CN1989137A

CN1989137A - 3- '4- {6-substituted alkanoyl) pyridin-3-yl} -3-phenyl! -5- (1h-1, 2, 3-triazol-1-ylmethyl) -1, 3-oxazolidin-2-ones as antibacterial agents

Info

Publication number: CN1989137A
Application number: CN 200580025063
Authority: CN
Inventors: M·B·格拉维斯托克; F·莱克; 周非
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2004-05-25
Filing date: 2005-05-24
Publication date: 2007-06-27
Also published as: ZA200609771B; GB0411593D0

Abstract

Compounds of formula (I) as well as pharmaceutically-acceptable salts and pro-drugs thereof are disclosed wherein R<1>, R<2>, R<3>, and R<4> are defined herein. Also disclosed are processes for making compounds of formula (I) as well as methods of using compounds of formula (I) for treating bacterial infections.

Description

3-4-{6-(alkyloyl of replacement) pyridin-3-yl as antiseptic-germicide }-3-phenyl-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

The present invention relates to Antibiotique composition, particularly contain the Antibiotique composition of the  oxazolidone ring of replacement.The present invention relates to the preparation method of described compound in addition, can be used for preparing the intermediate of described compound, and described compound is as the application of therapeutical agent and the pharmaceutical composition that comprises described compound.

A kind of so serious worry is constantly being expressed always by world microbiology group, i.e. the development of antibiotic resistance can produce the bacterial strain that present available antiseptic-germicide will become invalid.Usually, bacterial pathogen can be divided into Gram-positive pathogenic agent or gram-negative pathogens.Have effective active Antibiotique composition and be considered to have broad spectrum of activity usually resisting gram-positive pathogenic agent and gram-negative pathogens.Compound of the present invention is considered to effectively to resisting gram-positive pathogenic agent and some gram-negative pathogens.

Because in case form the just also development of the very difficult drug resistance strain of eradicating of intractable from hospital environment, Gram-positive pathogenic agent for example staphylococcus, enterococcus bacteria, suis and mycobacterium seems particularly important.The example of these bacterial strains is methicillin resistance staphylococcus (MRSA), methicillin resistance coagulase negative staphylococcus (MRCNS), penicillin resistance streptococcus pneumoniae and multidrug resistance faecium.

The effective microbiotic of main clinical that is used for the treatment of these resistance Gram-positive pathogenic agent is a vancomycin.Vancomycin is a kind of glycopeptide and relevant with the various toxicity that comprise renal toxicity.In addition, the most important thing is, antiseptic-germicide resistance also occurred anti-vancocin and other glycopeptide.This resistance increases with steady rate, makes that the validity of these antiseptic-germicides in the treatment of Gram-positive pathogenic agent is more and more lower.At present more and more higher resistance occurred as beta-lactam, quinolone and the macrolide that is used for the treatment of upper respiratory tract infection, also caused by some gram negative strain (comprising hemophilus influenzae and Catarrhal catarrhalis) at various medicines.

Some the antiseptic-germicide compound (for example, people's such as Walter A.Gregory J.Med.Chem.1990,33,2569-2578 and 1989,32 (8), the 1673-81 that contain  oxazolidone ring have been described in the art; People's such as Chung-Ho Park J.Med.Chem.1992,35,1156-1165).Bacterial drug resistance at known antimicrobial agents can form by for example following factor: (i) differentiation of active combining site in the bacterium, make the validity reduction or the described pharmacophore of previous active pharmacophore become unnecessary, and/or (ii) make the differentiation of the means of given pharmacophore chemistry inactivation and/or the (iii) differentiation of discharge path.Therefore, still need to develop new anti-bacterial agent, particularly have the useful activity and the compound of physico-chemical property with favourable pharmacological characteristics.

The physico-chemical property of pharmaceutically useful compound (as solubleness and bioavailability) be generally understood as be on the compound various substituent polarity and such as the balance between the factors such as molecular weight (for equal polar molecule, higher molecular weight reduces solubleness and bioavailability usually).The rigid/flex of other factors such as molecule also influences physico-chemical property such as solubleness usually.

Patent application WO 01/94342 (Dong A.Pharm.Co.Ltd) has described pyridyl- oxazolidone or pyrimidyl-phenyl- oxazolidinone compounds, and it has the methylacetamide side chain that is connected in  oxazolidone ring.Most of exemplary compounds in this patent application contains the substituted piperazine ring that is connected in pyridyl ring or pyrimidine-ring, perhaps contains other heterocycle such as piperidines,  diazole or the tetrazolium that are different from piperazine.

The inventor has had been found that one group of new pyridyl-phenyl- oxazolidinone compounds, and it has the triazole substituting group on  oxazolidone ring, and it is directly connected to the non-ring substituents on the pyridyl ring in addition, and described compound has useful anti-microbial activity.

Compound of the present invention has good physics and/or pharmacokinetic property generally, for example solubleness and bioavailability.

In addition, compound of the present invention has favourable low monoamine oxidase-A generally and suppresses active.

Therefore, the invention provides the compound shown in the formula (I) or its pharmacologically acceptable salt or its prodrug,

Wherein:

R ¹Be selected from hydrogen, halogen, cyano group, methyl, cyano methyl, methyl fluoride, difluoromethyl, trifluoromethyl, methyl sulfenyl and (2-4C) alkynyl;

R ²And R ³Be independently selected from hydrogen, fluorine, chlorine and trifluoromethyl;

R ⁴Be-C (O) R ⁵Or

R ⁴Be selected from-C (H)=N-OR ⁸,-C (R ⁵)=N-OH and-C (R ⁵)=N-OR ⁸

R ⁵Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group, HET-1 and NR by 1 or 2 ⁶R ⁷Substituting group replace);

Perhaps, R ⁵Be that (3-6C) cycloalkyl (is chosen wantonly and is selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 ⁶R ⁷Substituting group replace);

Perhaps, R ⁵Be HET-1;

R ⁶And R ⁷Be independently selected from hydrogen, methyl, cyclopropyl (optional), carboxyl methyl and (2-4C) alkyl (the optional substituting group replacement that is selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl) by methyl substituted;

Perhaps, R ⁶And R ⁷The nitrogen that is connected with them forms optional the saturated of 1 other heteroatoms (except being connected the N atom) that is independently selected from O, N and S or the heterocyclic ring that part is undersaturated 4,5 or 6 yuan of containing altogether, wherein-and CH ₂-group can choose wantonly by-C (O)-replacement and wherein the sulphur atom in the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and to be replaced by 1 or 2 (1-4C) alkyl that (condition is R ⁶And R ⁷The nitrogen that is connected is not thus by quaternized);

Perhaps, R ⁶And R ⁷The nitrogen that is connected with them forms imidazole ring altogether, and described ring is chosen wantonly on available carbon atom and replaced (wherein (1-4C) alkyl is optional is replaced by methoxy or ethoxy) by 1 or 2 (1-4C) alkyl;

R ⁸Be that (1-6C) alkyl (is chosen wantonly and is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace);

HET-1 contains 1 or 2 to be independently selected from the heteroatomic saturated of O, N and S or heterocyclic ring that part is undersaturated 4,5 or 6 yuan, wherein-and CH ₂-group can choose wantonly by-C (O)-replacement and wherein the sulphur atom in the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl.

In another aspect of this invention, provide the compound of above-mentioned formula (I), wherein:

R ⁶And R ⁷The nitrogen that is connected with them forms imidazole ring altogether, and described ring is chosen wantonly on available carbon atom and replaced by 1 or 2 (1-4C) alkyl; With

HET-1 is saturated or the undersaturated 5 or 6 yuan heterocyclic ring of part.

On the other hand, the present invention relates to the compound or pharmaceutically acceptable salt thereof of above-mentioned formula (I).

On the other hand, the present invention relates to compound or its prodrug of above-mentioned formula (I).The suitable example of the prodrug of formula (I) compound be formula (I) but the ester of hydrolysis in the body of compound.Therefore, on the other hand, the present invention relates to above-mentioned formula (I) but compound or its body in the ester of hydrolysis.

Be appreciated that the defined heterocyclic ring saturated or that part is undersaturated 4,5 or 6 yuan that contains 1 or 2 heteroatoms that is independently selected from O, N and S one of (no matter these heteroatomss whether be to be connected the N atom) does not contain any O-O, O-S or S-S key in any definition of this paper (for example definition of HET-1).

When optional substituting group is selected from " 0,1,2 or 3 " group, can understands this definition and comprise and all are selected from described group one group substituting group or are selected from described group two or more sets substituting group.Similarly custom is applicable to the substituting group that is selected from " 0,1 or 2 " group and " 1 or 2 " group.

In this manual, term ' alkyl ' comprise straight chain and branched structure.For example, (1-4C) alkyl comprises propyl group and sec.-propyl.Yet, mention that independent alkyl for example only refers in particular to linear form when " propyl group ", mention that independent branched-chain alkyl for example only refers in particular to the side chain form when " sec.-propyl ".Similarly custom is applicable to other group, and for example halo (1-4C) alkyl comprises 1-bromotrifluoromethane and 2-bromotrifluoromethane.In this manual, term " thiazolinyl " and " cycloalkenyl group " comprise all positional isomerss and geometrical isomer.

In this manual, the group that uses compound term description to comprise to surpass the functional group alkyl of the alkoxyl group of (1-4C) alkoxyl group-(1-4C)-(1-4C) for example.These terms can make an explanation according to the implication that the person skilled in the art understands for each integral part.For example (1-4C) alkoxyl group-(1-4C) alkoxyl group-(1-4C) alkyl comprises methoxymethoxy methyl, oxyethyl group methoxy base propyl group and propoxy-ethoxyl methyl.

Be appreciated that to be defined as optionally when being exceeded a substituting group and replacing when group that then the result of Qu Daiing forms chemically stable compound.For example, can form trifluoromethyl and can not form trihydroxy methyl.No matter where defined optional substituting group, this custom all is suitable for.

Below be some mentioned in this specification sheets substituting group and the specific meaning and suitable connotation of group.If suitably, above or in hereinafter disclosed any definition and the embodiment can use these connotations.Obscure each described classification representative special and aspect independently of the present invention for fear of causing.

(1-4C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl; (2-4C) example of alkyl comprises ethyl, propyl group, sec.-propyl and the tertiary butyl; (1-6C) example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, amyl group and hexyl; (3-6C) example of alkyl comprises propyl group, sec.-propyl, the tertiary butyl, amyl group and hexyl; The example of hydroxyl (1-4C) alkyl comprises hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; The example of hydroxyl (2-4C) alkyl comprises 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyl sec.-propyl and 2-hydroxyl sec.-propyl; (1-4C) example of alkoxy carbonyl comprises methoxycarbonyl, ethoxy carbonyl and propoxycarbonyl; (2-4C) example of thiazolinyl comprises allyl group and vinyl; (2-4C) example of alkynyl comprises ethynyl and 2-propynyl; (1-4C) example of alkyloyl comprises formyl radical, ethanoyl and propionyl; (1-4C) example of alkoxyl group comprises methoxyl group, oxyethyl group and propoxy-; (1-6C) alkoxyl group and (1-10C) example of alkoxyl group comprise methoxyl group, oxyethyl group, propoxy-and pentyloxy; (1-4C) example of alkyl sulfenyl comprises methyl sulfenyl and ethyl sulfenyl; (1-4C) example of alkylamino comprises methylamino, ethylamino and propyl group amino; Two-((1-4C) alkyl) amino examples comprise dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propyl group amino and dipropyl amino; The example of halogen group comprises fluorine, chlorine and bromine; (1-4C) alkoxyl group of alkoxyl group-(1-4C) and (1-6C) alkoxyl group-(1-6C) example of alkoxyl group comprises methoxymethoxy, 2-methoxy ethoxy, 2-ethoxy ethoxy and 3-methoxy propoxy; (1-4C) alkanoylamino and (1-6C) example of alkanoylamino comprise formamido-, acetamido and propionyl amino; (1-4C) alkyl S (O) _qThe example of-(wherein q is 0,1 or 2) comprises methyl sulfenyl, ethyl sulfenyl, methylsulfinyl, ethyl sulfinyl, methyl sulphonyl and ethylsulfonyl; Hydroxyl-(2-4C) example of alkoxyl group comprises 2-hydroxyl-oxethyl and 3-hydroxyl propoxy-; (1-6C) alkyl of alkoxyl group-(1-6C) and (1-4C) example of alkoxyl group (1-4C) alkyl comprise methoxymethyl, ethoxyl methyl and propoxy-ethyl; (1-4C) example of alkyl-carbamoyl comprises methylamino formyl radical and ethylamino formyl radical; The example of two ((1-4C) alkyl) formamyl comprises two (methyl) formamyls and two (ethyl) formamyl; The example of halogen group comprises fluorine, chlorine and bromine; The example of halo (1-4C) alkyl comprises halogenated methyl, 1-halogenated ethyl, 2-halogenated ethyl and 3-halopropyl; The example of dihalo (1-4C) alkyl comprises difluoromethyl and diaminomethyl; The example of three halos (1-4C) alkyl comprises trifluoromethyl; The example of amino (1-4C) alkyl comprises amino methyl, 1-amino-ethyl, 2-amino-ethyl and 3-aminopropyl; The example of cyano group (1-4C) alkyl comprises cyano methyl, 1-cyano ethyl, 2-cyano ethyl and 3-cyano group propyl group; (1-4C) example of alkanoyloxy comprises acetoxyl group, propionyloxy; (1-6C) example of alkanoyloxy comprises acetoxyl group, propionyloxy and uncle's butyryl acyloxy; (1-4C) example of alkyl amino-carbonyl comprises methylamino carbonyl and ethylamino carbonyl; The aminocarboxy example of two ((1-4C) alkyl) comprises dimethylamino carbonyl and diethylamino carbonyl.

Except as otherwise noted, otherwise when enumerating optional substituting group, described replacement preferably is not together with two replacements.If not in addition explanation is for described those substituting groups of similar group herein for the suitable optional substituting group of special groups.

Suitable pharmacologically acceptable salt comprises acid salt for example mesylate, fumarate, hydrochloride, Citrate trianion, maleate, tartrate and (more not preferred) hydrobromate.The salt that forms with phosphoric acid and sulfuric acid also is suitable.On the other hand, suitable salt is alkali salt, as an alkali metal salt sodium salt, alkaline earth salt for example triethylamine, morpholine, N-methyl piperidine, N-ethylpiperidine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N of calcium or magnesium salts, organic amine salt for example for example, N-DBHA, three-(2-hydroxyethyl) amine, the salt of N-methyl d-glycosamine and the salt of amino acid whose salt such as Methionin.According to the number and positively charged ion or anionic valent different of electrically charged functional group, may have positively charged ion or negatively charged ion above one.Preferred pharmacologically acceptable salt is a sodium salt.

So be, in order to help the separation of salt described in the preparation process, the preferred lower salt of the solvability in selected solvent, no matter whether it is that pharmacy is acceptable.

Compound of the present invention can prodrug forms be given usefulness, and described prodrug decomposes in human body or animal body and provides compound of the present invention.Can use prodrug to change or improve the physics and/or the pharmacokinetic properties of parent compound, and can form described prodrug when the group that forms prodrug or substituting group when parent compound comprises suitable can being derived.But the example of prodrug comprises ester or its pharmacologically acceptable salt of the interior hydrolysis of body of The compounds of this invention.But other example of prodrug comprises acid amides or its pharmacologically acceptable salt of the interior hydrolysis of body of The compounds of this invention.

The various forms of prodrug is known in this area, for example referring to:

A) Design of Prodrugs, H.Bundgaard edits, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p.309-396, K.Widder etc. edit (Academic Press, 1985);

B) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard edit, Chapter 5 " Design and Application ofProdrugs ", by H.Bundgaard is (1991) p.113-191;

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

D) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77, 285 (1988); With

E) N.Kakeya etc., Chem Pharm Bull, 32, 692 (1984).

The suitable prodrug of pyridine or triazole derivative comprises acyloxy picoline  salt or triazole  salt, for example halogenide; For example such as following prodrug

(referring to: .42 such as T.Yamazaki ^NdInterscience Conference on AntimicrobialAgents and Chemotherapy, San Diego, 2002; Abstract F820).

The suitable prodrug of hydroxyl is the acyl ester of the acetal-carbonates shown in formula RCOOC (R, the R ') OCO-, and wherein R is that (1-4C) alkyl and R ' are (1-4C) alkyl or H.Other suitable prodrug is carbonates and amino formate RCOO-and RNHCOO-.

But for example contain the ester of hydrolysis in the body of The compounds of this invention of carboxyl or hydroxyl or its pharmacologically acceptable salt and be the pharmaceutically useful ester that in human body or animal body hydrolysis generates parent alcohol.

The suitable pharmaceutically acceptable ester of carboxyl comprises for example methoxymethyl ester of (1-6C) alkoxy methyl ester, (1-6C) alkanoyloxymethyl ester oxy acid methyl neopentyl ester for example, phthalidyl ester, (3-8C) cyclo alkoxy carbonyl oxygen base (1-6C) alkyl ester 1-cyclohexyl-carbonyl oxygen base ethyl ester for example; 1,3-dioxane penta-2-ketone group methyl ester is the 5-methyl isophthalic acid for example, 3-dioxane penta-2-ylmethyl ester; (1-6C) alkoxy-carbonyl oxy ethyl ester 1-methoxycarbonyl oxygen base ethyl ester for example, and can form at any carboxyl place of The compounds of this invention.

But contain the ester of hydrolysis in the body of The compounds of this invention of one or more hydroxyls or its pharmacologically acceptable salt and comprise inorganic ester for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and alpha-acyloxy alkyl oxide and provide the result's of one/a plurality of parent hydroxy allied compound as hydrolytic cleavage in the body of ester.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.But the formation group about the ester of hydrolysis in the body of hydroxyl comprises (1-10C) alkyloyl (for example (1-4C) alkyloyl); benzoyl; the benzoyl of phenylacetyl and replacement and phenylacetyl; (1-10C) alkoxy carbonyl (to form the alkyl carbonate class); two-(1-4C) alkyl-carbamoyls and N-(two-(1-4C) alkylamino ethyls)-N-(1-4C) alkyl-carbamoyl (to form amino formate); two-(1-4C) alkylamino ethanoyl; carboxyl (2-5C) alkyl-carbonyl and carboxyl ethanoyl.The example of the ring substituents on phenylacetyl and the benzoyl comprises chloromethyl or amino methyl, (1-4C) alkylamino methyl and two-((1-4C) alkyl) amino methyl, is connected 4-morpholinyl or the piperazinyl that base is connected with the 3-or the 4-position of benzoyl basic ring with beginning from theheterocyclic nitrogen atom via methylene radical.But the ester of hydrolysis comprises in other interested body, for example, and R ^AC (O) O (1-6C) alkyl-CO-(R wherein ^ABe alkyl or the optional substituted phenyl of for example optional substituted benzyloxy-(1-4C); Suitable substituting group on the phenyl in this type of ester for example comprises the alkyl of the alkyl of the alkyl of 4-(1-4C) piperazinyl-(1-4C), piperazinyl-(1-4C) and 4-morpholinyl-(1-4C).

But the ester of hydrolysis is and amino acids formed ester in other suitable body.For example, the ester of the hydroxyl of compound and amino acid whose carboxylic acid reaction formation." amino acid " of this paper is meant any acid that is replaced by amino in alpha-position or other position (no matter whether being natural or the amino acid that exists of non-natural) and derivative thereof, for example by replacing the derivative that (for example by the alkylation on the amino nitrogen) forms.The amino acid whose use representative that natural or non-natural exists special and aspect independently of the present invention.The suitable a-amino acid and the example of derivative thereof are Xie Ansuan, leucine, Isoleucine, N-methyl Isoleucine, the N-tertiary butyl-Isoleucine, Methionin, glycine, sarcosine, N, N-N-methylsarcosine, L-Ala, glutamine (gluamine), l-asparagine, proline(Pro) and phenylalanine.In one embodiment, preferred amino acids is naturally occurring a-amino acid and N-alkyl derivative thereof.

Special and aspect independently of the present invention has been represented in amino acid whose use with neutrality and/or basic side chain.

Formula (I) but in the suitable body of compound the ester of hydrolysis as described below.For example, 1, the 2-glycol can circularize the pyrophosphate shown in cyclic ester shown in the accepted way of doing sth (PD1) or the formula (PD2), and 1, the 3-glycol can circularize the cyclic ester shown in the accepted way of doing sth (PD3),

Wherein (PD1), (PD2) and (PD3) in HO-functional group be the useful as intermediates of the described prodrug of preparation by the ester of formula (I) compound of (1-4C) alkyl, phenyl or benzyl protection.

But the ester of hydrolysis comprises phosphoramidate in other body, and wherein any free hydroxyl group forms the compound of the present invention of phosphorylic ester shown in the formula (PD4) (npd is 1) or inferior phosphoryl (phosphiryl) ester (npd is 0) independently:

To obscure for fear of causing, phosphono is-P (O) is (OH) ₂(1-4C) alkoxyl group (hydroxyl)-phosphoryl be-O-P (O) (OH) ₂The alkoxy derivative of list-(1-4C); With two-(1-4C) alkoxyl groups-phosphoryl be-O-P (O) is (OH) ₂Two-(1-4C) alkoxy derivative.

The useful as intermediates for preparing this ester comprises the compound that contains one or more groups shown in the formula (PD4), and one or two in its Chinese style (PD1)-OH base is independently by (1-4C) alkyl (this compound self also is interesting), phenyl or phenyl-(1-4C) alkyl (described phenyl is optional to be independently selected from (1-4C) alkyl, nitro, halogen and (1-4C) the group replacement of alkoxyl group by 1 or 2) protection.

Therefore; contain group as (PD1), (PD2), (PD3) and prodrug (PD4) can be by containing suitable one or more hydroxyls compound of the present invention with reacted by the phosphorylating agent of due care (for example containing chloro or dialkyl amido leavings group); oxidation then (if necessary) and deprotection prepare.

Other suitable prodrug comprises phosphono oxygen ylmethyl ether and salt thereof, for example all as shown in the formula the prodrug of R-OH:

When compound of the present invention contained many free hydroxyls, those groups that are not converted into prodrug functional group can be protected (for example using the tertiary butyl-dimetylsilyl), deprotection subsequently.In addition, can use enzyme catalysis method selectively alcohol functional group to be carried out phosphorylation or dephosphorylation.

But the example of amino prodrug comprises acid amides or its pharmacologically acceptable salt of hydrolysis in the body.But the group of hydrolysis comprises N-methoxycarbonyl and N-ethanoyl in the suitable body.Described acid amides can by amino (or alkylamino) and activatory acyl derivative for example activatory ester or chloride of acid for example (1-6C) alkyloyl chlorine (for example tBuCOCl or ethanoyl chlorine) or its substituted derivatives reaction form.

Contain carboxyl formula (I) but in the body of compound the suitable examples of the acid amides of hydrolysis be for example N-C _1-6Alkylamide or N, N-two-C _1-6Alkylamide, as N-methyl nitrosourea, N-buserelin, N-propyl amides, N, N-dimethylformamide, N-ethyl-N-methyl nitrosourea or N, N-diethylamide.Contain amine or carboxyl formula (I) but but but in the body of compound other suitable examples of acid amides of hydrolysis be with as herein about the acid amides of hydrolysis in the body of the ester definition of hydrolysis in the body and described amino acid reaction formation.

But under the situation of the pharmacologically acceptable salt of ester that can form hydrolysis in the body or acid amides, it can be realized according to conventional methods.Therefore, for example, contain formula (PD1), (PD2), (PD3) and/or (PD4) compound of group can ionization (partially or completely ionization), thereby form salt with the counter ion of proper number.Therefore, for example, if but the ester prodrugs of the interior hydrolysis of the body of The compounds of this invention contains two (PD4) groups, then contain four HO-P-functional groups at whole intramolecularly, each functional group can form suitable salt (that is, whole molecule can form for example single sodium, disodium, trisodium or tetra-na salt).

In one aspect, but suitable prodrug of the present invention is the ester of hydrolysis in the body, such as (1-4C) alkyl ester; (1-4C) alkyl ester that is replaced by (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, carboxyl, (1-4C) alkyl ester, amino, (1-4C) alkylamino, two (1-4C) alkylamino, three (1-4C) alkylamino (containing quaternized nitrogen-atoms thus), aminocarboxyl, carbamate, acid amides or heterocyclic radical (for example, passes through R ⁴Or R ⁵In hydroxyl and methoxyacetic acid, methoxypropionic acid, adipic acid monomethyl ester, the 4-dimethylaminobutyricacid acid, 2-methylamino butyric acid, the 5-aminovaleric acid, Beta-alanine, N, N-diethyl L-Ala, Xie Ansuan, leucine, Isoleucine, N-methyl Isoleucine, the N-tertiary butyl-Isoleucine, Methionin, glycine, N, the N-N-methylsarcosine, L-Ala, sarkosine, glutamine, l-asparagine, proline(Pro), phenylalanine, nicotinic acid, nicotinic acid-N-oxide compound, pyrimidine-carboxylic acid (for example pyrimidine-5-carboxylic acid), pyrazine-carboxylic acid (for example pyrazine-2-carboxylic acid), or the ester of piperidines-4-carboxylic acid reaction formation); (3-6C) cycloalkyl ester (optional) by (1-4C) alkoxy carbonyl, alkoxyl group or carboxyl substituted; The amino described carbonic ether that replaces of carbonic ether (for example carbonic acid (1-4C) alkyl ester and quilt (1-4C) alkoxyl group or two (1-4C) alkyl)); Sulfuric ester, phosphate ester and phosphoric acid ester; And carbamate (referring to for example embodiment 10); And pharmacologically acceptable salt.

Other suitable prodrug is to pass through R ⁴Or R ⁵In hydroxyl and carbonic ether, the particularly alkyl carbonate that replaces with the alkoxy prodrug that forms of carbonic acid methoxy-propyl ester reaction for example.

Other suitable prodrug is to pass through R ⁴Or R ⁵In hydroxyl and methoxyacetic acid, methoxypropionic acid, adipic acid monomethyl ester, the 4-dimethylaminobutyricacid acid, 2-methylamino butyric acid, the 5-aminovaleric acid, Beta-alanine, N, N-diethyl L-Ala, Xie Ansuan, leucine, Isoleucine, N-methyl Isoleucine, the N-tertiary butyl-Isoleucine, Methionin, glycine, N, the N-N-methylsarcosine, L-Ala, sarkosine, glutamine, l-asparagine, proline(Pro), phenylalanine, nicotinic acid, nicotinic acid-N-oxide compound, the pyrimidine-5-carboxylic acid, pyrazine-2-carboxylic acid or piperidines-4-carboxylic acid, the ester that 2-carboxyl-hexanaphthene-1-carboxylic acid reaction forms; And pharmacologically acceptable salt.

But particular compound of the present invention be with amino acids formed body in the ester and the pharmacologically acceptable salt thereof of hydrolysis.

Other particular compound of the present invention is and 4-dimethylaminobutyricacid acid, 2-methylamino butyric acid, 5-aminovaleric acid, Beta-alanine, N, N-diethyl L-Ala, Xie Ansuan, leucine, Isoleucine, N-methyl Isoleucine, the N-tertiary butyl-Isoleucine, Methionin, glycine, N, but the ester of hydrolysis in the body of N-N-methylsarcosine, L-Ala, sarkosine, glutamine, l-asparagine, proline(Pro), phenylalanine formation; And pharmacologically acceptable salt.

Other particular compound of the present invention is and Xie Ansuan, leucine, Isoleucine, N-methyl Isoleucine, the N-tertiary butyl-Isoleucine, Methionin, glycine, N, but the ester of hydrolysis in the body that N-N-methylsarcosine, L-Ala, sarkosine, glutamine, l-asparagine, proline(Pro) and phenylalanine form; And pharmacologically acceptable salt.

Compound of the present invention has chiral centre in the C-5 position of  oxazolidone ring.The diastereomer of pharmaceutical active is represented by formula (Ia):

It is (5R) configuration.

The present invention includes pure diastereomer or the mixture of diastereomer, for example racemic mixture.If use the mixture of enantiomorph, then need the same effect of bigger amount (ratio according to isomer is decided) to realize being realized with the pharmaceutical active enantiomorph of identical weight.

In addition, compounds more of the present invention can have other chiral centre.Be appreciated that the present invention includes all these has optical isomer and the diastereomer and the racemic mixture of anti-microbial activity.Known in this fieldly how to prepare optical activity form (for example synthetic by recrystallization, chirality, enzyme catalysis fractionation, bio-transformation or chromatographic separation technology split racemic form) and knownly how to determine anti-microbial activity as mentioned below.

The present invention relates to have all tautomeric forms of the The compounds of this invention of anti-microbial activity.

Be further appreciated that some compound of the present invention can solvation and the form of form such as for example hydrate of non-solventization exist.Be appreciated that the form that all these have the solvation of anti-microbial activity that the present invention includes.

Be further appreciated that some compound of the present invention can show polymorphic, and the present invention includes the form that all these have anti-microbial activity.

As previously mentioned, the inventor has found a large amount of compounds, they have the excellent activity of antagonism wide spectrum Gram-positive pathogenic agent (comprise known the most frequently used microbiotic is produced chemical sproof organism), and have the difficult gram-negative pathogens of supporting of antagonism such as the activity of hemophilus influenzae, Catarrhal catarrhalis, mycoplasma and chlamydozoan bacterial strain.Following compound has preferred pharmacy and/or physics and/or pharmacokinetic property.

Although the inventor does not wish to be bound by any theory,, it is believed that on pyridine ring introducing flexible substituting group has favorable influence to the solubleness of compound.For example, in the pH7.4 phosphate buffered saline buffer, the equilibrium solubility of reference example 4 is 35.1 μ M, the equilibrium solubility of reference example 5＜7.1 μ M.In comparative example 1, its equilibrium solubility is 1453 μ M (for hydrochloride).For example solubleness can be by any appropriate means measurement known in the art to be appreciated that each parameter.

In one embodiment of the invention, the compound of formula (I) is provided, in alternative embodiment, the pharmacologically acceptable salt of formula (I) compound is provided, in other alternative embodiment, provide formula (I) but the ester of hydrolysis in the body of compound, and, in other alternative embodiment, provide formula (I) but the pharmacologically acceptable salt of the ester of hydrolysis in the body of compound.In others, provide formula (I) but the acid amides of hydrolysis in the body of compound.

In one aspect, R ¹Be selected from hydrogen, halogen, cyano group, methyl, cyano methyl, methyl fluoride, difluoromethyl, trifluoromethyl, ethynyl and proyl.

On the other hand, R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride.

On the other hand, R ¹Be hydrogen.

In one aspect, R ²And R ³Be hydrogen or fluorine independently.

On the other hand, R ²And R ³All be hydrogen.

On the other hand, R ²And R ³One of be that hydrogen and another are fluorine.

In one aspect, R ⁴Be-C (O) R ⁵

On the other hand, R ⁴Be-C (H)=N-OR ⁸In an embodiment aspect this, R ⁸Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace).In another embodiment aspect this, R ⁸Be that (3-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace).In another embodiment aspect this, R ⁸Be that (1-4C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace).

On the other hand, R ⁴Be-C (R ⁵)=N-OH.The embodiment of this aspect be included in provide in any aspect of this paper and the embodiment about R ⁵Any one group of example.

On the other hand, R ⁴Be-C (R ⁵)=N-OR ⁸The embodiment of this aspect be included in provide in any aspect of this paper and the embodiment about R ⁸Any one group of example.

In one aspect, R ⁵Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group, HET-1 and NR by 1 or 2 ⁶R ⁷Substituting group replace).

On the other hand, R ⁵Be that (3-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group, HET-1 and NR by 1 or 2 ⁶R ⁷Substituting group replace).

On the other hand, R ⁵Be that (1-4C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group, HET-1 and NR by 1 or 2 ⁶R ⁷Substituting group replace).

Aspect this, R ⁵It preferably not hydroxymethyl.

As R ⁵In the suitable examples of substituent HET-1 on (1-6C) alkyl be morpholine, piperazine, N methyl piperazine, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines, tetramethyleneimine and tetrahydropyridine.As R ⁵In other suitable examples of substituent HET-1 on (1-6C) alkyl be azetidine.In one embodiment, as R ⁵In the suitable examples of substituent HET-1 on (1-6C) alkyl be piperidines and azetidine.

On the other hand, R ⁵Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace).

On the other hand, R ⁵Be that (3-6C) cycloalkyl (is chosen wantonly and is selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 ⁶R ⁷Substituting group replace);

On the other hand, R ⁵Be HET-1.R ⁵Suitable examples as HET-1 is morpholine, piperazine, N methyl piperazine, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines, tetramethyleneimine and tetrahydropyridine.R ⁵Other suitable examples as HET-1 is an azetidine.In one embodiment, R ⁵Be selected from piperidines and azetidine as HET-1.

On the other hand, R ⁵By NR ⁶R ⁷(1-6C) alkyl that replaces.On the other hand, R ⁵(and wherein sulphur is oxidized to S (O) or S (O) by morpholine, piperazine, N methyl piperazine, thiomorpholine ₂The derivative of group), (1-6C) alkyl of piperidines, tetramethyleneimine, tetrahydropyridine or imidazoles (optional) replacement by 1 or 2 methyl substituted.On the other hand, R ⁵Replaced (1-6C) alkyl by morpholine, imidazoles, Methylimidazole or methylimidazole.

On the other hand, R ⁵By NR ⁶R ⁷(1-6C) alkyl that replaces, wherein NR ⁶R ⁷Be selected from morpholine, piperazine, N methyl piperazine, imidazoles, Methylimidazole, methylimidazole, propyl imidazole, ethyl imidazol(e) and methoxymethyl imidazoles.

On the other hand, R ⁵By morpholine, imidazoles, glyoxal ethyline, 4-methylimidazole, 2,5-methylimidazole, 2,4-methylimidazole, 2-ethyl imidazol(e), 2-just-(1-6C) alkyl that propyl imidazole, 2 isopropyl imidazole or 2-methoxymethyl imidazoles replace.

In one aspect, R ⁶And R ⁷Be independently selected from hydrogen, methyl, cyclopropyl (optional), carboxyl methyl and (2-4C) alkyl (optional replaced) by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl by methyl substituted.

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, methyl, carboxyl methyl and (2-4C) alkyl (optional replaced) by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl.

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen and (1-4C) alkyl.

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, methyl, carboxyl methyl and (2-4C) alkyl (optional replaced) by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl and hydroxyl.

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, methyl and (2-4C) alkyl (optional replaced) by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos and hydroxyl.

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, methyl and (2-4C) alkyl (optional replaced) by 1 or 2 hydroxyl.

On the other hand, R ⁶And R ⁷The nitrogen that is connected with them forms optional the saturated of 1 other heteroatoms (except being connected the N atom) that is independently selected from O, N and S or the heterocyclic ring that part is undersaturated 4,5 or 6 yuan of containing altogether, wherein-and CH ₂-group can choose wantonly by-C (O)-replacement and wherein the sulphur atom in the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and to be replaced by 1 or 2 (1-4C) alkyl that (condition is R ⁵And R ⁶The nitrogen that is connected is not thus by quaternized).

Comprise R ⁶And R ⁷And the suitable examples of this ring of the nitrogen that they connected be azetidine, morpholine, piperazine, N methyl piperazine, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines, tetramethyleneimine and tetrahydropyridine.

On the other hand, R ⁶And R ⁷The nitrogen that is connected with them forms imidazoles, Methylimidazole or methylimidazole ring, particularly Methylimidazole or methylimidazole, more especially methylimidazole altogether.In one embodiment, R ⁶And R ⁷The nitrogen that is connected with them forms 2 altogether, the 4-methylimidazole.In another embodiment, R ⁶And R ⁷The nitrogen that is connected with them forms 2 altogether, the 5-methylimidazole.

Comprise R ⁶And R ⁷And other suitable examples of this ring of the nitrogen that they connected is that (and wherein sulphur is oxidized to S (O) or S (O) for morpholine, piperazine, N methyl piperazine and thiomorpholine ₂The derivative of group).

Comprise R ⁶And R ⁷And other suitable examples of this ring of the nitrogen that they connected is that (and wherein sulphur is oxidized to S (O) or S (O) for morpholine and thiomorpholine ₂The derivative of group).

Specific example is a morpholine.Other specific example is an imidazoles.Other specific example is a Methylimidazole.Also has other specific example methylimidazole.

In one aspect, R ⁸Be that (1-4C) alkyl (is chosen wantonly and is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace).

Of the present invention preferred aspect, the compound of formula (I) is the compound of formula (Ia).

In another aspect of this invention, provide compound or its pharmaceutically useful salt or the prodrug of aforesaid formula (Ia), wherein:

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently; With

R ⁴Be-C (O) R ⁵

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵With

R ⁵Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace).

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵

R ⁵Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group and NR by 1 or 2 ⁶R ⁷Substituting group replace);

R ⁶And R ⁷The nitrogen that is connected with them forms imidazoles, Methylimidazole or methylimidazole ring altogether.

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵

R ⁵By NR ⁶R ⁷(1-6C) alkyl that replaces;

R ⁶And R ⁷The nitrogen that is connected with them forms imidazoles, Methylimidazole, methylimidazole, ethyl imidazol(e), propyl imidazole or methoxymethyl imidazole ring altogether.

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵

R ⁵By NR ⁶R ⁷(1-6C) alkyl that replaces;

R ⁶And R ⁷The nitrogen that is connected with them forms imidazoles, Methylimidazole, methylimidazole, ethyl imidazol(e) or propyl imidazole ring altogether.

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵

R ⁵By NR ⁶R ⁷(1-6C) alkyl that replaces;

R ⁶And R ⁷The nitrogen that is connected with them forms imidazoles, Methylimidazole, 2 altogether, 4-methylimidazole, 2,5-methylimidazole, ethyl imidazol(e) or propyl imidazole ring.

R ¹Be hydrogen;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵

R ⁵By NR ⁶R ⁷(1-6C) alkyl that replaces;

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be-C (O) R ⁵With

R ⁵Be HET-1.

R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride;

R ²And R ³Be hydrogen or fluorine independently; With

R ⁴Be selected from-C (H)=N-OR ⁸,-C (R ⁵)=N-OH and-C (R ⁵)=N-OR ⁸

Particular compound of the present invention comprises the compound that each described in the embodiment is independent, and each embodiment provides one of the present invention independently aspect.On the other hand, the invention provides any two or more embodiment.

The method part:

In others of the present invention, but provide the method for preparing the ester of hydrolysis in compound or pharmaceutically acceptable salt thereof of the present invention or the body.Be appreciated that in some following process some substituting group may need protection to prevent that them from undesirable reaction taking place.When skilled chemist needs this protection and how that this protecting group is additional if can understanding, and how to remove subsequently.

About the example of protecting group referring to one of many general textbooks about this theme, for example, ' Protective Groups in Organic Synthesis ' by Theodora Green (publisher: John Wiley ﹠amp; Sons).Can by described in the document or the known any method easily that is fit to remove protecting group in question of skilled chemist remove protecting group, can select these methods so that the minimum interference of intramolecularly group is elsewhere realized removing of described protecting group.

Therefore, if reactant comprises that for example group may wish to protect these groups such as amino, carboxyl or hydroxyl in some reactions that this paper mentions.

The suitable protecting group of amino or alkylamino is an acyl group for example, as alkyloyl such as ethanoyl, and alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl or tertbutyloxycarbonyl, aryl methoxy carbonyl such as benzyloxycarbonyl, or aroyl benzoyl for example.The deprotection condition of above-mentioned protecting group is necessarily according to the difference of selected protecting group and difference.Therefore, for example, can remove acyl group such as alkyloyl or alkoxy carbonyl or aroyl by using suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide hydrolysis.Perhaps; acyl group such as tertbutyloxycarbonyl can be removed by for example using suitable sour example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid to handle, and aryl methoxy carbonyl such as benzyloxycarbonyl can be by for example carrying on the palladium hydrogenation or processing is removed as three (trifluoroacetic acid) boron by using Lewis acid at catalyzer such as charcoal.The alternative suitable protecting group of primary amine groups is a phthaloyl for example, and it can be by using for example dimethylaminopropyl amine or use hydrazine to handle to be removed of alkylamine.

The suitable protecting group of hydroxyl is acyl group alkyloyl such as ethanoyl, an aroyl such as benzoyl or arylmethyl benzyl for example for example for example.The deprotection condition of above-mentioned protecting group is necessarily according to the difference of selected protecting group and difference.Therefore, for example, can remove acyl group such as alkyloyl or aroyl by using suitable alkali such as alkali metal hydroxide such as lithium hydroxide or sodium hydroxide hydrolysis.Perhaps, for example, can remove arylmethyl such as benzyl by the hydrogenation on the catalyzer that carries palladium at for example charcoal.

The suitable protecting group of carboxyl is an esterified group for example; for example; by as use alkali such as removable methyl of sodium hydroxide hydrolysis or ethyl; perhaps; for example, by handling the removable tertiary butyl as organic acid such as trifluoroacetic acid, perhaps as use acid; for example, by as the removable benzyl of hydrogenation on the catalyzer that carries palladium as charcoal.Also can use resin as protecting group.

Use the known ordinary method of chemical field can remove protecting group in any stage easily of synthetic.

But the ester of hydrolysis can be by any known method preparation for preparing the chemofacies related compounds that is applicable in compound or pharmaceutically acceptable salt thereof of the present invention or the body.But described method is provided and sets forth in following exemplary embodiment as further feature of the present invention when being used to prepare the ester of hydrolysis in compound or pharmaceutically acceptable salt thereof of the present invention or the body.Necessary starting raw material can obtain (referring to for example Advanced Organic Chemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden derOrganischen Chemie) by the organic chemistry standard method.The preparation of these starting raw materials is stated in non-limiting example subsequently.Perhaps, by can be in organic chemist's common sense as can be known the similar approach of the described method in the scope obtain necessary starting raw material.The information of starting raw material that relevant preparation is necessary or allied compound (its may through revising to form necessary starting raw material) can find in some patent application is open, and the content of the disclosed method part of described patent application is incorporated herein by reference: for example WO 94/13649; WO 98/54161; WO 99/64416; WO99/64417; WO 00/21960; WO 01/40222; WO 01/94342; WO 03/022824, JP 2003335762 and WO 03/006440.

Especially, the inventor has quoted PCT patent application WO 99/64417 and the WO 00/21960 of oneself, has wherein provided the detailed instruction about the facilitated method of preparation  oxazolidinone compounds.

Skilled organic chemist can use and be modified in the information that institute comprises and mentions among the embodiment of above-mentioned document and the embodiment that wherein encloses and this paper, to obtain necessary starting raw material and product.

Therefore, but the present invention also provides the ester of hydrolysis in compound of the present invention and pharmacologically acceptable salt thereof and the body can pass through method (a) prepares (wherein, except as otherwise noted, otherwise each variable is suc as formula defined in (I)) to (m); And, afterwards, if necessary:

I) remove any protecting group;

Ii) form prodrug (but for example the ester of hydrolysis in the body); And/or

Iii) form pharmacologically acceptable salt;

Wherein said method (a) is to (m) (wherein except as otherwise noted otherwise the definition of each variable is the same) as described below:

A) by using the substituting group in other compound of standard chemical process change the present invention or in other compound of the present invention, introducing substituting group (referring to for example Comprehensive OrganicFunctional Group Transformations (Pergamon), Katritzky, Meth-Cohn﹠amp; Rees); For example:

Hydroxyl can be converted into the fluoro group; Be converted into acyloxy such as acetoxyl group; Amino; By the heterocyclic radical (choose wantonly on the different carbon atom of the carbon atom adjacent and be substituted) that nitrogen connects, for example optional substituted imidazoles-1-base with the N annular atoms that connects; (for example by acidylate or Mitsunobu reaction) can directly take place or be undertaken by the pilot process of one or more derivatives (for example methanesulfonates or trinitride) in this conversion of hydroxyl; Acyloxy can be converted into hydroxyl or be converted into the group that can derive from hydroxyl (directly carry out or through the intermediateness of perhydroxyl radical); The alkylogen group can be converted into hydroxyl; Amino; The sulfane base; Heterocyclic radical by the nitrogen connection; Hydroxyl can be oxidized to ketone group;

B) (wherein X is the leavings group that can be used in palladium [0] coupled reaction to a part by making formula (II) compound, for example chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) with the partial reaction of Compound I Ia, described formula IIa also has leavings group X, makes to replace phenyl X and pyridyl-X key with pyridyl-phenyl key; These methods are known at present, for example referring to S.P.Stanforth, and CatalyticCross-Coupling Reactions in Biaryl Synthesis, Tetrahedron, 54,1998,263-303; J.K.Stille, Angew Chem.Int.Ed.Eng., 1986,25,509-524; N.Miyaura and A Suzuki, Chem.Rev., 1995,95,2457-2483; D.Baranano, G.Mann and J.F.Hartwig, Current Org.Chem., 1997,1,287-305; S.P.Stanforth, Tetrahedron, 54 1998,263-303; P.R.Parry, C.Wang, A.S.Batsanov, M.R.Bryce; And B.Tarbit, J.Org.Chem., 2002,67,7541-7543;

Leavings group X in two molecules can be identical or different at (II) with (IIa);

For example:

C) by making pyridyl-phenylcarbamate derivative (III) and the reacting ethylene oxide that is suitably replaced form  oxazolidone ring;

About this method, wherein carbamate replaced by isocyanic ester or amine or/and wherein oxyethane by equivalent agent X-CH ₂CH (O-is optional protected) CH ₂Triazole R ₁(wherein X is a displaceable group) displaced method variant also is well known in the art, for example,

(d) for R ⁴For-COR ⁵, by making the compound of formula (IV):

Wherein X is replaceable substituting group (as chlorine, bromine, iodine, a trifluoromethyl sulfonyloxy), and Y be halogen or

With acylating reagent such as acyl chlorides or the reaction of Weinreb acid amides, for example:

E) for R ⁴For-COR ⁵, from the α halogenated derivative, by obtaining formula (IIa) compound with the nucleophilic reagent reaction, the compound with formula (II) reacts then, for example:

Thereby described nucleophilic reagent can protectedly be implemented in α halogenated ketone reaction in required regiospecificity, carry out deprotection steps subsequently then, for example:

F) for R ⁴For-COR ⁵, by the oxidation of alcohol derivate, for example:

G) for R ⁴Be oxime, by aldehydes or ketones and azanol or the reaction of O-alkylation hydroxylamine derivative, for example:

H) for R ⁴For-COR ⁵, by pyridyl-2-cyano derivative (V) and Grignard reagent (as R ⁵MgBr) or similarly metal alkyl reagent react is with posthydrolysis;

I) for R ⁴For-COR ⁵, be that carboxylates derivatives and Y are the alkylations of pyridyl-2-carboxylates derivatives of the formula (IV) of halogen by X wherein, then with the compound reaction of formula (II), for example:

J) by from wherein having formed R ⁴The suitably functionalized intermediate of the quilt of-pyridyl-benzyl ring system forms triazole ring, for example, and shown in following diagram:

K) by carrying out cycloaddition by means of trinitride and acetylene, for example by using Cu (I) catalyzer to make the reaction at room temperature in aqueous alcoholic solution for example of azido methyl  oxazolidone and terminal alkynes obtain 1 of 4-position replacement, 2,3-triazole (V.V.Rostovtsev, L.G.Green, V.V.Fokin and K.B.Sharpless, Angew.Chem.Int.Ed., 2002,41,2596-2599):

1) by making amino methyl  oxazolidone and 1,1-dihalo ketone alkylsulfonyl hydrazone reaction (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),

M) work as R ₁Be the 4-halogenic substituent, the compound of formula (I) also can by make azido methyl  oxazolidone and vinyl halides base SULPHURYL CHLORIDE under the temperature between 0 ℃-100 ℃ solvent-free or in inert diluent such as chloroform or dioxane prepared in reaction.

But the formation of the ester of hydrolysis or acid amides is in the common organic chemist's who uses standard technique the ken in the formation of the removing of any protecting group, pharmacologically acceptable salt and/or the body.In addition, about the details of these steps, but the prodrug of ester of hydrolysis in the preparation body for example provide, for example, in above-mentioned chapters and sections about these esters.

When the optics that needs The compounds of this invention is lived the t form, can use optical activity starting raw material (for example the asymmetric induction by the appropriate reaction step forms) to obtain described optical activity form according to one of above process, perhaps obtain described optical activity form by the racemic form that uses standard program to split compound or intermediate, perhaps the chromatographic separation by diastereomer (when generating diastereomer) obtains described optical activity form.Enzyme technology also can be used for preparing optically active compound and/or intermediate.

Similarly, when needing the pure regional isomer of The compounds of this invention, can use pure regional isomer to obtain described pure regional isomer by one of said process, perhaps obtain described pure regional isomer by the mixture that uses standard program to split regional isomer or intermediate as starting raw material.

Wherein X is that the compound of the formula (II) of iodine, tin or boron derivative can prepare according to method described in the WO 03/022824.

Wherein the compound (formula Ifc) of the formula of X=Br (II) can be from compound (formula IIb) preparation of the formula of X=H (II) wherein, uses from bromate, bromide and sour autochthonous bromine the solution of the compound of formula (IIb) is carried out direct bromination (R wherein ²And R ³Be H or F independently, and Rp be selected from hydrogen, halogen, cyano group, methyl, cyano methyl, methyl fluoride, difluoromethyl, trifluoromethyl and-Si[(1-4C) alkyl] ₃).

Be appreciated that in reaction medium, for example, generate bromine by the following reaction between bromate, bromide and acid,

BrO ₃-+6H ⁺+5Br-?→3Br ₂+3H ₂O

Be to avoid and degrade the in time route that makes things convenient for of relevant problem of bromine solutions.

Easily, acid and bromide can be provided together by hydrobromic use.Suitably, add the bromide of aqueous solution form, for example hydrobromic aqueous solution is as the hydrobromic acid aqueous solution of 48%w/w.Can use any this solution that makes things convenient for concentration.

Easily, bromate is an alkali metal bromate, as potassium bromate or sodium bromate.Suitably, add the bromate of aqueous solution form.

The compound of formula (IIb) dissolves in any suitable organic solvent.Here, suitable be meant described organic solvent must with water can be miscible and can not with other reagent react.

Appropriate solvent is an acetate.The compound of formula (Hb) dissolves in the mixture of described suitable organic solvent such as acetate and water.

Easily, the aqueous solution that adds bromide adds bromate solution then in the solution of formula (IIb) compound.

Reaction in the presence of acid between bromate and the bromide is heat release.Easily, can the container that contain reaction mixture be cooled off, for example in ice bath, still for the yield and quality that generate product, keep specified temp dispensable.Easily, in ice bath, the container that contains reaction mixture is cooled off, thereby the scope of the temperature of reaction during adding bromate is 10-30 ℃.

With respect to the usage quantity of formula (IIb) compound, suitably use the bromate and the bromide of slight molar excess.

The interpolation speed of bromate solution is not critical.Easily, its to add speed be to remain on the temperature of reaction of adding during the bromate between 10-30 ℃.

For example, under about envrionment temperature, can finish up to reaction by stirred reaction mixture.Usually, finished in reaction needed 3-4 hour, comprise and adding the required time of bromate.

After reaction is finished, wish before separated product, to remove any excessive bromine of generation.Easily, this can be by adding the solution of pyrosulfite, and for example the aqueous solution of Sodium Pyrosulfite is finished.The pyrosulfite that adds capacity with any residual bromine reaction.

Can be by any separated product of method easily, for example, by filtering, perhaps by being dissolved in other organic solvent and suitably washing and evaporate from reaction mixture.If product, can dissolve it again (for example by heated solution to for example about 80-85 ℃) easily from reaction mixture cured and make it carry out crystallization in a controlled manner.

According to a further aspect in the invention, provide the method for the compound of above-mentioned compound formula (IIc) from formula (IIb), described method comprises the solution of handling formula (IIb) compound with alkali metal bromate and Hydrogen bromide.

According to a further aspect in the invention, provide the method for the compound of above-mentioned compound formula (IIc) from formula (IIb), described method comprises:

A) handle the solution of formula (IIb) compound in the mixture of water and suitable organic solvent with hydrobromic acid aqueous solution; With

B) aqueous solution of interpolation alkali metal bromate.

A) handle the solution of formula (IIb) compound in the mixture of water and suitable organic solvent with hydrobromic acid aqueous solution;

B) aqueous solution of interpolation alkali metal bromate;

C) solution and any excessive bromine reaction of interpolation Sodium Pyrosulfite.

B) aqueous solution of interpolation alkali metal bromate;

C) solution and any excessive bromine reaction of interpolation Sodium Pyrosulfite;

D) product of separate type (IIc) compound.

B) aqueous solution of interpolation alkali metal bromate;

D) mixture that derives from step c) by heating has dissolved the product that then the solution cooling is come separate type (IIc) compound up to the compound crystal of formula (IIc) up to any solid.

The additional features according to the present invention, but the ester that is used for hydrolysis in the compound or pharmaceutically acceptable salt thereof of the present invention of the method by the therapy for treating human or animal body or body is provided.

The method of antibacterial effect is provided among warm-blooded animal that provides in this treatment of needs such as the people additional features according to the present invention, but comprises the ester of described animal to hydrolysis in the compound or pharmaceutically acceptable salt thereof of the present invention of using significant quantity or the body.

But the present invention also provides the ester as hydrolysis in the compound or pharmaceutically acceptable salt thereof of the present invention of medicine or the body; And but the ester of hydrolysis in compound or pharmaceutically acceptable salt thereof of the present invention or the body is used for producing application in the medicine of antibacterial effect warm-blooded animal such as people in production.

But in order to use the ester or the pharmacologically acceptable salt of hydrolysis in compound of the present invention, its body, but the pharmacologically acceptable salt that comprises the ester of hydrolysis in the body, (pharmaceutical composition that relates to compound of the present invention below this section) being used for the treatment of property (comprising preventative) treatment comprises people's Mammals, particularly treatment is infected, and the pharmacy practice according to standard is mixed with pharmaceutical composition with it usually.

Therefore, on the other hand, but the invention provides the pharmaceutical composition of the ester that comprises hydrolysis in the compound of the present invention, its body or the pharmacologically acceptable salt pharmacologically acceptable salt of the ester of hydrolysis in the body (but comprise) and acceptable diluents or carrier.

Composition of the present invention can be to be suitable for per os to give the form of usefulness (as being tablet, lozenge, hard capsule or soft capsule, water-based or oil-based suspension, emulsion, dispersible powder or granula, syrup or elixir), the form that is used for topical application is (as creme, paste, gelifying agent, or water-based or oily solution agent or suspension), be used for the administration of eye drops form, be used for inhalation (for example for finely divided pulvis or liquid aerosol), be used to be blown into administration (as finely divided pulvis) or be used for administered parenterally and (as be used for intravenously, subcutaneous, the hypogloeeis, the sterile aqueous of intramuscular dosed administration or oily solution agent or as the suppository of rectal dose administration).

Except that compound of the present invention, pharmaceutical composition of the present invention also can contain (promptly by common preparation) be selected from one or more following known drugs or can be selected from following one or more known drug co-administereds (side by side, sequentially or respectively), described known drug is selected from other useful clinically antiseptic-germicide (for example beta-lactam, macrolide, quinolone or aminoglycoside) and/or other anti-infective (for example anti-fungal triazole or amphotericin).These can comprise carbapenem for example meropenem or imipenum, to widen result of treatment.Usefulness be prepared or be given jointly to compound of the present invention also can jointly with increasing bactericidal properties/infiltrative protein (BPI) product or efflux pump inhibitor, to improve the antagonism Gram-negative bacteria and microorganism agent to be had the activity of chemical sproof bacterium.Compound of the present invention also can or be given usefulness jointly with the common preparation of vitamins, and described vitamins is a vitamin(e) B group for example, as Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid.Compound of the present invention also can be used with common preparation of cyclooxygenase (COX) inhibitor, particularly cox 2 inhibitor or common giving.

In one aspect of the invention, compound of the present invention is prepared the active antiseptic-germicide of resisting gram-positive bacteria jointly with having.

In another aspect of this invention, compound of the present invention is prepared jointly with the active antiseptic-germicide with antagonism Gram-negative bacteria.

In another aspect of this invention, compound of the present invention is given usefulness jointly with the active antiseptic-germicide that has resisting gram-positive bacteria.

In another aspect of this invention, compound of the present invention is given jointly with the active antiseptic-germicide with antagonism Gram-negative bacteria and is used.

Can use conventional drug excipient to obtain composition of the present invention by conventional process well known in the art.Therefore, being designed for per os can contain for example one or more tinting materials, sweeting agent, seasonings and/or sanitas for the composition of usefulness.The pharmaceutical composition that is designed for intravenous administration can advantageously contain (for example raising stability) suitable sterilant, antioxidant or reductive agent, or contains suitable sequestering agent.

The suitable pharmaceutically acceptable vehicle that is used for tablet comprises for example inert diluent such as lactose, yellow soda ash, calcium phosphate or lime carbonate; Granulating agent and disintegrating agent such as W-Gum or Lalgine; Tackiness agent such as starch; Lubricant such as Magnesium Stearate, stearic acid or talcum; Sanitas such as ethyl p-hydroxybenzoate or propyl ester; With antioxidant such as xitix.Tablet can have or not have dressing, thereby changes their slaking and the absorption of activeconstituents subsequently in gi tract, perhaps improves their stability and/or outward appearance, all uses the Drug coating and the dressing process of known routine in both cases.

Be used for per os and also can be the form of hard gelatin capsule for the composition of usefulness, wherein activeconstituents mixes with inert solid diluent such as lime carbonate, calcium phosphate or white bole; Perhaps be the form of soft gelatin capsule, wherein activeconstituents and water or oil are as peanut oil, Liquid Paraffin or mixed with olive oil.

Aqeous suspension contains activeconstituents and one or more suspension agents of fine powder form usually, as Xylo-Mucine, methylcellulose gum, HYDROXY PROPYL METHYLCELLULOSE, sodium alginate, polyvinyl-pyrrolidone, Tragacanth and Sudan Gum-arabic; The condensation product of dispersion agent or wetting agent such as Yelkin TTS or alkylene oxide and lipid acid (for example polyoxyethylene stearic acid ester), or the condensation product of oxyethane and long chain aliphatic alcohol is as 17 ethyleneoxy group hexadecanols, or oxyethane and derive from lipid acid and the condensation product of the partial ester of hexitol such as polyoxyethylene sorbitol monooleate, or the condensation product of oxyethane and long chain aliphatic alcohol 17 ethyleneoxy group hexadecanols for example, or oxyethane and derive from lipid acid and the condensation product of the partial ester of hexitol such as polyoxyethylene sorbitol monooleate, or oxyethane and derive from lipid acid and the condensation product of the partial ester of hexitan, for example polyethylene sorbitol anhydride monooleate.Aqeous suspension also can contain one or more sanitass (as ethyl p-hydroxybenzoate or propyl ester), antioxidant (xitix), tinting material, seasonings and/or sweet taste material (as sucrose, asccharin or aspartame).

Oil suspension can be by being suspended in activeconstituents in the vegetables oil (as peanut oil, sweet oil, sesame oil or Oleum Cocois) or being suspended in preparation in the mineral oil (as Liquid Paraffin).Oil suspension also can contain thickening material such as beeswax, paraffinum durum or hexadecanol.Can add sweet taste material (as above-mentioned sweet taste material) and seasonings so that agreeable to the taste oral preparations to be provided.These compositions can be preserved by adding antioxidant such as xitix.

Be suitable for containing activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass usually by adding dispersible powder and the granule that water prepares waterborne suspension.The example of suitable dispersion agent or wetting agent and suspension agent as mentioned above.Also can there be other vehicle such as sweeting agent, seasonings and tinting material.

Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetables oil such as sweet oil or peanut oil, or is mineral oil such as Liquid Paraffin, or the mixture of any of these material.Suitable emulsifying agent can be for example naturally occurring natural gum such as Sudan Gum-arabic Tragacanth, naturally occurring phosphatide as soybean phospholipid, Yelkin TTS, the ester that derives from lipid acid and hexitan or partial ester (for example sorbitol anhydride monooleate) and as described in the condensation product such as the polyoxyethylene sorbitol acid anhydride monooleate of partial ester and oxyethane.Emulsion also can contain sweeting agent, seasonings and sanitas.

Syrup and elixir can use the sweet taste material to prepare as using glycerine, propylene glycol, sorbyl alcohol, aspartame or sucrose, and can contain negative catalyst, sanitas, seasonings and/or tinting material.

Pharmaceutical composition also can be the water-based that aseptic injection uses or the form of oily suspensions, and suspension can use those one or more above-mentioned suitable dispersion agents or wetting agent and suspension agent to prepare according to known procedure.Aseptic injection is also at nontoxic non-enteron aisle acceptable diluent or aseptic injectable solution or the form of suspension in the solvent, as the solution in the 1,3 butylene glycol.Can use for example cyclodextrin of solubility enhancing agent.

The composition that is used for inhalation can be the conventional pressurised aerosol form of distributing activeconstituents with the aerosol form that contains finely divided solid or drop that is arranged to.Conventional aerosol propellant such as volatility hydrofluoric ether or hydrocarbon can be used, and the activeconstituents of aerosol device can be arranged easily with distribution and computation.

About the more detailed information of preparation, the reader can be referring to ComprehensiveMedicinal Chemistry the 5th volume the 25.2nd chapter (Corwin Hansch; Chairman ofEditorial Board), Pergamon Press 1990.

The amount that obtains the activeconstituents of single formulation with one or more excipient composition will be decided according to the main body of treatment and concrete route of administration.For example, be designed for and contain usually that for example 50mg is to the promoting agent of 5g for the preparation of usefulness to human oral, described promoting agent is mixed with vehicle suitable and that measure easily, and described vehicle can account for about 5 of total composition and arrive about 98 weight %.Dose unit contains the activeconstituents of 200mg to about 2g of having an appointment usually.About the more detailed information of route of administration and dosage, the reader can be referring to Comprehensive MedicinalChemistry the 5th volume the 25.3rd chapter (Corwin Hansch; Chairman of EditorialBoard), Pergamon Press 1990.

Suitable pharmaceutical composition of the present invention is form such as the tablet or the capsule that per os is given usefulness that be suitable for of unit dosage forms, and it contains the of the present invention compound of 1mg to 1g, preferably contains the compound of 100mg to 1g.Especially preferably contain tablet or the capsule of 50mg, particularly contain tablet or the capsule of 100mg to the compound of the present invention of 500mg to the compound of the present invention of 800mg.

On the other hand, pharmaceutical composition of the present invention is the form that is suitable for intravenously, subcutaneous or intramuscular injection, for example contains the injection of 0.1%w/v to 50%w/v (1mg/ml is to 500mg/ml) compound of the present invention.

Every patient for example can accept intravenously every day, subcutaneous or intramuscular dosage is 0.5mgkg ^-1To 20mgkg ^-1Compound of the present invention, composition every day is given with 1-4 time.In another scheme, it is 5mgkg that the day of The compounds of this invention is given with dosage ^-1To 20mgkg ^-1Intravenously, subcutaneous and intramuscular dosage can be injected (bolus injection) according to bolus and are given.Perhaps, intravenous dosages can give by the continuous infusion in certain period.Perhaps, every patient can accept to be about as much as oral dosage every day of non-enteron aisle dosage every day, and composition is given with 1-4 time every day.

With regard to pharmaceutical composition, process, method, application and the drug manufacture main points of above-mentioned other, optionally also being suitable for of The compounds of this invention with embodiment preferred.

Anti-microbial activity:

Pharmaceutically useful compound of the present invention is useful antiseptic-germicide, and it has the external activity spectrum of good antagonism standard gram-positive organism, and it can be used for screening the anti-microbial pathogen activity.Notably be that pharmaceutically acceptable compound of the present invention is to faecalis, streptococcus pneumoniae and methicillin resistance staphylococcus aureus strains, and coagulase negative staphylococcus and influenzae and catarrhalis bacterial strain demonstration activity.The antimicrobial spectrum of particular compound and effectiveness can be measured in the standard test system.

(antibiotic) performance of The compounds of this invention also can be carried out demonstration and evaluation in vivo in routine test, for example, by using standard technique warm-blooded mammals per os and/or intravenous dosages are carried out to drug compound.

Following result derives from standard in vitro tests system.Active is 10 to use inoculum size ⁴The minimum inhibitory concentration (minimum inhibitoryconcentration) that the agar that CFU/ is ordered-dilution technology is measured (MIC) is represented.Usually, compound has activity in the scope of 0.01-256 μ g/ml.

Using inoculum size is 10 ⁴The culture temperature of CFU/ point and 37 ℃ is carried out 24 hours standard test condition, tests staphylococcus on agar, expresses methicillin resistance.

On the agar that is supplemented with 5% defibrination horse blood, be 10 in inoculum size ⁴Under CFU/ point and the 37 ℃ of culture temperature, test suis and faecalis are 48 hours in 5% carbon dioxide atmosphere, need blood to be used for the growth of some test organism bodies.Difficult gram negative organism of supporting is tested in being supplemented with the Mueller-Hinton meat soup of ammonia protoferriheme and NAD, and 37 ℃ of grow aerobicallies 24 hours, and inoculum size was 5 * 10 ⁴The CFU/ hole.

For example, obtained the following result of the compound of embodiment 1.

Organism MIC (μ g/ml)

Streptococcus aureus: MSQS 0.25

MRQR 0.25

Streptococcus pneumoniae 0.13

Hemophilus influenzae 2

Catarrhal catarrhalis 0.5

Linezolid resistance streptococcus pneumoniae 0.5

MSQS=methicillin-sensitivity and quinolone susceptibility

MRQR=methicillin resistance and quinolone resistance

The inhibition of monoamine oxidase (MAO) is the known possible side effect (referring to for example WO 03/072575) of  oxazolidinone antibiotics class.Compound of the present invention is compared with the simple substituted pyridine compound of unsubstituted pyridine compound and other, has lower MAO-A inhibition level generally, and is as shown in the table.

The activity of the anti-MAO-A of The compounds of this invention is used as Biochem.Biophys.Res.Commun.1991, and 181,1084-1088 is described to be measured based on the standard in vitro tests with people's liver enzyme of yeast expression.When with above-mentioned test determination, the Ki value that compound of the present invention has usually＞5 μ M.The Ki value of embodiment 1＞5 μ M, the Ki value of reference example 2 are 15 μ M.

Be appreciated that described in the inventor's patent application WO 03/072575 compound with 4-alkyl triazole has lower MAO-A than similar unsubstituted triazole compounds usually to be suppressed.

Some intermediate hereinafter described and/or reference example place and are provided as other aspect of the present invention within the scope of the invention and can have useful activity.Concrete reference example is a reference example 1,2 and 3.

Except as otherwise noted, the present invention describes by following non-limiting example, wherein:

(i) evaporate by rotary evaporation in vacuo, and by carrying out last handling process after removing by filter residual solid;

(ii) operation is carried out at ambient temperature, that is to say, in 18-26 ℃ scope, carry out usually, and excluding air not, except as otherwise noted, perhaps, unless those skilled in the art will carry out under inert atmosphere;

(iii) use the column chromatography purifying compounds, except as otherwise noted, otherwise pass through in purification on normal-phase silica gel 60, the hurried process of 230-400 purpose, or pass through at reverse phase silica gel (C-18, RediSep, Isco, Inc.) the hurried process on, perhaps by (for example: Waters YMC-ODS AQ, C-18) HPLC on using Gilson 215 Platform at reverse phase silica gel;

The yield that (iv) provides only is used for the illustrative purpose, and not necessarily obtainable maximum yield;

(v) the structure of final product of the present invention confirms that by NMR and mass-spectrometric technique [except as otherwise noted, proton NMR spectrum is usually at DMSO-d usually ₆In measure, use 300,400 or the Bruker spectrometer of 500MHz; Chemical shift is to represent with respect to tetramethylsilane (as interior mark) or with respect to ppm downfield (δ scale) of solvent.The multiplicity at peak is expressed as follows: s, and unimodal; D, doublet; AB or dd, double doublet; Dt, two triplets; Dm, two multiplets; T, triplet; M, multiplet; Br, broad peak; Mass spectrum uses MicromassQuattro Micro mass spectrograph (ESP) and Agilent 1100 MSD instruments (APCI) to carry out; Opticity uses Perkin Elmer polariscope 341 to measure at 589nm down at 20 ℃];

(vi) each intermediate is purified to that to be used for the required standard of later step and enough at length to characterize with the structure of confirming a reservation be correct; Purity is measured by HPLC, LC-MS, TLC or NMR, and homogeny is measured by mass spectrum and/or nuclear magnetic resonance spectroscopy, depends on the circumstances;

(vii) wherein can use following abbreviation:

DMF is N, dinethylformamide; DMA is a N,N-dimethylacetamide; TLC is a tlc; HPLC is a high pressure lipuid chromatography (HPLC); NMP is a N-Methyl pyrrolidone; DMSO is a dimethyl sulfoxide (DMSO); CDCl ₃It is deuterochloroform; MS is a mass spectrum; ESP is an electrospray; EI is electron impact; CI is a chemi-ionization; APCI is the barometric point chemi-ionization; EtOAc is an ethyl acetate; MeOH is a methyl alcohol; Phosphoryl (Phosphoryl) is (HO) ₂-P (O)-O-; Inferior phosphoryl (Phosphiryl) is (HO) ₂-P-O-; THF is a tetrahydrofuran (THF); Ether is diethyl ether; THF is a tetrahydrofuran (THF); TFA is a trifluoroacetic acid;

(viii) temperature is with a ℃ expression.

Embodiment 1:(5R)-and 3-{3-fluoro-4-[6-(1H-imidazoles-1-base ethanoyl) pyridin-3-yl] benzene Base }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(1H-imidazoles-1-yl) ethyl ketone (intermediate 8) (195mg, 0.73mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] and  azoles alkane-2-ketone (intermediate 7,284mg, 0.73mmol) and yellow soda ash (233mg, 2.2mmol) be dissolved in/be suspended in DMF/ water (5mL, 10: 1) in, it is handled through the degassing, uses purging with nitrogen gas, add four (triphenylphosphines) close palladium (0) (85mg, 0.07mmol).Reaction mixture is at 75 ℃ of heating 3 hours, cool to room temperature, evaporating solvent.Resistates is by using the silica gel chromatography purifying of methylene chloride (10: 1) wash-out.The free alkali that so obtains is dissolved in Virahol/methylene dichloride (～20mL, 1: 1), and (1mL, 1M), most of methylene dichloride is removed in decompression to be added on HCl in the ether.Resistates is collected and drying by filtering, and obtains the product of 189mg (59%), is hydrochloride, colorless solid, mp＞230 ℃ (decomposition).

MS (ESP): C ₂₂H ₁₈FN ₇O ₃Be 448.15 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.97(m，1H)；4.31(m，1H)；4.86(d，2H)；5.20(m，1H)；6.12(s，2H)；7.45(dd，1H)；7.62(dd，1H)；7.70-7.82(m，5H)；8.11-8.20(m，2H)；8.29(m，1H)；9.05(d，1H)；14.62(brs，1H)。

The intermediate of embodiment 1 is prepared as follows:

Intermediate 1: acetate (5R)-3-(3-fluoro-phenyl)-2-oxo- azoles alkane-5-base methyl esters

Under nitrogen, pass through to stir with (5R)-3-(3-fluorophenyl)-5-hydroxymethyl  azoles alkane-2-ketone (40g, 0.189mol, referring to Upjohn WO 94-13649) be suspended in the anhydrous methylene chloride (400mL), add triethylamine (21g, 0.208mol) and 4-dimethylaminopyridine (0.6g, 4.9mmol), (20.3g 0.199mol) also continues to stir 18 hours in envrionment temperature to drip aceticanhydride subsequently in 30 minutes.Add saturated sodium bicarbonate aqueous solution (250mL), separate organic phase,, filter and evaporation, obtain required product (49.6g), be oily matter with the washing of 2% SODIUM PHOSPHATE, MONOBASIC, dry (sal epsom).

MS (ESP): C ₁₂H ₁₂FNO ₄Be 254 (MH ⁺)

NMR(300MHz)(CDCl ₃)δ：2.02(s，3H)；3.84(dd，1H)；4.16(t，1H)；4.25(dd，1H)；4.32(dd，1H)；4.95(m，1H)；6.95(td，1H)；7.32(d，1H)；7.43(t，1H)；7.51(d，1H)。

Intermediate 2: acetate (5R)-3-(3-fluoro-4-iodo-phenyl)-2-oxo- azoles alkane-5-base methyl esters

Under nitrogen with acetate (5R)-3-(3-fluoro-phenyl)-2-oxo- azoles alkane-5-base methyl esters (intermediate 1,15.2g 60mmol) are dissolved in the mixture of chloroform (100mL) and acetonitrile (100mL), interpolation trifluoroacetic acid silver (16.96g, 77mmol).(18.07g 71mmol) in the solution of vigorous stirring, and continues to stir 18 hours in envrionment temperature portioning interpolation iodine in 30 minutes, because reaction is not finished, (2.64g 12mmol), continues to stir 18 hours the trifluoroacetic acid silver of interpolation another part.After the filtration, with mixture be added to hypo solution (3%, 200mL) and in the methylene dichloride (200mL), separate organic phase, with Sulfothiorine (200mL), saturated sodium bicarbonate aqueous solution (200mL), salt solution (200mL) washing, dry (sal epsom) filters and evaporation.Raw product is suspended in the isohexane (100mL), and adds enough ether so that the stripping of brown impurity was also stirred 1 hour simultaneously.Filtration obtains required product (24.3g), is cream-colored solid.

MS (ESP): C ₁₂H ₁₁FINO ₄Be 380 (MH ⁺)

NMR(300MHz)(DMSO-d ₆)δ：2.03(s，3H)；3.82(dd，1H)；4.15(t，1H)；4.24(dd，1H)；4.30(dd，1H)；4.94(m，1H)；7.19(dd，1H)；7.55(dd，1H)；7.84(t，1H)。

Intermediate 3:(5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl  azoles alkane-2-ketone

In the mixture of methyl alcohol (800mL) and methylene dichloride (240mL), use salt of wormwood (16.4g at ambient temperature, 0.119mmol) processing acetate (5R)-3-(3-fluoro-4-iodophenyl)-2-oxo- azoles alkane-5-base methyl esters (intermediate 2,30g, 79mmol) continue 25 minutes, neutralize immediately by adding acetate (10mL) and water (500mL) then.Filtering precipitate washes with water and is dissolved in methylene dichloride (1.2L), and solution washs with saturated sodium bicarbonate, dry (sal epsom).Filter and evaporation, obtain required product (23g).

MS (ESP): C ₁₀H ₉FINO ₃Be 338 (MH ⁺)

NMR(300MHz)(DMSO-d ₆)δ：3.53(m，1H)；3.67(m，1H)；3.82(dd，1H)；4.07(t，1H)；4.70(m，1H)；5.20(t，1H)；7.21(dd，1H)；7.57(dd，1H)；7.81(t，1H)。

Intermediate 4: methylsulfonic acid [(5R)-and 3-(3-fluoro-4-iodophenyl)-2-oxo-1,3- azoles alkane-5-yl] Methyl esters

At 0 ℃, (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1, (intermediate 3,25.0g 74.2mmol) stir in methylene dichloride (250mL) 3- azoles alkane-2-ketone.(10.5g, 104mmol), (11.2g, 89.0mmol), reaction is stirred and is spent the night the room temperature of slowly rising again to add methylsulfonyl chloride subsequently to add triethylamine.Yellow solution dilutes with sodium bicarbonate, and compound uses methylene dichloride, and (3 * 250mL) extract.Organic layer filters and concentrates through super-dry (sal epsom), obtains required product, is light yellow solid (30.3g).

MS (ESP):C ₁₁H ₁₁FINO ₅S is 416 (MH ⁺)

¹H-NMR(300MHz)(DMSO-d ₆)：3.24(s，3H)；3.82(dd，1H)；4.17(t，1H)；4.43-4.52(m，2H)；4.99-5.03(m，1H)；7.21(dd，1H)；7.55(dd，1H)；7.83(t，1H)。

Intermediate 5:(5R)-and 5-(azido methyl)-3-(3-fluoro-4-iodophenyl)-1,3- azoles alkane-2-ketone

(intermediate 4,6.14g 14.7mmol) are dissolved in DMF (50mL) to methyl esters with methylsulfonic acid [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3- azoles alkane-5-yl].(1.92g 29.6mmol), is reflected at 75 ℃ of stirrings and spends the night to add sodiumazide.Yellow mixture is poured in the semi-saturation sodium bicarbonate, uses ethyl acetate extraction.Organic layer washes with water three times, and dry (sal epsom) filters and evaporation, obtains title compound, is yellow solid (4.72g).

MS (ESP):C ₁₀H ₈FIN ₄O ₂Be 363 (MH ⁺)

¹H-NMR(300MHz)(DMSO-d ₆)：3.72-3.82(m，3H)；4.14(t，1H)；4.89-4.94(m，1H)；7.22(dd，1H)；7.57(dd，1H)；7.83(t，1H)。

Intermediate 6:(5R)-and 3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-  azoles alkane-2-ketone

(5R)-and 5-(azido methyl)-3-(3-fluoro-4-iodophenyl)-1, (intermediate 5,30.3g 72.9mmol) 1, stir in the 4-dioxane 3- azoles alkane-2-ketone.Add dicyclo [2.2.1] heptan-2, (40.3g 437mmol), is reflected at 100 ℃ of heated overnight to the 5-diene.The brown mixture that obtains is through filtering, and required product obtains, and is light brown solid (14.8g).

MS (ESP):C ₁₂H ₁₀FIN ₄O ₂Be 389 (MH ⁺)

¹H-NMR(300Mz)(DMSO-d ₆)：3.90(dd，1H)；4.23(t，1H)；4.84(d，2H)；5.11-5.18(m，1H)，7.14(dd，1H)；7.49(dd，1H)；7.76(s，1H)；7.82(t，1H)；8.17(s，1H)。

Intermediate 7:(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentanes- The 2-yl) phenyl]-5-(1H-1.2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

(5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 6,2g, 5.15mmol), two (tetramethyl ethylene ketone base) two boron (bis (pinacolato) diboron), 2.62g (10.3mmol), potassium acetate, 2.5g (25.5mmol) and 1,1 '-[two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride title complex, 0.38g (0.52mmol) is suspended among the DMSO (15mL).Mixture obtains transparent dark solution 80 ℃ of heating 40 minutes, adds ethyl acetate (150mL) then, and mixture is by diatomite filtration, and (2 * 100mL) washings are with dried over sodium sulfate and evaporation with saturated brine.Dark resistates obtains product by chromatography purification (in hexane, 1-5% acetonitrile subsequently is in ethyl acetate for silica gel, 40-100% ethyl acetate), is the crystallization brown solid, 1.97g (98%).(annotate-wash-out goes out the very heavy impurity of color before the product band, needs to prolong wash-out to obtain product).

NMR(300Mz)(DMSO-d ₆)δ：1.28(s，12H)，3.91(dd，1H)；4.23(t，1H)；4.83(d，2H)；5.14(m，1H)；7.27(dd，1H)；7.37(dd，1H)；7.62(t，1H)；7.75(s，1H)；8.16(s，1H)。

Perhaps:

With (5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 6,5g, 12.9mmol), the tetramethyl ethylene ketone borine (2.9ml, 20mmol), triethylamine (5.4ml, (0.92g 1.3mmol) is dissolved in dioxane (70ml) 39mmol) to close palladium (II) with trans-dichloro two (triphenylphosphine).Mixture obtains dark solution 100 ℃ of heating 90 minutes, and it is dissolved in ethyl acetate through concentrating, and uses the salt water washing, with dried over sodium sulfate and evaporation.Resistates obtains product by column chromatography purifying (silica gel, the 0-5% methyl alcohol in methylene dichloride contains 1% triethylamine), is light brown solid, 3.1g.

Intermediate 8:1-(5-bromopyridine-2-yl)-2-(1H-imidazoles-1-yl) ethyl ketone

(intermediate 9,440mg 1.22mmol) are suspended in anhydrous THF (5mL) and be cooled to 0 ℃ to 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate.Add imidazoles (330mg, 4.85mmol), with its vigorous stirring 1 hour.Reaction mixture dilutes with methylene dichloride, washes and use dried over sodium sulfate with water.Use the silica gel chromatography of methylene chloride (15: 1) wash-out, obtain the product (61%) of 197mg, be pale solid.

¹H-NMR(DMSO-d ₆)δ：5.77(s，2H)；6.91(brs，1H)；7.13(brs，1H)；7.59(s，1H)；7.93(dd，1H)；8.34(dd，1H)；8.96(dd，1H)。

Intermediate 9:2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone

(5.65g 28.2mmol) is dissolved in methyl alcohol/acetate (50mL+70mL) to 1-(5-bromopyridine-2-yl) ethyl ketone (intermediate 10, WO 98/46605), is cooled to 0 ℃, adds the acetate (8mL) that contains 30%HBr.Drip that brominated (1.45mL, acetate 28.3mmol) (10mL) make the reaction mixture room temperature of rising again, be heated to 70 ℃ then and continue 1 hour, it is cooled to～50 ℃, adds the acetate (5mL) and the methyl alcohol (15mL) of brominated (0.4mL) again, be heated 70 ℃ and continue other 30 minutes.Reaction mixture is evaporated to dried, resistates obtains the hydrobromate of the rough product of 3.45g (34%) from the Virahol crystallization, is faint yellow solid.

MS (ESP): C ₇H ₅Br ₂NO is 277.95/279.95/281.94 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：4.96(s，2H)；7.93(m，1H)；8.29(m，1H)；8.87(m，1H)；9.19(brs，1H)。

Intermediate 10:1-(5-bromopyridine-2-yl) ethyl ketone

Referring to WO 98/46605

With 5-bromo-2-cyanopyridine (Markevitch, David Y.; Rapta, Miroslav; Hecker, Scott J.; Renau, Thomas E.; Synth.Commun.; 33; 19; 2003; 3285-3290) (8g 43.7mmol) is dissolved in anhydrous THF (200mL) and be cooled to-20 ℃.Drip methyl-magnesium-bromide (43.7mL, 3M) and maintain the temperature between-20 ℃ and-10 ℃ and kept 3 hours.Reaction mixture is cooled to-40 ℃, drips the water (15mL) that contains dense HCl (4.5mL).It was stirred 10 minutes at-35 ℃, under agitation be poured into then and contain potassium phosphate buffer (300mL, 1M is in beaker pH7).Add ethyl acetate (300mL), the organic phase dried over sodium sulfate.When concentrating under reduced pressure at room temperature during to～50mL, product crystallization, 2.4g, mp112 ℃.Mother liquor further concentrates and separates by silica gel chromatography, uses dichloromethane/ethyl acetate (100: 1), obtains other 3.25g product (merging yield is 65%).

¹H-NMR(DMSO-d ₆)δ：2.60(s，3H)；7.88(dd，1H)；8.25(dd，1H)；8.86(d，1H)。

Embodiment 2:(5R)-and 3-{3-fluoro-4-[6-(4-morpholine-4-base butyryl radicals) pyridin-3-yl] phenyl }-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

Tfa salt (the intermediate 11) (190mg of 1-(5-bromopyridine-2-yl)-4-morpholine-4-base butane-1-ketone, 0.44mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7) (173mg, 0.44mmol), yellow soda ash (141mg, 1.33mmol) and four (triphenylphosphines) close palladium (0), and (51mg 0.044mmol) as reaction as described in the embodiment 1, obtains the hydrochloride (54%) of the product of 119mg, be colorless solid, mp＞240 ℃ (decomposition).

MS (ESP): C ₂₅H ₂₇FN ₆O ₄Be 495.24 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.00-2.12(m，2H)；3.00-4.02(m，13H)；4.30(m，1H)；4.86(m，2H)；5.19(m，1H)；7.43(m，1H)；7.60(m，1H)；7.68-7.78(m，2H)；8.05(m，1H)；8.16-8.22(m，2H)；8.91(s，1H)；10.57(s，1H)。

The intermediate of embodiment 4 is prepared as follows:

Intermediate 11:1-(5-bromopyridine-2-yl)-4-morpholine-4-base butane-1-ketone

3-[(5-bromopyridine-2-yl) carbonyl] sodium salt (G.M.Sanders, M.Van Dijk, the H.C.van der Plas of dihydrofuran-2 (3H)-ketone, Heterocycles 15,1, and 1981,213-223) (1.05g 3.6mmol) heated 1 hour at 80 ℃ in dense HCl (5mL).With the reaction mixture cool to room temperature and be poured in the saturated sodium bicarbonate solution (100mL).(3 * 100mL) extract, with dried over sodium sulfate and removal of solvent under reduced pressure with methylene dichloride for it.The rough mixture of this muriate intermediate and quinolizine  salt was heated 3 hours at 85 ℃ in morpholine (3mL).Use the silica gel chromatography of hexane/acetone (5: 1) wash-out, on RediSep C-18, use the chromatography of the acetonitrile (contain 0.1%TFA) of 5-20% in water subsequently, obtain trifluoroacetic acid (TFA) salt (12%) of the product of 190mg, be colorless oil.

MS (ESP): be C ₁₃H ₁₇BrN ₂O ₂Be 313.07/315.07 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.99(m，2H)；2.98-3.30(m，6H)；3.46(m，2H)；3.64(t，2H)；3.97(m，2H)；7.90(m，1H)；8.29(m，1H)；8.87(m，1H)；9.79(brs，1H)。

Embodiment 3:5-{2-fluoro-4-[(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-  azoles alkane-3-yl] phenyl } pyridine-2-formaldehyde O-(tertiary butyl) oxime

5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-formaldehyde (reference example 2,200mg, 0.54mmol), O-tertiary butyl hydroxylamine hydrochloride (89mg, 0.71mmol) and yellow soda ash (35mg, 0.33mmol) according to reference example 3 described reactions, but the reaction times is 1 hour.It is diluted with methylene dichloride, wash and use dried over sodium sulfate with water.Removal of solvent under reduced pressure from the ethanol/hexane crystallization, obtains the product of 260mg, is colorless solid, 192 ℃ of mp.

MS (ESP): C ₂₂H ₂₃FN ₆O ₃Be 439.23 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.34(s，9H)；3.95(dd，1H)；4.29(dd，1H)；4.86(d，2H)；5.18(m，1H)；7.41(dd，1H)；7.58(dd，1H)；7.67(dd，1H)；7.77(s，1H)；7.91(d，1H)；8.02(m，1H)；8.14(s，1H)；8.18(s，1H)；8.77(s，1H)。

Reference example 1:(5R)-3-[4-(6-acetylpyridine-3-yl)-3-fluorophenyl]-5-(1H-1,2,3-three Azoles-1-ylmethyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl) ethyl ketone (intermediate 10,2.47g, 12.4mmol),), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] and  azoles alkane-2-ketone (intermediate 7,4.0g, 10.3mmol) and yellow soda ash (3.98g, 37.5mmol) be dissolved in/be suspended in DMF/ water (50mL, 10: 1).It is handled through the degassing, use purging with nitrogen gas, interpolation four (triphenylphosphines) close palladium (0) (1.2g, 1.03mmol).It was heated cool to room temperature and evaporating solvent 3 hours at 75 ℃.Use the silica gel chromatography of hexane/acetone (1: 1) to the acetone wash-out, from ethanol/methylene (4: 1, remove most of methylene dichloride by decompression in 50mL) product be precipitated out, obtain the product (50%) of 1.98g, be pale solid, mp＞210 ℃ (decomposition).

MS (ESP): C ₁₉H ₁₆FN ₅O ₃Be 382.13 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.66(s，3H)；3.96(dd，1H)；4.30(dd，1H)；4.86(d，2H)；5.19(m，1H)；7.43(dd，1H)；7.60(dd，1H)；7.72(dd，1H)；7.76(s，1H)；8.03(d，1H)；8.17(m，1H)；8.18(s，1H)；8.90(s，1H)。

Reference example 2:5-{2-fluoro-4-[(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-  azoles alkane-3-yl] phenyl } pyridine-2-formaldehyde

5-bromopyridine-2-formaldehyde (X.Wang etc., Tetrah.Lett.41 (2000), 4335) (450mg, 2.42mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,939mg, 2.42mmol), yellow soda ash (769mg, 7.26mmol) and four (triphenylphosphines) close palladium (O), and (280mg 0.24mmol) as reaction as described in the embodiment 1, but is to use the 10mL solvent and 70 ℃ of heating 10 hours.Use the silica gel chromatography of hexane/acetone (1: 1) wash-out, obtain the product of 535mg (60%), be colorless solid, mp＞180 ℃ (decomposition).

MS (ESP): C ₁₈H ₁₄FN ₅O ₃Be 368.05 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.97(dd，1H)；4.30(dd，1H)；4.86(d，2H)；5.19(m，1H)；7.45(dd，1H)；7.61(dd，1H)；7.75(dd，1H)；7.77(s，1H)；8.02(d，1H)；8.18(s，1H)；8.23(d，1H)；9.01(s，1H)；10.02(s，1H)。

Reference example 3:5-{2-fluoro-4-[(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-  azoles alkane-3-yl] phenyl } the pyridine-2-formaldehyde oxime

5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl pyridine-2-formaldehyde (reference example 2) (100mg, 0.272mmol) and hydroxylamine hydrochloride (25mg is 0.354mmol) methanol (1: 1, mix 5mL), (18mg, 0.163mmol), mixture was stirring at room 1 day to add yellow soda ash in water-soluble (1mL).Add hydroxylamine hydrochloride (10mg) again, mixture stirred other 16 hours.Add water (5mL), throw out is collected by filtering, and washes with water also dry.Use the silica gel chromatography of methylene chloride (15: 1) wash-out,, obtain the product of 41mg (39%), be colorless solid, mp＞230 ℃ (decomposition) according to embodiment 10 described generation precipitations.

MS (ESP): C ₁₈H ₁₅FN ₆O ₃Be 382.87 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.95(dd，1H)；4.29(dd，1H)；4.85(d，2H)；5.18(m，1H)；7.41(dd，1H)；7.58(dd，1H)；7.67(dd，1H)；7.77(s，1H)；7.87(d，1H)；8.00(m，1H)；8.12(s，1H)；8.18(s，1H)；8.75(s，1H)；11.76(s，1H)。

Reference example 4

Referring to WO 01/94342 (Dong A.Pharm.Co.Ltd) embodiment 139.

Reference example 5:(5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazolium-5-yl) pyridin-3-yl) benzene Base)-and 5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

(5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 6,370mg, 0.95mmol), two (tetramethyl ethylene ketone base) two boron (605mg, 2.4mmol) and potassium acetate (326mg, 3.3mmol) mixture in dimethyl sulfoxide (DMSO) (5mL) is handled through the degassing, use purging with nitrogen gas, with dichloro [1,1 '] two (diphenylphosphino) ferrocene] (69mg 10mol%) handles palladium (II) methylene dichloride adducts.Mixture heating up to 80 ℃ continues 1.5 hours, and cool to room temperature by diatomite filtration, is used ethyl acetate extraction.Organic phase is washed with aqueous ammonium chloride solution, with dried over mgso and be evaporated to dried.Non-volatilizable residue obtains (5R)-3-(3-fluoro-4-(4,4 by silica gel chromatography purifying [use hexane: ethyl acetate (3: 2) wash-out], 5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,2- azoles alkane-2-ketone and corresponding boric acid (210mg ,～0.54mmol, 57%) mixture, it need not to be further purified and can directly use.

The as above mixture of Zhi Bei boric acid ester and boric acid, 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (160mg, 0.67mmol) and salt of wormwood (448mg, 3.24mmol) at N, dinethylformamide and water (10mL, 7: 1) in mixture handle through the degassing, use purging with nitrogen gas, (62mg 0.054mmol) handles to close palladium (O) with four (triphenylphosphines).Reaction mixture was 80 ℃ of heating 1.5 hours, and cool to room temperature by diatomite filtration, is used ethyl acetate extraction, with dried over mgso and be evaporated to dried.Non-volatilizable residue obtains product by silica gel chromatography purifying [use ethyl acetate: hexane (3: 2) wash-out], is colourless amorphous solid (140mg, 61%).

MS (ESP): C ₁₉H ₁₆FN ₉O ₂Be 422.47 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.98(dd，1H)；4.31(dd，1H)；4.47(s，3H)；4.86(m，2H)；5.18(m，1H)；7.45(m，1H)；7.61(m，1H)；7.74(m，1H)；7.77(brs，1H)；8.12-8.27(m，3H)；8.93(s，1H)。

The intermediate preparation of this reference example is as follows:

5-bromo-2-tetrazolium-5-yl pyridines

3-bromo-6-cyano group-pyridine (2g, 10.9mmol), sodiumazide (0.85g, 13mmol) and ammonium chloride (0.59g, 11mmol) at N, the mixture in the dinethylformamide (20mL) 120 ℃ the heating 1 hour.(～100mL) dilution, product with the ethyl acetate washing, obtain title compound by filtering separation to reaction mixture then, for directly using the canescence amorphous solid that need not single step purification in the step down with ethyl acetate.

5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine and 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) Pyridine

Prepare 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine and 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine according to the described process of Dong A Pharmaceuticals (WO 01/94342).

6.5g unpurified 5-bromo-2-tetrazolium-5-yl pyridines [Dong A Pharmaceuticals (WO 01/94342)] (～28mmol) and sodium hydroxide (9g, 125mmol) the mixture reduction vaporization in dry DMF is to doing.(3.0mL 48mmol) handles pass through to drip methyl iodide under the ice bath temperature in the stirred solution of non-volatilizable residue in dry DMF (50mL).Stirred mixture is risen again to be kept 2 hours in room temperature then.Reaction mixture distributes between frozen water and ethyl acetate, and organic phase washes with water, uses dried over mgso, and reduction vaporization obtains resistates then, and it obtains by silica gel chromatography purifying [use methylene fluoride: ethyl acetate (60: 1) wash-out]:

1.5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine (1.397g) is colorless solid, (TLC: silica gel, hexane: ethyl acetate (4: 1), Rf:0.3), ¹H-NMR (DMSO-d ₆) (300MHz) δ: 4.38 (s, 3H); 8.17 (d, 1H); 8.35 (dd, 1H); 8.96 (d, 1H).

2.5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (1.07g) is colorless solid, (TLC: silica gel, hexane: ethyl acetate (4: 1), Rf:0.1). ¹H-NMR (DMSO-d ₆) (300MHz) δ: 4.46 (s, 3H); 8.09 (d, 1H); 8.28 (dd, 1H); 8.88 (d, 1H).

Based on the structural confirmation of NMR HMBC (heteronuclear multiple bond dependency) experiment, wherein, in the 1-of Rf=0.3 methyl isophthalic acid H-isomer, observed CH ₃Proton and the C5 of tetrazole ring large-scale coupling is arranged, but in the 2-of Rf=0.1 methyl-2H-isomer, do not observe.Therefore the compound that is known as 5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine is the isomer of Rf=0.3, and the compound that is known as 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine is the isomer of Rf=0.1.

Embodiment 4:(5R)-and 3-(3-fluoro-4-{6-[(2-methyl isophthalic acid H-imidazoles-1-yl) ethanoyl] pyridine-3- Base } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(2-methyl isophthalic acid H-imidazoles-1-yl) ethyl ketone (intermediate 12) (336mg, 1.2mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] and  azoles alkane-2-ketone (intermediate 7,388mg, 1.0mmol), yellow soda ash (300mg, 2.8mmol) and four (triphenylphosphines) close palladium (O) (115mg, 0.1mmol) according to embodiment 1 described reaction, obtain the product of 276mg (55%), be hydrochloride, colorless solid, mp＞240 ℃ (decomposition).

MS (ESP): C ₂₃H ₂₀FN ₇O ₃Be 462.29 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.55(s，3H)；3.97(m，1H)；4.31(m，1H)；4.87(d，2H)；5.20(m，1H)；6.05(s，2H)；7.46(dd，1H)；7.57-7.65(m，3H)；7.72-7.80(m，2H)；8.13(d，1H)；8.19(s，1H)；8.27(m，1H)；9.03(s，1H)；14.48(brs，1H)。

The intermediate of embodiment 4 is prepared as follows:

Intermediate 12:1-(5-bromopyridine-2-yl)-2-(2-methyl isophthalic acid H-imidazoles-1-yl) ethyl ketone

(intermediate 9,650mg 1.8mmol) are suspended in anhydrous THF (6mL) and be cooled to 0 ℃ to 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate.(593mg, 7.2mmol), mixture stirred 2 hours to add glyoxal ethyline.Reaction mixture dilutes with methylene dichloride, washes and use dried over sodium sulfate with water.Use the silica gel chromatography of methylene chloride (20: 1) wash-out, obtain the product (66%) of 336mg, be pale solid.

MS (ESP): C ₁₁H ₁₀BrN ₃O is 280.07/282.07 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.15(s，3H)；5.68(s，2H)；6.74(d，1H)；7.00(d，1H)；7.93(d，1H)；8.33(dd，1H)；8.96(d，1H)。

Embodiment 5:(5R)-and 3-(3-fluoro-4-{6-[(4-methyl isophthalic acid H-imidazoles-1-yl) ethanoyl] pyridine-3- Base } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(4-methyl isophthalic acid H-imidazoles-1-yl) ethyl ketone (intermediate 13) (170mg, 0.607mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] and  azoles alkane-2-ketone (intermediate 7,214mg, 0.552mmol), yellow soda ash (175mg, 1.65mmol) and four (triphenylphosphines) close palladium (O) (64mg, 0.05mmol) according to embodiment 1 described reaction, obtain the product of 155mg (56%), be hydrochloride, colorless solid, mp＞217 ℃ (decomposition).

MS (ESP): C ₂₃H ₂₀FN ₇O ₃Be 462.29 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.32(s，3H)；3.97(dd，1H)；4.31?(dd，1H)；4.87(d，2H)；5.20(m，1H)；6.06(s，2H)；7.40-7.49(m，2H)；7.62(dd，1H)；7.74-7.80(m，2H)；8.13(d，1H)；8.19(s，1H)；8.28(m，1H)；8.95(s，1H)；9.02(brs，1H)；14.57(brs，1H)。

The intermediate of embodiment x is prepared as follows:

Intermediate 13:1-(5-bromopyridine-2-yl)-2-(4-methyl isophthalic acid H-imidazoles-1-yl) ethyl ketone

(intermediate 9,1.2g 3.3mmol) are suspended in anhydrous THF (20mL) and be cooled to 0 ℃ to 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate.(1.09g, 13.3mmol), mixture stirred 2 hours to add 4-methylimidazole.Reaction mixture dilutes with methylene dichloride, washes and use dried over sodium sulfate with water.Use the silica gel chromatography of acetone/hexane (1: 1 to 2: 1) wash-out, obtain the product (18%) of 170mg, be pale solid (Rf=0.29, TLC: acetone/hexane 1: 1; Also formed 5-Methylimidazole analogue, Rf=0.21).

MS (ESP): C ₁₁H ₁₀BrN ₃O is 280.07/282.07 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.09(s，3H)；5.67(s，2H)；6.79(s，1H)；7.44(s，1H)；7.93(d，1H)；8.33(dd，1H)；8.94(d，1H)。Confirm 4-and 5-Methylimidazole isomer based on HMBC (heteronuclear multiple bond dependency NMR-experiment).

Embodiment 6:(5R)-and 3-{3-fluoro-4-[6-(piperidin-4-yl ethanoyl) pyridin-3-yl] phenyl }-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

Under vigorous stirring, dioxane solution (4M with HCl, 5mL) handle 4-[2-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-the 2-oxoethyl] piperidines-1-formic acid tertiary butyl ester (intermediate 14,630mg, dioxane 1.12mmol) (5mL) solution.Be reflected at stirred overnight at room temperature, solvent evaporated under reduced pressure, resistates obtains the product of 409mg (73%) from water/Virahol (33mL, 1: 10) recrystallization, is hydrochloride, colorless solid, mp＞196 ℃ (decomposition).

MS (ESP): C ₂₄H ₂₅FN ₆O ₃Be 465 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.45(m，2H)；1.83(m，2H)；2.19(m，1H)；2.88(m，2H)；3.16-3.26(m，4H)；3.97(dd，1H)；4.30(dd，1H)；4.87(d，2H)；5.20(m，1H)；7.43(dd，1H)；7.60(dd，1H)；7.72(dd，1H)；7.77(s，1H)；8.05(d，1H)；8.16-8.21(m，1H)；8.19(s，1H)；8.70(m，1H)；8.87-8.98(m，1H)；8.90(brs，1H)。

The intermediate of embodiment 6 is prepared as follows:

Intermediate 14:4-[2-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl first Base)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-the 2-oxoethyl] piperidines-1-formic acid tertiary butyl ester

4-[2-(5-bromopyridine-2-yl)-2-oxoethyl] and piperidines-1-formic acid tertiary butyl ester (intermediate 15) (590mg, 1.54mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] and  azoles alkane-2-ketone (intermediate 7,598mg, 1.54mmol), yellow soda ash (490mg, 4.6mmol) and four (triphenylphosphines) close palladium (O), and (178mg is 0.154mmol) according to embodiment 1 described reaction.Use the silica gel chromatography of hexane/acetone (2: 1) wash-out, obtain the product of 691mg (79%), be colorless solid, mp＞140 ℃.

MS (ESP): C ₂₉H ₃₃FN ₆O ₅Be 565.66 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.11(m，2H)；1.38(s，9H)；1.66(m，2H)；2.07(m，1H)；2.72(m，2H)；3.13(m，2H)；3.84-4.00(m，3H)；4.30(dd，1H)；4.86(d，2H)；5.19(m，1H)；7.43(dd，1H)；7.60(dd，1H)；7.72(dd，1H)；7.77(s，1H)；8.05(d，1H)；8.15-8.21(m，1H)；8.18(s，1H)；8.90(brs，1H)。

Intermediate 15:4-[2-(5-bromopyridine-2-yl)-2-oxoethyl] piperidines-1-formic acid tertiary butyl ester

(764mg, THF 2.69mmol) (10mL) solution is cooled to-10 ℃, and (2M, 1.35mL 2.63mmol), handle to drip the THF solution of iPrMgCl with 5-bromo-2-iodine pyridine.Reaction mixture stirred 30 minutes, added 4-{2-[methoxyl group (methyl) amino by syringe then]-the 2-oxoethyl } piperidines-1-formic acid tertiary butyl ester (intermediate 16,770mg, THF 2.69mmol) (5mL) solution.Reaction mixture was risen again in 2 hours 10 ℃, under agitation be poured into then potassium phosphate buffer (1M, pH7,200mL) in.It is extracted and use dried over sodium sulfate with ethyl acetate (150mL), use the silica gel chromatography of hexane/ethyl acetate (7: 1) wash-out, obtain the product of 591mg (57%), be colorless solid.

MS (ESP): C ₁₇H ₂₃BrN ₂O ₃Be 383.47/385.47 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.09(m，2H)；1.37(s，9H)；1.63(m，2H)；2.02(m，1H)；2.72(m，2H)；3.06(m，2H)；3.91(m，2H)；7.87(d，1H)；8.25(dd，1H)；8.85(d，1H)。

Intermediate 16:4-{2-[methoxyl group (methyl) amino]-the 2-oxoethyl } piperidines-1-formic acid uncle fourth The base ester

To boc-(4-carboxyl methyl)-piperidines (M.S.Egbertson etc., J.Med.Chem.37 (16), 2537-2551 (1994)) (1g, 4.11mmol) and two (2-oxo-3- oxazolidinyl) inferior phosphonyl chloride (bis (2-oxo-3-oxazolidinyl) phosphinic chloride) (1.05g, 4.11mmol) add N in the solution in DMF (4mL), and the O-dimethyl hydroxylamine hydrochloride (561mg, 5.57mmol), add subsequently diisopropyl ethyl amine (2.15mL, 12.3mmol).Reaction mixture stirred 30 minutes,, washed (2 * 50mL) and use dried over sodium sulfate with water with ethyl acetate (100mL) dilution.Use the silica gel chromatography of hexane/ethyl acetate (2: 1 to 1: 2) wash-out, obtain the product of 770mg (65%), be colorless oil.

MS (ESP): C ₁₄H ₂₆N ₂O ₄Be 187.25 (M-bocH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.02(m，2H)；1.37(s，9H)；1.61(m，2H)；1.85(m，1H)；2.29(m，2H)；2.68(m，2H)；3.06(s，3H)；3.62(s，3H)；3.89(m，2H)。

Embodiment 7:(5R)-3-(3-fluoro-4-{6-[4-(4-methylpiperazine-1-yl) butyryl radicals] pyridin-3-yl } Phenyl)-and 5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-4-(4-methylpiperazine-1-yl) butane-1-ketone (intermediate 17,580mg, 1.8mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,690mg, 1.8mmol), yellow soda ash (377mg, (205mg is 0.18mmol) according to embodiment 1 described reaction 3.55mmol) to close palladium (O) with four (triphenylphosphines), but be to use the solvent of 10mL, use the silica gel chromatography of methylene chloride (5: 1 to 3: 1) wash-out, obtain the product of 510mg (57%), be colourless rigid foam.With the free alkali of product (310mg 0.61mmol) is carried in the Virahol (10mL), under vigorous stirring, add HCl (diethyl ether solution of 1M, 2mL).After stirring 15 minutes, removal of solvent under reduced pressure, resistates obtains the dihydrochloride of the product of 261mg from water/Virahol (～30mL, 1: 15) crystallization, is colorless solid, mp＞240 ℃.

MS (ESP): C ₂₆H ₃₀FN ₇O ₃Be 508 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.09(m，2H)；2.82(s，3H)；3.13-3.88(m12H)；3.97(dd，1H)；4.30(dd，1H)；4.86(d，2H)；5.19(m，1H)；7.43(m，1H)；7.60(m，1H)；7.73(dd，1H)；7.77(s，1H)；8.06(d，1H)；8.15-8.23(m，2H)；8.91(brs，1H)。

The intermediate of embodiment 7 is prepared as follows:

Intermediate 17:1-(5-bromopyridine-2-yl)-4-(4-methylpiperazine-1-yl) butane-1-ketone

5-bromo-2-iodine pyridine (927mg, 3.27mmol) (2M is in THF, and 1.64mL is 3.27mmol) with N-methoxyl group-N-methyl-4-(4-methylpiperazine-1-yl) butyramide (intermediate 18 with isopropylmagnesium chloride, 749mg, 3.27mmol) basis is about intermediate 15 described process reactions.Use the silica gel chromatography of methylene chloride (10: 1 to 4: 1) wash-out, obtain the product of 582mg (55%), be colorless oil.

MS (ESP): C ₁₄H ₂₀BrN ₃O is 326.47/328.47 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.80(tt，2H)；2.04(s，3H)；2.02-2.35(m，10H)；3.07(t，2H)；7.87(d，1H)；8.25(m，1H)；8.85(m，1H)。

Intermediate 18:N-methoxyl group-N-methyl-4-(4-methylpiperazine-1-yl) butyramide

4-chloro-N-methoxyl group-N-methyl-butyramide (V.Selvamurugan etc., Synthesis 15,2239-2246,2001) (1g, 6.04mmol) and 1-methylpiperazine (1.2g, 12mmol) in DMSO (2mL), mix and be heated to 80 ℃ and continue 3 hours, reaction saturated sodium bicarbonate aqueous solution (～100mL) cancellation, (3 * 100mL) extract and use dried over sodium sulfate with methylene dichloride, (arrive at 18: 1: the 1) silica gel chromatography of wash-out to use methylene chloride, obtain the product of 749mg (54%), be light yellow oil.

MS (ESP): C ₁₁H ₂₃N ₃O ₂Be 326.47/328.47 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.63(tt，2H)；2.13(s，3H)；2.10-2.45(m，10H)；3.07(s，3H)；3.38(m，2H)；3.64(s，3H)。

Embodiment 8:(5R)-and 3-{3-fluoro-4-[6-(piperidin-4-yl carbonyl) pyridin-3-yl] phenyl }-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

4-[(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl) carbonyl] piperidines-1-formic acid benzyl ester (intermediate 19,305mg is 0.52mmol) at Pd/C (10%, moistening) go up at methyl alcohol (10mL, contain several acetate) in hydrogenation 2 hours under room temperature and normal pressure, the mixture that obtains is by 0.45 μ M membrane filtration, and removal of solvent under reduced pressure.Separate (using the RediSep post) in the enterprising circumstances in which people get things ready for a trip spectrum of C-18RP silica gel, use acetonitrile (the contain 0.1%TFA) wash-out of 0-20% in water.Merge the fraction and the removal of solvent under reduced pressure that contain product.Resistates is carried in the Virahol (20mL), under vigorous stirring, add the HCl (diethyl ether solution of 1M, 0.5mL), it is diluted with hexane (10mL), solid by filtration is collected and at 50 ℃ of drying under reduced pressure, obtain the hydrochloride of the product of 71mg (28%), be colorless solid, mp＞275 ℃ (decomposition).

MS (ESP): C ₂₃H ₂₃FN ₆O ₃Be 451.27 (MH ⁺)

¹H-NMR (DMSO-d ₆) δ: 1.79 (m, 2H); 2.04 (m, 2H); 3.10 (m, 2H); 3.97 (dd, 1H); 4.12 (m, 1H); 4.30 (dd, 1H); 4.86 (d, 2H); 5.19 (m, 1H); 7.44 (dd, 1H); 7.60 (dd, 1H); 7.73 (dd, 1H); 7.77 (s, 1H); 8.07 (d, 1H); 8.18 (s, 1H); 8.21 (m, 1H); 8.50 (m, 1H); 8.76 (m, 1H); 8.92 (brs, 1H); Two H in addition exist under solvent or under the HDO signal.

The intermediate of embodiment 8 is prepared as follows:

Intermediate 19:4-[(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl first Base)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl) carbonyl] piperidines-1-formic acid benzyl ester

4-[(5-bromopyridine-2-yl) carbonyl] and piperidines-1-formic acid benzyl ester (intermediate 20,250mg, 0.62mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,241mg, 0.62mmol), yellow soda ash (197mg, 1.86mmol) and four (triphenylphosphines) close palladium (O) (72mg be 0.06mmol) according to embodiment 1 described reaction.Use the silica gel chromatography of hexane/acetone (1: 1) wash-out, obtain the product of 339mg (93%), be light yellow rigid foam.

MS (ESP): C ₃₁H ₂₉FN ₆O ₅Be 585.41 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.47(m，2H)；1.87(m，2H)；3.01(m，2H)；3.93-4.12(m，4H)；4.30(dd，1H)；4.86(d，2H)；5.08(s，2H)；5.19(m，1H)；7.28-7.46(m，6H)；7.60(dd，1H)；7.73(dd，1H)；7.77(s，1H)；8.06(d，1H)；8.15-8.23(m，2H)；8.93(brs，1H)。

Intermediate 20:4-[(5-bromopyridine-2-yl) carbonyl] piperidines-1-formic acid benzyl ester

5-bromo-2-iodine pyridine (490mg, 1.73mmol) and isopropylmagnesium chloride (2M is in THF, and 0.86mL is 1.73mmol) with 4-{[methoxyl group (methyl) amino] carbonyl } piperidines-1-formic acid benzyl ester (intermediate 21,529mg, 1.73mmol) basis is about intermediate 15 described process reactions.Use the silica gel chromatography of hexane/ethyl acetate (5: 1) wash-out, obtain the product of 252mg (36%), be colorless solid.

MS (ESP): C ₁₉H ₁₉BrN ₂O ₃Be 403.19/405.19 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.42(m，2H)；1.83(m，2H)；2.99(m，2H)；3.93(m，1H)；4.04(m，2H)；5.07(s，2H)；7.26-7.40(m，5H)；7.90(d，1H)；8.28(d，1H)；8.88(d，1H)。

Intermediate 21:4-{[methoxyl group (methyl) amino] carbonyl } piperidines-1-formic acid benzyl ester

4-(chloroformyl) piperidines-1-formic acid benzyl ester (H.Harada etc., Bioorg.Med.Chem.Lett.12 (6), 967-970,2002) (1g, 3.55mmol) and N, and the O-dimethyl hydroxylamine hydrochloride (346mg, 3.55mmol) mixture in methylene dichloride (20mL) is cooled to-20 ℃, the interpolation pyridine (1.15mL, 14.2mmol).Make the reaction mixture room temperature of in 30 minutes, rising again, and stirred other 1 hour.It dilutes with methylene dichloride (100mL), and (3 * 100mL) wash and use dried over sodium sulfate for 1M, pH7 with potassium phosphate buffer.Use the silica gel chromatography of hexane/ethyl acetate (1: 1 to 0: 1) wash-out, obtain the product of 650mg (60%), be colorless oil.

MS (ESP): C ₁₆H ₂₂N ₂O ₄Be 307.25 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：140(m，2H)；1.66(m，2H)；2.80-2.99(m，3H)；3.08(s，3H)；3.67(s，3H)；4.01(m，2H)；5.06(s，2H)；7.26-7.45(m，5H).

Embodiment 9:(5R)-3-{4-[6-(chlorine heterocycle butane-3-base carbonyl) pyridin-3-yl]-the 3-fluorobenzene Base }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

Under vigorous stirring, use HCl (the dioxane solution of 4M, 2mL) handle 3-[(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl) carbonyl] azetidine-1-formic acid tertiary butyl ester (intermediate 22,220mg, 0.42mmol) dioxane (2mL) solution, with it stirring at room 1 hour, solvent evaporated under reduced pressure, chromatographic separation on C-18RP silica gel (using the RediSep post) is used acetonitrile (the contain 0.1%TFA) wash-out of 0-20% in water.Merge the fraction and the removal of solvent under reduced pressure that contain product.Resistates is carried in the Virahol (20mL), under vigorous stirring, add HCl (diethyl ether solution of 1M, 0.2mL).The throw out solid by filtration is collected and in reduced pressure at room temperature, is obtained the hydrochloride of the product of 44mg (23%), is the solid of green-emitting, mp＞90 ℃ (decomposition).

MS (ESP): C ₂₁H ₁₉FN ₆O ₃Be 423.25 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.97(dd，1H)；4.17-4.34(m，5H)；4.70(m，1H)；4.86(d，2H)；5.19(m，1H)；7.44(m，1H)；7.60(m，1H)；7.73(dd，1H)；7.77(s，1H)；8.11-8.27(m，3H)；8.81(m，1H)；8.90(brs，1H)；9.22(m，1H)。

The intermediate of embodiment 9 is prepared as follows:

Intermediate 22:3-[(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl first Base)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl) carbonyl] azetidine-1-formic acid tertiary butyl ester

3-[(5-bromopyridine-2-yl) carbonyl] azetidine-1-formic acid tertiary butyl ester (intermediate 23,447mg, 1.31mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,509mg, 1.31mmol), yellow soda ash (416mg, 3.93mmol) and four (triphenylphosphines) close palladium (O) (151mg, 0.13mmol) according to embodiment 1 described reaction, but be to use the 10mL solvent.Use the silica gel chromatography of hexane/acetone (1: 1) wash-out, obtain the product of 500mg (73%), be colourless rigid foam.

MS (ESP): C ₂₆H ₂₇FN ₆O ₅Be 523.37 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.37(s，9H)；3.93-4.18(m，5H)；4.30(dd，1H)；4.53(m，1H)；4.86(d，2H)；5.19(m，1H)；7.44(dd，1H)；7.60(dd，1H)；7.73(dd，1H)；7.77(s，1H)；8.10(d，1H)；8.18(s，1H)；8.20(m，1H)；8.88(brs，1H)。

Intermediate 23:3-[(5-bromopyridine-2-yl) carbonyl] azetidine-1-formic acid tertiary butyl ester

5-bromo-2-iodine pyridine (1.09g, 3.85mmol) and isopropylmagnesium chloride (2M, in THF, 1.83mL, 3.66mmol) and 3-{[methoxyl group (methyl) amino] carbonyl azetidine-1-formic acid tertiary butyl ester (intermediate 24,466mg, 1.9mmol) basis is about intermediate 15 described process reactions.Use the silica gel chromatography of hexane/ethyl acetate (7: 1) wash-out, obtain the product of 447mg (69%), be colorless solid.

MS (ESP): C ₁₄H ₁₇BrN ₂O ₃Be 341.11/343.11 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.36(s，9H)；3.92-4.14(m，4H)；4.44(m，1H)；7.93(d，1H)；8.28(dd，1H)；8.84(d，1H)。

Intermediate 24:3-{[methoxyl group (methyl) amino] carbonyl } azetidine-1-formic acid tertiary butyl Ester

To 1-(tert-butoxycarbonyl) azetidine-3-formic acid (H.Itani etc., Biorg.Med.Chem.Lett.12 (5), 757-762,2002) (0.5g, 2.48mmol) (0.633g 2.48mmol) adds N in the solution in DMF (4mL) with two (2-oxo-3- oxazolidinyl) inferior phosphonyl chlorides, O-dimethyl hydroxylamine hydrochloride (339mg, 3.48mmol), add subsequently diisopropyl ethyl amine (1.3mL, 7.45mmol).Make the thermopositive reaction cool to room temperature and stirred 2 hours.Excessive alkali is removed in decompression, and resistates is with ethyl acetate (100mL) dilution, with potassium phosphate buffer (1M, pH7,2 * 100mL) and water (2 * 100mL) wash, and use dried over sodium sulfate.Use the silica gel chromatography of hexane/acetone (3: 1) wash-out, obtain the product of 470mg (77%), be colorless solid.

MS (ESP): C ₁₁H ₂₀N ₂O ₄Be 267.23 (MNa ⁺)

¹H-NMR(DMSO-d ₆)δ：1.36(s，9H)；3.10(s，3H)；3.61(s，3H)；3.68(m，1H)；3.83-4.00(m，4H).

Embodiment 10:(5R)-and 3-(4-{6-[(2,5-dimethyl-1H-imidazoles-1-yl) ethanoyl] pyridine-3- Base }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(2,5-dimethyl-1H-imidazoles-1-yl) ethyl ketone (intermediate 25,985mg, 3.35mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2,3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,1.30g, 3.35mmol), yellow soda ash (887mg, (387mg is 0.35mmol) according to embodiment 1 described reaction 8.37mmol) to close palladium (O) with four (triphenylphosphines), but be to use the 15mL solvent and 75 ℃ the heating 6 hours, use the silica gel chromatography of methylene chloride (10: 1 to 8: 1) wash-out,, obtain the product of 658mg (41%) subsequently from alcohol crystal, be colourless spicule, mp112-115 ℃.

MS (ESP): C ₂₄H ₂₂FN ₇O ₃Be 476.16 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.01(s，3H)；2.15(s，3H)；3.97(dd，1H)；4.31(dd，1H)；4.86(d，2H)；5.19(m，1H)；5.64(s，2H)；6.51(s，1H)；7.46(dd，1H)；7.62(dd，1H)；7.75(dd，1H)；7.77(s，1H)；8.10(d，1H)；8.19(s，1H)；8.25(m，1H)；8.99(brs，1H)。

The intermediate of embodiment 10 is prepared as follows:

Intermediate 25:1-(5-bromopyridine-2-yl)-2-(2,5-dimethyl-1H-imidazoles-1-yl) ethyl ketone

1-[2-(5-bromopyridine-2-yl)-2-oxoethyl]-2, (intermediate 26,4.75g 7.7mmol) are dissolved in methylene dichloride (100mL) to 5-dimethyl-3-trityl-1H-imidazoles-3- bromide, add trifluoroacetic acid (15mL).Mixture is reflux 1.5 hours leniently.It is with methylene dichloride (200mL) dilution, with potassium phosphate buffer (pH7,1M ,～600mL) washing, water with dichloromethane extraction three times (3 * 100mL), the organic phase dried over sodium sulfate of merging.Use the silica gel chromatography of methylene chloride (20: 1) wash-out, obtain the product of 1.938g (77%), be pale solid.

MS (ESP): C ₁₂H ₁₂BrN ₃O is 294/296 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.98(s，3H)；2.12(s，3H)；5.57(s，2H)；6.49(s，1H)；7.93(m，1H)；8.35(m，1H)；8.98(m，1H)。

Intermediate 26:1-[2-(5-bromopyridine-2-yl)-2-oxoethyl]-2,5-dimethyl-3-triphen first Base-1H-imidazoles-3- bromide

2,4-dimethyl-1-trityl-1H-imidazoles (intermediate 27,4.5g, 13.4mmol), 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone (free alkali of intermediate 9,2.5g, 9mmol) (by using potassium phosphate buffer (pH7,1M) handle the suspension of intermediate 9 in ethyl acetate, generate free alkali from hydrobromate, and wash organic phase with water, use dried over sodium sulfate) and 2,6-two-tert .-butylpyridine (3mL, 13.35mmol) mixture 1, in the 4-dioxane (50mL) 75 ℃ the heating 30 minutes.Make the reaction mixture cool to room temperature, throw out is collected by filtration and (2 * 50mL) wash, and obtain the product of 4.75g (86%), are pale solid, mp＞150 ℃ (decomposition) with hexane.

MS (ESP): C ₃₁H ₂₇BrN ₃O is 535.95/537.95 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.82(s，3H)；2.21(s，3H)；5.95(s，2H)；7.07(s，1H)；7.12-7.18(m，6H)；7.44-7.65(m，9H)；7.98(m，1H)；8.36(m，1H)；8.98(m，1H)。

Intermediate 27:2,4-dimethyl-1-trityl-1H-imidazoles

At room temperature in 45 minutes with trityl chloride (15g, methylene dichloride 55mmol) (50mL) drips of solution is added to 2, (5g, 52mmol) (11.3mL is in the solution in mixture 81mmol) at methylene dichloride (100mL) and triethylamine for the 4-methylimidazole.Mixture stirs and spends the night, and uses methyl alcohol (4mL) cancellation then, and stirs other 30 minutes.Evaporating solvent is carried on resistates in the toluene (600mL), with potassium phosphate buffer (pH7,1M, 2 * 200mL) and water (200mL) wash.Organic phase is used dried over sodium sulfate with methylene dichloride (200mL) dilution, and concentrating under reduced pressure arrives～100mL.Add hexane (100mL), throw out is collected by filtration and (2 * 50mL) wash, and obtain the product of 14.76g (84%), are colorless solid with hexane.

¹H-NMR(CDCl ₃)δ：1.62(s，3H)；2.16(s，3H)；6.40(s，2H)；7.10-7.40(m，15H)。

Embodiment 11:(5R)-and 3-(3-fluoro-4-{6-[(2-propyl group-1H-imidazoles-1-yl) ethanoyl] pyridine- The 3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(2-propyl group-1H-imidazoles-1-yl) ethyl ketone (intermediate 28,255mg, 0.825mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,384mg, 0.99mmol), salt of wormwood (343mg, 2.48mmol) and four (triphenylphosphines) close palladium (O) (46mg, 0.04mmol) according to embodiment 1 described reaction, but be reflected at 80 ℃ of heating 30 minutes.Use the silica gel chromatography of hexane/acetone (1: 1 to 0: 1) wash-out, obtain the product of 171mg, be pale solid, mp81 ℃.

MS (ESP): C ₂₅H ₂₄FN ₇O ₃Be 490 (MH ⁺)

¹H-NMR(DMSO-d6)δ：0.89(m，3H)；1.63-1-70(m，2H)；2.88-2.93(m，2H)；3.44(m，2H)，3.98(m，1H)，4.25(s，1H)；4.96(m，1H)；5.24(s，1H)；6.09(s，2H)；7.59(m，1H)；7.70(m，2H)；7.77(m，2H)；8.12(s，1H)；8.19(m，1H)；8.26-8.28(m，1H)，9.03(s，1H)。

Intermediate 28:1-(5-bromopyridine-2-yl)-2-(2-propyl group-1H-imidazoles-1-yl) ethyl ketone

(intermediate 9,400mg 1.81mmol) are suspended in anhydrous THF (5mL) and be cooled to 0 ℃ to 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate.(487mg, 4.4mmol), mixture stirred 2 hours to add the 2-propyl imidazole.Reaction mixture dilutes with methylene dichloride, washes and use dried over sodium sulfate with water.Use the silica gel chromatography of methylene chloride (20: 1) wash-out, obtain the product of 256mg, be pale solid.

MS (ESP): C ₁₃H ₁₄BrN ₃O is 309 (MH ⁺)

Embodiment 12:(5R)-and 3-(3-fluoro-4-{6-[(2-sec.-propyl-1H-imidazoles-1-yl) ethanoyl] pyridine -3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(2-sec.-propyl-1H-imidazoles-1-yl) ethyl ketone (intermediate 29,255mg, 0.825mmoles), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,384mg, 0.99mmol), salt of wormwood (343mg, 2.48mmol) and four (triphenylphosphines) close palladium (O), and (46mg 0.04mmol) according to embodiment 11 described process reaction and purified products, obtains the product of 174mg, be pale solid, mp82-83 ℃.

MS (ESP): C ₂₅H ₂₄FN ₇O ₃Be 490 (MH ⁺)

¹H-NMR(DMSO-d6)δ：1.21(m，6H)；3.39(m，1H)；3.95-4.00(m，1H)，4.28(m，1H)，4.86(s，2H)；5.17-5.20(m，1H)；6.13(s，2H)；7.45-7.48(dd，1H)；7.59(m，1H)；7.70(m，2H)；7.77(m，2H)；8.12(s，1H)；8.19(m，1H)；8.26-8.28(m，1H)，9.03(s，1H)。

2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate (intermediate 9,400mg, 1.81mmol) and 2 isopropyl imidazole (487mg 4.4mmol) according to about intermediate 28 described process reactions, obtains the product of 255mg, is pale solid.

MS (ESP): C ₁₃H ₁₄BrN ₃O is 309 (MH ⁺).

Embodiment 13:(5R)-and 3-(4-{6-[(2,4-dimethyl-1H-imidazoles-1-yl) ethanoyl] pyridine-3- Base }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(2,4-dimethyl-1H-imidazoles-1-yl) ethyl ketone (intermediate 30,210mg, 0.714mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,333mg, 0.86mmol), (296mg 2.14mmol) closes palladium (0) (46mg with four (triphenylphosphines) to salt of wormwood, 0.04mmol) according to embodiment 11 described process reaction and purified products, obtain the product of 105mg, be pale solid, mp78 ℃.

MS (ESP): C ₂₄H ₂₂FN ₇O ₃Be 476 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.26(s，3H)；3.55(s，3H)；3.95(m，1H)，4.27(m，1H)；4.98(m，2H)；5.18-5.22(m，1H)；5.98(s，2H)；7.27(m，1H)；7.43-7.64(m，2H)；7.76(m，2H)；8.10(m，1H)；8.19(m，1H)；8.26-8.28(m，1H)，9.03(s，1H)。

Intermediate 30:1-(5-bromopyridine-2-yl)-2-(2,4-dimethyl-1H-imidazoles-1-yl) ethyl ketone

(1.81mmol) (422mg 4.4mmol) according to about intermediate 28 described process reactions, obtains the product of 210mg to 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate, is pale solid with 2,4 methylimidazoles for intermediate 9,400mg.

MS (ESP): C ₁₁H ₉BrN ₃O is 280 (MH ⁺)

Embodiment 14:(5R)-and 3-(4-{6-[(2-ethyl-1H-imidazoles-1-yl) ethanoyl] pyridin-3-yl }- The 3-fluorophenyl)-and 5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(2-ethyl-1H-imidazoles-1-yl) ethyl ketone (intermediate 31,237mg, 0.806mmoles), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,376mg, 0.97mmol), salt of wormwood (340mg, 2.41mmol) and four (triphenylphosphines) close palladium (O), and (46mg 0.04mmol) according to embodiment 11 described process reaction and purified products, obtains the product of 174mg, be pale solid, mp 77-79 ℃.

MS (ESP): C ₂₄H ₂₂FN ₇O ₃Be 476 (MH ⁺)

¹H-NMR(DMSO-d6)δ：1.21(m，3H)；2.89-2.96(m，2H)；3.52(m，2H)；3.98-3.98(m，1H)，4.28(m，1H)，4.86(s，2H)；5.17-5.20(m，1H)；6.08(s，2H)；7.42-7.44(dd，1H)；7.57-7.72(m，1H)；7.76(s，1H)；7.98-8.08(m，1H)；8.19(s，1H)；8.43-8.59(m，1H)；8.82(m，2H).

Intermediate 31:1-(5-bromopyridine-2-yl)-2-(2-ethyl-1H-imidazoles-1-yl) ethyl ketone

(1.81mmol) (427mg 4.4mmol) according to about intermediate 28 described process reactions, obtains the product of 237mg to 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate, is pale solid with the 2-ethyl imidazol(e) for intermediate 9,400mg.

MS (electrospray): C ₁₁H ₉BrN ₃O is 280 (MH ⁺)

Embodiment 15:(5R)-and 3-[3-fluoro-4-(6-{[2-(methoxymethyl)-1H-imidazoles-1-yl] acetyl Base } pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-[2-(methoxymethyl)-1H-imidazoles-1-yl] ethyl ketone (intermediate 32,400mg, 1.3mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl]  azoles alkane-2-ketone (intermediate 7,582mg, 1.5mmol), salt of wormwood (539mg, 3.9mmol) and four (triphenylphosphines) close palladium (O), and (75mg 0.065mmol) according to embodiment 11 described process reaction and purified products, obtains the product of 150mg, be pale solid, mp78-80 ℃.

MS (electrospray): C ₂₄H ₂₂FN ₇O ₄Be 492 (M+1)

¹H-NMR(DMSO-d ₆)δ：3.26(s，3H)；3.98(m，2H)；4.32(s，1H)；4.78(s，2H)；4.88(m，2H)；5.20(s，1H)；6.10(s，2H)；7.48(m，1H)；7.70(m，2H)；7.77(m，2H)；8.12(s，1H)；8.19(m，1H)；8.26-8.28(m，1H)；9.03(s，1H)。

Intermediate 32:1-(5-bromopyridine-2-yl)-2-[2-(methoxymethyl)-1H-imidazoles-1-yl] second Ketone

2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate (intermediate 9,795mg, 2.21mmol) and 2-(methoxymethyl) imidazoles (192mg 1.7mmol) according to about intermediate 28 described process reactions, obtains the product of 340mg, is pale solid.

MS (electrospray): C ₁₂H ₁₂BrN ₃O ₂Be 311 (MH ⁺).

Claims

1. the compound of formula (I) or its pharmaceutically useful salt or prodrug,

Wherein:

R ⁴Be-C (O) R ⁵Or

R ⁴Be selected from-C (H)=N-OR ⁸,-C (R ⁵)=N-OH and-C (R ⁵)=N-OR ⁸

Perhaps, R ⁵Be HET-1;

2. the compound or pharmaceutically acceptable salt thereof or the prodrug of the described formula of claim 1 (I), wherein R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride.

3. the compound or pharmaceutically acceptable salt thereof or the prodrug of claim 1 or 2 described formulas (I), wherein R ²And R ³Be independently selected from hydrogen and fluorine.

4. the compound or pharmaceutically acceptable salt thereof or the prodrug of claim 1 or 2 or 3 described formulas (I), wherein R ⁴Be-C (O) R ⁵

5. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I), wherein R in the aforementioned claim ⁵Be that (1-6C) alkyl (is independently selected from hydroxyl, carboxyl, (1-4C) alkoxyl group, HET-1 and NR by 1 or 2 ⁶R ⁷Substituting group replace).

6. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I) in the aforementioned claim, it is a compound shown in the formula (Ia)

7. the prodrug of each described compound in the aforementioned claim.

8. in warm-blooded animal, produce the method for antibacterial effect, but comprise described animal to ester with hydrolysis in each described compound or pharmaceutically acceptable salt thereof of the present invention among the claim 1-6 of significant quantity or the body.

9. but the ester of hydrolysis in each described compound or pharmaceutically acceptable salt thereof of the present invention or the body among the claim 1-6, it is as medicine.

But among the claim 1-6 in each described compound or pharmaceutically acceptable salt thereof of the present invention or the body ester of hydrolysis be used for producing application in the medicine of antibacterial effect in preparation warm-blooded animal.

11. pharmaceutical composition, but it comprises ester and the acceptable diluents or the carrier of hydrolysis in each described compound or pharmaceutically acceptable salt thereof of the present invention among the claim 1-6 or the body.

12. the described pharmaceutical composition of claim 11, wherein said composition comprise the compound of formula (I) and effectively to the combination of the antiseptic-germicide of resisting gram-positive bacteria.

13. the described pharmaceutical composition of claim 12, wherein said composition comprise the compound of formula (I) and the effectively combination of the antiseptic-germicide of antagonism Gram-negative bacteria.

14. the preparation described formula of claim 1 (I) but compound or pharmaceutically acceptable salt thereof or body in the method for ester of hydrolysis, this method comprises following method (a) to one of (m), and, afterwards, if necessary:

I) remove any protecting group;

Ii) form prodrug (but for example the ester of hydrolysis in the body); And/or

Iii) form pharmacologically acceptable salt;

Wherein said method (a) is to (m) (wherein except as otherwise noted otherwise the definition of each variable with the definition of claim 1) as described below:

A) change the substituting group in the additional compounds of the present invention or in additional compounds of the present invention, introduce substituting group;

B) partial reaction of the part (wherein X is the leavings group that can be used in palladium [0] coupled reaction) by making formula (II) compound and Compound I Ia, described Compound I Ia also has leavings group X, makes pyridyl-phenyl key replace phenyl-X key and pyridyl-X key;

Or by carbamate wherein replaced by isocyanic ester or amine or/and wherein oxyethane by equivalent agent X-CH ₂CH (O-is optional protected) CH ₂Triazole-R ¹(wherein X is a displaceable group) displaced this method variant carries out;

(d) for R ⁴For-COR ⁵, by making the compound of formula (IV):

Wherein X be replaceable substituting group and Y be halogen or

React with acylating reagent;

E) for R ⁴For-COR ⁵, from the α halogenated derivative, by obtaining formula (IIa) compound with the nucleophilic reagent reaction, the compound with formula (II) reacts then;

F) for R ⁴For-COR ⁵, by the oxidation of alcohol derivate;

G) for R ⁴Be oxime, by aldehydes or ketones and azanol or the reaction of O-alkylation hydroxylamine derivative;

H) for R ⁴For-COR ⁵, by pyridyl-2-cyano derivative (V) and Grignard reagent or similar metal alkyl reagent react, with posthydrolysis;

I) for R ⁴For-COR ⁵, be that carboxylates derivatives and Y are the alkylations of pyridyl-2-carboxylates derivatives of the formula (IV) of halogen by X wherein, then with the compound reaction of formula (II);

J) by from wherein having formed R ⁴The suitably functionalized intermediate of the quilt of-pyridyl-benzyl ring system forms triazole ring:

K) by carrying out cycloaddition by means of trinitride and acetylene;

L) by making amino methyl  oxazolidone and 1,1-dihalo ketone alkylsulfonyl hydrazone reaction:

M) work as R ₁During for the 4-halogen, by making the reaction of azido methyl  oxazolidone and vinyl halides base SULPHURYL CHLORIDE: