WO2024069378A1

WO2024069378A1 - Novel compounds for the treatment of mammalian infections

Info

Publication number: WO2024069378A1
Application number: PCT/IB2023/059482
Authority: WO
Inventors: Ranjit Desai; Vrajesh PANDYA
Original assignee: Zydus Lifesciences Ltd
Current assignee: Zydus Lifesciences Ltd
Priority date: 2022-09-26
Filing date: 2023-09-26
Publication date: 2024-04-04
Anticipated expiration: 2025-03-26
Also published as: TW202423920A

Abstract

The present invention provides novel compounds of Formula (I) or its pharmaceutically acceptable salts. The novel compounds reported in present invention are suitable for the treatment against infection caused by Gram-positive bacteria.

Description

NOVEL COMPOUNDS FOR THE TREATMENT OF MAMMALIAN INFECTIONS FIELD OF INVENTION The present invention relates to novel compounds of the Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation. These compounds show activity against bacterial infection.

BACKGROUND OF THE INVENTION As per World Health Organization (WHO) statistics, ∼50000 patients die from infectious diseases every day worldwide. Evolution of multi-drug-resistant bacteria especially methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant, vancomycin-resistant Enterococcus (VRE), Streptococcus pneumoniae (PRSP), and other Gram-positive bacteria make clinical treatment very challenging. Linezolid is approved antibiotic for Gram-positive bacterial infections. Linezolid and other oxazolidinone class of agents inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit and interfering with the placement of the aminoacyl-tRNA. They do not bind to mammalian cytoplasmic ribosomes, but do bind to mitochondrial ribosomes which is responsible for bone marrow toxicity. Thrombocytopenia is the most common adverse effect associated with Linezolid treatment especially in children (Arch Argent Pediatr 2017; 115(5): 470-475). Other major side effect includes peripheral & ocular neuropathy. There is a high unmet need in identifying novel oxazolidinones devoid of such toxicities and which can offer safer alternative to the linezolid treatment in tackling Gram-positive bacterial infections. WO 2017/156519 describes small molecules with activity against gram negative bacteria. WO 2017/070024 describes substituted oxazolidinone derivatives and use thereof as antibacterial agents. WO 2020/021468 describes novel compounds for the treatment of tuberculosis. The other documents that describe oxazolidinone class of inhibitors including, CN 1749256, WO 2010/058423, WO 2017/015106, WO 2014/141218, WO 2013/054275, WO 2010/036000, WO 2007/023507, WO 2005/005420 are also disclosed. SUMMARY OF THE INVENTION The present invention discloses novel compounds of the Formula (I). The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of bacterial protein synthesis. The compounds of this invention are therefore suitable for the treatment of bacterial infection especially related to Gram-positive bacteria. EMBODIMENTS OF THE INVENTION The main objective of the present invention is to provide novel compounds of Formula (I), novel intermediates involved in their synthesis, their stereoisomers, their suitable pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of bacterial infection. In another embodiment is provided pharmaceutical compositions containing compounds of Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts, solvates and their mixtures having suitable pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture. In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of mammalian infections such as skin infections, lung infections and tissue infections, by administering a therapeutically effective & non-toxic amount of the compound of Formula (I), or their pharmaceutically acceptable compositions to the mammals. In yet another embodiment is provided a method of treatment of the mammalian infection caused by Gram-positive bacteria using compound of Formula (I) or their pharmaceutically acceptable compositions to the mammals. In final embodiment is provided a pharmaceutical composition comprising the compound of Formula (I) and second therapeutic agent for the treatment of mammalian infections caused by Gram-positive bacteria. DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to compounds of the Formula (I) or their stereoisomers, their suitable pharmaceutically acceptable salts,

Wherein, Q represents O, NR₆, S(O)_p; p = 0-2 integer; Y represents OR3, NR3R4, NHC(O)R5; R₁ is selected from H, F, Cl, CH₃, CN, OH and OCH₃; m =1-4 integer; R₂ is selected from H, F, CH₃, OH; n = 1-8 integer; R₃ and R₄ is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl and heteroaryl each of which may be further optionally substituted; R₃ and R₄ taken together with the nitrogen to which they are attached may form a 4- to 8- membered heterocyclyl or heteroaryl with optionally 1 to 3 additional heteroatoms selected from O, S, or N and may be further be optionally substituted; wherein (C1- C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted by halo, hydroxyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)acyloxy, haloalkyl, NO₂, CN and NH₂; R₅ is independently selected from aminoalkyl, hydroxyalkyl, aryl and heteroaryl each of which may be further optionally substituted; wherein aryl and heteroaryl groups are optionally substituted by halo, hydroxyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)acyloxy, haloalkyl, NO2, CN and NH2; R₆ = H, CN, (C₁-C₆)alkyl, haloalkyl, -COCH₃; -COO(C₁-C₆)alkyl. The present invention also relates to compounds of the Formula (I-a) or their suitable pharmaceutically acceptable salts, Wherein Q, R₁, R₂ and Y are as defined above. In a preferred embodiment, Q represents O; Y represents NR₃R₄, NHC(O)R₅; R₁ is F; m =1-2; R2 is H. The present invention also relates to compounds of the Formula (I-b) or their suitable pharmaceutically acceptable salts,

Wherein Q, R₁, R₂ and Y are as defined above. In a preferred embodiment, Q represents O; Y represents NR₃R₄, NHC(O)R₅; R₁ is F; m =1-2; R2 is H. In a further embodiment the groups, radicals described above may be selected from: - the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like; - the “alkoxy” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbon attached to oxygen atom, selected from Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso- butoxy, pentyloxy, hexyloxy and the like; - the “acyloxy” group used either alone or in combination with other radicals, denotes a linear or branched radial containing acyl group attached to oxygen atom, selected from acetyloxy, propionyloxy and like; - the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; - the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - The term “hydroxyalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one or more hydrogen atom of the alkyl is replaced with a hydroxy group, as defined herein. - The term “aminoalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one or more hydrogen atom of the alkyl is replaced with an amino group, as defined herein. - the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like; - the “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen; In one embodiment, the heterocycle group, wherever applicable, may consists of appropriate number of carbon atoms and include from 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_p, p = 0-2; - the “heteroaryl” or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S; - the term “stereoisomers” used anywhere in the specification indicates that compounds of the present invention show (R) and (S) configuration. Further preferred embodiments are those disclosed below. Preferred “(C₁-C₆)alkyl” group of R₃, R₄ and R₅ is selected from methyl, ethyl, n-propyl, iso-propyl; Preferred “(C₃-C₆)cycloalkyl” group of R₃, R₄ and R₅ is selected from cyclopropyl and cyclobutyl; Preferred “heteroaryl” group of R₃ and R₄ is selected from triazolyl, isoxazolyl, thienyl, furyl. Suitable groups and substituents on the groups may be selected from those described anywhere in the specification. Preferred compounds according to the present invention include but are not limited to: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (R)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide; (R)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; 3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5-yl)methyl)- 2-hydroxyacetamide; (R)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)acetamide; (R)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 5-yl)methyl)acetamide; 3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one. The novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more of the reactants may be protected and deprotected for facile synthesis by techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their suitable salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be within the scope of the present invention. Scheme 1: Synthesis of compounds of general Formula (I)

The compound of the general Formula (I) can be prepared by following general scheme 1. The compound (IV) can be obtained by reacting compounds of the Formula (II) with (III) in the presence of base such as TEA, DIPEA, Na₂CO₃, K₂CO₃, NaH etc. in solvents such as THF, DMF, MeOH, CH₃CN etc. The compounds of general Formula (V) can be obtained by reduction using SnCl₂.2H₂O in EtOAc or catalytic hydrogenation using hydrogen gas and palladium charcoal as catalyst in solvents such as THF, MeOH etc. The compounds of the general Formula (VI) can be obtained by reacting (V) with benzyl oxy carbonyl chloride using NaHCO₃ as a base in solvents such as EtOAc, CH₃CN, THF etc. Compounds of the Formula (VII) can be obtained by treating it with racemic epichlorohydrin using base such as cesium carbonate, n-BuLi in appropriate solvents such as THF, DMF etc. It was then reacted with sodium azide in DMF at high temperature to get azide derivative (VIII). Reduction of (VIII) using Triphenyl phosphine in mixture of THF and water gave compounds (I, when Y = NH₂). Alternatively, reduction can also be achieved using catalytic hydrogenation using H₂/Pd- C system. It was further reacted with appropriate acid derivative using general amide bond formation techniques as described in Tetrahedron 2005, 61, 10827 to get compounds of the Formula (I) with amide linkage. Scheme 2: Synthesis of compounds of general Formula (I)

The compound of the general Formula (I) can also be prepared by following general scheme 2. Compound (VII) can also be reacted with appropriate amine derivatives to get compounds of the general Formula (I, when Y = NR₃R₄). Compoun

d of the general can be reacted with triazole in presence of

Formula (VII)

b

ase such as Na₂CO₃, K₂CO₃

etc. in solvents such as DMF, CH₃CN etc. to get compound (I

,

wh

en Y = triazole). Alternatively, compound (V

II

I

) c

an be

reacte

d with Norbornadiene or vinyl acetate under

refluxing conditio

n i

n p

resence or

ab

s

e

n

ce of solvent such as Dioxane to get triazole derivative (I)

. Compound (VII) can be reacted with (IX) in presence of base such as Na

2CO₃, K₂CO

₃ etc. in solvents such as DMF, CH₃C

N e

tc. f

ollowed

by

deprotection using TFA in

D

CM

to

get compound (I,

when Y = aminoisoox

az

ole

)

. Scheme 3: Synthesis of comp

o

unds of general Formula (I-a & I-b)

The compound (I) prepared following scheme 1 and scheme 2 can be converted into its

corresponding enantiomers (I-a) and (I-b) using chiral preparative HPLC purification

technique. Scheme 4: Synthesis of compounds of general Formula (I-a)

Alternatively, the compound of the general Formula (I-a) can be prepared by following general scheme 4. Compounds of the Formula (I-a, when Y = OH) can be obtained by treating (VI) with n-butyl lithium and R-glycidyl butyrate in THF. It was then converted into mesylate derivatives (X) using methane sulfonyl chloride and TEA in solvents such as THF, CH₃CN, DCM etc., which was then reacted with sodium azide in DMF at high temperature to get azide derivative (XI). Reduction of (XI) using Triphenyl phosphine in mixture of THF and water gave compounds (I-a, when Y = NH₂). Alternatively, reduction can also be achieved using catalytic hydrogenation using H₂/Pd-C system. It was further reacted with appropriate acid derivative using general amide bond formation techniques as described in Tetrahedron 2005, 61, 10827 to get compounds of the Formula (I-a) with amide linkage. Scheme 5: Synthesis of compounds of general Formula (I-a)

The compound of the general Formula (I-a) can also be prepared by following general scheme 5. Compound (X) can be reacted with appropriate amine derivatives to get compounds of the general Formula (I-a, when Y = NR₃R₄). Compound of the general Formula (X) can be reacted with triazole in presence of base such as Na₂CO₃, K₂CO₃ etc. in solvents such as DMF, CH₃CN etc. to get compound (I-a, when Y = triazole). Alternatively, compound (XI) can be reacted with Norbornadiene or vinyl acetate under refluxing condition in presence or absence of solvent such as Dioxane to get triazole derivative (I-a). Compound (X) can be reacted with (IX) in presence of base such as Na₂CO₃, K₂CO₃ etc. in solvents such as DMF, CH₃CN etc. followed by deprotection using TFA in DCM to get compound (I-a, when Y = aminoisooxazole). The invention is explained in greater detail by the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. The chemical shifts (δ) in

NMR spectra are reported in parts per million (ppm) relative to Tetramethyl silane (TMS), in either CDCl₃ or DMSO-d₆ solution. Mass spectra (ESI-MS) were obtained on Shimadzu LC-MS 2010-A spectrometer. List of Abbreviations CH₃CN: Acetonitrile CDCl₃: Deuterated chloroform DIPEA: Disopropyl ethyl amine DMF: Dimethyl formamide DCM: Dichloromethane DMSO-d₆: Hexadeuterodimethyl sulfoxide EDC.HCl: N-(3-Dimethyl aminopropyl)-N’-ethyl carbodiimide hydrochloride EtOH: Ethanol EtOAc: Ethyl acetate HOBT: 1-Hydroxy benzotriazole K₂CO₃: Potassium carbonate MeOH: Methanol Na₂CO₃: Sodium carbonate Na₂SO₄: Sodium sulfate NaH: Sodium Hydride NaHCO₃: Sodium bicarbonate Pd/C: palladium carbon SnCl2.2H2O: Stannous chloride dihydrate TEA: Triethyl amine TFA: Trifluoroacetic acid THF: Tetrahydrofuran ¹H NMR: Proton Nuclear Magnetic Resonance h: Hour(s) RT: room temperature [25-30 °C] min: Minute(s) J: Coupling constant in units of Hz Hz: Hertz Preparation of compounds EXAMPLE 1 Preparation of 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one

Step 1: tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate

To a stirring solution of tert-butyl piperazine-1-carboxylate (4.99 g, 26.8 mmol) and oxetan-3-one (1.93 g, 26.8 mmol) in DCM was added Sodium triacetoxyborohydride (8.5 g, 40.2 mmol) at 0-5°C and stirred for 16 h at 25-30°C. Reaction mixture was diluted with DCM and washed with aq NaHCO₃. Organic layer was separated, dried and evaporated under reduced pressure to get the product. ESI-MS (m/z) : 243.16 (M+H)⁺. Step 2: 1-(2,6-difluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine

To a stirring solution of product of step 1 (7.12 g, 29.42 mmol) in DCM was added TFA (13.6 ml, 176.3 mmol) at 0-5°C and stirred for 3 h at 25-30°C. After completion of reaction, DCM was evaporated under reduced pressure to get the crude product which was diluted with DMF (70 mL). To this was added K₂CO₃ (9.2 g, 66.8 mmol) and 1,2,3- trifluoro-5-nitrobenzene (4.26 g, 24.1 mmol) and stirred for 4 h at 80°C. Reaction mixture was then diluted with water and solid obtained was filtered to get the title product. ESI-MS (m/z): 300.1 (M+H)⁺. Step 3: 3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline To a stirring solution of product of step 2 (6.0 g, 20.05 mmol) in THF was added Pd/C (cat.) at RT and stirred it for 16 h under hydrogen atmosphere. After completion of reaction, it was filtered through celite and filtrate was evaporated to get the title product. ESI-MS (m/z): 270.13 (M+H)⁺. Step 4: benzyl (3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate

To a stirring solution of product of step 3 (16.3 g, 60.5 mmol) in THF was added NaHCO₃ (15.25 g, 18.2 mmol) and benzyl chloroformate (11.36 g, 66.63 mmol) at 0-5°C. The reaction mixture was stirred at 25-30°C for 2 h. Reaction mixture was diluted with EtOAc and water. Organic layer was separated, dried and evaporated under reduced pressure to get the product. ESI-MS (m/z) : 404.16 (M+H)⁺. Step 5: 5-(chloromethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl) oxazolidin-2-one

To a stirring solution of product of step 4 (1 g, 2.479 mmol) in dry THF was added n- butyl lithium (9.22 ml (2.5 M), 23.05 mmol) followed by rac-epichlorohydrin (0.213 mL, 2.73 mmol) at -78°C. The resultant solution was stirred at 50°C for 16 h. The reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na₂SO₄, and concentrated to get the title product. ESI-MS (m/z): 388.3 (M+H)⁺. Step 6: 5-(azidomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl) oxazolidin-2-one

To stirring solution of product of step 5 (1.2 g, 3.09 mmol) in DMF (40 ml) was added sodium azide (1.0 g, 15.47 mmol). Reaction mixture was stirred at 80⁰C for 3 h. After complete conversion of starting material, the reaction mixture was diluted with cold water and obtained white solid was filtered. ESI-MS (m/z): 395.3 (M+H)⁺. Step 7: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one

To stirring solution of product of step 6 (600 mg, 1.521 mmol) in Dioxane was added norbornadiene (0.93 mL, 9.13 mmol). Reaction mixture was stirred at 100⁰C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column

NMR (DMSO-d₆): 8.17 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.23-7.18 (m, 2H), 5.16-5.12 (m, 1H), 4.82 (d, J = 5.2 Hz, 2H), 4.55 (t, J = 6.4 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 4.19 (t, J = 9.2 Hz, 1H), 3.87-3.84 (m, 1H), 3.47-3.44 (m, 1H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 421.18 (M+H)⁺. EXAMPLE 2 Preparation of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one Step 1: (R)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- (hydroxymethyl)oxazolidin-2-one

To a stirring solution of product step (6.2 g, 15.38 mmol) in dry THF was added n-butyl lithium (9.22 ml (2.5 M), 23.05 mmol) at -78°C. The resultant solution was stirred at -78 °C for 1 h and then (R)-glycidyl butyrate (2.44 g, 16.91 mmol) was dropwise added at -78°C. The reaction mixture was stirred for an additional 1 h at -78°C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na₂SO₄, and concentrated to get the title product. ¹H NMR (DMSO-d6): 7.33-7.27 (m, 2H), 5.21 (t, 1H), 4.72-4.69 (m, 1H), 4.56-4.53 (m, 2H), 4.47-4.44 (m, 2H), 4.04 (t, 1H), 3.81-3.77 (m, 1H), 3.69-3.64 (m, 1H), 3.57-3.51 (m, 1H), 3.48-3.45 (m, 1H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 370.15 (M+H)⁺. Step 2: (R)-(3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl methanesulfonate

To a stirring solution of product obtained above in step 1 (3.5 g, 9.48 mmol) in DCM was added TEA (1.98 ml, 14.21 mmol) and methanesulfonyl chloride (0.89 ml, 11.37 mmol) at 0-5°C. Reaction mixture was stirred for 2 h at 25-30°C. After completion of reaction it was diluted with DCM and washed with water. DCM layer was separated, dried over Na₂SO₄ and evaporated to get the title product which was directly used for next step. Step 3: (R)-5-(azidomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one

To a stirring solution of product obtained above in step 2 (4.0 g, 8.95 mmol) in DMF (40 ml) was added sodium azide (2.9 g, 44.7 mmol). Reaction mixture was stirred at 80⁰C for 5 h. After complete conversion of starting material, the reaction mixture was diluted with cold water and solid obtained was filtered. ESI-MS (m/z): 395.16 (M+H)⁺. Step 4: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one

To a stirring solution of step g, 5.32 mmol) in Dioxane was added norbornadiene (3.3 mL, 31.9 mmol). Reaction mixture was stirred at 100⁰C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column chromatography. ¹H NMR (DMSO-d₆): 8.17 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.24-7.18 (m, 2H), 5.16-5.12 (m, 1H), 4.82 (d, J = 5.2 Hz, 2H), 4.55 (t, J = 6.6 Hz, 2H), 4.45 (t, J = 6.2 Hz, 2H), 4.19 (t, J = 9.2 Hz, 1H), 3.88-3.84 (m, 1H), 3.47-3.44 (m, 1H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 421.18 (M+H)⁺. EXAMPLE 3 Preparation of (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- ((isoxazol-3-ylamino)methyl)oxazolidin-2-one

Step 1: tert-butyl (R)-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)(isoxazol-3-yl)carbamate

To a stirring solution of product of step 2 (Example-2) (0.6 gm, 1.341 mmol) in DMF (6 ml) was added tert-butyl isoxazol-3-ylcarbamate (0.346 gm, 1.877 mmol) and K₂CO₃ (0.371 gm, 2.68 mmol) at RT. Reaction mixture was stirred for 16 h at 100^oC. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product. ESI-MS (m/z): 536.15 (M+H)⁺. Step 2: (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one

To a stirring solution of product obtained above in step 1 (0.66 gm, 1.232 mmol) in DCM (6 mL) was added TFA (1.9 mL, 24.64 mmol) at 0^oC. Reaction mixture was stirred for 2 h then diluted with DCM (30 mL) and washed with aq. NaHCO_3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title product. (DMSO-d₆): 8.40 (s, 1H), 8.39-7.25 (m, 2H), 6.55 (t, J = 6.0 Hz, 1H), 5.99 (d, J = 2.0 Hz, 1H), 4.89-4.86 (m, 1H), 4.56-4.53 (m, 2H), 4.46-4.44 (m, 2H), 4.11 (t, J = 9.0 Hz, 1H), 3.78-3.75 (m, 1H), 3.47- 3.41 (m, 3H), 3.09 (m, 4H), 2.36 (m, 4H). ESI-MS (m/z): 436.10 (M+H)⁺. EXAMPLE 4 Preparation of (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide

Step 1: (S)-5-(aminomethyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one

To stirring solution of product of step 3 (Example-2) (0.4 g, 1.014 mmol) in mixture of THF (10 mL) and EtOH (2 mL) was added Pd/C (30 mg) followed by sodium borohydride (0.23 gm, 6.09 mmol). The reaction mixture was stirred at RT for 1 h and passed it through hyflow. Filtrate was washed with water (30 mL) and extracted by DCM. Organic layer was separated, dried and evaporated under reduced pressure to get the product.¹H NMR (DMSO-d₆): 7.32-7.25 (m, 2H), 4.72-4.61 (m, 3H), 4.59-4.53 (m, 2H), 4.04 (t, 1H), 3.84-3.80 (m, 1H), 3.49-3.43 (m, 1H), 3.09 (s, 4H), 2.86-2.74 (m, 2H), 2.36 (s, 4H), 1.95 (bs, 2H). ESI-MS (m/z): 369.10 (M+H)⁺. Step 2: (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide To a stirring solution of product obtained above in step 1 (0.5 gm, 1.357 mmol) and HOBT (0.27 gm, 1.764 mmol) in DMF (5 ml) was added Glycolic acid (0.26 gm, 3.39 mmol) followed by DIPEA (0.71 ml, 4.07 mmol) and EDC.HCl (0.78 gm, 3.39 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get the crude product which was purified by preparative HPLC to get title

NMR (DMSO-d₆): 8.07 (t, J = 6.2 Hz, 1H), 7.30-7.22 (m, 2H), 5.56 (bs, 1H), 4.79-4.73 (m, 1H), 4.56-4.53 (m, 2H), 4.47-4.44 (m, 2H), 4.08 (t, J = 9.0 Hz, 1H), 3.83 (s, 2H), 3.79-3.75 (m, 1H), 3.51-3.40 (m, 3H), 3.09 (s, 4H), 2.36 (s, 4H). ESI-MS (m/z): 427.17 (M+H)⁺. EXAMPLE 5 Preparation of (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

Step 1: tert-butyl (S)-(2-(((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)amino)-2-oxoethyl)carbamate

To a stirring solution of step gm, 2.71 mmol) and HOBT (0.54 gm, 3.53 mmol) in DMF (10 ml) was added Boc-Gly-OH (0.95 gm, 5.43 mmol) followed by DIPEA (1.42 ml, 8.14 mmol) and EDC.HCl (1.56 gm, 8.14 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product which was used for next step. Step 2: (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide

To a stirring solution of product obtained above in step 1 (1.4 gm, 2.66 mmol) in DCM (15 mL) was added TFA (4.1 mL, 53.3 mmol) at 0^oC. Reaction mixture was stirred for 2 h then diluted with DCM (30 mL) and washed with aq.NaHCO_3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title product.

NMR (DMSO-d₆): 8.17 (bs, 1H), 7.28-7.25 (m, 2H), 4.78-4.71 (m, 1H), 4.56-4.53 (m, 2H), 4.47-4.44 (m, 2H), 4.07 (t, J = 9.0 Hz, 1H), 3.75 (m, 1H), 3.49-3.45 (m, 3H), 3.10 (s, 6H), 2.36 (s, 4H), 1.81 (bs, 2H). ESI-MS (m/z): 426.20 (M+H)⁺. EXAMPLE 6 Preparation of (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)oxazolidin-2-one

Step 1: 1-(2-fluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine

To a stirring solution of product of step 1 (Example-1) (1.0 g, 4.13 mmol) in DCM (10 mL) was added TFA (1.91 ml, 24.76 mmol) at 0-5°C and stirred it for 3 h at 25-30°C. After completion of reaction, DCM was evaporated under reduced pressure to get the crude product which was diluted with DMF (5 mL). To this was added K₂CO₃ (1.41 g, 10.20 mmol) and 1,2-difluoro-4-nitrobenzene (0.58 g, 3.67 mmol) and stirred for 4 h at 80°C. Reaction mixture was then diluted with water obtained solid was filtered to get the title product. ESI-MS (m/z): 282.13 (M+H)⁺. Step 2: 3-fluoro-4-(4-(oxetan-3- 1- aniline

To a stirring solution of product of step 1 (0.83 g, 2.95 mmol) in THF was added Pd/C (cat.) at RT and stirred it for 16 h under hydrogen atmosphere. After completion of reaction, it was filtered through celite and filtrate was evaporated to get the title product. ESI-MS (m/z): 252.15 (M+H)⁺. Step 3: benzyl (3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate

To a stirring solution of product of step 2 (0.73 g, 2.90 mmol) in THF was added NaHCO₃ (0.73 g, 8.71 mmol) and benzyl chloroformate (1.29 g, 3.78 mmol) at 0-5°C. The reaction mixture was stirred at 25-30°C for 2 h. After completion of reaction it was diluted with EtOAc and water. Organic layer was separated, dried and evaporated under reduced pressure to get the product. ESI-MS (m/z): 386.17 (M+H)⁺. Step 4: (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5- (hydroxymethyl)oxazolidin-2-one To a stirring solution of product of step 3 (1.5 g, 3.89 mmol) in dry THF (40 mL) was added n-butyl lithium (2.33 ml (2.5 M), 5.84 mmol) at -78°C. The resultant solution was stirred at -78 °C for 1 h and then (R)-glycidyl butyrate (0.62 g, 4.28 mmol) was dropwise added at -78°C. The reaction mixture was stirred for an additional 1 h at -78°C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted with water and EtOAc. Organic layer was separated, dried over Na₂SO₄, and concentrated to get the title product. ¹H NMR (DMSO-d₆): 7.53-7.50 (m, 1H), 7.49-7.18 (m, 1H), 7.08-7.04 (m, 1H), 5.21 (s, 1H), 4.71-4.65 (m, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.04 (t, J = 9.0 Hz, 1H), 3.81-3.77 (m, 1H), 3.68-3.64 (m, 1H), 3.57-3.50 (m, 1H), 3.48-3.44 (m, 1H), 3.00 (s, 4H), 2.33 (s, 4H). ESI-MS (m/z): 352.24 (M+H)⁺. Step 5: (R)-(3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl methanesulfonate

To a stirring solution of product of step 4 (1.35 g, 3.84 mmol) in DCM was added TEA (1.61 ml, 11.53 mmol) and methanesulfonyl chloride (0.39 ml, 4.99 mmol) at 0-5°C. Reaction mixture was stirred for 2 h at 25-30°C. After completion of reaction it was diluted with DCM and washed with water. DCM layer was separated, dried over Na₂SO₄ and evaporated to get the title product which was directly used for next step. Step 6: (R)-5-(azidomethyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one

To stirring solution of product of step 5 (1.6 g, 3.73 mmol) in DMF (10 ml) was added Sodium Azide (1.4 g, 22.35 mmol). Reaction mixture was stirred at 80⁰C for 5 h. After complete conversion of starting material, the reaction mixture was diluted with cold water and solid obtained was filtered. ESI-MS (m/z): 377.4 (M+H)⁺. Step 7: (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one

To stirring solution of product of step 6 (0.4 g, 1.06 mmol) in Dioxane was added norbornadiene (0.59 gm, 6.38 mmol). Reaction mixture was stirred at 100⁰C for 16 h. After complete conversion of starting material, the reaction mixture was concentrated and purified by column chromatography. ¹H NMR (DMSO-d₆): 8.17 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.42-7.37 (m, 1H), 7.13-7.03 (m, 2H), 5.15-5.09 (m, 1H), 4.82 (d, J = 4.8 Hz, 2H), 4.57-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.20 (t, J = 9.2 Hz, 1H), 3.87-3.83 (m, 1H), 3.49-3.34 (m, 1H), 3.00 (m, 4H), 2.33 (s, 4H). ESI-MS (m/z): 403.18 (M+H)⁺. EXAMPLE 7 Preparation of (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide

Step 1: (S)-5-(aminomethyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one

5 To stirring solution of product of step 6 (Example-6) (0.4 g, 1.06 mmol) in mixture of THF (10 mL) and EtOH (3 mL) was added Pd/C (Cat.) followed by sodium borohydride (0.24 gm, 6.38 mmol). The reaction mixture was stirred at RT for 1 h and passed it through hyflow. Filtrate was washed with water (30 mL) and extracted by DCM. Organic layer was separated, dried and evaporated under reduced pressure to get the

10 NMR (DMSO-d₆): 7.52-7.48 (m, 1H), 7.21-7.18 (m, 1H), 7.09-7.04 (m, 1H), 4.63-4.45 (m, 3H), 4.47-4.44 (m, 2H), 4.02 (t, J = 8.8 Hz, 1H), 3.84-3.80 (m, 1H), 3.50-3.44 (m, 1H), 3.00 (s, 4H), 2.87-2.76 (m, 2H), 2.33 (s, 4H), 1.89 (bs, 2H). ESI-MS (m/z): 351.19 (M+H)⁺. Step 2: (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin- 15 5-yl)methyl)-2-hydroxyacetamide

To a stirring solution of product of step 1 (0.5 gm, 1.43 mmol) and HOBT (0.28 gm, 1.85 mmol) in DMF (5 ml) was added Glycolic acid (0.27 gm, 3.57 mmol) followed by DIPEA (0.75 ml, 4.28 mmol) and EDC.HCl (0.82 gm, 4.28 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get the crude product which was purified by preparative HPLC to get title product.¹H NMR (DMSO-d₆): 8.07 (t, J = 6.0 Hz, 1H), 7.49-7.45 (m, 1H), 7.19-7.16 (m, 1H), 7.09-7.04 (m, 1H), 5.55 (t, J = 5.6 Hz, 1H), 4.77-4.71 (m, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.08 (t, J = 8.8 Hz, 1H), 3.83 (d, J = 6.0 Hz, 2H), 3.79-3.75 (m, 1H), 3.49-3.41 (m, 3H), 3.00 (s, 4H), 2.33 (s, 4H). ESI-MS (m/z): 409.16 (M+H)⁺. EXAMPLE 8 Preparation of (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)- 2-oxooxazolidin-5-yl)methyl)acetamide

Step 1: tert-butyl (S)-(2-(((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)amino)-2-oxoethyl)carbamate

To a stirring solution of product of step 1 (Example-7) (0.5 gm, 1.427 mmol) and HOBT (219 mg, 1.427 mmol) in DMF (5 ml) was added Boc-Gly-OH (0.5 gm, 2.85 mmol) followed by DIPEA (0.75 ml, 4.28 mmol) and EDC.HCl (821 mg, 4.28 mmol). Reaction mixture was stirred for 16 h at RT. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product. ESI-MS (m/z): 508.25 (M+H)⁺. Step 2: (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide To a stirring solution of product obtained above in step 1 (0.7 gm, 1.38 mmol) in DCM (10 mL) was added TFA (2.1 mL, 27.6 mmol) at 0^oC. Reaction mixture was stirred for 2 h then diluted with DCM (20 mL) and washed with aq.NaHCO_3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title

NMR (DMSO-d₆): 8.18 (bs, 1H), 7.49-7.45 (m, 1H), 7.18-7.16 (m, 1H), 7.09-7.04 (m, 1H), 5.76-4.69 (m, 1H), 4.58- 4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.08 (t, J = 9.0 Hz, 1H), 3.75-3.71 (m, 1H), 3.50-3.45 (m, 3H), 3.17 (s, 2H), 2.99 (m, 4H), 2.42 (m, 4H), 1.99 (bs, 2H). ESI-MS (m/z): 408.17 (M+H)⁺. EXAMPLE 9 Preparation of (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol- 3-ylamino)methyl)oxazolidin-2-one

Step 1: tert-butyl (R)-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)(isoxazol-3-yl)carbamate To a stirring solution of product of step 5 (Example-6) (0.25 gm, 0.582 mmol) in DMF (3 ml) was added tert-butyl isoxazol-3-ylcarbamate (0.129 gm, 0.699 mmol) and K₂CO₃ (0.161 gm, 1.164 mmol) at RT. Reaction mixture was stirred for 16 h at 100^oC. Reaction mixture was diluted with water and the precipitated solid was filtered to get title product. ESI-MS (m/z): 518.22 (M+H)⁺. Step 2: (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one

To a stirring solution of product obtained above in step 1 (0.3 gm, 0.58 mmol) in DCM (5 mL) was added TFA (0.89 mL, 11.59 mmol) at 0^oC. Reaction mixture was stirred for 2 h then diluted with DCM (15 mL) and washed with aq.NaHCO_3. Organic layer was separated, dried and evaporated under reduced pressure to get the crude product which was purified by preparative HPLC to get title

NMR (DMSO-d₆): 8.39 (d, J = 1.6 Hz, 1H), 7.52-7.47 (m, 1H), 7.19-7.16 (m, 1H), 7.09-7.04 (m, 1H), 6.56 (t, J = 6.2 Hz, 1H), 6.00 (d, J = 2.0 Hz, 1H), 4.89-4.84 (m, 1H), 4.58-4.54 (m, 2H), 4.47-4.44 (m, 2H), 4.11 (t, J = 9.0 Hz, 1H), 3.79-3.75 (m, 1H), 3.50-3.38 (m, 3H), 3.00 (m, 4H), 2.33 (m, 4H). ESI-MS (m/z): 418.16 (M+H)⁺. Biological evaluation: Minimum inhibitory concentration (MIC) determination: Following strains were used for MIC testing: Staphylococcus aureus (MRSA) ATCC 33591 Staphylococcus aureus (VRS2) NR-46411 Streptococcus pneumoniae (PRSP) ATCC 700904 MIC protocol: MIC determination was done by using the reference broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI). Briefly, bacterial cells were cultured on Mueller Hinton agar plates. Stock solutions of compounds and positive controls were prepared in DMSO. Subsequent dilutions of compounds were prepared in cation adjusted Mueller Hinton broth (CAMHB). Compounds were tested by serial double dilution in 96 well plates. Inoculum densities were maintained at 5 X 10⁴ cells per well. Plates were incubated at 37 ⁰C for 20-24 hrs before being read at 620 nm in Multiskan reader (Thermo). Linezolid was taken as positive control. All QC results were within specified ranges as published in CLSI document M100–S25 Mitochondrial protein synthesis (MPS) modulators assay: Human hepatocyte cell line, HepG2 was used to assess the mitochondrial protein synthesis inhibition of test compounds. The cells were plated at 6000 cell /well in 96 well tissue culture plates and allowed to grow for 16 h. To these cells, test compounds were added in desired concentrations and incubated for 96h. Chloramphenicol was used in the assay as MPS inhibition control. After 96 h, the cells were fixed with 4% paraformaldehyde for 20min, then treated with 0.5% acetic acid to stop alkaline phosphatase activity. The cells were then treated with permeabilization buffer (1% triton x-100) for 30min followed by blocking with the blocking buffer (AbCAM mitogenesis in cell ELISA kit #ab110217) for 2 h. The cells were then probed for COX-1 and SDH-A using the antibodies provided in the kit. The protein levels were measured in the kinetic mode using Spectramax (Molecular Devices, US) and the ratio of COX-1 to SDH-A expression was calculated. The ratio with respect to the concentration of the test compounds were utilized to derive the half-maximal inhibitory concentration using GraphPad Prism.

Compounds of the present invention show antibacterial activity against various Gram- positive bacterial strains as reflected in their MIC values described in Table 1. Further, compounds have shown lower potential for mitochondrial protein synthesis inhibition as reflected in higher MPS IC₅₀ of compounds of the present invention in MPS assay compared with Linezolid. Hence, compounds of the present invention have improved safety profile over Linezolid. Table 1:

The novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known. The compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts, or pharmaceutical compositions containing them are useful as a medicament for the mammalian infections and suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration. The quantity of active component, that is, the novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration. The novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known. The pharmaceutical compositions further comprise an effective amount of an antibacterial agent. The dosage of antibacterial agent may vary within wide limits and should be adjusted, in each particular case, to the individual conditions. 5 Use of the novel compounds of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts of the present invention use for the treatment of mammalian infection caused by Gram-positive bacteria. In some embodiments, the mammalian infection caused by Gram-positive bacteria includes but not limited to skin infections, lung infections and tissue infections. 10 In some embodiments, the present invention includes a method for the treatment of mammalian infection caused by Gram-positive bacteria at least one of but not limited to skin infections, lung infections and tissue infections by administering to a subject in need thereof a therapeutically effective amount of a compound or salt of the novel compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically 15 acceptable salts.

Claims

We claim: 1. Compounds of general Formula (I), their stereoisomers, their suitable pharmaceutically acceptable salts,

Wherein, Q represents O, NR6, S(O)p; p = 0-2 integer; Y is selected from OR₃, NR₃R₄, NHC(O)R₅; R₁ is selected from H, F, Cl, CH₃, CN, OH and OCH₃; m is selected from 1-4; R₂ is selected from H, F, CH₃, OH; n is selected from 1-8; R₃ and R₄ is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl and heteroaryl, each of which is substituted or unsubstituted; R₃ and R₄ taken together with the nitrogen to which they are attached to form a 4- to 8- membered heterocyclyl or heteroaryl with 1 to 3 additional heteroatoms selected from O, S, or N, which is substituted or unsubstituted; wherein substitutions on (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl and heteroaryl groups selected from halo, hydroxyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)acyloxy, haloalkyl, NO₂, CN and NH₂; R₅ is selected from aminoalkyl, hydroxyalkyl, aryl and heteroaryl each of which is substituted or unsubstituted; wherein substitutions on (C1-C6)alkyl, aryl, heterocyclyl and heteroaryl groups selected from halo, hydroxyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)acyloxy, haloalkyl, NO₂, CN and NH₂; R₆ = H, CN, (C₁-C₆)alkyl, haloalkyl, -COCH₃; -COO(C₁-C₆)alkyl. 2. The compound as claimed in claim 1 having Formula (I-a) or their suitable pharmaceutically acceptable salts Wherein, Q, R₁, R₂ and Y are as defined in claim 1. 3. The compound as claimed in claim 2, wherein Q is O; Y is selected from NR₃R₄, NHC(O)R₅; R₁ is F; m is selected form 1-2; R₂ H. 4. The compound as claimed in claim 1 having Formula (I-b) or their suitable pharmaceutically acceptable salts,

Wherein, Q, R₁, R₂ and Y are as defined in claim 1. 5. The compound as claimed in claim 4, wherein Q is O; Y is selected from NR₃R₄, NHC(O)R₅; R₁ is F; m is selected form 1-2; R₂ is H. 6. Compounds of Formula (I) or their suitable pharmaceutically acceptable salts as claimed in claim 1 are selected from: 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)oxazolidin-2-one; N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (R)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (R)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; 3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; 5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (R)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; (S)-5-((1H-1,2,3-triazol-1-yl)methyl)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)oxazolidin-2-one; N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (R)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; (S)-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2-oxooxazolidin-5- yl)methyl)-2-hydroxyacetamide; 2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (R)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; (S)-2-amino-N-((3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide; 3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (R)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one; (S)-3-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-5-((isoxazol-3- ylamino)methyl)oxazolidin-2-one. 7. Pharmaceutical composition comprising compound of Formula (I) or Formula (I- a) or Formula (I-b) or their suitable pharmaceutically acceptable salts as claimed in claim 1, 2 and 4 and suitable pharmaceutically acceptable excipients. 8. Use of the compounds as claimed in claim 1, 2 and 4 for the treatment of mammalian infections, by administering a therapeutically effective & non-toxic amount of the compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts, or their suitable pharmaceutically acceptable compositions to the mammals. 9. Use of the compounds as claimed in claim 8 for the treatment of mammalian infections wherein mammalian infections is caused by Gram-positive bacteria. 10. Method of treating mammalian infections in a subject which comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or Formula (I-a) or Formula (I-b) or their suitable pharmaceutically acceptable salts as claimed in claim 1, 2 and 4 or their suitable pharmaceutical composition. 11. Method of treating mammalian infections as claimed in claim 10 wherein mammalian infections is caused by Gram-positive bacteria.