FORM 2 THE PATENT ACT 1970 (39 of 1970) &The Patents Rules, 2003COMPLETE SPECIFICATION(Sec section l0and rulel3)
1. TITLE OK THE INVENTION:
OXAZOLIDINONE5 BEARING ANTIMICROBIAL ACTIVITY
COMPOSITION AND METHODS OF PREPARATION
2. APPLICANT (S)(a) NAME : Wockhardt Limited(b)NATIONALITY : Indian(c)ADDKESS : Wockhardl TowersBandra-Kurla Complex. Bandra (E) Mumbai-400 05 L India
3. PREAMBLE TO THE DESCRIPTION
The following speciflcatton particularly describes the invention and the manner in which it is to be performed.

Oxazolidinones bearing Antimicrobial Activity Composition and Methods of Preparation
Field of Invention
The present invention relates to the field of oxazohdinoncs having antimicrobial activity. The invention also relates to processes for preparation of the compounds, to pharmaceutical compositions containing the compounds and to methods of treating microbial infections with the compounds.
Background of Invention
Oxazofidinones represent a novel chemical class of synthetic antimicrobial agents, with Linezolid, as a first representative, of this class1'2 This advance enabled The profiling of the unique properties of the members of this class, which is that they display activity against important Gram-positive human arid veterinary pathogens including Methicillin-resisiant Staphylococcus aureus (MRSA), vancomycin resistant enterococci (VRE) and 3-faciam resistant Streptococcus pneumoniae (PRSP). The oxazolidi nones also show activity against Gram-negative aerobic bacteria and Gram-positive and Gram-negative anaerobes .
Some deficiencies of oxazolidi nones have also surfaced. They are inactive against Enterobacleriaceae*. Moreover their poiency for atypical respiratory pathogens such as Mycoplasma pneumoniae, M. hominis, Ureaplasma urealyiicium arid Chlamydia species is of a borderline range which could resuli inio unacceptable clinical efficacy for the treatment of respiratory tract infections'1.
Other limitations that have appeared through the clinical development studies and use of Linezolid and its potential successors in development arc that the class has a propensily to induce myclosuppression with consequent thrombocytopenia5. Inhibition or monoamine oxidase by oxazohdnoncs has prompted a recommendation made to clinicians that clinical use of members of this class be done with caution during concomitant usage of adrenergic or serotonergic agents and selective serotonin reuptake inhibitors .



Information Disclosure
There are several patents cited in [he literature, which refer to oxazolidinones having
antibacterial activity. Piperidmyl phenyl moiety bearing oxazolidinones arc described in
following patents;
WO95/2510& discloses substituted piperidino phenyloxazofidinones. This corresponds to US
5,668,286 and EPO7506I8,
WO 96/13502 discloses phenyloxazofidi nones having a multisubstiluted azetidiny] or
pyrrolidinyl moiety.
US application 10/475.735; 107616,888 and 10/935,708 PCT application PCT/JN03/00237,
PCT/JN03/00238 and PCT/IN04/00276 discloses pipcandinyl phenyl oxazolidinones or
antimicrobial use.
3

Pyrrolidinyl/piperidinyI phenyl oxazolidinone antibacterial agents are also described in Kim
H Y ct a!., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230.
However in all above cited patents, substituted or unsubstituted heteroaryl bearing
pipcridinophenyl oxazolidinonc compounds are not disclosed.
Similarly, following citations pertain to oxazofi din ones having biary! moiety attached to
oxazolidinonc ring.
WO 2004/048350 A2 describes pyridyl and pyrimidyl moiety as one of constituents of biaryl
oxazolidinonc compounds. However oxazolidinonc moicty bearing melhyl acetamide, or
methyl thioacetamide are not described. This application does not disclose halogen
substituted biphenyl oxazohdinone compounds with methyl acetamide moiety.
US 2004/147760 Al and WO 2003/072553 Al describe some biaryl oxazolidinonc
compounds but osazolidinones with methyl acetamide are not described.
WO 0194342 Al describes pyridinyl and pyrimidinyl moiety as one of constituents of biaryl
oxazolidmnne compounds. However oxazolidinonc biaryf compounds bearing
thromorpholine ai"c not described. This application does not disclose halogen substituted on
both biphenyl rings of oxazolidinonc compounds.
WO 04056819 Al also describes pyridinyl and pyrimidiny! moiety as one of constituents of
biaryl oxazolidinonc compounds. However examples of biaryl oxazolidinonc compounds
bearing methyl acetamide are not disclosed. This application does not describe halogen
substituted on both rings of bipheny] moiety.
WO 2O05/O5388G Al describe heterocyclic ring attached to biaryl compounds. However
examples of biaryl oxazolidinonc compounds bearing morpholino derivatives arc not
disclosed.
WO 2005/ 012271 A2 describes a process for synthesis of biaryl compounds where one of
the ring in biaryl moiety is either pyridine or desfluoro phenyl ring however biaryl ring with
both rings bearing fluorine atom are not described. WO 2005/ 012271 A2 does not describe
thiomorphohne moiety as one of the substituent on biaryf moiety.
The present inventors have found that the novel piperidmo substituted phenyloxazohdinones and biaryl ox azolidi nones of the invention herein described have a favorable in vitro and in vivo efficacy advantages.
4

US application 10/475J35, 10/616,888 and 10/935,708 and PCT application PCT/JN03/00237, PCT/IN03/00238 and PCT/IN04/00276 discloses a novel series of oxaxohdinoncs which display increased potency.
gujjinari_on nvc aiioQ:
The present invention relates to novel substituted phenylpiperidino and biaryl oxazolidinone compounds of Formula I.

Formula I
wherein Q is

X and Y may be same or different, represent^ CH, CF, N;
XI and Yl may be same or different, represent,
CH, CF, N, C-OCFTs, C-CH?-Ra; wherein Ra is hydrogen, amino, halogen, hydroxyl, azido, carboxamidc, NHCH2CONH^ MCHiCONl^;
R^and Rr maybe same or different, represent, hydrogen, methyl, hydroxy!, C|-Q afkoxyor halogen;
Rj is selected from the group comprising
a) OR,,
b) NRbRc;
wherein Rb is selected from hydrogen, C|-Cfj alkylcarbonyl;
Rc is selected from hydrogen, C(0)OCH2OC(0)Rci or CH(CH3)OC(0)Rc;
5


When Q is
%
W-(CH2)n^^N—
wherein n is 0, I or 2;
W represcnis 3-7 membered heierocyclyl bearing one or more hcteroaiom selected from N, (X 5, optionally subsiiluicd with one or more subsJimtems selected from the group comprising CJ-CG afkyl. Cj-Q aJkylcarbonyl, C|-Ce alkoxycarbonyl, curboxamide, cy;ino, hydroxy), amino, hetert>cyc]ylh substiiuled heierocyclyl, arylr substituted aryJ, hcicrouryl, substituted hcteroaryl
6

or
hctcroaryl bearing one or more hetcroatom selected from N, 0 S, optionally substituted with
one or more subsritutcnts selected from the group comprising
i. substituted or un substituted Q-C& alkyl with substiiuenls selected from tfie
group hydro* yl. halo, nitro, cyano, aryl or hetcroaryf;
ii. substituted or unsubstitutcd C2-C(, aJkenyl with subsiituems selected from the
group hydroxy!, halo, nitro, cyano, aryl or heieroaryl;
hi. C|-Chalkylcarbonyl;
lv. CrCfi alkoxyearbonyl;
v. Cr-Cr, ulkoxyearbonylalkyi;
vi, C|-Cfi a I kyf carbon yJaTkyJ:
vrE. C,-Cft haloafkyl;
,Mii formyf;
carboxy;
, carboxamide;
,i. cyano;
*„ amino;
„ii. nitro:
,i, Jiydroxyl;
M hafo:
NJL
R4
Formula [
wherein Q is

Xand Y may be same or different, represent, CH, CF, N;
Xr and Y* may be same or different, represent,
CH, CF, N, C-OCH3, C-CHj-Ra; wherein Ra is hydrogen, amino, halogen, hydroxy!, azido,
Ciirboxamido, NHCH2CONH2. N(CH2CONHz)z;
Rjand R^> may be same or different, represent, hydrogen, methyl, hydroxy!, C1-G5 alkoxyor halogen;
Rd is selected from the group comprising a) OR i> bj NR,,Rc;
wherein Rb is selected from hydrogen, C]-G, alkyfcarbonyl;
R, is selected from hydrogen, C(0)OCH^OC(0)Rd or CH(CH3)OC(0)Rc;
wherein Rd is hydrogen, Ci-C6 alkyl, substituted Ci-C* alkyl with substimicnts
selected from amino or C|-C* alkylamido
Rt is selected from hydrogen, C|-C& alkyl, substituted Ci-C6 alkyj;
c) formamide:
d) carbamate;
10


When Q is
%
W-(CH?)n^yJ-
wherein n is 0, I or 2;
W represents 3-7 membered heterocyclyl tearing one or more heicroatom selected from NT
Oh S, optionally subsiituied with one or more subsiilutcnts rejected from the group
comprising C,-C* alky], C|-C6 alkylcarbonyl, Ci-C6 ylkaxycarbonyl, carbox amide, cyano,
hydroxy], amino, heterocycly], substituted heterocyclyl, aryl, substituted uryl heteroaiyl,
substituted he ternary I
or
hetcroaryl bearing one OT more hetcroaiom selected from Nr 0 S, optionally substituted with
one or more substitutems selected from the group comprising
i. substituted or unsubsiituted C|-C& alky! with suhsiiiucnls selected from the
group hydroxyl, halo, niiro, cyano, aryl or heteroaryl:

ii, substituted or unsubstitutcdCz-C&alkenyl with substituenls selected from The
group hydroxyl, halo, nitro. cyano, aryl or hcieroaryl;
iii. C|-C&alkylcarbonyl;
iv. C|-Q, iilkoxycarbonyl;
v. C|-C& alkoxycarbunylalkyl,
vi. C|-C& alkylcarbonylalkyl;
,ii. Ci-Q haloalkyl;
y»i formyl;
in, carboxy;
* carb ox amide;
w. cyano;
w amino:
uii nitro;
Xlv hydroxyl;
*v halo;
nvi. morpholinocarbonylalkyl; xvii. hydroxy! minoa I kyl;
WIN.
al ky tea rbon y L ami n oal k y I;
alkoxyiminoalkyl;
ara I ky lox yi mi rioal k y I;
>\\.
hydroiminoaminoalkyl;
\MI.
aryl, substituted arylf with substituents selected from CrC& alkyl, nuroh cyano,
hydroxyl, halo, amino, heierocyclyl;
■ 1|
subsutuied or unsubstituied heicroaryl. with subsiiluents selected from CL-GS
alkyl, nitro, cyano, hydroxyl. halo, amino, heierocyclyl;
■ XIV.
substituted or unsubstiiuted heierocyclyl, wilh substituenls selected from C|-
Cft alkyl, Ci-Cfi alkylcarbonyl, aralkyl, nitroh cyanoh hydroxyl, halo, amino;
KW.
C|-C(talkyllhio;
Ilvi
C|-Cftalkylsu1fanylalkyl;
XHWk
C|-Charalkylsulfaiiyl;
A^vML.
C[-C6 alkyIsulfonylmethyl;
Ml'.
C[-Cft alkylsulfonyloxy;
ra,
NRtKc; „„ -(Cl-C6alky])'NRf-(C,-C6alkyl)-NRbRl::
12

wherein R<, and R*,' may be same or different, represent, hydrogen, hydroxy!, amino, azido, Ci-O, alkoxy, C]-C formyl, hydraxyl mcihyl, carbox amide, acetyl, !-methoxyimino-
methyl, 4-pyridinylh 3-pyridinyl, dieihylamino, methyisulfonylmethyl;
Rj is Ct-Ct alkylamido. acetamide, diflucroacet amide, thioacetamide, diflucro acetamide,
carbamate, ihiocarbamate, urea, J |,2,3}-triazolr |l,2,4j-triazoI.
R3 R3"
b) The compound of formula lb R2
Formula lb
wherein,
a is optional double bond;
X and Y each independently CH.CF or N;
X' and Y1 are each independently CH, CF, Nh C-CHy,
R?, RT, Rjund R3 are each independently hydrogen, methyl, hydroxy!, halogen;
ZisS, 50hSOj;
Rj is aceiamido* [lh2,31-lriazol, meihyi carbamate, t-butyl carbamate, OR| wherein Ri is
hydrogen, P(0)(OM)2, wherein M is hydrogen, No, methyf, ethyl, i-buiyl, phenyl; or R| is an
amino acid residue derived from one of the 20 naturally incurring amino acids viz alanine,
15

argtnine, asparaginc, aspartic acid, cysteine, glutamtne, glutamic acid, glycine, histidine, isoleucinc, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine, attached to the oxygen viacarbonyl of amino acid to form an ester linkage.
Description of terms:
The folfowing definitions are used, unless otherwise described.
The term "Cf-CftaJkyl" refers to samrdicd, straight or branched chum hydrocarbon having C C6numhei of carbon atoms such as methyl, ethyl, propyl, isopropyl and so on. "substituted CI-CG afkyi" refers to one or more hydrogen atom of rhealkyl group substituted with halogen, amino, hydroxy, carboaxldehyde, mercapto. nitro, carboxv. alkoxycarbonyl, carboxamide, aryl, heteroaryl, substituted aryl, substituted heteroaryl. "C2-CV, alkenyl1 means straight or branched chain hydrocarbon comprising C,-C& carbon atom containing one or more carbon-carbon double bonds for examples ethenyl, propenyl, butenyl, pentcnyl, hexenyJ.
'substituted CJ-CG alkenyl" refers to one or more hydrogen atom of the alkenyl group substituted with halogen, amino, hydroxy, carboaxldehyde, mercupto, nitro, carboxy, afkoxycarbonyj, carboxamide, aryl, heieroary!, substituted aryl, substituted hcteroaryl. "Q-Ct alkynyl1 means straight or branched chain hydrocarbon comprising Q-C& carbon atom containing one or more carbon-carbon triple bonds for examples ethynyl, propynyl, buiynyl, pcniynyl, hexynyl.
"Ci-Ct, alkylstilfonyloxy" means groups such as meihanesulfonyfoxy, ethanesulfonyloxy, propylsulfonyloxy and so on.
"C|-C6-alkoxycarbonyl" means group such us mcthoxyearbonyl (CH3O-CO), ethoxycabonyl (C;HjO-CO), propoxycarbonyl (C3H7O-CO) and so on.
"halogen" or "halo" means atom selected from atom such as fluorine, chlorine, bromine. "CI-CG alkykarbonyl" means groups such as acetyl, ethylcarbonyl, propylcarbonyf. "C|-Cb alkylthio" means groups such as methylthio, ethyfthio, propylthio.
lo"

"aryj" refers to a mono, fused bicyclic or fused tricyclic carbocyclic ring system having one or more aromatic rings including but not limited to phenyl, napthyf, indanyl, indenyf and so on.
"substituted ary!" refers to an aryl group as defined herein substituted by independent replacement of one or more hydrogen atoms thereon with C\, Br, F, I, OH, CN,C|-Cc alky], C|-C(, alkoxy, haloalkyl, amino, alkyfamino, dialkylamino, mercapto, nitro, carbox aldehyde, carboxy, alkoxycarbonyl, carboxamide.
"heteroaryl" refers to mono, fused bicyclic or tricyclic aromatic radical having 5-10 ring atoms of which one or more carbon atom of the ring is replaced by un atom selected from N, O, S, for example pyrrolyl, pyra/olyl, imidazolyl, [l,2,3|-triazoly|, [I,2,4)-tnazolyl, ictrazolyl, [L,2,4|-oxadiiizo]yl, [1,3,41-oxadiazolyl, furanyl, thiophenyl, J l,2,4]-thtadiazolyl, [J.3.4]-thiadiazolyl. thiazolyl, oxa/olyl, isoxazolyl, pyridyl, pyrimidinyl, ben?otriazolyl, quinohnyl, isoquinolinyl, and the like.
"substituted hetcroaryl" refers to a hcteroaryl group as defined herein substituted by independent replacement of one or more hydrogen atoms thereon with CI, Br, F, I, OH. CN, C|-Cft alkyl. Q-O alkoxy, haloalkyl, amino, alkylamino, dialkylarruno, mercapto, nilro, carbox aldehyde, carboxy, alkoxycdrbonyl, carboxamide,
"heterocyclyl" means mono-, hi- or tri- cyclic ring systems which may be partially or fully saturated having 3-J0 ring atoms. The individual rings may be 3-7 member bearing one or mnrc hetcroatom selected from N, 0, S. This includes aryf and hcteroaryl ring stems fused to nori aromatic ring. For example azindinyl, oxiranyl, pipcridinyl, ptperazinyl, moipholinyl, thiomorpholmyl, oxadiazolonyl, oxazolidinonyl, thiadia^olonyl, 5-thioxo-4,5-dihyd]o-[l,2.4]triazol-l-yl and so on.
"substituted heterocyclyl" refers to a heterocyclyl group as defined above substituted by independent replacement of one or more hydrogen atoms thereon with CJ, Br, F, J, OH. CN, Ci-Ct alkyl, C|-Cft alkoxy, haloalkyl, amino, alkylamino, dblkylamino. mercapto. niJro, cjrboxaldehyde, carboxy, alkoxycarbonyl, carboxamide. "aralkyl" means groups like benzyl, benhydryl, trityl and so on.
"haloalkyf" refers to C|-Co aJkyl group substituted with one or more halogen for example chloromerhyl, bromoelhyl and the like.
" hcteroaryl ox y group' means heteroaryf linked via ether linkage for example group such as isooxa/olyloxy, thiophenyloxy, pyridinyloxy,
'Ci-Cfh alkoxy" refers fortlieCi-Cft alkyl group linked via ether linkage for example mctho*y. ethoxy and so on.
17

"acelamido" stands for NHC(0)CH3. "formamidc,h stands for NH-CHO.
"Cj-Q. alkylamido'1 means an alkyl group attached to the carbonyl of [he amide. Examples of
alkyamido groups include acelamido. -NHC(0)-C2H5, -NHCfO-QiH? and so on.
"C|-Cft hyloalkylamido" means alkyl group substituted with halogen, for example -NHC(O)-
CHCI2. -NHC(0)-CHF2l -NHC{0)-CH2CHCl2 and so on.
"thioacetamido", stands for NHC(S)CHj.
"C]-Q thioalkylamjdo" refers to alkylamido group wherein carbonyl group is replaced by -
C=S group; examples of alkyamido groups include thioacctamido, -NHC(St-C^Hs, -NHC(S}-
CJHJ and so on.
"substituted C\-Cb thioalkylamido" refers to thioalkylamido group wherein alkyl group is
substituted with halogen; for example -NHC(S)-CHCI2l -NHC(S)-CHF2. -NHC(S)-
CH2CHCl?andsoon.
The term "carbox amide", refers to a group of the formula -CONH2, -C(0)NH(C|-C6alkyl) or
-C(0)N(Ci-C6alkyl)(C,-Cca]kyl).
"formyl", refers lo the group -CHO. "cyano" refers to the group -CN.
The term "ammo" refers to NHj. "hydroxy!" refers to OH. "nitro" stands for NO?, "azido"
stands for N3. The term "urea" stands for NH-CO-NHz.
"substituted amino" refers to one or both hydrogen of amino substituted with optionally
substituted CI-CG alkyl or optionally substituted C[-Cf» alkenyl.
"carboxy", as used herein refers to a group of the formula -COOH.
"hydroxyiminoalkyl", refers to -C=N(OH)(C[-Cft alkyl).
"alkoxyiminoalkyl", stands for-C=N(0-(CrCb alkyl))(CrQ alkyl).
"aralkyloxyiminoalkyl", stands for-C=N(0-(aralkyl)(Ci-Cft alkyl) for example
be nzy 10 x y i m i nom ethy I,
"hydroxy! mi noaminoa I kyl" refers to -C=NT(OH)NHi.
"C|-O,alkoxycarbonylalkyl" refers to (C|-Cflalkyl)-0-CO-(C|-Cfi alkyl) for example
CH^OCOCH;-.
"CrC^alkylcarbonylalkyl" refers to (C[-Cfialkyl)-CO-(Ci-C6 alkyl) Tor example
CH^COCHz-.
"morphohnocarbonylalkyl" refers to morphohnoearbonyl-fCi-Q alkyl) for example
morp h 011 n oc arbon y 1 me Ih y I.
"alkylcarbonylaminoalkyl" refers to (Ci-C* a I kyl) -CO -NHr(C,-C6 alkyl) for example
CHjCONHiCF-fe-.
"Ci-aalKylsulfanylalky!" refers to (C|-C* alkyl )-S-(C|-Q alkyl) for example CH-jSCH2
IE

"C,-Co a]kylsulfotiylmethyl" refers to (CrQ,alkyl)-S02-(C[-Cfialkyl) for example CH3SO2CH2-.
"C|-G, aralkylsuifanyl" refers to aralkyl group attached to sulfur for example PhCHjS-. 'carbamate" refers to NH-CO-O-alkyl, for example NH-CQ-O-CHi (methyl carb am ale), NHCQ^QHs (ethyl carbamate).
"thiocarbamate" refers to NH-CS-O-alkyl, for example NH-CS-O-CH^ (methyl thiocarbamate). NHCS-OC2H5 (ethyl thiocarbamatc) and the like.
"Mammal" refers to human or animals including livestock and companion animals. A "therapeutically effective amount" is an amount of a compound of the present invention lhal, when administered to a patrent, provides The desired effect; i.e,, lessening in the severity of the symptoms associated with a bacterial infection.
It will be appreciated by those skilled in the art that compounds of the invention having one or more chiral centers may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invenlion encompasses any racemic, optically-active, polymorphic, geometric, or stereoi somen c form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of The racemic form by recrysutlligation techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine activity or cytotoxicity using the standard tests described herein, or using other similar tests which are well known in the art.
Certain compounds of the invention are aiso useful as intermediates for preparing other compounds of the invention, a conversion which can occur both in vitro and in vivo.
Some of the compounds of the invention are capable of further forming pharmaceutical^ acceptable acid-addition and/or base salts. All of these fornis are within the scope of the present invention. Thus, pharmaceutical I y acceptable acid addilion salts of the compounds of the invention include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkancdioic acids, aromatic
19

acids, aliphatic and aromatic sulfonic acids, etc. Such sails thus include sulfate, pyrosulfatc, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogcnphosphatc, dihydrogcnphosphatc, metaphosphatc, pyrophosphate, acetate, tnfluoroaceiate, propionate, caprylale, isobutyrate, oxalate, malonate, succinates subcrate, sebacate, fumarate, maleate, man del ate, bcnzoate, chlorobenzoate, methylbenzoatc, dinitrohenzoate, ph that ate, bcnzensoulfonalc, tolucncsulfonate, phcnylacetate, citrate, lactate, malcatc. tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Bcrge, S. M, et, a!., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977:66:1-19).
The acid addition salt of said basic compounds arc prepared by contacting [he free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
Pharmnceutically acceptable base addition safts are formed with metals or amines, such as alkali and alkafine earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-di benzyl elhylenedi amine, chloroprocaine, choline, diethanolamine, dicyclohcxylaiwne, ethylencdiaminc, N-methyl glue amine, and procaine.
Preferred salts arc those of hydrochloride, hydrobromide. hydroiodide, sulphate, phosphate and sails of organic acids such as acetate, lactate, succinate, oxalate, maleate, fumarate, malate. tartrate, citrate, ascorbate, cinnamate, gluconate, benzoate, methane sulfonate and p-toluene sulfonate; lithium, sodium, magnesium, calcium and potassium salts, and amino acids salts such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycines histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan tyrosine or valine.
The base addition salts of said acidic compounds are prepared by contacting the free acid form with LI sufficient amount of the desired base to produce the salt in the conventional manner.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydratcd forms. In general, the solvyied forms, including hydrated
20

(S)-N-{3-[4-(4-(5 (4-nitrophenyJ>-2//-tetrazol-2-yI)-piperidin-1 -y])-3-fluorophenyJ |-2-nxo-oxazolidin-5-ylniethyl}-acctamidc;
117. (S|A,H3-(4-(4^5-(4-niirophenyl)-2//4etrazol-2vvl)^i|^riditi-l-yl)-3,5-drfluorophcnyl |-2-oxo-ox;izolidmo-yrmemyl ]-acei amide:
118. (S)-N-f3-[4-(4-(5-(4-pyndiny])-l/Mctra7ol-l-yl)-piperidin-l-yl)-3-nuoropheny]|-2-oxo-oxazolidin-5-yl methyl }-acctamide;
119. (S)-Nn^[4-(4-(5-(3-pyridinyl)-2//-tetmzol-2-yl)-piperidin-l-yl)^-nLiomphenyl]-2-oxo-oxutt>lidm-5-ylmethyl}-acctamide;
120. (S)-N^3-[4-(4-(5-(4-pyhdinyl)-l//-te[ry/o]-t-y])-pipendin-Nyf)-l>difluorophenyll-2-oxo-oxazo]idin-5-ylmcthyl J-acetamide;
121. (S)-N^3-[4-(4-(5-(3'pyndinyl)-2H-tcirazol-2-y|)-pjpcridin-i-yl)-3,^-diflunrophenylJ-2-oxo-oxa£olidin-5-yl methyl }-acctamide;
122. (S>N'(3-[4-(4-f5-amJno-2W-tetrazol-2-yl)-piperidin-l-yl)-3-nvioropheny]l-2"OxO' oxazolidin-5-yl methyl }-acelamide;
123 (S)-N-[3-(4-t4-(5-amino-2//-tet™^ oxazolidin-S-ylmethyll-acctamide;
124. tS)-N-{3-[4-(4-(5-tdie[hylamino)-2//-Lctra^ol-2-yl)-pLpcndJn-J-yl)-315^ dinuorophenyl]-2-oxo-oxazo|idin-5-ylmethyl}-acetamide;
125. (S)-N-{3-[4-f4-(5-Cpiperiizin-l-yl)-2H-fl,2l3,4l,-LcL.ayJol-2-y|)-pjpendin-I-ylJ-3-II uoropheny 1J - 2-oxo-oxazo lidin-5-yl methy I} -ac etami dc:
126. (S)-N-j3-f4-{4-(5-{piperazm-I-yl)-2H-lelT^o]-2-yl)-piperidin-l-yJ)-3,5-dJfluoroplienyJ|-2-oxo-oxiizolidin-5-ylmcthyl]-acetamidc:
127. fSJ-N-{3-(4-(4-(5-(4-meihylpipcrazin-l-yl>2//-teiraiol-2-yJ)-pipehdin-l-yl)-3-(1 u orop hen yI ] -2-o \ o - o x azot i di ti -5-yJ met h yJ} -aeetami do;
12S. (S)-N-{3-I4-(4-{5-(4-meihyIpiperazin-I-yl)-2/McuazoU2-yl)-p]peTidin-l-ylJ-3,5-dif]iJoroplicnyll-2-oxo-oxazolidin-5-y]mc[hyl}-acetamide;
129. tS)-N-{3-I4-(4-(5-(4-aceiyl-pipcrazJn-|-yL)-2/Me[ra/ol-2-ylJ-piperidin-I-yl)-3-fl uorophe n y 1 ] - 2-oxo-oxazo I i di n- 5 - y I meihy I} -ac eta mi de:
130. (S)-N-(3-[4-{4-(5-f4-acciy|-piperdZin-l-yl)-2//-le[razo]-2-yl)-piperidin-l-yl)-3.^ d]fluorophenyJ]-2-oxo-oxazolidin-5-ylmethyl]-aceiamide:
131. (S)-N-{3-(4-(4-(5<4-cyanopiperazin-l-yl)-2H-[etrjzol-2-yl)^pipciidin-l-ylJ-3-IluoropheflyII-2-oxo-oxazoIidin-5-ylmethyl}-acelam]de;
132. (S)-N-{3'f4-(4-(5-(4-cyanopiperdzin-l-y0-2//-te[razol-2 -yl)-pipendin-l-ylJ-3,5-dif]uorophcnyl]-2-oxQ-oxazolidm-5-ylmeihyl)-acctamide;
28

32

(R)-{3-L4-(4-(4-ethoxycarbonyl-l//-[l,2,3j-[rijzol-[ -yl)-pipcridin-l-yl)-3-fluorophenyl]-5-(l//-(l,2,3]-lriazol-l ylmcthyl>)-oxazo]idin-2-oiie; {R)-{3-[4-(4-(4^thoxyciirbonyl-l//-IK2,3l4riazo[-l-yl)-pipendin-l-yl)-3,5-difluorophcny[]-5-(I//-II,2131-tnazofc-l-ylmelhyO}-oxawlidfn-2-onc; fS)-N-{3-E4-(4-(4-carboxymido-lH-(L2,31-triazol-I -yl)-piperidin-l-yl)-3-nuorophenyl[-2-oxo-oxazo!idin-5-ylmethyl)-acc[amide;
(R)-{3-[4-(4-(4-carboxamido-l//-[L,23]-[riazol-l-yl)-pipcndin-l-yl)-3-fluorophenyJl-5-(l//-[l,23]-[iia7ol-l-y]meihyl)}-oxazolidin-2one;
tSVN^{3-|4-t4-(4-curboxam]do-[//-Il,23I-triazol-l-y!)-rnethyI'pipcndin-[-yl)-3-fluoro-phcnyl)-2-o\o-oxa7,oliditi-5-ylmcthy[}-aceiJinide,
{S)-NH3-[4-(4-(5-carboxamido-L^[l123]HnazoUl-yl)-melhyl-pi^ridin-l-yl)-3-fluoTO-phcnyl]-2-oxo-oxazolidin-5-ylmcihyl}-acelamide;
(S)-N-{3-|4-(4-(4"acetyl-l//-[l,23]-tria7.ol-!-yl)-pipcridin-l-yl)-3-flu(imphenyl]-2-oxo-oxazolidin-5-yImethyl)-acct amide;
(S)-N-(3'[4-(4-(4-acetyl-l//-|l,2,3Hnazol-l-yl)-pipendm-l-yl)-3,5-dif]uorophenylI-2-oxo-oxazolidin-5-ylmcmyl}-acetamide;
(S>N^3-[4-(4-((4-((E/Z)-2-cyano-vinyl)-]7i-[l,23]-ttiazo]-l-y])-piperidin-l-yl)-3-f>Liorop hen yI ] -2 -ox o-o x azol i d i n - 5 -yI met h y 1 ] -ac eta nu de:
(S)-N-{3-[4-(4-(4-hydroxyiiriJno-methyl)-l//-|l,2,3]-iriazol-l-yl)-pipcridin-l-yt)-3-fluorophcnyll-2oxo-oxazol]din-5ylmcihyl}-ai;eiamidc;
(S),N-{3-|4-(4p]pendm-]-yl)-3,5-fl uorophe n yl J -2 -o s o-ox azol idi n -5 -y 1 me I h y 1J - aceiami de; (S)-N-{3-|4-{4-(5-meihylsiilfonylmeihyl-[//-le(razol-l"yt)-piperidin-]-yl)-3,5-dJnuorophcnyl]-2-o\o-oxazolidin-5-ylmcthyl}-ai:elaiiiide, (S)-N-{3-[4-t4K5-(thiophcn-2-yUmcthyl)-l//-[elrazol-l-yl)-piperidin-l-yl)-3>5-dilluoruphenyl] -2-oxo- ox yzolidin-5-yl methyl }-aceiamidc;
(S)-N-(3-[4-(4-{5-(4-pyridiriyl)-IH-[c[riizol-l-y])-pipcridin-l-y])-3-nLJurophenyl]-2-oxo-oxazoljdin-5-ylmemyl}-aceiamidc;
CS)-NH3-[4<4-(5-(4-pyridinyl}-l//-tetr^Dl-l-yl)-pipcridin-1-yl)-3,5-dinuorophcnyl]-2-oxo-ox azolidi n-5-y I meth y 11-acctamidc;
(S)-N-(3-[4-(4-(5-amirio-2fMcirazol-l-yl)-pipeiidin-l-yl)-3,5-difluorophcnyl]-2-oxo-oxazolidiiv5-ylmethyl}-acet amide; (R)-{3-[4-(4-(W^r(iphenyl)-3-fluoropheiiyl]"2-
oxo-ox azoli di n-5-y I mc ih y IJ-ace i ami dc;
(S )-N - (3 - [4- (4-(4 -c y anometh y 1 i dene -pi pe ri di n-1 -y I )-3 - fl u orop heny I)- 3 - fl uo ro ph en y 11 -2 -
ox o - o x azol i di n - 5-y 1 met h y 1} -acetamide;
(S)-N-{3-|4-(4-(4-cyanomelhyl-3,4-dehydropiperidin-l-yl)-3-f]uorophcnyl)-3-
fluoropht;nyl]-2-oAO-oxiizolidin-5-ylmethyl]-aceiamide;
(S)-N-(3-[4-(4'(4-cyanomcmyl-piperidm-l-yl)"3-f]uorophonyl)-3-fliiorophenyl]-2-oxo-
o x azol i di n -5 -yI met hyl} -acetami de;
{S)"N-{3-[4-(4-(4-azidomethyl-4-hydroxy-piperidin-l-yl)-3-flLJorophenyl)-3-
fl uo ro phe ny 1 ] -2-ox o-ox azo I i di n - 5 -yl mei h y I} -ac et ami de,
(S)-N'-(3-[4-(4-f4-(///-//P2,.?/-Lna^o!-i-yl)-piperidiLi^I-yl)0-nuorophcnyl}-3-
nuorophcnyI)-2-oxo-oxazolidin-5-ylmethyl}-acelamide and isomer Thereof;
(R)-(3-[4-(4-(piperazin-l-yl)-3-nuorophenyl)-3-fluorophenyll-5-([,2,3-triazol-l-
vljmeihyl }-oxazolidin-2-onc hydrochloride;
(S)-N-{3-[4-{4-(4-(2-ui(roruran-S-yl-methy!)-pipcrazin-]'y|J-3-f1iiorophenyl)-3-
fluorophenylJ-2-oxo-oxazo3idin-5-ylmeihyl}-acctamide;
tS)-N-{3-|4-(4-(ihiomorpholin4-yl)-3-fliiorophenylJ-3-f]uoroplienyl]-2-oxo-oxazolidiri-
5-ylmethylJ-acetamide; (S)-N-|3-[4-(4-(S'OXO-Lhiomorpholin-4-y!)-3-nLioraphenyl)-3-nuorophenyl]-2-oxo-
ox azol idin-5 -y I meih y 11 -accta mi de; tS»-N-{3-|4-(4-fS,S-dioxo-thiomoTphohn-4-yl)-3-fliiorophcnyl)-3-Huorophenyl)-2-oxo-
o x azo I idi n-5-y I methy I) - acelami de; fS)-N-{3-[4-(6-(thiomorpholiri-4-yl)-pyridin-3-yl)-3-nuoropheriylt-2-oxo-oxazohditi-5-
ylmelhyl )-acciamide;
45

(S) -N-13- [ 4 -(6- (S-o x o 4h i omorphol i n -4-yl)- pyri di n -3 -y 1) -3- fl uorop h en y IJ - 2 -ox o -
ox azo 1 i d i n-5 -y 3 met h y 1} -ae eta mide;
(S)- N - [ 3 -(4-(6- (S ,S - di oxo -mi omorph o I i n-4- y I )-pyn d i n -3-y I) - 3 - f I uorophenv IJ -2- ox o-
oxazolidin-5-ylmethyl}-acetamide;
(S )-N- [ 3 - [4- (6 -(S ,S- di o x o- 3 - me L h y ] - Lh i om orpho! i n -4 -y I) -pyiidi n-3-yl )-3 - ft uorophcn y I) -
2-oxo-oxtao]idin-5-ylmethyl]-acet amide;
(S)-N-i3-[4-(6-(L4-Dioxa-S-azaspiro[4,51dec-E-yl)-pyridin-3-yl)-3-nuoropheny]]-2-oxo-
oxazolidm -5-ylmethyl}-acctamide;
(S)-N-(3-f4-(6-(4-Oxopiperidin-l-yl)-pyridin-3'y!)-3-fluorophcny11-2-oxo- oxazolidin-5-
ylmcihylj-acetamide:
(S)-N-{3-[4-l6-(4-Hydroxy-4-mc[hoxymcihylpiperidin-l-yl)-pyndin-3-yl)-3-
nuorophcnyl)-2-oxo-oxazolidm-5-y]me(hyl|-acctamide;
(R)-3-{4-f6-(S,S-Dioxo-lhiomorpholin-4-yl)-pyridin-3-y]]-3-IL|uorophcnyl)-5-
h y droxy me ih y I -ox azol idin-2- one;
(R)-Phosphoric acid mono (3-[4-(Ti-(S,S-dioxo-ihiomorpholin-4-yl)-pyridin-3-y!)-3-
£luorophenyl]-2-oxo-oxazolidin-5-ylmethyl} ester;
(R)-Phosphoric acid i3'l4-(6-{S.S-dioxo-lhiomorpliolin"4"y])-pyridin-3-yl)-3-
!luorophenyll-2-oxo-oxazolidin-5-yrmelhy!} ester disodium salt;
(IS,5R)-2-Amino-propionic acid 3-(4-|6"(S1S-dioxo-ihiomorpholin-4-yl)-p>Tidin-3-yl]-3-
tluoro-phenyl}-2-oxo-oxazolidin-5-yImethyl ester;
(2SP5R)-2-Amino-propionic acid 3-{4-J6-(ShS-dioxo-thiomorpholin-4-yl)-pyridin-3-yI)-3-
f]joro-phcnyi}-2-oxo-oxazolidin-5-ylmeihyl ester methancsulphonic acid sail;
(2S,5R)-2-Amino-3-methyl-butyric acid 3-{4-I6-(STS-dioxi}-lhiomorpho!in-4-y!)-pyridin-
3-ylt-3-fluoro-phcnyli-2-oxo-o\azo]idin-5-ylmethyl ester;
(2 S, 5 R )-2 - A mi n 0-3-methyl-butyric acid 3-{4-[6-(S,S-di ox o-thi omorphol i n-4-yl)-pyri din-
3-yll-3-fluoro-pheny])-2-oxo-oxazoMdin-5-y]memyl esternielhanesulphonic acid salt;
(5R)-Acetic acid 3-(4-[6-(S,S-dioxo-thiomorpholin-4-yl)-pyridin-3-yll-3-f]L:oro-pheny] }-
2 - o x o-ox azol i di n -5 -y 1 meth y 1 ester;
(RH3-[4-(6-(Thiomorpholin-4-yl) -pyndin-3-yl)-3'tluorophenylJ-2-oxo-oxa/olidin -5-
yl methyl J-methansulphonate;
(R)-{3-[4 (6-(S-Oxothiomorpholin-4-y 1 )-pyridin-3-yI}-3-fluoropheny\]-2-oxo-oxazoIidin-
5-ylmcihylJ-meThunsulphonate;
(R)- {3-L4-(6-(S,S-Dio\o-thiomorpholin-4-yI)-pyridin-3-yl)-3-fluorophenyl J-2-oxo-
oxazolidi n-5-yl methyl} -methansulphonatc;
46

(S)-N-[3-(4-(6-(Thiomotphulin4-y|)-pyridiii-3-yl)-3-fliioropheny[l-2-oxo-oxazolidm-5-
ylmethyl Hormamide:
(Sj-N-{3-(4-(6-(SfS-Dio>;o-rh]Oinorpholin-4-yI)-pyrid[n'3-y])-3'f]iiorophcriyll-2-oxo-
oxazolidin-5-ylmethyl}-formamidc;
(S)-N-[3-[^(6-(S-Oxo-S-(N-meihylJm]no)-lhiomorpholin^-yl)-pyridyl-3-ylJ-3-
fluorophenyl-l-yl)-2-oxo-oxazi)lidin-5-yl methyl j-ucetamidc;
(S)-N-{3-[4-(6-{S-Oxo-S-(N-aceIy|imino)-thiomorpholin-4-y])-pyridyl-3-yl)-3-
fl uorophe n yl -1 - yl) -2- ox o- ox azo I i di n- 5 -y I methy I} - acel ami dc;
(Sj-N-[3-[4"f6-(S-Oxo-S-fl-chlorDe[hylLirido)-thiomorpholiTi-4-yI)-pyTidyl-3-ylJ-3-
fl u o ro p hen y 1 -1 -y J)- 2-oxo-oxazo I ldj n - 5 -y I met hy I} - acctami dc;
(SJ'N-|3-14-(6-(S"Oxo-S-imino-thiomorpholin-4-yl)-pyridyl-3-yI)-3-fluorophenyl-I-yl]-
2-oxooxazolidin-5-yl methyl }-acetarnide,
(S)-N-[3-(4-t6-(S,S-Dio\o-thiomoipholiri-4-yl)-pyridin-3-y])-3-nucirciphenyl]-2-oxo-
oxuzolidin-5-yimethyl}-propionamide;
(S)-{3-l4-(G-(thiomorphol]n-4-yl)-pyridJn-3-y])-3-lluorophciwl|-2-(uo-oxa7olidin-5-
ylmethyl | -carbatnic acid methyl ester;
(S)-N'{3-|4-(6-(S1S-Dioxo-lhLomorpho[in-4-yl)-p>Tidm-3-yl)-3-nuorophei5y]]-2-oxo-
o\a7.olidin-5-ylmeihyl J-carbamic acid mcihyl ester;
N-Acelyl-(R)-N-(3-4-(2-(S,S-Dioxo ihiomorpholin-l-yl) -pyndyl-5-y]-3-fluorophenyl-L-
yl-]} -2-oxo-oxazolidin -5-yl methyl [aminocarbonyl-oxy methyl acetate;
(S)-(3-[4-(r>-ihiomoTpholin^-yl-pyridin-3-yl)-3-fluorophcryl]-5-flT2,3]-triazol-l-
y] methyl)-oxazo I idi n-2-one;
(S)-N-(3-l4-(6-(S,S-D]OXO-Lhiomorpholin-4-yl)-pyndiii-3-yl)-3-fluorophenyl]-5-| 1.2,3]-
triazol- I-ylmethyl }-oxazolidin-2-one: (S)-N-{3-j4-(6-(S-Oxo-3l3-dichloro-thLomorpholin-4-y[)-py[idir-3-yl)-3-nunTophenyl)-2-
oxo-oxa7olidin-5-yl methyl l-acctamide;
(S)'N-{3-14-(6-(S,S-Dioxo-thiomorpholin^l-yl)-pyridJn-3-yl|-3-flLioropheryl]-2-o\o-oxazolidJn-5-ylmcthyl }-urea:
(S)-NT-{3-|4-t6-{Thiomorpholin-4-y|)-pyridin-3-yl)-phenyl|-2-oxo-oxazolidJn-3-yl methyl )-acct amide;
(S)-N-{344-(6-(S-Oxo^hiomorpholin-4-yl)-pyridin-3-yl)-phenyll-2-uxfi-fixazolidin-5-yi methyl}-ace I amide;
(S)-N-(3-[4-(G-(S,S-Dioxo-ihiomDrpholin-4-yl)-pyridin-3-yl)'phenyl]-2-o\o-oxazolidin-5-ytmethyl 1-aceiamidc;
47

(S)-N-|3-[4-(6-(S-Oxo-S-(N-methylimino)"thiomorpholin-4-yl)-pyridin-3-ylJ-pheny]I -2-
nxo-oxazolidin-5-y]methyl)-acet amide;
(S)-N-{3-l4-(2-(S,S-Dioxo4hiomorpholin"4-y])"pyhmidir]-5-yl)-3-fluoropht:nyl]-2-oxo-
oxazolidin-5-ylmemyl)-carbamic acid methyl ester;
(R)-Phosphoric acid N-{3-l4-{2-(Thiomorpholin-4-yl) -pyrirnidin-5-yl}-3-fluor»phcnyl]}
-2-oxo-oxa/olidin -5-y] methyl [ester;
(R)-Phosphoric acid N-(3-{4-(2-(S-Oxo thiomorpholin-4-yl) -pyrimidin-5-yl)-3-
fhiorophenylj] -2-oxo-oxazolidin o-yl methyl|-ester;
(R)-Phosphoric acid N-{3-|4-{2-(S,S-Dioxo ihiomorpholin-4-yl) -pyrimidin-.'i-yl)^-
fluorophenyl|) -2-oxo-oxazohdin -5-yl methyl)-ester;
(R)-Phosphoric acid N-{3-{4-{2-(S,S-Dioxo thiomorpho!in-4-yl) -pyrimidin-5-yl)-3-
fljorophenyll} -2-oxo-oxazolidin -5-yl methyl ]-ester disodiumsalt;
(S)-N - (3 -14-(2-(S ,S-Di oxo-i h i omorph o 11 n-4-y IJ-py ri m i di n-5-y 1) - 3 - fl uorophe n y 11-2-oxo-
oxazolidin-5-ylmethyl}-acetamide;
(S)-N- (3-|4-(2-(S J>-Dioxo-lhiomorpholin-4-y l)-pyri midin-5-yi)-3-fluorophenyl ]-5-
(lT2,3)-triazoI-l-yImethy]}-oxazolidin-2-onc;
(S)-N-(3-[4-(6-(S,S-Dioxo-Ihiomorpholin-4-yl)-3-methylpyTidin-3-yl)-3-fluorophcnyl]-2-
oxo-oxa7olidin-5-ylmethyl}-carbamic acid methyl ester;
(S)-N-(3-I4-(6-{S,S-Dioxo-Ihiomorpholin-4-yI)-3-methy]pyridin-3-yl)-3-nuorophenyi|'5-
hydroxy methyl j-oxazolidin-2-one;
(R)-Phosphoric acid mono {3-[4-(6-(S,S-dioxo-ihiomorpholin-4-yl)-3-methylpyridin-3-
y I )-3 - fl uorophc nyl}-2-oxo-oxazolidin-5-yl methyl ] ester;
(R)-Phosphoric acid mono {3-(4-(6-(S-oxo-thiomorpholin^4-yl)-3-methylpyndin-3-yl)-3-
fluorophenyl|-2-oxo-nxazolidin-5-y!methyl| ester disodium salt;
(S)-N-f3-[4-(6'CS,S-Dioxo-lhiomorpholin-4-yl)-3-mcthylpyndin-3-yl)-3-fluorophcnyl)-2-
oxo-o\azolidin-5-ylmethyl}-acetamide,
(S)"N-{3-[4-(6-(S,S-Dioxo-thLomorpho]in-4-yl)-3-meThylpyndm-3-yl)-3-nuorophenyll-S-
11,2,31-triazol- l-ylmethyl )-oxazolidin-2-one;
(5S)-{3-|(3f5-Difluoro^-(fj-(4-ShS-dioxo-ihiomorpholLn-4-yl)-3-pyridinyl)phenyl)-2-oxo-
o\azolidin-5yl-meihyl}-acet amide.
A further embodiment of the invention is to provide methods of preparation of the compound
of the invention.
48

Following schemes describe the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared hy procedures described in US Patent 5,668,286 and in PCT patent application PCT/JNG3/O0237, PCT/JN03/00238 or hy procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the following Schemes are as defined above. Optically pure material could he obtained either by one of a number of asymmetric synthesis or alternatively by resolution from a racemic mixture. ,
Oxazolidinonc compounds bearing substituted heteroaryl and substituted hctcroarylmelhyl piperidine moiety may be prepared as per schemes described below:
1 N 2
A = CH2 or absent R10 = H,-COOC?HS or -CH?OH or COGH or CONH2
a) ethyl propionic or ethyl pmpiolatc then 0.1 N KOH or ethyl propiohte then NHdOH
b) pmpzirgy] alcohol, Cul
c) 2,5-norbomadiene
Scheme!
As per scheme-!, oxazolidmone compound of formula 1 is heated with ethyl propionic in a solvent such as toluene or xylene for 3 to 14 hours at a temperature between 100-120 °C to provide oxazolidmone compound 2, wherein Rm is CO2C2H5. On further hydrolysis in presence of a base such as potassium hydroxide or sodium hydroxide in tetrahydrofuran, water mixture to provide oxazolidinone compound 2 wherein Riu is CO^H. Alternately the compound 2 with Ru> as CO2C2H5 on further hydrolysis in presence of a base such as ammonium hydroxide in tetrahydrofuran, water mixture to provide oxazolidinone compound 2 wherein R,0 is CON'Hj. Optionally heteroaryimethyl oxazolidinone compound was reacted with 2,5-norbornadiene in dioxane at a temperature 0 - SO °C to provide oxazolidinone compound 2 of the invention.
49

R4
mi

*00&L

K
„_/ w^°


Hd
RJ

n = 0.1,
Rll = H,CH3, pyridyl
a) TMSNj, BUjSnO; or TMSN,, Bu^SnO then Mel
h) hydroxyliiminc then ethyl propiolute c) hydros yl a mine then RMCOCI
Scheme-2
As per scheme-2, oxazolidinone compound of formula 3 is heated With trimcthylsilylazide and tributyltinoxide in a solvent such as toluene or xylene for 3 to 14 hours at a temperature between 100-120 C to provide oxazolidinone compound 4 of the invention. Optionally oxazolidinone compound was alkylated with alkylhahdc such as methyljodide in presence of base such as sodium hydride in tetrahydrofuran lo provide oxazolidinone compound 4 of the invention.
Oxazolidinone compound 3 was reacted with hydroxylamine hydrochloride in presence of a base such as sodium bicarbonate in methanol at a temperature 30-50 °C to provide hydroxy liminomethylpieridino oxazolidinone compound which subsequently upon reaction with ethylpropiolate in diphenyl ether solvent at reflux temperature provided oxazolidinone compound 5 of the invention.
Optionally oxazolidinone compound was subsequently reacted with organic acid chloride in presence of base such as sodium bicarbonate provided oxazolidinone compound 6 of The invention.
.SO


X
>x
M-C VN
A
tiC *—J Y
3

R4

ihiosemicarbazlde A—( 7 -N U

Schcmc-3

As per scheme-3h oxazolidinone compound of formula 3 is reacted with thiosemicarbazide in
mcthanesulfonic acid for 3 Eo 14 hours at a temperature between 40-80 °C to provide
oxazohdinone compound 7 of the invention.
Q 0
/-0 R^COCI /—\ X-\ }^
R4
NHNH, e R1|AN.«
Rn = CH3l phenyl
Scheme-4
As per scheme-4, oxazohdinone compound of formula 8 is reacted with organic acid chloride in presence of base for example potassium carbonate, sodium carbonate, Iriethylamine for 3 to 14 hours at a temperature between 0-50 °C to provide oxazolidinone compound 9 of the invention.
10 it
R„ = CH-SO,- or p-tolyl-SO,- Het = unsubstituted or substituted
12 3 2 y 3 heleroaryl
Scheme-5
For the synthesis of substituted heleroaryl pi peri dine wherein the point of attachment is via the nitrogen atom of the heleroaryl. alkylsulfonyloxy or arylsulfonyioxy substituted piperidino oxazolidinone compound of formula 10 is reacted with unsubstituted or substituted heleroaryl for example imidazole, triazole. tetrazole in the presence of a base such as
51

potassium carbonate for 3 to 24 hours ai a temperature between 50-100 nC to provide oxazohdinone compound 11 of the invention (Schemed).
Oxaxolidinone compounds bearing biaryl moieties may be prepared as per schemes described below
R2 R2 R2
12 13o LJa 15a

K2 R2
X=v d )—\ ,X=

OH

Y_? v^ Y_? on
Ifa Hii


A \=/ NvJtv,H4

18a ^
H2 = H,CH1-F
Z = CH>: *OCH,CH,0-. PhCH,-N-:0. S
X and Y = CH: CF
A = P; Rr
A=Br,I
K4 = -OH; -OSO>CH3: -NHCOCHj 'OC(0)OCH3 hetemaryl
a) Base, acetonitnlc ; b| Reducing agent. Hydrogen source c) NaNO, or KNO;. HCl, Kl or Nal; d) trialkyl borate, n-BuLi, e) Pd(OAc)2, Ph-,Pt K^COj, THF, DME, water
Scheme-6A
As per scheme-6A, nitrogen bearing heterocyclc 12 (Z selected from CHi, -OCH?CH20-, PhCHjN-, (X S) rs reacted with compound 13a (A is either fluorine or bromine and X and Y selected from CH, CF) in presence of base such as tri ethyl amine or diisopropy I ethyl amine in solvent such as acctonitrilc or dimethyl formamidc or tetrahydrofuran, or mixture thereof at a temperature between 70-85 CC for I to 12 hours to provide compound 14a.
52

The compound 14a is reduced in presence of catalyst such as 5% or 10% palladium on carbon or 20% palladium hydroxide on carbon in presence of hydrogen source such as hydrogen gas optionally under pressure, or cyclohexene or ammonium formate in the presence of solvents such as methanol or ethanol or ethyl acetate at a temperature between 30-65 °C for I to 12 hours to provide heterocyclic aromatic amino compound 15a Optionally, the reduction is carried out in presence of metal such as iron or zinc in presence of hydrochloric acid in a solvent such as methanol or ethanol at a temperature between 30-65 °C for I to 12 hours to provide compound 15a,
The compound 15a is diazohzed with sodium nitrite or potassium nitrite in the presence of hydrochloric acid in a solvent such as water or ethanol or mixture thereof at a temperature between 0-10 °C for 1 to 2 hours, which upon further treatment with potassium iodide or sodium iodide in water at a temperature between 0-10 °C for 1 to 12 hours provided compound 16a.
The compound Ilia is treated with irialkyl borate such as trimethyl borate or methyl borate or tributyl borate in the presence of n-butyllithium in a solvent such as tetrahydrofuran or toluene or mixture thereof at a temperature between 0^10 °C for 1 to 24 hours there upon optional aqueous hydrochloric acid treatment furnished aryl boronic acid 17a.
The heterocyclic aromatic boronic acid 17a is reacted with compound 18a in presence of catalyst such as a mixture of palladium acetate and triphenyl phosphinc or tc Irakis tri phcnylphosphinc or bisdiphcnylphosphinc palladium acetate in presence of base such as potassium carbonate or trie thy I amine, in a solvent such as dimelhoxyethane or tetrahydrofuran or toluene, or aqueous ethanol, or mixture thereof at a temperature between 30-90 DC for 1 to 24 hours to furnish oxazohdinone compound 19a of the invention of formula I.
53

R2 R2

i MI + Br—^ A— Br —*- z N-^\ y>—BJ
\—/ n—f \ / N.
16b
12 Ub
R2 O
c
K /=\ .on ^ >-
17b 18b

b
*

R2 O


f %
N
R4

N^ Y 19h

R2 = H ; CHj; V
7. = C\Ij. -QCUfM2Q-, PhCHi-N-iO; S
X and Y = CH, CF, N
R4 = -OH; -OSOJCHJ ; -NKCOCIIji -OC{0)OC}^; heteroaryl
a) Base, N-mcthylpyrroljdinone; b) trialkyl borate, n-BuLi: c) Pd(OAc),, Ph3P, KjCO^, THF, DME, water.
Schemc-fiB
As per scheme-6B, nitrogen hearing helerocyde 12 (Z selected from CH2, -OCHJCHJO-, PI1CH2N-. 0. S) JS reacted with 2,5-dibromo-pyridine (13b) in presence of base such as inethylumine or dii so propyl ethyl amine in solvcni such as N-methylpyrrolidinone, acetonitrile, dimethyl formamide, or mixture (hereof at a temperature between 70-85 C for 1 to J 2 hours to provide compound 16hr
The compound 16b is (reared with trialkyl borate such as trimethyl borate or triethyl borate, tri butyl borate in the presence of n-butyllithium in a solvent such us tetrahydrofuran, toluene or mixture thereof at a temperature between 0-40 t for I to 24 hours there upon optional aqueous hydrochloric acid treatment furnished boronic acid 17b.
The boronic acid 17h JS reacted with compound 18b in presence of eaialyst such as a mixture of palladium acetate and iriphenyl phosphine or ten akistn phenyl phosphine or
54

bisdiphenylphosphine palladium acetate in presence of base such as potassium carbonate or iriethylamine, in a solvent such as dimelhoxyelhane or letrahydrofuram or mixture Thereof at a lempcralurc between 30-90 C for 1 to 24 hours to furnish oxazohdinonc compound 19b of the invention of formula I,
R2 R2
Z NH+ CI—.
N-fc J— Br *- ? N-<\ /)-B + I—(7 VN T
15c 17c 18c

19C
R2 = H ; CHj; F
Z = CH:; -OCHjCHp-i PhCH:-N-;0; S
XJIIK!Y = CH; CF; N
R4 = -OH; -OSOJCHJ ; -NHCOCH^ -OC(0)OCHj; heleroaryl
a) Base, cthano]; b) N-bromosucc in amide, acetonitrile; c) trialkyl borate, n-BuLi; d) Pd(OAc)2, Ph^P, K2COin THF, DME, water.
Scheme -GC
As per scheme-6C, nitrogen bearing hctcrocycle 12 (Z selected from CH^. -OCH2CH2O-, PhCH^N-. O, S) is reacted with 2-chloro-pyrimidinc (13c) in presence of base such as iriethylamine or diisoprupylelhylamine in solvent such as ethanol, or n-hutanol or mixture thereof at a temperature between 70-100 °C for 1 to 12 hours 10 provide compound 14c,
The compound 14c is reacted wjth brominating agent such as N-bromosuec in amide in a solvent such as acetonitrile or chloroform or mixture [hereof al a temperature 25-45QC for 5 -14 hours to furnish compound 15c
55

The compound 15c is treated with trialkyl borate such as trimelhyl borate or triethyl borate, trihutyl borate in the presence of n-butyllilhium in a solvent such as tetrahydrofuran or toluene or mi Mure thereof Lit a temperature between 0-40 C for I to 24 hours there upon optional aqueous hydrochloric acid treatment furnished boronic acid 17c.
The boronic acid 17c is reacted with compound 18c in presence of catalyst such as a mixture of palladium acetate and Iri phenyl phosphine or telrakistriphenylphosphine or hisdiphenyl phosphine palladium acetate in presence of base such as potassium carbonate or tnethylumine. in a solvent such as dimelhoxyethane or leirahydroFuran, or mixture thereof at a temperature between 30-90 C for ! to 24 hours to furnish oxa/oltdinone compound 19c of the invention of formula \.
R2 ' H3C R2 HX
z NH+ Br—(x h *- z N-^ h *

12 13d

1dd

R2 H.C R2 H-C

15d 17d 18d

R2 H3C 0

^ ^ f-\ >0

R4

19d
R2 = H ; CH^. F
Z = CH2; -OCHjCHnO-; PhCHj-N-; 0 ; S
XJIHI Y=CHb CPL N
R4 = -OH; -O50jCH3; -NHCGCHj -OC(0)OCHJ; heteroaryl
a) Pd(OAc)jf PdClj(DPPF)2: CH2C\2 complex, base, toluene;
b) N-bromosuccinatnide, acctonitrile; c) irialkyl borate, n-Bul-i d) Pd(OAc)2, Ph3Pf K?COj, THF, DME, water.
Scheme-6D
56

As per schcmc-(iD, nitrogen hearing heterocyele 12 {Z selected from CH;, -OCH2CH2O-, PhCH2N-, 0, S) is reacted with 2-bromo-3-methyl-pyridine (13d) in presence of palladium acetate and catalyst such as (1 J-bis(dipheylphosphino)-ferrocene]-dichloropalladium (II) complex with dichIoromethane 1:1 also known as PdCl2(DPPP);: CH2CI2 complex and base such as sodium tcrt-butoxidc in a solvent such as toluene or xylene or mixture thereof at a temperature between 70-140 °C for 5 to 12 hours to provide compound 14d.
The compound 14d is reacted with brominatmg agent such as N-bromosuccinamidc in a solvent such as aceionitnle or chloroform or mixture thereof at a temperature 25-45 °C lor 5 -14 hours to furnish compound lSd.
The compound 15d is treated with trialkyl borate such as tri methyl borate or tncthyl borate, tri butyl borate in the presence of n-butyl lithium in a solvent such as ten ahydrofuran h toluene or mixture thereof at a temperature between 0-40 °C lor I to 24 hours there upon optional aqueous hydrochloric acid treatment furnished heterocyclic aryl boronic acid 17d.
The boronic acid I7d is reacted with compound lSd in presence of catalyst such as a mixture of palladium acetate and triphenyl phosphine or tetrakistriphenylphosphine or btsdiphenylphosphine palladium acetate in presence of base such as potassium carbonate or trielhylamine, in a solvent such as dimcthoxycihane or tc 1 rahydrofuran, or mixture thereof at a temperature between 30-90 °C for 1 to 24 hours to furnish oxazolidmonc compound 19d of the invention of formula I.
20 21
X and Y * CH" CF, N
R4 = ^OH; -OSO;CH3; -NHCOCHj; -OCtO)OCH3; heteroaryl
Scheme-7
As per scheme-7, the oxazohdinone 20 (prepared as described in schemc-6A to 6D) is stirred with organic acid such as/j-toluene sulfonic acid or inorganic acid such as dilute hydrochloric acid or dilute sulfuric acid in solvent such as acetone or water or tetrah ydrof uran. or mixture
57

thercof at a temperature between 30-80 DC for 1 to 12 hours lo provide oxa/olidnone compound 21 of (he invention.

0

bj
R4
MtOH H- McQ
X3HK>iL,
base J\f 21 ^ *■
MeO ^ / 'Y-F V=/ ^-^S.^K4
23
Xand V=CII; CF; N
R4 = -OH- -OS02CH3; -NHCOCH3: -OC(0)OCH3; heieronryl
Scheme-8
As per scheme 8^ the oxazolidinonc compound 21 (prepared as described above) is reacted wilh tnmethylsulphoxonium iodide {(CH^SO*!) or trimcihylsulphoniLim iodide ((CH^S*!-) in the presence of a base such as sodium hydnde or potassium tert-butoxide or lithium diisoprapylamine or n-butyl lithium in a solveni such as dimethyl formamidc or tetrahydrofuran or mixture thereof at a temperature between 0-85 °C for I to 12 hours to provide oxazolidmone compound 22 of the invention.
As per schcme-S, the oxazolidinone compound 21 is stirred with p-tolucncsulfonic acid in methanol at a temperature between 0-85 °C for I to 12 hours to provide oxazolidinonc compounds 23 of the invention.

R4

R2 °>^ /=\ /-\ h019 NalO, y-\ /=\ /-\ ho24

Z = S Z = SO ; S02
XandY = CH; CF; N
R4 = -OH: -O.SO.CH,, -NHCOCH^ -QC{0)OCH3h heteioaryl
Scheme-9
As per Scheme-9, the oxazolidinone 19 is optionally oxidized with sodium peroidate in solvent such as aqueous methanol or rectified spirit at a temperature between 0-80 5C for 1 to 48 hours to provide oxa/olidinone compound 24 of the invention.
5S


0=Ob^

26
XandY = CII; Cl:; N
K4 = OH, pSOpJ,. ^NHCOCHj; -0C(0)OCE^ heleroaryl
RI3s}^CH,lCN;CGNHj:p>Tidyl
Scheme-10
As per schcmc-tO, the oxazohdmone compound 21 (prepared as described above) is reacted with appropriate Witlig reagent such as dicthylcyanomcthylphosphonate or diethyl-(l-cyanoelhyl) -phosphorate or dicihyl( I -cyano-2-carhox ami dome! hyl)-phosphonaie or diethyl (l-cyano-2-(3-pyridylmethy!)-phosphonaie in the presence of base such as tricmylaminc or diisopropylethylamine and lithium bromide in a solvent such as dimethyl formamide or tetrahydrofuran or mixture thereof at a temperature beiween 0-85 °C for 1 to 12 hours lo provide oxazolidinonc compound 25 of The invention.
Compound 25 is optionally reduced with reducing agent such as 5% or 10% palladium on carbon or 20% palladium hydroxide on carbon in presence of hydrogen source such as hydrogen gas optionally under pressure, or cyclohexcne or ammonium formate in the presence of solvents such as methanol or ethanol or ethyl acetate at a temperature between 30-65 nCfor 1 to 12 hours to provide oxazoldinone compound 26 of the invention.
59

38
-OCH>^L
_ R4
XanOY = CH; CF; N
R4 = -OH, -0SO3CH3; -NHCOCH3; -OC(0)OCH3; heteroaryl.
R5 = heieroaryl
R14 = CH$SOi-; p-CH3CflH4-SO?-
Schcme-ll
As per seheme-11, the oxaznlidinone compound 21 (prepared as described above) is reacted with appropriaie reducing reagent such as sodium borohydride in a solvent such as methanol or elhanol at a temperature between 0-35 C for I to 12 hours to provide oxazolidinone compound 27 of the invention.
Compound 27 is optionally reacted with alkylsulfonyl chloride such as met hanesu I Tony I chloride or cthancsulfonytchloride or ary! sulfonyl chloride such as p-toleunc sulfonylchloride or p-bromosulfonylchloridc in presence of base such as tricihylamine or pyridine or diisopropylelhylamine in a solvent such as dichloromelhane or chloroform or letrahydrofuran at a temperature between 0-35 C for I to 12 hours to provide o\azohdinone compound 2S of the invention.
Compound 28 is optionally reacted with heteroaryl amine such as pyrrole, or pyrazole, or imidazole or triazolc or teirazole or aliphatic cyclic amine such as pyrrolidine or piperidine or pipcrazinc or morpholine in presence of base such as potassium carbonate or sodium carbonate in a solvent such as dimethyl form amide or dio\ane at a temperature between 35-E0 C for I to 12 hours to provide oxazoldinone compound 28 of the invention.
60

^P^VKK^l
9
XandY = CH, CF; N
R4 = -OH; -OS02CH3; -NHCQCH,; -OC(0)OCH3; heteroaryl
Scheme-12

As per scheme-12, the oxazolidinone compound 21 (prepared us described above) is reacted with cyanoacetic acid and base such as pyridine or methyl amine or piperidine in presence or ammonium acetate in a solvent such as roleune or xylene at a temperature between 80-120 C for 1 to 12 hours lo provide oxazolidinone compounds 30 of the invention.

O H+ or NaN3
^■lH>X
A/ \ /X=\/*~\ ^"0 or NaCN or NaOCH3
R4
or amine
22

^ R4 31
»>V

XandY = CH; CF; N
R4 = -OH; -OS02CH3; -NHC0CM3; -OC(0)OCHj; hfHeroaryl
R15 = CN; OH, OCH3,N^; amine
Scheme-13
In accordance with scheme-13, oxazolidinone 22 (prepared as per procedure described ahove) is reacted with appropriate acid catalyst such as p-toluenc sulfonic acid or hydrochloric acid or sulfuric iicid or with a nuclcophilic reagent such as sodium azidc, sodium cyanide, sodium methoxide or amine such as methyl amine dimethyl amine or with a cyclic amines, such as pyrrolidine or piperidine, or with an aromatic amine such as imidazole or tnazole or tetrazole in a solvent such as dimethylformamide or dimethyl ace [amide or meihanol or ethanol or mixture thereof and stirred for 3 to 48 hours at a temperature between 10-100 °C to provide oxazolidinone 31 of the invention.
61


5

-*-

0 \-/ \_f \=/ \-~^R4

13 32
i = Ch^Ph, R3^H

33
R4 = -OH; -OSOjCH3; -NHCOCHj, -OC(0)OCH,; rielerraryl
a) 10% Pd on curbon, K2; b) 2-buiizyloxyaceiylchloiidc. K?C03 c) Pd(OFI),. H,
Schemo-14
In accordance with scheme-14, oxazolidinonc compound 19 (prepared as per procedure
described above) is stirred in hydrogen atmosphere in presence of catalyst such as 5% or 10%
palladium on carbon or 20% palladium hydroxide on carbon in a solvent such as methanol or
ethanol or ethylacetatc for 3 to 48 hours at a tempcratLire between 35-60 C to provide
oxuzohdmone 32 of the invention.
Optionally compound 32 is optionally reacted with ethanol hydrochloric acid to provide
hydrochloride salt of compound 32 of the invention.
Optionally compound 32 is reacted with 2-bcnzyloxyacctylchloridc in presence of potassium
carbonate or sodium carbonate in a acetone water mixture I to 14 hours at a temperature
between 0-35 C to provide oxazolidinone 33 of the invention.
Optionally compound 33 is stirred in hydrogen atmosphere in presence of catalyst such as 5%
or 10% palladium on carbon or palladium hydroxide in a solvent such as methanol or ethanol
or ethyl acetate for 3 to 48 hours at a temperature between 35-60 C to provide oxazolidinone
34 of the invention.
x^ x-* yQ
R4
Q

32
R4 - OH; -OS02CH3; -NHCOCHj: -OC(0)OCH3; haleroaryl a} 2-nilroluran-5-aldehyde, sodiumlnaceLoxyborohydride
Sch9m&-15
62

In accordance with scheme-15, oxazolidinone 32 (prepared as per procedure described above) is stirred with 2-nitro-furan-aldchyde in a solvent such as dichloromeihane or chloroform or methanol or eihanol followed by addition of sodiumtriacetoxyborohydride for 3 to 10 bours Lit a temperature hetween 35-60 C lo provide oxazolidinone 35 of the invention.
0=S N^v h-% VN ¥ *» U% N-(x }—<' VN I
36 37

%
R2.
~N
HCHO, HCOOK °y \/ \_A \_rfQ
H3C
38

CH3COCI. Et3N
37 *-
°*/ \|_rf Y_// T*_*f {
V N-4 7W VN ?
0 39
P1B-N=C=OH Ei3N
R,rVW Y Y ^^W
O *°
Xand¥=CH; CF; N
Rl6 = alkyl,aryl
R4 = -OH; -OSO^CH3, -NHCOCH,; -0C(O}OCH3; heteroaryl

Scheme-16 In accordance with scheme-16, oxazolidinone compound 36 (prepared as per procedure described above) is stirred with sodium azide and polypbosphoric acid (PPA) for 10 to 14 hours at a temperature between 50-60 C lo provide oxaxolidinone compound 37 of the invention.
The oxazolidinone compound 37, upon reacting wiih formic acid and aqueous formaldehyde mixture for 10 to 14 hours at a temperature between 60-80 C provided oxazolidinone compound 38 of the invention.
63

The oxuzolidmone compound 37, upon reacting with alky] chloride such as acetyl chloride and base such as trielhylamine or diisopiopyl ethylamine mixture for 10 to 14 hours at a temperature between 0-35 C provided oxazolidinone compound 39 of the invention.

-O^W
roM
42 °M

Z = O, S, SO, S02 XandY =CH; CF; N
iij I) Di-terL-buiyl-dii so propyl phosphu ram id ite* (eira/ole
2) H-,0, or m-chlor