Substituted phenyloxazolidinones for antimicrobial therapy

Abstract

To provide a compound having antibacterial activity. [Solution] The present invention relates to a novel oxazolidinone (formula I) having ring A characterized by a monocyclic, bicyclic, or spirocyclic substituent containing nitrogen. The present invention relates to TIFF2026092059000321.tif3764 or pharmaceutically acceptable salts thereof, their preparations, and their use alone or in combination with other anti-infective agents as drugs for treating Mycobacterium tuberculosis and other microbial infections. The present invention generally relates to compounds having antibacterial activity, more specifically, anti-tuberculosis properties. In particular, the present invention relates to substituted phenyloxazolidinone compounds useful for treating tuberculosis in patients requiring treatment for tuberculosis.

Description

[Technical Field]

[0001] Field of Invention This invention relates to compounds that have antibacterial activity in general, and more specifically, to compounds that have anti-tuberculosis properties. In particular, this invention relates to substituted phenyloxazolidinone compounds that are useful for treating tuberculosis in patients requiring treatment for tuberculosis.

[0002] All documents cited or relied upon below are expressly incorporated herein by reference. [Background technology]

[0003] Background of the Invention Linezolid is a first-in-class drug and was approved in 2000 for numerous clinical uses, including the treatment of hospital-acquired and community-acquired pneumonia and skin infections caused by Staphylococcus aureus / methicillin-resistant S. aureus, vancomycin-resistant Enterococci, and Streptococcus pneumoniae (Pen-S). Linezolid is used in the treatment of Mycobacterium tuberculosis, including multidrug-resistant (MDR) and broadly drug-resistant (XDR) strains. It exhibits in vitro bacteriostatic activity at a minimum inhibitory concentration (MIC) of less than 1 μg / ml. However, this only demonstrates moderate activity in a mouse model of tuberculosis. Nevertheless, linezolid has been used off-label in combination regimens to treat multidrug-resistant tuberculosis.

[0004] Currently, oxazolidinones in clinical development exhibit myelotoxicity in animals after long-term administration (i.e., more than one month), thought to be related to mitochondrial protein synthesis (MPS) inhibition, with very narrow or no safety margins. Since the antimicrobial action of this class of compounds is inhibition of microbial protein synthesis, the MPS inhibition and resulting myelotoxicity exhibited by these compounds are considered mechanism-specific. These oxazolidinones generally exhibit high clearance, so high doses (e.g., 500 mg to 1600 mg per day) are required in the clinical treatment of TB or other indications, which are the development targets of these oxazolidinones, to achieve effective exposure. Therefore, it would be highly desirable to identify a new generation of oxazolidinones for TB treatment that demonstrate reduced MPS inhibition and associated myelotoxicity, resulting in improved efficacy and efficacy against TB, reduced systemic clearance to allow for daily dose reductions to less than 500 mg, and improved safety margins for long-term administration. [Overview of the Initiative] [Means for solving the problem]

[0005] Summary of the Invention The present invention relates to a novel oxazolidinone of formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof: [ka] [In the formula, R is independently OR1, OC(O)R2, OC(O)NHR2, OS(O2)R2, NHS(O)2R2, NR3R4, NHC(O)R5. R' and R'' are independently H, F, Cl, or OMe. Each R1 is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with 1 to 4 groups selected from halo, hydroxy, C1-C6 alkyl, or C1-C6 alkyloxy. Each R2 is independently a C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl, or aryl, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. Each R3 and R4 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, or aryl, or R3 and R4, together with the nitrogen to which they are bonded, form a 4-8 membered heterocyclyl or heteroaryl having 1-3 additional heteroatoms selected from O, S, or N, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with 1-4 groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, CF3, NO2, or CN. Each R5 is independently a C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, heteroaryl, or aryl group, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl group is optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. Ring A is, [ka] [In the formula, Each of R6 and R7 is independently H, F, CH3, CH2CH3, CF3, and phenyl. X = O, S, SO, SO2, Y = O, S, SO, SO2 and NR8, m is either 1 or 2. n is either 1 or 2. p is either 1 or 2. q is either 1 or 2. R8 is independently H, C1-C4 alkyl, C3-C6 cycloalkyl, COCH3 [and p-toluenesulfonyl, where the alkyl and cycloalkyl groups are optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2] [Selected from] Regarding.

[0006] In a further embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of formula I or a salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and / or additives.

[0007] In a further embodiment, the present invention provides a method for treating a microbial infection in humans by administering a therapeutically effective amount of a compound of formula I or a salt, hydrate, or solvate thereof to a patient requiring treatment for a microbial infection.

[0008] In a further embodiment, the present invention comprises a pharmaceutical composition of formula I or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective agents.

[0009] In a further embodiment, the present invention relates to a compound according to formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use as an anti-tuberculosis (TB) agent in humans. [Modes for carrying out the invention]

[0010] Detailed description of the invention One aspect of the present invention is to provide a novel compound according to Formula I as shown and described above. Specifically, the compounds of the present invention are useful antimicrobial agents effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria, Mycobacterium tuberculosis, Mycobacterium avium, and the like. As a result, the present invention provides a novel compound according to Formula I, and its pharmaceutically acceptable salts, hydrates, or solvates. The values ​​of the variables in Formula I are provided in the following paragraphs.

[0011] Table 1 below shows some specific examples of the compounds of the present invention, by displaying their structures, as well as their in vitro activity against Mycobacterium tuberculosis H37Rv strain and in vitro MPS inhibitory activity when tested as described in Examples 9 and 10 below. As shown in Table 1 below, potent anti-tuberculosis agents exhibit low MIC values ​​(certain compounds with an MIC of less than 1 μg / mL). Conversely, high MPS inhibitory IC values... 50 This represents a decrease in mitochondrial protein synthesis activity in vitro and a reduction in myelosuppressive toxicity in vivo. In certain embodiments of the present invention, the compound having the best therapeutic index is a relatively high MPS inhibitory IC20 with a relatively low MIC value. 50 These are compounds that exhibit the following characteristics. Representative compounds of the present invention are shown in Table 1 (in the table, the item "NA" (i.e., "Unavailable") indicates that a specific value could not be measured). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15]

[0012] definition Where used herein, unless otherwise indicated, “alkyl” includes branched and straight saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout this specification; for example, methyl is referred to as “Me” or the conventional abbreviation containing CH3, or as the symbol for an extended bond without a defined terminal group, e.g., [ka] It can be represented by, for example, ethyl is represented by "Et" or CH2CH3, propyl is represented by "Pr" or CH2CH2CH3, and butyl can be represented by "Bu" or CH2CH2CH2CH3.1~6 "Alkyl" (or "C1-C6 alkyl") refers to a branched or linear alkyl group containing a specified number of carbon atoms, including all isomers. 1~6 Alkyl includes all hexylalkyl and pentylalkyl isomers, as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, ethyl, and methyl. Unless otherwise specified, 1 to 10 carbon atoms are intended for linear or branched alkyl groups. 1~6 The alkyl group may be unsubstituted, or it may be substituted with 1 to 3 fluorine atoms or 1 to 3 chlorine atoms.

[0013] "Cycloalkyl" refers to a C without heteroatoms. 3~10 It refers to a carbon ring. For example, cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and decahydronaphthyl.

[0014] "Aryl" refers to monocyclic and bicyclic aromatic rings containing 6 to 12 carbon atoms. Examples of aryls include, but are not limited to, phenyl, naphthyl, and indenyl. Aryls also include monocyclic rings fused to an aryl group. Examples include tetrahydronaphthyl and indanyl.

[0015] Unless otherwise specified, a "heterocyclyl" is a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered monocyclic saturated ring containing 1 or 2 heteroatoms selected from N, O, and S. This refers to compounds whose bonding sites can be carbon or nitrogen. Examples of "heterocyclyls" include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, oxazolidinyl, and imidazolidinyl. The term also includes non-aromatic partially unsaturated monocyclic rings, such as 2- or 4-pyridone bonded via nitrogen, or N-substituted (1H,3H)-pyrimidine-2,4-dione (N-substituted uracil). Heterocyclyls may also include such parts in charged forms, such as piperidinium.

[0016] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring or ring system having 5 to 10 atoms and containing 1 to 3 heteroatoms selected from N, O, and S. Examples, but not limited to, include oxadiazolyl, thiadiazolyl, pyrrolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyrimidinyl, pyridadinyl, pyrazinyl, isoxazolyl, triazolyl, isothiazolyl, pyrazolyl, imidazolyl, pyridyl, pyridinyl, oxazolyl, thiazolyl, tetrazolyl, and others. Heteroaryls also include aromatic heterocyclic groups fused to non-aromatic or partially aromatic heterocyclic rings, and aromatic heterocyclic groups fused to cycloalkyl rings. Further examples of heteroaryls, but not limited to, include imidazopyridinyl, imidazopyridazinyl, pyrazolopyrazolyl, indazolyl, thienopyrazolyl, pyrazolopyridinyl, and imidazothiazolyl. Heteroaryls also include charged forms of such groups, such as pyridinium. In some embodiments, heteroaryls are triazolyl, imidazolyl, oxadiazolyl, pyrazolyl, oxazolyl, and pyridinyl.

[0017] Unless otherwise specified, "heterocyclic alkyl" includes both branched and linear saturated aliphatic hydrocarbon groups bonded to the carbon or nitrogen atom of the heterocyclyl as described above.

[0018] "Halogen (or halo)" includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iod). In one embodiment, the halogen is chlorine or fluorine.

[0019] Substitution by the specified substituent is possible on any atom in a ring (e.g., an aryl, heteroaryl ring or saturated heterocyclic ring), provided that such ring substitution is chemically acceptable and results in a stable compound. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can be made to remain essentially unchanged, over a period of time sufficient for the use of the compound for the purposes described.

[0020] Under the standard nomenclature used throughout this disclosure, the terminal portion of the specified side chain is described first, followed by the adjacent functional groups proceeding towards the point of attachment. For example, C 1~5 alkyl COOR is

Chemical formula

[0021] When variables (e.g., R, R x etc.) appear more than once in any component or formula, their definitions at each appearance are independent of their definitions at all other appearances. In addition, combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0022] In the selection of the compounds of the present disclosure, those skilled in the art will recognize that various substituents, namely, R 1 , R 2 , R, etc. should be selected in accordance with the general principles of chemical structure connectivity and stability.

[0023] The term "substituted" is used to include multiple degrees of substitution by the specified substituent. Where multiple substituents are claimed, the substituted compound may be independently substituted by one or more of these disclosed substituents. Independently substituted means that the substituents (two or more) may be the same or different.

[0024] If a substituent or variable has multiple definitions, it is defined as one selected from the group of specified definitions.

[0025] salt: Compounds of structural formula I also include pharmaceutically acceptable salts. The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable base or acid, including an inorganic or organic base or acid. A pharmaceutically acceptable salt of a basic compound refers to a non-toxic salt of the compound of the present invention, which is generally prepared by mixing a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, butyrate, camphorate, camphorsulfonate, cansylate, carbonate, clavulanate, citrate, edetate, edisylate, estolate, Esylate, fumarate, gluceptate, gluconate, gluta These include minates, hydrobroms, hydrochlorides, lactobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl sulfates, methanesulfons, phosphates / diphosphates, polygalacturonic acids, propions, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, theoclates, thiocyans, tosylates, triethiodides, valers, etc. Appropriate pharmaceutically acceptable salts of acids encompassed by Formula I include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese triphosphate, potassium, sodium This includes salts produced from inorganic bases, such as zinc. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0026] Solvates and hydrates of the compound of formula I are also included in the present invention.

[0027] The present invention also discloses a process for synthesizing the compound of formula I, as described below.

[0028] One aspect of the present invention relates to a compound according to formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use in a method for treating microbial infections in humans.

[0029] Another aspect of the present invention relates to a human patient requiring treatment for a microbial infection. A method for treating a disease, comprising administering to the patient a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0030] In a further embodiment, the present invention provides a pharmaceutical composition of formula I or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective agents.

[0031] In a further embodiment, the present invention relates to a compound according to formula I or a pharmaceutically acceptable salt, hydrate, or solvate thereof for use as an anti-tuberculosis (TB) agent in humans.

[0032] Although it may be possible to administer the compounds of the present invention as starting chemical substances, it is preferred to present them as pharmaceutical compositions. Thus, according to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more of its pharmaceutical carriers and optionally one or more other therapeutic components. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to its recipient.

[0033] Preparations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intra-articular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend on the condition and disorder of the recipient. Tablets, capsules, intraocular topical preparations and parenteral solutions are common for aminoglycosides. The preparations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (the "active ingredient") with a carrier which constitutes one or more accessory ingredients. In general, the preparations are prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired preparation.

[0034] Preparations of the present invention suitable for oral administration can be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0035] Tablets can be prepared by compression or molding, optionally with one or more auxiliary components. Compressed tablets can be prepared by compressing, in a suitable machine, an active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, glidant, surfactant or dispersant. Molded tablets can be prepared by molding, in a suitable machine, a mixture of powdered compounds moistened with an inert liquid diluent. Tablets can be optionally coated or scored and formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

[0036] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents, and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents. The formulations may be presented in unit dose form in a multiple-dose container, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state which requires only the addition of a sterile liquid carrier, for example, saline, phosphate-buffered saline (PBS), etc., immediately prior to use. Solutions and suspensions for immediate injection can be prepared from sterile powders, granules and tablets of the type described above. of sterile powders, granules and tablets.

[0037] Preferred unit dosage formulations contain an active ingredient in an effective dose or an appropriate fraction thereof as described hereinbelow.

[0038] It should be understood that, in addition to the particularly mentioned ingredients, the formulations of the present invention may include other conventional agents in the art related to the type of formulation in question, for example, formulations suitable for oral administration may include flavoring agents.

[0039] Abbreviations Throughout the following synthetic schemes and examples, the abbreviations are used with the following meanings, unless otherwise indicated. Ac stands for acetate or acetyl. aq. is water-based, Ar is aryl, Bn is benzyl, BnNH2 is a benzylamine, Boc is tert-butylcarbamoyl, br is wide, Bu is butyl, t Bu is tert-butyl, n-BuLi is n-butyllithium, CbzCl is benzyl chloroformate, CFU is a colony-forming unit, CO2 is carbon dioxide, COX-1 is cyclooxygenase I, c Pr is cyclopropyl, DCM is dichloromethane, DIPEA is N,N-diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMEM is Dulbecco's modified Eagle medium. DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, ELISA is an enzyme-linked immunosorbent assay. ESI is electrospray ionization. Et is ethyl, Et3N is triethylamine, Et2O is diethyl ether, EtOH is ethanol, siRNA is ethyl acetate, FBS is fetal bovine serum. Halo is a halogen (for example, fluorine or chlorine), 1H-NMR is proton nuclear magnetic resonance, 13 C-NMR is carbon nuclear magnetic resonance, H9C2 is a cell line derived from rat cardiomyoblasts, HPLC is high performance liquid chromatography, HRMS is high resolution mass spectrometry, Hz is hertz, i is iso, IC 50 is the half maximal inhibitory concentration, Kg is kilogram, M is molar concentration, Me is methyl, μg is microgram, MeCN is acetonitrile, MeOH is methanol, MsCl is methanesulfonyl chloride, MHz is megahertz, mm is millimeter, μL is microliter, mM is millimolar concentration, μM is micromolar concentration, mmol is millimole, MABA is microplate alamar blue assay, MIC is the minimum inhibitory concentration, MPS is mitochondrial protein synthesis, m / z is mass-to-charge ratio, n is normal, NEAA is non-essential amino acid, nm is nanometer, nPr is n-propyl, p is para, PE is petroleum ether, Ph is phenyl, Pr is propyl, rt is room temperature, sec is second, SDH-A is succinate dehydrogenase-A, tert is the third, TFA is trifluoroacetic acid, TsCl is p-toluenesulfonyl chloride, TMSI is trimethylsilyl iodide, TPP is triphenylphosphine, TsNH2 is a p-toluenesulfonamide, Tosyl is p-toluenesulfonyl, THF is tetrahydrofuran, TLC is a thin-layer chromatography technique. [Examples]

[0040] Synthetic methods for preparing representative compounds of the present invention are illustrated in the following examples. Starting materials can be commercially available or prepared by procedures known in the art or by procedures illustrated herein. The following examples are intended to illustrate the present invention and are not intended to limit its scope, nor should they be constructed to do so.

[0041] (Example 1) [1,4] Preparation of thiazepane (1a) [ka]

[0042] Step 1: Synthesis of dihydro-2H-thiopyran-4(3H)-oneoxime(1a-1) [ka] To a solution of dihydro-2H-thiopyran-4(3H)-one (10 g, 0.086 mol) and hydroxylamine hydrochloride (10.4 g, 0.15 mol) in H2O (100 mL) and ethanol (40 mL), sodium acetate (13.1 g, 0.16 mol) was added. The mixture was refluxed for 4 hours, the organic solvent was removed under vacuum, the residue was cooled in an ice bath, and 8.92 g of solid was obtained by filtration in a yield of 79%. 1 H-NMR (400 MHz, CDCl3) δ: 2.88 (m, 2H), 2.80 (m, 2H), 2.74 (m, 2H), 2.57 (m, 2H).

[0043] Step 2: Synthesis of 1,4-thiazepan-5-one (1a-2) [ka] A mixture of dihydro-2H-thiopyran-4(3H)-oneoxime (4.01 g, 0.03 mol) in polyphosphate was heated at 115°C for 15 minutes, cooled to room temperature, ice water was added, and the mixture was extracted five times with siRNA. The combined organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 2.4 g of the product as a brown solid in 60% yield. 1 H-NMR (400 MHz, CDCl3) δ: 6.79 (brs, 1H), 3.63 (m, 2H), 2.94 (m, 2H), 2.74 (m, 4H).

[0044] Step 3: Synthesis of 1,4-thiazepane(1a) [ka] To a solution of 1,4-thiazepan-5-one (2.07 g, 15.7 mmol) in dry THF, LiAlH4 (0.66 g, 17.3 mmol) was added at 0°C, and the mixture was then stirred at room temperature for 4 hours. H2O (0.7 mL), 15% NaOH (0.7 mL), and H2O (2.1 mL) were successively added to the reaction. The mixture was filtered to obtain 1.77 g of product in 96% yield. 1H-NMR (400 MHz, CDCl3) δ: 3.07 (m, 2H), 2.98 (m, 2H), 2.75 (m, 4H), 1.93 (m, 2H).

[0045] (Example 2) Preparation of 1,5-thiazocan hydrochloride (1b) [ka] [ka]

[0046] Step 1: Synthesis of dimethyl (1b-1) 3,3'-(benzylazanediyl)dipropanoate [ka] A solution of benzylamine (10.7 g, 0.1 mol) in MeOH (50 mL) was added dropwise to a solution of methyl acrylate (18.9 g, 0.022 mol) in MeOH (100 mL) at room temperature. The resulting mixture was refluxed for 8 hours and evaporated under vacuum to obtain 27.9 g of product in quantitative yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.28 (m., 5H), 3.64 (s, 2H), 3.59 (s, 6H), 2.80 (m, 4H), 2.47 (m, 4H).

[0047] Step 2: Synthesis of 3,3'-(benzylazanediyl)bis(propan-1-ol)(1b-2) [ka] To a solution of dimethyl 3,3'-(benzylazanediyl)dipropanoate (4.47 g, 16.0 mmol) in dry THF, LiAlH4 (0.77 g, 20.2 mmol) was added at 0°C, and the mixture was stirred at room temperature for 24 hours. MeOH (1.5 mL), 15% NaOH (1.0 mL), and H2O (1.0 mL) were successively added to the reaction. The mixture was filtered to obtain 3.4 g of product in 91% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.31 (m, 5H), 3.68 (t, J = 5.6 Hz, 5.6 Hz, 4H), 3.57 (s, 2H), 2.63 (t, J = 6.4 Hz, 6.0 Hz, 4H), 1.76 (m, 4H).

[0048] Step 3: Synthesis of N-benzyl-3-bromo-N-(3-bromopropyl)propan-1-amine (1b-3) [ka] To a solution of 3,3'-(benzylazanediyl)bis(propan-1-ol) (447 mg, 2.0 mmol) in dry CH2Cl2, PBr3 was added dropwise at 0°C, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. 0.43 g of the product was obtained as a yellow oil in 61% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.27 (m, 5 H), 3.56 (s, 2 H), 3.44 (t, J = 6.8 Hz, 6.4 Hz, 4 H), 2.58 (t, J = 6.4 Hz, 6.4 Hz, 4 H), 2.02 (m, 4 H).

[0049] Step 4: Synthesis of 5-benzyl-1,5-thiazocan (1b-4) [ka] To a solution of N-benzyl-3-bromo-N-(3-bromopropyl)propan-1-amine (1.0 g, 2.9 mmol) in ethanol, Na2S·9H2O (697 mg, 2.9 mmol) was added. The mixture was refluxed for 18 hours. The mixture was then cooled to room temperature, and the solvent was removed under vacuum. H2O and Et2O were added to the residue. The aqueous layer was extracted with Et2O, the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude product was used without purification.

[0050] Step 5: Synthesis of 1,5-thiazocan hydrochloride (1b) [ka] To a solution of 5-benzyl-1,5-thiazocane (8.6 g, 39 mmol) in CH2Cl2, (6.15 g, 43 mmol) was added at 0°C. The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under vacuum, and the residue was refluxed in MeOH for 3 hours. The mixture was concentrated and washed with Et2O. The crude product was used without purification.

[0051] (Example 3) Preparation of (1R,5S)-3-thia-6-azabicyclo[3.1.1]heptane (1c) [ka]

[0052] Step 1: Synthesis of 2,4-dibromopentanedioate diethyl (1c-1) [ka] To a solution of dihydro-2H-pyran-2,6(3H)-dione (11.4 g, 0.1 mol) and PBr3 (0.1 mL), Br2 (32 g, 0.2 mol) was added dropwise at 100 °C, and the mixture was stirred at 100 °C for 7 hours, then cooled to room temperature. HCl / EtOH (10 mL) was added to the reaction mixture and stirred overnight at room temperature. After evaporating the EtOH, Et2O was added to the residue, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated to obtain 32 g of product, which was used in the next step without purification.

[0053] Step 2: Synthesis of (2R,4S)-1-benzylazetidine-2,4-dicarboxylate diethyl (1c-2) [ka] A mixture of (2R,4S)-2,4-dibromopentanediate diethyl (54 g, 156 mmol), benzylamine (17 g, 159 mmol), and K2CO3 (25.9 g, 187.2 mmol) in toluene was refluxed for 24 hours. The mixture was washed with brine, dried, and concentrated. The crude product was purified by chromatography on silica gel to obtain 18.39 g of product in 41% yield. HRMS(ESI): m / z[M+H] + C 16 H 22 Calculated value for NO4: 292.1549; Measured value: 292.1542.

[0054] Step 3: Synthesis of ((2R,4S)-1-benzylazetidine-2,4-diyl)dimethanol (1c-3) [ka] A solution of (2R,4S)-1-benzylazetidine-2,4-dicarboxylate diethyl (0.8g, 2.75 mmol) in EtOH / MeOH (9:1; 10 mL) is prepared by adding CaCl 2 (0.92 g, 8.25 mmol) was added at room temperature. Then, NaBH4 (0.63 g, 16.5 mmol) was added in small amounts to the resulting stirred mixture. The reaction mixture was stirred overnight at room temperature. After that, H2O (5 mL) was added and the mixture was stirred for 30 minutes. The mixture was then concentrated under vacuum and partitioned between H2O (10 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted with CH2Cl2 (2 × 10 mL), the organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain 0.25 g of the product as a yellow oil. This product was used in the next step without further purification. MS(ESI): m / z[M+H] + :208.1477.

[0055] Step 4: Synthesis of (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate benzyl(1c-4) [ka] To a solution of ((2R,4S)-1-benzylazetidine-2,4-diyl)dimethanol (0.52 g, 2.9 mmol) in MeOH (10 mL), Pd(OH)2 (0.13 g) was added, and the mixture was stirred under H2 at room temperature for 2 hours. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in anhydrous CH2Cl2 (30 mL). To the resulting solution, DIPEA (0.37 g, 2.9 mmol) was added, followed by dropwise addition of CbzCl (0.44 g, 2.56 mmol). The mixture was stirred at room temperature for 2 hours, then quenched with H2O (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography using silica gel (5% MeOH in CH2Cl2) to obtain 0.33 g of the product as a yellow oily substance in 45% yield.

[0056] Step 5: Synthesis of (2R,4S)-benzyl-2,4-bis(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate(1c-5) [ka] To a solution of (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate benzyl (51 mg, 0.2 mmol) in CH2Cl2 (15 mL), Et3N (61 mg, 0.6 mmol) and then MsCl (70 mg, 0.6 mmol) were added dropwise. The mixture was stirred at room temperature for 5 hours, the reaction mixture was washed with 1N HCl and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography (5% MeOH in CH2Cl2) to obtain 65 mg of the product as a yellow oil in 80% yield. HRMS(ESI):m / z[M+H] + C 15 H 22 Calculated value for NO8S2: 408.0787; Measured value: 408.0780.

[0057] Step 6: Synthesis of (2R,4S)-benzyl-2,4-bis(bromomethyl)azetidine-1-carboxylate (1c-6) [ka] (2R,4S)-benzyl-2,4-bis(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (65 mg, 0.16 mm) in acetone (15 mL) A mixture of 139 mg and 1.6 mmol of LiBr was refluxed for 10 hours. The reaction mixture was evaporated, and H2O (20 mL) and Et2O (20 mL) were added to the residue. The aqueous layer was extracted with Et2O (2 × 20 mL), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain 51 mg of the product as a yellow oil in 85% yield. HRMS (ESI): m / z [M + H] + C 13 H 15 Calculated value of Br2NO2: 375.9548; Measured value: 375.9558.

[0058] Step 7: Synthesis of (1R,5S)-3-thia-6-azabicyclo[3.1.1]heptane-6-carboxylate benzyl(1c-7) [ka] To a solution of (2R,4S)-2,4-bis(bromomethyl)azetidine-1-carboxylate benzyl (0.77 g, 2.05 mmol) in DMF (5 mL), Na2S·9H2O (0.59 g, 2.46 mmol) was added. The mixture was stirred at room temperature for 45 minutes. H2O (20 mL) and HCl (25 mL) were added to the solution. The aqueous layer was extracted with HCl (2 × 20 mL), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (20-30% HCl in PE) to obtain 0.15 g of the product as a colorless oil in 28.7% yield. HRMS(ESI): m / z[M+H] + C 13 H 17 Calculated value of NO2S: 250.0902; Measured value: 250.0900.

[0059] Step 8: Synthesis of (1R,5S)-3-thia-6-azabicyclo[3.1.1]heptaneiodate (1c) [ka] To a solution of (1R,5S)-benzyl-3-thia-6-azabicyclo[3.1.1]heptane-6-carboxylate (0.19 g, 0.8 mmol) in anhydrous CH2Cl2 (20 mL), TMSI (0.39 g, 1.9 mmol) was added under Ar at 0°C. The resulting mixture was stirred at room temperature for 2 hours, and MeOH (5 mL) was added dropwise to the reaction. The resulting solution was stirred for a further 0.5 hours, and then evaporated to remove the solvent. The residue was washed with PE / siRNA (2:1) to obtain 0.24 g of crude product as a brown solid, which was used without purification.

[0060] (Example 4) Preparation of (1R,5S)-3-thia-8-azabicyclo[3.2.1]octaniodate (1d) [ka]

[0061] Step 1: Synthesis of cis-1-benzylpyrrolidine-2,5-dicarboxylate diethyl (1d-1) [ka] To a stirred solution of diethyl 2,5-dibromohexanediate (10.8 g, 30 mmol) and benzylamine (3.2 g, 30 mmol) in toluene (45 mL) and H2O (9 mL), K2CO3 (5 g, 36 mmol) was added at room temperature. The mixture was refluxed under Ar for 20 hours and then poured into H2O (30 mL). The aqueous layer was extracted with ELISA (2 × 20 mL), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, and purified by silica gel chromatography (10-20% ELISA in PE) to obtain 6.1 g of the product as a yellow oil in 67% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.35-7.22 (m, 5 H), 4.06-4.00 (m, 4 H), 3.97 (s, 2 H), 3.46 (brs, 2 H), 2.08-2.04 (m, 4 H), 1.19 (t, J = 7.1 Hz, 6 H).HRMS(ESI):m / z[M+H] + C 17 H 24 NO4 Calculated value: 306.1705; Measured value: 306.1695.

[0062] Step 2: Synthesis of cis-1-2,5-diethylpyrrolidine-1,2,5-tricarboxylate benzyl (1d-2) [ka] To a solution of cis-1-benzylpyrrolidine-2,5-dicarboxylate diethyl (5.4 g, 17.7 mmol) in MeOH (100 mL), 10% Pd / C (0.54 g) was added, and the mixture was shaken in a Parr shaker at 50 psi under H2 for 4 hours at room temperature. The suspension was filtered through a short Celite pad and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in anhydrous CH2Cl2 (50 mL) and cooled to 0°C. To the resulting solution, Et3N (2.2 g, 21.6 mmol) was added, followed by dropwise addition of CbzCl (3.7 g, 21.6 mmol). The mixture was stirred overnight at room temperature, and then quenched with H2O (50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was chromatographed on silica gel (5-20% ethyl acetate in PE). The product was purified by [method] and 5.22 g of the product was obtained as a yellow oily substance in 84% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.33-7.29 (m, 5 H), 5.19-5.10 (m, 2 H), 4.47 (m, 1 H), 4.40 (m, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 4.09 (q, J = HRMS(ESI):m / z[M+H] + C 18 H 24 Calculated value for NO6: 350.1604; Measured value: 350.1649.

[0063] Step 3: Synthesis of cis-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate benzyl(1d-3) [ka] To a solution of cis-1-2,5-diethylpyrrolidine-1,2,5-tricarboxylate benzyl (5.75 g, 16.4 mmol) in EtOH / MeOH (10:1; 300 mL), CaCl2 (5.5 g, 49.2 mmol) was added at room temperature. Then, NaBH4 (3.75 g, 98.4 mmol) was added in small increments to the resulting stirred mixture. The reaction mixture was stirred overnight at room temperature. Subsequently, H2O (50 mL) was added, and the mixture was stirred for 30 minutes. The mixture was then concentrated under vacuum and partitioned between H2O (100 mL) and siRNA (100 mL). The aqueous layer was extracted with siRNA (2 × 50 mL), the organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum to obtain 4.57 g of the product as a colorless oil. This product was used in the next step without further purification. 1 H-NMR (400 MHz, CDCl3) δ: 7.39-7.33(m, 5 H), 5.16 (s, 2 H), 4.09-3.82 (m, 4 H), 3.56 (d, J = 8.1 Hz, 2 H), 2.91 (brs, 2 H), 2.04-1.97 (m, 4 H).HRMS(ESI):m / z[M+Na] + C 14 H 19 Calculated value of NNaO4: 288.1206; measured value: 288.1196.

[0064] Step 4: Synthesis of cis-2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate benzyl(1d-4) [ka] A solution of the compounds cis-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate benzyl (4.35 g, 16.4 mmol), Et3N (3.65 g, 36.1 mmol), and DMAP (4.01 g, 32.8 mmol) in CH2Cl2 (50 mL) was cooled to 0°C. p-toluenesulfonyl chloride (6.88 g, 36.1 mmol) was added to this mixture all at once, and the resulting mixture was stirred overnight at room temperature. The mixture was then washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column chromatography (30-40% ethyl acetate in PE) to obtain 8.97 g of the product as a semi-solid in 95% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.73 (brs, 4 H), 7.36-7.29 (m, 9 H), 5.03-4.96 (m, 2 H), 4.15-3.89 (m, 6 H), 2.44 (s, 6 H), 1.87-1.83 (m, 4 H). 13 C-NMR (100 MHz, CDCl3) δ (rotamer): 165.30, 154.49, 144.90, 135.88, 132.61, 129.90, 128.55, 128.19, 127.89, 69.16, 68.87, 67.28, 57.30, 56.56, 26.61, 25.44, 21.63.HRMS(ESI):m / z[M+H] + C 28 H 32 Calculated value for NO8S2: 574.1564; Measured value: 574.1547.

[0065] Step 5: (1R, 5S)-benzyl-3-thia-8-azabicyclo[3.2.1]o Synthesis of cutan-8-carboxylate (1d-5) [ka] To a solution of cis-2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate benzyl (4.1 g, 7.1 mmol) in ethanol (25 mL) and H2O (25 mL), Na2S·9H2O (5.12 g, 21.3 mmol) was added. The mixture was refluxed for 5 hours. The mixture was then cooled to room temperature, and the solvent was removed under vacuum. H2O (20 mL) and siRNA (25 mL) were added to the residue. The aqueous layer was extracted with siRNA (2 × 20 mL), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (20-30% siRNA in PE) to obtain 1.38 g of the product as a colorless oil in 73% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.37-7.30 (m, 5 H), 5.16 (s, 2 H), 4.52-4.47 (m, 2 H), 3.22 (d, J = 11.6 Hz, 1 H), 3.11 (d, J = 10.8 Hz, 1 H), 2.12 (d, J = 12.8 Hz, 2 H), 2.06 (d, J = 1.2 Hz, 4 H). 13 C-NMR (100 MHz, CDCl3) δ: 152.95, 136.59, 128.40, 127.93, 127.80, 66.73, 53.94, 32.72, 32.08, 28.82, 27.99.HRMS(ESI):m / z[M+H] + C 14 H 18 Calculated value of NO2S: 264.1058; Measured value: 264.1113.

[0066] Step 6: Synthesis of (1R,5S)-3-thia-8-azabicyclo[3.2.1]octaniodate (1d) [ka] To a solution of (1R,5S)-benzyl-3-thia-8-azabicyclo[3.2.1]octane-8-carboxylate (0.24 g, 0.91 mmol) in anhydrous CH2Cl2 (20 mL), TMSI (0.44 g, 2.18 mmol) was added under Ar at 0°C. The resulting mixture was stirred at room temperature for 0.5 hours, and MeOH (0.26 mL) was added dropwise to the reaction. The resulting solution was stirred for a further 0.5 hours, and then evaporated to remove the solvent. The residue was washed with PE / siRNA (1:2) to obtain 0.21 g of the product as a yellow solid in 91% yield. Mp: 208~210°C. 1 H-NMR (400 MHz, CDCl3) δ: 8.92 (brs, 1 H), 8.72 (brs, 1 H), 4.38 (s, 2 H), 3.78 (d, J = 14.0 Hz, 2 H), 2.41-2.35 (m, 4 H), 2.24-2.22 (d, J = 7.6Hz, 2H). 13 C-NMR (100 MHz, CDCl3) δ: 55.67, 31.42, 27.23.HRMS(ESI):m / z[M+H] + C6H 12 Calculated value of NS: 130.0685; Measured value: 130.0686.

[0067] (Example 5) Preparation of 2-thia-6-aza-spiro[3.3]heptane(1e) [ka]

[0068] Step 1: Synthesis of 6-tosyl-2-oxa-6-azaspiro[3,3]heptane(1e-1) [ka] To a solution of KOH (9.04 g, 161 mmol) and 3-bromo-2,2-bis(bromomethyl)propan-1-ol (15.3 g, 47.0 mmol) in 500 mL of ethanol, p-tosylamide (17.9 g, 104 mmol) was added at room temperature, and the reaction mixture was refluxed for 20 hours. The solvent was removed by evaporation, and 100 mL of 8% NaOH solution was added. The suspension was stirred for a further 2 hours. The mixture was filtered, and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried to obtain the title product. Yield: 6.1 g (40.2%). 1 H-NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 4.59 (s, 4 H), 3.91 (s, 4 H), 2.46 (s, 3 H).HRMS(ESI-TOF + ):m / z[M+H] + C 12 H1 Calculated value of 6NO3S: 254.0825; Measured value: 254.0851.

[0069] Step 2: Synthesis of (3-(bromomethyl)-1-tosylazetidine-3-yl)methanol (1e-2) [ka] A suspension of 6-(p-toluenesulfonyl)-2-oxa-6-azaspiro[3.3]heptane (1e-1) (9.79 g, 38.7 mmol) in Et2O (200 mL) was met with dropwise addition of a hydrobromic acid solution (approximately 33% in AcOH) at 0°C. The resulting solution was stirred at room temperature for 30 minutes and adjusted to pH=8 with 1 mol / L NaOH. The phases were separated, and the aqueous phase was extracted with Et2O (3 × 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to obtain the title compound as a colorless solid. Yield: 10.0 g (77.4%). 1 H-NMR (400 MHz, CDCl3) δ: 7.74 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 3.68 (s, 2 H), 3.68 (s, 2 H), 3.62 (d, J = 8.4 Hz, 2 H), 3.55 (d, J = 8.4 Hz, 2 H), 3.45 (s, 2 H), 2.47 (s, 3 H).

[0070] Step 3: Synthesis of 3,3-bis(bromomethyl)-1-tosylazetidine (1e-3) [ka] (3-(bromomethyl)-1-tosylazetidine-3-yl)methanol (1e-2) (10.0 g, 30.0 mmol) was dissolved in CH2Cl2, and CBr4 (16.4 g, 49.4 mmol) was added. The resulting solution was cooled to 0°C, and PPh3 (17.9 g, 104 mmol) was added. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (5-10% ethyl acetate in PE) to obtain the pure title compound. Yield: 8.85 g (74.8%). 1 H-NMR (400 MHz, CDCl3) δ: 7.73 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 3.59 (s, 4 H), 3.53 (s, 4 H), 2.47 (s, 3 H).

[0071] Step 4: Synthesis of 6-tosyl-2-thia-6-azaspiro[3.3]heptane(1e-4) [ka] To a solution of 3,3-bis(bromomethyl)-1-tosylazetidine (1e-3) (8.82 g, 7.9 mmol) in a mixture of CH3CN (90 mL) and H2O (9 mL), Na2S·9H2O (10.7 g, 44.7 mmol) was added. The reaction mixture was stirred at 50°C for 4 hours and then concentrated to dryness. SiO2 (100 mL) and NaHCO3 solution (100 mL) were added to separate the phases. The aqueous phase was extracted with SiO2 (2 × 100 mL). The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum to obtain the title compound. Yield: 5.46 g (90.1%). 1 H-NMR (400 MHz, CDCl3) δ: 7.71 (d J = 8.0 Hz, 2 H), 7.37 (d J = 8.0 Hz, 2 H), 3.78 (s, 4 H), 3.14 (s, 4 H), 2.46(s, 3 H).HRMS(ESI-TOF + ):m / z[M+H] + C 12 H 16 Calculated value of NO2S2: 270.0622; Measured value: 270.0621.

[0072] Step 5: Synthesis of 2-thia-6-azaspiro[3,3]heptane(1e) [ka] 6-Tosyl-2-thia-6-azaspiro[3.3]heptane (1e-4) (2.0 g, 7.9 mmol) was dissolved in MeOH (40 mL). Magnesium powder (1.0 g) was added to the resulting solution, and the reaction mixture was sonicated at room temperature for approximately 3 hours. The reaction mixture was concentrated under vacuum, and the crude product was used in the next step without purification.

[0073] (Example 6) Preparation of 2-oxa-6-aza-spiro[3.3]heptane (1f) [ka]

[0074] Step 1: Synthesis of 6-tosyl-2-oxa-6-azaspiro[3.3]heptane [ka] This product was synthesized as described in Example 5, Step S, Step 1.

[0075] Step 2: Synthesis of 2-oxa-6-azaspiro[3,3]heptane(1f) [ka] 6-Tosyl-2-oxa-6-azaspiro[3.3]heptane (6.3 g, 25.0 mmol) was dissolved in MeOH (50 mL). Magnesium powder (6.0 g) was added to the resulting solution, and the reaction mixture was sonicated at room temperature for approximately 3 hours. The reaction mixture was concentrated under vacuum, and the crude product was used in the next step without purification.

[0076] (Example 7) Preparation of N-Boc-protected 2,6-diazaspiro[3.3]heptane (1g) [ka]

[0077] Step 1: Synthesis of (3-(bromomethyl)-1-(p-toluenesulfonyl)azetidine-3-yl)methanol (1g-1) [ka] A suspension of 6-(p-toluenesulfonyl)-2-oxa-6-azaspiro[3.3]heptane (6.25 g, 24.7 mmol) (obtained according to Step 1 of Example 5) in Et2O (100 mL) was added at 0°C to hydrobromic acid (approximately 33% of AcOH) in Et2O (5 mL). A 4.1 mL (24.7 mmol) solution was added dropwise over 15 minutes. The resulting mixture was heated to room temperature and stirred for 45 minutes. The resulting colorless solution was poured into a saturated aqueous solution of NaHCO3 (100 mL). The organic phase was separated, and the aqueous phase was extracted with Et2O (100 mL). The combined organic layers were dried over (MgSO4), filtered, and concentrated under vacuum to obtain 7.74 g of the title compound as a colorless solid. The crude product was of sufficient purity for further conversion.

[0078] Step 2: Synthesis of 3,3-bis(bromomethyl)-1-(p-toluenesulfonyl)azetidine (1g-2) [ka] 1 g-1 (7.74 g, 23.1 mmol) of the crude product was dissolved in CH2Cl2 (100 mL), and CBr4 (13.7 g, 41.2 mmol) was added all at once. The resulting solution was cooled to 0°C, and PPh3 (26.26 g, 41.2 mmol) was added all at once. The reaction mixture became a dark orange solution, which was stirred at 0°C for 1.5 hours, then warmed to room temperature and stirred for a further 8 hours. The mixture was concentrated under reduced pressure to obtain a dark orange oily substance, which was purified by chromatography (hexane:siRNA 4:1) to obtain 7.61 g of the title compound. 1 H-NMR (400 MHz, CDCl3) δ: 7.73 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H), 3.60 (s, 4 H), 3.53 (s, 4 H), 2.48 (s, 3 H).

[0079] Step 3: Synthesis of 2-benzyl-6-(p-toluenesulfonyl)-2,6-diazaspiro[3.3]heptane (1g-3) [ka] 1 g-2 (7.61 g, 19.1 mmol) of dibromide was dissolved in CH3CN (100 mL). Benzylamine (4.1 g, 38.3 mmol) and DIPEA (12.4 g, 95.5 mmol) were added to the mixture, and the reaction mixture was heated under reflux for 3 days. The yellowish solution was then cooled to room temperature and concentrated to approximately 1 / 6 of the initial volume. The residue was partitioned between CH2Cl2 (100 mL) and 1 mol / L NaOH (100 mL). The organic phase was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by chromatography (hexane:siRNA:Et3N gradient 1:1:1%~1:2:1%) to obtain 4.0 g of the title compound. 1 H-NMR (400 MHz, CDCl3) δ: 7.69 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.32-7.11 (m, 5 H), 3.82 (s, 4 H), 3.47 (s, 2 H), 3.13 (s, 4 H), 2.44 (s, 3 H).

[0080] Step 4: Synthesis of 6-(p-toluenesulfonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (1g-5) [ka] Benzyl azetidine 1 g-3 (2.70 g, 7.88 mmol) was dissolved in MeOH (40 mL), and Pd / C (10% on charcoal; 0.54 g) was added to the above mixture. A hydrogen atmosphere (50 PSI) was created, and the mixture was heated to 45°C and stirred at this temperature for 48 hours. The reaction mixture was then cooled to room temperature and filtered through Celite. The filtered cake was then filtered through MeOH (2 The mixture was thoroughly washed with 20 mL of water. Boc2O (1.77 g, 7.88 mmol) was added to the above solution of the intermediate Ts-protected azetidine (1 g - 4 oz) in MeOH (approximately 80 mL). The resulting solution was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was purified by chromatography (hexane:SiO2 gradient 1:1 to 1:2) to obtain the pure title compound. 1 H-NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 7.6 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 3.85 (s, 4 H), 3.84 (s, 4 H), 2.46 (s, 3 H), 1.39 (s, 9 H).

[0081] Step 5: Synthesis of 2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (1g) [ka] 1 g-5 (3.50 g, 10.0 mmol) of the above product was dissolved in MeOH (30 mL). Mg powder (1.92 g, 80.0 mmol) was added, and the mixture was sonicated for 6 hours. The reaction mixture was concentrated under vacuum to obtain a dark gray solid, which can be used in further reactions without purification.

[0082] (Example 8) General synthesis method: Preparation of oxazolidinone compounds [ka] [In the formula, [ka] This represents the ring A as already defined in equation I, where X = H or F.

[0083] The general procedure for preparing (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)acetamide (OTB-114) and its sulfoxide (OTB-124) is shown below. [ka]

[0084] Step A: 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocan [ka] A solution of 3,4-difluoronitrobenzene (4.92 g, 31 mmol) and N,N-diisopropylethylamine (8.81 g, 68 mmol) in CH3CN (30 mL) was treated with 1,5-thiazocane hydrochloride (5.2 g, 31 mol) at ambient temperature, and the reaction mixture was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with H2O and CH2Cl2, and the aqueous layer was extracted with CH2Cl2 (50 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / CH2Cl2 = 10:1) to obtain 3.36 g (40%) of the title compound as a yellow solid. 1 H-NMR (400 MHz, CDCl3) δ: 7.92 (m, 2H), 6.80 (t, J = 9.2 Hz, 8.8 Hz, 1H), 3.67 (t, J = 6.0 Hz, 5.6 Hz, 4H), 2.72 (t, J = 5.6 Hz, 6.0 Hz, 4H), 2.08 (m, 4H).

[0085] Step B: Benzyl (3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)carbamate [ka] To a solution of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane (3.0 g, 12.5 mmol) in MeOH / THF, 10% Pd / C (0.3 g) was added, and the mixture was shaken under H2 at room temperature for 4 hours. The suspension was filtered through a short Celite pad and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in THF / H2O (50 mL). To the resulting solution, NaHCO3 (2.12 g, 25.2 mmol) was added, followed by the dropwise addition of CbzCl (2.58 g, 15.1 mmol). The mixture was stirred overnight at room temperature and concentrated. H2O (50 mL) was added to the residue, and it was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by chromatography using silica gel (PE / ԅ=5:1) to obtain 4.6 g of the product as a colorless solid in 98% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.30 (m, 5H), 6.96 (m, 2H), 6.76 (s, 1H), 4.11 (m, 2H), 3.30 (m, 4H), 2.74 (m, 4H), 1.93 (m, 4H).

[0086] Step C: (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methanol [ka] A solution of benzyl (3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)carbamate (2.44 g, 6.5 mmol) in dry THF (20 mL) was cooled to -78°C under N2 (dry ice / acetone bath). n-butyllithium (2.5 M solution in hexane, 2.9 mL, 7.2 mmol) was added to the reaction mixture over 10 minutes. The resulting pale yellow solution was stirred at -78°C for 50 minutes, and then (R)-(-)-glycidyl butyrate (0.95 mL, 6.9 mmol) was added dropwise. The reaction mixture was stirred at -78°C for a further 30 minutes, and then the cooling bath was removed. The reaction mixture was heated overnight to ambient temperature. Saturated aqueous NH4Cl (50 mL) was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography using silica gel (PE / Depositphotos = 1:2) to obtain 1.33 g of the product as a colorless solid in 59% yield. 1 H-NMR (400 MHz, CDCl3) δ: 7.37 (dd, J = 14.8 Hz, 2.4 Hz, 1H), 7.09 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.00 (m, 1H), 4.73 (m, 1H), 3.95 (m, 3H), 3.76 (m, 1H), 3.35 (m, 4H), 2.74 (m, 4H), 1.97 (m, 4H).

[0087] Step D: (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methylmethanesulfonate [ka] A solution of (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methanol (1.0 g, 2.94 mmol) in dry CH2Cl2 was cooled in an ice bath and treated with Et3N (446 mg, 4.41 mmol) and methanesulfonyl chloride (404 mg, 3.53 mmol). The mixture was stirred at room temperature for 2 hours and washed with H2O, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The product was used in the next step without purification.

[0088] Step E: (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methylazide [ka] (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methylmethanesulfonate (85) in dry DMF A solution of 9 mg (2.1 mmol) was treated with solid NaN3 (683 mg, 10.5 mmol) at room temperature. The mixture was then heated at 65°C for 8 hours, cooled to room temperature, and the reaction mixture was quenched with H2O and extracted with siRNA. The combined organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. The product was used in the next step without purification.

[0089] Step F: (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)acetamide [ka] To a solution of (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl azide (216 mg, 0.59 mmol) in MeOH / THF, 10% Pd / C (22 mg) was added, and the mixture was shaken under H2 at room temperature for 4 hours. The suspension was filtered through a short pad of Celite and eluted with additional MeOH. The solvent was removed under vacuum. The residue was dissolved in CH2Cl2 and treated with Et3N (121 mg, 1.2 mmol) and AcCl (56 mg, 1.2 mmol). The reaction mixture was quenched with H2O and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 / MeOH = 100:1) to obtain 0.1 g of the product as a colorless solid in 44% yield. mp 78~80°C. [α] D 20 -15.4 (c0.25, cHCl3). 1 H-NMR (400 MHz, CDCl3) δ: 7.34 (m, 1H), 7.02 (m, 2H), 6.23 (m, 1H), 4.75 (m, 1H), 4.00 (t, J = 8.8 Hz, 8.8 Hz, 1H), 3.73 (m, 2H), 3.64 (m, 1H), 3.36 (t, J = 6.4 Hz, 6.0 Hz, 4H), 2.73 (m, 4H), 2.04 (s, 3H), 1.97 (m, 4H). 13 C-NMR (125 MHz, CDCl3) δ: 171.4, 155.2 (d, J = 243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J = 26.8 Hz), 71.9 , 48.1, 47.8, 42.0, 31.9, 29.7, 23.1.HR-MS(ESI-TOF):m / z[M+H] + C 18 H 25 O3N Calculated value for 3FS: 382.1595; Measured value: 382.1620.

[0090] Step G: (S)-N-[[3-(3-fluoro-4-(1-oxide-1,5-thiazocan-5-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]acetamide [ka] A solution of sodium metaperiodate (30 mg, 0.14 mmol) in H2O (2 mL) was cooled to 0°C. (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)acetamide (50 mg, 0.13 mmol), followed by MeOH (3 mL), was added. The reaction mixture was stirred at 0°C for 2 hours and then concentrated. H2O was added to the residue, and then extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (CH2Cl2 / MeOH = 100:1) to obtain 39 mg of the product as a colorless solid in 75% yield. mp 69~70°C. 1 H-NMR (400 MHz, CDCl3) δ: 7.46 (dd, J = 2.8 Hz, 14.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 8.8 Hz, 1H), 7.07 (m, 1H), 6.15 (m, 1H), 4.78 (m, 1H), 4.03 (t, J = 9.2 Hz, 8.8 Hz, 1H), 3.74 (m, 3H), 3.31 (m, 1H), 3.18 (m, 4H), 2.98 (m, 2H), 2.17 (m, 4H), 2.03 (s, 3H). 13 C-NMR (125 MHz, CDCl3) δ: 171.0, 154.2, 134.0, 128.5, 127.3, 122.6, 113.9, 108.1 (d, J = 26.9 Hz), 71.9, 53.1, 51.7, 47.7, 42.0, 29.7, 25.0, 23.2.HR-MS(ESI):m / z[M+H] + C 18 H 25 O4N Calculated value of 3FS: 398.1544; Measured value: 398.1540.

[0091] (Example 9) In vitro assay for antimicrobial susceptibility The antimicrobial susceptibility test was performed in a 96-well microplate. The initial drug dilution (6.4 mg / ml) was prepared in dimethyl sulfoxide, and subsequent two-fold dilutions were performed in 0.1 ml of 7H9 broth medium (BD) in the microplate. The final drug concentration was approximately 0.008 μg / ml. The test compound at all concentrations was added to two wells. The control wells consisted of bacteria and a positive drug (linezolid). The plate was incubated at 37 °C. The final bacterial titer was H 37 For Rv, 1×10 6 CFU / ml. Starting from the 7th day of incubation, 20 μl of 10× alamar blue solution (Life Technologies) and 12.5 μl of 20% Tween 80 (Sigma-Aldrich) were added to each well, and the plate was re-incubated at 37 °C. The wells were observed at the 24-hour time point, and the color of all wells was recorded. The visual MIC was defined as the lowest amount of drug that prevented the color change from blue to pink. Fluorescence was measured in the bottom reading mode at an excitation of 530 nm and an emission of 590 nm in a microplate fluorometer. For the fluorescence photometric MIC, the lowest drug concentration that resulted in ≥90% inhibition was considered the MIC. The MIC results are shown in Table 1 above.

[0092] (Example 10) In vitro assay for MPS inhibition H9C2 cells were incubated at 37°C and 5% CO2 in DMEM (Hyclone, GE Life Sciences) containing 10% FBS (Gibco, Life Technologies), 1× glutamine (Gibco, Life Technologies), and NEAA (Gibco, Life Technologies) in 1500 cells / well in 384-well plates. After 18 hours of incubation, the test compounds were added, followed by incubation for 5 days. Reduction in COX-1 protein (cyclooxygenase I) and SDH-A (succinate dehydrogenase-A) formation was measured by ELISA assay (MitoBiogenesis® In-Cell ELISA kit (Colorimetric, Abcam)). The results of the MPS assay are shown in Table 1 above.

[0093] (Example 11) Specific compounds synthesized according to general methods

[0094] OTB-107 (R)-5-[(1H-1,2,3-triazol-1-yl)methyl]-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.94 (s, 1 H), 7.75 (s, 1 H), 7.17 (dd, J = 15.2 Hz, 1.2 Hz, 1 H), 6.89 (dd, J = 8.8 Hz, 1.6 Hz, 1 H), 6.82 (t, J = 9.6 Hz, 8.8 Hz, 1 H), 5.03 (m, 1 H), 4.78 (s, 2 H), 4.10 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.87 (m, 1 H), 3.68 (m, 4 H), 2.87 (m, 2 H), 2.68 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.06 (m, 2 H). 13 C-NMR (100 MHz, CDCl3) δ: 153.4, 151.0, 134.3, 124.9, 1 16.8, 115.1, 108.7 (d, J = 27.3 Hz), 70.2, 56.1, 51.9, 51.3, 47.4, 34.0, 31.5, 30.3. HR-MS(ESI): m / z [M+H] + C 17 H 21 O2N Calculated value of 5FS: 378.1395; Measured value: 378.1396.

[0095] OTB-106 (R)-5-[(2H-1,2,3-Triazol-2-yl)methyl]-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]oxazolidin-2-one

Chemical Structure

[0096] OTB-109 (S)-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-5-[(methylamino)methyl]oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.30 (dd, J = 15.6 Hz, 2.4 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 6.82 (t, J = 9.6 Hz, 9.6 Hz, 1 H), 4.83 (m, 1 H), 4.02 (t, J = 8.8 Hz, 8.4 Hz, 1 H), 3.79 (t, J = 8.0 Hz, 7.2 Hz, 1 H), 3.67 (m, 4 H), 2.97 (m, 2 H), 2.87 (m, 2 H), 2.68 (m, 2 H), 2.54 (s, 3 H), 2.05 (m, 2 H).HR-MS(ESI):m / z[M+H] + C 16 H 23 Calculated value of O2N3FS: 340.1490; Measured value: 340.1484.

[0097] OTB-108 (R)-[3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl butyrate [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.34 (dd, J = 15.6 Hz, 2.4 Hz, 1 H), 7.05 (dd, J = 9.2 Hz, 2.0 Hz, 1 H), 6.89 (m, 1 H), 4.84 (m, 1 H), 4.37 (dd, J = 16.0 Hz, 4.0 Hz, 1 H), 4.31 (dd, J = 12.0 Hz, 4.8 Hz, 1 H), 4.06 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.76 (m, 1 H), 3.68 (m, 4 H), 2.89 (m, 2 H), 2.70 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.34 (t, J = 7.6 Hz, 7.2 Hz, 2 H), 2.08 (m, 2 H), 1.65 (m, 2 H), 0.94 (t, J = 7.6 Hz, 7.2 Hz, 3 H). 13 1C-NMR (125 MHz, CDCl3) δ: 173.3, 154.4, 152.7 (d, J = 241.6 Hz), 134.9 (d, J = 8.3 Hz), 129.5 (d, J = 10.1 Hz), 117.2 (d, J = 5.4 Hz), 114.7 (d, J = 2.9 Hz), 108.5 (d, J = 27.5 Hz), 70.2, 64.1, 56.3, 51.7, 47.5, 36.0, 34.4, 31.9, 30.7, 18.4, 13.7.HR-MS(ESI-TOF):m / z[M+H] + C 19 H 26 O4N2FS calculated value: 397.1592; measured value: 397.1613.

[0098] OTB-111 (S)-N-[(3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-2-oxo-oxazolidine-5-yl)methyl]furan-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.47 (s, 1 H), 7.32 (dd, J = 16.0 Hz, 2.0 Hz, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.01 (dd, J = 8.8 Hz, 1.6 Hz, 1 H), 6.87 (m, 1 H), 6.81 (m, 1 H), 6.52 (s, 1 H), 4.82 (m, 1 H), 4.04 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.89 (m, 1 H), 3.76 (m, 2 H), 3.67 (m, 4 H), 2.88 (m, 2 H), 2.69 (t, J = 6.4 Hz, 6.0 Hz, 2 H), 2.07 (m, 2 H). 13 C-NMR (125 MHz, CDCl3) δ: 159.0, 154.4, 152.6 (d, J = 241.9 Hz), 147.1, 144.5, 134.5, 129.3, 117.2, 115.1, 114.7, 112.3, 108.5 (d, J = 27.4 Hz), 71.9, 56.3, 51.7, 47.9, 41.6, 34.1, 31.7, 30.5.HR-MS(ESI-TOF):m / z[M+H] + C 20 H 23 Calculated value for O4N3FS: 420.1388; Measured value: 420.1400.

[0099] OTB-112 (S)-N-[(3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]-2-oxo-oxazolidine-5-yl)methyl]thiophene-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.34 (m, 1 H), 7.02 (m, 2 H), 6.23 (m, 1 H), 4.75 (m, 1 H), 4.00 (t, J = 8.8 Hz, 8.8 Hz, 1 H), 3.73 (m, 2 H), 3.64 (m, 1 H), 3.36 (t, J = 6.4 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 2.04 (s, 3 H), 1.97 (m, 4 H). 13 C-NMR (125 MHz, CDCl3) δ: 171.4, 155.2 (d, J = 243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J = 26.8 Hz), 71.9 , 48.1, 47.8, 42.0, 31.9, 29.7, 23.1.HR-MS(ESI-TOF):m / z[M+H] + C 18 H 25 O3N3F Calculated value of S: 382.1595; Measured value: 382.1620.

[0100] OTB-115 (S)-N-[[3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]pivalamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.34 (dd, J = 15.6 Hz, 2.0 Hz, 1 H), 7.01 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.89 (m, 1 H), 6.12 (m, 1 H), 4.74 (m, 1 H), 3.99 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.74 (m, 1 H ), 3.67 (m, 6 H), 2.89 (t, J = 5.6 Hz, 5.2 Hz, 2 H), 2.70 (t, J = 6.4 Hz, 6.4 Hz, 2 H), 2.08 (m, 2 H), 1.17 (s, 9H). 13 C-NMR (125 MHz, CDCl3) δ: 179.7, 154.6, 152.7 (d, J = 241.6 Hz), 134.8, 129.5, 117.2 (d, J = 5.4 Hz), 114.7 (d, J = 2.9 Hz), 108.5 (d, HR-MS(ESI-TOF):m / z[M+H] + C 20 H 29 Calculated value for O3N3FS: 410.1908; Measured value: 410.1942.

[0101] OBD-005 (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.42-7.23 (m, 2 H), 7.01 (dd, J = 8.9, 2.3 Hz, 1 H), 6.04 (s, 1 H), 4.75 (ddd, J = 9.0, 7.9, 4.6 Hz, 1 H), 4.00 (t, J = 9.0 Hz, 1 H), 3.79-3.05 (m, 7 H), 2.91 (dd, J = 16.2, 10.1 Hz, 2 H), 2.70 (t, J = 6.3 Hz, 2 H), 2.28-2.13 (m, 2 H), 2.13-1.97 (m, 2 H), 1.82-1.25 (m, 3 H), 0.92 (t, J = 7.4 Hz, 3 H), 0.01 (s, 1 H). LC-MS(ESI): m / z = 395.9 [M + H] + .

[0102] OTB-116 (R)-N-[[3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]butan-1-sulfonamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 15.6 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 1 H), 6.88 (m, 1 H), 4.92 (t, J = 6.8 Hz, 6.4 Hz, 1 H), 4.78 (m, 1 H) ), 4.02 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.90 (m, 1 H), 3.69 (m, 4 H), 3.54 (m, 1 H), 3.43 (m, 1 H), 3.07 (m, 2 H), 2.94 (m, 2 H), 2.69 (m, 2 H), 2.08 (m, 2 H), 1.79 (m, 2 H), 1.46 (m, 2 H), 0.95 (t, J = 7.2 Hz, 7.2 Hz, 3 H). 13C-NMR (125 MHz, CDCl3) δ: 154.2, 152.5 (d, J = 241.8 Hz), 134.8 (d, J = 8.3 Hz), 129.2 (d, J = 10.5 Hz), 117.2, 115.0, 108.6 (d, J = 27.5 Hz), 71.5, 56.3, 53.2, 51.6, 47.5, 45.5, 34.1, 31.7, 30.5, 25.6, 21.5, 13.5.HR-MS(ESI-TOF):m / z[M+H] + C 19 H 29 O4N 3FS2 calculated value: 446.1578; measured value: 446.1623.

[0103] OTB-119 (R)-5-[(1H-1,2,4-triazol-1-yl)methyl]-3-[3-fluoro-4-(1,4-thiazepan-4-yl)phenyl]oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 8.24 (s, 1 H), 7.96 (s, 1 H), 7.22 (m, 1 H), 6.97 (m, 1 H), 6.89 (m, 1 H), 5.02 (m, 1 H), 4.54 (d, J = 4.8 Hz, 2 H), 4.10 (t, J = 9.2 Hz, 9.2 Hz, 1 H), 3.94 (m, 1 HR-MS(ESI-TOF):m / z[M+H] + C 17 H 21 Total O2N5FS Calculated value: 378.1395; Measured value: 378.1421.

[0104] OTB-412 (S)-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.29-7.33 (m, 1 H), 7.03-7.05 (m, 1 H), 6.82 (t, J = 8.8 Hz, 1 H), 5.10 (m, 1 H), 4.73 (m, 1 H), 3.99 (t, J = 9.9 Hz, 1 H), 3.69-3.74 (m, 1 H), 3.67 (s, 3 H), 3.66-3.67 (m, 4 H), 3.61 (m, 1 H), 3.50-3.55 (m, 1 H), 2.87 (m, 1 H), 2.68 (m, 2 H), 2.04-2.07 (m, 2 H). 13 C-NMR (150 MHz, CDCl3) δ: 157.5, 154.3, 153.3, 151.7, 134.8, 134.7, 129.3, 129.2, 117.0, 117.0, 114.7, 114.7, 108.5, 108.4, 71.7, 56.2, 56.2, 51.5, 47.7, 43.7, 34.3, 31.8, 30.6.HR-MS(ESI-TOF):m / z[M+H] + C 17 H 23 Calculated value for O4N3FS: 384.1388; Measured value: 384.1371.

[0105] OTB-413 (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclopropanecarboxamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.29-7.33 (m, 1 H), 7.03-7.00 (m, 1 H), 6.81 (t, J = 9.6 Hz, 1 H), 6.09 (m, 1 H), 4.74 (m, 1 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.73-3.74 (m, 1 H), 3.67-3.71 (m, 4 H), 3.62-3.66 (m, 1 H), 2.87 (t, J = 4.8 Hz, 2 H), 2.68 (t, J = 10.0 Hz, 2 H), 2.04-2.07 (m, 2 H), 1.36-1.43 (m, 1 H), 1.05-1.07 (m, 1 H), 0.93-0.97 (m, 2 H), 0.77-0.78 (m, 1 H). 13 C-NMR (150 MHz, CDCl3) δ: 174.5, 154.5, 153.3, 151.7, 134.8, 134.7, 129.2, 129.2, 117.0, 114.7, 108.6, 108.4, 72.0, 56.2, 51.5, 47.8, 42.1, 34.3, 31.8, 30.6, 14.7, 7.7.HR-MS(ESI-TOF):m / z[M+H] + C 19 H 25 O3 N3FS calculated value: 394.1595; measured value: 394.1580.

[0106] OTB-414 (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.29-7.34 (m, 1 H), 7.03-7.00 (m, 1 H), 6.82 (t, J = 9.6 Hz, 1 H), 5.84 (m, 1 H), 4.75 (m, 1 H), 3.99 (t, J = 8.8 Hz, 1 H), 3.72-3.76 (m, 1 H), 3.67-3.71 (m, 4H), 3.63-3.66 (m, 1 H), 3.14-3.23 (m, 2 H), 2.68 (m, 1 H), 1.89-2.35 (m, 10H). 13 C-NMR (150 MHz, CDCl3) δ: 180.2, 176.0, 154.5, 134.8, 134.8, 129.2, 129.1, 117.0, 117.0, 114.7, 114.7, 108.5, 108.4, 72.0, 56.2, 56.2, 51.5, 51.5, 47.9, 42.0, 39.7, 37.8, 34.3, 31.8, 30.6, 25.2, 18.4.HR-MS(ESI-TOF):m / z[M+H] + C 20 H 27 Calculated value for O3N3FS: 408.1752; Measured value: 408.1736.

[0107] OTB-407 (S)-N-((3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 10.4 Hz, 2 H), 6.08 (m, 1 H), 4.76-4.77 (m, 1 H), 3.98 (t, J = 9.2 Hz, 1 H), 3.59-3.70 (m, 3 H), 3.45-3.48 (m, 4 H), 2.89 (t, J = 6.0 Hz, 2 H), 2.77-2.80 (m, 2 H), 2.02 (s, 3 H). 13 C-NMR (150 MHz, CDCl3) δ: 171.1, 159.8, 159.7, 158.1, 158.1, 154.0, 133.3, 126.0, 102.5, 102.3, 71.9, 58.8, 54.1, 47.5, 41.9, 36.1, 31.8, 31.6, 23.1.HR-MS(ESI-TOF): m / z[M+H] + C 17 H 22 Calculated value for O3N3F2S: 386.1344; Measured value: 386.1330.

[0108] OTB-410 (S)-((3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1 H-NMR (500 MHz, CDCl3) δ: 7.09 (d, J = 10.0 Hz, 2 H), 5.09 (m, 1 H), 4.76 (m, 1 H), 3.99 (t, J = 9.0 Hz, 1 H), 3.74-3.76 (m, 1 H), 3.73 (s, 3 H), 3.61 (m, 1 H), 3.52-3.55 (m, 1 H), 3.46-3.47 (m, 4 H), 2.90 (t, J = 6.0 Hz, 1 H), 2.78-2.80 (m, 2 H), 1.94-1.98 (m, 2 H). 13C-NMR (125 MHz, CDCl3) δ: 157.5, 154.3, 153.3, 151.7, 134.8, 134.7, 129.3, 129.2, 117.0, 117.0, 114.7, 114.7, 108.4, 108.4, 71.3, 56.2, 56.2, 51.5, 47.8, 43.7, 34.3, 31.8, 30.6.HR-MS(ES I-TOF): m / z [M+H] + C 17 H 22 Calculated value for O4N3F2S: 402.1297; Measured value: 402.1287.

[0109] OTB-408 (S)-5-((cyclopropylamino)methyl)-3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 10.8 Hz, 2 H), 6.06 (m, 1 H), 4.76 (m, 1 H), 3.96 (t, J = 8.8 Hz, 1 H), 3.66-3.75 (m, 3 H), 3.43-3.47 (m, 3 H), 2.89 (t, J = 9.2 Hz, 2 H), 2.78-2.80 (m, 3 H), 1.94-1.97 (m, 2 H), 1.37-1.39 (m, 1 H), 0.97 (m, 1 H), 0.93 (m, 1 H), 0.77-0.79 (m, 2 H). 13 C-NMR (150 MHz, CDCl3) δ: 174.7, 159.8, 159.7, 158.2, 158.1, 154.0, 133.4, 126.0, 102.6, 102.4, 72.0, 58.8, 54.1, 47.5, 42.0, 36.1, 31.8, 31.6, 14.7, 7.8, 7.7.HR-MS(ESI-TOF):m / z[M+H] + C 19 H 24 Calculated value for O3N3F2S: 412.1501; Measured value: 412.1485.

[0110] OTB-409 (S)-5-((cyclobutylamino)methyl)-3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.07 (d, J = 10.8 Hz, 2 H), 5.81 (m, 1 H), 4.75 (m, 1 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.72-3.76 (m, 1 H), 3.64-3.66 (m, 2 H), 3.45-3.46 (m, 3 H), 3.01 (t, J = 8.8 Hz, 1 H), 2.90 (t, J = 6.4 Hz, 2 H), 2.77-2.80 (m, 2 H), 2.13-2.26 (m, 4 H), 1.92-1.96 (m, 3 H). 13 C-NMR (150 MHz, CDCl3) δ: 176.0, 159.8, 159.8, 158.2, 158.1, 154.0, 133.3, 126.0, 102.5, 102.3, 72.0, 58.8, 54.1, 47.5, 41.9, 39.7, 36.1, 31.8, 31.6, 25.4, 25.3, 18.1.HR- MS (ESI-TOF): m / z [M+H] + C 20 H 26 Calculated value for O3N3F2S: 426.1658; Measured value: 426.1643.

[0111] OTB-411 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J = 11.2 Hz, 2 H), 6.95 (d, J = 10.4 Hz, 2 H), 5.04-5.07 (m, 1 H), 4.78 (d, J = 4.0 Hz, 2 H), 4.10 (t, J = 9.2 Hz, 1 H), 3.86-3.90 (m, 1 H), 3.44-3.46 (m, 4 H), 2.88 (t, J = 6.4 Hz, 2 H), 2.76-2.79 (m, 2 H), 1.91-1.97 (m, 2H). 13 C-NMR (125 MHz, CDCl3) δ: 159.8, 159.8, 157.9, 157.8, 153.0, 134.6, 125.1, 102.8, 102.5, 70.3, 58.7, 54.0, 51.9, 47.1, 36.1, 31.8, 31.6.HR-MS(ESI-TOF):m / z[M+H] + C 17 H 20 Calculated value for O2N5F2S: 396.1300; Measured value: 396.1296.

[0112] OTB-126 [(5R)-3-[3-fluoro-4-(1-oxide-1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl butyrate [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.45 (dd, J = 14.8 Hz, 1.6 Hz, 1 H), 7.07 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 6.96 (t, J = 9.2 Hz, 9.2 Hz, 1 H), 4.85 (m, 1 H), 4.37 (dd, J = 12.0 Hz, 4.0 Hz, 1 H), 4.30 (dd, J = 12.4 Hz, 4.8 Hz, 1 H), 4.07 (m, 1 H), 3.78 (m, 2 H), 3.40 (m, 2 H), 3.19 (m, 4 H), 2.98 (m, 1 H), 2.72 (m, 1 H), 2.33 (t, J = 7.6 Hz, 7.2 Hz, 2 H), 2.04 (m, 1 H), 1.63 (m, 2 H), 0.92 (t, J = 7.6 Hz, 7.2 Hz, 3 H). 13 ¹¹C-NMR (125 MHz, CDCl3) δ: 173.2, 154.1, 154.0 (d, J = 241.8 Hz), 136.6, 131.4, 118.1 (d, J = 4.3 Hz), 114.0, (d, J = 2.9 Hz), 107.8 (d, J = 26.9 Hz), 70.1, 63.9, 52.8, 49.6, 47.2, 46.4, 43.7, 35.8, 18.3, 16.2, 13.6.HR-MS(ESI-TOF):m / z[M+H] + C 19 H 26 Calculated value for O5N2FS: 413.1541; Measured value: 413.1573.

[0113] OTB-127 N-[[(5S)-3-(3-fluoro-4-(1-oxide-1,4-thiazepan-4-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]furan-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.47 (s, 1 H), 7.42 (m, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.04 (m, 1 H), 6.87 (m, 2 H), 6.51 (m, 1 H), 4.85 (m, 1 H), 4.05 (m, 1 H), 3.81 (m, 4 H), 3.38 (m, 2 H), 3.15 (m, 2 H), 3.04 (m, 3 H), 2.70 (m, 1 H), 2.03 (m, 1 H).HR- MS (ESI-TOF): m / z [M+H] + C 20 H 23 Calculated value for O5N3FS: 436.1337; Measured value: 436.1371.

[0114] OTB-137 (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1-oxide-1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1 H), 7.75 (s, 1 H), 7.30-7.25 (m, 1 H), 6.91-6.89 (m, 2 H), 5.07-5.02 (m, 1 H), 4.78 (d, J = 4.0 Hz, 2 H), 4.11 (t, J = 9.2 Hz, 1 H), 3.93-3.88 (m, 1 H), 3.82-3.76 (m, 1 H), 3.43-3.36 (m, 2 H), 3.24-2.91 (m, 4 H), 2.75-2.69 (m, 1 H), 2.04-2.02 (m, 2 H).HR-MS(ESI):m / z[M+H] + C 17 H 21Calculated value for O3N5FS: 394.1344; Measured value: 394.1328.

[0115] OTB-138 (5R)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(1-oxide-1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2 H), 7.39 (d, J = 14.4 Hz, 1 H), 7.04-6.98 (m, 2 H), 5.15-5.09 (m, 1 H), 4.86 (dd, J = 14.0, 4.4 Hz, 1 H), 4.75 (dd, J = 14.0, 6.8 Hz, 1 H), 4.06 (dt, J = 2.76-2.71 (m, 1 H), 2.04-2.02 (m, 2 H).HR-MS(ESI):m / z[M+H] + C 17 H 21 Calculated value for O3N5FS: 394.1344; Measured value: 394.1338.

[0116] OTB-140 (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1-oxide-1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one [ka] 1H-NMR (400 MHz, CDCl3) δ: 8.24 (s, 1 H), 7.94 (s, 1 H), 7.35 (d, J = 14.4 Hz, 1 H), 7.0-6.96 (m, 2 H), 5.02-4.99 (m, 1 H), 4.55 (d, J = 4.4 Hz, 2 H), 4.10 (dt, J = 8.8, 2.0 Hz, 1 H), 3.99-3.95 (m, 1 H), 3.86-3.82 (m, 1 H), 3.45-3.38 (m, 2 H), 3.29-3.09 (m, 3 H), 3.00-2.94 (m, 1 H), 2.77-2.71 (m, 1 H), 2.07-2.03 (m, 2 H).H R-MS(ESI): m / z[M+H] + C 17 H 21 Calculated value for O3N5FS: 394.1344; Measured value: 394.1339.

[0117] OBD-006 N-(((5S)-3-(3-fluoro-4-(1-oxide-1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.52 (d, J = 15.0 Hz, 1 H), 7.16 (s, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 5.99 (s, 1 H), 4.78 (s, 1 H), 4.02 (t, J = 8.8 Hz, 2 H), 3.88-3.56 (m, 3 H), 3.55-2.92 (m, 7 H), 2.77 (s, 1 H), 2.20 (t, J = 7.1 Hz, 3 H), 1.64 (dd, J = 14.9, 7.4 Hz, 2 H), 0.91 (t, J = 7.4 Hz, 3 H). LC-MS(ESI): m / z = 411.8[M+H] + .

[0118] OBD-007 (S)-N-((3-(4-(1,1-dioxide-1,4-thiazepan-4-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.51 (d, J = 14.7 Hz, 1 H), 7.10 (d, J = 9.9 Hz, 2 H), 5.92 (s, 1 H), 4.78 (s, 1 H), 4.03 (t, J = 9.0 Hz, 1 H), 3.87-3.39 (m, 7 H), 3.27 (d, J = 5.7 Hz, 2 H), 2.39 (d, J = 6.2 Hz, 2 H), 2.20 (t, J = 7.2 Hz, 2 H), 1.64 (dd, J = 14.8, 7.4 Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H). LC-MS(ESI): m / z = 427.8[M+H] + .

[0119] OTB-110 (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2 [Oxo-5-oxazolidinyl]methylbutyrate [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.36 (dd, J = 14.8 Hz, 4.0 Hz, 1 H), 7.09 (dd, J = 8.8 Hz, 2.4 Hz, 1 H), 7.04 (t, J = 10.4 Hz, 9.2 Hz, 1 H), 4.85 (m, 1 H), 4.37 (m, 1 H), 4.31 (m, 1 H), 4.08 (m, 1 H), 3.78 (m, 1 H), 3.37 (m, 4 H), 2.75 (m, 4 H), 2.34 (t, J = 7.6 Hz, 7.2 Hz, 2 H), 1.97 (m, 4 H), 1.64 (m, 2 H), 0.93 (t, 7.6 Hz, J = 7.2 Hz, 3 H). 13 C-NMR (125 MHz, CDCl3) δ: 173.3, 155.4 (d, J = 243.5 Hz), 154.3, 134.5 (d, J = 8.3 Hz), 131.1 (d, J = 10.1 Hz), 128.2, 127.1, 120.0 (d, J = 4.9 Hz), 114.3 (d, J = 3.0 HR-MS(ESI-TOF):m / z[M+H] + C 20 H2 Calculated value for 8O4N2FS: 411.1748; Measured value: 411.1786.

[0120] OTB-113 (R)-5-[(2H-1,2,3-triazol-2-yl)methyl]-3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]oxazolidine-2-one [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2 H), 7.30 (d, J = 14.8 Hz, 1 H), 7.03 (m, 2 H), 5.10 (m, 1 H), 4.85 (dd, J = 14.0 Hz, 4.8 Hz, 1 H), 4.74 (dd, J = 14.0 Hz, 7.2 Hz, 1 H), 4.06 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.97 (m, 1 H), 3.37 (t, J = 6.0 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 1.97 (m, 4 H). 13 ¹¹C-NMR (125 MHz, CDCl3) δ: 155.2 (d, J = 243.5 Hz), 135.2, 134.4 (d, J = 8.1 Hz), 130.8 (d, J = 10.3 Hz), 119.8 (d, J = 4.9 Hz), 114.5 (d, J = 3.1 Hz), 108.4 (d, J = 26.6 Hz), 70.0, 56.3, 48.3, 47.9, 31.9, 29.6.HR-MS(ESI-TOF):m / z[M+H] + C 18 H 23 Calculated value for O2N5FS: 392.1551; Measured value: 392.1590.

[0121] OTB-114 (R)-[3-[3-fluoro-4-(1,5-thiazocan-5-yl)phenyl]-2-oxo-5-oxazolidinyl]methylacetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.34 (m, 1 H), 7.02 (m, 2 H), 6.23 (m, 1 H), 4.75 (m, 1 H), 4.00 (t, J = 8.8 Hz, 8.8 Hz, 1 H), 3.73 (m, 2 H), 3.64 (m, 1 H), 3.36 (t, J = 6.4 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 2.04 (s, 3 H), 1.97 (m, 4 H). 13 C-NMR (125 MHz, CDCl3) δ: 171.4, 155.2 (d, J = 243.5 Hz), 154.4, 134.5, 130.2, 119.9, 114.3, 108.3 (d, J = 26.8 Hz), 71.9 , 48.1, 47.8, 42.0, 31.9, 29.7, 23.1.HR-MS(ESI-TOF):m / z[M+H] + C 18 H 25 O3N3F Calculated value of S: 382.1595; Measured value: 382.1620.

[0122] OTB-117 (S)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]furan-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.47 (s, 1 H), 7.36 (d, J = 14.4 Hz, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.01 (m, 2 H), 6.78 (m, 1 H), 6.51 (m, 1 H), 4.84 (m, 1 H), 4.05 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.88 (m, 1 H), 3.80 (m, 2 H), 3.36 (t, J = 6.0 Hz, 6.0 Hz, 4 H), 2.73 (m, 4 H), 1.96 (m, 4 H). 13C-NMR (125 MHz, CDCl3) δ: 159.0, 155.2 (d, J = 243.6 Hz), 154.3, 147.1, 144.5, 134.3, 130.9, 119.8, 115.1, 114.3 (d, J = 3.0 Hz), 112.3, 108.4 (d, J = 26.8 Hz), 71.9, 47.9, 41.5, 31.9, 29.6.HR-MS(ESI-TOF):m / z[M+H ] + C 21 H 25 Calculated value for O4N3FS: 434.1544; Measured value: 434.1581.

[0123] OTB-118 (S)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]thiophene-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.54 (m, 1 H), 7.52 (m, 1 H), 7.34 (m, 1 H), 7.10 (m, 1 H), 7.04 (m, 1 H), 7.00 (m, 1 H), 6.57 (t, J = 6.0 Hz, 6.0 Hz, 1 H), 4.86 (m, 1 H), 4.07 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 4.07 (m, 1 H), 3.82 (m, 2 H), 3.36 (t, J = 6.0 Hz, 6.0 Hz, 4 H), 2.74 (m, 4 H), 1.96 (m, 4 H). 13C-NMR (125 MHz, CDCl3) δ: 162.7, 155.2 (d, J = 243.5 Hz), 154.5, 137.9, 130.8, 128.7, 127.8, 119.8, 114.5 (d, J = 3.0 Hz), 108.5 (d, J = 26.8 Hz), 72.1, 48.0, 42.5, 31.9, 29.6.HR-MS(ESI-TOF):m / z[M+H] + C 21 H 25 Calculated value for O4N4FS2: 450.1316; Measured value: 450.1356.

[0124] OTB-120 (R)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]butan-1-sulfonamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.42 (d, J = 14.4 Hz, 1 H), 7.08 (m, 2 H), 4.94 (m, 1 H), 4.79 (m, 1 H), 4.04 (t, J = 8.8 Hz, 8.8 Hz, 1 H), 3.93 (m, 1 H), 3.55 (m, 1 H), 3.43 (m, 5 H), 3.07 (m, 2 H), 2.76 (m, 4 H), 2.01 (m, 4 H), 1.80 (m, 2 H), 1.45 (m, 2 H), 0.95 (t, J = 7.6 Hz, 7.2 Hz, 3 H). 13 ¹¹C-NMR (125 MHz, CDCl3) δ: 155.2 (d, J = 243.6 Hz), 154.2, 134.5, 130.7, 119.8 (d, J = 4.9 Hz), 114.5 (d, J = 3.0 Hz), 108.5 (d, J = 26.8 Hz), 71.5, 53.1, 47.9, 47.4, 45.5, 31.9, 29.6, 25.6, 21.5, 13.5.HR-MS(ESI-TOF ):m / z[M+H] + C 20 H 31 Calculated value for O4N3FS2: 460.1735; Measured value: 460.1778.

[0125] OTB-121 (S)-N-[[3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]pivalamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J = 14.4 Hz, 1 H), 7.04 (m, 2 H), 6.11 (m, 1 H), 4.74 (m, 1 H), 4.00 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.76 (m, 1 H), 3.67 (m, 2 H), 3.39 (m, 4 H), 2.74 (m, 4 H), 1.98 (m, 4 H), 1.17 (s, 9 H). 13 C-NMR (125 MHz, CDCl3) δ: 179.6, 155.2 (d, J = 243.6 Hz), 154.4, 134.3 (d, J = 8.0 Hz), 130.9 (d, J = 5.4 Hz), 128.8, 119.8 (d, J = 4.9 Hz), 114.2 (d, J = 2.9 Hz), 108.2 (d, J = 26.9 Hz), 72.0, 47.9, 47.8, 42.2, 38.9, 31.9, 29.6, 27.5.HR-MS(ESI-TOF):m / z[M+H] + C 21 H 31 Calculated value for O3N3FS: 424.2065; Measured value: 424.2096.

[0126] OBD-001 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.76 (d, J = 17.6 Hz, 2 H), 7.41-7.09 (m, 1 H), 7.11-6.73 (m, 2 H), 5.04 (d, J = 3.0 Hz, 1 H), 4.78 (d, J = 3.4 Hz, 2 H), 4.12 (t, J = 9.2 Hz, 1 H), 3.88 (dd, J = 9.2, 6.1 Hz, 1 H), 3.36 (t, J = 6.0 Hz, 3 H), 2.92-2.59 (m, 4 H), 2.01 (dd, J = 27.9, 7.3 Hz, 4 H). LC-MS(ESI): m / z = 391.9[M+H] + .

[0127] OBD-003 (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.50 (s, 2 H), 7.03 (d, J = 6.1 Hz, 1 H), 5.99 (s, 1 H), 4.77 (d, J = 5.7 Hz, 1 H), 4.02 (t, J = 9.0 Hz, 2 H), 3.70 (ddd, J = 20.7, 15.2, 7.7 Hz, 4 H), 3.48 (s, 4 H), 2.95-2.68 (m, 4 H), 2.20 (t, J = 7.2 Hz, 3 H), 2.06 (d, J = 6.1 Hz, 4 H), 1.64 (dd, J = 14.8, 7.4 Hz, 4 H), 0.91 (t, J = 7.4 Hz, 4 H). LC-MS(ESI): m / z = 409.9[M+H] + .

[0128] OBD-008 (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (300 MHz, CDCl3) δ: 8.24 (s, 1 H), 7.97 (s, 1 H), 7.00 (s, 2 H), 5.12-4.91 (m, 1 H), 4.56 (d, J = 4.7 Hz, 2 H), 4.24-3.83 (m, 2 H), 3.38 (t, J = 6.0 Hz, 4 H), 2.95-2.59 (m, 4 H), 1.98 (s, 5 H). LC-MS(ESI): m / z = 391.9[M+H] + .

[0129] OTB-124 (S)-N-[[3-(3-fluoro-4-(1-oxide-1,5-thiazocan-5-yl)phenyl)-2-oxo-oxazolidine-5-yl]methyl]acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.46 (dd, J = 2.8 Hz, 14.8 Hz, 1 H), 7.14 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 7.07 (m, 1 H), 6.15 (m, 1 H), 4.78 (m, 1 H), 4.03 (t, J = 9.2 Hz, 8.8 Hz, 1 H), 3.74 (m, 3 H), 3.31 (m, 1 H), 3.18 (m, 4 H), 2.98 (m, 2 H), 2.17 (m, 4 H), 2.03 (s, 3 H). 13 C-NMR (125 MHz, CDCl3) δ: 171.0, 154.2, 134.0, 128.5, 127.3, 122.6, 113.9, 108.1 (d, J = 26.9 Hz), 71.9, 53.1, 51.7, 47.7, 42.0, 29.7, 25.0, 23.2.HR-MS(ESI):m / z[M+H] + C 18 H 25 Calculated value for O4N3FS: 398.1544; Measured value: 398.1540.

[0130] OBD-002 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1-oxide-1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one [ka] 1H-NMR (300 MHz, CDCl3) δ: 7.92-7.67 (m, 2 H), 7.32 (d, J = 16.8 Hz, 1 H), 7.12 (t, J = 9.0 Hz, 1 H), 6.96 (d, J = 8.1 Hz, 1 H), 5.07 (s, 1 H), 4.81 (d, J = 4.0 Hz, 2 H), 4.15 (t, J = 9.0 Hz, 1 H), 4.01-3.83 (m, 1 H), 3.32 (d, J = 14.2 Hz, 5 H), 3.11-2.87 (m, 2 H), 2.59 (s, 2 H), 2.19 (s, 4 H). LC-MS(ESI): m / z = 407.8[M+H] + .

[0131] OBD-004 (S)-N-((3-(3-fluoro-4-(1-oxide-1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.44 (dd, J = 14.7, 2.4 Hz, 1 H), 7.19-6.99 (m, 2 H), 6.44 (s, 1 H), 4.84-4.71 (m, 1 H), 4.02 (t, J = 8.9 Hz, 1 H), 3.78 (dd, J = 9.0, 6.6 Hz, 1H), 3.66 (t, J = 4.6 Hz, 2 H), 3.38-3.09 (m, 6 H), 2.99 (dd, J = 12.6, 6.3 Hz, 2 H), 2.20 (dd, J = 9.4, 5.3 Hz, 6 H), 1.71-1.56 (m, 2 H), 0.91 (dd, J = 9.6, 5.1 Hz, 3 H). LC-MS(ESI): m / z = 425.8[M+H] + .

[0132] OBD-009 (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1-oxide-1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (300 MHz, CDCl3) δ: 8.24 (s, 1 H), 7.93 (s, 1 H), 7.41-7.20 (m, 1 H), 7.19-6.92 (m, 2 H), 5.10-4.92 (m, 1 H), 4.56 (d, J = 4.7 Hz, 2 H), 4.12 (t, J = 9.0 Hz, 1 H), 3.97 (dd, J = 9.2, 6.2 Hz, 1 H), 3.28 (dd, J = 13.0, 6.9 Hz, 2 H), 3.12 (dd, J = 12.5, 5.9 Hz, 4 H), 3.02-2.83 (m, 2 H), 2.22-1.99 (m, 5 H), 1.26 (d, J = 9.4 Hz, 4 H). LC-MS(ESI): m / z = 407.8[M+H] + .

[0133] OTB-227 N-(((5S)-3-(4-(3-thia-6-azabicyclo[3.1.1]heptan-6-yl)-3-fluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J = 14.4 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 6.60 (t, J = 9.2 Hz, 1 H), 6.35 (brs, 1 H), 4.76-4.74 (m, 1 H), 4.56-4.54 (m, 2 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.76-3.65 (m, 2 H), 3.62-3.57 (m, 1 H), 3.43 (d, J = 12.0 Hz, 2 H), 2.93-2.87 (m, 1 H), 2.74 (d, J = 12.0 Hz, 2 H), 2.09 (s, 1 H), 2.03 (s, 3 H). 13 C-NMR (100 MHz, CDCl3) δ: 171.1, 154.5, 151.8 (d, J = 238.5 Hz), 131.9 (d, J = 11.8 Hz), 129.2 (d, J = 9.5 Hz), 115.2 (d, J = 6.2 Hz), 114.7 (d, J = 2.8 Hz), 108.0 (d, J = 24.9 Hz), 71.9, 60.8, 47.8, 41.9, 29.4, 25.3, 23.2.HRMS(ESI- TOF+): m / z [M+H] + C 17 H 21 Calculated value for FN3O3S: 366.1288; Measured value: 366.1277.

[0134] OTB-501 (R)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J = 12.8 Hz, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 6.90 (t, J = 9.2 Hz, 1 H), 4.74 (m, 1 H), 4.43 (s, 2 H), 3.99-3.96 (m, 3 H), 3.79-3.75 (m, 1 H), 3.48 (d, J = 13.2 Hz, 2 H), 2.21-2.10 (m, 6 H).HRMS(ESI):m / z[M+H] + C 16 H 20 Calculated value of N2O3FS: 339.1179; Measured value: 339.1169.

[0135] OTB-502 N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.36 (dd, J = 15.2, 2.4 Hz, 1 H), 7.06 (dd, J = 8.8, 1.8 Hz, 1 H), 6.83 (t, J = 9.2 Hz, 1 H), 6.18 (s, 1 H), 4.77-4.75 (m, 1 H), 4.40 (s, 2 H), 4.00 (t, J = 8.8 Hz, 1 H), 3.76-3.72 (m, 2 H), 3.68-3.62 (m, 1 H), 3.37 (d, J = 12.8 Hz, 2 H), 2.26-2.04 (m, 6 H), 2.02 (s, 3 H). 13C-NMR (100 MHz, CDCl3) δ: 171.1, 154.5, 152.8 (d, J = 241.7 Hz), 132.2 (d, J = 8.6 Hz), 130.2 (d, J = 10.4 Hz), 118.1 (d, J = 5.0 Hz), 114.7, 108.4 (d, J = 27.2 Hz), 71.9 , 57.4, 47.8, 42.0, 30.2, 28.4, 23.1.HR-MS(ESI-TOF):m / z[M+H] + C 18 H 23 Calculated value of N3O3FS: 380.1444; Measured value: 380.1435.

[0136] OTB-504 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.80 (s, 1 H), 7.76 (s, 1 H), 7.24 (m, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 6.83 (t, J = 8.8 Hz, 1 H), 5.07-5.04 (m, 1 H), 4.79 (s, 2 H), 4.40 (s, 2 H), 4.11 (t, J = 8.0 Hz, 1 H), 3.90-3.87 (m, 1 H), 3.42 (d, J = 12.8 Hz, 2 H), 2.20-2.07 (m, 6 H).HR-MS(ESI-TOF):m / z[M+H] + C 18 H2 Calculated value of 1N5O2FS: 390.1400; Measured value: 390.1385.

[0137] OTB-236 N-(((R)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)methanesulfonamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.47-7.41 (m, 1 H), 7.13 (d, J = 9.6 Hz, 1 H), 7.02 (t, J = 9.6 Hz, 1 H), 4.76-4.70 (m, 1 H), 4.34 (s, 2 H), 4.08 (t, J = 9.2 Hz, 1 H), 3.76 (t, J = 8.8 Hz, 1 H), 3.29-3.26 (m, 2 H), 3.11 (d, J = 12.8 Hz, 2 H), 2.93 (s, 3 H), 2.11 (d, J = 12.4 Hz, 2 H), 2.02 (s, 4 H).HR-MS(ESI-TOF):m / z[M+H] + C 17 H 23 Calculated value for N3O4FS2: 416.1114; Measured value: 416.1097.

[0138] OTB-237 (((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J = 15.2 Hz, 1 H), 7.07 (d, J = 8.8 Hz, 1 H), 6.81 (t, J = 9.2 Hz, 1 H), 5.18 (brs, 1 H), 4.74 (brs, 1 H), 4.39 (s, 2 H), 4.01 (t, J = 8.8 Hz, 1 H), 3.76 (t, J = 7.6 Hz, 1 H), 3.69 (s, 3 H), 3.56-3.51 (m, 1 H), 3.33 (d, J = 12.8 Hz, 2 H), 2.18-2.07 (m, 6 H).HR-MS(ESI-TOF):m / z[M+H] + C 18 H 23 Calculated value of N3O4FS: 396.1393; Measured value: 396.1388.

[0139] OBD-016 N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, DMSO-d6) δ: 8.18 (s, 1 H), 7.42 (d, J = 16.0 Hz, 1 H), 7.35-6.88 (m, 2 H), 4.71 (s, 1 H), 4.35 (s, 2 H), 4.07 (t, J = 8.7 Hz, 1 H), 3.77-3.57 (m, 1 H), 3.51-3.27 (m, 2 H), 3.12 (d, J = 12.4 Hz, 2 H), 2.09 (dd, J = 20.9, 12.2 Hz, 8 H), 1.47 (dd, J = 14.0, 7.1 Hz, 2 H), 0.80 (dd, J = 8.0, 6.7 Hz, 3 H). LC-MS(ESI): m / z = 407.9[M+H] + .

[0140] OBD-021 (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidine-2-one [ka] 1 H-NMR (300 MHz, DMSO-d6) δ: 8.57 (s, 1 H), 8.01 (s, 1 H), 7.36 (dd, J = 15.8, 2.1 Hz, 1 H), 7.18-6.92 (m, 2 H), 5.06 (dd, J = 8.9, 4.8 Hz, 1 H), 4.72-4.52 (m, 2 H), 4.36 (s, 2 H), 4.17 (t, J = 9.1 Hz, 1 H), 3.84 (dt, J = 49.3, 24.7 Hz, 1 H), 3.12 (d, J = 12.8 Hz, 2 H), 2.16 (s, 1 H), 2.11 (s, 1 H), 2.04 (s, 4 H). LC-MS(ESI): m / z = 389.9[M+H] + .

[0141] OTB-506 N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclopropanecarboxamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.37 (d, J = 13.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.85 (brs, 1 H), 6.22 (t, J = 6.0 Hz, 1 H), 4.79-4.73 (m, 1 H), 4.41 (brs, 2 H), 3.99 (t, J = 7.2 Hz, 1 H), 3.77-3.64 (m, 3 H), 3.39 (d, J = 12.8 Hz, 2 H), 2.20-2.09 (m, 6 H), 1.43-1.37 (m, 1 H), 0.98-0.90 (m, 2H), 0.82-0.75 (m, 2 H).HR-MS(ESI-TOF):m / z[M+H] + C 20 H 25 Calculated value of N3O3FS: 406.1595; Measured value: 406.1527.

[0142] OTB-507 N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.45 (d, J = 12.4 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 1 H), 7.05 (t, J = 8.8 Hz, 1 H) 5.95 (m, 1 H), 4.78 (m, 1 H), 4.51 (brs, 2 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.84-3.74 (m, 3 H), 3.66 (m, 2 H), 3.02 (m, 1 H), 2.28-2.15 (m, 10 H), 1.95 (m, 1 H), 1.85 (m, 1 H). 13C-NMR (100 MHz, CDCl3) δ: 175.9, 154.3, 153.0 (d, J = 242.9 Hz), 131.2, 127.0, 118.6 (d, J = 4.4 Hz), 114.5 (d, J = 2.9 Hz), 108.3 (d, J = HRMS(ESI):m / z[M+H] + C 21 H 27 Calculated value of N3O3SF: 420.1757; Measured value: 420.1736.

[0143] OTB-510 N-(((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.08 (m, 2 H), 6.00 (m, 1 H), 4.76 (m, 1 H), 4.24 (brs, 2 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.75-3.60 (m, 3 H), 3.38 (m, 2 H), 2.21 (m, 2 H), 2.14 (s, 4 H), 2.03 (s, 3 H). 13 C-NMR (100 MHz, CDCl3) δ: 171.2, 155.3 (dd, J = 241.5, 9.5 Hz), 154.1, 130.6 (t, J = 13.6 Hz), 122.9 (t, J = 12.4 Hz), 102.9 (dd, J = 20.7, 11.3 Hz), 71.9, 60.4, 47.4, 41.9, 33.7, 29.2, 23.1.HRMS(ESI):m / z[M+H] + C 18 H 22 Calculated value of N3O3SF2: 3 98.1350; Measured value: 398.1329.

[0144] OTB-512 (((S)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.09 (m, 2 H), 5.08 (m, 1 H), 4.76 (m, 1 H), 4.24 (brs, 2 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.75-3.50 (m, 6 H), 3.38 (m, 2 H), 2.20 (m, 2 H), 2.14 (s, 4 H). 13 C-NMR (100 MHz, CDCl3) δ: 157.5, 155.3 (dd, J = 241.6, 9.4 Hz), 153.9, 130.7 (t, J = 13.6 Hz), 122.9 (t, J = 12.3 Hz), 102.9 (dd, J = 20.7, 11.3 Hz), 71.8, 60.4, 52.6, 47.3, 43.6, 33.7, 29.2.HRMS(ESI):m / z[M+H] + C 18 H 22 Calculated value of N3O4SF2: 414.1294; measured value: 414.1278.

[0145] OTB-511 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-((1R,5S)-3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.78 (s, 1 H), 7.76 (s, 1 H), 6.94 (d, J = 11.6 Hz, 2 H), 5.07-5.04 (m, 1 H), 4.79 (d, J = 3.6 Hz, 2 H), 4.20 (brs, 2 H), 4.09 (t, J = 8.8 Hz, 1 H), 3.88-3.83 (m, 1 H), 3.32 (d, J = 12.8 Hz, 2 H), 2.19-2.11 (m, 6 H). 13 C-NMR (100 MHz, CDCl3) δ: 155.3 (d, J = 242.1 Hz), 155.2 (d, J = 242.1 Hz), 153.1, 134.5, 129.9 (t, J = 13.6 Hz), 125.1, 123.3 (t, J = 12.3 Hz), 103.3 (dd, J = 20.7, 11.2 Hz), 70.3, 60.4, 52.0, 47.2, 33.8, 29.2.HRMS(ESI):m / z[M+H] + C 18 H 20 Calculation of N5O2SF2 Value: 408.1300; Measured value: 408.1295.

[0146] OTB-508 N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclopropanecarboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.05 (m, 2 H), 6.12 (m, 1 H), 4.76 (m, 1 H), 4.21 (brs, 2 H), 3.95 (t, J = 9.2 Hz, 1 H), 3.72-3.65 (m, 3 H), 3.34 (m, 2 H), 2.21-2.12 (m, 6 H), 1.37 (m, 1 H), 0.99-0.75 (m, 4 H). 13 C-NMR (100 MHz, CDCl3) δ: 174.8, 155.3 (dd, J = 241.7, 9.5 Hz), 154.2, 130.5 (t, J = 13.6 Hz), 123.0 (t, J = 12.5 Hz), 103.0 (dd, J = 20.8, HRMS(ESI):m / z[M+H] + C 20 H 24 N3O Calculated value for 3SF2: 420.1506; Measured value: 424.1484.

[0147] OTB-509 N-(((S)-3-(4-((1R,5S)-3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.09 (m, 2 H), 5.78 (m, 1 H), 4.75 (m, 1 H), 4.23 (brs, 2 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.73 (m, 1 H), 3.65 (m, 2 H), 3.36 (m, 2 H), 2.99 (m, 1 H), 2.27-2.14 (m, 9 H), 1.97 (m, 1 H), 1.85 (m, 2 H). 13 C-NMR (100 MHz, CDCl3) δ: 176.0, 155.3 (dd, J = 243.4, 9.5 Hz), 154.1, 130.6 (t, J = 13.5 Hz), 122.9 (t, J = 12.2 Hz), 102.9 (dd, J = 20.7, HRMS(ESI):m / z[M+H] + C 21 H 26 Calculated value of N3O3SF2: 438.1663; measured value: 438.1642.

[0148] OTB-503 N-(((5S)-3-(3-fluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.45 (dd, J = 16.0, 2.8 Hz, 1 H), 7.12 (dd, J = 8.8, 2.0 Hz, 1 H), 6.83 (t, J = 9.2 Hz, 1 H), 6.14 (s, 1 H), 4.78-4.77 (m, 1 H), 4.61 (s, 2 H), 4.00 (t, J = 8.8 Hz, 1 H), 3.77-3.64 (m, 3 H), 3.45 (d, J = 9.6 Hz, 2 H), 2.85 (d, J = 12.4 Hz, 2 H), 2.22-2.20 (m, 2 H), 2.03 (s, 3 H), 1.92-1.88 ( m, 2 H).HR-MS(ESI-TOF):m / z[M+H] + C 18 H 23 Calculated value of N3O4FS: 396.1388; Measured value: 396.1379.

[0149] OTB-505 (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1 H), 7.75 (s, 1 H), 7.30 (dd, J = 15.2, 2.0 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.79 (t, J = 9.2 Hz, 1 H), 5.07-5.05 (m, 1 H), 4.79 (s, 2 H), 4.58 (s, 2 H), 4.12 (t, J = 9.2 Hz, 1 H), 3.91-3.89 (m, 1 H), 3.43 (d, J = 11.6 Hz, 2 H), 2.88-2.81 (m, 2 H), 2.21-2.18 (m, 2 H), 1.89-1.87 (m, 2 H).HR-MS(ESI-TOF):m / z[M+H] + C 18 H 21 N5 O3FS calculated value: 406.1349; measured value: 406.1339.

[0150] OTB-513 N-(((5S)-3-(3,5-difluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 12.0 Hz, 2 H), 5.97 (brs, 1 H), 4.77-4.75 (m, 1 H), 4.45 (s, 2 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.74 (t, J = 8.4 Hz, 1 H), 3.66 (t, J = 5.2 Hz, 2 H), 3.54 (d, J = 9.2 HRMS(ESI):m / z[M+H] + C 21 H 26 Calculated value of N3O4SF2: 454.1606; measured value: 454.1588.

[0151] OTB-514 N-(((5S)-3-(3,5-difluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.12 (d, J = 12.0 Hz, 2 H), 6.15 (brs, 1 H), 4.81-4.75 (m, 1 H), 4.45 (s, 2 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.74-3.63 (m, 3 H), 3.56 (d, J = 9.2 Hz, 2 H), 2.92 (d, J = 12.4 Hz, 2 H), 2.20-2.17 (m, 2 H), 2.03 (s, 3 H), 1.89-1.83 (m, 2 H).HRMS(ESI):m / z[M+H] + C 18 H 22 Total N3O4SF2 Calculated value: 414.1293; Measured value: 414.1275.

[0152] OBD-017 N-(((5S)-3-(3-fluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide [ka] 1 H-NMR (300 MHz, CDCl3) δ: 7.39 (dd, J = 15.8, 2.3 Hz, 1 H), 7.03 (d, J = 6.1 Hz, 2 H), 6.78 (t, J = 9.3 Hz, 1 H), 4.72 (s, 1 H), 4.55 (s, 2 H), 3.94 (t, J = 8.9 Hz, 1 H), 3.81-3.66 (m, 1 H), 3.58 (s, 2 H), 3.42 (d, J = 10.3 Hz, 2 H), 2.77 (d, J = 11.9 Hz, 2 H), 2.17 (dd, J = 25.1, 17.8 Hz, 4 H), 1.84 (d, J = 7.9 Hz, 2 H), 1.56 (dd, J = 14.5, 7.2 Hz, 2 H), 0.83 (t, J = 7.4 Hz, 3 H). LC-MS(ESI): m / z = 423.8[M+H] + .

[0153] OBD-018 (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (300 MHz, DMSO-d6) δ: 12.17 (s, 1 H), 8.69 (d, J = 2.9 Hz, 1 H), 8.20 - 8.03 (m, 1 H), 7.44 (d, J = 16.2 Hz, 1 H), 7.28-7.02 (m, 2 H), 5.08 (dd, J = 8.5, 5.1 Hz, 1 H), 4.68-4.52 (m, 4 H), 4.20 (t, J = 9.1 Hz, 1 H), 3.91 (dd, J = 8.7, 6.0 Hz, 1 H), 3.56 (d, J = 11.1 Hz, 2 H), 2.48 (d, J = 12.3 Hz, 2 H), 2.06 (d, J = 5.1 Hz, 2 H), 1.79 (d, J = 7.6 Hz, 2 H). LC-MS(ESI): m / z = 405.8[M+H] + .

[0154] OTB-260 (R)-3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one [ka] 1H-NMR (400 MHz, CDCl3) δ:7.38 (d, J = 14.0 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.55 (t, J = 8.8 Hz, 1 H), 4.72 (brs, 1 H), 4.02 (s, 4 H), 3.99-3.89 (m, 3 H), 3.76-3.73 (m, 1 H), 3.42 (s, 4 H). 13 C-NMR (100 MHz, CDCl3) δ: 154.8, 152.2 (d, J = 240.8 Hz), 135.9 (d, J = 11.7 Hz), 130.2 (d, J = 9.3 Hz), 114.6 (d, J = 5.2 Hz), 114.5 (d, J = HRMS(ESI):m / z[M+H] + C 15 H 18 F N2O3S: Calculated value of 325.1022; Measured value: 325.1010.

[0155] OTB-261 (S)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 14.0 Hz, 1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.48 (t, J = 8.8 Hz, 1 H), 6.20 (brs, 1 H), 4.75-4.73 (m, 1 H), 3.98-3.96 (m, 5 H), 3.73-3.66 (m, 2 H), 3.62-3.57 (m, 1 H), 3.41 (s, 4 H), 2.01 (s, 3 H).HRMS(ESI):m / z[M+H] + C 17 H 21 Calculated value for FN3O3S: 366.1288; Measured value: 366.1274.

[0156] OTB-241 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1 H), 7.75 (s, 1 H), 7.22 (dd, J = 13.6, 2.0 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.51 (t, J = 9.2 Hz, 1 H), 5.06-5.00 (m, 1 H), 4.78-4.77 (m, 2 H), 4.08 (t, J = 9.2 Hz, 1 H), 4.01 (s, 4 H), 3.89-3.85 (m, 1 H), 3.40 (s, 4 H). 13C-NMR (100 MHz, CDCl3) δ: 153.6, 152.0 (d, J = 243.1 Hz), 136.3 (d, J = 11.1 Hz), 134.5, 129.1 (d, J = 9.0 Hz), 125.1, 115.0 (d, J = 3.2 HRMS(ESI):m / z[M+H] + C 17 H 19 Calculated value for FN5O2S: 376.1244; Measured value: 376.1231.

[0157] OTB-516 (R)-3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.03 (d, J = 12.0 Hz, 2 H), 4.74-4.70 (m, 1 H), 4.18 (s, 4 H), 3.98 (dd, J = 12.8, 3.2 Hz, 1 H), 3.93-3.85 (m, 2 H), 3.75 (dd, J = 12.4, 4.0 Hz, 1 H), 3.41 (s, 4 H). HRMS(ESI):m / z[M+H] + C 15 H 17 Calculated value of N2O3SF2: 343.0922; measured value: 343.0912.

[0158] OTB-515 (S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J = 11.6 Hz, 2 H), 5.99 (brs, 1 H), 4.74-4.72 (m, 1 H), 4.16 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.71-3.65 (m, 2 H), 3.61-3.55 (m, 1 H), 3.40 (s, 4 H), 2.01 (s, 3 H). 13 C-NMR (100 MHz, CDCl3) δ: 171.1, 154.2, 152.6 (dd, J = 240.6, 11.1 Hz), 153.1, 134.5, 128.5 (t, J = 12.6 Hz), 124.7 (t, J = 13.3 Hz), 102.8 (dd, J = 18.2, 10.7 Hz), 71.9, 68.7, 47.6, 45.2, 42.0, 36.5, 23.1.HRMS(ESI):m / z[M+H] + C 17 H 20 Calculated value of N3O3SF2: 384.1188; measured value: 384.1168.

[0159] OTB-242 (S)-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1 H NMR (400 MHz, CDCl3) δ: 7.00 (d, J = 11.6 Hz, 2 H), 5.16 (brs, 1 H), 4.81-4.67 (m, 1 H), 4.16 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.68 (s, 3 H), 3.56-3.50 (m, 3 H), 3.40 (s, 4 H).HRMS(ESI):m / z[M+H] + C 17 H 20 Calculated value for F2N3O4S: 400.1143; Measured value: 400.1125.

[0160] OTB-245 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one [ka] 1 H NMR (400 MHz, CDCl3) δ: 7.77 (s, 1 H), 7.74 (s, 1 H), 6.87 (d, J = 11.6 Hz, 2 H), 5.03-5.01 (m, 1 H), 4.77-4.76 (m, 2 H), 4.15 (s, 4 H), 4.06 (t, J = 9.2 Hz, 1 H), 3.86-3.82 (m, 1 H), 3.41 (s, 4 H).HRMS(ESI):m / z[M+H] + C 17 H 18 F2N5O2S Calculated value: 394.1149; Measured value: 394.1129.

[0161] OTB-243 (S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclopropanecarboxamide [ka] 1 H NMR (400 MHz, CDCl3) δ: 6.98 (d, J = 11.6 Hz, 2 H), 6.25-6.24 (m, 1 H), 4.77-4.71 (m, 1 H), 4.16 (s, 4 H), 3.92 (t, J = 8.8 Hz, 1 H), 3.71 - 3.56 (m, 3 H), 3.40 (s, 4 H), 1.40-1.38 (m, 1 H), 1.04-0.87 (m, 2 H), 0.82-0.73 (m, 2 H).HRMS(ESI):m / z[M+H] + C 19 H 22 Calculated value of F2N3O3S: 410.1350; Measured value: 410.1331.

[0162] OTB-244 (S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1 H NMR (400 MHz, CDCl3) δ: 6.99 (d, J = 11.6 Hz, 2 H), 5.83 (brs, 1 H), 4.82-4.68 (m, 1 H), 4.17 (s, 4 H), 3.93 (t, J = 8.8 Hz, HRMS(ESI):m / z[M+H] + C 20 H 24 F2N3 O3S calculated value: 424.1506; measured value: 424.1483

[0163] OTB-201 (R)-3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ:7.42 (dd, J = 14.0, 2.0 Hz, 1 H), 7.03 (dd, J = 8.8, 2.0 Hz, 1 H), 6.62 (t, J = 8.8 Hz, 1 H), 4.85 (s, 4 H), 4.73 (m, 1 H), 4.17 (s, 4 H), 4.00-3.95 (m, 2 H), 3.93-3.89 (m, 1 H), 3.77-3.74 (m, 1 H). 13 C-NMR (100 MHz, CDCl3) δ: 155.2, 152.3 (d, J = 240.7 Hz), 135.9 (d, J = 11.3 Hz), 130.4 (d, J = HRMS(ESI) :m / z[M+H] + C 15 H 18 Calculated value of FN2O4: 309.1251; Measured value: 309.1269.

[0164] OTB-202 (S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1H-NMR (300 MHz, CDCl3) δ: 7.35 (d, J = 14.1 Hz, 1 H), 7.00 (d, J = 8.7 Hz, 1 H), 6.51 (t, J =9.0 Hz, 1 H), 6.03(s, 1 H), 4.84 (s, 4 H), 4.74 (m, 1 H), 4.12 (s, 4 H), 3.99 (t, J =8.7 Hz, 1 H), 3.73-3.69 (m, 2 H), 3.61 (m, 1 H), 2.02 (s, 3 H). 13 C-NMR (100 MHz, CDCl3) δ: 171.4, 154.8, 152.4 (d, J = 240.8 Hz), 136.1 (d, J = 11.9 Hz), 130.1 (d, J = 9.2 Hz), 114.7 (d, J = 3.1 Hz), 114.6 (d, J = HRMS(ESI):m / z[M+H] + C 17 H 21 Calculated value for FN3O4: 350.1516; Measured value: 350.1497.

[0165] OTB-203 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.78 (s, 1 H), 7.75 (s, 1 H), 7.18 (d, J = 13.6 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 6.46 (t, J = 9.2 Hz, 1 H), 5.03 (m, 1 H), 4.83 (s, 4 H), 4.78 (m, 2 H), 4.10-4.07 (m, 5 H), 3.91-3.85 (m, 1 H). 13 C-NMR (100 MHz, CDCl3) δ: 153.6, 152.1 (d, J = 241.4 Hz), 136.1 (d, J = 10.6 Hz), 134.5, 129.2 (d, J = 9.3 Hz), 125.1, 115.0 (d, J = 2.9 Hz), 114.5 (d, J = 4.7 Hz), 108.1 (d, J = 23.7 Hz), 81.0, 70.4, 62.9, 52.1, 47.7, 39.8.HRMS(ESI):m / z[M+H] + C 17 H 19 Calculated value for FN5O3: 360.1472; Measured value: 360.1451.

[0166] OTB-204 (R)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-f Luoro-4-(2-oxa-6-azapiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2 H), 7.31 (d, J = 14.4, 2.4 Hz,1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.59 (t, J = 9.2 Hz, 1 H), 5.14-5.07 (m, 1 H), 4.88-4.83 (m, 5 H), 4.77-4.71 (m, 1 H), 4.16 (s, 4 H), 4.07-4.02 (m, 1 H), 3.98-3.92 (m, 1 H). 13 C-NMR (100 MHz, CDCl3) δ: 158.99, 154.38, 147.08, 144.53, 135.18, 115.11, 114.43, 112.30, 107.91, 107.87, 81.04, 71.85, 70.04, 62.91, 48.38, 48.02, 41.57, 39.85.HRMS(ESI):m / z[M+H] + C 17 H 19 Calculated value of FN5O3 :360.1472; Measured value:360.1451.

[0167] OTB-205 (S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)furan-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.46 (s, 1 H), 7.32 (dd, J = 14.0, 2.4 Hz, 1 H), 7.14 (d, J = 3.2 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.81 (t, J = 6.4 Hz, 1 H), 6.51 (d, J = 3.2 Hz, 1 H), 6.45 (t, J = 9.2 Hz, 1 H), 4.83 (brs, 5 H), 4.08 (s, 4 H), 4.03 (t, J = 8.8 Hz, 1 H), 3.92-3.85 (m, 1 H), 3.79-3.73 (m, 2 H). 13C-NMR (100 MHz, CDCl3) δ: 159.2, 154.6, 152.4 (d, J = 240.8 Hz), 147.3, 144.7, 136.5, 130.5 (d, J = 9.4 Hz), 115.3, 114.7 (d, J = 3.1 HRMS(ESI):m / z[M+H] + C 20 H 21 FN3O5 calculation Value: 402.1465; Measured value: 402.1561.

[0168] OTB-206 (S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)thiophene-2-carboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.53 (d, J = 3.2 Hz, 1 H), 7.50 (d, J = 4.8 Hz, 1 H), 7.32 (d, J = 14.0 Hz, 1 H), 7.09-6.96 (m, 2 H), 6.66 (m, 1 H), 6.45 (t, J = 9.2 Hz, 1 H), 4.82 (s, 4 H), 4.09-4.01 (m, 6 H), 3.81-3.79 (m, 1 H), 3.78-3.73 (m, 2 H). 13 C-NMR (100 MHz, CDCl3) δ: 162.9, 154.7, 152.5 (d, J = 241.1 Hz), 150.1, 140 .8, 138.1, 130.9, 128.9, 128.0, 114.9 (d, J = 2.8 Hz), 114.2 (d, J = 3.2 Hz), 108.1 (d, J = 23.9 Hz), 81.20 72.2, 63.2, 48.3, 42.7, 40.0.HRMS(ESI):m / z[M+H] + C 20 H 21 Calculated values ​​for FN3O4S :418.1237; Measured value: 418.1331.

[0169] OTB-222 (R)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)methanesulfonamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.44-7.35 (m, 1 H), 7.07- 6.97 (m, 1 H), 6.69-6.59 (m, 1 H), 4.98-4.91 (m, 1 H), 4.85 (s, 4 H), 4.81-4.75 (m, 1 H), 4.24-4.14 (m, 4 H), 4.13-4.09 (m, 1 H), 4.06-3.98 (m, 1 H), 3.92-3.86 (m, 1 H), 3.63-3.53 (m, 1 H), 3.47-3.36 (m, 1 H), 3.03 (s, 3 H). 13 C-NMR (100 MHz, DMSO-d6) δ: 154.5, 151.7 (d, J = 237.7 Hz), 135.9 (d, J = 11.0 Hz), 130.5 (d, J = 9.4 Hz), 115.2 (d, J = 5.4 Hz), 115.1 (d, J = 2.8 Hz), 107.3 (d, J = 23.8 Hz), 80.2, 71.7, 62.7, 47.6, 45.5.HRMS(ESI):m / z[M+H] + C 16 H21 Calculated value for FN3O5S: 386.1186; Measured value: 386.1185.

[0170] OTB-223 (S)-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.39 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 6.61 (t, J = 9.2 Hz, 1 H), 5.11 (brs, 1 H), 4.84 (s, 4 H), 4.73 (brs, 1 H), 4.16 (s, 4 H), 3.99 (t, J = 8.8 Hz, 1 H), 3.77-3.75 (m, 1 H), 3.68 (s, 3 H), 3.64-3.60 (m, 1 H), 3.55-3.50 (m, 1 H).HRMS(ESI):m / z[M+H] + C 17 H 21 Calculated value for FN3O5: 366.1465; Measured value: 366.1466.

[0171] OTB-238 (S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclopropanecarboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.35 (dd, J = 14.0, 2.4 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.51 (t, J = 9.2 Hz, 1 H), 6.13 (brs, 1 H), 4.84 (s, 4 H), 4.75-4.73 (m, 1 H), 4.12 (s, 4 H), 3.97 (t, J = 8.8 Hz, 1 H), 3.75-3.65 (m, 3 H), 1.39-1.36 (m, 1 H), 0.97-0.91 (m, 2 H), 0.79-0.75 (m, 2 H). 13 C-NMR (100 MHz, CDCl3) δ: 174.8, 154.6, 151.6 (d, J = 240.8 Hz), 136.0 (d, J = 11.3 Hz), 129.8 (d, J = 9.2 Hz), 114.5 (d, J = 3.1 Hz), 114.6 (d, J = 3.1 Hz), 114.3 (d, J = HRMS(ESI):m / z[M+H] + C 19 H 23 Calculated value for FN3O4: 376.1673; Measured value: 376.1652.

[0172] OTB-239 (S)-N-((3-(3-fluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.49 (d, J = 14.4 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.85 (t, J = 9.2 Hz, 1 H), 5.82 (brs, 1 H), 4.86 (s, 4 H), 4.76 (brs, 1 H), 4.27 (s, 4 H), 4.00 (t, J = 9.2 Hz, 1 H), 3.78-3.65 (m, 3 H), 3.03-2.99 (m, 1 H), 2.26-2.13 (m, 4 H), 1.99-1.85 (m, 2 H). 13 C-NMR (100 MHz, CDCl3) δ: 176.0, 154.5, 152.1 (d, J = 240.9 Hz), 136.0 (d, J = 11.2 Hz), 129.8 (d, J = 9.2 Hz), 114.4 (d, J = 3.1 Hz), 114.3 (d, J = 5.2 Hz), 107.7 (d, J = 23.9 Hz), 81.1, 71.9, 62.8, 47.9, 41.9, 39.7, 25.4, 25.3, 18.2.HRMS(ESI):m / z[M+H] + C 20 H 25 Calculated value for FN3O4: 390.1829; Measured value: 390.1808.

[0173] OTB-229 (R)-3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.03 (d, J = 10.8 Hz, 2 H), 4.82 (s, 4 H), 4.72 (brs, 1 H), 4.28 (s, 4 H), 3.99-3.85 (m, 3 H), 3.75-3.72 (m, 1 H). 13 C-NMR (100 MHz, CDCl3) δ: 154.6, 152.6 (dd, J = 240.2, 10.8 Hz), 128.9 (t, J = 12.8 Hz), 124.3 (t, J = 13.3 Hz), 102.8 (dd, J = 18.2, 10.7 Hz), 81.0, 72.9, 64.9, 62.6, 46.3, 40.8.HR MS(ESI): m / z[M+H] + C 15 H 17 Calculated value of F2N2O4: 327.1156; measured value: 327.1135.

[0174] OTB-230 (S)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 6.97 (d, J = 10.0 Hz, 2 H), 6.49 (brs, 1 H), 4.81 (s, 4 H), 4.75 (brs, 1 H), 4.27 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.70-3.63 (m, 3 H), 2.02 (s, 3 H). 13 C-NMR (100 MHz, CDCl3) δ: 171.2, 154.2, 152.5 (dd, J = 240.5, 10.9 Hz), 128.6 (t, J = 12.6 Hz), 124.5 (t, J = 13.4 Hz), 102.8 (dd, J = 18.2, HRMS(ESI) :m / z[M+H] + C 17 H 20 Calculated value for F2N3O4: 368.1422; Measured value: 368.1418.

[0175] OTB-231 (S)-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)carbamate methyl [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.04 (d, J = 10.8 Hz, 2 H), 5.08 (brs, 1 H), 4.83 (s, 4 H), 4.74 (brs, 1 H), 4.34 (s, 4 H), 3.96 (t, J = 9.2 Hz, 1 H), 3.72-3.51 (m, 6 H). 13 ¹¹C-NMR (100 MHz, CDCl3) δ: 157.5, 154.0, 152.6 (dd, J = 240.4, 10.9 Hz), 128.7 (t, J = 12.8 HRMS(ESI):m / z[M+H] + C 17 H 20Calculated value of F2N3O5: 384.1371; Measured value: 384.1367.

[0176] OTB-232 (R)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)methanesulfonamide [ka] 1 H-NMR (400 MHz, DMSO-d6) δ: 7.8 (d, J = 12.4 Hz, 2 H), 4.74-4.69 (m, 5 H), 4.23 (s, 4 H), 4.06 (t, J = 8.8 Hz, 1 H), 3.74-3.70 (m, 1 H), 3.31-3.27 (m, 2 H), 2.94 (s, 3 H). 13 C-NMR (100 MHz, DMSO-d6) δ: 154.3, 152.2 (dd, J = 237.8, 11.3 Hz), 129.5 (t, J = 13.0 Hz), 124.4 (t, J = 13.6 Hz), 102.9 (dd, J = 18.2, 10.5 Hz), 80.0, 71.8, 64.7, 47.4, 45.5, 40.7.HRMS(ESI):m / z[M+H] + C 16 H 20 Calculated value for F2N3O5S: 404.1092; Measured value: 404.1087.

[0177] OTB-233 (S)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)cyclopropanecarboxamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J = 10.0 Hz, 2 H), 6.36 (brs, 1 H), 4.82 (s, 4 H), 4.75 (brs, 1 H), 4.28 (s, 4 H), 3.93 (t, J = 8.8 Hz, 1 H), 3.72-3.65 (m, 3 H), 1.42-1.40 (m, 1 H), 0.96-0.88 (m, 2 H), 0.77-0.75 (m, 2 H). 13 C-NMR (100 MHz, CDCl3) δ: 174.9, 154.4, 152.5 (dd, J = 240.4, 10.3 Hz), 128.6 (t, J = 12.7 Hz), 124.4 (t, J = 13.4 Hz), 102.8 (dd, J = 18.2, 10.6 Hz), 80.9, 72.2, 64.8, 47.6, 41.9, 40.8, 14.5, 7.7.HRMS(ESI):m / z[M+H] + C 19 H 22 Calculated value of F2N3O4: 394.1578; Measured value: 394.1575.

[0178] OTB-234 (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.77 (s, 1 H), 7.75 (s, 1 H), 6.86 (d, J = 11.6 Hz, 2 H), 5.03-5.02 (m, 1 H), 4.81 (s, 4 H), 4.77-4.76 (m, 2 H), 4.27 (s, 4 H), 4.06 (t, J = 9.2 Hz, 1 H), 3.86-3.82 (m, 1 H). 13 C-NMR (100 MHz, CDCl3) δ: 153.2, 152.4 (dd, J = 240.7, 11.0 Hz), 134.5, 127.8 (t, J = 12.8 Hz), 125.1, 124.8 (t, J = 13.3 Hz), 103.1 (dd, J = 18.1, 10.7 Hz), 80.9, 70.4, 64.8, 52.0, 47.3, 40.8.HRMS(ESI):m / z[M+H] + C 17 H 18 Calculated value of F2N5O3: 378.1378; Measured value: 378.1365.

[0179] OTB-240 (S)-N-((3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)cyclobutanecarboxamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.00 (d, J = 12.0 Hz, 2 H), 5.87 (t, J = 6.0 Hz, 1 H), 4.82 (s, 4 H), 4.77-4.71 (m, 1 H), 4.28 (s, 4 H), 3.94 (t, J = 8.8 Hz, 1 H), 3.72-3.64 (m, 3 H), 3.03-2.99 (m, 1 H), 2.26-2.13 (m, 4 H), 1.99-1.82 (m, 2 H).HRMS(ESI):m / z[M+H] + C 20 H 24 Calculated value for F2N3O4: 408.1735; Measured value: 408.1716.

[0180] OTB-701 (R)-N-((3-(3-fluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CDCl3) δ: 7.38 (d, J = 14.4 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.58 (t, J = 9.2 Hz, 1 H), 4.76 (m, 2 H), 4.30 (s, 4 H), 4.10 (s, 4 H), 3.76 (m, 1 H), 3.54 (m, 2 H), 1.96 (s, 3 H). 13 C-NMR (100 MHz, CDCl3) δ: 172.6, 155.4, 153.2, 150.8, 135.6, 130.5, 114.4, 107.3, 72.0, 62.2, 55.0, 48.0, 41.7, 37.2, 21.0.HRMS(ESI):m / z[M+H] + C 17 H 22 Calculated value for FN4O3: 349.1671; Measured value: 349.1662.

[0181] OTB-702 (R)-N-((3-(3-fluoro-4-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J = 14.4 Hz, 1 H), 7.08 (d, J = 8.8 Hz, 1 H), 6.57 (t, J = 9.2 Hz, 1 H), 4.75 (m, 1 H), 4.10 (t, J = 9.2 Hz, 1 H), 4.01 (s, 4 H), 3.74 (m, 1 H), 3,73 (s, 4 H), 3.53 (m, 2 H), 2.52 (s, 3 H), 1.96 (s, 3 H). 13 C NMR (100 MHz, CDCl3) δ: 172.6, 155.4, 153.2, 150.8, 136.1, 130.3, 114.4, 107.3, 72.0, 64.9, 62.6, 48.0, 43.0, 41.7, 34.8, 21.0.HRMS(ESI):m / z[M+H] + C 18 H 24 Calculated value for FN4O3: 363.1827, measured value: 363.1819.

[0182] OTB-704 (R)-N-((3-(3,5-difluoro-4-(2,6-diazaspiro[3,3]heptan-2-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CD3OD) δ: 7.12 (d, J = 9.6 Hz, 2 H), 4.76, (m, 1 H), 4.30 (s, 4 H), 4.24 (s, 4 H), 4.06 (m, 1 H), 3.73 (m, 1 H), 3.53 (m, 2 H), 1.96 (s, 3 H). 13C NMR (100 MHz, CD3OD) δ: 172.6, 155.0, 153.7, 151.3, 129.6, 129.4, 102.7, 102.5, 72.0, 64.3, 55.0, 48.0, 41.6, 38.3, 21.0. HRMS(E SI): m / z[M+H] + C 17 H 21 Calculated value of F2N4O3: 367.1583, measured value: 367.1576.

[0183] OTB-705 (R)-N-((3-(3,5-difluoro-4-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)phenyl)-2-oxo-oxazolidine-5-yl)methyl)acetamide [ka] 1 H-NMR (400 MHz, CD3OD) δ: 7.12 (d, J = 10.0 Hz, 2 H), 4.75 (m, 1 H), 4.22 (s, 4 H), 4.05 (m, 1 H), 3.78 (s, 4 H), 3.73 (m, 1 H), 3.53 (m, 2 H), 2.55 (s, 3 H), 1.96 (s, 3 H). 13 1C-NMR (100 MHz, CD3OD) δ: 172.6, 155.0, 153.7, 151.3, 129.4, 102.8, 72.0, 64.7, 64.6, 48.0, 42.7, 41.7, 22.4, 21.0.HRMS(ESI):m / z[M+H] + C 18 H 23 Calculated value of F2N4O3: 381.1733, measured value: 381.1725.

[0184] (Example 12) Synthesis of Additional Embodiments of the Invention Procedure for preparing (6): [ka] Experimental ethyl 5-oxothiopan-4-carboxylate (2). To a solution of tetrahydrothiopyran-4-one (100 g, 862 mmol) in Et2O (150 mL), BF3-Et2O (120 mL, 948 mmol) was added at -30°C. The reaction mixture was then stirred at -30°C for 2 hours under a nitrogen atmosphere. Subsequently, a solution of 2-ethyl 2-diazoethyl acetate (147 g, 1293 mmol) in Et2O (100 mL) was added to the mixture at -30°C. The mixture was then warmed to room temperature and stirred overnight. The mixture was quenched with K2CO3, the solvent was concentrated, and dried to obtain ethyl 5-oxothiopan-4-carboxylate (2) (80 g, 46%) as a brown oil.

[0185] Chiepan-4-on(3). A mixture of ethyl 5-oxothiepan-4-carboxylate (2) (80 g, 396 mmol) and lithium chloride (16.6 g, 396 mmol) in DMSO (100 mL) and H2O (5 drops) was stirred at 180°C for 2 hours. The reaction mixture was cooled to room temperature, poured into ice water, extracted with EA, and the organic layer was concentrated under reduced pressure to obtain thiepan-4-one (3) (15.9 g crude product, 31%) as a brown solid.

[0186] (Z)-Chiepan-4-oneoxime(4). To a solution of thiepan-4-one (3) (15.9 g, 122 mmol) in EtOH (150 mL) and H2O (50 mL), NH2OH-HCl (8.47 g, 122 mmol) was added, and the reaction mixture was stirred at 75°C for 4 hours under a nitrogen gas atmosphere. The mixture was then concentrated and dried to obtain (Z)-thiepan-4-one oxime (4) (9.97 g, 56%) as a brown solid.

[0187] 1,5-thiazocan-4-one(5). A mixture of (Z)-thiepan-4-one oxime (4) (9.97 g, 68.7 mmol) and polyphosphate (50 g) was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to 8 using potassium carbonate solution. Extraction was performed with EA, and the organic layer was concentrated under reduced pressure to obtain 1,5-thiazocan-4-one (5) (3 g crude product, 30%) as a brown solid.

[0188] 1,5-Thiazocane(6). To a solution of 1,5-thiazocan-4-one (5) (3 g, 20.7 mmol) in THF (100 mL), BH3 (31 mL, 31.1 mmol) in THF was added at 0°C, followed by reflux for 12 hours. The reaction was quenched with CH3OH (50 mL). The solvent was evaporated to obtain 1,5-thiazocan (6) as a white oily substance (1.7 g, 63%), and the crude substance was used in the next reaction without further purification. LC-MS(ESI)m / z=132[M+H] + . [ka]

[0189] Step 1: Preparation of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocan (8): [ka] To a solution of 1,5-thiazocane (6) (1 g, 7.6 mmol) and 1,2-difluoro-4-nitrobenzene (1.2 g, 7.6 mmol) in DMF (10 mL), K2CO3 (1.05 g, 7.6 mmol) was added at 25°C, and the reaction mixture was then subjected to a nitrogen gas atmosphere. The mixture was stirred at 80°C for 2 hours under atmospheric pressure and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE=3:1) to obtain 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane(8) (1.5g, 74%) as a yellow solid. LC-MS(ESI)m / z=271[M+H] + .

[0190] Step 2: 3-Fluoro-4-(1,5-thiazocan-5-yl)benzeneamine (9): [ka] A solution of 5-(2-fluoro-4-nitrophenyl)-1,5-thiazocane(8) (1.5 g, 5.7 mmol) and palladium carbon (200 mg) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 3-fluoro-4-(1,5-thiazocan-5-yl)benzeneamine(9) (1.2 g, 91%) as a white oil, and the crude substance was used in the next reaction without further purification. LC-MS(ESI)m / z=241[M+H] + .

[0191] Step 3: 3-Fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate benzyl(10): [ka] Benzyl carbonochloride (1.76 g, 10.4 mmol) was added to a suspension of 3-fluoro-4-(1,5-thiazocan-5-yl)benzeneamine (9) (1.2 g, 5.2 mmol) and triethylamine (1.05 g, 10.4 mmol) in DCM (200 mL) under a nitrogen atmosphere at -20°C. The reaction mixture was then stirred at 0°C for 30 minutes and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 10:1) to obtain 3-fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate benzyl (10) (740 mg, 38%) as a white solid. LC-MS(ESI)m / z=375[M+H] + .

[0192] Step 4: (R)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one(11): [ka] To a solution of benzyl(10) 3-fluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (740 mg, 1.97 mmol) in THF (10 mL), n-BuLi (1.3 ml, 2.96 mmol) was added at -78°C under a nitrogen atmosphere, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, a solution of (R)-oxiran-2-ylmethyl butyrate (427 mg, 2.96 mmol) in THF was added to the mixture at -78°C. The mixture was then heated to room temperature, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (R)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one (11) (382 mg, 57%) as a white solid. LC-MS(ESI)m / z=341[M+H] + .

[0193] Step 5: (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfone (12): [ka] 4-methylbenzene-1-sulfonyl chloride (418 mg, 2.2 mmol) was added to a suspension of (R)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one (11) (382 mg, 1.1 mmol) and Et3N (222 mg, 2.2 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (12 (407 mg, 75%) was obtained as a white solid. LC-MS(ESI)m / z=495[M+H] + .

[0194] Step 6: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (OBD-001): [ka] (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzase in DMF (5 mL) To a solution of insulfonate (12) (200 mg, 0.4 mmol) and 1H-1,2,3-triazole (56 mg, 0.8 mmol), K2CO3 (110 mg, 0.8 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 2:1) to obtain (R)-5-((1H-1,2,3-triazole-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (OBD-001) (70 mg, 45%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.76 (d, J = 17.6 Hz, 2H), 7.41 - 7.09 (m, 1H), 7.11 - 6.73 (m, 2H), 5.04 (d, J = 3.0 Hz, 1H), 4.78 (d, J = 3.4 Hz, 2H), 4.12 (t, J = 9.2 Hz, 1H), 3.88 (dd, J = 9.2, 6.1 Hz, 1H), 3.36 (t, J = 6.0 Hz, 3H), 2.92 - 2.59 (m, 4H), 2.01 (dd, J = 27.9, 7.3 Hz, 4H). LC-MS(ESI)m / z=391.9[M+H] + .

[0195] Step 7: Preparation of (OBD-002): [ka] To a solution of (R)-5-((1H-1,2,3-triazole-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (OBD-001) (50 mg, 0.13 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (80 mg, 0.13 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude substance was purified by silica gel column chromatography (DCM:MeOH=80:1) to obtain (OBD-002) (22 mg, 41%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.92 - 7.67 (m, 2H), 7.32 (d, J = 16.8 Hz, 1H), 7.12 (t, J = 9.0 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 5.07 (s, 1H), 4.81 (d, J = 4.0 Hz, 2H), 4.15 (t, J = 9.0 Hz, 1H), 4.01 - 3.83 (m, 1H), 3.32 (d, J = 14.2 Hz, 5H), 3.11 - 2.87 (m, 2H), 2.59 (s, 2H), 2.19 (s, 4H). LC-MS(ESI)m / z=407.8[M+H] + . [ka]

[0196] Step 1: (R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (OBD-008): [ka] (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzase in DMF (5 mL) To a solution of insulfonate (12) (200 mg, 0.4 mmol) and 1H-1,2,4-triazole (56 mg, 0.8 mmol), K2CO3 (110 mg, 0.8 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 2:1) to obtain (R)-5-((1H-1,2,4-triazole-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (OBD-008) (84 mg, 54%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 8.24 (s, 1H), 7.97 (s, 1H), 7.00 (s, 2H), 5.12 - 4.91 (m, 1H), 4.56 (d, J = 4.7 Hz, 2H), 4.24 - 3.83 (m, 2H), 3.38 (t, J = 6.0 Hz, 4H), 2.95 - 2.59 (m, 4H), 1.98 (s, 5H). LC-MS(ESI)m / z=391.9[M+H] + .

[0197] Step 2: Preparation of (OBD-009): [ka] To a solution of (R)-5-((1H-1,2,3-triazole-1-yl)methyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (OBD-008) (50 mg, 0.13 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (80 mg, 0.13 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude substance was purified by silica gel column chromatography (DCM:MeOH=80:1) to obtain (OBD-009) (22 mg, 41%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 8.24 (s, 1H), 7.93 (s, 1H), 7.41 - 7.20 (m, 1H), 7.19 - 6.92 (m, 2H), 5.10 - 4.92 (m, 1H), 4.56 (d, J = 4.7 Hz, 2H), 4.12 (t, J = 9.0 Hz, 1H), 3.97 (dd, J = 9.2, 6.2 Hz, 1H), 3.28 (dd, J = 13.0, 6.9 Hz, 2H), 3.12 (dd, J = 12.5, 5.9 Hz, 4H), 3.02 - 2.83 (m, 2H), 2.22 - 1.99 (m, 5H), 1.26 (d, J = 9.4 Hz (4H). LC-MS(ESI)m / z=407.8[M+H] + . [ka]

[0198] Step 1: (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one(13): [ka] (R)-(3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylben in DMF (10 mL) To a solution of zensulfonate (12) (800 mg, 1.62 mmol) and sodium azide (105 mg, 1.62 mmol), K2CO3 (447 g, 3.24 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,5-thiazo Can-5-yl)phenyl)oxazolidine-2-one (13) (470 mg, 80%) was obtained as a white solid. LC-MS(ESI)m / z=366[M+H] + .

[0199] Step 2: (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one(14): [ka] To a solution of (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (13) (470 mg, 1.3 mmol) in MeOH (10 mL), palladium carbon (100 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (14) (374 mg, 85%) as a white solid. LC-MS(ESI)m / z=340[M+H] + .

[0200] Step 3: (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-005): [ka] To a solution of (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (14) (374 mg, 1.1 mmol) and butyric acid (97 mg, 1.1 mmol) in DCM (10 mL), HOBt (223 mg, 1.65 mmol), EDCI (420 mg, 2.2 mmol), and DIPEA (284 mg, 2.2 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C under a nitrogen atmosphere for 2 hours and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-003) (252 mg, 56%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.50 (s, 2H), 7.03 (d, J = 6.1 Hz, 1H), 5.99 (s, 1H), 4.77 (d, J = 5.7 Hz, 1H), 4.02 (t, J = 9.0 Hz, 2H), 3.70 (ddd, J = 20.7, 15.2, 7.7 Hz, 4H), 3.48 (s, 4H), 2.95 - 2.68 (m, 4H), 2.20 (t, J = 7.2 Hz, 3H), 2.06 (d, J = 6.1 Hz, 4H), 1.64 (dd, J = 14.8, 7.4 Hz, 4H), 0.91 (t, J = 7.4 Hz, 4H). LC-MS(ESI)m / z=409.9[M+H] + .

[0201] Step 4: Preparation of (OBD-004): [ka] To a solution of (S)-N-((3-(3-fluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-003) (150 mg, 0.37 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (225 mg, 0.37 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude product was purified by preparative HPLC to obtain (OBD-004) (48 mg, 31%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.44 (dd, J = 14.7, 2.4 Hz, 1H), 7.19 - 6.99 (m, 2H), 6.44 (s, 1H), 4.84 - 4.71 (m, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.78 (dd, J = 9.0, 6.6 Hz, 1H), 3.66 (t, J = 4.6 Hz, 2H), 3.38 - 3.09 (m, 6H), 2.99 (dd, J = 12.6, 6.3 Hz, 2H), 2.20 (dd, J = 9.4, 5.3 Hz, 6H), 1.71 - 1.56 (m, 2H), 0.91 (dd, J = 9.6, 5.1 Hz, 3H). LC-MS(ESI)m / z=425.8[M+H] + . [ka]

[0202] Step 1: Preparation of 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazocan (8): [ka] To a solution of 1,5-thiazokane(6) (1 g, 7.6 mmol) and 1,2,3-trifluoro-5-nitrobenzene (1.35 g, 7.6 mmol) in DMF (10 mL), K2CO3 (2.1 g, 15.2 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 3:1) to obtain 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazokane(8) (1.64 g, 75%) as a yellow solid. LC-MS(ESI)m / z=289[M+H] + .

[0203] Step 2: 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzeneamine (9): [ka] A solution of 5-(2,6-difluoro-4-nitrophenyl)-1,5-thiazocane(8) (1.64 g, 5.7 mmol) and palladium carbon (200 mg) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzeneamine(9) (1.4 g, 94%) as a white oil, and the crude substance was used in the next reaction without further purification. LC-MS(ESI)m / z=259[M+H] + .

[0204] Step 3: 3,5-Difluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate benzyl(10): [ka] Benzyl carbonochloride (1.87 g, 10.6 mmol) was added to a suspension of 3,5-difluoro-4-(1,5-thiazocan-5-yl)benzeneamine (9) (1.4 g, 5.3 mmol) and triethylamine (1.07 g, 10.6 mmol) in DCM (200 mL) under a nitrogen atmosphere at -20°C. The reaction mixture was then stirred at 0°C for 30 minutes and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 10:1) to obtain benzyl 3,5-difluoro-4-(1,5-thiazocan-5-yl)phenylcarbamate (10) (872 mg, 42%) as a white solid. LC-MS(ESI)m / z=393[M+H] + .

[0205] Step 4: (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one(11): [ka] 3,5-difluoro-4-(1,5-thiazocan-5-yl) in THF (10 mL) To a solution of benzyl(10) phenylcarbamate (872 mg, 2.23 mmol), n-BuLi (1.4 ml, 3.34 mmol) was added at -78°C under a nitrogen atmosphere, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, a solution of (R)-oxiran-2-ylmethyl butyrate (480 mg, 3.34 mmol) in THF was added to the mixture at -78°C. The mixture was added, then heated to room temperature, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one (11) (519 mg, 65%) as a white solid. LC-MS(ESI)m / z=359[M+H] + .

[0206] Step 5: (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenes Iuhonate (12): [ka] 4-methylbenzene-1-sulfonyl chloride (550 mg, 2.9 mmol) was added to a suspension of (R)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one (11) (519 mg, 1.45 mmol) and Et3N (292 mg, 2.9 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonyl chloride. Honate (12) (594 mg, 80%) was obtained as a white solid. LC-MS(ESI)m / z=513[M+H] + .

[0207] Step 6: (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one(13): [ka] (R)-(3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methyl in DMF (10 mL) To a solution of benzenesulfonate (12) (594 g, 1.2 mmol) and sodium azide (75 mg, 1.2 mmol), K2CO3 (160 mg, 2.4 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (13) (400 mg, 87%) as a white solid. LC-MS(ESI)m / z=384[M+H] + .

[0208] Step 7: (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one(14): [ka] To a solution of (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (13) (400 g, 1.04 mmol) in MeOH (10 mL), palladium carbon (100 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (14) (331 g, 89%) as a white solid. LC-MS(ESI)m / z=358[M+H] + .

[0209] Step 8: (S)-N-((3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-026): [ka] To a solution of (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (14) (165 mg, 0.46 mmol) and butyric acid (52 mg, 0.46 mmol) in DCM (10 mL), HOBt (95 mg, 0.7 mmol), EDCI (175 mg, 0.92 mmol), and DIPEA (118 mg, 0.92 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C under a nitrogen atmosphere for 2 hours and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain (S)-N-((3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-026) (82 mg, 42%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.14 (d, J = 11.1 Hz, 1H), 5.93 (s, 1H), 4.81 (s, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.70 (s, 2H), 3.31 (s, 3H), 2.87 (s, 2H), 2.22 (s, 2H), 1.90 (s, 5H), 1.66 (d, J = 7.3 Hz, 2H), 0.93 (t, J = 7.4 Hz, 2H). LC-MS(ESI)m / z=428[M+H] + .

[0210] Step 9: N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-027): [ka] To a solution of (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(1,5-thiazocan-5-yl)phenyl)oxazolidine-2-one (14) (165 mg, 0.46 mmol) and butyric acid (52 mg, 0.46 mmol) in DCM (10 mL), HOBt (95 mg, 0.7 mmol), EDCI (175 mg, 0.92 mmol), and DIPEA (118 mg, 0.92 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C under a nitrogen atmosphere for 2 hours and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-027) (82 mg, 45%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.23 - 6.85 (m, 2H), 6.00 (s, 1H), 4.90 - 4.66 (m, 1H), 4.17 - 3.86 (m, 1H), 3.71 (s, 2H), 3.28 (s, 2H), 2.84 (s, 3H), 2.04 (s, 3H), 1.88 (s, 5H). LC-MS(ESI)m / z=400[M+H] + .

[0211] Synthesis pathway: [ka] Experimental tetrahydrothiopyran-4-one oxime (2). To a solution of tetrahydrothiopyran-4-one (20 g, 172 mmol) in EtOH (150 mL) and H2O (50 mL), NH2OH-HCl (11.9 g, 172 mmol) was added, and the reaction mixture was stirred at 75°C for 4 hours under a nitrogen gas atmosphere. The mixture was then concentrated and dried to obtain tetrahydrothiopyran-4-one oxime (2) (14.7 g, 66%) as a brown solid.

[0212] 1,4-thiazepan-5-on(3). A mixture of tetrahydrothiopyran-4-one oxime (2) (14.7 g, 112 mmol) and polyphosphate (50 g) was stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to 8 using potassium carbonate solution. Extraction was performed with EA, and the organic layer was concentrated under reduced pressure to obtain 1,4-thiazepan-5-one (3) (11.9 g crude product, 81%) as a brown solid.

[0213] 1,4-thiazepane(4). To a solution of 1,4-thiazepan-5-one (3) (11.9 g, 105 mmol) in THF (100 mL), BH3 (158 mL, 158 mol) in THF was added at 0°C, followed by reflux for 12 hours. The reaction was quenched with CH3OH (50 mL). The solvent was evaporated to obtain 1,4-thiazepane (4) as a white oily substance (10.7 g, 87%), and the crude substance was used in the next reaction without further purification. LC-MS(ESI)m / z=118[M+H] + . [ka]

[0214] Step 1: Preparation of 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane (6): [ka] To a solution of 1,4-thiazepane(4) (7 g, 59.8 mmol) and 1,2-difluoro-4-nitrobenzene (10.4 g, 65.8 mmol) in DMF (10 mL), K2CO3 (16.5 g, 119.6 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 3:1) to obtain 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane(6) (10 g, 65%) as a yellow solid. LC-MS(ESI)m / z=257[M+H] + .

[0215] Step 2: 3-Fluoro-4-(1,4-thiazepan-4-yl)benzeneamine (7): [ka] A solution of 4-(2-fluoro-4-nitrophenyl)-1,4-thiazepane (6) (8 g, 31.2 mmol) and palladium carbon (500 mg) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 3-fluoro-4-(1,4-thiazepane-4-yl)benzeneamine (7) (6.4 g, 93%) as a white oil, and the crude product was further purified. It was used in the next reaction without any prior discussion. LC-MS(ESI)m / z=227[M+H] + .

[0216] Step 3: 3-Fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate benzyl(8): [ka] Benzyl carbonochloride (9.6 g, 56.6 mmol) was added to a suspension of 3-fluoro-4-(1,4-thiazepan-4-yl)benzeneamine (7) (6.4 g, 28.3 mmol) and triethylamine (5.7 g, 56.6 mmol) in DCM (200 mL) under a nitrogen atmosphere at -20°C. The reaction mixture was then stirred at 0°C for 30 minutes and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 10:1) to obtain 3-fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate benzyl (8) (2.34 g, 23%) as a white oil. LC-MS(ESI)m / z=361[M+H] + .

[0217] Step 4: (R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one(9): [ka] To a solution of benzyl(8) 3-fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate (8) (2.34 g, 6.5 mmol) in THF (10 mL), n-BuLi (4 ml, 9.7 mmol) was added under a nitrogen atmosphere at -78°C, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, (R)-oxiran-2-ylmethyl=bu in THF was added. A solution of tilate (1.4 g, 9.7 mmol) was added to the mixture at -78°C, then heated to room temperature, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one (9) (1.16 g, 55%) as a white solid. LC-MS(ESI)m / z=327[M+H] + .

[0218] Step 5: (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfone (10): [ka] 4-methylbenzene-1-sulfonyl chloride (1.4g, 7.2 mmol) is added to (R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-5-(hydroxymethyl)oxazolidine-2-one (9) (1.16g) in DCM (10mL). (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl-4-methylbenzenesulfonate (10)(10)(2)(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl-4-methylbenzenesulfonate (10)(2)(2)(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl-4-methylbenzenesulfonate (10)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(2)(3)(2 1.41 g (41%) was obtained as a white solid. LC-MS(ESI)m / z=481[M+H] + .

[0219] Step 1: (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one(11): [ka] (R)-(3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=4-methylben in DMF (10 mL) To a solution of zensulfonate (10) (1.41 g, 2.95 mmol) and sodium azide (190 mg, 2.95 mmol), K2CO3 (814 g, 5.9 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one (11) (830 mg, 80%) as a white solid. LC-MS(ESI)m / z=352[M+H] + .

[0220] Step 2: (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one(12): [ka] To a solution of (R)-5-(azidomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one (11) (830 mg, 2.4 mmol) in MeOH (10 mL), palladium carbon (100 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one (12) (654 mg, 85%) as a white solid. LC-MS(ESI)m / z=326[M+H] + .

[0221] Step 3: (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-005): [ka] To a solution of (S)-5-(aminomethyl)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)oxazolidine-2-one (12) (654 mg, 2 mmol) and butyric acid (177 mg, 2 mmol) in DCM (10 mL), HOBt (405 mg, 3 mmol), EDCI (764 mg, 4 mmol), and DIPEA (516 mg, 4 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-005) (286 mg, 34%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.42 - 7.23 (m, 2H), 7.01 (dd, J = 8.9, 2.3 Hz, 1H), 6.04 (s, 1H), 4.75 (ddd, J = 9.0, 7.9, 4.6 Hz, 1H), 4.00 (t, J = 9.0 Hz, 1H), 3.79 - 3.05 (m, 7H), 2.91 (dd, J = 16.2, 10.1 Hz, 2H), 2.70 (t, J = 6.3 Hz, 2H), 2.28 - 2.13 (m, 2H), 2.13 - 1.97 (m, 2H), 1.82 - 1.25 (m, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.01 (s, 1H). LC-MS(ESI)m / z=395.9[M+H] + .

[0222] Step 4: Preparation of (OBD-006 and OBD-007): [ka] To a solution of (S)-N-((3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-005) (150 mg, 0.38 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (233 mg, 0.38 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude product was purified by preparative HPLC to obtain (OBD-006) (50 mg, 32%) as a white solid and (OBD-007) (24 mg, 15%) as a white solid.

[0223] (OBD-006) 1 H NMR (301 MHz, CDCl3) δ 7.52 (d, J = 15.0 Hz, 1H), 7.16 (s, 1H), 7.03 (d, J = 8.7 Hz, 1H), 5.99 (s, 1H), 4.78 (s, 1H), 4.02 (t, J = 8.8 Hz, 2H), 3.88 - 3.56 (m, 3H), 3.55 - 2.92 (m, 7H), 2.77 (s, 1H), 2.20 (t, J = 7.1 Hz, 3H), 1.64 (dd, J = 14.9, 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). LC-MS(ESI)m / z=411.8[M+H] + .

[0224] (OBD-007) 1 H NMR (301 MHz, CDCl3) δ 7.51 (d, J = 14.7 Hz, 1H), 7.10 (d, J = 9.9 Hz, 2H), 5.92 (s, 1H), 4.78 (s, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.87 - 3.39 (m, 7H), 3.27 (d, J = 5.7 Hz, 2H), 2.39 (d, J = 6.2 Hz, 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.64 (dd, J = 14.8, 7 .4 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS(ESI)m / z=427.8[M+H] + .

[0225] Procedure for preparing R: [ka] Step 1: Preparation of (2S,5R)-1-benzylpyrrolidine-2,5-dicarboxylate diethyl (2): [ka]

[0226] A mixture of (2R,5S)-2,5-dibromohexanediate diethyl (1) (100 g, 278 mmol), BnNH2 (44.6 g, 416 mmol), and K2CO3 (76.84 g, 556 mmol) in toluene / H2O was stirred overnight at 110°C and monitored by TLC. The mixture was extracted with ethyl acetate, washed with water and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2S,5R)-1-benzylpyrrolidine-2,5-dicarboxylate diethyl (2) (63.75 g, 75%) as a white oil. LC-MS(ESI)m / z=306[M+H] + .

[0227] Step 2: (2S,5R)-pyrrolidine-2,5-diethyl dicarboxylate (3): [ka] To a solution of (2S,5R)-1-benzylpyrrolidine-2,5-dicarboxylate diethyl (2) (63.75 g, 209 mmol) and palladium carbon (2 g) in MeOH (15 mL), CH3COOH (5 mL) was added. The reaction mixture was then stirred at 50°C for 5 hours under a hydrogen gas atmosphere and 4 atm, and monitored by TLC. The filtered mixture was concentrated under reduced pressure, and the crude product was used in the next reaction without further purification. LC-MS(ESI)m / z=216[M+H] + .

[0228] Step 3: (2S,5R)-1-benzyl=2,5-diethyl=pyrrolidine-1,2,5-tricarboxylate (4): [ka] (2S,5R)-diethyl=pyrrolidine-2,5-dicarb in DCM (100 mL) To a solution of xylate (3) (62 g, 288 mmol) and Et3N (58 g, 577 mmol), benzyl carbonochloride (98 g, 577 mmol) was added under a nitrogen atmosphere at -20°C. The reaction mixture was then stirred at room temperature for 5 hours and monitored by TLC. The mixture was extracted with DCM, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2S,5R)-1-benzyl=2,5-die Tyl-pyrrolidine-1,2,5-tricarboxylate (4) (80g, 80%) is white It was obtained as an oily substance. LC-MS(ESI)m / z=350[M+H] + .

[0229] Step 4: (2S,5R)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate benzyl(5): [ka] CaCl2 (76g, 688mmol) and NaBH4 (43g, 1146mmol) are mixed in (2S,5R)-1-benzyl in EtOH-MeOH (9:1; 200mL) 2,5-Diethyl=pyrrolidine-1,2,5-tricarboxylate (4) (80g, 2 The mixture was added to a 29 mmol (29 mmol) stirred solution under a nitrogen atmosphere at room temperature, and the reaction mixture was stirred for 5 hours and monitored by TLC. 5 mL of H2O was added, and the mixture was stirred for a further 15 minutes. The mixture was then concentrated under vacuum. The mixture was extracted with dimethyl, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (2S,5R)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate benzyl(5) (32 g, 52%) as a white oil. LC-MS(ESI)m / z=266[M+H] + .

[0230] Step 5: (2S,5R)-2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate benzyl(6): [ka] 4-methylbenzene-1-sulfonyl chloride (92 g, 483 mmol) was added at 0°C under a nitrogen atmosphere to a stirred solution of (2S,5R)-2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate benzyl (5) (32 g, 121 mmol) and Et3N in DCM (200 mL). The reaction mixture was then heated to room temperature, stirred for 5 hours, and monitored by TLC. The mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE=2:1). Lysine-1-carboxylate benzyl(6) (30g, 43%) was obtained as a white solid. LC-MS(ESI)m / z=574[M+H] + .

[0231] Step 6: 8-benzyl-3-thia-8-aza-bicyclo[3.2.1]octane-1-carboxylate(7): [ka] Sodium sulfide hydrate (38 g, 157 mmol) was added at room temperature to a stirred solution of (2S,5R)-2,5-bis(tosyloxymethyl)pyrrolidine-1-carboxylate benzyl (6) (30 g, 50 mmol) in EtOH (50 mL) and water (50 mL). The reaction mixture was then stirred at 90 °C for 2 hours and monitored by TLC. The mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE = 10:1) to obtain 8-benzyl-3-thia-8-aza-bicyclo[3.2.1]octane-1-carboxylate (7) (10 g, 73%) as a white solid. LC-MS(ESI)m / z=264[M+H] + .

[0232] Step 7: 3-thia-8-azabicyclo[3.2.1]octaneoidone(8): [ka] Iodotrimethylsilane (15 g, 75 mmol) was added at 0°C under a nitrogen atmosphere to a stirred solution of 8-benzyl-3-thia-8-aza-bicyclo[3.2.1]octane-1-carboxylate (7) (10 g, 38 mmol) in DCM (200 mL). The reaction mixture was then heated to room temperature, stirred for 30 minutes, and monitored by TLC. The mixture was extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain 3-thia-8-aza-bicyclo[3.2.1]octane iodide (8) (8.13 g, 84%) as a brown solid. LC-MS(ESI)m / z=130[M+H] + [ka]

[0233] Step 1: Preparation of 8-(2-fluoro-4-nitrophenyl)-3-thia-8-azabicyclo[3.2.1]octane(10): [ka] To a solution of 3-thia-8-azabicyclo[3.2.1]octane iodide (8) (5.58 g, 21.7 mmol) and 1,2-difluoro-4-nitrobenzene (3.8 g, 23.8 mmol) in DMF (10 mL), K2CO3 (6 g, 43.4 mmol) was added at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 80°C for 2 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE=3:1) to obtain 8-(2-fluoro-4-nitrophenyl)-3-thia-8-azabicyclo[3.2.1]octane (10) (4.89 g, 84%) as a yellow solid. LC-MS(ESI)m / z=269[M+H] + .

[0234] Step 2: 4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzeneamine(11): [ka] A solution of 8-(2-fluoro-4-nitrophenyl)-3-thia-8-aza-bicyclo[3.2.1]octane(10) (4.89 g, 18.2 mmol) and palladium carbon (200 mg) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorobenzeneamine(11) (4.08 g, 94%) as a white oil, and the crude product was used in the next reaction without further purification. LC-MS(ESI)m / z=239[M+H] + .

[0235] Step 3: 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenylcarbamate benzyl(12): [ka] 6.38 g, 25.6 mmol of carbonate,2,5-dioxo-1-pyrrolidinyl=phenylmethyl ester was added to a suspension of 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorobenzeneamine (11) (4.08 g, 17.1 mmol) in THF (30 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE=10:1) to obtain benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenylcarbamate (12) (4.34 g, 68%) as a white solid. LC-MS(ESI)m / z=373[M+H] + .

[0236] Step 4: (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one(13): [ka] To a solution of benzyl(12)(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenylcarbamate (12) (4.34 g, 11.6 mmol) in THF (10 mL), n-BuLi (7.3 ml, 17.5 mmol) was added under a nitrogen atmosphere at -78 °C, and the mixture was then stirred at -78 °C for 30 minutes. Subsequently, (R)-oxiran-2-ylmethyl butyrate (2.5 g, 17.4 mmol) in THF was added. The solution was added to the mixture at -78°C, then heated to room temperature, stirred overnight, and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (13) (3.03 g, 77%) as a white solid. LC-MS(ESI)m / z=339[M+H] + .

[0237] Step 5: ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14): [ka] 4-methylbenzene-1-sulfonyl chloride (3.41 g, 17.9 mmol) is added to (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (13) (3.03 g, 8.9 mmol) and Et3N (1.8) in DCM (10 mL). The mixture was added to a suspension of (g, 17.9 mmol) under a nitrogen atmosphere at 0°C, and the reaction mixture was stirred overnight at room temperature and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14)(3.74 g, 85%) was obtained as a white solid. LC-MS(ESI)m / z=493[M+H] + .

[0238] Step 6: (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidine-2-one (OBD-021): [ka] ((R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14) (500 mg, 1 mmol) in DMF (10 mL) To a solution of (5R) and 1H-1,2,4-triazole (140 mg, 2 mmol), K2CO3 (280 mg, 2 mmol) was added at 25°C, and the reaction mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 2:1) to obtain (5R)-5-((1H-1,2,4-triazole-1-yl)methyl)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidine-2-one (OBD-021) (177 mg, 45%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.01 (s, 1H), 7.36 (dd, J = 15.8, 2.1 Hz, 1H), 7.18 - 6.92 (m, 2H), 5.06 (dd, J = 8.9, 4.8 Hz, 1H), 4.72 - 4.52 (m, 2H), 4.36 (s, 2H), 4.17 (t, J = 9.1 Hz, 1H), 3.84 (dt, J = 49.3, 24.7 Hz, 1H), 3.12 (d, J = 12.8 Hz, 2H), 2.16 (s, 1H), 2.11 (s, 1H), 2.04 (s, 4H). LC-MS(ESI)m / z=390[M+H] + .

[0239] Step 7: Preparation of (OBD-018): [ka] To a solution of (5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)oxazolidine-2-one (OBD-021) (100 mg, 0.26 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (157 mg, 0.26 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude substance was purified by silica gel column chromatography (DCM:MeOH=80:1) to obtain (OBD-018) (52 mg, 50%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.69 (d, J = 2.9 Hz, 1H), 8.20 - 8.03 (m, 1H), 7.44 (d, J = 16.2 Hz, 1H), 7.28 - 7.02 (m, 2H), 5.08 (dd, J = 8.5, 5.1 Hz, 1H), 4.68 - 4.52 (m, 4H), 4.20 (t, J = 9.1 Hz, 1H), 3.91 (dd, J = 8.7, 6.0 Hz, 1H), 3.56 (d, J = 11.1 Hz, 2H), 2.48 (d, J = 12.3 Hz, 2H), 2.06 (d, J = 5.1 Hz, 2H), 1.79 (d, J = 7.6 Hz, 2H). LC-MS(ESI)m / z=405.8[M+H] + . [ka]

[0240] Step 1: (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidine-2-one(15): [ka] ((R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14) (2g, 4 mmol) in DMF (10 mL) To a solution of sodium azide (265 mg, 4 mmol), K2CO3 (1.1 g, 8 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidine-2-one (15) (1.01 g, 70%) as a white solid. LC-MS(ESI)m / z=364[M+H] + .

[0241] Step 2: (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-081): [ka] To a solution of (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidine-2-one (15) (1.01 g, 2.8 mmol) in MeOH (10 mL), palladium carbon (100 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (5S)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-081) (800 mg, 85%) as a white solid. LC-MS(ESI)m / z=338[M+H] + .

[0242] Step 3: N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-016): [ka] To a solution of (5S)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-081) (200 mg, 0.59 mmol) and butyric acid (52 mg, 0.59 mmol) in DCM (10 mL), HOBt (95 mg, 0.7 mmol), EDCI (170 mg, 0.88 mmol), and DIPEA (115 mg, 0.88 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C under a nitrogen atmosphere for 2 hours and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-016) (156 mg, 65%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.42 (d, J = 16.0 Hz, 1H), 7.35 - 6.88 (m, 2H), 4.71 (s, 1H), 4.35 (s, 2H), 4.07 (t, J = 8.7 Hz, 1H), 3.77 - 3.57 (m, 1H), 3.51 - 3.27 (m, 2H), 3.12 (d, J = 12.4 Hz, 2H), 2.09 (dd, J = 20.9, 12.2 Hz, 8H), 1.47 (dd, J = 14.0, 7.1 Hz, 2H), 0.80 (dd, J = 8.0, 6.7 Hz, 3H). LC-MS(ESI)m / z=407.9[M+H] + .

[0243] Step 4: Preparation of (OBD-017): [ka] To a solution of N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-016) (100 mg, 0.25 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (157 mg, 0.26 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude product was purified by preparative HPLC to obtain (OBD-017) (16 mg, 15%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.39 (dd, J = 15.8, 2.3 Hz, 1H), 7.03 (d, J = 6.1 Hz, 2H), 6.78 (t, J = 9.3 Hz, 1H), 4.72 (s, 1H), 4.55 (s, 2H), 3.94 (t, J = 8.9 Hz, 1H), 3.81 - 3.66 (m, 1H), 3.58 (s, 2H), 3.42 (d, J = 10.3 Hz, 2H), 2.77 (d, J = 11.9 Hz, 2H), 2.17 (dd, J = 25.1, 17.8 Hz, 4H), 1.84 (d, J = 7.9 Hz, 2H), 1.56 (dq, J = 14.5, 7.2 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). LC-MS(ESI)m / z=423.8[M+H] + .

[0244] Step 4: Preparation of (OBD-085): [ka] To a solution of (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-081) (100 mg, 0.29 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (182 mg, 0.29 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude product was purified by preparative HPLC to obtain (OBD-085) (28 mg, 28%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J = 16.4, 2.2 Hz, 1H), 7.24 (dd, J = 8.9, 2.0 Hz, 1H), 7.13 (t, J = 9.6 Hz, 1H), 4.58 (dd, J = 14.1, 4.9 Hz, 3H), 4.04 (t, J = 8.9 Hz, 1H), 3.84 (dd, J = 8.7, 6.5 Hz, 1H), 3.56 (d, J = 10.0 Hz, 2H), 2.81 (dd, J = 9.3, 4.9 Hz, 2H), 2.46 (s, 2H), 2.17 - 1.99 (m, 2H), 1.79 (dd, J = 17.3, 9.5 Hz, 4H). LC-MS(ESI)m / z=354[M+H] + . [ka]

[0245] Step 1: Preparation of 8-(2,6-difluoro-4-nitrophenyl)-3-thia-8-azabicyclo[3.2.1]octane(10): [ka] To a solution of 3-thia-8-azabicyclo[3.2.1]octane iodide (8) (5.0 g, 19.4 mmol) and 1,2,3-trifluoro-5-nitrobenzene (4.13 g, 23.3 mmol) in DMF (10 mL), K2CO3 (5.35 g, 38.8 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE=3:1) to obtain 8-(2,6-difluoro-4-nitrophenyl)-3-thia-8-azabicyclo[3.2.1]octane (10) (3.6 g, 65%) as a yellow solid. LC-MS(ESI)m / z=287[M+H] + .

[0246] Step 2: 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzeneamine(11): [ka] The reaction mixture was then prepared in a chamber under a hydrogen gas atmosphere by adding a solution of 8-(2-fluoro-4-nitrophenyl)-3-thia-8-azabicyclo[3.2.1]octane (10) (3.6 g, 12.5 mmol) and palladium carbon (200 mg) in MeOH (15 mL). The mixture was stirred overnight at warm temperature and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzeneamine (11) (2.9 g, 90%) as a white oil, which was used in the next reaction without further purification of the crude product. LC-MS(ESI)m / z=257[M+H] + .

[0247] Step 3: 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate benzyl(12): [ka] 5.57 g, 22.4 mmol of carbonate,2,5-dioxo-1-pyrrolidinyl phenylmethyl ester was added to a suspension of 4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzeneamine (11) (2.9 g, 11.2 mmol) in THF (30 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 10:1) to obtain 4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate benzyl (12) (3.0 g, 68%) as a white solid. LC-MS(ESI)m / z=391[M+H] + .

[0248] Step 4: (5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one(13): [ka] To a solution of 4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate benzyl(12) (3.0 g, 7.7 mmol) in THF (10 mL), n-BuLi (4.8 ml, 11.5 mmol) was added under a nitrogen atmosphere at -78 °C, and the mixture was then stirred at -78 °C for 30 minutes. Subsequently, (R)-oxiran-2-ylmethyl butyrate (1.66 g, 11.5 mmol) was added to the THF. The solution of l) was added to the mixture at -78°C, then heated to room temperature, stirred overnight, and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (13) (2.3 g, 84%) as a white solid. LC-MS(ESI)m / z=357[M+H] + .

[0249] Step 5: ((R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14): [ka] 4-methylbenzene-1-sulfonyl chloride (2.45 g, 13 mmol) was added to a suspension of (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (13) (2.3 g, 6.5 mmol) and Et3N (1.3 g, 13 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14)(2.8 1 g, 85% was obtained as a white solid. LC-MS(ESI)m / z=511[M+H] + .

[0250] Step 6: (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one(15): [ka] ((R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (14) (2.81g, 5. To a solution of (52 mmol) and sodium azide (360 mg, 5.52 mmol), K2CO3 (1.52 mg, 11.04 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (15) (1.85 g, 88%) as a white solid. LC-MS(ESI)m / z=382[M+H] + .

[0251] Step 7: (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-083): [ka] In a solution of (5R)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (15) (1.85 g, 4.87 mmol) in MeOH (10 mL), para Dium carbon (100 mg) was added at 25°C, and the reaction mixture was stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-083) (1.6 g, 90%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 7.34 - 7.15 (m, 2H), 4.59 (td, J = 11.0, 5.0 Hz, 1H), 4.10 (s, 2H), 3.99 (t, J = 8.9 Hz, 1H), 3.79 (dd, J = 8.9, 6.4 Hz, 1H), 3.11 (dd, J = 12.6, 1.6 Hz, 2H), 2.79 (qd, J = 13.7, 4.9 Hz, 2H), 2.26 (dd, J = 12.4, 3.3 Hz, 2H), 2.01 (s, 4H), 1.72 (d, J = 59.8 Hz, 2H). LC-MS(ESI)m / z=356[M+H] + .

[0252] Step 8: Preparation of (OBD-087): [ka] To a solution of (5S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-083) (100 mg, 0.28 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (173 mg, 0.28 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude product was purified by preparative HPLC to obtain (OBD-087) (31 mg, 30%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 7.32 (t, J = 9.4 Hz, 2H), 4.61 (dd, J = 8.8, 6.0 Hz, 0H), 4.34 (s, 1H), 4.02 (t, J = 8.9 Hz, 1H), 3.82 (dd, J = 8.9, 6.4 Hz, 1H), 3.68 (dd, J = 12.4, 3.7 Hz, 1H), 2.81 (qd, J = 13.7, 4.9 Hz, 1H), 2.58 (d, J = 11.6 Hz, 1H), 2.12 - 1.98 (m, 1H), 1.78 (q, J = 6.9 Hz, 2H). LC-MS(ESI)m / z=372[M+H] + .

[0253] Step 9: N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-029): [ka] To a solution of (5S)-3-(4-(3-thia-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-083) (200 mg, 0.56 mmol) and butyric acid (52 mg, 0.59 mmol) in DCM (10 mL), HOBt (95 mg, 0.7 mmol), EDCI (170 mg, 0.88 mmol), and DIPEA (115 mg, 0.88 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C under a nitrogen atmosphere for 2 hours and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=80:1) to obtain N-(((S)-3-(4-(3-thia-8-aza-bi Cyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-029) (119 mg, 50%) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.22 (d, J = 12.2 Hz, 2H), 4.73 (d, J = 3.6 Hz, 1H), 4.07 (dd, J = 19.1, 10.0 Hz, 3H), 3.68 (dd, J = 9.1, 6.2 Hz, 1H), 3.41 (s, 2H), 3.12 (d, J = 11.3 Hz, 2H), 2.26 (dd, J = 12.4, 3.0 Hz, 2H), 2.05 (dd, J = 16.8, 9.5 Hz, 6H), 1.47 (dd, J = 14.7, 7.3 Hz, 2H), 0.79 (t, J = 7.4 Hz, 3H). LC-MS(ESI)m / z=426[M+H] + .

[0254] Step 10: Preparation of (OBD-242): [ka] To a solution of N-(((S)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl)butylamide (OBD-029) (100 mg, 0.23 mmol) in THF (10 mL) and 10 drops of water, potassium peroxomonosulfate (144 mg, 0.23 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours and monitored by TLC. Quenched with sodium thiosulfate, the crude product was purified by preparative HPLC to obtain (OBD-242) (30 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 5.6 Hz, 1H), 7.28 (d, J = 12.7 Hz, 3H), 4.77 - 4.69 (m, 1H), 4.34 (s, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.67 (d, J = 9.0 Hz, 3H), 3.40 (dd, J = 11.0, 5.5 Hz, 1H), 2.56 (d, J = 11.9 Hz, 1H), 2.06 (t, J = 7.3 Hz, 4H), 1.82 - 1.72 (m, 2H), 1.51 - 1.40 (m, 2H), 0.78 (t, J = 7.4 Hz, 3H). LC-MS(ESI)m / z=442[M+H] + . [ka]

[0255] Step 1: Preparation of (3): A solution of p-toluenesulfonamide (57 g, 330 mmol) and potassium hydroxide (49.8 g, 890 mmol) in ethanol (1000 mL) contains 3-bromo-2, 2-bis(bromomethyl)propan-1-ol (90 g, 270 mmol) was added at 25°C, and the reaction mixture was then stirred at 100°C for 48 hours. The mixture was concentrated under reduced pressure, and the crude substance was poured into a potassium hydroxide solution (75 mL) and stirred for 2 hours to obtain a filtered cake (3) (10 g, 59%) as a white solid. LC-MS(ESI)m / z=254[M+H] + .

[0256] Step 2: Preparation of (4): A mixture of (3) (10 g, 39.5 mmol) and magnesium (6.7 g) in methanol (15 mL) was sonicated at 40°C for 1 hour, then the solvent was removed under reduced pressure to obtain a viscous gray residue. Et2O and sodium sulfate were added, and the resulting gray mixture was vigorously stirred for 30 minutes and then filtered. A solution of oxalic acid in ethanol was added to the filtrate. A white precipitate immediately formed, which was the target product (4) (3.7 g, 5 The result was 0%, and the crude material was used in the next reaction without further purification.

[0257] Step 3: Preparation of (5): To a solution of (4) (3.7 g, 19.5 mmol) and 1,2,3-trifluoro-5-nitrobenzene (3.81 g, 21.5 mmol) in DMF (10 mL), K2CO3 (5.38 g, 39 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen gas atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 3:1) to obtain (5) (1.9 g, 38%) as a yellow solid. LC-MS(ESI)m / z=257[M+H] + .

[0258] Step 4: Preparation of (6): A solution of (5) (1.9 g, 7.4 mmol) and palladium carbon (200 mg) was added to methanol (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain (6) (1.5 g, 90%) as a white oily substance, which was used in the next reaction without further purification of the crude material. LC-MS(ESI)m / z=227[M+H] + .

[0259] Step 5: Preparation of (7): 3.3 g, 13.3 mmol of carbonic acid, 2,5-dioxo-1-pyrrolidinyl=phenylmethyl ester was added to a suspension of (6) (1.5 g, 6.7 mmol) in THF (30 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 10:1) to obtain (7) (1.6 g, 68%) as a white solid. LC-MS(ESI)m / z=361[M+H] + .

[0260] Step 6: Preparation of (8): To a solution of (7) (1.6 g, 4.6 mmol) in THF (10 mL), n-BuLi (2.8 ml, 6.8 mmol) was added at -78°C under a nitrogen gas atmosphere, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, a solution of (R)-oxiran-2-ylmethyl butyrate (980 mg, 6.8 mmol) in THF was added to the mixture at -78°C, and then... The mixture was heated to room temperature, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (8) (1.2g, 84%) as a white solid. LC-MS(ESI)m / z=327[M+H] + .

[0261] Step 7: Preparation of (9): (E)-N1,N1,N2-trimethyldiazene-1,2-dicarboxamide (443 mg, 2.6 mmol) was added at 0°C under a nitrogen atmosphere to a suspension of (8) (560 mg, 1.7 mmol), isoxazole-3-ylcarbamate tert-butyl (380 mg, 2.1 mmol), and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 mL). The reaction mixture was then stirred overnight at 60°C and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 10:1) to obtain (9) (309 mg, 37%) as a white solid. LC-MS(ESI)m / z=493[M+H] + .

[0262] Step 8: Preparation of (OBD-061): To a solution of (9) (309 g, 0.6 mmol) in CH2Cl2 (10 mL), trifluoroacetic acid (1 ml) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes and monitored by TLC. Quenched with ammonium chloride, extracted with CH2Cl2, the organic layer was concentrated under reduced pressure, and the crude substance was purified by preparative HPLC to obtain (OBD-061) (93 mg, 38%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.01 (d, J = 12.1 Hz, 2H), 5.85 (d, J = 1.7 Hz, 1H), 4.92 (s, 1H), 4.82 (s, 4H), 4.29 (s, 4H), 3.99 (s, 2H), 3.75 (s, 2H), 3.60 (s, 2H) LC-MS(ESI)m / z=392.9[M+H] + . [ka]

[0263] Step 1: Preparation of (9): 4-methylbenzene-1-sulfonyl chloride (2.45 g, 13 mmol) was added at 0°C to a suspension of (8) (2.3 g, 6.5 mmol) and Et3N (1.3 g, 13 mmol) in DCM (10 mL). The reaction mixture was then stirred overnight at room temperature under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (9) (2.65 g, 85%) as a white solid. LC-MS(ESI)m / z=481[M+H] + .

[0264] Step 2: Preparation of (10): To a solution of (9) (2.65 g, 5.52 mmol) and sodium azide (360 mg, 5.52 mmol) in DMF (10 mL), K2CO3 (1.52 mg, 11.04 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (10) (1.7 g, 88%) as a white solid. LC-MS(ESI)m / z=352[M+H] + .

[0265] Step 3: Preparation of (OBD-062): To a solution of (10) (1.7 g, 4.86 mmol) in MeOH (10 mL), palladium carbon (100 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (OBD-062) (1.3 g, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 6.98 (m, 2H), 4.70 (s, 4H), 4.59 (dt, J = 11.3, 5.1 Hz, 1H), 4.23 (d, J = 2.2 Hz, 4H), 3.99 (dd, J = 20.9, 12.0 Hz, 1H), 3.78 (dd, J = 8.9, 6.4 Hz, 1H), 2.80 (ddd, J = 24.5, 13.6, 4.9 Hz, 2H), 1.99 (s, 2H). LC-MS(ESI)m / z=326.1[M+H] + . [ka]

[0266] Step 1: Preparation of (3): To a solution of (1) (3.7 g, 19.5 mmol) and 1,2-difluoro-4-nitrobenzene (3.41 g, 21.5 mmol) in DMF (10 mL), K2CO3 (5.38 g, 39 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 3:1) to obtain (3) (1.7 g, 38%) as a yellow solid. LC-MS(ESI)m / z=239[M+H] + .

[0267] Step 2: Preparation of (4): A solution of (3) (1.7 g, 7.4 mmol) and palladium carbon (200 mg) was added to methanol (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain (4) (1.4 g, 90%) as a white oily substance, which was used in the next reaction without further purification of the crude product. LC-MS(ESI)m / z=209[M+H] + .

[0268] Step 3: Preparation of (7): 3.3 g, 13.3 mmol of carbonic acid, 2,5-dioxo-1-pyrrolidinyl=phenylmethyl ester was added to a suspension of (6) (1.4 g, 6.7 mmol) in THF (30 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude product was chromatographed using silica gel column chromatography. The solution was purified using a solution (EA:PE=10:1) to obtain (7) (1.6g, 70%) as a white solid. LC-MS(ESI)m / z=343[M+H] + .

[0269] Step 4: Preparation of (8): To a solution of (7) (1.6 g, 4.7 mmol) in THF (10 mL), n-BuLi (2.9 ml, 7.0 mmol) was added at -78°C under a nitrogen atmosphere, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, a solution of (R)-oxiran-2-ylmethyl butyrate (1 g, 7.0 mmol) in THF was added to the mixture at -78°C, and then the mixture was heated to room temperature. The mixture was heated, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (8) (1.2g, 84%) as a white solid. LC-MS(ESI)m / z=309[M+H] + .

[0270] Step 5: Preparation of (9): (E)-N1,N1,N2-trimethyldiazene-1,2-dicarboxamide (443 mg, 2.6 mmol) was added at 0°C under a nitrogen atmosphere to a suspension of (8) (523 mg, 1.7 mmol), isoxazole-3-ylcarbamate tert-butyl (380 mg, 2.1 mmol), and tributylphosphine (521 mg, 2.6 mmol) in toluene (30 mL). The reaction mixture was then stirred overnight at 60°C and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 10:1) to obtain (9) (298 mg, 37%) as a white solid. LC-MS(ESI)m / z=475[M+H] + .

[0271] Step 6: Preparation of (OBD-056): To a solution of (9) (298 mg, 0.6 mmol) in CH2Cl2 (10 mL), trifluoroacetic acid (1 ml) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with CH2Cl2, and the organic layer was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain (OBD-056) (84 mg, 38%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.39 (d, J = 14.4 Hz, 1H), 7.25 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.83 (t, J = 8.9 Hz, 1H), 5.14 (s, 1H), 4.73 (s, 1H), 4.39 (s, 2H), 4.00 (t, J = 8.8 Hz, 1H), 3.84 - 3.42 (m, 8H), 3.05 (dd, J = 23.2, 11.2 Hz, 5H), 2.13 - 1.88 (m, 5H). LC-MS(ESI)m / z=375[M+H] + . [ka]

[0272] Step 1: Preparation of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane(3): To a solution of 8-oxa-3-azabicyclo[3.2.1]octane(1) (5.0 g, 44.2 mmol) and 1,2,3-trifluoro-5-nitrobenzene (8.6 g, 48.6 mmol) in DMF (10 mL), K2CO3 (12.2 g, 88.4 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE=3:1) to obtain 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane(3) (9.3 g, 78%) as a yellow solid. LC-MS(ESI)m / z=271[M+H] + .

[0273] Step 2: Preparation of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzeneamine (4): A solution of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane(3) (9.3 g, 34.4 mmol) and palladium carbon (1 g) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzeneamine(4) (7.8 g, 95%) as a white oil, and the crude substance was used in the next reaction without further purification. LC-MS(ESI)m / z=241[M+H] + .

[0274] Step 3: Preparation of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenylcarbamate benzyl(5): Carbonate, 2,5-dioxo-1-pyrrolidinyl=phenylmethyl ester (12 g, 48.7 mmol) was added to a suspension of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzeneamine (4) (7.8 g, 32.5 mmol) in THF (100 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA:PE=10:1) to obtain 4-(8- Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenylcarbamate benzyl(5) (8.2g, 68%) was obtained as a white solid. LC-MS(ESI)m / z=375[M+H] + .

[0275] Step 4: Preparation of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (OBD-114): To a solution of benzyl 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenylcarbamate (5) (8.2 g, 22.1 mmol) in THF (10 mL), n-BuLi (13.8 ml, 33.1 mmol) was added at -78°C under a nitrogen atmosphere, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, (R)-oxiran-2-ylmethyl butyrate (4.7 g, 33.1 mmol) was added to the THF. A solution of (ol) was added to the mixture at -78°C, then heated to room temperature, stirred overnight, and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (OBD-114) (4.5 g, 60%) as a white solid. LC-MS(ESI)m / z=341[M+H] + .

[0276] Step 5: Preparation of (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7): 4-methylbenzene-1-sulfonyl chloride (5 g, 26.6 mmol) was added to a suspension of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (OBD-114) (4.5 g, 13.3 mmol) and Et3N (2.7 g, 26.6 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7)(5.58 g, 85%) was obtained as a white solid. LC-MS(ESI)m / z=495[M+H] + .

[0277] Step 6: Preparation of 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)oxazolidine-2-one (OBD-054): (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7) (300 mg, 0.6 mmol) in DMF (10 mL) To a solution of l) and 1H-1,2,3-triazole (42 mg, 0.6 mmol), K2CO3 (166 mg, 1.2 mmol) was added at 25°C, and the reaction mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain 5-((1H-1,2,3-triazole-1-yl)methyl)-3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)oxazolidine-2-one (OBD-054) (82 mg, 35%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.14 (d, J = 1.0 Hz, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.17 (d, J = 11.7 Hz, 2H), 5.11 (d, J = 3.5 Hz, 1H), 4.79 (d, J = 5.0 Hz, 2H), 4.18 (dd, J = 23.1, 13.7 Hz, 3H), 3.91 - 3.70 (m, 1H), 3.23 (d, J = 10.9 Hz, 3H), 2.72 (d, J = 10.7 Hz, 3H), 2.07 - 1.61 (m, 7H). LC-MS(ESI)m / z=392[M+H] + . [ka]

[0278] Step 1: Preparation of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8): (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7) (4g, 8 mmol) in DMF (10 mL) and To a solution of sodium azide (526 mg, 8 mmol), K2CO3 (2.2 mg, 16 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8) (2.57 g, 88%) as a white solid. LC-MS(ESI)m / z=366[M+H] + .

[0279] Step 2: Preparation of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-115): To a solution of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8) (2.57 g, 7 mmol) in MeOH (10 mL), palladium carbon (300 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-115) (2.1 g, 85%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.40 - 7.20 (m, 2H), 4.62 (td, J = 10.9, 4.9 Hz, 1H), 4.28 (s, 2H), 4.02 (t, J = 8.9 Hz, 1H), 3.81 (dd, J = 8.9, 6.3 Hz, 1H), 3.27 (d, J = 10.4 Hz, 2H), 2.81 (ddd, J = 28.3, 18.6, 7.7 Hz, 4H), 2.21 (s, 2H), 2.04 - 1.94 (m, 2H), 1.88 - 1.71 (m, 2H). LC-MS(ESI)m / z=340[M+H] + .

[0280] Step 3: Preparation of (OBD-048, 049, 252, 253, 254): To a solution of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-115) (200 mg, 0.59 mmol) and R-OH (0.59 mmol) in DCM (10 mL), HOBt (119 mg, 0.88 mmol), EDCI (225 mg, 1.18 mmol), and DIPEA (152 mg, 1.18 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C under a nitrogen atmosphere for 2 hours and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain (OBD-048, 049, 252, 253, 254) as white solids.

[0281] OBD-048 1 H NMR (300 MHz, CDCl3) δ 7.06 (d, J = 10.9 Hz, 2H), 5.98 (s, 1H), 4.75 (s, 1H), 4.33 (s, 2H), 3.98 (t, J = 8.8 Hz, 1H), 3.68 (dd, J = 19.8, 11.0 Hz, 3H), 3.45 (d, J = 10.9 Hz, 3H), 2.78 (d, J = 11.1 Hz, 2H), 2.11 (d, J = 6.6 Hz, 3H), 1.98 (d, J = 24.1 Hz, 6H). LC-MS(ESI)m / z=426[M+H] + .

[0282] OBD-049 1H NMR (301 MHz, CDCl3) δ 7.06 (d, J = 11.0 Hz, 2H), 5.15 (s, 1H), 4.75 (s, 1H), 4.32 (s, 2H), 3.97 (t, J = 9.0 Hz, 2H), 3.80 - 3.70 (m, 4H), 3.56 (d, J = 5.9 Hz, 2H), 3.42 (s, 2H), 2.77 (d, J = 11.1 Hz, 2H), 2.10 (d, J = 6.4 Hz, 2H), 1.92 (d, J = 5.0 Hz, 2H). LC-MS(ESI)m / z=397.7[M+H] + 。

[0283] OBD-252 1 H NMR (301 MHz, CDCl3) δ 7.07 (d, J = 11.0 Hz, 2H), 6.19 (s, 1H), 4.77 (s, 1H), 4.35 (s, 2H), 3.97 (t, J = 8.9 Hz, 1H), 3.78 - 3.62 (m, 3H), 3.46 (d, J = 10.1 Hz, 2H), 2.79 (d, J = 11.1 Hz, 2H), 2.12 (d, J = 6.5 Hz, 2H), 1.94 (d, J = 4.5 Hz, 2H), 1.43 - 1.33 (m, 1H), 0.95 (dd, J = 9.5, 4.4 Hz, 2H), 0.78 (d, J = 6.4 Hz, 2H). LC-MS(ESI)m / z=408.1[M+H] + 。

[0284] OBD-253 1H NMR (301 MHz, CDCl3) δ 7.07 (d, J = 11.0 Hz, 2H), 5.88 (s, 1H), 4.76 (s, 1H), 4.34 (s,2H), 3.98 (t, J = 9.0 Hz, 1H), 3.79 - 3.59 (m, 3H), 3.45 (d, J = 10.8 Hz, 2H), 3.12 - 2.97 (m, 1H), 2.79 (d, J = 11.3 Hz, 2H), 2.38 - 2.10 (m, 6H), 2.00 - 1.79 (m, 4H). LC-MS(ESI) m / z = 422.1 [M+H] + .

[0285] OBD-254 1 H NMR (301 MHz, CDCl3) δ 7.17 - 6.96 (m, 2H), 6.07 (s, 1H), 4.78 (s, 1H), 4.34 (s, 2H), 3.98 (t, J = 8.9 Hz, 1H), 3.82 - 3.64 (m, 3H), 3.45 (d, J = 10.0 Hz, 2H), 2.79 (d, J = 11.2 Hz, 2H), 2.38 - 2.06 (m, 4H), 1.98 - 1.78 (m, 2H), 1.63 (dq, J = 14.7, 7.3 Hz, 2H), 1.26 (s, 1H), 0.90 (t, J = 7.4 Hz, 3H). LC-MS(ESI)m / z=410.1[M+H] + .

change

[0286] Modulation: To a solution of 8-oxa-3-azabicyclo[3.2.1]octane(1) (5.0 g, 44.2 mmol) and 1,2-difluoro-4-nitrobenzene (7.7 g, 48.6 mmol) in DMF (10 mL), K2CO3 (12.2 g, 88.4 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE = 5:1) to obtain 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane(3) (9.1 g, 82%) as a yellow solid. LC-MS(ESI)m / z=253[M+H] + .

[0287] Step 2: Preparation of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorobenzeneamine (4): A solution of 3-(2-fluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane(3)(3) (9.1 g, 36.2 mmol) and palladium carbon (1 g) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorobenzeneamine(4) (7.3 g, 91%) as a white oil, and the crude product was used in the next reaction without further purification. LC-MS(ESI)m / z=223[M+H] + .

[0288] Step 3: 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl) Preparation of benzyl 3-fluorophenylcarbamate (5): 16.4 g, 65.88 mmol of carbonic acid,2,5-dioxo-1-pyrrolidinyl=phenylmethyl ester was added to a suspension of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorobenzeneamine (4) (7.3 g, 32.9 mmol) in THF (100 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (PE:EA=10:1) to obtain benzyl 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenylcarbamate (5) (7.1 g, 61%) as a white solid. LC-MS(ESI)m / z=357[M+H] + .

[0289] Step 4: Preparation of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (OBD-112): To a solution of benzyl (5) (7.1 g, 20.1 mmol) 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenylcarbamate in THF (10 mL), n-BuLi (12.5 ml, 30.1 mmol) was added at -78°C under a nitrogen atmosphere, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, (R)-oxiran-2-ylmethyl butyrate (4.3 g, 30.1 mmol) in THF was added. The solution was added to the mixture at -78°C, then heated to room temperature, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude substance was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (OBD-112) (3.9 g, 60%) as a white solid. 1H NMR (301 MHz, DMSO-d6) δ 7.46 (dd, J = 15.4, 2.5 Hz, 1H), 7.14 (d, J = 6.5 Hz, 1H), 7.03 - 6.84 (m, 1H), 5.18 (s, 1H), 4.64 (d, J = 3.3 Hz, 1H), 4.31 (s, 2H), 4.00 (t, J = 9.0 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.57 (d, J = 24.9 Hz, 2H), 3.00 (d, J = 11.2 Hz, 3H), 2.85 (d, J = 10.9 Hz, 2H), 2.08 - 1.63 (m, 5H). LC-MS(ESI)m / z=323[M+H] + .

[0290] Step 5: (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl= Preparation of 4-methylbenzenesulfonate (7): 4-methylbenzene-1-sulfonyl chloride (2.3 g, 24 mmol) was added to a suspension of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (OBD-112) (3.9 g, 12 mmol) and Et3N (1.2 g, 24 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7) (4.86g, 85%) as a white solid. I acquired it physically. LC-MS(ESI)m / z=477[M+H] + .

[0291] Step 6: 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidine-2-one( Preparation of 8): (3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7) (4.86 g, 10.2 mmol) in DMF (10 mL) To a solution of sodium azide (663 mg, 10.2 mmol), K2CO3 (1.4 g, 20.4 mmol) was added at 25°C, and the reaction mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8) (2.97 g, 84%) as a white solid. LC-MS(ESI)m / z=348[M+H] + .

[0292] Step 7: Preparation of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-113): To a solution of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8) (2.97 g, 8.5 mmol) in MeOH (10 mL), palladium carbon (300 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-113) (2.2 g, 81%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.53 - 7.35 (m, 1H), 7.09 (d, J = 8.9 Hz, 1H), 6.96 - 6.73 (m, 1H), 4.66 (s, 1H), 4.40 (s, 1H), 4.00 (t, J = 8.7 Hz, 1H), 3.89 - 3.74 (m, 1H), 3.06 (dd, J = 21.9, 11.0 Hz, 6H), 2.27 - 1.85 (m, 4H). LC-MS(ESI)m / z=322[M+H] + .

[0293] Step 8: Preparation of (OBD-110, 111): To a solution of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-fluorophenyl)-5-(aminomethyl)oxazolidine-2-one (OBD-113) (200 mg, 0.62 mmol) and R-OH (0.62 mmol) in DCM (10 mL), HOBt (126 mg, 0.96 mmol), EDCI (237 mg, 1.24 mmol), and DIPEA (160 mg, 1.24 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain (OBD-110, 111) as a white solid.

[0294] OBD-110 1 H NMR (301 MHz, CDCl3) δ 7.51 - 7.32 (m, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.83 (t, J = 9.1 Hz, 1H), 6.07 (s, 1H), 4.74 (s, 1H), 4.39 (s, 2H), 4.00 (t, J = 8.9 Hz, 1H), 3.85 - 3.49 (m, 3H), 3.05 (dd, J = 23.2, 10.6 Hz, 4H), 2.32 - 1.67 (m, 8H). LC-MS(ESI)m / z=426[M+H] + .

[0295] OBD-111 1H NMR (301 MHz, CDCl3) δ 7.41 (s, 1H), 7.03 (s, 1H), 6.17 (s, 0H), 5.20 - 5.02 (m, 1H), 4.85 - 4.62 (m, 1H), 4.41 (s, 1H), 4.01 (s, 1H), 3.68 (s, 3H), 3.09 (d, J = 7.9 Hz, 2H), 2.05 (d, J = 42.7 Hz, 3H), 1.83 - 1.35 (m, 3H). LC-MS(ESI)m / z=397.7[M+H] + . [ka]

[0296] Step 1: Preparation of 8-(2,6-difluoro-4-nitrophenyl)-3-oxa-8-azabicyclo[3.2.1]octane(3): To a solution of 3-oxa-8-azabicyclo[3.2.1]octane(1) (5.0 g, 44.2 mmol) and 1,2,3-trifluoro-5-nitrobenzene (8.6 g, 48.6 mmol) in DMF (10 mL), K2CO3 (12.2 g, 88.4 mmol) was added at 25 °C. The reaction mixture was then stirred at 80 °C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (EA:PE=3:1) to obtain 8-(2,6-difluoro-4-nitrophenyl)-3-oxa-8-azabicyclo[3.2.1]octane(3) (9.3 g, 78%) as a yellow solid. LC-MS(ESI)m / z=271[M+H] + .

[0297] Step 2: Preparation of 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzeneamine (4): A solution of 3-(2,6-difluoro-4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane(3) (9.3 g, 34.4 mmol) and palladium carbon (1 g) was added to MeOH (15 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure to obtain 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorobenzeneamine(4) (7.8 g, 95%) as a white oil, and the crude substance was used in the next reaction without further purification. LC-MS(ESI)m / z=241[M+H] + .

[0298] Step 3: Preparation of 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate benzyl(5): Carbonate, 2,5-dioxo-1-pyrrolidinyl=phenylmethyl=ester (12g, 48 0.7 mmol) was added to a suspension of 4-(3-oxa-8-azabicyclo[3.2.1]octan-3-yl)-3,5-difluorobenzeneamine (4) (7.8 g, 32.5 mmol) in THF (100 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 50°C for 5 hours and monitored by TLC. The mixture was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (PE:EA=10:1) to obtain 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate benzyl (5) (8.2 g, 68%) as a white solid. LC-MS(ESI)m / z=375[M+H] + .

[0299] Step 4: Preparation of (5R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (6): To a solution of 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate benzyl(5) (8.2g, 22.1 mmol) in THF (10 mL), n-BuLi (13.8 ml, 33.1 mmol) was added under a nitrogen atmosphere at -78°C, and the mixture was then stirred at -78°C for 30 minutes. Subsequently, (R)-oxiran-2-ylmethyl butyrate (4.7 g, 33.1 mmol) was added to the THF. A solution of (1) was added to the mixture at -78°C, then heated to room temperature, stirred overnight, and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=70:1) to obtain (5R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (6) (4.5 g, 60%) as a white solid. LC-MS(ESI)m / z=341[M+H] + .

[0300] Step 5: Preparation of ((R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7): 4-methylbenzene-1-sulfonyl chloride (5 g, 26.6 mmol) was added to a suspension of (5R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidine-2-one (6) (4.5 g, 13.3 mmol) and Et3N (2.7 g, 26.6 mmol) in DCM (10 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred overnight at room temperature and monitored by TLC. Quenched with ammonium chloride, extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain ((R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7)(5 0.58 g, 85% was obtained as a white solid. LC-MS(ESI)m / z=495[M+H] + .

[0301] Step 6: Preparation of (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)oxazolidine-2-one (OBD-055): ((R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7) (300 mg, 0. To a solution of 6 mmol) and 1H-1,2,3-triazole (42 mg, 0.6 mmol), K2CO3 (166 mg, 1.2 mmol) was added at 25°C. The reaction mixture was then stirred at 80°C for 1 hour under a nitrogen gas atmosphere and monitored by TLC. The mixture was quenched with um, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain (5R)-5-((1H-1,2,3-triazole-1-yl)methyl)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)oxazolidine-2-one (OBD-055) (82 mg, 35%) as a white solid. 1 H NMR (301 MHz, CDCl3) δ 7.76 (d, J = 5.7 Hz, 2H), 6.94 (d, J = 12.1 Hz, 2H), 5.06 (s, 1H), 4.78 (d, J = 4.1 Hz, 1H), 4.08 (t, J = 9.0 Hz, 1H), 3.90 (t, J = 8.9 Hz, 4H), 3.58 (d, J = 10.4 Hz, 2H), 2.04 (t, J = 8.0 Hz, 4H), 1.76 (s, 2H). LC-MS(ESI)m / z=391.8[M+H] + . [ka]

[0302] Step 1: Preparation of (5R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one(8): ((R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-2-oxoxazolidine-5-yl)methyl=4-methylbenzenesulfonate (7) (4g, 8 mmol) in DMF (10mL) To a solution of (5R) and sodium azide (526 mg, 8 mmol), K2CO3 (2.2 g, 16 mmol) was added at 25°C, and the reaction mixture was stirred at 80°C for 1 hour under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with EA, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain (5R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8) (2.4 g, 82%) as a white solid. LC-MS(ESI)m / z=366[M+H] + .

[0303] Step 2: Preparation of (5S)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (9): To a solution of (5R)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(azidomethyl)oxazolidine-2-one (8) (2.4 g, 6.5 mmol) in MeOH (10 mL), palladium carbon (300 mg) was added at 25 °C. The reaction mixture was then stirred overnight at room temperature under a hydrogen gas atmosphere and monitored by TLC. The filtrate was concentrated under reduced pressure, and the crude substance was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain (5S)-3 -(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (9) (1.9 g, 86%) was obtained as a white solid. LC-MS(ESI)m / z=340[M+H] + .

[0304] Step 3: Preparation of (OBD-051, 052): To a solution of (5S)-3-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(aminomethyl)oxazolidine-2-one (9) (200 mg, 0.59 mmol) and R-OH (0.59 mmol) in DCM (10 mL), HOBt (119 mg, 0.88 mmol), EDCI (224 mg, 1.18 mmol), and DIPEA (152 mg, 1.18 mmol) were added at 25°C. The reaction mixture was then stirred at 25°C for 2 hours under a nitrogen atmosphere and monitored by TLC. The mixture was quenched with ammonium chloride, extracted with DCM, and the organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 80:1) to obtain (OBD-051, 052) as a white solid.

[0305] OBD-051 1 H NMR (301 MHz, CDCl3) δ 6.99 (t, J = 9.3 Hz, 2H), 5.38 (s, 1H), 4.84 - 4.69 (m, 1H), 3.98 - 3.86 (m, 4H), 3.75 - 3.60 (m, 4H), 2.24 - 1.97 (m, 8H). LC-MS(ESI)m / z=381.9[M+H] + .

[0306] OBD-052 1 H NMR (301 MHz, CDCl3) δ 7.06 (d, J = 12.4 Hz, 2H), 5.10 (s, 1H), 4.75 (s, 1H), 4.02 - 3.86 (m, 4H), 3.68 (s, 2H), 3.58 (d, J = 9.6 Hz, 2H), 2.02 (d, J = 7.7 Hz, 2H), 1.80 (s, 4H), 0.98 (d, J (= 6.7 Hz, 3H). LC-MS(ESI)m / z=398.0[M+H] + .

[0307] (Example 13) Synthesis of Additional Embodiments of the Invention The following compound was prepared using the same method as disclosed in Examples 8 and 12 above: OTB-518 [ka] (((5S)-3-(3-fluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)carbamate methyl 1H-NMR (400 MHz, CDCl3) δ: 7.45 (d, J = 16.4 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 6.83 (t, J = 9.2 Hz, 1 H), 5.17-5.12 (m, 1 H), 4.80-4.74 (m, 1 H), 4.62 (brs, 2 H), 4.02 (t, J = 8.4 Hz, 1 H), 3.77 (t, J = 8.0 Hz, 1 H), 3.69-3.53 (m, 4 H), 3.45 (d, J = 10.4 Hz, 2 H), 2.86 (d, J = 12.0 Hz, 2 H), 2.22 (m, 2 H), 1.90-1.88 (m, 2 H). HRMS(ESI): m / z[M+H]+ C 18 H 23 Calculated value for FN3O5S: 412.1344; Measured value: 412.1359

[0308] OTB-519 [ka] (((5S)-3-(3,5-difluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)carbamate methyl 1H-NMR (400 MHz, CDCl3) δ: 7.13 (d, J = 12.4 Hz, 2 H), 5.10 (m, 1 H), 4.80-4.74 (m, 1 H), 4.46 (brs, 2 H), 3.98 (t, J = 8.8 Hz, 1 H), 3.76-3.69 (m, 4 H), 3.60-3.49 (m, 3 H), 2.94 (d, J = 12.0 Hz, 2 H), 2.20-2.18 (m, 2 H), 1.87-1.85 (m, 2 H). HRMS(ESI): m / z[M+H]+ C 18 H 22 Calculated value for F2N3O5S: 430.1248; Measured value: 430.1259

[0309] OTB-517 [ka] (5R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-((1R,5S)-3-oxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)phenyl)oxazolidine-2-one 1H-NMR (400 MHz, CDCl3) δ: 7.79 (s, 1 H), 7.77 (s, 1 H), 6.98 (d, J = 12.0 Hz, 2 H), 5.10-5.04 (m, 1 H), 4.79 (d, J = 4.0 Hz, 2 H), 4.43 (brs, 2 H), 4.10 (t, J = 9.2 Hz, 1 H), 3.91-3.87 (m, 1 H), 3.55 (d, J = 12.4 Hz, 2 H), 2.92 (d, J = 10.4 Hz, 2 H), 2.19-2.16 (m, 2 H), 1.88-1.83 (m, 2 H). HRMS(ESI): m / z[M+H]+ C 18 H 20 Calculated value for F2N5O3S: 424.1249; Measured value: 424.1271

[0310] OTB-523 [ka] (S)-N-((3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxoxazolidine-5-yl)methyl)acetamide 1H-NMR (400 MHz, CDCl3) δ: 7.34 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.8 Hz, 1 H), 6.41 (t, J = 8.8 Hz, 1 H), 6.12 (t, J = 6.0 Hz, 1 H), 4.76-4.73 (m, 1 H), 4.01-3.90 (m, 7 H), 3.74-3.66 (m, 2 H), 3.62-3.56 (m, 1 H), 3.45-3.40 (m, 2 H), 2.02 (s, 3 H). HRMS(ESI): m / z[M+H]+ C17H21FN3O4S Calculated value: 382.1237; Measured value: 382.1217

[0311] OTB-515 [ka] (S)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxoxazolidine-5-yl)methyl)acetamide HNMR (400 MHz, CDCl3) δ: 7.03-6.94 (m, 2 H), 6.09 (t, J = 5.6 Hz, 1 H), 4.75(q, J = 3.2 Hz, J = 2.8 Hz, 1 H), 4.16 (s, 4 H), 3.95 (t, J = 8.8 Hz, 1 H), 3.72-3.61 (m, 3 H), 3.40 (s, 4 H), 2.03 (s, 3 H). m / z[M+Na]+ C 17 H 19 Calculated value for F2N3O3S: 383.1115; Measured value: 384.0

[0312] OTB-248 [ka] (S)-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxoxazolidine-5-yl)methyl)carbamate methyl HNMR (400 MHz, CDCl3) δ: 7.33 (q, J = 2.0 Hz, J = 11.6 Hz, 2 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.44 (t, J = 9.2 Hz, 1 H), 5.15 (bs, 1 H), 4.77-4.73 (m, 1 H), 4.01-3.97 (m, 4 H), 3.76-3.52 (m, 6 H), 3.42 (s, 4 H). m / z[M+Na]+ C 17 H 20 Calculated value for FN3O4S: 381.1159; Measured value: 404.1

[0313] OTB-256 [ka] (S)-((3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)carbamate methyl 1H-NMR (400 MHz, CDCl3) δ: 7.51 (d, J = 14.4 Hz, 1 H), 7.04 (d, J = 8.4 Hz, 1 H), 6.80 (t, J = 8.8 Hz, 1 H), 5.09 (brs, 1 H), 4.76 (brs, 1 H), 4.16 (d, J = 13.2 Hz, 4 H), 4.01-3.98 (m, 3 H), 3.77-3.75 (m, 1 H), 3.69 (s, 3 H), 3.61-3.55 (m, 2 H), 3.46-3.44 (m, 2 H). HRMS(ESI): m / z[M+H]+ C 17 H 21 Calculated value for FN3O5S: 398.1186; Measured value: 398.1166

[0314] OTB-247 [ka] (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one HNMR(400 MHz, CDCl3) δ: 7.78 (d, J = 0.8 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.18 (dd, J = 13.6, 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 1.6 Hz, 1H), 6.37 (t, J = 9.2 Hz, 1H), 5.04 - 5.00 (m, 1H), 4.77 (d, J = 3.6 Hz, 2H), 4.08 (t, J = 9.2 Hz, 1H), 3.96 (dd, J = 10.4, 1.6 Hz, 4H), 3.92 - 3.89 (m, 3H), 3.42 - 3.39 (m, 2H). m / z[M+H]+ C 17 H 18 Calculated value for FN5O3S: 391.1114; Measured value: 392.0

[0315] OTB-249 [ka] (S)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclopropanecarboxamide 1H-NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 14.0 Hz, 1 H), 6.99 (d, J = 8.8 Hz, 1 H), 6.47 (t, J = 9.2 Hz, 1 H), 6.13 (brs, 1 H), 4.73 (m, 1 H), 3.98-3.95 (m, 5 H), 3.73-3.66 (m, 3 H), 3.42 (s, 4 H), 1.39-1.37 (m, 1 H), 0.97-0.91 (m, 2 H), 0.78-0.76 (m, 2 H). HRMS(ESI): m / z[M+H]+ C 19 H 23 Calculated value for FN3O3S: 392.1444; Measured value: 392.1426

[0316] OTB-255 [ka] (S)-N-((3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclopropanecarboxamide 1H-NMR (400 MHz, CDCl3) δ: 7.35 (d, J = 14.0 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.44 (t, J = 9.2 Hz, 1 H), 6.13 (brs, 1 H), 4.74 (m, 1 H), 4.00-3.91 (m, 7 H), 3.75-3.62 (m, 3 H), 3.47-3.41 (m, 2 H), 1.38-1.37 (m, 1 H), 0.97-0.92 (m, 2 H), 0.78-0.76 (m, 2 H). HRMS(ESI): m / z[M+H]+ C19H23FN3O4S Calculated value: 408.1393; Measured value: 408.1378

[0317] OTB-250 [ka] (S)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclobutanecarboxamide HNMR (400 MHz, CDCl3) δ: 7.76 (d, J = 8.8 Hz, 2 H), 6.92-6.83 (m, 2 H), 5.04 (m, 1 H), 4.78 (q, J = 0.8 Hz, J = 3.2 Hz 2 H), 4.15 (t, J = 2.4 Hz, 4 H), 3.85 (t, J = 6.0 Hz, 1 H), 3.72-3.63 (m, 3 H), 3.40 (s, 4 H), 3.05-2.99 (m, 1 H), 2.24-2.13 (m, 4 H), 1.97-1.60 (m,2 H). m / z[M+Na]+ C 20 H 24 Calculated value for FN3O3S: 405.1522; Measured value: 428.2

[0318] OTB-254 [ka] (S)-N-((3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclobutanecarboxamide 1H-NMR (400 MHz, CDCl3) δ: 7.36 (d, J = 14.4 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.47 (t, J = 9.2 Hz, 1 H), 5.80 (brs, 1 H), 4.73 (brs, 1 H), 4.00 (d, J = 12.0 Hz, 4 H), 3.95-3.92 (m, 3 H), 3.76-3.72 (m, 1 H), 3.65-3.62 (m, 2 H), 3.47-3.41 (m, 2 H), 3.02-2.96 (m, 1 H), 2.26-2.13 (m, 4 H), 1.98-1.84 (m, 2 H). HRMS(ESI): m / z[M+H]+ C 20 H 25 Calculated value for FN3O4S: 422.1549; Measured value: 422.1531

[0319] OTB-260-2A [ka] (R)-N-((3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxoxazolidine-5-yl)methyl)methanesulfonamide HNMR (400 MHz, CDCl3) δ: 7.04 - 6.95 (m, 2H), 5.05 (s, 1H), 4.80 - 4.77 (m, 1H), 4.15 (t, J = 2.4 Hz, 4H), 3.97 (t, J = 8.8 Hz, 1H), 3.86 (dd, J = 6.4, 8.8 Hz, 1H), 3.56 (dd, J = 3.6, 14.4 Hz, 1H), 3.43 - 3.39 (m, 5H), 3.01 (s, 3H). m / z[M+H]+ C 16 H 20 Calculated value for FN3O4S2: 401.0879; Measured value: 402.1

[0320] OTB-260-2B [ka] (R)-N-((3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxoxazolidine-5-yl)methyl)methanesulfonamide HNMR (400 MHz, CDCl3) δ: 7.32 (dd, J = 14.0, 2.4 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.41 (t, J = 9.6 Hz, 1H), 4.86 - 4.77 (m, 2H), 4.04 - 3.95 (m, 8H), 3.93 (dd, J = 9.6, 3.2 Hz, 1H), 3.43 - 3.40 (m, 3H), 3.02 (s, 3H). m / z[M+H]+ C 16 H 20 Calculated value for FN3O5S2: 417.0828; Measured value: 418.0

[0321] OTB-260-5A [ka] (R)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one HNMR (400 MHz, CDCl3) δ: 7.64 (s, 2H), 7.24 - 7.21 (m, 1H), 6.99 (dd, J = 8.8, 1.6 Hz, 1H), 6.41 (t, J = 9.6 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.87 - 4.82 (m, 1H), 4.75 - 4.72 (m, 1H), 4.05 - 4.01 (m, 1H), 3.96 - 3.93 (m, 5H), 3.40 (s, 4H). m / z[M+H]+ C 17 H18 Calculated value for FN5O2S: 375.1165; Measured value: 376.1

[0322] OTB-260-5B [ka] (R)-5-((2H-1,2,3-triazol-2-yl)methyl)-3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)oxazolidine-2-one HNMR (400 MHz, CDCl3) δ: 7.64 (s, 2H), 7.27 - 7.23 (m, 1H), 6.99 (dd, J = 8.8, 2.0 Hz, 1H), 6.39 (t, J = 9.2 Hz, 1H), 5.11 - 5.06 (m, 1H), 4.87 - 4.82 (m, 1H), 4.76 - 4.70 (m, 1H), 4.06 - 4.03 (m, 1H), 3.98 - 3.90 (m, 7H), 3.43 - 3.40 (m, 2H). m / z[M+H]+ C 17 H 18 Calculated value for FN5O3S: 391.1114; Measured value: 392.1

[0323] OTB-260-4A [ka] (R)-(3-(3-fluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=methylcarbame te HNMR (400 MHz, CDCl3) δ: 7.33 (dd, J = 2.4, 13.6 Hz, 1H), 7.04 (dd, J = 1.6, 8.4 Hz, 1H), 6.44 (t, J = 9.2 Hz, 1H), 4.88 - 4.72 (m, 2H), 4.33 (t, J = 4.0 Hz, 2H), 4.02 (t, J = 9.2 Hz, 1H), 3.97 (d, J = 1.6 Hz, 4H), 3.77 (dd, J = 6.4, 8.8 Hz, 1H), 3.42 (s, 4H), 2.80 (d, J = 4.8 Hz, 3H). m / z[M+H]+ C 17 H 20 Calculated value for FN3O4S: 381.1159; Measured value: 382.0

[0324] OTB-260-4B [ka] (R)-(3-(3-fluoro-4-(2-oxide-2-thia-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl= Methylcarbamate HNMR (400 MHz, CDCl3) δ: 7.35 (dd, J = 2.0, 11.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.42 (t, J = 9.2 Hz, 1H), 4.89 - 4.70 (m, 2H), 4.42 - 4.26 (m, 2H), 4.08 - 3.88 (m, 7H), 3.84 - 3.71 (m, 1H), 3.47 - 3.37 (m, 2H), 2.81 (m, 3H). m / z[M+H]+ C 17 H 20 Calculated value for FN3O5S: 397.1108; Measured value: 398.0

[0325] OTB-520 [ka] (S)-N-((3-(3,5-difluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)acetamide 1H-NMR (400 MHz, CDCl3) δ: 7.02 (d, J = 12.0 Hz, 2 H), 5.92 (brs, 1 H), 4.75-4.74 (m, 1 H), 4.16 (d, J = 12.0 Hz, 4 H), 3.97-3.90 (m, 2 H), 3.72-3.65 (m, 4 H), 3.41-3.37 (m, 2 H), 2.02 (s, 3 H).HRMS(ESI):m / z[M+H]+ C 17 H 20 Calculated value for F2N3O4S: 400.1143; Measured value: 400.1158

[0326] OTB-253 [ka] (S)-((3-(3,5-difluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)carbamate methyl 1H-NMR (400 MHz, CDCl3) δ: 7.00 (d, J = 10.8 Hz, 2H), 5.36 (m, 1H), 4.72 (m, 1H), 4.14 (d, J = 12.0 Hz, 4H), 3.92 (m, 3H), 3.69 (m, 1H), 3.67 (s, 3H), 3.52 (m, 2H), 3.39 (d, J = 12.4 Hz, 2H). HRMS(ESI) C 17 H 20 The calculated value for F2N3O5S[M+H]+ is 416.1086, and the measured value is 416.1073.

[0327] OTB-522 [ka] HNMR (400 MHz, CDCl3) δ: 7.75 (d, J = 8.0 Hz, 2H), 6.92 - 6.83 (m, 2H), 5.05 - 5.01 (m, 1H), 4.77 (d, J = 4.0 Hz, 2H), 4.15 (dt, J = 11.6, 2.4 Hz, 4H), 4.05 (t, J = 9.2 Hz, 1H), 3.92 - 3.89 (m, 3H), 3.40 - 3.37 (m, 2H). m / z[M+H]+ C 17 H 17 Calculated value for F2N5O3S: 409.1020; Measured value: 410.1

[0328] OTB-252 [ka] (S)-N-((3-(3,5-difluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclopropanecarboxamide 1H-NMR (400 MHz, CDCl3) δ: 6.98 (d, J = 11.6 Hz, 2H), 6.60 (m, 1H), 4.73 (m, 1H), 4.13 (d, J = 12.4 Hz, 4H), 3.91 (m, 3H), 3.70 (m, 1H), 3.64 (m, 2H), 3.79 (d, J = 10.4 Hz, 2H),1.41 (m, 1H), 0.94 (m, 1H), 0.87 (m, 1H), 0.74 (m, 2H) HRMS(ESI) C 19 H 22 Calculated value of F2N3O4S[M+H]+: 426.1294, measured value: 426.1278

[0329] OTB-251 [ka] (S)-N-((3-(3,5-difluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)cyclobutanecarboxamide 1H-NMR (400 MHz, CDCl3) δ: 6.99 (d, J = 10.4 Hz, 2H), 6.06 (m, 1H), 4.74 (m, 1H), 4.14 (d, J = 12.4 Hz, 4H), 3.93 (m, 3H), 3.70 (m, 1H), 3.62 (m, 2H), 3.38 (d, J = 12.4 Hz, 2H), 3.00 (m, 1H), 2.21 (m, 1H), 2.11 (m, 3H), 1.92 (m, 1H), 1.83 (m, 1H) HRMS(ESI)C 20 H 24 Calculated value of F2N3O4S[M+H]+: 440.1450, measured value: 440.1441

[0330] OTB-516-2A [ka] (R)-N-((3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)2-oxoxazolidine-5-yl)methyl)methanesulfonamide

[0331] HNMR (400 MHz, CDCl3) δ: 7.04 - 6.95 (m, 2H), 5.05 (s, 1H), 4.80 - 4.77 (m, 1H), 4.15 (t, J = 2.4 Hz, 4H), 3.97 (t, J = 8.8 Hz, 1H), 3.86 (dd, J = 6.4, 8.8 Hz, 1H), 3.56 (dd, J = 3.6, 14.4 Hz, 1H), 3.43 - 3.39 (m, 5H), 3.01 (s, 3H). m / z[M+H]+ C 16 H 19 Calculated value for F2N3O4S2: 419.0785; Measured value: 420.1 OTB-516-2B [ka] (R)-N-((3-(3,5-difluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl)methanesulfonamide

[0332] HNMR (400 MHz, CDCl3) δ: 7.03 - 7.00 (m, 2H), 4.81 - 4.78 (m, 2H), 4.18 - 4.14 (m, 4H), 3.98 - 3.93 (m, 1H), 3.91 - 3.85 (m, 3H), 3.60-3.41 (m, 4H), 3.40 - 3.37 (m, 3H), 3.02 (s,3H). m / z[M+H]+ C 16 H 19 Calculated value for F2N3O5S2: 435.0734; Measured value: 436.0 OTB-516-4A [ka] (R)-(3-(3,5-difluoro-4-(2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=methyl methyl phenyl Rubamate HNMR (400 MHz, CDCl3) δ: 7.08 - 6.91 (m, 2H), 4.91 - 4.70 (m, 2H), 4.38 - 4.28 (m, 2H), 4.16 (t, J = 2.4 Hz, 4H), 3.98 (t, J = 9.2 Hz, 1H), 3.74 (dd, J = 6.4, 8.8 Hz, 1H), 3.43 - 3.37 (m, 4H), 2.81 (d, J = 4.8 Hz, 3H). m / z[M+H]+ C 17 H 19 Calculated value for F2N3O4S: 399.1064; Measured value: 400.1

[0333] OTB-516-4B [ka] (R)-(3-(3,5-difluoro-4-(2-oxide-2-thia-6-azaspiro[3,3]heptan-6-yl)phenyl)-2-oxoxazolidine-5-yl)methyl=methylcarbamate HNMR (400 MHz, CDCl3) δ: 7.10 - 6.95 (m, 2H), 4.89 - 4.69 (m, 2H), 4.30 - 4.36 (m, 2H), 4.17 (d, J = 11.6 Hz, 4H), 4.02 - 3.89 (m, 3H), 3.74 (dd, J = 6.4, 8.6 Hz, 1H), 3.44 - 3.33 (m, 2H), 2.81 (d, J = 4.8 Hz, 3H). m / z[M+H]+ C 17 H 19 Calculated value for F2N3O5S: 415.1013; Measured value: 416.0

[0334] OTB-204 [ka]

[0335] (R)-5-((1H-1,2,3-tTriazol-1-yl)methyl)-3-(3-fluoro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)oxazolidin-2-one) 1H-NMR (400 MHz, CDCl3) δ: 7.65 (s, 2 H), 7.31 (d, J = 14.4, 2.4 Hz,1 H), 6.99 (d, J = 8.4 Hz, 1 H), 6.59 (t, J = 9.2 Hz, 1 H), 5.14-5.07 (m, 1 H), 4.88-4.83 (m, 5H), 4.77-4.71 (m, 1 H), 4.16 (s, 4 H), 4.07-4.02 (m, 1 H), 3.98-3.92 (m, 1 H) HRMS(ESI): m / z[M+H]+ C 17 H 19 Calculated value for FN5O3: 360.1472; Measured value: 360.1451

[0336] The present invention will be further described, without limitation, by the following numbered paragraphs. 1. [ka] [In the formula, R is independently OR1, OC(O)R2, OC(O)NHR2, OS(O2)R2, NHS(O)2R2, NR3R4, NHC(O)R5. R' and R'' are independently H, F, Cl, or OMe. Each R1 is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with 1 to 4 groups selected from halo, hydroxy, C1-C6 alkyl, or C1-C6 alkyloxy. Each R2 is independently a C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl, or aryl, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. Each R3 and R4 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, or aryl, or R3 and R4, together with the nitrogen to which they are bonded, form a 4-8 membered heterocyclyl or heteroaryl having 1-3 additional heteroatoms selected from O, S, or N, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with 1-4 groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, CF3, NO2, or CN. Each R5 is independently a C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, heteroaryl, or aryl, where the alkyl, cycloalkyl, and heteroaryl are the same. The telocyclyl, heteroaryl, or aryl is optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. Ring A is, [ka] [In the formula, Each of R6 and R7 is independently H, F, CH3, CH2CH3, CF3, and phenyl. X = O, S, SO, SO2, Y = O, S, SO, SO2 and NR8, m is either 1 or 2. n is either 1 or 2. p is either 1 or 2. q is either 1 or 2. R8 is independently H, C1-C4 alkyl, C3-C6 cycloalkyl, COCH3, and p-toluenesulfonyl, where the alkyl and cycloalkyl groups are optionally substituted with 1-4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. [Selected from] A compound of formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 2. The aforementioned compound, Formula II [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl, or R3 and R4 together with the nitrogen to which they are bound form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. R6 and R7 are independently H, F, CH3, CH2CH3, and CF3. If X = O, S, SO, SO2, and R' = H, R'' = F, then R5 cannot be CH3. The compound described in paragraph 1, represented by [the given expression]. 3. The aforementioned compound, Formula III [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl or phenyl, or R3 and R4 together with the nitrogen to which they are bound form morpholine, thiamorpholine, piperazine and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. R6 and R7 are independently H, F, CH3, CH2CH3, and CF3. X = O, S, SO, SO2] The compound described in paragraph 1, represented by [the given expression]. 4. The aforementioned compound is, Formula IV [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-membered or 6-membered heteroaryl or phenyl, or R3 and R4 together with the nitrogen to which they are bound to form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. X = O, S, SO, SO2] The compound described in paragraph 1, represented by [the given expression]. 5. The aforementioned compound is, Formula V [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-membered or 6-membered heteroaryl or phenyl, or R3 and R4 together with the nitrogen to which they are bound to form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. X = O, S, SO, SO2] The compound described in paragraph 1, represented by [the given expression]. 6. The aforementioned compound is, Formula VI [ka] The compound described in paragraph 1, represented by [the given expression]. 7. The aforementioned compound is formula VII, formula VIII, or formula IX [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-membered or 6-membered heteroaryl or phenyl, or R3 and R4 together with the nitrogen to which they are bound to form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. X = O, S, SO, SO2] The compound described in paragraph 6, represented by [the given expression]. 8. The compound is of formula IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIIa, VIIb, VIIIa, VIIIb, IXa, or IXb [ka] [ka] [ka] [In the formula, R is independently OH, OCH3, OCH2CH3, OC(O)CH3, NH2, NHCH3, NHC6H5, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, NHS(O)2R2, NHC(O)R5, R2 is independently a C1-C6 alkyl group. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, furan, thiophene, or phenyl, and in formula IIa, R5 cannot be CH3. X = O, S, SO, SO2] The compound described in paragraph 1, represented by [the given expression]. 9. The aforementioned compound, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound described in paragraph 1. 10. A pharmaceutical composition comprising at least one compound of formula I or a salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and / or additives. 11. A pharmaceutical composition of formula I or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective agents. 12. A method for preventing and treating microbial infections in humans by administering a therapeutically effective amount of the compound of formula I or its salt, hydrate, or solvate to patients who require prevention and treatment of microbial infections. 13. The method according to paragraph 12, wherein the microbial infection is caused by Mycobacterium tuberculosis.

[0337] It should be understood that the present invention is not limited to the specific embodiments described above, as variations of certain embodiments may still fall within the scope of the attached claims.

[0338] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) [ka] [In the formula, R is independently OR1, OC(O)R2, OC(O)NHR2, OS(O2)R2, NHS(O)2R2, NR3R4, NHC(O)R5. R' and R'' are independently H, F, Cl, or OMe. Each R1 is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with 1 to 4 groups selected from halo, hydroxy, C1-C6 alkyl, or C1-C6 alkyloxy. Each R2 is independently a C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl, or aryl, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. Each R3 and R4 is independently H, C1-C6 alkyl, C3-C8 cycloalkyl, heterocyclyl heteroaryl, or aryl, or R3 and R4, together with the nitrogen to which they are bonded, form a 4-8 membered heterocyclyl or heteroaryl having 1-3 additional heteroatoms selected from O, S, or N, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with 1-4 groups selected from halo, C1-C6 alkyl, C1-C6 alkoxy, CF3, NO2, or CN. Each R5 is independently a C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, heteroaryl, or aryl group, where the alkyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl group is optionally substituted with 1 to 4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. Ring A is, [ka] [In the formula, Each of R6 and R7 is independently H, F, CH3, CH2CH3, CF3, and phenyl. X = O, S, SO, SO2, Y = O, S, SO, SO2 and NR8, m is either 1 or 2. n is either 1 or 2. p is either 1 or 2. q is either 1 or 2. R8 is independently H, C1-C4 alkyl, C3-C6 cycloalkyl, COCH3, and p-toluenesulfonyl, where the alkyl and cycloalkyl groups are optionally substituted with 1-4 groups selected from halo, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 acyloxy, CF3, NO2, CN, and NH2. [Selected from] A compound of formula I, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. (Section 2) The aforementioned compound, Formula II [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or phenyl, or R3 and R4 together with the nitrogen to which they are bound form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. R6 and R7 are independently H, F, CH3, CH2CH3, and CF3. If X = O, S, SO, SO2, and R' = H, R'' = F, then R5 cannot be CH3. The compound described in item 1 above, represented by [the formula shown]. (Section 3) The aforementioned compound, Formula III [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl or phenyl, or R3 and R4 together with the nitrogen to which they are bound form morpholine, thiamorpholine, piperazine and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. R6 and R7 are independently H, F, CH3, CH2CH3, and CF3. X = O, S, SO, SO2] The compound described in item 1 above, represented by [the formula shown]. (Section 4) The aforementioned compound is, Formula IV [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-membered or 6-membered heteroaryl or phenyl, or R3 and R4 together with the nitrogen to which they are bound to form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. X = O, S, SO, SO2] The compound described in item 1 above, represented by [the formula shown]. (Section 5) The aforementioned compound is, Formula V [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-membered or 6-membered heteroaryl or phenyl, or R3 and R4 together with the nitrogen to which they are bound to form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. X = O, S, SO, SO2] The compound described in item 1 above, represented by [the formula shown]. (Section 6) The aforementioned compound is, Formula VI [ka] The compound described in item 1 above, represented by [the formula shown]. (Section 7) The aforementioned compound is formula VII, formula VIII, or formula IX [ka] [In the formula, R is independently OR1, OC(O)R2, NR3R4, NHS(O)2R2, NHC(O)R5, R' and R'' are independently H or F. R1 is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. R2 is independently a C1-C6 alkyl or a C3-C6 cycloalkyl. R3 and R4 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, 5-membered or 6-membered heteroaryl or phenyl, or R3 and R4 together with the nitrogen to which they are bound to form morpholine, thiamorpholine, piperazine, and triazole. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-membered or 6-membered heteroaryl or phenyl. X = O, S, SO, SO2] The compound described in item 6 above, represented by the above. (Section 8) The aforementioned compounds are those of formulas IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb , VIIa, VIIb, VIIIa, VIIIb, IXa or IXb [ka] [ka] [ka] [In the formula, R is independently OH, OCH3, OCH2CH3, OC(O)CH3, NH2, NHCH3, NHC6H5, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, NHS(O)2R2, NHC(O)R5, R2 is independently a C1-C6 alkyl group. R5 is independently a C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, furan, thiophene, or phenyl, and in formula IIa, R5 cannot be CH3. X = O, S, SO, SO2] The compound described in item 1 above, represented by [the formula shown]. (Section 9) The aforementioned compound, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound described in item 1 above. (Section 10) A pharmaceutical composition comprising at least one compound of formula I or a salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers and / or additives. (Section 11) A pharmaceutical composition of formula I or a salt, hydrate, or solvate thereof, further comprising one or more additional anti-infective agents. (Section 12) A method for preventing and treating microbial infections in humans by administering a therapeutically effective amount of the compound of formula I or its salt, hydrate, or solvate to patients who require prevention and treatment of microbial infections. (Section 13) The method according to item 12, wherein the microbial infection is caused by Mycobacterium tuberculosis.

Claims

[Claim 1] The need to develop novel oxazolidinone compounds.

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