CN1989134A

CN1989134A - 3- {4- (pyridin-3-yl) phenyl} -5- (1h-1, 2, 3-triazol-1-ylmethyl) -1, 3-oxazolidin-2-ones as antibacterial agents

Info

Publication number: CN1989134A
Application number: CN 200580025002
Authority: CN
Inventors: M·B·格拉维斯托克; F·莱克; F·周
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: GB0411592D0

Abstract

Compounds of formula (I), as well as pharmaceutically-acceptable salts and pro-drugs thereof, are disclosed wherein R1, R2, R3, and R4 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-(pyridin-3-yl) phenyl as antiseptic-germicide }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

The present invention relates to Antibiotique composition, particularly contain replacement _ Antibiotique composition of oxazolidone ring.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.

Described in the art and contained _ some 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 of oxazolidone ring; 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) described pyridyl-_ oxazolidone or pyrimidyl-phenyl-_ oxazolidinone compounds, it has and is connected in _ the methylacetamide side chain of 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 contain other heterocycle that is different from piperazine such as piperidines, _ diazole or tetrazolium.

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

Compound of the present invention has favourable physics and/or pharmacokinetic property generally, for example solubleness and/or 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 (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁵,-C (O) R ⁵,-OC (O) R ⁵, carboxyl ,-C (O) NR ⁵R ⁶,-OC (O) NR ⁵R ⁶,-S (O) ₂R ⁵,-S (O) ₂NR ⁵R ⁶,-NR ⁵R ⁶,-NHC (O) R ⁵With-NHS (O) ₂R ⁵Substituting group replace; And choose wantonly and replaced by cyclopropyl in addition];

R ⁵And R ⁶Be 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;

Perhaps, R ⁵And R ⁶The 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);

Perhaps, R ⁵And R ⁶The 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;

Condition is R ⁴It can not be hydroxymethyl.

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.

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.

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.

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; 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) example of alkyl S (O) q-(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 dichloromethyl; 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 for example sodium salt, alkaline earth salt for example calcium or magnesium salts, organic amine salt for example triethylamine, morpholine, N-methyl piperidine, N-ethyl piperidine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N, 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.

Yet, 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: T.Yamazaki etc., 42 ^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 chromatography isolation technique 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 pH 7.4 phosphate buffered saline buffers, the equilibrium solubility of reference example 5 is 35.1 μ M, the equilibrium solubility of reference example 6＜7.1 μ M.By contrast, the equilibrium solubility of embodiment 4 is 210 μ M.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.

In yet another aspect, R ¹Be selected from hydrogen, chlorine, bromine, methyl and methyl fluoride.

In one aspect, 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 (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-OC (O) R ⁵,-OC (O) NR ⁵R ⁶Substituting group replace; And choose wantonly and replaced by cyclopropyl in addition].

In one aspect, R ⁴Be (1-4C) alkyl [by 1 be selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-OC (O) R ⁵,-OC (O) NR ⁵R ⁶Substituting group replace; And choose wantonly and replaced by cyclopropyl in addition].

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

On the other hand, R ⁴Be that (1-4C) alkyl [is selected from-C (O) OR by 1 ⁵,-C (O) R ⁵, carboxyl and-C (O) NR ⁵R ⁶Substituting group replace].

On the other hand, R ⁴Be that (1-4C) alkyl [is selected from-S (O) by 1 ₂R ⁵With-S (O) ₂NR ⁵R ⁶Substituting group replace].

On the other hand, R ⁴Be that (1-4C) alkyl [is independently selected from-NR by 1 or 2 ⁵R ⁶,-NHC (O) R ⁵With-NHS (O) ₂R ⁵Substituting group replace].

On the other hand, R ⁴Be (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁵,-C (O) R ⁵,-OC (O) R ⁵, carboxyl ,-C (O) NR ⁵R ⁶,-OC (O) NR ⁵R ⁶With-NR ⁵R ⁶Substituting group replace].

On the other hand, R ⁴Be (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-OC (O) R ⁵, carboxyl ,-C (O) NR ⁵R ⁶,-OC (O) NR ⁵R ⁶With-NR ⁵R ⁶Substituting group replace].

On the other hand, R ⁴Be (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-OC (O) R ⁵, carboxyl and-NR ⁵R ⁶Substituting group replace].

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

On the other hand, R ⁴Be (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl and-NR ⁵R ⁶Substituting group replace].

In one aspect, R ⁵And R ⁶Be 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 ⁵And R ⁶Be 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 ⁵And R ⁶Be independently selected from hydrogen and (1-4C) alkyl, on the other hand, R ⁵And R ⁶Be independently selected from hydrogen and methyl.

On the other hand, R ⁵And R ⁶Be 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 ⁵And R ⁶Be 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 ⁵And R ⁶Be independently selected from hydrogen, methyl and (2-4C) alkyl (optional replaced) by 1 or 2 hydroxyl.

On the other hand, R ⁵And R ⁶The 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).In yet another aspect, this ring is saturated.

Comprise R ⁵And R ⁶And the suitable examples of this ring of the nitrogen that is 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.

Comprise R ⁵And R ⁶And other suitable examples of this ring of the nitrogen that is 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 ⁵And R ⁶And other suitable examples of this ring of the nitrogen that is connected is that (and wherein sulphur is oxidized to S (O) or S (O) for morpholine and thiomorpholine ₂The derivative of group).

Object lesson is a morpholine.

On the other hand, R ⁵And R ⁶The nitrogen that is connected with them forms imidazoles, Methylimidazole or methylimidazole ring, particularly Methylimidazole or methylimidazole, more especially methylimidazole altogether.

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 (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁵,-C (O) R ⁵,-OC (O) R ⁵, carboxyl ,-C (O) NR ⁵R ⁶,-OC (O) NR ⁵R ⁶With-NR ⁵R ⁶Substituting group replace.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁵,-C (O) R ⁵,-OC (O) R ⁵, carboxyl ,-C (O) NR ⁵R ⁶,-OC (O) NR ⁵R ⁶With-NR ⁵R ⁶Substituting group replace; With

R ⁵And R ⁶Be 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.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁵And R ⁶Be independently selected from hydrogen, methyl and (2-4C) alkyl (optional replaced) by 1 or 2 hydroxyl.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁵And R ⁶The nitrogen that is connected with them is azetidine, morpholine, piperazine, N methyl piperazine altogether, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines, tetramethyleneimine and tetrahydropyridine.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁵And R ⁶The 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 (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-OC (O) R ⁵, carboxyl and-NR ⁵R ⁶Substituting group replace]; With

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

R ²And R ³Be hydrogen or fluorine independently;

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

R ²And R ³Be hydrogen or fluorine independently;

R ¹Be hydrogen;

R ²And R ³Be hydrogen or fluorine independently;

Particular compound of the present invention comprises the compound that each described in the embodiment is independent, and each embodiment provides independently aspect of the present invention.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, JP2003335762 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 to (n); 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 (o) (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 fluorin radical; 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 connecting the N annular atoms; (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 alkyl halide group can be converted into hydroxyl, amino, and the sulfane base is by the heterocyclic radical of nitrogen connection; Ketone group can be reduced to hydroxyl or saturated alkyl;

B) (wherein X is the leavings group that can be used in palladium [0] coupled reaction to through type (II) compound, for example chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) with Compound I Ia reaction, described Compound I Ia also has leavings group X, makes to replace phenyl-X key and pyridyl-X key with pyridyl-phenyl key; These methods are known, for example referring to S.P.Stanforth, and Catalytic Cross-CouplingReactions in Biaryl Synthesis, Tetrahedron, 54,1998,263-303; J.K.Stille, Angew Chem.Int.Ed.Eng., 1 986,25,509-524; 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 formation _ oxazolidone ring that is suitably replaced;

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

(d) 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 reaction, carry out the reduction of ketone then, (when Y is halogen) is according to above b then) described in react with formula (II) compound;

For example:

Wherein R is (optional substituted) alkyl;

E) from the α halogenated derivative of formula (IV) (wherein X is that the definition of ketone and Y is the same), by with the nucleophilic reagent reaction, carry out the reduction of ketone then, then according to above b) described in the compound reaction of formula (II); For example:

Nu=is as OH, NRR ¹, SR, OR

F) be the alkylation of the 2-picoline group in the compound of formula (IV) of halogen by Y wherein, obtain the compound of formula (IIa), then with the compound reaction of formula (II), for example:

G) be epoxide and Y such as above d by X wherein) in the compound of formula (IV) of definition in epoxide and nucleophilic reagent reaction, (when Y is halogen) is according to above b then) described in the compound reaction of formula (II); For example:

Nu=is for example: RR ¹N, OH, OR, SR

H) by pyridyl-2-formaldehyde derivatives (V) and Grignard reagent or similar metal alkyl reagent react;

I) reduction amination by aldehyde radical, for example in (V):

J) by vinyl pyridine being carried out the anti-horse formula addition of amine, for example:

(M.Beller etc., Eur.J.Inorg.Chem.1999,1121-1132)

K) 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:

L) 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):

M) 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);

N) work as R ¹Be 4-halo substituting group, 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.

O) by using the ketone precursor reduction of sodium borohydride for example with formula V; For example:

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 needing the optical activity form of The compounds of this invention, 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, perhaps separate the described optical activity form that obtains by the chromatography of diastereomer (when generating diastereomer) by the racemic form that uses standard program to split compound or intermediate.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 IIc) 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 (IIb) 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.

B) aqueous solution of interpolation alkali metal bromate; With

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

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;

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, in both cases, all uses the Drug coating and the dressing process of known routine.

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 inhibitoryoncentration) 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 teichmann's crystals 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 1

MRQR 1

Streptococcus pneumoniae 0.25

Hemophilus influenzae 4

Linezolid resistance streptococcus pneumoniae 2

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 generally and suppresses, 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 is 94 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, participate-reform compound 1 and 7 are illustrational as mentioned.

Hereinafter described some intermediate and/or reference example place can have useful activity within the scope of the invention and/or also, and are provided as other aspect of the present invention.Concrete intermediate is an intermediate 14,20 and 21.Concrete reference example is a reference example 1,2,3,4 and 7.

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 Micromass Quattro 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-PO-; SYNTHETIC OPTICAL WHITNER (Bleach) is " Clorox " 6.15% clorox; THF is a tetrahydrofuran (THF); Ether is diethyl ether; TFA is a trifluoroacetic acid;

(viii) temperature is with a ℃ expression.

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

With 1-(5-bromopyridine-2-yl)-2-morpholine-4-base ethanol (intermediate 8) (388mg, 1.35mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] _ azoles alkane-2-ketone (intermediate 7) (525mg, 1.35mmol) and yellow soda ash (430mg 4.05mmol) is dissolved in/is suspended in N, in dinethylformamide/water (5mL, 10: 1).Mixture is handled through the degassing, with purging with nitrogen gas and add four (triphenylphosphines) close palladium (0) (156mg, 0.135mmol).It was heated 3 hours cool to room temperature and evaporating solvent, the silica gel chromatography of use methylene chloride (10: 1) wash-out at 75 ℃.So the free alkali that obtains is dissolved in Virahol/methylene dichloride (～20mL, 1: 1), and (1.5mL, 1M), most of methylene dichloride is removed in decompression to be added on HCl in the ether.Collect resistates and dry by filtering, obtain the hydrochloride (74%) of the product of 507mg, be colorless solid, mp＞194 ℃ (decomposition).

MS (ESP): C ₂₃H ₂₅FN ₆O ₄Be 469.21 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.00-4.20(m，11H)；4.29(dd，1H)；4.86(d，2H)；5.14-5.40(m，2H)；6.61(brs，1H)；7.40(m，1H)；7.52-7.75(m，3H)；7.77(s，1H)；8.05(d，1H)；8.19(s，1H)；8.71(s，1H)；10.58(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, (5R)-3-(3-fluorophenyl)-5-hydroxymethyl _ azoles alkane-2-ketone (40g, 0.189mol is referring to Upjohn WO 94-13649) is suspended in the anhydrous methylene chloride (400ml) by stirring.Add triethylamine (21g, 0.208mol) and 4-dimethylaminopyridine (0.6g, 4.9mmol), (20.3g 0.199mol), continues stirring 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) be dissolved in the mixture of chloroform (100ml) and acetonitrile (100ml), add trifluoroacetic acid silver (16.96g, 77mmol), (18.07g 71mmol) in the solution of vigorous stirring, 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, add mixture 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 the ether that adds capacity is to stir the stripping of brown impurity simultaneously 1 hour.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 in envrionment 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 the methylene dichloride (1.2L), and solution is with saturated sodium bicarbonate washing and dry (sal epsom).Filter and evaporate and 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

In methylene dichloride (250ml), stir (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1 at 0 ℃, and 3-_ azoles alkane-2-ketone (intermediate 3,25.0g, 74.2mmol).(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 N to methyl esters, dinethylformamide (50ml) 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 concentrates, and 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

1, stir (5R)-5-(azido methyl)-3-(3-fluoro-4-iodophenyl)-1 in the 4-dioxane, 3-_ azoles alkane-2-ketone (intermediate 5,30.3g, 72.9mmol).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 obtains required product through filtering, 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 (2.62g, 10.3mmol), potassium acetate (2.5g, 25.5mmol) and 1,1 '-(0.38g 0.52mmol) is suspended among the DMSO (15ml) [two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride title complex.80 ℃ of heated mixt 40 minutes, obtain transparent dark solution.Add ethyl acetate (150ml) then, mixture passes through diatomite filtration, with saturated brine (2 * 100ml) washings, with dried over sodium sulfate and evaporation, black residue is by chromatography purification (silica gel, the ethyl acetate in hexane of 40-100%, follow the acetonitrile in ethyl acetate by 1-5%), obtain product, be 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 chromatography purification (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-morpholine-4-base ethanol

(600mg 1.67mmol) is suspended among the anhydrous THF (5mL) and is cooled to 0 ℃ 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate (intermediate 9).(0.58mL, 6.7mmol), it was 0 ℃ of vigorous stirring 1 hour to add morpholine.(190mg 5mmol), adds methyl alcohol (4mL) subsequently to add sodium borohydride.Mixture stirred 30 minutes at 0 ℃, used concentrated hydrochloric acid to be acidified to pH＜2 then.Removal of solvent under reduced pressure uses potassium hydroxide aqueous solution (1M) to regulate pH to pH=10.Product is with dichloromethane extraction and use dried over sodium sulfate.Use hexane/acetone (1: 1) wash-out, use the silica gel chromatography of acetone wash-out then, obtain the product of 388mg (81%), be faint yellow solid.

MS (ESP): C ₁₁H ₁₅BrN ₂O ₂Be 287.03/289.03 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.40-2.65(m，6H)；3.53(dd，4H)；4.73(ddd，1H)；4.86(d，2H)；5.37(d，1H)；7.47(m，1H)；8.02(m，1H)；8.59(m，1H)。

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

(5.65g 28.2mmol) is dissolved in methyl alcohol/acetate (70mL+70 mL), adds the acetate (8mL) that contains 30%HBr with 1-(5-bromopyridine-2-yl) ethyl ketone (intermediate 10) (WO 9846605).Drip that brominated (1.45mL, acetate 28.3mmol) (15mL), reaction mixture are heated to 70 ℃ and continue 2 hours.Reaction mixture is evaporated to dried, and resistates obtains the hydrobromate of the rough product of 3.45 g (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 WO98/46605

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 continue 3 hours.Reaction mixture is cooled to-40 ℃ and also drips the water (15mL) that contains dense HCl (4.5mL), and it stirred 10 minutes at-35 ℃, under agitation was poured into then in the beaker that contains potassium phosphate buffer (pH 7 for 300mL, 1M).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, 112 ℃ of mp.Mother liquor further concentrates and separates by silica gel chromatography, uses dichloromethane/ethyl acetate (100: 1), obtains 3.25 other g products (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)-3-(4-{6-[2-(dimethylamino)-1-hydroxyethyl] pyridin-3-yl }-3- Fluorophenyl)-and 5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

1-(5-bromopyridine-2-yl)-2-(dimethylamino) alcoholic acid tfa salt (intermediate 11) (200mg, 0.56mmol), (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) (216mg, 0.56mmol), yellow soda ash (177mg, 1.67mmol) and four (triphenylphosphines) close palladium (0) (64mg, 0.056mmol), as described in embodiment 1, reacted 9.5 hours at 75 ℃.Use the silica gel chromatography of acetonitrile/water (5: 1) wash-out, and from ethanol by be added on HCl in the ether (1M ,～0.7mL) generate precipitation, obtain the hydrochloride of the product of 125mg (48%), be colorless solid, mp＞115 ℃ (decomposition).

MS (ESP): C ₂₁H ₂₃FN ₆O ₃Be 427.17 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.88(s，6H)；3.25-3.75(m，3H)；3.96(m，1H)；4.29(dd，1H)；4.86(d，2H)；5.12-5.20(m，2H)；7.39(m，1H)；7.52-7.75(m，3H)；7.75(s，1H)；8.05(d，1H)；8.20(s，1H)；8.69(s，1H)；10.20(brs，1H)。

The intermediate of embodiment 2 is prepared as follows:

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

(500mg 1.8mmol) is dissolved in methyl alcohol (20mL) and be cooled to-10 ℃, drips dimethylamine (0.9mL, the THF solution of 2M), adds triethylamine (0.25mL) subsequently with 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone (intermediate 9).After 30 minutes, add dimethylamine solution (0.25mL) again, it stirred 1.5 hours at-10 ℃ to-5 ℃.Portioning adds sodium borohydride, and (205mg, 5.4mmol), reaction mixture stirred 1 hour in addition at-5 ℃, used concentrated hydrochloric acid to be acidified to pH＜2 then.Removal of solvent under reduced pressure uses potassium hydroxide aqueous solution (1M) to regulate pH to pH=10.Separate at the enterprising circumstances in which people get things ready for a trip spectrometry of C-18 post ((RediSep, Isco Inc.)), use the acetonitrile in water of 0-5%, contain 0.1%TFA, obtain the tfa salt (34%) of the product of about 220mg, and the tfa salt of dimethylamine and triethylamine.Product need not purifying and can directly use.

MS (ESP): C ₉H ₁₃BrN ₂O is 245.07/247.07 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.87-3.15(m，3H)；3.02(s，6H)；4.70(m，1H)；7.20(d，1H)；7.77(dd，1H)；8.29(s，1H)；9.53(brs，1H)。

Embodiment 3:(5R)-and 3-(3-fluoro-4-{6-[1-hydroxyl-2-(sec.-propyl amino) ethyl] 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-(sec.-propyl amino) ethanol, and tfa salt (intermediate 12) (241mg, 0.65mmol), (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) (361mg, 0.93mmol), yellow soda ash (296mg, 2.79mmol) and four (triphenylphosphines) close palladium (0), and (108mg is 0.093mmol) as reaction as described in the embodiment 1.Use acetonitrile/water (6: 1) wash-out, use the silica gel chromatography of methylene chloride (5: 1) wash-out then, as described in embodiment 1, be settled out hydrochloride subsequently, obtain the hydrochloride (63%) of the product of 193mg, be colorless solid, mp＞170 ℃ (decomposition).

MS (ESP): C ₂₂H ₂₅FN ₆O ₃Be 441.22 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.27(m，6H)；3.12(m，1H)；3.37(m，2H)；3.96(m，1H)；4.30(dd，1H)；4.86(d，2H)；5.11-5.22(m，3H)；7.40(m，1H)；7.53-7.75(m，3H)；7.77(s，1H)；8.13(d，1H)；8.20(s，1H)；8.67(brs，1H)；8.75(s，1H)；9.15(brs，1H)。

The intermediate of embodiment 3 is prepared as follows:

Intermediate 12:1-(5-bromopyridine-2-yl)-2-(sec.-propyl amino) ethanol

2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone hydrobromate (intermediate 9) (600mg, 1.67mmol) and Isopropylamine (0.57mL, 6.7mmol) as process reaction as described in about intermediate 8, at C-18 post (RediSep, Isco Inc.) goes up chromatography and separate, adopt the acetonitrile of 0-30% in water, contain 0.1%TFA, obtain the tfa salt (39%) of the product of 241mg, be colorless oil.

MS (ESP): C ₁₀H ₁₅BrN ₂O is 259.11/261.11 (MH ⁺)

¹H-NMR(MeOH-d ₄)δ：1.34?and?1.36(2xd，6H)；3.22(m，1H)；3.38-3.55(m，2H)；4.98(dd，1H)；7.59(d，1H)；8.04(dd，1H)；8.64(s，1H)。

Embodiment 4:(5R)-3-{4-[6-(1, the 2-dihydroxy ethyl) pyridin-3-yl]-the 3-fluorophenyl }-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

1-(5-bromopyridine-2-yl) ethane-1,2-glycol (323mg, 1.48mmol) (intermediate 13), (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) (575mg, 1.48mmol), yellow soda ash (471mg, 4.44mmol) and four (triphenylphosphines) close palladium (0), and (171mg is 0.148mmol) as reaction as described in the embodiment 1.Use the silica gel chromatography of methylene chloride (5: 1) wash-out and, obtain the product (66%) of 388mg, be colorless solid, 175 ℃ of mp from the ethanol/hexane crystallization.

MS (ESP): C ₁₉H ₁₈FN ₅O ₄Be 400.16 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.52(m，1H)；3.71(m，1H)；3.95(m，1H)；4.28(dd，1H)；4.63(m，1H)；4.73(m，1H)；4.85(d，2H)；5.18(m，1H)；5.45(m，1H)；7.39(m，1H)；7.53-7.64(m，3H)；7.76(s，1H)；7.94(m，1H)；8.17(s，1H)；8.64(s，1H)。

The intermediate of embodiment 4 is prepared as follows:

Intermediate 13:1-(5-bromopyridine-2-yl) ethane-1, the 2-glycol

2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone (intermediate 9) (700mg, 2.51mmol) and sodium formiate (683mg 10.04mmol) mixes in 85% ethanol (5mL) and is heated to 50 ℃ and continues 3 hours.With its cool to room temperature, the most of solvent of reduction vaporization.It dilutes with methylene dichloride and water (5mL).Water dichloromethane extraction 3 times merge organic phase, use dried over sodium sulfate.Removal of solvent under reduced pressure, resistates are carried in the methyl alcohol (20mL) and are cooled to 0 ℃.Portioning adds sodium borohydride, and (285mg 7.5mmol), stirs it 1 hour at 0 ℃.Regulate pH to～pH2 by adding dense HCl, and removal of solvent under reduced pressure.Resistates is carried in methylene dichloride (100mL) and the saturated sodium bicarbonate solution (10mL), water dichloromethane extraction 3 times.The organic phase dried over sodium sulfate that merges.Use the silica gel chromatography of hexane/acetone (2: 1) wash-out, obtain the product of 223mg (41%), be colorless solid.

MS (ESP): C ₇H ₈BrNO ₂Be 218.05/220.05 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.47(m，1H)；3.65(m，1H)；4.55(m，1H)；4.71(ddd，1H)；5.50(dd，1H)；7.45(m，1H)；8.01(m，1H)；8.59(m，1H)。

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

2-(5-bromopyridine-2-yl) propane-2-alcohol (X.Wang etc., Tetrah.Lett.41 (2000), 4335) (500mg, 2.31mmol), (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) (900mg, 2.32mmol), yellow soda ash (740mg, 7mmol) and four (triphenylphosphines) close palladium (0) (268mg, 0.232mmol) as reaction as described in the embodiment 1, but 70 ℃ of heating 7.5 hours in the 10mL solvent.Use methylene chloride (17: 1) wash-out, use the silica gel chromatography of methylene dichloride/DMF (20: 1) wash-out then, (20: 1,20mL) the middle hexane that uses precipitated, and obtains the product of 247mg (27%), is colorless solid, 180 ℃ of mp from methylene dichloride/DMF.

MS (ESP): C ₂₀H ₂₀FN ₅O ₃Be 397.89 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.46(s，6H)；3.95(dd，1H)；4.29(dd，1H)；4.85(d，2H)；5.18(m，1H)；5.27(s，1H)；7.38(dd，1H)；7.55(dd，1H)；7.62(dd，1H)；7.73(d，1H)；7.76(s，1H)；7.92(m，1H)；8.18(s，1H)；8.64(s，1H)。

Embodiment 6:(5R)-and 3-[4-(6-{[(2,3-dihydroxypropyl) (methyl) amino] methyl } pyridine-3- Base)-the 3-fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

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 (intermediate 14) (100mg, 0.272mmol) in anhydrous THF (3mL), stir, at room temperature add 3-(methylamino) propane-1, and the 2-glycol (29mg, 0.272mmol).After 15 minutes, (81mg 0.381mmol), stirs them 3 days to add sodium triacetoxy borohydride.Removal of solvent under reduced pressure, resistates separates by silica gel chromatography, uses acetonitrile/water (10: 1 to 5: 1) wash-out, from the ethyl acetate/hexane crystallization, obtains the product of 25mg (20%), is colorless solid, 123 ℃ of mp.

MS (ESP): C ₂₂H ₂₅FN ₆O ₄Be 457.15 (MH ⁺)

¹H-NMR(DMSOd- ₆)δ：2.23(s，3H)；2.32-2.75(m，2H)；3.30-3.75(m，4H)；3.95(dd，1H)；4.01(m，1H)；4.29(dd，1H)；4.45-4.55(m，2H)；4.85(d，2H)；5.18(m，1?H)；7.39(dd，1H)；7.52-7.67(m，3H)；7.76(s，1H)；7.93(m，1H)；8.18(s，1H)；8.64(s，1H)。

The intermediate of embodiment 6 is prepared as follows:

Intermediate 14:5-{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

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 (0) (280mg, 0.24mmol) as reaction as described in the embodiment 1, but be 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)。

Embodiment 7:(5R)-and 3-[3-fluoro-4-(6-{[(2-hydroxyethyl) (methyl) amino] methyl } pyridine- The 3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

Use and embodiment 6 described identical process, (20.5mg, 0.272mmol) (100mg 0.272mmol) reacts 2-(methylamino) ethanol, obtains the product of 58mg (50%), is colorless solid, 137 ℃ of mp with intermediate 14.

MS (ESP): C ₂₁H ₂₃FN ₆O ₃Be 427.14 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.23(s，3H)；2.32-2.75(m，2H)；3.52(m，2H)；3.67(s，2H)；3.95(dd，1H)；4.29(dd，1H)；4.44(dd，1H)；4.85(d，2H)；5.18(m，1H)；7.39(dd，1H)；7.52-7.67(m，3H)；7.77(s，1H)；7.93(m，1H)；8.18(s，1H)；8.64(s，1H)。

Embodiment 8:(5R)-and 3-(4-{6-[(dimethylamino) methyl] pyridin-3-yl }-the 3-fluorophenyl)- 5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

Use and embodiment 6 described identical process, (0.272mmol) (100mg 0.272mmol) reacts dimethylamine, obtains the product of 23mg (21%), is colorless solid, 160 ℃ of mp with intermediate 14 for the THF solution of 2M, 0.136mL.

MS (ESP): C ₂₀H ₂₁FN ₆O ₂Be 427.14 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.21(s，6H)；3.55(s，2H)；3.95(dd，1H)；4.29(dd，1H)；4.85(d，2H)；5.18(m，1H)；7.39(dd，1H)；7.49-7.67(m，3H)；7.77(s，1H)；7.93(m，1H)；8.18(s，1H)；8.64(s，1H)。

Embodiment 9:(5R)-and 3-{3-fluoro-4-[6-(morpholine-4-ylmethyl) pyridin-3-yl] phenyl }-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

4-[(5-bromopyridine-2-yl) methyl] and morpholine (intermediate 15,185mg, 0.72mmol), (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 7,279mg, 0.72mmol), yellow soda ash (305mg, 2.88mmol) and four (triphenylphosphines) close palladium (0) (83mg, 0.072mmol) as reaction as described in the embodiment 1, but 70 ℃ of heating 5 hours.Use the silica gel chromatography of methylene chloride (12: 1) wash-out, and use hexane to generate precipitation, obtain the product of 172mg (55%), be colorless solid, 175 ℃ of mp from methylene dichloride.

MS (ESP): C ₂₂H ₂₃FN ₆O ₃Be 439.04 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.43(t，4H)；3.59(t，4H)；3.62(s，2H)；3.95(dd，1H)；4.29(dd，1H)；4.86(d，2H)；5.18(m，1H)；7.39(m，1H)；7.52-7.66(m，3H)；7.77(s，1H)；7.93(m，1H)；8.18(s，1H)；8.66(s，1H)。

The intermediate of embodiment 9 is prepared as follows:

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

Use and embodiment 6 described identical process 5-bromopyridine-2-formaldehyde (X.Wang etc., Tetrah.Lett.41 (2000), 4335) (200mg, 1.08mmol) and morpholine (0.094mL, 1.08mmol) with sodium triacetoxy borohydride (319mg, 1.51mmol) reaction.Use hexane/acetone (3: 1) wash-out, the back silica gel chromatography of hexane/ethyl acetate (1: 1), obtain the product of 185mg (67%), be colorless oil to ethyl acetate/methanol (50: 1) wash-out.

MS (ESP): C ₁₀H ₁₃BrN ₂O is 257.07/259.11 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.38(t，4H)；3.55(s，2H)；3.56(t，4H)；7.41(dd，1H)；8.00(dd，1H)；8.60(d，1H)。

Embodiment 10:(5R)-and 3-(3-fluoro-4-{6-[(1R)-1-hydroxyethyl] pyridin-3-yl } phenyl)- 5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

(1R)-1-(5-bromopyridine-2-yl) ethanol (intermediate 16,430mg, 2.13mmol), (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 7,826mg, 2.13mmol), yellow soda ash (677mg, 6.4mmol) and four (triphenylphosphines) close palladium (0) (246mg, 0.213mmol) as reaction as described in the embodiment 1, but 70 ℃ of heating 4 hours in the 10mL solvent.Use the silica gel chromatography of methylene chloride (12: 1) wash-out and, obtain the product of 421mg (52%), be colorless solid, 190 ℃ of mp from the ethanol/hexane crystallization.

MS (ESP): C ₁₉H ₁₈FN ₅O ₃Be 384.16 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.39(d，3H)；3.95(dd，1H)；4.29(dd，1H)；4.76(m，1H)；4.85(d，2H)；5.18(m，1H)；5.42(d，1H)；7.38(dd，1H)；7.52-7.66(m，3H)；7.77(s，1H)；7.95(m，1H)；8.18(s，1H)；8.63(s，1H)。

The intermediate of embodiment 10 is prepared as follows:

Intermediate 16 and 17:(1R)-1-(5-bromopyridine-2-yl) ethanol and (1S)-1-(5-bromopyridine-2- Base) ethanol

(1.0g 5.4mmol) is dissolved in anhydrous THF (25mL) and be cooled to 0 ℃ with 5-bromopyridine-2-formaldehyde (X.Wang etc., Tetrah.Lett.41 (2000), 4335).Under agitation drip methyl-magnesium-bromide (1.4M, in toluene/THF (3: 1), 4.6mL, 6.45mmol).Reaction mixture dilutes with ethyl acetate, washs and use dried over sodium sulfate with potassium phosphate buffer (pH 7).Use the silica gel chromatography of hexane/ethyl acetate (2: 1) wash-out, obtain the racemic product of 1.013g (93%), be colorless oil.

MS (ESP): C ₇H ₈BrNO is 202.02/204.02 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.33(d，3H)；4.68(m，1H)；5.45(d，1H)；7.48(d，1H)；8.01(dd，1H)；8.57(d，1H)。

The racemic mixture of two products separates on chiralpak AD post, uses 95% hexane, 5% ethanol/methyl alcohol (1: 1).The specific rotation of first isomer of wash-out is [α] from the post _D ²⁰=-42.2 (ethanol c=1), is confirmed as the S-configuration, obtains 400mg; The specific rotation of second isomer of wash-out is [α] _D ²⁰=+38.3 (ethanol c=1) and be confirmed as the R-configuration, obtains 430mg.

Embodiment 11:(5R)-and 3-(3-fluoro-4-{6-[(1S)-1-hydroxyethyl] pyridin-3-yl } phenyl)-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

(1S)-1-(5-bromopyridine-2-yl) ethanol (intermediate 17) (400mg, 1.98mmol), (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) (769mg, 1.98mmol), yellow soda ash (630mg, 5.9mmol) and four (triphenylphosphines) close palladium (0) (228mg, 0.198mmol) as reaction as described in the embodiment 1, but 70 ℃ of heating 4 hours in the 10mL solvent.Use the silica gel chromatography of methylene chloride (12: 1) wash-out and, obtain the product of 287mg (38%), be colorless solid, 183 ℃ of mp from the ethanol/hexane crystallization.

MS (ESP): C ₁₉H ₁₈FN ₅O ₃Be 384.16 (MH ⁺)

Embodiment 12:(5R)-3-[4-(two (2-hydroxyethyl) amino of 6-{[] methyl } pyridin-3-yl)-3- Fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

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 (intermediate 14,200mg 0.55mmol) is suspended in anhydrous THF (15mL), adds diethanolamine (63mg, 0.6mmol) add, mixture stirred 20 minutes.(233mg, 1.1mmol), mixture at room temperature stirs and spends the night to add sodium triacetoxy borohydride.React with 1 M HCl cancellation, regulate pH to pH8 with saturated sodium bicarbonate then, it extracts with methylene dichloride (20mL * 3), use dried over mgso, concentrate and by hurried chromatography purification, use contains the methylene dichloride of 15% methyl alcohol and 1% ammonium hydroxide, obtains product, is colourless water absorbability solid (64mg).

MS (ESP): C ₂₂H ₂₅FN ₆O ₄Be 457.24 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.01(m，4H)；3.35(s，2H)；3.65(m，4H)；4.00(m，1H)；4.25(dd，1H)；4.86(d，2H)；5.18(m，1H)；7.42(d，1H)；7.61(t，1H)；7.65(m，2H)；7.81(s，1H)；8.05(d，1H)；8.22(s，1H)；8.75(s，1H)。

(not observing two OH protons).

Embodiment 13: morpholine-4-formic acid (5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl) methyl esters

The sealing the microwave reaction container in (5R)-3-{3-fluoro-4-[6-(hydroxymethyl) pyridin-3-yl] phenyl-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (intermediate 18) (20mg, 0.054mmol) and morpholine-4-carbonyl chlorine (24.3mg, 0.163mmol) be dissolved in pyridine (3mL) and in the Smith microwave reactor 180 ℃ the heating 25 minutes.Removal of solvent under reduced pressure, (HPLC C-18), uses acetonitrile (the contain 0.1%TFA) wash-out of 5-75% in water to resistates, obtains title compound (18mg), mp 131-133 ℃ by the reverse-phase chromatography purifying.

MS (ESP): C ₂₃H ₂₃FN ₆O ₅Be 483.19 (MH ⁺)

¹H-NMR?300?MHz(DMSO-d ₆)δ：3.45(m，4H)；3.62(m，4H)；3.95(m，1H)；4.32(dd，1H)；4.86(d，2H)；5.18(m，1H)；5.19(s，2H)；7.35～7.70(m，4H)；7.77(s，1H)；8.01(d，1H)；8.18(s，1H)；8.72(s，1H)。

Intermediate 18:(5R)-and 3-{3-fluoro-4-[6-(hydroxymethyl) pyridin-3-yl] phenyl }-5-(1H- 1,2,3-triazoles-1-ylmethyl)-1,3-_ azoles alkane-2-ketone

(5-bromopyridine-2-yl) methyl alcohol (X.Wang etc., Tetrah.Lett.41 (2000), 4335) (200mg, 1.06mmol), (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 7,413mg, 1.06mmol), yellow soda ash (450mg, 4.25mmol) and four (triphenylphosphines) close palladium (0), and (122mg 0.106mmol) according to embodiment 1 described reaction, but heated 4 hours at 70 ℃.Use the silica gel chromatography of methylene chloride (10: 1) wash-out, and use hexane to generate precipitation, obtain the product of 191mg (49%), be colorless solid, 177 ℃ of mp from hot methanol.

MS (ESP): C ₁₈H ₁₆FN ₅O ₃Be 370.04 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.95(dd，1H)；4.29(dd，1H)；4.60(d，2H)；4.86(d，2H)；5.18(m，1H)；5.48(t，1H)；7.39(m，1H)；7.52-7.66(m，3H)；7.77(s，1H)；7.96(m，1H)；8.18(s，1H)；8.64(s，1H)。

Embodiment 14:(5R)-and 3-{3-fluoro-4-[6-(1-hydroxyl-3-oxo butyl) pyridin-3-yl] benzene Base }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } (intermediate 14,3.2g 8.72mmol) are dissolved in acetone (30mL) to pyridine-2-formaldehyde, (4.45g, 32.2mmol), mixture refluxed 30 minutes to add salt of wormwood.Removal of solvent under reduced pressure is dissolved in methylene dichloride with resistates and washes with water.The silica gel chromatography of the methanol-eluted fractions of use 5% in methylene dichloride obtains product, is colorless solid (3.25g) mp 130-135 ℃.

MS (ESP): C ₂₁H ₂₀FN ₅O ₄Be 426.23 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.17(s，3H)；2.77(dd，1H)；2.93(dd，1H)；3.97(m，1H)；4.30(dd，1H)；4.86(d，2H)；5.09(m，1H)；5.18(m，1H)；5.69(d，1H)；7.40(d，1H)；7.61(m，3H)；7.78(s，1H)；7.98(d，1H)；8.20(s，1H)；8.65(s，1H)。

Embodiment 15:(5R)-3-{4-[6-(1,3-dihydroxyl butyl) pyridin-3-yl]-the 3-fluorophenyl }-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

(5R)-and 3-{3-fluoro-4-[6-(1-hydroxyl-3-oxo butyl) pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 14 for 3-_ azoles alkane-2-ketone, 500mg 1.18mmol) is suspended in the dehydrated alcohol (10mL), adds sodium borohydride (131mg at 0 ℃, 3.53mmol), the mixture that the obtains ambient temperature overnight of slowly rising again.Be reflected at 0 ℃ with 1M HCl (several) cancellation, solvent evaporated under reduced pressure, resistates obtains title compound by reverse-phase chromatography purifying (C-18), is colorless solid (151mg).

MS (ESP): C ₂₁H ₂₂FN ₅O ₄Be 428.19 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：1.12(m，3H)；3.40(m，3H)；3.79(m，2H)；3.95(m，1H)；4.21(dd，1H)；4.70(m，1H)；4.81(m，2H)；5.18(m，1H)；7.40(m，1H)；7.61(m，3H)；7.70(s，1H)；7.98(m，1H)；8.13(s，1H)；8.65(s，1H)。

Embodiment 16:(5R)-3-(4-{6-[cyclopropyl (hydroxyl) methyl] pyridin-3-yl }-the 3-fluorophenyl)- 5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

(5-bromopyridine-2-yl) (cyclopropyl) methyl alcohol (intermediate 19,300mg, 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 7,510mg, 1.31mmol), salt of wormwood (543mg, 3.93mmol) and PS-PPh ₃-Pd (Argonaut TechnologiesInc.) (0.13mmol, 0.11mmol/g) ethylene glycol/ethanol/water (2: 2: 1, mix in 10mL) and be incorporated in 75 ℃ of heated overnight.With its cool to room temperature, by diatomite filtration, filtrate is extracted with ethyl acetate and water (10mL+5mL).Organic layer concentrates and passes through the hurried silica gel chromatography purifying of the methanol-eluted fractions of use 5% in methylene dichloride through dried over mgso, obtains product, is colorless solid (70 mg), mp 160-163 ℃.

MS (ESP): C ₂₁H ₂₀FN ₅O ₃Be 410.14 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：0.40(m，4H)；1.12(m，1H)；3.92(m，1H)；4.18(m，1H)；4.24(m，1H)；4.81(m，2H)；5.18(m，1H)；5.32(d，1H)；7.35(m，1H)；7.60(m，3H)；7.71(s，1H)；7.93(d，1H)；8.19(s，1H)；8.65(s，1H)。

Intermediate 19:(5-bromopyridine-2-yl) (cyclopropyl) methyl alcohol

(470mg 2.5mmol) is dissolved in anhydrous THF and be cooled to-20 ℃ to 5-bromopyridine-2-formaldehyde (X.Wang etc., Tetrah.Lett.41,2000).Drip cyclopropyl bromination magnesium (5mmol, the THF solution of 0.5M), make the mixture ambient temperature overnight of rising again.Reaction is used ethyl acetate extraction with several 1 M HCl cancellation, uses dried over mgso.Use the silica gel chromatography of methylene dichloride wash-out to obtain product, be colorless oil (300mg) that it need not to be further purified and can be directly used in down the step.

MS (ESP): C ₉H ₁₀BrNO is 230.05 (MH ⁺)

Embodiment 17:(5R)-and 3-(3-fluoro-4-{6-[(methylsulfinyl) methyl] pyridin-3-yl } benzene Base)-and 5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

With

Embodiment 18:(5R)-and 3-(3-fluoro-4-{6-[(methyl sulphonyl) methyl] pyridin-3-yl } phenyl)- 5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

(5R)-and 3-(3-fluoro-4-{6-[(methyl sulfenyl) methyl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 19 for 3-_ azoles alkane-2-ketone, 140mg 0.35mmol) is dissolved in anhydrous methylene chloride (10mL), is cooled to 0 ℃, add m-chlorobenzoic acid (0.35mmol), mixture at room temperature stirred 3 hours then.(2M, 5mL), mixture stirred 20 minutes to add aqueous solution of sodium bisulfite.Organic phase is used dried over mgso with saturated sodium bicarbonate aqueous solution (10mL * 2) and salt water washing.The silica gel chromatography of the methanol-eluted fractions of use 2.5% in methylene dichloride, at first wash-out goes out embodiment 18, is colorless solid (61mg, mp 224-228 ℃) that wash-out goes out embodiment 17 subsequently, is colorless solid (22mg, mp 205-210 ℃).

Embodiment 17: MS (ESP): C ₁₉H ₁₈FN ₅O ₃S is 416.11 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.62(s，3H)；3.92(m，1H)；4.12(m，1H)；4.34(m，2H)；4.81(d，2H)；5.18(m，1H)；7.30～7.7(m，4H)；7.71(s，1H)；7.93(d，1H)；8.19(s，1H)；8.75(s，1H)。

Embodiment 18: MS (ESP): C ₁₉H ₁₈FN ₅O ₄S is 432.12 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.02(s，3H)；3.92(m，1H)；4.28(dd，1H)；4.72(s，2H)；4.81(d，2H)；5.18(m，1H)；7.38(d，1H)；7.65(m，3H)；7.71(s，1H)；8.01(d，1H)；8.19(s，1H)；8.75(s，1H)。

Embodiment 19:(5R)-and 3-(3-fluoro-4-{6-[(methyl sulfenyl) methyl] pyridin-3-yl } phenyl)-5- (1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

With imino-thiocarbamate (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) methyl ester (intermediate 20) (450mg, 0.89mmol) and methyl iodide (251mg, 1.77mmol) (15% the aqueous solution is 15mL) and in the mixture of methylene dichloride (30mL) to add sodium hydroxide to.Add Tetrabutyl amonium bromide (catalytic amount), mixture vigorous stirring 4 hours.(2 * 10mL) extract water layer, and the organic layer of merging is with 1M HCl and salt water washing, with dried over mgso and concentrating under reduced pressure with methylene dichloride.The silica gel chromatography of the methanol-eluted fractions of use 2.5% in methylene dichloride obtains product, is colorless solid (140mg).

MS (ESP): C ₁₉H ₁₈FN ₅O ₂S is 400.13 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.02(s，3H)；3.80(s，2H)；3.92(m，1H)；4.28(dd，1H)；4.82(d，2H)；5.18(m，1H)；7.34(d，1H)；7.43(m，1H)；7.58(m，1H)；7.60(m，1H)；7.71(s，1H)；7.91(d，1H)；8.20(s，1H)；8.70(s，1H)。

Intermediate 20: imino-thiocarbamate (5-{2-fluoro-4-[(5R)-2-oxo-5-(1H- 1,2,3-triazoles-1-ylmethyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl) methyl ester

(5R)-3-{4-[6-(brooethyl) pyridin-3-yl]-the 3-fluorophenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (intermediate 21) (483mg, 1.12mmol) and thiocarbamide (89mg, 1.17mmol) in ethanol (15mL), mix and refluxed 2.5 hours, with its cool to room temperature, filter, dilute with ether (30mL), the throw out that obtains is collected by filtering, and obtains product, is colourless water absorbability solid (450mg).

MS (ESP): C ₁₉H ₁₈FN ₇O ₂S is 428.15 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.95(m，1H)；4.28(dd，1H)；4.65(s，2H)；4.87(d，2H)；5.18(m，1H)；7.41(d，1H)；7.58～7.68(m，3H)；7.79(s，1H)；8.05(d，1H)；8.20(s，1H)；8.75(s，1H)；9.01(brs，2H)；9.55(brs，1H)。

Intermediate 21:(5R)-3-{4-[6-(brooethyl) pyridin-3-yl]-the 3-fluorophenyl }-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

(5R)-and 3-{3-fluoro-4-[6-(hydroxymethyl) pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (intermediate 18) (1.8g, 4.88mmol) and carbon tetrabromide (1.94g 5.85mmol) mixes in anhydrous methylene chloride (80mL) and is cooled to-5 ℃.Add PS-PPh ₃(Argonaut Technologies Inc.) (7.32mmol, 1.41mmol/g), mixture stirred the ambient temperature overnight of rising again then 10 minutes at 4 ℃.It is through filtering, and filtrate is through concentrating, and resistates obtains product by using the silica gel chromatography purifying of eluent ethyl acetate, is colorless solid (484mg).

MS (ESP): C ₁₈H ₁₅BrFN ₅O ₂Be 433.99 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.95(m，1H)；4.28(dd，1H)；4.75(s，2H)；4.82(d，2H)；5.18(m，1H)；7.40(d，1H)；7.43(m，1H)；7.58(d，1H)；7.68(m，2H)；8.0(d，1H)；8.20(s，1H)；8.71(s，1H)。

Embodiment 20:(5R)-3-(4-{6-[2-(2,5-dimethyl-1H-imidazoles-1-yl)-1-hydroxyethyl] Pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

Under low-grade fever with (5R)-3-(4-{6-[(2; 5-dimethyl-1H-imidazoles-1-yl) ethanoyl] pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1; 2; 3-triazol-1-yl methyl)-1; 3-_ azoles alkane-2-ketone (intermediate 22; 100mg 0.21mmol) is dissolved in 1: 1 dioxane: methyl alcohol (5mL).In transparent and still warm solution, add sodium borohydride (20mg, 0.53mmol).Mixture at room temperature stirred 10 minutes, water (10mL) dilution, and (20mL 10mL) extracts secondary with ethyl acetate.The organic layer that merges is used dried over mgso with saturated sodium-chloride (10mL) washing, is concentrated into the volume of 2-3mL then, obtains suspension.Suspension dilutes with ether (15mL), and supersound process was also placed 15 minutes.Collect solid,, obtain title compound, be white powder (39mg) mp 195-200 ℃ with ether rinse and 50 ℃ of vacuum-dryings.

MS (ESP): C ₂₄H ₂₄FN ₇O ₃Be 478.21 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.16(s，3H)；2.33(s，3H)；4.00(m，2H)；4.29(m，2H)；4.85(m，1H)；4.86(d，2H)；5.18(m，1H)；6.00(d，1H)；6.67(s，1H)；7.40(dd，1H)；7.57(dd，1H)；7.64(m，2H)；7.77(s，1H)；8.02(d，1H)；8.18(s，1H)；8.73(s，1H)。

Intermediate 22:(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 23,985mg, 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 (0) 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, mp 112-115 ℃.

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)。

Intermediate 23:1-(5-bromopyridine-2-yl)-2-(2,5-dimethyl-1H-imidazoles-1-yl) ethyl ketone

1-[2-(5-bromopyridine-2-yl)-2-oxoethyl]-2, (intermediate 24,4.75g 7.7mmol) are dissolved in methylene dichloride (100mL) to 5-dimethyl-3-trityl-1H-imidazoles-3-_ bromide, add trifluoroacetic acid (15mL).Be heated gentle reflux 1.5 hours of mixture.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 24:1-[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 25,4.5g, 13.4mmol), 2-bromo-1-(5-bromopyridine-2-yl) ethyl ketone (free alkali of intermediate 9,2.5g, 9mmol) ((pH 7 by using potassium phosphate buffer, 1M) handle the suspension of intermediate 9 in ethyl acetate, generate free alkali from hydrobromate, 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.With the reaction mixture cool to room temperature, throw out is by filter collecting, with hexane wash (2 * 50mL), obtain the product of 4.75g (86%), be pale solid, mp＞150 ℃ (decomposition).

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 25:2,4-dimethyl-1-trityl-1H-imidazoles

At room temperature in 45 minutes with trityl chloride (15g, 55mmol) drips of solution in methylene dichloride (50mL) 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 in addition 30 minutes.Evaporating solvent is carried on toluene (600mL) with resistates, with potassium phosphate buffer (pH 7,1M, 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 by filter collect and with hexane wash (2 * 50mL), obtain the product of 14.76g (84%), be colorless solid.

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

Reference example 1:5-{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-nitrile

5-bromo-2-cyanopyridine (212mg, 1.16mmol), (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) (449mg, 1.16mmol), yellow soda ash (368mg, 3.47mmol) and four (triphenylphosphines) close palladium (0) (134mg, 0.116mmol) according to embodiment 1 described reaction, but 70 ℃ of heating 4.5 hours.Use the silica gel chromatography of methylene chloride (20: 1) wash-out, and, obtain the product of 191mg (45%), be colorless solid, mp＞215 (decomposition) according to embodiment 1 described generation precipitation.

MS (ESP): C ₁₈H ₁₃FN ₆O ₂Be 364.79 (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(m，1H)；7.61(m，1H)；7.74(dd，1H)；7.76(s，1H)；8.15(d，1H)；8.18(s，1H)；8.24(d，1H)；8.95(s，1H)。

Reference example 2:(5R)-3-[3-fluoro-4-(6-picoline-3-yl) phenyl]-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3-_ azoles alkane-2-ketone

5-bromo-2-picoline (160mg, 0.93mmol), (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 (362mg, 0.93mmol), salt of wormwood (514mg, 3.72mmol) and PS-PPh ₃(0.093mmol is 0.11mmol/g) according to embodiment 16 described reactions for-Pd (Argonaut Technologies Inc.).The silica gel chromatography of the methanol-eluted fractions of use 3% in methylene dichloride obtains product, is pale solid (120mg).

MS (ESP): C ₁₈H ₁₆FN ₅O ₂Be 354.14 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.31(s，3H)；3.96(m，1H)；4.28(dd，1H)；4.86(d，2H)；5.18(m，1H)；7.38(m，2H)；7.60(m，2H)；7.82(s，1H)；7.86(d，1H)；8.21(s，1H)；8.61(s，1H)。

Reference example 3:(5R)-and 3-{3-fluoro-4-[6-(hydroxymethyl) pyridin-3-yl] phenyl }-5-(1h- 1,2,3-triazoles-1-ylmethyl)-1,3-_ azoles alkane-2-ketone

(5-bromopyridine-2-yl) methyl alcohol (X.Wang etc., Tetrah.Lett.41 (2000), 4335) (200mg, 1.06mmol), (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) (413mg, 1.06mmol), yellow soda ash (450mg, 4.25mmol) and four (triphenylphosphines) close palladium (0) (122mg be 0.106mmol) as reaction as described in the embodiment 1.Use the silica gel chromatography of methylene chloride (10: 1) wash-out, and use hexane to generate precipitation, obtain the product of 191mg (49%), be colorless solid, 177 ℃ of mp from hot methanol.

MS (ESP): C ₁₈H ₁₆FN ₅O ₃Be 370.04 (MH ⁺)

Reference example 4:(5R)-3-(3-fluoro-4-pyridin-3-yl phenyl)-5-(1H-1,2,3-triazol-1-yl first Base)-1,3-_ azoles alkane-2-ketone

The 3-bromopyridine (245mg, 1.55mmol), (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 (500mg, 1.29mmol), salt of wormwood (713mg, 5.16mmol) and four (triphenylphosphines) close palladium (0) (75mg, 0.065mmol) according to embodiment 1 described reaction, but 75 ℃ of heated overnight.The chromatography of the methanol-eluted fractions of use 5% in methylene dichloride obtains product, is pale solid (220mg).

MS (ESP): C ₁₇H ₁₄FN ₅O ₂Be 340.12 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：3.96(m，1H)；4.31(dd，1H)；4.86(d，2H)；5.18(m，1H)；7.40(dd，1H)；7.52(m，2H)；7.62(t，1H)；7.75(s，1H)；7.96(d，1H)；8.19(s，1H)；8.59(s，1H)；8.72(s，1H)。

Reference example 5

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

Reference example 6:(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, mixture (the 210mg ,～0.54mmol of 2-_ azoles alkane-2-ketone and corresponding boric acid, 57%), it need not to be further purified and can directly use.

With the boric acid ester of as above preparation and mixture, 5-bromo-2-(2-methyl-2H-tetrazolium-5-yl) pyridine (160mg of boric acid, 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 (0) 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 of this reference example is prepared 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 is separated by filtering, and with the ethyl acetate washing, obtains title compound then, is using the linen amorphous solid that need not to be further purified in the step down with ethyl acetate for reaction mixture.

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 at room temperature to be kept 2 hours then.Reaction mixture distributes between frozen water and ethyl acetate.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 dichloride: ethyl acetate (60: 1) wash-out]:

1.5-bromo-2-(1-methyl isophthalic acid H-tetrazolium-5-yl) pyridine (1.397g), 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), 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.

Reference example 7:5-(2-fluoro-4-{ (5R)-5-[(4-methyl isophthalic acid H-1,2,3-triazol-1-yl) methyl]-2- Oxo-1,3-_ azoles alkane-3-yl } phenyl) pyridine-2-nitrile

5-bromopyridine-2-nitrile (118mg, 0.64mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-[(4-methyl isophthalic acid H-1,2, the 3-triazol-1-yl) methyl]-1,3-_ azoles alkane-2-ketone (WO 2003072576) (259mg, 0.64mmol), salt of wormwood (356mg, 2.58mmol) and PS-PPh ₃(0.032mmol is 0.11mmol/g) according to embodiment 16 described reactions for-Pd (Argonaut Technologies Inc.).The silica gel chromatography of the methanol-eluted fractions of use 3% in methylene dichloride obtains product (42mg), is colorless solid, mp 210-212 ℃.

MS (ESP): C ₁₉H ₁₅FN ₆O ₂Be 379.09 (MH ⁺)

¹H-NMR(DMSO-d ₆)δ：2.18(s，3H)；3.92(m，1H)；4.28(dd，1H)；4.78(d，2H)；5.18(m，1H)；7.38(d，1H)；7.60(d，1H)；7.72(t，1H)；7.81(s，1H)；8.10(d，1H)；8.19(d，1H)；8.93(s，1H)。

Claims

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

Wherein:

Condition is R ⁴It can not be hydroxymethyl.

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 (1-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-OC (O) R ⁵, carboxyl and-NR ⁵R ⁶Substituting group replace].

5. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I), wherein R in the aforementioned claim ⁵And R ⁶Be independently selected from hydrogen, methyl, cyclopropyl (optional), carboxyl methyl by methyl substituted and (2-4C) alkyl (optionally 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.

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, the method comprising the steps of (a) to (n); 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;

A) by changing the substituting group in other compound of the present invention or in other compound of the present invention, introducing substituting group;

B) through type (II) compound (wherein X is the leavings group that can be used in palladium [0] coupled reaction) and Compound I Ia reaction, described Compound I Ia also has leavings group X, makes to replace phenyl-X key and pyridyl-X key with pyridyl-phenyl key;

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

(d) by making the compound of formula (IV):

Wherein X be displaceable group and Y be halogen or

Wherein R is (optional substituted) alkyl;

E) from the α halogenated derivative of formula (IV) (wherein X is that the definition of ketone and Y is the same), by with the nucleophilic reagent reaction, carry out the reduction of ketone then, (when Y is halogen) is according to above b then) described in the compound reaction of formula (II);

F) be the alkylation of the 2-picoline group in the compound of formula (IV) of halogen by Y wherein, obtain the compound of formula (IIa), then with the compound reaction of formula (II);

G) be epoxide and Y such as above d by X wherein) in the compound of formula (IV) of definition in epoxide and nucleophilic reagent reaction, (when Y is halogen) is according to above b then) described in the compound reaction of formula (II);

I) reduction amination by aldehyde radical,

J) by vinyl pyridine being carried out the anti-horse formula addition of amine;

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

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

M) by making amino methyl _ oxazolidone and 1,1-dihalo ketone alkylsulfonyl hydrazone reaction;

N) work as R ¹During for the 4-halo, by making the reaction of azido methyl _ oxazolidone and vinyl halides base SULPHURYL CHLORIDE;