KR20070022784A - 3-4-2-dihydroisoxazol-3-ylpyridin-5-ylphenyl-5-triazol-1-ylmethyloxazolidin-2-one derivaives as mao inhibitors for the treatment of bacterial infections - 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.

Antibiotic compounds, substituted oxazolidinone rings, isoxazolin rings, antibacterial activity, mono-amine oxidase-A inhibitory activity

Description

3- (4- (2-dihydroisoxazol-3-ylpyridin-5-yl) phenyl) -5-triazol-1-ylmethyloxazolidin-2-one as a MAO inhibitor for the treatment of bacterial infections Derivatives {3- (4- (2-DIHYDROISOXAZOL-3-YLPYRIDIN-5-YL) PHENYL) -5-TRIAZOL-1-YLMETHYLOXAZOLIDIN-2-ONE DERIVAIVES AS MAO INHIBITORS FOR THE TREATMENT OF BACTERIAL INFECTIONS}

The present invention relates to antibiotic compounds, in particular antibiotic compounds containing substituted oxazolidinone rings and isoxazolin ring. 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 Imperial's (Enterococcus), streptococcus (Streptococcus), and mycobacteria (mycobacterium) is difficult to treat is to eradicate when the hospital environment once the composition This is particularly important because it develops into resistant strains that become difficult. 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. Bacterial resistance to known antibacterial agents may include, for example, (i) the generation of active binding sites of the bacterium, which reduces or neutralizes the effects of pharmacophores that were active, and / or (ii) By means of generating means for chemically inactivating a given pharmacological step, and / or (iii) generating an efflux pathway. Thus, there is still a need for new antibacterial agents with good pharmacological profile, especially compounds containing new pharmacological action groups.

Our patent application WO 03/022824 discloses various strains and / or aminoglycosides which are resistant to Gram-positive pathogens including MRSA and MRCNS, in particular vancomycin and / or linezolid and are used clinically. E. with resistance to both β-lactams. In addition to having useful activity against fascium strains, H. Influenza, M. Catalalis, Mycoplasma spy. (. Mycoplasma spp) and chlamydia (Chlamydia) is rigid (fastidious) culture, such as strains Gram-non-containing having a useful activity even for negative pathogens, the two substituted oxazolidinone ring and / or isoxazolyl sleepy ring - A group of bi-aryl antibiotic compounds is described. Thus, these compounds may be linked to two groups that can act as pharmacological end groups, either of which can independently bind to the pharmacological end binding site, or one of these groups to the pharmacological end binding site, and the other to act Different functions in the mechanism).

In this patent application, the oxazolidinone ring and the isoxazolin ring are each in the 5-position, generally selected from substituents known in the art as being suitable for antibacterial agents, for example methylacetamide (e.g. For example, see WO 93/09103), methylamino-bonded heterocycles (see eg WO 00/21960) and heterocyclylmethyl groups (see eg WO 01/81350).

Also known are oxazolidinone-containing compounds that are mono amine oxidase (MAO) inhibitors (see, eg, GB 2028306A). In fact, since the inhibitory activity of MAO is a potential cause of unwanted side effects seen in oxazolidinone antibacterial agents, such properties are generally preferably minimized in any potential antibacterial agent (eg WO 03 / 072575). In particular, oxazolidinones having amine-containing and ether-containing substituents at the 5-position of the oxazolidinone ring have been described as having strong MAO inhibitory activity (eg, GB 2028306A; J. Pharm Pharmacol, 1983, 161-165; J. Am. Chem. Soc, 111, 8891-8895; and references in these references).

Unexpectedly, we have a group of non-aryl compounds that contain one oxazolidinone ring and one isoxazolin ring, contain ether or substituted ether side chains on isoxazolin and triazole rings on oxazolidinone It has been found in the present invention to have this useful antibacterial activity and at the same time an acceptable level of MAO 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 cyanomethyl, carboxymethyl, —CH ₂ C (O) NR ⁵ R ⁶ , or [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, hydroxy ( 2-4C) alkoxy, cyano, -OC (O) R ⁵ , carboxy, -C (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 substituted with one or two substituents independently selected from (2-4C) 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- 1C or 2 substituents independently selected from alkoxy or hydroxy, wherein the (1-4C) alkylamino group or the di- (1-4C) alkylamino group is carboxylated on its (1-4C) alkyl chain Or (2-4C) alkyl optionally substituted with); or

R ⁵ and R ⁶ together with the nitrogen to which they are attached contain 4, 5 or 6 membered saturated heterocyclyl optionally containing one additional heteroatom independently selected from O, N or S (in addition to the N atom connecting them) To form a ring, wherein the -CH ₂ -group can be optionally replaced with -C (O)-, and the sulfur atoms in the ring can be optionally oxidized with an S (O) group or an S (O) ₂ group; 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 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.

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.

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.

A 4, 5 or 6 membered saturated heterocyclyl ring containing one or two heteroatoms independently selected from O, N or S, wherein one of these heteroatoms may be an N atom for bonding is disclosed herein. As defined in all definitions of, it will be understood that it contains no OO, OS or SS bonds.

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 the benzoyl ring from a ring nitrogen atom via a methylene linking group. Morpholino or piperazino bonded to the 3-position or 4-position. 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.

Suitable in vivo hydrolyzable esters also include (2-4C) alkyl wherein R ⁴ is —CH ₂ C (O) OR ⁵ , or (substituted by —C (O) OR ⁵ when R ⁵ is not H). There is a compound of formula I as described above.

Compounds of the invention have a chiral center at the C-5 position of the oxazolidinone ring and the isoxazolin ring. Pharmaceutically active diastereomers are compounds of formula la:

In one aspect, preferred diastereomers are compounds of Formula (Ib) In another aspect, preferred diastereomers are compounds of Formula (Ic)

If epimer mixtures on oxazolidinone chiral centers are used, higher amounts (determined by the proportion of diastereomers) will be required to achieve the same effect as pharmaceutically active enantiomers of the same weight.

In addition, certain compounds of the present invention may have another chiral center (eg, on substituent R ⁴ ). It is to be understood that the present invention includes all optical isomers, diastereomers and racemic mixtures having antibacterial activity. A method of preparing an optically active form (eg, via recrystallization techniques, chiral synthesis, enzymatic separation, in vivo conversion or chromatographic separation), and methods of 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.

In addition, it is 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 Gram-negative pathogens that are difficult to culture have been found, such as catarrhalis, mycoplasma and chlamydia strains. The following compounds have desirable pharmaceutical and / or physical and / or pharmacokinetic properties (eg, solubility and / or bioavailability).

In general, the substituted ethers of the present invention have improved pharmaceutical and / or physical and / or pharmacokinetic properties (eg, solubility and / or bioavailability) over unsubstituted ethers such as simple methyl ethers.

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 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 embodiment, R ⁴ is cyanomethyl, carboxymethyl, —CH ₂ C (O) NR ⁵ R ⁶ , or [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) Alkoxy, hydroxy (2-4C) alkoxy, cyano, -OC (O) R ⁵ , carboxy, -C (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 optionally substituted with one or two substituents independently selected from (2-4C) alkyl do.

In another aspect, R ⁴ is selected from cyanomethyl, carboxymethyl or —CH ₂ C (O) NR ⁵ R ⁶ . In another aspect, R ⁴ is selected from carboxymethyl or —CH ₂ C (O) NR ⁵ R ⁶ .

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

In another aspect, R ⁴ is one or two independently selected from [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy or hydroxy (2-4C) alkoxy] Substituted with a substituent] (2-4C) alkyl.

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

In another aspect, R ⁴ is carboxymethyl, —CH ₂ C (O) NR ⁵ R ⁶ , or [hydroxy, (1-4C) alkoxy, —NR ⁵ R ⁶ , —NHS (O) ₂ R ⁵ , Substituted with one or two substituents independently selected from -NHC (O) R ⁵ or -OC (O) R ⁵ ].

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, carboxy , One or two substituents independently selected from (1-4C) alkoxy or hydroxy, wherein the (1-4C) alkylamino group or the di- (1-4C) alkylamino group is a (1-4C) alkyl chain thereof And (2-4C) alkyl optionally substituted with carboxy) in the group;

In another aspect, R ⁵ and R ⁶ are hydrogen, methyl, carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1-4C) alkoxy or hydroxide One or two substituents independently selected from hydroxy, wherein the (1-4C) alkylamino group or di- (1-4C) alkylamino group may be optionally substituted with carboxy on its (1-4C) alkyl chain Independently selected from (2-4C) alkyl.

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 hydrogen, carboxymethyl, or from (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1-4C) alkoxy or hydroxy A substituent selected (substituted with a (1-4C) alkylamino group or a di- (1-4C) alkylamino group which may be optionally substituted with carboxy on its (1-4C) alkyl chain) (2-4C) Independently selected from alkyl.

In another aspect, R ⁵ and R ⁶ are independently selected from hydrogen, carboxymethyl, or (2-4C) alkyl (substituted with a substituent selected from carboxy, (1-4C) alkoxy or hydroxy).

In another aspect, R ⁵ and R ⁶ together with the nitrogen to which they are attached contain 4, 5 or 6 optionally containing one additional heteroatom independently selected from O, N or S (in addition to the N atoms connecting them) To form a membered saturated heterocyclyl ring, wherein -CH ₂ -group can be optionally replaced by -C (O)-, and the sulfur atom in the ring is optionally oxidized to S (O) group or S (O) ₂ group Can be); 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.

Any substituent suitable for a ring comprising R ⁵ and R ⁶ together with the nitrogen to which they are attached is one or two methyl groups.

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) ) And its derivatives oxidized in _two groups), piperidine and pyrrolidine.

Further suitable compounds are morpholine, thiomorpholine, piperazine and N-methyl piperazine.

Further suitable compounds are morpholine, piperazine and N-methyl piperazine.

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 From (2-4C) alkyl optionally substituted with a (1-4C) alkylamino group or a di- (1-4C) alkylamino group optionally substituted with carboxy on its (1-4C) alkyl chain Independently selected; or

R ⁵ and R ⁶ together with the nitrogen to which they are attached form a morpholine or piperazine ring optionally substituted with a methyl group.

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 selected from carboxymethyl or —CH ₂ C (O) NR ⁵ R ⁶ ;

R ⁵ and R ⁶ are independently selected from hydrogen, methyl, carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1-4C) alkoxy or hydroxy Optionally substituted with one or two substituents, wherein the (1-4C) alkylamino group or the di- (1-4C) alkylamino group may be optionally substituted with carboxy on its (1-4C) alkyl chain) There is provided a compound of Formula (Ia) as defined above, or a pharmaceutically acceptable salt or prodrug thereof, independently selected from (2-4C) alkyl.

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 carboxymethyl or —CH ₂ C (O) NR ⁵ R ⁶ ;

R ⁵ and R ⁶ together with the nitrogen to which they are attached, (in addition to the N atom connecting them) O, N, or 4, 5 or 6 membered containing 1 additional heteroatoms independently selected from S, optionally saturated heterocyclyl, To form a ring, wherein the -CH ₂ -group can be optionally replaced with -C (O)-, and the sulfur atoms in the ring can be optionally oxidized with an S (O) group or an S (O) ₂ group; The ring 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 is attached is not quaternized by such substitution 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 substituted with one or two substituents independently selected from hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy or hydroxy (2-4C) alkoxy] There is provided a compound of Formula (Ia) as defined above, or a pharmaceutically acceptable salt or prodrug thereof, which is (2-4C) alkyl.

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 [-OC (O) R ⁵ , carboxy, -C (O) NR ⁵ R ⁶ , -S (O) ₂ R ⁵ , -S (O) ₂ NR ⁵ R ⁶ , -NR ⁵ R ⁶ , [2-4C] alkyl substituted with one or two substituents independently selected from -NHC (O) R ⁵ or -NHS (O) ₂ R ⁵ ;

R ⁵ and R ⁶ are independently selected from hydrogen, methyl, carboxymethyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino, carboxy, (1-4C) alkoxy or hydroxy Optionally substituted with one or two substituents, wherein the (1-4C) alkylamino group or the di- (1-4C) alkylamino group may be optionally substituted with carboxy on its (1-4C) alkyl chain) There is provided a compound of Formula (Ia) as defined above, or a pharmaceutically acceptable salt or prodrug thereof, independently selected from (2-4C) alkyl.

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 substituted with one or two substituents independently selected from —C (O) NR ⁵ R ⁶ , —S (O) ₂ NR ⁵ R ⁶ or —NR ⁵ R ⁶ ] (2-4C) Alkyl;

R ⁵ and R ⁶ together with the nitrogen to which they are attached, (in addition to the N atom connecting them) O, N, or 4, 5 or 6 membered containing 1 additional heteroatoms independently selected from S, optionally saturated heterocyclyl, To form a ring, wherein the -CH ₂ -group can be optionally replaced with -C (O)-, and the sulfur atoms in the ring can be optionally oxidized with an S (O) group or an S (O) ₂ group; The ring 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 is attached is not quaternized by such substitution There is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt or prodrug thereof.

Particular compounds of the present invention include each of the individual compounds described in the Examples below, each of which provides an independent additional aspect of the present 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. 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 by treating with esterifiable groups, for example methyl or ethyl groups, which can be removed by hydrolysis with bases such as sodium hydroxide, or with organic acids such as acids, for example trifluoroacetic acid. There are t-butyl groups that can be removed, or benzyl groups that can 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 references, the examples included in the references, and the examples herein, to obtain the necessary starting materials and products.

Therefore, the present invention also provides any one of the following processes a) to j); 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, the hydroxy group can be converted to an acyloxy group, for example an acetoxy group; 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); 1,2,3-triazol-1-yl groups are introduced by introducing new ring substituents or by refunctionalizing existing ring substituents (eg, 4- of the 4-substituted 1,2,3-triazol-1-yl groups). Modifying substituents or introducing 4-substituents into unsubstituted 1,2,3-triazol-1-yl groups); The alcohol group can be converted to an ether group by first converting to a leaving group such as a halide, or a sulfonate ester such as para toluenesulfonate and then to another ether under basic conditions to convert to an ether; Alcohols can be converted to imidates such as trifluoroacetimidadate, for example, by treatment with trifluoroacetonitrile and base, and then ether is produced by treating the imidate with another alcohol under acidic conditions. Can be; Functionalized ether derivatives are, for example, treated with carboxylic acids (or esters), ketones or Weinreb amide derivatives with organometallic derivatives such as alkyl Grignard or alkyl lithium reagents, respectively, to form tertiary alcohols, May be further modified by producing secondary alcohol or ketone derivatives;

Reducing the carboxylic acid, ester, ketone or aldehyde to produce an alcohol;

Hydrolyzing esters to acids;

Treating the activated carboxylic acid derivative with an amine to produce an amide;

A process for oxidizing the alkene, for example with peracid, to convert it to an epoxide;

Treating epoxides with nucleophiles such as amines, thiolates or alkoxides to produce 2-hydroxy amines, thioethers or ethers;

Oxidizing thioether with sulfone or sulfoxide;

Converting the alkene to, for example, osmium tetraoxide to 1,2-diol;

1,2-diol, for example, by treatment with sodium periodate to convert aldehydes, or alternatively ozonation of alkenes (after treatment with ozone and treatment with reducing agents such as dimethylsulfide) to produce aldehydes. ;

Converting the aldehyde to an amine by reductive amination;

Oxidizing alcohols to aldehydes, ketones or carboxylic acids;

Acylating the alcohol with an activated carboxylic acid derivative, isocyanate or chloroformate derivative to produce an ester, carbamate or carbonate, respectively;

The alcohol is converted to a leaving group such as a halide or to a sulfonate ester such as para toluenesulfonate and subsequently to an amine precursor such as azide or phthalimide (alternatively, Mitsuno to this type of conversion Mitsunobu-type conditions (e.g. triphenylphosphine, diethylazodicarboxylate and hydrazoic acid may be used), amine precursors, for example azide (e.g., Reducing to amines using aqueous triphenylphosphine) or hydrolyzing phthalimide (eg using hydrazine) to amines; or

A process for converting an amino group to a substituted amino group by, for example, alkylation, reductive alkylation, acylation or sulfonylation can be performed;

The amines can be alkylated with alkyl halides or other activators such as sulfonate esters; The amines can be reductive alkylated by treatment with carbonyl compounds such as aldehydes, and reducing agents such as sodium triacetoxy borohydride; Amides can be produced by acylating amines with activated carboxylic acid derivatives or active esters, such as acyl chloride, urea can be produced by acylating with isocyanate derivatives, or carbamate by acylating with chloroformate derivatives. Can be generated; The amines can be converted, for example, to isocyanates by first converting them to formamide derivatives and then treating them with dehydrating agents, and subsequently treating the resulting isocyanate derivatives with amines or alcohols to produce urea or carbamate derivatives, respectively. There is; Sulfonamide can be produced by treating an amine with an activated sulfonic acid derivative such as sulfonyl chloride;

b) leaving groups useful for palladium [0] coupling, for example chloride, bromide, iodide, trifluoromethylsulfonyloxy, trimethylstannyl, trialkoxysilyl or boronic acid residues A portion of the compound is reacted with a portion of the compound of formula IIa, and then reacted with leaving group X (Y is an ether or a functionalized derivative thereof) to react the phenyl-X bond and the pyridyl-X bond with pyridyl- Processes for Substituting Phenyl Bonds (e.g., Scheme b) (This method is well known and described, for example, in SP Stanforth, Catalytic Cross-Coupling Reactions in Biaryl Synthesis, Tetrahedron, 54, 1998, 263-303). JK 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 JF Hartwig, Current Org.Chem., 1997, 1, 287-305; SP Stanforth, Tetrahedron, 54, 1998, 26 3-303; P. R. Parry, C. Wang, A. S. Batsanov, M. R. Bryce; and B. Tarbit, J. Org. Chem., 2002, 67, 7541-7543;

Wherein the leaving group X may be the same or different from each other in the two molecules of Formula II and IIa);

c) a process in which Y reacts a pyridyl-phenyl carbamate derivative of formula III, as defined above, with an appropriately substituted oxirane to form an oxazolidinone ring as illustrated in Scheme c below [ 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 Process variations are also well known in the art (eg, Scheme c ′);

(d) reacting a compound of formula IV with a compound of formula V;

Wherein X and X 'are replaceable substituents (e.g. chloride, bromide, iodide or trifluoromethylsulfonyloxy, trimethylstannyl, trialkoxysilyl or boronic acid residues) and palladium (0 Transition metals such as c) are selected as complementary substituent pairs known in the art to be suitable as complementary substrates for the catalyzed coupling reaction, and Y is as defined above;

e) a process of reacting a 3-pyridylphenylbiaryl aldehyde derivative of formula (VI) to form an isoxazolin ring at an undeveloped heteroaryl position, as illustrated in Scheme (E): Modifications to the above processes, in which reactive intermediates (nitrile oxides of formula VII ') are obtained by reactions other than the oxidation of oximes, are also well known in the art;

Wherein Y is as defined above;

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

Wherein Y is as defined above;

g) a process of converting acetylene by cyclization addition reaction through an azide, as illustrated in Scheme g below (e.g., azidomethyl oxazolidinone in an aqueous alcohol solution at room temperature with terminal alkyne and Cu (I) catalysts) Reaction under action to produce 4-substituted 1,2,3-triazoles (VV Rostovtsev, LG Green, VV Fokin, and KB Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596- 2599]);

Wherein Y is as defined above;

h) A process for reacting aminomethyloxazolidinone with 1,1-dihaloketone sulfonylhydrazone, as illustrated in Scheme h below (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];

Wherein Y is as defined above;

i) when R ¹ is a 4-halo substituent, as illustrated in Scheme i below, the azido methyl oxazolidinone is free of solvent or in an inert diluent such as chlorobenzene, chloroform or dioxane at a temperature of 0-100 ° C. A process for preparing a compound of formula (I) by reacting with halovinylsulfonyl chloride in the case where the halogen of the vinylsulfonylchloride reagent exemplified below is bromine, see CS Rondestvedt, Jr. and PK Chang, J. Amer. Chem. Soc., 77, 1955, 6532-6540; see preparation of 1-bromo-1-ethenesulfonyl chloride by CS Rondestvedt, Jr., J. Amer.Chem. Soc., 76, 1954, 1926-1929. [The azide derivatives are prepared using 1-chloro-1-ethenesulfonyl chloride at 0 to 100 ° C., preferably at room temperature, without inert solvent, preferably chlorobenzene, chloroform or dioxane, more preferably without solvent. By cyclization addition reaction R ¹ a Forming a compound of formula (I) wherein is 4-chloro-1,2,3-triazole;

Wherein Y is as defined above;

j) Enantioselective hydrolysis of racemic mixtures of esters by esterase at pro-chiral centers to yield preferred single (substituted) hydroxyalkyl epimers on isoxazoline rings Another route to produce is the process (undesired isomers may be recycled) (eg, Scheme j below).

The compounds of the formulas (II) and (IIa) used in process b) can be formed by any method known in the art for synthesizing this type of compound (see for example WO 03/022824).

<Formula II>

<Formula IIa>

Wherein each X is independently a leaving group useful for palladium [0] coupling, for example chloride, bromide, iodide, trifluoromethylsulfonyloxy, trimethylstannyl, trialkoxysilyl or boronic acid residues to be.

For example, when R ¹ a is a triazole ring, the 3-ring system of the compound of Formula II can be assembled in a variety of ways, as illustrated below for unsubstituted triazoles. Similar methods can be used when R ¹ a is substituted triazole or other compound. It will be appreciated that the X in Formula II, as shown in the scheme below, may be the same throughout the assembly process of the 3-ring system, or may be changed at an appropriate point prior to coupling with the compound of Formula IIa (eg, Compounds of formula (II) wherein X is I or Br may be converted to compounds or compounds of formula (IIa) with suitable substituents X, for example Br or I, after being converted to compounds or trimethylstanyl derivatives where X is boronic acid or ester has exist). Alternatively, compounds of formula (IIa) or trimethylstannyl derivatives wherein X is boronic acid or ester may be reacted with compounds of formula (II) wherein X is a suitable halo derivative, for example I or Br.

Compounds of formula (IIa) may be derived from oxime-substituted pyridine derivatives wherein X is Br or I as shown below. The oxime derivative itself can be derived from an aldehyde-halopyridine from a simple halo-pyridine derivative. If a single enantiomer is required, selectivity can be achieved by any method known in the art, for example by separating an ester group using an enzyme such as a lipase to introduce a chiral center on the isoxazole ring. While this process is illustrated below for butyl esters, it will be appreciated that other alkyl or alkenyl esters can be used and that separation and hydrolysis can be achieved in a single step by enzyme-catalyzed selective ester hydrolysis. . It will also be appreciated that separation can be achieved by enzyme-catalyzed esterification of the hydroxy groups and subsequent hydrolysis to produce chiral alcohols as set out below. The hydroxy group can then be treated to produce the desired compound of formula IIa. It will be appreciated that the X in formula (IIa), as shown in the scheme below, may be the same throughout the assembly process of the 2-ring system, or may be altered at appropriate points prior to coupling with the compound of formula (II).

Forming OR ⁴ substituents from hydroxymethyl substituents can be performed with protection and deprotection as needed at any stage of the synthesis procedure. Suitable synthetic precursors for the OR ⁴ group include, for example, hydroxyl groups, halo groups (or other leaving groups (LG) such as mesylate or tosylate esters) and imidates (eg trifluoroacetimi) Date). The conversion process for ether formation is shown below.

Since the synthetic procedures set forth in the scheme below can be applied at any suitable stage during the assembly process of the compounds, G in the scheme below is suitably substituted pyridyl, pyridyl-phenyl, pyridyl-phenyl-oxazolidinone or pyridyl It will be appreciated that the -phenyl-oxazolidinone-methyltriazole ring system can be represented.

For the compounds of the present invention, any of the reaction procedures well known in the art can be used if the R ⁴ a group must be further converted to produce the desired R ⁴ a group (eg, the following scheme).

Compounds of formula (IIa) wherein X is boronic acid or ester and Y is OR ⁴ are novel compounds and form independent aspects of the present invention. Particular compounds of this aspect of the invention are compounds of formula (IIa) as R ⁴ is defined in any aspect or embodiment of the invention described above or below.

Compounds of formula (IIa) wherein X is halogen and Y is OR ⁴ are novel compounds and form independent aspects of the present invention. Particular compounds of this aspect of the invention are intermediates 14, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.

"X is boronic acid or ester" means that X is a -B (OR ^A ) (OR ^B ) group, wherein R ^A and R ^B are hydrogen or (1-4C) alkyl groups (e.g., methyl, ethyl and iso Propyl), or R ^A and R ^B together form a two or three-carbon bridge between two oxygen atoms attached to a boron atom to form a five or six membered ring, respectively, wherein 2 or 3-carbon crosslinking is optionally substituted with 1 to 4 methyl groups, for example forming 1,1,2,2-tetramethylethylene crosslinking), or R ^A and R ^B together are 1,2- To form a phenyl group, whereby a catechol ester is produced].

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 can 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 Or by separating the racemic forms of the compounds or intermediates using standard methods, or by chromatographic separation of the diastereomers (if generated). Enzymatic techniques may also be useful for the preparation of optically active compounds and / or intermediates.

Similarly, where pure regioisomers of the compounds of the present invention are desired, pure regioisomers may be carried out using pure regioisomers as starting materials or by purely separating the mixture of regioisomers or intermediates by standard methods. Isomers can be obtained.

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 Can be prepared by direct bromination, wherein each X is independently H or F, and Rp 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 method of forming a compound of formula (IIc) from a compound of formula (IIb) comprising treating a solution of a compound of formula (IIb) with alkali metal bromate and hydrobromic acid as defined above 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 aspect of the invention, there is provided an anti-animal agent 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 a bacterial 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 and methods well known in the art (in any of these), to alter 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. The tablet formulation may or may not be coated using.

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 sucrose) , 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 4.

organism MIC (µg / mL) Staphylococcus aureus MSQS MRQR 0.25 0.5 Streptococcus pneumoniae 0.06 Haemophilus influenzae 8 Moraxella Catarrhalis 0.5 Linezolid-resistant Streptococcus pneumoniae One MSQS = methicillin-sensitive and quinolone-sensitive MRQR = methicillin-resistant and quinolone-resistant

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. In the compounds of the Examples, Ki values of 5 μM or more were measured by the above assay. In Example 4, a Ki value of 8 μM was shown.

As described in our patent application WO 03/072575, it will be appreciated that compounds with 4-alkyl triazoles generally exhibit lower MAO-A inhibitory activity than similar unsubstituted triazole compounds.

In addition, the present inventors, R ⁴ is (a carbon-carbon double bond optionally substituted with one, two or three (1-4C) alkyl substituted on) an allyl compound of formula I as described above, and R ⁴ is azido A compound that is (2-4C) alkyl substituted with Such compounds, for example References 2 and 9, have antibacterial activity and may further be useful as intermediates for other compounds of formula (I, in particular, R ⁴ is (2-4C) alkyl substituted with azido) have.

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. In particular, another aspect of the present invention is Reference Example 11.

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; MPLC is medium pressure liquid chromatography; 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; DMAP is 4-dimethylaminopyridine; THF is tetrahydrofuran; TFA is trifluoroacetic acid; RT is room temperature; cf. is a comparison.

(viii) The temperature is shown in ° C.

(ix) MP carbonate resin is a solid-phase resin for acid scavenging (Argonaut Technologies) having a chemical structure of PS-CH ₂ N (CH ₂ CH ₃ ) ₃ ⁺ (CO ₃ ^2- ) _0.5 Possible).

Prodrug Example 1: tert-butyl {[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetate

tert-butyl {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetate (Intermediate 12, 175 mg, 0.47 mmol) , (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 (intermediate 7, 201 mg, 0.52 mmol), potassium carbonate (200 mg, 1.45 mmol) and tetrakis (Triphenylphosphino) palladium (0) (54 mg, 0.047 mmol) was suspended in DMF (2.5 mL) and water (0.25 mL). The mixture was heated at 80 ° C. for 1 h, poured into water, extracted with ethyl acetate, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 1-5% methanol in dichloromethane). The resulting material was triturated with dichloromethane: diethyl ether: hexane (1: 5: 5) and then filtered and washed with diethyl ether: hexane (1: 1). The title compound was obtained as an off-white solid (110 mg). Melting point: 186 ° C.

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 was stirred 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 to afford the desired product 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 NaCl (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: 5-Bromo-N-hydroxypyridine-2-carboximidoyl chloride

5-bromopyridine-2-carbaldehyde oxime (49.5 g, 246.3 mmol) was dissolved in DMF (150 mL) followed by the addition of N-chlorosuccinimide (39.5 g, 295.5 mmol). The solution was then bubbled with HCl gas for 20 seconds to initiate the reaction and then stirred for 1 hour. The reaction was poured into distilled water (1 L) and the precipitate was collected by vacuum filtration. The filter cake was washed with distilled water (2 x 500 mL) and then dried in a vacuum oven (-30 inches Hg) at 60 ° C. overnight to give the product as a white powder (55 g).

Caution: Teardrop material.

Intermediate 8a: 5-bromopyridine-2-carbaldehyde oxime

After addition of 5-bromo-pyridine-2-carbaldehyde (X. Wang et al, Tetrahedron Letters 41 (2000), 4335-4338]) (60 g, 322 mmol) to methanol (700 mL) Water (700 mL) was added, followed by hydroxylamine hydrochloride (28 g, 403 mmol). Sodium carbonate (20.5 g, 193.2 mmol) in water (200 mL) was added and the reaction stirred for 30 minutes. Then water (500 mL) was added, the precipitate was filtered off and washed with water (2 × 300 mL) to afford the desired product (60 g).

Intermediate 9: [3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methyl butyrate

To EtOAc (200 mL) add 5-bromo-N-hydroxypyridine-2-carboximidoyl chloride (Intermediate 8, 46 g, 195.7 mmol) followed by allyl butyrate (145 mL, 1020.4 mmol) The solution was cooled to 0 ° C. Triethylamine (30 mL, 215.8 mmol) in EtOAc (100 mL) was then added dropwise over 1 hour. The reaction was then stirred for 1 h at 0 ° C. and then EtOAc (1 L) was added. The precipitate was removed by vacuum filtration and the filtrate was concentrated in vacuo to give the product (65 g).

Intermediate 10: (5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methyl butyrate

Chem. Lett. 1993 p. 1847, and is a (+) isomer classified as (5S).

Racemic [3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methyl butyrate (intermediate 9, 80 g, 0.244 mol) is dissolved in acetone (4 L) And vigorously stirred with addition of 0.1 M potassium phosphate buffer (pH about 7, 4 L) to give a clear yellow solution. PS-lipase (1.45 g, Sigma List No. L-9156) was added and the mixture was slowly stirred at room temperature for 42 hours. The solution was divided into three equal volumes of about 2.6 L, each extracted with dichloromethane (2 x 1 L), and the combined organic phases were dried over sodium sulfate and evaporated. Flash column chromatography with unreacted [(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methyl butyrate (9: 1 hexanes: ethyl acetate ) As a clear yellow oil (36.4 g, 45.5%).

Intermediate 11: [(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol

[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methyl butyrate (intermediate 10, 16.88 g, 0.051 mol) in methanol (110 mL) Dissolved in. 50% aqueous sodium hydroxide solution (3.6 mL, 0.068 mol) was added. The solution was stirred for 15 min at room temperature, 1 M HCl (75 mL) was added, and then concentrated in vacuo to a total volume of about 100 mL. Water (about 50 mL) was added and the white precipitate collected and washed with water. The filtrate was extracted twice with ethyl acetate, the organic layers were combined, dried over sodium sulfate and evaporated. The solid residue was collected, washed with 10: 1 hexanes: ethyl acetate, then combined with the initial precipitate and dried in vacuo to yield the title compound as 12.3 g (93%) of white solid crystals. Analysis by chiral HPLC showed less than 0.5% of the (-) isomer. [a] _D = +139 (c = 0.01 g / mL in methanol).

Intermediate 12: tert-butyl {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetate

[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (intermediate 11, 200 mg, 0.78 mmol) and tetrabutyl ammonium iodide (2 mg, catalyst amount) was dissolved in THF (3 mL), sodium hydride (60% dispersion in mineral oil, 65 mg, 1.63 mmol) was added carefully and the suspension was stirred for 5 minutes and then cooled to 0 ° C. . tert-butyl bromoacetate (0.25 mL, 1.69 mmol) was added and the suspension was stirred for 5 hours at room temperature. The mixture was carefully diluted with water and 1 M HCl and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over sodium sulfate and evaporated and purified via chromatography (silica gel, 10-20% ethyl acetate in hexanes). Fractions containing the target product were evaporated and dried under vacuum to afford tert-butyl {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] Methoxy} acetate was obtained as a thick oil (179 mg).

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

2-{(5S) -5-[(allyloxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine (intermediate 13, 210 mg, 0.71 mmol), (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 (intermediate 7, 302 mg, 0.78 mmol), potassium carbonate (293 mg, 2.12 mmol) and tetrakis (triphenylforce) Pino) palladium (0) (82 mg, 0.071 mmol) was suspended in DMF (4 mL) and water (0.4 mL). The mixture was heated at 80 ° C. for 1 h, poured into water, extracted with ethyl acetate, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 1-5% methanol in dichloromethane). The resulting material was triturated with dichloromethane: diethyl ether: hexane (1: 5: 5) and then filtered and washed with diethyl ether: hexane (1: 1). The title compound was obtained as an off-white solid (160 mg). Melting point: 162 ° C.

Intermediate 13: 2-{(5S) -5-[(allyloxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine

[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (200 mg, 0.78 mmol) and tetrabutyl ammonium iodide (2 mg , Catalyst amount) was dissolved in THF (3 mL), sodium hydride (60% dispersion in mineral oil, 65 mg, 1.63 mmol) was added carefully and the suspension was stirred for 5 min and then cooled to 0 ° C. Allyl bromide (0.15 mL, 1.74 mmol) is added and the suspension is stirred for 5 hours at room temperature. The mixture was carefully diluted with water and 1 M HCl and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over sodium sulfate and evaporated and purified via chromatography (silica gel, 10-20% ethyl acetate in hexanes). Fractions containing the target product were evaporated and dried under vacuum to afford 2-{(5S) -5-[(allyloxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine Was obtained as a thick oil (214 mg).

Example 3: {[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl ) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetic acid

tert-butyl {[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetate (Prodrug Example 1, 940 mg, 1.7 mmol) was combined with trifluoroacetic acid (12 mL) and stirred to give a clear brown solution. The mixture was stirred for 45 min at room temperature and then concentrated to give a dark brown oil. This material was sonicated with diethyl ether to give a solid residue, the ether was decanted off and the procedure was repeated again with diethyl ether followed by diethyl ether: dichloromethane (1: 1), The solid was dried under vacuum. The title compound was obtained as an off-white solid (840 mg). Melting point: 190 ° C.

Example 4: 2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole-1- Monomethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} -N-methylacetamide

{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1, 3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetic acid (Example 3, 500 mg, 1.0 mmol), pentafluor Rophenol (370 mg, 2.0 mmol), 4- (dimethylamino) pyridine (3 mg, 0.025 mmol) and DMF (1 mL) were combined to give a clear solution. 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (390 mg, 2.0 mmol) was added and the solution was stirred at rt for 4 h and diluted with ethyl acetate. The mixture was washed with water and saturated sodium chloride, dried over sodium sulfate and evaporated to give the reactive pentafluorophenyl ester as a crude viscous solid (662 mg) which was used without further purification or characterization. Pentafluorophenyl ester (331 mg, 0.5 mmol) was combined with methylamine (2 M THF solution, 3 mL, 6 mmol) and dioxane (3 mL). The mixture was warmed to 60 ° C. for 1.5 h, evaporated, redissolved in methanol and adsorbed onto silica gel. It was purified by flash chromatography (silica gel, 0.5-5% methanol / dichloromethane) and the solid obtained was triturated with ether and dried in vacuo to yield the title compound as an off-white solid (135 mg). Mp 153 to 156 ° C.

Example 5: 2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole-1- Ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} -N, N-dimethylacetamide

{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1, 3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetic acid (Example 3, 500 mg, 1.0 mmol), pentafluor Rophenol (370 mg, 2.0 mmol), 4- (dimethylamino) pyridine (3 mg, 0.025 mmol) and DMF (1 mL) were combined to give a clear solution. 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (390 mg, 2.0 mmol) was added and the solution was stirred at rt for 4 h and diluted with ethyl acetate. The mixture was washed with water and saturated sodium chloride, dried over sodium sulfate and evaporated to give the reactive pentafluorophenyl ester as a crude viscous solid (662 mg) which was used without further purification or characterization. Pentafluorophenyl ester (331 mg, 0.5 mmol) was combined with methylamine (2 M THF solution, 3 mL, 6 mmol) and dioxane (3 mL). The mixture was warmed to 60 ° C. for 1.5 h, evaporated, redissolved in methanol and adsorbed onto silica gel. It was purified by flash chromatography (silica gel, 0.5-5% methanol / dichloromethane) and the solid obtained was triturated with ether and dried in vacuo to yield the title compound as an off-white solid (155 mg). Mp 166 to 168 ° C.

Example 6: (5R) -3- {3-fluoro-4- [6-((5S) -5-{[2- (4-methylpiperazin-1-yl) -2-oxoethoxy] Methyl} -4,5-dihydroisoxazol-3-yl) pyridin-3-yl] phenyl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxa Zolidin-2-one

{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl) -1, 3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetic acid (Example 3, 200 mg, 0.4 mmol), pentafluor Rophenol (150 mg, 0.82 mmol), 4- (dimethylamino) pyridine (3 mg, 0.025 mmol) and DMF (2 mL) were combined to give a clear solution. 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (160 mg, 0.83 mmol) was added and the solution was stirred for 45 minutes at room temperature and diluted with ethyl acetate. The mixture was washed with water and saturated sodium chloride, dried over sodium sulfate and evaporated to give the reactive pentafluorophenyl ester as a crude viscous solid (265 mg) which was used without further purification or characterization. Pentafluorophenyl ester was combined with 1-methylpiperazine (0.25 mL, 2.26 mmol) and dioxane (4 mL). The mixture was warmed to 60 ° C. for 20 minutes, evaporated, redissolved in methanol and adsorbed onto silica gel. This was purified by flash chromatography (silica gel, 0.5-20% methanol / dichloromethane) to warm the solid (135 mg) dissolved in dioxane (10 mL). HCl (0.4 M solution in dioxane, 0.68 mL, 0.272 mmol) was added to give a precipitate. The suspension was diluted with diethyl ether (10 mL), filtered, washed with diethyl ether and dried in vacuo to yield the title compound as an off-white solid (140 mg). Mp 165-175 캜.

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

3-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} propan1-ol (intermediate 14, 370 mg, 1.17 mmol), (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 (intermediate 7, 457 mg, 1.18 mmol), potassium carbonate (460 mg, 3.33 mmol) and Tetrakis (triphenylphosphino) palladium (0) (140 mg, 0.12 mmol) was suspended in DMF (5 mL) and water (0.5 mL). The mixture was heated at 80 ° C. for 35 minutes, adsorbed directly onto silica gel and dried under vacuum. It was purified by column chromatography (silica gel, 0.5-10% methanol in dichloromethane) to give an off-white solid. The resulting material was warmed while dissolved in methanol (4 mL) and cooled to afford a precipitate. The mixture was diluted with diethyl ether (20 mL) and sonicated to produce a fine solid, which was collected, washed with diethyl ether and dried under vacuum. Pure title compound was obtained as an off-white solid (235 mg). Melting point: 176 캜.

Intermediate 14: 3-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} propan1-ol

2-{(5S) -5-[(allyloxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine (intermediate 12, 350 mg, 1.18 mmol) and 9-bora Bicyclo [3.3.1] nonane (BBN, 0.5 M solution in THF, 7 mL, 3.5 mmol) was combined at 0 ° C. The cooling bath was removed and the solution was stirred for 45 minutes at room temperature. After the solution was cooled to 0 ° C., sodium hydroxide (50% aqueous solution, 1 mL) and hydrogen peroxide (30% aqueous solution, 0.5 mL) were carefully added. The cold bath was removed and the mixture was stirred for 1.5 hours at room temperature. The mixture was diluted with ethyl acetate and washed with water followed by saturated sodium chloride and then dried over sodium sulfate. After evaporation it was filtered through a small pad of silica gel and washed with 50% ethyl acetate in hexanes to afford 3-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydro Soxazol-5-yl] methoxy} propan-1-ol was obtained as dark yellow oil (370 mg).

Example 8: (5S) -3- [3-fluoro-4- [6-((5S) -5-{[(2-hydroxyethyl)] methyl} -4,5-dihydroisoxazole- 3-yl) pyridin-3-yl] phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethanol (intermediate 15, 0.302 g, 0.84 mmol), (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 (intermediate 7, 313 mg, 0.81 mmol), potassium carbonate (223 mg, 1.62 mmol) and tetrakis ( Triphenylphosphino) palladium (0) (0.049 g, 0.042 mmol) was suspended in DMF (5.6 mL) and water (0.56 mL). The mixture was heated at 85 ° C. for 1 h and extracted with ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 100% ethyl acetate-30% methanol in ethyl acetate). The title compound was obtained as off-white solid (0.160 g). Melting point: 162 ° C.

Intermediate 15: {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetaldehyde

2-{(5S) -5-[(allyloxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine (intermediate 13, 0.500 g, 1.7 mmol) was diluted with THF: water. Dissolve / Slurify in (1: 1, 8 mL). A catalytic amount of osmium tetraoxide was added to the stirring reaction mixture. Sodium periodate (1.80 g, 8.4 mmol) was added and the reaction mixture was vigorously stirred. A large amount of precipitate formed. The reaction was monitored by TLC, which was complete after stirring for 20 minutes at room temperature. The reaction mixture was partitioned between dichloromethane and water. The dichloromethane layer was dried over magnesium sulfate and evaporated. The title product was obtained as dark oil (0.525 g).

Intermediate 16: 2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethanol

{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetaldehyde (intermediate 15, 0.525 g, 0.18 mmol) was added to MeOH. After dissolving in (10 mL), it was cooled to 0 ° C. using an ice water bath. Sodium borohydride (0.131 g, 0.36 mmol) was added slowly. After the addition was complete, the mixture was stirred until it reached room temperature and then stirred for 30 minutes. The solution was diluted with ethyl acetate, washed twice with water, dried over magnesium sulfate and evaporated. It was purified by column chromatography (silica gel, 100% hexanes to 100% ethyl acetate) to give the title compound (0.287 g).

Reference Example 9: (5R) -3- [4- (6-{(5S) -5-[(2-azidoethoxy) methyl] -4,5-dihydroisoxazol-3-yl} pyridine- 3-yl) -3-fluorophenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

2-{(5S) -5-[(2-azidoethoxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine (intermediate 17, 360 mg, 1.1 mmol) , (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 (intermediate 7, 425 mg, 1.1 mmol), potassium carbonate (460 mg, 3.33 mmol) and tetrakis (Triphenylphosphino) palladium (0) (132 mg, 0.11 mmol) was suspended in DMF (5 mL) and water (0.5 mL). The mixture was heated at 80 ° C. for 40 minutes, adsorbed directly onto silica gel and dried under vacuum. This was purified by column chromatography (silica gel, 0.5-5% methanol in dichloromethane) to give a dark oil. The oil was dissolved in dichloromethane (4 mL), diluted with diethyl ether (20 mL) and sonicated to produce a fine solid, which was collected, washed with diethyl ether and dried under vacuum. The title compound was obtained as an off-white solid (205 mg). Melting point: 148 ° C.

Intermediate 17: 2-{(5S) -5-[(2-azidoethoxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine

2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethanol (intermediate 16, 320 mg, 1.06 mmol) and Triphenylphosphine (500 mg, 1.9 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to 0 ° C. Diphenylphosphoryl azide (0.46 mL, 2.1 mmol) was added and then diisopropylazodicarboxylate (0.42 mL, 2.1 mmol) was added dropwise over 10 minutes. The ice bath was removed and the solution stirred for 30 minutes at room temperature. The cloudy solution was cooled to 0 ° C. and then methanol (1 mL) was added. The ice bath was removed and the mixture was stirred at rt for 1.5 h. The solution was stirred for 5 minutes and then concentrated in vacuo to give a thick oil. It was purified by column chromatography (silica gel, 100-25% ethyl acetate in hexanes) to afford the title compound as a clear oil (285 mg).

Example 10: (5S) -3- [3-fluoro-4- (6-{(5S) -5-[(2-morpholin-4-ylethoxy) methyl] -4,5-dihydro Soxazol-3-yl} pyridin-3-yl) phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

4- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihyroisoxazol-5-yl] methoxy} -ethyl) morpholine (intermediate 18, 405 mg, 1.09 mmol), (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 (intermediate 7, 493 mg, 1.3 mmol), potassium carbonate (360 mg, 2.6 mmol) and tetrakis (triphenylphosphino) palladium (0) (0.075 g, 0.065 mmol) were suspended in DMF (8.9 mL) and water (0.89 mL). The mixture was heated under nitrogen at 85 ° C. for 1 h. After the reaction was completed, the reaction mixture was poured into water. The precipitate formed was filtered off and washed with water. The wet filter cake was dissolved in 1: 1 methanol: acetonitrile and then purified by column chromatography (silica gel, 1: 1 ethyl acetate: methanol). The title compound was obtained as beige solid crystals (0.350 g). Melting point: 171 ° C.

Intermediate 18: 4- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) morpholine

{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetaldehyde (intermediate 15, 0.068 g, 0.23 mmol) was purged with nitrogen. In anhydrous dichloromethane (3 mL). Morpholine (0.018 g, 0.21 mmol) was added to the reaction mixture followed by sodium triacetoxy borohydride (0.063 g, 0.29 mmol). The reaction was stirred at rt for 18 h. Saturated sodium bicarbonate solution was added to the reaction mixture. Dichloromethane was added and the layers separated. The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated. The dark oil was purified by chromatography (10% hexanes in ethyl acetate → 40% hexanes in ethyl acetate). The title compound was obtained as an oil (0.030 g).

Reference Example 11: (5S) -3- (4- {6-[(5S) -5- (ethoxymethyl) -4,5-dihydroisoxazol-3-yl] pyridin-3-yl} -3 -Fluorophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

5-bromo-2-[(5S) -5- (ethoxymethyl) -4,5-dihydroisoxazol-3-yl] pyridine) (intermediate 19, 240 mg, 0.84 mmol), (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 (intermediate 7, 310 mg, 0.80 mmol), potassium carbonate (350 mg, 2.5 mmol) and tetrakis (triphenylphosphino) Palladium (0) (50 mg, 0.04 mmol) was suspended in DMSO (4.3 mL) and water (0.43 mL). The mixture was heated under nitrogen at 85 ° C. for 1 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 100% dichloromethane-10% methanol in dichloromethane). The collected solid was recrystallized in dichloromethane / ether. The title compound was obtained as beige solid crystals (122 mg). Melting point: 171 ° C.

Intermediate 19: 5-Bromo-2-[(5S) -5- (ethoxymethyl) -4,5-dihydroisoxazol-3-yl] pyridine

{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (intermediate 11, 300 mg, 1.0 mmol) was dissolved in anhydrous THF ( 4.5 mL). To the reaction mixture being stirred is added sodium hydride (60% dispersion in mineral oil) (100 mg, 2.3 mmol). The reaction mixture was cooled to 0 ° C. Ethyl iodide (0.2 mL, 2.3 mmol) was added slowly. The reaction was warmed to room temperature and monitored by TLC. It took 18 hours to complete the reaction. The mixture was quenched with methanol, diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over sodium sulphate and evaporated and purified via chromatography (silica gel, 10-20% ethyl acetate in hexanes). Fractions containing the target product were evaporated and dried in vacuo to yield the title compound as a thick oil (240 mg).

Example 12: (5S) -3- (4- {6-[(5S) -5- (ethoxymethyl) -4,5-dihydroisoxazol-3-yl] pyridin-3-yl} -3 -Fluorophenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

5-bromo-2-{(5S) -5-[(2-methoxyethoxy) methyl] -4,5-dihydroisoxazol-3-yl] pyridine (intermediate 20, 375 mg, 1.2 mmol) , (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 (intermediate 7, 443 mg, 1.14 mmol), potassium carbonate (315 mg, 2.3 mmol) and tetrakis (Triphenylphosphino) palladium (0) (69 mg, 0.06 mmol) was suspended in DMF (6.75 mL) and water (0.68 mL). The mixture was heated under nitrogen at 85 ° C. for 1 h. After the reaction was completed, the reaction mixture was poured into water. The precipitate formed was filtered off and washed with water. The filter cake was crystallized in methanol / acetonitrile, filtered and washed with ether. The title compound was obtained as beige solid crystals (152 mg). Melting point: 150.9 ° C.

Intermediate 20: 5-bromo-2-{(5S) -5-[(2-methoxyethoxy) methyl] -4,5-dihydroisoxazol-3-yl] pyridine

2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethanol (intermediate 16, 393 mg, 1.3 mmol) Dissolve in anhydrous THF (13 mL) under nitrogen. To the reaction mixture being stirred is added sodium hydride (60% dispersion in mineral oil) (91 mg, 3.9 mmol). The reaction mixture was cooled to 0 ° C. Methyl iodide (0.163 mL, 2.0 mmol) was added slowly. The reaction mixture was monitored by TLC. It took 1 hour to complete the reaction, which was allowed to warm to room temperature overnight. The mixture was quenched with methanol, diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried over sodium sulfate and evaporated. Evaporation gave the title compound as a thick oil (375 mg).

Example 13: N- (2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) methanesulfonamide

N- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) methanesulfonamide (intermediate 22, 270 mg, 0.71 mmol), (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 (intermediate 7, 280 mg, 0.72 mmol), potassium carbonate (300 mg, 2.17 mmol) and tetrakis (triphenylphosphino) palladium (0) (100 mg, 0.087 mmol) were suspended in DMF (4 mL) and water (0.5 mL). The mixture was heated at 80 ° C. for 1 h, adsorbed directly onto silica gel and dried under vacuum. It was purified by column chromatography (silica gel, 1-10% methanol in dichloromethane) to give an off white solid. The solid was heated while dissolved in methanol (4 mL), and the precipitate obtained by cooling to room temperature was diluted with diethyl ether (10 mL), sonicated to give a fine solid, which was collected, washed with diethyl ether and And dried under vacuum. Pure title compound was obtained as off-white solid (70 mg). Melting point: 170 ° C.

Intermediate 21: (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) amine

2-{(5S) -5-[(2-azidoethoxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine (intermediate 17, 630 mg, 1.93 mmol) Was dissolved in dichloromethane (20 mL) and methanol (6 mL) and water (1.5 mL) were added to produce a biphasic mixture. Triphenylphosphine-linked polystyrene resin (Agonot Technologies Inc., Foster City, CA) (1.57 mmol / g, 3.2 g, 5.02 mmol) was added and the resulting suspension was stirred at room temperature for 3 days. . The resin was filtered off and washed with methanol: dichloromethane (1: 3, 200 mL). The filtrate was concentrated to give the title compound as dark yellow oil (575 mg). This crude material was used as intermediate without further purification.

Intermediate 22: N- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) methanesulfonamide

(2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) amine (Intermediate 21, 280 mg, 0.93 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol) were dissolved in dichloromethane (2 mL) and pyridine (1 mL) and then cooled to 0 ° C. Methanesulfonyl chloride (0.37 mL, 4.76 mmol) was added dropwise and the solution was stirred at 0 ° C. for 1 h, diluted with dichloromethane and washed with 0.2 M HCl followed by saturated sodium chloride. The solution was dried over sodium sulfate, evaporated, triturated with ether: hexanes (1: 1) and dried in vacuo to afford the crude title compound as a thick oil (275 mg) which was used as an intermediate without further purification.

Example 14 N- (2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) acetamide

N- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) acetamide (intermediate 23, 295 mg, 0.86 mmol), (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 (intermediate 7, 340 mg, 0.88 mmol), potassium carbonate (360 mg, 2.61 mmol) and tetrakis (triphenylphosphino) palladium (0) (120 mg, 0.104 mmol) were suspended in DMF (4 mL) and water (0.5 mL). The mixture was heated at 80 ° C. for 1 h, adsorbed directly onto silica gel and dried under vacuum. It was purified by column chromatography (silica gel, 1-20% methanol in ethyl acetate) to give an off white solid. The solid was heated while dissolved in methanol (4 mL), and the precipitate obtained by cooling to room temperature was diluted with diethyl ether (10 mL), sonicated to give a fine solid, which was collected, washed with diethyl ether and And dried under vacuum. The title compound was obtained as an off-white solid (200 mg). Melting point: 134 ° C.

Intermediate 23: N- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) acetamide

(2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) amine (Intermediate 21, 280 mg, 0.93 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol) were dissolved in dichloromethane (2 mL) and pyridine (1 mL) and then cooled to 0 ° C. Methanesulfonyl acetic anhydride (0.45 mL, 4.76 mmol) was added dropwise and the solution was stirred at 0 ° C. for 1 h, diluted with dichloromethane and washed with 0.2 M HCl followed by saturated sodium chloride. The solution was dried over sodium sulfate and evaporated to afford the crude title compound as off white solid (300 mg) which was used as an intermediate without further purification.

Example 15: {[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl ) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetonitrile

{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetonitrile (intermediate 24, 165 mg, 0.56 mmol), ( 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 (intermediate 7, 240 mg, 0.62 mmol), potassium carbonate (250 mg, 1.81 mmol) and tetrakis (tri Phenylphosphino) palladium (0) (64 mg, 0.055 mmol) was suspended in DMF (3 mL) and water (0.5 mL). The mixture was heated at 80 ° C. for 30 min, filtered and evaporated and purified by column chromatography (silica gel, 0.5-5% methanol in dichloromethane). The resulting material was crystallized in methanol: dichloromethane (10: 1), then filtered and washed with diethyl ether. The title compound was obtained as an off-white solid (110 mg). Melting point: 90 to 115 ° C.

Intermediate 24: {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetonitrile

[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (intermediate 11, 325 mg, 1.26 mmol) and tetrabutyl ammonium iodide (2 mg, catalyst amount) was dissolved in THF (5 mL), sodium hydride (60% dispersion in mineral oil, 110 mg, 2.75 mmol) was added carefully, the suspension was stirred for 5 minutes and then cooled to 0 ° C. . Bromoacetonitrile (0.20 mL, 2.87 mmol) was added and the suspension was stirred for 6 hours at room temperature. The mixture was carefully diluted with water and 1 M HCl and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over sodium sulfate and evaporated and purified via chromatography (silica gel, 10-30% ethyl acetate in hexanes). Fractions containing the target product were evaporated and dried in vacuo to yield the title compound as a thick oil (169 mg).

Example 16: (5R) -3- [3-fluoro-4- (6-{(5S) -5-[(2-hydroxy-2-methylpropoxy) methyl] -4,5-dihydro Soxazol-3-yl} pyridin-3-yl) phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

1-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} -2-methylpropan-2-ol (intermediate 26 , 235 mg, 0.71 mmol), (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 (intermediate 7, 280 mg, 0.72 mmol), potassium carbonate (320 mg , 2.32 mmol) and tetrakis (triphenylphosphino) palladium (0) (88 mg, 0.076 mmol) were suspended in DMF (3 mL) and water (0.5 mL). The mixture was heated at 80 ° C. for 60 min, diluted with acetonitrile (15 mL), filtered and evaporated and purified by column chromatography (silica gel, 0.5-5% methanol in dichloromethane). The resulting material was crystallized in methanol: diethyl ether (1: 1), then filtered and washed with diethyl ether. The title compound was obtained as an off-white solid (140 mg). Melting point: 180-187 ° C.

Intermediate 25: ethyl {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetate

[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (intermediate 11, 2.0 g, 7.78 mmol) in THF (25 mL) Dissolved, cooled to 0 ° C., sodium hydride (60% dispersion in mineral oil, 0.58 g, 14.5 mmol) was added carefully, the cooling bath was removed, the suspension was stirred for 30 minutes and then cooled back to 0 ° C. . Tetrabutyl ammonium iodide (10 mg, catalytic amount) and ethyl bromoacetate (1.3 mL, 11.7 mmol) were added and the suspension was stirred and slowly warmed to room temperature for 16 h. The mixture was carefully diluted with 0.5 M HCl (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with saturated sodium chloride, dried over sodium sulfate and evaporated and purified via chromatography (silica gel, 20% ethyl acetate in hexanes). The thick oil obtained by evaporating the fractions containing the target product was combined with 10 mL of hexanes and cooled with stirring to give a white solid. Hexane was removed by decantation, the solid was resuspended in hexane, decanted and dried under vacuum to yield ethyl {[(5S) -3- (5-bromopyridin-2-yl) -4,5-di Hydroisoxazol-5-yl] methoxy} acetate was obtained as a white solid (2.2 g).

Intermediate 26: 1-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} -2-methylpropan2-ol

Ethyl {[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetate (Intermediate 25, 255 mg, 0.74 mmol) THF (5 mL), cooled to -70 ° C, methyl magnesium bromide (3M solution in diethyl ether, 0.65 mL, 1.95 mmol) was added dropwise over several minutes and the solution stirred at -70 ° C for 1.5 h. The cooling bath was removed, and the mixture was further stirred at room temperature for 1.25 hours. The mixture was poured into 0.5 M HCl (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated sodium chloride, dried over sodium sulfate and evaporated to afford the title compound as a thick oil (239 mg).

Example 17: 2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole-1- Monomethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl L-isoleucineate

(5S) -3- [3-fluoro-4- [6-((5S) -5-{[(2-hydroxyethyl)] methyl} -4,5-dihydroisoxazol-3-yl) Pyridin-3-yl] phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (Example 8, 400 mg, 0.83 mmol ) Was stirred while dissolved in anhydrous DMF (8 mL) under nitrogen. A catalytic amount of DMAP was added. BOC-L-isoleucine (383 mg, 1.70 mmol) was added to the reaction mixture followed by 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (336 mg, 1.67 mmol). The reaction was stirred for 18 hours. After the reaction was completed, the reaction mixture was worked up with ethyl acetate / water. The ethyl acetate layer was dried over magnesium sulfate and evaporated. The residue as a dark oil was purified by column chromatography (silica gel, 100% ethyl acetate → 10% methanol in ethyl acetate). The collected solid was recrystallized in dichloromethane / ether. Tert-butyl {(1S, 2S) -1-[(2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H) -1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] Methoxy} ethoxy) methyl] -2-methylbutyl} carbamate was dissolved in anhydrous dioxane (2 mL) and 4 M HCl in dioxane (2.5 mL) was added. The reaction mixture was stirred under nitrogen. The precipitated solid was filtered off and washed with ether. After drying in vacuo at 80 ° C. for 18 hours the title compound (as HCl salt) was obtained as a solid (340 mg). Melting point: 119 ° C.

Example 18: 2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole-1- Monomethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl N, N dimethylglycinate hydro Chloride

(5S) -3- [3-fluoro-4- [6-((5S) -5-{[(2-hydroxyethyl)] methyl} -4,5-dihydroisoxazol-3-yl) Pyridin-3-yl] phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (Example 8, 400 mg, 0.83 mmol ) Was stirred while dissolved in anhydrous DMF (8 mL) under nitrogen. A catalytic amount of DMAP (300 mg, 2.8 mmol) was added. Dimethyl glycine (206 mg, 2.0 mmol) was added to the reaction mixture followed by 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (403 mg, 2.0 mmol). The reaction was stirred for 3 hours. After the reaction was completed, the reaction mixture was worked up with ethyl acetate / water. The ethyl acetate layer was dried over magnesium sulfate and evaporated. The oily residue was purified by crystallization in dichloromethane / ether. The solid was dissolved in anhydrous dioxane (3 mL) and 4 M HCl in dioxane (0.15 mL, 0.6 mmol) was added. The reaction mixture was stirred under nitrogen. The precipitated solid was filtered off, washed with ether and dried in vacuo at 40 ° C. for 18 hours to afford the title compound as a solid (340 mg).

Example 19: ((5R) -3- {4- [6-((5S) -5-{[3- (dimethylamino) -2-hydroxypropoxy] methyl} -4,5-dihydroisoxe Sazol-3-yl) pyridin-3-yl] -3-fluorophenyl} -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidine-2- On

1-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} -3- (dimethylamino) propan2-ol ( Intermediate 28, 215 mg, 0.60 mmol), (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 (intermediate 7, 285 mg, 0.73 mmol), potassium carbonate ( 250 mg, 1.8 mmol) and tetrakis (triphenylphosphino) palladium (0) (70 mg, 0.06 mmol) were suspended in DMF (4 mL) and water (0.4 mL). The mixture was heated at 80 ° C. for 1 h, cooled, filtered and adsorbed onto silica gel. The adsorbed material was purified by column chromatography [silica gel, in dichloromethane (1-10% methanol, 0.1-2% triethylamine)]. The obtained material was triturated with diethyl ether and then filtered and washed with diethyl ether to give the free base (180 mg) of the title compound. This material was dissolved in warm dioxane (5 mL), HCl (4 M solution in dioxane, 0.1 mL) was added and then diluted with diethyl ether to give a precipitate. The solid was collected and washed with diethyl ether to give the hydrochloride salt of the title compound as off white solid (170 mg). Melting point: 110-115 ° C.

Intermediate 27: 5-Bromo-2-{(5S) -5-[(oxirane-2-ylmethoxy) methyl] -4,5-dihydroisoxazol-3-yl} pyridine

2-{(5S) -5-[(allyloxy) methyl] -4,5-dihydroisoxazol-3-yl} -5-bromopyridine (intermediate 13, 220 mg, 0.74 mmol) and 3-chloro Roperbenzoic acid (70-75% aqueous slurry, 230 mg, 0.93 mmol) was combined in dichloromethane (2 mL) and stirred at rt for 16 h. The suspension was diluted with ethyl acetate and washed with aqueous sodium thiosulfate solution, 0.2 M sodium hydroxide and saturated sodium chloride. The organic solution was dried over sodium sulfate and purified by chromatography (silica gel, 10-100% ethyl acetate / hexanes) to give the title compound as a white solid (100 mg).

Intermediate 28: 1-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} -3- (dimethylamino) propane2 -All

5-bromo-2-{(5S) -5-[(oxirane-2-ylmethoxy) methyl] -4,5-dihydroisoxazol-3-yl} pyridine (intermediate 27, 195 mg, 0.62 mmol ) Was dissolved in THF (1 mL) and isopropanol (2 mL). Dimethylamine (2 M solution in THF, 1 mL, 2 mmol) was added and the solution was stirred for 1 day at room temperature. The solution was concentrated in vacuo to afford the title compound as crude oil (215 mg).

Intermediate 29: (5R) -3- (3-fluoro-4- {6-[(5S) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] pyridine-3- Phenyl) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one

[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methanol (intermediate 11, 0.277 g, 1.08 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxane saborolan-2-yl) phenyl] -5- (1H-1,2,3-tria Zol-1-ylmethyl) -1,3-oxazolidin-2-one (intermediate 7, 0.35 g, 0.9 mmol), potassium carbonate (0.622 g, 4.5 mmol) and tetrakis (triphenylphosphino) palladium ( 0) (0.1 g, 0.09 mmol) was combined and suspended in DMF (7 mL) and water (1 mL). The mixture was heated at 75 ° C. for 2 hours and then poured into cold water (30 mL). The solid formed was collected, washed with water and washed with dichloromethane (2 × 10 mL), then the solid was dissolved in warmed trifluoroethanol (2 mL) and column chromatography (8% methanol in dichloromethane) Eluting) gave the title compound as a white solid (0.193 g).

Intermediate 30: [(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazol-1-ylmethyl)- 1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methyl 4-nitrophenyl carbonate

(5R) -3- (3-fluoro-4- {6-[(5S) -5- (hydroxymethyl) -4,5-dihydroisoxazol-3-yl] pyridin-3-yl} phenyl ) -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (intermediate 29, 200 mg, 0.46 mmol) in DMF (3 mL) and It was dissolved in pyridine (0.5 mL) and then cooled to 0 ° C. 4-nitrophenyl chloroformate (140 mg, 0.70 mmol) was added and the mixture was stirred for 2 h at 0 ° C. Additional amount of 4-nitrophenylchloroformate (110 mg, 0.55 mmol) is added and the mixture is stirred for 2 hours at room temperature, diluted with ethyl acetate, washed with 0.2 M HCl, followed by saturated sodium chloride, and over sodium sulfate Dried and evaporated. The residue was suspended in dichloromethane: diethyl ether (1: 1) and the solids were filtered off and washed with dichloromethane: diethyl ether (1: 1) to afford the title compound as an off-white solid (115 mg). .

Example 20 N- (2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole -1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) -N-methyl Glycine

tert-butyl N- (2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3-triazole- 1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) -N-methylglycol Sinate (intermediate 31, 115 mg, 0.19 mmol) was dissolved in 15 mL of trifluoroacetic acid and then warmed to 60 ° C. for 6 hours. The solution was concentrated to dryness and the residue dissolved in water (1 mL). The product solution was filtered through a small column (2 g C18 reversed phase silica, 0-20% acetonitrile in water) and the eluate was evaporated. The residue was dissolved in methanol: dichloromethane (2: 1, 3 mL), then ether (20 mL) was added and the resulting solid collected and dried in vacuo to yield the title compound as an off-white solid (75 mg). Obtained. Mp 135-140 ° C.

Intermediate 31: tert-butyl N- (2-{[(5S) -3- (5- {2-fluoro-4-[(5R) -2-oxo-5- (1H-1,2,3- Triazol-1-ylmethyl) -1,3-oxazolidin-3-yl] phenyl} pyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) -N Methylglycinate

tert-butyl N- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl) -N-methyl Glycinate (intermediate 32, 0.19 g, 0.44 mmol), (5R) -3- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboro Lan-2-yl) phenyl] -5- (1H-1,2,3-triazol-1-ylmethyl) -1,3-oxazolidin-2-one (0.26 g, 0.67 mmol), potassium carbonate (0.20 g, 1.45 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.051 g, 0.044 mmol) were combined in DMF (3 mL) and distilled water (0.3 mL) and then heated to 80 ° C. for 30 minutes. . The reaction mixture was adsorbed directly on silica gel, then the crude residue obtained by purification by column chromatography (silica gel; 0.5-5% MeOH in dichloromethane) was dissolved in warm methanol (3 mL). , Ether (20 mL) was added and the resulting solid was collected and washed with ether to give the title compound as off white solid (0.116 g).

Intermediate 32: tert-butyl N- (2-{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} ethyl)- N-methylglycinate

{[(5S) -3- (5-bromopyridin-2-yl) -4,5-dihydroisoxazol-5-yl] methoxy} acetaldehyde (intermediate 15, 170 mg, 0.57 mmol) in methanol (3 mL). Sarcosine-t-butyl ester hydrochloride (310 mg, 1.70 mmol) was added and the solution was stirred at room temperature for 15 minutes before cooling to 0 ° C. Sodium triacetoxyborohydride (193 mg, 0.91 mmol) is added, the cooling bath is removed, the mixture is stirred for 2.5 hours, diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over sodium sulfate and evaporated I was. This material was purified by flash chromatography (silica gel, 20-100% ethyl acetate in hexanes) to afford the title compound as dark yellow oil (160 mg).

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 cyanomethyl, carboxymethyl, —CH ₂ C (O) NR ⁵ R ⁶ , or [hydroxy, (1-4C) alkoxy, (1-4C) alkoxy (1-4C) alkoxy, hydroxy ( 2-4C) alkoxy, cyano, -OC (O) R ⁵ , carboxy, -C (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 substituted with one or two substituents independently selected from (2-4C) 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 One or two substituents independently selected from alkoxy or hydroxy, wherein the (1-4C) alkylamino group or the di- (1-4C) alkylamino group is carboxylated on its (1-4C) alkyl chain Or (2-4C) alkyl optionally substituted with); or R ⁵ and R ⁶ together with the nitrogen to which they are attached contain 4, 5 or 6 membered saturated heterocyclyl optionally containing one additional heteroatom independently selected from O, N or S (in addition to the N atom connecting them) To form a ring, wherein the -CH ₂ -group can be optionally replaced with -C (O)-, and the sulfur atoms in the ring can be optionally oxidized with an S (O) group or an S (O) ₂ group; 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. 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. The compound according to claim 1, wherein R ⁴ is carboxymethyl, —CH ₂ C (O) NR ⁵ R ⁶ , or [hydroxy, (1-4C) alkoxy, —NR ⁵ R ⁶ , -NHS (O) ₂ R ⁵ , -NHC (O) R ⁵ or -OC (O) R ⁵ substituted with one or two substituents independently selected from (2-4C) alkyl A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof. 5. The compound of claim 1, wherein R ⁵ and R ⁶ are independent from hydrogen, methyl, or (amino, (1-4C) alkylamino, di- (1-4C) alkylamino or hydroxy. Optionally substituted with one or two substituents, wherein the (1-4C) alkylamino group or the di- (1-4C) alkylamino group may be optionally substituted with carboxy on its (1-4C) alkyl chain Independently selected from (2-4C) alkyl; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a morpholine or piperazine ring optionally substituted with a methyl group, or a pharmaceutically acceptable salt or prodrug thereof. The 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 la. <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 portion of the compound of formula II, where X is a leaving group useful for palladium [0] coupling, with a portion of the compound of formula IIa, again leaving group X (Y is an ether or a functionalized derivative thereof) ) To replace phenyl-X and pyridyl-X bonds with pyridyl-phenyl bonds. <Formula II>

<Formula 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 a compound of formula <Formula IV>

<Formula V>

Wherein X and X 'are replaceable substituents and are selected as complementary substituent pairs known in the art to be suitable as complementary substrates for the catalytic coupling reaction of a transition metal such as palladium (0), and Y Is as defined above); e) reacting a 3-pyridylphenylbiaryl aldehyde derivative of formula VI to form a isoxazolin ring at an undeveloped heteroaryl position

, or A variant of the process wherein a reactive intermediate (nitrile oxide of formula (VII ′)) is obtained by a reaction other than oxidation of the oxime of formula (VII) <Formula VII '>

; f) forming a triazole ring from a suitably functionalized intermediate in which the isoxazole-pyridyl-phenyl ring system is previously formed

; g) the process of conversion to acetylene by cycloaddition reaction through azide

; h) a process of reacting aminomethyloxazolidinone with 1,1-dihaloketone sulfonylhydrazone

; i) when R ¹ is a 4-halo substituent, reacting azidomethyl oxazolidinone with halovinylsulfonyl chloride

; j) a process for enantioselective hydrolysis of racemic mixtures of esters by esterase at pro-chiral centers (undesired isomers may be recycled)

Variables including any of the above (unless otherwise stated in the above formulas and schemes, as defined in claim 1), where necessary 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.