FIELD OF THE INVENTION :

The invention relates to substituted biaryl oxazolidinones. The invention also relates to a process for preparation of these compounds, pharmaceutical compositions containing these compounds and to methods of treating or preventing microbial infections using these compounds.

BACKGROUND OF THE INVENTION :

Oxazolidinone represent a novel chemical class of synthetic antimicrobial agents. Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive pathogens including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and ß-lactam Resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria, Gram-positive and Gram-negative anaerobes (Diekema D J et al., Lancet 2001; 358: 1975-82).

There are several patents and patent applications in the literature, which refer to oxazolidinones having antibacterial activity. For example, U.S. 7,148,219; US 7,141,588; US 6,689,779 and US 5,565,571; U.S. 20060116386; US 20060052399; US 2004/020734 and US 20070155798; WO 2001/94342, WO 2005/005420, WO 2005/058886 and WO 2005/005398; Indian Patent Application No. 635/MUM/2008 and 1535/MUM/2008.

SUMMARY OF THE INVENTION :

In one general aspect, there are provided compounds of Formula (I),

wherein:
n is 0 or 1;
R1 is O, S, SO, SO2 or NR; wherein R is hydrogen, unsubstituted or substituted alkyl, alkoxycarbonyl, alkanoyl, or alkylsulfonyl;
R2 is OH, OR7, CN, or COOR;
R3 is N, CH, or CF;
Ring A is optionally substituted with alkyl, OH, or CN;
Each of R4 and R5 independently is H or halogen;
R6 is H, alkyl, CN or halogen;
R7 is (a) COR8 wherein R8 is C1-C6 alkyl optionally substituted with halogen; or
(b) PO(OH)2, or
(c)

wherein, M is a monovalent or a divalent cation selected from Na+, K+, Mg2+, Ca2+, and Zn2+ ; and k is 2 for monovalent cation and 1 for divalent cation; or

(d) amino acid residue attached via carbonyl of the amino acid, wherein the amino acid residue is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof; or

(e) salts of amino acid;
and a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, there are provided pharmaceutical compositions comprising therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a method for treating or preventing microbial infection in a subject, comprising administering to a subject in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, there is provided a method for treating infection caused by a microorganism in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In another general aspect, there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof

In another general aspect, there is provided a method of treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable excipient.

In some other embodiments, there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally with one or more pharmaceutically acceptable excipient.

In some embodiments, there is provided a process for the preparation of compounds of Formula (I).

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the following description including claims.

DETAILED DESCRIPTION OF THE INVENTION :

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the inventions as illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

In general, the following definitions are used, unless otherwise described.

The term "stereoisomer" refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. These include enantiomers, diastereomers, geometrical isomers, atropisomer and comformational isomers. Geometric isomers may occur when a compound contains a double bond or some other feature that gives the molecule a certain amount of structural rigidity. An enantiomer is a stereoisomer of a reference molecule that is the nonsuperimposable mirror image of the reference molecule. A diastereomer is a stereoisomer of a reference molecule that has a shape that is not the mirror image of the reference molecule. An atropisomer is a conformation of a reference compound that converts to the reference compound only slowly on the NMR or laboratory time scale. Conformational isomers (or conformers or rotational isomers or rotamers) are stereoisomers produced by rotation about s bonds, and are often rapidly interconverting at room temperature. Racemic mixtures are also encompassed within the scope of this invention. Some of the compounds of the present invention may have trans and cis isomers and geometric E- and Z- isomers. The wavy bond indicates that the compounds may be present as either of E- or Z- isomer. Also some of the compounds according to this invention may exist as diastereomers. In addition, where the process for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers, may be separated by conventional techniques such as preparative chromatography and HPLC. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomer.

The term "polymorphs, solvates and hydrates” has meaning as discussed herewith. The compounds of invention may exists as different polymorphs such as crystalline or amorphous forms and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates), which contains various amounts of water, for instance the hydrate, hemihydrate and sesquihydrate forms. Also the compound can form solvates with common organic solvents. Such solvates and hydrates are intended to be included within the scope of this invention.

The term “alkyl” refers to saturated, straight or branched chain hydrocarbon radicals containing between one and twelve six carbon atoms. Examples of C1-C12 alkyl radicals include but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and their branched isomers such as iso-propyl, iso-butyl or tert-butyl.

The term “pharmaceutically acceptable salt” as used herein refers to one or more salts of the free base of the invention which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. The salts are suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable acid. These salts may be obtained from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, perchloric acid, hydrobromic acid, sulphuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, oxalic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulphonic acid, p-toluene sulphonic acid, salicyclic acid and the like. Also included are the salts with various amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine or the optically active isomers thereof or the racemic mixtures thereof or dipeptides, tripeptides and polypeptides derived from the monoaminoacid units thereof.

Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salt of an acid moiety in the compound can also be prepared by reacting with a suitable base. These suitable salts are furthermore those of the inorganic or organic bases. Inorganic bases such as KOH, NaOH, Ca(OH)2, Al(OH)3. The organic base salts from basic amines such as ethylamine, triethylamine, diethanolamine, ethylenediamine, guanidine or heterocyclic amines such as piperidine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, morpholine, piperazine, N-methyl piperazine and the like or basic amino acids such as optically pure and racemic isomers of arginine, lysine, histidine, tryptophan and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The term "therapeutically effective amount" means that amount of compound(s) or pharmaceutical agent(s) that elicit the biological or medicinal response in a tissue system, animal or human sought by a researcher, veterinarian, medical doctor or other clinician, which response includes alleviation of the symptoms of the disease or disorder being treated. The specific amount of active compound(s) or pharmaceutical agent(s) needed to elicit the biological or medicinal response will depend on a number of factors, including but not limited to the disease or disorder being treated, the active compound(s) or pharmaceutical agent(s) being administered, the method of administration, and the condition of the patient.

The term “treat”, “treating” or “treatment” as used herein refers to administering a pharmaceutical composition or a compound for prophylactic and/or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who is not yet infected, but who is susceptible to, or otherwise at a risk of infection. The term "therapeutic treatment" refers to administering treatment to a subject already suffering from infection. Thus, in preferred embodiments, treating is the administration to a subject (either for therapeutic or prophylactic purposes) of therapeutically effective amount of compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof

The term "subject" as used herein refers to vertebrate or invertebrate, including a mammal. The term “subject” includes human, animal, a bird, a fish, or an amphibian. Typical, non-limiting examples of a "subject" includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.

The term "microorganism" or "microbe" as used herein includes bacteria, fungi, protozoa, yeast, mold, and mildew.

The term "infection" as used herein includes presence of a microorganism in or on a subject, which, if its growth were inhibited, would result in a benefit to the subject. As such, the term "infection" in addition to referring to the presence of microorganisms also refers to normal flora, which are not desirable. The term "infection" includes infection caused by bacteria, fungi, protozoa, yeast, mold, or mildew.

Typical, non-limiting examples of infections include those such as pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chiamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae. Bacterial infections and protozoa infections and disorders related to such infections that may be treated or prevented in animals include the following: bovine respiratory diseases related to infection by P. haem., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.

In one general aspect, there are provided compounds of Formula (I),

wherein:
n is 0 or 1;
R1 is O, S, SO, SO2 or NR; wherein R is hydrogen, unsubstituted or substituted alkyl, alkoxycarbonyl, alkanoyl, or alkylsulfonyl;
R2 is OH, OR7, CN, or COOR;
R3 is N, CH, or CF;
Ring A is optionally substituted with alkyl, OH, or CN;
Each of R4 and R5 independently is H or halogen;
R6 is H, alkyl, CN or halogen;
R7 is (a) COR8 wherein R8 is C1-C6 alkyl optionally substituted with halogen; or
(b) PO(OH)2, or
(c)

wherein, M is a monovalent or a divalent cation selected from Na+, K+, Mg2+, Ca2+, and Zn2+ ; and k is 2 for monovalent cation and 1 for divalent cation; or

(d) amino acid residue attached via carbonyl of the amino acid, wherein the amino acid residue is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof; or

(e) salts of amino acid;

and a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2; and R2 is OH or OR7.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2; R2 is OH or OR7; and R3 is N.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2; R2 is OH or OR7; R3 is N; and R4 is H.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2; R2 is OH or OR7; R3 is N; R4 is H; and R5 is F.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2; R2 is OH or OR7; R3 is N; R4 is H; R5 is F; R6 is H; and R7 is

wherein, M is a monovalent or a divalent cation selected from Na+, K+, Mg2+, Ca2+, and Zn2+ ; and k is 2 for monovalent cation and 1 for divalent cation.

In some embodiments, there are provided compounds of Formula (I), wherein R1 is SO2; R2 is OH or OR7; R3 is N; R4 is H; R5 is F; R6 is H; and R7 is PO(OH)2

The following compounds illustrate compounds contemplated within the scope of the invention:

(i) (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one;

(ii) 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate;

(iii) 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate di-potassium salt;
(iv) (5S)- (5-Methyl-Isoxazol-3-yl)-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one;

(v) 4-[5-(2-fluoro-4-{(5R)-5-[(N-isoxazol-3-yl)aminomethyl]-2-oxo-1,3-oxazolidin-3-yl} phenyl) pyridin-2-yl]tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;

and a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

The intermediates of the invention may be prepared by procedures known to those of ordinary skills in the art or by procedures described in the Indian Patent Application No. 635/MUM/2008, 1535/MUM/2008; Other procedures and methods involved in the preparations of biaryl compounds as described in International (PCT) Publication Nos. WO 2001/94342, WO 2005/058886; J. Org. Chem., 66 (2001), 7008-7012; Bioorganic & Medicinal Chemistry, 12 (2004), 4645-4665; Heterocycles, 15 (1981), 179-82 and Canadian Journal of Chemistry, 80 (2002), 155-162 could also be used

In some embodiments, there is provided a process for preparation of compound of Formula (I), comprising:

(a) reacting a compound of Formula (II) with a sulfonating reagent like methanesulfonyl chloride, optionally in presence of a solvent like DCM, at temperatures from –5oC to + 40oC to obtain a compound of Formula (IIa);

(b) reacting a compound of Formula (IIa) with a suitably protected 3-amino-isoxazole in presence of a base such as anhydrous potassium carbonate and a suitable solvent such as DMF, at temperatures between 25-100 oC, to obtain a compound of Formula (III) as shown below.

(c) reacting a compound of Formula (III) with a suitable de-protecting agent dilute mineral acids like aqueous Hydrochloric acid or organic acids like trifluoroacetic acid, optionally in presence of a solvent like DCM, EDC, THF, Acetone etc., at temperatures between –5oC to + 40oC to obtain a compound of Formula (I).

In general, compounds of formula (I) may be prepared according synthetic steps described in Scheme 1, below:

In some embodiments, according to Scheme 1, the compound of formula (IIa) is obtained from compound of formula (II) by treating the compound with methane sulfonyl chloride in presence of a suitable base like triethylamine, pyridine, N-ethyldiisopropyl amine sodium bicarbonate, sodium carbonate, potassium carbonate etc. in a suitable solvent like DCM, chloroform, EDC, ethyl acetate, acetone, toluene etc. at temperatures ranging from –10oC to + 40oC.THF, DEE, 1,4-dioxane. The compound of formula (II) is converted into compound of formula (III) by reacting the compound with N-tert-butoxy-3-amino-isoxazole in the presence of a base like sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate in solvents like THF, 1,4-dioxane, DEE, DMF, DMAC, DMSO, toluene at temperatures ranging from –15oC to +100oC. The compound of Formula is converted into compound of Formula (I) by further treating with a suitable de-protecting reagent like trifluoroacetic acid, acetic acid, dilute acids like hydrochloric, sulfuric, phosphoric, HF triethylamine, HF-pyridine etc, in solvents like DCM, chloroform, EDC, THF, DEE, ethyl acetate, acetonitrile, toluene etc. at temperatures ranging from –10oC to + 40oC.

Another process (scheme-2) involves reacting compound of formula (IV) with suitable tin compound -(V)in presence of a palladium catalyst such as palladium on carbon, tetrakistriphenylphosphine palladium (0) or dichlorobistriphenyphosphine palladium (II) or palladium (II) chloride, or palladium acetate in an aprotic organic solvent such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, toluene, xylene, ethyl acetate or hexamethylphosphorotriamide at a temperature between 80 ºC to 140 ºC to provide intermediate compound of formula (III), this is further converted compound Formula-(I) as described in Scheme-1

In another aspect, oxidation of compound of Formula (3a) is carried out using oxidizing agent such as sodium periodate, m-chloroperbenzoic acid or hydrogen peroxide in aqueous alcohol such as methanol, ethanol, propanol, isopropanol or butanol at a temperature between 40 ºC to 120 ºC to furnish oxidized oxazolidinone compound of Formula (3b) of the invention (Scheme-3).

In a further aspect of the patent the compound of the Formula (I) is converted into their prodrug (Scheme-4) viz phosphate or amino acid.(natural or unnatural). Thus compound of Formula (I) is reacted with dibenzylphosphoramidite to furnish the dibenyl derivative (Scheme-4). This dibenyl derivative (Ic) is transformed into the phosphate(Id) which could be converted into its di-sodium, di-potassium or Calcium, Magnesium or Zinc salt. Similarly the compound of Formula-(I) could be converted into N-protected amino-acid derivative. The protecting group is cleaved to reveal the free amine which is further converted into its hydrochloride or mesylate salts.

In some embodiments, there are provided pharmaceutical compositions comprising therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable excipient” refers to a substance other than the active ingredient and includes pharmaceutically acceptable carriers, diluents, stabilizers binders, coloring agents, buffers, lubricants, disintegrating agents, surfactants, glidants, plasticizers, fillers, extenders, emollients, wetting agents, and so on. The pharmaceutically acceptable excipient often facilitates delivery of the active ingredient. The type and amount of any the excipient used depends largely on the therapeutic response desired and other factors such as route of administration and so on.

Any suitable route of administration may be employed for providing the patient with an effective dosage of the compounds of the invention. For example, oral, rectal, vaginal, parenteral (subcutaneous, intramuscular, intravenous), nasal, transdermal, topical and like forms of administration may be employed. Suitable dosage forms include tablets, pills, powders, troches, dispersions, solutions, suspensions, emulsions, capsules, injectable preparations, patches, ointments, creams, lotions, shampoos, and the like.

In some embodiments, the pharmaceutical compositions according to the invention are administered parenterally or orally.

In some embodiments, there is provided a method for treating or preventing microbial infection in a subject, comprising administering to a subject in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some embodiments, there is provided a method for treating infection caused by a microorganism in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

In some other embodiments, there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof

In some other embodiments, there is provided a method for treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipient.

In some other embodiments, there is provided a method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipient.

The prophylactic or therapeutic dose of the compounds of Formula (I) and pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, in the acute or chronic management of disease will vary with the severity of condition to be treated, and the route of administration. In addition, the dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose range, for the compounds of the invention, for the conditions described herein, is from about 10 mg to about 5000 mg. It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art.

Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient’s response.

The compounds of this invention are useful antimicrobial agents, effective against various human and veterinary pathogens, including multiple-resistant staphylococci and streptococci, enteroccoci, as well as anaerobic organisms such bacteroides and clostridia species.

Test Example 1

MIC Determination: Overnight grown cultures of S. aureus organisms in Tryptic Soya broth were diluted in Mueller Hinton Broth to give optical density matching with MacFarland tube 0.5 standard. Cultures were further diluted 1:10 in Mueller Hinton broth. Using Denley''s mutipoint inoculator, 104 cells were deposited on Mueller Hinton agar (Difco) containing range of 2 fold dilutions of test compounds. These plates were incubated for 24 hrs at 35°C and MIC results recorded. MIC is defined as minimum drug concentration that inhibits test organisms. For determining MIC of test compounds against Streptococcus pneumoniae, Mueller Hinton agar containing 5% sheep blood was employed. The following strains were used to screen the compounds of invention: Staphylococcus aureus ATCC 25923, Staphylococcus aureus 014, Staphylococcus epidermidis 110, Enterococcus faecalis 401, Enterococcus faecium 303, Streptococcus pneumoniäe 49619, Streptococcus pneumoniae 706, Streptococcus pyogenes 801, Streptococcus pyogenes 805 and Haemophilus influenzae 49247.

Compounds of this invention when tested using this in-vitro protocol, exhibited MIC values in the range of 0.125 to 8 mg.mL.

EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

The following abbreviation are used in the text: n-BuLi for n-Butyl lithium, TLC for thin layer chromatography, MP for melting point, MF for molecular Formula, RT for room temperature, THF for tetrahydrofuran, DMF for dimethylformamide, DCM for dichloromethane, TEA for triethylamine, DIPEA for N-ethyldiisopropylamine, TPP for triphenylphosphine and DIAD for diisopropylazodicarboxylate.

Preparation of Intermediates

I. Preparation of (5S)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-[(N-tert-butoxycarbonyl N-isoxazol-3-yl)aminomethyl]-1,3-oxazolidin-2-one

A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-[(N-tert-butoxycarbonyl-N-isoxazol-3-yl) aminomethyl]-1,3-oxazolidin-2-one (1.5 g, 1.0 eq), hexabutylditin (3.23 g, 1.5 eq), and dichlorobistriphenylphosphine palladium (II) catalyst (150 mg, 0.1 mol %) in 1,4-dioxane (30 ml) was heated at 90 oC for 16 hours. The reaction mixture was filtered over celite bed, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography using v/v 98.5:1.5 mixture of Chloroform: Methanol. Concentration of the combined fractions gave the product as a buff colored solid, 1.4 g.

The following intermediates (II and III) were prepared as per the procedures described in Patent Applications filed Substituted_biaryl oxazolidinones_IN 635_MUM_2008 and Substituted biaryl oxazolidinones_1535 IN_MUM _2008

II. Preparation of (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

Step-1: Preparation of (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (10 g, 29.67 mmol), 6-(4-hydroxytetrahydro-2H-thiopyran-4-yl)- pyridin-3-yl]boronic acid (12 g, 52.32 mmol) and sodium carbonate (12.46 g, 120.0 mmol) in N,N-dimethyl formamide (120 ml) was flushed with continuous flow of argon under stirring for 15 min. Tetrakis(triphenyphospine)palladium (0.750 g) was added to the reaction mixture under argon. Reaction mixture was heated at 110 ºC for 20 hr. It was cooled to room temperature, and filtered through celite bed. The bed was washed with ethyl acetate. Filtrate was diluted with ethyl acetate was washed with water (100 ml). Layers were separated. Organic layer was concentrated and the residue was purified by flash column chromatography to obtain the product as off white solid 6.5 g, 86 % yield.

Step-2: (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

A mixture of (5R)-3-{3-fluoro-4-[6-(4-hydroxytetrahydro-2Hthiopyran-4-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one (6.5 g, 16.66 mmol) and sodium periodate (14 g, 65.42 mmol) was suspended in 50% aqueous methanol (70 ml) and stirred at 80 ºC for 6 hrs. Reaction mixture was cooled to room temperature and solvent was evaporated to provide a residue. The residue was triturated with 100 ml water; solid obtained was filtered and washed with 100 ml water, dried under vacuum to provide title compound in 72% yield (5.1 g) as white solid.
Mp: 226-228 ºC; MS: 438 (M+1); MF: C20H21N2O6FS = 437.1

III. Preparation of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} pyridin-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide

Step-1: Preparation of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} pyridin-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile

To a solution of 4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbonitrile (0.7 g, 1.4 mmol) in DMF (10ml) were added (5R)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one (0.54g, 1.4mmol), triethylamine (0.43g, 4.2mmol), and bis(triphenylphosphine)palladium (II) dichloride catalyst (0.07 g). The reaction mixture was heated with stirring at 90oC for 14 hours. The resulting mixture was filtered over celite bed and the filtrate poured into water (20ml) and extracted with ethyl acetate (3x20ml). The ethyl acetate extract was concentrated under reduced pressure and the residue obtained purified by column chromatography. Elution with a v/v mixture of 98:2 Chloroform: Methanol and concentration of the combined fractions gave the product as white solid, 0.22 g, yield 34 %.

Step-2: Preparation of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} pyridin-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide

To 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} pyridine-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile (2.4g, 5.8mmol) in 1: 1 mixture of methanol: water was added sodium periodate (6.21g, 29mmol). The reaction mixture was heated with stirring for 4 hours at 100oC. The resulting mixture was concentrated under reduced pressure and the residue triturated with water(10ml). The separated solid was filtered and further purified by flash column chromatography to obtain the product as off-white solid 1.4 g; yield 55 %.

Example-1

Preparation of: (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one

Method A:
Step-1: Preparation of (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl-methyl-methanesulfonate

To a solution of (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one (3.7 g, 8.48 mmol) in dichloromethane (37 ml), was added triethylamine (1.71 g, 16.9 mmol) under stirring. Methanesulfonyl chloride (1.26 g, 11 mmol) was added over 10 min to the solution at RT and the reaction mixture was stirred for further 1.5 h. The reaction mixture was diluted with water (10ml), the resulting mixture stirred for 10min. and the organic layer separated. The solvent from the organic layer was evaporated to obtain the product as off-white solid, 4.0 g, 92% yield.
MS: 514 (M+H, 100%) for M.F.: C21H23FN2O8S2

Step-2: Preparation of (5S)-[(N-tert-Butoxycarbonyl- N-Isoxazol-3-yl)-aminomethyl]-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl –1,3-oxazolidin-2-one

To a solution of (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-2-oxo-oxazolidin-5-yl-methyl-methanesulfonate (4 g, 7.8 mmol) in DMF (50 ml) was added 3-tertiary butoxycarbonyl amino-isoxazole (2.15 g, 11 mmol) and potassium carbonate (2.15 g, 15.6mmol) and the mixture was heated to 80oC for 6 h., with stirring. The resulting mixture was cooled to RT and poured in ice-cold water (200ml). The separated solid was filtered under suction. The residue was washed with fresh water (25ml) and dried at RT to obtain the crude product. This was further purified by column chromatography using 1.5 % MeOH in CHCl3 as eluant. Evaporation of the combined fractions gave the product as white solid 4 g, 85% yield.
MS: 602 ( M+ 100%) for M.F.: C28H31FN4O8S

Step-3: Preparation of (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one

To a cooled trifluoroacetic acid (15 ml) at 5oC was added (5R)-[N-Isoxazol-3-yl-(N-tert-butoxycarbonyl)aminomethyl]-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyloxazolidin-2-one (3.3 g, 5.48mmol) in small portions. The resulting solution was allowed to warm to RT and stirring continued further for 45min. TFA was evaporated under reduced pressure and the residue was triturated with saturated sodium bicarbonate solution (25ml). The separated solid was filtered under suction and the residue purified by column chromatography. Elution with a mixture of Chloroform: methanol (9:1) and concentration of the combined fractions gave the title compound as a white solid, 2.1 g, 85%.
M.P: 227-232oC(dec.); MS: 502(M+); MF: C23H23FN4O6S.

Method B:
Step-1: Preparation of (5S)-[(N-tert-Butoxycarbonyl- N-Isoxazol-3-yl)-aminomethyl]-3-{3-fluoro-4-[6-(4-hydroxy-tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl –1,3-oxazolidin-2-one

To a solution of (5R)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-[(N-tert-butoxycarbonyl-N-isoxazol-3-yl) aminomethyl]-1,3-oxazolidin-2-one (1.4g, 1 eq) in DMF (15 ml) was added 4-hydroxy-4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran (0.756g, 1.1 eq), triethylamine (1.0 ml, 3 eq), and dichloro bis(triphenylphosphine)palladium (II) catalyst.(1mol%). The reaction mixture was heated with stirring, under argon, at 80oC for 14 hours. The resulting mixture was filtered through celite bed. The filtrate was diluted with water (80 ml) stirred well and extracted with ethyl acetate (3 x 75 ml). The combined extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography, using v/v 9.5:0.5 mixture of chloroform: methanol to obtain the product as a white solid, 0.3 g.

Step-2: Preparation of (5S)-[(N-tert-Butoxycarbonyl- N-Isoxazol-3-yl)-aminomethyl]-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl –1,3-oxazolidin-2-one

To a suspension of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}phenyl)pyridin-2-yl]tetrahydro-2H-thiopyran-4-carbonitrile (0.300 g, 1.0 eq) in 1:1 methanol: water mixture (10 ml) was added sodium periodate (5 eq) and the resulting mixture was heated with stirring at 80oC for 4 hours. The resulting mixture was concentrated under reduced pressure and the residue triturated with water (10 ml). The separated solid was filtered, and purified by flash column chromatography, using mixtures of chloroform: methanol, to obtain the product as a white solid; 0.200 g; yield 60%.

Step 3: Preparation of (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one

This preparation was carried out as described in Step –3 in Method A to obtain the titled compound in 80% yield.

Method C:
Step-1: Preparation of (5S)-[(N-tert-Butoxycarbonyl- N-Isoxazol-3-yl)-aminomethyl]-3-{3-fluoro-4-[6-(4-hydroxy-tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl –1,3-oxazolidin-2-one

To a solution of (5R)-3-[3-fluoro-4-iodophenyl]-5-[(N-tert-butoxycarbonyl-N-isoxazol-3-yl) aminomethyl]-1,3-oxazolidin-2-one (1.4g, 1 eq) in DMF (15 ml) was added 4-hydroxy-4-tetrahydro-2H-thiopyran-pyridin-2-yl –5-borate (0.756g, 1.1 eq), Sodium carbonate (1.0 g, 3 eq), and tetrakis(triphenylphosphine)palladium (0.075g) catalyst.(1mol%). The reaction mixture was heated with stirring, under argon, at 135oC for 14 hours. The resulting mixture was filtered through celite bed. The filtrate was diluted with water (80 ml) stirred well and extracted with ethyl acetate (3 x 75 ml). The combined extract was dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography, using v/v 9.5:0.5 mixture of chloroform: methanol to obtain the product as a white solid, 1.0 g.

Step-2: Preparation of (5S)-[(N-tert-Butoxycarbonyl- N-Isoxazol-3-yl)-aminomethyl]-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl –1,3-oxazolidin-2-one

This preparation was carried out as described in Step –2 in Method A to obtain the titled compound in 80% yield.

Step 3: Preparation of (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one

This preparation was carried out as described in Step –3 in Method A.

Example-2

Preparation of: (5S)- (5-Methyl-isoxazol-3-yl)-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one

Step-1: (5R)-[5-Methyl-N-isoxazol-3-yl-(N-tert-butoxycarbonyl)aminomethyl]-3-{3-Ffluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl-1,3-oxazolidin-2-one
To a solution of (5R)-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-2-oxo-oxazolidin-5-yl-methyl-methanesulfonate (4 g, 7.8 mmol) in DMF (50 ml) was added 3-tertiary butoxycarbonyl amino-5-methylisoxazole (2.15 g, 11 mmol) and potassium carbonate (2.15 g, 15.6mmol) and the mixture was heated to 80oC for 6 h., with stirring. The resulting mixture was cooled to RT and poured in ice-cold water (200ml). The separated solid was filtered under suction. The residue was washed with fresh water (25ml) and dried at RT to obtain the crude product. This was further purified by column chromatography using 1.5 % MeOH in CHCl3 as eluant. Evaporation of the combined fractions gave the product as white solid 4 g, 85% yield.
MS: 614 ( M+ 100%) for M.F.: C29H33FN4O8S

Step-2: (5S)-(5-Methylisoxazol-3-yl)-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}oxazolidin-2-one

To a cooled trifluoroacetic acid (15 ml) at 5oC was added (5R)-[5-methyl-N-isoxazol-3-yl-(N-tert-butoxycarbonyl)aminomethyl]-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyloxazolidin-2-one (3.3 g, 5.48mmol) in small portions. The resulting solution was allowed to warm to RT and stirring continued further for 45min. TFA was evaporated under reduced pressure and the residue was triturated with saturated sodium bicarbonate solution (25ml). The separated solid was filtered under suction and the residue purified by column chromatography. Elution with a mixture of Chloroform: methanol (9:1) and concentration of the combined fractions gave the product as white solid, 2.1 g, 85%.
M.P: 187-190oC(dec.); MS: 514(M+); MF: C24H25FN4O6S.

Example-3

Preparation of: (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-cyano-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one

Step-1: (5R)-3-{3-Fluoro-4-[6-(4-cyano-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-2-oxo-oxazolidin-5-yl-methyl-methanesulfonate

To a solution of (5R)-3-{3-Fluoro-4-[6-(4-cyano-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one (1.0 g, 2.25 mmol) in dichloromethane (10 ml), was added triethylamine (0.341 g, 3.37 mmol) under stirring. Methanesulfonyl chloride (0.309 g, 2.7 mmol) was added over 10 min to the solution at RT and the reaction mixture was stirred for further 1.5 h. The reaction mixture was diluted with water (10ml), the resulting mixture stirred for 10min. and the organic layer separated. The solvent from the organic layer was evaporated to obtain the product as off-white solid, 1.1 g, 93% yield.
MS: 524 ( M+H, 100%) for M.F.: C22H22FN3O7S2

Step-2: (5R)-[N-Isoxazol-3-yl-(N-tert-butoxycarbonyl)aminomethyl]-3-{3-Fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyloxazolidin-2-one

To a solution of (5R)-3-{3-Fluoro-4-[6-(4-cyano-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-2-oxo-oxazolidin-5-yl-methyl-methanesulfonate (0.6 g, 1.147 mmol) in DMF (6 ml) was added 3-tertiary butoxycarbonyl amino-isoxazole (0.253 g, 1.376 mmol) and potassium carbonate (0.317 g, 2.294 mmol) and the mixture was heated to 90oC for 4h., with stirring. The resulting mixture was cooled to RT and poured in ice-cold water (50ml). The separated solid was filtered under suction. The residue was washed with fresh water (25ml) and dried at RT to obtain the crude product. This was further purified by column chromatography using 1.5 % MeOH in CHCl3 as eluant. Evaporation of the combined fractions gave the product as white solid 0.530 g, 75% yield.
MS: 612 ( M+H, 100%) for M.F.: C29H30FN5O7S

Step-3: (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-cyano-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}-1,3-oxazolidin-2-one
To a cooled trifluoroacetic acid (5 ml) at 5oC was added (5R)-[N-Isoxazol-3-yl-(N-tert-butoxycarbonyl)aminomethyl]-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyloxazolidin-2-one (0.530g, mmol) in small portions. The resulting solution was allowed to warm to RT and stirring continued further for 45min. TFA was evaporated under reduced pressure and the residue was triturated with saturated sodium bicarbonate solution (10ml). The separated solid was filtered under suction and the residue purified by column chromatography. Elution with a mixture of Chloroform: methanol (9:1) and concentration of the combined fractions gave the product as white solid, 0.220 g, 43%.
M.P: 218-220oC(dec.); MS: 512(M+); MF: C24H22FN5O5S.

Example-4

Preparation of: 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl}pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate
Step-1: Preparation of: 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl}pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dibenzyl phosphate

A solution of (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}oxazolidin-2-one (2.1g, 4.18mmol) and 5-methyl-1H-tetrazole(3.16g, 37.6mmol) in DCM(63ml) was cooled to –5 to –10oC, with stirring. Dibenzyl-N,N-diisopropylphosphoramidite (75%, 10.82g, 31.3mmol) was drop-wise added to the above solution. Stirring was further continued at the same temp for 4h. The resulting mixture was cooled further to –10 to -15 oC and 55% mCPBA ( 9.78g, 31.3mmol) was added in small portions. The resulting mixture was allowed to warm to 0-5 oC and stirring continued further for 2h. The reaction mixture was diluted with a an aqueous saturated sodium bicarbonate solution (50ml), stirred for 15min and the DCM layer separated. The organic layer was dried and the solvent evaporated under reduced pressure to obtain an oily residue. This was further purified by column chromatography over a silica gel column. Elution with a mixture of 0.25 to 0.5% methanol in chloroform and concentration of the combined fractions gave the product as a pale yellow oil, 2.2g, 69% yield.
MS: 763(M+H); MF: C37H36FN4O9PS

Step-2: Preparation of: 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl}pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate
To trifluoroacetic acid(30ml) was added Step-I compound (2.2g, 1.67mmol) in small portions and the solution stirred at RT for 6h. The resulting solution was concentrated under reduced pressure and the residue diluted with diethyl ether (50ml), well stirred and decanted. The residue was once again washed with fresh diethyl ether (50ml) and dried under reduced pressure to obtain the product as a white hygroscopic solid, 1.68g, 100% yield.
MS: 583(M+H); MF: C23H24FN4O9PS

Example-5
Preparation of: 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl}pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate di-potassium salt

A suspension of 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl}pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate (1.68g, 2.88mmol) in chloroform (25ml) was cooled to 0-5 oC. Anhydrous potassium carbonate (390mg, 2.82 mmol) was added to the reaction mixture followed by addition of 35ml of methanol. The mixture was stirred for 45min. The resulting suspension was concentrated under reduced pressure to obtain a solid. The solid was suspended in ethyl acetate (67ml) containing a catalytic amount of water and the mixture stirred for 2h at RT. The separated solid was filtered under suction and dried under reduced pressure to obtain the product as a white solid, 1.64g, 86% yield.
MP: 185-205 oC(dec.); MS; 583(M+H) parent; MF: C23H22FN4O9PS.2K

We claim:

1. A compound of Formula (I)

wherein:
n is 0 or 1;
R1 is O, S, SO, SO2 or NR; wherein R is hydrogen, unsubstituted or substituted alkyl, alkoxycarbonyl, alkanoyl, or alkylsulfonyl;
R2 is OH, OR7, CN, or COOR;
R3 is N, CH, or CF;
Ring A is optionally substituted with alkyl, OH, or CN;
Each of R4 and R5 independently is H or halogen;
R6 is H, alkyl, CN or halogen;
R7 is (a) COR8 wherein R8 is C1-C6 alkyl optionally substituted with halogen; or
(b) PO(OH)2, or
(c)

wherein, M is a monovalent or a divalent cation selected from Na+, K+, Mg2+, Ca2+, and Zn2+ ; and k is 2 for monovalent cation and 1 for divalent cation; or

(d) amino acid residue attached via carbonyl of the amino acid, wherein the amino acid residue is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof; or
(e) salts of amino acid;

and a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

2. A compound of Claim 1, wherein R1 is SO2.

3. A compound of Claim 1, wherein R1 is SO2; and R2 is OH or OR7.

4. A compound of Claim 1, wherein R1 is SO2; R2 is OH or OR7; and R3 is N.

5. A Compound of Claim 1, wherein R1 is SO2; R2 is OH or OR7; R3 is N; and R4 is H.

6. A compound of Claim 1, wherein R1 is SO2; R2 is OH or OR7; R3 is N; R4 is H; and R5 is F.

7. A compound of claim 1, wherein R1 is SO2; R2 is OH; R3 is N; R4 is H; R5 is F; R6 is H;

8. A compound of claim 1, wherein R1 is SO2; R2 is OR7; R3 is N; R4 is H; R5 is F; R6 is H; and R7 is PO(OH)2

9. A compound of Claim 1, wherein R1 is SO2; R2 is OR7; R3 is N; R4 is H; R5 is F; R6 is H; and R7 is

wherein, M is a monovalent or a divalent cation selected from Na+, K+, Mg2+, Ca2+, and Zn2+ ; and k is 2 for monovalent cation and 1 for divalent cation.

10. A compound of claim 1, selected from the group consisting of

(i) (5S)-Isoxazol-3-yl-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one;

(ii) 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate;

(iii) 4-(5-{2-fluoro-4-[(5S)-2-oxo-5-isoxazol-3-yl-aminomethyl)-1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl dihydrogen phosphate di-potassium salt;
(iv) (5S)- (5-Methyl-Isoxazol-3-yl)-aminomethyl-3-{3-fluoro-4-[6-(4-hydroxy-1,1-dioxido tetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]phenyl}1,3-oxazolidin-2-one;

(v) 4-[5-(2-fluoro-4-{(5R)-5-[(N-isoxazol-3-yl)aminomethyl]-2-oxo-1,3-oxazolidin-3-yl} phenyl) pyridin-2-yl]tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;

and a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

11. A process for preparation of compound of Formula (I), comprising:

(d) reacting a compound of Formula (II) with a sulfonating reagent like methanesulfonyl chloride, optionally in presence of a solvent like DCM, at temperatures from –5oC to + 40oC to obtain a compound of Formula (IIa);

(e) reacting a compound of Formula (IIa) with a suitably protected 3-amino-isoxazole in presence of a base such as anhydrous potassium carbonate and a suitable solvent such as DMF, at temperatures between 25-100 oC, to obtain a compound of Formula (III) as shown below.

(f) reacting a compound of Formula (III) with a suitable de-protecting agent dilute mineral acids like aqueous Hydrochloric acid or organic acids like trifluoroacetic acid, optionally in presence of a solvent like DCM, EDC, THF, Acetone etc., at temperatures between –5oC to + 40oC to obtain a compound of Formula (I).

12. A process for preparation of compound of Formula (I) according to claim 9, comprising:

(a) The compound of formula I, wherein R2 is OH is reacted with a suitable phosphorylating reagent (N, N diisopropyl dibenzyl phosphoramidite) in a suitable solvent such as DCM or mixtures of solvent such as DCM plus THF, from temperatures ranging from –20 to RT followed by oxidation to obtain the dibenzyl phosphate of formula (Ic).

(b) The compound of formula (Ic) is de-benzylated either by hydrogenation or by reacting with a de-alkylating reagent like trifluoroacetic acid, at temperatures from –5oC to 40oC, in solvents like DCM, Chloroform, Ethyl acetate to obtain the compound of formula (Id).

(c) The compound of formula (Id) is reacted with a suitable base like potassium carbonate, potassium hydroxide etc. in a suitable solvent such THF or chloroform along with methanol, and temperatures ranging from –5oC to + 40oC to obtain the compound of formula (I).

13. A pharmaceutical composition comprising a compound of Claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents.

14. A method of treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

15. A method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of compound of Claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof.

16. A method of treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a pharmaceutical composition according to claim 13.

17. A method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a pharmaceutical composition according to claim 13.