KR20070023765A - 3-?4-pyridin-3-ylphenyl?-5-1h-1,2,3-triazol-1-ylmethyl-1,3-oxazolidin-2-ones as antibacterial agents - Google Patents

Abstract

The present invention discloses compounds of formula (I), wherein R ¹ , R ² , R ³ and R ⁴ are as defined herein, and pharmaceutically acceptable salts and prodrugs thereof. The present invention also discloses methods of preparing compounds of formula (I), and methods of using compounds of formula (I) to treat bacterial infections.

Pyridyl-phenyl-oxazolidinone compound, antibacterial activity, mono-amine oxidase-A inhibitory activity

Description

3- ｛4- (pyridin-3-yl) phenyl｝ -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one as an antibacterial agent {3- ｛4- (PYRIDIN-3-YL) PHENYL｝ -5- (1H-1,2,3-TRIAZOL-1-YLMETHYL) -1,3-OXAZOLIDIN-2-ONES AS ANTIBACTERIAL AGENTS}

The present invention relates to antibiotic compounds, in particular antibiotic compounds containing substituted oxazolidinone rings. The present invention further relates to methods for their preparation, intermediates useful for their preparation, their use as therapeutic agents, and pharmaceutical compositions containing them.

The International Society for Microbiology expresses significant interest that the efficacy of strains of currently available antibacterial agents can be neutralized due to the development of antibiotic resistance in these strains. In general, bacterial pathogens can be classified as gram-positive pathogens or gram-negative pathogens. Antibiotic compounds having effective activity against both Gram-positive and Gram-negative pathogens are generally considered to have a wide range of activities. Compounds of the invention are believed to be effective against both Gram-positive pathogens and certain Gram-negative pathogens.

Gram-positive pathogens, such as Staphylococcus (Staphylococcus), Enterobacter nose kusu (Enterococcus), streptococcus (Streptococcus), and mycobacteria (mycobacterium) is difficult to treat is to eradicate when the hospital environment once the composition This is especially important because it becomes difficult to develop into resistant strains. Examples of such strains include methicillin-resistant Staphylococcus (MRSA), methicillin-resistant coagulase-negative Staphylococcus (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple resistance enterotropes. There is the Cocous Passium ( Enterococcus faecium ).

The main clinically effective antibiotic for the treatment of Gram-positive pathogens with this resistance is vancomycin. Vancomycin is a glycopeptide associated with a variety of toxicities, including nephrotoxicity. In addition, antibacterial resistance to vancomycin and other glycopeptides has also been shown, which is of paramount importance. This resistance is increasing at a steady rate that gradually reduces the effects of the therapeutic agents in the treatment of Gram-positive pathogens. Also, H. Influenza ( H. influenzae ) and M. influenzae . Increased resistance to therapeutic agents such as β-lactams, quinolone and macrolides used in the treatment of upper respiratory tract infections caused by certain Gram-negative strains, including M. catarrhalis see.

See, eg, Walter A. Gregory et al., J. Med. Chem. 1990, 33, 2569-2578 and 1989, 32 (8), 1673-81; Chung-Ho Park et al., J. Med. Chem. 1992, 35, 1156-1165, describe certain antibacterial compounds containing oxazolidinone rings. Bacteria's resistance to known antibacterial agents may include, for example, (i) the generation of active binding sites of bacteria, which reduce or neutralize the effects of pharmacophores that were active, and / or (ii) given By means of generating means for chemically inactivating the pharmacological action stage and / or (iii) generating an efflux pathway. Thus, there is still a need for new antibacterial agents with good pharmacological profiles, especially compounds with useful activity and physicochemical properties.

In general, it is understood that the physicochemical properties (eg, solubility and bioavailability) of a pharmaceutical compound are in a balanced state of the polarity of various substituents on the compound and factors such as molecular weight (generally, when the polarity is the same Solubility and bioavailability decrease). In addition, other factors, such as the stiffness / flexibility of the molecule, also generally affect physicochemical properties such as solubility.

Patent application WO 01/94342 (Dong A. Pharm. Co. Ltd.) discloses pyridyl- or pyrimidyl-phenyl-oxazolidinone compounds containing a methylacetamide side chain attached to an oxazolidinone ring. It is described. Most of the compounds exemplified in this patent application contain a substituted piperazine ring attached to a pyridyl or pyrimidyl ring, or contain other heterocycles such as piperidine, oxadiazole or tetrazole rather than piperazine.

We have discovered a new family of pyridyl-phenyl-oxazolidinone compounds having useful antibacterial activity, containing triazole substituents on an oxazolidinone ring, wherein the substituted alkyl substituents are directly linked to the pyridyl ring.

In general, the compounds of the present invention have good physical and / or pharmacokinetic properties such as solubility and / or bioavailability.

In addition, the compounds of the invention generally have low mono-amine oxidase-A inhibitory activity.

Accordingly, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof.

In the formula,

R ¹ is selected from hydrogen, halogen, cyano, methyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methylthio or (2-4C) alkynyl;

R ² and R ³ are independently selected from hydrogen, fluoro, chloro or trifluoromethyl;

R ⁴ is [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy, -C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ , -S (O) ₂ R ⁵ , -S (O) ₂ NR ⁵ R ⁶ , —NR ⁵ R ⁶ , —NHC (O) R ⁵ or —NHS (O) ₂ R ⁵ is substituted with one or two substituents independently selected from; Optionally, further substituted with cyclopropyl] (1-4C) alkyl;

R ⁵ and R ⁶ are hydrogen, methyl, cyclopropyl (optionally substituted with methyl), carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1 -4C) alkyl (optionally substituted with one or two substituents independently selected from alkoxy or hydroxy) (2-4C) alkyl; or

R ⁵ and R ⁶ together with the nitrogen to which they are attached are saturated or partially unsaturated 4, 5 optionally containing one additional heteroatom independently selected from O, N or S (in addition to the N atom connecting them) Or to form a six-membered heterocyclyl ring, wherein -CH ₂ -group can be optionally replaced with -C (O)-, wherein the sulfur atom is optionally substituted with an S (O) group or an S (O) ₂ group Can be oxidized); The ring is optionally substituted on one or two (1-4C) alkyl groups on the available carbon or nitrogen atoms, provided that the nitrogen to which R ⁵ and R ⁶ is attached is not quaternized by such substitution; or

R ⁵ and R ⁶ together with the nitrogen to which they are attached form an imidazole ring optionally substituted with one or two (1-4C) alkyl on the available carbon atoms, provided that R ⁴ is hydroxymethyl none).

In another aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above.

In another aspect, the invention relates to a compound of formula (I) or a prodrug thereof as defined above. Suitable examples of prodrugs of compounds of formula (I) are in vivo hydrolyzable esters of compounds of formula (I). Thus, in another aspect, the invention relates to a compound of formula (I) or an in vivo hydrolyzable ester thereof as defined above.

Where any substituents are selected from "0, 1, 2 or 3" groups, such definitions refer to cases where all substituents are selected from one of the groups shown, or when substituents are selected from two or more of the groups shown. It should be understood to include. Similar rules apply when the substituent is selected from "0, 1 or 2" groups and "1 or 2" groups.

Saturated, partially unsaturated, 4, 5 or 6 members containing one or two heteroatoms independently selected from O, N or S, wherein one of these heteroatoms may be an N atom for bonding It will be appreciated that the heterocyclyl ring does not contain OO, OS or SS bonds, as defined in all definitions herein.

As used herein, the term 'alkyl' includes straight or branched structures. For example, (1-4C) alkyl includes propyl and isopropyl. However, references to individual alkyl groups such as "propyl" are limited only to straight chains, and references to individual branched alkyl groups such as "isopropyl" are limited to branched cases only. Similar rules apply to other groups, such as halo (1-4C) alkyl, including 1-bromoethyl and 2-bromoethyl. As used herein, the terms 'alkenyl' and 'cycloalkenyl' include all regioisomers and geometric isomers.

In this specification, the composite term is used to describe groups comprising two or more functional groups, such as (1-4C) alkoxy- (1-4C) alkoxy- (1-4C) alkyl. These terms should be interpreted according to the meanings understood by those skilled in the art for each component. For example, (1-4C) alkoxy- (1-4C) alkoxy- (1-4C) alkyl includes methoxymethoxymethyl, ethoxymethoxypropyl and propoxymethoxymethyl.

When a given group is defined as being optionally substituted with two or more substituents, such substitution is such that a chemically stable compound is formed. For example, trifluoromethyl groups may be allowed, but trihydroxymethyl groups are not allowed. Such rules apply to all parts where any substituent is defined.

Specific compounds suitable as specific substituents and groups mentioned herein are described below. Such compounds may be used with any definitions and embodiments disclosed above or below where appropriate. For clarity, the specified species each represent a specific aspect independent of the present invention.

Examples of “(1-4C) alkyl” include methyl, ethyl, propyl, isopropyl and t-butyl; Examples of “(2-4C) alkyl” include ethyl, propyl, isopropyl and t-butyl; Examples of “(1-6C) alkyl” include methyl, ethyl, propyl, isopropyl, t-butyl, pentyl and hexyl; Examples of “hydroxy (1-4C) alkyl” include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; Examples of "hydroxy (2-4C) alkyl" include 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl and 2-hydroxyisopropyl Is included; Examples of “(1-4C) alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; Examples of “(2-4C) alkenyl” include allyl and vinyl; Examples of “(2-4C) alkynyl” include ethynyl and 2-propynyl; Examples of “(1-4C) alkanoyl” include formyl, acetyl and propionyl; Examples of “(1-4C) alkoxy” include methoxy, ethoxy and propoxy; Examples of “(1-6C) alkoxy” and “(1-10C) alkoxy” include methoxy, ethoxy, propoxy and pentoxy; Examples of “(1-4C) alkylthio” include methylthio and ethylthio; Examples of “(1-4C) alkylamino” include methylamino, ethylamino and propylamino; Examples of “di-((1-4C) alkyl) amino” include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino and dipropylamino; Examples of “halo” groups include fluoro, chloro and bromo; Examples of "(1-4C) alkoxy- (1-4C) alkoxy" and "(1-6C) alkoxy- (1-6C) alkoxy" are methoxymethoxy, 2-methoxyethoxy, 2-ethoxy Ethoxy and 3-methoxypropoxy; Examples of “(1-4C) alkanoylamino” and “(1-6C) alkanoylamino” include formamido, acetamido and propionylamino; Examples of "(1-4C) alkylS (O) _q- " wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsul Ponyls are included; Examples of “hydroxy- (2-4C) alkoxy” include 2-hydroxyethoxy and 3-hydroxypropoxy; Examples of “(1-6C) alkoxy- (1-6C) alkyl” and “(1-4C) alkoxy (1-4C) alkyl” include methoxymethyl, ethoxymethyl and propoxyethyl; Examples of “(1-4C) alkylcarbamoyl” include methylcarbamoyl and ethylcarbamoyl; Examples of “di ((1-4C) alkyl) carbamoyl” include di (methyl) carbamoyl and di (ethyl) carbamoyl; Examples of “halo” groups include fluoro, chloro and bromo; Examples of “halo (1-4C) alkyl” include halomethyl, 1-haloethyl, 2-haloethyl and 3-halopropyl; Examples of “dihalo (1-4C) alkyl” include difluoromethyl and dichloromethyl; Examples of “trihalo (1-4C) alkyl” include trifluoromethyl; Examples of “amino (1-4C) alkyl” include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; Examples of “cyano (1-4C) alkyl” include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; Examples of “(1-4C) alkanoyloxy” include acetoxy, propanoyloxy; Examples of “(1-6C) alkanoyloxy” include acetoxy, propanoyloxy and tert-butanoyloxy; Examples of “(1-4C) alkylaminocarbonyl” include methylaminocarbonyl and ethylaminocarbonyl; Examples of "di ((1-4C) alkyl) aminocarbonyl" include dimethylaminocarbonyl and diethylaminocarbonyl.

If any substituents are listed, unless otherwise specified, the substitution is preferably not geminal disubstituted. Unless stated otherwise, any substituent suitable for a particular group is a substituent mentioned herein for a similar group.

Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citrate, maleate, tartrate, and (less preferably) hydrobromide. Salts formed by phosphoric acid and sulfuric acid are also suitable. In another aspect, suitable salts are base salts such as alkali metal salts such as sodium salts, alkaline earth metal salts such as calcium or magnesium salts, organic amine salts such as triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N, N-dibenzylethylamine, tris- (2-hydroxyethyl) amine, N-methyl d-glucamine and amino acids , For example lysine. Depending on the number of charged functional groups and the valence of the cation or anion, two or more cations or anions may be present. Preferred pharmaceutically acceptable salts are sodium salts.

However, salts with lower solubility in selected solvents may be preferred, whether or not pharmaceutically acceptable, to facilitate isolation of salts during manufacture.

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 can be used to alter or improve the physical and / or pharmacokinetic profile of the parent compound and be formed when the parent compound contains suitable groups or substituents that can be derivatized to form the prodrug. Can be. Examples of prodrugs include in vivo hydrolyzable esters of a compound of the invention or a pharmaceutically acceptable salt thereof. Another example of a prodrug includes an in vivo hydrolyzable amide of a compound of the present invention or a pharmaceutically acceptable salt thereof.

Various forms of prodrugs are known in the art, see eg, the literature below.

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);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); And

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

Suitable prodrugs for the pyridine or triazole derivatives include acyloxymethyl pyridinium or triazium salts (eg halides), for example prodrugs such as the following compounds.

(See T. Yamazaki et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 2002; Abstract F820).

Suitable prodrugs in the case of hydroxyl groups include the formula RCOOC (R, R ') OCO-, wherein R is (1-4C) alkyl and R' is (1-4C) alkyl or H). Acyl esters of acetal-carbonate esters. Further suitable prodrugs are carbonates and carbamate esters having the formulas RCOO- and RNHCOO-, respectively.

In vivo hydrolyzable esters of the compounds of the present invention or pharmaceutically acceptable salts thereof containing a carboxyl or hydroxy group are, for example, pharmaceutically acceptable esters which are hydrolyzed in the body of a human or animal to produce the parent alcohol.

Suitable pharmaceutically acceptable esters in the case of carboxy are (1-6C) alkoxymethyl esters such as methoxymethyl, (1-6C) alkanoyloxymethyl esters such as pivaloyloxymethyl, phthali Dill esters, (3-8C) cycloalkoxycarbonyloxy (1-6C) alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolane-2-onylmethyl ester, for example 5-methyl-1,3-dioxolan-2-ylmethyl; And (1-6C) alkoxycarbonyloxyethyl esters such as 1-methoxycarbonyloxyethyl, which esters may be formed at any carboxy group in the compounds of the present invention.

In vivo hydrolyzable esters of the compounds of the present invention or pharmaceutically acceptable salts thereof containing hydroxy group (s) include inorganic esters such as phosphate esters (including phosphoramide acid cyclic esters) and α-acyloxyalkyl ethers. And related compounds, in which the ester is decomposed by hydrolysis in vivo to produce the parent hydroxy group (s). Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. In the case of hydroxy, the in vivo hydrolyzable ester-forming groups selected include (1-10C) alkanoyl (e.g. (1-4C) alkanoyl), benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1 -10C) alkoxycarbonyl (produces alkyl carbonate esters), di- (1-4C) alkylcarbamoyl and N- (di- (1-4C) alkylaminoethyl) -N- (1-4C ) Alkylcarbamoyl (which produces carbamate), di- (1-4C) alkylaminoacetyl, carboxy (2-5C) alkylcarbonyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include chloromethyl or aminomethyl, (1-4C) alkylaminomethyl and di-((1-4C) alkyl) aminomethyl, and a benzoyl ring from a ring nitrogen atom via a methylene bond group Morpholino or piperazino bound to the 3- or 4-position of. Examples of other beneficial in vivo hydrolyzable esters include R ^A C (O) O (1-6C) alkyl-CO-, wherein R ^A is, for example, optionally substituted benzyloxy- (1-4C) alkyl, Or optionally substituted phenyl), and examples of suitable substituents on the phenyl group of such esters include 4- (1-4C) piperazino- (1-4C) alkyl, piperazino- (1-4C) alkyl and Morpholino- (1-4C) alkyl.

Further suitable in vivo hydrolyzable esters are esters formed from amino acids, for example esters formed by the reaction of a hydroxy group of a compound with a carboxylic acid of an amino acid. The term "amino acid" is used herein to refer to any natural or other (ie, non-natural) α- or other substituted amino acids, and derivatives thereof, such as substitutions (eg, alkylation of amino groups on nitrogen). Means those formed by. The use of natural or non-natural amino acids represents certain independent aspects of the present invention. Examples of suitable α-amino acids and derivatives thereof are valine, leucine, iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine, lysine, glycine, N-methylglycine, N, N-dimethyl glycine, alanine, glue Amine, asparagine, proline and phenylalanine. In one embodiment, preferred amino acids are natural α-amino acids and their N-alkylated derivatives.

The use of amino acids having neutral and / or basic side chains represents certain independent aspects of the present invention.

Suitable in vivo hydrolyzable esters of compounds of formula (I) are described below. For example, 1,2-diol can be cyclized to form a cyclic ester of formula PD1 or a pyrophosphate of formula PD2, and 1,3-diol can be cyclized to form a cyclic ester of formula PD3 Can be formed.

Esters of compounds of formula (I) wherein the HO-functional group (s) of formulas PD1, PD2 and PD3 are protected by (1-4C) alkyl, phenyl or benzyl are useful intermediates for the preparation of such prodrugs.

Further in vivo hydrolyzable esters include compounds of the invention wherein the phosphoramic acid ester and any free hydroxy group independently form a phosphoryl (npd = 1) or phosphyl (npd = 0) ester of the formula PD4 This includes.

To be clear, the phosphono is -P (O) (OH) ₂ ; (1-4C) alkoxy (hydroxy) -phosphoryl is a mono- (1-4C) alkoxy derivative of -OP (O) (OH) ₂ ; Di- (1-4C) alkoxyphosphoryl is a di- (1-4C) alkoxy derivative of -OP (O) (OH) ₂ .

Useful intermediates for the preparation of such esters include both or one of the —OH groups of formula PD1 (1-4C) alkyl (these compounds are of themselves beneficial compounds), or phenyl or phenyl- (1- 4C) alkyl (where these phenyl groups are optionally substituted with one or two groups independently selected from (1-4C) alkyl, nitro, halo or (1-4C) alkoxy) (S) are included.

Thus, prodrugs containing groups such as the formulas PD1, PD2, PD3 and PD4 may suitably protect compounds of the invention containing suitable hydroxy group (s) with phosphorylating agents (e.g., chloro or dialkylamino leaving). Containing a group), followed by oxidation (if necessary) and deprotection.

Other suitable prodrugs include phosphonooxymethyl ethers and salts thereof, for example prodrugs of R-OH such as the following compounds.

When the compounds of the present invention contain a large number of free hydroxy groups, the groups which are not converted to prodrug functional groups can be protected (eg by t-butyl-dimethylsilyl groups) and later deprotected. In addition, enzymatic methods can be used to selectively phosphorylate or dephosphorylate alcohol functional groups.

Examples of prodrugs for amino groups include in vivo hydrolyzable amides or pharmaceutically acceptable salts thereof. Suitable in vivo hydrolyzable groups include N-carbomethoxy and N-acetyl. Such amides include amino groups (or alkylamino groups) and activated acyl derivatives, such as activated esters or acid chlorides, such as (1-6C) alkanoylchlorides (eg tBuCOCl or acetyl chloride), or substituted groups thereof. It can be formed by the reaction of derivatives.

Suitable compounds as in vivo hydrolyzable amides of compounds of formula I containing carboxyl groups are, for example, NC _1-6 alkyl or N, N-di-C _1-6 alkyl amides, for example N-methyl, N -Ethyl, N-propyl, N, N-dimethyl, N-ethyl-N-methyl or N, N-diethyl amide. Further compounds suitable as in vivo hydrolyzable amides of compounds of formula (I) containing amine groups or carboxyl groups include in vivo hydrolyzable forms formed by reaction with amino acids, as defined and described herein for in vivo hydrolyzable esters. There are amides.

If pharmaceutically acceptable salts of hydrolyzable esters or amides in vivo can be formed, this is accomplished by conventional techniques. Thus, for example, compounds containing groups of the formulas PD1, PD2, PD3 and / or PD4 can be ionized (partially or completely) to form salts with the appropriate number of counterions. Thus, for example, if the in vivo hydrolyzable ester prodrug of a compound of the invention contains two groups of formula PD4, there are four HO-P-functional groups throughout the molecule, each of which forms an appropriate salt. (Ie, the entire molecule can, for example, form mono-, di-, tri- or tetra-sodium salts).

In one aspect, suitable prodrugs of the present invention include in vivo hydrolyzable esters, such as (1-4C) alkyl esters; (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, carboxy, (1-4C) alkyl ester, amino, (1-4C) alkylamino, di (1-4C) alkylamino, tri (1-4C) alkylamino (by such substitutions contain quaternized nitrogen atoms), (1-4C) alkyl esters substituted with aminocarbonyl, carbamate, amide or heterocyclyl groups (eg, A hydroxy group of R ⁴ or R ⁵ , methoxy acetic acid, methoxypropionic acid, adipic acid methyl ester, 4-dimethylaminobutanoic acid, 2-methylaminobutanoic acid, 5-amino pentanic acid, β-alanine, N, N-diethylalanine, valine, leucine, iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine, lysine, glycine, N, N-dimethyl glycine, alanine, sarcosine, glutamine, asparagine, proline, phenylalanine , Nicotinic acid, nicotinic acid-N-oxide, pyrimidine-carboxylic acid (eg, pyrimidine-5-carboxylic acid), pyrazine-carboxylic acid (eg , Pyrazine-2-carboxylic acid) or piperidin-4-ester formed by the reaction of a carboxylic acid); (3-6C) cycloalkyl esters (optionally substituted with (1-4C) alkoxycarbonyl, alkoxy or carboxyl groups); Carbonates (eg, (1-4C) alkylcarbonates, and (1-4C) alkylcarbonates substituted with (1-4C) alkoxy or di (1-4C) alkyl) amino); Sulfates; Phosphate and phosphate esters; And carbamate (see, eg, Example 10); And their pharmaceutically acceptable salts.

Further suitable prodrugs are those formed by the reaction of hydroxy groups of R ⁴ or R ⁵ with carbonates, in particular alkoxy-substituted alkyl carbonates, for example methoxypropylcarbonate.

Further suitable prodrugs include hydroxy groups of R ⁴ or R ⁵ , methoxy acetic acid, methoxypropionic acid, adipic acid methyl ester, 4-dimethylaminobutanoic acid, 2-methylaminobutanoic acid, 5-amino pentanic acid , β-alanine, N, N-diethylalanine, valine, leucine, iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine, lysine, glycine, N, N-dimethyl glycine, alanine, sarcosine, Glutamine, asparagine, proline, phenylalanine, nicotinic acid, nicotinic acid-N-oxide, pyrimidine-5-carboxylic acid, pyrazine-2-carboxylic acid, piperidine-4-carboxylic acid or 2-carboxy-cyclohexane Esters formed by the reaction of -1-carboxylic acids; And pharmaceutically acceptable salts thereof.

Particular compounds of the invention are in vivo hydrolyzable esters formed from amino acids and pharmaceutically acceptable salts thereof.

In addition, particular compounds of the present invention are 4-dimethylaminobutanoic acid, 2-methylaminobutanoic acid, 5-amino pentanic acid, β-alanine, N, N-diethylalanine, valine, leucine, iso-leucine, N- In vivo hydrolysable esters formed from methyl isoleucine, N-tert-butyl-isoleucine, lysine, glycine, N, N-dimethyl glycine, alanine, sarcosine, glutamine, asparagine, proline or phenylalanine; And pharmaceutically acceptable salts thereof.

In addition, particular compounds of the invention are valine, leucine, iso-leucine, N-methyl isoleucine, N-tert-butyl-isoleucine, lysine, glycine, N, N-dimethyl glycine, alanine, sarcosine, glutamine, asparagine, proline Or in vivo hydrolysable esters formed from phenylalanine; And pharmaceutically acceptable salts thereof.

Compounds of the invention have a chiral center at the C-5 position of the oxazolidinone ring. Pharmaceutically active diastereomers are compounds of formula la having the 5R configuration.

The present invention includes pure diastereomers or diastereomeric mixtures, for example racemic mixtures. If enantiomeric mixtures are used, higher amounts (depending on the proportion of enantiomers) will be required to achieve the same effect as the pharmaceutically active enantiomers of the same weight.

In addition, certain compounds of the invention may have another chiral center. It is to be understood that the present invention includes all optical isomers and diastereomers having antibacterial activity. Methods for preparing optically active forms (eg, via recrystallization techniques, chiral synthesis, enzymatic separation, in vivo conversion or chromatographic separation), and methods for measuring the antibacterial activity described below Is well known in the art.

The present invention relates to all tautomeric forms of the compounds of the present invention having antibacterial activity.

It is also to be understood that certain compounds of the present invention may exist in solvated forms (eg, hydrated forms) as well as non-solvated forms. It is to be understood that the present invention encompasses all solvated forms having antibacterial activity.

In addition, certain compounds of the present invention may exhibit polymorphism, and it is to be understood that the present invention includes all polymorphic forms having antibacterial activity.

As mentioned above, the inventors of H. H., with excellent activity against a wide range of Gram-positive pathogens, including organisms known to be resistant to the most commonly used antibiotics. Influenza, M. A series of compounds with activity against fastidious Gram-negative pathogens have been found, such as catarrhalis , Mycoplasma and Chlamydia strains. The following compounds have desirable pharmaceutical and / or physical and / or pharmacokinetic properties.

While not wishing to be bound by theoretical considerations, the incorporation of a flexible substituent on the pyridine ring is believed to have a beneficial effect on the solubility of the compound. For example, in pH 7.4 phosphate buffer, Reference Example 5 has an equilibrium solubility of 35.1 μM and Reference Example 6 has an equilibrium solubility of less than 7.1 μM. In contrast, Example 4 has an equilibrium solubility of 210 μM. It will be appreciated that parameters such as solubility can be measured by any suitable technique known in the art.

In one embodiment of the present invention there is provided a compound of formula (I), in another embodiment there is provided a pharmaceutically acceptable salt of the compound of formula (I), and in another embodiment there is provided an in vivo hydrolyzable ester of the compound of formula (I). In another embodiment, provided is a pharmaceutically acceptable salt of an in vivo hydrolyzable ester of a compound of formula (I). In another aspect there is provided an in vivo hydrolyzable amide of a compound of formula (I).

In one aspect, R ¹ is selected from hydrogen, halogen, cyano, methyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethynyl or propynyl.

In another aspect, R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl.

In another aspect, R ¹ is hydrogen.

In one aspect, R ² and R ³ are independently hydrogen or fluoro.

In another aspect, both R ² and R ³ are hydrogen.

In another aspect, one of R ² and R ³ is hydrogen and the other is fluorine.

In one aspect, R ⁴ is [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ or -OC (O) is substituted with one or two substituents independently selected from NR ⁵ R ⁶ ; Optionally, further substituted with cyclopropyl] (1-4C) alkyl.

In one aspect R ⁴ is selected from [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ or -OC ( O) is substituted with one substituent independently selected from NR ⁵ R ⁶ ; Optionally, further substituted with cyclopropyl] (1-4C) alkyl.

In another aspect, R ⁴ is substituted with one or two substituents independently selected from [-C (O) OR ⁵ , -C (O) R ⁵ , carboxy or -C (O) NR ⁵ R ⁶ ] (1-4C) alkyl.

In another aspect, R ⁴ is substituted with one substituent independently selected from —C (O) OR ⁵ , —C (O) R ⁵ , carboxy or —C (O) NR ⁵ R ⁶ ] (1 -4C) alkyl.

In another aspect, R ⁴ is [1-4C) alkyl [substituted with one substituent independently selected from —S (O) ₂ R ⁵ or —S (O) ₂ NR ⁵ R ⁶ .

In another aspect, R ⁴ is substituted with 1 or 2 substituents independently selected from —NR ⁵ R ⁶ , —NHC (O) R ⁵ or —NHS (O) ₂ R ⁵ ] (1-4C Alkyl.

In another aspect, R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy, -C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ substituted with one or two substituents independently selected from: (1-4C) alkyl to be.

In another aspect, R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ , carboxy, -C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ substituted with one or two substituents independently] (1-4C) alkyl.

In another aspect, R ⁴ is one independently selected from hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, —OC (O) R ⁵ , carboxy or —NR ⁵ R ⁶ Or substituted with two substituents] (1-4C) alkyl.

In another aspect, R ⁴ is substituted with one or two substituents independently selected from hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy or —NR ⁵ R ⁶ ] (1 -4C) alkyl.

In another aspect, R ⁴ is (1-4C) alkyl [substituted with one or two substituents independently selected from hydroxy or —NR ⁵ R ⁶ ].

In one aspect, R ⁵ and R ⁶ are hydrogen, methyl, cyclopropyl (optionally substituted with methyl), carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carbo Is independently selected from (2-4C) alkyl optionally substituted with one or two substituents independently selected from (1-4C) alkoxy or hydroxy.

In one aspect, R ⁵ and R ⁶ are hydrogen, methyl, carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1-4C) alkoxy or hydroxy Independently selected from (2-4C) alkyl optionally substituted with one or two substituents independently.

In another aspect, R ⁵ and R ⁶ are independently selected from hydrogen or (1-4C) alkyl. In another aspect, R ⁵ and R ⁶ are independently selected from hydrogen or methyl.

In another aspect, R ⁵ and R ⁶ are independently selected from hydrogen, methyl, carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy or hydroxy And (2-4C) alkyl optionally substituted with 2 or 2 substituents.

In another aspect, R ⁵ and R ⁶ are one or two substituents independently selected from hydrogen, methyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino or hydroxy Independently selected from (2-4C) alkyl.

In another aspect, R ⁵ and R ⁶ are independently selected from hydrogen, methyl, or (2-4C) alkyl (optionally substituted with one or two hydroxy).

In another aspect, R ⁵ and R ⁶ together with the nitrogen to which they are attached are saturated or partially optionally containing one additional heteroatom independently selected from O, N or S (in addition to the N atom connecting them) To form an unsaturated 4, 5 or 6 membered heterocyclyl ring, wherein the -CH ₂ -group may be optionally replaced by -C (O)-, wherein the sulfur atom in the ring is an S (O) group or S (O) optionally oxidized to ₂ groups); The ring is optionally substituted with one or two (1-4C) alkyl groups on the available carbon or nitrogen atoms, provided that the nitrogen to which R ⁵ and R ⁶ are attached is not quaternized by such substitution. In another aspect, the ring is a saturated ring.

Compounds suitable as rings containing R ⁵ and R ⁶ together with the nitrogen to which they are attached include azetidine, morpholine, piperazine, N-methylpiperazine, thiomorpholine (and sulfur in the S (O) group or S (O) Derivatives oxidized in _two groups), piperidine, pyrrolidine and tetrahydropyridine.

Additional compounds suitable as rings comprising R ⁵ and R ⁶ together with the nitrogen to which they are attached include morpholine, piperazine, N-methylpiperazine and thiomorpholine (and sulfur is an S (O) group or S (O) Derivatives oxidized in _two groups).

Further compounds suitable as rings comprising R ⁵ and R ⁶ together with the nitrogen to which they are attached include morpholine and thiomorpholine (and derivatives of sulfur oxidized to S (O) or S (O) ₂ groups). have.

The ring is in particular morpholine.

In another aspect, R ⁵ and R ⁶ together with the nitrogen to which they are attached imideazole, methylimidazole or dimethylimidazole ring, in particular methylimidazole or dimethylimidazole, more particularly dimethylimidazole Form.

In a preferred aspect of the invention, the compound of formula I is a compound of formula la above.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy,- As defined above, wherein is (1-4C) alkyl substituted with one or two substituents independently selected from C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ There is provided a compound of Formula Ia, or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy,- C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ substituted with one or two substituents independently selected from (1-4C) alkyl;

R ⁵ and R ⁶ are hydrogen, methyl, cyclopropyl (optionally substituted with methyl), carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1- 4C) a compound of formula (Ia) as defined above, or a pharmaceutically acceptable salt thereof, independently selected from (2-4C) alkyl optionally substituted with one or two substituents independently selected from alkoxy or hydroxy Or prodrugs are provided.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy,- C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ substituted with one or two substituents independently selected from (1-4C) alkyl;

A compound of formula (Ia) as defined above, or a pharmaceutically acceptable thereof, wherein R ⁵ and R ⁶ are independently selected from hydrogen, methyl, or (2-4C) alkyl (optionally substituted with one or two hydroxy) Salts or prodrugs are provided.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy,- C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ substituted with one or two substituents independently selected from (1-4C) alkyl;

R ⁵ and R ⁶ together with the nitrogen to which they are attached, azetidine, morpholine, piperazine, N-methylpiperazine, thiomorpholine (and derivatives thereof in which sulfur is oxidized to S (O) or S (O) ₂ groups) ), Piperidine, pyrrolidine or tetrahydropyridine are provided, or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy,- C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ or -NR ⁵ R ⁶ substituted with one or two substituents independently selected from (1-4C) alkyl;

Or a pharmaceutically acceptable salt or prodrug thereof, as defined above, wherein R ⁵ and R ⁶ together with the nitrogen to which they are attached form an imidazole, methylimidazole or dimethylimidazole ring This is provided.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is selected from one or two substituents independently selected from hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ , carboxy or -NR ⁵ R ⁶ Substituted] (1-4C) alkyl;

R ⁵ and R ⁶ are hydrogen, methyl, cyclopropyl (optionally substituted with methyl), carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1- 4C) a compound of formula (Ia) as defined above, or a pharmaceutically acceptable salt thereof, independently selected from (2-4C) alkyl optionally substituted with one or two substituents independently selected from alkoxy or hydroxy Or prodrugs are provided.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is selected from one or two substituents independently selected from hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ , carboxy or -NR ⁵ R ⁶ Substituted] (1-4C) alkyl;

R ⁵ and R ⁶ together with the nitrogen to which they are attached, azetidine, morpholine, piperazine, N-methylpiperazine, thiomorpholine (and derivatives thereof in which sulfur is oxidized to S (O) or S (O) ₂ groups) ), Piperidine, pyrrolidine or tetrahydropyridine are provided, or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect of the invention,

R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is selected from one or two substituents independently selected from hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ , carboxy or -NR ⁵ R ⁶ Substituted] (1-4C) alkyl;

Or a pharmaceutically acceptable salt or precursor thereof, as defined above, wherein R ⁵ and R ⁶ together with the nitrogen to which they are attached form an imidazole, methylimidazole or dimethylimidazole ring Drugs are provided.

In another aspect of the invention,

R ¹ is hydrogen;

R ² and R ³ are independently hydrogen or fluoro;

R ⁴ is selected from one or two substituents independently selected from hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -OC (O) R ⁵ , carboxy or -NR ⁵ R ⁶ Substituted] (1-4C) alkyl;

Or a pharmaceutically acceptable salt or prodrug thereof, as defined above, wherein R ⁵ and R ⁶ together with the nitrogen to which they are attached form an imidazole, methylimidazole or dimethylimidazole ring This is provided.

Particular compounds of the invention include each individual compound described in the Examples below, each of which provides an independent aspect of the invention. In another aspect of the invention, any two or more of the following embodiments are provided.

Manufacturing method section:

In another aspect, the present invention provides a process for preparing a compound of the present invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. It will be appreciated that certain parts of the following reaction procedures may require the protection of certain substituents to prevent undesirable reactions. The skilled chemist will know when such protection is needed and how to introduce and later remove the protecting group.

As for examples of protecting groups, one of the numerous general literatures on protecting groups, for example, Theodora Green's 'Protective Groups in Organic Synthesis' (John Wiley & Sons). The protecting group can be removed by any convenient method described in the literature or known to the skilled chemist suitable for the removal of the protecting group, which method provides for the removal of the protecting group with minimal interference with groups in other parts of the molecule. Is selected to perform.

Thus, if the reactants include groups such as, for example, amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

Suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example alkanoyl groups, for example acetyl groups, alkoxycarbonyl groups, for example methoxycarbonyl groups, ethoxycarbonyl groups or t-butoxycarbonyl groups, aryl Methoxycarbonyl groups such as benzyloxycarbonyl, or aroyl groups such as benzoyl. Of course, the deprotection conditions of the protecting group depend on the protecting group selected. Thus, for example, acyl groups such as alkanoyl groups, alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with suitable bases such as alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Can be. Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed by treatment with a suitable acid such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups For example, it can be removed by hydrogenation on a catalyst such as palladium on carbon or by treatment with Lewis acid, for example boron tris (trifluoroacetate). Examples of other protecting groups suitable for primary amino groups are phthaloyl groups which can be removed by treatment with alkylamines such as dimethylaminopropylamine, or hydrazine.

Examples of suitable protecting groups for the hydroxy group are acyl groups such as alkanoyl groups such as acetyl, aroyl groups such as benzoyl, or arylmethyl groups such as benzyl. Of course, the deprotection conditions of the protecting group depend on the protecting group selected. Thus, for example, acyl groups such as alkanoyl groups or aroyl groups can be removed by hydrolysis with suitable salts, for example alkali metal hydroxides such as lithium hydroxide or sodium hydroxide. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation, for example on a catalyst such as palladium on carbon.

Examples of suitable protecting groups for carboxyl groups are removed by treatment with esterizable groups, for example methyl or ethyl groups, which can be removed by hydrolysis with a base such as sodium hydroxide, or with an organic acid such as an acid, for example trifluoroacetic acid. T-butyl groups, which may be used, or benzyl groups, which may be removed by hydrogenation on a catalyst such as palladium on carbon. Resin can also be used as a protecting group.

The protecting group may be removed at any convenient stage of the synthesis process by conventional techniques well known in the chemical art.

The compounds of the present invention, or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, may be prepared by any method known to be applicable to the preparation of chemically related compounds. Such a method is provided as another feature of the invention when used in the preparation of a compound of the invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and is exemplified by the following representative examples. Necessary starting materials can be obtained by standard methods of organic chemistry (see, for example, Advanced Chemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Organischen Chemie). The preparation of starting materials is described in the non-limiting examples included herein. Alternatively, the necessary starting materials can be obtained by methods similar to those exemplified, which are within the ordinary skill of the organic chemist. Information on the preparation of the necessary starting materials or related compounds (which can be modified to form the required starting materials) can be found in the specific patent application publications, for example WO 94/13649; WO 98/54161; WO 99/64416; WO 99/64417; WO 00/21960; WO 01/40222, WO 01/94342; Also found in WO 03/022824, JP2003335762 and WO 03/006440, the contents of the relevant manufacturing method sections included therein are hereby incorporated herein by reference.

In particular, the inventors have referred to our PCT patent applications WO 99/64417 and WO 00/21960, which give detailed instructions on a convenient method for preparing oxazolidinone compounds.

A skilled organic chemist will be able to use and modify the information included and referred to in the above references, the examples included in the references, and the examples herein to obtain the necessary starting materials and products.

Accordingly, the present invention also provides any one of the following processes a) to o); And later if necessary

i) removing any protecting group;

ii) forming a prodrug (eg, a hydrolyzable ester in vivo); And / or

iii) forming a pharmaceutically acceptable salt

Compounds of the Invention, and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof, which may be prepared by the present invention, wherein the variables are as defined above unless otherwise stated:

a) a process of modifying a substituent in another compound of the invention using standard chemistry or introducing a substituent to another compound of the invention (e.g., Comprehensive Organic Functional Group Transformations (Pergamon), Katritzky, Meth- Cohn & Rees] [For example, a hydroxy group is a fluoro group, an acyloxy group, for example, an acetoxy group, an amino group, or a heterocyclyl group linked through nitrogen (carbon not a carbon atom adjacent to a nitrogen ring atom to which it is linked). Optionally substituted in the phase), for example, an optionally substituted imidazol-1-yl group, and the conversion of such hydroxy groups is carried out directly (e.g., by acylation or by Mitsunobu reaction) or , Via mediation of one or more derivatives (eg mesylate or azide); The acyloxy group can be converted to a hydroxy group or to a group that can be obtained from the hydroxy group (directly or through the mediation of the hydroxy group); The alkyl halogenide group can be converted to a hydroxyl group, an amino group, a thioalkyl group, or a heterocyclyl group linked through nitrogen; The keto group can be reduced to a hydroxyl group or a saturated alkyl group;

b) reacting a compound of formula (II) with a compound of formula (IIa) and then reacting with leaving group X to replace phenyl-X bonds and pyridyl-X bonds with pyridyl-phenyl bonds (e.g., Scheme b) [These methods are well known and are described, for example, in SP Stanforth, Catalytic Cross-Coupling Reactions in Biaryl Synthesis, Tetrahedron, 54, 1998, 263-303; J.K. Stille, Angew Chem. Int. Ed. Eng., 1986, 25, 509-524; [N. Miyaura and A Suzuki, Chem. Rev., 1995, 95, 2457-2483; [D. Baranano, G. Mann, and J.F. Hartwig, Current Org. Chem., 1997, 1, 287-305; [S.P. Stanforth, Tetrahedron, 54, 1998, 263-303; [P.R. Parry, C. Wang, A.S. Batsanov, M.R. Bryce]; And [B. Tarbit, J. Org. Chem., 2002, 67, 7541-7543;

Wherein X is a leaving group useful for palladium [0] coupling, for example chloride, bromide, iodide, trifluoromethylsulfonyloxy, trimethylstannyl, trialkoxysilyl or boronic acid moiety May be the same or different from each other in the two molecules of II and IIa);

c) reacting a pyridyl-phenyl carbamate derivative of formula III with an appropriately substituted oxirane to form an oxazolidinone ring [where the carbamate is replaced by an isocyanate or an amine and / or the oxirane is Modifications of the above process, replaced by the equivalent reagent X-CH ₂ CHO (optionally protected) CH ₂ -triazoleR ¹ , wherein X is a releasable group, are also well known in the art (eg, X Is Br: Scheme c ')];

d) reacting a compound of formula (IV) with an acylating agent followed by reduction of the ketone (if Y is halo) and then reacting with a compound of formula (II) as described in step b) above (e.g. Scheme d) which is an (optionally substituted) alkyl group;

임);Wherein X is a replaceable substituent (e.g., chloride, bromide, iodide or trifluoromethylsulfonyloxy), and Y is halo or

being);

Wherein R is an (optionally substituted) alkyl group;

e) reacting an alpha-halo ketone derivative of formula (IV) as defined above with X being a ketone and nucleophile followed by reduction of the ketone and then (if Y is halo) a formula as described in step b) above Reacting with a compound of II (eg, Scheme e);

f) alkylating the 2-picolin group of the compound of formula IV wherein Y is halo to obtain a compound of formula IIa, and then reacting it with a compound of formula II (eg, Scheme f below);

g) X is an epoxide and Y is reacted with a nucleophilic epoxide of a compound of formula IV as defined in step d) above (if Y is halo) and then formula II as described in step b) above Reacting with a compound of (eg, Scheme g below);

h) reacting a pyridyl-2-carbaldehyde derivative of formula V with a Grignard reagent or similar metal alkyl reagent;

i) reductive amination of, for example, an aldehyde group of formula V;

j) A process for converting amines to vinylpyridine by an anti-Markovnikov addition reaction (eg, Scheme j below) (M. Beller et al, Eur. J. Inorg. Chem. 1999, 1121-1132];

k) forming, for example, a triazole ring from a suitably functionalized intermediate in which the R ⁴ -pyridyl-phenyl ring system is previously formed, as illustrated in Scheme k below;

l) a process of conversion to acetylene by a cycloaddition reaction through an azide (e.g., at room temperature, for example, by reacting azidomethyl oxazolidinone with an end alkyne and Cu (I) catalysis in an aqueous solution of -Substituted 1,2,3-triazole) (VV Rostovtsev, LG Green, VV Fokin, and KB Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596-2599);

m) Reaction of aminomethyloxazolidinone with 1,1-dihaloketone sulfonylhydrazone (Sakai, Kunihazu; Hida, Nobuko; Kondo, Kiyosi; Bull. Chem. Soc. Jpn., 59, 1986 179-183] [Sakai, Kunikazu; Tsunemoto, Daiei; Kobori, Takeo; Kondo, Kiyoshi; Hido, Noboko EP 103840 A2 19840328];

n) when R ¹ is 4-halo, the compound of formula (I) by reacting azidomethyl oxazolidinone with halovinylsulfonyl chloride without solvent or in an inert diluent such as chloroform or dioxane at a temperature of 0 to 100 ° C. Process for producing a;

o) a process of reducing a ketone precursor of formula Va, for example by sodium borohydride (eg, Scheme o below).

The removal of any protecting groups, the formation of pharmaceutically acceptable salts and / or the formation of hydrolyzable esters or amides in vivo is within the skill of the conventional organic chemist using standard techniques. Further details of these steps, for example the preparation of hydrolyzable ester prodrugs in vivo, are provided in the section above on such esters, for example.

If an optically active form of a compound of the invention is desired, the optically active form may be carried out using one of the above methods using an optically active starting material (eg, formed by asymmetric induction of a suitable reaction step), Or by separating the racemic forms of the compounds or intermediates using standard methods, or by chromatographic separation of diastereomers (if generated). Enzymatic techniques may also be useful for the preparation of optically active compounds and / or intermediates.

Similarly, when pure regioisomers of the compounds of the present invention are desired, one can perform one of the above methods using pure regioisomers as starting materials, or by separating the mixture of regioisomers or intermediates by standard methods. Regioisomers can be obtained.

Compounds of formula II wherein X is an iodine, tin or boron derivative can be prepared according to the method described in WO 03/022824.

A compound of formula (II) wherein X is Br (compound of formula IIc) is a solution of a compound of formula (II) (compound of formula IIb) wherein X is H, using bromine produced in situ from bromate, bromide and acid It can be prepared by direct bromination.

Wherein R ² and R ³ are independently H or F and R p is hydrogen, halogen, cyano, methyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl or -Si [(1 -4C) alkyl] ₃ ).

According to the following scheme, the formation of bromine by reaction of, for example, bromate, bromide and acid in the reaction medium is a convenient way to avoid the problems associated with the decomposition of bromine solution over time.

_{^{BrO 3 - + 6H + + 5Br}} - → 3Br 2 + 3H 2 O

Conveniently, hydrobromic acid can be used to provide the acid and bromide together. The bromide is suitably added as an aqueous solution, for example an aqueous solution of hydrobromic acid, such as 48% w / w aqueous hydrobromic acid solution. Any convenient concentration of solution can be used.

Bromate is conveniently an alkali metal bromate such as potassium bromate or sodium bromate. The bromate is preferably added as an aqueous solution.

The compound of formula (IIb) may be dissolved in any suitable organic solvent. In the context, “suitable” means that the organic solvent is water miscible and should not react with other reagents.

Suitable solvent is acetic acid. The compound of formula (IIb) may be dissolved in such a suitable organic solvent, for example a mixture of acetic acid and water.

It is convenient to add an aqueous bromide solution to the solution of the compound of formula IIb, followed by the bromate solution.

The reaction of bromate with bromide in the presence of acid is an exothermic reaction. Conveniently, the vessel containing the reaction mixture can be cooled, for example, in an ice bath, but it is not critical to maintain a certain temperature in the yield or quality of the resulting product. The vessel containing the reaction mixture is conveniently cooled in an ice bath such that the reaction temperature is in the range of 10 to 30 ° C. during the addition of the bromate.

It is suitable to use bromate and bromide in slightly molar excess relative to the amount of the compound of formula (IIb) used.

The rate of addition of the bromate solution is not critical. It is convenient to add the bromate solution at a rate such that the reaction temperature is maintained at 10 to 30 ° C. while adding the bromate.

The reaction mixture can be stirred, for example, at room temperature until the reaction is complete. Typically, it may take 3 to 4 hours (including the time required to add bromate) until the reaction is complete.

After the reaction is complete, it is preferred to isolate the product after removing any excess bromine produced. Conveniently, the removal can be accomplished by adding a metabisulfite solution, for example an aqueous metabissulfite solution. Sufficient amount of metabisulfite is added for reaction with any residual bromine.

The product can be isolated by any convenient means, for example by filtration of the reaction mixture, or by dissolution in other organic solvents and appropriate washing and evaporation. If the product solidifies from the reaction mixture, it may be convenient to redissolve it (eg, heat the solution, for example to about 80 to 85 ° C.) and crystallize in a controlled manner.

According to another aspect of the invention, a process for forming a compound of formula IIc from a compound of formula IIb comprising treating a solution of a compound of formula IIb as defined above with alkali metal bromate and hydrobromic acid Is provided.

According to another aspect of the invention,

a) treating a solution of a compound of formula (IIb) as defined above with an aqueous hydrobromic acid solution in a mixture of water and a suitable organic solvent; And

b) adding an alkali metal bromate aqueous solution

Provided is a method of forming a compound of Formula IIc from a compound of Formula IIb.

According to another aspect of the invention,

a) treating a solution of a compound of formula (IIb) as defined above with an aqueous hydrobromic acid solution in a mixture of water and a suitable organic solvent;

b) adding an alkali metal bromate aqueous solution; And

c) adding sodium metabisulfite solution to react with any excess bromine

Provided is a method of forming a compound of Formula IIc from a compound of Formula IIb.

According to another aspect of the invention,

a) treating a solution of a compound of formula (IIb) as defined above with an aqueous hydrobromic acid solution in a mixture of water and a suitable organic solvent;

b) adding an alkali metal bromate aqueous solution;

c) adding sodium metabisulfite solution to react with any excess bromine; And

d) isolating the compound of formula IIc as a product

Provided is a method of forming a compound of Formula IIc from a compound of Formula IIb.

According to another aspect of the invention,

a) treating a solution of a compound of formula (IIb) as defined above with an aqueous hydrobromic acid solution in a mixture of water and a suitable organic solvent;

b) adding an alkali metal bromate aqueous solution;

c) adding sodium metabisulfite solution to react with any excess bromine; And

d) isolating the compound of formula (IIc) as a product by heating the mixture resulting from step c) until all the solids are dissolved and then cooling the solution until the compound of formula (IIc) crystallizes.

Provided is a method of forming a compound of Formula IIc from a compound of Formula IIb.

According to another 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 treating a human or animal body by therapy.

According to another feature of the invention, in an animal comprising administering to a warm blooded animal such as a human in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof A method of producing an antibacterial effect is provided.

The present invention also provides a compound of the invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a medicament; And the manufacture of a medicament for use in producing antibacterial effects in warm blooded animals such as humans, the use of a compound of the invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.

Therapeutic treatment (including prophylactic treatment) of mammals, including humans, in particular for the treatment of infections, the compounds of the invention, or in vivo hydrolysable esters or pharmaceutically acceptable salts thereof, in pharmaceutically acceptable forms of hydrolysable esters in vivo Including acceptable salts) In order to use [hereafter referred to as “compounds of the invention” in this section of the pharmaceutical compositions), they are generally formulated into pharmaceutical compositions according to standard pharmaceutical practice.

Thus, in another aspect, the invention provides a compound of the invention, or an in vivo hydrolysable ester or pharmaceutically acceptable salt thereof (including pharmaceutically acceptable salts of in vivo hydrolyzable esters), and a pharmaceutically acceptable diluent or A pharmaceutical composition comprising a carrier is provided.

The compositions of the present invention are suitable for oral use (eg tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), suitable for topical use. Forms (e.g. creams, ointments, gels, or aqueous or oily solutions or suspensions), forms suitable for eye drop administration, forms suitable for inhalation administration (e.g. finely divided powders or liquid aerosols), Aqueous or oily sterile solutions suitable for intravenous, subcutaneous, sublingual or intramuscular administration (e.g., powders suitable for parenteral administration), or forms suitable for parenteral administration (e.g., Or suppositories for rectal administration).

In addition, the pharmaceutical compositions of the present invention, in addition to the compounds of the present invention, may be used in addition to other clinically useful antibacterial agents (e.g., β-lactam, macrolides, quinolone or aminoglycosides) and / or other anti-infective agents (e. For example, one or more known drugs selected from antifungal triazoles or amphotericin) are contained via co-formulation, or with (at the same time, sequentially or with) one or more known drugs Separately). The pharmaceutical composition of the present invention may include carbapenem, for example meropenem or imipenem, to enhance the therapeutic efficacy. In addition, the compounds of the present invention are formulated with bactericidal / permeability-increasing protein (BPI) products or discharge pump inhibitors to improve activity against gram-negative bacteria and bacteria that are resistant to antimicrobial agents. Or administered. In addition, the compounds of the present invention may be formulated or administered with vitamins such as vitamin B, such as vitamin B2, vitamin B6, vitamin B12 and folic acid. In addition, the compounds of the present invention may be formulated or administered with cyclooxygenase (COX) inhibitors, in particular COX-2 inhibitors.

In one aspect of the invention, the compounds of the invention are formulated with antibacterial agents having activity against Gram-positive bacteria.

In another aspect of the invention, the compounds of the invention are formulated with antibacterial agents having activity against Gram-negative bacteria.

In another aspect of the invention, the compound of the invention is administered with an antibacterial agent having activity against Gram-positive bacteria.

In another aspect of the invention, the compound of the invention is administered with an antibacterial agent having activity against Gram-negative bacteria.

The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients, which are well known in the art. Thus, oral compositions may contain, for example, one or more colorants, sweeteners, flavors and / or preservatives. Pharmaceutical compositions administered intravenously may be advantageous to contain suitable fungicides, antioxidants or reducing agents, or suitable sequestering agents (eg, to enhance stability).

Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; Binders such as starch; Lubricants such as magnesium stearate, stearic acid or talc; Preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants such as ascorbic acid. Conventional coatings well known in the art (in any of these), to change the disintegration rate and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve the stability and / or appearance of the tablet formulation, and The method may be used to coat or not coat the tablet formulation.

Oral compositions are in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is water or oil such as peanut oil, liquid paraffin or olive oil. It may be in the form of mixed soft gelatin capsules.

Generally, aqueous suspensions contain the active ingredient in the form of fine powder at least one suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum traga Kant and gum acacia; Dispersing or wetting agents, for example lecithin, or condensation products of alkylene oxy and fatty acids (eg polyoxetylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethylene jade Condensation products of cycetanol or partial esters derived from fatty acids with hexitol and ethylene oxide, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and long-chain aliphatic alcohols, for example heptadeca Condensation products of ethyleneoxycetanol or partial esters derived from fatty acids with hexitol and ethylene oxide, for example polyoxyethylene sorbitol monooleate, or partial esters derived from fatty acids and hexitol anhydride with ethylene oxide With condensation products, for example polyethylene sorbitan monooleate It contains. In addition, the aqueous suspension may contain one or more preservatives (eg, ethyl or propyl p-hydroxybenzoate, antioxidants (eg, ascorbic acid), colorants, flavors and / or sweeteners (eg, water Cros, saccharin or aspartame).

Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (eg, peanut oil, olive oil, sesame oil or coconut oil) or mineral oil (eg liquid paraffin). The oily suspension may also contain a thickener such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. Such compositions can be preserved by adding antioxidants such as ascorbic acid.

In general, dispersible powders and granules suitable for the addition of water to prepare an aqueous suspension contain the active ingredient in combination with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Further excipients may also be present, for example sweetening, flavoring and coloring agents.

In addition, the pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or any mixture thereof. Suitable emulsifiers are for example esters or partial esters derived from natural gums such as gum acacia or gum tragacanth, natural phospholipids such as soybean, lecithin, fatty acids and hexitol anhydrides (eg sorbitan Monooleate), and the condensation product of said partial ester with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening, flavoring and preservatives.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may contain demulcents, preservatives, flavoring agents and / or coloring agents.

In addition, the pharmaceutical compositions may be in the form of aqueous or oily sterile injectable suspensions, which forms may be formulated according to known methods using one or more of the appropriate dispersing or wetting agents and suspending agents mentioned above. In addition, the sterile preparation for injection may be a sterile solution or suspension for injection in a parenterally acceptable non-toxic diluent or solvent, for example a solution in 1,3-butanediol. Solubility enhancers such as cyclodextrins may also be used.

Compositions for inhalation administration may be in the form of conventional pressurized aerosols designed to spray the active ingredient, such as aerosols containing finely divided solid droplets or droplets. Conventional aerosol propellants can be used, for example volatile fluorinated hydrocarbons or hydrocarbons, and the aerosol device is conveniently designed to inject the active ingredient in a metered amount.

For further information on formulation, see Volume 5, chapter 25.2, of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Of course, the amount of active ingredient that produces a single dosage form with one or more excipients will vary depending upon the host to be treated and the particular route of administration. For example, formulations for oral administration to humans generally include, for example, 50 mg to 5 g of the agent together with an appropriate and convenient amount of excipient, which may range from about 5 to about 98 weight percent of the total composition. Will contain. Unit dosage forms will generally contain about 200 mg to about 2 g of active ingredient. For further information on the route of administration and dosing regimen, see Volume 3, chapter 25.3, of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

Suitable pharmaceutical compositions of the invention are compositions suitable for oral administration in unit dosage form, for example tablets or capsules containing 1 mg to 1 g, preferably 100 mg to 1 g of a compound of the invention. Particular preference is given to tablets or capsules containing 50 mg to 800 mg, in particular 100 mg to 500 mg, of the compounds of the invention.

In another aspect, a pharmaceutical composition of the invention is a composition suitable for intravenous, subcutaneous or intramuscular injection, for example injections containing 0.1 to 50% w / v (1 to 500 mg / mL) of the compound of the invention .

For example, each patient may be administered a daily intravenous, subcutaneous or intramuscular dose of 0.5 to 20 mgkg ⁻¹ of a compound of the invention, wherein the composition is administered 1 to 4 times per day. In another embodiment, a daily dose of 5-20 mgkg ⁻¹ of a compound of the invention is administered. Intravenous, subcutaneous and intramuscular doses can be administered by bolus injection. Alternatively, the intravenous dose may be administered by continuous infusion over a long time. Alternatively, each patient may be administered an oral daily dose, which may be approximately equivalent to a parenteral daily dose, wherein the composition is administered 1 to 4 times per day.

In the above pharmaceutical compositions, processes, methods, uses and other features of the manufacture of a medicament, another preferred embodiment of the compounds of the invention described herein also applies.

Antibacterial Activity:

Pharmaceutically acceptable compounds of the invention are useful antibacterial agents that have an excellent in vitro activity spectrum for standard Gram-positive organisms used to screen for activity against pathogenic bacteria. Notably, pharmaceutically acceptable compounds of the present invention are enterococcus , Pneumococcus , methicillin resistant S. aureus. It represents a negative Staphylococcus strains, as well as a brush to Loose (Haemophilus) and morak activity even for Cellar (Moraxella) strain aureus (S. aureus), and coagulation enzymes. Antibacterial spectra and potency of certain compounds can be measured with standard test systems.

In addition, the (antibacterial) properties of the compounds of the invention can be demonstrated and evaluated in vivo by conventional tests, for example by oral and / or intravenous compound administration to warm blooded mammals using standard techniques. .

The following results were obtained with a standard in vitro test system. Activity is described as the minimum inhibitory concentration (MIC) measured by agar-dilution technique (inoculation amount: 10 ⁴ CFU per spot). Typically, the compound has activity in the range of 0.01-256 μg / mL.

Staphylococcus was tested at an incubation rate of 10 ⁴ CFU / spot (standard test conditions for the expression of methicillin resistance) at an incubation temperature of 37 ° C. on agar for 24 hours.

Streptococcus and enterococcus were tested at an inoculation of 10 ⁴ CFU / point in a 5% carbon dioxide atmosphere at 37 ° C. incubation temperature for 48 hours on agar supplemented with 5% defibrinated horse blood (some of the test organisms) Need blood for growth). Intricate Gram-negative organisms were tested in inoculation amounts of 5 × 10 ⁴ CFU / well under aerobic growth conditions at 37 ° C. for 24 hours in Mueller-Hinton broth supplemented with hemin and NAD.

For example, the following result was obtained about the compound of Example 1.

organism MIC (µg / mL) Staphylococcus aureus MSQS MRQR 1 1 Streptococcus pneumoniae 0.25 Haemophilus influenzae 4 Linezolid-resistant Streptococcus pneumoniae 2 MSQS = methicillin-sensitive and quinolone-sensitive MRQR = methicillin-resistant and quinolone-resistant

The inhibitory activity of mono-amine oxidase (MAO) is a known potential side effect of oxazolidinone antibiotics (see eg WO 03/072575). In general, the compounds of the present invention have lower levels of MAO-A inhibitory activity than those indicated by unsubstituted and other simple substituted pyridine compounds, as shown in the table below.

Biochem. Biophys. Res. Commun. 1991, 181, 1084-1088, the activity of the compounds of the present invention on MAO-A was tested using standard in vitro assays based on human liver enzymes expressed in yeast. Typically, the compounds of the present invention exhibited Ki values of greater than 5 μM as measured by the assay. In Example 1, a Ki value of 94 μM was shown.

As described in our patent application WO 03/072575, compounds with 4-alkyl triazoles are generally lower in MAO-A than similar unsubstituted triazole compounds, as exemplified above for reference compounds 1 and 7 It will be appreciated that it exhibits inhibitory activity.

Certain intermediates and / or reference examples described below may be included within the scope of the present invention and / or have useful activity and are provided as further features of the present invention. Particular intermediates are intermediates 14, 20 and 21. Specific reference examples are Reference Examples 1, 2, 3, 4 and 7.

The invention is now illustrated by the following examples, without being limited thereto, unless otherwise specified

(i) The evaporation was carried out by rotary evaporation under vacuum and the post-treatment procedure was carried out after the residual solids were removed by filtration.

(ii) at room temperature, typically in the range of 18 to 26 ° C., unless otherwise specified or otherwise skilled in the art, the operation was carried out without excluding air.

(iii) unless otherwise stated, by column chromatography, by flash method on normal phase silica gel 60 (230-400 mesh), or reverse phase silica gel (C-18, RediSep, Isco) The Gilson 215 Platform was mounted by flash method on Incorporated (Isco, Inc.) or on reversed phase silica gel (e.g., Waters YMC-ODS AQ, C-18). The compound was purified by HPLC used.

(iv) Yields are presented for illustrative purposes only, and maximums may not necessarily be achieved.

(v) In general, the structure of the final product of the present invention was confirmed by NMR and mass spectral techniques [unless otherwise indicated, 300, 400 or 500 MHz using a Bruker spectrometer in DMSO-d ₆ Proton magnetic resonance spectra at were measured; Chemical shifts are reported in parts per million (downfield) from tetramethylsilane as internal standard (δ scale), or on a solvent basis. Accordingly, peak multiplicity [s, single peak; d, double peak; AB or dd, double peak, double peak; dt, triple peak, triple peak; dm, double peak of multiple peaks; t, triple peak; m, multiple peaks; br, broad; Mass spectrometry was performed using a Micromass's Quattro Micro mass spectrometer (for ESP) and an Agilent 1100 MSD instrument (for APCI); The linearity at 589 nm was measured using a Perkin Elmer polarimeter 341 at 20 ° C.

(vi) each intermediate was purified with the standard material required in the next step and characterized in sufficient detail to confirm that the designated structure was correct; Purity was assessed by HPLC, LC-MS, TLC or NMR; If necessary, the structure was determined using mass spectrometry and / or NMR spectroscopy.

(vii) The following abbreviations may be used.

DMF is N, N-dimethylformamide; DMA is N, N-dimethylacetamide; TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; NMP is N-methylpyrrolidone; DMSO is dimethyl sulfoxide; CDCl ₃ is 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; THF is tetrahydrofuran; Ether is diethyl ether; TFA is trifluoroacetic acid.

(viii) The temperature is shown in ° C.

Example 1: (5R) -3- {3-fluoro-4- [6- (1-hydroxy-2-morpholin-4-ylethyl) pyridin-3-yl] phenyl} -5- (1H -1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

1- (5-bromopyridin-2-yl) -2-morpholin-4-ylethanol (intermediate 8) (388 mg, 1.35 mmol), (5R) -3- [3-fluoro-4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxa Zolidin-2-one (intermediate 7) (525 mg, 1.35 mmol) and sodium carbonate (430 mg, 4.05 mmol) were dissolved / suspended in N, N-dimethyl formamide / water (5 mL, 10: 1). The mixture was degassed, flushed with nitrogen and tetrakis (triphenylphosphine) palladium (0) (156 mg, 0.135 mmol) was added. It was heated at 75 ° C. for 3 hours, cooled to room temperature and the solvent was evaporated. It was chromatographed by dichloromethane / methanol (10: 1) on silica gel. The free base obtained was dissolved in isopropanol / dichloromethane (about 20 mL, 1: 1), HCl in ether (1.5 mL, 1 M) was added and most of the dichloromethane was removed under reduced pressure. The residue was collected by filtration and dried to give 507 mg (74%) of the hydrochloride salt of the target product as a colorless solid. mp> 194 ° C. (decomposition).

The intermediate of Example 1 was prepared as follows.

Intermediate 1: acetic acid (5R) -3- (3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester

(5R) -3- (3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one (40 g, 0.189 mol, see Upjohn WO 94-13649) under anhydrous dichloromethane Suspension by stirring in (400 mL). After addition of triethylamine (21 g, 0.208 mol) and 4-dimethylaminopyridine (0.6 g, 4.9 mmol), acetic anhydride (20.3 g, 0.199 mol) was added dropwise over 30 minutes and at room temperature for 18 hours. Stirring was continued. Saturated aqueous sodium bicarbonate solution (250 mL) was added, the organic phase was separated, washed with 2% sodium dihydrogen phosphate, dried (magnesium sulfate), filtered and evaporated to afford the desired product (49.6 g) as an oil.

Intermediate 2: acetic acid (5R) -3- (3-fluoro-4-iodo-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester

Acetic acid (5R) -3- (3-fluoro-phenyl) -2-oxo-oxazolidin-5-ylmethyl ester (intermediate 1, 15.2 g, 60 mmol) was diluted with chloroform (100 mL) and acetonitrile under nitrogen. (100 mL) was dissolved and silver trifluoroacetate (16.96 g, 77 mmol) was added. Iodine (18.07 g, 71 mmol) was added to the vigorously stirred solution in portions over 30 minutes and stirring continued at room temperature for 18 hours. Since the reaction was not complete, an additional amount of silver trifluoroacetate (2.64 g, 12 mmol) was added and stirring continued for 18 hours. The mixture was filtered and then added to sodium thiosulfate solution (3%, 200 mL) and dichloromethane (200 mL), the organic phase was separated, sodium thiosulfate (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), brine ( 200 mL), dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 mL) and a sufficient amount of diethyl ether was added with stirring for 1 hour to dissolve the brown impurities. It was filtered to give the desired product (24.3 g) as a cream solid.

Intermediate 3: (5R) -3- (3-fluoro-4-iodophenyl) -5-hydroxymethyloxazolidin-2-one

Acetic acid (5R) -3- (3-fluoro-4-iodophenyl) -2-oxo-oxazolidin-5-ylmethyl ester (intermediate 2, 30 g, 79 mmol) was dissolved in methanol (at room temperature for 25 minutes) 800 mL) and treated with potassium carbonate (16.4 g, 0.119 mmol) in a mixture of dichloromethane (240 mL) and immediately neutralized 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). It was filtered and evaporated to give the desired product (23 g).

Intermediate 4: [(5R) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate

(5R) -3- (3-fluoro-4-iodophenyl) -5- (hydroxymethyl) -1,3-oxazolidin-2-one (intermediate 3, 25.0 g, 74.2 mmol) was 0 Stir in dichloromethane (250 mL) at ° C. Triethylamine (10.5 g, 104 mmol) was added followed by methanesulfonyl chloride (11.2 g, 89.0 mmol) and the reaction stirred overnight and slowly warmed to room temperature. The yellow solution was diluted with sodium bicarbonate and the compound was extracted using dichloromethane (3 x 250 mL). The organic layer was dried (magnesium sulfate), filtered and concentrated to afford the desired product as a pale yellow solid (30.3 g).

Intermediate 5: (5R) -5- (azidomethyl) -3- (3-fluoro-4-iodophenyl) -1,3-oxazolidin-2-one

[(5R) -3- (3-fluoro-4-iodophenyl) -2-oxo-1,3-oxazolidin-5-yl] methyl methanesulfonate (intermediate 4, 6.14 g, 14.7 mmol) Was dissolved in N, N-dimethylformamide (50 mL). Sodium azide (1.92 g, 29.6 mmol) was added and the reaction stirred overnight at 75 ° C. The yellow mixture was poured into semi-saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed three times with water, dried (magnesium sulfate), filtered and concentrated to give the title compound as a yellow solid (4.72 g).

Intermediate 6: (5R) -3- (3-Fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine- 2-on

(5R) -5- (azidomethyl) -3- (3-fluoro-4-iodophenyl) -1,3-oxazolidin-2-one (intermediate 5, 30.3 g, 72.9 mmol) Stir in, 4-dioxane. Bicyclo [2.2.1] hepta-2,5-diene (40.3 g, 437 mmol) was added and the reaction was heated at 100 ° C overnight. The resulting brown mixture was filtered and the desired product was obtained as a light brown solid (14.8 g).

Intermediate 7: (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(5R) -3- (3-fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (Intermediate 6, 2 g, 5.15 mmol), 2.62 g (10.3 mmol) bis (pinacolato) diboron, 2.5 g (25.5 mmol) potassium acetate and 1,1 '-[bis (diphenylphosphino) ferrocene] 0.38 g (0.52 mmol) of dichloropalladium (II) dichloromethane complex was suspended in 15 mL of DMSO. The mixture was heated at 80 ° C. for 40 minutes to give a clear black solution. Then ethyl acetate (150 mL) was added and the mixture was filtered through celite, washed with saturated brine (2 × 100 mL), dried over sodium sulfate and evaporated. The dark residue was purified by chromatography (silica gel, 40-100% ethyl acetate in hexanes, then 1-5% acetonitrile in ethyl acetate) to yield 1.97 g (98%) of the product as a crystalline tan solid. . (Note: An additional amount of eluent is required to obtain the product, since dark colored impurities are eluted prior to the product band).

Alternative:

(5R) -3- (3-fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (Intermediate 6, 5 g, 12.9 mmol), 2.9 mL (20 mmol) pinacolborane, 5.4 mL (39 mmol) triethylamine and 0.92 g (1.3 mmol) p-dichlorobis (triphenylphosphine) palladium (II) ) Was dissolved in 70 mL of dioxane. The black solution obtained by heating the mixture at 100 ° C. for 90 minutes was concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography (silica gel, 0-5% methanol in dichloromethane + 1% triethylamine) to give 3.1 g of the product as a light brown solid.

Intermediate 8: 1- (5-Bromopyridin-2-yl) -2-morpholin-4-ylethanol

2-bromo-1- (5-bromopyridin-2-yl) ethanone hydrobromide (intermediate 9) (600 mg, 1.67 mmol) was suspended in dry THF (5 mL) and cooled to 0 ° C. Morpholine (0.58 mL, 6.7 mmol) was added and it was vigorously stirred at 0 ° C. for 1 h. Sodium borohydride (190 mg, 5 mmol) was added followed by methanol (4 mL). The mixture was stirred for 30 min at 0 ° C. and then acidified to less than pH 2 with concentrated hydrochloric acid. After the solvent was removed under reduced pressure, the pH was adjusted to 10 using aqueous potassium hydroxide solution (1 M). The product was extracted with dichloromethane and dried over sodium sulfate. It was chromatographed on hexane / acetone (1: 1) on silica gel followed by acetone to give 388 mg (81%) of the product as a pale yellow solid.

Intermediate 9: 2-bromo-1- (5-bromopyridin-2-yl) ethanone

Dissolve 1- (5-bromopyridin-2-yl) ethanone (intermediate 10) (WO 98/46605) (5.65 g, 28.2 mmol) in methanol / acetic acid (70 mL + 70 mL), 30 in acetic acid % HBr (8 mL) was added. Bromine (1.45 mL, 28.3 mmol) in acetic acid (15 mL) was added dropwise and the reaction mixture was heated to 70 ° C. for 2 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was crystallized in isopropanol to give 3.45 g (34%) of the crude hydrobromide salt of the target product as a pale yellow solid.

Intermediate 10: 1- (5-bromopyridin-2-yl) ethanone

See WO 98/46605.

5-bromo-2-cyanopyridine (Markevitch, David Y .; Rapta, Miroslav; Hecker, Scott J .; Renau, Thomas E .; Synth. Commun .; 33; 19; 2003; 3285-3290) ) (8 g, 43.7 mmol) was dissolved in anhydrous THF (200 mL) and cooled to -20 ° C. Methylmagnesium bromide (43.7 mL, 3 M) was added dropwise and the temperature was maintained at -20 to -10 ° C for 3 hours. The reaction mixture was cooled to -40 ° C and concentrated HCl (4.5 mL) in water (15 mL) was added dropwise. It was stirred for 10 min at -30 ° C and then poured into a beaker containing potassium phosphate buffer (300 mL, 1 M, pH 7). Ethyl acetate (300 mL) was added and the organic phase was dried over sodium sulfate. When concentrated to ˜50 mL under fitting at room temperature, 2.4 g (mp 112 ° C.) of the product crystallized. The mother liquor was further concentrated and chromatographed on silica gel with dichloromethane / ethylacetate (100: 1) to give an additional 3.25 g of product (integrated yield 65%).

Example 2: (5R) -3- (4- {6- [2- (dimethylamino) -1-hydroxyethyl] pyridin-3-yl} -3-fluorophenyl) -5- (1H-1 , 2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

1- (5-bromopyridin-2-yl) -2- (dimethylamino) ethanol, TFA salt (intermediate 11) (200 mg, 0.56 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] Oxazolidin-2-one (intermediate 7) (216 mg, 0.56 mmol), sodium carbonate (177 mg, 1.67 mmol) and tetrakis (triphenylphosphine) palladium (0) (64 mg, 0.056 mmol) were 9.5 hours Reaction at 75 ° C. as described in Example 1. It was chromatographed on acetonitrile / water (5: 1) on silica gel, HCl (1 M, about 0.7 mL) in ether was added and precipitated in ethanol to give 125 mg (48%) of the hydrochloride salt of the target product. ) Was obtained as a colorless solid. mp> 115 ° C. (decomposition).

The intermediate of Example 2 was prepared as follows.

Intermediate 11: 1- (5-bromopyridin-2-yl) -2- (dimethylamino) ethanol

2-bromo-1- (5-bromopyridin-2-yl) ethanone (intermediate 9) (500 mg, 1.8 mmol) was dissolved in methanol (20 mL) and cooled to -10 ° C. Dimethylamine (0.9 mL, 2 M in THF) was added dropwise, followed by triethyl amine (0.25 mL). After 30 minutes, an additional amount of dimethyl amine solution (0.25 mL) was added and stirred for 1.5 h at -10 to -5 ° C. Sodium borohydride (205 mg, 5.4 mmol) was added in portions and the reaction mixture was stirred for an additional hour at -5 ° C and then acidified to less than pH 2 with concentrated hydrochloric acid. The solvent was removed under reduced pressure and the pH was adjusted to 10 using aqueous potassium hydroxide solution (1 M). This was chromatographed with 0-5% acetonitrile in water containing 0.1% TFA on a C-18 column (Redcepte, Isco Inc.) to obtain approximately 220 mg (34%) of the TFA salt of the target product. Obtained with TFA salt of dimethyl amine and triethyl amine. The product was used without further purification.

Example 3: (5R) -3- (3-fluoro-4- {6- [1-hydroxy-2- (isopropylamino) ethyl] pyridin-3-yl} phenyl) -5- (1H- 1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

1- (5-bromopyridin-2-yl) -2- (isopropylamino) ethanol, TFA salt (intermediate 12) (241 mg, 0.65 mmol), (5R) -3- [3-fluoro-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl ] Oxazolidin-2-one (intermediate 7) (361 mg, 0.93 mmol), sodium carbonate (296 mg, 2.79 mmol) and tetrakis (triphenylphosphine) palladium (0) (108 mg, 0.093 mmol) The reaction was carried out as described in Example 1. It was chromatographed with acetonitrile / water (6: 1) followed by dichloromethane / methanol (5: 1) on silica gel, followed by precipitation of the hydrochloride salt as described in Example 1 to hydrolyze the target product. 193 mg (63%) of chloride salt were obtained as a colorless solid. mp> 170 ° C. (decomposition).

The intermediate of Example 3 was prepared as follows.

Intermediate 12: 1- (5-bromopyridin-2-yl) -2- (isopropylamino) ethanol

As described for intermediate 8, 2-bromo-1- (5-bromopyridin-2-yl) ethanone hydrobromide (intermediate 9) (600 mg, 1.67 mmol) wasopropyl amine (0.57 mL, 6.7 mmol). This was chromatographed with 0-30% acetonitrile in water containing 0.1% TFA on a C-18 column (Receptep, Isco Inc.) to colorize 241 mg (39%) of the TFA salt of the target product. Obtained as an oil.

Example 4: (5R) -3- {4- [6- (1,2-dihydroxyethyl) pyridin-3-yl] -3-fluorophenyl} -5- (1H-1,2,3 -Triazol-1-ylmethyl) -1,3-oxazolidin-2-one

1- (5-bromopyridin-2-yl) ethane-1,2-diol (323 mg, 1.48 mmol) (intermediate 13), (5R) -3- [3-fluoro-4- (4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidine- 2-one (Intermediate 7) (575 mg, 1.48 mmol), sodium carbonate (471 mg, 4.44 mmol) and tetrakis (triphenylphosphine) palladium (0) (171 mg, 0.148 mmol) as described in Example 1 Reacted together. It was chromatographed on silica gel with dichloromethane / methanol (5: 1) and crystallized in ethanol / hexanes to give 388 mg (66%) of the product as a colorless solid. mp 175 ° C.

The intermediate of Example 4 was prepared as follows.

Intermediate 13: 1- (5-Bromopyridin-2-yl) ethane-1,2-diol

2-bromo-1- (5-bromopyridin-2-yl) ethanone (intermediate 9) (700 mg, 2.51 mmol) and sodium formate (683 mg, 10.04 mmol) were added to 85% ethanol (5 mL). Mixed in and heated at 50 ° C. for 3 h. It was cooled to room temperature and the solvent evaporated mostly under reduced pressure. It was diluted with dichloromethane and water (5 mL). The aqueous phase was extracted three times with dichloromethane and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in methanol (20 mL) and cooled to 0 ° C. Sodium borohydride (285 mg, 7.5 mmol) was added in portions and stirred for 1 h at 0 ° C. Concentrated HCl was added to adjust the pH to about 2 and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate. It was chromatographed on silica gel with hexane / acetone (2: 1) to give 223 mg (41%) of the product as a colorless solid.

Example 5: (5R) -3- {3-fluoro-4- [6- (1-hydroxy-1-methylethyl) pyridin-3-yl] phenyl} -5- (1H-1,2 , 3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

2- (5-bromopyridin-2-yl) propan-2-ol (X. Wang et al, Tetrah. Lett. 41, except for heating in 10 mL of solvent at 70 ° C. for 7.5 hours). (2000), 4335]) (500 mg, 2.31 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxabo Loran-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate 7) (900 mg, 2.32 mmol), sodium carbonate ( 740 mg, 7 mmol) and tetrakis (triphenylphosphine) palladium (0) (268 mg, 0.232 mmol) were reacted as described in Example 1. It is chromatographed on silica gel with dichloromethane / methanol (17: 1) followed by dichloromethane / DMF (20: 1) and precipitated in dichloromethane / DMF (20: 1, 20 mL) and hexane to give the product. 247 mg (27%) were obtained as a colorless solid. mp 180 ° C.

Example 6: (5R) -3- [4- (6-{[(2,3-dihydroxypropyl) (methyl) amino] methyl} pyridin-3-yl) -3-fluorophenyl] -5 -(1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-3-yl ] Phenyl} pyridine-2-carbaldehyde (intermediate 14) (100 mg, 0.272 mmol) is stirred in anhydrous THF (3 mL) and 3- (methylamino) propane-1,2-diol (29 mg, 0.272 mmol) was added at room temperature. After 15 minutes, sodium triacetoxyborohydride (81 mg, 0.381 mmol) was added and it was stirred for 3 days. The solvent was removed under reduced pressure, the residue was chromatographed on acetonitrile / water (10: 1 to 5: 1) on silica gel and crystallized in ethyl acetate / hexanes to give 25 mg (20%) of the product as a colorless solid. Obtained as. mp 123 ° C.

The intermediate of Example 6 was prepared as follows.

Intermediate 14: 5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine- 3-yl] phenyl} pyridine-2-carbaldehyde

5-bromopyridine-2-carbaldehyde (X. Wang et al, Tetrah. Lett. 41 (2000), 4335), except that it was heated in 10 mL of solvent at 70 ° C. for 10 hours. 450 mg, 2.42 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate 7) (939 mg, 2.42 mmol), sodium carbonate (769 mg, 7.26 mmol) and tetra Keys (triphenylphosphine) palladium (0) (280 mg, 0.24 mmol) was reacted as described in Example 1. It was chromatographed on silica gel with hexane / acetone (1: 1) to give 535 mg (60%) of the product as a colorless solid. mp> 180 ° C. (decomposition).

Example 7: (5R) -3- [3-fluoro-4- (6-{[(2-hydroxyethyl) (methyl) amino] methyl} pyridin-3-yl) phenyl] -5- (1H -1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

Reaction of 2- (methylamino) ethanol (20.5 mg, 0.272 mmol) with intermediate 14 (100 mg, 0.272 mmol) using the same procedure as described in Example 6 to give 58 mg (50%) of the product as a colorless solid. It was. mp 137 ° C.

Example 8: (5R) -3- (4- {6-[(dimethylamino) methyl] pyridin-3-yl} -3-fluorophenyl) -5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-2-one

Reaction of dimethylamine (2M in THF, 0.136 mL, 0.272 mmol) with intermediate 14 (100 mg, 0.272 mmol) using the same procedure as described in Example 6 to give 23 mg (21%) of the product as a colorless solid It was. mp 160 ° C.

Example 9: (5R) -3- {3-fluoro-4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] phenyl} -5- (1H-1,2,3- Triazol-1-ylmethyl) -1,3-oxazolidin-2-one

4-[(5-bromopyridin-2-yl) methyl] morpholine (Intermediate 15, 185 mg, 0.72 mmol), (5R) -3- [3, except for heating at 70 ° C. for 5 hours. -Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazole- 1-yl) methyl] oxazolidin-2-one (intermediate 7, 279 mg, 0.72 mmol), sodium carbonate (305 mg, 2.88 mmol) and tetrakis (triphenylphosphine) palladium (0) (83 mg, 0.072 mmol) was reacted as described in Example 1. It was chromatographed on dichloromethane / methanol (12: 1) on silica gel and precipitated in dichloromethane and hexanes to give 172 mg (55%) of the product as a colorless solid. mp 175 ° C.

The intermediate of Example 9 was prepared as follows.

Intermediate 15: 4-[(5-bromopyridin-2-yl) methyl] morpholine

5-bromopyridine-2-carbaldehyde (X. Wang et al, Tetrah. Lett. 41 (2000), 4335) (200 mg, 1.08 mmol) using the same procedure as described in Example 6. And morpholine (0.094 mL, 1.08 mmol) was reacted with sodium triacetoxyborohydride (319 mg, 1.51 mmol). It was chromatographed on silica gel with hexane / acetone (3: 1) followed by hexane / ethyl acetate (1: 1)-> ethyl acetate / methanol (50: 1) to give 185 mg (67%) of the product as a colorless solid. Obtained as.

Example 10: (5R) -3- (3-fluoro-4- {6-[(1R) -1-hydroxyethyl] pyridin-3-yl} phenyl) -5- (1H-1,2, 3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(1R) -1- (5-bromopyridin-2-yl) ethanol (Intermediate 16, 430 mg, 2.13 mmol), (5R), except heating in 10 mL of solvent at 70 ° C. for 4 hours. -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2, 3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate 7, 826 mg, 2.13 mmol), sodium carbonate (677 mg, 6.4 mmol) and tetrakis (triphenylphosphine) palladium (0) (246 mg, 0.213 mmol) was reacted as described in Example 1. It was chromatographed on silica gel with dichloromethane / methanol (12: 1) and crystallized in ethanol / hexanes to give 421 mg (52%) of the product as a colorless solid. mp 190 ° C.

The intermediate of Example 10 was prepared as follows.

Intermediates 16 and 17: (1R) -1- (5-bromopyridin-2-yl) ethanol and (1S) -1- (5-bromopyridin-2-yl) ethanol

5-bromopyridine-2-carbaldehyde (X. Wang et al, Tetrah. Lett. 41 (2000), 4335) (1.0 g, 5.4 mmol) is dissolved in anhydrous THF (25 mL), Cool to 0 ° C. Methylmagnesium bromide (1.4 M in toluene / THF (3: 1), 4.6 mL, 6.45 mmol) was added dropwise with stirring. The reaction mixture was diluted with ethyl acetate, washed with potassium phosphate buffer (pH 7) and dried over sodium sulfate. It was chromatographed on silica gel with hexane / ethyl acetate (2: 1) to afford 1.013 g (93%) of racemic product as colorless oil.

The racemic mixture of the two products was separated by 95% hexane, 5% ethanol / methanol (1: 1) on a Chiralpak AD column. The first isomer eluted from the column had an abundance of [α] _D ²⁰ = -42.2 (ethanol, c = 1) and was classified as an S-array (yield: 400 mg), and the eluted second isomer was [α] _D ²⁰ = -38.3 (ethanol, c = 1) and was classified as R-array (yield: 430 mg).

Example 11: (5R) -3- (3-fluoro-4- {6-[(1S) -1-hydroxyethyl] pyridin-3-yl} phenyl) -5- (1H-1,2, 3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(1S) -1- (5-bromopyridin-2-yl) ethanol (Intermediate 17) (400 mg, 1.98 mmol), (5R), except heating in 10 mL of solvent at 70 ° C. for 4 hours. ) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2 , 3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate 7) (769 mg, 1.98 mmol), sodium carbonate (630 mg, 5.9 mmol) and tetrakis (triphenylphosphine) palladium ( 0) (228 mg, 0.198 mmol) was reacted as described in Example 1. It was chromatographed on dichloromethane / methanol (12: 1) on silica gel and crystallized in ethanol / hexanes to give 287 mg (38%) of the product as a colorless solid. mp 183 ° C.

Example 12: (5R) -3- [4- (6-{[bis (2-hydroxyethyl) amino] methyl} pyridin-3-yl) -3-fluorophenyl] -5- (1H-1 , 2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-3-yl ] Phenyl} pyridine-2-carbaldehyde (intermediate 14, 200 mg, 0.55 mmol) is suspended in anhydrous THF (15 mL), diethanolamine (63 mg, 0.6 mmol) is added and the mixture is stirred for 20 minutes. It was. Sodium triacetoxyborohydride (233 mg, 1.1 mmol) was added and the mixture was stirred at rt overnight. The reaction was quenched with 1 M HCl and the pH was adjusted to 8 with saturated sodium bicarbonate. It was extracted with dichloromethane (20 mL × 3), dried over magnesium sulfate, concentrated and purified by flash chromatography (15% methanol in dichloromethane and 1% ammonium hydroxide) to give the product a colorless hydroscopic. ) As a solid (64 mg).

Example 13: (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazoli Din-3-yl] phenyl} pyridin-2-yl) methyl morpholine-4-carboxylate

(5R) -3- {3-fluoro-4- [6- (hydroxymethyl) pyridin-3-yl] phenyl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (intermediate 18) (20 mg, 0.054 mmol) and morpholine-4-carbonyl chloride (24.3 mg, 0.163 mmol) were pyridine (3 in a closed microwave reaction vessel. mL) and heated at 180 ° C. for 25 minutes in a Smith microwave reactor. The solvent was removed under reduced pressure and the residue was purified by reverse phase chromatography (HPLC, C-18) using 5-75% acetonitrile in water (containing 0.1% TFA) to afford the title compound (18 mg). . mp 131-133 ° C.

Intermediate 18: (5R) -3- {3-fluoro-4- [6- (hydroxymethyl) pyridin-3-yl] phenyl} -5- (1H-1,2,3-triazole-1- Monomethyl) -1,3-oxazolidin-2-one

(5-bromopyridin-2-yl) methanol (X. Wang et al, Tetrah. Lett. 41 (2000), 4335) except for heating at 70 ° C. for 4 hours (200 mg, 1.06 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[ (1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate 7, 413 mg, 1.06 mmol), sodium carbonate (450 mg, 4.25 mmol) and tetrakis (triphenyl Phosphine) palladium (0) (122 mg, 0.106 mmol) was reacted as described in Example 1. It was chromatographed on silica gel with dichloromethane / methanol (10: 1) and precipitated in hot methanol and hexanes to give 191 mg (49%) of the product as a colorless solid. mp 177 ° C.

Example 14 (5R) -3- {3-fluoro-4- [6- (1-hydroxy-3-oxobutyl) pyridin-3-yl] phenyl} -5- (1H-1,2, 3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-3-yl ] Phenyl} pyridine-2-carbaldehyde (intermediate 14, 3.2 g, 8.72 mmol) was dissolved in acetone (30 mL), potassium carbonate (4.45 g, 32.2 mmol) was added and the mixture was refluxed for 30 minutes. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. It was chromatographed on silica gel with 5% methanol in dichloromethane to afford the product as a colorless solid (3.25 g). mp 130-135 ° C.

Example 15: (5R) -3- {4- [6- (1,3-dihydroxybutyl) pyridin-3-yl] -3-fluorophenyl} -5- (1H-1,2,3 -Triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(5R) -3- {3-fluoro-4- [6- (1-hydroxy-3-oxobutyl) pyridin-3-yl] phenyl} -5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-2-one (Example 14, 500 mg, 1.18 mmol) is suspended in anhydrous ethanol (10 mL) and sodium borohydride (131 mg, 3.53 mmol). ) Was added at 0 ° C and the resulting mixture was allowed to slowly warm to room temperature overnight. The reaction was quenched with 1 M HCl (a few drops) at 0 ° C., the solvent was evaporated under reduced pressure and the residue was purified by reverse phase chromatography (C-18) to afford the title compound as a colorless solid (151 mg). .

Example 16: (5R) -3- (4- {6- [cyclopropyl (hydroxy) methyl] pyridin-3-yl} -3-fluorophenyl) -5- (1H-1,2,3- Triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(5-Bromopyridin-2-yl) (cyclopropyl) methanol (intermediate 19, 300 mg, 1.31 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate) 7, 510 mg, 1.31 mmol), potassium carbonate (543 mg, 3.93 mmol) and PS-PPh ₃ -Pd (Argonaut Technologies Inc.) (0.13 mmol, 0.11 mmol / g) Mix in ethylene glycol / ethanol / water (2: 2: 1, 10 mL) and heat at 75 ° C. overnight. It was cooled to rt, filtered through celite and the filtrate was extracted with ethyl acetate and water (10 mL + 5 mL). The organic layer was dried over magnesium sulfate, concentrated and purified by flash chromatography using 5% methanol in dichloromethane on silica gel to give the product as a colorless solid (70 mg). mp 160 to 163 ° C.

Intermediate 19: (5-bromopyridin-2-yl) (cyclopropyl) methanol

5-bromopyridine-2-carbaldehyde (X. Wang et al, Tetrah. Lett. 41, 2000) (470 mg, 2.5 mmol) was dissolved in anhydrous THF and cooled to -20 ° C. Cyclopropylmagnesium bromide (5 mmol, 0.5 M in THF) was added dropwise and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with a few drops of 1 M HCl, extracted with ethyl acetate and dried over magnesium sulfate. Chromatography with dichloromethane on silica gel gave the product as a colorless oil (300 mg) which was used directly in the next step without further purification.

Example 17: (5R) -3- (3-fluoro-4- {6-[(methylsulfinyl) methyl] pyridin-3-yl} phenyl) -5- (1H-1,2,3-tria Zol-1-ylmethyl) -1,3-oxazolidin-2-one

And

Example 18: (5R) -3- (3-fluoro-4- {6-[(methylsulfonyl) methyl] pyridin-3-yl} phenyl) -5 (1H-1,2,3-tria Zol-1-ylmethyl) -1,3-oxazolidin-2-one

(5R) -3- (3-fluoro-4- {6-[(methylthio) methyl] pyridin-3-yl} phenyl) -5- (1H-1,2,3-triazol-1-yl Methyl) -1,3-oxazolidin-2-one (Example 19, 140 mg, 0.35 mmol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0 ° C, m-chloroperbenzoic acid (0.35 mmol) was added and the mixture was stirred at rt for 3 h. Aqueous sodium bisulfite solution (2 M, 5 mL) was added and the mixture was stirred for 20 minutes. The organic phase was washed with saturated aqueous sodium bicarbonate solution (10 mL × 2) and brine and dried over magnesium sulfate. This was chromatographed on silica gel with 2.5% methanol in dichloromethane, whereby the compound of Example 18 was eluted first as a colorless solid (61 mg, mp 224 to 228 ° C.), and then the compound of Example 17 was colorless solid ( 22 mg, mp 205-210 ° C.).

Example 17:

Example 18:

Example 19: (5R) -3- (3-fluoro-4- {6-[(methylthio) methyl] pyridin-3-yl} phenyl) -5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-2-one

(5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine-3- Il] phenyl} pyridin-2-yl) methyl imidothiocarbamate (intermediate 20) (450 mg, 0.89 mmol) and iodomethane (251 mg, 1.77 mmol) were mixed with sodium hydroxide (15% aqueous solution, 15 mL). To a mixture of dichloromethane (30 mL). Tetrabutylammonium bromide (catalyst amount) was added and the mixture was vigorously stirred for 4 hours. The aqueous layer was extracted with dichloromethane (2 × 10 mL) and the combined organic layers were washed with 1 M HCl and brine, dried over magnesium sulfate and concentrated under reduced pressure. It was chromatographed on silica gel with 2.5% methanol in dichloromethane to afford the product as a colorless solid (140 mg).

Intermediate 20: (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine -3-yl] phenyl} pyridin-2-yl) methyl imidothiocarbamate

(5R) -3- {4- [6- (bromomethyl) pyridin-3-yl] -3-fluorophenyl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (intermediate 21) (483 mg, 1.12 mmol) and thiourea (89 mg, 1.17 mmol) were mixed in ethanol (15 mL) and refluxed for 2.5 h. It was cooled to rt, filtered, diluted with ether (30 mL) and the resulting precipitate was collected by filtration to give the product as a colorless, hydrous solid (450 mg).

Intermediate 21: (5R) -3- {4- [6- (bromomethyl) pyridin-3-yl] -3-fluorophenyl} -5- (1H-1,2,3-triazole-1- Monomethyl) -1,3-oxazolidin-2-one

(5R) -3- {3-fluoro-4- [6- (hydroxymethyl) pyridin-3-yl] phenyl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (intermediate 18) (1.8 g, 4.88 mmol) and carbon tetrabromide (1.94 g, 5.85 mmol) were mixed in anhydrous dichloromethane (80 mL) and brought to -5 ° C. Cooled. PS-PPh ₃ (Agonot Technologies Inc.) (7.32 mmol, 1.41 mmol / g) was added and the mixture was stirred at 4 ° C. for 10 min and then warmed to rt overnight. It was filtered, the filtrate was concentrated and the residue was purified by chromatography using ethyl acetate on silica gel to give the product as a colorless solid (484 mg).

Example 20: (5R) -3- (4- {6- [2- (2,5-dimethyl-1H-imidazol-1-yl) -1-hydroxyethyl] pyridin-3-yl} -3 -Fluorophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(5R) -3- (4- {6-[(2,5-dimethyl-1H-imidazol-1-yl) acetyl] pyridin-3-yl} -3-fluorophenyl) -5- (1H- 1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (intermediate 22, 100 mg, 0.21 mmol) is dissolved in 1: 1 dioxane: methanol (5 mL) Warmed slightly. While still warmed, sodium borohydride (20 mg, 0.53 mmol) was added to this clear solution. The mixture was stirred at rt for 10 min, diluted with water (10 mL) and extracted twice with ethyl acetate (20 mL, 10 mL). The combined organic layers were washed with saturated sodium chloride (10 mL), dried over magnesium sulfate and concentrated to a volume of 2-3 mL to give a suspension. This suspension was diluted with ether (15 mL), sonicated and left for 15 minutes. The solid was collected, washed with ether and dried at 50 ° C. in vacuo to yield the title compound as a white powder (39 mg). mp 195-200 ° C.

Intermediate 22: (5R) -3- (4- {6-[(2,5-dimethyl-1H-imidazol-1-yl) acetyl] pyridin-3-yl} -3-fluorophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

1- (5-bromopyridin-2-yl) -2- (2,5-dimethyl-1H-imidazole-1, except using 15 mL of solvent and heating at 75 ° C. for 6 hours -Yl) ethanone (intermediate 23, 985 mg, 3.35 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxa Bororan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (intermediate 7, 1.30 g, 3.35 mmol), sodium carbonate ( 887 mg, 8.37 mmol) and tetrakis (triphenylphosphine) palladium (0) (387 mg, 0.35 mmol) were reacted as described in Example 1. It was chromatographed with dichloromethane / methanol (10: 1 → 8: 1) on silica gel and then crystallized in ethanol to give 658 mg (41%) of the product as a colorless precipitate. mp 112 to 115 ° C.

Intermediate 23: 1- (5-Bromopyridin-2-yl) -2- (2,5-dimethyl-1H-imidazol-1-yl) ethanone

1- [2- (5-bromopyridin-2-yl) -2-oxoethyl] -2,5-dimethyl-3-trityl-1H-imidazole-3-'bromide (intermediate 24, 4.75 g, 7.7 mmol) was dissolved in dichloromethane (100 mL) and trifluoroacetic acid (15 mL) was added. The mixture was heated with reflux slowly for 1.5 h. It is diluted with dichloromethane (200 mL), washed with potassium phosphate buffer (pH 7, 1 M, about 600 mL), the aqueous phase is extracted three times with dichloromethane (3 x 100 mL) and the combined organic phases are sodium sulfate Dried over phase. It was chromatographed on silica gel with dichloromethane / methanol (20: 1) to yield 1.938 g (77%) of product as off-white solid.

Intermediate 24: 1- [2- (5-bromopyridin-2-yl) -2-oxoethyl] -2,5-dimethyl-3-trityl-1H-imidazole-3-'bromide

2,4-dimethyl-1-trityl-1H-imidazole (intermediate 25, 4.5 g, 13.4 mmol), 2-bromo-1- (5-bromopyridin-2-yl) ethanone (intermediate 9 Free base, 2.5 g, 9 mmol) (suspension of intermediate 9 in ethyl acetate is treated with potassium phosphate buffer (pH 7, 1 M), the organic phase is washed with water and dried over sodium sulfate, resulting from hydrobromide salts Free base) and 2,6-di-tert-butylpyridine (3 mL, 13.35 mmol) were heated in 1,4-dioxane (50 mL) at 75 ° C. for 30 min. The reaction mixture was cooled to rt and the precipitate was collected by filtration and washed with hexane (2 × 50 mL) to give 4.75 g (86%) of the product as an off-white solid. mp> 150 ° C. (decomposition).

Intermediate 25: 2,4-dimethyl-1-trityl-1H-imidazole

A solution of trityl chloride (15 g, 55 mmol) in dichloromethane (50 mL) at room temperature was added with 2,4-dimethyl imidazole (5 in a mixture of dichloromethane (100 mL) and triethylamine (11.3 mL, 81 mmol). g, 52 mmol) was added dropwise over 45 minutes. The mixture was stirred overnight, then quenched with methanol (4 mL) and stirred for another 30 minutes. The solvent was evaporated and the residue was dissolved in toluene (600 mL) and washed with potassium phosphate buffer (pH 7, 1 M, 2 x 200 mL) and water (200 mL). The organic phase was diluted with dichloromethane (200 mL), dried over sodium sulphate and concentrated to about 100 mL under reduced pressure. Hexane (100 mL) was added and the precipitate was collected by filtration and washed with hexane (2 x 50 mL) to give 14.76 g (84%) of the product as a colorless solid.

Reference Example 1: 5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine -3-yl] phenyl} pyridine-2-carbonitrile

5-bromo-2-cyanopyridine (212 mg, 1.16 mmol), (5R) -3- [3-fluoro-4- (4,4,), except that it was heated at 70 ° C. for 4.5 hours. 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidine-2 -One (intermediate 7) (449 mg, 1.16 mmol), sodium carbonate (368 mg, 3.47 mmol) and tetrakis (triphenylphosphine) palladium (0) (134 mg, 0.116 mmol) as described in Example 1 Reacted. It was chromatographed on silica gel with dichloromethane / methanol (20: 1) and precipitated as described in Example 1 to give 191 mg (45%) of the product as a colorless solid. mp> 215 (decomposition).

Reference Example 2: (5R) -3- [3-fluoro-4- (6-methylpyridin-3-yl) phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

5-bromo-2-methylpyridine (160 mg, 0.93 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (362 mg, 0.93 mmol), potassium carbonate (514 mg, 3.72 mmol) and PS-PPh ₃ -Pd (Agonot Technologies, Inc.) (0.093 mmol, 0.11 mmol / g) were reacted as described in Example 16. It was chromatographed on silica gel with 3% methanol in dichloromethane to give the product as off white solid (120 mg).

Reference Example 3: (5R) -3- {3-fluoro-4- [6- (hydroxymethyl) pyridin-3-yl] phenyl} -5- (1H-1,2,3-triazole-1 -Ylmethyl) -1,3-oxazolidin-2-one

(5-bromopyridin-2-yl) methanol (X. Wang et al, Tetrah. Lett. 41 (2000), 4335) (200 mg, 1.06 mmol), (5R) -3- [3- Fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazole-1 -Yl) methyl] oxazolidin-2-one (intermediate 7) (413 mg, 1.06 mmol), sodium carbonate (450 mg, 4.25 mmol) and tetrakis (triphenylphosphine) palladium (0) (122 mg, 0.106 mmol) was reacted as described in Example 1. It was chromatographed on silica gel with dichloromethane / methanol (10: 1) and precipitated in hot methanol and hexanes to give 191 mg (49%) of the product as a colorless solid. mp 177 ° C.

Reference Example 4: (5R) -3- (3-Fluoro-4-pyridin-3-ylphenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3- Oxazolidin-2-one

3-bromopyridine (245 mg, 1.55 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-, except heating overnight at 75 ° C. 1,3,2-dioxaborolan-2-yl) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl] oxazolidin-2-one (500 mg, 1.29 mmol), potassium carbonate (713 mg, 5.16 mmol) and tetrakis (triphenylphosphine) palladium (0) (75 mg, 0.065 mmol) were reacted as described in Example 1. It was chromatographed on silica gel with 5% methanol in dichloromethane to give the product as off white solid (220 mg).

Reference Example 5

See Example 139 of WO 01/94342 (Dong-A Pharmaceutical Co., Ltd.).

Reference Example 6: (5R) -3- (3-Fluoro-4- (6- (2-methyl-2H-tetrazol-5-yl) pyrid-3-yl) phenyl) -5- (1H- 1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

(5R) -3- (3-fluoro-4-iodophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (Intermediate 6, 370 mg, 0.95 mmol), a mixture of bis (pinacolato) diboron (605 mg, 2.4 mmol), and potassium acetate (326 mg, 3.3 mmol) in dimethylsulfoxide (5 mL) was degassed and , Flushed with nitrogen and treated with dichloro [1,1 '] bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (69 mg, 10 mol%). The mixture was heated to 80 ° C. for 1.5 h, cooled to rt, filtered through celite and extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride solution, dried over magnesium sulfate and evaporated to dryness. The nonvolatile residue was purified by chromatography on silica gel eluting with hexanes: ethyl acetate (3: 2) to give (5R) -3- (3-fluoro-4- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,2-oxazoli A mixture of din-2-one and the corresponding boronic acid (210 mg, about 0.54 mmol, 57%) was obtained, which was used without further purification.

A mixture of boronate ester and boronic acid prepared previously, 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) pyridine (160 mg, 0.67 mmol), and N, N-dimethyl form A mixture of amide and potassium carbonate (448 mg, 3.24 mmol) in water (10 mL, 7: 1) was degassed, flushed with nitrogen, tetrakis (triphenylphosphine) palladium (0) (62 mg, 0.054 mmol). The reaction mixture was heated at 80 ° C. for 1.5 h, cooled to rt, filtered through celite, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The nonvolatile residue was purified by chromatography on silica gel eluting with ethyl acetate: hexanes (3: 2) to afford the product as a colorless amorphous solid (140 mg, 61%).

The intermediate of the reference example was prepared as follows.

5-bromo-2-tetrazol-5-ylpyridine

3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol) and ammonium chloride (0.59 g, 11 mmol in N, N-dimethylformamide (20 mL) ) Was heated at 120 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (about 100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound as an off-white amorphous solid, which was used in the next step without further purification.

5-bromo-2- (2-methyl-2H-tetrazol-5-yl) pyridine and 5-bromo-2- (1-methyl-1H-tetrazol-5-yl) pyridine

5-bromo-2- (2-methyl-2H-tetrazol-5-yl) pyridine and 5-bromo-2- (1-methyl-1H-tetrazol-5-yl) pyridine from Dong-A Pharmaceutical Co., Ltd. It was prepared according to the method described in WO 01/94342.

Of crude 5-bromo-2-tetrazol-5-ylpyridine [Dong-A Pharmaceutical Co., Ltd. (WO 01/94342)] (6.5 g, about 28 mmol) and sodium hydroxide (9 g, 125 mmol) in anhydrous DMF The mixture was evaporated to dryness under reduced pressure. Iodomethane (3.0 mL, 48 mmol) was added dropwise to a stirred solution of nonvolatile residue in dry DMF (50 mL) at ice bath temperature. The stirred reaction mixture was warmed and then kept at room temperature for 2 hours. The reaction mixture was partitioned between ice water and ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and then the residue obtained by evaporation under reduced pressure was purified by chromatography [eluting with dichloromethane: ethyl acetate (60: 1)] on silica gel to give the following two compounds: Obtained.

5-bromo-2- (1-methyl-1H-tetrazol-5-yl) pyridine (1.397 g), colorless solid, (TLC: silica gel, hexane: ethyl acetate (4: 1), Rf: 0.3).

2. 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) pyridine (1.07 g), colorless solid, (TLC: silica gel, hexanes: ethyl acetate (4: 1), Rf: 0.1).

Structures were classified based on NMR HMBC (dinuclear multiple bond correlation) experiments (a wide range of coupling from the protons of CH ₃ to C5 of the tetrazole ring was observed in the 1-methyl-1H-isomer of Rf 0.3, but Rf Not observed in the 2-methyl-2H-isomer of 0.1). Thus, the compound referred to as 5-bromo-2- (1-methyl-1H-tetrazol-5-yl) pyridine is an isomer of Rf 0.3 and 5-bromo-2- (2-methyl-2H-tetra The compound called sol-5-yl) pyridine is an isomer of Rf 0.1.

Reference Example 7: 5- (2-Fluoro-4-{(5R) -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -2-oxo-1 , 3-oxazolidin-3-yl} phenyl) pyridine-2-carbonitrile

5-bromopyridine-2-carbonitrile (118 mg, 0.64 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) phenyl] -5-[(4-methyl-1H-1,2,3-triazol-1-yl) methyl] -1,3-oxazolidin-2-one (WO 2003/072576) (259 mg, 0.64 mmol), potassium carbonate (356 mg, 2.58 mmol) and PS-PPh ₃ -Pd (Agonot Technologies Inc.) (0.032 mmol, 0.11 mmol / g) The reaction was carried out as described in Example 16. It was chromatographed on silica gel with 3% methanol in dichloromethane to give the product as a colorless solid (42 mg). mp 210 to 212 ° C.

Claims (14)

A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof. <Formula I>

In the formula, R ¹ is selected from hydrogen, halogen, cyano, methyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methylthio or (2-4C) alkynyl; R ² and R ³ are independently selected from hydrogen, fluoro, chloro or trifluoromethyl; R ⁴ is [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, hydroxy (2-4C) alkoxy, -C (O) OR ⁵ , -C (O) R ⁵ , -OC (O) R ⁵ , carboxy, -C (O) NR ⁵ R ⁶ , -OC (O) NR ⁵ R ⁶ , -S (O) ₂ R ⁵ , -S (O) ₂ NR ⁵ R ⁶ , —NR ⁵ R ⁶ , —NHC (O) R ⁵ or —NHS (O) ₂ R ⁵ is substituted with one or two substituents independently selected from; Optionally, further substituted with cyclopropyl] (1-4C) alkyl; R ⁵ and R ⁶ are hydrogen, methyl, cyclopropyl (optionally substituted with methyl), carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1 -4C) alkyl (optionally substituted with one or two substituents independently selected from alkoxy or hydroxy) (2-4C) alkyl; or R ⁵ and R ⁶ together with the nitrogen to which they are attached are saturated or partially unsaturated 4, 5 optionally containing one additional heteroatom independently selected from O, N or S (in addition to the N atom connecting them) Or to form a six-membered heterocyclyl ring, wherein -CH ₂ -group can be optionally replaced with -C (O)-, wherein the sulfur atom is optionally substituted with an S (O) group or an S (O) ₂ group Can be oxidized); The ring is optionally substituted on one or two (1-4C) alkyl groups on the available carbon or nitrogen atoms, provided that the nitrogen to which R ⁵ and R ⁶ is attached is not quaternized by such substitution; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form an imidazole ring optionally substituted with one or two (1-4C) alkyl on the available carbon atoms, provided that R ⁴ is hydroxymethyl none). The compound of formula I, or a pharmaceutically acceptable salt or prodrug thereof, according to claim 1, wherein R ¹ is selected from hydrogen, chloro, bromo, methyl or fluoromethyl. The compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, according to claim 1 or 2, wherein R ² and R ³ are independently selected from hydrogen or fluoro. 4. The compound of claim 1, wherein R ⁴ is [hydroxy, (1-4C) alkoxy, hydroxy (2-4C) alkoxy, —OC (O) R ⁵ , carboxy or —NR ^5. Or (1-4C) alkyl substituted with one or two substituents independently selected from R ⁶ , or a pharmaceutically acceptable salt or prodrug thereof. 5. The compound of claim 1, wherein R ⁵ and R ⁶ are hydrogen, methyl, cyclopropyl (optionally substituted with methyl), carboxymethyl, or (amino, (1-4C) alkylamino, di A chemical formula independently selected from (2-4C) alkyl optionally substituted with one or two substituents independently selected from-(1-4C) alkylamino, carboxy, (1-4C) alkoxy or hydroxy A compound of I, or a pharmaceutically acceptable salt or prodrug thereof. 6. A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, according to any one of claims 1 to 5, which is a compound of formula (Ia). <Formula Ia>

Prodrug of a compound of any one of claims 1 to 6. A method for producing an antibacterial effect in a warm blooded animal comprising administering to the warm blooded animal an effective amount of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a medicament. Use of a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, in the manufacture of a medicament for use in producing an antibacterial effect in a warm blooded animal. A pharmaceutical composition comprising the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable diluent or carrier. The pharmaceutical composition of claim 11 comprising a compound of formula (I) together with an antibacterial agent having activity against Gram-positive bacteria. 13. A pharmaceutical composition according to claim 12 comprising a compound of formula (I) together with an antibacterial agent having activity against gram-negative bacteria. a) modifying a substituent in another compound of the present invention or introducing a substituent into another compound of the present invention; b) reacting a compound of formula (II) with a compound of formula (IIa) and then reacting with leaving group X to replace phenyl-X bonds and pyridyl-X bonds with pyridyl-phenyl bonds <Formula II>

<Formula IIa>

Wherein X is a useful leaving group for palladium [0] coupling and may be the same or different from each other in the two molecules of formula II and IIa)

; c) a process of reacting a pyridyl-phenyl carbamate derivative of formula III with an appropriately substituted oxirane to form an oxazolidinone ring

, or Carbamate replaced with isocyanate or amine and / or oxirane replaced with equivalent reagent X-CH ₂ CHO (optionally protected) CH ₂ -triazole R ¹ , wherein X is a removable group Variant of process

; d) reacting a compound of formula (IV) with an acylating agent followed by reduction of the ketone and (if Y is halo) and then reacting with a compound of formula (II) as described in step b) above <Formula IV>

Wherein X is a replaceable substituent and Y is halo or

being),

Wherein R is an (optionally substituted) alkyl group; e) reacting an alpha-halo ketone derivative of formula IV as defined above with Y being a ketone and nucleophile followed by reduction of the ketone and then (if Y is halo) Reaction with the compound of II

; f) alkylating the 2-picolin group of a compound of formula IV wherein Y is halo to obtain a compound of formula IIa, and then reacting it with a compound of formula II

; g) X is an epoxide and Y is reacted with a nucleophilic epoxide of a compound of formula IV as defined in step d) above (if Y is halo) and then formula II as described in step b) above Process of reacting with compound of

; h) a process of reacting a pyridyl-2-carbaldehyde derivative of formula V with a Grignard reagent or similar metal alkyl reagent

; i) Reducing Amination of Aldehyde Groups

; j) a process for converting amines to vinylpyridine by anti-Markovnikov addition reaction

; k) a process for forming a triazole ring from a suitably functionalized intermediate, with a preformed R ⁴ -pyridyl-phenyl ring system

; l) conversion to acetylene by cycloaddition reaction through azide

; m) reacting aminomethyloxazolidinone with 1,1-dihaloketone sulfonylhydrazone

; n) a process in which azidomethyl oxazolidinone is reacted with halovinylsulfonyl chloride when R ¹ is 4-halo

; o) a process for reducing a ketone precursor of formula Va, for example by sodium borohydride

And any other variable as defined above, unless otherwise stated in the above formulas and schemes, if necessary thereafter. i) removing any protecting group; ii) forming a prodrug (eg, a hydrolyzable ester in vivo); And / or iii) forming a pharmaceutically acceptable salt To prepare a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.