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 la (VII) can be reacted with triazole in presence of
b

Formu

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 O

2C 3, K2CO

3 etc. in solvents such as DMF, CH3CN e
tc. f
ollowed by
deprotection A in

using TF D
C
M
to g

et 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 100oC. 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 0oC. Reaction mixture was stirred for 2 h then diluted with DCM (30 mL) and washed with aq. NaHCO3. 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 0oC. Reaction mixture was stirred for 2 h then diluted with DCM (30 mL) and washed with aq.NaHCO3. 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)+.

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.