N-[(3-{6-[4-(6-chloronicotinamide)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide. The product is a yellow oil. 1H-NMR (400MHz, DMSO-d6) δ8.52(d,J=2.4Hz,1H),8.25(t,J=6.0Hz,1H),8.23(d,J=2.8H z,1H),7.96(dd,J=8.0,2.4Hz,1H),7.82(dd,J=9.2,2.8Hz,1H),7.64(d,J=8.0Hz,1H), 6.93(d,J=9.2Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.71–3.68(m, 1H),3.61–3.55(m,2H),3.48–3.45(m,4H),3.42–3.40(m,4H),1.84(s,3H). 13 C-NMR(75MHz,DMSO-d6)δ 170.6,163.3,155.7,155.0,138.9,130.3,129.9,127.0,126.6,115.1,108.0,72.3,56.2,47.9,44.9,42.0,22.9.

[0187] Example 17 Preparation of (S)-N-[(3-{6-[4-(furan-2-carbonyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide

[0188] 336 mg of p-trifluoromethylbenzoic acid (3 mmol) was reacted with 5 mL of thionyl chloride and 1 drop of N,N-dimethylformamide for 30 min. After distilling off the thionyl chloride, 5 mL of dichloromethane was added to dissolve the thionyl chloride. 159.5 mg of compound B-6 (0.5 mmol) was added under ice bath conditions, and the mixture was stirred overnight under ice bath conditions. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from PE / EA yielded the target product (S)-N-[(3-{6-[4-(furan-2-carbonyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide. The product was a white solid with a melting point of 191.2–191.8 °C. 1H-NMR (400MHz, DMSO-d6) δ8.25(t,J=6.0Hz,1H),8.23(d,J=2.8Hz,1H),7.87(d,J=1.6 Hz,1H),7.82(dd,J=9.2,2.8Hz,1H),7.04(d,J=3.6Hz,1H),6.93(d,J=9.2Hz,1H),6.65(dd,J =3.6,1.6Hz,1H),4.73–4.69(m,1H),4.09–4.06(m,1H),3.78–3.74(m,2H),3.71–3.69(m,1H), 3.69–3.46(m,4H),3.42–3.40(m,4H),1.85(s,3H). 13 C-NMR(75MHz,DMSO-d6)δ170.7, 166.4,156.1,155.1,151.5,148.7,139.1,131.5,130.0,126.9,124.8,107.8,72.3,48.0,46.2,42.0,22.9.

[0189] Example 18: Preparation of (S)-N-[(3-{6-[4-(3-phenylpropionyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide

[0190] 79.75 mg of compound B-6 (0.25 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of 56.3 mg of phenylpropionic acid (0.375 mmol), 6.1 mg of 4-dimethylaminopyridine (0.05 mmol), and 72 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.375 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product PE / EA. Recrystallization yielded the target product (S)-N-[(3-{6-[4-(3-phenylpropionyl)piperazin-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide. The product is a gray solid with a melting point of 133.2–133.3 °C. 1H-NMR(400MHz,DMSO-d6)δ8.25(t,J=6.0Hz,1H),8.21(d,J =2.8Hz,1H),7.80(dd,J=9.2,2.8Hz,1H),7.31–7.23(m,5H),6.90(d,J=9.2Hz,1H),4.73–4. 69(m,1H),4.09–4.06(m,1H),3.70–3.68(m,1H),3.65–3.49(m,6H),3.42–3.40(m,4H),2.84 (t, J=7.6Hz, 2H), 2.67 (t, J=7.6Hz, 2H), 1.84 (s, 3H). 13 C-NMR(75MHz,DMSO-d6)δ170.5, 164.7,154.8,151.7,149.9,148.2,145.4,133.0,129.5,115.4,114.5,113.0,72.6,48.5,47.6,45.3,41.9,22.9.

[0191] Example 19 Preparation of (S,E)-N-[(3-(6-{4-[3-(furan-2-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide

[0192] 191.4 mg of compound B-6 (0.6 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of 166 mg of furanoacrylate (1.2 mmol), 14.6 mg of 4-dimethylaminopyridine (0.12 mmol), and 172 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.9 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product PE / EA. Recrystallization yielded the target product (S, E)-N-[(3-(6-{4-[3-(furan-2-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide. The product is a yellow solid with a melting point of 182.1–184.2 °C. 1H-NMR(400MHz,DMSO-d6)δ8.26(t,J=6.0Hz,1H),8.23(d, J=2.8Hz,1H),7.84–7.71(m,2H),7.37(d,J=15.2Hz,1H),6.97(d,J=15.2Hz,1H),6.93(d,J= 9.2Hz,1H),6.88(d,J=3.2Hz,1H),6.64–6.60(m,1H),4.73–4.69(m,1H),4.09–4.06(m,1H), 3.76–3.72(m,2H),3.73–3.63(m,4H),3.53–3.50(m,5H),1.85(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ174.2,170.6,156.3,155.1,139.2,130.0,126.8,107.7,72.3,48.0,42.0,29.6,26.1,25.6, 22.9.

[0193] Example 20: Preparation of (S)-N-[(3-(6-(4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide

[0194] 144 mg of compound B-6 (0.358 mg) was dissolved in 10 mL of dichloromethane, followed by the addition of 131 mg of p-trifluoromethylbenzenesulfonyl chloride (0.537 mmol) and 0.14 mL of triethylamine (1 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1], yielding the target product (S)-N-[(3-(6-(4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl]acetamide. The product is a brown solid with a melting point of 226.4–226.9 °C. 1H-NMR (400MHz, DMSO-d6) δ8.23(t,J=6.0Hz,1H),8.18(d,J=2.8Hz,1H),8.04(d, J=8.4Hz,2H),7.99(d,J=8.4Hz,2H),7.78(dd,J=9.2,2.8Hz,1H),6.89(d,J=9.2Hz,1H),4.7 1–4.67(m,1H),4.06–4.03(m,1H),3.68–3.65(m,1H),3.58–3.56(m,4H),3.40–3.38(m,2H), 3.06–3.04(m,4H),1.83(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ170.7,159.0,156.2,155.1,146.3, 139.2,130.1,126.8,116.3,111.8,107.7,72.3,48.0,46.2,45.6,42.0,22.9.

[0195] Example 21: Preparation of (S)-N-{[3-(6-{4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide

[0196] 159.5 g of compound B-6 (0.5 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of 155 mg of p-methoxybenzenesulfonyl chloride (0.75 mmol) and 0.14 mL of triethylamine (1 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1], yielding the target product (S)-N-{[3-(6-{4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide. The product is a brown solid with a melting point of 175.8–177.1 °C. 1H-NMR (400MHz, DMSO-d6) δ8.23(t,J=6.0Hz,1H),8.17(d,J=2.8Hz,1H),7.77(dd,J=9.2, 2.8Hz,1H),7.69(d,J=8.8Hz,2H),7.16(d,J=8.8Hz,2H),6.87(d,J=9.2Hz,1H),4.71–4.67( m,1H),4.06–4.03(m,1H),3.84(s,3H),3.68–3.66(m,1H),3.57–3.55(m,4H),3.40–3.39(m, 2H),2.94–2.92(m,4H),1.83(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ170.6,157.4,156.5,155.1, 139.1,130.0,126.6,107.7,72.3,49.7,48.0,45.4,43.5,33.6,25.6.

[0197] Example 22 Preparation of (S)-N-{[3-(6-{4-[(4-nitrophenyl)sulfonyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide

[0198] 159.5 g of compound B-6 (0.5 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of 222 mg of p-nitrobenzenesulfonyl chloride (1 mmol) and 0.14 mL of triethylamine (1 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1], yielding the target product (S)-N-{[3-(6-{4-[(4-nitrophenyl)sulfonyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide. The product is a brown solid with a melting point of 209.0–209.3 °C. 1H- NMR (400MHz, DMSO-d6) δ8.44(d,J=8.8Hz,1H),8.24(t,J=6.0Hz,1H),8.17(d,J=2.8Hz, 1H),8.04(d,J=8.8Hz,2H),7.77(dd,J=9.2,2.8Hz,1H),6.89(d,J=9.2Hz,1H),4.74–4.67(m ,1H),4.05–4.02(m,1H),3.69–3.65(m,1H),3.59–3.57(m,4H),3.42–3.38(m,2H),3.08–3.06 (m,4H),1.83(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ170.6,156.4,155.3,140.0,139.2,130.0, 128.6,126.7,125.8,121.5,107.8,72.3,48.0,45.4,43.8,42.0,22.9.

[0199] Example 23: Preparation of (S)-4-{5-[5-(acetamidomethyl)-2-oxazolidinone-3-yl]pyridin-2-yl}-N-cyclohexylpiperazine-1-carboxamide

[0200] 159.5 g of compound B-6 (0.5 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of 0.13 mL of cyclohexyl isocyanate (1 mmol) and 0.1 mL of triethylamine (0.75 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target product (S)-4-{5-[5-(acetamidomethyl)-2-oxazolidinone-3-yl]pyridin-2-yl}-N-cyclohexylpiperazin-1-carboxamide. The product was a white solid, mp 216.0–216.7℃. 1 H-NMR (400MHz, DMSO-d6) δ8.22(d,J=2.8Hz,1H),7.80(dd,J=9.2,2.8Hz,1H),6.92(d,J=9.2Hz,1H),6.25(t, J=6.0Hz,1H),5.67(d,J=8.0Hz,1H),4.73–4.69(m,1H),4.09–4.05(m,1H),3.72–3 .68(m,1H),3.40–3.35(m,10H),1.84(s,3H),1.78–1.47(m,5H),1.32–1.00(m,5H).13 C-NMR (75 MHz, DMSO-d6) δ170.6,156.2,151.7,139.2,129.4,126.8,114.5,107.7,72.3,48.0,45.9,45.40, 42.0,42.0,22.9.

[0201] Example 24: Preparation of (S)-4-{5-[5-(acetamidomethyl)-2-oxazolidinone-3-yl]pyridin-2-yl}-N-(4-chlorophenyl)piperazine-1-carboxamide

[0202] 114 g of compound B-6 (0.358 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of 109.6 mg of p-chlorophenyl isocyanate (0.716 mmol) and 0.1 mL of triethylamine (0.75 mmol). The mixture was stirred overnight in an ice bath. The reaction was monitored by TLC until complete. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and washed with saturated brine. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 80:1] to obtain the target product (S)-4-{5-[5-(acetamidomethyl)-2-oxazolidinone-3-yl]pyridin-2-yl}-N-(4-chlorophenyl)piperazin-1-carboxamide. The product was a white solid, mp 248.2–249.1 °C. 1 H- NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 8.25 (t, J = 6.0Hz, 1H), 8.23 ​​(d, J = 2.8Hz, 1H), 7.82 (dd, J=9.2,2.8Hz,1H),7.52(d,J=8.8Hz,2H),7.29(d,J=8.8Hz,2H),6.95(d,J=9.2Hz,1H),4.7 3–4.69(m,1H),4.09–4.07(m,1H),3.71–3.69(m,1H),3.67–3.53(m,4H),3.52–3.48(m,4H), 3.42–3.41(m,2H),1.85(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ170.6,168.3,156.2,155.1, 140.4,139.1,130.0,128.3,126.9,126.0,107.8,72.4,48.0,42.0,22.9.

[0203] Example 25: Preparation of (S)-N-({3-[5-fluoro-6-(4-propionylpiperazin-1-yl)pyridin-3-yl]-2-oxazolidinone-5-yl}methyl)acetamide

[0204] 140 mg of intermediate C-6 (0.32 mmol) was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral, and the solvent was removed under reduced pressure. Under an ice-water bath, 0.7 mL of TEA, 5 mL of dichloromethane, and 36 μL of propionyl chloride (0.416 mmol) were added, and the reaction was allowed to proceed overnight. The mixture was allowed to rise naturally to room temperature, and the reaction was monitored by TLC until completion. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and evaporated to dryness. Recrystallization from PE / EA yielded (S)-N-({3-[5-fluoro-6-(4-propionylpiperazin-1-yl)pyridin-3-yl]-2-oxazolidinone-5-yl}methyl)acetamide, a brown solid with a melting point of 173.0–173.6 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.25(t,J=6.0Hz,1H),8.13(d,J=2.4Hz, 1H),7.92(dd,J=14.4,2.4Hz,1H),4.77–4.73(m,1H),3.76–3.68(m,1H),3.59–3.70(m,4H), 3.43–3.41(m,2H),3.29–3.28(m,1H),3.11–3.09(m,4H),2.36(q,J=7.6Hz,2H),1.84(s,3H), 1.01(t,J=7.6Hz,3H). 13 C-NMR (75MHz, DMSO-d6) δ170.6,152.9,139.1,129.1,128.6,125.9, 121.5,120.3,72.6,48.0,47.6,46.2,44.0,41.9,22.9,9.1.

[0205] Example 26 Preparation of (S)-N-[(3-{6-[4-(cyclohexanecarbonyl)piperazin-1-yl]-5-fluoropyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide

[0206] 48 mg of intermediate C-6 (0.11 mmol) was dissolved in 2 mL of dichloromethane. 0.5 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral, and the solvent was removed by vacuum evaporation. Under an ice-water bath, 3 mg of 4-dimethylaminopyridine, 33 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 mmol), and 30 mg of cyclohexanecarboxylic acid (0.22 mmol) were added, and the mixture was heated to 90 °C overnight. The reaction was monitored by TLC until completion. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and evaporated to dryness. Recrystallization of PE / EA yields (S)-N-[(3-{6-[4-(cyclohexanecarbonyl)piperazin-1-yl]-5-fluoropyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide, a brown solid with a melting point of 198.1–199.4 °C. 1 H-NMR (400MHz, DMSO-d6) δ8.23(t,J=6.0Hz,1H),8.13(d,J=2.0Hz,1H),7.92(dd,J=14.4,2.0Hz,1H),4.77– 4.73(m,1H),4.13–4.10(m,1H),3.74–3.72(m,1H),3.63–3.57(m,4H),3.43–3.41(m,2H), 3.29–3.27(m,4H),2.66–2.56(m,1H),1.84(s,3H),1.75–1.59(m,5H),1.43–1.20(m,5H). 13 C- NMR (75MHz, DMSO-d6) δ174.0,170.5,154.8,148.3,145.8,133.0,129.9,115.4,72.6,48.6,47.6, 45.0,41.9,41.2,29.6,26.1,25.6,22.9.

[0207] Example 27 Preparation of (S)-N-[(3-{5-fluoro-6-[4-(3-phenylpropionyl)-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide

[0208] 140 mg of intermediate C-6 (0.32 mmol) was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral. The solvent was removed by vacuum evaporation to obtain intermediate C-7. 270 mg of phenylpropionic acid (3.6 mmol) was dissolved in 4 mL of thionyl chloride. One drop of N,N-dimethylformamide was added, and the reaction was heated to 70 °C for 2 h. The reaction was completed, and thionyl chloride was removed by evaporation. Under an ice-water bath, the evaporated product was dissolved in 5 mL of dichloromethane. 0.7 mL of triethylamine and 108 mg of intermediate C-7 (0.32 mmol) were added, and the reaction was allowed to proceed overnight. The mixture was allowed to cool to room temperature naturally. After 2 h, TLC confirmed the reaction was complete, and the system was clean. Extracted with dichloromethane and water (3 × 10 mL), the organic phases were combined and evaporated to dryness to give (S)-N-[(3-{5-fluoro-6-[4-(3-phenylpropionyl)-1-yl]pyridin-3-yl}-2-oxazolidinone-5-yl)methyl]acetamide, a brown solid with a melting point of 143.0–143.6 °C. 1 H-NMR(400MHz,DMSO-d6)δ8.28(t,J=6.0Hz,1H),8.12(d,J=2.4Hz,1H),7.92 (dd,J=14.4,2.4Hz,1H),7.30–7.20(m,5H),4.77–4.73(m,1H),4.13–4.11(m,1H),3.75–3.72 (m,1H),3.60–3.58(m,2H),3.43–3.38(m,4H),3.28–3.26(m,4H),2.67(t,J=7.6Hz,2H),2.53 (t,J=7.6Hz,1H),1.84(s,3H). 13 C-NMR(75MHz,DMSO-d6)δ172.0,170.5,170.0,154.8,150.0, 148.3,145.9,139.0,133.0,128.7,127.9,115.5,72.6,47.6,46.2,44.9,41.9,26.0,22.9.

[0209] Example 28 Preparation of (S,E)-N-{[3-(5-fluoro-6-{4-[3-(furan-2-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide

[0210] 110 mg of intermediate C-6 (0.25 mmol) was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral. The solvent was removed under reduced pressure to obtain intermediate C-7. 84.25 mg of intermediate C-7 (0.25 mmol) was dissolved in 5 mL of dichloromethane. 6.1 mg of 4-dimethylaminopyridine (0.05 mmol), 72.3 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 mmol), and 69.5 mg of 2-tetrahydrofuranacrylic acid (0.5 mmol) were added. The reaction was allowed to proceed overnight, and TLC confirmed completion. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and evaporated to dryness. Recrystallization of PE / EA yields (S,E)-N-{[3-(5-fluoro-6-{4-[3-(furan-2-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide, a white solid with a melting range of 200.7–202.3 °C. 1 H-NMR (400MHz, DMSO-d6) δ8.16(t,J=6.0Hz,1H),8.06(d,J=2.4Hz,1H),7.86(dd,J=14.4,2.4Hz,1H),7.73(d, J=1.6Hz,1H),7.30(d,J=15.2Hz,1H),6.89(d,J=15.2Hz,1H),6.81(d,J=3.2Hz,1H),6.54( dd,J=3.2,1.6Hz,1H),4.75–4.58(m,1H),4.06–4.03(m,1H),3.79–3.58(m,5H),3.36–3.33 (m,2H),3.31–3.27(m,4H),1.77(s,3H). 13 C-NMR (75MHz, DMSO-d6) δ170.5,164.6,154.8, 150.6,149.9,145.7,138.7,135.0,133.0,131.4,124.3,120.7,72.6,47.6,46.1,41.9,22.9.

[0211] Example 29 Preparation of (S,E)-N-{[3-(5-fluoro-6-{4-[3-(pyridin-3-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide

[0212] 140 mg of intermediate C-6 (0.32 mmol) was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral. The solvent was removed under reduced pressure to obtain intermediate C-7. 536 mg of 3-pyridineacrylic acid (3.6 mmol) was dissolved in 4 mL of thionyl chloride. One drop of N,N-dimethylformamide was added, and the reaction was heated to 70 °C for 2 h until completion. The thionyl chloride was removed by evaporation. Under an ice-water bath, the evaporated product was dissolved in 5 mL of dichloromethane. 0.7 mL of triethylamine and 108 mg of intermediate C-7 (0.32 mmol) were added, and the reaction was allowed to proceed overnight. The mixture was allowed to rise naturally to room temperature, and the reaction was monitored by TLC after 2 h until completion. Extracted with dichloromethane and water (3 × 10 mL), the organic phases were combined and evaporated to dryness, and recrystallized with PE / EA to give (S,E)-N-{[3-(5-fluoro-6-{4-[3-(pyridin-3-yl)acryloyl]piperazin-1-yl}pyridin-3-yl)-2-oxazolidinone-5-yl]methyl}acetamide, the product being a brown solid with a melting point of 201.5–202.9 °C. 1 H-NMR (400MHz, DMSO-d6) δ8.90(d,J=2.0Hz,1H),8.56(dd,J=4.8,2.0Hz,1H),8.25(t,J=6.0Hz,1H),8.21(d,J=8.4Hz,1H),8.15(d,J=2.4Hz,1H),7.94(dd, J=14.4,2.4Hz,1H),7.56(d,J=15.2Hz,1H),7.47(d,J=15.2Hz,1H),7.46(dd,J=8.4,4.8Hz, 1H),4.78–4.74(m,1H),4.13–4.10(m,1H),3.90–3.88(m,2H),3.75–3.72(m,4H),3.43–3.41 (m,4H),3.12–3.08(m,1H),1.85(s,3H). 13 C-NMR(75MHz,DMSO-d6)δ174.2,170.6,158.8, 154.8,149.9,148.2,145.8,141.8,133.0,130.1,126.4,118.7,116.7,115.5,72.6,45.1,41.9,35.7,34.4,31.2,30.8,22.9.

[0213] Example 30: Preparation of (S)-4-{5-[5-(acetaminomethyl)-2-oxazolidinone-3-yl]-3-fluoropyridin-2-yl}-N-(4-chlorophenyl)piperazine-1-carboxamide

[0214] 100 mg of intermediate C-6 (0.23 mmol) was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral. The solvent was removed by vacuum evaporation to obtain intermediate C-7. 77.51 mg of intermediate C-7 (0.23 mmol) was dissolved in 5 mL of dichloromethane under an ice-water bath. 0.7 mL of TEA and 70.5 mg of propionyl chloride (0.46 mmol) were added, and the reaction was allowed to proceed overnight. The mixture was allowed to rise naturally to room temperature, and the reaction was monitored by TLC until completion. The mixture was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined and evaporated to dryness. Recrystallization from PE / EA yielded (S)-4-{5-[5-(acetaminomethyl)-2-oxazolidinone-3-yl]-3-fluoropyridin-2-yl}-N-(4-chlorophenyl)piperazin-1-carboxamide, a brown solid with an mp of 218.7–220.2 °C. 1 H-NMR (400MHz, DMSO-d6)δ8.73(s,1H),8.25(t,J=6.0Hz,1H),8.14(d,J=2.4Hz,1H),7.94(dd,J= 14.4,2.4Hz,1H),7.48(d,J=8.4Hz,2H),7.33(d,J=8.4Hz,2H),4.78–4.74(m,1H),4.13–4.10 (m,1H),3.75–3.72(m,1H),3.67–3.56(m,4H),3.43–3.41(m,2H),3.40–3.34(m,4H),1.85(s, 3H). 13 C-NMR (75MHz, DMSO-d6) δ172.1,170.6,158.8,156.3,155.1,139.2,130.1,128.7,127.9, 126.7,107.7,72.3,48.0,42.0,41.1,26.0,22.9.

[0215] Table 2. Structural formulas and chemical names of the compounds prepared in Examples 31-62.

[0216]

[0217]

[0218]

[0219]

[0220] Example 31 (S)-N-((3-(6-(4-(2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0221] Preparation of (S)-N-((3-(6-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide in Example 32

[0222] 218 mg of intermediate C-6 (0.5 mmol) was dissolved in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid was added at 0 °C and the reaction proceeded for 2 h. The reaction was monitored by TLC until completion. Triethylamine was added to the reaction system at 0 °C to adjust the pH to neutral, and the solvent was removed by vacuum distillation. 3 mL of ethanol was added to the system to dissolve the product, followed by 0.14 mL of triethylamine (1 mmol) and 97 mg of 2,4-dichloropyrimidine (0.65 mmol). The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol):V(triethylamine) = 50:1:1], yielding Examples 31 and 32.

[0223] Example 31 is a brown solid with a yield of 5.8% and a melting point of 171.1–173.1 °C. 1 H NMR(600MHz,DMSO-d6) δ8.32(t,J=6.0Hz,1H),8.14(d,J=2.4Hz,1H),8.11(d,J=6.0Hz,1H),7.94(dd,J=14.4,2.4H z,1H),6.88(d,J=6.0Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.79–3.72(m,5H),3.46– 3.40(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.6,163.0,160.0,158.0,154.8, 149.1(d,J C-F =257.1Hz),145.6,133.0,130.0,115.4,102.9,72.6,55.4,47.6,47.4,41.9,22.9.

[0224] Example 32 is a white solid with a yield of 40.4% and a melting point of 160.0–161.1 °C. 1H NMR(600MHz,DMSO-d6) δ8.35(d,J=5.4Hz,1H),8.25(t,J=6.0Hz,1H),8.14(d,J=2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),6.77(d,J=5.4H z,1H),4.79–4.72(m,1H),4.14–4.10(m,1H),3.89–3.81(m,4H),3.76–3.60(m,1H),3.46–3.39(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,161.5, 160.5,154.8,149.1(d,J C-F =257.1Hz),145.9,133.0,130.0,128.7,115.4,109.7,72.6,47.7,46.1, 43.7,41.9,22.9.

[0225] Example 33: Preparation of (S)-N-((3-(6-(4-(2-(benzylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0226] 150 mg of Example 31 (0.33 mmol) was dissolved in 5 mL of dioxane. 17.1 mg of p-toluenesulfonic acid monohydrate (0.09 mmol) and 0.36 mL of benzylamine (3.33 mmol) were added at room temperature. The mixture was refluxed and reacted overnight. The reaction was monitored by TLC until completion, and the solvent was removed by vacuum distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol):V(triethylamine) = 100:1:1] to obtain the product of Example 33. The product was a white solid, with a yield of 41.5% in Example 33 and a melting point of 202.7–204.6 °C. 1H NMR (600MHz, DMSO-d6) δ8.24(t,J=6.0Hz,1H),8.13(d,J=2.4Hz,1H),7.93(dd,J=14.4,2.4Hz,1H),7.82(d,J=6.0Hz,1H),7.32 –7.24(m,5H),7.22–7.16(m,1H),6.07(d,J=6.0Hz,1H),4.79–4.72(m,1H),4.14–4.10(m, 1H),3.74–3.72(m,1H),3.74–3.64(m,4H),3.47–3.38(m,2H),3.36–3.34(m,4H),1.84(s, 3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.6,162.3,154.8,150.0(d,J C-F =256.7Hz),146.0, 145.9,141.7,133.0,129.8,128.5,127.6,126.8,115.5,115.4,72.6,47.8,44.5,43.5,41.9,22.9.

[0227] Example 34: Preparation of (S)-N-((3-(6-(4-(2-morpholinidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0228] 150 mg of Example 31 (0.33 mmol) was dissolved in 5 mL of morpholine, and 17.1 mg of p-toluenesulfonic acid monohydrate (0.09 mmol) was added at room temperature. The mixture was heated to reflux and reacted overnight. The reaction was monitored by TLC until completion. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was recrystallized from the crude product with ethyl acetate to obtain the product of Example 34. The product was a white solid, and the yield of the product of Example 34 was 46.1%, with a melting point of 191.3–192.1 °C. 1 H NMR(600MHz,DMSO-d6)δ8.24(t,J= 6.0Hz,1H),8.13(d,J=2.4Hz,1H),7.96–7.90(m,2H),6.17(d,J=6.0Hz,1H),4.79–4.72(m, 1H),4.13–4.10(m,1H),3.74–3.72(m,1H),3.70–3.69(m,4H),3.64–3.63(m,8H),3.47–3.35 (m,6H),1.84(s,3H). 13C NMR(150MHz,DMSO-d6)δ170.5,162.6,161.6,157.1,154.8,150.0(d, J C-F =256.7Hz),146.0,133.0,129.9,115.5,115.4,94.1,72.6,66.6,47.7,44.4,43.6,41.9,22.9.

[0229] Example 35: Preparation of (S)-N-((3-(6-(4-(2-(methylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0230] 200 mg (0.44 mmol) of Example 31 was dissolved in 4 mL of methanesulfonic acid solution and reacted at room temperature for 3 days. The reaction was monitored by TLC until completion, and ethanol was removed by evaporation. The product was extracted with dichloromethane and water (3 × 10 mL), the organic phases were combined, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 35. The product was a pale yellow solid with a yield of 40.5% and a melting point of 193.3–195.1 °C. 1 H NMR(600MHz,DMSO-d6)δ8.27(t,J=6.0Hz,1H),8.14(d,J =2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),7.86(d,J=6.6Hz,1H),7.31–7.30(s,1H),6.31(d,J =6.6Hz,1H),4.78–4.73(m,1H),4.13–4.10(m,1H),3.84–3.78(s,4H),3.75–3.73(m,1H),3.43 –3.42(m,6H),2.82(d,J=4.8Hz,3H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5, 162.0,154.8,149.1(d,J C-F =257.1Hz),145.7,145.7,133.0,133.0,130.0,115.6,115.5,72.6,47.7, 47.6,43.9,41.9,28.1,22.9.

[0231] Example 36: Preparation of (S)-N-((3-(5-fluoro-6-(4-(2-(isopropylamino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0232] 200 mg (0.44 mmol) of Example 31 was dissolved in 4 mL of isopropylamine solution, sealed, and reacted at 50 °C for 3 days. The reaction was monitored by TLC until completion, and the isopropylamine was removed by evaporation. The product was extracted with dichloromethane and water (3 × 10 mL), the organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 36. The product was a pink solid with a yield of 44.4% and a melting point of 196.8–199.5 °C. 1 H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H), 8.13(d,J=2.4Hz,1H),7.93(dd,J=14.4,2.4Hz,1H),7.82(d,J=6.0Hz,1H),6.31(s,1H),6. 04(d,J=6.0Hz,1H),4.79–4.72(m,1H),4.12–4.10(m,1H),4.04–3.95(m,1H),3.74–3.72(m, 1H), 3.68–3.66 (m, 4H), 3.49–3.36 (m, 5H), 1.84 (s, 3H), 1.12 (d, J = 6.6Hz, 6H), 1.08–0.94 (m, 1H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.7,161.7,157.2,154.8,149.1(d,J C-F =256.3Hz), 146.0,133.0,129.9,115.5,115.4,72.6,47.8,47.7,47.6,43.5,42.2,41.9,23.1,22.9.

[0233] Example 37 Preparation of (S)-N-((3-(5-fluoro-6-(4-(2-(((3-morpholinopropyl)amino)amino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0234] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 144 mg of 3-aminopropylmorpholine (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 50:1] to obtain the product of Example 37. The product was a brown oil with a yield of 48.7%. 1H NMR (600MHz, DMSO-d6) δ8.28(t,J=6.0Hz,1H),8.12(d,J=2.4Hz,1H),7.92(dd,J=14.4, 2.4Hz,1H),7.81(d,J=6.0Hz,1H),6.57(s,1H),6.03(d,J=6.0Hz,1H),4.77–4.73(m,1H),4. 12–4.09(m,1H),3.75–3.73(m,1H),3.67–3.65(m,4H),3.57–3.56(m,4H),3.44–3.42(m,4H), 3.38–3.35(m,4H),3.27–3.23(m,2H),2.33–2.30(m,4H),1.85(s,3H),1.66–1.64(m,2H). 13 C NMR(150MHz,DMSO-d6)δ170.6,162.7,162.3,157.2,154.8,149.1(d,J C-F =257.1Hz),145.9, 132.9,129.8,115.5,115.3,72.6,66.7,56.7,53.8,47.7,46.1,43.5,41.9,26.5,22.9,7.6.

[0235] Example 38: Preparation of (S)-N-((3-(6-(4-(4-methylpiperidin-1-yl)pyrimidine)4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0236] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 0.12 mL of 4-methylpiperidine (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 40:1] to obtain the product of Example 38. The product was a pink solid with a yield of 64.4% and a melting point of 198.1–200.5 °C. 1H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H),8.13(d,J=2.4Hz, 1H),7.93(dd,J=14.4,2.4Hz,1H),7.89(d,J=6.0Hz,1H),6.08(d,J=6.0Hz,1H),4.79–4.72(m ,1H),4.62–4.59(m,2H),4.13–4.10(m,1H),3.74–3.72(m,1H),3.68–3.66(m,4H),3.43–3.41 (m,2H),3.41–3.37(m,4H),2.77–2.73(m,2H),1.84(s,3H),1.64–1.56(m,2H),1.04–0.98(m,2H),0.91(d,J=6.6Hz,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.7,161.4,157.1,154.8, 149.1(d,J C-F =256.3Hz),146.0,133.0,129.9,115.5,115.4,93.2,72.6,47.7,44.0,43.6,41.9,34.1, 31.3,22.9,22.4.

[0237] Example 39 Preparation of (S)-N-((3-(6-(4-(2-(naphth-1-ylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0238] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 143 mg of 1-naphthylamine (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 39. The product was a brown solid with a yield of 59.3% and a melting point of 221.8–223.1 °C. 1H NMR (600MHz, DMSO-d6) δ9.60 (s, 1H), 8.35 (t, J = 6.0Hz, 1H), 8.13–8.11 (m,2H),7.99–7.90(m,3H),7.80(d,J=7.2Hz,1H),7.74(d,J=8.4Hz,1H),7.54–7.50(m,3H) ,6.42(d,J=6.6Hz,1H),4.77–4.75(m,1H),4.12–4.09(m,1H),3.78–3.75(m,1H),3.73–3.71 (m,4H),3.43–3.42(m,2H),3.38–3.34(m,4H),1.85(s,3H). 13 C NMR(150MHz,DMSO-d6)δ 170.6,162.1,154.8,152.4,149.1(d,J C-F =257.1Hz),146.0,145.7,134.9,134.4,133.0,130.0,128.7, 128.6,126.4,126.1,126.0,125.1,123.4,121.7,115.6,115.4,95.8,72.6,63.1,52.5,22.9,7.7.

[0239] Example 40: Preparation of (S)-N-((3-(6-(4-(2-((2,2-difluoroethyl)amino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0240] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 0.07 mL of 2,2-difluoroethylamine (1 mmol) were added. The mixture was sealed and reacted overnight at 75 °C. The reaction was monitored by TLC until completion, and dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 40. The product was a pink solid with a yield of 66.7% and a melting point of 228.1–231.2 °C. 1H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H),8.13(d,J =2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),7.87(d,J=6.0Hz,1H),7.02(s,1H),6.20(d,J=6. 0Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.76–3.73(m,1H),3.73–3.68(m,5H),3.68– 3.58(m,2H),3.46–3.38(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.5, 154.8,149.1(d,J C-F =257.2Hz), 145.9, 145.8, 133.1, 133.0, 129.9, 115.6, 115.4, 72.6, 47.7, 47.64, 43.9 (t, J = 26.7Hz), 43.7, 43.6, 41.9, 22.9.

[0241] Example 41: Preparation of (S)-N-((3-(6-(4-(2-(quinolin-5-ylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0242] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 150 mg of 5-aminoquinoline (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 41. The product was a white solid with a yield of 43% and a melting point of 226.2–232.2 °C. 1H NMR (600MHz, DMSO-d6) δ9.15 (s, 1H), 8.87 (dd, J = 4.2, 1.8Hz, 1H), 8.53– 8.48(m,1H),8.24(t,J=6.0Hz,1H),8.15–8.12(m,1H),7.99–7.90(m,2H),7.87(dd,J=7.2,1 .2Hz,1H),7.77–7.71(m,2H),,7.489–7.47(m,1H),6.33(d,J=6.0Hz,1H),4.79–4.72(m,1H), 4.13–4.10(m,1H),3.74–3.72(m,1H),3.68–3.66(m,4H),3.43–3.41(m,2H),3.39–3.37(m,4H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.5,161.1,157.3,154.8,149.7(d,J C-F =259.1Hz),148.3,145.9,136.9,133.0,132.6,129.9,129.6,124.7,123.6,120.7,120.6,115.6,115.4, 107.8,95.9,72.6,47.7,43.5,41.9,22.9.

[0243] Example 42: Preparation of (S)-N-((3-(6-(4-(2-(phenylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0244] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 91.15 μL of aniline (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 42. The product was a white solid with a yield of 43% and a melting point of 190.6–194.4 °C. 1H NMR (600MHz, DMSO-d6) δ9.17 (s, 1H), 8.24 (t, J = 6.0Hz, 1H), 8.14 (d, J = 2.4Hz, 1H),8.00(d,J=6.0Hz,1H),7.95(dd,J=14.4,2.4Hz,1H),7.73–7.68(m,2H),7.30–7.24(m,2 H),6.92(t,J=7.2Hz,1H),6.36(d,J=6.0Hz,1H),4.79–4.72(m,1H),4.14–4.11(m,1H),3.79 –3.77(m,4H),3.75–3.72(m,1H),3.48–3.39(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,165.2,162.5,154.8,149.1(d,J C-F =256.2Hz),145.7,141.2,140.8,133.0,129.8,128.9, 121.8,119.4,117.3,115.6,95.8,72.6,47.7,43.8,41.9,22.9.

[0245] Example 43: Preparation of (S)-N-((3-(6-(4-(2-(allylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0246] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 75 μL of 2-allylamine (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 43. The product was a white solid with a yield of 68.1% and a melting point of 182.1–184.6 °C. 1H NMR(600MHz,DMSO-d6)δ8.25(t,J=6.0Hz,1H),8.14(d,J=2.4Hz, 1H),7.94(dd,J=14.4,2.4Hz,1H),7.85(d,J=6.6Hz,1H),7.51–7.08(m,1H),6.28(d,J=6.0H z,1H),5.92–5.86(m,1H),5.19(d,J=17.4Hz,1H),5.08(d,J=10.2Hz,1H),4.77–4.73(m,1H), 4.13–4.10(m,1H),3.93–3.91(m,2H),3.78–3.75(m,4H),3.74–3.72(m,1H),3.43–3.39(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.0,154.8,149.1(d,J C-F =257.5Hz), 145.8,138.1,136.4,133.0,130.0,128.5,126.0,115.6,115.4,72.6,47.6,43.9,43.4,41.9,22.9,21.2.

[0247] Example 44 Preparation of (S)-N-((3-(6-(4-(2-(propynylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0248] 150 mg of Example 31 (0.33 mmol) was dissolved in 4 mL of dioxane solution, and 11.4 mg of p-toluenesulfonic acid monohydrate (0.066 mmol) and 69 μL of 2-propyneamine (1 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 44. The product was a white solid with a yield of 44.9% and a melting point of 185.6–188.7 °C. 1H NMR(600MHz,DMSO-d6)δ8.29(t,J=6.0Hz,1H),8.14(d,J=2.4Hz,1H), 7.94(dd,J=14.4,2.4Hz,1H),7.88(d,J=6.0Hz,1H),7.22(s,1H),6.23(d,J=6.0Hz,1H),5.33( s,1H),4.77–4.73(m,1H),4.13–4.10(m,1H),4.04–4.03(m,2H),3.78–3.72(m,4H),3.44–3.34 (m,7H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.4,154.8,149.1(d,J C-F =256.9 Hz),145.9,145.8,133.1,133.0,130.0,115.6,115.4,72.6,63.1,52.5,47.7,43.7,41.9,30.6,22.9,7.7.

[0249] Example 45: Preparation of (S)-N-((3-(6-(4-(2-(((6-chloropyridin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0250] 200 mg of Example 31 (0.44 mmol) was dissolved in 4 mL of dioxane solution, and 17 mg of p-toluenesulfonic acid monohydrate (0.09 mmol) and 171 mg of 2-propyneamine (1.3 mmol) were added. The mixture was refluxed overnight, and the reaction was monitored by TLC until completion. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL), and the organic phases were combined. The solvent was removed by vacuum distillation to obtain the crude product. The crude product was separated by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 45. The product was a white solid with a yield of 45.8% and a melting point of 134.4–135.6 °C. 1H NMR (600MHz, DMSO-d6) δ9.46 (s, 1H), 8.74 (d, J = 3.0Hz, 1H), 8.27–8.19 (m, 2H), 8.14(d,J=2.4Hz,1H),8.05(d,J=6.0Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),7.40 (d,J=9.0Hz,1H),6.40(d,J=6.0Hz,1H),4.79–4.72(m,1H),4.14–4.11(m,1H),3.78–3.71(m,5H),3.47–3.42(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.5,159.5,157.1, 154.8,149.1(d,J C-F =256.5Hz),145.8,141.3,140.2,137.9,133.0,129.9,129.2,124.2,115.6,115.4, 96.6,72.6,47.6,43.7,41.9,22.9.

[0251] Example 46: Preparation of (S)-N-((3-(6-(4-(6-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0252] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the pH to alkalinity. After removing the solvent, the product was dissolved in 4 mL of ethanol solution. 83 μL of triethylamine (0.6 mmol) and 60 mg of 4,6-dichloropyrimidine (0.4 mmol) were added, and the mixture was refluxed overnight. The reaction was monitored by TLC until complete. The ethanol was removed by TLC. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 46. The product was a white solid with a yield of 45.1% and a melting point of 190.0–191.1 °C. 1H NMR(600MHz,DMSO-d6)δ8.37(s,1H),8.24(t,J=6.0Hz,1H),8.14(d,J =2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),7.02(s,1H),4.79–4.72(m,1H),4.14–4 .10(m,1H),3.81–3.75(m,4H),3.74–3.71(m,1H),3.43–3.42(m,6H),1.84(s,3H). 13 C NMR(150MHz, DMSO-d6)δ170.5,162.7,159.7,158.5,154.8,148.2(d,J C-F =256.7Hz),145.6,133.0,129.99,115.6, 102.3,72.6,47.6,47.5,43.8,41.9,22.9.

[0253] Example 47 Preparation of (S)-4-(4-(5-(5-(acetamidomethyl)-2-oxazolidinone-3-yl)-3-fluoropyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidine-5-ethyl acetate

[0254] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the pH to alkalinity. After removing the solvent, the product was dissolved in 4 mL of ethanol solution. 83 μL of triethylamine (0.6 mmol) and 93 mg of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid (0.4 mmol) were added, and the mixture was refluxed overnight. The reaction was monitored by TLC until complete. The ethanol was removed by TLC. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 50:1] to obtain the product of Example 47. The product was a white solid with a yield of 50.6% and a melting point of 210.1–213.1 °C. 1H NMR (600MHz, DMSO-d6) δ8.45 (s, 1H), 8.26 (t, J = 6.0 Hz,1H),8.11(d,J=2.4Hz,1H),7.92(dd,J=14.4,2.4Hz,1H),4.79–4.72(m,1H),4.36–4.17(m ,2H),4.14–4.09(m,1H),3.76–3.72(m,1H),3.68–3.66(m,4H),3.46–3.44(m,4H),3.43–3.41 (m,2H),2.48(s,3H),1.85(s,3H),1.37–1.25(m,3H). 13 C NMR(150MHz,DMSO-d6)δ172.6, 170.5,165.9,159.8,159.3,154.8,149.0(d,J C-F =257.0Hz),145.6,132.9,129.8,115.3,105.7,72.6, 61.4,47.6,47.5,47.3,41.9,22.9,14.5,14.1.

[0255] Example 48 Preparation of (S)-N-((3-(5-fluoro-6-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0256] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the pH to alkalinity. After removing the solvent, the product was dissolved in 4 mL of ethanol solution. 83 μL of triethylamine (0.6 mmol) and 51 mg of 2-chloro-5-methylpyrimidine (0.4 mmol) were added, and the mixture was refluxed overnight. The reaction was monitored by TLC until complete. The ethanol was removed by TLC. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 50:1] to obtain the product of Example 47. The product was a white solid with a yield of 49.4% and a melting point of 195.1–197.3 °C. 1H NMR(600MHz,DMSO-d6)δ8.26–8.23(m,3H),8.13(d,J=2.4Hz,1H), 7.93(dd,J=14.4,2.4Hz,1H),4.77–4.73(m,1H),4.13–4.10(m,1H),3.85–3 .80(m,4H),3.76–3.70(m,1H),3.43–3.37(m,6H),2.10(s,3H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ 160.7,158.2,154.8,149.2(d,J C-F =255.3Hz),146.1,133.0,130.0,119.1,115.5,115.4,72.6,47.9, 46.2,43.9,22.9,14.1,9.1.

[0257] Example 49 (S)-N-((3-(6-(4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)ethyl

[0258] Preparation of amides and Example 50 (S)-N-((3-(6-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0259] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 83 μL of triethylamine (0.6 mmol) and 45 μL of 2,4,6-trichloropyrimidine (0.4 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:3] to obtain the products of Example 49 and Example 50, respectively. Both products were white solids with yields of 13.8% and 44.7%, respectively, and melting points of 191.3–192.5 °C and 195.2–197.1 °C, respectively.

[0260] Product of Example 49: 1H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H),8.14(d,J=2.4Hz, 1H),7.94(dd,J=14.4,2.4Hz,1H),6.98(s,1H),4.77–4.73(m,1H),4.14–4.10 (m,1H),3.88–3.84(m,4H),3.75–3.72(m,1H),3.44–3.41(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6) δ170.5,161.6,160.5,154.8,148.2(d,J=256.7Hz),145.7,132.9,130.0,115.4,108.2,72.6,47.6,47.5,43.9,41.9,22.9.

[0261] Product of Example 50: 1 H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H),8.14(d,J=2.4Hz, 1H),7.94(dd,J=14.4,2.4Hz,1H),7.08(s,1H),4.77–4.74(m,1H),4.13–4.10(m,1H),3.87–3.71(m,5H),3.44–3.42(m,6H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,163.4, 159.6,159.0,154.8,149.1(d,J C-F =257.1Hz),145.5,133.0,130.0,115.4,101.4,72.6,47.6,47.4, 43.7,41.9,22.9.

[0262] Example 51: Preparation of (S)-N-((3-(6-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0263] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the pH to alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 83 μL of triethylamine (0.6 mmol) and 174 mg of 2-chloro-5-bromopyrimidine (0.4 mmol) were added, and the mixture was refluxed overnight. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 51. The product was a white solid with a yield of 47.6% and a melting point of 196.1–196.3 °C. 1 H NMR (600MHz, DMSO-d6) δ8.50(s,2H),8.24(t,J=6.0Hz, 1H),8.13(d,J=2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),4.77–4.73(m,1H),4.14–4.10(m, 1H),3.88–3.83(m,4H),3.74–3.71(m,1H),3.43–3.33(m,6H),1.84(s,3H). 13 C NMR (150 MHz, DMSO-d6) δ170.5,166.3,160.0,158.5,154.8,150.8(d,J C-F =253.7Hz),133.0,129.9,115.3, 106.1,72.6,47.6,43.8,41.9,39.0,22.9.

[0264] Example 52: Preparation of (S)-N-((3-(6-(4-(2,5-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0265] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 83 μL of triethylamine (0.6 mmol) and 46 μL of 2,4,5-trichloropyrimidine (0.4 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 52. The product was a white solid with a yield of 48.6% and a melting point of 193.5–194.2 °C. 1 H NMR (600MHz, DMSO-d6) δ8.35 (s, 1H), 8.24 (t, J = 6.0Hz, 1H),8.14(d,J=2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),4.77–4.73(m,1H),4.14–4.10(m ,1H),3.91–3.86(m,4H),3.75–3.72(m,1H),3.51–3.46(m,4H),3.43–3.41(m,2H),1.84(s, 3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,160.4,159.1,157.1,154.8,148.3(d,J C-F =256.7Hz), 133.0,130.0,115.5,115.1,72.6,47.6,47.6,47.0,41.9,22.9.

[0266] Example 53 Preparation of (S)-N-((3-(6-(4-(5-bromo-2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0267] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 83 μL of triethylamine (0.6 mmol) and 50 μL of 2,4-dichloro-5-bromopyrimidine (0.4 mmol) were added. The reaction was carried out overnight at 70 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol) = 30:1] to obtain the product of Example 53. The product was a white solid with a yield of 82.8% and a melting point of 196.7–197.6 °C. 1 H NMR (600MHz, DMSO-d6) δ8.46 (s, 1H), 8.24 (t, J = 6.0Hz, 1H),8.14(d,J=2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),4.77–4.73(m,1H),4.14–4.10(m ,1H),3.87–3.83(m,4H),3.75–3.72(m,1H),3.50–3.46(m,4H),3.43–3.41(m,2H),1.84(s, 3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,162.7,161.8,157.8,154.8,149.1(d,J C-F =257.1Hz), 145.6,133.0,130.0,115.5,104.1,72.6,47.6,47.6,47.3,41.9,22.9.

[0268] Example 54 Preparation of (S)-N-((3-(5-fluoro-6-(4-(2,5,6-trichloropyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0269] 130 mg of intermediate C-6 (0.3 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 83 μL of triethylamine (0.6 mmol) and 85 mg of 2,4,5,6-tetrachloropyrimidine (0.4 mmol) were added. The reaction was carried out overnight at 70 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:5] to obtain the product of Example 54. The product was a white solid with a yield of 71.4% and a melting point of 210.0–211.1 °C. 1 H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H),8.14(d,J =2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),4.79–4.72(m,1H),4.13–4.10(m,1H),3.9 2–3.81(m,4H),3.75–3.72(m,1H),3.52–3.47(m,4H),3.44–3.39(m,2H),1.84(s,3H). 13 C NMR (150 MHz, DMSO-d6) δ170.5,161.9,159.0,155.1,154.8,149.1(d,J C-F =255.8Hz),145.6,133.0,129.8, 115.4,112.4,72.6,47.8,47.6,47.5,41.9,22.9.

[0270] Example 55: Preparation of (S)-N-((3-(6-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0271] 80 mg of intermediate C-6 (0.18 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 2 mL of dioxane solution. 100 μL of triethylamine (0.72 mmol) and 28 μL of 2,4-dichloro-5-methylpyrimidine (0.24 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from petroleum ether and ethyl acetate yielded the product of Example 55. The product was a white solid with a yield of 58.9% and a melting point of 198.8–200.8 °C. 1 H NMR(600MHz,DMSO-d6)δ8.24(t,J=6.0Hz,1H),8.14(d,J=2.4Hz,1H),8.06(s, 1H),7.93(dd,J=14.4,2.4Hz,1H),4.79–4.72(m,1H),4.14–4.10(m,1H),3.74–3.72(m, 1H),3.70–3.65(m,4H),3.48–3.44(m,4H),3.43–3.41(m,2H),2.24(s,3H),1.84(s,3H). 13 C NMR (150MHz, DMSO-d6)δ170.5,165.0,160.0,157.2,154.8,149.1(d,J C-F =257.1Hz),145.8,133.0, 130.0,116.2,115.4,72.6,47.8,47.6,46.9,41.9,22.9,17.3.

[0272] Example 56 Preparation of (S)-N-((3-(6-(4-(2-chloro-5-fluoropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0273] 80 mg of intermediate C-6 (0.18 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 2 mL of dioxane solution. 100 μL of triethylamine (0.72 mmol) and 40 mg of 2,4-dichloro-5-fluoropyrimidine (0.24 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Recrystallization from petroleum ether and ethyl acetate yielded the product of Example 55. The product was a white solid with a yield of 70.1% and a melting point of 204.4–205.5 °C. 1 H NMR (600MHz, DMSO-d6) δ8.25–8.21(m,2H),8.14(d,J=2.4Hz,1H),7.94(dd,J =14.4,2.4Hz,1H),4.79–4.72(m,1H),4.14–4.10(m,1H),3.90–3.86(m,4 H),3.75–3.71(m,1H),3.48–3.46(m,4H),3.43–3.41(m,2H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5, 154.8,153.5,152.5,149.1(d,J C-F =257.0Hz), 147.1(d,J C-F =256.4Hz),145.6,144.7,133.0,130.0, 115.6,72.6,47.6,45.8,41.9,40.5,22.9.

[0274] Example 57 Preparation of (S)-N-((3-(6-(4-(2-aminopyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0275] 150 mg of intermediate C-6 (0.35 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 200 μL of triethylamine (1.4 mmol) and 58.3 mg of 2-amino-4-chloropyrimidine (0.45 mmol) were added. The reaction was carried out overnight at 70 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol):V(triethylamine) = 30:1:1] to obtain the product of Example 57. The product was a white solid with a yield of 60.9% and a melting point of 195.6–196.7 °C. 1 H NMR(600MHz,DMSO-d6)δ8.28–8.25 (m,1H),8.15(d,J=2.4Hz,1H),7.97–7.88(m,3H),7.89(dd,J=7.8,2.4Hz,1H),6.57(d,J=7.8 Hz,1H),4.78–4.74(m,1H),4.14–4.11(m,1H),3.75–3.72(m,1H),3.47–3.46(m,4H),3.43–3.41(m,4H),1.84(s,3H). 13 C NMR(150MHz,DMSO-d6)δ170.5,161.7,155.1,154.8,149.1(d, J C-F =256.4Hz),145.4,143.4,133.0,130.1,115.6,115.5,95.4,72.7,47.6,47.5,41.9,22.9.

[0276] Example 58 Preparation of (S)-N-((3-(6-(4-(4-aminopyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0277] 150 mg of intermediate C-6 (0.35 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 34 mg of p-toluenesulfonic acid monohydrate (0.175 mmol) and 136 mg of 4-amino-2-chloropyrimidine (1.05 mmol) were added. The reaction was carried out overnight at 70 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(dichloromethane):V(methanol):V(triethylamine) = 30:1:1] to obtain the product of Example 58. The product was a white solid with a yield of 60.9% and a melting point of 196.6–197.7 °C. 1 H NMR(600MHz, DMSO-d6)δ 8.25(t,J=6.0Hz,1H),8.14(d,J=2.4Hz,1H),7.94(dd,J=14.4,2.4Hz,1H),7.77(d,J=6.0Hz, 1H),7.48–7.10(m,2H),5.94(d,J=6.0Hz,1H),4.79–4.72(m,1H),4.13–4.10( m,1H),3.80–3.78(m,4H),3.75–3.72(m,1H),3.43–3.40(m,6H),1.84(s,3H). 13 CNMR(150MHz,DMSO-d6) δ170.5,164.5,154.8,149.1(d,J C-F =256.7Hz),145.9,138.1,133.0,130.0,128.5,126.0,115.6,72.6, 47.7,43.9,41.9,22.9,21.3.

[0278] Preparation of intermediate D-1

[0279] 1.00 g of 1-amino-3-chloropropane-2-ol hydrochloride (6.85 mmol) was dissolved in 50 mL of dichloromethane. Then, 1.63 mL of dichloroacetyl chloride (17.1 mmol) and 2.86 mL of triethylamine (20.55 mmol) were added. The mixture was stirred overnight under reflux. After cooling, 20 mL of water was added, followed by extraction with 3 × 20 mL of dichloromethane. The organic phases were combined, washed with saturated brine, concentrated by vacuum distillation, and precipitated by cooling at -78 °C with petroleum ether to obtain intermediate D-1, the target product. The product was a yellow solid with a yield of 87.7% and a melting point of 37.4–39.7 °C. 1H NMR (600MHz, DMSO-d6) δ 8.80 (t, J = 6.0 Hz, 1H), 6.83 (s, 1H), 6.45 (s, 1H), 5.25–5.21 (m, 1H), 3.96–3.77 (m, 2H), 3.51–3.49 (m, 2H).

[0280] Preparation of intermediate D-2

[0281] At 0 °C, 100 mg of compound C-5 (0.23 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran under nitrogen protection. At -78 °C, 100 mg of lithium tert-butoxide (1.15 mmol) was added to a three-necked flask, and the mixture was stirred for 20 min. Then, 232 mg of intermediate D-1 (0.7 mmol) dissolved in 1 mL of anhydrous tetrahydrofuran was added. The mixture was reacted at -78 °C for 1 h, then allowed to rise naturally to room temperature and stirred for 16 h. The reaction was monitored by TLC until complete. The reaction was quenched with water, the solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate and water (3 × 40 mL). The organic phases were combined, washed with saturated brine, and the solvent was removed by distillation under reduced pressure to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:1] to obtain the target product intermediate D-2. The product was a white solid with a yield of 68.5% and a melting point of 150.1–153.2 °C. 1 HNMR(600 MHz, DMSO-d6)δ8.98(t,J=6.0Hz,1H),8.11(d,J=2.4Hz,1H),7.91(dd,J=14.4,2.4Hz,1H), 6.50(s,1H),4.86–4.82(m,1H),4.17–4.14(m,1H),3.75–3.73(m,1H), 3.55–3.54(m,2H),3.46–3.45(m,4H),3.29–3.28(m,4H),1.42(s,9H).

[0282] Example 59 Preparation of (S)-2,2-dichloro-N-(3-(6-(4-(2,5-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0283] 100 mg of intermediate D-2 (0.2 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 111 μL of triethylamine (0.8 mmol) and 30 μL of 2,4,5-trichloropyrimidine (0.26 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:1] to obtain the product of Example 59. The product was a white solid with a yield of 45.9% and a melting point of 100.7–101.5 °C. 1 H NMR (600MHz, DMSO-d6) δ9.07 (t, J=6.0Hz, 1H), 8.34 (s, 1H),8.13(d,J=2.4Hz,1H),7.93(dd,J=14.4,2.4Hz,1H),6.54(s,1H),4.85–4.83(m,1H),4. 17–4.14(m,1H),3.89–3.87(m,4H),3.78–3.75(m,1H),3.56–3.53(m,2H),3.49–3.47(m,4H). 13 C NMR(150MHz,DMSO-d6)δ165.0,160.4,159.0,157.1,154.6,149.0(d,J C-F =256.3Hz),145.7, 133.1,129.8,115.6,115.1,72.1,67.1,52.5,47.0,42.7,7.7.

[0284] Example 60: Preparation of (S)-N-((3-(6-(4-(5-bromo-2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)-2,2-dichloroacetamide

[0285] 100 mg of intermediate D-2 (0.2 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 111 μL of triethylamine (0.8 mmol) and 33 μL of 2,4-dichloro-5-bromopyrimidine (0.26 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:1] to obtain the product of Example 60. The product was a white solid with a yield of 33.9% and a melting point of 104.1–104.8 °C. 1 H NMR (600MHz, DMSO-d6) δ9.01 (t, J=6.0Hz, 1H), 8.46(s,1H),8.13(d,J=2.4Hz,1H),7.93(dd,J=14.4,2.4Hz,1H),6.51(s,1H),4.86–4.82(m ,1H),4.17–4.14(m,1H),3.86–3.84(m,4H),3.78–3.73(m,1H),3.56–3.54(m,2H),3.49–3.47 (m,4H). 13 C NMR(150MHz,DMSO-d6)δ165.0,162.0,157.8,154.6,149.1(d,J C-F =257.1Hz), 145.7,133.0,129.9,115.6,115.5,104.1,72.1,67.1,47.6,47.3,46.1,42.7.

[0286] Example 61: Preparation of (S)-2,2-dichloro-N-((3-(6-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0287] 100 mg of intermediate D-2 (0.2 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 111 μL of triethylamine (0.8 mmol) and 30 μL of 2,4-dichloro-5-methylpyrimidine (0.26 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:1] to obtain the product of Example 61. The product was a white solid with a yield of 47.6% and a melting point of 157.0–157.6 °C. 1 H NMR (600MHz, DMSO-d6) δ9.04(t,J=6.0Hz,1H), 8.13(d,J=2.4Hz,1H),8.06(s,1H),7.92(dd,J=14.4,2.4Hz,1H),6.53(s,1H),4.86–4.82(m, 1H),4.17–4.14(m,1H),3.77–3.75(m,1H),3.68–3.66(m,4H),3.56–3.51(m,2H),3.47–3.44(m,4H),2.24(s,3H). 13 C NMR(150MHz,DMSO-d6)δ165.0,160.1,157.2,154.6,149.1(d,J C-F = 256.4Hz),145.8,133.1,129.8,116.2,115.6,115.5,72.1,67.1,47.8,46.9,46.0,42.7,17.3.

[0288] Example 62: Preparation of (S)-2,2-dichloro-N-((3-(6-(4-(2-chloro-5-fluoropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide

[0289] 100 mg of intermediate D-2 (0.2 mmol) was dissolved in 5 mL of dichloromethane. The mixture was reacted with 1 mL of trifluoroacetic acid under ice bath conditions for 2 h. The reaction was monitored by TLC until complete. Triethylamine was added to adjust the alkalinity. After removing the solvent, the product was dissolved in 4 mL of dioxane solution. 111 μL of triethylamine (0.8 mmol) and 43 mg of 2,4-dichloro-5-fluoropyrimidine (0.26 mmol) were added. The reaction was carried out overnight at 50 °C. The reaction was monitored by TLC until complete. Dioxane was removed by distillation. The product was extracted with dichloromethane and water (3 × 10 mL). The organic phases were combined, and the solvent was removed by vacuum distillation to obtain the crude product. Separation was performed by silica gel column chromatography [V(petroleum ether):V(ethyl acetate) = 1:1] to obtain the product of Example 62. The product was a white solid with a yield of 28.3% and a melting point of 126.9–127.6 °C. 1 H NMR (600MHz, DMSO-d6) δ9.03 (t, J=6.0Hz, 1H), 8.23 ​​(d, J=6.6Hz,1H),8.13(d,J=2.4Hz,1H),7.93(dd,J=14.4,2.4Hz,1H),6.52(s,1H),4.86–4.82(m ,1H),4.17–4.14(m,1H),3.88–3.86(m,4H),3.77–3.74(m,1H),3.56–3.54(m,2H),3.49–3.46 (m,4H). 13 C NMR(150MHz,DMSO-d6)δ165.0,154.6,153.4,152.5,149.1(d,J C-F =256.3Hz), 147.1(d,J) C-F =256.4Hz),144.8,133.1,129.9,115.6,115.5,72.1,67.1,47.7,46.0,45.8,42.7.

[0290] Experimental Example 1: In vitro antibacterial activity experiment of the compound of the present invention

[0291] 1. Test samples: Compounds synthesized in Examples 1-62.

[0292] 2. Experimental Methods

[0293] After sterilization, the test samples were serially diluted with MH broth to a series of concentrations, with the highest concentration being 128 μg / mL. 100 μL of MH broth was added to the 12th well of each row of a 96-well plate as a blank control, 50 μL of MH broth was added to the 11th well, and 50 μL of the experimental solution was added sequentially from the 10th well to the 1st well, in ascending order of concentration.

[0294] Select appropriate amounts of the test strain and standard strain and inoculate them into MH broth suitable for their growth. Incubate at 37°C for 24 hours. Dilute the grown bacterial solution with MH broth to obtain the test bacterial solution. Inoculate 50 μL of the bacterial solution into wells 1-11, mix thoroughly by pipetting, and incubate at 37°C for 18-24 hours. Observe the experimental results against a black background. Wells with bacterial growth will show turbidity or bacterial sediment at the bottom, while wells without bacterial growth will have clear and transparent culture without sediment. The lowest drug concentration contained in wells without bacterial growth is the minimum inhibitory concentration, or MIC.

[0295] 3. Experimental Results

[0296] The experimental results are shown in Tables 3 and 4.

[0297] Table 3. MIC (μg / mL) of the compounds prepared in Examples 1-30 against Gram-positive bacteria.

[0298]

[0299]

[0300] Note: ATCC-25923 is Staphylococcus aureus; ATCC-49619 is Streptococcus pneumoniae; ATCC-29212 is Enterococcus faecalis; ATCC-6633 is Bacillus subtilis; ATCC-35924 is Staphylococcus xylose.

[0301] Table 4. MIC (μg / mL) of the compounds prepared in Examples 31-62 against Gram-positive bacteria.

[0302]

[0303]

[0304] Note: ATCC-25923 is Staphylococcus aureus; ATCC-49619 is Streptococcus pneumoniae; BNCC-109047 is Bacillus subtilis; ATCC-29212 is Enterococcus faecalis; ATCC-35924 is Staphylococcus xylose; ATCC-19111 is Listeria monocytogenes.

[0305] In vitro antibacterial activity tests showed that the pyridine-containing bioxazolidinone compounds provided by this invention all have definite antibacterial activity.

Claims

1. A compound containing pyridine bioxazolidinones, characterized in that, Selected from any of the following compounds: (S)-N- ((3-(6-(4-(2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N- ((3-(6-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-(benzylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-morpholinidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(5-fluoro-6-(4-(2-(methylamino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N- ((3-(5-Fluoro-6-(4-(2-(isopropylamino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(5-Fluoro-6-(4-(2-(((3-morpholinopropyl)amino)pyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(4-methylpiperidin-1-yl)pyrimidin)4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-(naphth-1-ylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-(((2,2-difluoroethyl)amino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -(3-(6-(4-(2-(quinolin-5-ylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -(3-(6-(4-(2-(phenylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-(allylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -(3-(6-(4-(2-(propyrylamino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-(((6-chloropyridin-3-yl)amino)pyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(6-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)- 4-(4-(5-(5-(acetamidomethyl)-2-oxazolidinone-3-yl)-3-fluoropyridin-2-yl)piperazin-1-yl)-2-(methylthio)pyrimidine-5-ethyl acetate; (S)-N -((3-(5-fluoro-6-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(4,6-dichloropyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S) -N-((3-(6-(4-(2,6-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2,5-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(5-bromo-2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(5-fluoro-6-(4-(2,5,6-trichloropyrimidin-4-yl)piperazin-1-yl)pyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S) -N-((3-(6-(4-(2-chloro-5-fluoropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S) -N-((3-(6-(4-(2-aminopyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S) -N-((3-(6-(4-(4-aminopyrimidin-2-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S) -2,2-Dichloro- N -(3-(6-(4-(2,5-dichloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S)-N -((3-(6-(4-(5-bromo-2-chloropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)-2,2-dichloroacetamide; (S) -2,2-Dichloro- N -((3-(6-(4-(2-chloro-5-methylpyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide; (S) -2,2-Dichloro- N -((3-(6-(4-(2-chloro-5-fluoropyrimidin-4-yl)piperazin-1-yl)-5-fluoropyridin-3-yl)-2-oxazolidinone-5-yl)methyl)acetamide.

2. The use of the pyridine-containing bioxazolidinone compound of claim 1 in the preparation of an antibacterial drug; wherein the bacteria are Gram-positive bacteria.

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