 Oxazolidinone and/or isoxazoline as antibacterial agents
专利摘要:
The present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof, wherein C is for example (D), (E), (F); A and B are independently selected from (i) and (ii); R 2a to R 3b are independently selected from hydrogen and fluorine; R 1a and R 1b are independently selected from, for example, hydroxy, —NHC (═W) R 4 , (a) and (b); Wherein W is O or S; R 4 is, for example, hydrogen, amino, (1-4C) alkyl; HET-1 is, for example, a C-linked 5 membered heteroaryl ring; HET-2 is useful in that compounds represented by formula (I), which are, for example, N-linked 5-membered, fully or partially unsaturated heterocyclic rings, are useful as antimicrobial agents and methods for their preparation and pharmaceutical compositions comprising the same Described. <Formula I> <Formula D> <Formula E> <Equation F> <Formula i> <Formula ii> <Formula a> <Formula b> 公开号:KR20040044886A 申请号:KR10-2004-7003558 申请日:2002-09-09 公开日:2004-05-31 发明作者:마이클 베리 그레이브스톡；네일 제임스 할레스；마이클 린가드 스웨인；쉐일라 아이렌 하우크；스튜어트 데네트 밀스 申请人:아스트라제네카 아베； IPC主号:
专利说明:
OXAZOLIDINONE AND / OR ISOXAZOLINE AS ANTIBACTERIAL AGENTS} [2] The international microbiological community continues to be seriously concerned that antibiotic resistance in strains can lead to the effectiveness of currently available antimicrobials. In general, bacterial pathogens can be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds having effective activity against both Gram-positive and Gram-negative pathogens are generally considered to have a broad spectrum of activity. Compounds of the present invention are considered effective against both Gram-positive and certain Gram-negative pathogens. [3] Gram-positive pathogens such as staphylococci, enterococci, streptococci and acidophilic bacteria are particularly important because of the development of resistant strains that, once developed, are difficult to eradicate from the hospital environment and are difficult to treat. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant plasma coagulation enzyme negative staphylococci (MRCNS), penicillin resistant streptococcus pneumoniae and multiply resistant enterococcus paesium to be. [4] The main clinically effective antibiotic for the treatment of these resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ditoxicity. Moreover, and most importantly, antimicrobial resistance to vancomycin and other glycopeptides is also emerging. The resistance is steadily increasing and makes the agent less and less effective in the treatment of Gram-positive pathogens. In addition, the emergence of resistance to drugs such as β-lactam, quinolone and macrolide, which are also used in the treatment of upper respiratory tract infections, also caused by certain Gram-negative strains, including H. influenza and M. catarrhalis, is currently increasing. Doing. [5] Certain antibacterial compounds containing oxazolidinone rings have been described in the art (see, eg, Walter A. Gregory et al in J. Med. Chem. 1990, 33, 2569-2578 and 1989, 32 (8). ), 1673-81; Chung-Ho Park et al in J. Med. Chem. 1992,35, 1156-1165). For example, (i) the evolution of active binding sites in bacteria that make previously less active or less active pharmacogenetic groups, and / or (ii) chemically inactivate certain pharmacochromophores. Evolution of the means, and / or (iii) evolution of the efflux pathway, etc., may result in the development of bacterial resistance to known antimicrobials. Thus, there remains a continuing need for novel antibacterial agents with desirable pharmacological profiles, especially compounds containing new, more potent pharmacodynamic chromophores. [6] We are resistant to Gram-positive pathogens, including MRSA and MRCNS, and in particular to a variety of strains and aminoglycosides that are resistant to vancomycin and / or linezolid and both clinically used β-lactams. In H. influenza, as well as paesium strains, M. catarrhalis, mycoplasma spp. And a class of antibiotic compounds with potentially two drug chromophores containing two substituted oxazolidinones and / or isoxazoline rings having effective activity against demanding Gram-negative strains, such as the clinical strain It was. We use the term “bipharmacophoric” to refer to two substituted oxazolidinones and / or isoxazolin pharmacophores capable of independently binding to a pharmacophore binding site. Wherein the sites may be similar or different, and similar or different sites may be filled simultaneously or non-simultaneously in a single organism, or the relative importance of different modes of binding to similar or different sites may differ. May differ between the two organisms. [1] The present invention relates to antibiotic compounds and in particular antibiotic compounds containing substituted oxazolidinone and / or isoxazolin ring. The present invention also relates to methods for their preparation, intermediates useful for their preparation, their use as therapeutic agents, and pharmaceutical compositions containing them. [7] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof. [8] [9] In formula (I), C is a biaryl residue C'-C " [10] [11] Wherein C ′ and C ″ are independently aryl or heteroaryl rings such that the central residue C represents any of the following D to L groups: [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] Wherein the D to L groups can be linked to rings A and B in any direction; [22] Where A and B are independently [23] i) And ii) [24] Selected from [25] Wherein, i) and (or) ii) is (I) is connected to the C in the 3-position, as shown in, (I) at the 5-position and -CH 2 -R -CH 2 -R 1a, as shown in Substituted by 1b ; R 2a , R 2b , R 3a and R 3b are independently hydrogen or fluorine; R 1a and R 1b are independently hydroxy, —OSi (tri- (1-6C) alkyl), wherein the three (1-6C) alkyl groups are independently selected from all possible (1-6C) alkyl groups), -NR 5 C (= W) R 4 , -OC (= O) R 4 , [26] a) b) And c) [27] Independently selected from [28] Wherein W is O or S; [29] R 4 is hydrogen, amino, (1-8C) alkyl, -NHR 12 , -N (R 12 ) (R 13 ), -OR 12 or -SR 12 , (2-4C) alkenyl, (1-8C) Alkylaryl, mono-, di-, tri- and per-halo (1-8C) alkyl,-(CH 2 ) p (3-6C) cycloalkyl or-(CH 2 ) p (3-6C) cycloalkenyl Wherein p is 0, 1 or 2; [30] here, [31] in a) HET-1 is a C-linked 5 membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, said ring being selected from (1-4C) alkyl, (2-4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy On the available nitrogen atoms optionally substituted with one or two substituents independently selected from (1-4C) alkoxycarbonyl, halogen and cyano, provided that the ring does not quaternize Optionally under the conditions) (1-4C) alkyl; or [32] HET-1 is a C-linked 6 membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, wherein the ring is (1-4C) alkyl, (2-4C) alkenyl, (3) on any available C atom -6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkoxycarbonyl, (1-4C) alkyl on a nitrogen atom optionally substituted with one, two or three substituents independently selected from halogen and cyano, provided that the ring does not thereby quaternize Optionally substituted with; [33] In b), HET-2 is an N-linked 5 membered member containing (i) 1 to 3 additional nitrogen heteroatoms or (ii) an additional heteroatom selected from O and S together with any additional nitrogen heteroatoms. And, as a fully or partially unsaturated heterocyclic ring, said ring is optionally substituted with an oxo or thioxo group on C atom and / or (1-4C) alkyl, (2- 4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1 -4C) optionally substituted with 1, 2 or 3 substituents independently selected from alkoxycarbonyl, halogen and cyano and / or on the available nitrogen atoms provided that the ring does not thereby quaternize Optionally substituted with (1-4C) alkyl; or [34] HET-2 is an N-linked 6-membered di-hydro-heteroaryl ring containing up to 3 nitrogen heteroatoms (including linking heteroatoms) in total, which ring is formed on the appropriate C atom with oxo or thioxo. Or (1-4C) alkyl, (2-4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, on any available C atom, Optionally substituted with 1, 2 or 3 substituents independently selected from di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkoxycarbonyl, halogen and cyano Is optionally substituted with (1-4C) alkyl on the available nitrogen atom provided that the ring is not quaternary nitrogenized thereby; [35] The substituents on HET-1 and HET-2, or alkyl, alkenyl, cycloalkyl cycloalkenyl, at each occurrence in R 4 , are optionally substituted with 1, 2, 3, or more F, Cl or CN; [36] In c), R 5 is hydrogen, (3-6C) cycloalkyl, phenyloxycarbonyl, tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, (1-6C) alkyl (cyano Or optionally substituted with (1-4C) alkoxycarbonyl), -CO 2 R 8 , -C (= 0) R 8 , -C (= 0) SR 8 , -C (= S) R 8 , P ( O) (OR 9 ) (OR 10 ) and —SO 2 R 11 , wherein R 8 , R 9 , R 10 and R 11 are as defined below; [37] R 6 is cyano, -COR 12 , -COOR 12 , -CONHR 12 , -CON (R 12 ) (R 13 ), -SO 2 R 12 , -SO 2 NHR 12 , -SO 2 N (R 12 ) ( R 13 ) or NO 2 , wherein R 12 and R 13 are as defined below; [38] R 7 is hydrogen, amino, (1-8C) alkyl, -NHR 12 , -N (R 12 ) (R 13 ), -OR 12 or -SR 12 , (2-4C) alkenyl, (1-8C) Alkylaryl, mono-, di-, tri- and per-halo (1-8C) alkyl,-(CH 2 ) p (3-6C) cycloalkyl or-(CH 2 ) p (3-6C) cycloalkenyl Wherein p is 0, 1 or 2; [39] R 8 is hydrogen, (3-6C) cycloalkyl, phenyl, benzyl, (1-5C) alkanoyl, (1-6C) alkyl ((1-5C) alkoxycarbonyl, hydroxy, cyano, 3 or less Halogen atom and —NR 14 R 15 wherein R 14 and R 15 are selected from hydrogen, phenyl (halogen, (1-4C) alkyl and (1-4C) alkyl substituted with 1, 2, 3, or more halogen atoms Optionally substituted with one or more substituents) and (1-4C) alkyl (optionally substituted with one, two, three, or more halogen atoms), or for any N (R 14 ) (R 15 ) groups, R 14 and R 15 may optionally form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group together with the nitrogen atom to which they are linked; [40] R 9 and R 10 are independently selected from hydrogen and (1-4C) alkyl; [41] R 11 is (1-4C) alkyl or phenyl; [42] R 12 and R 13 are optionally substituted with one or more substituents selected from hydrogen, phenyl (halogen, (1-4C) alkyl and (1-4C) alkyl substituted with 1, 2, 3 or more halogen atoms) and ( Independently selected from 1-4C) alkyl (optionally substituted with 1, 2, 3 or more halogen atoms), or for any N (R 12 ) (R l3 ) groups, R 12 and R 13 are linked to Together with the nitrogen atom may form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group; [43] Provided that the C group is an I or J group, the A and B groups are both oxazolidinones and the oxazolidinone (A or B) linked to the pyridyl group at C is a hydroxymethyl group or an acetoxymethyl group (R 1a respectively) When having -CH 2 or R 1b -CH 2 ), the oxazolidinone (B or A) linked to the phenyl group at C is not substituted with an acetamidomethyl group (R 1b -CH 2 or R 1a -CH 2, respectively ) . [44] A further aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof, [45] Wherein in groups D to L, R 2a , R 2b , R 3a and R 3b are independently hydrogen or fluorine when connected to a phenyl ring; Hydrogen when connected to a thienyl or pyridyl ring; [46] R 1a and R 1b are hydroxy, -NHC (= W) R 4 , -OC (= O) R 4 , [47] a) b) And c) [48] Are independently selected from [49] here, [50] W is O or S; [51] R 4 is hydrogen, amino, (1-4C) alkyl, -NH (1-4C) alkyl, -N (di- (1-4C) alkyl), -0 (1-4C) alkyl or -S (1- 4C) alkyl, (2-4C) alkenyl,-(CH 2 ) p (3-6C) cycloalkyl or-(CH 2 ) p (3-6C) cycloalkenyl, where p is 0,1 or 2; [52] In a), HET-1 is a C-linked 5 membered heteroaryl containing 2 to 4 heteroatoms independently selected from N, O and S, wherein the ring is selected from the group of available (1-4C) alkyl, (2-4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy On a nitrogen atom optionally substituted with one or two substituents independently selected from (1-4C) alkoxycarbonyl, halogen, cyano and trifluoromethyl, provided that the ring is thus quaternary nitrogen Optionally substituted with (1-4C) alkyl, provided that it is unsubstituted; or [53] HET-1 is a C-linked 6 membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, wherein the ring is (1-4C) alkyl, (2-4C) alkenyl, (3) on any available C atom -6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkoxycarbonyl, On a nitrogen atom that is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano and trifluoromethyl and / or available (provided that the ring does not thereby quaternize nitrogen) ( Optionally substituted with 1-4C); [54] In b), HET-2 is an N-linked 5 membered member containing (i) 1 to 3 additional nitrogen heteroatoms or (ii) an additional heteroatom selected from O and S together with any additional nitrogen heteroatoms. And, as a fully or partially unsaturated heterocyclic ring, said ring is optionally substituted with an oxo or thioxo group on the C atom and / or (1-4C) alkyl, (2-4C) alk on an available C atom Kenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) Optionally substituted with 1, 2 or 3 substituents independently selected from alkoxycarbonyl, halogen, cyano and trifluoromethyl, and / or on the available nitrogen atoms provided that the ring is not quaternized Is optionally substituted with (1-4C) alkyl; or [55] HET-2 is an N-linked 6-membered di-hydro-heteroaryl ring containing up to 3 nitrogen heteroatoms (including linking heteroatoms) in total, which ring is formed on the appropriate C atom with oxo or thioxo. Or (1-4C) alkyl, (2-4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, on any available C atom, 1, 2 independently selected from di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkoxycarbonyl, halogen, cyano and trifluoromethyl Or optionally substituted with 3 substituents and / or optionally substituted with (1-4C) alkyl on the available nitrogen atom provided that the ring is not quaternized by this; [56] Substituents on HET-1 and HET-2, or alkyl, alkenyl, cycloalkyl cycloalkenyl at each occurrence in R 4 are optionally substituted with one or more F, Cl or CN; [57] In c), R 5 is hydrogen, (3-6C) cycloalkyl, phenyloxycarbonyl, tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, (1-6C) alkyl (cyano Or optionally substituted with (1-4C) alkoxycarbonyl), -CO 2 R 8 , -C (= 0) R 8 , -C (= 0) SR 8 , -C (= S) R 8 , P ( O) (OR 9 ) (OR 10 ) and —SO 2 R 11 , wherein R 8 , R 9 , R 10 and R 11 are as defined below; [58] R 6 is cyano, -COR 12 , -COOR 12 , -CONHR 12 , -CON (R 12 ) (R 13 ), -SO 2 R 12 , -SO 2 NHR 12 , -SO 2 N (R 12 ) ( R 13 ) or NO 2 , wherein R 12 and R 13 are as defined below; [59] R 7 is hydrogen, (1-8C) alkyl, -OR 12 , -SR 12 , amino, -NHR 12 , -N (R 12 ) (R 13 ), (1-8C) alkylaryl, mono-, di- , Tri- and per-halo (1-8C) alkyl; [60] R 8 is hydrogen, (3-6C) cycloalkyl, trifluoromethyl, phenyl, benzyl, (1-5C) alkanoyl, (1-6C) alkyl ((1-5C) alkoxycarbonyl, hydroxy, cya No, 3 or less halogen atoms and -NR 14 R 15, wherein R 14 and R 15 are optionally substituted with substituents independently selected from hydrogen, phenyl and (1-4C) alkyl; [61] R 9 and R 10 are independently selected from hydrogen and (1-4C) alkyl; [62] R 11 is (1-4C) alkyl or phenyl; [63] R 12 and R 13 are independently selected from hydrogen, alkyl and aryl, or for any N (R 12 ) (R 13 ) group, R 12 and R 13 are unsubstituted or substituted with the nitrogen atom to which they are linked Pyrrolidinyl, piperidinyl or morpholinyl groups may be formed. [64] As used herein, a C-linked 6-membered heteroaryl ring containing HET-1 and 2 or 3 nitrogen heteroatoms as a C-linked 5-membered heteroaryl ring containing 2-4 heteroatoms independently selected from N, O and S HET-1 as is a fully unsaturated ring system. [65] As used herein, HET-2 as an N-linked 5-membered heterocyclic ring is a heterocyclic ring that is fully or partially unsaturated, provided that there is some degree of unsaturation in the ring. [66] Specific examples of 5-membered heteroaryl rings containing 2 to 4 heteroatoms independently selected from N, O and S (without OO, OS or SS bonds) are pyrazole, imidazole, 1,2,3-triazole , 1,2,4-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1 , 3,4-oxadiazole, isothiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole and 1,2,3-thiadiazole. [67] Specific examples of six-membered heteroaryl ring systems containing up to three nitrogen heteroatoms include pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine and 1,3, 5-triazine. [68] N-linked 5 membered, fully or partially unsaturated hetero, containing (i) 1 to 3 additional nitrogen heteroatoms or (ii) optional additional nitrogen heteroatoms with additional heteroatoms selected from O and S. Specific examples of cyclic rings include, for example, pyrazole, imidazole, 1,2,3-triazole (preferably 1,2,3-triazol-1-yl), 1,2,4- Triazoles (preferably 1,2,4-triazol-1-yl) and tetrazole (preferably tetrazol-2-yl) and furazane. [69] Specific examples of N-linked six-membered di-hydro-heteroaryl rings containing up to three nitrogen heteroatoms (including linked heteroatoms) include pyrimidine, pyridazine, pyrazine, 1,2,3- Compounds as di-hydrides of triazine, 1,2,4-triazine, 1,3,5-triazine and pyridine. [70] Particular examples of halogen-substituted alkyl substituents in HET-1 and HET-2 are monofluoromethyl, difluoromethyl and trifluoromethyl. [71] Particular example of R 8 as halogen-substituted alkyl group is trifluoromethyl. [72] The term 'alkyl' herein includes both straight and branched chain structures. [73] For example, (1-4C) alkyl includes propyl and isopropyl. However, what is referred to as "propyl" for an individual alkyl group is specified only for the straight chain, and what is referred to as "isopropyl" for the individual alkyl group is specified only for the branched chain. As used herein, the terms 'alkenyl' and 'cycloalkenyl' include all positional and geometric isomers. As used herein, the term 'aryl' is an unsubstituted carbocyclic aromatic group, in particular phenyl, 1- and 2-naphthyl. [74] Specific and appropriate values referring to specific substituents and groups herein are as follows. These values may be used in any definitions and aspects disclosed above or below where appropriate. In order to avoid uncertainty each discussed species represents a specific and independent aspect of the invention. [75] Examples of (1-4C) alkyl include methyl, ethyl, propyl and isopropyl; Examples of (1-6C) alkyl include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl; Examples of (2-4C) alkenyl include vinyl, propenyl, allyl, butenyl; Examples of (1-4C) alkanoyl include acetyl and propionyl; Examples of (1-5C) alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and pentoxycarbonyl; Examples of (1-4C) alkoxy include methoxy, ethoxy and propoxy; Examples of (1-4C) alkylamino include methylamino, ethylamino and propylamino; Examples of di- (1-4C) alkylamino include dimethylamino, methylethylamino and ethylpropylamino; Examples of (1-4C) alkylthio are methylthio and ethylthio; Examples of (3-6C) cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Examples of (3-6C) cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl; Examples of (1-8C) alkylaryl are benzyl; Examples of halo groups include fluoro, chloro and bromo. [76] Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric acid and sulfuric acid. In another embodiment, suitable salts are alkali metal salts such as sodium, alkaline earth metal salts such as calcium or magnesium, organic amine salts such as triethylamine, morpholine, N-methylpiperidine, N-ethylpiperi Dine, procaine, dibenzylamine, N, N-dibenzylethylamine, tris- (2-hydroxyethyl) amine, N-methyl d-glucamine and amino acid salts such as lysine. There may be one or more cations and anions depending on the number of charged functional groups of the cation or anion and the number of outermost electrons. Preferred pharmaceutically acceptable salts are sodium salts. [77] However, to facilitate separation in the manufacturing process, salts that are less soluble in the selected solvent, whether or not pharmaceutically acceptable, may be desirable. [78] The compounds of the present invention can be administered in the form of prodrugs that are degraded in the human or animal body to provide the compounds of the present invention. Prodrugs may be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and may be formed when the parent compound contains suitable groups or substituents that can be derivatized to form the prodrug. Examples of prodrugs include in vivo hydrolyzable esters of a compound of the invention or a pharmaceutically acceptable salt thereof. [79] Various forms of prodrugs are known in the art. For example, note the following: [80] a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); [81] b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Produrug", by H. Bundgaard p. 113-191 (1991); [82] c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); [83] d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); And [84] e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). [85] In vivo hydrolyzable esters of the compounds of the present invention or pharmaceutically acceptable salts thereof containing hydroxy groups are, for example, pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol. [86] In vivo hydrolyzable esters of the compounds of the present invention or pharmaceutically acceptable salts thereof containing hydroxy groups or hydroxy groups include phosphate esters (including phosphoamidic cyclic esters) and in vivo valences of α-acyloxyalkyl ethers and esters Inorganic esters, such as related compounds, that decompose as a result of degradation to give the parent hydroxyl group (s). Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. In vivo hydrolyzable ester forming groups for hydroxy (1-10C) alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-10C) alkoxycarbonyl (forms alkyl carbonate esters) , Di- (1-4C) alkylcarbamoyl and N- (di- (1-4C) alkylaminoethyl) -N- (1-4C) alkylcarbamoyl (forms carbamate), di- (1-4C) alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl are chloromethyl or aminomethyl, (1-4C) alkylaminomethyl and di-((1-4C) alkyl) aminomethyl, and methylene to the 3- or 4-position of the benzoyl ring Morpholino or piperazino linked from a ring nitrogen atom via a linking group. Other in vivo hydrolyzable esters of interest are, for example, R A C (0) O (1-6C) alkyl-CO-, wherein R A is, for example, optionally substituted benzyloxy- (1 -4C) alkyl, or optionally substituted phenyl), suitable substituents on the phenyl in the ester are, for example, 4- (1-4C) piperazino- (1-4C) alkyl, piperazino- ( 1-4C) alkyl and morpholino- (1-4C) alkyl. [87] Further in vivo hydrolyzable esters are phosphoramidic esters, and also any free hydroxy group independently forming a phosphoryl (npd is 1) or phosphyl (npd is 0) ester of formula (PD1). Compounds of the invention also include: [88] [89] Useful intermediates in the preparation of such esters are those in which one or both of the —OH groups in (PD1) are independently (1-4C) alkyl (the compound is itself a compound of interest), phenyl or phenyl- (1-4C) alkyl (wherein the phenyl group is optionally substituted with one or two groups independently selected from (1-4C) alkyl, nitro, halo and (1-4C) alkoxy) Compound containing the group (s). [90] Thus, prodrugs containing groups such as (PD1) react the compounds of the present invention containing the appropriate hydroxy group (s) with a suitably protected phosphorylating agent (e.g. containing chloro or dialkylamino leaving groups). It can then be prepared by oxidation (if necessary) and deprotection. [91] If the compounds of the present invention contain a large number of free hydroxy groups, the groups that are not converted to prodrug functional groups can be protected (eg using t-butyl-dimethylsilyl groups) and later deprotected. Enzymatic methods may also be used for selective phosphorylate or diphosphoryl alcohol functional groups. [92] If pharmaceutically acceptable salts of hydrolyzable esters in vivo can be formed, this can be achieved by conventional techniques. Thus, for example, a compound containing a group of formula (PD1) can be ionized (partially or completely) to form a salt with an appropriate number of counter ions. Thus, for example, if the in vivo hydrolyzable ester prodrugs contain two (PD1) groups, there are four HO-P-functional groups in the total molecule, each of which will form an appropriate salt. (Ie, the entire molecule may form a mono-, di-, tri- or tetra-sodium salt, for example). [93] Compounds of the invention have both chiral centers at the C-5 position of the oxazolidinone and / or isoxazolin ring. Pharmaceutically active diastereomers of formula (IA) are as follows: [94] [95] The present invention relates to pure diastereomers (described herein as 'bis (5R)') or mixtures of bis (5R) and bis (5S) diastereomers, such as racemic mixtures, or one ring Diastereomers ('(5R, 5'S) and (5S, 5'R)') that are 5R configuration and the other is 5S. At the same weight of the pharmaceutically active enantiomer, if a mixture of enantiomers (a mixture of bis (5R) and bis (5S) or a mixture of (5R, 5'S) and (5S, 5'R)) is used Higher amounts (depending on the proportion of enantiomers) will be required to achieve such an effect. While certain compounds (depending on the nature of R 1a , R 1b , A and B) are, for example, bis (5S) enantiomers, or (5R, 5 ′S) enantiomers, the enantiomers shown above are generally bis ( 5R) enantiomers (depending on the nature of R1a, R1b, A and B). For better understanding, Examples 1 and 2 are shown below; Here, depending on the nature of the side chain, the preferred compounds (as shown) become bis (5S) and bis (5R) enantiomers, respectively. [96] Example 1: (5S, 5S ')-N- (3- {4'-[5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2,2'-difluoro Rho-biphenyl-4-yl-2-oxo-oxazolidin-5-ylmethyl) -acetamide [97] [98] Example 2: Acetic acid (5R, 5R ')-3- [4'-(5-acetoxymethyl-2-oxo-oxazolidin-3-yl) -2,2'-difluoro-biphenyl- 4-yl] -2-oxo-oxazolidin-5-ylmethyl ester [99] [100] Moreover, certain compounds of the present invention may have other chiral centers. It should be noted that the present invention includes all such optical and diastereoisomers, and racemic mixtures, having antimicrobial activity. Methods of preparing optically active forms (eg, degradation of racemic forms, chiral synthesis, enzymatic digestion, bioconversion or chromatographic separation by recrystallization techniques) and methods of determining antimicrobial activity are described below. Known in the art. [101] The present invention relates to all tautomeric forms of the compounds of the present invention having antimicrobial activity. [102] It should be noted that certain compounds of the present invention may exist in unsolvated forms as well as solvated forms such as, for example, hydrated forms. It should be noted that the present invention includes all such solvated forms having antimicrobial activity. [103] It should be noted that certain compounds of the present invention exhibit allotropes and that the present invention includes all such forms having antimicrobial activity. [104] As mentioned above, the present inventors have been challenged with H. influenzae, M. catarrhalis, mycoplasma and chlamydia strains, with a wide range of Gram-positive pathogens, including organisms known to be resistant to the most commonly used antibiotics. A class of compounds with good activity against gram negative pathogens has been found. The following compounds possess desirable pharmaceutical and / or physical and / or pharmacokinetic properties. [105] Compounds of formula (I) wherein C is selected from any one of D to L groups, or pharmaceutically acceptable salts or in vivo hydrolyzable esters thereof, represent individual and independent aspects of the present invention. [106] Particularly preferred compounds of the invention are those in which the abovementioned substituents A, B, R 1a , R 1b , R 2a , R 2b , R 3a and R 3b and other substituents have the above mentioned values or any of the following values ( Compounds of the invention, or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, having the above or any of the following definitions and embodiments, may be appropriate: [107] In one embodiment there is provided a compound as defined in formula (I), wherein the C group is a D group (two phenyl rings). [108] In another embodiment are provided compounds as defined in formula (I), wherein the C group is an E group and R 2a is hydrogen. [109] In another embodiment are provided compounds as defined in formula (I), wherein the C group is an H group, and R 2a and R 2b are hydrogen. [110] In another embodiment, there is provided a compound of Formula (I), wherein the C group is selected from the D, E, F, G, H, I, and J groups as defined herein. [111] In another embodiment, there is provided a compound of Formula (I), wherein the C group is selected from D, E, F, G, H, K, and L as defined herein. [112] In another embodiment, there is provided a compound of Formula (I), wherein the C group is selected from D, E, F, G, and H as defined herein. [113] In another embodiment, there is provided a compound of Formula (I), wherein the C group is selected from D, E, G, and I as defined herein. [114] In another embodiment, there is provided a compound of Formula (I), wherein the C group is selected from D, E, J, and I as defined herein. Preferably C is D or E. [115] In one embodiment, preferably, A and B are both oxazolidinone rings. [116] In another embodiment, preferably, one of A or B is an oxazolidinone ring and the other is an isoxazolin ring. [117] In another embodiment, preferably, both A and B are isoxazolin ring. [118] Preferably, R 2a and R 2b are hydrogen, one of R 3a or R 3b is hydrogen and the other is fluorine. More preferably, R 2a and R 2b are hydrogen and R 3a and R 3b are both fluorine. [119] In other embodiments, R 2a and R 3a are both fluorine and R 2b and R 3b are both hydrogen. [120] In another embodiment, R 2a , R 2b , R 3a and R 3b are selected to provide compounds having three fluorine atoms on the central phenyl ring. [121] In one embodiment, when C is E, F, G, H, I, J or L, R 2a , R 2b , R 3a and R 3b are all hydrogen. [122] In one aspect, when the C group is an I group or a J group and A and B are both oxazolidinones, the oxazolidinone linked to the phenyl group in C is not substituted with methyl acetamide. In another aspect, the C group is an I group or a J group, A and B are both oxazolidinones and the oxazolidinone (B or A) linked to the phenyl group is an acetamidomethyl group (R 1b -CH 2 or R, respectively). When substituted with 1a- CH 2 ), the oxazolidinone (A or B) linked to the pyridyl group in C is as defined above. [123] a) , b) And c) Having substituents selected from (R 1a -CH 2 or R 1b -CH 2, respectively ). [124] In one embodiment, R 1a and R 1b are hydroxy, —NHC (═W) R 4 , —OC (═O) R 4 , and [125] [126] Are independently selected from wherein W, R 5 and R 6 are as defined above and R 4 is hydrogen, amino, (1-4C) alkyl, -NH (1-4C) alkyl, -N (di- (1 -4C) alkyl), -0 (1-4C) alkyl, -S (1-4C) alkyl, (2-4C) alkenyl,-(CH 2 ) p (3-6C) cycloalkyl and-(CH 2 ) p (3-6C) cycloalkenyl, where p is 0, 1 or 2; R 7 is hydrogen, (1-8C) alkyl, -OR 12 , -SR 12 , amino, NHR 12 , N (R 12 ) (R 13 ), (1-8C) alkylaryl and mono-, di-, tri -And per-halo (1-8C) alkyl. [127] In other embodiments, R 1a and R 1b are hydroxy, -NHC (= W) R 4 , -OC (= 0) R 4 , and [128] [129] Are independently selected from wherein W, R 4 , R 5 , R 6 and R 7 are as defined above, in particular where R 4 is (1-4C) alkyl, (1-4C) alkoxy, cycloalkyl (especially Cyclopropyl) or haloalkyl (especially dichloromethyl). [130] In other embodiments, R 1a and R 1b are hydroxy, -NHC (= W) R 4 , -OC (= 0) R 4 , and [131] [132] Are independently selected from wherein W, R 4 , R 5 , R 6 and R 7 are as defined above, in particular where R 4 is (1-4C) alkyl or (1-4C) alkoxy. [133] Particular values for R 5 (which may be appropriate in connection with any of the definitions and embodiments described above or below) are hydrogen, tert-butoxycarbonyl and benzyloxycarbonyl. More particularly, R 5 is hydrogen. [134] In one aspect, R 12 and R 13 are independently selected from hydrogen, alkyl and aryl, or for any N (R 12 ) (R 13 ) group, R 12 and R 13 are unsubstituted with the nitrogen atom to which they are linked Can form a substituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group; R 14 and R 15 are independently selected from hydrogen, phenyl and (1-4C) alkyl). [135] Preferably, R 1a and R 1b are hydroxy, -NHCO (1-4C) alkyl, -NHCS (1-4C) alkyl, -NHCOO (1-4C) alkyl, -OCO (1-4C) alkyl,- Independently from HN-HET-1 and HET-2. [136] More preferably, R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NHCS (1-4C) alkyl, —HN-HET-1 and HET-2. [137] In one embodiment, R 1a and R 1b are independently selected from hydroxy, -NHCOMe and -NHCOOMe. [138] In another embodiment, R 1a is hydroxy, -NHCO (1-4C) alkyl (especially -NHCOMe), -NHCS (1-4C) alkyl (especially -NHCSMe), -NHCOO (1-4C) alkyl (especially -NHCO) Me) and -OCO (1-4C) alkyl (especially -OCOMe) and R 1b is HET-2. [139] In another embodiment, R 1a is hydroxy, -NHCO (1-4C) alkyl (particularly -NHCOMe), -NHCS (1-4C) alkyl (particularly -NHCSMe), -NHCOO (1-4C) alkyl (particularly -NHC (O) Me) and -OCO (1-4C) alkyl (particularly -OCOMe) and R 1b is HN-HET-1. [140] In other embodiments, R 1a and R 1b are both -NHCO (1-4C) alkyl (especially -NHCOMe) or ET-2 (especially 1,2,3-triazol-1-yl or tetrazol-2- Is). [141] In another embodiment, R 1a is —NHCO (1-4C) alkyl (particularly —NHCOMe) and R 1b is HET-2 (particularly 1,2,3-triazol-1-yl or tetrazol-2-yl )to be. [142] In another embodiment, R 1a and R 1b are hydroxy, acetamido, 1,2,3-triazol-1-yl, methyl-1,2,3-triazol-1-yl and isoxazolyl Independently selected from amino. [143] In one embodiment, HET-1 and HET-2 are unsubstituted. When substituted, preferred substituents are selected from (1-4C) alkyl, in particular methyl, and trifluoromethyl. [144] 5-membered rings HET-1 and HET-2, in particular isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl HET-1, and 1,2,3-triazol-1-yl or Preference is given to HET-2 which is tetrazol-2-yl. [145] In one aspect of the invention, HET-2 which is 1,2,3-triazol-1-yl is preferably substituted by methyl or trifluoromethyl. [146] Preferred group of compounds are that both A and B are oxazolidinone rings; R 2 a and R 2 b are both hydrogen; R 3 a and R 3 b are both hydrogen or both fluorine; R 1 a and R 1 b are independently compounds of formula (I) having two central phenyl rings selected from hydroxy, -NHCOMe and -NHCOOMe. [147] Another preferred group of compounds is that both A and B are oxazolidinone rings; R 2 a and R 2 b are both hydrogen; R 3 a and R 3 b are both hydrogen or both fluorine; R 1 a is hydroxy and R 1 b is a compound of formula (I) having two central phenyl rings, which are HET-2, in particular 1,2,3-triazol-1-yl (optionally substituted). [148] Another preferred group of compounds is that both A and B are oxazolidinone rings; R 2 a and R 2 b are both hydrogen; R 3 a and R 3 b are both hydrogen or both fluorine; R 1 a is acetamido and R 1 b is a compound of formula (I) having two central phenyl rings wherein H 1-2 is, in particular, 1,2,3-triazol-1-yl (optionally substituted) . [149] Another preferred group of compounds is that both A and B are oxazolidinone rings; R 2 a and R 2 b are both hydrogen; R 3 a and R 3 b are both hydrogen or both fluorine; R 1 a and R 1 b are —NH-HET-1 and HET-2, in particular HET-1 which is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and (optionally substituted) 1, Compound of formula (I) independently selected from HET-2 which is 2,3-triazol-1-yl or tetrazol-2-yl and having two central phenyl rings. [150] Another preferred group of compounds is that both A and B are oxazolidinone rings; R 2 a and R 2 b are both hydrogen; R 3 a and R 3 b are both hydrogen or both fluorine; R 1 a and R 1 b are hydroxy, —NHCOMe, —NHCOOMe, —NH-HET-1 and HET-2, in particular HET- which is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl 1 and (optionally substituted) 1,2,3-triazol-1-yl or tetrazol-2-yl are compounds of formula (I) independently selected. [151] Another preferred group of compounds is one of A and B is an oxazolidinone ring and the other is an isoxazoline ring; R 2 a and R 2 b are both hydrogen; R 3 a and R 3 b are both hydrogen or both fluorine; R 1 a and R 1 b are hydroxy, —NHCOMe, —NHCOOMe, —NH-HET-1 and HET-2, in particular HET- which is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl 1 and (optionally substituted) 1,2,3-triazol-1-yl or tetrazol-2-yl are compounds of formula (I) independently selected. [152] Another preferred group of compounds is that both A and B are oxazolidinone rings; One of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the other is hydrogen; R 1 a and R 1 b are compounds of formula (I) having two central phenyl rings independently selected from hydroxy, —NHCOMe and —NHCOOMe. [153] Another preferred group of compounds is that both A and B are oxazolidinone rings; One of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the other is hydrogen; R 1 a is hydroxy and R 1 b is a compound of formula (I) having two central phenyl rings which are HET-2, in particular 1,2,3-triazol-1-yl (optionally substituted). [154] Another preferred group of compounds is that both A and B are oxazolidinone rings; One of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the other is hydrogen; R 1 a is acetamido and R 1 b is a compound of formula (I) having two central phenyl rings which are HET-2, in particular 1,2,3-triazol-1-yl (optionally substituted) . [155] Another preferred group of compounds is that both A and B are oxazolidinone rings; One of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the other is hydrogen; R 1 a and R 1 b are NH-HET-1 and HET-2, in particular HET-1 which is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl, and (optionally substituted) 1, Compound of formula (I) having two central phenyl rings independently selected from HET-2 which is 2,3-triazol-1-yl. [156] Another preferred group of compounds is one of A and B is an oxazolidinone ring and the other is an isoxazoline ring; One of R 2 a, R 2 b, R 3 a and R 3 b is fluorine and the other is hydrogen; R 1 a and R 1 b are hydroxy, NHCOMe, NHCOOMe, -NH-HET-1 and HET-2, in particular HET-1 which is isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and A compound of formula (I) having two central phenyl rings independently selected from HET-2 which is (optionally substituted) 1,2,3-triazol-1-yl or tetrazol-2-yl. [157] Preferred compounds of the present invention include each individual compound described in the Examples, [158] In particular, (5S, 5S ')-N- (3- {4'-[5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2,2'-difluoro- Biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) -acetamide; [159] N-[((5S, 5'RS) -3- {4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4 -Yl] -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide; [160] (5R, 5RS ')-3- {2-fluoro-4'-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'biphenyl-4- Il} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one; [161] N-[((5S) -3- {4 '-[(5R) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4 -Yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide; [162] N-[((5S) -3- {4 '-[(5S) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4 -Yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide; And [163] (5R) -3- (3-fluoro-4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [164] This includes. [165] How-to section: [166] In a further aspect of the invention there is provided a process for preparing a compound of the invention or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof. It will be appreciated that some of the procedures below may require the protection of certain substituents to prevent unwanted reactions. The skilled chemist will know when such protection is needed, how such a protecting group can be placed, and then how to remove it. [167] One example of a protecting group is presented in one of a number of general textbooks, for example in Protective Groups in Organic Synthesis, Theodora Green (publisher: John Wiley & Sons). The protecting group can be removed by any convenient method known to the skilled chemist or appropriated to remove the protecting group in question, and such method will be chosen to remove the protecting group while minimizing interference of other groups in the molecule. . [168] Thus, if the reactants include groups such as, for example, amino, carboxy or hydroxy, it will be desirable to protect those groups in some of the reactions mentioned herein. [169] Suitable protecting groups for amino or alkylamino groups are, for example, acyl groups such as alkanoyl groups such as acetyl, alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, Arylmethoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. The deprotection conditions for the protecting group should depend on the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group is hydrolyzed using, for example, a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Can be removed by Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed by treatment with, for example, a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxy Carbonyl groups such as benzyloxycarbonyl groups can be removed, for example, by hydrogenation on a catalyst, for example palladium on carbon, or by treatment with a Lewis acid such as boron tris (trifluoroacetate). . Suitable alternative protecting groups for primary amino groups are phthaloyl groups which can be removed, for example, by treatment with alkylamines such as dimethylaminopropylamine or hydrazine. [170] Suitable protecting groups for hydroxy groups are, for example, acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl or arylmethyl groups such as benzyl. Deprotection conditions for the protecting group will depend on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed by hydrolysis with suitable bases such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively, arylmethyl groups, such as benzyl groups, can be removed, for example, by hydrogenation on a catalyst, for example palladium on carbon. [171] Suitable protecting groups for carboxyl groups are, for example, methyl or ethyl groups or acids, for example organic acids, for example trifluoroacetic acid, which can be removed by hydrolysis with an esterification group, for example a base such as sodium hydroxide. T-butyl groups which can be removed by a benzyl group which can be removed by hydrogenation on a catalyst such as for example palladium on carbon. Resins can also be used as protecting groups. [172] The protecting group can be removed at any convenient step using conventional techniques known in the chemical art. [173] The compounds of the present invention or their pharmaceutically acceptable salts or in vivo hydrolyzable esters may be prepared by any method known to be applicable to the preparation of chemically related compounds. When such a method is used to prepare a compound of the present invention or a pharmaceutically acceptable salt or hydrolysable ester thereof in vivo, it may be provided as an additional feature of the present invention and may be exemplified by the following exemplary embodiments. Necessary starting materials can be obtained by standard methods of organic chemistry (see, for example, Advanced Organic Chemistry (Wiley-Interscience), Jerry March). The preparation of such starting materials is described in the following non-limiting examples. Optionally, the necessary starting materials can be obtained by the exemplified analogous methods belonging to the general techniques of organic chemists. Information on the preparation of the necessary starting materials or related compounds (which may be adapted to form the necessary starting materials) may be presented in certain patent application publications, the contents of which are related to the process parts of which are incorporated herein by reference: For example WO 94-13649; WO 98-54161; WO 99-64416; WO 99-64417; WO 00-21960; WO 01-40222. [174] The skilled organic chemist will be able to apply the information contained in and referenced in the above references and the embodiments thereof and the embodiments herein to obtain the necessary starting materials and products. For example, the skilled chemist will be able to apply the teachings herein for compounds of formula (I) in which two central phenyl groups are present to produce compounds in which the C group is any E to L group as defined above. Similarly, the skilled chemist in the process exemplified below teaches for preparing compounds in which rings A and B are both isoxazolin and one of rings A and B is isoxazoline and the other is oxazolidinone Could be applied. [175] Thus, the present invention also provides that the compounds of the present invention and their pharmaceutically acceptable salts and in vivo hydrolyzable esters may be prepared by the following processes (a) to (d), where there is no indication Variables are as defined above): [176] a) by altering a substituent using standard chemistry methods or by introducing a substituent into another compound of the invention (e.g., Comprehensive Organic Functional Group Transformations (Pergamon), Katritzky, Meth-Cohn & Rees) Reference); For example, hydroxy groups are silyloxy, for example acylamino or thioacylamino groups, for example acetamide groups (optionally substituted or protected on amido-nitrogen atoms) acyloxy groups, for example acetoxy groups, hetero Cyclylamino groups (optionally substituted or protected on amino-nitrogen atoms) such as isoxazol-3-ylamino groups or 1,2,5-thiadiazol-3-ylamino groups, nitrogen (with linked nitrogen ring atoms Optionally substituted on carbon other than adjacent carbon atoms), eg, optionally 4-substituted 1,2,3-triazol-1-yl groups, or amidino groups, eg 1 Can be converted to a-(N-cyanoimino) ethylamino group; The conversion of the hydroxy group can be carried out directly (eg by acylation or Mitsunobu reaction) or via an intermediate of one or more derivatives (eg mesylate or azide); Acyloxy groups can be converted (either directly or through intermediates of hydroxy groups) to hydroxy groups or to groups obtainable from hydroxy groups; Silyloxy groups can be converted (either directly or through intermediates of hydroxy groups) to hydroxy groups or to groups obtainable from hydroxy groups; Acylamino group or thioacylamino group is another acylamino group or thioacylamino group, a heterocyclylamino group (optionally substituted or protected on an amino nitrogen atom), optionally substituted on carbon other than carbon adjacent to the connecting nitrogen atom ) Can be converted to a heterocyclyl group linked through nitrogen, for example, optionally a 4-substituted 1,2,3-triazol-1-yl group, or an amidino group; The conversion of the acylamino group can be carried out directly or through one or more derivatives such as amino groups; Heterocyclylamino groups (optionally substituted or protected on amino nitrogen atoms) are either refunctionalized by refunctionalization of amino-nitrogen atoms, for example by protection or deprotection, by the introduction of new ring substituents, Or can be converted to another heterocyclyl amino group (optionally substituted or protected on an amino-nitrogen atom) by refunctionalization of the ring substituent present; Heterocyclyl groups linked through nitrogen (optionally substituted on carbon other than the carbon atoms adjacent to the linked nitrogen ring atoms) are either by the introduction of new ring substituents or by refunctionalization of the ring substituents present, for example, 4- Another hetero linked via nitrogen (optionally substituted on a carbon atom other than a carbon atom adjacent to the linking nitrogen ring atom) by modifying the 4-substituent of the substituted 1,2,3-triazol-1-yl group Can be converted to a cyclyl group. [177] For example, an embodiment of a method of converting a hydroxy group to an optionally substituted triazole group is illustrated by the following scheme: [178] [179] Embodiments of the range of regioselective methods performed under very mild conditions include 4-substituted 1,2,3-tra by addition of Cu (I) -catalyzed cycloaddition at ambient temperature of azide and final alkyne in aqueous alcoholic solution Illustrated by the following scheme showing the provision of azoles (VV Rostovtsev, LG Green, VV Fokin, and KB Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599): [180] [181] b) aryl-aryl, hetero, by reaction of two molecules of a compound of formula (II), wherein X is a leaving group useful in palladium coupling, for example boronate, trimethyl tin, iodo and bromo An aryl-aryl or heteroaryl-heteroaryl bond is substituted with two aryl-X or heteroaryl-X bonds. Such methods are currently known (see, eg, S. P. Stanforth, Catalytic Cross-Coupling Reactions in Biaryl Synthesis, Tetrahedroit, 54 1998, 263-303). [182] [183] The leaving group X may be the same or different in the two molecules of formula (II). [184] Illustrated as follows: [185] [186] Similarly, these chemical reactions suggest that ring A is not identical to ring B, and X is appropriately selected to allow asymmetric coupling such that an aryl-aryl, heteroaryl-aryl or heteroaryl-heteroaryl bond can be substituted for two other aryl-X Or a heteroaryl-X bond. [187] Illustrated as follows [188] [189] Furthermore, these chemistries also show that two dissimilar molecules of formula II, ring C 'are not identical to ring C ", and X is suitably selected to allow asymmetric coupling such that aryl-aryl, heteroaryl-aryl or heteroaryl -Heteroaryl bonds can be applied to compounds in which two other aryl-X or heteroaryl-X bonds are substituted. [190] Illustrated as follows: [191] [192] c) Form an oxazolidinone ring at the ungrown aryl position by reaction of the (hetero) biaryl derivative (III) carbamate with an appropriately substituted oxirane. [193] [194] Carbamate is substituted (is substituted) with an isocyanate or amine and the oxirane is substituted with the same amount of reagent X—CH 2 CH (O—optionally protected) CH 2 R 1 a, where X is a substitutable group Alternative processes of this process are known in the art. [195] Illustrated as follows: [196] [197] d) reaction of (hetero) biaryl derivative (IV) to form isoxazoline ring at ungrown aryl position. [198] [199] Alternative methods of the present methods wherein the reactive intermediates (nitrile oxide IV ") are obtained by methods other than oxidation of oxime (IV ') are known in the art. [200] [201] For example, oxidation of an appropriately substituted biphenyl carboxaldehyde oxime in the presence of an appropriately substituted allyl derivative provides the isoxazoline of the required structure. [202] [203] Removal of any protecting groups, formation of pharmaceutically acceptable salts, and / or formation of hydrolyzable esters in vivo is within the general skill of organic chemists using standard techniques. Further details of these steps, for example the preparation of hydrolyzable ester prodrugs in vivo, are provided in the section on such esters, for example. [204] If an optically active form of a compound of the invention is desired, one of the above methods using an optically active starting material (for example formed by asymmetric induction of the appropriate reaction step), or a compound or intermediate using standard methods Can be obtained by dividing the racemic form of or by chromatographic separation of diastereomers (if generated). Enzymatic techniques can also be used to prepare optically active compounds and / or intermediates. [205] Similarly, where pure regioisomers of the compounds of the present invention are desired, by performing one of the above methods using pure regioisomers as starting material or by cleavage of mixtures of regioisomers or intermediates using standard methods Can be obtained. [206] According to a further feature of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of treatment of the human or animal body. [207] According to a further feature of the invention there is provided an antimicrobial agent for administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof or a hydrolysable ester in vivo to a warm-blooded animal in need of antimicrobial treatment, eg, a human. Provides a way to provide an effect. [208] The invention also relates to the preparation of a compound of the invention for use as a medicament or a pharmaceutically acceptable salt or hydrolyzable ester thereof in vivo and a medicament for use in providing an antimicrobial effect to a warm blooded animal such as a human. The use of a compound, a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo is provided. [209] In vivo hydrolyzable esters or pharmaceutically acceptable salts thereof, including compounds of the present invention, in vivo hydrolyzable esters pharmaceutically acceptable salts (hereinafter referred to as "compounds of the present invention" for pharmaceutical compositions) Is generally formulated according to standard pharmaceutical methods as a pharmaceutical composition for use in the treatment (including prevention) of mammals, including humans, in particular for the treatment of infections. [210] Thus, in another aspect of the invention, in vivo hydrolyzable esters or pharmaceutically acceptable salts thereof, including the compounds of the invention, pharmaceutically acceptable salts of in vivo hydrolyzable esters, and pharmaceutically acceptable diluents or carriers It provides a pharmaceutical composition comprising a. [211] Pharmaceutical compositions of the invention may be administered in standard manner for disease states that require treatment, for example by oral, rectal or parenteral administration. For this purpose the compounds of the invention can be prepared by known methods, for example tablets, capsules, aqueous or oily solutions or suspensions, lipids (emulsions), dispersible powders, suppositories, ointments, creams, aerosols (or sprays), drops and sterile. It may be formulated in the form of an injectable aqueous or oily solution or suspension. [212] In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain other clinically useful antibacterial agents (eg, 6-lactam or aminoglycosides) and / or other anti-infective agents (eg, antifungal triazoles). Or amphotericin) together with one or more known drugs, or co-administered (simultaneously, continuously, or separately). These may include carbapenems such as meropenem or imipenem, which extend the therapeutic effect. Compounds of the present invention may also be included or coadministered with sterile / permeable-increasing protein (BPI) products or effluent pump inhibitors that increase activity against Gram-negative and antibiotic resistant bacteria. [213] Suitable pharmaceutical compositions of the present invention are those suitable for oral administration in unit dosage form, eg, in tablets or capsules containing from 1 mg to 1 g of a compound of the invention, preferably from 100 mg to 1 g of a compound. Especially preferred are tablets or capsules comprising 50 mg to 800 mg, in particular 100 mg to 500 mg of the compound of the invention. [214] In another aspect of the invention intravenous, subcutaneous or intramuscular injection of a pharmaceutical composition of the invention, for example from 0.1% w / v to 50% w / v (1 mg / ml to 500 mg / ml) of a compound of the invention It is suitable for injection containing. [215] Each patient may be taken daily intravenously, subcutaneously or intramuscularly, for example at a dose of 0.5 mg / kg to 20 mg / kg of a compound of the invention, and the composition may be administered 1 to 4 times a day. In another embodiment, a daily dose of 5 mg / kg to 20 mg / kg of a compound of the invention is administered. Intravenous, subcutaneous and intramuscular administration can be performed by bolus injection. Alternatively, intravenous administration may be performed by continuous infusion over the period. Alternatively, each patient may be given a daily oral dose, which may be approximately equivalent to a daily rectal dose, and the composition may be administered 1 to 4 times per day. [216] Pharmaceutical compositions taken intravenously may preferably comprise an appropriate pesticide, antioxidant or reducing agent or suitable sequestrant (for example to enhance stability). [217] Other pharmaceutical compositions, processes, methods, uses and pharmaceutical preparation features, as well as optional preferred embodiments of the compounds of the present invention, may also apply. [218] Antimicrobial activity: [219] Pharmaceutically acceptable compounds of the present invention are useful antimicrobial agents with an excellent spectrum of in vivo activity against standard Gram-positive organisms and have been screened for activity against pathogens. As is well known, the pharmaceutically acceptable compounds of the present invention are enterococcci, pneumococci and S. aureus together with haemophilus and Moraxella strains. And the activity against methicillin resistant strains of coagulase negative staphylococci. The antimicrobial spectrum and effectiveness of certain compounds can be measured in standard test systems. [220] The (antibacterial) properties of the compounds of the present invention can also be demonstrated and analyzed in vivo in conventional trials, for example, by taking the compounds in warm-blooded mammals orally and / or intravenously using standard techniques. [221] The following results were performed on a standard in vitro system. Activity is shown as the minimum inhibitory concentration (MIC) measured by agar-dilution technique using an inoculum size of 10 4 CFU / spot. Generally compounds are active in the range of 0.01 to 256 μg / ml. [222] Staphylococci were tested using standard test conditions for the expression of methicillin resistance for 24 hours at an inoculum of 10 4 CFU / spot on agar and an incubation temperature of 37 ° C. [223] Streptococci and enterocoxy were assessed for 48 h in an atmosphere of 5 4 carbon dioxide at an inoculum of 10 4 CFU / spot and incubation temperature of 37 ° C. on agar supplemented with 5% de-fibrinated horse blood, and blood was Required for the growth of some of the test organisms. Pastidius gram negative organisms were tested in Mueller Hinton broth (MHB) using 5 × 10 4 CFU / well of inoculum, supplemented with hemin and NAD, and grown aerobicly at 37 ° C. for 24 hours. [224] For example, the following results were obtained for the compound of Example 1: [225] organismM1C (gg / ml) [226] Staphylococcus aureus: MSQS 0.25 [227] (Staphylococcus aureus) MRQR 0.5 [228] Streptococcus pneumoniae 0.06 [229] Streptococcus pyogenes 0.13 [230] Haemophilus influenzae 2.0 [231] Moraxella catarrhalis 0.5 [232] MSQS = methicillin sensitivity and quinolone sensitivity [233] MRQR = methicillin resistance and quinolone resistance [234] Certain intermediates and / or reference examples described below are included within the scope of the present invention, and may also have useful activities, and are provided as additional features of the present invention. [235] The present invention is illustrated by, but not limited to, the following examples, unless otherwise indicated: (1) evaporation is carried out by rotary evaporator in vacuum, and the finishing process is carried out after removal of residual solids by filtration; (ii) the operation is carried out at ambient temperature, which is generally in the range of 18 to 26 ° C. and does not vent air unless otherwise technical or skilled in the art does not work in an inert atmosphere; (iii) column chromatography (by flash process) was used to purify the compound and was carried out on Merck Kisselel silica (Art. 9385) unless otherwise indicated; (iv) yields are given by way of example and are not necessarily the maximum possible values; (v) The structure of the final product of the present invention is generally confirmed by NMR and mass structure techniques [the proton magnetic resonance spectrum is a Varian Gemini 2000 spectrometer or 250 MHz magnetic field operating at a magnetic field of 300 MHz unless otherwise stated. Measured in DMSO-d 6 used in Bruker AM250 spectrometer operated at, chemical shifts are given in ppm downfield from tetramethylsilane as internal standard, peak multiplicity is s, singlet; d, doublet; AB or dd, doublet of doublets; dt, triplet of triplets; dm, doublet of multiplets; t, triplet; m, multiplet; br, presented broadly; Fast-atom bombardment (FAB) mass spectrometry data is generally obtained using a platform spectrometer (supplied by micromass) run by electrospray and, where appropriate, cation data or anion data collected; Optical rotation was measured at 589 nm at 20 ° C. in 0.1 M solution in methanol using a Perkin Elmer polarimeter 341; (vi) each intermediate was purified to the standards required in subsequent steps and characterized with sufficient detail to confirm the accuracy of the designated structure; Purity was analyzed by HPLC, TLC or NMR, and identity was determined by infrared (red) analysis, mass spectrometry or NMR analysis as appropriate; (vii) The following abbreviations may be used: [236] DMF is N, N-dimethylformamide; DMA is N, N-dimethylacetamide; TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; DMSO is dimethyl sulfoxide; CDCl 3 deuterated chloroform; MS is mass spectrometry; ESP is electrospray; EI is an electron impact; CI is chemical ionization; APCI is atmospheric pressure chemical ionization; EtOAc is ethyl acetate; MeOH is methanol; Phosphoryl is (HO) 2 -P (O) -O-; Phosphyryl is (HO) 2 -PO-; Bleach is “Clorox” 6.15% sodium hypochlorite; [237] (viii) Temperature is shown in degrees Celsius (° C.). [238] In some cases the synthesis of the intermediates used will be described below. [239] [3- (4-Bromo-phenyl) -4,5-dihydro-isoxazol-5-yl] -methanol [240] [241] 4-Bromo-benzaldehyde oxime (162 g, 789.9 mmol) and allyl alcohol (130.5 ml) were added with tetrahydrofuran (1000 ml) followed by bleach (5305 ml). The reaction was cooled to 0 ° C. and stirred for 3 hours. The precipitate was collected and washed with water (2x300 ml) to afford the desired product (137 g). [242] [243] Methanesulfonic acid 3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl ester [244] [245] [3- (4-Bromo-phenyl) -4,5-dihydro-isoxazol-5-yl] -methanol (84.3 g, 328 mmol) was added with anhydrous dichloromethane (500 ml), followed by triethyl Amine (64.1 ml, 459.2 mmol) was added. The solution was cooled to 0 ° C. and methane sulfonyl chloride (30.65 ml, 396 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 2 hours, then aqueous sodium bicarbonate (200 ml) was added. After further extraction of dichloromethane (2x200 ml), the organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (110 g). [246] [247] 5-azidomethyl-3- (4-bromo-phenyl) -4,5-dihydro-isoxazole [248] [249] Methanesulfonic acid 3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl ester (55 g, 164.2 mmol) is added with dimethyl formamide (200 ml), followed by sodium azide (21.4 g, 328.4 mmol) was added. The mixture was heated to 75 ° C. for 6 h, then added with aqueous sodium chloride (300 ml) and extracted with ethyl acetate (3 × 300 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (52 g). [250] [251] [3- (4-Bromo-phenyl) -4,5-dihydro-isoxazol-5-yl] -methylamine [252] [253] 5-azidomethyl-3- (4-bromo-phenyl) -4,5-dihydro-isoxazole (52 g, 184.4 mmol) was dissolved in dichloromethane: methanol: water 16: 5: 1 (440 ml). After dissolving, 200 grams of polystyrene-linked triphenylphosphine resin (1.6 mmol / g) was added. The mixture was stirred for 16 hours and filtered. The resin was washed with dichloromethane (200 ml) and methanol (100 ml), and then the solvent was concentrated in vacuo to afford the desired product (47 g). [254] [255] N- [3- (4-Bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -acetamide [256] [257] [3- (4-Bromo-phenyl) -4,5-dihydro-isoxazol-5-yl] -methylamine (10 g, 39.1 mmol) and triethylamine (8.2 ml, 58.6 mmol) were diluted with anhydrous dichloromethane. (100 ml) and cooled to 0 ° C. Acetyl chloride (3.0 ml, 43.6 mmol) was then added dropwise, the reaction was stirred for 3 hours and ethyl acetate (200 ml) was added. The precipitate was collected, washed with water (2 x 100 ml) and finally with ethyl ether (2 x 50 ml) to afford the desired product (6.9 g). [258] [259] 1- [3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -1H- [1,2,3] triazole [260] [261] 5-azidomethyl-3- (4-bromo-phenyl) -4,5-dihydro-isoxazole (12.3 g, 43.6 mmol) and bicyclo [2.2.1] hepta-2,5-diene (23.6 ml, 218.1 mmol) was added with dioxane (200 ml), heated to 100 ° C. and stirred for 6 hours. The reaction mixture was concentrated in vacuo, then ethyl ether (200 ml) was added. The precipitate was collected, washed with ethyl ether (3 x 20 ml) and dried under nitrogen to give the desired product (8.8 g). [262] [263] 1- [3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -4-methyl-1H- [1,2,3] triazole [264] [265] [3- (4-Bromo-phenyl) -4,5-dihydro-isoxazol-5-yl] -methylamine (10 g, 39.1 mmol) and diisopropylethylamine (33.9 ml, 195.3 mmol) were made anhydrous. Methanol (100 ml) was added and N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonylhydrazide (14.9 g, 50.8 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature and then ethyl acetate was added. The precipitate was collected and washed with water (2 x 50 ml) to afford the desired product (4.49 g). [266] [267] [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-yl] -methanol [268] [269] 4-Bromo-3-fluoro-benzaldehyde oxime (55.7 g, 265.3 mmol) and allyl alcohol (44 ml) were added with tetrahydrofuran (300 ml) followed by bleach (1791 ml). The reaction was stirred for 4 hours and extracted with tetrahydrofuran (2 × 200 ml). The organic layers were combined, dried over sodium sulphate and concentrated in vacuo to afford the desired product (66 g). [270] [271] Methanesulfonic acid 3- (4-bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl ester [272] [273] [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-yl] -methanol (30 g, 112.4 mmol) was added with anhydrous dichloromethane (300 ml). Triethylamine (21.8 ml, 157.3 mmol) was added. The solution was cooled to 0 ° C. and methane sulfonyl chloride (10.4 ml, 134.8 mmol) was added dropwise. The reaction was stirred for 2 h at 0 ° C. and then aqueous sodium bicarbonate (100 ml) was added. After dichloromethane (2x100 ml) was extracted, the organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (38.7 g). [274] [275] 5-azidomethyl-3- (4-bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazole [276] [277] Methanesulfonic acid 3- (4-bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl ester (38.6 g, 111.9 mmol) was added as dimethyl formamide (100 ml). Then, sodium azide (14.5 g, 223.8 mmol) was added. The mixture was heated to 75 ° C. for 5 hours, then added with aqueous sodium chloride (200 ml) and then extracted with ethyl acetate (3 × 200 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (31 g). [278] [279] [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-yl] -methylamine [280] [281] 5-Azidomethyl-3- (4-bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazole (31 g, 106.2 mmol) was added to dichloromethane: methanol: water 16: 5: 1 (215 ml) and 100 grams of polystyrene bound triphenylphosphine resin (1.6 mmol / g) were added. The mixture was stirred for 16 hours and filtered. The resin was washed with dichloromethane (100 ml) and methanol (50 ml), then the solvent was concentrated in vacuo to afford the desired product (27.9 g). [282] [283] N- [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -acetamide [284] [285] [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-yl] -methylamine (9 g, 33.8 mmol) and triethylamine (7 ml, 50.8 mmol) was added with anhydrous dichloromethane (100 ml) and cooled to 0 ° C. Acetyl chloride (2.8 ml, 40.6 mmol) was then added dropwise, the reaction was stirred for 3 hours and ethyl acetate (200 ml) was added. The precipitate was collected and washed with water (2 x 50 ml) to afford the desired product (5 g). [286] [287] 1- [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-ylmethyl] -4-methyl-1H- [1,2,3] triazole [288] [289] [3- (4-Bromo-3-fluoro-phenyl) -4,5-dihydro-isoxazol-5-yl] -methylamine (9 g, 33.8 mmol) and diisopropylethylamine (21.8 ml , 169.5 mmol) was added with anhydrous methanol (100 ml), followed by N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonylhydrazide (12.9 g, 43.9 mmol) Was added. The reaction was stirred at rt for 4 h and then ethyl acetate was added. The precipitate was collected and washed with water (2 × 50 ml) to afford the desired product (3.89 g). [290] [291] 5-Bromo-pyridine-2-carbaldehyde oxime [292] [293] 5-Bromo-pyridine-2-carbaldehyde (60 g, 322 mmol) was added with methanol (700 ml), followed by water (700 ml), followed by hydroxylamine hydrochloride (28 g 403 mmol) was added. Sodium carbonate (20.5 g, 193.2 mmol) in water (200 ml) was added and the reaction stirred for 30 minutes. Water (500 ml) was then added and the precipitate was filtered off and washed with water (2 × 300 ml) to afford the desired product (60 g). [294] [295] [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-yl] -methanol [296] [297] 5-Bromo-pyridine-2-carbaldehyde oxime (60 g, 298.5 mmol) and allyl alcohol (49.7 ml) were added with tetrahydrofuran (200 ml) followed by bleach (2016 ml). The reaction was stirred for 4 hours and then tetrahydrofuran (2 × 200 ml) was extracted. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (38. 8 g). [298] [299] Methanesulfonic acid 3- (5-bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl ester [300] [301] [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-yl] -methanol (38.8 g, 150.5 mmol) was added with anhydrous dichloromethane (200 ml) Then triethylamine (29.2 ml, 210.7 mmol) was added. The solution was cooled to 0 ° C. and then methane sulfonyl chloride (12.3 ml, 180.6 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 2 hours and then aqueous sodium bicarbonate (100 ml) was added. Further extraction with dichloromethane (2 x 100 ml), organic layers were combined, dried over sodium sulphate and concentrated in vacuo to afford the desired product (30.5 g). [302] [303] 5-azidomethyl-3- (5-bromo-pyridin-2-yl) -4,5-dihydro-isoxazole [304] [305] Methanesulfonic acid 3- (5-bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl ester (30.5 g, 90.77 mmol) was added with dimethyl formamide (50 ml) Then, sodium azide (11.8 g, 181. 5 mmol) was added. The mixture was heated to 75 ° C. for 5 hours, then added with aqueous sodium chloride (100 ml) and then extracted with ethyl acetate (3 × 200 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (15 g). [306] [307] [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-yl] -methylamine [308] [309] 5-azidomethyl-3- (5-bromo-pyridin-2-yl) -4,5-dihydro-isoxazole (4.4 g, 115.6 mmol) was added to dichloromethane: methanol: water 16: 5: 1 ( 88 ml) and then 25 grams of polystyrene bound triphenylphosphine resin (1.6 mmol / g) was added. The mixture was stirred for 16 hours and filtered. The resin was washed with dichloromethane (50 ml) and methanol (25 ml), and then the solvent was concentrated in vacuo to afford the desired product (3 g). [310] [311] N- [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -acetamide [312] [313] 5-azidomethyl-3- (5-bromo-pyridin-2-yl) -4,5-dihydro-isoxazole (3 g, 10.6 mmol) and thioacetic acid (10 ml) were combined and stirred for 52 hours I was. The reaction mixture was concentrated in vacuo, then ethyl acetate (20 ml) was added. The resulting precipitate was filtered and then washed with ethyl acetate (2 × 20 ml) to afford the desired product (1.8 g). [314] [315] 1- [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -1 H-1,2,3-triazole [316] [317] 5-azidomethyl-3- (5-bromo-pyridin-2-yl) -4,5-dihydro-isoxazole (1 g, 3.5 mmol) and bicyclo [2.2.1] hepta-2,5- Diene (1 ml) was combined with dioxane (2 ml) and added to microwave radiation in a Smith Personal Synthesizer at 900C for 900 seconds. The reaction mixture was concentrated in vacuo to add ethyl acetate (5 ml). The precipitate was filtered off and extracted with ethyl acetate (2 × 5 ml) to afford the desired product (417 mg). [318] [319] 1- [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -4-methyl-1H-1,2,3-triazole [320] [321] [3- (5-Bromo-pyridin-2-yl) -4,5-dihydro-isoxazol-5-yl] -methylamine (3.4 g, 13.3 mmol) and diisopropylethylamine (11.8 ml, 66.3 mmol) was added with anhydrous methanol (25 ml), followed by N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonylhydrazide (5.1 g, 17.3 mmol). Added. The reaction was stirred at rt for 4 h and then ethyl acetate was added. The precipitate was collected and washed with water (2 x 25 ml) to afford the desired product (793 mg). [322] [323] [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-yl] -methanol [324] [325] 5-Bromo-thiophene-2-carbaldehyde oxime (40.2 g, 195.2 mmol) and allyl alcohol (32.4 ml) were added with tetrahydrofuran (200 ml) followed by bleach (1318 ml). . The reaction was stirred for 4 hours and extracted with tetrahydrofuran (2 × 200 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (19 g). [326] [327] Methanesulfonic acid 3- (5-bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl ester [328] [329] [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-yl] -methanol (10.7 g, 40.6 mmol) was added with anhydrous dichloromethane (200 ml) , Triethylamine (7.9 ml, 56.9 mmol) was added. The solution was cooled to 0 ° C. and methane sulfonyl chloride (3.8 ml, 48.7 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 2 hours and then aqueous sodium bicarbonate (100 ml) was added. After extraction with dichloromethane (2 x 100 ml), the organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (9 g). [330] [331] 5-azidomethyl-3- (5-bromo-thien-2-yl) -4,5-dihydro-isoxazole [332] [333] Methanesulfonic acid 3- (5-bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl ester (9 g, 26.4 mmol) was added with dimethyl formamide (25 ml) Then, sodium azide (3.4 g, 52.8 mmol) was added. The mixture was cooled to 75 ° C. for 5 hours, then added with aqueous sodium chloride (100 ml) and then extracted with ethyl acetate (3 × 200 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the desired product (7.4 g). [334] [335] [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-yl] -methylamine [336] [337] 5-azidomethyl-3- (5-bromo-thien-2-yl) -4,5-dihydro-isoxazole (5 g, 17.4 mmol) was added to dichloromethane: methanol: water 16: 5: 1 (88 in ml), and then 20 g of polystyrene-bound triphenylphosphine resin (1.6 mmol / g) was added. The mixture was stirred for 16 hours and filtered. The resin was washed with dichloromethane (50 ml) and methanol (25 ml), and then the solvent was concentrated in vacuo to afford the desired product (4.3 g). [338] [339] N- [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -acetamide [340] [341] [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-yl] -methylamine (2.1 g, 8 mmol) and triethylamine (1.7 ml, 12 mmol ) Was added with anhydrous dichloromethane (50 ml) and cooled to 0 ° C. Acetyl chloride (0.670 ml, 9.6 mmol) was then added dropwise, the reaction was stirred for 3 hours and ethyl acetate (100 ml) was added. The precipitate was collected and washed with water (2 x 25 ml) to afford the desired product (1.2 g). [342] [343] 1- (3- (5-Bromo-thien-2-yl) -4 5-dihydro-isoxazol-5-ylmethyl] -1H-1,2,3-triazole [344] [345] 5-azidomethyl-3- (5-bromo-thien-2-yl) -4,5-dihydro-isoxazole (500 mg, 1.74 mmol) and bicyclo [2.2.1] hepta-2,5 Diene (1 ml) was combined using dioxane (2 ml) and microwave radiated in a Smith personal synthesizer at 125 ° C. for 900 seconds. The reaction mixture was concentrated in vacuo and ethyl acetate (5 ml) was added. The precipitate was filtered off, washed with ethyl acetate (2 x 5 ml) to afford the desired product (234 mg). [346] [347] 1- [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-ylmethyl] -4-methyl-1H-1,2,3-triazole [348] [349] [3- (5-Bromo-thien-2-yl) -4,5-dihydro-isoxazol-5-yl] -methylamine (2.2 g, 8. 4 mmol) and diisopropylethylamine (7.3 ml, 42 mmol) was added with anhydrous methanol (50 ml), followed by N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonohydrazide (3.2 g, 10.9 mmol ) Was added. The reaction was stirred at rt for 4 h and then ethyl acetate was added. The precipitate was collected and washed with water (2 × 25 ml) to afford the desired product (793 mg). [350] [351] (5R) -3- (5-bromopyrid-2-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate [352] [353] (5R) -3- (5-bromopyrid-2-yl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one (15.4 g, 56.4 mM) in methylene chloride (150 ml )). Triethylamine (8.00 g, 78. 9 mM) was added and the solution was degassed. Methanesulfonyl chloride (7.75 g, 67.7 mM) was added dropwise and the reaction stirred for 0-4 hours. The mixture was diluted with aqueous sodium bicarbonate and the compound extracted with methylene chloride. The organic layer was washed with brine, dried (magnesium sulfate) and evaporated to give a bright orange solid (21.24 g). [354] [355] (5R) -5- (azidomethyl) -3- (5-bromopyrid-2-yl) -1,3-oxazolidin-2-one [356] [357] (5R) -3- (5-Bromopyrid-2-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate (21.24 g, 56.4 mM) in N, N- It was dissolved in dimethylformamide (200 ml). Sodium azide (7.33 g, 113 mM) was added and the reaction heated at 75 ° C. for 16.5 h. The mixture was cooled, diluted with ethyl acetate, washed with sodium bicarbonate, then with water, dried (magnesium sulfate) and evaporated in vacuo to give a pale yellow solid (16.8 g). [358] [359] (5R) -3- (5-bromopyrid-2-yl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [360] [361] (5R) -5- (azidomethyl) -3- (5-bromopyrid-2-yl) -1,3-oxazolidin-2-one (5.60 g, 18.7 mM) in 1,4-di It was dissolved in oxane (12 ml). Bicyclo [2.2.1] hepta-2,5-diene (10.3 g, 112 mM) was added and the yellow solution was stirred at 100 ° C. for 16 h. The brown solution was concentrated and the residue was purified by flash chromatography eluting with ethyl acetate. The relevant fractions were combined to give the desired product (4.36 g) as a beige solid. [362] [363] N-{[(5S) -3- (5-bromopyrid-2-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [364] [365] (5R) -5- (azidomethyl) -3- (5-bromopyrid-2-yl) -1,3-oxazolidin-2-one (5.60 g, 18.7 mM) in thioacetic acid (10 ml ) To give a yellow solution. The solution was degassed and stirred at room temperature for 20 hours. The thick slurry was concentrated and the desired product was crystallized from acetone (100 ml) to give a pale yellow solid (3.25 g). [366] [367] (5S) -5- (aminomethyl) -3- (5-bromopyrid-2-yl) -1,3-oxazolidin-2-one [368] [369] (5R) -5- (azidomethyl) -3- (5-bromopyrid-2-yl) -1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in acetonitrile: water ( 100: 10 ml). Triphenylphosphine (5.42 g, 20.7 mM) was added. The reaction mixture was degassed and stirred for 48 hours at room temperature. The light yellow liquid was concentrated and the residue was purified by flash chromatography eluting with ethyl acetate followed by 6% methanol in ethyl acetate. The relevant fractions were combined to give the desired product as a pale yellow solid (4.54 g). [370] [371] (5R) -3- (5-bromopyrid-2-yl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazoli Din-2-one [372] [373] (5S) -5- (aminomethyl) -3- (5-bromopyrid-2-yl) -1,3-oxazolidin-2-one (4.54 g, 16.7 mM) in methanol (100 ml) Dissolved. Diisopropylethylamine (5.86 g, 20.9 mM) was added and the reaction was cooled to 0 ° C. in a cold water bath. Toluenesulfonic acid 2- (2,2-dichloro-1-methylethylidene) hydrazide (5.86 g, 20.9 mM) was added as an orange solution. The reaction was stirred overnight while slowly warming to room temperature. The desired product was precipitated into a yellow solid (4.10 g) and filtered. [374] [375] (5R) -3- (4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [376] [377] (5R) -5- (azidomethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one (10.0 g, 29.1 mmol) in 1,4-dioxane (100 ml )). Bicyclo [2.2.1] hepta-2,5-diene (9.4 ml, 87.2 mmol) was added and the mixture was heated to 100 ° C. for 24 h. The solution was cooled and purified by silica flash chromatography (using 1-10% methanol in dichloromethane as eluent) to give 7.2 g of the desired product. [378] [379] (5S) -5- (aminomethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one [380] [381] (5R) -5- (azidomethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one (8.0 g, 23.2 mmol) was dissolved in acetonitrile (160 ml) and water ( 16 ml). Triphenylphosphine (7.3 g, 27.9 mmol) was added and the mixture was stirred at rt overnight. The volatiles were removed by concentration in vacuo and the resulting residue was partitioned between water (200 ml) and dichloromethane (200 ml). The aqueous layer was extracted with dichloromethane (2 x 200 ml) and dried over sodium sulfate. The crude material was purified by flash chromatography on silica gel using 0-10% methanol in dichloromethane as eluent to afford the desired product (6.0 g). [382] [383] (5R) -3- (4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine-2- On [384] [385] (5S) -5- (aminomethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one (6.0 g, 18.9 mmol) was added to methanol (150 ml, c = 0.1 M). Dissolved in and cooled to 0 ° C. Diisopropylethylamine (13.1 ml, 75.4 mmol) was added and the reaction stirred at 0 ° C. for 5 minutes; Toluene sulfonic acid 2- (2,2-dichloro-1-methylethylidene) hydrazide was then added and the reaction stirred overnight. The volatiles were concentrated in vacuo, dichloromethane was added and some product crystallized out of solution; The residue was purified by flash chromatography on silica gel using 0-5% methanol in dichloromethane as eluent. The relevant fractions were combined to give 5.5 g of the desired product. [386] [387] (5R) -5- (azidomethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one [388] [389] [(5R) -3- (4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate (27 g, 68 mmol) was added to dimethylacetamide (300 ml). In water. Sodium azide (13.1 g, 202 mmol) was added carefully and the solution was heated to 80 ° C. for 3 hours. After cooling to rt, the mixture was diluted with ethyl acetate (500 ml), washed with water (2 ×), brine and dried over sodium sulfate. Purification by flash chromatography using 0-1% methanol in dichloromethane as eluent gave the desired product (19 g). [390] [391] [(5R) -3- (4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate [392] [393] [(5R) -3-phenyl-2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate (41 g, 152 mmol) was dissolved in chloroform / acetonitrile (250/250 ml). . Silver trifluoroacetate (50 g, 228 mmol) was added and iodine (58 g, 228 mmol) was added dropwise. The reaction was stirred overnight and the silver iodine was filtered off and the filtrate was washed with a solution of 5% sodium thiosulfate (2x500ml), saturated sodium bicarbonate (500ml), brine and dried over magnesium sulfate. The dry solution was evaporated to afford the desired product as a yellow solid (32 g) which was used without further purification. [394] [395] [(5R) -3-phenyl-2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate [396] [397] J. Med. Chem. (W.A. Gregory et al., 32, 1673-1681 (1989)) [398] [5R) -5- (hydroxymethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one [399] [400] WO 99/64417 (M.B. Gravestock) [401] [(5R) -3- (4-iodophenyl) -2-oxo-1,3-oxazolidin-5-ylmethyl acetate [402] [403] J. Med. Chem. (W.A. Gregory et al., 33,2569-2578 (1990)). [404] [(5R) -3-phenyl-2-oxo-1,3-oxazolidin-5-yl] methyl acetate [405] [406] J. Med. Chem. (W.A. Gregory et al., 32, 1673-1681 (1989)). [407] Example [408] Example 1: (5S, 5'S) -N- (3- {4 '-[5- (acetylamino-methyl) -2-oxo-oxazolidin-2-yl] -2,2'-difluoro -Biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) -acetamide [409] [410] (5S) -N- [3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] acetamide (150 mg, 0.4 mM; upzone WO 94-13649 And tetrabutylammonium bromide (129 mg, 0.4 mM) in a mixture of N, N-dimethylformamide (0.5 ml) and triethylamine (210 mg, 2 mM) and degassing by passing nitrogen through a bubble It was. Palladium (II) acetate (8 mg, 0.04 mM) was added and the whole was heated at 70 ° C. for 18 hours. The mixture was cooled, diluted with ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2x20 ml), dried (magnesium sulfate) and evaporated. The residue was purified by chromatography eluting with 0-100% gradient ethyl acetate in dichloromethane with increased polarity on a 10 g silica mega bond Elut® column, followed by 0-20% methanol in dichloromethane. It was. The relevant fractions were combined and triturated with a small amount of methanol to afford the desired product (47 mg). [411] [412] Example 2: Acetic acid (5R, 5'R) -3- [4 '-(5-acetoxymethyl-2-oxo-oxazolidin-3-yl) -2,2'-difluoro-biphenyl -4-yl] -2-oxo-oxazolidin-5-ylmethyl ester [413] [414] Essentially using the procedure of Example 1 but acetic acid (5R) -3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester (3.79 g, 10 mM) was used as starting material to give the title compound (0.94 g) after chromatography. [415] [416] Intermediates for the compounds were prepared as follows: [417] Acetic acid (5R) -3- (3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester [418] (5R) -3- (3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one (40 g, 0.189 M, upzone WO 94-13649) in anhydrous dichloromethane (400 ml) under nitrogen It was suspended with stirring. Triethylamine (21 g, 0.208 M) and 4-dimethylaminopyridine (0.6 g, 4.9 mM) were added followed by the dropwise addition of acetic anhydride (20.3 g, 0.199 M) over 30 minutes and ambient temperature for 18 hours. Stirring was continued at. Saturated aqueous sodium bicarbonate (250 ml) was added and the organic phase was separated, washed with 2% sodium bicarbonate, dried (magnesium sulfate), filtered and evaporated to afford the desired product as an oil (49.6 g). [419] [420] Acetic acid (5R) -3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester [421] Acetic acid (5R) -3- (3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester (15.2 g, 60 mM) under a nitrogen mixture of acetonitrile (100 ml) and chloroform (100 ml) In water and silver trifluoroacetate (16.96 g, 77 mM) was added. Iodine (18.07 g, 71 mM) was added portionwise to the vigorously stirred solution for 30 minutes and stirring continued at ambient temperature for 18 hours. A small amount of silver trifluoroacetate (2.64 g, 12 mM) was added before the reaction was complete and stirring continued for 18 hours. After filtration, the mixture is added with sodium thiosulfate solution (3%, 200 ml) and dichloromethane (200 ml), the organic phase is separated, sodium thiosulfate (200 ml), aqueous sodium bicarbonate (200 ml), brine (200 ml) Washed with, dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 ml) and sufficient diethyl ether was added and stirred for 1 hour to dissolve the brown impurities. The filtrate provided the desired product (24.3 g) as a cream solid. [422] [423] Example 3: (5R, 5'R) -4,4'-bis- (5-hydroxymethyl-2-oxo-oxazolidin-3-yl) -2, 2'-difluoro-biphenyl [424] [425] Acetic acid (5R, 5'R) -3- [4 '-(5-acetoxymethyl-2-oxo-oxazolidin-3-yl) -2,2'-difluoro-biphenyl-4-yl ] -2-oxo-oxazolidin-5-ylmethyl ester (940 mg, 1.86 mM) is stirred in a mixture of methanol (70 ml) and dichloromethane (60 ml) and potassium carbonate (600 mg, 4.34 mM) Was added and stirred at ambient temperature for 20 minutes. After addition of the minimum amount of acetic acid, the mixture was diluted with water (50 ml) and the organic solvent was evaporated to give an aqueous suspension. The solid was filtered off, washed with water and a small amount of diethyl ether and dried to afford the desired product (740 mg). [426] [427] Example 4: (5S, 5'S) -4,4'-bis- (5-isoxazol-3-ylaminomethyl-2-oxo-oxazolidin-3-yl) -2,2'-difluoro Biphenyl [428] [429] N- (5R, 5'R)-(3- {4 '-[5-N- (tert-butoxycarbonyl) isoxazol-3-ylamino-methyl) -2-oxo-oxazolidine-3 -Yl] -2,2'-difluoro-1,1'-biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) N-isoxazol-3-yl-carbamic acid tert-butyl ester (150 mg, 0.2 mM) was dissolved in dichloromethane (5 ml), treated with trifluoroacetic acid (5 ml), stirred at ambient temperature for 1 hour and the solvent was evaporated. The residue was treated with dilute aqueous ammonia, extracted with ethyl acetate (20 ml) and the organic layer was washed with water (10 ml), brine (10 ml), dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on a 10 g silica mega bond eluting column eluting with a gradient that increases the polarity of 0-10% methanol in dichloromethane. The relevant fractions were combined to give the title product (39 mg). [430] [431] Intermediates for the present compounds were prepared as follows: [432] (5R) -3- (3-fluoro-4-iodophenyl) -5-hydroxymethyloxazolidin-2-one [433] Acetic acid (5R) -3- (3-fluoro-4-iodophenyl) -2-oxo-oxazolidin-5-ylmethyl ester (30 g, 79 mM) was added to methanol (800 ml) for 25 minutes at ambient temperature. And potassium carbonate (16.4 g, 0.119 mM) in a mixture of dichloromethane (240 ml), followed by neutralization immediately by addition of acetic acid (10 ml) and water (500 ml). The precipitate was filtered off, washed with water, dissolved in dichloromethane (1.2 L) and the solution washed with saturated sodium bicarbonate and dried (magnesium sulfate). Filtration and evaporation gave the desired product (23 g). [434] [435] Methanesulfonic acid (5R) -3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester [436] (5R) -3- (3-fluoro-4-iodophenyl) -5- (hydroxymethyl) oxazolidin-2-one (6.07 g, 18 mM) in anhydrous dichloromethane (200 ml) was added under nitrogen. Treated with triethylamine (2.54 g, 25 mM) and methanesulfonyl chloride (2.47 g, 22 mM) was added dropwise at 0 ° C. over 30 minutes. After stirring at 0 ° C. for 2 hours, the mixture is diluted with water (200 ml), the organic layer is separated, hydrochloric acid (2N, 100 ml), sodium bicarbonate solution (5%, 100 ml), brine (100 ml) Washed with and dried (magnesium sulfate). After evaporation the residue was dissolved in a minimum amount of dichloromethane and excess isohexane was added to precipitate the desired product (7.05 g). [437] [438] N- (5R)-[3- (3-Fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] N-isoxazol-3-yl-carbamic acid [439] [440] N-isoxazol-3-yl-carbamic acid in N, N-dimethylformamide (10 ml) with sodium hydride (60% in oil, 9.04 mM) suspended in anhydrous N, N-dimethylformamide (10 ml) under nitrogen. tert-butyl ester (1.66 g, 9.04 mM) was added dropwise at ambient temperature. Methane sulfonic acid (5R) -3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxozolidin-5-ylmethyl ester (2.5 g, in N, N-dimethylformamide (10 ml) 6.02 mM) was slowly added dropwise and the mixture was heated to 75 ° C. for 2 hours. After cooling, the mixture was diluted with aqueous sodium bicarbonate (5%, 300 ml) and extracted with ethyl acetate (3 × 100 ml). The organic phase was washed with water (100 ml) and brine (100 ml), dried (magnesium sulfate), evaporated and chromatographed on a 50 g silica mega bond elut® column eluted with dichloromethane. Purified. The relevant fractions were combined to give the title compound (1.73 g). [441] [442] N- (5R)-[3- (3-Fluoro-4-trimethylstananyl-phenyl) -2-oxo-oxazolidin-5-ylmethyl] N-isoxazol- 3-yl-carbamic acid tert- Butyl ester [443] [444] N- (5R)-[3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] N-isoxazole-3- in dioxane anhydride (150 ml) The mono-carbamic acid tert-butyl ester (1.44 g, 2.86 mM) was degassed by passing nitrogen through a bubble, and a solution of hexamethylditin in dioxane (50 ml) (slight molar equivalent, excess) was then added. Bis (triphenylphosphine) palladium (II) chloride (0.1 mol, equivalent) was added. The mixture was heated at 110 ° C. for 20 hours, filtered through celite and the solvent was evaporated. The residue was purified by chromatography on 50 g silica mega bond elut® eluting with a 0% to 100% gradient of dichloromethane in isohexane. The relevant fractions were combined to give the desired product (1.2 g). [445] [446] N- (5R, 5'R)-(3- (4 '-[5-N (tert-butoxycarbonyl) isoxazol-3-ylamino-methyl) -2-oxo-oxazolidine-3- Ill] -2,2'-difluoro-biphenyl-4-yl} -2-oxo-oxazolidin-5-ylmethyl) N-isoxazol-3-yl-carbamic acid tert-butyl ester [447] [448] N- (5R)-[3- (3-Fluoro-4-trimethylstannyl-phenyl) -2-oxo-oxazolidin-5-ylmethyl] N-isoxazol-3-yl-carbamic acid tert- Butyl ester (540 mg, 1 mM) and copper iodide (I) (0.2 molar equivalents) were suspended in anhydrous N, N-dimethylformamide (3 ml) and degassed by passing nitrogen through a bubble. Tetrakis (triphenylphosphine) palladium (0) (0.05 molar equivalents) was added and the mixture was then heated under nitrogen at 70 ° C. for 18 hours. After cooling, a solution of potassium fluoride (10%, 10 ml) was added and the mixture was stirred for 15 minutes. After dilution with water (50 ml), the organic material is extracted with ethyl acetate (40 ml), the organic layer is washed with water (2x20 ml), brine (20 ml), dried (magnesium sulfate) and evaporated I was. The residue was purified by chromatography on a 20 g silica mega bond Elut® column eluting with an increased polarity of 0-100% gradient ethyl acetate in dichloromethane. The relevant fractions were combined to give the title compound (191 mg). [449] [450] Example 5: ((5R, 5'RS) -3- [2-Fluoro-4 '-[5'-(hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1, 1'-biphenyl-4-yl] -2-oxo-1,3-oxazolidin-5-yl) methyl acetate [451] [452] [(5R) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl acetate in tetrahydrofuran (6 ml) (500 mg, 1.32 mM; see Upon WO 94-13649) and triethylamine (0.55 mL) as a solution of dichloro [1,1'-bis (diphenylphosphinyl) ferrocene] palladium (II) dichloromethane additive (32 mg, 0.04 mM) , 3.96 mM), and pinacolborane (0.57 ml, 3.96 mM) was added. The mixture was stirred at 65 ° C. under nitrogen. After about 16 hours, water (600 μL), potassium carbonate (547 mg, 3.96 mM), palladium (II) acetate (15 mg, 0.07 mM), 2- (di-t-butylphosphinyl) biphenyl (79 mg , 0.26 mM) and [3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol (280 mg, 1.09 mM, see WO 98-07708 from Pharmacia Upzone) and produced The resulting mixture was stirred at 65 ° C. for about 36 hours. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. The residue was purified on silica gel with 75% ethyl acetate / hexanes to give 38 mg of the desired product. [453] [454] Example 6: N-[(5S, 5'RS) -3- {4 '-{5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole-3 -Yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide . [455] [456] N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acetamide (800 mg, 2.01 mM), ( 5RS) -3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole (746 mg, 2.01 mM), tris (di Benzylidene acetone) dipaladium (0) chloroform additive (83 mg, 0.080 mM), and tri-2-furylphosphine (37 mg, 0.16 mM) were placed under nitrogen atmosphere. Tetrahydrofuran (10 mL) was added and the solution was heated at 65 ° C. for 16 h. Additional tris (dibenzylideneacetone) dipaladium (0) chloroform additive (42 mg, 0.04 mM) and tri-2-furylphosphine (18 mg, 0.08 mM) are added and the solution is further 25 at 65 ° C. h stirred. The solution was cooled, adsorbed directly onto silica gel and chromatographed with neat ethyl acetate to give 870 mg of the desired product. [457] [458] The intermediate was prepared as follows: [459] (5RS) -3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole [460] [461] (5RS)-[3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol (6.0 g, 0.023 M, see Pharmacia & Upjohn WO98-07708), triethyl amine (3.9 mL, 0.028 M), and 4- (dimethylamino) pyridine (0.56 g, 4.58 mM) were combined in dichloromethane (36 mL). A solution of tert-butyldimethylsilyl chloride (1M in dichloromethane, 26 mL, 0.028 M) was added and the resulting mixture was stirred at rt for 16 h. The resulting mixture was poured into water and extracted with dichloromethane. The combined organics were dried (magnesium sulfate), filtered and evaporated. The crude was purified by chromatography on silica gel with 50% ethyl acetate / hexanes to give 8.4 g of the desired product. [462] [463] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole [464] See Example 8 for the preparation of this compound. [465] Example 7 N-[((5S, 5'RS) -3- {4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'- Biphenyl-4-yl-2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide. [466] [467] N-[((5S, 5'RS) -3- {4 '-{5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-di in tetrahydrofuran (20 ml) Hydroisoxazol-3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide (790 mg, 1.51 mM) solution To this was added 1.5 ml of a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran. This solution was stirred at room temperature for 45 min. Water (50 ml) was added and the solid product precipitated out. The solid was recrystallized from acetone to give the title compound (153 mg). [468] [469] Example 8 tert-Butyl N-((5R, 5'RS) -3- {4 '-[5-([[tert-butyl (dimethyl) silyl] oxy} methyl) -4-5-dihydroisox Sazol-3-yl] -2-fluoro-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl N- (isoxazol-3- I) carbamate. [470] [471] N- (5R)-[3- (3-Fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] -N-isoxazol-3-yl carbamic acid tert-butyl Ester (580 mg, 1.15 mM), tris (dibenzylidineacetone) dipaldium (0) (48 mg, 0.052 mM) and tri-2-furylphosphine (21 mg, 0.090 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (6 ml) was added. The resulting magenta solution was heated at 100 ° C. Within minutes, the solution turned brown and became 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4 in dioxane (2 ml), 5-dihydroisoxazole (733 mg, 1.61 mM) solution was added. The solution was stirred at 100 ° C. for 16 h. The reaction mixture was cooled down, adsorbed onto silica gel, eluted with 20% ethyl acetate / hexanes and chromatographed to give the desired product (636 mg). [472] [473] Intermediates of this compound were prepared as follows: [474] (5RS) -5-([tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole [475] [476] (5RS) -3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole (3.0 g, 8.10 mM) and bis ( Triphenylphosphine) palladium (II) chloride (285 mg, 0.41 mM) was placed under nitrogen. Anhydrous dioxane (30 ml) was added and the suspension was heated to 90 ° C. Hexamethylditin (3.00 g, 9.16 mM) was added and the resulting solution was stirred at 90 ° C. for 16 h. The solution is cooled and the solvent is evaporated. The residue was then eluted with 5% ethyl acetate / hexanes and purified by chromatography to give the desired product (3.4 g). [477] [478] Example 9 tert-butyl N-((5R, 5'RS) -3- {2-fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl ] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl N- (isoxazol-3-yl) carbamate. [479] [480] Tert-butyl N-((5R, 5'RS) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4-5 in tetrahydrofuran (10 ml) -Dihydroisoxazol-3-yl] -2-fluoro-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl N- (iso) To a solution of sazol-3-yl) carbamate (620 mg, 0.93 mM) was added a 1 M solution of tetrabutylammonium fluoride (1.00 ml, 1.00 mM) in tetrahydrofuran. The solution was stirred at rt for 1 h. Water (about 50 ml) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on silica gel using 75% ethyl acetate / hexanes to give the desired product as a white solid (477 mg). [481] [482] Example 10: (5S, 5'RS) -3- {2-Fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1' -Biphenyl-4-yl-5-[(isoxazol-3-ylamino) methyl] -1,3-oxazolidin-2-one. [483] [484] Tert-butyl N-((5R, 5'RS) -3- {2-fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazole- in dichloromethane (10 ml) 3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl N- (isoxazol-3-yl) carbamate (474 mg, 0.86 mM) trifluoroacetic acid (5 mL) was added and the solution stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel using 75% ethyl acetate / hexanes to 100% ethyl acetate to give 227 mg of the desired product. [485] [486] Example 11: (5R, 5'R) -4,4'-bis- (5- (1H-1,2,3-triazol-1-yl) methyl-2-oxo-oxazolidine-3- Yl) -2,2'-difluoro-biphenyl [487] [488] (5R) -3- (3-fluoro-4- (trimethylstannyl) phenyl) -5- (1H-1,2,3-triazol-1-ylmethyl)-in dimethylformamide (5 ml) A stirred mixture of 1,3-oxazolidin-2-one (425 mg, 1.0 mmol), 2-bromo-5-cyano-thiazole (189 mg, 1.0 mmol), and copper iodide (I) Purge with slow flowing nitrogen for 20 minutes, then tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol) was added. The stirred reaction mixture was kept at 70 ° C. for 5 hours in a nitrogen atmosphere. The stirred reaction mixture was treated with aqueous potassium fluoride (10%, 20 ml) and then stirred for 30 minutes and treated with ethyl acetate (20 ml). The precipitate was isolated by filtration to give a crude product A fraction. The organic layer was separated and dried (MgSO 4 ), treated with silica gel (500 mg) and evaporated under reduced pressure to leave a solid free-runnning. The solid was added to a silica gel column and eluted with dichloromethane-methanol (0% -10% methanol gradient) to give an additional non-pure fraction B. Fractions A and B were dissolved in DMSO (6 ml total), combined and purified by reverse phase hplc to afford the desired product (18 mg). [489] [490] Intermediates of this compound were prepared as follows: [491] (5R) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine- 2-on [492] [493] (5R) -3- (3-fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3- in dioxane (50 ml) A mixture of oxazolidin-2-one (5.39 g, 13.9 mmol) and hexamethylditin (5 g, 15.3 mmol) was added to dichlorobis (triphenylphosphine) palladium (II) (487 mg, 0.69 mmol) under nitrogen atmosphere. Treatment was followed by 90 minutes at 90 ° C. under a nitrogen atmosphere. Silica gel (5 g) was added, and then the solvent was removed under reduced pressure. The residual powder was placed on top of a silica gel column (100 g) (elutation of dichloromethane 1% methanol to 2.5% methanol in dichloromethane) to afford the desired product (4.545 g). [494] [495] Example 12: (5R) -3- {2-Fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl- 4-yl-5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl-1,3-oxazolidin-2-one [496] [497] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2-fluoro-1, 1'-biphenyl-4-yl} -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one (283 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature. Tetrabutylammonium fluoride 1M solution in tetrahydrofuran (0.5 ml, 0.5 mmol) was added and the reaction mixture was stirred for 30 minutes. The solvent was removed in vacuo and then dichloromethane (50 ml) was added. It was washed with water (50 ml), separated, dried (magnesium sulfate), filtered and then concentrated in vacuo on silica (2 ml). This was then chromatographed (silica gel lOg bond elut; 0-6% methanol / dichloromethane) to afford 150 mg (66%) of the desired compound. [498] [499] Intermediates of this compound were prepared as follows. [500] 3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole [501] [502] [3- (4-Bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol (4.44 g, 17 mmol) was added triethylamine (2.9 ml, 19 mmol) and dichloromethane (100 ml) Was dissolved in the mixture. The resulting solution was cooled to 0 ° C. and then a 1M solution of tert-butyldimethylsilylchloride (19 ml) in dichloromethane was added dropwise over 5 minutes. 4-dimethylamino pyridine (0.423 g, 3.4 mmol) was added and the remaining reaction mixture was stirred at rt overnight. A portion (19 ml) of tert-butyldimethylsilylchloride (2.9 ml, 19 mmol) in secondary dichloromethane and triethylamine was added and the remaining reaction mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and then dissolved in dichloromethane (200 ml) and washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo on silica gel (5 ml). These were again subjected to column chromatography (50 g silica gel bond elut: 0% to 50% ethyl acetate / hexanes) to give 5.405 g (84%) of the desired compound as white crystals. [503] [504] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole [505] [506] 3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole (5.403 g, 14.6 mmol) was dried 1,4-di It was dissolved in oxane (50 ml). The solution was placed under argon atmosphere. Hexamethylditin (5.26 g, 16 mmol) was added followed by bis (triphenylphosphine) palladium (II) chloride (0.512 g, 0.73 mmol). The reaction mixture was stirred at 90 ° C. for 90 minutes under argon atmosphere. The solvent was removed in vacuo and then the crude product was dissolved again in ethyl acetate (100 ml). Silica gel (5 ml) was added and the mixture was concentrated in vacuo. Then it was column chromatographed (50 g silica gel bond elute: 0% to 50% ethyl acetate / hexanes) to give 4.893 g (74%) of the desired compound as a colorless oil. [507] [508] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2-fluoro-1, 1'-biphenyl-4-yl} -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one [509] [510] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole (436 mg, 0.96 mmol), (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine- 2-one (386 mg, 0.96 mmol) and 2-trifurylphosphine (22 mg, 0.096 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture was placed under argon atmosphere. Tris (dibenzylideneacetone) dipaladium (0) chloroform additive (50 mg, 0.05 mmol) was added and the reaction mixture was stirred at 90 ° C. for 16 h. Secondary 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl-4,5-dihydroisoxazole (436 mg, 0.96 mmol), 2 -Trifurylphosphine (22 mg, 0.096 mmol) and tris (dibenzylidineacetone) dipaladium (0) chloroform additive (50 mg, 0.05 mmol) portions are added and the reaction mixture is further stirred at 90 ° C. for 20 hours. It was. Silica gel (2 g) was added and the mixture was concentrated in vacuo. It was purified by column chromatography (20 g silica gel bond ilut: 30% to 100% ethyl acetate / hexanes) to give 283 mg (52%) of the desired compound. [511] [512] Example 13: N-[((5S) -3- {2-fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1' -Biphenyl-4-yll-2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [513] [514] N-[((5S) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2-fluoro Rho-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide (164 mg, 0.3 mmol) was added tetrahydrofuran (5 ml). A solution of tetrabutylammonium fluoride in tetrahydrofuran (1M; 0.3 ml, 0.3 mmol) was added and the reaction mixture was stirred for 30 minutes. The solvent was removed in vacuo, then dichloromethane (2 ml) was added. Purification by chromatography (SiO 2 lOg bond ilut; 0-6% methanol / dichloromethane) gave a white solid. It was washed with water (50 ml) to give 37.9 mg (29%) of the desired product. [515] [516] Intermediates of this compound were prepared as follows. [517] N-[((5S) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2-fluoro Rho-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [518] [519] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole (427 mg, 0.94 mmol), N- { [(5S) -3- {3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide (355 mg, 0.96 mmol) and 2- Trifurylphosphine (22 mg, 0.094 mmol) was dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture was placed under argon atmosphere. Tris (dibenzylideneacetone) dipaladium (0) chloroform additive (49 mg, 0.05 mmol) was added and the reaction mixture was stirred at 90 ° C. for 16 h. Secondary 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole (427 mg, 0.94 mmol), 2-trifurylphosphine (22 mg, 0.094 mmol) and tris (dibenzylideneacetone) dipaladium (0) chloroform additive (49 mg, 0.05 mmol) are added and the reaction mixture is stirred at 90 ° C. for an additional 20 hours. It was. Silica gel (2 g) was added and the mixture was concentrated in vacuo. Purification by column chromatography (20 g silica gel bond elut: 30% to 100% ethyl acetate / hexanes) gave 170 mg (33%) of the desired compound. [520] [521] Example 14 N-[(3- {2-fluoro-4 '-[(5R) -5- (hydroxymethyl) -2-oxo-1,3-oxazolidin-3-yl] -1 , 1'-bisphenyl-4-yl} -4,5-dihydroisoxazol-5-yl) methyl] acetamide [522] [523] N-(({3- [3-fluoro-4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl] methyl} acetamide (600 mg, 1.5 mmol), (5S ) -5- (hydroxymethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one (319 mg, 1.0 mmol) and 2-trifurylphosphine (23 mg, 0.1 mmol) was dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture was placed under argon atmosphere. [524] Tris (dibenzylideneacetone) dipalladium (0) chloroform additive (52 mg, 0.05 mmol) was added and the reaction mixture was stirred at 90 ° C. for 16 h. Silica gel (0.5 g) was added and the mixture was concentrated in vacuo. Purification by column chromatography yielded a grayish white solid (lOg silica gel bond ilut: 0% to 5% methanol / dichloromethane). It was dissolved in dimethylsulfoxide (0.5 ml) and purified by reverse phase preparative HPLC using a 20% acetonitrile / water to 70% acetonitrile / water gradient to give 3.7 mg of the desired compound. [525] [526] The following example was prepared by a procedure similar to Example 14 above. [527] Example 15: N-[(3- {2,2'-difluoro-4 '-{(5R) -5 [(4-methyl-1H-1,2,3-triazol-1-yl) Methyl])-2-oxo-1,3-oxazolidin-3-yl] -1,1'-biphenyl-4-yl} -4,5-dihydroisoxazol-5-yl) methyl] acet amides [528] [529] [530] Example 16: N-[(3- {2,2'-difluoro-4 '-{(5R, S) -5-acetamidomethyl-4,5-dihydroisoxazol-5-yl] -1,1'-biphenyl-4-yl} -4,5-dihydroisoxazol-5-yl) methyl] acetamide [531] [532] [533] Intermediates of these compounds were prepared as follows. [534] [3- (4-bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methane sulfonate [535] [536] [3- (4-Bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methanol (7.668 g, 28 mmol) was added triethylamine (4.68 ml, 35 mmol) and dichloro It was dissolved in a mixture of methane (100 ml). The resulting solution was cooled to 0 ° C., then methane sulfonyl chloride (2.38 ml, 31 mmol) was added. The reaction mixture was stirred at 0 ° C. for 20 minutes and then warmed up to room temperature. Water (100 ml) was added, the organic layer was then separated, dried over magnesium sulfate, filtered and then concentrated in vacuo to afford 9.85 g of the desired compound. [537] [538] 5- (azidomethyl) -3- (4-bromo-3-fluorophenyl) -4,5-dihydroisoxazole [539] [540] [3- (4-Bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methane sulfonate (9.85 g, 28 mmol) was dissolved in dry DMF (100 ml). Sodium azide (2.73 g, 42 mmol) was added and the reaction mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was concentrated in vacuo and then azeotropic with xylene (20 ml). The crude product was taken up in ethyl acetate (100 ml) and washed with water (100 ml). The organic layer was separated, dried over magnesium sulfate, filtered and then concentrated in vacuo to afford 8.046 g of the desired compound. [541] [542] [3- (4-bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methylamine [543] [544] 5- (azidomethyl) -3- (4-bromo-3-fluorophenyl) -4,5-dihydroisoxazole (8.046 g, 26.9 mmol) was dissolved in acetonitrile (40 ml) and water (4 ml). In a mixture of Triphenylphosphine (8.48 g, 32.3 mmol) was added and the reaction mixture was stirred at rt for 48 h. The reaction mixture was then poured onto a silica gel chromatography column (400 ml). The product was eluted with 10% -20% water / acetonitrile and then lyophilized to give 2.67 g of the desired product. [545] [546] N- [3- (bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methyl} acetamide [547] [548] [3- (4-Bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methylamine (1.583 g, 5.8 mmol) was converted to pyridine (4.7 ml, 58 mmol) and dichloromethane. (50 ml) was dissolved in the mixture. Acetic anhydride (2.74 ml, 29 mmol) was added and the reaction mixture was stirred for 16 h at room temperature in a nitrogen atmosphere. Water (100 ml) was added, the organic layer was then separated, dried over magnesium sulfate, filtered and then concentrated in vacuo on silica gel (1 g). This was subjected to column chromatography (silica gel bond ilut; 40% to 100% ethyl acetate / hexanes) to give 1.303 g of the desired compound. [549] [550] N- (3- [3-fluoro-4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl] methylacetamide [551] [552] N-{[3- (bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methyl} acetamide (1.303 g, 4.13 mmol) was dried 1,4-dioxane ( 20 ml). The solution was placed under argon atmosphere. Hexamethylditin (1.49 g, 4.55 mmol) was added followed by bis (triphenylphosphine) palladium (II) chloride (0.216 g, 0.31 mmol). The reaction mixture was stirred at 90 ° C. under argon atmosphere for 4 hours. The solvent was removed in vacuo and then the crude product was dissolved again in ethyl acetate (100 ml). Silica gel (5 ml) was added and the mixture was concentrated in vacuo. It was then subjected to column chromatography (20 g silica gel bond elut: 0% to 100% ethyl acetate / hexanes) to give 1.201 g (73%) of the desired compound as a white solid. [553] [554] Example 17: N-{[(5S)-(2,2'-difluoro-4 '-{5- [4-methyl-1H-1,2,3-triazol-1-yl) methyl] -4,5-dihydroisoxazol-3-yl} -1,1'-biphenyl-4-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [555] [556] 1-({3- [3-fluoro-4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -4-methyl-1H-1,2,3- Triazole (427 mg, 1.0 mmol), N-{[(5S) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl } Acetamide (254 mg, 0.67 mmol) and 2-trifurylphosphine (16 mg, 0.067 mmol) were dissolved in dry 1,4-dioxane (10 ml) and the reaction mixture was placed under argon atmosphere. Tris (dibenzylideneacetone) dipaladium (0) chloroform additive (35 mg, 0.033 mmol) was added and the reaction mixture was stirred at 90 ° C. for 16 h under argon atmosphere. The reaction mixture was subjected to column chromatography (20 g silica gel bond elut; 0% to 50% methanol / dichloromethane) to give 19 mg (5%) of the desired compound. [557] [558] The following example was prepared in a similar manner to Example 17 above: [559] Example 18: 1-([3- {2,2'-Difluoro-4 '-[(5R, S) -5- (4-methyl-1H-1,2,3-triazole-1- Monomethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl} -4,5-dihydroisoxazol-5-yl] methyl) -4-methyl -1H-1,2,3-triazole. [560] [561] [562] Intermediates of this compound were prepared as follows. [563] 1-{[3- (4-bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methyl} -4-methyl-1H-1,2,3-triazole [564] [565] [3- (4-Bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methylamine (0.856 g, 3.1 mmol) was converted to diisopropylethylamine (2.18 ml, 12.5 mmol ) And dry methanol (10 ml). N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonylhydrazide (1.16 g, 3.1 mmol) was added and the reaction mixture was stirred for 16 hours under a nitrogen atmosphere. Silica gel (4 ml) was added and the mixture was concentrated in vacuo. It was purified again by column chromatography (20 g silica gel bond elute: 60% to 100% ethyl acetate / hexanes) to give 0.834 g (78%) of the desired compound as a white solid. [566] [567] 1-({3- [3-fluoro-4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -4-methyl-1H-1,2,3- Triazole [568] [569] 1-{[3- (4-bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methyl} -4-methyl-1H-1,2,3triazole (1.33 g, 3.9 mmol) was dissolved in dry 1,4-dioxane (20 ml). The solution was placed under argon atmosphere. Hexamethylditin (1.41 g, 4.3 mmol) was added followed by bis (triphenylphosphine) palladium (II) chloride (0.138 g, 0.2 mmol). The reaction mixture was stirred at 90 ° C. for 3 hours under argon atmosphere. The solvent was removed in vacuo and then the crude product was dissolved again in ethyl acetate (100 ml). Silica gel (5 ml) was added and the mixture was concentrated in vacuo. It was purified by column chromatography (20 g silica gel bond elut: 50% to 100% ethyl acetate / hexanes) to give 0.855 g (52%) of the desired compound as a white solid. [570] [571] Example 19: N-[((5S) -3- {2,2'-difluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl]- 1,1'-biphenyl-4-yl] -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [572] [573] N-[((5S) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2,2 '-Difluoro-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide (416 mg, 0.74 mmol) was dichloromethane at room temperature. It was dissolved in methane (25 ml). Tetrabutylammonium fluoride (0.82 ml, 0.82 mmol) 1M solution in tetrahydrofuran was added and the reaction mixture was stirred for 300 minutes. Water (50 ml) was added and the dichloromethane layer was separated, dried over magnesium sulfate, filtered and then concentrated on silica in vacuo (2 ml). This was purified by chromatography (20 g silica gel bond ilut; 0-6% methanol / dichloromethane) to give 125 mg (38%) of the desired compound. [574] [575] The following example was prepared in a similar manner to Example 19 above. [576] Example 20 (5R) -3- {2,2'-difluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1' -Biphenyl-4-yl-5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one [577] [578] [579] Example 21: (5R) -3- {2,2'-difluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1' -Biphenyl-4-yl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [580] [581] [582] Example 22 tert-butyl N-((5R) -3- {2,2'-difluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl ] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl N- (isoxazol-3-yl) carbamate [583] [584] [585] Example 23: (5R) -3- {2'-Fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl -4-yl} -5- (hydroxymethyl) -1,3-oxazolidin-2-one [586] [587] [588] Example 24 N-[((5S) -3- {2'-fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1 '-Biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [589] [590] [591] Example 25 {3- [2,2'-Difluoro-4 '-(5-hydroxymethyl-4,5-dihydro-isoxazol-3-yl) -1,1'-biphenyl- 4-yl] -4,5-dihydro-isoxazol-5-yl} methanol [592] [593] [594] Intermediates for Examples 19-25 were prepared as follows. [595] 3- (4-bromo-3-fluorophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole [596] [597] [3- (4-Bromo-3-fluorophenyl) -4,5-dihydroisoxazol-5-yl] methanol (7.518 g, 27.4 mmol) was added triethylamine (4.59ml, 33.0 mmol) and dichloro It was dissolved in a mixture of methane (100 ml). [598] The resulting solution was cooled to 0 ° C. and then a tert-butyldimethylsilylchloride 1M solution (30.2 ml) in dichloromethane was added dropwise for 30 minutes. 4-dimethylamino pyridine (0.67 g, 5.48 mmol) was added and the remaining reaction mixture was stirred at rt overnight. The reaction mixture was washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give 9.263 g (87%) of the desired compound as a colorless oil. [599] [600] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole [601] [602] 3- (4-bromo-3-fluorophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole (5.403 g, 14.6 mmol) was dried It was dissolved in 1,4-dioxane (50 ml). The solution was placed under argon atmosphere. Hexamethylditin (5.26 g, 16 mmol) was added followed by bis (triphenylphosphine) palladium (II) chloride (0.512 g, 0.73 mmol). The reaction mixture was stirred at 90 ° C. for 90 minutes under argon atmosphere. The solvent was removed in vacuo and the crude product was then dissolved again in ethyl acetate (100 ml). Silica gel (5 ml) was added and the mixture was concentrated in vacuo. Then it was column chromatographed (50 g silica gel bond elute: 0% to 50% ethyl acetate / hexanes) to give 4.893 g (74%) of the desired compound as a colorless oil. [603] [604] N-[((5S) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2,2 '-Difluoro-1,1'-biphenyl-4-yl] -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [605] [606] N-{[(5S) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide (378 mg, 1.0 mmol) And copper iodide (I) (39 mg, 0.2 mmol) was dissolved in dry 1-methyl-2-pyrrolidinone (2 ml) and the reaction mixture was placed under argon atmosphere. Tetrakis (triphenylphosphine) palladium (0) (58 mg, 0.05 mmol) followed by 5-({[tert-butyl (dimethyl) silyl] oxy} in 1-methyl-2-pyrrolidinone (2 ml) Methyl) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole (525 mg, 1.1 mmol) is added and the reaction mixture is stirred at 90 ° C. for 16 h. It was. Water (20 ml) and ethyl acetate (20 ml) were added and insoluble material was filtered off. The ethyl acetate layer was separated, dried over magnesium chloride, filtered and concentrated with silica gel (2 g). It was purified by column chromatography (20 g silica gel bond elut: 25% to 100% ethyl acetate / hexanes) to give 416 mg (74%) of the desired compound. [607] [608] The following intermediate examples were prepared by similar procedures to those used in the above intermediate examples. [609] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2,2'-difluoro Rho-1,1'-biphenyl-4-yl} -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine-2 -On [610] [611] [612] The following intermediate examples were prepared by a procedure similar to the above example except that 0.4 mmol of copper iodide and 0.1 mmol of tetrakis (triphenylphosphine) palladium (0) were used. [613] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2,2'-difluoro Rho-1,1'-biphenyl-4-yl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [614] [615] [616] tert-butyl N-((5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2 , 2'-difluoro-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl N- (isoxazol-3-yl) carba Mate [617] [618] [619] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2'-fluoro-1 , 1'-biphenyl-4-yl} -5- (hydroxymethyl) -1,3-oxazolidin-2-one [620] [621] [622] N-[((5S) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2'- Fluoro-1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [623] [624] [625] 3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -2,2'-difluoro-1, 1'-biphenyl-4-yl]}-5- [tert-butyl (dimethyl) silyl] oxymethyl-4,5-dihydroisoxazole [626] [627] [628] Example 26: (5S, 5'S) -N- (3- {4 '-[5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -biphenyl-4-yl}- 2-oxo-oxazolidin-5-ylmethyl-acetamide [629] [630] N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acetamide (0.36 g, 1 mM), N -{[(5S) -3- (4-iodophenyl) -2-oxo-1,3-oxazolidin-5yl] methyl} acetamide (0.40 g, 1.2 mM), tris (dibenzylideneacetone ) Dipalladium (0) (0.037 g, 0.040 mM), and tri-2-furylphosphine (0.019, 0.080 mM) were weighed into a flask and degassed. 1-methyl-2-pyrrolidinone (3 mL) was added and the reaction was heated at 90 ° C. for 21 h. The black mixture was diluted with 1-methyl-2-pyrrolidinone (10 ml) and filtered through celite, the brown band portion collected and transferred through the pad. Water was added to the solution to precipitate a light brown solid. The mixture was refrigerated for 2 hours and then filtered to afford the desired product as a brown solid (0.037 g). [631] [632] Example 27: (5R, 5'R) -3- [2,2'-difluoro-4 '-(5- [4-methyl-1H-1,2,3-triazolyl-1-ylmethyl ] -2-oxo-1,3-oxazolidin-3-yl) -1,1'-biphenyl-4-yl] -5-[(4-methyl-1H-1,2,3-triazole -1-ylmethyl] -1,3-oxazolidin-2-one [633] [634] (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxa Zolidin-2-one (0.40 g, 1.00 mM) and (5R) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -5-[(4-methyl-1H-1,2, The title compound was obtained as a brown solid, starting from 3-triazol-1yl) methyl] -1,3-oxazolidin-2-one (0.53 g 1.20 mM) and using essentially the same procedure as in Example 26 ( 0.50 g). [635] [636] The intermediate for Example 27 was prepared as follows: [637] (5R) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1, 3-oxazolidin-2-one [638] [639] (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxa Zolidin-2-one (5.12 g, 12.7 mM) and bis (triphenylphosphine) palladium (II) chloride (0.45 g, 0.05 mM) were placed in a flask and degassed. Dioxane (50 ml) was then added with hexamethylditin (5.00 g, 15.3 mM) and the reaction was degassed. The mixture was heated at 90 ° C. for 20 hours, cooled and adsorbed with silica gel. The residue was purified by flash chromatography using 50% hexanes / ethyl acetate to ethyl acetate. The relevant fractions were combined to give the desired product as a brown solid (3.91 g). [640] [641] (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxa Zolidin-2-one [642] [643] Silver trifluoroacetate (0.52 g, 2.35 mM) was added to (5R) -3- (3-fluorophenyl) -5-[(4-methyl-1H-1,2,3- in dichloromethane (15 mL). Triazol-1-yl) methyl] -1,3-oxazolidin-2-one (0.50 g, 1. 81 mM) was added to the solution. Iodine (0.55 g, 2.17 mM) was added over 1.5 hours and the reaction mixture was stirred overnight. After 16h, the solids were removed by filtration and additional silver trifluoroacetate (0.38 g, 1.72 mM) and iodine (0.27 g, 1.06 mM) were added. After a further 24 h, the reaction mixture was filtered. The filtered cake was washed with methanol. The methanol filtrate was concentrated in vacuo to give 0.31 g of the title product. [644] [645] (5R) -3- (3-fluorophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine-2- On [646] [647] N, N-diisopropylethylamine (3.20 mL, 18.35 mM) was dissolved in anhydrous methanol (25 mL) (5S) -5- (aminomethyl) -3- (3-fluorophenyl) -1,3-oxa To Zolidin-2-one (0.77 g, 3.57 mM; see Pharmaceuticals WO 0194342) solution. The solution was cooled to 0 ° C. and N '-[2,2-dichloro-1-methylethylidene] -4-methylbenzenesulfonohydrazide (1.28 g, 4.58 mM) was added. The solution was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and chromatographed on silica gel with 2% methanol / dichloromethane to give 0.71 g of the title compound. [648] [649] Example 28: (5R) -5- (hydroxymethyl) -3- {4 '-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-3-yl] -1,1'-biphenyl-4-yl] -1,3-oxazolidin-2-one [650] [651] (5R) -3- (4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (0.39 g, 1.00 mM), tris (dibenzylideneacetone) dipaladium (0) (0.037 g, 0.040 mM), and tri-2-furylphosphine (0.0199, 0.080 mM) were weighed into a flask and degassed. 1-methyl-2-pyrrolidinone (3 ml) was added and the flask was degassed. (5R) -5-({tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-2-one (0.71 g, 1.50 mM) was added and the flask was degassed. The reaction was stirred at 90 ° C. for 22 hours. The black mixture was adsorbed onto silica gel and chromatographed with ethyl acetate to give an oily solid (1.78 g) which was taken up in DMSO and subjected to reverse phase HPLC (acetonitrile-water-1% trifluoroacetic acid). The protecting group, tert-butyldimethylsilyl-group, was exogenously removed in reverse phase purification to obtain directly as a pale yellow solid (0.98 g). [652] [653] Example 29 Intermediate (5R) -5-({tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-2-one Described in; Intermediate (5R) -3- (4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one was previously described One of the intermediates described in 1. [654] Example 29: (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4 '-{(5R) -5-[(4-methyl-1H-1,2 , 3-triazol-1-yl) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl) -1,3-oxazolidine 2-on [655] [656] (5R) -3- (4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine-2- Starting with the temperature (0.34 g, 1.00 mM), the title compound was obtained as a white solid using the same procedure as in Example 28 (0.016 g). [657] [658] The intermediate for Example 29 was prepared as follows: [659] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-2-one [660] [661] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one (2.45 g, 5.66 mM) Essentially preceding (5R) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -5-[(4-methyl-1H-1,2,3-triazol-1-yl Using the same procedure as) methyl] -1,3-oxazolidin-2-one, the hexanes were then chromatographed using 20% ethyl acetate / hexanes to give the title compound as a white solid (1.59 g). [662] [663] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one [664] [665] (5R) -5- (hydroxymethyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one (2.00 g, 1.00 mM) was dissolved in methylene chloride (12 ml). N, N-dimethylaminopyridine (0.76 g, 7.52 mM) and triethylamine (0.76 g, 7.52 mM) were added and the solution was degassed. A solution of tert-butyldimethylsilyl chloride 1N in methylene chloride (7 ml) was added and the reaction was stirred at rt for 16 h. The yellow solution was diluted with water and the product extracted with methylene chloride (3x200 ml). The organic layer was dried (magnesium sulfate), filtered and concentrated to afford the desired product as a pale yellow solid (2.54 g). [666] [667] Example 30: (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (2'-fluoro-4 '-{(5R) -5-[(4-methyl -1H-1,2,3-triazol-1-yl) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl) -1 , 3-oxazolidin-2-one [668] [669] Essentially the same procedure as in Example 28, but with (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4-iodophenyl) -1,3-oxazolidine Starting from 2-one (0.43 g, 1.00 mM) and (5R) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -5-[(4-methyl-1H-1, 2, 3-triazol-1-yl) methyl-1,3-oxazolidin-2-one (0.66 g, 1.50 mM) was added to afford the title compound as a white solid (0.025 g). [670] [671] Example 31 N-[((5S) -3- {4 '-[(5R) -5-({[tert-butyl (dimethyl) silyl] oxy} -methyl) -2-oxo-1,3- Oxazolidin-3-yl] -2,2'-difluoro-1,1'-biphenyl-1-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acet amides [672] [673] Using essentially the same procedure as in Example 28, but with N-{[(5S) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidine-5- (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [3-fluoro-4- (trimethyl) starting from il] methyl} acetamide (0.38 g, 1.00 mM) Stannyl) phenyl] -1,3-oxazolidin-2-one (0.73 g, 1.50 mM) was added to give the title compound as a pale yellow solid (0.334 g). [674] [675] The intermediate for Example 31 was prepared as follows: [676] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [3-fluoro-4- (trimethylstannyl) phenyl] -1,3-oxazolidine-2- On [677] [678] As described for (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-2-one (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (3-fluoro-4-iodophenyl) -1,3- Oxazolidin-2-one (1.97 g, 4.37 mM) was added and the hexanes were then chromatographed using 20% ethyl acetate / hexanes to give the title compound as a white solid (1.75 g). [679] [680] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (3-fluoro-4-iodophenyl) -1,3-oxazolidin-2-one [681] [682] Essentially the same procedure as in the previous (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4-iodophenyl) -1,3-oxazolidin-2-one But using (5R) -3- (3-fluoro-4-iodophenyl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one (2.0 g, 1.0 mM) Starting and chromatography with 50% ethyl acetate / hexanes gave the title compound as a pale yellow solid (1.94 g). [683] [684] Example 32: (5R) -3- {2-Fluoro-4 '-[(5R) -5- (hydroxymethyl) -2-oxo-1,3-oxazolidin-3-yl] -1 , 1'-biphenyl-4-yl} -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl-1,3-oxazolidin-2-one [685] [686] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4 '-{(5R) -5-[(4-methyl-1H-1,2,3-tria Zol-1-yl) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl) -1,3-oxazolidin-2-one (0.016 g, 0.030 mM) was suspended in tetrahydrofuran (0.5 ml) and tetrabutylammonium fluoride 1N solution (0.03 ml) in tetrahydrofuran was added. The reaction was stirred at rt for 1 h. The hazy suspension was concentrated to a white residue. [687] [688] Example 33: (5R) -5- (hydroxymethyl) -3- (4 '-[(5R) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) Methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl) -1,3-oxazolidin-2-one [689] [690] (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (4 '-{(5R) -5-[(4) using essentially the same procedure as in Example 32 -Methyl-1H-1,2,3-triazol-1-yl) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl) Starting with -1,3-oxazolidin-2-one (0.025 g, 0.043 mM) the title compound was obtained as a white residue. [691] [692] Example 34 (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -1,1 '-Biphenyl-4-yl-5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl-1,3-oxazolidin-2-one [693] [694] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole (0.70 g, 1.6 mmol), (5R) -3- (4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one (0.5 g, 1.29 mmol), tri-2-furyl phosphine (0.06 g, 0.26 mmol) and tris (dibenzylideneacetone) palladium (0) (0.12 g, 0.13 mmol) in 1,4-dioxane (5 ml) It was dissolved and degassed three times. The mixture was then heated to 90 ° C. and stirred for 18 hours. LCMS found that the reaction was not complete, cooled, and further tris (dibenzylidene acetone) palladium (0) (0.12 g, 0.13 mmol) was added. The mixture was degassed and heated again to 110 ° C. for 3 hours and at 25 ° C. for 40 hours. The solution was concentrated in vacuo and purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent to afford 0.2 g of desired product as a yellow solid. [695] [696] Starting materials for Example 34 were prepared as follows: [697] 1- {3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2,3-triazole [698] [699] 1-{[3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methyl} -1H-1,2,3-triazole (3.7 g, 12.1 mmol) and trans- Dichlorobis (triphenylphosphine) palladium (II) was dissolved in 1,4-dioxane (50 ml) and the solution was degassed three times. Hexamethylditin (5 g, 15.3 mmol) was added and the solution was degassed. The solution was stirred and heated to 90 ° C. for 16 h. The black reaction mixture was filtered through celite and the celite was washed with methanol. The methanol layer was concentrated in vacuo and then purified by silica flash chromatography with 1.5-3% methanol in dichloromethane as eluent to afford 4.6 g of the title compound. [700] [701] Example 35: (5R) -5- (1H-1,2,3-triazol-1-ylmethyl) -3- [4'-5- (1H-1,2,3-triazole-1- Ilmethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl} -1,3-oxazolidin-2-one [702] [703] 1-({3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2,3-triazole (0.33 g, 0.84 mmol) , (5R) -3- (4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (0.26 g, 0.7 mmol) and tri-2-furylphosphine (0.033 g, 0.14 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris (dibenzylideneacetone) palladium (0) (0.064 g, 0.07 mmol) was added and the solution was degassed three times. The solution was stirred and heated to 110 ° C. for 3 hours and then placed at 25 ° C. for 40 hours. The reaction was not found to be complete via LCMS, additional tris (dibenzylideneacetone) palladium (0) (0.09 g, 0.1 mmol) was added, the mixture was degassed and then at 90 ° C. for 6 hours. Heat and leave at 25 ° C. for 12 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent to afford 0.05 g of the desired product. [704] [705] Example 36: (5R) -3- {2-fluoro-4 '-[5- (1H-1,2,3-triazol-1-ylmethyl) -4,5-dihydroisoxazole-3 -Yl] -1,1'-biphenyl-4-yl} -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine 2-on [706] [707] 1-({3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2,3-triazole (0.33 g, 0.84 mmol) , (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3- Oxazolidin-2-one (0.27 g, 0.69 mmol) and tri-2-furylphosphine (0.033 g, 0.14 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris (dibenzylideneacetone) palladium (0) (0.064 g, 0.07 mmol) was added and the solution was degassed three times. The solution was stirred, heated at 110 ° C. for 3 hours and then placed at 25 ° C. for 40 hours. Knowing that the reaction was not complete by LCMS, additional tris (dibenzylideneacetone) palladium (0) (0.09 g, O.lmmol) was added and the mixture was degassed and then heated at 90 ° C. for 6 hours. . The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent to afford 0.223 g of the desired product. [708] [709] Example 37: (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol3-yl] -1,1' -Biphenyl-4yl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [710] [711] 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazole (0.5 g, 1.1 mmol), (5R) -3- (4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (0.49 g, 1.32 mmol), And tri-2-furylphosphine (0.051 g, 0.22 mmol) was dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris (dibenzylideneacetone) palladium (0) (0.1 g, 0.11 mmol) was added and the solution was degassed three times. The solution was stirred and heated at 90 ° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent to afford 0.24 g of the desired product. [712] [713] Example 38 N-[((5S) -3- {2-fluoro-4 '-[5- (1H-1,2,3-triazol-1-ylmethyl) -4, 5-dihydroi Soxazol-3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [714] [715] 1-({3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2, 3-triazole (0.62 g, 1.58 mmol) , N-{[(5S) -3- (3-fluoro-4-iodophenyl) -2-oxo-1, 3-oxazolidin-5-yl] methyl} acetamide (0.5 g, 1.32 mmol ) And tri-2-furylphosphine (0.08 g, 0.34 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris (dibenzylideneacetone) palladium (0) (0.16 g, 0.18 mmol) was added and the solution was degassed three times. The solution was stirred and heated at 90 ° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent to afford 0.20 g of the desired product. [716] [717] Example 39: (5R) -3- {4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1, 1'-biphenyl-4-yl}- 5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one [718] [719] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl -4-yl} -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one (0.2 g, 0.37 mmol) Was dissolved in THF (5 ml) at 25 ° C. Tetrabutylammonium fluoride.3H 2 0 (0.1 Ig, 0.40 mmol) was added as a solid and the reaction was stirred at 25 ° C. for 1.5 h. The mixture was then diluted with ethyl acetate (50 ml) and poured into water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by silica flash chromatography using 5-10% methanol in dichloromethane as eluent to afford 0.025 g of the desired product. [720] [721] Example 40: (5R) -3- {4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl}- 5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [722] [723] (5R) -3- {4 '-[5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl -4-yl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (0.24 g, 0.45 mmol) at 25 ° C. in THF ( 5 ml). Tetrabutylammonium fluoride.3H 2 0 (0.138 g, 0.495 mmol) was added as a solid and the reaction was stirred at 25 ° C for 1.5 h. The mixture was then diluted with ethyl acetate (50 ml) and poured into water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The resulting yellow oil was purified by silica flash chromatography using 5-10% methanol in dichloromethane as eluent to afford 0.05 g of the desired product. [724] [725] Example 41: N-{[(5S, 5'RS) -3- (2-Fluoro-4 '-{5-[(4-methyl-1H-1,2,3-triazol-1-yl ) Methyl] -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acet amides [726] [727] (5S) -N- [3- (3-Fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl] acetamide (336 mg, 1.00 mM), tris (dibenzyl Lidineacetone) dipaladium (0) (36 mg, 0.039 mM) and tri-2-furylphosphine (19 mg, 0.082 mM) were placed in the flask. The solid was degassed and placed under argon. Anhydrous N-methylpyrrolidinone (5 ml) was added and the resulting magenta solution turned brown in a few minutes. 4-methyl-1-({3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2,3-triazole (486 mg , 1.20 mM) and degassing the solution again. The solution was heated at 90 ° C. for about 24 hours. The reaction mixture was filtered through celite and water was added to the filtrate to precipitate the crude product. This crude was purified by reverse phase chromatography using reverse phase chromatography polar end capped ether-linked phenyl phase column (250 × 50 mm, 10 μ). The mobile phase was 0.1% trifluoroacetic acid, 0.1% trifluoroacetic acid / acetonitrile and water. The organic phase was increased from 20 to 95% at a flow rate of 100 ml / min over 35 minutes. Sample collection was monitored at 254 nm. A total of 97 mg of the desired product were obtained. [728] [729] Intermediates of this compound were prepared as follows: [730] 4-methyl-1- {3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2,3triazole. [731] [732] 1-{[3- (4-bromo-phenyl) -4,5-dihydro-isoxazol-5-yl] methyl} -4-methyl-1H-1,2,3-triazole (1.78 g, 5.55 mM) was dissolved in 1,4-dioxane (20 ml). Bis (triphenylphosphine) palladium (II) chloride (195 mg, 0.28 mM) was added and the solution was degassed. Hexamethylditin (2.00 g, 6.10 mM) was added and the resulting solution was heated at 90 ° C. for about 20 hours. The reaction mixture was adsorbed onto silica gel and chromatographed with 50% ethyl acetate / hexanes to yield 1.83 g of the desired product. [733] [734] Example 42: (5R, 5'RS) -3- (2-Fluoro-4 '-{5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl]- 4,5-dihydroisoxazol-3-yl} -1,1'-biphenyl-4-yl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one. [735] [736] (5R, 5'RS) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (2-fluoro-4 '-{5- [(4-methyl-1H-1, 2,3-triazol-1-yl) methyl] -4,5-dihydroisoxazol-3-yl} -1,1'-biphenyl-4-yl) -1,3-oxazolidine-2 -One (90 mg, 0.16 mM) was dissolved in tetrahydrofuran (5 ml) and 1M solution of tetrabutylammonium fluoride in THF (0.2 ml, 0.19 mM) was added. After 30 minutes the reaction mixture was poured into ethyl acetate and washed with water. The phases were separated and the organic phase was concentrated in vacuo. The crude product was purified by reverse phase chromatography using a C8 column (100 × 21.2 mm, 5u). The mobile phase was 0.1% trifluoroacetic acid and 0.1% trifluoroacetic acid / acetonitrile and water. The organic phase was increased from 20 to 95% at a flow rate of 20 ml / min over 14 minutes. Sample collection was monitored at 280 nm. A total of 59 mg of the title product was obtained. [737] [738] Intermediates of this compound were prepared as follows: [739] (5R, 5'RS) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (2-fluoro-4 '-{5- [(4-methyl-1H-1, 2,3-triazol-1-yl) methyl] -4,5-dihydroisoxazol-3-yl} -1,1'-biphenyl-4-yl) -1,3-oxazolidine-2 -On. [740] [741] The procedure of Example 41 was used, but (5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- (3-fluoro-4-iodophenyl) -1,3- Oxazolidin-2-one (180 mg, 0.40mM), and 4-methyl-1-({3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} Start with methyl) -1H-1,2,3-triazole (194 mg, 0.48 mM). The reaction mixture was filtered through celite. Water was added to precipitate the product, which was adsorbed onto silica gel and chromatographed with 50% ethyl acetate / dichloromethane to give 95 mg of the title product. [742] [743] Example 43: (5R, 5'RS) -3- {2-Fluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1' -Biphenyl-4-yl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [744] [745] Use essentially the same procedure as described in Example 41 but using (5R) -3- (3-fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-yl Methyl) -1,3-oxazolidin-2-one (412 mg, 1.06 mM), and 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3- [4- (trimethylstannyl ) The product was obtained as silyl ether starting from phenyl] -4,5-dihydroisoxazole (579 mg, 1.27 mM). Purification by reverse phase chromatography using 0.1% trifluoroacetic acid and 0.1% trifluoroacetic acid / acetonitrile and water as mobile phase simultaneously removed the silyl protecting group to give 84 mg of the title product. [746] [747] Example 44: N-[((5S) -3- {4 '-[(5R) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'- Biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide. [748] [749] Tetrabutylammonium fluoride solution (1M, 0.69 ml, 0.69 mM) in THF was added with N-[((5S) -3- {4 '-[(5R) -5-({[tert-butyl (dimethyl)) in THF. Silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) (5 ml) was added to a solution of methyl] acetamide (300 mg, 0.57 mM). After about 2 hours ethyl acetate was added and the suspension obtained was filtered. The filter cake was washed with water and ethyl acetate to give 140 mg of the title product. [750] [751] Intermediates of this compound were prepared as follows: [752] N-[((5S) -3- (4 '-[(5R) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [753] [754] Using the procedure of Example 41, but with N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acet Amide (476 mg, 1.20 mM) and (5R) -3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole ( 370 mg.1.00 mM), the desired product was obtained after 7 hours at 90 ° C. Purification by chromatography on silica gel with 90% ethyl acetate / hexanes gave 398 mg of the title product. [755] [756] (5R) -3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole [757] [758] (5R) -3- (4-bromophenyl) -5-({[tert from (5R)-[3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol Preparation of -butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole is the same as shown in Example 6 for racemate. The title product was obtained in 99% yield. Analytical data is also indistinguishable from that of racemate. [759] Chiracel OJ column (500) using racemic [3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol mixture at 30 mL / min flow rate with 30% isopropanol in hexane mm x 50 mm, 10p). Separation was monitored at 254 nm. The first peak was designated as the R structure [α D ] = -126.8 ° The designation of the absolute conformation was made by comparing the rotational symbols and the elution order of analogous compounds (DP Curran et al., Tet. Letters, 1988, 29 (29), 3555-3558; C. Ticozzi and A. Zanarotti, Tet.Letters, 1994,35 (40), 7421-7424]. [760] Example 45 N-[((5S) -3- {4 '-[(5S) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'- Biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide. [761] [762] Preparation of the title compound was carried out using N-[((5S) -3- {4 '-[(5S) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole -3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide (200 mg, 0.38 mM) as starting material Similar to that shown in Example 44 except for the points used. The crude product was recrystallized from N-methyl-pyrrolidinone and water to give 41 mg of the title product. [763] [764] Intermediates for this compound were prepared as follows: [765] N-[((5S) -3- {4 '-[(5S) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide [766] [767] N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acetamide (476 mg, 1.20 mM) and ( 5S) -3- (4-bromophenyl) -5-([[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole (370 mg, 1.00 mM) as starting material The desired product was obtained after about 20 hours at 90 ° C. using the procedure of Example 41. Purification by chromatography on silica gel using 90% ethyl acetate / hexanes gave 284 mg of the title product. [768] [769] (5S) -3- (4-bromophenyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole [770] [771] (5S) -3- (4-bromophenyl) -5-({[tert- from (5S) -3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol Preparation of butyl (dimethyl) silyl] oxy} methyl) -4,5-dihydroisoxazole was the same as in Example 6 for racemate. The title product was obtained in 97% yield. Analytical data was also indistinguishable from the data for racemates. [772] The racemic [3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol mixture was subjected to a Kiracel OJ column (500 mm x 50) using isopropanol in hexane at a flow rate of 100 mL / min. mm, 10μ). Separation was monitored at 254 nm. The second peak was designated as the S structure. [α D ] = +103.8. [773] The designation of the absolute conformation is made by comparing the rotational codes and elution sequences of analogous compounds (DP Curran et al., Tet. Letters, 1988, 29 (29), 3555-3558; C. Ticozzi and A. Zanarotti). , Tet. Letters, 1994, 35 (40), 7421-7424]. [774] Example 46: (5S) -3- (2-fluoro-4'-5-[(4-methyl) -1H-1,2,3-triazol-1-yl) methyl] -4,5- Dihydroisoxazol-3-yl] -1,1'-biphenyl-4-yl) -5-[(isoxazol-3-ylamino) methyl] -1,3-oxazolidinone-2-one. [775] [776] Tert-butyl N-[(5R) -3- (2-fluoro-4 '-{5-[(4-methyl) -1H-1,2,3-triazole-1- in dichloromethane (1 ml) Yl) methyl] -4,5-dihydroisoxazol-3-yl} -1,1'-biphenyl-4-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl N To a solution of (isoxazol-3-yl) carbamate (41 mg, 0.067 mM) was added trifluoroacetic acid (0.5 ml). After about 30 min, the solution was concentrated in vacuo to yield 33 mg of the title compound. [777] [778] Intermediates for this compound were prepared as follows: [779] tert-butyl N-[(5R) -3- (2-fluoro-4 '-{5-[(4-methyl) -1H-1,2,3-triazol-1-yl) methyl] -4 , 5-dihydroisoxazol-3-yl} -1,1'-biphenyl-4-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl N- (isoxazol-3 -Working) carbamate. [780] [781] 4-methyl-1-({3- [4- (trimethylstannyl) phenyl] -4,5-dihydroisoxazol-5-yl} methyl) -1H-1,2,3-triazole (729 mg , 1.80 mM) and N- (5R)-[3- (3-fluoro-4-iodo-phenyl) -2-oxo-1,3-oxazolidin-5-ylmethyl] -N-isoxazole The procedure of Example 41 was used with 3--3-yl carbamic acid tert-butyl ester (755 mg, 1.50 mM) as starting material. A total of 269 mg of the title product was obtained after purification using reverse phase chromatography (250 × 50 mm, 10 μ) using a polar endcapped ether-linked phenyl phase column. The mobile phase was 0.1% trifluoroacetic acid, 0.1% trifluoroacetic acid / acetonitrile and water. The organic phase was increased from 20 to 95% at a flow rate of 100 ml / min over 35 minutes. Sample collection was monitored at 280 nm. [782] [783] Example 47 [3- (4 '-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl -4-yl) -4,5-dihydroisoxazol-5-yl] methyl di-tert-butyl phosphate [784] [785] [3- (4-Bromophenyl) -4,5-dihydroisoxazol-5-yl] methyl di-tert-butyl phosphate (0.25 g, 0.55 mmol), N-(((5S) -2-oxo -3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acetamide (0.25 g, 0.66 mmol), tri-2-furylphosphine (0.026 g, 0.11 mmol) and tris (dibenzylideneacetone) palladium (0) (0.05 g, 0.55 mmol) were dissolved in 1,4-dioxane (5 ml) and degassed three times The mixture was heated to 90 ° C. and stirred for 5 hours And then stirred for 12 h at 25 ° C. The solution was concentrated in vacuo and purified by silica flash chromatography using 5-10% methanol in dichloromethane as eluent to afford 0.12 g of the desired product. [786] [787] Phosphate intermediates for Example 47 were prepared as follows: [788] [3- (4-bromophenyl) -4,5-dihydroisoxazol-5-yl] methyl di-tert-butyl phosphate [789] [790] [3- (4-Bromophenyl) -4,5-dihydroisoxazol-5-yl] methanol (2.5 g, 9.8 mmol) was dissolved in dichloromethane (100 ml). To this solution, di-tert-butyl-N, N-diethylphosphoroamidite (3.3 ml, 11.7 mmol) and 1H-tetrazole (1.2 g, 17.6 mmol) were added sequentially. After 1.5 h, stirred at room temperature, the solution was cooled to 0 ° C. and m-chloroperoxide acid (70%; 3.6 g, 14.7 mmol) was added. After 1.5h the reaction is warmed to room temperature; Sodium bisulfite solution was added and the mixture was stirred for about 5 minutes. After dilution with dichloromethane, the aqueous layer was extracted with dichloromethane (2x) and the combined organics were washed with saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The crude residue was purified by chromatography on silica gel with 0-5% methanol in dichloromethane to give 4.1 g of the desired product. [791] [792] Example 48: [3- (4 '-[(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl] -1,1'-biphenyl -4-yl) -4,5-dihydroisoxazol-5-yl] methyl dihydrogen phosphate [793] [794] [3- (4 '-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl ) -4,5-dihydroisoxazol-5-yl] methyl di-tert-butyl phosphate (95 mg, 0.16 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.1 ml) was added. . The solution was stirred at ambient temperature for 1 hour and then concentrated in vacuo. Dichloromethane was added and the volatiles were removed in vacuo. This was repeated twice with dichloromethane and five times with diethyl ether. A pale yellow solid corresponding to the desired product was obtained (78 mg). [795] [796] [3- (4 '-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl ) -4,5-dihydroisoxazol-5-yl] methyl disodium phosphate [797] [798] [3- (4 '-{(5S) -5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -1,1'-biphenyl-4-yl ) -4,5-hydroisoxazol-5-yl] methyl dihydrogen phosphate (78 mg) was suspended in water (15 ml). The pH was slowly adjusted to between about pH 3.5 and about pH 7.5 using saturated sodium bicarbonate solution. The water was removed by lyophilization to give 130 mg white solid (desired product + excess sodium bicarbonate). [799] Example 49: N-{[(5S) -3- (4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [800] [801] N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acetamide (500 mg, 1.26 mM), [ 3- (5-Bromothien-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (330 mg, 1.26 mM), tris (dibenzylideneacetone) dipaladium (0) -chloroform Additive (130 mg, 0.126 mM) and tri-2-furylphosphine (58 mg, 0.252 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (10 ml) was added and the suspension was heated at 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (220 mg). [802] [803] Example 50: (5R) -3- (4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl) -5- ( 1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [804] [805] (5R) -3- (4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (214 mg, 0.58 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), tris (dibenzylideneacetone) Dipalladium (0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (100 mg). [806] [807] Intermediates for this compound were prepared as follows. [808] [3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol [809] [810] [3- (5-Bromothien-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (3.7 g, 14.10 mM) and bis (triphenylphosphine) palladium (II) chloride ( 593 mg, 0.847 mM) was placed in the flask. Anhydrous dioxane (50 ml) was added and the suspension was heated to 90 ° C. Hexamethylditin (5.00 g, 15.53 mM) was added and the resulting solution was heated at 90 ° C. for 16 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (2.5 g). [811] [812] Example 51: (5R) -3- (4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl) -5- [ (4-methyl-1H-1,2,3-triazol-1-yl) methyl} -1,3-oxazolidin-2-one [813] [814] (5R) -3- (4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidine-2- On (222 mg, 0.58 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), Tris ( Dibenzylideneacetone) dipalladium (0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated to 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (90 mg). [815] [816] Example 52: N-{[(5S) -3- (3-fluoro-4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thiene-2 -Yl} phenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [817] [818] N-{[(5S) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide (273 mg, 0.72 mM) , {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (250 mg, 0.72 mM), tris (dibenzylideneacetone) dipalladium (0) -Chloroform additive (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (180 mg). [819] [820] Example 53: (5R) -3- (3-fluoro-4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl ) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [821] [822] (5R) -3- (3-fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (280 mg, 0.72 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (250 mg, 0.72 mM), tris (di Benzylideneacetone) dipalladium (0) -chloroform additive (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in the flask. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (170 mg). [823] [824] Example 54: (5R) -3- (3-fluoro-4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl ) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one [825] [826] (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxa Zolidin-2-one (232 mg, 0.58 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), Tris (dibenzylideneacetone) dipaladium (0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (160 mg). [827] [828] Example 55 (5R) -3- (3-fluoro-4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl ) -5- (hydroxymethyl) -1,3-oxazolidin-2-one [829] [830] (5R) -3- (3-fluoro-4-iodophenyl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one (195 mg, 0.58 mM), {3- [ 5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), tris (dibenzylideneacetone) dipaladium (0) -chloroform Additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed into the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 16 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (60 mg). [831] [832] Example 56: N-({((5S) -3- [4- (5- {5-[(acetylamino) methyl] -4,5-dihydroisoxazol-3-yl} thien-2-yl ) Phenyl] -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [833] [834] N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl] methyl) acetamide (500 mg, 1.26 mM), N -{[3- (5-bromothien-2-yl) -4, 5-dihydroisoxazol-5-yl] methyl} acetamide (382 mg, 1.26 mM), tris (dibenzylideneacetone) di Palladium (0) -chloroform additive (130 mg, 0.126 mM) and tri-2-furylphosphine (58 mg, 0.252 mM) were placed into the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 5 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (85 mg). [835] [836] Example 57 N- (5R) -3- (5- {5- (5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} pyrid-2 -Yl) -2-oxo-1,3-oxazolidin-5-ylmethyl acetamide [837] [838] N-{[(5S) -3- (5-bromopyrid-2-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide (181 mg, 0.58 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), tris (dibenzylideneacetone) dipalladium ( 0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed in the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 5 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (118 mg). [839] [840] Example 58: (5R) -3- (5- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl} thien-2-yl} pyrid-2-yl ) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [841] [842] (5R) -3- (5-bromopyrid-2-yl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one ( 187 mg, 0.58 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), tris (di Benzylideneacetone) dipalladium (0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed into the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 5 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (99 mg). [843] [844] Example 59: (5R) -3- (5- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} pyrid-2-yl ) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one [845] [846] (5R) -3- (5-bromopyrid-2-yl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1, 3-oxazoli Din-2-one (195 mg, 0.58 mM), {3- [5- (trimethylstannyl) thien-2-yl] -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), tris (dibenzylideneacetone) -dipalladium (0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed into the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 5 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (72 mg). [847] [848] Example 60 N-([(5S) -3- (4- {2- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] pyrid-5-yl} phenyl ) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [849] [850] N-({(5S) -2-oxo-3- [4- (trimethylstannyl) phenyl] -1,3-oxazolidin-5-yl} methyl) acetamide (300 mg, 0.76 mM), [ 3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (194 mg, 0.76 mM), tris (dibenzylideneacetone) dipaladium (0) -chloroform Additive (78 mg, 0.076 mM) and tri-2-furylphosphine (35 mg, 0.152 mM) were placed into the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 15 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (83 mg). [851] [852] Example 61: (5R) -3- (3-fluoro-4- {2- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] pyrid-5-yl] Phenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one [853] [854] (5R) -3- (3-fluoro-4-iodophenyl) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl-1,3-oxazoli Din-2-one (236 mg, 0.58 mM), {3- [5- (trimethylstannyl) pyridin-2-yl) -4,5-dihydroisoxazol-5-yl} methanol (200 mg, 0.58 mM), tris (dibenzylideneacetone) dipaladium (0) -chloroform additive (60 mg, 0.058 mM) and tri-2-furylphosphine (27 mg, 0.116 mM) were placed into the flask. The solid was degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90 ° C. for 5 hours. The reaction mixture was cooled down and the solvent was evaporated. The residue was eluted with 5% methanol in dichloromethane and chromatographed on silica gel to give the title compound (70 mg). [855] [856] Intermediates for this compound were prepared as follows: [857] {3- [5- (trimethylstannyl) pyrid-2-yl) -4,5-dihydroisoxazol-5-yl} methanol [858] [859] [3- (5-Bromopyrid-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (3.6 g, 14.0 mM) and bis (triphenylphosphine) palladium (II) chloride ( 982 mg, 1.4 mM) was placed under nitrogen atmosphere. Anhydrous dioxane (50 ml) was added and the suspension was heated to 90 ° C. Hexamethylditin (5.00 g, 15.4 mM) was added and the resulting solution was stirred at 90 ° C. for 16 hours. The solution was cooled and the solvent evaporated. The residue was chromatographed by elution with 5% methanol in dichloromethane on silica gel to give the desired product (2.0 g). [860] [861] Example 62: N-{[(5S) -3- (5 '-{5-[(acetylamino) methyl] -2-oxo-1,3-oxazolidin-3-yl} -2,2' -Bithien-5-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl} acetamide [862] [863] tert-butyl N-acetyl N-{[(5S) -3- (5-iodothien-2-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl} carbamate ( 233 mg, 0.50 mM), 4- (trimethylstannyl) pyridine (143 mg, 0.60 mM), dichloro bis (triphenylphosphine) palladium (II) (63 mg, 0.089 mM) and triethylamine (0.170 ml) Was placed in a flask. The solid was degassed and placed under nitrogen. Anhydrous dimethylformamide (5 ml) was added and the suspension was heated at 60 ° C for 18 h. The reaction mixture was cooled down and the solvent was evaporated. The residue was chromatographed on silica gel (eluent: 55% ethyl acetate in hexane) to give the title compound (51 mg). The compound was dissolved in dichloromethane (5 mL) and then treated with trifluoroacetic acid (1 mL). The solution was stirred at rt for 1 h. The solvent was evaporated and the residue was evaporated again with dichloromethane to afford the desired product as a solid (28 mg). [864] [865] Tert-butyl N-acetyl-N-{[(5S) -3- (5-iodothien-2-yl) -2-oxo-1,3-oxazolidin-5-yl] used in the reaction Methyl} carbamate tert N-((5S)-[3- (5-iodothien-2-yl) -2-oxo-1,3-oxazolidin-5-yl] methyl) acetamide -Protected with butoxycarbonyl groups (Riedl, Bernd; Haebich, Dieter; Stolle, Andreas; Wild, Hanno; Endermann, Rainer; Bremm, Klaus Dieter; Kroll, Hein-Peter; Labischinski, Harald; Schaller , Klaus; Werling, Hans-Otto.Preparation of 3-heteroacyl-2-oxzolidinones as antibaterials.EP 693491 Al (1996)). [866] The following example was prepared in a similar procedure to Example 19 above: [867] Example 63: (5S) -3- {2,2'-difluoro-4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1' -Biphenyl-4-yl} -5-[(isoxazol-3-ylamino) methyl] -1,3-oxazolidin-one [868] [869] [870] Example 64 [871] The following are compounds of the invention, in vivo hydrolyzable esters or pharmaceutically acceptable salts thereof (including pharmaceutically acceptable salts of hydrolyzable esters in vivo) for use in therapeutic or prophylactic use in humans ( Representative pharmaceutical dosage forms containing Compound X hereinafter) are exemplified. [872] (a) Tablet I mg / tablet [873] Compound X ... [874] Lactose Ph. Eur ........................ 430 [875] Sodium croscarmellose .............. 40 [876] Polyvinylpyrrolidone ............... 20 [877] Magnesium Stearate ..................... 10 [878] (b) tablet II mg / tablet [879] Compound X ... [880] Lactose Ph. Eur ........................ 179 [881] Sodium croscarmellose .......................... 12 [882] Polyvinylpyrrolidone ...................... 6 [883] Magnesium Stearate ............... 3 [884] (c) tablets III mg / tablet [885] Compound X ... [886] Lactose Ph. Eur ........... 229 [887] Sodium croscarmellose ......................... 12 [888] Polyvinylpyrrolidone ......................................... 6 [889] Magnesium Stearate ............... 3 [890] (d) tablets IV mg / tablet [891] Compound X ..................................... 1 [892] Lactose Ph. Eur ........... 92 [893] Sodium croscarmellose ......... 4 [894] Polyvinylpyrrolidone ... [895] Magnesium Stearate ............... 1 [896] (e) capsule mg / capsules [897] Compound X ... [898] Lactose Ph. Eur ..................... 389 [899] Sodium croscarmellose ........... 100 [900] Magnesium Stearate ..................................... 1 [901] (f) Injection I [902] Compound X ... % w / v [903] Isotonic aqueous solution ..................... 100% [904] (g) Injection II (e.g., bolus) [905] Compound X ... 10% w / v [906] Isotonic Aqueous Solution ............... 100% [907] (h) Injection III [908] Compound X ... .. 5% w / v [909] Isotonic aqueous solution ..................... 100% [910] (i) Injection IV (eg infusion) [911] Compound X ... .. 1% w / v [912] Isotonic aqueous solution ..................... 100% [913] Buffers, pharmaceutically acceptable surfactants, co-solvents or oils such as polyethylene glycol, polypropylene glycol, glycerol or ethanol, glidants (e.g. silicon dioxide) or (e.g. hydroxypropyl β-cyclo Complexing agents such as dextrin or sulfobutylether β-cyclodextrin can be used to aid in the formulation. In addition, if desired, the water solubility can be improved, for example, by conjugating a compound of the present invention with a phospholipid (eg, (phospho) choline derivative) to form a micelle emulsion. [914] Note: Such formulations are described, for example, in "Remington: The Science & Practice of Pharmacy" Vols. I & II (Ed. AR Gennaro (Chairman) et al; Publisher: Mack Publishing Company, Easton, Pennsylvania; 19th Edition-1995) and "Pharmaceutics-The Science of Dosage Form Design" (Ed. ME Aulton; Publisher: Churchill Livingstone first published 1988), according to conventional procedures known in the pharmaceutical art. Tablets (a) to (d) may be (polymeric) coated by conventional means, for example to provide an enteric coating of cellulose acetate phthalate. [915] Example 65: (5R) -3- (3-fluoro-4- (6- (5-hydroxymethyl-4,5-dihydroisoxazol-3-yl) pyridin-3-yl) phenyl)- 5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one [916] [917] (5R) -3- (3-fluoro-4-iodophenyl) -5- (lH-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (342 mg, 0.88 mM), {3- [5- (trimethylstannyl) pyridin-2-yl) -4,5-dihydroisoxazol-5-yl} methanol (300 mg, 0.88 mM), tris ( Dibenzylideneacetone) Dipalladium (0) -chloroform adduct (91 mg, 0.088 mM, 0.1 equiv) and tri-2-furylphosphine (41 mg, 0.176 mM, 0.2 equiv) were placed in the flask. The contents of the flask were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the mixture was heated at 90 ° C. for 5 hours and then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was chromatographed (silica gel; 5% methanol in eluent dichloromethane) to afford the title compound (170 mg). [918]
权利要求:
Claims (20) [1" claim-type="Currently amended] A compound of formula (I), or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof, <Formula I> In formula (I), C is a biaryl residue C'-C " Wherein C ′ and C ″ are independently aryl or heteroaryl rings such that the central residue C represents any of the following D to L groups: <Formula D> <Formula E> <Equation F> <Formula G> <Formula H> <Formula I> <Formula J> <Formula K> <Formula L> Wherein the D to L groups can be linked to rings A and B in any direction; Where A and B are independently i) And ii) Selected from Wherein, i) and (or) ii) is (I) is connected to the C in the 3-position, as shown in, (I) at the 5-position and -CH 2 -R -CH 2 -R 1a, as shown in Substituted by 1b ; R 2a , R 2b , R 3a and R 3b are independently hydrogen or fluorine; R 1a and R 1b are independently hydroxy, —OSi (tri- (1-6C) alkyl), wherein the three (1-6C) alkyl groups are independently selected from all possible (1-6C) alkyl groups), -NHC (= W) R 4 , -OC (= O) R 4 , a) b) And c) Independently selected from Wherein W is O or S; R 4 is hydrogen, amino, (1-8C) alkyl, -NHR 12 , -N (R 12 ) (R 13 ), -OR 12 or -SR 12 , (2-4C) alkenyl, (1-8C) Alkylaryl, mono-, di-, tri- and per-halo (1-8C) alkyl,-(CH 2 ) p (3-6C) cycloalkyl or-(CH 2 ) p (3-6C) cycloalkenyl Wherein p is 0, 1 or 2; here, in a) HET-1 is a C-linked 5 membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, said ring being selected from (1-4C) alkyl, (2-4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy On the available nitrogen atoms optionally substituted with one or two substituents independently selected from (1-4C) alkoxycarbonyl, halogen and cyano, provided that the ring does not quaternize Optionally under the conditions) (1-4C) alkyl; or HET-1 is a C-linked 6 membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, wherein the ring is (1-4C) alkyl, (2-4C) alkenyl, (3) on any available C atom -6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkoxycarbonyl, (1-4C) alkyl on a nitrogen atom optionally substituted with one, two or three substituents independently selected from halogen and cyano, provided that the ring does not thereby quaternize Optionally substituted with; In b), HET-2 is an N-linked 5 membered member containing (i) 1 to 3 additional nitrogen heteroatoms or (ii) an additional heteroatom selected from O and S together with any additional nitrogen heteroatoms. And, as a fully or partially unsaturated heterocyclic ring, said ring is optionally substituted with an oxo or thioxo group on C atom and / or (1-4C) alkyl, (2- 4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1 -4C) optionally substituted with 1, 2 or 3 substituents independently selected from alkoxycarbonyl, halogen and cyano, and / or on the available nitrogen atoms provided that the ring does not thereby quaternize Optionally substituted with (1-4C) alkyl; or HET-2 is an N-linked 6-membered di-hydro-heteroaryl ring containing up to 3 nitrogen heteroatoms (including linking heteroatoms) in total, which ring is formed on the appropriate C atom with oxo or thioxo. Or (1-4C) alkyl, (2-4C) alkenyl, (3-6C) cycloalkyl, amino, (1-4C) alkylamino, on any available C atom, Optionally substituted with 1, 2 or 3 substituents independently selected from di- (1-4C) alkylamino, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkoxycarbonyl, halogen and cyano Is optionally substituted with (1-4C) alkyl on the available nitrogen atom provided that the ring is not quaternary nitrogenized thereby; The substituents on HET-1 and HET-2, or alkyl, alkenyl, cycloalkyl cycloalkenyl, at each occurrence in R 4 , are optionally substituted with 1, 2, 3, or more F, Cl or CN; In c), R 5 is hydrogen, (3-6C) cycloalkyl, phenyloxycarbonyl, tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, (1-6C) alkyl (cyano Or optionally substituted with (1-4C) alkoxycarbonyl), -CO 2 R 8 , -C (= 0) R 8 , -C (= 0) SR 8 , -C (= S) R 8 , P ( O) (OR 9 ) (OR 10 ) and —SO 2 R 11 , wherein R 8 , R 9 , R 10 and R 11 are as defined below; R 6 is cyano, -COR 12 , -COOR 12 , -CONHR 12 , -CON (R 12 ) (R 13 ), -SO 2 R 12 , -SO 2 NHR 12 , -SO 2 N (R 12 ) ( R 13 ) or NO 2 , wherein R 12 and R 13 are as defined below; R 7 is hydrogen, amino, (1-8C) alkyl, -NHR 12 , -N (R 12 ) (R 13 ), -OR 12 or -SR 12 , (2-4C) alkenyl, (1-8C) Alkylaryl, mono-, di-, tri- and per-halo (1-8C) alkyl,-(CH 2 ) p (3-6C) cycloalkyl or-(CH 2 ) p (3-6C) cycloalkenyl Wherein p is 0, 1 or 2; R 8 is hydrogen, (3-6C) cycloalkyl, phenyl, benzyl, (1-5C) alkanoyl, (1-6C) alkyl ((1-5C) alkoxycarbonyl, hydroxy, cyano, 3 or less Halogen atom and —NR 14 R 15 wherein R 14 and R 15 are selected from hydrogen, phenyl (halogen, (1-4C) alkyl and (1-4C) alkyl substituted with 1, 2, 3, or more halogen atoms Optionally substituted with one or more substituents) and (1-4C) alkyl (optionally substituted with one, two, three, or more halogen atoms), or for any N (R 14 ) (R 15 ) groups, R 14 and R 15 may be optionally substituted with a substituent independently selected from which they may form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group together with the nitrogen atom to which they are linked; R 9 and R 10 are independently selected from hydrogen and (1-4C) alkyl; R 11 is (1-4C) alkyl or phenyl; R 12 and R 13 are optionally substituted with one or more substituents selected from hydrogen, phenyl (halogen, (1-4C) alkyl and (1-4C) alkyl substituted with 1, 2, 3 or more halogen atoms) and ( Independently selected from 1-4C) alkyl (optionally substituted with 1, 2, 3 or more halogen atoms), or for any N (R 12 ) (R l3 ) groups, R 12 and R 13 are linked to Together with the nitrogen atom may form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl group; Provided that the C group is an I or J group, the A and B groups are both oxazolidinones and the oxazolidinone (A or B) linked to the pyridyl group at C is a hydroxymethyl group or an acetoxymethyl group (R 1a respectively) When having -CH 2 or R 1b -CH 2 ), the oxazolidinone (B or A) linked to the phenyl group at C is not substituted with an acetamidomethyl group (R 1b -CH 2 or R 1a -CH 2, respectively ) . [2" claim-type="Currently amended] The compound of claim 1, wherein C is a D group; R 2a and R 2b are both hydrogen; Both R 3a and R 3b are hydrogen or both fluorine; R 1a and R 1b are independently selected from hydroxy, -NHCO (1-4C) alkyl, -NHCS (1-4C) alkyl, -NHCOO (1-4C) alkyl, -NH-HET-1 and HET-2 Wherein HET-1 and HET-2 are compounds or pharmaceutically acceptable salts as defined in claim 1, or in vivo-hydrolyzable esters thereof. [3" claim-type="Currently amended] The compound of claim 1 or 2, wherein C is a D group; R 2a and R 2b are both hydrogen; R 3a and R 3b are both hydrogen or both fluorine; R 1a and R 1b are independently selected from hydroxy, -NHCO (1-4C) alkyl, -NH-HET-1 and HET-2, wherein HET-1 and HET-2 are as defined in claim 1 Compounds or pharmaceutically acceptable salts, or in vivo-hydrolysable esters thereof. [4" claim-type="Currently amended] The compound or pharmaceutically acceptable salt of any one of claims 1-3, wherein A and B are oxazolidinone rings and the other is isoxazolin ring, or in vivo-hydrolyzable thereof. ester. [5" claim-type="Currently amended] The compound of claim 1, wherein C is a D group; Both A and B are oxazolidinone rings; R 2a and R 2b are both hydrogen; R 3a and R 3b are both hydrogen or both fluorine; R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or Isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl, or a pharmaceutically acceptable salt thereof, or an in vivo-hydrolyzable ester thereof. [6" claim-type="Currently amended] The compound of claim 1, wherein C is a D group; One of A or B is an oxazolidinone ring and the other is an isoxazolin ring; R 2a and R 2b are both hydrogen; R 3a and R 3b are both hydrogen or both fluorine; R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or Isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl, or an in vivo-hydrolyzable ester thereof. [7" claim-type="Currently amended] 7. Compounds or pharmaceutically acceptable salts of claims 5 or 6, wherein HET-2 is 1,2,3-triazol-1-yl substituted with methyl or trifluoromethyl, or in vivo-hydrolysis thereof Available esters. [8" claim-type="Currently amended] The compound of claim 1, wherein C is selected from E, J and I groups; Both A and B are oxazolidinone rings; R 2a and R 2b are both hydrogen; R 3a and R 3b are both hydrogen or both fluorine; R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or Isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl, or a pharmaceutically acceptable salt thereof, or an in vivo-hydrolyzable ester thereof. [9" claim-type="Currently amended] The compound of claim 1, wherein C is selected from E, J and I groups; One of A and B is an oxazolidinone ring and the other is an isoxazolin ring; R 2a and R 2b are both hydrogen; R 3a and R 3b are both hydrogen or both fluorine; R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or Isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl, or a pharmaceutically acceptable salt thereof, or an in vivo-hydrolyzable ester thereof. [10" claim-type="Currently amended] The compound or pharmaceutically acceptable salt thereof, or in vivo-hydrolysis thereof, according to claim 8 or 9, wherein HET-2 is 1,2,3-triazol-1-yl substituted with methyl or trifluoromethyl. Available esters. [11" claim-type="Currently amended] The compound of claim 1, wherein C is selected from E, J and I groups; Both A and B are oxazolidinone rings; One of R 2a , R 2b , R 3a and R 3b is fluorine and the others are hydrogen; R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or Isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl, or a pharmaceutically acceptable salt thereof, or an in vivo-hydrolyzable ester thereof. [12" claim-type="Currently amended] The compound of claim 1, wherein C is selected from E, J and I groups; One of A and B is an oxazolidinone ring and the other is an isoxazolin ring; One of R 2a , R 2b , R 3a and R 3b is fluorine and the others are hydrogen; R 1a and R 1b are independently selected from —NHCO (1-4C) alkyl, —NH-HET-1 and HET-2, wherein HET-1 is isoxazolyl, 1,2,5-thiadiazolyl or Isothiazolyl and HET-2 is 1,2,3-triazol-1-yl or tetrazol-2-yl, or a pharmaceutically acceptable salt thereof, or an in vivo-hydrolyzable ester thereof. [13" claim-type="Currently amended] The compound or pharmaceutically acceptable salt thereof, or in vivo-hydrolysis thereof, according to claim 11 or 12, wherein HET-2 is 1,2,3-triazol-1-yl substituted with methyl or trifluoromethyl. Available esters. [14" claim-type="Currently amended] Compounds or pharmaceutically acceptable salts selected from the following compounds, or in vivo-hydrolyzable esters thereof: (5S, 5S ')-N- (3- {4'-[5- (acetylamino-methyl) -2-oxo-oxazolidin-3-yl] -2,2'-difluoro-biphenyl -4-yl} -2-oxo-oxazolidin-5-ylmethyl) -acetamide; N-[((5S, 5'RS) -3- {4 '-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4 -Yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide; (5R, 5RS ')-3- {2-fluoro-4'-[5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'biphenyl-4- Il} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one; N-[((5S) -3- {4 '-[(5R) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4 -Yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide; N-[((5S) -3- {4 '-[(5S) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] -1,1'-biphenyl-4 -Yl} -2-oxo-1,3-oxazolidin-5-yl) methyl] acetamide; And (5R) -3- (3-fluoro-4- {5- [5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] thien-2-yl} phenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one. [15" claim-type="Currently amended] A prodrug of a compound of any one of claims 1-14. [16" claim-type="Currently amended] Showing an antimicrobial effect in a warm-blooded animal, comprising administering to the warm-blooded animal an effective amount of the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, or in vivo hydrolyzable ester thereof. Way. [17" claim-type="Currently amended] The compound of claim 1, or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof, for use as a medicament. [18" claim-type="Currently amended] Use of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof, for use in the manufacture of a medicament for use in a warm-blooded animal to have an antimicrobial effect. [19" claim-type="Currently amended] A pharmaceutical composition comprising the compound of any one of claims 1-14, or a pharmaceutically acceptable salt, or an in vivo hydrolyzable ester thereof, and a pharmaceutically acceptable diluent or carrier. [20" claim-type="Currently amended] (a) changing the substituents in the other compounds of the present invention using standard chemical methods or introducing substituents into said compounds; (b) by reacting two molecules of a compound of formula (II) such that an aryl-aryl, heteroaryl-aryl, or heteroaryl-heteroaryl bond replaces two aryl-X or heteroaryl-X bonds fair: <Formula II> (Wherein X is a leaving group useful for palladium coupling); (c) forming an oxazolidinone ring at an undeveloped aryl position by reaction of the following (hetero) biaryl derivative (III) carbamate with an appropriately substituted oxirane; Or in the process in which carbamate is replaced by isocyanate or amine and oxirane is replaced by equivalent amount of reagent X-CH 2 CH (O-optionally protected) CH 2 R 1a where X is a leaving group Process by deformation; (d) form an isoxazolin ring at an aryl position that is not developed by the reaction of the following (hetero) biaryl derivative (IV); Or a process by process modification wherein the reaction intermediate (nitrile oxide IV ") is obtained by a method other than oxidation of the following oxime (IV ') A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt of claim 1, or an in vivo hydrolyzable ester thereof, comprising one of: <Formula IV ">
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同族专利:
公开号 | 公开日 WO2003022824A1|2003-03-20| US20100137243A1|2010-06-03| ES2244802T3|2005-12-16| JP2005507386A|2005-03-17| RU2004111285A|2005-10-10| NZ531621A|2005-06-24| DE60205030D1|2005-08-18| IS7175A|2004-03-10| BR0212458A|2004-10-19| NO327010B1|2009-04-06| IL160739D0|2004-08-31| US7396847B2|2008-07-08| HK1065789A1|2005-12-30| US20050107435A1|2005-05-19| HU0401005A2|2004-08-30| CO5560609A2|2005-09-30| PT1427711E|2005-11-30| AR036778A1|2004-10-06| HU0401005A3|2007-11-28| NO20041428L|2004-06-08| EP1427711A1|2004-06-16| MXPA04002303A|2004-06-29| DK1427711T3|2005-10-17| EP1427711B1|2005-07-13| CN1639136A|2005-07-13| PL369183A1|2005-04-18| AU2002329393B2|2008-06-12| CA2459766A1|2003-03-20| AT299502T|2005-07-15| SI1427711T1|2005-12-31| DE60205030T2|2006-04-20|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
2001-09-11|Priority to GB0121942.7 2001-09-11|Priority to GB0121942A 2002-07-04|Priority to GB0215420.1 2002-07-04|Priority to GB0215420A 2002-09-09|Application filed by 아스트라제네카 아베 2002-09-09|Priority to PCT/GB2002/004120 2004-05-31|Publication of KR20040044886A
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申请号 | 申请日 | 专利标题 GB0121942.7|2001-09-11| GB0121942A|GB0121942D0|2001-09-11|2001-09-11|Chemical compounds| GB0215420.1|2002-07-04| GB0215420A|GB0215420D0|2002-07-04|2002-07-04|Chemical compounds| PCT/GB2002/004120|WO2003022824A1|2001-09-11|2002-09-09|Oxazolidinone and/or isoxazoline as antibacterial agents| 相关专利
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