WO2005082899A1 - Oxazolidinone derivatives as antimicrobials - Google Patents

Abstract

The present invention relates to certain substituted phenyl oxazolidinones of formula (I) and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing such compounds 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 such compounds 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. Background of the Invention Increasing antibacterial resistance in Gram positive bacteria has presented a formidable treatment problem. The enterococci, although traditionally non-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 a modified target penicillin binding protein- 2', leading to less affinity for β lactam antibiotics and a phenotype known as Methicillin Resistant S. aureus (MRSA). These strains, till recently were susceptible to vancomycin, which despite 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 across the globe. Oxazolidinones are a new 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 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics. WO 03/008389 discloses substituted phenyl oxazolidinones, which are said to be useful antimicrobial agents, 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, effective against number of human and veterinary pathogens. WO 02/06278 application discloses phenyloxazolidinone derivatives as putative antimicrobial agents. WO 00/32599 discloses phenyl oxazolidinyl described to be useful as antimicrobial agents. WO 98/01446 describes 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms, attached to the piperazinyl oxazolidinyl core. WO 98/01447 discloses pyridyl ring (optionally substituted) attached to the piperazinyl oxazolidinyl core. WO 97/10223 describes aminoaryloxazolidinone N- oxides. WO 93/23384 application discloses phenyloxazolidinones containing a substituted diazine moiety and their uses as antimicrobial agents. WO 93/09103 application discloses substituted aryl and heteroaryl- phenyl-oxazolidinones said to be useful as antibacterial agents. WO 90/02744 application discloses 5-indolinyl-5β-amidomethyloxazolidinones, 3-(fused ring substituted) phenyl-5β-amidomethyloxazolidinones which are described as useful antibacterial agents. European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones. European Patent Application 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones. U.S. Patent No. 5,254,577 discloses nitrogen heteroaromatic rings attached to phenyloxazolidinone. U.S. Patent Nos. 5,547,950 and 5,700,799 also disclose the 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 the piperazinyl oxazolidinyl core. U.S. Patent No. 5,736,545 describes azolyl piperazinyl phenyl oxazolidinones which contains azolyl ring as a five membered heterocyclic ring wherein in all the cases 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 five 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 ed. Chem., (1989); 32: 1673-81; Gregory W.A., et al., J. Med. Chem., (1990), 33: 2569-78; J. Med. Chem. (1998), 4h 3727-3735; describes pyridine, diazene, triazene, heteroaromatic rings directly attached to the piperazinyl oxazolidinone core; J. Med. Chem. (2002), 45,3953-3962 describes structure activity relationship (SAR) studies on selected novel tricyclic oxazolidinones; Wang C, et al, Tetrahedron, (1989), 45: 1323-26; Brittelli, et al, JMed. Chem., (1992), 35: 1156; Ann. Rep. Med. Chem., 35, 135-144; Bio-org. and Med. Chem. Lett., (1999); 9: 2679-84; Pae A. N., et al., Bioorg. Med. Chem. Lett. 9, 2685-2690, (1999) disclose oxazolidinone derivatives, which are said to be active against gram-positive strains including the resistant strains of Staphylococcus and Enter ococcus; 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 Oxazolidinone molecules are provided, which have good activity against multiply- resistant gram-positive pathogens like methicillin resistant Staphylococcus aureus

(MRSA), vancomycin-resistant Enterococci (VRE) and penicillin resistant Streptococcus pneumoniae (PRSP). Some of these molecules have activity against multidrug resistant tuberculosis (MDR-TB) and mycobacterium avium intracellulase (MAI) strains, while others have significant activity against important anaerobic bacteria. The compounds provided herein contain substituted phenyloxazolidinone ring structures and also have a diazine moiety attached to the phenyloxazolidinone, which is further substituted by heteroaromatic ring. The compounds have superior antibacterial activity. Processes for production of the phenyloxazolidinones derivatives are also provided. These compounds exhibit significantly greater antibacterial activity than that available with known compounds against multiply-resistant gram-positive pathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains and gram-negative pathogens like Moraxella catarrhalis and Haemophilus influenza, in order to provide safe and effective treatment of bacterial infections. There are provided processes for the synthesis of phenyloxazolidinone derivatives represented by Formula I:

FORMULA I and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein

Ri can be NHWR wherein W is no atom, CO or CS, and R₇ is selected from H, CH₃,

OCH₃, OCH₂CH₃, CF₃ or CH₂C1;

R₂ can be selected from H or F; R₃ can be selected from H or CH₃;

X can be selected from N or CHNCH₃;

Q can be selected from O or S;

R ₎ Rs, R_fi can be independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or

CONRgRio wherein R₈ is H or CH , R and Rio are independently selected from H, Cj-C₄ alkyl or benzyl; and the ring C may form the structure of Formula

where n is an integer 1 or 2. Compounds provided herein are useful as antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic 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 by this invention, 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 substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be a 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 can contain for example 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-prop yl ene 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, flavours, stabilizing and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. Ointment preparations can contain heavy-metal salts of compounds 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. Merely incorporating or homogeneously admixing finely divided compounds may prepare suitable compositions with the hydrophilic carrier or base or ointment. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, 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 utilized in pharmaceutical compositions can be administered at initial dosages of from about 3 mg to about 40 mg per kilogram daily for example. The dosages, however, may be varied depending upon the requirements of the patient and the compound being employed. Determination of the proper dosage for a particular situation is within the ability of those of ordinary skill in the art. For example, small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired. There are provided processes for the synthesis of compounds of Formula I. Pharmaceutically acceptable non-toxic acid addition salts of the compounds of Formula I may be formed with inorganic or organic acids, by methods well-known in the art. Prodrugs of the compound of Formula I are also provided. 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. The invention also includes pharmaceutically acceptable salts, enantiomers, solvates, polymorphs, diastereomers, N-oxides, metabolites in combination with pharmaceutically acceptable carriers and optionally included excipients. Other objects and advantages of the invention 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. The objects and the advantages of the invention may be realized and obtained by means of the mechanism and combination pointed out in the appended claims. Detailed Description of the Invention The compounds provided herein may be prepared for example by following the illustrative reaction sequences as depicted in the schemes defined below.

Different amines of Formula II

Formula II

identified as six different molecular cores, namely

-(S)-N-({3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-oxazolidin-5-yl}methyl)acetamide (Core I);

-(+)-N-({3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-oxazolidin-5-yl}methyl)acetamide (Core II);

-(S)-N-({3-[3-Fluoro-4-(3-methyl-piperazin-l-yl)phenyl]-2-oxo-oxazolidin-5-yl} methyl) acetamide (Core III);

-(S)-N-({3-[3-Fluoro-4-(4-aminomethyl-piperidin-l-yl) phenyl]-2-oxo-oxazolidin-5-yl} methyl) acetamide (Core IV);

-(S)-N- [(3 - {3 -Fluoro-4- [3 -( 1 α,5 α,6α)-6-(N-methyl-N-amino)-3 -azabicyclo- [3.1.0]hexyl]phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide (Core V);

-(S)-N-({3-[3,5-Difluoro-4-(piperazin-l-yl)phenyl]-2-oxo-oxazolidin-5-yl}methyl) acetamide (Core VI) were used for analoguing purposes. Key intermediate amines of Formula II for the analogue preparation were prepared from commercially available reagents wherein amines of Formula II are defined as: M can be NH, CHNHCH₃, and Ri, R₂ and R₃ can be as defined for Formula I. Optically pure amines of Formula II could be obtained either by one of a number of asymmetric syntheses or alternatively by resolution from a racemic mixture by, for example, selective crystallization of a salt prepared, with an appropriate optically active acid such as dibenzoyl tartrate or 10-camphorsulfonic acid, followed by for example treatment with base to afford the optically pure amine. The compounds of the present invention represented by general Formula I may be prepared by the method of reaction in Schemes I, II, III, IV, V and VI: SCHEME-I

FORMULA I In Scheme I, the heteroaromatic group with any corresponding substituents can be introduced on the nitrogen atom of ring C of compounds of Formula II by, for example, methods described below, to give Formula I, wherein Rι₂ is a leaving group well known to one of ordinary skill in the art, such as fluoro, chloro, bromo, iodo, -SCH₃, -SO₂ CH ,- SO₂CF₃,ToS or -OC₆H etc., and Ri, R₂, R₃, R , R₅, R^, X and Q are the same as defined earlier. The amine of Formula II can be reacted with a heteroaromatic compound of Formula III to give a compound of Formula I. The reaction can be carried out in a solvent, such as dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide or ethylene glycol, at a temperature in the range of from about -70°C to about 180°C to afford compounds of Formula I. The presence of a base such as triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate, dipotassiumhydrogenphosphate useful in some cases to improve reaction yields. Alternatively, for the preparation of compounds of Formula I, heteroaromatic compounds of the Formula III, such as 2-bromo-thiophene, can be reacted with amines of Formula II in the presence of ligands such as palladium dibenzyhdene acetone [Pd₂(dba) ] or Pd(OAc)₂ with 2,2'-Bis-(diphenylphosphino)-l,l '-binapthyl (BINAP) and bases such as cesium carbonate or sodium t-butoxide (Ref: J. Org. Chem. (1999), 64, 6019-6022 and J. Org. Chem. (2000), 65, 1144-1157). Other ligands such as ethylenediamine or TMEDA along with bases such as cesium carbonate or potassium phosphate may also be used (Synlett, (2002), 3, 427-430).

SCHEME-II

FORMULA V

In Scheme II, a compound of Formula IV, wherein Rι is selected from -COOH, COOCH₃ or CHO, can be reacted with an organic base such as ammonia, hydroxylamine hydrochloride, dimethylamine, ethylamine or t-butylamine, to give a compound of Formula V, wherein R₁₄ is -CH=NOH, -CONH₂, -CON(CH₃)₂, -CONHC₂H₅ or - CONHC(CH₃)₃. The reaction can be carried out in a solvent such as tetrahydrofuran, ethanol, dimethylformamide, dimethylsulphoxide, diethylether, methanol, propanol or n- butanol, in the optional presence of a reagent such as sodium acetate, N-methylmorpholine or 1-hydroxybenzotriazole, and/or a coupling agent such as l-ethyl-3-[3- dimethylamino]propyl carbodiimide, 1,3-dicyclohexyl carbodiimide or 1,8- diazobicyclo[5.4.0]undec-7-ene.

SCHEME-1II

In Scheme III, a compound of Formula VI can be hydrolyzed to give a compound of Formula VII, wherein R₂, R₃, R_t, R , R and Q are the same as defined earlier, which on reaction with ClCOOCH₃, ClCOOC₂H₅, ClCH₂COCl, HCOOC₂H₅ or (CF₃CO)₂O gives a compound of Formula VIII, wherein R₁₅ is selected from H, OCH₃, OC₂Hs, CH₂C1, or CF₃. The hydrolysis can be carried out in the presence of a mineral acid such as hydrochloric acid in a solvent such as methanol, ethanol, propanol or n-butanol. The reaction of a compound of Formula VII to give a compound of Formula VIII can be carried out in the optional presence of an organic base such as triethylamine, trimethylamine, diisopropylethylamine or dimethylamine, in a solvent such as dichloromethane, tetrahydrofuran, dimehylformamide, dimethylsulphoxide or diethylether.

FORMULA IX

In Scheme IV, a compound of Formula VII can be reacted with CS₂ and ClCOOC H₅ to give a compound of Formula IX, wherein R₂, R₃, R , R₅, Rβ and Q are the same as defined earlier, which on reaction with methanol gives a compound of Formula X. The reaction of a compound of Formula VII to give a compound of Formula IX can be carried out in the presence of an organic base such as triethylamine, trimethylamine, diisopropylethyl amine or dimethylamine, in a solvent such as dichloromethane, tetrahydrofuran, dimehylformamide, dimethylsulphoxide or diethylether. The reaction of a compound of Formula IX to give a compound of Formula X can be carried out in the presence of an inorganic base such as sodium hydride, lithium hydride or sodium hydroxide.

SCHEME-V

FORMULA XI

FORMULA XII

In Scheme V, a compound of Formula XI can be reacted with monoperoxyphthahc acid magnesium salt hexahydrate to give a compound of Formula XII, wherein Ri, R₂, R₃, R₄, R₅, R_ and Q are the same as defined earlier. The reaction can be carried out in a solvent such as dichloromehane, dimethylformamide, tetrahydrofuran or dimethylsulphoxide .

SCHEME-VI

In Scheme VI, a compound of Formula XIII can be reacted with Lawesson's reagent to give a compound of Formula XIV, wherein R₂, R₃, R₄, R₅, R^ and Q are the same as defined earlier and Rι₆ is selected from H or CH3. The reaction is carried out in a solvent such as dioxane, dimethylformamide, dimethylsulphoxide or tetrahydrofuran. The transformations effected are described in the experimental section. In the above synthetic methods where specific acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. are mentioned, it is to be understood that the other acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. may also be used. Similarly, the reaction temperature and duration of the reaction may be adjusted as described. An illustrative list of particular compounds and capable of being produced by the above mentioned schemes include:

(S)-N-[(3-{3-Fluoro-4-[4-(5-carboxymethyl-furan-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 1)

(S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-2-nitro-thiophen-3-yl)-piperazin-l-yl] phenyl} -2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 2)

(S)-N-[(3-{3-Fluoro-4-[4-(5-difluoromethyl-2-nitro-thiophen-3-yl)-piperazin-l-yl] phenyl} -2-oxo-oxazolidin-5-yl) methyl] acetamide (Compound No. 3)

(S)-N-{[3-(3-Fluoro-4-{4-[(5-carboxyl-2-nitro)-thiophen-3-yl]-piperazin-l-yl} phenyl)-2- oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 4) (S)-N- {[3-(3-Fluoro-4- {4-[5-(carboxymethyl)-2-nitro-thiophen-3-yl]-piperazin-l -yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 5)

(S)-N- { [3 -(3-Fluoro-4- {4- [5 -(methylcarboxamido)-2-nitro-thiophen-3 -yl] - 1 -piperazinyl } phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 6)

(S)-N-{[3-(3-Fluoro-4-{4-[5-(n-butylcarboxamido)-2-nitro-thiophen-3-yl]-l -piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 7)

(S)-N-{[3-(3-Fluoro-4-{4-[5-(isopropylcarboxamido)-2-nitro-thiophen-3-yl]-l- piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 8)

(S)-N-{[3-(3-Fluoro-4-[4-{5-(benzylcarboxamido)-2-nitro-thiophen-3-yl]-l -piperazinyl] phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 9) (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-furan-2-yl)-piρerazin-l-yl]phenyl}-2-oxo-oxazolidin- 5-yl) methyl] acetamide (Compound No. 10)

(S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 11) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] amine (Compound No. 12)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] carbamic acid methyl ester (Compound No. 13)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] carbamic acid ethyl ester (Compound No. 14)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] thioacetamide (Compound No. 15)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] thioformamide (Compound No. 16) (S)-N-[(3-{3-Fluoro-4-[4-(5-carboxamido-2-nitro-thiophen-3-yl)-piperazin-l-yl] phenyl}- 2-oxo-oxazolidin-5-yl) methyl] acetamide (Compound No. 17)

(S)-N-{[3-(3-Fluoro-4-{4-[5-(hydroxyimino-methyl)-2-nitro-thiophen-3-yl]-piperazin-l- yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 18)

(S)-N-{[3-(3-Fluoro-4-{4-[5-(N,N-dimethylcarboxamido)-2-nitro-thiophen-3-yl]-l- piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 19)

(S)-N-[(3- (3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)- 1 -oxy-piperazin- 1 -yl]phenyl} -2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 20)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] trifluoroacetamide (Compound No. 21) (S)-N- [(3 - { 3 -Fluoro-4- [4-(5 -nitro-thiophen-2-yl)-piperazin- 1 -yl]phenyl} -2-oxo- oxazolidin-5-yl) methyl] chloroacetamide (Compound No. 22)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] formamide (Compound No. 23) (S)-N-{[3-(3-Fluoro-4-{4-[5-(ethylcarboxamido)-2-nitro-thiophen-3-yl]-l-piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 24)

(S)-N-{[3-(3-Fluoro-4-{4-[5-(t-butylcarboxamido)-2-nitro-thiophen-3-yl]-l -piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 25) (±)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-l-piperazinyl]phenyl}-2-oxo-oxazolidin- 5-yl) methyl] acetamide (Compound No. 26)

(S)-N-[(3-{3-Fluoro-4-[3-methyl-4-(5-nitro-furan-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 27)

(S)-N- { [3 -(3 -Fluoro-4- { 3 -methyl-4- [(5 -difluoromethyl-2-nitro)-thiophen-3 -yl]-piperazin- 1-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 28)

(S)-N- { [3 -(3 -Fluoro-4- { 3 -methyl-4- [(5 -cyano-2-nitro-)-thiophen-3 -yl] -piperazin- 1 -yl } phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 29)

(S)-N-{[3-(3-Fluoro-4-{3-methyl-4-[(5-carboxymethyl-2-nitro)-thiophen-3-yl]-piperazin- 1-yl} phenyl) -2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 30) (S)-N- {[3-(3-Fluoro-4- {4-amino-[N-methyl,N-(5-cyano-2-nitro)-thiophen-3-yl]-piperidin- l-yl}phenyl)-2-oxo-oxazolidin-5-yl]methyl} acetamide (Compound No. 31)

(S)-N-{[3-(3-Fluoro-4-{3-(lα,5α,6α)-6-[N-methyl-N-(5-nitro-furan-2-yl)amino]-3- azabicyclo- [3.1.0] hexyl}phenyl)-2-oxo-oxazolidin-5-yl]methyl}acetamide (Compound No. 32) (S)-N-[(3-{3,5-Difluoro-4-[4-(5-nitro-thioρhen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 33)

(S)-N-[(3-{3,5-Difluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] triflouromethyl acetamide (Compound No. 34)

(S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl)methyl]thiocarbamic acid methyl ester (Compound No. 35)

Pharmacological Testing The compounds provided herein displayed antibacterial activity when tested by the agar incorporation method. 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 DMSO and doubling dilution of the compounds was incorporated into Meer Hilton agar before solidification. Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbility to

0.5 Macfarland turbidity standard tables (1.5 x 10^ CFU/ml), after appropriate dilutions,

10^ CFU/spot was transferred into the surface of dried plate and incubated for 18 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 MIC's against standard antibiotics were within the acceptable range. The following minimum inhibitory concentrations (μg/ml) were obtained for representative compounds that are given below in the following Table I.

GUIDE TO TABLE ABBREVIATIONS:

1) S. aureus ATCC 25923 —Staphylococus aureus ATCC 25923

2) MRS A 15187 —Methicillin Resistant Staphylococcus aureus

3) Ewt. faecalis ATCC 29212 -Enterococcus faecalis ATCC 29212

4) Ent. faecium 6 A. — Enterococcus faecium 6A Van® ,Cipro®

5) Strep, pne. ATCC 6303 —Streptococcus pneumoniae ATCC 6303

6) Strep, pyog. ATCC 19615 Streptococcus pyogenes

7) M. cata. M₂ - Moraxella catarrhalis

8) H. z^'n/49247 —Haemophillus influenza

TABLE-1

The compounds of the present invention may be prepared by the method of reaction in Schemes I, II, III, IN, V and VI. Key intermediate amines of Formula II for the analogue preparation were prepared by the synthetic procedures described below or from commercially available reagents. Most of the compounds were characterized using ΝMR, IR and were purified by chromatography. Crude products were subjected to column chromato graphic purification using silica gel (100-200, 60-120 or 230-400 mesh) as stationary phase. The examples mentioned below demonstrate the general synthetic procedure as well as the specific preparation for the preferred compound. The examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.

Example 1: Preparation of Analogues of (S)-Ν-((3-[3-Fluoro-4-(Ν-piperazinyl,phenyl]-2- oxo-oxazolidin-5-yl} methyl) acetamide (Core I)

The heteroaromatic group with the corresponding appendage can be introduced on nitrogen atom of ring C of compounds of Formula I by the general methods described. The amine of Formula II is reacted with a heteroaromatic compound of Formula III having Rι₂ as a suitable leaving group such as fluoro, chloro, bromo, iodo, SCH₃, - SO₂CH₃, -SO₂CF₃, Tos or OC₆H₅ etc. as defined earlier for Scheme I. Q, 1^, R₅ and R₆ as defined for Formula I. The reaction is carried out in a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide or ethylene glycol at a temperature in the range of -70°C to 180°C to afford compounds of Formula I. The presence of a base such as triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate, dipotassium hydrogenphosphate can be useful in some cases to improve the yield of the reaction. The following compounds were made following this method:

Compound No. 1: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-carboxymethyl-furan-2- yl)-piperazin-l-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide

Step a: Preparation of methyl 5-bromo-2-furoate To 5-bromo-2-furoic acid (6 g) in methanol (17 mL), concentrated sulfuric acid (2.5 mL) was added and stirred at room temperature for about 48 hours. Further methanol (10 mL) and concentrated sulfuric acid (2 mL) were added and stirred for about 17 hours. The reaction mixture was evaporated and the residue was taken in dichloromethane, washed with sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to yield 1.97 g of product. Step b: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-carboxymet__yl-furan-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl] -2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (1.15 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 11.5 mmol) and methyl 5-bromo-2-furoate was added and heated at 80 °C for about 48 hrs. Further 2 mL of N-ethyl-diisopropylamine was added and the reaction mixture was heated for further 24 hrs. The reaction mixture was cooled; water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 0.03 g of the title compound.

1H NMR (CDC1₃) δppm: 7.47 (d, IH), 7.16 (d, IH), 7.08 (d, IH), 6.95 (t, IH), 6.18 (t, IH), 5.25 (d, IH), 4.77 (m, IH), 4.02 (t, IH), 3.72 (s, 3H), 3.49 (m, 4H), 3.15 (m, 4H), 2.02 (s, 3H) M+H -461 LR (cm^'1): 1743, 1705, 1668 m.p. = 190.6-192.9 °C

Compound No. 2: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-2-nitro-thiophen- 3-yl)-piperazin-l-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide

Step a: Preparation of 4-bromo-5-nitro-thiophene-2-carboxaldehyde oxime To a solution of 4-bromo-5-nitro-thiophene-2-carboxaldehyde (0.0163 mole) in ethanol, sodium acetate (0.057 mol) and hydroxylamine hydrochloride (0.0491 mole) were added. The reaction mixture was stirred at room temperature for 18 hrs. After completion of the reaction, solvent was removed under reduced pressure. The residue obtained was partitioned between ethyl acetate and aqueous potassium carbonate solution .The organic layer was separated and dried over anhydrous sodium sulphate and then concentrated under reduced pressure and dried under high vaccum to yield 1.6 gm of the title compound. Η NMR (CDCI3) δppm: 8.15 (s, IH), 7.67-7.69 (d, IH)

Step b: Preparation of 4-bromo-2-cyano-5-n_trot__iophene To a solution of 4-bromo-5-nitro-thiophene-2-carboxaldehyde oxime (1.992 mmol) in dichloromethane (10 ml) was added triethylamine (3.989 mmol). The reaction mixture was cooled to -78°C and then triflic anhydride was added dropwise while maintaining the temperature between -78°C to -65°C. After addition the reaction mixture temperature was brought to the room temperature over a period of 4 hours stirring. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The crude product obtained was purified by column chromatography using silica gel 100-200 mesh size and eluent 2-5 % ethyl acetate in hexane. Yield : 0.18 gm

Η NMR (CDCI₃) δppm: 7.582 (s, IH). IR in KBr: CN^" = 2223.4 cm-1 Step c: Preparation of (S)-N-[(3-{3-FIuoro-4-[4-(5-cyano-2-nitro-thiophen-3-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl]-2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.668 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (1.2 mL, 6.68 mmol) and 4-bromo-2-cyano-5-nitrothiophene (0.755 mmole) was added and the reaction mixture was heated at 60°C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 0.2 gm of the title compound. Η NMR (DMSO) δppm: 8.24 (t, IH), 8.02 (s, IH), 7.52(d, IH), 7.08-7.21 (m, 2H), 4.68- 4.73 (m, IH), 4.09(t, IH), 3.715(t, IH), 3.59(m, 4H), 3.14(m, 4H), 1.836(s, 3H).

Compound No.3: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-difluoromethyl-2-nitro- thiophen-3-yl)-piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyI]acetamide

Step a: Preparation of 3-bromo-5-diflouoromethyI-2- nitro-thiophene To a solution of 4-bromo-5-nitro-thiophene-2-carboxaldehyde (600 mg, 2.521 mmole) in dichloromethane was added diethylaminosulphur trifluoride (6.302 mmol) at 0 C. The reaction mixture was stirred at room temperature for 4hours. It was diluted with dichloromethane and washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried on anhydrous sodium sulphate and evaporated under reduced pressure to get 510 mg of the title compound. Η NMR (CDC1₃) δppm: 7.228(s, IH), 6.794(t, IH)

Step b: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-difluoromethyl-2-nitro-t__iopt_en- 3-yl)-piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl] -2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.917 mmol) in acetonitrile (20 mL), N-ethyl-diisopropylamine (2 mL, 9.17 mmol) and 3- bromo-5-difluoromethyl-2-nitrothiophene (1.0 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield the title compound.

Η NMR (DMSO) δppm: 8.24(m, IH), 7.44-7.54 (dd, 2H), 7.08-7.25(m, 3H), 4.71(m, IH), 4.09(t, IH), 3.71(tlH), 3.60(m, 4H), 3.26(m, 4H), 1.84(s, 3H)

Compound No. 4: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[(5-carboxyl-2-nitro)- thiophen-3-y_]-piperazin-l-yl}pheny_)-2-oxo-oxazolidin-5-yl]methyl} acetamide Step a: Preparation of of 4-bromo-5- nitro-thiophene-2-carboxylic acid To a solution of 4-bromo-5-nitro-thiophene-2-carboxaldehyde (l.Ogm, 0.0042 mole) sodium carbonate (0.00084 mole) (dissolved in 5ml of water) and potassium permanganate (0.00546 mole, dissolved in 20 ml of water) was added at 0 C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a celite bed and washed with water. The filtrate was acidified with concentrated H₂SO₄ up to pH- 2, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure. The residue obtained was triturated with hexane, filtered and dried to get 595mg of the title compound. Step b: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[(5-carboxyl-2-nitro)-thiophen-3-yl]- piperazin-l-yI}phenyl)-2-oxo-oxazolidin-5-yl]methyl}acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl] -2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.802 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 8.02 mmol) and 4-bromo -5-nitrothiophene-2-carboxylic (0.883 mmole) acid was added and the reaction mixture was heated to 60 °C for about 24 hours. The reaction mixture was concentrated under reduced pressure, residue obtained was treated with saturated solution of citric acid to acidify. The solid separated was filtered, washed with water and then dried. The crude product obtained was then dissolved in dichloromethane and methanol mixture to make clear solution and then dried on anhydrous sodium sulphate and concentrated under reduced pressure. Residue obtained was triturated with ether, solid separated was filtered and dried to yield 150 mg of the title compound.

1H NMR (DMSO) δppm: 8.25(m, IH), 7.51(d, 2H), 7.13-7.21(m,2H), 4.71(m,lH), 4.09(t,lH), 3.69-3.74(m,3H), 3.57(m,4H), 3.14(m,4H), 1.84(s,3H).

Compound No. 5: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(carboxymethyl)-2- nitro-thiophen-3-yl]-piperazin-l-yl}phenyl)-2-oxo-oxazolidin-5-yl]methyl] acetamide

Step a: Preparation of of 4-bromo-5- nitro-thiophene-2-carboxylic acid methyl ester To a solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid (350mg, 1.14mmole) in methanol (5ml) was added concentrated H SO₄ (3ml). The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was taken in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was triturated with hexane; solid separated was filtered and dried to get 220 mg ofthe title compound.

Η NMR (CDC1₃) δppm: 7.71(s, IH), 3.96(s, 3H)

Step b: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(carboxymethyl)-2-nitro-thiophen- 3-yl]-piperazin-l-yl}phenyl)-2-oxo-oxazolidin-5-yl]methyI] acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl] -2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.802 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 8.02 mmol) and 4-bromo-5-nitrothiophene-2-carboxylic acid methyl ester (0.802 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled, solid separated was filtered, washed with ether and dried to yield 336 mg of the title compound. 1H NMR (DMSO) δppm: 8.23(t,lH), 7.68(s,lH), 7.49(d,lH), 7.12-7.2 l(m,2H), 4.70 m,lH), 4.09 (t,lH),3.89(s,3H), 3.71(t,lH), 3.68(m,2H), 3.59(m,4H), 3.13(m,4H), 1.836(s,3H).

Compound No. 6: Preparation of (S)-N- {[3-(3-Fluoro-4- {4-[5-(methylcarboxamido)- 2-nitro-thiophen-3-yl]-l-piperazinyl}phenyl]-2-oxo-oxazolidin-5-yl]methyl} acetamide

Step a: Preparation of 4-bromo-5-nitrothiophene-2-carboxylic acid methylamide To a solution of 4-bromo-5-nitrothiophene-2-carboxylic acid (0.793 mmole) in tetrahydrofuran (15mL) were added N-methyl morpholine (2.38 mmole) and isobutyl chloro formate (0.793 mmole) at -10 to 0 C under nitrogen. The reaction mixture was stirred at this temperature for about 1 hour, and then methylamine hydrochloride (1.19 m. mole) was added. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, dried under high vacuum to yield 180 mg of the title compound.

Step b: Preparation of (S)-N- {[3-(3-Fluoro-4- {4-[5-(methylcarboxamido)-2-nitro- thiophen-3-yl]-l-piperaz_nyI}phenyl]-2-oxo-oxazolidin-5-y_]methyl} acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl] -2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.630 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 6.30 mmol) and 4- bromo-5-nitrothiophene-2-carboxylic acid methylamide (0.63 mmole) was added and the reaction mixture was heated to 60 °C for about 20 hours. The reaction mixture was cooled, water was added and stirred at room temperature for about 10 minutes, and solid separated was filtered out. The crude obtained was digested with ethanol and ether (1 :4), then filtered and dried to yield 105 mg of the title compound. 1H NMR (DMSO) δppm: 8.84-8.85(m, IH), 8.22-8.24(m, IH), 7.67(s, IH), 7.49-7.54(d, IH), 7.12-7.20(m, 2H), 4.70(m, IH), 4.106-4.122(t, IH), 3.69-3.74(t, IH), 3.55(m, 4H), 3.42-3.44(m, 2H), 3.26 (m, 4H), 1.83(s, 3H). m.p. = 260-262 °C

Compound No. 7: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(n-butylcarboxamido)- 2-nitro-thiophen-3-yl]-l-piperazinyl}phenyl)-2-oxo-oxazolidin-5-yl]methyl}acetamide

Step a: Preparation of 4-bromo-5-nitrothiophene-2-carboxylic acid n-butyl amide To a solution of 4-bromo-5 -nitro thiophene-2-carboxylic acid (0.793 m. mole) in terahydrofuran (15mL) were added N-methyl morpholine (2.38 m. mole) and isobutyl chloroformate (0.793 m. mole) at -10 to 0 °C under nitrogen. The reaction mixture was stirred at this temperature for about 1 hour, and then n-butyl amine (1.19 m. mole) was added. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried on anhydrous sodium sulphate and concentrated under reduced pressure, dried under high vacuum to yield 180 mg of the title compound.

Step b: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(n-butylcarboxamido)-2-nitro- thiophen-3-yl]-l-piperazinyl}phenyl)-2-oxo-oxazolidin-5-yl]methyl}acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl]-2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.630 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 6.30 mmol) and 4-bromo -5-nitrothiophene-2-carboxylic acid -n-butylamide (0.630 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled, water was added and then stirred at room temperature for about 15 minutes, solid separated was filtered and dried. The crude obtained was digested with ethanol and ether (1:4), solid separated was filtered, and dried to yield 125 mg of the title compound.

Η NMR (DMSO) δppm: 8.82-8.84(m,lH), 8.22-8.30(m,lH), 7.71(s,lH), 7.49- 7.54(d,lH), 7.12-7.21(m,2H), 4.71(m,lH), 4.06-4.12(t,lH), 3.69-3.74(t,lH), 3.56(m,4H), 3.27-3.29 (m,2H),3.17(m,4H), 1.83(s,3H),1.48-1.53(m,2H), 1.26-1.37(m,2H), 0.88-0.933 (t,3H). m.p. = 229.4-231.5 ° C Compound No. 8: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5- (isopropylcarboxamido)-2-nitro-thiophen-3-yl]-l-piperazinyl}phenyl)-2-oxo- oxazolidin-5-yl] methyl} acetamide

Step a: Preparation of 4-bromo-5-nitrothiop__ene-2-carboxylic acid isopropylamide To a solution of 4-bromo-5-nitrothiophene-2-carboxylic acid (0.793 m. mole) in tetrahydrofuran 15mL) were added N-methyl morpholine (2.38 m. mole) and isobutyl chloro formate (0.793 m. mole) at -10 to 0 °C under nitrogen. The reaction mixture was stirred at the same temperature for about 1 hour, and then isopropyl amine (1.19 mmole) was added. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure, and dried under high vacuum to yield 184 mg of the title compound.

Step b: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(isopropylcarboxamido)-2-nitro- thiophen-3-yl]-l-piperazinyl}phenyl)-2-oxo-oxazolidin-5-yl]methyl} acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl]-2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.57 mmol) in acetonitrile (10 L), N-ethyl-diisopropylamine (2 mL, 5.73 mmol) and 4- bromo-5-nitrothiophene-2-carboxylic acid isopropylamide (0.573 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to yield 200 mg of the title compound.

1H NMR (DMSO) δppm: 8.61-8.64(m, IH), 8.21-8.25(m, IH), 7.75(s, IH), 7.49-7.54(d, IH), 7.13-7.22(m, 2H), 4.70(m, IH), 4.06-4.09 (t, IH), 3.63-3.65(t, IH), 3.56-3.65(m, 6H), 3.42(m, IH), 3.12-3.27 (m, 4H), 1.83(s, 3H), 1.26-1.28(d, 6H). m.p.=130-132° C Compound No. 9: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(benzylcarboxamido)-2- nitro-thiophen-3-yl}-l-piperazinyl}pheny_)-2-oxo-oxazolidin-5-yl}methyl] acetamide

Step a: Preparation of 4-bromo-5-nitrothiophene-2-carboxylic acid benzyl amide To a solution of 4-bromo-5-nitrothiophene-2-carboxylic acid (0.527 mmole) in tetrahydrofuran (15mL) were added N-methyl morpholine (1.58 mmole) and isobutyl chloroformate (0.527 m. mole) at -10 to 0°C under nitrogen. The reaction mixture was stirred this same temperature for about 1 hour, and then benzyl amine (0.686 mmole) was added. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure, and dried under high vacuum to yield 140 mg of the title compound.

Step b: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(benzylcarboxamido)-2-nitro- thiophen-3-yl}-l-piperazinyl}phenyl)-2-oxo-oxazolidin-5-yl}methyl] acetamide To a solution of (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl) phenyl]-2-oxo-oxazolidin- 5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.401 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 4.01 mmol) and 4- bromo-5 -nitro thiophene-2-carboxylic acid benzylamide (0.401 m. mole) was added and the reaction mixture was heated to 60 °C for about 17 hours. Further 2 mL of N-ethyl- diisopropylamine was added and the reaction mixture was heated for further 24 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to yield 105 mg of the title compound. 1H NMR (DMSO) δppm: 9.39(m, IH), 8.20-8.24(m, IH), 7.80(s, IH), 7.49-7.54(d, IH), 7.27-7.38(m, 5H), 7.12-7.18(m, 2H), 4.71(m, IH), 4.48 (s, 2H), 4.06-4.12(t, IH), 3.69- 3.74(t, IH), 3.61-3.65(m, 4H), 3.42(m, 2H), 3.16-3.23(m, 4H), 1.83(s, 3H). m.p. = 146.3-147.5 ° C

Compound No. 10: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-furan-2-yl)- piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl] acetamide Step a: Preparation of 5-bromo-2-furyloxime To 5-bromo-2-furaldehyde (4 g, 0.023 mole) in absolute alcohol (40 mL), hydroxylamine hydrochloride (1.9 g, 0.027 mole), and pyridine (9 g, 0.114 mol) were added and stirred at room temperature for about 17 hours. The reaction mixture was evaporated in vacuo. The residue in dichloromethane was washed with citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to yield 4 g of a semi solid product.

Step b: Preparation of 2-bromo-5-cyanofuran 5-bromo-2-furyloxime (2 g) in acetic anhydride (20 mL) was heated to 100 °C for about 17 hours. The reaction mixture was cooled, saturated sodium bicarbonate solution was added and stirred for about 30 minutes. The reaction mixture was extracted with dichloromethane and washed with sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography 0-1% ethyl acetate in hexane to yield 0.3 g of product.

Step c: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-furan-2-yl)-piperazin-l- yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl] acetamide To (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl)phenyl]-2-oxo-oxazolidin-5-yl}methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.5 g, 1.48 mmol) in dry dimethylformamide, 2-bromo-5-cyanofuran (0.26g, 1.48 mmol), cesium carbonate (0.58g, 1.78mmol), rac-2, 2' bis(diphenylphosphino)-l,l'-binaphthyl (0.074g,0.12mmol), tris(dibenzylideneacetone)dipalladium (0) ( 0.054 g, 0.06 mmol), were added and heated to 95 °C for about 10 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography using 1-3 % methanol/dichloromethane to yield 0.052 g of the title compound. Η NMR (CDC1₃) δppm: 7.46 (dd, IH), 7.09 (dd. IH), 7.03 (d, IH), 6.95 (t, IH), 5.99 (t, IH), 5.18 (d, IH), 4.76 (m, IH), 3.99 (t, IH), 3.6-3.8 (m, 3H), 3.46 (m, 4H), 3.15 (m, 4H), 2.0 (s, 3H) M+H = 428 IR (cm-l): 2205, 1748, 1646 m.p. =164-171 °C

Compound No. 11: Preparation of (S)-N-[(3-{3-FIuoro-4-[4-(5-cyano-thiophen-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide

Step a: Preparation of 5-bromo-thiophen-2yl-oxime To 5-bromo-2-thiophene carboxaldehyde (5 g, 0.026 mol) in absolute ethanol (40 mL), hydroxylamine hydrochloride (2.18 g, 0.031 mol), and pyridine (10.35 g, 0.13 mol) were added and stirred at room temperature for about 17 hours. The reaction mixture was evaporated in vacuo. The residue in dichloromethane was washed with citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was triturated in hexane and filtered to yield 3.9 g product. Step b: Preparation of 2-bromo-5-cyanothiophene 5-bromo-thiophen-2-yl-oxime (0.75 g) in acetic anhydride (5 mL) was heated to 100 °C for about 17 hours. The reaction mixture was cooled and saturated sodium bicarbonate solution was added and stirred for about 30 minutes. The reaction mixture was extracted with dichloromethane, washed with sodium bicarbonate solution, water and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography 0-0.5% ethyl acetate in hexane to yield 0.25 g of product.

Step c: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-thiophen-2-yl)-piperazin-l- yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl)phenyl]-2-oxo-oxazolidin-5-yl}methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (0.5 g, 1.48 mmol) in dry dimethylformamide, 2-bromo-5-cyanothiophene (0.27g, 1.48 mmol), cesium carbonate (0.58g,1.78mmol), rac-2, 2' bis(diphenylphosphino)-l,l'-binaphthyl (0.074g, 0.12 mmol), _ris(dibenzylideneacetone)dipalladium (0) ( 0.055 g, 0.06 mmol), were added and heated to 95 °C for about 10 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography using 1-3 % methanol/dichloromethane to yield 0.037 g of the title compound. 1H NMR (DMSO) δppm: 8.25 (t, IH), 7.64 (d, IH), 7.51 (dd, IH), 7.19 (dd, IH), 7.13 (t, IH), 6.32 (d, IH), 4.72 (m, IH), 4.1 (t, IH), 3.70 (m, 2H), 3.14 (m, 4H), 1.83 (s, 3H) M+H = 444 m.p. = 204-207° C

Compound No.12: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] amine Step a: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l- yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To (S)-N-({3-[3-Fluoro-4-(piperazin-l-yl)phenyl]-2-oxo-oxazolidin-5-yl} methyl]) acetamide trifluroacetate prepared by the method given in U.S. Patent No. 5,700,799 (4.58 mmol) in acetonitrile (40 ml), N-ethyl-diisopropylamine (5.9 g, 0.045 mol) and 2-bromo- 5-nitro-thiophene (0.86g, 5.27 mmol) (commercially available) were added and heated at 60°C for 4 hrs. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water and saturated sodium chloride solution. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using dichloromethane500mL, 1% methanol/dichloromethane 200 mL, 2% methanol/dichloromethane 200 mL, 3% methanol/dichloromethane 500mL. The product eluted in 3% methanol/dichloromethane. The product was sonicated in diethylether for 10 min, filtered and dried in air to get 0.493 g of the title compound. m.p. 171-174°C

1H NMR (CDC1₃) δppm: 7.8 (d, IH), 7.5 (dd, IH), 6.97 (t, IH), 6.02 (m, 2H), 4.77 (m, IH), 4.01 (t, IH), 3.5-3.85 (m, 7H), 3.23 (m, 4H), 2.03 (s, 2 H)

M+l=464,M+Na=486,M+K=502,M-NO₂ = 418

Step b: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)-piperazin-l- yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] amine To a suspension of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l- yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]acetamide (6.9 g) in absolute ethanol (140 mL), 3N hydrochloric acid (140 mL) was added and heated to 90-100 °C for 8 hrs. The reaction mixture was cooled and made alkaline to pH 10-12 with 3N sodium hydroxide. The product precipitated was filtered and washed with water and dried in a vacuum dessicator over phosphorus pentoxide to yield 3.5 g of the title compound. 1H NMR (CDCI₃ + DMSO) δppm: 7.81 (d, IH), 7.52 (IH), 7.14 (d, IH), 6.99 (t, 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)

Compound No. 13: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-y_)- piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-y_)methyl]carbamic acid methyl ester To (S)-N- [(3 - {3 -Fluoro-4- [4-(5 -nitro-thioρhen-2-yl)-piperazin- 1 -yl]phenyl} -2- oxo-oxazolidin-5-yl)methyl]amine (0.14 g, 0.33 mmol) in dry dichloromethane (lOmL) under nitrogen balloon, triethylamine (0.07 g, 0.73 mmol) and methylchloroformate (0.034 g, 0.36 mmol) was added and the reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product was sonicated in ether and filtered to yield 0.065 g of the title compound. Η NMR (CD₃CN) δppm: 7.81 (d, IH), 7.5 (dd, IH), 7.16 (d, IH), 7.07 (t, IH), 6.17 (d, IH), 5.84 (m, IH), 4.7 (m, IH), 4.04 (t, IH), 3.73 (t, IH), 3.58 (m, 7H), 3.44 (m, 2H), 3.18 (m, 4H) M+H = 480, M+Na = 502 m.p. = 229-231 °C

Compound No. 14: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] carbamic acid ethyl ester To (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)-piperazin-l-yl] phenyl}-2- oxo-oxazolidin-5-yl) methyl] amine (0.4g, 0.95 mmol) in dry dichloromethane (lOmL) under nitrogen balloon, triethylamine (0.07 g, 0.73 mmol) and ethylchloroformate (0.12g, 1.14 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product was sonicated in ether and filtered to get (0.18g) of the title compound.

Η NMR (CDC1₃) δppm: 7.8 (d, IH), 7.49 (dd, IH), 7.12 (d, IH), 6.95 (t, IH), 6.01 (d, IH), 5.09 (t, IH), 4.77 (m, IH), 4.11 (m, 2H), 4.03 (t, IH), 3.8 (t, IH), 3.56 (m, 6H), 3.21 (m, 4H), 1.23 (t, 3H) M+H = 494.5, M+Na = 516.4, M-NO2 = 448.2 m.ρ.= 169-170 °C

Compound No. 15: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiop__en-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] thioacetamide To (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)-piperazin-l-yl] phenyl}-2- oxo-oxazolidin-5-yl) methyl] acetamide (0.5 g, 1.07 mmol) in dioxane (15 mL),

Lawesson's reagent (0.46 g, 1.13 mmol) was added and heated to 80 °C for about 3 hours.

The reaction mixture was cooled and diluted with water and extracted with ethyl acetate.

The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product eluted in 1 % methanol/dichloromethane and was sonicated in diethyl ether and filtered to yield 0.2 g of the title compound. 1H NMR (DMSO) δppm: 10.36 (t, IH), 7.95 (d, IH), 7.52 (dd, IH), 7.21 (d, IH), 7.13 (t, IH), 6.41 (d, IH), 4.94 (m, IH), 4.14 (t, IH), 3.91 (m, 2H), 3.80 (t, IH), 3.62 (m, 4H), 3.14 (m, 4H), 2.44 (s, 3H) m.p: 181-183 °C Compound No. 16: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)- piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]thioformamide To (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)-piperazin-l-yl] phenyl}-2- oxo-oxazolidin-5-yl) methyl] formamide (0.4g, 0.86 mmol) in dioxane (15 mL), Lawesson's reagent (0.37g, 0.9 mmol) was added and heated to 80-90 °C for about 8 hours. The reaction mixture was cooled and diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product eluted in 1 % methanol/dichloromethane and was sonicated in diethylether and filtered to yield 0.07 g of the title compound. 1H NMR (DMSO) δppm: 10.6 (m, IH), 9.36 (d, IH), 7.94 (d, IH), 7.54 (dd, IH), 7.2 (d,lH), 7.12 (t, IH), 6.41 (d, IH), 4.96 (m, IH), 4.15 (t, IH), 3.97 (t, 2H), 3.8 (t, IH), 3.62 (m,4H), 3.25 (m, 4H)

M+H = 466, M+Na = 488, M-NO₂ = 420

Compound No. 17: Preparation of (S)-N- [(3-{3-FIuoro-4- [4-(5-carboxamido-2-nitro- thiophen-3-yl)-piperazin-l-y_] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To a solution of (S)-N- {[3-(3-Fluoro-4- {4-[5-(carboxymethyl)-2-nitro-thiophen- 3-yl]-piperazin-l-yl}phenyl)-2-oxo-oxazolidin-5-yl]methyl}acetamide(100mg) in tetrahydrofuran, ammonia solution (10 ml in excess) was added and stirred at 10-20° C for about 6 hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum to get crude product, which was purified by column chromatography using silica gel of 100-200-mesh size. The product was eluted in 1% to 3% methanol in dichloromethane and concentrated under reduced pressure. The residue obtained was triturated with diethyl ether, filtered and air dried to yield 60 mg of the title compound. 1H NMR (DMSO) δppm: 8.32(s, IH), 8.25(t, IH), 7.95(s, IH), 7.73(s, IH), 7.50-7.55(d, IH), 7.10-7.22(m, 2H), 4.71(m, IH), 4.09(t, IH), 3.71(t, IH), 3.55(m, 4H), 3.49(m, 2H), 3.26(m, 4H), 1.83(s, 3H). m.p. =242.5-243.8 ° C

Compound No. 18: Preparation of (S)-N- {[3-(3-Fluoro-4- {4-[5-(hydroxyimino- methyl)-2-nitro-thiophen-3-yl]-piperazin-l-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide To a solution of (S)-N- [(3-{3-Fluoro-4- [4-(5-carboxaldehyde-5-nitro-thiophen-4- yl)-piperazin-l-yl] phenyl} -2-oxo-oxazolidin-5-yl) methyl] acetamide (120 mg, 0.260 mmol) in ethanol, sodium acetate (74.89 mg, 0.913 mmol) and hydroxylamine hydrochloride (54.38 mg, 0.782 mmole) were added. The reaction mixture was stirred at room temperature for about 18 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was triturated with water (25ml), solid separated was filtered and washed with ether. The crude product was then digested with ether: ethanol (25ml) (4:1) and filtered, dried under high vacuum to get 43 mg of the title compound.

Η NMR (DMSO) δppm: 8.65(s, IH), 8.26(t, IH), 7.49-7.54(d, IH), 7.13-7.17(m, 2H), 6.55(s, IH), 4.71(m, IH), 4.09(t, IH), 3.71(t, IH), 3.56(m, 4H), 3.44(m, 2H), 3.13(m, 4H), 1.83(s, IH). m.p. = 199-201 ° C

Compound No. 19: Preparation of (S)-N-{[3-(3-Fluoro-4-{4-[5-(N,N-dimethyl - carboxamido)-2-nitro-thiophen-3-yl]l-piperazinyl}phenyl)-2-oxo-oxazolidin-5- yl] methyl} acetamide To a solution of (S)-N- {[(3 -(3 -Fluoro-4- {4-[5-(carboxymethyl)-2-nitro-thiophen- 3-yl]-piperazin-l-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (lOOmg) in tetrahydrofuran was added aqueous dimethyl amine. The reaction mixture was heated at 40°C in a closed system for about 4 hours. The reaction mixture was concentrated under reduced pressure at 50°C. The residue obtained was purified by column chromatography using silica gel 100-200 mesh size using 1-2% methanol in dichloromethane as eluant to yield 50 mg of the title compound.

Η NMR (DMSO) δppm: 8.197-8.217(m, IH), 7.475-7.525(d, IH), 7.306(s,!H), 7.089- 7.172(m,2H), 4.699(m,lH), 4.080(t,lH), 3.696(t,lH), 3.578(m,4H), 3.41(m,2H), 3.30(s,6H), 3.13(m,4H), 1.822(s,3H). Compound No. 20: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- 1-oxy-piperazin-l-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thioρhen-2-yl)-piperazin-l-yl] phenyl}-2- oxo-oxazolidin-5-yl) methyl] acetamide (0.5 g, 1.07 mmol) in methanol (20 mL), monoperoxyphthahc acid magnesium salt hexahydrate was added. To it dichloromethane (30 mL) was added and the reaction mixture was stirred for about 2 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was made slurry with silica gel (100-200 mesh) and purified by column chromatography using 0-10% methanolic ammonia chloroform. The product eluted in 10 % methanolic ammonia chloroform. The product was sonicated in di ethyl ether and filtered to yield 0.25 g of the title compound.

1H NMR (DMSO) δppm: 8. 6 (t, IH), 8.27(m, IH), 7.98 (d, IH), 7.70 (dd, IH), 7.47 (d, IH), 6.46 (d, IH), 4.78 (m, IH), 4.15 (m, 5H), 3.80 (m, 3H) 3.15 (m, 2H), 1.84 (s, 3H) M+H = 480.4, M+Na = 501.9, M-NO₂ = 434.4 m.p.: 167-169 °C.

Compound No 21: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] trifluoroacetamide To a stirred suspension of (S)-N- [(3- {3 -Fluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-1-yl] phenyl} -2-oxo-oxazolidin-5-yl) methyl] amine (0.4 g, 0.95 mmol) in tetrahydrofuran (20 mL), triethylamine (0.15 g, 1.42 mmol) and trifluoroacetic anhydride (0.25 g, 1.23 mmol) was added and stirred at room temperature for about 6 hours. Further 0.25 g of trifluoroacetic anhydride was added and the reaction mixture was stirred for about 17 hours. The reaction mixture was diluted with dichloromethane and washed with water, sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product was sonicated in ether and filtered to yeild 0.27 g of the title compound.

Η NMR (CDC1₃ + DMSO) δppm: 7.84 (d, IH), 7.47 (d, IH), 7.12 (d, IH), 7.00 (t, IH), 6.10 (d, IH), 4.84 (m, IH), 4.13 (m, IH), 3.5-3.85 (m, 7H), 3.24 (m, 4H) M+H = 518, M-NO₂ = 472 m.p.: 227-228 °C. Compound No. 22: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] chloroacetamide To a solution of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)-piperazin-l-yl] phenyl} -2-oxo-oxazolidin-5-yl) methyl] amine (0.2 g, 0.475 mmol) in N, N dimethylformamide (10 mL) cooled to 5 °C, chloroacetylchloride (0.064 g, 0.57 mmol) was added and stirred for about 3 hours allowing the reaction mixture to warm to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product was sonicated in ether and filtered to yield 0.15 g of the title compound.

Η NMR (DMSO) δppm: 8.61 (br s, IH), 7.94 (br s, IH), 7.52 (d, IH), 7.17 (m, 3H), 6.41 (br s, IH), 4.75 (m, IH), 4.09 (s, 3H), 3.62 (m, 5H), 3.14 (m, 4H), 2.41(s, IH), 2.3 (s, IH). M+H = 498, M+NH₄ ⁺= 515, M-NO₂ = 452 m.p. = 217-218 °C Compound No. 23: Preparation of (S)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl] methyl] formamide (S)-N- [(3-{3- Fluoro-4- [4-(5-nitro-thiophen-2-yl)-piperazin-l-yl] phenyl} -2-oxo-oxazolidin-5-yl) methyl] amine (0.22 g) in ethylformate (lOmL) was heated to reflux for about 17 hours. The reaction mixture was evaporated in vacuo. The residue was purified by column chromatography using 0-2% methanol/dichloromethane. The product was triturated in ether and filtered to get 0.12 yield of the title compound.

1H NMR (CDC1₃) δppm: 8.29 (s, IH), 7.79 (d, IH), 7.54 (dd, IH), 7.13 (m, 2H), 6.12 (t, IH), 6.02 (d, IH), 4.82 (m, IH), 4.05 (t, IH), 3.7-3.9 (m, 3H), 3.6 (m, 4H), 3.29 (m, 4H) M+H = 450, M+Na = 472 m.p. = 174-176 °C m.p. = 70-71 °C

Compound No. 24: Preparation of (S)-N- {[3-(3-Fluoro-4- {4-[5-(ethylcarboxamido)- 2-nitro-thiophen-3-yl]-l-piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide To a solution of (S)-N- {[3-(3-Fluoro-4- {4-[5-(carboxymethyl)-2-nitro-thiophen-

3-yl)-piperazin-l-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (150mg) in tetrahydrofuran was added aqueous ethylamine. The reaction mixture was heated at 40°C under closed system for about 4 hours. The reaction mixture was concentrated under reduced pressure at 50°C. The residue obtained was purified by column chromatography using silica gel 100-200 mesh size and using 1-2% methanol in dichloromethane as eluant to yield 85 mg of the title compound.

1H NMR (DMSO) δppm: 8.86 (m, IH), 8.25(m, IH), 7.71 (s, IH), 7.50-7.54(d, IH), 7.10- 7.18(m, 2H), 4.71(m, IH), 4.09(t, IH), 3.71(t, IH), 3.56 (m, 4H), 3.41(m, 4H), 3.17 (m, 4H), 1.83 (s, 3H), 1.14(t, 3H).

Compound No. 25: Preparation of (S)-N- {[3-(3-Fluoro-4- {4-[5-(t- butylcarboxamido)-2-nitro-thiophen-3-yl]-l-piperazinyI} phenyl)-2-oxo-oxazolidin-5- yl] methyl} acetamide To a solution of (S)-N- {[3-(3-Fluoro-4- {4-[(5-carboxyl-2-nitro)-thiophen-3-yl]- piperazin-1-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (90mg, 0.177 mmole) in dimethylformamide were added N-methyl morpholine, 1-hydroxybenzotriazole (0.213 mmole) and tert-butylamine (51.8mg 0.710 mmole) at 0°C. The reaction mixture was stirred at this temperature for about 1.5 hours, then l-ethyl-3- [3-dimethylamino propyl] carbodiimide (40.6 mg, 0.213mmole) was added to it and then it was stirred overnight at room temperature. 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 silica gel 100-200 mesh size and eluent is 1-2% methanol in dichloromethane to yield 35 mg of the title compound.

Η NMR (DMSO) δppm: 8.30 (m, IH), 8.16(m, IH), 7.79(s, IH), 7.49-7.54(d, IH), 7.10- 7.21(m, 2H), 4.72 (m, IH), 4.09(t, IH), 3.71(t, IH), 3.55 (m, 4H), 3.43(m, 2H), 3.17(m, 4H), 1.84(s, 3H), 1.38(s, 9H). m.p. =215-217.2 ° C Compound No. 35: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)- piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]thiocarbamic acid methyl ester

Step a: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l- yl]phenyl}-2-oxo-oxazolidin-5-yl)-methyl]isothiocyanate To (S)-N-([3-{3-Fluoro-4-[4-(5-nitro-thioρhen-2-yl)-piperazin-l-yl]phenyl}-2- oxo-oxazolidin-5-yl]methyl)amine (4 g, 9.5 mmol) in dry tetrahydrofuran (50 mL) under nitrogen, carbon disulfide (1.2 mL, 19.9 mmol) and triethylamine (3 mL) added and stirred for about 10 hours. Then ethylchloroformate (0.9 mL) added and stirred for about 1 hour. 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. Evaporation in vacuo and purification by column chromatography yielded the product (2.3 g).

Step b: Preparation of (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l- yl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]thiocarbamic acid methyl ester To (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2- oxo-oxazolidin-5-yl)-methyl]-isothiocyanate (0.25 g, 0.54 mmol) in dry methanol (20 mL), sodium hydride (0.041 g, 1.71 mmol) was added and stirred for about 17 hours. The reaction mixture was diluted with water, acidified with concentrated hydrochloric acid to pH 2. The solid precipitated was filtered, dried in high vacuum over phosphorus pentaoxide to yield 0.11 g of title compound.

'H NMR (CDC1₃+ DMSO) δppm: 9.14 (t, IH), 7.81 (d, IH), 7.52 (dd, IH), 7.13 (d, IH), 7.0 (t, IH), 6.14 (d, IH), 4.95 (m, IH), 4.07 (m, 2H), 3.96 (s, 3H), 3.88 (m, 2H), 3.59 (m, 4H), 3.22 (m, 4H) M+H = 496, M+NH₄ = 513, M+Na = 518 m.p. = 199-205 °C

Example 2: Preparation of analogues of (±)-N- ({3-|^"3-Fluoro-4- (N-piperazinyl) phenyll- 2-oxo-oxazolidin-5-yl} methyl) acetamide (Core II)

Compound No. 26: Preparation of (±)-N- [(3-{3-Fluoro-4- [4-(5-nitro-thiophen-2-yl)- 1-piperazinyl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To a solution of (±)-N- ({3-[3-Fluoro-4- (piperazin-1-yl) phenyl]-2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 93/23384 (1.15 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2.6 mL, 15 mmol) and 2-bromo-5-nitrothiophene (0.28g, 1.3 mmole) (commercially available) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 0.24 g of the title compound.

1H NMR (DMSO) δppm: 8.23 (t, IH), 7.94(d, IH), 7.16(dd, IH), 7.20(dd, IH), 7.12 (t, IH), 6.41 (d, IH), 4.70(m, IH), 4.09(t, IH), 3.71 (m, 2H), 3.62(m, 4H), 3.14(m, 4H), 1.83(s, 3H).

Example 3: Preparation of analogues of (S)-N- ( .3-.3-fluoro-4- (3-methyl-piperazin-l-yl) phenyl]-2-oxo-oxazolidin-5-yl| methyl) acetamide (Core III) Preparation of (S)-N- ({3-[3-fluoro-4- (3-methyl-piperazin-l-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide (Core III) was similar to the synthesis of (S)-N- [{3- [3-Fluoro-4 - (N-piperazinyl) phenyl]-2-oxo-oxazolidin-5-yl] methyl} acetamide (Core I) using 2-methyl piperazine instead of piperazine.

Compound No. 27: Preparation of (S)-N- [(3-{3-Fluoro-4- [3-methyI-4- (5-nitro- furan-2-yl)-piperazin-l-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide

Step a: Preparation of 2-bromo-5-nitro-furan To acetic anhydride (21 mL) cooled to -10 °C, fuming nitric acid (21 mL) was added. Then 5-bromo-2-furoic acid (5 g) dissolved in acetic anhydride (25 mL) was added dropwise in about 45 minutes. The reaction mixture was stirred at -10 °C for about 1 hour, then allowing to warm to 0 °C in about 2 hours and then stirred at 0 °C for about 1 hour. The reaction mixture was poured onto crushed ice and saturated with sodium chloride. The resulting mixture was extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was sonicated with hexane and decanted. The residual oil was purified by column chromatography 0-3% ethyl acetate in hexane to yield 0.5 g product. Step b: Preparation of (S)-N- [(3-{3-Fluoro-4- [3-methyl-4- (5-nitro-furan-2-yl)- piperazin-1-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To a solution of (S)-N- ({3-[3-Fluoro-4- (3-methyl-piperazin-l-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate (1.11 mmol) in dimethylformamide (10 mL), potassium carbonate (2.22 mmol) and 2-bromo-5-nitro-furan (1.22 mmole) was added and the reaction mixture was stirred at room temperature for about 24 hours. The reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 105 mg of the title compound. 1H NMR (DMSO) δppm: 8.227-8.244(m, IH), 7.826-7.840(d, IH), 7.495-7.544(d, IH), 7.068-7.204(m, 2H), 5.941-5.955(d, IH), 4.691-4.736 (m, IH), 4.255(m, IH), 4.05-4.1 l(t, IH), 3.822-3.865(d, IH), 3.708(t, IH), 3.526(t, IH), 3.409(m, 2H), 3.23(m, 2H), 2.931(t, 2H), 1.83(s, 3H), 1.395-1.416(d, 3H). m.p. =117-119.5 °C

Compound No. 28: Preparation of (S)-N- {[3-(3-Fluoro-4- {3-methyl-4- [(5- difluoromethyl-2-nitro)-thiophen-3-yl]-piperazin-l-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide To a solution of (S)-N- ({3-[3-Fluoro-4- (3-methyl-piperazin-l-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate (0.888 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 8.88 mmol) and 3-bromo -5-diflouromethyl-2- nitrothiophene (0.977 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 105 mg of the title compound. Η NMR (DMSO) δppm: 8.25(m, IH), 7.49-7.54 (d, IH), 7.44(s, IH), 7.08-7.17(m, 2H), 4.71(m, IH), 4.06-4.12 (m, 2H), 3.70-3.73(m, 3H), 3.47-3.52(m, 2H), 3.18(m, 2H), 2.96(m, 2H), 1.83(s, 3H), 1.42-1.44 (d, 3H). m.p. =191-193.5 ° C Compound No. 29: Preparation of (S)-N- {[3-(3-Fluoro-4- {3-methyl-4- [(5-cyano-2- nitro-)-thiophen-3-yI]-piperazin-l-yl} phenyI)-2-oxo-oxazolidin-5-yl] methyl} acetamide To a solution of (S)-N- ({3-[3-Fluoro-4- (3-methyl-piperazin-l-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate prepared (1.41 mmol) in acetonitrile (20 mL), N-ethyl-diisopropylamine (2 mL, 14.1 mmol) and 4-bromo-2-carbonitrile-5- nitrothiophene (1.22 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was concentrated under reduced pressure, water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 178 mg of the title compound.

1H NMR (DMSO) δppm: 8.262(m, IH), 8.022(s, IH), 7.476-7.525(d, IH), 7.046-7.198(m, 2H), 4.68-4.713(m, IH), 4.082(m, 2H), 3.679-3.729(m, 3H), 3.49-3.57(m, 2H), 3.16- 3.290(m, 2H), 2.95-3.00(m, 2H), 1.834(s, 3H), 1.41-1.43(d, 3H). m.p. =178-180 ° C

Compound No. 30: Preparation of (S)-N- {[3-(3-Fluoro-4- {3-methyl-4- [(5- carboxymethyl-2-nitro)-thiophen-3-yl]-piperazin-l-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide To a solution of (S)-N- ({3-[3-Fluoro-4- (3-methyl-piperazin-l-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate prepared (0.777 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 7.77 mmol) and 4-bromo-5-nitrothiophene-2- carboxylic acid methyl ester (0.777 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled, solvent was removed, water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 40 mg of the title compound.

Η NMR (DMSO) δppm: 8.217(m, IH), 7.673(s, IH), 7.470-7.518(d, IH), 7.051-7.185(m, 2H), 4.693(m, IH), 4.045-4.125(m, 2H), 3.876(s, 3H), 3.690-3.805(m, 2H), 3.391- 3.490(m, 3H), 3.189(m, 2H), 2.894-2.99(m, 2H), 1.82(s, 3H), 1.38-1.40(d, 3H). Example 4: Preparation of analogues of (S)-N- (|3- 3-fluoro-4- (4-aminomethyl- piperidin-l-yl) phenyl]-2-oxo-oxazolidin-5-yl} methyl) acetamide (Core IV)

Compound No. 31: Preparation of (S)-N- {[3-(3-Fluoro-4- {4-amino- [N-methyl, N- (5-cy ano-2-nitro)-thiophen-3-yl] -piperidin-1 -yl} phenyl)-2-oxo-oxazolidin-5-yI] methyl} acetamide To a solution of (S)-N- ({3-[3-Fluoro-4- (4-aminomethyl-piperazin-l-yl) phenyl]- 2-oxo-oxazolidin-5-yl} methyl) acetamide trifluoroacetate prepared by the method given in WO 02/06278 (0.646 mmol) in acetonitrile (10 mL), N-ethyl-diisopropylamine (2 mL, 6.46 mmol) and 4-bromo-2-carbonitrile-5-nitrothiophene (0.646 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was concentrated under reduced pressure, water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography. The residue obtained was digested with ethanol, filtered and dried to yield 110 mg of the title compound.

Η NMR (DMSO) δppm: 8.235(m, IH), 8.059(s, IH), 7.452-7.501 (d, IH), 7.054- 7.183(m, 2H), 4.699(m, IH), 4.080(t, IH), 3.67-3.822(m, 3H), 3.402(m, 4H), 3.255(m, IH), 3.017(s, 3H), 2.786(m, 2H), 2.012(m, 2H), 1.83(s, 3H)

Example 5: Preparation of Analogues of (S)-N- |^"(3-{3-Fluoro -4-[3-(lα,5α.6α)-6-(N- methyl-N-amino)-3-azabicvclo- 3.1.0]hexyl]phenyl}-2-oxo-oxazolidin-5- yPmethyl] acetamide (Core V)

Compound No. 32: Preparation of (S)-N- {[3-(3-Fluoro -4-{3-(lα,5α,6α)-6-[N-methyl- N-(5-nitro-furan-2-yl)amino]-3-azabicyclo-[3.1.0]hexyl}phenyl)-2-oxo-oxazolidin-5- yl] methyl} acetamide To a solution of (S)-N- [(3-{3-Fluoro-4-[3-(lα,5α,6α)-6-(N-methyl-N-amino)-3- azabicyclo-[3.1.0]hexyl]phenyl}-2-oxo-oxazolidin-5-yl)methyl]acetamide trifluoroacetate prepared by the method given in WO 02/06278 (0.868 mmol) in dimethylformamide (10 mL), potassium carbonate (8.68 mmol) and 2-bromo-5-nitro-furan (1.12 mmole) was added and the reaction mixture was stirred at room temperature for overnight. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 110 mg of the title compound.

1H NMR (DMSO) δppm: 8.223(m, IH), 7.81-7.82(d, IH), 7.38-7.43 (d, IH), 7.09-7.12(d, IH), 6.80(t, IH), 5.87-5.88(d, IH), 4.66(m, IH), 4.02(t, IH), 3.77-3.80(d, 2H), 3.67(t, IH), 3.41(m, 4H), 3.17(s, 3H), 2.81(m, IH), 2.07-2.13(m, 2H), 1.83(s, 3H).

Example 6: Preparation of analogues of (S)-N- ({3-|^"3,5-Difluoro-4- (piperazin-1-yl) phenyl] -2-oxo-oxazolidin-5-yl} methyl) acetamide (Core VI)

Compound No. 33: Preparation of (S)-N- [(3-{3,5-difluoro-4- [4-(5-nitro-thiophen-2- yl)-piperazin-l-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] acetamide To a solution of (S)-N-({3-[3,5-Difluoro-4-(piperazin-l-yl) phenyl] -2-oxo- oxazolidin-5-yl} methyl) acetamide trifluoroacetate (0.0026 mmol.), prepared by the method given in U.S. Patent No. 5,547,950 in acetonitrile (60 mL), N-ethyl- diisopropylamine (2 mL, 0.0264 mmol) and 2-bromo -5-nitrothiophene (0.0029 mmole) was added and the reaction mixture was heated to 60 °C for about 17 hours. The reaction mixture was cooled; water was added and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography to yield 700 mg of the title compound.

Η NMR (DMSO) δppm: 8.22(m, IH), 7.92-7.94(d, IH), 7.28-7.31(d, 2H), 6.38-6.40(d, IH), 4.7(m, IH), 4.06-4.12 (t, IH), 3.70-3.73(t, IH), 3.58(m, 4H), 3.40-3.42(m, 2H), 3.22(m, 4H), 1.83(s, 3H).

Compound No. 34: Preparation of (S)-N- [(3-{3,5-difluoro-4- [4-(5-nitro-thiophen-2- yl)-piperazin-l-yl] phenyl}-2-oxo-oxazolidin-5-yl) methyl] triflouromethyl acetamide To a stirred suspension of (S)-N- [(3-{3,5-difluoro-4- [4-(5-nitro-thiophen-2-yl)- piperazin-l-yl]phenyl}-2-oxo-oxazolidin-5-yl) methyl] amine (0.4 g, 0.95 mmol) in tetrahydrofuran (20 mL), triethylamine (0.15 g, 1.42 mmol) and trifluoroacetic anhydride (0.25 g, 1.23 mmol) was added and stirred at room temperature for 6 hours. Further 0.25 g of trifluoroacetic anhydride was added and the reaction mixture was stirred for 17 hours. The reaction mixture was diluted with dichloromethane and washed with water, sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography using 0-1% methanol/dichloromethane. The product was sonicated in ether and filtered to yield 0.155 g of the title compound.

1H NMR (DMSO) δppm: 9.77(m, IH), 7.92-7.94(d, IH), 7.27-7.31 (d, 2H), 6.38-6.40(d, IH), 4.82-4.85(m, IH), 4.11-4.14(t, IH), 3.77-3.80(t, IH), 3.57(m, 4H), 3.41(m, 2H), 3.24(m, 4H). 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 intended to be included within the scope of the present invention.

Claims

We Claim:

1. A compound having the structure of Formula I:

FORMULA I

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein

Ri is NHWR₇ wherein W is no atom, CO or CS, and R₇ is selected from H, CH₃, OCH₃,

OCH₂CH₃, CF₃ or CH₂C1;

R₂ is selected from H or F;

R₃ is selected from H or CH₃;

X is selected from N or CHNCH₃;

Q is selected from O or S;

R₄, R₅, R_ύ are independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or

CONR₉Rιo wherein R₈ is H or CH₃, R and Rio are independently selected from H, Cι-C₄ alkyl or benzyl; and the ring C may form the structure of Formula

where n is an integer 1 or 2.

2. A compound selected from

(S)-N-[(3-{3-Fluoro-4-[4-(5-carboxymethyl-furan-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 1)

(S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-2-nitro-thiophen-3-yl)-piperazin-l-yl] phenyl }-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 2) (S)-N-[(3-{3-Fluoro-4-[4-(5-difluoromethyl-2-nitro-thiophen-3-yl)-piperazin-l-yl] phenyl} -2-oxo-oxazolidin-5-yl) methyl] acetamide (Compound No. 3) (S)-N-{[3-(3-Fluoro-4-{4-[(5-carboxyl-2-nitro)-thiophen-3-yl]-piperazin-l-yl} phenyl)-2- oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 4) (S)-N-{[3-(3-Fluoro-4-{4-[5-(carboxymethyl)-2-nitro-thiophen-3-yl]-piperazin-l-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 5) (S)-N-{[3-(3-Fluoro-4-{4-[5-(methylcarboxamido)-2-nitro-thiophen-3-yl]-l-piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 6) (S)-N-{[3-(3-Fluoro-4-{4-[5-(n-butylcarboxamido)-2-nitro-thiophen-3-yl]-l-piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 7) (S)-N-{[3-(3-Fluoro-4-{4-[5-(isopropylcarboxamido)-2-nitro-thiophen-3-yl]-l- piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 8) (S)-N-{[3-(3-Fluoro-4-[4-{5-(benzylcarboxamido)-2-nitro-thiophen-3-yl]-l-piperazinyl] phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 9) (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-furan-2-yl)-piperazin-l-yl]phenyl}-2-oxo-oxazolidin- 5-yl) methyl] acetamide (Compound No. 10) (S)-N-[(3-{3-Fluoro-4-[4-(5-cyano-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. i l) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] amine (Compound No. 12) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] carbamic acid methyl ester (Compound No. 13) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] carbamic acid ethyl ester (Compound No. 14) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] thioacetamide (Compound No. 15) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] thioformamide (Compound No. 16) (S)-N-[(3-{3-Fluoro-4-[4-(5-carboxamido-2-nitro-thiophen-3-yl)-piperazin-l-yl] phenyl}- 2-oxo-oxazolidin-5-yl) methyl] acetamide (Compound No. 17) (S)-N-{[3-(3-Fluoro-4-{4-[5-(hydroxyimino-methyl)-2-nitro-thiophen-3-yl]-piperazin-l- yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 18) (S)-N-{[3-(3-Fluoro-4-{4-[5-(N,N-dimethylcarboxamido)-2-nitro-thiophen-3-yl]-l- piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 19) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-l-oxy-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 20) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] trifluoroacetamide (Compound No. 21) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] chloroacetamide (Compound No. 22) (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] formamide (Compound No. 23) (S)-N-{[3-(3-Fluoro-4-{4-[5-(ethylcarboxamido)-2-nitro-thiophen-3-yl]-l -piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 24) (S)-N-{[3-(3-Fluoro-4-{4-[5-(t-butylcarboxamido)-2-nitro-thiophen-3-yl]-l -piperazinyl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 25) (+)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-l-piperazinyl]phenyl}-2-oxo-oxazolidin- 5-yl) methyl] acetamide (Compound No. 26) (S)-N- [(3 - {3 -Fluoro-4- [3 -methyl-4-(5 -nitro -furan-2-yl)-piperazin- 1 -yl]phenyl } -2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 27) (S)-N- {[3 -(3 -Fluoro-4- {3-methyl-4-[(5-difluoromethyl-2-nitro)-thiophen-3-yl]-piperazin- 1-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 28) (S)-N- { [3 -(3 -Fluoro-4- { 3 -methyl-4- [(5 -cyano-2-nitro -)-thiophen-3 -yl] -piperazin- 1-yl} phenyl)-2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 29) (S)-N- { [3 -(3 -Fluoro-4- { 3 -methyl-4-[(5 -carboxymethyl-2-nitro)-thiophen-3 -yl] -piperazin- 1-yl} phenyl) -2-oxo-oxazolidin-5-yl] methyl} acetamide (Compound No. 30) (S)-N- {[3 -(3 -Fluoro-4- {4-amino-[N-methyl,N-(5-cyano-2-nitro)-thiophen-3-yl]-piperidin- l-yl}phenyl)-2-oxo-oxazolidin-5-yl]methyl}acetamide (Compound No. 31)

(S)-N-{[3-(3-Fluoro-4-{3-(lα,5α,6α)-6-[N-methyl-N-(5-nitro-furan-2-yl)amino]-3- azabicyclo-[3.1.0]hexyl}phenyl)-2-oxo-oxazolidin-5-yl]methyl} acetamide (Compound No. 32) (S)-N- [(3 - { 3 ,5 -Difluoro-4- [4-(5 -nitro-thiophen-2-yl)-piperazin- 1 -yfjpiienyl } -2-oxo- oxazolidin-5-yl) methyl] acetamide (Compound No. 33) (S)-N-[(3-{3,5-Difluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl) methyl] triflouromethyl acetamide (Compound No. 34), and (S)-N-[(3-{3-Fluoro-4-[4-(5-nitro-thiophen-2-yl)-piperazin-l-yl]phenyl}-2-oxo- oxazolidin-5-yl)methyl]thiocarbamic acid methyl ester (Compound No. 35).

3. A pharmaceutical composition comprising the compound of claims 1 or 2 and a pharmaceutical acceptable carrier.

4. A pharmaceutical composition for treating microbial infections comprising a pharmaceutically effective amount of compound according to claims 1 or 2, or a physiologically acceptable acid addition salt thereof with a pharmaceutical acceptable carrier.

5. A method of treating or preventing microbial infections in a mammal comprising administering to said mammal, the pharmaceutical composition according to claim 4.

6. The method according to claim 5 wherein the microbial infections are caused by gram- positive and gram-negative bacteria.

7. The method according to claim 6 wherein the gram-positive bacteria are selected from the group consisting oi Staphylococcus spp., Streptococuus spp., Bacillus spp., Corynebacterum spp., Clostridia spp., Peptostreptococus spp., Listeria spp. and Legionella spp.

8. The method according to claim 6 wherein the gram-negative bacteria are selected from the group consisting of Moraxella catarrhalis and Haemophilus influenza.

9. A method of treating or preventing aerobic and anaerobic bacterial infections in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound having the structure of Formula I.

FORMULA I

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein

R, is NHWR₇ wherein W is no atom, CO or CS, and R₇ is selected from H, CH₃, OCH₃,

OCH₂CH₃, CF₃ or CH₂C1;

R₂ is selected from H or F;

R₃ is selected from H or CH₃;

X is selected from N or CHNCH₃;

Q is selected from O or S;

R4, R , Re are independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or

CONR₉Rιo wherein R₈ is H or CH₃, R₉ and Rio are independently selected from H, Cι-C₄ alkyl or benzyl; and the ring C may form the structure of Formula

where n is an integer 1 or 2.

10. A method of treating or preventing catheter infections and foreign body or prostheses infections in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound having the structure of Formula I

FORMULA I and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein Ri is NHWR₇ wherein W is no atom, CO or CS, and R₇ is selected from H, CH₃, OCH₃, OCH₂CH₃, CF₃ or CH₂C1; R₂ is selected from H or F; R₃ is selected from H or CH₃; X is selected from N or CHNCH₃ ; Q is selected from O or S; R₄, R₅, Re are independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or CONR₉Rιo wherein R₈ is H or CH₃ and R and Rio are independently selected from H, Cj- C₄ alkyl or benzyl; and the ring C may form the structure of Formula

where n is an integer 1 or 2.

11. A process for preparing a compound of Formula I

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein R, is NHWR₇ wherein W is no atom, CO or CS, and R₇ is selected from H, CH₃, OCH₃, OCH₂CH₃, CF₃ or CH₂C1; R₂ is selected from H or F; R₃ is selected from H or CH₃; X is selected from N or CHNCH₃; Q is selected from O or S; R₄, R_5, Re are independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or CONR Rιo wherein R₈ is H or CH₃, R₉ and Rio are independently selected from H, Cι-C₄ alkyl or benzyl; and the ring C may form the structure of Formula

where n is an integer 1 or 2; which comprises reacting an amine of Formula II

Formula II with a heteroaromatic compound of Formula III, wherein R_]2 is a leaving group to give a compound of Formula I, wherein Ri, R , R₃, R , R₅, Re, X and Q are the same as defined earlier.

12. The process of claim 11 wherein the heteroaromatic compound of Formula III is reacted with the amine of Formula II in the presence of ligands selected from of Pd₂(dba)₃ and Pd(Oac)₂.

13. The process of claim 11 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of a solvent selected from dimethylformamide, dimethylacetamide, acetonitrile, dimethylsulfoxide and ethylene glycol.

14. The process of claim 11 wherein the reaction of a compound of Formula II with a compound of Formula III is carried out in the presence of a base selected from triethylamine, diisopropylethylamine, potassium carbonate, sodium bicarbonate and dipotassiumhydrogenphosphate.

15. A process for preparing a compound of Formula V

FORMULA V

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein

Ri is NHWR₇ wherein W is no atom, CO or CS, and R₇ is selected from H, CH₃, OCH₃,

OCH₂CH₃, CF₃ or CH₂C1;

R₂ is selected from H or F;

R₃ is selected from H or CH ; and

Rj₄ is selected from -CH=NOH, -CONH₂, -CON(CH₃)₂, -CONHC₂H₅ or

CONHC(CH₃)₃; which comprises reacting a compound of Formula IV, wherein R₁₃ is selected from

COOH, COOCH₃ or CHO,

with an organic base selected from ammonia, hydroxylamine hydrochloride, dimethylamine, ethylamine and t-butylamine to give a compound of Formula V, wherein Ri, R₂, R₃ and Rι₄ are the same as defined above.

16. The process of claim 15 wherein the reaction of a compound of Formula IV to give a compound of Formula V is carried out in the presence of a solvent selected from tetrahydrofuran, ethanol, dimethylformamide, dimethylsulphoxide, diethylether, methanol, propanol and n-butanol.

17. The process of claim 15 wherein the reaction of a compound of Formula IV to give a compound of Formula V is carried out in the optional presence of a suitable reagent and a coupling agent selected from sodium acetate, N-methylmorpholine, 1- hydroxybenzotriazole, l-ethyl-3-[3-dimethylamino]propyl carbodiimide, 1,3-dicyclohexyl carbodiimide and l,8-diazobicyclo[5.4.0]undec-7-ene.

18. A process for preparing a compound of Formula VIII

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein R₂ is selected from H or F; R₃ is selected from H or CH₃; R4, R_5> Re are independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or CONR Rιo wherein R₈ is H or CH₃, R₉ and Rio are independently selected from H, Cι-C₄ alkyl or benzyl; Ris is selected from H, OCH₃, OC₂H₅, CH₂C1, or CF₃; and Q is selected from O or S;

which comprises hydrolyzing a compound of Formula VI

to give a compound of Formula VII, wherein R , R₃, R , R₅, R and Q are the same as defined earlier,

FORMULA VII

which on reaction with C1COOCH,, ClCOOC₂H₅, ClCH₂COCl, HCOOC₂H₅ or (CF₃CO)₂O gives a compound of Formula VIII.

19. The process of claim 18 wherein the hydrolysis of a compound of Formula VI to give a compound of Formula VII is carried out in the presence of hydrochloric acid, in a solvent selected from methanol, ethanol, propanol and n-butanol.

20. The process of claim 18 wherein the reaction of a compound of Formula VII to give a compound of Formula VIII is carried out in a solvent selected from dichloromethane, tetrahydrofuran, dimehylformamide, dimethylsulphoxide and diethylether.

21. The process of claim 18 wherein the reaction of a compound of Formula VII to give a compound of Formula VIII is carried out in the optional presence of an organic base selected from triethylamine, trimethylamine, diisopropylethylamine and dimethylamine.

22. A process for preparing a compound of Formula X

and its phannaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein

R₂ is selected from H or F;

R is selected from H or CH ;

R₄, R₅, Re are independently selected from H, NO₂, CN, CHF₂, CH=NOH, COOR₈ or

CONR_.R10 wherein R₈ is H or CH₃, R and Rio are independently selected from H, Cι-C₄ alkyl or benzyl; and

Q is selected from O or S; which comprises reacting a compound of Formula VII with CS₂ and ClCOOC₂H₅

FORMULA VII

to give a compound of Formula IX, wherein R₂, R₃, R_ι, R₅, R₆ and Q are the same as defined earlier,

FORMULA IX which on reaction with methanol gives a compound of Formula X.

23. The process of claim 22 wherein the reaction of a compound of Formula VII to give a compound of Formula IX is carried in a solvent selected from dichloromethane, tetrahydrofuran, dimehylformamide, dimethylsulphoxide and diethylether.

24. The process of claim 22 wherein the reaction of a compound of Formula VII to give a compound of Formula IX is carried out in the presence of an organic base selected from triethylamine, trimethylamine, diisopropylethyl amine and dimethylamine.

25. The process of claim 22 wherein the reaction of a compound of Formula IX to give a compound of Formula X is carried out in the presence of an inorganic base selected from sodium hydride, lithium hydride and sodium hydroxide.

26. A process for preparing a compound of Formula XII

FORMULA XII

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein Ri is NHWR₇ wherein W is no atom, CO, CS; and R₇ is selected from H, CH₃, OCH₃, OCH₂CH₃, CF₃ or CH₂Cl; R₂ is selected from H or F; R₃ is selected from H or CH₃; R4, R₅₎ Re are independently selected from H, NO₂, CN, CH₂F, CH=NOH, COOR₈ or CONR9.R10 wherein R₈ is H or CH3 and R and Rio are independently selected from H, Ci- C₄ alkyl or benzyl; and Q is selected from O or S; which comprises reacting a compound of Formula XI with monoperoxyphthahc acid magnesium salt hexahydrate

FORMULA XI to give a compound of Formula XII, wherein Ri, R₂, R₃, R4, R₅, Re and Q are the same as defined earlier.

27. The process of claim 26 wherein the reaction of a compound of Formula XI to give a compound of Formula XII is carried out in a solvent selected from dichloromehane, dimethylformamide, tetrahydrofuran and dimethylsulphoxide.

28. A process for preparing a compound of Formula XIV

and its pharmaceutically acceptable salts, solvates, polymorphs, enantiomers, diastereomers, N-oxides, prodrugs or metabolites, wherein

R₂ is selected from H or F;

R₃ is selected from H or CH₃;

R4, R₅, Re are independently selected from H, NO₂, CN, CH₂F, CH=NOH, COOR₈ or

CONR₉Rιo wherein R₈ is H or CH₃ and R₉ and Rio are independently selected from H, C_\-

C₄ alkyl or benzyl;

Q is selected from O or S; and

Ri6 is selected from H or CH₃; which comprises reacting a compound of Formula XIII with Lawesson's reagent

to give a compound of Formula XIV, wherein R₂, R₃, R^ R₅, Re, R_]6 and Q are the same as defined earlier.

29. The process of claim 28 wherein the reaction of a compound of Formula XIII to give a compound of Formula XIV is carried out in a solvent selected from dioxane, dimethylformamide, dimethylsulphoxide and tetrahydrofuran.