WO2006035283A1

WO2006035283A1 - Oxazolidinone derivatives as antimicrobials

Info

Publication number: WO2006035283A1
Application number: PCT/IB2005/002840
Authority: WO
Inventors: Biswajit Das; Sonali Rudra; Mohammad Salman; Ashok Rattan
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-09-27
Filing date: 2005-09-26
Publication date: 2006-04-06

Abstract

The present invention relates to substituted phenyl oxazolidinones and processes for preparing thereof. This invention also relates to pharmaceutical compositions comprising compounds of the present invention. Such compounds can be useful antimicrobial agents that can be particularly effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria (e.g., multiple-resistant staphylococci, streptococci and enterococci), anaerobic organisms (e.g., Bacterioides spp. and Clostridia spp. species), and acid-fast organisms (e.g., Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp).Formula (I).

Description

OXAZOLIDINONE DERIVATIVES AS ANTIMICROBIALS

Filed of the Invention

The present invention relates to substituted phenyl oxazolidinones and processes for preparing thereof. This invention also relates to pharmaceutical compositions comprising compounds of the present invention. Such compounds can be useful antimicrobial agents that can be particularly effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria (e.g., multiple-resistant staphylococci, streptococci and enterococci), anaerobic organisms (e.g., Bacterioides spp. and Clostridia spp. species), and acid-fast organisms (e.g., Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp).

Background of the Invention

Increasing antibacterial resistance in Gram-positive bacteria has presented a formidable treatment problem. The Enterococci, although traditionally no virulent pathogens, have been shown, when associated with Vancomycin resistance, to have an attributable mortality of approximately 40 %. Staphylococcus aureus, the traditional pathogen of postoperative wounds, was reportedly resistant to Penicillin due to production of penicillinases. This resistance was overcome by the development of various penicillinase stable β lactams. However, the pathogen responded by synthesizing modified target penicillin binding protein- 2' leading to less affinity for β-lactam antibiotics and a phenotype known as Methicilline Resistant S. aureus (MRSA). Until recently, these strains were susceptible to Vancomycin, which in spite of its various drawbacks has become the drug of choice for MRSA infections. Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until recently, Streptococcus pneumoniae was highly susceptible to penicillin, however different PBP 2' strains with different susceptibility to penicillin have been reported from across the globe.

Oxazolidinones are a new class of synthetic antimicrobial agents, which kill gram- positive pathogens by inhibiting a very early stage of protein synthesis. In particular, oxazolidinones inhibit the formation of ribosomal initiation complex involving 3OS and 5OS ribosomes leading to prevention of initiation complex formation. These compounds are generally active against pathogens resistant to other clinically useful antibiotics.

J. Med. Chem., (1998), 41, 3727-3735 discloses pyridine, diazine, triazine, heteroaromatic rings directly attached to the piperazinyl oxazolidinone core. J. Org. Chem., (1999), 64, 6019-6022 and J. Org. Chem., (2000), 65, 1144-1157. Bioorg. Med. Chem. Lett., (2001), ϋ, 1829-1832 discloses oxazolidinone derivatives, which are active against gram positive strains including the resistant strains of Staphylococcus and Enterococcus. J. Med. Chem., (1968), 11, 305-311 discloses the synthesis of various benzo-2,1,3-oxadiazoles and their N-oxides. Org. Proc. Res. Dev., (2003), 7,436-445 describes the synthesis of 5-bromobenzofurazan. J. Cardiovasc. Pharmacol., (1982), 4, 344 discloses a new benzoxadiazolyl dihydropyridine derivative.

WO 04/056817 discloses substituted biaryl-oxazolidinyl derivatives said to be effective against Gram-positive and Gram-negative pathogens. WO 04/056818 discloses substituted biaryl-oxazolidinyl derivatives described as effective against Gram-positive and Gram-negative pathogens. WO 04/014392 discloses piperazinyl oxazolidinyl acetamide derivatives as antimicrobials. WO 03/008389 discloses substituted phenyl oxazolidinones, which are apparently useful antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria, for example, multiple-resistant Staphylococci, Streptococci and Enterococci as well as anaerobic organisms, for example, Bactericides spp. Clostridium spp. and acid-fast organisms, for example, Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.

WO 03/007870 discloses oxazolidinone derivatives, which are reportedly useful antimicrobial agents, effective against human and veterinary pathogens. WO 03/072575 discloses 3-cyclyl-5-(nitrogen containing 5-membereed ring) methyl oxazolidinones and their putative use as antimicrobials. WO 03/022824 discloses oxazolidinone and/or isoxazoline as antibacterial agents. WO 03/072553 discloses N-aryl-2-oxazolidinone-5- carboxamides and their derivatives and their use as antibacterial agents. WO 03/006447 discloses oxazolidinone compounds having thiocarbonyl functionality as antibacterial agents. WO 03/022824 discloses oxazolidinone and/or isoxazoline as antibacterial agents. WO 02/06278 discloses phenyl oxazolidinone derivatives as antimicrobial agents. WO 01/94342 and U.S. Patent No. 6,689,779 disclose oxazolidinone derivatives having pyridine or pyrimidine moiety and a process for the preparation thereof. WO 01/80841 discloses use of thioamide oxazolidinones for the treatment of bone resorption and osteoporosis. WO 00/29396 discloses substituted phenyloxazolidione derivatives for producing antibacterial medicament for treating human beings and animals. WO 00/32599 discloses oxazolidinone compounds having thiocarbonyl functionality as antibacterial agents. WO 99/64416 discloses substituted oxazolidinyl derivatives as antimicrobials. WO 99/64417 discloses substituted oxazolidinyl derivatives as antimicrobials. WO 98/01446 discloses 6-membered heteroaryl ring containing 2 or 3 ring nitrogen atoms, attached to the piperazinyl oxazolidinyl derivatives as antimicrobial agents. WO 98/01447 discloses pyridyl-piperazinyl oxazolidinyl derivatives as antimicrobial agents. WO 98/54161 and U.S. Patent No. 6,255,304 disclose oxazolidinone antibacterial agents having a thiocarbonyl functionality. WO 93/23384 discloses substituted aryl and heterocyclylphenyl oxazolidinones that are reportedly useful antibacterial agents. WO 93/09103 discloses substituted aryl and heteroarylphenyl oxazolidinones that are reportedly useful antibacterial agents. EP 352 781 discloses phenyl-methyl and pyridinyl-methyl substituted oxazolidinones. U.S. Patent Nos. 5,547,950 and 5,700,799 disclose substituted aryl and heterocyclylphenyl oxazolidinones that are reportedly useful antibacterial agents.

U.S. Patent No. 5,719,154 describes substituted or unsubstituted 2-pyrimidinyl, 4- pyrimidinyl, or 3-pyridazinyl rings directly attached to the piperazinyl oxazolidinyl core. U.S. Patent No. 5,736,545 discloses substituted piperazinyl oxazolidinyl derivatives as antimicrobial agents. U.S. Patent Nos. 5,565,571, 5,801,246, 5,756,732, 5,654,435, and 5,654,428 disclose substituted aryl and heteroaryl phenyloxazolidinones which are reportedly useful antibacterial agents.

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

However, in view of the above, there remains a need for novel oxazolidinones and particular, novel oxazolidinones that can be effective antimicrobials.

Summary of the Invention

Oxazolidinone derivatives have good activity against multiple resistant gram- positive pathogens, for example, methicilline resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and Streptococcus pneumonia. Such oxazolidinone derivatives have activity against multiple drug resistant tuberculosis (MDR- TB) strain, while others have significant activity against important anaerobic bacteria.

Provided are benzoxadiazole phenyloxazolidinones derivatives exhibiting antibacterial activity against Gram-positive pathogens, for example, MRSA, VRE and PRSP; against MDR-TB and MAI strains, Gram-negative pathogens, for example, Moraxella catarrhalis and Haemophilus influenza. Such derivatives provide safe and effective treatment of bacterial infections.

Thus in one aspect, provided are compounds of Formula I,

or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, wherein

Ri can be OR,_, SR_j, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl; wherein

Rj can be hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl;

Yi can be (C=O), (C=S) or SO₂

Rf can be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; and

Rq can be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl;

U and V each can independently be hydrogen, lower (C_1-6)alkyl or halogen;

Y and W each can independently be no atom, O, CH₂, CO, CH₂NH, -NHCH₂, - CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(Re)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and

R_e can be hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_{1 6} alkoxy, C_{1 6} alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and A can be no group or can be selected from;

wherein

X can be CH, CH-S, CH-O or N; Q can be O, N or S; n can be an integer 0-1 ; and m can be an integer from 0-2. In another aspect, provided are compounds selected from:

N-({(5 S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (Compound No.l); N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (Compound No. 2);

(5 R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-(lH-1,2,3- triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Compound No. 3);

(5 R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-(2H-1,2,3- triazol-2-ylmethyl)-1,3-oxazolidin-2-one (Compound No. 4);

(5 R)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-(lH-1,2,3- triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Compound No. 5);

(5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-[(isoxazol-3- ylamino)methyl]-1,3-oxazolidin-2-one (Compound No. 6); (5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-[(isoxazol- 3-ylamino)methyl]-1,3-oxazolidin-2-one (Compound No. 7);

(5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-(isoxazol-3- ylmethyl)-1,3-oxazolidin-2-one (Compound No. 8);

(5 R)-3 -(4- { [ 1 -(2, 1 ,3-benzoxadiazol-5 -yl)piperidin-4-yl]oxy} -3 -fluorophenyl)-5 - [(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one (Compound No. 9);

N-{[(5S)-3-(3-fluoro-4-{4-[(oxido-2,1,3-benzoxadiazol-5-yl)methyl] piperazin-1- yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (Compound No. 10); N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-ylmethyl)piperazin-1-yl]-3-fluorophenyl}-2-oxo- 1,3-oxazolidin-5-yl)methyl]acetamide (Compound No. 11); N-{[(5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-2-oxo- l,3-oxazolidin-5-yl]methyl}acetamide (Compound No. 12);

N-[((5 S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-2-oxo-1,3- oxazolidin-5-yl)methyl]acetamide (Compound No. 13); N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3,5-difluorophenyl}-2-oxo- l,3-oxazolidin-5-yl)methyl]acetamide (Compound No. 14), or pharmaceutically acceptable salts and solvates thereof.

In another aspect, provided are pharmaceutical compositions comprising a pharmaceutically effective amount of one or more compounds described herein or their pharmaceutically acceptable salts thereof and one or more pharmaceutical acceptable carriers.

In yet another aspect, provided herein are methods of treating or preventing microbial infections in a mammal comprising administering to the mammal one or more compounds described herein. Such methods may include one or more of the following embodiments. For example, the microbial infections can be caused by Gram-positive or Gram-negative bacteria. Gram-positive bacteria can be Staphylococcus spp., Streptococcus spp., Bacillus spp., Corynebacterum spp., Clostridia spp., Peptostreptococus spp., Listeria spp. or Legionella spp. The microbial infections can be aerobic or anaerobic bacterial infections.

In another aspect, provided are processes for preparing a compound of Formula IV

Formula IV

or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising reacting a compound of Formula II

Formula Il with a compound of Formula III

Formula

to form a compound of Formula IV, wherein,

U and V each can independently be hydrogen, lower (C_1-6)alkyl or halogen; R₁ can be OR_j, SR_j, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl; wherein

R_j can be hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl;

Yi can be (C=O), (C=S) or SO₂;

R_f can be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl;

R_q can be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl.

Such processes can include one or more of the following embodiments. For example, the compound of Formula II can be reacted with the compound of Formula III in the presence of one or more bases, for example, triethylamine, 4-dimethylamino pyridine, N-methyl morpholine or mixtures thereof. The compound of Formula II can also be reacted with the compound of Formula III in the presence of one or more catalysts, for example, palladium catalysts selected from dichlorobistriphenylphosphine palladium (II), tetrakistriphenylphosphine palladium (0) or mixtures thereof. In another aspect, also provided are processes for preparing a compound of

Formula IX

Formula IX or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising the steps of: a) reacting a compound of Formula V

Formula V

with a compound of Formula VI

Het— H Formula Vl to form a compound of Formula VII;

Formula VII

b) deprotecting the compound of Formula VII to form a compound of Formula VIII;

Formula VIII and c) reacting the compound of Formula VIII with compound of Formula III

Formula III

to form a compound of Formula IX, wherein,

U and V each can independently be hydrogen, lower (C_1-6)alkyl or halogen; W can be no atom or can be selected from O, CH₂, CO, CH₂NH, -NHCH₂, -

CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and

R_e can be hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

Het can be a heterocyclyl or heteroaryl; A can be no group or can be selected from;

wherein

X can be CH, CH-S, CH-O or N;

Q can be O, N or S; and m can be an integer from 0-2;

Such processes can include one or more of the following embodiments. For example, the reaction of compound of Formula V with a compound of Formula VI to form a compound of Formula VII can be carried out in the presence of one or more bases, for example, Group I hydrides selected from sodium hydride, potassium hydride, lithium hydride or mixtures thereof. The compound of Formula VII can be deprotected to form the compound of Formula VIII in the presence of one or more deprotection agents, for example, trifiuoroacetic acid in dichloromethane or hydrochloric acid in ethanol. The reaction of the compound of Formula VIII with the compound of Formula III to form the compound of Formula IX can be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof. The reaction of the compound of Formula VIII with the compound of Formula III to form the compound of Formula IX can be carried out in the presence of one or more catalysts and one or more ligands. The one or more catalysts can be selected from tris-(dibenzylideneacetone) dipalladium(O), palladium diacteate, palladium dichloride or mixtures thereof; and the one or more ligands can be selected from 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert- butylphosphine, di-1-adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

In another aspect, provided are processes for preparing a compound of Formula

XIII

Formula XIII or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising the steps of: a) reacting a compound of Formula V

Formula V with a compound of Formula X

H Het— N— P

Formula X

to form a compound of Formula XI,

Formula Xl

b) deprotecting the compound of Formula XI to form a compound of Formula XII,

Formula XII and

c) reacting the compound of Formula XII with a compound of Formula III

Formula

to form a compound of Formula XIII, wherein,

U and V each can independently be hydrogen, lower (C_1-6)alkyl or halogen; W can be no atom or can be selected from O, CH₂, CO, CH₂NH, -NHCH₂, - CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(Re), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl,

Het can be a heterocyclyl or heteroaryl; and A can be no group or can be selected from,

wherein

X can be CH, CH-S, CH-O or N;

Q can be O, N or S; m can be an integer from 0-2. Such processes can include one or more of the following embodiments. For example, the reaction of the compound of Formula V with the compound of Formula XIV to form the compound of Formula XI can be carried out in the presence of one or more bases, for example, Group I hydrides selected from sodium hydride, potassium hydride, lithium hydride or mixtures thereof. The deprotection of the compound of Formula XI to form the compound of Formula XII can be carried out in the presence of one or more deprotection agents, for example, trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol. The reaction of the compound of Formula XII with the compound of Formula III to form the compound of Formula XIII can be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof. The reaction the compound of Formula XII with the compound of Formula III to form the compound of Formula XIII can be carried out in the presence of one or more catalysts and one or more ligands. The one or more catalysts can be selected from tris- (dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride, or mixtures thereof; and the one or more suitable ligands can be selected from 1 , 1 '-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 - adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

In another aspect, provided are processes for preparing a compound of Formula XVII

Formula XVII

or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising the steps of: a) reacting a compound of Formula V

Formula V

with a compound of XIV

Het— OH Formula XIV to form a compound of Formula XV,

Formula XV

b) deprotecting the compound of Formula XV to form a compound of Formula XVI,

Formula XVI

and

c) reacting the compound of Formula XVI with a compound of Formula III

Formula III to form a compound of Formula XVII, wherein, U and V each can independently be hydrogen, lower (C_1-6)alkyl or halogen;

W can be no atom or can be selected from O, CH₂, CO, CH₂NH, -NHCH₂, - CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and R_c can be hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

Het can be a heterocyclyl or heteroaryl; A can be no group or can be selected from,

wherein

X can be CH, CH-S, CH-O or N;

Q can be O, N or S; m can be an integer from 0-2. Such processes can include one or more of the following embodiments. For example, the reaction of the compound of Formula V with a compound of Formula XIV to form a compound of Formula XV can be carried out in the presence of one or more coupling agents, for example, diethyl diazocarboxylate, diisopropyl diazocarboxylate or mixtures thereof. The reaction of the compound of Formula V with a compound of Formula XIV to form a compound of Formula XV can be carried out in the presence of one or more catalysts, for example, triphenyl phosphine, trioctyl phosphine, tributyl phosphine or mixtures thereof. The compound of Formula XV can be deprotected to form the compound of Formula XVI in the presence of one or more deprotection agents, for example, trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol. The reaction of the compound of Formula XVI with the compound of Formula III to form the compound of Formula XVII can be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof. The reaction of the compound of Formula XVI with the compound of Formula III to form the compound of Formula XVII can be carried out in the presence of one or more catalysts and one or more ligands. The one or more catalysts can be selected from Tris -(dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride or mixtures thereof; and the one or more ligands can be selected from l,r-binaphthalene-2,2'- diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

In yet another aspect, provided can be processes for preparing a compound of Formula XX

or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising the steps of: a) reacting a compound of Formula XVIII

Formula XVIII

with 5-formylbenzofuroxan

to form a compound of Formula XIX,

Formula XIX

and b) deoxygenating the compound of Formula XIX to form a compound of Formula XX, wherein,

R₁ can be OR_j, SR_j, NHY₁R_f, NR_fRq, heterocyclyl or heteroaryl, wherein

Yi can be (C=O), (C=S) or SO₂ and R_f can be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; and

R_q can be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl;

U and V each can independently be hydrogen, lower (C_1-6)alkyl or halogen; Y and W can be no atom or selected from O, CH₂, CO, CH₂NH, -NHCH₂, -

CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_{1 6} alkoxy, C_{1 6} alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and

R_e can be hydrogen, optionally substituted C_1-12 alkyl, C_{3 12} cycloalkyl, C_{1 6} alkoxy, C_{1 6} alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

A can be no group or selected from group consisting of;

wherein

X can be CH, CH-S, CH-O or N;

Q can be O, N or S; and m can be an integer from 0-2.

Such processes can include one or more of the following embodiments. For example, the reaction of compound of Formula XVIII with 5-formylbenxofuroxan to form the compound of Formula XIX can be carried out in the presence of one or more reducing agents, for example, sodium triacetoxy borohydride, sodium borohydride, sodium cyano borohydride, or mixtures thereof. The deoxygenation of compound of Formula XIX to form the compound of Formula XX can be carried out in presence of one or more catalysts, for example, triphenyl phosphine, trioctyl phosphine, tributyl phosphine or mixtures thereof.

In another aspect, provided are processes for preparing a compound of Formula XXII

Formula XXII

or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising reacting a compound of Formula XXI

Formula XXI

with a compound of Formula III

to form a compound of Formula XXII, wherein,

Ri can be OR_j, SR,, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl; wherein

CH₂NHCH₂, -CH₂-N (R_n)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and R can be hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

A can be no group or can be selected from,

wherein

X can be CH, CH-S, CH-O or N;

Q can be O, N or S; m can be an integer from 0-2.

Such processes can include one or more of the following embodiments. For example, the reaction of the compound of Formula XXI with the compound of Formula III to form the compound of Formula XXII can be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, diisopropyl ethylamine, triethylamine, N-methyl morpholine or mixtures thereof. The reaction of the compound of Formula XXI with the compound of Formula III to form the compound of Formula XXII can be carried out in the presence of one or more catalysts and one or more ligands. The one or more catalysts can be selected from tris-(dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride, or mixtures thereof; and the one or more suitable ligands can be selected from 1,1'-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert- butyl)phosphine or mixtures thereof.

Detailed Description of the Invention

Provided are processes for synthesizing benzoxadiazole phenyloxazolidinones derivatives represented by Formula I,

and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, prodrugs or polymorphs, wherein,

R₁ can be OR_j, SR_j, NHY₁R_f, NR_fRq, heterocyclyl or heteroaryl, wherein R_j can be hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl,

Yi can be (C=O), (C=S) or SO₂,

R_f can be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, and R_q can be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl;

U and V can be independently hydrogen, lower C_1-6 alkyl or halogen (e.g., Cl, F or Br);

Y and W can be no atom or selected from O, CH₂, CO, CH₂NH, NHCH₂, CH₂NHCH₂, CH₂-N(Re)CH₂, CH₂(R_e)N, CH(R₁₁), S, CH₂(CO), NH, NR_e,

(CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ can be optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and

R_e can be hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; A can be no group or selected from

wherein, X can be CH, CH-S, CH-O or N; Q can be O, N or S; n is an integer 0-1 ; and m is an integer from 0-2.

Compounds disclosed herein can be useful antimicrobial agents that are effective against a number of human and veterinary pathogens, particularly aerobic and Gram- positive bacteria {e.g., multiply-antibiotic resistant Staphylococci and Streptococci) and anaerobic organisms {e.g., Mycobacterium tuberculosis and other Mycobacterium species).

Also provided are pharmaceutical compositions comprising compounds described herein, their enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, N-oxides or metabolites in combination with one or more pharmaceutically acceptable carriers and optionally included excipients. For preparing pharmaceutical compositions comprising compounds described herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories and ointments. Solid carriers can comprise one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or disintegrating agents. Solid carriers can also be finely divided solids in admixture with the finely divided active compound. For preparing tablets, active compounds can be mixed with one or more carriers having necessary binding properties in suitable proportions and compacted into desired shapes and sizes. Powders and tablets preferably comprise from about 5 to about 70 percent of one or more compounds described herein. Suitable solid carriers include, for example, lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter and the like. The term "preparation," unless otherwise specified, refers to a formulation comprising one or more active compounds (i.e., compounds described herein) with encapsulating material as carrier and providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, capsules can be used, as solid dosage forms suitable for oral administration. Liquid form preparations include solutions, suspensions and emulsions. One example includes water or water-propylene glycol solutions for parenteral injection. Such solutions can be prepared to be acceptable to/compatible with biological systems (particularly in terms of isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving one or more active components (i. e. , compounds described herein) in water and adding one or more suitable colorants, flavors, stabilizing, or thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing finely divided active components (i.e., compounds described herein) in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose or other well-known suspending agents.

Ointment preparations can comprise compounds described herein with one or more physiologically acceptable carriers. Carriers can be conventional water-dispersible hydrophilic or oil-in-water carriers, particularly conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsions. Suitable compositions may be prepared by incorporating or homogeneously admixing finely divided compounds described herein with one or roe hydrophilic carriers or bases or ointments.

Pharmaceutical preparations can be in unit dosage form. In such forms, preparations can be subdivided into unit doses comprising appropriate quantities of one or more active components (i.e., compounds described herein). Unit dosage forms can be packaged preparations, the package containing discrete capsules, powders in vials or ampoules and ointments, cachets, tablets, gels, or creams itself ,or it can be the appropriate number of any of these packaged forms.

Quantities of active ingredients, i.e., compounds described herein, in a unit dose of preparation may be varied or adjusted from less than 1 mg to several grams according to the particular application and the potency of the active ingredient. Compounds described herein can be administered at initial dosages of about 3 mg to about 40 mg per kilogram daily to a patient in need of treating bacterial infections. The dosages, however, may be varied depending upon the requirements of the patient and the compound(s) being employed. Proper dosages can be determined for a particular situation and utilize small dosages that are less than optimum doses. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.

In another aspect, processes for synthesizing compounds of Formula I are provided. Pharmaceutically acceptable acid addition salts of the compounds of Formula I may be formed with one or more inorganic or organic acids and by methods known to one of ordinary skill in the art.

In general, prodrugs of compounds described herein can be functional derivatives of such compounds, which can readily be converted in vivo into defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known to one of ordinary skill in the art.

The following definitions apply to terms as used herein;

The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)R_m, -NR_mR_n, -C(=O)NR_mR_n,

-NHC(=O)NR_mR_n, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NR_mR_n {wherein R_m and R_n are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SO₂R₆ (wherein R₆ is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, carboxy, -NR_mR_n, -C(=O)NR_mR_n, -OC(=O)NR_mR_n, -NHC(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), hydroxy, alkoxy, halogen, CF₃, cyano, and -SO₂R₆, (wherein R₆ are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NR₃- {wherein R_a is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)OR_m (wherein R_m is the same as defined earlier), SO₂R₆ (wherein R₆ is as defined earlier), or -C(=O)NR_mR_n (wherein R_m and R_n are as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NR_mR_n, -C(=O)NR_mR_n, -O-C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier) hydroxy, alkoxy, halogen, CF₃, cyano, and -SO₂R₆ (wherein R₆ is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above.

The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC(=O)R_m, -NR_mR_n, -C(=O)NR_mR_n, -NHC(=O)NR_mR_n, -O-C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, nitro, or SO₂R₆ (wherein R₆ are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF₃, cyano, -NR_mR_n, -C(=O)NR_mR_n, -O-C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier) and -SO₂R₆ (wherein R₆ is same as defined earlier).

The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=O)R_m, -NR_mR_n, -NHC(=O)NR_mR_n,

-C(=O)NR_mR_n, -O-C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), or -SO₂R₆ (wherein R₆ is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF₃, -NR_mR_n, -C(=O)NR_mR_n, -NHC(=O)NR_mR_n, -C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), cyano, or -SO₂R₆ (wherein R₆ is same as defined earlier).

The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NR_mR_n, -NHC(=O)NR_mR_n, -NHC(=O)R_m, -C(=O)NR_mR_n, -O-C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or SO₂R₆ (wherein R₆ is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl ' substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF₃, -NR_mR_n, -C(=O)NR_mR_n, -NHC(=O)NR_mR_n, -OC(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), cyano or -SO₂R₆ (wherein R₆ is same as defined earlier). "Cycloalkylalkyl" refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier. The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above.

The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or naphthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF₃, cyano, nitro, COOR_P (wherein R_p is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)R_m, -NR_mR_n, -C(=O)NR_mR_n, -NHC(=O)NR_mR_n, -O-C(=O)NR_mR_n (wherein R_m and R_n are the same as defined earlier), -SO₂R₆ (wherein R₆ is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.

The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like.

The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NR_mR_n, CH=NOH, -(CH₂)_wC(=O)R_g {wherein w is an integer from 0-4 and R_g is hydrogen, hydroxy, OR_m, NR_mR_n, -NHOR_z or -NHOH}, -C(=O)NR_mR_n and -NHC(=O)NR_mR_n, -SO₂R₆, -O-C(=O)NR_mR_n, -O-C(=O)R_m, -O-C(=O)OR_m (wherein R₆, R_m and R_n are as defined earlier, and R_z is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like. The term "heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)R_m, -O-C(=O)OR_m, -C(=O)NR_mR_n, SO₂R₆, -O-C(=O)NR_mR_n, -NHC(=O)NR_mR_n, -NR_mR_n (wherein R₆, R_m and R_n are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl.

The term "acyl" refers to -C(=O)R" wherein R" is selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.

"Substituted amino" unless and otherwise specified refers to a group -N(R_k)₂ wherein each R_k is independently selected from the group hydrogen (provided that both R_k groups are not hydrogen (defined as "amino")), alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, SO₂R₆ (wherein R₆ is the same as defined above), -C(=T)NR_mR_n or NHC(=T)NR_mR_π (wherein T, R_m and R_n are the same as defined earlier). The term "leaving group" refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals and the like. The term "protecting groups" refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2^nd Ed., John Wiley and Sons, New York, N. Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatized moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.

The term "pharmaceutically acceptable salts" refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.

The present invention includes all isotopes of atoms occurring in the compounds described herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include ¹³C and ¹⁴C.

The compounds of this invention contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly encompassed by the present invention. Each stereogenic carbon may have the R or S configuration. Although specific compounds described herein may be depicted in a particular stereochemical configuration, such compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention. Although amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are encompassed herein.

The compounds described herein can be represented by general Formula I and may be prepared by techniques well known to one of ordinary skill in the art. In addition, the compounds of the present invention may be prepared by the following reaction sequence as depicted in Schemes I, II, III, IV and V. Scheme I

Compounds of Formula IV can be prepared by following Scheme I.

Scheme I

Formula Il Formula IV

Thus, compounds of Formula II (wherein U, V and Ri are same as defined earlier) can be reacted with compounds of Formula III (wherein hal can be chlorine, bromine or fluorine) to yield compounds of Formula IV. This reaction can be carried out in one or more organic solvents, for example, dimethyl formamide, 1 ,4-dioxane, tetrahydrofuran or mixture thereof. This reaction can also be carried out in the presence of one or more bases, for example, triethylamine, 4-dimethylamino pyridine, N-methyl morpholine or mixtures thereof. This reaction can also be carried out in the presence of one or more palladium catalysts, for example, dichlorobistriphenylphosphine palladium (II), tetrakistriphenylphosphine palladium (0) or mixture thereof.

Compounds which may be prepared following Scheme I include, for example:

N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (Compound No. 1)

N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (Compound No. 2) Scheme II

Compounds of Formula IX can be prepared by following Scheme II.

Scheme Il

Formula VII

Formula V deprotection

Formula IX Formula VIII

Thus, compounds of Formula V (wherein U, V, W and A are as defined earlier, P can be a protecting group and G can be H or a leaving group, e.g. , mesyl, tosyl or triflyl) can be reacted with compounds of Formula VI (wherein Het can be a heterocyclyl or heteroaryl) to form compounds of Formula VII. Compounds of Formula VII can be deprotected to form compounds of Formula VIII. Compounds of Formula VIII can be reacted with compounds of Formula III to form compounds of Formula IX. Compounds of Formula V can be reacted with compounds of Formula VI to form compounds of Formula VII in one or more organic solvents, for example, dimethyl formamide, 1,4-dioxane, tetrahydrofuran or mixtures thereof. This reaction can also be carried out in the presence of one or more bases, for example, Group I hydrides, e.g., sodium hydride, potassium hydride, lithium hydride or mixtures thereof. Compounds of Formula VII can be deprotected to form compounds of Formula

VIII in the presence of one or more deprotection agents, for example, one or more strong protic acids in suitable solvents, e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.

Compounds of Formula VIII can be reacted with compounds of Formula III to form compounds of Formula IX in one or more organic solvents, for example, tetrahydrofuran, benzene, dimethylformamide, carbon tetrachloride or mixtures thereof. This reaction can also be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof. This reaction can also be carried out in the presence of one or more catalysts, for example, Tris -(dibenzylideneacetone) dipalladium(O), palladium diacteate, palladium dichloride or mixtures thereof; and one or more suitable ligands , for example, 1,1-binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert- butyl)phosphine or mixtures thereof.

Compounds which may be prepared following Scheme II include, for example: (5 R)-3- {4-[4-(2, 1 ,3-benzoxadiazol-5-yl)piperazin- 1 -yl]-3-fluorophenyl} -5-( IH- 1 ,2,3- triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Compound No. 3);

(5 R)-3- {4-[4-(2, 1 ,3-benzoxadiazol-5-yl)piperazin- 1 -yl]-3-fluorophenyl} -5-(2H-1 ,2,3- triazol-2-ylmethyl)-1,3-oxazolidin-2-one (Compound No. 4);

(5R)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-(lH-1,2,3- triazol-1-ylmethyl)-l ,3-oxazolidin-2-one (Compound No. 5).

Scheme III

Compounds of Formulae XIII and XVII can be prepared following Scheme III.

Scheme III

Fomnula V

Formula Xl Formula XV

Formula XVII

Path A: Compounds of Formula V (wherein U, V, W, A, P and G are as defined earlier) can be reacted with compounds of Formula X (Het and P are same as defined earlier) to form compounds of Formula XI. Compounds of Formula XI can be deprotected to form compounds of Formula XII. Compounds of Formula XII can be reacted with compounds of Formula III to form compounds of Formula XIII.

Path B: Compounds of Formula V (wherein U, V, W, A, P and G are as defined earlier) can be reacted with compounds of Formula XIV (wherein Het is same as defined earlier) to form compounds of Formula XV. Compounds of Formula XV can be deprotected for form compounds of Formula XVI. Compounds of Formula XVI can be reacted with compounds of Formula III to form compounds of Formula XVII.

Compounds of Formula V can be reacted with compounds of Formula X (Path A) to form compounds of Formula XI in one or more organic solvents, for example, dimethyl formamide, 1 ,4-dioxane, tetrahydrofuran or mixtures thereof. This reaction can also be carried out in the presence of one or more bases, for example, Group I hydrides, e.g., sodium hydride, potassium hydride, lithium hydride or mixtures thereof.

Compounds of Formula XI can also be deprotected to form compounds of Formula XII in the presence of one or more deprotection agents, for example, one or more strong protic acids in suitable solvents, e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.

Compounds of Formula XII can be reacted with compounds of Formula III to form compounds of Formula XIII in one or more organic solvents, for example, tetrahydrofuran, benzene, dimethylformamide, carbon tetrachloride or mixtures thereof. This reaction can be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof. This reaction can also be carried out in the presences of one or more catalysts, for example, Tris -(dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate; palladium dichloride or mixtures thereof; and one or more suitable ligands, for example, 1,1'-binaphthalene-2,2'- diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

Compounds of Formula V can be reacted with compounds of Formula XIV (Path B) to form compounds of Formula XV in one or more organic solvents, for example, tetrahydrofuran, benzene, dimethylformamide, carbon tetrachloride or mixtures thereof. This reaction can also be carried out in the presence of one or more suitable coupling agents, for example, diethyl diazocarboxylate, diisopropyl diazocarboxylate or mixtures thereof. This reaction can also be carried out in the presence of one or more catalysts, for example, triphenyl phosphine, trioctyl phosphine, tributyl phosphine or mixtures thereof. Compounds of Formula XV can be deprotected to form compounds of Formula XVI in the presence of one or more deprotection agents, for example, one or more strong protic acids in suitable solvents, e.g., trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol. Compounds of Formula XVI can be reacted with compounds of Formula III to form compounds of Formula XVII in one or more organic solvents, for example, tetrahydrofuran, benzene, dimethylformamide, carbon tetrachloride or mixtures thereof. This reaction can also be carried out in the presence of one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof. This reaction can also be carried out in the presence of one or more catalysts, for example, Tra-(dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride or mixtures thereof; and one or more suitable ligands, for example, 1,1'-binaphthalene-2,2'- diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

Compounds which may be prepared following Scheme III include, for example: (5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-[(isoxazol-3- ylamino)methyl]-1,3-oxazolidin-2-one (Compound No. 6);

(5iS)-3-(4- {[ 1 -(2, 1 ,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy} -3-fluorophenyl)-5-[(isoxazol- 3-ylamino)methyl]-1,3-oxazolidin-2-one (Compound No. 7);

(5i?)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-(isoxazol-3- ylmethyl)-1,3-oxazolidin-2-one (Compound No. 8);

(5i?)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5- [(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one (Compound No. 9). Scheme IV

Compounds of Formulae XIX and XX can be prepared following Scheme IV.

Scheme IV

Formula XVIII

Formula XX

Thus, compounds of Formula XVIII can be coupled with 5-formylbenzofuroxan to form compounds of Formula XIX. Compounds of Formula XIX can be deoxygenated to form compounds of Formula XX.

Compounds of Formula XVIII can be reacted with 5-formylbenzofuroxan to form compounds of Formula XIX in one or more organic solvents, for example, tetrahydrofuran, dimethyl formamide, 1,4-dioxane or mixtures thereof. This reaction can also be carried out in the presence of one or more reducing agents, for example, sodium triacetoxy borohydride, sodium borohydride, sodium cyano borohydride, or mixtures thereof.

Compounds of Formula XIX can be deoxygenated to form compounds of Formula XX in one or more organic solvents, for example, alcohols, e.g., ethanol, methanol or mixtures thereof. This reaction can also be carried out in the presence of one or more catalysts, for example, phosphines, e.g., triphenyl phosphine, trioctyl phosphine, tributyl phosphine or mixtures thereof.

Compounds which may be prepared following Scheme IV include, for example:

N-{[(5S)-3-(3-fluoro-4-{4-[(oxido-2,1,3-benzoxadiazol-5-yl)methyl]piperazin-1- yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (Compound No. 10);

N-[((5S)-3- {4-[4-(2, 1 ,3-benzoxadiazol-5-ylmethyl)piperazin-l -yl]-3-fluorophenyl} -2-oxo- l,3-oxazolidin-5-yl)methyl]acetamide (Compound No. 11).

Scheme V

Compounds of Formula XXII can be prepared according to Scheme V.

Scheme V

Formula I

Formula XXlI

Formula XXI

Thus, compounds of Formula XXI can be coupled with compounds of Formula III to form compounds of Formula XXII.

Compounds of Formula XXI can be reacted with compounds of Formula III to form compounds of Formula XXII in one or more solvents, for example, acetonitrile, chloroform, carbon tetrachloride or mixtures thereof; and in presence of one or more bases, for example, sodium carbonate, potassium carbonate, diisopropyl ethylamine, triethylamine, N-methyl morpholine or mixtures thereof. Alternatively, this reaction can also be carried out in one or more organic solvents, for example, acetonitrile, tetrahydrofuran, benzene, dimethylformamide, carbon tetrachloride or mixtures thereof; one or more bases, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof, and in the presence of one or more catalysts, for example, Tris -(dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride or mixtures thereof; and one or more suitable ligands, for example, 1,1'-binaphthalene-2,2'- diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

Compounds which may be prepared following Scheme V include, for example: N-{[(5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-2-oxo- 1,3-oxazolidin-5-yl]methyl}acetamide (Compound No. 12);

N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluoroρhenyl} -2-oxo-1,3- oxazolidin-5-yl)methyl]acetamide (Compound No. 13);

N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3,5-difluorophenyl}-2-oxo- 1,3-oxazolidin-5-yl)methyl]acetamide (Compound No. 14).

TABLE I - Compound Moieties of Formula I

wherein U is F and the following groups being:

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

Examples

Example 1: Synthesis of N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2- oxo-1,3 -oxazolidin-5 -yl} methyl)acetamide

5-bromo-2,1,3-benzoxadiazole (0.17 g) (which can be prepared according to Org. Proc. Res. Dev., (2003), 7, 436-445 at page 437), triethylamine (0.11 g) and dichlorobistriphenyl-phosphine palladium (II) (0.12 g) were added to a solution of N- ({(5S)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (0.18 g) (which can be prepared according to Example 8 of WO 01/94342, page 52) in dry dimethyl formamide (15 mL) and the reaction mixture was heated at 100 °C for about 3 hours, cooled and diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (0.14 g). Melting point: 156-165 °C; EMS (m/z): 388 (M+H); ¹HNMR(CDCB): δ 7.91 (m, 2H), 7.62 (m, 2H), 7.52 (t, 1H), 7.35 (dd, 1H), 6.10 (t, 1H), 4.84 (m, 1H), 4.12 (t, 1H), 3.87 (t, 1H), 3.71 (m,2H), 2.02 (s, 3H).

Example 2: Synthesis of N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3,5-difluorophenyl]-2- oxo-1,3-oxazolidin-5-vl}methyl)acetamide

Triethylamine (0.12 g), 5-bromo-2,1,3-benzoxadiazole (0.19 g) and dichlorobistriphenylphosphine palladium(II) (0.13 g) were added to a solution of N-({(5S)- 3 - [3 , 5 -difluoro-4-(trimethylstannyl)phenyl] -2-oxo- 1 ,3 -oxazolidin-5 -yl } methyl)acetamide (0.21 g) (which can be prepared according to Example 8 of WO 01/94342, at page 52) in dry dimethyl formamide (15 mL) and the reaction mixture was heated at 100 °C for about 3 hours. The reaction mixture was filtered and diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (0.035 g).

Melting point: 165-168 °C; EMS (m/z): 388;

¹HNMR(CDC13): δ 7.92 (m, 2H), 7.48 (dd, 1H), 7.32 (dd, 2H), 5.98 (t, 1H), 4.85 (m, 1H), 4.09 (t, 1H), 3.84 (m, 1H), 3.72 (m, 2H), 2.03 (s, 3H).

Example 3: Synthesis of (5RV3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-(1H-1,2.3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

Step a: Synthesis of tert-butyl 4-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1- ylmethyl)-1,3-oxazolidin-3-yl]phenyl}piperazine-1-carboxylate. Sodium hydride (0.61 g) and lH-1,2,3-triazole (0.7 mL) were added to a solution of tert-butyl 4-[2-fluoro-4-((5 R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-1,3-oxazolidin- 3-yl)phenyl]piperazine-1-carboxylate (4 g) (which can be prepared according to Example l(h) of WO93/23384, page 13) in dry dimethylformamide (15 mL) and the reaction mixture was stirred at 80 °C for about 17 hours and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using (4 %) methanol in dichloromethane as eluent to yield the title compound (1.45 g).

Step b: Synthesis of (5R)-3-(3-fluoro-4-piperazin-1-ylphenyl)-5-(1Η-1,2,3-triazol-1- ylmethyl)-1,3-oxazolidin-2-one. Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl-4- {2-fluoro-4-

[(5R)-2-oxo-5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}piperazine-1- carboxylate (0.7 g) (obtained from Step a) in dichloromethane (15 mL) and the reaction mixture was stirred for about 2 hours. The reaction mixture was concentrated and to the residue thus obtained was added ethyl acetate (20 mL) followed by 10 % sodium hydroxide (10 mL) until the pH was about 12-14. The organic layer was separated and washed with water, dried over sodium sulfate and concentrated to yield the title compound (0.98 g).

Step c: Synthesis of (5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-(1H-1,2,3-triazoI-1-ylmethyl)-1,3-oxazolidin-2-one. 5-bromo-2,1,3-benzoxadiazol (0.56 g), cesium carbonate (1.1 g), 2,2'- bis(diphenylphosphino)-1,r-binapthyl(0.14 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.1 g) were added to a solution of (5R)-3-(3-fluoro-4-piperazin-1- ylphenyl)-5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one(0.98 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 °C for about 17 hours. The reaction mixture was filtered, the solvent was removed by evaporation and the crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane to yield the title product (0.17 g).

Melting point: 153-173 °C; EIMS (m/z): 465.17; ¹HNMR(DMSO): δ 8.17 (s, 1H), 7.90-7.87 (d, 1H), 7.74 (t, 2H), 7.44 (dd, 1H), 7.13 (m, 2H), 6.89 (s, 1H), 5.15-5.10 (m, 1H), 4.83 (d, 2H), 4.21 (t, 1H), 3.89-3.84 (t, 1H), 3.48 (m, 4H), 3.14 (m, 4H).

Example 4: Synthesis (5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-(2H-1,2,3-triazol-2-ylmethyl)-1,3-oxazolidin-2-one Step a: Synthesis of tert-butyl 4-{2-fluoro-4-[(5R)-2-oxo-5-(2H-1,2,3-triazol-1- ylmethyl)-1,3-oxazolidin-3-yl]phenyl}piperazine-1-carboxylate

Sodium hydride (0.61 g) and 2H-1,2,3-triazole (0.7 mL) were added to a solution of tert-butyl 4-[2-fluoro-4-((5R )-5- { [(methylsulfonyl)oxy]methyl} -2-oxo- 1 ,3-oxazolidin- 3-yl)phenyl]piperazine-1-carboxylate (4 g) (which can be prepared according to Example 1 (h) of WO93/23384, page 13) in dry dimethylformamide (15 mL) and the reaction mixture was stirred at 80 °C for about 17 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography using (3 %) methanol in dichloromethane as eluent to yield the title compound (0.9 g). Step b: Synthesis of (5R)-3-(3-fIuoro-4-piperazin-1-ylphenyl)-5-(2H-1,2,3-triazol-1- ylmethyl)-1,3-oxazolidin-2-one.

Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-{2-fluoro-4- [(5R)-2-oxo-5-(2H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}piperazine-1- carboxylate (0.7 g) (obtained from Step a) in dichloromethane (15 mL) and the reaction mixture was stirred for about 2 hours. The reaction mixture was concentrated and to the residue thus obtained was added ethyl acetate (20 mL) followed by 10 % sodium hydroxide (10 mL) until the pH was about 12-14. The organic layer separated out and was washed with water, dried over sodium sulfate and concentrated to yield the title compound (0-7 g). Step c: Synthesis of (5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-(2H-1,2,3-triazoI-1-ylmethyl)-1,3-oxazolidin-2-one.

5-bromo-2,1,3-benzoxadiazole (0.4 g), cesium carbonate (0.79 g), 2,2'- bis(diphenylphosphino)-1,1 '-binapthyl (0.1 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.74 g were added) to (5R)-3-(3-fluoro-4-piperazin-1-ylphenyl)-5-(2H- l,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.7 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 °C for about 17 hours. The reaction mixture was filtered, the solvent was evaporated and the crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane to yield the title product (0.2g). Melting point: 215-220 °C; EIMS (m/z): 465.21;

¹HNMR(DMSO): δ 7.91-7.83 (m,3H), 7.73 (d, 1H), 7.43 (dd, 1H), 7.13 (d, 2H), 6.89 (s, 1H), 5.18 (m, 1H), 4.86 (d, 2H), 4.22 (t, 1H), 3.91-3.86 (m, 1H), 3.48 (m, 4H), 3.14 (m, 4H).

Example 5: Synthesis of (5R)-3-(4-([1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3- fluorophenyl)-5-(1H-1,2.3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

Step a: Tert-butyl 4-{4-[(5R)-2-oxo-5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3- yl]phenoxy}piperidine-1-carboxylate.

Sodium hydride (0.3 g) and lH-1,2,3-triazole (0.3 mL) were added to a solution of tert-butyl 4-[2-fluoro-4-((5 R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-1,3-oxazolidin-3- yl)phenoxy]piperidine-1-carboxylate (2 g) (which can be prepared according to Example 6, after the first step in the conversion of compound 6 to 7, in Biorg. Med. Chem. Lett., 11 (2001), 1829-1832, at page 1830) in dry dimethylformamide (15 mL) and the reaction mixture was stirred at 80 °C for about 17 hours. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The crude thus obtained was purified by column chromatography using (2 %) methanol in dichloromethane as eluent to yield the title compound (0.68 g).

Step b: Synthesis of (5R)-3-[3-fiuoro-4-(piperidin-4-yloxy)phenyl]-5-(1H-1,2,3- triazol-1-ylmethyl)-1,3-oxazolidin-2-one. Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 4-{4-[(5R)-2-oxo-

5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yl]phenoxy}piperidine-1-carboxylate (0.68 g) (obtained from Step a) in dichloromethane (10 mL) and the reaction mixture was stirred for about 2 hours. The reaction mixture was concentrated and to the residue thus obtained was added ethyl acetate (20 mL) followed by 10 % sodium hydroxide (10 mL) until the pH was about 12-14. The organic layer, which separated out, was washed with water, dried over sodium sulfate and concentrated to yield the title compound (1 g).

Step c: Synthesis of (5R)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3- fluorophenyl)-5-(lH-l,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one.

5-bromo-2,1,3-benzoxadiazole (0.61 g), cesium carbonate (1.2 g), 2,2'- bis(diphenylphosphino)-1,1' -binapthyl (0.51 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.11 g) were added to a solution (5R)-3-[3-fluoro-4-(piperidin-4- yloxy)phenyl]-5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (1 g) (obtained from Step b) in dry dimethylformamide (10 mL) and the reaction mixture was heated at 100 °C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.15g).

Melting point: 148-150°C; EIMS (m/z): 480.02;

¹HNMR(DMSO): δ 7.85 (d, 3H), 7.68 (d, 1H), 7.46 (dd, 1H), 7.28 (t, 1H), 7.15 (d, 1H), 6.85 (s, 1H), 5.2 (m, 1H), 4.86-4.85 (d, 2HO, 4.6 (m, 1HO, 4.22 (t, 1H), 3.9 (m, 1H), 3.72- 3.68 (m, 2H), 3.47-3.46 (d, 1H), 2.04 (m, 2H), 1.76 (m, 2H).

Example 6: Synthesis of (5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidm-2-one (Path A)

Step a: Synthesis of tert-butyl 4-(2-fiuoro-4-{(5S)-5-[(isoxazol-3-ylamino)methyl]-2- oxo-1,3-oxazolidin-3-yl}phenyl)piperazine-1-carboxyIate. Sodium hydride (0.23 g) and tert-butyl isoxazol-3-ylcarbamate (0.88 g) were added to a solution of tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2- oxo-1,3-oxazolidin-3-yl)phenyl]piperazine-1-carboxylate(l g) (which can be prepared according to Example l(h) given in WO93/23384, at page 13) in dry dimethylformamide (10 mL) and the reaction mixture was stirred at 80 °C for about 17 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (1 g). Step b: Synthesis of (5S)-3-(3-fluoro-4-piperazin-1-ylphenyl)-5-[(isoxazol-3- ylamino)methyl]-1,3-oxazolidin-2-one.

Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 4-(2-fluoro-4- {(5S)-5-[(isoxazol-3-ylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}phenyl)piperazine-1- carboxylate (1 g) (obtained from Step a in) dichloromethane (10 mL) and the reaction mixture was stirred for about 2 hours. The reaction mixture was concentrated and to the residue thus obtained was added ethyl acetate (15 mL) followed by 10 % sodium hydroxide (10 mL) until the pH was about 12-14. The organic layer, which separated out, was washed with water, dried over sodium sulfate and concentrated to yield the title compound (1.36 g crude weight) Step c: Synthesis of (5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one.

5-bromo-2,1,3-benzoxadiazol (0.75 g), cesium carbonate (1.47 g), 2,2'- bis(diphenylphosphino)-1,1' -binapthyl (0.18 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.13 g) were added to a solution of (5S)-3-(3-fluoro-4-piperazin-1- ylphenyl)-5-[(isoxazol-3-ylamino)methyl]-1 ,3-oxazolidin-2-one (1.36 g) (obtained from Step b) in dry dimethylformamide(10 mL) and the reaction mixture was heated at 100 °C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.1 g). Melting point: 213-215 °C; EMS (m/z): 480.26, M+Na 502.22; ¹HNMR(DMSO): δ 8.38 (s, 1H), 7.88 (d, 1H), 7.72 (d, 1H), 7.53 (dd, 1H), 7.15 (m, 2H), 6.89 (s, 1H), 6.54 (t, 1H), 6.0 (s, 1H), 4.86 (m, 1H), 4.13 (t, 1H), 3.79 (t, 1H), 3.53 (m, 4H), 3.15 (m, 4H).

Example 7: Synthesis of (5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3- fluorophenyl)-5-[(isoxazol-3-ylamino)methyl1-1,3-oxazolidin-2-one (Path A)

Step a: Synthesis of tert -butyl 4-[4-((5R)-5-{[(tert-butoxycarbonyl)(isoxazol-3- yl)amino]methyl}-2-oxo-1,3-oxazolidin-3-yl)-2-fluorophenoxy]piperidine-1- carboxylate.

Sodium hydride (0.15 g) and tert-butyl isoxazol-3-ylcarbamate (0.87 g) were added to a solution of tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2- oxo-1,3-oxazolidin-3-yl)phenoxy]piperidine-1-carboxylate (1.5 g) (which can be prepared according to Example 6, after the first step in the conversion of the compound 6 to 7, in Biorg. Med. Chem. Lett., 11 (2001), 1829-1832, at page 1830) in dry dirnethylformamide (10 mL). The reaction mixture was stirred at 80 °C for about 17 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (2 g).

Step b: Synthesis of (5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3- ylamino)methyl]-1,3-oxazolidin-2-one.

Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 4-[4-((5R)-5- {[(tert-butoxycarbonyl)(isoxazol-3-yl)amino]methyl}-2-oxo-1,3-oxazolidin-3-yl)-2- fluorophenoxy]piperidine-1-carboxylate (2 g) obtained from Step a in dichloromethane (15 mL) and stirred for about 2 hours. The reaction mixture was concentrated and to the residue thus obtained was added ethyl acetate (20 mL) followed by 10 % sodium hydroxide (10 mL) until the pH was about 12-14. The organic layer, which separated out, was washed with water, dried over sodium sulfate and concentrated to yield the title compound (5 g).

Step c: Synthesis of (5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3- yIamino)methyl]-1,3-oxazolidin-2-one. 5-bromo-2,1,3-benzoxadiazol (2.74 g) (which can be prepared according to Org. Proc. Res. Dev., (2003), 7, 436-445), cesium carbonate (5.38 g), 2,2'- bis(diphenylphosphino)-1,1'-binapthyl (0.68 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.5 g) were added to a solution of (5S)-3-[3-fluoro-4-(piperidin-4- yloxy)phenyl]-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one (5 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 °C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.4g). Melting point: 134-140 °C; EIMS (m/z): 495.25;

¹HNMR(DMSO): δ 8.41 (s, 1H), 7.88 (d, 1H), (d, 1H), 7.6 (dd, 1H), 7.32 (t, 1H), 7.25 (d, 1H), 6.88 (s, 1H), 6.56 (t, 1H), 6.03 (s, 1H), 4.8 (m, 1H), 4.63-4.62 (m, 1H), 4.17 (t, 1H), 3.81 (m, 4H), 3.49-3.43 (m, 3H), 2.07 (m, 2H), 1.8 (m, 2H).

Example 8: Synthesis of (5R)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3- fluorophenyl)-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one (Path B)

Step a: Synthesis of tert-butyl 4-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo- 1,3-oxazolidin-3-yl}phenoxy)piperidine-1-carboxylate

Triphenyl phosphine(0.99 g) and 3-hydroxy-isoxazole (0.25 g) and diethylazodicarboxylate (0.75 mL) were added under nitrogen atmosphere to a solution of tert-butyl 4- {2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo- 1 ,3-oxazolidin-3- yl]phenoxy}piperidine-1-carboxylate (1 g) (which can be prepared according to Example 6, after the first step in the conversion of the compound 6 to 7, in Biorg. Med. Chem. Lett., 11 (2001), 1829-1832, at page 1830) in dry tetrahydrofuran (10 mL) and the reaction mixture was stirred at room temperature for about 17 hours. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography using 0.5 % methanol in dichloromethane as eluent to yield the title compound (0.81 g).

Step b: Synthesis of (5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3- ylamino)methyl]-1,3-oxazolidin-2-one. Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 4-(2-fluoro-4- {(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}phenoxy)piperidine-1- carboxylate (0.81 g) (obtained from Step a) in dichloromethane (20 mL) and the reaction mixture was stirred for about 2 hours. The reaction mixture was concentrated and to the residue thus obtained was added ethyl acetate (20 mL) followed by 10 % sodium hydroxide (10 mL) until the pH was about 12-14. The organic layer, which separated out, was and washed with water, dried over sodium sulfate and concentrated to yield the title compound (1.3 g).

Step c: Synthesis of (5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3- ylamino)methyl]-1,3-oxazolidin-2-one.

5-bromo-2,1,3-benzoxadiazole (0.71 g), cesium carbonate (1.4 g), 2,2'- bis(diphenylphosphino)-1,r-binapthyl (0.17 g) and Tris-(dibenzylideneacetone) dipalladium(O) (0.13g) were added to a solution of (5S)-3-[3-fluoro-4-(piperidin-4- yloxy)phenyl]-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one (1.3 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 °C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.07g).

Melting point: 75-100 °C; EIMS (m/z): 534.21; ¹HNMR(DMSO): δ 8.16 (s, 1H), 7.66 (d, 1H), 7.48 (dd, 1H), 7.3 (m, 2H), 7.17 (d, 1H), 7.08-7.05 (t, 1H), 6.75 (s, 1H), 4.99 (m, 1H), 4.53 (m, 3H), 4.14-4.11 (t, 1H), 3.95 (t, 1H), 3.61 (m, 2H), 3.3 (m, 2H), 2.04 (m, 4H).

Example 9: Synthesis (5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-(isoxazol-3-ylmethyl)-1,3-oxazolidin-2-one (Path B) Step a: Synthesis of tert-butyl 4-(2-fluoro-4-{(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo- 1,3-oxazolidin-3-yl}phenyl)piperazine-1-carboxylate

Triphenyl phosphine (1.49 g) and 3-hydroxy-isoxazole (0.38 g) and diethylazodicarboxylate (1.12 mL) were added under nitrogen atmosphere to a solution of tert-butyl 4- {2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3- yl]phenyl}piperazine-1-carboxylate (1.5 g) (which can be prepared according to Example l(g) given in WO93/23384, at page 13) in dry tetrahydrofuran (10 mL) and the reaction mixture was stirred at room temperature for about 17 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane as eluent to yield the title compound (1.4 g).

Step b: Synthesis of (5R)-3-(3-fluoro-4-piperazin-1-ylphenyl)-5-[(isoxazol-3- yIoxy)methyl]-1,3-oxazolidin-2-one.

Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl 4-(2-fluoro-4- {(5R)-5-[(isoxazol-3-yloxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}phenyl)piperazine-1- carboxylate (1.4 g) (obtained from Step a) in dichloromethane (15 mL). The organic layer, which separated out, was washed with water, dried over sodium sulfate and concentrated to yield the title compound (0.91 g).

Step c: Synthesis of (5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl}-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one.

5-bromo-2,1,3-benzoxadiazole (0.52 g), cesium carbonate (1.01 g), 2,2'- bis(diphenylphosphino)-1,1' -binapthyl (0.13 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.09 g) were added to a solution of (5R)-3-(3-fluoro-4-piperazin-1- ylphenyl)-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one (0.91 g) (obtained from Step b) in dry dimethylformamide (15 mL) and heated at 100 °C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 80 % ethyl acetate in hexane to yield the title product (0.03g).

Melting point: 125-143 °C; EIMS (m/z): 481.25; ¹HNMR(DMSO): δ 8.69 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.53 (dd, 1H), 7.24 (d, 1H), 7.15 (t, 1H), 6.89 (s, 1H), 6.39 (s, 1H), 4.99 (m, 1H), 4.47 (m, 2H), 4.18 (t, 1H), 3.91 (t, 1H), 3.53 (m, 4H), 3.15 (m, 4H). Example 10: Synthesis of N-{[(5S)-3-(3-fluoro-4-{4-[(oxido-2,1,3-benzoxadiazol-5- yl)methyl]piperazin-1-yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide

5-formyl benzofuroxan (0.34 g) and molecular sieves were added to a solution of N-{[(5S)-3-(3-fluoro-4-piperazin-1-ylphenyl)-2-oxo-1,3-oxazolidin-5- yl]methyl} acetamide trifluoroacetate (1.72mmoles) (which can be prepared according to Example l(k) in WO93/23384 at page 14) in tetrahydrofuran (20 mL) and the reaction mixture was stirred for 5 minutes. Sodium triacetoxy borohydride (1.45 g) was then added and the reaction mixture was stirred for 3 hours and filtered. The crude product thus obtained was purified by column chromatography using 4 % methanol in dichloromethane as eluent to yield the title compound (0.41 g).

Melting point: 66-70°C; EIMS (m/z): 388;

¹HNMR(CDCl₃): δ 8.24 (t, 1H), 7.83 (br m, 2H), 7.5 (d, 2H), 7.15 (m, 2H), 4.69 (m, 1H), 4.33 (m, 2H), 4.08 (t, 1H), 3.69 (t, 1H), 3.23 (m, 8H), 1.83 (s, 3H)

Example 11: Synthesis ofN-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-ylmethyl)piperazin-1- yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide

Triphenylphosphine (0.15 g) was added to a solution of N-{[(5S)-3-(3-fluoro-4-{4- [(oxido-2,1,3-benzoxadiazol-5-yl)methyl]piperazin-1-yl}phenyl)-2-oxo-1,3-oxazolidin-5- yljmethyl} acetamide (obtained in Example 10) in absolute ethanol (10 mL) and the reaction was refluxed for about 3 hours at 85 °C. The reaction mixture was concentrated and the crude product thus obtained was purified by column chromatography using 3 % methanol in dichloromethane to yield the title compound (0.08 g).

Melting point: 165-168 °C; EEVIS (m/z): 469;

¹HNMR(DMSO): δ 8.22 (t, 1H), 8.01 (dd, 1H), 7.91 (s, 1H), 7.61 (d, 1H), 7.46 (dd, 1H), 7.15 (d, 1H), 7.07 (t, 1H), 4.69 (m, 1H), 4.06 (t, 1H), 3.69 (m, 4H), 3.39 (m, 2H), 3.01 (m, 4H), 2.61 (m, 4H), 1.83 (s, 3H).

Example 12: Synthesis of N-{[(5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4- yl]oxyl-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide (Path A)

5-bromo-2,1,3-benzoxadiazole (0.14 g) and diisopropyl ethylamine (1.16 mL) were added to a solution of tert-butyl 4-(4-{(5S)-5-[(acetyl amino)methyl]-2-oxo-1,3- oxazolidin-3-yl}-2-fluorophenoxy)piperidine-1-carboxylate (0.3 g) (which can be prepared according to Example 7 in Biorg. Med. Chem. Lett., 11 (2001), 1829-1832 at page 1830) in acetonitrile and the reaction mixture was heated at 80 °C for about 48 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by preparative thin layer chromatography using 5 % methanol in dichloromethane to yield the title product (0.03 g).

Melting point: 96-100 °C; EIMS (m/z): 470.13;

¹HNMR(CDCl₃): δ 7.6 (dd, 1H), 7.47 (dd, 1H), 7.30 (d, 1H), 7.06 (m, 2H), 6.73 (dd, 1H), 5.94 (6s, 1H), 4.76 (m, 1H), 4.49 (m, 1H), 4.03 (t, 1H), 3.76-3.44 (m, 6H, 3.28 (m, 1H), 2.03 (m, 7H).

Example 13: Synthesis of N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3- fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (Path B)

Cesium carbonate (0.46 g), 5-bromo-2,1,3-benzoxadiazole (0.23 g), 2,2'- bis(diphenylphosphino)-1,1'-binapthyl (0.074 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.054 g) were added to a solution of N-{[(5S)-3-(3-fluoro-4-piperazin-1- ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.4 g) (which can be prepared according to Example l(k) in WO 93/23384, at page 14) in dry dimethyl formamide (15 mL) and the reaction mixture was heated at 100 °C for 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane and sonicated in ether to yield the title compound (0.12 g).

Melting point: 201-222 °C; EIMS (m/z): 455;

¹HNMR(CDCl₃): δ 7.71 (d, 1H), 7.48 (dd, 1H), 7.33 (dd, 1H), 7.12 (dd, 1H), 6.98 (t, 1H), 6.79 (s, 1H), 5.99 (t, 1H), 4.76 (m, 1H), 4.02 (t, 1H), 3.85-3.55 (m, 3H), 3.47 (m, 4H), 3.24 (m, 4H), 2.03 (s, 3H).

Example 14: Synthesis of N-[((5S)-3-{4-[4-(2,1,3 -benzoxadiazol-5-yl)piperazin-1-yl]- 3.5 -difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl] acetamide(Path B)

Cesium carbonate (0.23 g), 2,2'-bis(diphenylphosphino)-1,1'-binapthyl (0.06 g), 5- bromo-2,1,3-benzoxadiazol (0.12 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.1 g) were added to a solution of N-{[(5S)-3-(3,5-difluoro-4-piperazin-1-ylphenyl)-2-oxo- l,3-oxazolidin-5-yl]methyl}acetamide (0.21 g) (which can be prepared according to Example 32(i) in U.S. Patent No. 5,547,950 at page 25) in dry dimethyl formamide (10 mL) and the reaction mixture was heated at 100 °C for 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (0.025 g).

Melting point: 207-213 °C; EMS (m/z): 388;

¹HNMR(CDCl₃): δ 7.91 (m, 2H), 7.62 (m, 2H), 7.52 (t, 1H), 7.35 (dd, 1H), 6.10 (t, 1H), 4.84 (m, 1H), 4.12 (t, 1H), 3.87 (t, 1H), 3.71 (m,2H), 2.02 (s, 3H).

Example 15: Assay for in vitro Antibacterial Activity

Compounds described herein displayed antibacterial activity when tested by the agar incorporation method. The following minimum inhibitory concentrations (μg/mL) were obtained for representative compounds of the invention, which are given below. hi vitro (μg/mL) activity data:

S. aureus ATCC 25923 -Staphylococcus aureus ATCC 25923;MIC was about 0.5-16 μg/mL with Linezolid 2 μg/mL; about 0.5 to 8 μg/mL with Linezolid 2 μg/mL; and even about 0.5 to 4 μg/mL with Linezolid 2 μg/mL.

S. aureus ATCC 15187 -Staphylococcus aureus ATCC 15187; MIC was about 0.25-16 μg/mL with Linezolid 2 μg/mL; about 0.25 to 8 μg/mL with Linezolid 2 μg/mL; and even about 0.25 to 4 μg/mL with Linezolid 2 μg/mL.

S. aureus MRSA ATCC562 —Methicilline Resistant Staphylococcus aureus ATCC562; MIC was about 0.25-16 μg/mL with Linezolid 2 μg/mL; about 0.25 to 4 μg/mL with Linezolid 2 μg/mL; and even about 0.25 to 2 μg/mL with Linezolid 2 μg/mL. S. aureus MRSA ATCC33 -Methicilline Resistant Staphylococcus aureus ATCC33; MIC was about 0.25-16 μg/mL with Linezolid 2 μg/mL; about 0.25 to 8 μg/mL with Linezolid 2 μg/mL; and even about 0.25 to 4 μg/mL with Linezolid 2 μg/mL. Ent.faecalis ATCC 29212 -Enterococcus faecalis ATCC 29212; MIC was about 0.25-16 μg/mL with Linezolid 2 μg/mL; about 0.25 to 8 μg/mL with Linezolid 2 μg/mL; and even about 0.25 to 4 μg/mL with Linezolid 2 μg/mL.

VRE — Vancomycin-resistant Enterococci ATCC 6 A; MIC was about 0.25-16 μg/mL with Linezolid 2 μg/mL; about 0.25 to 8 μg/mL with Linezolid 2 μg/mL; and even about 0.25 to 4 μg/mL with Linezolid 2 μg/mL.

Strep, pyog. ATCC 19615 -Streptococcus pyogenes ATCC 19615; MIC was about 0.125- 8 μg/mL with Linezolid 2 μg/mL; about 0.125 to 2 μg/mL with Linezolid 2 μg/mL; and even about 0.125 to 1 μg/mL with Linezolid 2 μg/mL. Strep. pnem . AB34 DRSP Streptococcus pneumoniae AB34 DRSP; MIC was about 0.25-8 μg/mL with Linezolid 2 μg/mL; about 0.25 to 4 μg/mL with Linezolid 2 μg/mL; and even about 0.25 to 1 μg/mL with Linezolid 2 μg/mL. Strep . pnem. ATCC6303 —Streptococcus pneumoniae ATCC 6303; MIC was about 0.125- 8 μg/mL with Linezolid 1 μg/mL; about 0.125 to 4 μg/mL with Linezolid 1 μg/mL; and even about 0.125 to 2 μg/mL with Linezolid 1 μg/mL.

M.catt — Moraxella catarrhalis ATCC 8176; MIC was about 2-8 μg/mL with Linezolid 2 μg/mL.

H. influ.— Haemophilus influenzae ATCC 49247; MIC was about 8-32 μg/mL with Linezolid 8 μg/mL; even about 8-16 μg/mL with Linezolid 8 μg/mL. B.fragillus— Bacillus fragillus ATCC 25285; MIC was about 0.5-16 μg/mL with

Linezolid 4 μg/mL; about 0.5 to 8 μg/mL with Linezolid 4 μg/mL; and even about 0.5 to 1 μg/mL with Linezolid 4 μg/mL.

For Linezolid resistant strains.

S. aureus MRSA 32 — Methicilline Resistant Staphylococcus aureus 32; MIC was 4-16 μg/mL with Linezolid 32 μg/mL

Ent. faecalis 303 —Enterococcus faecalis 303; MIC was 0.125-4 μg/mL with Linezolid 16 μg/mL

Strep, pnem. ATCC6303 —Streptococcus pneumoniae ATCC 6303; with Linezolid >16 μg/mL. The in vitro antibacterial activity of the compounds was demonstrated by the agar dilution method (NCCLS M 7-A5 and M 100-S8 documents). In general, the compounds were dissolved in dimethylsulfoxide and doubling dilution of the compounds was incorporated into Muller Hilton agar before solidification. Inoculum was prepared by direct colony suspension in normal saline solution and adjusting the turbidity to 0.5 Macfarland turbidity and subsequently diluting as per NCCLS guidelines in order to obtain 10⁴ CFU/spot. CFU/mL of few randomly selected cultures was performed. The cultures were replicated on agar plate using Denley's multipoint replicator. The agar plates were incubated for 18 hours-24 hours (24 hours for MRSA studies) at 35+ 2 °C. Q.C. strains were also included in each run of the study.

The in vitro activity for Haemophilus MICs were performed by using a Micro broth dilution method as follows:

Media used: Mueller Hinton Broth (MHB-Difco) - Cation adjusted + 5 grams per liter Yeast extract + supplements Preparation of drug concentrations in 96 well microtitre plates was done as per the

NCCLS method. Inoculum was prepared by direct colony suspensions in normal saline and adjusted to 1 McFarland turbidity and subsequently diluted in broth 100 times as per NCCLS guidelines in order to obtain 10⁵ CFU/spot.

The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded only when the MICs against standard antibiotics were within an acceptable range. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

WE CLAIM: 1. A compound of Formula I,

Formula I

R₁ is OR_j, SR_j, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl; wherein

R_j is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl;

Y₁ is (C=O), (C=S) or SO₂

R_f is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; and

R_q is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl;

U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen;

Y and W are each independently no atom, O, CH₂, CO, CH₂NH, -NHCH₂, - CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(Re)CON(R_e), N(Re)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ is optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and

R_e is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl; and A is no group or is selected from;

wherein X is CH, CH-S, CH-O or N; Q is O, N or S; n is an integer 0-1 ; and m is an integer from 0-2. 2. A compound selected from: N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (Compound No.1); N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3,5-difluorophenyl]-2-oxo-1,3- oxazolidin-5-yl}methyl)acetamide (Compound No. 2); (5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)ρiperazin-1-yl]-3-fluorophenyl}-5-(lH- 1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Compound No. 3); (5 R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-(2H- 1,

2,3-triazol-2-ylmethyl)-1,

3-oxazolidin-2-one (Compound No.

4); (5R)-3-(4- {[ 1 -(2, 1 ,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy} -3-fluorophenyl)-5- (1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Compound No.

5); (5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5- [(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one (Compound No.

6); (5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5- [(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one (Compound No.

7); (5S)-3- {4-[4-(2, 1 ,3-benzoxadiazol-5-yl)piperazin- 1 -yl]-3-fluorophenyl} -5- (isoxazol-3-ylmethyl)-1,3-oxazolidin-2-one (Compound No.

8); (5R)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5- [(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one (Compound No.

9); N- {[(5S)-3-(3-fluoro-4- {4-[(oxido-2, 1 ,3-benzoxadiazol-5-yl)methyl] piperazin- 1 - yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (Compound No.

10); N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-ylmethyl)piperazin-1-yl]-3- fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (Compound No.

11); N-{[(5S)-3-(4-{[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)- 2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (Compound No.

12); N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-2- oxo-1,3-oxazolidin-5-yl)methyl]acetamide (Compound No.

13); N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3,5-difluorophenyl}-2- oxo-1,3-oxazolidin-5-yl)methyl]acetamide (Compound No.

14), or pharmaceutically acceptable salts and solvates thereof. 3. A pharmaceutical composition comprising a pharmaceutically effective amount of one or more compounds of claim 1 or their pharmaceutically acceptable salts thereof and one or more pharmaceutical acceptable carriers. 4. A method of treating or preventing microbial infections in a mammal comprising administering to the mammal one or more compounds of claim 1. 5. The method of claim 4, wherein the microbial infections are caused by Gram- positive or Gram-negative bacteria. 6. The method of claim 4, wherein the Gram-positive bacteria is Staphylococcus spp., Streptococcus spp., Bacillus spp., Corynebacterum spp., Clostridia spp., Peptostreptococus spp., Listeria spp. or Legionella spp. 7. The method of claim 4, wherein the microbial infections are aerobic or anaerobic bacterial infections. 8. A process for preparing a compound of Formula IV

Formula IV

Formula Il

with a compound of Formula III

Formula III

to form a compound of Formula IV, wherein,

U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen;

R₁ is OR_j, SR_j, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl; wherein

Y, is (C-O), (C=S) or SO₂;

R_f is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; R_q is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl. 9. The process of claim 8, wherein the compound of Formula II is reacted with the compound of Formula III in the presence of one or more bases. 10. The process of claim 9, wherein the one or more bases are selected from triethylamine, 4-dimethylamino pyridine, N-methyl morpholine or mixtures thereof. 11. The process of claim 8, wherein the compound of Formula II is reacted with the compound of Formula III in the presence of one or more catalysts. 12. The process of claim 11, wherein the one or more catalysts are palladium catalysts selected from dichlorobistriphenylphosphine palladium (II), tetrakistriphenylphosphine palladium (0) or mixtures thereof. 13. A process for preparing a compound of Formula IX

Formula IX

or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising the steps of: b) reacting a compound of Formula V

with a compound of Formula VI

Het— H Formula Vl to form a compound of Formula VII;

Formula VII

b) deprotecting the compound of Formula VII to form a compound of Formula VIII;

Formula VIII

and c) reacting the compound of Formula VIII with a compound of Formula III

to form a compound of Formula IX, wherein, U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen; W is no atom or is selected from O, CH ₂, CO, CH₂NH, -NHCH₂, -CH₂NHCH₂, - CH₂-N (R₁ OCH₂-, CH₂(Re)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(Re)CON(Re), N(Re)C(=S)N(Re), SO₂ or SO, wherein R₁₁ is optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_{1 6} alkoxy, C_{1 6} alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and R_e is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

Het is a heterocyclyl or heteroaryl; A is no group or is selected from;

wherein X is CH, CH-S, CH-O or N; Q is O, N or S; and m is an integer from 0-2; 14. The process of claim 13, wherein the reaction of compound of Formula V with a compound of Formula VI to form a compound of Formula VII is carried out in the presence of one or more bases.

15. The process of claim 14, wherein the one or more bases are Group I hydrides selected from sodium hydride, potassium hydride, lithium hydride or mixtures thereof

16. The process of claim 13, wherein the compound of Formula VII is deprotected to form the compound of Formula VIII in the presence of one or more deprotection agents.

17. The process of claim 16, wherein the one or more deprotection agents is selected from trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.

18. The process of claim 13 , wherein the reaction of the compound of Formula VIII with the compound of Formula III to form the compound of Formula IX is carried out in the presence of one or more bases.

19. The process of claim 18, wherein the one or more bases are selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.

20. The process claim 12, wherein the reaction of the compound of Formula VIII with the compound of Formula III to form the compound of Formula IX is carried out in the presence of one or more catalysts and one or more ligands.

21. The process of claim 20, wherein the one or more catalysts is selected from tris- (dibenzylideneacetone) dipalladium(O), palladium diacteate, palladium dichloride or mixtures thereof; and the one or more ligands are selected from 1,1'-binaphthalene-2,2'- diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 -adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

22. A process for preparing a compound of Formula XIII

Formula V

with a compound of Formula X

H Het— N— P

Formula X to form a compound of Formula XI,

Formula Xl b) deprotecting the compound of Formula XI to form a compound of Formula XII,

Formula XII

and c) reacting the compound of Formula XII with a compound of Formula III

Formula III

to form a compound of Formula XIII, wherein,

U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen;

W is no atom or is selected from O, CH₂, CO, CH₂NH, -NHCH₂, -CH₂NHCH₂, - CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(Re), N(Re)C(=S)N(Re), SO₂ or SO, wherein R₁₁ is optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, R_e is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

Het is a heterocyclyl or heteroaryl; and A is no group or is selected from,

wherein X is CH, CH-S, CH-O or N; Q is O, N or S; m is an integer from 0-2.

23. The process of claim 22, wherein the reaction of the compound of Formula V with the compound of Formula XIV to form the compound of Formula XI is carried out in the presence of one or more bases.

24. The process of claim 23, wherein the one or more bases are Group I hydrides selected from sodium hydride, potassium hydride, lithium hydride or mixtures thereof.

25. The process of claim 22, wherein the deprotection of the compound of Formula XI to form the compound of Formula XII is carried out in the presence of one or more deprotection agents.

26. The process of claim 25, wherein the one or more deprotection agents is selected from trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.

27. The process of claim 22, wherein the reaction of the compound of Formula XII with the compound of Formula III to form the compound of Formula XIII is carried out in the presence of one or more bases.

28. The process of claim 27, wherein the one or more bases are selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.

29. The process of claim 22, wherein the reaction the compound of Formula XII with the compound of Formula III to form the compound of Formula XIII is carried out in the presence of one or more catalysts and one or more ligands.

30. The process of claim 29, wherein the one or more catalysts are selected from tris- (dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride, or mixtures thereof; and the one or more suitable ligands are selected from 1,1'- binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di-1- adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

31. A process for preparing a compound of Formula XVII

Formula XVII

Formula V with a compound of XIV

Het— OH Formula XIV

to form a compound of Formula XV,

Formula XV b) deprotecting the compound of Formula XV to form a compound of Formula XVI,

Formula XVI

and

c) reacting the compound of Formula XVI with a compound of Formula III

Formula III to form a compound of Formula XVII, wherein, U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen; W is no atom or is selected from O, CH₂, CO, CH₂NH, -NHCH₂, -CH ₂NHCH₂, - CH₂-N (R_{1 1})CH₂-, CH₂(R_e)N-, CH(R_{1 1}), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(R_e)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R_{1 1} is optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and R is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

Het is a heterocyclyl or heteroaryl; A is no group or is selected from,

wherein X is CH, CH-S, CH-O or N; Q is O, N or S; m is an integer from 0-2.

32. The process of claim 31, wherein the reaction of the compound of Formula V with a compound of Formula XIV to form a compound of Formula XV is carried out in the presence of one or more coupling agents.

33. The process of claim 32, wherein the one or more coupling agents are selected from diethyl diazocarboxylate, diisopropyl diazocarboxylate or mixtures thereof.

34. The process of claim 31 , wherein the reaction of the compound of Formula V with a compound of Formula XIV to form a compound of Formula XV is carried out in the presence of one or more catalysts.

35. The process of claim 34, wherein the one or more catalysts are selected from triphenyl phosphine, trioctyl phosphine, tributyl phosphine or mixtures thereof.

36. The process of claim 31 , wherein the compound of Formula XV is deprotected to form the compound of Formula XVI in the presence of one or more deprotection agents.

37. The process of claim 36, wherein the one or more deprotection agents are selected from trifluoroacetic acid in dichloromethane or hydrochloric acid in ethanol.

38. The process of claim 31 , wherein the reaction of the compound of Formula XVI with the compound of Formula III to form the compound of Formula XVII is carried out in the presence of one or more bases.

39. The process of claim 38, wherein the one or more bases are selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.

40. The process of claim 31 , wherein the reaction of the compound of Formula XVI with the compound of Formula III to form the compound of Formula XVII is carried out in the presence of one or more catalysts and one or more ligands.

41. The process of claim 40, wherein the one or more catalysts are selected from Tris- (dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride or mixtures thereof; and the one or more ligands is selected from 1,1'- binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di- 1 - adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.

42. A process for preparing a compound of Formula XX

Formula XX

Formula XVIII with 5-formylbenzofuroxan

to form a compound of Formula XIX,

Formula XIX

R₁ is OR,, SR_J, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl, wherein

Y₁ is (C=O), (C=S) or SO₂ and Rf is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; and

Rq is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl;

U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen;

Y and W are each independently no atom or selected from O, CH₂, CO, CH₂NH, - NHCH₂, -CH₂NHCH₂, -CH₂-N (R_{1 1})CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NR_e, (CO)CH₂, N(Re)CON(R_e), N(R_e)C(=S)N(R_e), SO₂ or SO, wherein R₁₁ is optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and R_e is hydrogen, optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

A is no group or selected from group consisting of;

wherein X is CH, CH-S, CH-O or N; Q is O, N or S; and m is an integer from 0-2.

43. The process of claim 42, wherein the reaction of compound of Formula XVIII with 5-formylbenxofuroxan to form the compound of Formula XIX is carried out in the presence of one or more reducing agents.

44. The process of claim 43, wherein the one or more reducing agents are selected from sodium triacetoxy borohydride, sodium borohydride, sodium cyano borohydride, or mixtures thereof.

45. The process of claim 42, wherein the deoxygenation of compound of Formula XIX to form the compound of Formula XX is carried out in presence of one or more catalysts.

46. The process of claim 45, wherein the one or more catalysts are selected from triphenyl phosphine, trioctyl phosphine, tributyl phosphine or mixtures thereof.

47. A process for preparing a compound of Formula XXII

Formula XXII or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or polymorphs, comprising reacting a compound of Formula XXI

Formula XXI

with a compound of Formula III

Formula III to form a compound of Formula XXII, wherein, R₁ is OR_J, SR_j, NHY₁R_f, NR_fR_q, heterocyclyl or heteroaryl; wherein R_j is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl; Y₁ is (C=O), (C=S) or SO₂ and R_f is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; and Rq is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclyl; U and V are each independently hydrogen, lower (C_1-6)alkyl or halogen; Y and W are each independently no atom or selected from O, CH₂, CO, CH₂NH, - NHCH₂, -CH₂NHCH₂, -CH₂-N (R₁₁)CH₂-, CH₂(R_e)N-, CH(R₁₁), S, CH₂(CO), NH, NRe, (CO)CH₂, N(Re)CON(Re), N(Re)CC=S)N(R_e), SO₂ or SO, wherein R₁₁ is optionally substituted C_1-12 alkyl, C_3-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl, and R_e is hydrogen, optionally substituted C_1-12 alkyl, C_1-12 cycloalkyl, C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkylcarbonyl, C_1-6 alkylcarboxy, aryl or heteroaryl;

A is no group or is selected from,

wherein X is CH, CH-S, CH-O or N; Q is O, N or S; m is an integer from 0-2.

48. The process of claim 47, wherein the reaction of the compound of Formula XXI with the compound of Formula III to form the compound of Formula XXII is carried out in the presence of one or more bases.

49. The process of claim 48, wherein the one or more bases are selected from sodium carbonate, potassium carbonate, diisopropyl ethylamine, triethylamine, N-methyl morpholine or mixtures thereof.

50. The process of claim 47, wherein the reaction of the compound of Formula XXI with the compound of Formula III to form the compound of Formula XXII is carried out in the presence of one or more catalysts and one or more ligands.

51. The process of claim 50, wherein the one or more catalysts are selected from tris- (dibenzylideneacetone) dipalladium(O), Pd₂(dba)₃, palladium diacteate, palladium dichloride, or mixtures thereof; and the one or more suitable ligands are selected from 1,1'- binaphthalene-2,2'-diylbis(diphenylphosphine), tri-tert-butylphosphine, di-1- adamantyl(butyl)phosphine, biphenyl-2-yl(di-tert-butyl)phosphine or mixtures thereof.