WO2006043121A1 - Oxazolidinone derivatives as antimicrobials - Google Patents

Abstract

The present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiple-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

Description

OXAZOLIDINONE DERIVATIVES AS ANTIMICROBIALS

Field of the Invention

The present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiple-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bactericides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

Background of the Invention

Increasing antibacterial resistance in Gram-positive bacteria has presented a formidable treatment problem. The enterococci, although traditionally not virulent pathogens, have been shown, when associated with vancomycin resistance, to have an attributable mortality of approximately 40%. Staphylococcus aureus, the traditional pathogen of postoperative wounds, has been resistant to penicillin due to production of penicillinases. This resistance was overcome by the development of various penicillinase-stable β lactams. But the pathogen responded by synthesizing modified target penicillin binding protein- 2' leading to less affinity for β lactam antibiotics and a phenotype known as Methicilline Resistant S. aureus (MRSA). These strains, till recently were susceptible to vancomycin, which in spite of its various drawbacks, has become the drug of choice for MRSA infections. Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin. Recently though, different PBP 2' strains with different susceptibility to penicillin have been reported from across the globe.

Oxazolidinones are a class of synthetic antimicrobial agents which kill Gram-positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 3OS and 5OS ribosomes leading to prevention of initiation complex formation. Due to their mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics. WO 04/014392 discloses piperazinyl oxazolidinyl acetamide derivatives which are described as antimicrobials. WO 03/008389 discloses substituted phenyl oxazolidinones, which are said to be useful antimicrobial agents, described as effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria such as multiply- resistant Staphylococci, Streptococci and Enterococci as well as anaerobic organisms such as Bactericides spp., Clostridium spp. and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. WO 03/007870 discloses oxazolidinone derivatives, which are described as useful antimicrobials agents, said to be effective against number of human and veterinary pathogens. WO 03/072575 discloses 3- cyclyl-5-(nitrogen containing 5-membered ring) methyl oxazolidinone derivatives and their use as antibacterial agents.

Bioorg. Med. Chem. Let, 12 (2003), 4179-4186, discloses antibacterial oxazolidinone with C-5, methylene O-linked heterocyclic side chain. Bioorg. Med. Chem. Lett, ϋ (2003), 35-41, discloses synthesis and antibacterial activity of 5-substituted oxazolidinones. WO 02/06278 discloses phenyl oxazolidinone derivatives described as antimicrobial agents. J Med. Chem. 2002,45,3953-3962 describes synthesis of conformationally constrained analogues of linezolid, and structure activity relationship (SAR) studies on selected tricyclic oxazolidinones. WO 00/32599 discloses phenyl oxazolidinyl described as antimicrobial agents.

Pae A. N., et al., Bioorg. Med. Chem. Lett, 9, 2679-2684, (1999) and Pae A. N., et al,

Bioorg. Med. Chem. Lett, 9, 2685-2690, (1999) disclose oxazolidinone derivatives, which are apparently active against Gram-positive strains including the resistant strains of Staphylococcus and Enterococcus.

WO 99/64416 and WO 99/64417 disclose substituted oxazolidinyl described as antimicrobials agents. J Med. Chem. 4_i (1998), 3727-3735 describes pyridine, diazine, triazine, heteroaromatic rings directly attached to a piperazinyl oxazolidinone core. WO 98/01446 describes 6-membered heteroaryl rings containing 2 or 3 ring nitrogen atoms, attached to a piperazinyl oxazolidinyl core. WO 98/01447 discloses pyridyl rings (optionally- substituted) attached to a piperazinyl oxazolidinyl core. WO 97/10223 describes aminoaryloxazolidinone N- oxides. WO93/23384 application discloses phenyloxazolidinones containing a substituted diazine moieties and their uses as antimicrobial agents.

WO93/09103 application discloses substituted aryl and heteroaryl- phenyl¬ oxazolidinones said to be useful as antibacterial agents. WO90/02744 application discloses 5-indolinyl-5β-amidomethyloxazolidinones, 3-(fused ring substituted) phenyl-5β- amidomethyloxazolidinones which are described as useful as antibacterial agents. EP 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones. EP 312,000 discloses phenyl methyl and pyridinylmethyl substituted phenyl oxazolidinones.

U.S. Patent No. 5,254,577 discloses heteroaromatic nitrogen rings attached to phenyloxazolidinones. U.S. Patent Nos. 5,547,950 and 5,700,799 also disclose phenyl piperazinyl oxazolidinones. U.S. Patent No. 5,719,154 describes substituted or unsubstituted 2-pyrimidinyl, 4-pyrimidinyl, or 3-pyridazinyl rings directly attached to a piperazinyl oxazolidinyl core.

U.S. Patent No. 5,736,545 describes azolyl piperazinyl phenyl oxazolidinones which contain azolyl rings as fϊve-membered heterocyclic rings wherein the piperazine nitrogen atom is attached to the carbon atom of the carbon nitrogen double bond of the five-membered heterocyclic ring. The heterocycle ring contains more than one heteroatom. The fϊve- membered ring heterocycle (azolyl ring) is of the general formula:

wherein A, B, and C are independently oxygen (O), nitrogen (N), sulfur (S) or carbon (C).

Other references disclosing various phenyloxazolidinones include U.S. Patent Nos. 4,801,600 and 4,921,869; Gregory W.A., et al, J. Med. Chem., 1989; 32: 1673-81; Gregory W.A., et al, J. Med. Chem., 1990; 33: 2569-78; Wang C, et al, Tetrahedron, 1989; 45: 1323-26; Brittelli, et al, J. Med. Chem., 1992; 35: 1156; Ann. Rep. Med. Chem., VoI 35, pp 135-144; Bio-org. Med. Chem. Lett, 1999; 9: 2679-84; Antibacterial & Antifungal Drug Discovery & Development Summit, Strategic Research Institute, June 28-29, 2001, Amsterdam, The Netherlands, Posters No. 1822, 1823, 1824, 1825, 1826, 1827, 1828, 1829, 1830, 1831, 1832, 1833 and 1834; 40^th Interscience Conference on Antimicrobial Agents and Chemotherapy, Sept 17-20, (2000), Toronto, Canada, and Posters No 1023, 1040, 1041, 1042, 1043, 1044,1045, 1046, 1047, 1048, 1049, 1050, and 1051; 41^st Interscience Conference on Antimicrobial Agents and Chemotherapy, December 16-19, (2001), Chicago, USA.

Summary of the Invention

The synthesis, identification and profiling of oxazolidinone molecules that have activity against multiply-resistant Gram-positive pathogens like MRSA, VRE and PRSP are provided. Some of these molecules have activity against MDR-TB and MEAI strains, while others have significant activity against important anaerobic bacteria.

Processes for the synthesis of phenyloxazolidinone derivatives which can exhibit significant antibacterial activity against multiply resistant gram positive pathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections are provided. In accordance with one aspect of the invention, there are provided compounds having the structure of Formula I

FORMULA I

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites.

Ri can be NHC(=O)R₂; NHC(=S)R₂; NH-R₄; NHCHO; NHC(=O)OR₃; OC(=0)R₃; NR₃; SR₃; or OR₃, [wherein R₄ is heteroaryl, heterocyclyl or aryl; R₃ is hydrogen, alkyl or R₂; and R₂ is acyl, aryloxy, thiocarbonyl, substituted thiocarbonyl, amines, substituted amines, aryl, heteroaryl, heterocyclyl, aralkyl or aralkenyl, (wherein the heteroaryl and heterocyclic rings may contain one or more heteroatoms selected from O, S and N; the aryL, heteroaryl, aralkyl and aralkenyl rings may be unsubstituted or substituted with one or more of alkyl, halogen, nitro, amino or methylenedioxy, and also when R₁ is NR₃, SR₃ or OR₃ then the hetero atoms, together with R₃ can form a heterocyclyl or a heteroaryl ring)].

U can be hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, or C_1-12 alkyl substituted with one or more of F, Cl, Br, I. n is an integer 0, 1, 2 or 3.

Q can be O, S or NR₁₁ (wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl).

G can be hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH=N-OR₁₀, -C=CH-R₅, OR₅, SR₅, - C(R₉)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, (wherein R₄ is as defined above); (wherein R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl, or C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH); (wherein R₆ and R₇ are independently hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl or Ci_-6 alkoxy); (wherein R₈ and R₉ are independently hydrogen, C_1-6 alkyl, F, Cl, Br, I, or C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₅, SR₄, or NR₆₃R₇); and (wherein R_1O is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, aryl or heteroaryl).

Compounds disclosed herein can be useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic and Gram-positive bacteria, including multiply-antibiotic resistant Staphylococci and Streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other Mycobacterium species.

For preparing pharmaceutical compositions from the compounds described herein, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. A solid carrier can be one or more substance which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound. For the preparation of tablets, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient. Suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, capsules can be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, for example, natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other well-known suspending agents.

Ointment preparations can contain pharmaceutically acceptable salts of a compound of Formula I with a physiologically acceptable carrier. The carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.

The pharmaceutical preparation can be in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient. In therapeutic use as agents for treating bacterial infections the compounds utilised in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. The dosages, however, may be varied dependirxg upon the requirements of the patient and the compound being employed. Determination! of the proper dosage for a particular situation is within the smaller dosages, which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.

In another aspect, processes for the synthesis of compounds of Formula I are provided. Pharmaceutically acceptable non-toxic acid addition salts of the compounds of Formula I disclosed herein may be formed with inorganic or organic acids, by methods well known in the art.

The present invention also includes within its scope prodrugs of the compounds of Formula I. In general, such prodrugs will be functional derivatives of these compounds, which readily get converted in vivo into defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan of ordinary skill in the art.

Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters ₃ enantiomers, diastereomers, N-oxides, polymorphs, prodrugs, metabolites in combination with a pharmaceutically acceptable carrier and optionally included excipients are also provided.

Other aspects will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention.

Detailed Description of the Invention

The compounds described herein are represented by general Formula I, and may be prepared by techniques well known in the art and familiar to the skilled synthetic orgaαnic chemistry. In addition the compounds of the present invention may be prepared by the; following reaction sequences generally depicted in Schemes I, II, III, IV, V and VI. SCHEME

In Scheme I, the compound of Formula II (wherein U is as defined earlier) is reacted with the compound of Formula III (wherein P is an amine protecting group for example tert-butyloxycarbonyl (t-BOC), 9-fluorenylmethoxycarbonyl (Fmoc) and het represents heterocyclic group), (path a), to give compound of Formula IV. The reaction can be carried out in presence of a base such as sodium hydride or lithium hydride aααd an organic solvent such as dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsulphoxide or ethylene glycol.

The compound of Formula IV is further deprotected and reacted in situ with compound of Formula V (path a') or VI (path b') to give compounds of Formulae ^"V⁷II and VIII, respectively (wherein G, Q and het are as defined earlier and hal is halogen selected from Cl, Br, or I). The deprotection of Formula IV can be carried out in the presence of solvent such as dichloromethane, diethyl ether or chloroform in the presence of a reagent such as trifluoroaceticacid or ethanolic hydrochloric acid.

The reaction of the deprotected compound with a compound of Formula V (jpath a') can be carried out in the presence of a base such as disopropyl-ethylamine or potassium carbonate in a solvent such as acetonitrile or dimethylformarnide to give a compound of Formula VII.

Alternatively the reaction of the deprotected compound with a compound of Formula VI (path b') can be carried out in the presence of a reducing agent such as triacetoxy sodium borohydrϊde or sodium cyanoborohydride and in a solvent such as tetrahydrofuran, ethyl acetate, isopropyl alcohol, dichloromethane or the like, to give compound of Formula VIII.

For the preparation of compound of Formula XI, a compound of Formula IΣ can be reacted with compound of Formula IX (where R_a is alkyl or aryl)(path b). The reaction can be carried out in presence of a base such as sodium hydride or lithium hydride and in an organic solvent such as dimethyl formamide, acetonitrile, dimethylsufoxide or ethylene glycol to give compound o Jf Formula X, which can be deprotected in the presence of a solvent such as dichloromethane or chloroform in presence of a reagent such as trifluoroaceticacid and ethanolic hydrochloric acid. The deprotected compound is further reacted with a compound of Formula ^"V

(wherein G, Q & hal are as defined earlier) in the presence of a base such as diisopropylethylamine or potassium carbonate and an organic solvent such as acetonitrile or dimethylformamide to obtain compound of Formula XI (wherein G, Q &s R_a are as defined earlier).

SCHEME Il

In Scheme II, compound of Formula XIV can be prepared by following either of the two paths indicated;

Path a: A compound of Formula XII (wherein U is as defined earlier) is reacted with a compound of Formula XIII (wherein Rb can be O-het or het and het is as defined earlier) to give a compound of Formula XIV₅, in the presence of a coupling agent such as diethyl azodicarboxylate or disopropyl azodicarboxylate, and a suitable catalyst such as triphenylphospine, trimethyl phosphine, tributyl phosphine or di-1- adamantyl(butyl)phospbine in a solvent such as tetrahydrofuran or dimetfrylforrnamide.

Path b: A compound of Formula II is reacted with a compound of Formula XIII( where R_b is as defined earlier) to give a compound of Formula XIV, in the presence of a base such as sodium hydride or lithium hydride and an organic solvent such as dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsufoxide or ethylene glycol. Further, the compound of Formula XIV can be deprotected in the presence of a solvent such as with dichloromethane or chloroform in the presence of reagents such as trifluoroaceticacid and reacted with a compound of Formula VI (wherein G, Q & hal are as defined earlier) in presence of a base such as diisopropoylethylamiine or potassium carbonate and organic solvents such as acetonitrile or dimethylformamide to obtain a compound of Formula XV (wherein G, Q & Rb are as defined earlier).

SCHEME III

In Scheme III, the compound of Formula XVI (prepared as described in PCT WO 02/06278) (wherein G, Q, U and n are as defined earlier) is hydrolysed with hydrochloric acid to yield the corresponding amine of Formula XVII, which on reacting with compound of Formula XVIII (where R₀ is alkyl or aryl) in the presence of a base such as triethylamine or dispropylethylamine gives a compound of Formula XIX (Path a).

Alternatively amine of Formula XVII is converted to corresponding isothiocyanate of Formula XX (Path b), by reacting with carbon disulfide and ethyl chloroformate in the presence of a base such as triethylamine, diisopropoylethylamine or pyridine and an organic solvent such as dichloromethane, dichloroethane or chloroform. The isothiocyanate of Formula XX on reaction with a compound of Formula XXI (R_f and K._g can be selected from hydrogen or alkyl group) gives a compound of Formula XXI, in trxe presence of a base such as triethylamine or diisopropoylethylamine and an organic solvent such as dichloromethane, dichloroethane or methanol.

Alternatively, the amine of Formula XVII is converted to (un)substituted thiourea of Formula XXTV(Path c), on reaction with (un)substituted isothiocyanate of Formula X)CIII (R_d is alkyl or aryl), in the presence of a base such as triethylamine, diisopropylethyl amine or sodium hydride.

SCHEME IV

In Scheme IV, the compound of Formula XVII (wherein G, Q, U and n are as defined earlier) can be reacted with the acid of Formula XXV (wherein R^ is a substituted heterocyclic group) to give a compound of Formula XXVI (Path a) in the presence of a coupling agent like 1,3-dicyclohexylcarbodimide (DCC) or l-ethyl-3-(3'- dimethylaminopropyl)carbodimide hydrochloride (EDC) in the presence of an additive such as 1-hydroxybenzotriazole (HOBt)or l-hydroxy-7-azabenzotriazole (HOAt) and a base such as N-methylmorpholine, diisopropoylethylamine, or collidine in solvent such as dimethylformamide, tetrahydrofuran or acetonitrile. The compound of Formula XXVII is prepared by reacting a compound of Formula XVII with ethylformate at reflux temperature (path b) to give a compound of Formula XXVIII.

SCHEME V

Scheme V, a compound of Formula XII (wherein U is as defined earlier) is O- protected with compound of Formula XXVIII (where R_x can be alkyl or aryl) to form a compound of Formula XXIX which can be deprotected with ethanolic hydrochloric acid or trifluoroacetic acid to yield a compound of Formula XXX. The compound of Formula XXX can be reacted with a compound of Formula V in the presence of a base such as diisopropoylethylamine, triethylamine or potassium carbonate and an organic solvent such as acetonitrile or dimethylformamide to yield a compound of Formula XXXI (where G, Q & R_x are as defined earlier) which is hydrolysed with hydrochloric acid to give compound of Formula XXXII (where G & Q are as defined earlier).

10

SCHEME Vl

In Scheme VI, Path a: The compound of Formula XXXII (wherein G, Q and U are as defined earlier) can be reacted with a compound of Formula XXXIII in the presence of a base such as sodium hydride or lithium hydride and an organic solvent such as dimethyl

25. formamide, acetonitrile, dimethylacetamide, dimethylsufoxide or ethylene glycol (where R_h is aryl/ alkyl and T is oxygen or sulphur) to give a compound of Formula XXXIV.

Path b: A compound of Formula XXXVI can be prepared by reacting a compound of Formula XXXII with compound of Formula XXXV (where Rpalkyl/aryl & hal is as defined earlier) in the presence of a base such as sodium hydride or lithium hydride and an

30 organic solvent such as dimethyl formamide, acetonitrile, dimethylacetamide or dimethylsufoxide. Path c: A compound of Formula XXXVIII can be prepared by reacting a compound of Formula XXXII with a compound of Formula XXXVII (where R, is alkyl/aryl) in the presence of a coupling agent such as diethyl azodicarboxylate and a catalyst such as triphenylphospine, trimethyl phosphine, tributyl phosphine or di-1- adamantyl(butyl)phosphine in a solvent such as dimethylformamide, toluene or tetrahydrofuran.

An illustrative list of particular compounds according to the invention and capable of being produced by the above mentioned schemes include:

(5,S)-3-(3-fluoro-4-{4-[(5-nitro-2-thienyl)methyl]piperazin-l-yl}phenyl)-5-[(isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 1);

(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}phenyl)-5-|](isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 2);

(5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 3); (55)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- ylamino)methyl]-l,3-oxazolidm-2-one (Compound No. 4);

(5R)-5-[(ethylthio)methyl]-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)ρiρerazm- 1 -yl]ρhenyl} -1,3- oxazolidin-2-one (Compound No. 5);

(5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]phenyl} -5-[(heptylthio)methyl]- l,3-oxazolidin-2-one (Compound No. 6);

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(2- naphthylthio)methyl]-l,3-oxazolidin-2-one(Comρound No. 7);

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 8); 5-[4-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3- yl}phenyl)piρerazin-l-yl]-2-furaldehyde (Compound No. 9);

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(pyriclin-4- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 10); (5R)-3-{3-fluoro-4-[4-(5-ni1xo-2-thienyl)piperazin-l-yl]plienyl}-5-[(pyridin-3- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 11);

(5R)-3-{3-flαoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(pyrazin-2- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 12); (5R)-3- {3-flu-oro-4- [4-(5 -nitro-2-thienyl)piperazin- 1 -yl]phenyl} -5 - [(pyridin-2- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 13);

1 -[((5 S)-3- {3 -fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 , 3 -oxazolidin- 5-yl)methyl]pyridin-2(lH)-one (Compound No. 14);

5-[4_(4- {(5S) -5-[(l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-l ,3 -oxazolidin- 3-yl}-2-fluorophenyl)piperazin-l~yl]-2-furaldehyde (Compound No. 15);

2-[((5S)-3-{3 -fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l-3-oxazolidin- 5-yl)methyl]-lH-isoindole-l,3(2H)-dione (Compound No. 16);

(5R)-3-{3-flιxoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-(lH-imidazol-l- ylmethyl)-l,3-oxazolidin-2-one (Compound No. 17); phenyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyljcarbamate (Compound No. 18); ethyl [((5S)-3 - {3-fluoro-4-[4-(5-nitro-2-furyl)piperazin-l -yl]ρhenyl} -2-oxo- 1 ,3- oxazolidin-5-yl)methyl]carbamate (Compound No. 19); methyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl] carbamate (Compound No. 20); methyl [((5S>3 - {3 -fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 ,3 - oxazolidin-5-yl)methyl]carbamate (Compound No. 21); ethyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazin-l-yl]ρhenyl}-2-ox: o-l,3- oxazolidin-5-yl)methyl] carbamate (Compound No. 22); N-cycloρropyl-N'-[((5S)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)ρiρerazin-l-yl]phenyl} -2- oxo-l,3-oxazolidin-5-yl)methyl]thiourea (Compound No. 23);

N-(4-chlorophenyl)-N'-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- l-yl]phenyl}- 2-oxo-l,3-ox:azolidin-5-yl)methyl]thiourea (Compound No. 24); N'-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piρerazin-l-yl]ρhenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]-lSr,N-diniethyltliiourea (Compound No. 25);

N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]pheiiyl}-2-oxo-l,3-oxazolidin- 5~yl)methyl]thiourea (Compound No. 26) N-[((5 S)-3- {3-fluoro-4- [4-(5 -nitro-2-thienyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 ,3 -oxazolidin- 5-yl)methyl]-N'-methylthiourea (Compound No. 27); tert-butyl 2-({[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]ρhenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl] amino} carbonothioyl)hydrazinecarboxylate (Compound No. 28);

N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin- 5-yl)methyl]-N'-isopropylthiourea (Compound No. 29);

N-{[(5S)-3-(3-fluoro-4- -(4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}ρhenyl)-2-oxo-l,3- oxazolidin-5-yl]methyl} -S-nitrothiophene^-carboxamide (Compound No. 30);

N-{[(5S)-3-(3-fluoro-4- {4-[(5-mtxo-2-furyl)methyl]piρerazin-l-yl}phenyl)-2-oxo-l,3- oxazolidin-5-yl]methyl} -5-nitro-2-furamide (Compound No. 31); 5-bromo-N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]pipeτazin-l-yl}phenyl)-2- oxo-l,3-oxazolidin-5-yl]methyl}-2-raramide (Compound No. 32);

N-{[(5S)-3-(3-fluoro-4- {4-[(5-mtro-2-furyl)methyl]piperazin-l-yl}phenyl)-2-oxo-l,3- oxazolidin-5-yl]methyl}- formamide (Compound No. 33);

((5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yljphenyl} -2-oxo- 1 ,3-oxazolidin-5- yl)methyl acetate (Compound No. 34);

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazm-l-yl]ph.enyl}-5-(hydroxymethyl)-l,3- oxazolidin-2-one (Compound No. 35);

((5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 ,3-oxazolidin-5- yl)methyl (phenylsulfonyl)carbamate (Compound No. 36); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l₅3-oxazolidin-5- yl)methyl [4-(trifluoromethyl)phenyl]carbamate (Compound No. 37);

((5R)-3- {3-fluoro-4-[4- (5-nitro-2-thienyl)piperazin- 1 -yljphenyl} -2-oxo- 1 ,3-oxazolidin-5- yl)methyl (4-fluorophenyl)carbamate (Compound No. 38); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin-5- yl)methyl [(2-methylphenyl)sulfonyl]carbamate (Compound No. 39);

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin-5- yl)methyl [(4-methylphenyl)sulfonyl]carbamate (Compoumd No. 40) ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin-5- yl)methyl-n-butylcarbamate (Compound No. 41);

O-[((5R)-3-{3-jEluoro-4-[4-(5-nitro-2-tbienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl] (4-chlorophenyl)thiocarbamate (Compound No. 42);

O-[((5R)-3- {3-Jfluoro-4-[4-(5-nitro-2-thienyl)ρiperazin-l -yljphenyl} -2-oxo-l ,3- oxazolidin-5-yl)methyl] (2,4-difluorophenyl)thiocarbama.te (Compound No. 43);

O-[((5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l -yl]phenyl} -2-oxo-l ,3- oxazolidin-5-yl)methyl] isopropylthiocarbamate (Compound No. 44);

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazm-l-yl]phenyl}-5-(methoxymetliyl)-l,3- oxazolidin-2-one (Compound No. 45); (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-{[(6-methylpyridin-2- yl)oxy]methyl}-l,3-oxazolidin-2-one (Compound No. 46).

Ten different Cores have been identified, namely

(5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- ylωnino)methyl]-l,3-oxazolidin-2-one (Core 1); (5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- ylaminojmethyl] -1 ,3 -oxazolidin-2-one (Core 2);

(5R)-5-[(ethylthio)methyl]-3-(3-fluoro-4-{4-[(5~nitro-2-thienyl)methyl]piperazin-l- yljphenyl)- 1,3- oxazolidin-2-one (Core 3);

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]jphenyl}-5-[(isoxazol-3- yloxy)methyl]-l,3-oxazolidin-2-one (Core 4);

(5R)-5-[(ethylthio)methyl]-3-{3~fluoro-4-[4-(5-nitro-2-tfιienyl)piperazin-l-yl]phenyl}-l,3- oxazolidin-2-one (Core 5);

N-cyclopropyl-N'-ffftSJS-β-fluoro^-β-β-nitro^-thi&nylJpiperazin-l-ylJphenylJ^-oxo- 1, 3 -oxazolidin-5-yl)methyl] thiourea (Core 6); N'-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2 '-oxo-1, 3-oxazolidin- 5-yl)methyl]-N,N-dimethylthiourea (Core 7);

N-{[(5S)~3-(3-fluoro-4-{4~[(5-nitro-2-furyl)methyl]piperazin-l-yl}phe?nyl)-2-oxo-l,3- oxazolidin-5-yl] methyl} -5 -nitrothiophene-2-carboxamide (Core 8); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin-5- yl)methyl acetate (Core 9);

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin-5- yl)methyl (phenylsulfonyl) carbamate (Core 10).

The examples mentioned below demonstrate the general syntlxetic procedure as well as the specific preparation for the preparation for the preferred compound. The examples are given to illustrate the details of the invention and should, do not limit the scope of the present invention.

Example 1: Analogues of (5S)-3-(3-fluoro-4-{4-r(5-nitro-2-thienyl)rriethyl1piperazm-l- yl}phenyiy5-r(isoxazol-3-ylammo)methyri-l ,3-oxazolidin-2-one (Core 1) (5S)-3-C3-fluoro-4-{4-f(5-nitm-2-thienyl)methylJpiperazin-l-yl}phenyl)-5-f(isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 1)

Step a: Synthesis of (S)-N-(3- {3-Fluoro-4-[4-N-(tert-butoxycarbonyl)-piperazin- 1 - ylJphenyll-l-oxo-oxazolidin-S-ylmethy^-N-Isoxazol-S-yl-N-tert-butoxycarboxamide .

To a solution of tert-butyl 4-[2-fluoro-4-((5i?)-5-{[(methylsulfonyl)oxy]methyl}-2- oxo-l,3-oxazolidin-3-yl)phenyl]piperazine-l-carboxylate (prepared axcording to the procedure given in WO 93/23384) (1.5g) in dimethylformamide(20ml) was added ter- butyl-isoxzol-3-yl-carbamate(0.65g) in presence of sodium hydride at O⁰C and the reaction mixture was heated at 80° C for I hour. The reaction mixture was cooled, quenched with cold water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound(l .52g)

Step b: Synthesis of tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3-yla3nmo)methyl]-2-oxo- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate:

To a solution of (S)-N-(3-{3-Fluoro-4-[4-N-(tert-butoxycarbonyl)-piperazin-l- yl]phenyl}-2-oxo-oxazolidin-5-ylmethyl)-N-Isoxazol-3-yl-N-tert-butoxycarboxamide (0.35 g) in dichloromethane (8 ml) was added trifluoroacetic acid (3 ml). The reaction mixture was stirred for 2 hrs. The resulting reaction mixture was evaporated, the residue left was taken in ethyl acetate. The solution was made alkaline with ammonium hydroxide solution. The ethyl acetate layer was then washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. (0.17gm)

Step c: Synthesis of (5S)-3-(3-fluoro-4-{4-[(5-nitro-2-thienyl)methyl]piperazin-l- yl}phenyl)-5-[(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one:

To a solution of tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3-ylamino)methyl]-2- oxo-l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (0.17 g) obtained from Step b above in tetrahydrofuran was added 5-nitro-2-thiophene carboxaldehyde (0.081 g) and the reaction mixture was stirred for 30 min followed by the addition of sodium triacetoxy borohydride (0.4 g) and further stirred for 17 hrs. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue left was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography eluting in 1% methanol-dichloromethane to get the title compound as a sticky solid (0.04gm)

¹H NMR (CDCl₃) δppm: 8.06 (s, IH), 7.80 (d, IH), 7.44 (dd, IH), 7.09 (dd, IH), 6.9 (m, 2H), 5.86 (s, IH), 4.98 (m, IH), 4.32 (t, IH), 4.06 (t, IH), 3.78 (m, 4H), 3.59 (m, IH), 3.10 (m, 4H), 2.72 (m, 4H),

Mass: M+H= 503, M+Na= 525

(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}phenyl)-5-[(isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 2)

To a solution of tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3-ylammo)methyl]-2- oxo-l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (0.4g) obtained from Step b from compound 1 in tetrahydrofuran(lθml) was added 5-nitro-2-furaldehyde (0.085g) .The reaction mixture was stirred for 30 min followed by the addition of sodium triacetoxy borohydride (0.47 g) and further stirred for 17 hrs. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue left was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography eluting in 1% methanol-dichloromethane to get the title compound as a sticky solid. (O.lg)

¹H NMR (CDCl₃) δppm: 8.06 (s, IH), 7.43 (dd, IH), 7.07 (dd, IH), 6.92 (t, IH), 6.5 (bs, IH), 5.86 (s, IH), 4.92 (m, IH), 4.31 (m, IH), and 4.05. (t, IH), 3.9-3.5 (m, 3H), 3.09 (m,4H), 2.72 (m, 4H);

Mass: M+H= 487.3, M+Na=-509.3

Example 2: Analogues of (5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazm-l- yl]phenyl}-5-(^"(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one (Core 2)

(5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]plienyl}-5-[(isoxazol-3- yIamino)methyl]-l,3-oxazolidin-2-one (Compound No.3).

To the solution of compound tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3- ylamino)methyl]-2-oxo- 1 ,3-oxazolidin-3-yl}phenyl)piperazine- 1 -carboxylate obtained from the Step b of Compound No. 1, in acetonitrile (10 ml) was added 2-bromo-5-nitro- thiophene , in presence of N-ethyl-diisopropylamine (1.49 g). The reaction mixture was heated at 60 ⁰C for 17 hrs and the resulting solution was evaporated under reduced pressure. The residue left was taken in dichloromethane, w^ashed with water, dried over anhydrous sodium sulphate and evaporated. The residue was purified by column chromatography using 1% methanol-dichloromethane as eluant. The product was sonicated in ether and filtered to get the title compound (0.O43 g). Melting point = 234-238⁰C.

¹H NMR (DMSO) δppm: 8.38 (s, IH), 7.95 (d, IH), 7.53 (dd, IH), 7.21 (dd, IH)₅ 7.12 (t, IH), 6.55 (t, IH), 6.41 (d, IH), 6.00 (s, IH), 4.85 (m, IH), 4.13 (t, 2H), 3.79 (m, 2H), 3.13(m, 4H);

Mass: M+H = 489.3, M+Na = 511.3, M+K = 527.4, M-ND₂= 443.3 (5S)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 4)

To a solution of compound tert-butyl 4-(2-fluoro-4-{(5S)-5-[(isoxazol-3- ylamino)methyl]-2-oxo-l,3-oxazolidin-3-yl}phenyl)pipera2;ine-l-carboxylate (0.35 g) obtained from the Step b of Compound No. 1, in N,N-dimethylformamide (15 ml) was added potassium carbonate (0.27 g) and 2-bromo-5-nitro-furan (0.15 g) and stirred for 2 hrs. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated lander reduced pressure. The residue was purified by column chromatography using 2°/o methanol- dichloromethane as eluant. The product was sonicated in ether and filtered to get the title compound (0.2 g). Melting point: 216-219 ⁰C

¹H NMR (CDC13+ DMSO) δppm: 8.15 (s,lH), 7.60 (d,lH), 7.54 (dd,lIT), 7.14 (dd,lH), 7.02 (t, IH), 5.95 (s,lH), 5.71 (d,lH), 4.90 (m,lH), 4.11 (t,2H), 3.83 (t, 2H), 3.68 (m, 4H), 3.18 (m, 4H)

Mass: M+H= 473.4, M+Na=495.2, M+K= 511.2 Example 3 : Analogues of (5RV5-[(ethylthio)rnethyl1-3- {3-fluoro-4-r4-f 5-nitro-2- thienvDpiperazm-l-yllphenyl>-l,3-oxazolidin-2-one (Core 3)

(5R)-5-[(ethylthio)methyI]-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}- l,3-oxazolidin-2-one (Compound No. 5)

Step a: Synthesis of tert-butyl 4-f4-{f5R)-5-rfethylthio)methyl1-2-oxo-L 3-oxazolidin-3- yl}-2-fluorophenyl)piperazine-l-carboxylate

To a solution of tert-butyl 4-[2-fluoro-4-((5i?)-5-{[(methylsulfonyl) oxy] methyl}- 2-oxo-l,3-oxazolidin-3-yl)phenyl]piperazine-l-carboxylate (prepared according to the procedure given in WO 93/23384) (Ig) in dimethylformamide (20 ml) was added sodium ethane thiolate (0.31 g). The reaction mixture was heated at 55 ⁰C for about 5-6 hrs and then quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. M The residue was purified by column chromatography using dichloromethane. The pxoduct was recrystallized from dichloromethane and hexane to yield of title compound (0.5 g).

Step b: Synthesis of (5RV5-rrethylthio)methyll-3-{3-fluoro-4-r4-r5-nitro-2- thienvDpiperazin- 1 -yl]phenyl> - 13 -oxazoridin-2-one

To a solution of tert-butyl 4-(4-{(5R)-5-[(ethylthio)methyl]-2-oxo-l,3-oxazolidin- 3-yl}-2-fiuorophenyl)piperazine-l-carboxylate (0.23g) obtained ftomsrtep a above in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirredL for 2 hrs, the solvent was removed under reduced pressure. To the residue in acetonitrile (15ml) was added 2-bromo-5-mtro-thiophene (0.13g) in presence ofN-ethyl-diisopropylamine (0.97ml) and heated at 60 ⁰C for 17 hrs. and evaporated under reduced pressure. The residue was then taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure and the residue was purified by column chromatography, eluting in 1% methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.14g). Melting point: 166-167 ⁰C.

¹H NMR (CDC13) δppm: 7.8 (d, IH), 7.50 (dd, IH), 7.15 (dd, IH), 6.96 (t, IH), 6.01 (d, IH), 4.79(m, IH), 4.10 (t, IH), 3.84(m, IH), 3.54 (m, 4H), 3.21(m, 4H), 2.97(m, IH), 2.86 (m, IH), 2.66 (m, 2H), 1.29 (t, 3H),

Mass: M+l = 467.3, M+NH₄ ⁺= 484, M-NO₂ = 421.4 (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5- [(heptylthio)methyl]-l,3-oxazolidin-2-one (Compound No. 6)

Step a: Synthesis of tert-butyl 4-α-fluoro-4-{(5R)-5-rCheρtylthio)methyll-2-oxo-l,3- oxazolidm-3-yl}phenyl)piperazme-l-carboxylate.

To a solution of tert-butyl 4-[2-fluoro-4-((5i?)-5-{[(methylsulfonyl) oxy] methyl} - 2-oxo-l ,3-oxazolidin-3-yl)phenyl]piperazine-l -carboxylate (prepared according to the procedure given in WO 93/23384) (Ig) in dimethylformamide (20 ml) was added sodium hydride (O.lg) and heptane-thiol (0.32g) and then heated at 55 ⁰C for 6 hrs. The reaction mixture was diluted with water. The product was precipitated washed with water to yield of title compound (0.9Ig). Step b: Synthesis of (5R)-3-(3-fluoro-4-r4-(5-nitro-2-thienyl)piperazin-l-vnphenvU-5- [(heptylthio)methyli - 1 ,3-oxazolidin-2-one

To a solution of tert-butyl 4-(2-fluoro-4-{(5R)-5-[(heptylthio)methyl]-2-oxo-l,3- oxazolidin-3-yl}phenyl)piperazine-l -carboxylate (0.4g) obtained from step a above in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 hours, the solvent was concentrated. To the residue in acetonitrile (20ml) was added 2-bromo-5- nitro-thiophene (0.19g) in presence of N-ethyl-diisopropylamine (Ig) and heated at 60 ⁰C for 17 hrs and evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1% methanol- dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.09Ig). Melting point: 119-12O ⁰C

¹H NMR (DMSO) δppm: 7.94 (d, IH), 7.55 (dd, IH), 7.24 (dd, IH), 7.12 (t, IH), 6.41 (d, IH), 4.87 (m, IH), 4.17 (t, IH), 3.78 (m, IH), 3.63 (m, 4H), 3.15 (m, 4H), 2.93 (m, 2H), 2.62 (m, 2H), 1.55 (m, 2H), 1.27 (m, 8H), 0.87 (t, 3H). Mass:537

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yI]phenyl}-5-[(2- naphthylthio)methyl]-l,3-oxazolidin-2-one (Compound No. 7)

Step a: Synthesis of tert-butyl 4-(2-fluoro-4-{(5RV5-r(2-naphthylthio)methyll-2-oxo-L3- oxazolidin-3-vUphenvDpiperazme-l-carboxylate. To a solution of tert-bvAyl 4-[2-fluoro-4-((5i?)-5-{[(methylsulfonyl)oxy]methyl}-2- oxo-l,3-oxazolidin-3~yl)phenyl]piperazine-l~carboxylate (prepared according to the procedure given in WO 93/23384) (1.5g) in dry dimethyl formamide (20 rnL) and sodium hydride (0.25g) and 2-naphthalene-thiol (0.6Ig). The reaction mixture was heated at 80 ⁰C for 15 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was sonicated in ether to yield of title compound (0.43g).

Step b: Synthesis of (5R)-3-{3-fluoro-4-r4-(^'5-nitro-2-thienvnpiperazin-l-yllphenvU-5- r(2-naphthylthio)methyl]-l,3-oxazolidin-2-one To a solution of tert-butyl 4-(2-fluoro-4- {(5R)-5-[(2-naρhthylthio)methyl]-2-oxo- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate. (0.4g) obtained from step a above in dichloromethane(lθmi) was added trifluoroacetic acid (2ml) and stirred for 2 hours and concentrated The residue was taken in acetonitrile (15ml) and to it was added 2-bromo-5- nitro-thiophene (0.19g) in presence of N-ethyl-diisopropylamine (l.Olg). The reaction mixture was heated at 60 ⁰C for 2 hrs. The reaction mixture was evaporated and the residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was triturated in a mixture of 50% methanol-dichloromethane and filtered to get the title compound (0.2 g). Melting point: 212-214⁰C ¹H NMR (DMSO) δppm: 8.05- 7.75 (m, 5H), 7.6-7.45(m, 4H), 7.13 (m, 2H), 6.43 (d, IH), 4.9 (m, IH), 4.21 (m, IH), 3.83 (m, IH), 3.57 (m, 6H), 3.14 (m, 4H) Example 4: Analogues of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l- yl]phenyl}-5-[(isoxazol-3-yloxy)methyl]-l,3-oxazolidin-2-one (Core 4)

Method a:

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenvU-5-[(isoxazol-3- yloxyhnethyl] -1 ,3-oxazolidin-2-one ^Compound No. 8)

To a

4-(2-fluoro-4-{(5i?)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3- oxazolidin-3~yl}phenyl)piperazine-l-carboxylate (prepared by procedures similar to that in WO 99/64416 and WO 99/64417) (0.5Ig) in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 hours, the solvent was concentrated .To the residue, in acetonitrile (15ml) was added 2-bromo-5-nitro-thiophene (0.27g) in presence of N-ethyl-diisopropylamine (1.47g) and heated at 60 ⁰C for 17 hrs. The reaction mixture was then evaporated .The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 0.5% methanol-dichloromethane. Tlie product was sonicated in ether and filtered to get the title compound (0.72 g). Melting point: 201-202⁰C

¹H NMR (CDC13) δppm: 8.16 (s, IH), 7.8 (d, IH), 7.62 (dd, IH), 7.14 (dd, IH), 6.02 (m, 2H), 5.03 (m, IH), 4.7-4.4 (m, 2H), 4.15 (t, IH), 3.96 (t, IH), 3.66 (m, 4H), 3.4(m, 4H),

Mass: M +1 = 490.4, M + Na = 512.2, M-NO₂ = 444.5 5-[4-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyI]-2-oxo-l,3-oxazoIidin-3- yl}phenyl)piperazin-l-yI]-2-furaldehyde. (Compound No. 9) (By method a)

To a solution of tert-butyl 4-(2-fluoro-4-{(5i?)-5-[(isoxazol-3-yloxy)methyL]-2- oxo-l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (prepared by procedures similar to that in WO 99/64416 and WO 99/64417)(0.3g)in dichloromethane(lθml) was axlded trifluoroacetic acid (2ml) and stirred for 2 hours and the solvent was concentrated -To the residue, in acetonitrile (15ml) was added 5-bromo-2-furaldehyde (0.13g) in presence of N-ethyl-diisopropylamine (0.84g) and heated at 80 ⁰C for 24 hrs. The solvent was concentrated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1% methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.02g). Melting point: 161-163⁰C

¹H NMR (DMSO) δppm: 9.01(bs, IH), 8.69 (d, IH), 7.55 (m, 2H), 7.22 (dd, IH), 7.13 (t, IH), 6.38 (d, IH), 5.70 (d, IH), 5.07 (m, IH), 4.47 (m, 2H), 4.18 (t, IH), 3.91 (m, IH), 3.55 (m, 4H), 3.10 (m, 4H); Mass: M+l = 457, M+Na = 479.2;

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(pyridin-4- yloxy)methyl]-l,3-oxazolidin~2-one (Compound No. 10) (by method a)

To a solution of tert-butyl 4-(2-fluoro-4-{(55)-2-oxo-5-[(pyridin-4-yloxy)methyl]- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (prepared by procedures similar to that in WO 99/64416 and WO 99/64417) (QAg) in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 hours and the solvent was concentrated. The residue was taken into acetonitrile (15ml) na dot it was added 2-bromo-5-nitro-thiophene (0.2g) in presence of N-ethyl-diisopropylamine (Ig) and heated at 60⁰C for 17 hrs. The solvent was and the solvent was evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure and purified by column chromatography, eluting in 1% methanol- dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.2 g) Melting point: 221-223⁰C ¹H NMR (CDCl₃ + DMSO) δppm: 8.41 (m, 2H), 7.83 (d, IH), 7.57 (dd, IH), 7.19 (dd,

IH), 7.05 (t, IH)₅ 6.92 (m, 2H), 6.24 (d, IH), 5.09 (m, IH), 4.3 (m, 3H), 3.98 (t, IH), 3.61 (m, 4H), 3.23 (m, 4H)

Mass: M+H = 500.3, M+Na = 522.3

(5RV3-(3-fluoro-4-r4-(5-nitro-2-thienvDpiperazin-l-yl1phenyl>-5-r(pyridm-3- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 11) (by method a)

To a solution of tert-butyl 4-(2-fluoro-4-{(55)-2-oxo-5-[(pyridin-3-yloxy)methyl]- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (prepared by procedures similar to that in WO 99/64416 and WO 99/64417) (0.35g), in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 hours, the solvent was concentrated. The residue was taken in acetonitrile (10ml) and to it was added 2-bromo-5-nitro-thiophene

(0.18g) in presence of N-ethyl-diisopropylamine (0.95g). The reaction mixture was heated. at 60⁰C for 48 hrs and the solvent was evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.96 g).

Melting point: 199-205⁰C

¹H NMR (DMSO) δppm: 8.32 (m, IH), 8.21 (t, IH), 7.95 (d, IH), 7.57 (dd, IH), 7.44 (dd, IH), 7.38 (m, IH), 7.24 (dd, IH), 7.16 (t, IH), 6.42 (d, IH), 5.07 (m, IH), 4.3-4.4 (m, 2H), 4.2 (t, IH), 3.92 (t, IH), 3.62 (m, 4H), 3.15 (m, 4H)₅ Mass: M +1 = 500.1, M+NTa = 522.2

(^"5RV3-{3-fluoro-4-[4-(5-rLitro-2-thienvDpiperazin-l-yl1phenyl}-5-[(pyrazin-2- yloxy)methyl1-l,3-oxazolidm~2-one (Compound No. 12) (by method a)

To a solution of tert-butyl 4-(2-fluoro-4-{(5R)-2-oxo-5-[(pyrazin-2-yloxy)methyl]- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (prepared by procedures similar to that in WO 99/64416 and ^"WO 99/64417) (0.26g), in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 hours, the solvent was concentrated. To the residue, in acetonitrile (lOml) was added 2-bromo-5-nitro-thiophene(0.13g) in presence of N-ethyl-diisopropylamine (0.7Ig). The reaction mixture was heated to 60 ⁰C for 24 hrs and the solvent was evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1% methanol- dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.06 g). Melting point: 159-167⁰C ¹H NMR (CDCl₃) δppm: 8.28 (s, IH), 8.21 (d, IH), 8.09 (d, IH), 7.8 (d, IH), 7.52 (dd, IH), 7.18 (dd, 1 H), 6.97 (t, IH), 6.01(d, IH), 5.3 (m, IH), 4.61(m, 2H), 4.17 (t, IH), 3.96 (t, IH), 3.55 (m, 4H), 3.22 (m, 4H),

Mass:M+l = 501.3, M+N^"a = 523, M-NO₂= 455.1 (5R)-3-{3-fluoro-4-[4-(5-iiiti~o-2-thienyl)piperaziii-l-yl]phenyl}-5-[(pyridin-2- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 13). (by method a)

To a solution of tert-tmtyl 4-(2-fluoro-4-{(5S)-2-oxo-5-[(pyτidin-2-yloxy)methyl]- l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (0.25g)(prepared by procedures similar to that in WO 99/64416 and WO 99/64417),in acetonitrile (2OmI) was added 2- bromo-5-nitro-thiophene (0.12g) in presence of N-ethyl-diisopropylamine (0.7g). The reaction mixture was heated at 60 ⁰C for 17 hrs. and the solvent wa.s evaporated. The residue was taken in dichloroxnethane, washed with water, dried o^er anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1 % methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.07 g). Melting point: 194-197⁰C

¹H NMR (DMSO) δppm: 8.20 (d, IH), 7.99 (d, IH), 7.76 (t, IH), 7.59 (dd, IH), 7.27 (dd, IH), 7.16 (t, IH), 7.05 (t, IH), 6.88 (d, IH), 6.46 (d, IH), 5.09 (m, IH), 4.55 (m, 2H), 4.22 (t, IH), 3.94 (t, IH), 3.66 (m, 4H), 3.17 (m, 4H)

Mass: M+l=500.5, M+Na - 522.2, M-NO2 = 454.5 l-[Y(5R)-3- {3-fluoro-4-[4-(5 -mtro-2-thienvDpiperazin-l-yl]phenyl> -2-oxo-l ,3-oxazolidin- 5-yl)methyllpyridin-2(lHVone (Compound No. 14). (method a)

To a solution of tert-hutyl 4-(2-fluoro-4-{(5S)-2-oxo-5-[(2-oxopyridin-l(2H)- yl)methyl]-l,3-oxazolidin-3-yl}phenyl)piperazine-l-carboxylate (Prepared according to Poster No. 1825, 40^th ICAAC, 2000) (0.35g),in acetonitrile (20ml> was added 2-bromo-5- nitro-thiophene (0.18g) in presence of N-ethyl-diisopropylamine (O.95g). The reaction mixture was heated at 60⁰C for 24 hrs and the solvent was evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydroiαs sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1% methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.15 g). Melting point: 220 ⁰C (dec).

¹H NMR (DMSO) δppm: 7.96 (d, 1Η), 7.68 (d, 1Η), 7.49 (m, 2Η), 7.16 (m, 2H), 6.42 (m, 2H), 6.27 (t, IH), 4.99 (m, IH), 4.4-4.10 (m, 3H), 3.85 (m, IH), 3 .62 (m, 4H), 3.14 (m, 4H) Mass: M+l= 500.3, M-NO₂ = 454.1 Method b:

5-[4-(4-{(5S)-5-[(l ,3-dioxo-l,3-dihvdro-2H-isoindol-2-γl)methyl] '-2-oxo-l ,3 -oxazolidin-3- yl}-2-fluorophenyl)piperazin-l-yl]-2-furaldehvde (Compound No. 15) Step a: Synthesis of tert-butyl 4-(4-{(5S)-5-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl] -2-oxo-l, 3-oxazolidin-3-yl}-2-fluorophenyl)piperazine-l-carboxylate.

To a solution of tert-butyl 4-[2-fluoro-4-((5i?)-5-{[(methylsulfonyl)oxy]metliyl}-2-oxo- l,3-oxazolidin-3-yl)phenyl]piperazine-l-carboxylate (0.75 g) (prepared according to the procedure given in WO 93/23384) in dimethyl formamide (15 mL) was added potassium phthallimide (0.35 g) and heated at 60⁰C for 17 hrs. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to give the product (0.54g).

Step b: Synthesis of 5-F4-f4- {(5SV5-|Y13-dioxo-l 3-dihvdro-2H-isoindol-2-yl)methyl1-2- oxo-l^-oxazolidin-S-yll-Σ-fluorophenvDpiperazin-l-yll-Σ-furaldehyde.

To a solution of tert-butyl 4-(4-{(5S)-5-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluorophenyl)piperazine-l-carboxylate (0.2g) in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 hours, the solvent was concentrated. To the residue in acetonitrile (10ml) was added 5-bromo-2- furaldehyde (0.08g) in presence of N-ethyl-diisopropylamine (0.5g). The reaction mixture was heated at 80 ⁰C for 17 hrs. The reaction mixture was then evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by colunrn chromatography, eluting in 1% methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.17 g). Melting point: 131-135 (dec) 182-183 ⁰C

¹H NMR (DMSO) δppm: 8.98 (s, IH), 7.87 (m, 4H), 7.47 (m, 2H), 7.12 Cm, 2H), 5.7 (d, IH), 4.91 (m, IH), 4.15 (t, IH), 3.93 (m, 3H), 3.52 (m, 4H)₅ 3.06 (m, 4H),

Mass:M+l=519, M+Na = 541. 2-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]-lH-isoindole-l,3(2H)-dione (Compound No. 16). (method b) To a solution of 5-[4-(4-{(5S)-5-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]~2-oxo- 1 ,3-oxazolidin-3-yl} -2-fluorophenyl)piperazin- 1 -yl]-2-furaldeliyde obtained from step b of^" Compound No. 15 (0.35g) in dichloromethane(lθml) was added trifluoroacetic acid (2inl) and stirred for 2 hours, the solvent was concentrated. To the residue, in acetonitrile (10ml) was added 5-nitro-2-bromo-thiophene (0.16g) in presence of N-ethyl-diisopropylarnine (0.86g). The reaction mixture was heated at 60 ⁰C for 48 hrs. and the solvent was evaporated. The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1% methanol- dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.14 g). Melting point: 240 (dec), 254-257⁰C

¹H NMR (DMSO) δppm: 6.67 (m, 5H), 6.25 (dd, IH), 5.9 (m, 2H), 5.19 (d, IH), 3.70(m, IH), 2.95 (t, IH), 2.85-2.6 (m, 3H), 2.4 (m, 4H), 1.91 (m, 4H), Mass: M+l = 552, M+NH₄ ⁺ = 569, M+Na=574.1,M+K = 590.

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-(lH-imidazol-l- ylmethyl)-l,3-oxazolϊdin-2-one (Compound No. 17). (by method b)

Step a: Synthesis of tert-butyl 4-{2-fluoro-4-r(5R)-5-(lH-imidazol-l-vhnethvn-2-oxo- l,3-oxazolidin-3-yl]pfaenyl}piperazine-l-carboxylate. To a solution of tert-butyl 4-[2-fluoro-4-((5i?)-5- {[(methylsulfonyl)oxy]methyl) -

2-oxo-l,3-oxazolidin-3-yl)phenyl]piperazine-l-carboxylate (0.75 g) (prepared according to the procedure given in WO 93/23384) in dimethylformamide (10 ml), was added imidazole (0.1 Ig) and. sodium hydride (0.06 g 60% w/w suspension in mineral oil) and heated at 80 ⁰C for 10 hrs. The reaction mixture was diluted with water and ex/tracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to give the product (0.24gm)

Step b: Synthesis of (5R)-3-f3-fluoro-4-f4-(^'5-nitro-2-thienyl)piperazin-l-vnplienyl>-5- (lH-imidazol-l-ylmethyl)-l,3-oxazolidin-2-one

To a solution of tert-butyl 4-{2-fluoro-4-[(5i?)-5-(lH-imidazol-l-ylmethyl)-2-oxo- l,3-oxazolidin-3-yl]phenyl}piperazine-l-carboxylatey7-ø/M step a above (0.235g) in dichloromethane(lθml) was added trifluoroacetic acid (2ml) and stirred for 2 tiours, the solvent was concentrated. To the residue, in acetonitrile (15ml) was added 2-bromo-5- nitro-thiophene (0.126g) in presence of N-ethyl-diisopropylamine (0.9Ig). The reaction mixture was heated at 80 ⁰C for 17 hrs. The reaction mixture was then evaporated . The residue was taken in dichloromethane, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography, eluting in 1% methanol-dichloromethane. The product was sonicated in ether and filtered to get the title compound (0.085 g). Melting point: 222-223 ⁰C

¹H NMR (DMSO) δppm: 7.94 (d, IH), 7.79 (s, IH), 7.46 (dd, IH), 7.26 (s, IH), 7.15 (m, 2H), 6.97 (s, IH), 6.40 (d, IH), 4.98 (m, IH), 4.41 (m, 2H), 4.15 (t, IH), 3.78 (m, 1 H), 3.62 (m, 4H), 3.14 (m, 4H)

Mass: M+l = 454

Example 5: Analogues of phenyl [rr5S)-3-{3-fluoro-4-r4-(5-nitro-2-thienyl)piperazin-l- yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]carbarnate (Core 5) phenyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl] carbamate (Compound No. 18).

Step a: Synthesis of (5S)-5-(aminomethylV3-(3-fluoro-4-[^"4-(5-nitro-2-thienyl)piperazin- 1 -vilphenyl) - 1 ,3-oxazolidin-2-one.

To a solution of N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l- yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]acetamide (6.9 g) [prepared according to the procedure described in WO 04/014392) in absolute ethanol (140 ml), was added 31Sf hydrochloric acid (140 ml) and heated at 90-100 ⁰C for 8 hrs. The reaction mixture was cooled and made alkaline to pH 10-12 with 3N sodium hydroxide. The product was precipitated, filtered and washed with water and dried to yield of title compound (3.5 g) ¹H NMR (CDCl₃ + DMSO) δppm: 7.81 (d, IH)₅ 7,52 (IH), 7.14 (d, IH), 6.99 (t, 1 IH), 6.11 (d, IH), 4.72 (m, IH), 4.05 (t, IH), 3.87 (t, IH), 3.58 (m, 4H), 3.22 (m,4H), 3.10 (m, 2 H).

Step b: Synthesis of phenyl f((5S)-3-{3-fluoro-4-[^"4-(^'5-mtro-2-thienyl)piperazm-l- yl]phenvU -2-oxo-l ,3-oxazolidin-5-yl)methyl]carbamate.

To a solution of (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitro-2- thienyl)piperazin- 1 -yl]phenyl} - 1 ,3-oxazolidin-2-one (0.48 g) in dry dichloromethane (15 ml) was added phenylchloro formate (0.2g) in presence of triethylamine (0.25 g) and the reaction mixture was stirred for 17hrs. The reaction mixture was diluted with dichloromethane and the organic layer washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography to yield of title compound (0.18g) Melting point = 201.-202°C

¹H NMR (DMSO) δppm: 8.16 (t, IH), 7.95 (d,lH), 7.54 (dd,lH), 7.36 (m, 2H), 7.25-6.95 (m, 5H), 6.41 (d,lH), 4.79 (m, IH), 4.15 (t,lH), 3.82 (m, IH), 3.62 (rn,4H), 3.15 (m,4H),

Mass: M+H = 542.2 M+Na= 564.4 ethyl |^"(^"(^"5SV3-{3-fluoro-444-(^"5-nitro-2-furvnpiperazin-l-yllphenyl}-2-oxo-1.3-. oxazolidin-5-yl)methyl1carbamate (Compound No. 19)

To a solution of (5iS)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitτo-2-furyl)piperazin- l-yl]phenyl}-l,3-oxazolidin-2-one ( 0.4g)(prepared similar to the procedure described in the step a of Compound No. 18) in dry dichloromethane (10ml) under inert atmosphere was added ethylchloroformate 0.124g) in the presence of triethylamine ( 0.22g). The reaction mixture was stirred at room temperature for 17 hrs. and diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography using 1% methanol-dichloromethane. The crude product was sonicated in ether and filtered to get title compound.(105mg) Melting point: 103-104⁰C

¹H NMR (CDCl₃) δppm: 7.49-7.44(d,lH), 7.31-7.30(d,2H), 7.08-7.05(d,lH), 6.96- 6.90(t,lH), 5.08(bm,lH),4.75(m,lH), 4.14-4.10(t,lH), 4.07-4.01(t,lH), 3.98-3.96(t,lH), 3.91(m,2H), 3.80-3.75(t,lH), 3.60-3.48(m,3H), 3.23(s,4H), 2.92(s,4H), 1.25-1.20(t,3H).

Mass: M+l= 492 methyl IY(5S)-3- |3-fluoro-4-r4-C5-nitro-2-furyl)piperazin- 1 -yl]phenvU -2-oxo- 1 ,3- oxazoh^'dm-5-yl)methyl]carbamate (Compound No. 20)

To a solution of (55)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin- l-yl]phenyl}-l,3-oxazolidin-2-one ( 0.4g) (prepared similar to the procedure described in the step a of Compound No. 18) in dry dichloromethane (10ml) under inert atmosphere was added methyl chloroformate (0.12g) in the presence of triethylamine ( 0.2Ig). The reaction mixture was stirred at room temperature for 17 hrs. and then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified t>y column chromatography using 1% methanol-dichloromethane. The crude product was sonicated in ether and filtered to get title compound.(l lOmg) Melting point: 165.3-167 ⁰C

¹H NMR (CDCl₃) δppm: 7.50-7.45(d,lH), 7.33-7.3 l(d,2H), 7.08-7.05(d,lH), 6.97- 6.91(t,lH), 5.30(bm,lH), 4.76(m,lH), 4.05-3.97(m,3H), 3.80-3.75(t,lH), 3.68(s,3H),3.62- 3.44(m,2H), 3.26(s,4H),2.98(s,4H).

Mass: M+l= 478.1 methyl r((5SV3-(3-fluoro-4-r4-(5-nitro-2-thienvnpiperazm-l-yllphenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl] carbamate (Compound No. 21)

To a solution of (5S)-5-(aminomemyl)-3-{3-fluoro-4-[4-(5-nitro-2- thienyl)piperazin-l-yl]phenyl}-l,3-oxazolidin-2-one ( 0.3g) obtained from step a of Compound No. 18, in dry dichloromethane (10ml) under inert atmosphere was added methyl chloroformate (78.2mg) in the presence of triethylamine ( 0.154mg). The reaction mixture was stirred at room temperature for 17 hrs and then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography using 1% methanol-dichloromethane as eluant. The crude product was sonicated in ether and filtered to get title compound.(82mg) Melting point: 125-126 ⁰C

¹H NMR (CDCl₃) δppm: 7.81-7.79(d,lH), 7.46-7.41(d,lH), 7.10-7.07(d,lH), 6.97- 6.88(m,2H), 5.12(bm,lH), 4.75(m,lH), 4.05-3.99(t, IH), 3.79-3.77(m,3H), 3.68(s,3Η), 3.60-3.50(m,2H), 3.10(s,4H), 2.73(s,4H). M+l= 494.0 ethyl rf(5SV3-(3-fluoro-4-f4-(5-nitro-2-t3hienyl^>)piperazin-l-yl1phenyl>-2-oxo-1.3- oxazolidin-5-yl)methyl]carbamate (Compound No. 22)

To a solution of with (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitro-2- thienyl)piperazin-l-yl]phenyl}-l,3-oxazolidin-2-one ( 0.3g) obtained from step a of Compound No. 18, in dry dichloromethane 10ml under inert atmosphere was added ethylchloroforaiate (29.7mg) in the presence of triethylamine ( 0.153mg). The reaction mixture was stirred at room temperature for 17 hrs. and then diluted with dichlorooiethane and washed with brine and water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography using 1% methanol-dichloromethane as eluant. The crude product was sonicated in ether and filtered to get title compound (0.07g) Melting point: 117.5-119 ⁰C

¹H NMR (CDCl₃) δppm: 7.81-7.79(d,lH), 7.46-7.42(dd,lH), 7.09-7.06(d,lH), 6.97- 6.88(m,2H), 5.10(bm,lH), 4.75(m,lH), 4.15-3.99(m,3H), 3.80-3.77(m,3H), 3.59- 3.50(q,2H), 3.10(s,4H), 2.73(s,4H), 1.25-1.20(t,3H).

M+l=108 Example 6: Analogues of N-cvclopropyl-N'-r((5SV3-{3-fluoro-4-[^"4-(^'5-nitro-2- thienyl)piperazin-l-vnphenyl|-2-oxo-l,3-oxazolidin-5-yl)methyl]thiourea (^'Core 6)

N-cycIopropyl-N'-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2- oxo-l,3-oxazolidin-5-yl)methyI]thiourea (Compound No. 23).

To a solution of (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitro-2- thienyl)piperazin-l-yl]phenyl}-l,3-oxazolidin-2-one ( 0.3 g) obtained from step a of Compound No. 18, in tetrahydrofuran (10 ml) under nitrogen atmosphere , was added cyclopropyl isothiocyanate (0.084g) in presence of triethylarnine (0.16 g) and stirred for 17 hrs. The reaction mixture was filtered and purified by column chromatography using 1% methanol-dichloromethane as eluant, to get the title compound (0.2 g). Melting point: 192-193⁰C

¹H NMR (DMSO) δppm: 8.2-7.65 (m, 3H), 7.54 (dd, IH), 7.20 (m, 2H), 6.43 (d, IH), 4.91

(m, IH)₅ 4.12 (t, IH), 3.91 (m, 3H)₅ 3.62 (m₅ 4H), 3.15 (m₅ 4H), 0.68 (m, 2H), 0.44 (m,

2H)

Mass: M+l = 521.4 (S)-l-(4-Chloro-phenyl)-3-(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]- phenyl}-2-oxo-oxazolidin-5-yl-methyl)-thiourea (Compound No. 24).

To a solution of (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitro-2- thienyl)piperazin-l-yl]phenyl}-l,3-oxazolidin-2-one ( 0.3g) obtained from step a of Compound No. 18, in tetrahydrofuran (10ml) under nitrogen atmosphere, was added 4- chloro-phenyl isothiocyanate (0.15g) in presence of triethyl amine (0.16g) and stirred for 17 hrs. The reaction mixture was filtered and purified by column chromatography using 1% methanol-dichloromethane as eluant, to get the title compound (0.08g). Melting point: 207⁰C

¹H NMR (DMSO) δppm: 9.78 (bs, IH), 8.12 (bs, IH), 7.94 (d, IH), 7.54 (dd, IH), 7.45 (d, 2H), 7.34 (d, 2H), 7.22 (dd, IH), 7.12 (t, IH), 6.41 (d, IH), 4.94 (m, IH), 4.14 (t, IH), 3.87 (m, 3H), 3.63 (m, 4H), 3.15 (m, 4H)

Mass: M+H = 591.1

Example 7: Analogues of N'-[(C5S)-3-{3-fluoro-4-(^'4-(^'5-nitro-2-thienyl)piperazm-l- yl]phenyl} -2-oxo-l ,3-oxazolidin-5-yDmethyll-N,N-dimethylthiourea (Core 7) N'-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]-N,N-dimethylthiourea (Compound No. 25).

Step a: Synthesis of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl^')piperazin-l-yl]phenyl)-5- (isothiocvanatomethylVl,3-oxazolidin-2-one

To a solution of (5S)-5-(aminomethyl)-3-{3-fluoro-4-[4-(5-nitro-2- thienyl)piperazin- 1 -yljphenyl} - 1 ,3 -oxazolidin-2-one obtained from step a of Compound No. 18 (4 g) in dry tetrahydrofuran (50 ml) under nitrogen atmosphere was added carbon disulfide (1.8 ml) in presence of triethylamine (3 ml) and stirred for 10 hrs followed by the addition of ethylchloroformate (0.9 ml) and further stirred for 1 hr. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine water and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure and purified by column chromatography to yield the title compound. (2.3 g)

Step b: Synthesis of N'-[((^"5S)-3-{3-fluoro-4-r4-r5-nitro-2-thienyl)piperazin-l-yl]phenvU- 2-oxo- 13 -oxazolidin-5 -vDmethyll -N,N-dimethylthiourea To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-

5-(isothiocyanatomethyl)-l,3-oxazolidin-2-one (0.25 g) in methanol (15 ml) was added dimethylamine hydrochloride (0.17 g) in presence of triethylamine (0.3 ml) and stirred at room temperature for 2 hrs. The reaction mixture was filtered and the solid filtered, was washed with ether and dried to yield the title compound (0.265 g). Melting point: 204-206⁰C. IH NMR (DMSO) δppm: 7.93 (d, IH), 7.68 (m, IH), 7.50 (dd, IH), 7.22-7.0 (m, 2H), 6.40 (d, IH), 4.92 (m, IH), 4.08 (t, IH), 3.85 (m, 3H), 3.61 (m, 4H), 3.14 (m, 10H),

Mass: M+l = 509.3

N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazo!idin-5-yl)methyI] thiourea (Compound No. 26).

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5- (isothiocyanatomethyl)-l,3-oxazolidin-2-one obtained from the step a of Compound No. 25, (0.25 g) in methanol (5 ml) was added saturated solution of methanolic ammonia (5 ml). The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was filtered. The solid filtered was purified by column chromatography using 2% methanol-dichloromethane as eluant, to get the title compound (0.07 g) Melting point: 211-214⁰C

¹H NMR (DMSO) δppm: 7.94 (m, 2H), 7.53 (dd, IH), 7.15 (m, 3H), 6.42 (d, IH), 4.83 (m, IH), 4.10 (t, IH), 3.81 (m, 3H), 3.62 (m, 4H), 3.14 (m, 4H), Mass: M +l = 481.1, M +Na = 503.1

N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyI)piperazin-l-yI]phenyI}-2-oxo-l,3- oxazolidin-5-yl)methyl]-N'-methylthiourea (Compound No. 27)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-

(isothiocyanatomethyl)-l,3-oxazolidin-2-one (0.25g)obtained from step a of Compound No. 25, in methanol (15 ml) was added methylamine hydrochloride (0.14 g) in presence of triethylamine (0.3ml). The reaction mixture was stirred at room temperature for 12 hrs.

The reaction mixture was filtered. The solid filtered was washed with ether and dried to yield the title compound (0.24g).

Melting point: 188-189⁰C. ¹H NMR (DMSO) δppm: 7.94 (d, IH), 7.74 (t, IH), 7.52 (dd, 2H), 7.2 (dd, IH), 7.11 (t,

IH), 6.40 (d, IH), 4.84 (m, IH), 4.08 (t, IH)₅ 3.78 (m, 3H), 3.61 (m, 4H), 3.13 (m, 4H),

2.81 (m, 3H),

Mass: M+l = 495, M-NO₂ - 449.1 tert-butyl 2-({[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]pheαyl}-2-oxo- l^-oxazolidin-S-y^methyyaminoJcarbonothioy^hydrazinecarboxylate (Compound

No. 28).

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}- 5-(isothiocyanatomethyl)-l,3-oxazolidin-2-one (0.3 g) obtained from step a of Compound No. 25, in dichloromethane (15 ml)was added t-butylcarbazate (0.34g) in presence of triethylamine (0.36 ml) and stirred for 8 hrs at room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer λvas dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield the title compound (0.35 g).

Melting point: 139-141⁰C

¹H NMR (DMSO) δppm: 9.33 (bs, IH), 8.88 (b s, IH), 8.26 (bs, IH), 7.94 (d, L H), 7.48

(dd, IH), 7.16 (m, 2H), 6.40 (d, IH), 4.88 (m, IH), 4.4-3.5 (m, 8H), 3.12 (m, 4H), 1.38 (s,

9H) Mass: M+l = 596.2, M+NH₄ = 613.4, M + Na = 618.3

N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l-_>3- oxazolidin-5-yl)methyl]-N'-isopropylthiourea (Compound No. 29)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-

(isothiocyanatomethyl)-l,3-oxazolidin-2-one (0.25g) obtained from step a of Compound No. 25 in methanol (15 ml) was added isopropyl amine (0.178g) in presence of^" triethylamine (0.3ml) and stirred at room temperature for 12 hrs. The reaction mixture was filtered. The solid filtered was washed with ether and dried to yield the title compound

(0.25g).

Melting point: 145-147 ⁰C. ¹H NMR (CDCl₃) δppm: 7. 80 (d, IH), 7.48 (dd, IH), 7.09 (dd, IH)₅ 6.95 (t, IH), 6.17 (m,

IH), 6.02 (m, 2H), 4.91 (m, IH), 4.42-4.0 (m, 5H), 3.53 (m, 4H), 3.21 (m, 4H), 1.21 (m,

6H)

Mass: M+l = 523.3, M-NO₂ = 476.8 Example 8: Analogues of N-{r(5SV3-(3-fluoro-4-(4-[(5-nitro-2-furyl^')methyl1piperazin-l- yl)phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl>-5-nitrothiophene-2-carboxamid-e (Core 8)

N-{[C5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}phenyl)-2-oxo-l,3- oxazolidin-5-yI]methyl}-5-nitrothiophene-2-carboxamide (Compound No. 30) Step a: Synthesis of (5SV5-(aniinomethyl)-3-(3-flιιoro-^{4-r(S-nitro-2- furyl^methyl]piperazin- 1 -yllphenyiy 1 ,3-oxazolidin-2-one

To a solution of N-{[(5S)-3-(3-fiuoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l- yl}plienyl)-2-oxo-l,3-oxazolidin-5-yl]niethyl}acetamide hydrochloride (3.2 g), (prepared as described in WO 02/06278) in IN hydrochloric acid (32 mL) was heated to reflux for 4 hrs. The reaction mixture was cooled and extracted with dichloromethane. The aqueous layer was made alkaline with IN ammonium hydroxide and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude product was crystallized with ethyl acetate/hexane to yield of the title compound (1.8 g). Step b : N- { |T5 SV 3 -(3 -fluoro-4- (4-r(5-nitro-2-furyl)methyllρiperazin- 1 - yliphenvD-2-oxo- 1.3-oxazolidin-5-yl1methyU-5-nitrothiophene-2-carboxamide

To a solution of S-nitro-thiophene^-carboxylic acid (0.223g) in dimethylformamide (10ml) were added 1-hydroxy-benzotriazole (0.175g) and. (3S)-5- (anxinomethyl)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}pherLyl)-l,3- oxazolidin-2-one (0.45g obtained from Step a above) in the presence of N-methyl- morpholine (0.138g), at 0 ⁰C. The reaction mixture was stirred at the same temperature for 1.5 hrs, and then l-ethyl-3-(3'-dimethylammopropyl)carbodimide hydroch.loride (0.25g) was added to it and stirred at room temperature for 17 hrs. The reaction mixture was quenched with water and extracted with dichloromethane. The organic laryer was dried on sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using 1% methanol in dichloromethane to get the title compound (75mg). Melting point: 149-150⁰C ¹H IS[MR (CDCI₃+DMSO) δppm: 9.19(lH,bm), 7.85-7.80(2H, dd), 7.52-7.42<3H₃m), 7.07- 7.04(d,lH), 6.95-6.90(t,lH), 6.56(d,lH), 4.88(m,lH), 4.11-4.06(t,lH), 3.85-3 .72(m,5H), 3.083(s,4H), 2.72(s,4H). N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}phenyl)-2-oxo-l,3- oxazolidin-5-yl] methyl} -5-nitro-2-fur amide (Compound No. 31)

To a solution of 5-nitro-furan-2-carboxylic acid (0.185g) in dimethylformamide (10ml) were added l-hydroxy~benzotriazole (0.185g) and (5S)-5-(ammomethyl)-3-(3- fluoro-4- {4-[(5-nitro-2-furyl)methyl]ρiperazin- 1 -yl}phenyl)- 1 ,3-oxazolidin-2-one (0.45g obtained from Step a of Compound No. 30) in the presence of N-methyl-morpholine (0.138g), at 0 ⁰C. Trie reaction mixture was stirred at the same temperature for 1.5 hrs, then l-ethyl-3-(3'-dirnethylaminopropyl) carbodimide hydrochloride (0.25g) was added to it and then stirred at room temperature for 17 hrs. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried on sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using 1% methanol in dichloromethane to get the title compound (80mg). Melting point:84-86°C ¹H NMR (CDCl₃) δppm: 7.42-7.35(dd,2H), 7.28-7.26(m,3H), 7.09-7.06(d,lH), 6.94- 6.91(t,lH), 6.51(bm, lH), 4.86(m,lH), 4.10-4.08(t,lH), 3.94(t,lH), 3.80-3.71(m,4H), 3.09(s,4H), 2.72(s,4H).

M+H= 559.

5-bromo-N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}phenyl)-2- oxo-l,3-oxazoIidin-5-yϊ]methyI}-2-furamide (Compound No. 32.)

To a solution of 5-bromo-furan-2-carboxylic acid (0.225g) in dimethylformamide(lθml) were added 1-hydroxy-benzotriazole (0.175g) and (5S)-5- (aminomethyl)-3-(3 -fluoro-4- {4-[(5-nitro-2-furyl)methyl]piperazin-l-yl}ρhenyl)-l ,3- oxazolidin-2-one (0.45g obtained from Step a of Compound No. 30) in the presence of N- methyl-morpholine (0.138g), at O ⁰C. The reaction mixture was stirred at the same temperature for 1.5 hrs, then l-ethyl-3-(3'-dimethylaminopropyl) carbodimide hydrochloride (0.25 g) was added to it and then stirred at room temperature for 17 hrs. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried on sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using 1% methanol in dichloromethane to get the title compound (120mg). Melting ρoint:lO8-110.5 ⁰C

¹H NMR (CDCl₃) δppm: 7.44-7.39(d,lH), 7.29-7.26(d,lH), 7.087.06(d,2H), 6.94- 6.88(t,lH), 6.77Cbm,lH), 6.51-6.45(d,2H), 4.83(m,lH), 4.09-4.03(t,lH), 3.93-3.88(t,lH), 3.81-3.70(m,4H), 3.09(s,4H), 2.71(s,4H). M+H=593.

Example 9: N- { r(5SV3-π-fluoro-4-{44(5-nitro-2-furvDmethyllpiτ>erazm-l-vUυhenylV2- oxo-l,3~oxazolidin-5-yllmethyl|foπnamide (Compound No. 33)

To a solution of (5S)-5-(aminomethyl)-3-(3-fluoro-4-{4-[(5-nitro-2- furyl)methyl]piperazin-l-yl}phenyl)-l,3-oxazolidm-2-one (0.30 g) obtained from step a of Compound No. 30, was added ethylformate (1OmL) and the reaction mixture was reflux for 17 hrs. The solvent was evaporated. The residue was purified by column chromatography using 1% methanol-dichloromethane as eluant. Product was triturated in ether and filtered, to get of title compound (0.18 g).

Melting point:149.2-151.5 ⁰C ¹H NMR (CDCl₃) δppm: 8.28(s,lH), 7.47-7.41(dd,lH), 7.31-7.30(d, IH), 7.07-7.04(d,lH),

6.95-6.89(t,lH), 6.71(m,lH), 6.24(m,lH), 4.82-4.76(m,lH), 4.06-4.00(t,lH),3.87(m,2H),

3.80-3.70(m,3H), 3.20(s,4H), 2.89(s,4H).

Mass:M+l= 448.0

Example 10: Analogues of ((5RV3-{3-fluoro-4-r4-(5-nitro-2-thienyl)piperazin-l- yl1phenyl|-2-oxo-l,3-oxazolidin-5-yr)methyl acetate CCore 9)

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin- 5-yl)methyl acetate (Compound No. 34)

Step a: Synthesis of tert-butyl 4-(4-{(^"5R)-5-[(acetyloxy)methyll-2-oxo-L3-oxazolidin-3- yl> -Σ-fluorophenvDpiperazine- 1 -carboxylate To a solution of tert-butyl 4-{2-fluoro-4-[(5i?)-5-(hydroxymethyl)-2-oxo-l,3- oxazolidm-3-yl]ρhenyl}piperazine-l-carboxylate (10.8 g), prepared as per described in WO 93/23384) in pyridine (22.09 mL) was added acetic anhydride (3.9 ml) and stirred for 17 hrs. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with citric acid, water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield the title compound (11.3 g)-

Step b: Synthesis of ((5RV3-{3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazm-l-yl1phenvU-2- oxo-1 ,3-oxazolidm-5-yr)methyl acetate To a solution of tert-butyl 4-(4- {(5R)-5-[(acetyloxy)methyl]-2-oxo-l,3-oxazolidin-

3-yl}-2-fluorophenyl)piperazine-l-carboxylate (0.5g) was added ethanolic-HCl (60 ml, 0.296 N) at 0 ⁰C and stirred for 6 hrs allowing the reaction mixture to warm to room temperature. The reaction mixture was evaporated and dried. The residue was taken in acetonitrile (20 mL) and to it was added N-ethyl-diisopropylamine (2 mL), 2-bromo-5- nitro-thiophene (0.27 g) and heated at 60 ⁰C for 30 hrs. The solvent was evaporated and the residue in ethyl acetate was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue Λvas purified by column chromatography to yield of title compound (0.2Ig). Melting point = 203-204⁰C ¹H NMR (DMSO) δppm: 7.95 (d, IH), 7.53 (dd, IH), 7.22(dd, IH), 7.12 (t, IH), 6.42 (d, IH), 4.92 (m, IH), 4.27 (m, 2H), 4.13 (t, IH), 3.8 (t, IH), 3.62 (m, 4H), 3.14 (m, 4H), 2.04 (s, 3H)

Mass: M+H = 465.4, M-NO₂ - 419.4

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-(hydroxymethyl)- l,3-oxazolidin-2-one (Compound No. 35)

To ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piρerazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl acetate(3.4 g) (Compound No. 34) was added 3N hydrochloric acid ( 200 ml) and heated at 100 ⁰C for 2hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The product was triturated in diethyl ether and filtered to get the title compound (0.88 g). Melting point = 216-219 ⁰C

¹H NMR (DMSO) δppm: 7.95 (d, IH), 7.55 (dd, IH), 7.22 (dd, IH), 7.11 (t, IH), 6.42 (d, IH), 5.22 (t, IH), 4.69 (m, IH), 4.05 (t, IH), 3.80 (m, IH) 3.7-3.4 (m, 6H), 3.13 (m, 4H) Mass: M+H = 423.6, M-NO₂ = 377.6 Example 11: Analogues of ((5R)-3-{3-fluoro-4-[^'4-(5-mtro-2-thienyl)piperazm-l- yl]phenyl|-2-oxo-l,3-oxazolidin-5-yl)methyl (phenylsulfonvDcarbamate (Core 10)

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperaziii-l-yl]phenyl}-2-oxo-l,3- oxazo!idin-5-yl)methyl (phenylsulfbnyl)carbamate (Compound No. 36) To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-

(hydroxymethyl)-l,3-oxazolidin-2-one (0.175 g) (Compound No. 35) in dry tetrahydrofuran (25 ml) cooled to 0 ⁰C, was added sodium hydride (0.02g, 60% w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added benzene sulphonyl isocyanate (0.11 ml) and stirred for another 1 hr. The reaction mixture was warmed to room temperature and to the reaction mixture was added ethyl acetate and washed with water. The organic layer was dried over sodium sulphate and evaporated, under reduced pressure and the crude product obtained was purified by column chromatogrphay using 2% methanol-dichorornethane as eluant.The product was triturated in diethylether and filtered to yield the title compound (0.163 g). Melting point: 136-149 ⁰C.

¹U NMR (DMSO) δppm: 12.25 (bs, IH), 7.95 (d, IH), 7.87 (m, 2H), 7.75-7.45 (m, 4H), 7.15 (m, 2H), 6.42 (d,lH), 4.87 (m,lH), 4.24 (m, 2H), 4.07 (t,lH), 3.68 (m, 5H), 3.14 (m,4H)

Mass: M+l = 606.4, M-NO₂ = 560.3 ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)pIperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin- 5-yl)methyl [4-(trifluoromethyl)phenyl]carbamate (Compound No. 37)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]pheny-l}-5- (hydroxymethyl)-l,3-oxazolidin-2-one (0.175 g) (Compound No. 35) in dry tetrahydrofuran (25 ml) cooled to 0 ⁰C, sodiixm hydride (0.02g, 60% w/w suspension Ln mineral oil) was added and stirred for 10 mirα. To the reaction mixture was added 4-

(trifluoromethyl) phenyl isocyanate (0.12g) and stirred for 9 hr. The reaction mixture was warmed to room temperature. To the reaction mixture ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatogrphay using 2% methanol-dichoromethane as eluarxt. The product was triturated in diethylether and filtered to yield the title compound (0.055g). Melting point: 236-237 ⁰C

¹H NMR (DMSO) δppm: 10.26 (s, IH), 7.96 (d, IH), 7.58 (m, 5H), 7.24(dd, IH), 7.12 (t, IH), 6.42 (d, IH), 4.99 (m, IH), 4.41 (m, 2H), 4.16 (t, IH), 3.86 (m, IH), 3.62 (m, 4H), 3.13 (m, 4H) Mass: M+H = 610, M-N0₂+l = 564.5, M+Na=632

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin- 5-yl)methyl (4-fluorophenyl)carbamate (Compound No. 38)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5- (hydroxymethyl)-l,3-oxazolidin-2-one (0.175 g) (Compound No. 35) (0.175 g) in dry tetrahydrofiiran (25 ml) cooled to 0 ⁰C, sodium hydride (0.02g, 60% w/w suspension in mineral oil) was added and stirred for 10 min. To the reaction mixture was added 4- fluoro-phenyl isocyanate (O.lg) and stirred for 9 hr. The reaction mixture was warmed to room temperature. To the reaction mixture ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatogrphay using 2% methanol-dichoromethane as eluant. The product was triturated in diethylether and filtered to yield the title compound (0.196 g). Melting point: 221-223 ⁰C ¹H NMR (DMSO) δppm: 9.86 (bs, IH), 7.95 (d, IH), 7.6-7.4 (m, 3H), 7.23 (dd, IH), 7.15 (m, 3H), 6.41 (d, IH), 4.96 (m, IH), 4.36 (m, 2H), 4.15 (t, IH), 3.84 (m, IH), 3.62 (m, 4H), 3.13 (m, 4H)

Mass: M+l = 560.5, M-NO₂ - 514.4

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin~5-yl)methyl [(2-methyϊphenyl)suIfonyl] carbamate (Compound No. 39) To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]pheny^rl}-5-

(hydroxymethyl)-l,3-oxazolidin-2-one (0.175 g) (Compound No. 35) in dry tetrahydrofuran (25 ml) cooled to 0⁰C was added sodium hydride (0.02g, 60% w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added o- toluene sulphonyl-isocyanate (0.13g) and stirred for another 1 hr. The reaction mixture was warmed to room temperature. To the reaction mixture ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatogrphay using 1.5% mefhanol-dichoromethane as eluant. The product was triturated in diethyle∑ther and filtered to yield the title compound (0.158 g). Melting point: 104-109⁰C ¹H NMR (DMSO) δppm: 9 (bs, IH), 7.94 (d, IH), 7.77 (dd, IH), 7.52 (dd, IH), 7.3-7.O (m, 5H), 6.41 (d, IH), 4.77 (m, IH), 4.02 (m, 3H), 3.66 (m, 5H), 3.07 (m)

Mass:M+l = 620.4, M+Na = 642.3

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyI)piperazin-l-yI]phenyI}-2-oxo-l,3- oxazolidin-5-yl)methyl [(4-metltyIphenyl)suIfonyl] carbamate (Compound No. 40) To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-

(hydroxymefhyl)-l,3-oxazolidin-2~one (0.175 g) (Compound No. 35) in dry tetrahydrofuran (25 ml) cooled to 0 ⁰C was added sodium hydride (002g, 60% w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added p- toluene sulphonyl-isocyanate (0.13g) and stirred for another 1 hr. The reaction mixture was warmed to room temperature. To the reaction mixture ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatography using 1.5% methanol-dichoromethane as eluant. The product was triturated in diethyl ether and filtered to yield the title compound (0.25 g). Melting point: 82-86 ⁰C

¹H NMR (CDCl₃) δppm: 7.95 (d, IH)₅ 7.55 (m, 3H), 7.14 (m, 4H), 6.41 (d, IH), 4.8 (in, IH), 4.01 (t, IH), 3.94 (m, 2H), 3.65 (m, 6H), 3.14 (m, 4H), 2.30 (s, 3H)

Mass: M+H = 620.8, M+Na = 642.3

((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3-oxazolidin- 5-yl)methyl-n-butylcarbamate (Compound No. 41)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]pheny^rl}-5- (hydroxymethyl)-l,3-oxazolidm-2-one (0.175 g) (Compound No. 35),in dry tetrahydrofuran (25 ml) cooled to 0 ⁰C was added sodium hydride (0.02g, 60% w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added n- butyl-isocyanate (0.1ml) and stirred for 25 hr. The reaction mixture was warmed to room temperature and acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatogrphay using 2 % methanol-dichoromethane as eluant. The product was triturated in diethylether and filtered to yield the title compound (0.O49 g). Melting point: 200 ⁰C ¹H NMR (DMSO) δppm: 7.94 (d, IH), 7.55 (dd, IH), 7.0-7.30(m, 3H), 6.41 (d, IH), 4.89 (m, IH), 4.14 (m, 3H), 3.77 (m, IH), 3.62 (m, 4H)₅ 3.14(m, 4H), 2.96 (m, 2H), 1.3 (m, 4H), 0.84 (t, 3H)

Mass: M+l = 522.3, M+Na = 544.3, M-NO₂ = 476.2

0-[((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazoIidin-5-yl)methyl] (4-chlorophenyI)thiocarbamate (Compound No. 42)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-mtro-2-mienyl)piperazin-l-yl] phenyl} -5- (hydroxymethyl)-l,3-oxazolidin-2-one (0.175 g) (Compound No. 35), in dry tetrahydrofuran (25 ml) cooled to 0⁰C was added sodium hydride (0.015g, 60%» w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added 4- chlorophenyl-isothiocyanate (O.lg) and stirred for 12 hr. The reaction mixture was warmed to room temperature and ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatogrphay using 5 % methanol- dichoromethane as eluant. The product was triturated in diethylether and filtered to yield the title compound (0.07 g). Melting point: 196 ⁰C

¹H NMR (DMSO) δppm: 11.36 (br s, IH), 7.95 (s, IH), 7.75-6.8 (m, 7H), 6.42 (s, IH), 5.07 (m, IH), 4.78 (m, IH), 4.65 (m, IH), 4.15 (m, IH), 3.89 (m, IH), 3.63 (m, 4H), 2.97 (m, 4H) Mass: M+l = 592.1, M+Na = 614.0

O- [((5R)-3- {3-fluoro-4- [4-(5-nitro-2-thienyl)piperazin-l -yl] phenyI}-2-oxo-L ,3- oxazolidin-5-yl)methyl] (2,4-difluorophenyl)thiocarbamate (Compound No. 43)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5- (hydroxymethyl)-l,3-oxazolidin-2-one (0.175 g) (Compound No. 35), in dry tetrahydrofuran (25 ml) cooled to 0⁰C was added sodium hydride (0.025g, 60% w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added 2,4- difluorophenyl-isothiocyanate (0.12ml) and stirred for 17 hr. The reaction mixture was warmed to room temperature and ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatography using 30-40% ethyl acetate hexane as eluant. The product was triturated in diethylether and filtered to yield ttie title compound (0.104 g). Melting point: 201-205⁰C.

¹R NMR (DMSO) δppm: 1 l(bs, IH)₅ 7.97 (d, IH), 7.47 (m, 2H), 7.3-6.5 (m, 4H), 6.43 (d, IH), 4.95 (m, IH), 4.69 (m, IH), 4.6-3.7 (m, 3H), 3.64 (m, 4H), 3.15 (m, 4H). Mass: M+H - 594, M-N02 - 548

0-[((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-y]]phenyl}-2-oxo-l,3- oxazoIidin-5-yl)methyl] isopropylthiocarbamate (Compound No. 44)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]plienyl}-5- (hydroxymethyl)-l,3-oxazolidin-2-one (Compound No. 35), (0.2g) in dry tetrahydrofuran (25 ml) cooled to 0⁰C was added sodium hydride (0.023g, 60% w/w suspension in mineral oil) and stirred for 10 min. To the reaction mixture was added isopropyl- isothiocyanate (0. Ig) and stirred for 1 hr. The reaction mixture was warmed to room temperature and ethyl acetate was added and washed with water. The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The crude obtained was purified by column chromatography using 2 % methanol-dichoromethane as eluant. The product was triturated in diethylether and filtered to yield the title compound as an oily substance (0.104g).

¹H NMR (DMSO) δppm: 9.27 (m, IH), 7.94 (d, IH), 7.55 (dd, IH), 7.22 (dd, IH), 7.12 (t, IH), 6.41 (d, IH), 4.98 (m, IH), 4.61 (m, 2H), 4.15 (m, 2H), 3.84 (m, IH), 3.62 (xn, 4H), 3.14 (m, 4H), 1.2-0.75 (m, 6H)

Mass: M+l = 524.1, M+Na = 545.9

Examplel2: Preparation of (5R)-3- {3-fluorσ-4-[4-(^"5-m^'tro-2-thienyl)piperazin-l- yliphenyl} -5-(methoxymethyl)-l ,3-oxazolidin-2-one.

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yI]phenyl}-5-(methoxyiriethyl)- l,3-oxazolidin-2-one (Compound No. 45) To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5- (hydroxymethyl)-l,3-oxazolidin-2-one (Compound No. 35), (0.4 g) in dry tetrahydrofuran ( 15 mL) cooled to 0 ⁰C under nitrogen atmosphere was added sodium hydride (0.245g)and stirred for 10 min followed by the addition of methyl iodide (2.6ml), and the reaction mixture was stirred for 55 hrs. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography using 1% methanol-dichloromethane as eluant to yield of title product (0.134g). Melting point 147-149° C

¹H NMR (CDCl₃) δppm: 7.80 (d, IH), 7.50 (dd, IH), 7.17 (dd, IH), 6.96 (t, IH), 6.01 (d, IH), 4.76 (m, IH), 3.99 (t, IH), 3.89 (t, IH), 3.64 (m, 2H), 3.54 (m, 4H), 3.44 (s, 3H), 3.22 (m, 4H)

Mass:M+l = 437.1, M+Na = 459.0 Examplel 3 : Preparation of (5R)-3 - (3 -fluoro-4-[4-(5-nitxo-2-thienyr)piperazin- 1 - yl]phenyl| -5- { [(6-methylpyridin-2-yl)oxy1methyl) - 1 ,3 -oxazolidin-2-one.

(5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-{[(6-methylpyridin- 2~yl)oxy]methyl}-l,3-oxazolidm-2~one (Compound No. 46)

To a solution of (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}- 5-(hydroxymethyl)-l,3-oxazolidin-2-one (Compound No. 35), (0.3 g) in dry dimethyl formamide (10 mL) was added triphenylphospine (0.28 g), 2-hydroxy-6-methyl-pyridine (0.093 g) and diethyl diazadicarboxylate (0.2 mL) and the reaction mixture was stirred at room temperature for 17 hrs. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography using l%methanol-dichloromethane as eluant to yield of title product (0.175 g). Melting point: 194-195 ⁰C

¹H NMR (CDCl₃) δppm: 7.80 (d, IH), 7.49 (m, 2H), 7.17 (dd, IH), 6.95 (t, IH)₅ 6.76 (d, IH), 6.55 (d, IH), 6.01 (d, IH), 5.0 (m, IH), 4.58 (m, 2H), 4.10 (t, IH), 3.97 (m, IH), 3.54 (m, 4H), 3.21 (m, 4H), 2.43 (s,3H)

Mass: M+l = 514.2 Pharmacological Testing

The compounds of the invention displayed antibacterial activity when tested by the agar incorporation method. Minimum inhibitory concentrations (μg/ml) obtained for representative compounds provided herein were in the ranges given below. Staphylococcus aureus ATCC 25923; from about 0.1 μg/ml to about 16 μg/ml.

Methicilline Resistant Staphylococcus aureus ATCCl 5187; from about 0.1 μg/ml to about

16 μg/ml.

Methicilline Resistant Staphylococcus aureus ATCC562; from about O.I μg/ml to about 16 μg/ml. Methicilline Resistant Staphylococcus aureus ATCC33; from about O.I μg/ml to about 16 μg/ml.

Enterococcus faecalis ATCC 29212; from about 0.1 μg/ml to about S μg/ml.

Vancomycin-Resistant enterococci 6 A; from about 0.1 μg/ml to about 8 μg/ml.

Streptococcus pneumoniae ATCC 6303; from about 0.1 μg/ml to aboTit 4 μg/ml. Streptococcus pneumoniae AB34 DRSP; from about 0.1 μg/ml to about 8 μg/ml.

Streptococcus pyogenes ATCC 19615; from about 0.1 μg/ml to about 4 μg/ml.

The in vitro antibacterial activity of the compounds was demonstrated by the agar incorporation method (NCCLS M 7 and M 100-S8 documents). Briefly, the compounds were dissolved in dimethylsulphoxide and doubling dilution of the compounds were incorporated into Meer Hilton agar before solidification. Inoculums was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbidity to 0.5 McFarland turbidity standard tables (1.5 x 10^ CFU/ml), after appropriate dilutions,

ICH CFU/spot was transferred into the surface of dried plate and incubated for 1 8 hours (24 hours for MRSN studies). The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded only when the MICs against standard antibiotics were within the acceptable range.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

WE CLAIM: 1. A compound having the structure of formula 1 :

FORMULA I and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; R₁ is NHC(O)R₂; NHC(=S)R₂; NH-R₄; NHCHO; NHC(=0)0R₃; OC(=O)R₃; NR₃; SR₃; or OR₃, [wherein R₄ is heteroaryl, heterocyclyl or aryl; R₃ is hydrogen, alkyl or R₂; and R₂ is acyl, aryloxy, thiocarbonyl, substituted thiocarbonyl, amines, substituted amines, aryl, heteroaryl, heterocyclyl, aralkyl or aralkenyl, (wherein the heteroaryl and heterocyclic rings may contain one or more heteroatoms selected from O, S and N; the aryl, heteroaryl, aralkyl and araUcenyl rings may be unsubstituted or substituted with one or more of alkyl, halogen, nitro, amino or methylenedioxy, and also when R₁ is NR₃, SR₃ or OR₃ then the hetero atoms, together with R₃ can form a heterocyclyl or a heteroaryl ring)]; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, or C_1-I2 alkyl substituted with one or more of F, Cl, Br, I; n is an integer O, 1, 2 or 3; Q is O, S or NR_n (wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl); and G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH=N-OR₁₀, -C=CH-R₅, OR₅, SR₅, - C(Rg)=C(R₉)NO₂, C_1-I2 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, (wherein R₄ is as defined above); (wherein R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl, or C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH); (wherein R₆ and R₇ are independently hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl or C_1-6 alkoxy); (wherein R₈ and R₉ are independently hydrogen, C_1-6 alkyl, F, Cl, Br₅ I, or C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₅, SR₄, or NR₆,R₇); and (wherein R₁₀ is hydrogen, optionally substituted C₁-I₂ alkyl, C_3-12 cycloalkyl, Ci_-6 alkoxy, Ci_-6 alkyl, aryl or heteroaryl).

1 2. A compound selected from a group consisting of: (55)-3-(3-fluoro-4- {4-[(5-nitro-2-thienyl)methyl]piperazm- 1 -yl}phenyl)-5- [(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 1); (5S)-3-(3-fluoro-4-{4-[(5-nitro-2-ruryl)methyl]piperazin-l-yl}phenyl)-5- [(isoxazol-3-ylamino)methyl]-l,3-oxazolidin-2-one (Compound No. 2); (5S)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yljpheiryl} -5-[(isoxazol-3- ylamino)methyl]-l ,3-oxazolidin-2-one (Compound No. 3);

8 (55)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin-l-yl]pheny-l}-5-[(isoxazol-3- ylamino)methyl]-l,

3-oxazolidin-2-one (Compound No.

4); 0 (5R)-5-[(ethylthio)methyl]-3-{3-fluoro-4-[4-(5-nitro-2-thieiiyl)piperazin-l- L yljphenyl} - 1 ,3-oxazolidin-2-one (Compound No.

5); (5R)-3 - {3 -fluoro-4- [4-(5 -nitro-2-thienyl)piperazin- 1 -yl]phenyl} -5 - 3 [(heptylthio)methyl]-l,3-oxazolidin-2-one (Compound No.

6); (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(2- 5 naphthylthio)methyl]-l,3-oxazolidin-2-one(CompoundNo- 7); 6 (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(isoxazol-3- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 8); 8 5-[4-(2-fluoro-4- {(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo- 1 ,3-oxazolidin-3- 9 yl}phenyl)piperazin-l-yl]-2-furaldehyde (Compound No. 9); 0 (5R)-3-{3-jEluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-[(pyridin-4- 1 yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 10); (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piρerazin-l-yl]ρh_enyl}-5-[(pyridin-3- 3 yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 11); (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phLenyl}-5-[(pyrazin-2- 5 yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 12); 6 (5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]ph.enyl} -5-[(pyridin-2- yloxy)methyl]-l,3-oxazolidin-2-one (Compound No. 13); l-[((5S)-3-{3-fluoro-4-[4-(5-mtro-2-thienyl)piρerazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]pyridin-2(lH)-one (Compound No. 14); 5-[4-(4-{(5S)-5-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)inethyl]-2-oxo-l,3- oxazolidin-3-yl}-2-fluorophenyl)piperazin-l-yl]-2-furaldehyde (Compound No. 15); 2-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piρerazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]-lH-isoindole-l,3(2H)-dione (Compound No. 16); (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazin-l-yl]phenyl}-5-(lH-imidazol-l- ylmethyl)-l,3-oxazolidin-2-one (Compound No. 17); phenyl [((5S)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo- 1 ,3-oxazolidin-5-yl)methyl]carbamate (Compound No. 18); ethyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin- l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]carbamate (Compound No. 19); methyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-furyl)piperazin- l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl] carbamate (Compound No. 20); methyl [((5S)-3- {3-fluoro-4-[4-(5-rήtro-2-ttaenyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 ,3-oxazolidin-5-yl)methyl]carbamate (Compound No. 21) ; ethyl [((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]carbamate (Compound No. 22); N-cyclopropyl-N'-[((5S)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l - yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]thiourea (Compound No. 23); N-(4-chlorophenyl)-N'-[((5S)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazin- 1 - yl]phenyl}-2-oxo-l,3-oxazolidin-5-yl)methyl]thiourea (Compound No. 24); N'-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazin-l-y-l]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]-N,N-dimethylthiourea (Compound No. 25); N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]thiourea (Compound No. 26); N-[((5 S)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 ,3- oxazolidin-5-yl)methyl]-N'-methylthiourea (Compound No. 27); tert-butyl 2-({[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2- oxo-l^-oxazolidin-S-y^memyljaminoJcarbonomioytyhydrazinecarboxylate (Compound No. 28); N-[((5S)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]plienyl}-2-oxo-l,3- oxazolidin-5-yl)methyl]~N'-isopropylthiourea (Compound No. 29); N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperazin_-l-yl}phenyl)-2-oxo- l,3-oxazolidin-5-yl]methyl}-5-nitxothiophene-2-carboxamide (Compound No. 30); N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]piperaziix-l-yl}phenyl)-2-oxo- l,3-oxazolidin-5-yl]methyl}-5-nitro-2-furamide (Compound INo. 31); 5-bromo-N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]ρiperazin-l- yl}phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}-2-furamide (Compound No. 32); N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]ρiperazirL-l-yl}phenyl)-2-oxo- l,3-oxazolidin-5-yl]methyl}formamide (Compound No. 33); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piρerazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5 -yl)methyl acetate (Compound No . 34) ; (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phen_yl}-5- (hydroxymethyl)-l ,3-oxazolidin-2-one (Compound No. 35); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5 -yl)methyl (plienylsulfonyl)carbamate (Compouαnd No. 36); ((5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazin- 1 -yl]phenyl} -2-oxo- 1 ,3- oxazolidin-5 -yl)methyl [4-(trifluoromethyl)phenyl]carbamate (Compound No. 37); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piρerazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl (4-fluorophenyl)carbamate (Compound No. 38); ((5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin- 1 -yl]phenyl} -2-oxo- 1 ,3- oxazolidin-5 -yl)methyl [(2-methylphenyl)sulfonyl]carbamate (Compound No. 39); ((5R)-3-{3-fluoro-4-[4-(5-mtro-2-thienyl)piperazin-l-yl]phenyl}-2-oxo-l,3- oxazolidin-5-yl)methyl [(4-methylphenyl)sulfonyl]carbamate (Compound No. 40); ((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]pliexiyl}-2-oxo-l_:>3- oxazolidin-5~yl)methyl-n-butylcarbamate (Compound No. 41); 86 O-tCCS^-S-IS-fluoro^-t^CS-nitro^-thienyOpiperazin-l-yljphenyll^-oxo-l^-

87 oxazolidin-5-yl)methyl] (4-chlorophenyl)thiocarbamate (Compound No. 42);

88 O-[((5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)ρiperazin-l-yl]phenyl}-2-oxo-l,3-

89 oxazolidin-5-yl)methyl] (2,4-difluorophenyl)thiocarbamate (Compound No. 43);

90 O-[((5R)-3- {3-fluoro-4-[4-(5-nitro-2-thienyl)ρiρerazin- 1 -yl]ρhenyl} -2-oxo- 1 ,3-

91 oxazolidin-5-yl)methyl] isopropylthiocarbamate (Compound No. 44);

92 (5R)-3-{3-fluoro-4-[4-(5-nitxo-2-tbienyl)piperazin-l-yl]plienyl}-5-

93 (methoxymethyl)-l,3-oxazolidin-2-one (Compound No. 45);

94 (5R)-3-{3-fluoro-4-[4-(5-nitro-2-thienyl)piperazin-l-yl]phenyl}-5-{[(6-

95 methylpyridin-2-yl)oxy]methyl}-l,3-oxazolidin-2-one (Compound No. 46).

1 3. A pharmaceutical composition comprising the compounds of claim 1 and claim 2 2 and a pharmaceutical acceptable carrier.

1 4. A pharmaceutical composition comprising the compounds of claim 1 and claim 2

2 or a physiologically acceptable acid addition salts thereof with a pharmaceutical

3 acceptable carrier for treating microbial infection.

1 5. A method of treating or preventing microbial infections in a mammal comprising

2 administering to the said mammal, the pharmaceutical composition according to claim 4.

1 6. The method according to claim 5 wherein the microbial infections are caused by

2 gram-positive and gram-negative bacteria.

1 7. The method according to claim 6, wherein the gram-positive bacteria are selected

2 from the group consisting of Staphylococcus spp., Streptococcus spp., Bacillus spp.,

3 Corynebacterum spp., Clostridia spp., Peptostreptococus spp., Listeria spp. and

4 Legionella spp.

1 8. A method of treating or preventing aerobic and anaerobic bacterial infections in a

2 mammal comprising administering to said mammal, a therapeutically effective amount of

3 a compound having the structure of Formula I:

FORMULA I

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein Ri is NHC(=O)R₂; NHC(=S)R₂; NH-R₄; NHCHO; NHC(O)OR₃; OC(=O)R₃; NR₃; SR₃; or OR₃, [wherein R₄ is heteroaryl, heterocyclyl or aryl; R₃ is hydrogen, alkyl or R₂; and R₂ is acyl, aryloxy, thiocarbonyl, substituted thiocarbonyl, amines, substituted amines, aryl, heteroaryl, heterocyclyl, aralkyl or aralkenyl, (wherein the heteroaryl and heterocyclic rings may contain one or more heteroatoms selected from O, S and N; the aryl, heteroaryl, aralkyl and aralkenyl rings may be unsubstituted or substituted with one or more of alkyl, halogen, nitro, amino or methylenedioxy, and also when R₁ is NR₃, SR₃ or OR₃ then the hetero atoms, together with R₃ can form a heterocyclyl or a heteroaryl ring)]; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, or C_1-12 alkyl substituted with one or more of F, Cl, Br, I; n is an integer 0, 1, 2 or 3; Q is O, S or NR₁₁ (wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl); and G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, 3Sf(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH=N-OR₁₀, -C-CH-R₅, OR₅, SR₅, - C(Rg)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, (wherein R₄ is as defined above); (wherein R₅ is hydrogen, Ci_-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl, or C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH); (wherein R₆ and R₇ are independently hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl or C_1-6 alkoxy); (wherein R₈ and R₉ are independently hydrogen, Ci_-6 alkyl, F, Cl, Br, I, or Ci_-12 alkyl substituted with one or more of F, Cl, Br, I, OR₅, SR₄, or NR₆₅R₇); and (wherein R₁₀ is hydrogen, optionally substituted C_1-I₂ alkyl, C₃-I₂ cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, aryl or heteroaryl). 9. A process for preparing compounds of Formulae VII and VIII,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH - N-ORi₀, -C=CH-R₅, OR₅, SR₅, ^■ C(R₉)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄., SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; Q is O, S or NR₁₁, wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroajtyl; R₆ and R₇ are independently hydrogen, optionally substituted C_1-I2 alkyl, C_3-I2 cycloa-lkyl or C_1-6 alkoxy; and het represents heterocyclic group, which comprises reacting a compound of Formula II,

with a compound of Formula III

P — N-het I

FormulaIII

wherein P is amine protecting group as tert-butyloxy carbonyl(t-boc) or 9- fluorenylmethoxycarbonyl (Fmoc) and het represents heterocyclic group to give a compound of Formula IV,

which on further deprotection and reaction with a compound of Formula V (wherein hal is as defined earlier) and VI respectively,

/ — hal ^G — V /^CHO

Formula V Formula Vl

to give a compound of Formula VII and Formula VIII respectively.

10. The process according to claim 9 wherein the reaction of compound of Formula II with a compound of Formula III to give a compound of Formula IV, is carried out in the presence of a solvent selected from acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulphoxide and ethylene glycol.

11. The process according to claim 9 wherein the reaction of compound of Formula II with a compound of Formula III to give a compound of Formula IV, is carried out in the presence of a base selected from sodium hydride and lithiumh hydride.

12. The process according to claim 9 wherein the reaction of compound of Formula IV with a deprotecting agent is carried out with hydrochloric acid in ethanol and trifluoroacetic acid in dichloromethane.

13. The process according to claim 9 wherein the reaction of deprotected compound of Formula IV with a compound of Formula V to give a compound of Formula VII, is carried out in the presence of a solvent selected from acetonitrile and dimethylformamide.

14. The process according to claim 9 wherein the reaction of deprotected compound of Formula IV with a compound of Formula V, to give a compound of Formula VII, is carried out in the presence of a base selected from diisopropylethylamine and potassium carbonate.

15. The process according to claim 9 wherein the reaction of deprotected compound of Formula IV with a compound of Formula VI (Path b') to give a compound of Formula VIII, is carried out in the presence of a solvent selected from tetrahydrofuran, ethyl acetate and isopropyl alcohol.

16. The process according to claim 9 wherein the reaction of deprotected compound of Formula IV with a compound of Formula VI, to give a compound of Formula VIII, is carried out in presence of a reducing agent selected from triacetoxy sodium borohydride and sodium cyanoborohydride.

17. A process for preparing a compound of Formula XI,

Formula Xl and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-ORi₀, -C=CH-R₅, OR₅, SR₅, ^■ C(Rg)=C(R₉)NO₂, Ci_-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-I2 cycloalkyl, Ci_-6 alkoxy, aryl or heteroaryl; Ci_-6 alkyl substituted with one or more of F, Cl, Br, I or OH; Q is O, S or NRn, wherein Rn is hydrogen, optionally substituted Ci-I₂ alkyl, C_3-I2 cycloalkyl, Ci_-6 alkoxy, Ci_-6 alkyl carbonyl, Ci_-6 alkylcarboxy, aryl or heteroaryl; R₆ and R₇ are independently hydrogen, optionally substituted Ci_-I2 alkyl, C_3-I2 cycloalkyl or C_1-6 alkoxy; and R₃ is alkyl or aryl which comprises reacting a compound of Formula II,

with a compound of Formula IX

Ra-SH Formula IX

to give a compound of Formula X,

S

Ra which on reacting with a compound of Formula V,

Formula V

gives a compound of Formula XI.

18. The process according to claim 17 wherein the reaction of compound of Formula II with a compound of Formula IX, to give a compound of Formula X, is carried out in a solvent selected from dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsufoxide and ethylene glycol.

19. The process according to claim 17 wherein the reaction of compound of Formula II with a compound of Formula IX to give a compound of Formula X, is carried out in the presence of a base selected from sodium hydride and lithium hydride.

20. The process according to claim 17 wherein the deprotection of compound of Formula X is carried out in a solvent selected from dichloromethane and chloroform.

21. The process according to claim 17 wherein the compound of Formula X is deprotected with trifluoroaceticacid.

22. The process according to claim 17 wherein the reaction of deprotected amine with a compound of Formula V to give compound of Formula XI is carried out in a solvent selected from acetonitrile and dimethylformamide.

23. The process according to claim 17 wherein the reaction of deprotected amine with a compound of Formula V to give compound of Formula XI is carried out in presence of a base selected from diisopropoylethylamiine and potassium carbonate.

24. A process for preparing a compound of Formula XV (path a and path b ),

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-I2 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, Ci_-6 alkyl, F, Cl, Bx, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, Rio), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-ORi₀, -C=CH-R₅, OR₅, SR₅, -

C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, Ci_-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; Ci_-6 alkyl substituted with one or more of F, Cl, Br, I or OH; Q is O, S or NRn, wherein Rn is hydrogen, optionally substituted CM₂ alkyl, C_3-I2 cycloalkyl, Ci_-6 alkoxy, Ci_-6 alkyl carbonyl, Ci_-6 alkylcarboxy, aryl or heteroaryl; and R_b is O-het or het and het is as defined earlier which comprises of reacting a compound of Formula XII (path a) or Formula II (path b) respectively , with, a compound of Formula XIII (wherein R_b is as defined earlier)

Rb-H

Formula XIII

to give a compound of Formula XIV,

which on further reaction with compound of Formula VI,

^G ^v. / ^CHO Formula Vl

gives a compound of Formula XV.

25. The process according to claim 24 wϊierein the reaction of compound of Formula II with a compound of Formula XIII, to give a compound of Formula XIV is carried out in a solvent selected from tetrahydrofuran, dimethylformamide, dioxane and diethylether.

26. The process according to claim 24 wherein the reaction of compound of Formula II with a compound of Formula XIII, to give a compound of Formula XIV is carried out in the presence of a coupling agent selected from diethyl azodicarboxylate and disopropyl azodicarboxylate.

27. The process according to claim 24 wherein the reaction of compound of Formula II with a compound of Formula XIII, to give a compound of Formula XIV is carried out in the presence of a catalyst selected from triphenyl phosphine, trimethyl phosphine_^ tributyl phosphine and di-l-adamantyl(butyl)phosphine.

28. The process according to claim 24 wherein the of compound of Formula XIV is deprotected with txifluoroaceticacid or ethanolic hydrochloric acid.

29. The process according to claim 24 wherein the reaction of deprotected amine with a compound of Formula VI, to give a compound of Formula XV is carried out in a. solvent selected from dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsufoxide and ethylene glycol.

30. The process according to claim 24 wherein the reaction of deprotected arnizne with a compound of Formula VI, to give a compound of Formula XV is carried out in the presence of a base selected from diisopropoylethylamiine and potassium carbonate.

31. A process for preparing a compound of Formula XIX,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, - C(Rg)=C(R₉)NO₂, Ci_-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, Ci_-12 alkyl, C_3-12 cycloalkyl, C₁^ slkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; n is an integer in the range from 0 to 3; Q is O, S or NR₁₁, wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and Rc is alkyl/aryl; which comprises reacting a compound of Formula XVI

with a hydrolyzing agent to give a compound of Formula XVII,

which on reaction with, a compound of Formula XVIII

Formula XVlIl gives a compound of Formula XIX.

32. The process according to claim 31 wherein the reaction of compound of Formula XVI to give a compound of Formula XVII is carried out in hydrochloric acid.

33. The process according to claim 31 wherein the reaction of compound of Formula XVII with a compound of Formula XVIII to give a compound of Formula XIX, is carried out the presence of a base selected from triethylamine and dispropylethylamine.

34. A process for preparing a compound of Formula XXII,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, Ci_-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, - C(Rg)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-I₂ cycloalkyl, Ci_-6 alkoxy, aryl or heteroaryl; Ci_-6 alkyl substituted with one or more of F, Cl, Br, I or OH; n is an integer in the range from O to 3; Q is O, S or NRn, wherein R₁₁ is hydrogen, optionally substituted C_1-I2 alkyl, C_3-I2 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and R_f and Rg can be selected from hydrogen or alkyl group; which comprises of reacting a compound of Formula XVII with carbon disulphide.,

to give the compound of Formula XX

which on further reaction with the compound of Formula XXI

H Formula XXI

gives a compound of Formula XXII.

35. The process according to claim 34 wherein the reaction of compound of Tormula XVII with carbon disulphide, to give the compound of Formula XX is carried out in the presence of ethyl chloroformate.

36. The process according to claim 34 wherein the reaction of compound of .Formula XVII with a carbon sulphide, to give the compound of Formula XX is carried out in a solvent selected from dichloromethane and chloroform.

37. The process according to claim 34 wherein the reaction of compound of Formula XVII with a carbon sulphide, to give the compound of Formula XX is carried out in the presence of a base selected from triethyl amine and diisopropylamine.

38. The process according to claim 34 wherein the reaction of compound of Formula XX with a compound of Formula XXI to give the compound of Formula XXII is carried out in a solvent selected from dichloromethane, dichloroethane and methanol.

39. The process according to claim 34 wherein the reaction of compound of Formula XX with a compound of Formula XXI to give the compound of Formula XXII Is carried out in presence of a base selected from triethyl amine and diisopropylamine.

40. A process for preparing a compound of Formula XXIV,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with. one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₃R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, C(Rg)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is H, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; n is an integer in the range from O to 3; Q is O, S or NR₁₁, wherein R₁₁ is hydrogen, optionally substituted C_M2 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and Ra is alkyl or aryl. which comprises of reacting a compound of Formula XVII with a compound of Formula XXIII,

Rd — N= C=S

Formula XXIII

to give a compound of Formula XXIV.

41. The process according to claim 40 wherein the reaction of compound of Formula XVII with a compound of Formula XXIII, to give the compound of Formula XXIV is carried out in the presence of a base such as triethyl amine and diisopropylamine.

42. A process for preparing a compound of Formula XXVI,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, - C(R₉)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; n is an integer in the range from O to 3; Q is O, S or NR₁₁, wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and R_e is as substituted heterocyclic group; which comprises of reacting a compound of Formula XVII,

with a compound of Formula XXV,

R₆ COOH

Formula XXV

to give compound of Formula XXVI.

43. The process according to claim 42 wherein the reaction of compound of Formula XVII with a compound of Formula XXV, to give the compound of Formula XXVI is carried out in the presence of a solvent selected from dimethylformamide, tetrahydrofuran and acetonitrile.

44. The process according to claim 42 wherein the reaction of compound of Formula XVII with a compound of Formula XXV, to give the compound of Formula XXVI is carried out in the presence of a base selected from N-methyl morpholine, diisopropylamine and collidine.

45. The process according to claim 42 wherein the reaction of compound of Formula XVII with a compound of Formula XXV, to give the compound of Formula XXVI is carried out in the presence of a coupling agent selected from S-dicyclohexylcarbodimide (DCC) and l-ethyl-3-(3'-dimethylaminoρropyl)carbodimide hydrochloride (EDCI).

46. A process according to claim 42 wherein the reaction of compound of Formula XVII with a compound of Formula XXV, to give the compound of Formula XXVI is carried out in the presence of an additive selected from 1-hydroxybentriazole (HOBt) and l-hydroxy-7-azabenzotriazole (HOAt).

47. A process for preparing a compound of Formula XXVII (path b),

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, Rio), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-ORi₀, -C=CH-R₅, OR₅, SR₅, -

C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; n is an integer in the range from O to 3; and Q is O, S or NR₁₁, wherein R₁₁ is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, Ci_-6 alkoxy, Ci_-6 alkyl carbonyl, Ci_-6 alkylcarboxy, aryl or heteroaryl; which comprises reacting a compound of Formula XVII with ethylformate, to give compound of Formula XXVII.

48. A process for preparing a compound of Formula XXXII,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, Ci_-I2 alkyl substituted with one or more of F, Cl, Br, I;

G is hydrogen, Ci_-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, Ri₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, C(R₉)^C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, Ci_-I2 alkyl, C_3-12 cycloalkyl, Ci_-6 alkoxy, aryl or heteroaryl; Ci_-6 alkyl substituted with one or more of F, Cl, Br, I or OH; and Q is O, S or NRn, wherein R₁₁ is hydrogen, optionally substituted Ci-I₂ alkyl, C_3-I₂ cycloalkyl, Ci_-6 alkoxy, Ci_-6 alkyl carbonyl, Ci_-6 alkylcarboxy, aryl or heteroaryl; which comprises reacting a compound of Formula XII

with a compound of Formula XXVIII ( wherein R_x can be alkyl or aryl)

Rx (CO)₂O Formula XXVIII

to give a compound of Formula XXIX,

which is deprotected to give a compound of Formula XXX,

Formula V the compound of Formula XXX on reaction with the compound of Formula V, gives a compound of Formula XXXI,

which on further hydrolysis gives the compound of Formula XXXII.

49. The process according to the claim 48 wherein the reaction compound of Formula XII, with the compound of Formula XXVIII to give the compound of Formula XXIX is carried out in the presence of acetic anhydride and pyridine.

50. The process according to the claim 48 wherein the of Formula XXIX deprotected to give the compound of Formula XXX in the presence of ethanolic hydrochloric acid or trifluoroacetic acid.

51. The process according to the claim 48 wherein the reaction of Formula XXX with the compound of Formula V to give the compound of Formula XXXI is carried out in the presence of a solvent selected from dimethylformamide, tetrahydrofuran and acetonitrile.

52. The process according to the claim 48 wherein the reaction of compound Formula XXX with the compound of Formula V to give the compound of Formula XXXI is carried out in the presence of a base selected from triethyl amine and diisopropylamine.

53. The process according to the claim 48 wherein the reaction of compound of Formula XXXI is hydrolysed to give the compound of Formula XXXII is carried out in the presence of acid such as hydrochloric acid.

54. A process for preparing a compound of Formula XXXIV,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted Ci_-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), TSHCOC(R₈, R₉, Rio), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH - N-ORi₀, -C=CH-R₅, OR₅, SR₅, C(R₉)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; Q is O, S or NR_n, wherein Rn is hydrogen, optionally substituted C₁-I₂ alkyl, C_3-12 cycloalkyl, Ci_-6 alkoxy, C_1-6 alkyl carbonyl, Ci_-6 alkylcarboxy, aryl or h.eteroaryl; R_h is aryl/ alkyl; and T is sulphur or oxygen; which comprises reacting a compound of Formula XXXII with a compound of Formula XXXIII ,

R_n N=C=T

Formula XXXIII to give a compound of Formula XXXIV.

55. The process according to the claim 54 wherein the reaction of the compound Formula XXXII with a compound of Formula XXXIII to give the compound of Formula XXXrV is carried out in a solvent such as dimethyl formamide, acetonitrile, dimethylacetamide, dimethylsufoxide and ethylene glycol.

56. The process according to the claim 54 wherein the reaction of the compound of Formula XXXII with a compound of Formula XXXIII to give the compound of Formula XXXrV is carried out in the presence of a base such as sodium hydride and lithium hydride.

57. A process for preparing a compound of Formula XXXVI,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₅R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, C(Rg)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; Q is O, S or NR₁₁, wherein R₁₁ is hydrogen, optionally substituted C_\-u alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and Ri is aryl/ alkyl; which comprises reacting a compound of Formula XXXII,

with a compound of Formula XXXV, Rj hal

Formula XXXV to give a compound of Formula XXXVI.

58. The process according to the claim 57 wherein the /reaction of compound of Formula XXXII with a compound of Formula XXXV to give the compound of Formula XXXVI is carried out in a solvent selected from dimethyl formamide, acetonitrile, dimethylacetamide and dimethylsufoxide.

59. The process according to the claim 57 wherein the reaction of compound of Formula XXXII with a compound of Formula XXXV to give the compound of Formula XXXVI is carried out in the presence of a base selected from sodium hydride and lithium hydride.

60. A process for preparing a compound of Formula XXXVIII,

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, prodrugs or metabolites, wherein; U is hydrogen, optionally substituted C_1-6 alkyl, F, Cl, Br, I, C_1-12 alkyl substituted with one or more of F, Cl, Br, I; G is hydrogen, C_1-6 alkyl, F, Cl, Br, I, -CN, COR₅, COOR₅, N(R₆₉R₇), NHCOC(R₈, R₉, R₁₀), CON(R₆, R₇), CH₂NO₂, NO₂, CH₂R₈, CHR₉, -CH = N-OR₁₀, -C=CH-R₅, OR₅, SR₅, C(Rg)=C(R₉)NO₂, C_1-12 alkyl substituted with one or more of F, Cl, Br, I, OR₄, SR₄, wherein R₄ is as defined above; R₅ is hydrogen, C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, aryl or heteroaryl; C_1-6 alkyl substituted with one or more of F, Cl, Br, I or OH; Q is O, S or NR₁₁, wherein Rn is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl carbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and R_j is aryl/ alkyl; which comprises reacting a compound of Formula XXXII with a compound of Formula XXXVII,

to give a compound of Formula XXXVIII.

Rj OH

Formula XXXVII

61. The process according to the claim 60 wherein the reaction of Formula XXXII with a compound of Formula XXXVII to give the compound of Formula XXXVIII is carried out in a solvent selected from dimethyl formamide, toluene, and tetrahydrofuran.

62. The process according to the claim 60 wherein the reaction of compound of Formula XXXII with a compound of Formula XXXVII to give the compound of Formula XXXVIII is carried out in the presence of a coupling agent diethyl azodicarboxylate.

63. The process according to the claim 60 wherein the reaction of a compound Formula XXXII with a compound of Formula XXXVII to give the compound of Formula XXXVIII is carried out in presence of catalyst selected from triphenylphospine, trimethyl phosphine, tributyl phosphine and di-1-adamantyl (butyl) phosphine.