FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION
SUBSTITUTED BIARYL OXAZOLIDINONES

2. APPLICANT(S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS : D-4, M.I.D.C. Area, Chikalthana, Aurangabad-431210
(M.S.) India
3. PREAMBLE TO THE DESCRIPTION
The invention relates to substituted biaryl oxazolidinones.
The following specification particularly describes the invention and the manner in which it is to be performed.

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The invention relates to substituted biaryl oxazolidinones. The invention also relates to the process for preparation, to pharmaceutical compositions containing the compounds and to methods for treating or preventing microbial infections using the substituted biaryl oxazolidinones compounds 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 p-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 cited in the literature, which refer to oxazolidinones having antibacterial activity. Biaryl moiety bearing oxazolidinones are described in following patents and patent applications; U.S. Patent No. 7,148,219, U.S. Patent No. 7,141,588, U.S. Patent No. 6,689,779, U.S. Patent Publication No. 20060116386, U.S. Patent Publication No. 20060052399, U.S. Patent Publication No. 20070155798, International (PCT) Publication Nos. WO 2001/94342, WO 2005/005420, WO 2005/058886 and WO 2005/005398.
In one general aspect, the invention provides substituted biaryl oxazolidinones of Formula-(I),
wherein,
X is selected from the group consisting of O, S, SO, SO2 and -NR5;;
wherein R5 is selected from the group consisting of H, alkylsulfonyl, alkoxycarbonyl,
alkanoyl, alkyl and substituted alkyl; R] is selected from the group consisting of -CN, -NO2, -(CH2)m-NR7Rg, carboxy, alkoxycarbonyl, -CONH2 and formyl;
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wherein m is 0 or 1; R2 and R3 are independently selected from -H or halogen;
R4 is selected from the group consisting of-OR6, heteroaryl, substituted heteroaryl, heterocyclyl, -NR7R8 and azido;
wherein R6 is selected from the group consisting of -H, alkylsulfonyl, heterocyclyl,
heteroaryl and substituted heteroaryl;
R7 and Rg are independently selected from the group of -H, alkyl, alkanoyl and
alkoxycarbonyl; Q is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine and pyridazine optionally substituted with substituents selected from the group consisting of halogen, -NH2, -OH, -CN, -N02, -CHO and -COOH; n is Oor 1; and pharmaceutically acceptable salts or prodrugs thereof.
In another aspect, the invention provides a process for preparation of substituted biaryl oxazolidinones of Formula-(I).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula-(I) and a pharmaceutically acceptable excipient.
In another aspect, the invention provides method for treating or preventing microbial infections using the compounds of the invention.
Other aspects will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention.
The term "alkyl" refers to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and six carbon atoms by removal of a single hydrogen atom. Exemplary Ci-Cg alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, neopentyl, and n-hexyl.
The term "substituted alkyl" refers to an "alkyl" group as previously defined, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with substituents
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including, but not limited to, halogen, -COOH, -CHO; -Nri2; -OH, -N02, -CN, C3-C8-cycIoalkyI, aryl, heteroaryl or alkoxy group.
The term "C3-C8-cycloalkyr denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopemyl and cyclohexyl.
The term "aryl" refers to a mono-, fused bicyclic or fused tricyclic carbocyclic ring system having one or more aromatic rings including, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, anthracenyl, phenanthrenyl, biphenylenyl and fluorenyl.
The term "alkanoyl" unless otherwise indicated, includes -C(0)-alkyl wherein "alkyl" is as defined above.
The term "alkylsulfonyl" unless otherwise indicated, includes -S02-alkyl wherein "alkyl" is as defined above.
The term "alkoxycarbonyl" represents an ester group, i.e. ah alkoxy group, attached to the parent molecular moiety through a carbonyl group. Examples include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
The term "alkoxy" refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy group include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butfoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "formyl" refers to the group -CHO.
The term "carboxy" as used herein refers to a group of the formula -COOH.
The term "halogen" or "halo" means atom selected from fluorine, chlorine, bromine or iodine.
The term "heterocyclyl" means mono-, bi- or tri- cyclic rirtg systems which may be partially or fully saturated having 3-10 ring atoms. The individual rings may be 3-8 membered bearing one
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or more heteroatom selected from N, O, S or groups such as SO, S02. This includes aryl and heteroaryl ring stems fused to non-aromatic ring. For example, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl;
The term "heteroaryl" refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; one, two,or three ring atoms may be additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms. Representative examples include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, quinolinyl and isoquinolinyl.
The term "Substituted heteroaryr" as used herein reters to a heteroaryf group as defined above substituted by independent replacement of one, two or three of the hydrogen atoms thereon with -CI, -Br, -F, -I, -OH, cyano, alkyl, alkoxy, alkoxy substituted with aryl, haloalkyl, thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, mercapto, -S03H, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, arylalkyl, cycloalkyl, heteroaryl, or heterocycloalkyl group.
The term "pharmaceutically acceptable salts" refers to those carboxylate salts, esters, and prodrugs of the compound of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwiuerionic forms, where possible, of the compounds of the invention. Pharmaceutically acceptable salts are well known in the art and refer to the relatively non-toxic, inorganic and organic acid addition salts of the compound of the present invention. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) which is incorporated herein by reference. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid; hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include
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adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate. undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, 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, loweralkyl sulfonate and aryl sulfonate.
The term "patient" as used herein is taken to mean birds, fishes and mammals, for example, humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
The term "therapeutically effective amount" is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of microbial infection.
The term "prodrug" refer to any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I are prepared by modifying one or more functional group(s) present in the compound of Formula I in such a way that the modification(s) may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula I wherein a hydroxy, amino or carboxy group in a compound of Formula I is bonded to any group such as an amino acid residue, 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 or valine. The prodrugs also include esters (e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters groups (e.g. ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl), N-Mannich bases and Schiff bases of amino functional groups, in compounds of Formula I, that may be cleaved in vivo to regenerate the free hydroxyl, carboxy or amino group, respectively.
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The term "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agant, stabilizer, isotonic agent, solvent, or emulsifier known to the person skilled in the art.
Representative compounds of the invention include:
N-{[(5S)-3-(4-{5-[4-cyano-l-(methylsulfonyl) piperidin-4--yl] pyridin-2-yl}-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl} acetamide;
tert-butyl 4-[5-(4-{(5S)-5-[(acetylamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluorophenyl) pyridin-2-yl]-4-cyanopiperidine-1 -carboxylate;
Trifluoroacetic acid salt of N-{[(5S)-3-{4-[5-(4-cyanopiperidin-4-yl)pyridin-2-yl]-3-fluoro phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
yl]methyl}acetamide;
N-{[(5S)-3-{4-[5-(l-acetyl-4-cyanopiperidin-4-yl) pyrithn-2-yl]-3-fluorophenyl}-2-oxo-l,3-
oxazolidin-5-yl]methyl}acetamide;
4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-lJ3-oxazolidin-3-yl] phenyl} pyridine-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile;
4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy) methyl]-2-oxo-l,3-oxazoridin-3-yl}phenyl) pyridin-2-yl] tetrahydro-2H-thiopyran-4-carboni tri 1 e;
4-(5-{2-fluoro-44(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethy1)-l,3-oxazolidin-3-yl]phenyl}pyr idin -2-yl)terrahydro-2H-hiopyran-4-carbonitrile;
7V-{[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
Methyl {[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl} carbamate;
N-{[(55)-3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3-fluoro phenyl} -2-oxo-1,3-oxazoIidin-5-yl]methyl }acetamide;
Methyl {[(5S)-3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]-3-fluoro phenyl} -2-oxo-1,3-oxazolidin-5-yl]methyl} carbamate;
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4-(5-{2-fluoro-4-(5R)-2-oxo-5-(lH-l,2)3-triazol-l-ylmethyl)-l,3-oxazolidin-3-yl]phenyl} pyridin-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;
4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l)3-oxazolidin-3-yl} phenyl) pyridin-2-yI]tetrahydro-2H-thiopyran-4-carbonitrile 1,1 -dioxide;
4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)tetra hydro-2H-thiopyran-4-carbonitrile 1,1 -dioxide;
N-{[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-pyran-4-yl) pyridin-2-yl]-3-fluorophenyI}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
Methyl .{[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-pyran-4-yl)' pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazoIidin-5-yl]methyl}carbamate;
4-(5-{2-fluoro-4-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyl)-i,3-oxazolidin-3-yl]phenyl} pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile;
4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}pyridine-2-yl )tetrahydro-2H-pyran-4- carbonitrile;
4-(5-{2,6-difluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-I,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile;
4-[5-(2-fluoro-4-}(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-i,3-oxazolidin-3-yl} phenyl) pyridin-2-yl]tetrahydro-2H-pyran-4-carbonitrile;
Trifluoroacetic acid salt of 4-(5-{2-fluoro-4-[(5R)-5-(hyt|roxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl }pyridin-2-yl)piperidine-4-carbonitrile;
l-acetyl-4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)piperidine-4-carbonitrile;
4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} pyridine-2-yl)-l-(methylsulfonyI)piperidine-4-carbonitrile;
N-{[(5S)-3-(4-{5-[4-cyano-l-(methylsulfonyl) piperidin-4-y]] pyridin-2-yl}-3-fluoro phenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
4-(5-{2-fluoro-4-[(5R)-2-oxo-5-(lH-l,23-triazol-l-ylmethyl)-l,3-oxazolidin-3-yl]phenyI} pyridin-2-yl)-l-(methylsuIfonyl)piperidine-4-carbonitrile;
4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-ls3-oxazolidin-3-yl} phenyl) pyridin-2-yl]-l-(methylsulfonyl)piperidine-4-carbonitrile;
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I-acetyl-4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyi]-2-oxo-l,3-oxazolidin-3-yl} phenyl) pyridin-2-yl]piperidine-4-carbonitrile;
4-[5-(2-fluoro-4"{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-3-oxazolidin-3-yl} phenyl) pyridin-2-yI]-l-methylpiperidine-4-carbonitrile;
4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazoHdin-3-yl] phenyl}pyridine-2-yl)-l-methylpiperidine-4-carbonitrile;
N-{[(5.S)-3-{4-[5-(4-cyano-l-methylpiperidin-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl] methyl} acetamide;
N- {[(5S)-3- {4-[2-(4-cyano-l, 1 -dioxidotetrahydro-2H-thiopy-4-yl)pyrimidin-5-yl]-3-fluoro phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
N-{[(55)-3-{4-[5-(4-cyano-tetrahydro-2H-thiopyran-4-yl) pyridazin-2-yl]-3-fluoro phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
N-{[(55)-3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridazin-2-yl]-3-fluoro phenyl}-2 -oxo-1,3-oxazolidin-5-yl]methyl}acetamide;
A^-{[(5.S)-3-{4-[5-(4-cyanotetrahydro-2//-thiopyran-4-yl) Pyridin-2-yl]-3,5-difluoro phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide;
N- {[(5S)-3- {4-[5-(4-cyano-l, 1 -dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3,5-difluoro phenyl} -2-oxo-1,3-oxazolidin-5-yl]methyl} acetamide;
N-({(5S)-3-[4'-(4-cyanotetrahydro-2H-thiopyran-4-yl)-2,3,-difluorobiphenyl-4-yI]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide;
N-{[(5S)-3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3-fluoro phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl} acetamide;
4-{2')3-difluoro-4'-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]biphenyl-4-yl} tetrahydro -2H-thiopyran-4- carb oni trile;
4-(2',3-difluoro-4,-{(5R)-5-[(isoxazol-3-yloxy) methyl]-2-oxo-l,3-oxazolidin-3-yl} biphenyl-4-yl)tetrahydro-2H-thiopyran-4-carbonitrile;
4-(2',3-difluoro-4,-{(5i?)-5-[(isoxazol-3-yloxy) methyl]-2-oxo-l,3-oxazolidin-3-yl} biphenyl-4-yl)tetrahydro-2H-thiopyran-4-carbonitrile 1,1 -dioxide;
4-{2,,3-difluoro-4'-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylme%l) -l,3-oxazolidin-3-yl] biphenyI-4-yl} tetrahydro-2H-thiopyran-4-carbonitrile;
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4-{2,,3-difluoro-4,-[(5R)-2-oxo-5-(lH-l,2;3-triazol-l-ylmethyl) -l,3-oxazolidin-3-yl] biphenyl-4-yl}tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide;
4-{2',3-difluoro-4,-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]biphenyl-4-yl} tetrahydro -2H-thiopyran-4-carbonitrile 1,1-dioxide and
N-({(55)-3-[4'-(4-cyanotetrahydro-2H-yran-4-yl)-2,3,-difluorobiphenyl-4-yl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide.
Following reaction schemes describe the preparation of compounds of Formula-(I) of the invention. The starting materials may be prepared by procedures that would be well known to one of ordinary skill in organic chemistry including 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. The variables used in the following schemes are as defined above.
In another aspect, the invention provides process of preparation of compound of Formula-(I) by converting the compound of Formula-(l) to compound of Formula-(2) which is then converted to compound of Formula-(I).
The process involves reacting compound of Formula-(l) with suitable hexaalkylditin reagent such as hexamethylditin or hexabutylditin 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, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, toluene, xylene, ethylacetate or hexamethylphosphorotri amide at a temperature between 80 °C to 110 °C to provide intermediate tin compound of Formula-(2). The intermediate tin compound of Formula-(2) is further condensed with compound of Formula-(3), wherein Q' is halo substituted Q, in presence of a base like triethylamine, pyridine or N-ethyldiisopropylamine, diisopropylamine in an aprotic organic solvent such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethyIformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, toluene, xylene or hexamethylphosphorotri amide in presence of a catalyst like palladium on carbon, tetrakistriphenylphosphine palladium (0) or dichlorobistriphenyphosphine palladium (II) or
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palladium (II) chloride, or palladium acetate at a temperature of 70 to 100 °C to provide compounds of Formula-(I) ( scheme 1).

Formula-(l)

Formula-(2)

Formula-(3)

R
Foonula-(I)
Scheme 1
In another aspect, oxidation of compound of Formula-(Ia) 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 80 °C to 120 °C to furnish oxidized oxazolidinone compound of Formula (lb) of the invention (scheme-2).

In yet another aspect, the compound of Formula-(3), wherein Q' is halo substituted Q, is reacted with suitable hexaalkylditin reagent such as hexamethylditin or hexabutylditin in presence of palladium catalyst such as palladium on carbon, tetrakistriphenylphosphine palladium or dichlorobistriphenyphosphine palladium (II) or palladium (II) chloride, or palladium acetate in an aprotic organic solvent such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone, toluene, xylene or hexamethylphosphorotriamide at a temperature between 80 °C to 110 °C to provide tin compound of Formula-(4), wherein Q" is trialkyl tin substituted Q. The compound of Formula-
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(4), wherein Q" is trialkyl tin substituted Q, is further heated with compound of Formula-(l) in presence of a base like triethylamine, N-ethyldiisopropylamine, isopropylamine or pyridine and a palladium catalyst such as palladium on carbon, tetrakistriphenylphosphine palladium or dichlorobistriphenyphosphine palladium (II) or palladium (II) chloride, or palladium acetate in an aprotic organic solvent such as tetrahydrofuran, dimethyl sulfoxide, N,N-dimethyl form amide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone or hexamethylphosphorotriamide at a temperature between 80 °C to 110 °C to provide compound of Formula-(I) (scheme 3).

Formula-(I) Scheme 3 In yet another aspect, a compound of Formula-(Iz) wherein R4 is —OH, is stirred with a hydroxy compound such as 3-hydroxyisoxazole in presence of a organophosphorus compound such as triphenyl phosphine and an azo reagent such as diisopropyl azo dicarboxylate or diethyl azodicarboxylate using an aprotic organic solvent such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, acetone or hexamethylphosphorotriamide at room temperature to obtain a compound of Formula-(Ic) of the invention. Alternatively, a compound of Formula-(I) wherein R4-is -OH, is stirred with methanesulphonyl chloride in the presence of a base such as triethylamine or pyridine or sodium bicarbonate using a solvent such as THF, chloroform, dichloromethane or carbon tetrachloride below room temperature to give the compound of Formula-(Id) of the invention. The compound of Formula-(Id) is further converted into compound of Formula-(Ie) by treating compound (Id) with sodium azide in a solvent such as
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dimethylsulfoxide, dimethyl formamide or dimethylacetamide at 80 to 120 °C. The compound of Formula-(Ie) is further heated with vinyl acetate in a sealed pressure reaction flask at 120-150 °C hours to obtain a compound of Formula-(If) (scheme 4).

In yet another aspect, the invention provides a pharmaceutical composition comprising compound of Formula-(I) and a pharmaceutically acceptably excipient and/or carrier wherein the composition may comprise a composition preparation which include, but are not limited to, solid compositions like tablets, pills, capsules, dispersible powders, granules, hard capsules and soft capsules, liquid compositions like emulsions, solutions, suspensions, syrups and elixirs or other compositions for oral administration or as injections like sterile aqueous, non-aqueous solutions, suspensions and emulsions, liniments or suppositories for parenteral administration.
In another aspect, the invention provides oxazolidinone componds for treatment of microbial infections. The microbial infection can be caused by Grampositive including -multi-resistant
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bacteria, Gram-negative bacteria, anaerobic organism, acid-fast organism. These compounds are useful for the treatment of Gram-positive or Gram-negative microbial infections in animals and human. The animals which can be treated by bacterial infections include but not limited to birds, mammals, fishes. These compounds are useful for the treatment of microbial infections by either parenteral, oral or topical administration. The infection in human and animals can be systemic or topical.
The compounds of this invention may be used to prevent infections caused by Gram-positive and Gram-negative bacteria by administering the compound to a subject that is at risk for developing an infection caused by Gram- positive or Gram-negative bacteria.
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 Test Method : 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
Strains: Staphylococcus aureus ATCC 25923, Staphylococcus aureus 014, Staphylococcus epiderinidis 110, Enterococcusfaecalis 401, Enterococcus faeciuin 303, Streptococcus pneumoniae 49619, Streptococcus pneumoniae 706, Streptococcus pyogenes 801, Streptococcus pyogenes 805 and Haenlophilus influenzae 49247.
The MIC values of the selected oxazolidinone compounds of the invention have displayed antibacterial activity in the range of 0.5 to 8 mcg/ml.
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The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.
EXPERIMENTAL
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice this invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.
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 [Bis(2-methanesuIfonoxy ethyl) sulfide}
To a solution of [Bis(2-hydroxyethyl)sulfide] (62 g , 0.507 mol, 1 eq) in THF (1200 ml) was added triethylamine (204.8 g, 2.028 mol, 5.0 eq.) and the resulting solution cooled to 0-5°C. To this, methanesulphonyl chloride (144.2 g, 1.265 mol, 3 eq) was added dropwise while stirring. The reaction mixture was allowed to warm to RT and stirring continued further for 4 hours. The resulting mixture was filtered and the filtrate was used as such for the next reaction without further concentration or purification. Yield considered as 98g (70%).
II. Preparation of [Bis(2-methanesuIfonoxy ethyl) ether]
To a solution of diethyleneglycol (25 g, 0.236 moles, 1 eq) in DCM (250 ml) was added triethylamine (119 g, 1.178 moles, 5.0 eq) and the solution cooled to 0-5°C. To this, methanesulphonyl chloride (81 g, 0.708 moles, 3 eq) was added dropwise while stirring. The
15

reaction mixture was allowed to warm to RT and stirring continued further for 1 hour. The resulting mixture was poured into water (250 ml), stirred well and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 x 100 ml). The combined extracts were concentrated under reduced pressure. The residue obtained was chromatographed on a column of silica gel. Elution with a mixture of v/v Hexane:Ethyl acetate (1:1) and concentration of the combined fractions gave the product as a pale yellow solid, 40 g; yield 61%.
III. Preparation of [(Methylsulfonyl)imino]diethane-2,l-diyl-dimethanesulfonate
Methanesulfonyl chloride (34.2 g, 0.3 moles) was added to a solution of diethanolamine (10.5 g, 0.1 mole) and triethylamine (40 ml, 0.3 moles) in dichloromethane (300 ml), at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, allowed to warm to RT and further stirred for 1 hour. The resulting mixture was diluted with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated on rotary evaporator to afford the product as a pale yellow liquid, 30.7 g, 85 % yield. This was used as such without further purification.
IV. Preparation of [(tert-ButoxycarbonyI)imino]diethane-2,l-diyl-dimethane sulfonate
Methanesulfonyl chloride (34.0 g, 0.3 moles) was added to a solution of fcrt-butyl bis(2-hydroxyethyl)carbamate(20.5 g, 0.1 mole) and triethylamine (40 ml, 0.3 mole) in dichloromethane (300 ml), at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, allowed to warm to RT and further stirred for 1 hour. The resulting mixture was diluted with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated on rotary evaporator to afford the product as a pale yellow liquid, 38.9 g , 80 % yield. This was used as such without further purification.
V. Preparation of 4-(5-bromopyridin-2-yl)-tetrahydro-2H-pyran-4-carbonitriIe
To a suspension of sodium hydride (0.3 g , 4 eq) in THF (15ml) was added a solution of 2-(5-bromopyridin-2-yl)acetonitrile (0.5 g , 1 eq) in THF(5ml) dropwise at 0°C. The reaction mixture was stirred at RT for 30 min. The reaction mixture was cooled to 0°C, followed by the addition of a solution of Bis(2-methanesulfonoxy ethyl) ether (0.802 g , 1.2 eq) in THF (3ml) at 0° C dropwise. The reaction mixture was then stirred at RT for 14h. The resulting mixture was diluted with water (20ml) and then extracted with ethyl acetate (2x25ml). The solvent was evaporated under reduced pressure and the residue purified by column chromatography over silica gel Elution with a v/v 95:5 mixture of Hexane: Ethyl acetate and concentration of the combined fractions gave the product, 0.236 g, yield , 48 %.
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VI. Preparation of 4-(5-bromopyridin-2-yi)-tetrahydro-2H-thiopyran-4-carbonitrile
To a suspension of sodium hydride (44.14 g , 1.012 mol) in THF (800ml) was added a solution of 2-(5-bromopyridin-2-yl)acetonitrile (50 g , 0.253 mmol) in THF(150ml) dropwise at 0° C. The reaction mixture was stirred at RT for 30 min. The reaction mixture was cooled to 0°C, followed by a dropwise addition of a solution of Bis(2-methanesulfonoxy ethyl) sulfide (98g, 1.2 eq) in THF (1.2L) . The reaction mixture was then stirred at RT for 14h. The resulting mixture was diluted with water (500ml) and then extracted with ethyl acetate (2x1.5L). The solvent was evaporated under reduced pressure and the residue purified by column chromatography over silica gel Elution with a v/v 95:5 mixture of Hexane: Ethyl acetate and concentration of the combined fractions gave the product as a buff colored solid, 34.4 g, 48 % yield.
VII. Preparation of 4-(5-bromopyridin-2-yI)-l-(methylsiilfonyl) piperidine-4-carbonitrile
To a solution of 2-(5-bromopyridin-2-yl)acetonitrile (16.3 g, 0.083 moles) in THF (150ml), sodium hydride (6.63 g, 0.166 moles) was added by maintaining temperature between 0-5 °C. Then the reaction mixture was stirred for 1 hour at RT. A solution of [(methylsulfonyl) imino] diethane-2,l-diyl dimethanesulfonate (29.5 g, 0.083 moles) in THF (60ml) was then added under argon atmosphere at 0°C. Reaction mass was stirred at sametemperature and then stirred at room temperature for 10 hours. The resulting mixture was quenched with ammonium chloride and extracted with ethyl acetate (2x100ml). The solvent was Evaporated under reduced pressure to obtain the product as a pale yellow solid, 18.58 g. in 65% yield. ES: MS: 459 (MH+, 100%) for M.F: C28H37FN4O3S; M.P. U6-148°C.
VIII. Preparation of tert-buryl-4-(5-bromopyridin-2-yl)-4-cyanopiperidine-l-carboxylate
To a solution of 2-(5-bromopyridin-2-yl) acetonitrile (16.3 g, 0.083 moles) in THF, (75ml), 55%sodium hydride (6.63 g, 0.166 moles) was added by maintaining temperature between 0-5°C. Then the reaction mixture was stirred for 1 hour at RT. A solution of [(tert-Butoxycarbonyl) imino] diethane-2,l-diyl dimethanesulfonate(17.0 g, 0.083 inoles) in THF (60ml) was then added under argon atmosphere. Reaction mass stirred at same temperature and then stirred at room temperature for 10 hours. The resulting mixture was quenched with ammonium chloride and extracted with ethyl acetate (2x 100ml). The solvent was Evaporated under reduced pressure to obtain the product as a pale yellow solid, 18.0 g, 63% yield.
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IX. Preparation of 4-(4-Bromo-2-fluorophenyI)-tetrahydro-pyran-4-carbonitriIe
To a suspension of 55% sodium hydride (0.280 g, 5.84 mmol) in THF (6 ml) was added (4-Bromo-2-fluorophenyl)-acetonitrile (0.5 g, 2.33 mmol) in THF (6 ml) drop wise at 0 °C over period of 10 minutes. The reaction mixture was stirred at RT for 30 minutes, followed by dropwise addition, at 0°C, of THF solution (4ml) of Bis(2-methanesulfonoxy ethyl) ether (0.732 g, 2.796 mmol). The reaction mixture was then allowed to stir at RT for 15 hours. The resulting mixture was diluted with water (30 ml) and then extracted with ethyl acetate (3x30 ml). The ethyl acetate extract was concentrated and the residue obtained was purified by column chromatography to obtain product as pale yellow oil, 0.31 g, 46% yield. MW: 284, MF: C12HHBrFNO.
X. Preparation of 4-(4-Bromo-2-fluoro-phenyl)-tetrahydro-thiopyran-4-carbonitriIe
To the suspension of 55%sodium hydride (5.6 g, 116 mmol) in THF (100 ml) was added (4-Bromo-2-fluoro-phenyl)-acetonitrile (10 g, 46.7 mmol) in THF (30ml), dropwise, at 0°C, over a period of 30 minutes. The reaction mixture was stirred at RT for 30 minutes, followed by the addition of THF solution of Bis(2-methanesulfonoxy ethyl) sulfide solution in THF ( -15.6 g, 56.0 mmol), dropwise, at 0°C . The reaction mixture was then allowed to stir at RT for 15 hours. The resulting mixture was diluted with water (50 ml) and then extracted with ethyl acetate (3x50 ml). The ethyl acetate extract was concentrated and the residue purified by column chromatography to obtain product as pale yellow solid, 6 g, 43% yield. ES: MS 299.9(M)+, MF: C12H11BrFNS.
XI. Preparation of (SJO-S-tf-fluoro-4-(tributyl stannanyl) phenyl]-5-(lH-l,2,3-triazol-l-
ylmethyi)-l,3-oxazolidin-2-one
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(lH-lJ2,34ri.azoI-l-ylmethyl)-l,3-oxazolidin-2-one (9 g, 23.13 mmol), hexabutylditin (20.2 g, 34.80 mmol) and dichlorobistriphenylphosphine palladium (II) catalyst (900 mg, 0.1 moI%) in 1,4-dioxane (90 ml) was heated at 90°C for 16 hours. The reaction mixture was filtered over celite bed. The filtrate was concentrated and residue purified by flash column chromatography to obtain the product as buff colored solid 8.5 g, yield 67%. ES: MS: 552 (M+l); MF C24H37FN402Sn.
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XII. Preparation of N-{(5S)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-l,3-oxazohdin-
5-yl}methyl)acetamide
A mixture of N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl} acetamide (20 g, 52.3 mmol), hexabutylditin (46 g, 79.31 mmol) and dichlorobistriphenylphosphine palladium (II) (2 g, 0.1 %) in 1,4-dioxane (200 ml) was heated at 90°C for 16 hours. The reaction mixture was filtered over celite bed, the filtrate concentrated under reduced pressure and the residue purified by column chromatography by using chloroform: methanol (98.5:1.5) as a mobile phase to afford 23.2 g of product in 35% yield. ES: MS = 542 (M+l); MF: C24H39FN2O3S11.
XIII. Preparation of Methyl ({(5S)-3-[3-fluoro-4-(tributylstannanyl)phenyI]-2-oxo-l,3-
oxazolidin-5-yl}methyI)carbamate
A mixture of methyl {[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-
y]]methy)} carbamate (03 g, 0.76 mmoJ), JiexabutyJditJD (0.55 m), 0.94 mmoJ) and dichlorobistriphenylphosphine palladium (II) (30 mg, 0.1 mol %) in l,4-dioxane(10 ml) was heated at 90°C for 16 hours. The reaction mixture was filtered over celite bed, the filtrate evaporated and the residue purified by column chromatography by using a v/v 98.5:1.5 mixture of chloroform: methanol as a mobile phase to afford the product, 0.49 g , 90% yield. ES: MS: 544 (M+l); MF C23H37FN204Sn.
XIV. Preparation of (5R)-3-[3-fIuoro-4-(triburyIstannanyl)phenyl]-5-[(isoxazol-3-
yloxy)methyl]-l,3-oxazo!idin-2-one
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-[(isoxazol-3-yloxy)methyl]-l,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 °C 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-
XV. Preparation of {(5R)-3-[3-fluoro-4-(triburylstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-
yl} methyl acetate
The [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl acetate
19

(7.35 g, 16.1 mmol) was taken in 1,4-dioxane (75 ml) along with hexabutylditin (14 g, 24.2 mmol) followed by the addition of Bis(triphenylphosphine)palladium (II) dichloride catalyst (0.73 g). The reaction mixture was then heated at 90°C for 16h. The resulting mixture was filtered over celite bed and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography using a v/v 98.5:1.5 mixture Chloroform: Methanol to obtain the product, as a buff colored solid, 9 g, 90% yield.
XVI. Preparation of (5R)-3-[3-fluoro-4-(tributylstannajiyl)pheiiyl]-5-(hydroxy methyl)-1,3-oxazolidin-2-one
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyI)-l,3-oxazolidin-2-one (2 g, 5.93 mmol), hexabutylditin (4.48 g, 7.70 mmol) dichlorobistriphenylphosphine palladium (II) catalyst (150 mg, 0.1 mol %) in 1,4-dioxane (20 ml) was heated at 90°C for 16 hours. The resulting mixture was filtered over celite bed, the filtrate was evaporated under reduced pressure and the residue was purified by coiumn chromatography using v/v 95:5 mixture of Ch)oroform: Methanol, concentration of the combined fraction gave the product as a buff colored solid, 1.3 g, 44% yield.
XVII: Preparation of N-({(5S)-3-[3,5-difluoro-4-Ctfibutylstannany}phenyl]-2-oxo-l,3-oxazolidin-5-yI}methyl)acetamide
N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-.yi]methyl}acetamide (15 g, 37.8 mmol) was taken in 1,4-dioxane (150 ml) along with hexabutylditin (33 g, 56.8 mmol) followed by the addition of Bis(triphenylphosphine)palladium (II) dichloride catalyst (1.5 g). The reaction mixture was then heated with stirring at 90°C for 16h. The resulting mixture was filtered over celite bed and the filtrate concentrated. The residue obtained was purified by column chromatography using v/v 98.5:1.5 mixture of Chloroform: Methanol. Concentration of the combined fractions gave the product as buff colored solid.l8g, 85% yield. ES: MS: (M+l) 561; MF: C24H38F2N203Sn
XVIII. Preparation of 4-(5-(tributylstannyl)pyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbonitrile
To a solution of 4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbonitrile (1.4 g, 0.00495 mol) in 1,4-dioxane (35 ml) was added bis(tributyl)tin (4.3 g, 0.00742 mol) followed by the addition of bis(triphenylphosphine)palladium dichloride (0.35 mg, 0.00049 mol). The reaction mixture was heated at 90°C for 4 hours, followed by filtration over celite bed. The filtrate was
20

concentrated and the residue purified by column chromatography. Elution with a v/v 95:5 mixture of Hexane: Ethyl acetate and concentration of the combined fractions gave the product as a colorless liquid, 1.28 g, 52% yield. ES:MS:495(M++1).
XIX. Preparation of 4-(5-(tributylstannyl)pyridin-2-yI)-tetrahydro-2H-pyran-4-carbonitrile
To a solution of 4-(5-bromopyridin-2-yl)-tetrahydro-2H-pyran-4-carbonitrile (1.4 g, 0.00495 mol) in 1,4-dioxane (35 ml) was added bis(tributyl)tin (4.3 g, 0.00742 mol) followed by the addition of bis(triphenylphosphine)palladium dichloride (0.35 mg, 0.00049 mol). The reaction mixture was heated at a temperature of 90°C for 4 hours, followed by filtration over celite bed, concentration and then purification over column chromatography. Elution with a v/v 95:5 mixture of Hexane: Ethyl acetate and concentration of the combined fractions gave the product as a colorless liquid, 1.28 g, 52% yield. ES:MS:479(M++1).
XX. Preparation of 4-(5-(tributylstannyl)pyndin-2-yl)-l-aceryl-piperidin-l-yI)-4-
carbonitrile
A mixture of l-acetyl-4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (2.6 g, 8.48 mmol), bis(tributyltin) (7.37 g, 12.7 mmol) and dichlorobis(triphenylphosphine) palladium (II) (240 mg, 0.1 mol %) in 1,4-dioxane (20 ml) was heated at 90°C for 16 hours. The resulting mixture was filtered over celite bed, the filtrate was concentrated and the residue purified by column chromatography using a v/v 98.5:1.5 mixture of Chloroform: Methanol. Concentration of the combined fractions gave the product, 3 g, 68% yield. ES: MS: 519(M+1); MF: C25H4lN30Sn.
XXI. Preparation of 4-(5-(tributyIstannyI)pyridin-2-yl)-l-mesyIpiperidine-4-carbonitriIe
A mixture of 4-(5-bromopyridin-2-yl)-l-mesylpiperidine-4-carbonitrile (2.9 g, 8.48 mmol), bis(tributyltin) (7.37 g, 12.7 mmol) and dichlorobis(triphenylphosphine) palladium (II) (240 mg, 0.1 mol %) in 1,4-dioxane (20 ml) was heated at 90°C for 16 hours. The resulting mixture was filtered over celite bed and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography using v/v 98.5:1.5 mixture of Chloroform: Methanol. Concentration of the combined fractions gave the product, 3.5 g, 76% yield. ES: MS: 545(M+1); MF: C24H41N3O2SSN .
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XXII. Preparation of 4-(5-(tributyIstannyl)pyridin-2-yl)-l-methylpiperidine-4-carbonitrile
A mixture of 4-(5-bromopyridin-2-yl)-l-methyIpiperidine-4-carbonitrile (2.3 g, 8.48 mmol), bis(tributyltin) (7.37 g, 12.7 mmol) and dichlorobis(triphenylphosphine) palladium (II) (240 mg, 0.1 mol %) in 1,4-dioxane (20 ml) was heated at 90°C for 16 hours. The resulting mixture was filtered over celite bed and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography using v/v 98.5:1.5 mixture of Chloroform: Methanol. Concentration of the combined fractions gave the product, 3 g, 74% yield. ES: MS: 492 (M+l); MF: C24H4]N3Sn.
Example 1: Preparation of N-{[(5S)-3-(4-{5-[4-cyano-l-(methyl sulfonyl) piperidin-4-yI] pyridin-2-yI}-3-fluorophenyI)-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide
To a solution of 4-(5-bromopyridin-2-yl)-l-(methylsulfonyl) piperidine-4-carbonitrile (18 g, 0.052 moles) and N-({(5S)-3-[3-fluoroA-(tributy\stannanyl)pheny\]-2-oxo-l,3-oxazohdin-5-yl}methyl)acetamide (28.3 g, 0.052 moles) in DMF(200 ml), diisopropylethylamine (27.1 ml,0.156 moles) and tetrakistriphenylphosphine palladium (0)( 1.8 g ) were added under argon atmosphere . The reaction mixture was stirred at 110 °C for 6 hours.. The solvent was evaporated under reduced pressure and the residue suspended in water ( 100ml). The mixture was extracted with ethyl acetate (2x 150ml). The organic layer was separated and dried over sodium sulfate and concentrated on rotary evaporator to obtain the product 14.79 g, 55% yield.
Example 2: Preparation of terf-butyl 4-[5-(4-{(5S)-5-[(acetyiamino) methyl]-2-oxo-l,3-oxazolidin-3-yl}-2-fluorophenyI)pyridin-2-yl]-4-cyanopiperidine-l-carboxyIate
To a solution of tert-butyl 4-(5-bromopyridin-2-yl)-4-cyanopiperidine-l-carboxylate (2 g, 5.4
mmol) and 7V-({(55)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-
yl}methyl)acetamide (3.26 g, 6 mmol) in DMF (20 ml) diisopropylethylamine (1.86 ml, 10.8 mmol) and tetrakistriphenylphosphine palladium (0) (200 mg) were added under argon atmosphere. The reaction mixture was stirred at 110 °C for 6 hours. The solvent was evaporated under reduced pressure and the residue suspended in water (200ml). the mixture was extracted with ethyl acetate (2x 40ml). The organic layer was separated and dried over sodium sulfate and concentrated on rotary evaporator to obtain the product 1.63 g, 55% yield.
Example 3: Preparation of trifluoroacetic acid salt of N-{[(5S)-3-{4-|5-(4-cyanopiperidin-4-yl)pyridin-2-yl]-3-fluorophenyI}-2-oxo-l,3-oxazolidin-5-yI]methyl}acetamide
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To a 2:1 mixture of DCM: trifluoroacetic acid (10 ml), at 0-5°C, tert-butyl 4-[5-(4-{(5S)-5-[(acetyl amino) methyI]-2-oxo-l,3-oxazolidin-3-yl}-2-fluorophenyl)pyridin-2-yl]-4- further 2 hours. The reaction mixture was concentrated on rotary evaporator to obtain the product as off-white solid 0.92g, 90% yield.
Example 4: Preparation of N-{[(5S)-3-{4-[5-(4-cyanopiperidin-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-dxazolidin-5-yl]methyl}acetamide
A suspension of Trifluoroacetic acid salt of N-{[(5S)-3-{4-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide (0.5g) on in DCM (5ml) was neutralized with aqueous sodium bicarbonate (Ig in 10 ml water). The solid was filtered and the filtrate concentrated to obtain the product as an off-white solid, 0.35g, 90% yield.
Example 5: Preparation of N-{[(5S)-3-{4-[5-(l-acetyl-4-cyanopiperidin-4-yl)pyridin-2-yl]-3-fluoro phenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide
A solution of N-{[(5S)-3-{4-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide (0.2g, 0.45mmol) in DCM (5 ml) and containing triethylamine (0.073ml, 0.55mmol), at 0°C, was treated with acetyl chloride (0.043ml, 0.55mmol). Stirring was further continued for 1 hour at RT. The reaction mixture was diluted with water (2ml). The organic layer was separated, dried over sodium sulfate and concentrated on rotary evaporator to obtain the product as a off-white solid, 0.2g, 95% yield
Example 6: Preparation of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yI]phenyl} pyridine-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile
To a solution of 4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbonitriIe (0.7 g, 1.4 mmol) in DMF (10ml) were added (5R)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-(hydroxyrnethyl)-l,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 90°C 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 %.
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Example 7: Preparation of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}phenyl)pyridin-2-yI]tetrahydro-2H-thio|pyran-4-carbonitriIe
To a solution of (5R)-3-[3-fluoro-4-(tributylstannanyl)phetiyl]-5-[(isoxazol-3-yloxy)methyl]-l,3-oxazolidin-2-one (1.4g, 1 eq) in DMF (15 ml) was added 4-(5-bromopyridm-2-yl)-tetrahydro-2H-thiopyran-4-carbonitrile (0.756g, 1.1 eq), tri ethyl amine (1.0 ml, 3 eq), and dichloro bis(triphenylphosphine)palladium (II) catalyst.(lmol%). The reaction mixture was heated with stirring, under argon, at 80°C 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.
Example 8: Preparation of 4-(5-{2-fluoro-4-[(5R)-2-oxo.5-(liy-l,2,3-triazoI-l-ylmethyl)-l,3-
To a solution of (5R)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-2-one (8.5g, 1 eq) in DMF (50ml) was added 4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbonitrile (4.8g, 1.1 eq), tri ethyl amine (4.7g, 3 eq), and dichloro bis(triphenylphosphine)palladium (II) catalyst (480 mg). The reaction mixture was heated, under argon, at 80°C for 14 hours. The resulting mixture was filtered through celite bed. The filtrate was diluted with water (180 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 mixtures of chloroform: methanol (9.5:0.5) to obtain the product as a white solid; 2.4 g, Yield 38%.
Example 9: Preparation of N-{[(55)-3-{4-[5-(4-cyanotetrahydro-2H-thiopyran-4-yl)pyridin-2-yI]-3-fluorophenyl}-2-oxo-l,3-oxazoiidin-5-yl]methyl}acetamide
To a solution of N-( {(5S)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-l ,3-oxazolidin-5-yl}methyl)acetamide (7.5 g, 1 eq) in DMF (40 ml) were added 4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbomtrile (4.3 g, 1.1 eq), triethylamine (4.2 g, 3 eq), and palladium (II) catalyst (430 mg). The reaction mixture was heated, under argon, at 80 °C for 14 hours. The resulting mixture was filtered through celite bed. The filtrate was diluted with water (180 ml) stirred well and extracted with ethyl acetate (3 x 75 ml), "The combined extract was dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure. The residue was
24

purified by flash column chromatography, using mixture 0f chloroform:methanol (9.5:0.5) to obtain the product as a white solid; 2.4 g; 38%.
Example 10: Preparation of Methyl {[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-tliiopyran-4-yl)pyridin-2-yl]-3-fluorophenyI}-2-oxo-l,3-oxazolidin-5-yi]methyl} carbamate
To a solution of Methyl N-({(5S)-3[-3-fluoro-4-(tributylstannany1)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)carbamate (1.44 g, 1 eq) in DMF (20 ml) were added 4-(5-bromopyridin-2-yI)-tetrahydro-2H-thiopyran-4-carbonitrile (0.7 g, 1.1 eq), triethylamine (0.78 g, 3 eq), and dichloro bis(triphenphenylphosphine) palladium (II) catalyst (70 mg). The reaction mixture was heated, under argon, at 80°C for 14 hours. The resulting mixture was filtered through celite bed. The filtrate was diluted with water (180 ml), stirred well and extracted with ethyl acetate (3 x 75 ml). The combined extract was dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography, using mixture of chloroform: methanol (9.5:0.3) to obtain the product as a white solid; 0.425 g; Yield 38%.
Example 11: Preparation of N-{[(5S)-3-{4-[5-(4-cyano-l,i-dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-S-yi]methyl}acetamide
To a suspension of N-{[(5S)-3-{4-[6-(4-cyanotetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide (2.4 g, 1.0 eq) in 1:1 methanol:water mixture (30 ml) was added sodium periodate (5 eq) and the resulting mixture was heated at 80°C for 4 hours. The reaction 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 (8.5:1.5) to obtain the product as a white solid; 1.4 g; yield 55%.
Example 12: Preparation of Methyl {[(5S)-3-{4-[6-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yI)pyridin-3-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}carbamate
To a suspension of methyl{[(5S)-3-{4-[6-(4-cyanotetrahydro-2H-thiopyran-4-yl)pyridin-3-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}carbamate (0.425 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 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue triturated with water (10 ml). The separated solid was filtered
25

and purified by flash column chromatography, using mixtures of chloroform:methanol, to obtain the product as a white solid; 0.290 g; yield 60%.
Example 13: Preparation of 4-(5-{2-fluoro-4-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyI)-l,3-oxazoHdin-3-yl]phenyl}pyridin-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide
To a suspension of 4-(5-{2-fluoro-4-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)tetrahydro-2H-thiopyran-4-carbonitrile (2.4 g, 1.0 eq) in 1:1 methanol: water mixture (30 ml) was added sodium periodate (5 eq) and the resulting mixture was heated at 80 °C for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue triturated with water (10 ml). The separated solid was filtered. The solid was then purified by flash column chromatography, using mixtures of chloroform: methanol to obtain the product as a white solid; 1.5 g; yield 60%.
Example 14: Preparation of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3-yl}phenyl) pyridin-2-yI]tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide
To a suspension of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3-yI}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 80°C 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%.
Example 15: Preparation of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyI)-2-oxo-l,3-oxazoIidin-3-yI]phenyl} pyridin-2-yI)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide
To 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,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 100°C. 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 16: Preparation of N-[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-pyran-4-yI)pyridm-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide
26

To a solution of N-({(5S)-3-[3-fluoro-4-(tributyIstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (0.4 g, 1 eq) in DMF (5 ml) were added successively 4-(5-bromopyridin-2-yl)-tetrahydro-2H-pyran-4-carbonitrile (0.236 g. 1.1 eq), N-Ethyldiisopropylamine (0.397 ml, 3 eq), and palladium (0) catalyst (24 nig). The reaction mixture was heated at 80°C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate diluted with water (20 ml). The mixture was then extracted with ethyl acetate (3 x 20 ml). The solvent from the combined extracts was evaporated under reduced pressure and the residue purified by flash column chromatography using a v/v 98.5:1.5 mixture of chloroform: methanol. The combined fractions were evaporated to obtain the product as white solid; 0.15 g; Yield 46 %; ES:MS:439(M++1).
Example 17: Preparation of Methyl {[(5S)-3-{4-[5-(4-cyanotetrahydro-2H-pyran-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yI]methyl}carbamate
To solution of Methyl ({(5S}-3-[3-fiuoro-4-(tributylstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl) carbamate (0.4 g, 1 eq) in DMF (10. ml) were added of 4-(5-bromopyridin-2-yl)-tetrahydro-2H-pyran-4-carbonitrile (0.25 g, 1.3 eq), N-Ethyl diisopropylamine (0.39 ml, 3 eq) and palladium (0) catalyst (25 mg). The reaction mixture was heated at 80°C for 14 hours. The resulting mixture was filtered over celite bed and diluted with water(25ml) followed by extraction using ethyl acetate(3x25). The solvent was evaporated and the residue purified flash column chromatography using a v/v 98.5:1.5 mixture of chloroform: methanol. The combined fractions were evaporated to obtain the product as white solid 0.17 g, Yield 52 %. ES:MS :454(M++1).
Example 18: Preparation of 4-(5-{2-fluoro-4-I(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-3-yl]phenyI}pyridin-2-yI)tetrahydro-2H-pyran-4-carbonitriIe
To a solution of (5R)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-2-one (1.0 g,l eq) in DMF (15 ml) were added 4-(5-bromopyridin-2-yl)-tetrahydro-2H-pyran-4-carbonitrile (0.53 g, 1.1 eq), triethylamine (0.55 g, 3 eq) and palladium (II) catalyst (53 mg). The reaction mixture was heated at 80 °C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate diluted with water (35ml) followed by extraction using ethyl acetate(3x35ml). The solvent was evaporated and the residue purified flash column chromatography using a v/v 98.5:1.5 mixture of chloroform: methanol. The combined fractions were evaporated to obtain the product as white solid 0.42 g, yield 52 %. ES:MS : 449.2 (M++l).
27

Example 19: Preparation of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazoIidin-3-yI]phenyI}pyridine-2-yl)tetrahydro-2H-pyran-4-carbonitriie
To a solution of (R)-3-(4-(tributylstannyI)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (1.3 g ,1 eq) in DMF (15 ml) were added 4-(5-bromopyridin-2-yl)-tetrahydro-2H-pyran-4-carbonitrile (0.9 g ,1.3 eq) N-Ethyldiisopropylamine (1.4 ml, 3 eq) and Pd (0) catalyst (0.15 g, 0.1 mol %). The reaction mixture was heated at 90°C for 14 hours. The resulting mixture was filtered over celite bed the filtrate diluted with water (35ml) followed by extraction using ethyl acetate(3x35ml). The solvent was evaporated and the residue purified flash column chromatography using a v/v 98:2 mixture of chloroform: methanol. The combined fractions were evaporated to obtain the product as white solid 0.48 g; yield 46 %; ES:MS:398(M++1).
Example 20: Preparation of 4-(5-{2,6-difluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl] phenyl} pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitriIe
To a solution of (R)-3-(4-(tributylstannyl)-3,5-Difluorophenyl)-5-(hydroxymethyl) oxazolidin-2-one (1.3 g, 2.60 mmol) in DMF(13mI) were added 2-(5-bromopyridin-2-yl) acetonitrile (0.9 g, 3.30 mmol), N-Ethyldiisopropylamine (1.4 ml, 10.76 mmol) and Pd (0) catalyst (0.15 g, 0.1 mol %). The reaction mixture was heated at 90°C for 14 hrs. The resulting mixture was filtered over celite bed the filtrate diluted with water (35ml) followed by extraction using ethyl acetate (3x35ml). The solvent was evaporated and the residue purified flash column chromatography using a v/v 98:2 mixture of chloroform: methanol. The combined fractions were evaporated to obtain the product as white solid 0.48 g,yield : 46.0%; ES:MS=416(M+1).
Example 21: Preparation of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yIoxy)methyI]-2-oxo-l,3-oxazoHdm-3-yI}phenyl)pyridin-2-yl]tetrahydro-2H-pyran-4-carbonitrile
To a solution of 4-(5- {2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l ,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.15 g, 1 eq) in THF( 10ml) were added 3-Hydroxyisoxazole (0.048 mg, 1.1 eq) and triphenylphosphine (0.2 g, 2 eq). The reaction mixture was then cooled to 0°C, followed by the addition of DIAD (0.153 mg, 2 eq). The reaction mixture was stirred at RT for 14 hours. The solvent was evaporated under reduced pressure and the residue suspended in water (2ml). The suspension was extracted with ethyl acetate (3x15ml). The solvent was evaporated and the residue purified by flash column
28

chromatography using a v/v 8:2. mixture of Hexane: Ethyl acetate, The combined fractions were evaporated to obtain the product as white solid 0.1 g. ES: MS: 465.4 (M++l).
Example 22: Preparation of trifluoroacetic acid salt of 4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}pyridin-2-yI)piperidine-4-carbonitrile
To a stirring (2:1) mixture of DCM:trifluoroacetic acid (10ml), tert-buty\ 4-cyano-4-(5-(2-fluoro-4-((R)-5-(hydroxymethyI)-2-oxooxazolidin-3-yl)phenyl)pyridin-2-yl)piperidine-l-carboxylate lg (2.01 mmol) was added and stirring continued for further 2 hours. The resulting mixture was concentrated on rotary evaporator to obtain the trifluoro acetic acid salt of 4-(5-(2-fluoro-4-((R)-5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)pyridin-2-yl)piperidine-4-carbonitrile in (0.92g) 90% yield. ES: MS: 397(M+1); MF: C23H22F4N4O5
Example 23: Preparation of l-acetyl-4-(5-{2-fluoro-4-[(5R)-5-(hydroxymethyI)-2-oxo-l,3-oxa2oIidin-3-yl]phenyI}pyridin-2-yl)piperidine-4-carbonitrile
4-(5-(2-fluoro-4-((R)-5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)pyridin-2-yl)piperidine-4-carbonitrile (0.5g, 1.26 mmol) in DCM (5ml) was treated with acetyl chloride (0.11ml,1.38 mmol) in presence triethylamine 0.185 ml (1.38 mmol) at 0°C to RT for 1 hour. The resulting mixture was diluted with water (2ml). Organic layer was separated, dried over sodium sulfate and concentrated on rotary evaporator to obtain the product as a white solid, 0.49g, yield 89%. ES: MS: 439 (M+l); MF: C23H23FN4O4.
Example 24: Preparation of 4-(5-{2-fIuoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} pyridine-2-yl)-l-(methylsulfonyI)piperidine-4-carbonitrile
To the solution of 4-(5-bromopyridin-2-yl)-l-(methylsulfonyl) piperidine-4-carbonitrile (4.66 g, 13.6 mmol) and (R)-3-(4-(tributylstannyl)-3-fluorophenyl)-5-(hydroxymethyl) oxazolidin-2-one (6.86 g, 13.6 mmol) in DMF (25 ml) diisopropylethylamine (7 ml, 10.8 mmol) and tetrakistriphenylphosphine palladium (0) (0.5 g) was added under argon atmosphere. Stirred the content at 110°C for 6 hours. The resulting mixture was cooled to RT, filtered through celit bed and the filtrate diluted with water(75ml) and extracted with ethyl acetate (3x75ml). The ethyl acetate layer was dried over sodium sulfate and concentrated on rotary evaporator. The residue was purified by column chromatography. Elution with a v/v 98.5: 1.5 mixture of chloroform:
29

methanol and concentration of the combined fractions gave the product as off white solid, 5.1g,
in 70% yield.
ES: MS : 474 (M+l); MF: C22H23FN4O5S.
Example 25: Preparation of 7V-{[(5S)-3-(4-{5-[4-cyano-l-(methylsulfonyl)piperidin-4-yl]pyridin-2-yl}-3-fluorophenyI)-2-oxo-l,3-oxazolidin-5-yl]methyI}acetamide
To a solution of 4-(5-bromopyridin-2-yl)-l-(methylsulfonyl) piperidine-4-carbonitrile (18.0 g, 0.052 mol) and N-({(5S)-3-[3-fluoro-4-(tributylstannanyl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (28.3 g ,0.052 mol) in DMF (200 ml) were added diisopropylethylamine (27.1 ml, 0.156 mol) and tetrakistriphenylphosphine palladium (1.8 g) under argon atmosphere. The resulting mixture was stirred at 110°C for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into water (500 ml), stirred for 15 minutes and extracted with ethyl acetate (2 x 200 ml). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on a column of silica gel to obtain the product as a white solid; 14.79 g; 55% yield; ES: MS (M+l) -516 (MH+, 100%) for M.F. C24H26FN606S.
Example 26: Preparation of 4-(5-{2-fluoro-4-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)-l-(methylsulfonyl)piperidine-4-carbonitrile
To the solution of 4-(5-(tributylstannyl)pyridin-2-yl)-l-mesylpiperidine-4-carbonitrile (5 g, 9.0 mmol) and (R)-5-((lH-l,2,3-triazoI-l-yl)methyl)-3-(3-fluoro-4-iodophenyl)oxazolidin-2-one (3.5 g, 9 mmol) in DMF (25 ml), diisopropylethylamine (4.3 ml, 27 mmol) and 0.5 g of tetrakistriphenylphosphine palladium (0) were added under argon atmosphere. The reaction mixture was heated with stirring at 110°C for 6 hours. The resulting mixture was diluted with water (75ml) and extracted with ethyl acetate(3x75ml). The organic layer was separated, dried over sodium sulfate and concentrated on rotary evaporator to obtain the product as off white solid, 2.7g, 58% yield. ES: MS: 526 (M+l); MF: C24H24FN7O4S.
Example 27: Preparation of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3-yl}phenyl)pyridin-2-yl]-l-(methyIsulfonyI)piperidine-4-carbonitrile
To a solution of 4-(5-(tributylstannyl)pyridin-2-yl)-l-mesylpiperidine-4-carbonitrile (5 g, 9 mmol) and (R)-3-(3-fluoro-4-iodophenyl)-5-((isoxazol-3-yloxy)methyl)oxazolidin-2-one (3.63 g,
30

9 mmol) in DMF (25ml), diisopropylethyl amine (4.3 ml, 27 mmol) and 0.5 g of tetrakistriphenylphosphine palladium (0) were added under argon atmosphere. The reaction mixture was heated with stirring at 110°C for 6 hours. The resulting mixture was diluted with water (75ml) and extracted with ethyl acetate(3x75ml). The organic layer was separated, dried over sodium sulfate and concentrated on rotary evaporator to obtain the product as off white solid' 2.6g, 55% yield. ES: MS: 542 (M+l); MF: C25H24FN5O6S.
Example 28: Preparation of l-acetyl-4-[5-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3-yI}phenyl)pyridin-2-yl]piperidine-4-carbonitrile
To a solution of 1 -acetyl-4-(5-(2-fluoro-4-((R)-5-(hydroxymethyI)-2-oxooxazolidin-3 -yl)phenyl)pyridin-2-yl) piperidine-4-carbonitrile (2 g, 4.5 mmol), 3-HydroxyisoxazoIe (0.39 g, 4.5 mmol) in tetrahydrofuran ( 20ml) was added triphenylphosphine (2.35 g, 9 mmol). The reaction mass was cooled to 0°C and of DIAD (1.82g was added dropwise over a time period of 15 minutes. The reaction mixture was then allowed to warm to RT and stirring continued for 14 hours. The solvent was evaporated under reduced pressure and the residue suspended in water (10ml). The suspension was extracted with ethyl acetate (3x15ml). The solvent was evaporated and the residue purified by flash column chromatography using a v/v 8:2. mixture of Hexane: Ethyl acetate, The combined fractions were evaporated to obtain the product as white solid 1.38g, 60% yield. ES: MS: 506 (M+l); MF: C26H24FN505.
Example 29: Preparation of 4-[5-(2-fluoro-4-{(5R)-5-[(isoxazoI-3-yloxy)methyI]-2-oxo-l,3-oxazolidin-3-yI}phenyl)pyridin-2-yI]-l-methyIpiperidine-4-carbonitrile
To a solution of 4-(5- {2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}pyridine-2-yl)-l-methylpiperidine-4-carbonitrile (1.84 g, 4.5 mmol) , 3-Hydroxyisoxazole (0.39 g, 4.5 mmol) in THF(15ml) was added triphenylphosphine (2.35 g, 9 mmol). The reaction mass was cooled to 0°C and DIAD(1.82g) of was added dropwise over a time period of 15 min. The reaction mixture was then allowed to warm to RT and stirring continued for 14 hours. The solvent was evaporated under reduced pressure and the residue suspended in water (10ml). The suspension was extracted with ethyl acetate (3xI5mI). The solvent was evaporated and the residue purified by flash column chromatography using a v/v 9.9:0.1 mixture of chloroform: methanol, The combined fractions were evaporated to obtain the product as white solid, 1.3 g, 62% yield.
31

ES: MS: 478 (M+l); MF: C25H24FN504.
Example 30: Preparation of 4-(5-{2-fluoro-4-I(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}pyridine-2-yl)-l-methylpiperidine-4-carbonitrile
Triethylamine 0.22 ml (1.64 mmol) was added to the precooled solution of trifluoroacetic acid
salt of 4-(5-(2-fluoro-4-((R)-5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)pyridin-2.
yl)piperidine-4-carbonitrile (0.4g, 0.78 mmol) in dichloromethane (4ml). To this methyl iodide (0.049ml, 0.78 mmol) was added drop wise and stirring continued further at RT for 2h.. The resulting mixture was diluted with water (2ml). The DCM layer was separated, dried andd concentrated on rotary evaporator to obtain the product as a white solid, 0.27g, yield 85%. ES: MS: 410 (M+l); MF: C22H23FN403.
Example 31: Preparation of N-{[(5S)-3-{4-[5-(4-cyano-l-methylpiperidin-4-yI)pyridin-2-yI]v 3-fluorophenyl}-2-ox0-1,3-oxazolidin-5-yI] methyl} acetamide
Triethylamine 0.25 ml (1.89 mmol) was added to the precooled solution of trifluoroacetic acid salt of N-{[(5S)_3_{4-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-3-fluorophenyl}-2-oxo-l,3N oxazolidin-5-yl] methyl} acetamide (0.5g,0.9 mmol) in dichloromethane(5 ml). To this methyl iodide (0.057ml, 0.9 nimol) was added dropwise and stirring continued further at RT for 2h. ThQ resulting mixture was diluted with water (2ml). The DCM layer was separated, dried and concentrated on rotary evaporator to afford the product as a white solid, 0.3 5g, 85% yield. ES: MS: 452 (M+l); MF: C24H26FN503.
Example 32: Prepamtioa of N-{{{5S)-3-{4-[2-(4-cyano-l,l-diox2dotetrahydro-2H-thiopyran 4-yl)pyrimidin-5-yl]-3-fluorophenyI}-2-oxo-l,3-oxazolidin-5-yl]methyI}acetamide
Step-I: To a solution of N-({(5S)-3-(3-fluoro-4-(tributylstannany(pheny)-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide; (7.5 g; 13,8 mmol) in DMF (75 ml) was added 4-(5-bromopyrimidin-2-yl)-tetrahydro-2H-thiot)yran-4-carbonitrile (4.3 g, 13.8 mmol), triethylamine (4.2 ml, 41.5 mmol), and palladium (H) catalyst (0.75 g). The reaction mixture was heated at 80°C for 14 hours. The reaction mixture was celite bed and diluted with water(150ml) followed by extraction with ethyl acetate( 3xi50ml). the ethyl acetate layer was separated and the solvent evaporated under reduced pressure. The crude product was used as such for the next step. Step-II. The crude step-l product, obtained, was taken in 1:1 mixture of methanol: water and sodium periodate (5.64 g, 26.3 mmol) added. The reaction mixture was heated with stirring for 4 hours at 100°C. The i-eaction mixture was concentrated under reduced pressure and triturated
32

with water(5ml). The separated solid was filtered and purified by flash column chromatography to obtain the product as a white solid 1.4 g, yield 55 %.
Example 33: Preparation of N-{[(5S)-3-{4-[5-(4-cyano-tetrahydro-2H-thiopyran-4-yI)pyridazin-2-yl]-3-fluorophenyI}-2-oxo-l,3-oxazolidin-5-yI]methyl}acetamide
To a solution of 4-(6-Tributylstannanyl-pyridazin-3-yl)-tetrahydro-thiopyran-4-carbonitrile (2.2 g, 4.45 mmol) in DMF (10ml) were added ((R)-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazoIidin-5-ylmethyl]-acetamide (1.68 g, 4.45 mmol), triethylamine (1.34 g, 13.35 mmol) and dich]orobis(triphenylphosphine)palIadium (II) (0.22 g, 0.1 mol %). The reaction mixture was heated at 90°C for 14 hours The resulting mixture was filtered over celite bed and the filtrate poured into water (25ml) and extracted with ethyl acetate (3x 25ml). The ethyl acetate extracts were concentrated under reduced pressure and the residue purified by column chromatography. Elution with v/v 9.8:0.2 mixture of Chloroform: Methanol and evaporation of the combined fractions gave the product as a white solid, 0.647g, 32% yield.
Example 34: Preparation of N-{[(5S)-3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridazin-2-yI]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyI}acetamide
To N-(3-{4-[5-(4-Cyano-tetrahydro-thiopyran-4-yl)-pyridazin-2-yl]-3-fluoro-phenyl}-2-oxo-
oxazolidin-5-ylmethyl)-acetamide (0.647 g, 1.42 mmol) in 1:1 mixture of methanol: water (10ml) was added sodium periodate (1.52 g, 7.1 mmol) and the reaction mixture heated for 4 hours at 80°C. The resulting mixture was concentrated under reduced pressure and the residue triturated with water (5ml). The separated solid was filtered and purified by flash column chromatography to obtain the product as a white solid, 0.570g, 82% yield. ES: MS: (M+l) 487 MF: C22H22FN5O5S.
.Example 35: Preparation of N-{[(55)-3-{4-[5-(4-cyanotetrahydro-2H-thiopyran-4-yI)pyridin-2-yl]-3,5-difluorophenyl}-2-oxo-l,3-oxazo!idin-5-yl]methyI}acetamide
To a solution of N-[3-(3,5-Difluoro-4-tributylstannanyl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (7.5 g, 13.4 mmol) in DMF (40ml) were added 4-(5-bromopyridin-2-yl)-tetrahydro-2H-thiopyran-4-carbonitrile (4.17 g, 14.74 mmol), triethylamine (4.06 g, 40.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.75 g, 0.1 mol%). The reaction mixture was heated at 90°C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate was diluted with water (100ml) followed by extraction with ethyl acetate (3x100ml). The ethyl
33

acetate extract was concentrated and the residue purified by flash column chromatography to obtain the product as a ofrwhite solid 2.21 g, 35 % yield. ES: MS: (M+l) 473; MF: C23H22F2N403S.
Example 36: Preparation of Af-{[(5S)3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yI)pyridin-2-yl]-3,5-difluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl}acetamide
To a suspension of N-(3-{4-[5-(4-Cyano-tetrahydro-thiopyran-4-yl)-pyridin-2-yl]-3,5-difluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (2.21 g, 4.69 mmol) in 1:1 mixture of methanol: water (20ml) was added sodium periodate (5.01 g, 23.45 mmol). The reaction mixture was heated for 4 hours at 80°C. The reaction mixture was concentrated under reduced pressure and the residue triturated with water (10ml). The separated solid was filtered and purified by flash column chromatography to obtain the product as a white solid, 1.2 g , 51 % yield. ES: MS: (M+l) 505; MF: C23H22F2N4OSS..
Example 37: Preparation of N-({(55)-3-[4,-(4-cyanotetrahydro-2H-thiopyran-4-yI)-2,3'-difluorobiphenyl-4-yl]-2-oxo-l,3-oxazolidin-5-yl}methyI)acetamide
To a solution of N-[3-(3-fluoro-4-tributylstannanyl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (3g, 5.55 mmol) in DMF (10 ml) were added 4-(4-Bromo-2-fluorophenyl)-tetrahydro-thiopyran-4-carbonitrile (2 g, 6.66 mmol), triethylamine (2.78 ml, 41.5 mmol), and dichlorobis(triphenylphosphine)palladium (II) (0.2 g, 0.1 %) and reaction mixture was heated at 90°C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate diluted with water (30ml) followed by extraction using ethyl acetate(3x30ml). The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography to obtain the product as a pale yellow solid 0.6g, 19% yield. ES: MS: 472 (M+l); MF: C24H23F2N3O3S
Example 38: Preparation of N-{[(5S)3-{4-[5-(4-cyano-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)pyridin-2-yl]-3-fluorophenyl}-2-oxo-l,3-oxazolidin-5-yl]methyl} acetamide
To N-( {(5S)-3-[4'-(4-cyanotetrahydro-2H-thiopyran-4-yl)-2,3'-difluorobiphenyl-4-yl]-2-oxo-l ,3-oxazolidin-5-yl}methyl)acetamide (0.58g, 1.23 mmole) in 1:1 a mixture of methanol: water (10ml) was added sodium periodate (1.31 g, 6.157 mmol) and the reaction mixture was heated with stirring for 4 hours at 100°C. The resulting mixture was concentrated under reduced pressure and the residue triturated with water (5ml). The separated solid filtered and purified by flash column chromatography to obtain the product as a white solid 0.335g, 55% yield.
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ES: MS: 504(M+1); MF: C24H23F2N3O5S.
Example 39: Preparation of 4-{2',3-difluoro-4'-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yIlbiphenyl-4-yl}tetrahydro-2if-thiopyran-4-carbonitrile
To a solution of [3-(4-Tributylstannyl-3-fluorophenyl)-5-hydroxymethyl]-oxazolidin-2-one (1.66 g, 3.33 mmol) in DMF (5 ml) were added successively 4-(4-Bromo-2-fluoro-phenyl)-tetrahydro-thiopyran-4-carbonitrile (1.0 g, 3.33 mmol), triethylamine (1.0 ml, 9.99 mmol), and dichlorobis (triphenylphosphine) palladium (II) (150 mg). The reaction mixture was heated with stirring at 90°C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate diluted with water (20 ml) followed by extraction using ethyl acetate (3x20 ml). The ethyl acetate extract was concentrated under reduced pressure and the residue purified using flash column chromatography to obtain product as pale yellow solid, 0.460 g, 33% yield. ES: MS: 431.3 (M+H)+ , MF: C22H20F2N2O3S.
Example 40: Preparation of 4-(2',3-difluoro-4,-{(5R)-5-[(isoxazol-3-yloxy)methyI]-2-oxo-l,3-oxazolidm-3-yl}biphenyl-4-yl)tetrahydro-2H-thiopyran-4-carbonitrile
To a solution of 4- {2,,3-difluoro-4'-[(5R)-5-(hydroxymethyl)-2-oxo-l ,3-oxazoIidin-3-yl]biphenyl-4-yl}tetrahydro-2H-thiopyran-4-carbonitrile (0.45 g, 1.046 mmol) in tetrahydrofuran (5 ml) were added 3-Hydroxyisoxazole (0.097 g, 1.151 mmole) and triphenylphosphine (0.544 g, 2.092 mmol). The reaction mass was cooled to 0°C and DIAD (0.422 g, 2.092 mmol) was added drop wise over 15 minutes. The reaction mixture was then allowed to warm to RT, and stirred at the same temperature for 4 hours. The solvent was evaporated under reduced pressure and the residue purified by column chromatography to obtain product as pale yellow solid, 0.45 g, 86% yield. MW: 497, MF: C25H2iF2N304S.
Example 41; Preparation of 4-(2',3-difluoro-4'-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-1,3-oxazoUdin-3-yl}biphenyl-4-yi)tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide
4-(2,,3-difluoro-4'-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-l,3-oxazolidin-3-yl}biphenyl-4-yl)tetrahydro-2H-thiopyran-4-carbonitrile (0.45 g, 0.905 mmol) was taken in 1:1 mixture of methanol: water (10 ml) and sodium periodate (0.964 g, 4.52 mmol) added. The reaction mixture was heated with stirring for 4 hours at 100°C. The resulting mixture was concentrated under reduced pressure and the residue triturated with water. The solid obtained was filtered and purified by flash column chromatography to obtain product as white solid, 0.230 g, 48% yield.
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MW; 529, MF: C25H2,F2N306S.
Example 42: Preparation of 4-{2',3-difluoro-4'-[(5 R)-2-oxo-5-(lH-l,2,3-triazoI-l-yImethyI)-l,3-oxazolidin-3-yl]biphenyl-4-yl}tetrahydro-2H-thiopyran-4-carbonitrile
To a solution of 5-((5H-l,2,3-triazole-4-yl)-methyl)-3-(4-tributylstannyl-3-fluorophenyl))-oxazolidin-2-one (1.83 g, 3.33 mmol) in DMF (5 ml) were added 4-(4-Bromo-2-fluoro-phenyl)-tetrahydro-thiopyran-4-carbonitrile (1.0 g, 3.33 mmol), triethylamine(1.01 ml, 9.99 mmol), and dichlorobis(triphenylphosphine) palladium (II) (150 mg). The reaction mixture was heated with stirring, at 90°C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate diluted with water (20 ml) followed by extraction using ethyl acetate (3x30 ml). The ethyl acetate extract was concentrated and the residue obtained was purified using flash column chromatography to obtain product as pale yellow solid, 0.480 g, 30% yield. MW 481, MF: C24H21F2N5O2S.
Example 43: Preparation of 4-{2',3-difIuoro-4,-[(5R)-2-oxo-5-(lH-l,2,3-triazol-l-ylmethyI)-l,3-oxazoIidin-3-ylJbiphenyl-4-yI}tetrahydro-2H-thiopyran-4-carbonitriIe 1,1-dioxide
4-{2',3-difluoro-44(5R)-2-oxo-5(lH-l,2,3-m
yl}tetrahydro-2H-thiopyran-4-carbonitrile (0.47 g, 0.977 mmol) was taken in a 1:1 mixture of methanol: water (10 ml) and sodium periodate (1.04 g, 4.88 mmol) was added. The mixture was heated with stirring for 4 hours at 80°C. The reaction mixture was concentrated under reduced pressure and the residue triturated with water(lOml) and the separated solid filtered. The solid was purified by flash column chromatography to obtain product as white solid, 0.2 g, 40% yield. ES: MS: 514.3 (M+H)+ , MF: C24H21F2N5O4S.
Example 44: Preparation of 4-{2,,3-difluoro-4'-[(5R)-5-(hydroxymethyI)-2-oxo-l,3-oxazolidin-3-yI]biphenyl-4-yl}tetrahydro-2H-thiopyran-4-carbonitrile 1,1-dioxide
To 4-{2',3-difluoro-4,-[(5R)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]biphenyl-4-
yl}tetrahydro-2H-thiopyran-4-carbonitrile (0.45 g, 0.905 mmol) taken in a 1:1 mixture of methanol: water (20 ml) was added sodium periodate (1.1 g, 5.23 mmol) and the mixture heated with stirring for 4 hours at 100°C. The reaction mixture was concentrated under reduced pressure and the residue triturated with water (10 ml) and the separated solid filtered. The solid was purified by flash column chromatography to obtain product as white solid, 0.180 g, 37% yield. ES: MS: 463.2 (M+H)+, MF: C22H2oF2N205S.
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Example 45: Preparation of N-{(5S)-3-[4'-(4-cyanotetrahydro-H-pyran-4-yI)-2,3'-difluorobiphenyl-4-yl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide
To a solution of N-[3-(3-Fluoro-4-tributylstannanyl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (0.438 g, 0.81 mmol) in DMF (5 ml) were added 4-(4-Bromo-2-fluoro-phenyl)-tetrahydro-pyran-4-carbonitrile (0.3 g, 1.056 mmol), triethylamine (0.42 ml), and dichlorobis(triphenylphosphine)palladium (II) (30 mg, 0.1 mol%). The reaction mixture was heated at 90°C for 14 hours. The resulting mixture was filtered over celite bed and the filtrate diluted with water (20 ml) followed by extraction using ethyl acetate (3x20 ml). Ethyl acetate extract was concentrated under reduced pressure and the residue was purified by flash column chromatography to obtain product as pale yellow solid, 85 mg, 17% yield. ES: MS: 456.1 (M+H)+, MF: C24H23F2N3O4.
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We Claim:
1. Compounds having the structure of Formula-(I),

Formula-(I)
wherein,
X is selected from the group consisting of O, S, SO, SO2 and -NR5;
wherein R5 is selected from the group consisting of H, alkylsulfonyl, alkoxycarbonyl,
alkanoyl, alkyl and substituted alkyl; Ri is selected from the group consisting of -CN, -NO2, -(CH2)m-NR7R8, carboxy, alkoxycarbonyl, -CONH2 and formyl;
wherein m is 0 or 1; R2 and R3 are independently selected from -H or halogen;
R4 is selected from the group consisting of-OR6, heteroaryl, substituted heteroaryl, heterocyclyl, -NR7R8 and azido;
wherein Re is selected from the group consisting of -H, alkylsulfonyl, heterocyclyl,
heteroaryl and substituted heteroaryl;
R7 and Kg are independently selected from the group of -H, alkyl, alkanoyl and
alkoxycarbonyl; Q is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine and pyridazine optionally substituted with substituents selected from the group consisting of halogen, -NH2, -OH, -CN, -N02, -CHO and -COOH; n is 0 or 1; and pharmaceutically acceptable salts or prodrugs thereof.
2. A pharmaceutical composition comprising a compound of Formula-(I) as claimed in claim 1 and a pharmaceutically acceptable excipient.
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39
3. A method of treating or preventing microbial infections which comprises administering to a patient in need thereof, an therapeutically effective amount of compound as claimed in claim 1.