CN1989135A

CN1989135A - 3- (4- (2-dihydroisoxazol-3-ylpyridin-5-yl) phenyl) -5-triazol-1-ylmethyloxazolidin-2-one derivaives as mao inhibitors for the treatment of bacterial infections

Info

Publication number: CN1989135A
Application number: CN 200580025003
Authority: CN
Inventors: M·B·格拉维斯托克; D·R·卡卡纳古
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: GB0411595D0

Abstract

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

Description

3-(4-(the different  azoles of 2-dihydro-3-yl pyridines-5-yl) the phenyl)-5-triazol-1-yl methyl  oxazolidin-2-ketone derivatives that is used for the treatment of infectation of bacteria as the MAO inhibitor

The present invention relates to Antibiotique composition, particularly contain the  oxazolidone ring of replacement and the Antibiotique composition of different  oxazoline 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.

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

The class of having described our application WO 03/022824 contains  oxazolidone ring and/or both biaryl Antibiotique compositions of different  oxazoline ring of replacement, it has the activity that useful antagonism comprises the Gram-positive pathogenic agent of MRSA and MRCNS, particularly resist and variously vancomycin and/or Linezolid are shown chemical sproof bacterial strain and/or antagonism aminoglycoside and the beta-lactam that uses are clinically all had chemical sproof manure enterococcin strain, also difficult foster gram negative strain such as hemophilus influenzae of antagonism, the Catarrhal catarrhalis, mycoplasma and chlamydozoan bacterial strain.Therefore, these compounds contain the group of two energy as pharmacophore, and they can be independently in the combination of pharmacophore combining site, perhaps, group can the pharmacophore combining site in conjunction with and another group is brought into play different effects in mechanism of action.

In this patent application, each comfortable 5-position of  oxazolidone ring and different  oxazoline ring has substituting group, described substituting group is selected from this area and it has been generally acknowledged that the substituting group that is suitable for described antiseptic-germicide, for example methylacetamide (referring to for example WO 93/09103), the heterocycle (referring to for example WO 00,/21 960) and the heterocyclyl methyl group (referring to for example WO 01/81350) that are connected with methylamino.

The also known compound that contains the  oxazolidone (referring to for example GB 2028306A) as monoamine oxidase (MAO) inhibitor.The actual MAO inhibition that takes place may be the potential cause of the unwanted side effect of  oxazolidone antiseptic-germicide, therefore, wishes usually to make this character minimize (referring to for example WO 03/072575) in any potential antiseptic-germicide.Especially, pointed out that having the substituent  oxazolidone that contains amine and ether in the 5-position of  oxazolidone ring has powerful MAO inhibition activity (referring to for example GB 2028306A; J.Pharm Pharmacol, 1983,161-165; J.Am.Chem.Soc, 111,8891-8895; And reference wherein).

We find unexpectedly that at present a class contains a  oxazolidone ring and different  oxazoline ring, has ether or replace the ether side chain and have triazole ring on different  azoles quinoline on the  oxazolidone biaryl compound has acceptable MAO inhibition level, has useful anti-microbial activity simultaneously.

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 selected from cyano methyl, carboxyl methyl ,-CH ₂C (O) NR ⁵R ⁶(2-4C) 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, cyano group ,-OC (O) R ⁵, carboxyl ,-C (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];

R 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; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted);

Perhaps, R ⁵And R ⁶The nitrogen that is connected with them forms optional 14,5 or 6 yuan the saturated heterocyclic basic ring that is independently selected from other heteroatoms (except being connected the N atom) of O, N and S that contains 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).

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.

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.

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 defined 4,5 or 6 yuan the saturated heterocyclic basic ring 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, 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) andMethods 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 triazolium 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 methoxy-ether and 2,2-dimethyl propylene acyloxy methoxy-ether.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 phosphorylic ester (phosphiryl) (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.

But the ester of hydrolysis is R wherein in other suitable body ⁴Be-CH ₂C (O) OR ⁵Or quilt-C (O) OR ⁵(R ⁵The compound of the above-mentioned formula (I) of (2-4C) alkyl of Qu Daiing no=H).

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

In one aspect, preferred diastereomer is formula (Ib).In yet another aspect, preferred diastereomer is formula (Ic).

If use the mixture of the epimer on  oxazolidone chiral centre, then need the same effect of bigger amount (ratio according to diastereomer 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, for example in substituent R ⁴On.Be appreciated that the present invention includes all these has the active optical isomer of anti-mattress and diastereomer and racemic mixture.Known in this fieldly how to prepare optical activity form (for example synthetic by recrystallization, chirality, enzyme catalysis fractionation, bio-transformation or chromatographic separation technology split racemic form) and knownly how to determine anti-microbial activity as mentioned below.

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

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

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

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

Replacement ether of the present invention is not compared with replacing ether (as simple methyl ether), has pharmacy and/or the physics and/or the pharmacokinetic property of improvement usually, for example, and solubleness and/or bioavailability.

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

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

On the other hand, R ¹Be hydrogen.

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

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

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

In one embodiment, R ⁴Be selected from cyano methyl, carboxyl methyl ,-CH ₂C (O) NR ⁵R ⁶, and (2-4C) alkyl [optional 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, cyano group ,-OC (O) R ⁵, carboxyl ,-C (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].

On the other hand, R ⁴Be selected from cyano methyl, carboxyl methyl and-CH ₂C (O) NR ⁵R ⁶More on the one hand, R ⁴Be selected from the carboxyl methyl and-CH ₂C (O) NR ⁵R ⁶

On the other hand, R ⁴Be selected from (2-4C) 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, cyano group ,-OC (O) R ⁵, carboxyl ,-C (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].

On the other hand, R ⁴Be selected from (2-4C) alkyl [being replaced] by 1 or 2 substituting group that is independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group and hydroxyl (2-4C) alkoxyl group.

On the other hand, R ⁴Being selected from (2-4C) alkyl [is independently selected from-OC (O) R by 1 or 2 ⁵, carboxyl ,-C (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].

More on the one hand, R ⁴Be selected from the carboxyl methyl ,-CH ₂C (O) NR ⁵R ⁶(2-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group ,-NR ⁵R ⁶,-NHS (O) ₂R ⁵,-NHC (O) R ⁵With-OC (O) R ⁵Substituting group replace].

In one aspect, R 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; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

On the other hand, R ⁵And R ⁶Be independently selected from hydrogen, methyl, carboxyl methyl 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; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

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, carboxyl methyl and (2-4C) alkyl (substituting group that is selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl replaces; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

On the other hand, R ⁵And R ⁶Be independently selected from hydrogen, carboxyl methyl and (2-4C) alkyl (substituting group that is selected from carboxyl, (1-4C) alkoxyl group and hydroxyl replaces).

More on the one hand, R ⁵And R ⁶The nitrogen that is connected with them forms optional 14,5 or 6 yuan the saturated heterocyclic basic ring that is independently selected from other heteroatoms (except being connected the N atom) of O, N and S that contains 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).

For comprising R ⁵And R ⁶And the suitable optional substituting group of this ring of the nitrogen that they connected is 1 or 2 methyl.

For comprising R ⁵And R ⁶And the suitable examples of this ring of the nitrogen that they connected be azetidine, morpholine, piperazine, N methyl piperazine, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines and tetramethyleneimine.

Other suitable examples is morpholine, thiomorpholine, piperazine and N methyl piperazine.

Other suitable examples is morpholine, piperazine and N methyl piperazine.

On the other hand, R ⁵And R ⁶Be independently selected from hydrogen, methyl, 1 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 and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted);

Perhaps, R ⁵And R ⁶The nitrogen that is connected with them forms morpholine or piperazine ring altogether, and is optional by methyl substituted.

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

In others of the present invention, compound or its pharmaceutically useful salt or the prodrug of aforesaid formula (Ia) is provided, wherein:

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be selected from the carboxyl methyl and-CH ₂C (O) NR ⁵R ⁶

R ⁵And R ⁶Be independently selected from hydrogen, methyl, carboxyl methyl 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; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be selected from the carboxyl methyl and-CH ₂C (O) NR ⁵R ⁶

R ⁵And R ⁶The nitrogen that is connected with them forms optional 14,5 or 6 yuan the saturated heterocyclic basic ring that is independently selected from other heteroatoms (except being connected the N atom) of O, N and S that contains 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).

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Be selected from (2-4C) alkyl [being replaced] by 1 or 2 substituting group that is independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group and hydroxyl (2-4C) alkoxyl group.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Being selected from (2-4C) alkyl [is independently selected from-OC (O) R by 1 or 2 ⁵, carboxyl ,-C (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];

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴Being selected from (2-4C) alkyl [is independently selected from-C (O) NR by 1 or 2 ⁵R ⁶,-S (O) ₂NR ⁵R ⁶With-NR ⁵R ⁶Substituting group replace];

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

The method part:

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

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

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

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

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

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

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

But the ester of hydrolysis can be by any known method preparation for preparing the chemofacies related compounds that is applicable in compound or pharmaceutically acceptable salt thereof of the present invention or the body.But described method is provided and sets forth in following exemplary embodiment as further feature of the present invention when being used to prepare the ester of hydrolysis in compound or pharmaceutically acceptable salt thereof of the present invention or the body.Necessary starting raw material can obtain (referring to for example Advanced OrganicChemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Organischen 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; WO99/64416; WO 99/64417; 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 (j); 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 (j) (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 acyloxy such as acetoxyl group; Acyloxy can be converted into hydroxyl or be converted into the group that can derive from hydroxyl (directly carrying out or the intermediateness by hydroxyl);

1,2, the 3-triazol-1-yl can be by introducing new ring substituents or by existing ring substituents is carried out once more functionalized the conversion, for example, introduce unsubstituted 1 by the 4-bit substituent of change substituted 1,2,3-triazoles-1-base or with the 4-bit substituent in the 4-position, 2, carry out on the 3-triazol-1-yl;

Alcohol radical can be converted into ether, and alcohol radical at first is converted into leavings group such as halogenide or sulphonate such as p-toluenesulfonic esters, further is converted into ether with other alcohol processing under alkaline condition then;

Alcohol can be converted into imido-ester such as imido for trifluoro-acetate, for example by using trifluoro acetonitrile and alkaline purification; Then, imido-ester can be handled with other alcohol under acidic conditions, obtains ether;

Functionalized ether derivant can further be modified below for example:

Use Organometallic derivatives such as alkyl Grignard reagent or alkyl lithium reagents to handle carboxylic acid (or ester) or ketone or Weinreb amide derivatives, obtain the tertiary alcohol, secondary alcohol or ketone derivatives respectively;

By reduction carboxylic acid, ester, ketone or aldehyde, obtain alcohol;

Hydrolysis by ester obtains acid;

Obtain acid amides by using amine to handle the activatory carboxylic acid derivative;

Oxidation by alkene obtains epoxide, for example uses peracid;

Obtain 2-oxyamine, thioether or ether by using nucleophilic reagent such as amine, thiolate or alkoxide to handle epoxide;

By sulfide oxidation being obtained sulfone or sulfoxide;

By the alkene oxidation is obtained 1, the 2-glycol for example uses perosmic anhydride;

By with 1, the 2-glycol is converted into aldehyde, for example uses sodium periodate; Perhaps, alkene can obtain aldehyde through ozonation treatment (use ozonize, use reductive agent such as methyl-sulfide to handle then);

By reduction amination aldehyde is converted into amine;

By pure oxidation is obtained aldehyde, ketone or carboxylic acid;

By using activatory carboxylic acid derivative, isocyanic ester or chloroformate derivative to carry out the acidylate of alcohol, obtain ester, carbamate or carbonic ether respectively;

By alcohol being converted into leavings group such as halogenide or sulphonate such as p-toluenesulfonic esters, further be converted into amine precursor such as trinitride or phthalic imidine then, perhaps, can use Mitsunobu type condition (for example triphenylphosphine, diethylazodicarboxylate and hydrazoic acid) to be used for such conversion, amine precursor can be converted into amine then, for example by trinitride reduction (for example using moisture triphenylphosphine) or phthalic imidine hydrolysis (for example by handling with hydrazine);

By amino being converted into the amino of replacement, for example undertaken by alkylation, reductive alkylation, acidylate or sulfonylation;

Amine can use alkylogen or other activating reagent such as sulphonate to carry out alkylation; The reductive alkylation of amine can be undertaken by using carbonyl compound such as aldehyde and reductive agent such as triacetyl oxygen base sodium borohydride to handle;

Amine can use activated carboxylic acid derivatives such as chloride of acid or active ester to carry out the acidylate processing and obtain acid amides, uses isocyanate derivates to handle and obtains urea, or use the chloroformate derivative processing to obtain carbamate;

Amine can be converted into isocyanic ester, for example by at first being converted into carboxamides derivatives, handles with dewatering agent then; The isocyanate derivates that obtains can use amine or alcohol to handle then, obtains urea or carbamate derivatives respectively;

Amine can use activation sulfonic acid such as SULPHURYL CHLORIDE to handle and obtain sulphonamide;

B) (wherein X is the leavings group that can be used in palladium [0] coupled reaction to a part of through type (II) compound, for example chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) with the partial reaction of Compound I Ia, described formula IIa also has leavings group X, (wherein Y is ether or its functional derivative) makes to replace phenyl-X key and pyridyl-X key with pyridyl-phenyl key; These methods are known at present, for example referring to S.P.Stanforth, and Catalytic Cross-Coupling Reactions in BiarylSynthesis, Tetrahedron, 54,1998,263-303; J.K.Stille, Angew Chem.Int.Ed.Eng., 1986,25,509-524; N.Miyaura and A Suzuki, Chem.Rev., 1995,95,2457-2483; D.Baranano, G.Mann, and J.F.Hartwig, Current Org.Chem., 1 997,1,287-305; S.P.Stanforth, Tetrahedron, 541998,263-303; 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) (wherein the definition of Y is the same) as follows makes pyridyl-phenylcarbamate derivative (III) and the reacting ethylene oxide that is suitably replaced form  oxazolidone ring;

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

(d) make the compound of formula IV:

Wherein X is the compound reaction of replaceable substituting group (as chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) and formula V:

Wherein X ' is a replaceable substituting group (as chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) the and wherein definition of Y is the same; Wherein selecting substituent X and X ' is well known in the art being suitable for as right by the complementary substituting group of the complementary substrate of transition metal such as palladium (O) catalyzed coupling reaction;

E) make 3-pyridyl phenyl biaryl aldehyde derivatives (VI) reaction, thereby form different  oxazoline ring (wherein the definition of Y is the same) in the position of unshaped (undeveloped) heteroaryl:

About this method, wherein this method variant that obtains active intermediate (nitrile oxide VII ') of the oxidation by oxime (VII) is not well known in the art yet;

F) form triazole ring from the suitably functionalized intermediate of quilt that has wherein formed different  azoles-pyridyl-benzyl ring system, for example, shown in following diagram (wherein the definition of Y is the same):

G) as follows, by carrying out cycloaddition, 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 1,2 of 4-position replacement by means of trinitride and acetylene, 3-triazole (V.V.Rostovtsev, L.G.Green, V.V.Fokin, and K.B.Sharpless, Angew.Chem.Int.Ed., 2002,41,2596-2599) (wherein the definition of Y is the same);

H) as follows, 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) (wherein the definition of Y is the same);

I) as follows, at R ₁During for the 4-halogenic substituent, the compound of formula (I) also can by make azido methyl  oxazolidone and vinyl halides base SULPHURYL CHLORIDE under the temperature between 0 ℃-100 ℃ solvent-free or in inert diluent such as chlorobenzene, chloroform or dioxane prepared in reaction (wherein the definition of Y is the same);

When the halogen in the above-mentioned vinyl SULPHURYL CHLORIDE reagent is bromine, referring to C.S.Rondestvedt, Jr. and P.K.Chang, J.Amer.Chem.Soc., 77,1955,6532-6540; 1-bromo-1-ethene SULPHURYL CHLORIDE prepares referring to C.S.Rondestvedt, Jr., and J.Amer.Chem.Soc., 76,1954,1926-1929);

Forming wherein R ₁It is 4-chloro-1,2, in the method for the formula of 3-triazole (I) compound, the cycloaddition reaction of 1-chloro-1-ethene SULPHURYL CHLORIDE and azide derivatives 0 ℃-100 ℃, preferably at room temperature, at inert solvent, preferably in chlorobenzene, chloroform or dioxane, more preferably under solvent-free condition, carry out.

J) the alternative route that obtains preferably single (replacement) hydroxyalkyl epimer on the different  oxazoline ring is that racemic mixture by ester carries out the enantio-selectivity esterase hydrolyzed at the prochiral center place, but wherein unwanted isomer recirculation, for example

At above-mentioned b) in formula (II) and (IIa) formation of compound used:

Wherein each X is the leavings group that can be used in palladium [0] coupled reaction independently, for example chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue, can be undertaken by any method that is used to assemble such compound known in the art, referring to for example WO 03/022824.

For example, work as R ₁When a was triazole ring, 3 member ring systems of the compound of formula (II) can be by the not many different methods assemblings of substituted triazole that are used for of the following stated.Can use triazole that similar method is used to replace and other R ₁A.Be appreciated that the X in the formula shown in the following diagram (II) can be identical in the whole assembling process of 3 member ring systems, perhaps with the coupling of formula (IIa) compound before the appropriate time point be changed; For example, wherein X is that the compound of the formula (II) of I or Br can be converted into wherein that X is the compound of boric acid or ester or trimethylammonium stannyl derivative, then with have for example compound coupling of the formula (IIa) of Br or I of suitable substituent X.Perhaps, wherein X is that the compound of the formula (IIa) of boric acid or ester or trimethylammonium stannyl derivative can be the compound reaction of the formula (II) of suitable halogen derivative such as I or Br with X wherein.

As follows, the compound of formula (IIa) can derive from the pyridine derivate that is replaced by oxime, and wherein X is Br or I.9 oxime derivate self can derive from simple halo-pyridine derivate via aldehyde-haloperidid.When the needs single enantiomer, can any method known in the art on different  azoles ring, introduce chiral centre, for example, by the fractionation of ester group, the selectivity of for example using enzyme such as lipase to finish enantiomorph splits.In this following method be the example explanation with the butyl ester, yet, be appreciated that and can use other alkyl ester or alkenyl esters, and can in one step, realize fractionation and hydrolysis by the hydrolysis of enzymatic selectivity ester.It can also be appreciated that fractionation can be by enzymatic hydroxy esterification as follows, hydrolysis obtains chiral alcohol and finishes then.Can change the compound that obtains required formula (IIa) to hydroxyl then.Be appreciated that the X in the formula shown in the following diagram (IIa) can be identical in the whole assembling process of 2 member ring systems, perhaps with the coupling of formula (II) compound before the appropriate time point be changed;

Form OR from the hydroxymethyl substituting group ⁴Substituting group can carry out in any stage of synthetic order, if necessary, can use protection or deprotection.Obtain OR ⁴The suitable synthetic precursor of base be for example hydroxyl, halogen [or other leavings group (LG) is as methanesulfonates or tosylate] and imido-ester such as imido for trifluoro-acetate.The conversion example that ether forms is as follows.

Be appreciated that, synthetic order shown in the following diagram can be suitable in any suitable stage of compound between erecting stage, and, therefore, the G in the following diagram can represent pyridyl, pyridyl-phenyl, pyridyl-phenyl- oxazolidone or pyridyl-phenyl- oxazolidone-methyl-triazole ring-type system of suitably being replaced;

When compound of the present invention needs further with R ₄The a groups converted is required OR ⁴During group, can use any reaction sequence well known in the art, for example:

Wherein X is that boric acid or ester and Y are OR ⁴The compound of formula (IIa) be novelty and constituted the independent aspect of the present invention.The particular compound of this aspect of the present invention is R wherein ⁴As mentioned or the compound of of the present invention any aspect hereinafter described or the defined formula of scheme (IIa).

Wherein X is that halogen and Y are OR ⁴The compound of formula (IIa) be novelty and constituted the independent aspect of the present invention.The particular compound of this aspect of the present invention is an intermediate 14,16,18,19,20,21,22,23,24,25,26,27 and 28.

Be appreciated that " X is boric acid or ester " is meant that X is-B (OR ^A) (OR ^B) group, wherein R ^AAnd R ^BBe independently selected from hydrogen and (1-4C) alkyl (as methyl, ethyl and sec.-propyl), perhaps, R ^AAnd R ^BForm the carbon bridge of 2 or 3 carbon atoms together between two Sauerstoffatoms, these two Sauerstoffatoms link to each other with the boron atom respectively, and (wherein the carbon bridge of 2 or 3 carbon atoms is optional by 1-4 methyl substituted, for example forms 1 for 5 or 6 yuan of rings of formation, 1,2,2-tetramethyl-ethylene bridge), perhaps, R ^AAnd R ^BForm 1 together, 2-phenyl (thereby obtaining the catechu phenolic ester).

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 by the racemic form that uses standard program to split compound or intermediate, perhaps the chromatographic separation by diastereomer (when generating diastereomer) obtains described optical activity form.Enzyme technology also can be used for preparing optically active compound and/or intermediate.

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

Wherein the compound (formula IIc) of the formula of X=Br (II) can be from wherein compound (formula IIb) preparation of the formula of X=H (II), use from bromate, bromide and sour autochthonous bromine to the solution of the compound of formula (IIb) carry out direct bromination (wherein each X is 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 avoids 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 yield that generates product and quality, 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, add enough pyrosulfites with any residual bromine reaction.

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

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

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

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

B) aqueous solution of interpolation alkali metal bromate.

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

B) aqueous solution of interpolation alkali metal bromate; With

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

B) aqueous solution of interpolation alkali metal bromate;

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

D) product of separate type (IIc) compound.

B) aqueous solution of interpolation alkali metal bromate;

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

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

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

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

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

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

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

Except that compound of the present invention, pharmaceutical composition of the present invention also can contain (promptly by common preparation) be selected from one or more following known drugs or can be selected from following one or more known drug co-administereds (side by side, sequentially or respectively), described known drug is selected from other useful clinically antiseptic-germicide (for example beta-lactam, macrolide, quinolone or aminoglycoside) and/or other anti-infective (for example anti-fungal triazole or amphotericin).These can comprise carbapenem for example meropenem or imipenum, to widen result of treatment.Usefulness be prepared or be given jointly to compound of the present invention also can jointly with increasing bactericidal properties/infiltrative protein (BPI) product or efflux pump inhibitor, to improve the antagonism Gram-negative bacteria and microorganism agent to be had the activity of chemical sproof bacterium.Compound of the present invention also can or be given usefulness jointly with the common preparation of vitamins, and described vitamins is a vitamin(e) B group for example, as Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid.Compound of the present invention also can be used with common preparation of cyclooxygenase (CO0X) inhibitor, particularly cox 2 inhibitor or common giving.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Anti-microbial activity:

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

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

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

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

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

Organism MIC (MIC/ml)

Streptococcus aureus: MSQS 0.25

MRQR 0.5

Streptococcus pneumoniae 0.06

Hemophilus influenzae 8

Catarrhal catarrhalis 0.5

Linezolid resistance streptococcus pneumoniae 1

MSQS=methicillin-sensitivity and quinolone susceptibility

MRQR=methicillin resistance and quinolone resistance

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 of the compound of embodiment 〉=5 μ M.The Ki value of embodiment 4 is 8 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.

It wherein is R that the inventor further discloses ⁴The compound of the above-mentioned formula (I) of allyl group (choose wantonly on carbon-to-carbon double bond by 1,2 or 3 (1-4C) alkyl and replace) and R wherein ⁴The compound that is replaced (2-4C) alkyl by azido-.These compounds as reference example 2 and 9, have anti-microbial activity, and can be additionally as the compound of other formula of acquisition (I) (R wherein particularly ⁴The compound that is replaced (2-4C) alkyl by azido-) intermediate.

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.Especially, another aspect of the present invention is a reference example 11.

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, by 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 the Bruker spectrometer of 300,400 or 500 MHz; 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); MPLC is the medium pressure liquid chromatography method; DMSO is a dimethyl sulfoxide (DMSO); CDCl ₃It is deuterochloroform; MS is a mass spectrum; ESP is an electrospray; EI is electron impact; CI is a chemi-ionization; APCI is the barometric point chemi-ionization; EtOAc is an ethyl acetate; MeOH is a methyl alcohol; Phosphoryl (Phosphoryl) is (HO) ₂-P (O)-O-; Inferior phosphoryl (Phosphiryl) is (HO) ₂-P-O-; SYNTHETIC OPTICAL WHITNER (Bleach) is " Clorox " 6.15% clorox; DMAP is a 4-dimethylaminopyridine; THF is a tetrahydrofuran (THF); TFA is a trifluoroacetic acid; RT is a room temperature; Cf.=relatively;

(viii) temperature is with a ℃ expression;

(ix) the MP carbonate resin is for the solid-phase resin of the usefulness of deacidification, derives from ArgonautTechnologies, and chemical structure is PS-CH ₂N (CH ₂CH ₃) ₃ ⁺(CO ₃ ^2-) _0.5

Prodrug embodiment 1:{[(5S)-3-(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)- 4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ra-butyl acetate

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ra-butyl acetate (intermediate 12,175mg, 0.47mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,201mg, 0.52mmol), salt of wormwood (200mg, 1.45mmol) and four (triphenylphosphines) close palladium (0) (54mg 0.047mmol) be suspended in DMF (2.5ml) and the water (0.25ml).Mixture is poured in the water 80 ℃ of heating 1 hour, uses ethyl acetate extraction, with dried over sodium sulfate and evaporation.Resistates is by column chromatography purifying (silica gel, 1 to 5% methyl alcohol in methylene dichloride).So the material that obtains is with methylene dichloride: ether: hexane (1: 5: 5) grinds, and subsequent filtration is also used ether: hexane (1: 1) rinsing.So obtain title compound, be pale solid (110mg): fusing point: 186 ℃.

MS (electrospray): C ₂₇H ₂₉FN ₆O ₆Be 553 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：1.41(s，9H)；3.36(dd，1H)；3.52(dd，1H)；3.62(dd，1H)；3.67(dd，1H)；3.96(dd，1H)；4.04(s，2H)；4.29(t，1H)；4.86(d，2H)；4.92(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.82(s，1H)。

Intermediate 1: acetate (5R)-3-(3-fluoro-phenyl)-2-oxo- azoles alkane-5-Ji Jia Ester

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 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 -Ji methyl esters

Under nitrogen with acetate (5R)-3-(3-fluoro-phenyl)-2-oxo- azoles alkane-5-base methyl esters (intermediate 1,15.2g 60mmol) are dissolved in the mixture of chloroform (100ml) and acetonitrile (100ml), interpolation trifluoroacetic acid silver (16.96g, 77mmol).(18.07g, 71mmol) portioning adds in the solution of vigorous stirring, continues to stir 18 hours in envrionment temperature with 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), adds enough ether so that the stripping of brown impurity was stirred 1 hour simultaneously.Filtration obtains required product (24.3g), is cream-colored solid.

MS (ESP):C ₁₂H ₁₁FINO ₄Be 380 (MH ⁺)

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

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

In the mixture of methyl alcohol (800ml) and methylene dichloride (240ml), use salt of wormwood (16.4g at ambient temperature, 0.119mmol) processing acetate (5R)-3-(3-fluoro-4-iodophenyl)-2-oxo- azoles alkane-5-base methyl esters (intermediate 2,30g, 79mmol) 25 minutes, neutralize immediately by adding acetate (10ml) and water (500ml) then.Filtering precipitate washes with water and is dissolved in methylene dichloride (1.2L), and solution 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 the gained 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 is with washing 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)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazole-1- Ylmethyl)-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)-and 3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron are assorted Pentamethylene-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.Mixture obtained transparent black solution in 40 minutes 80 ℃ of heating.Add ethyl acetate (150ml) then, mixture is by diatomite filtration, and (2 * 100ml) washings are with dried over sodium sulfate and evaporation with saturated NaCl.Blackish resistates obtains product by chromatography purification (in hexane, 1-5% acetonitrile subsequently is in ethyl acetate for silica gel, 40-100% ethyl acetate), is the crystallization brown solid, 1.97g (98%).(annotate-wash-out goes out the very heavy impurity of color before the product band, needs to prolong wash-out to obtain product).

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

Perhaps:

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

Intermediate 8:5-bromo-N-pyridone-2-imido is for formyl radical chlorine

With 5-bromopyridine-2-formoxime (49.5g 246.3mmol) is dissolved in DMF (150ml), add then N-chlorosuccinimide (39.5g, 295.5mmol).With continuing 20 seconds with initiation reaction in the HCl gas bubbling feeding solution, stirred then 1 hour then.Reactant is poured in the distilled water (1L), by vacuum filtration collecting precipitation thing.(2 * 500ml), dried overnight (30 inches Hg) obtains product to filter cake in 60 ℃ of vacuum drying ovens then, is white powder (55g) with distilled water wash.

¹H-NMR(300Mz)(CDCl ₃)δ：7.73(d，1H)；8.09(d，1H)；8.73(s，1H)；12.74(s，1H)。

Annotate: it is a lachrymator.

Intermediate 8a:5-bromopyridine-2-formoxime

Add 5-bromo-pyridine-2-formaldehyde (X.Wang etc., Tetrahedron Letters41 (2000), 4335-4338) (60g 322mmol) in methyl alcohol (700ml), adds water (700ml) then, add then oxammonium hydrochloride (28g, 403mmol).Add and contain yellow soda ash (20.5g, water 193.2mmol) (200ml), reaction stirring 30 minutes.Add water (500ml) then, filtering precipitate also washes that (2 * 300ml) obtain required product (60g) with water.

NMR(DMSO-d ₆)δ：7.75(d，1H)；8.09(t，2H)，8.72(s，1H)；11.84(s，1H)。

Intermediate 9: butyric acid [3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first Ester

(195.7mmol) in EtOAc (200ml), (145ml, 1020.4mmol), solution is cooled to 0 ℃ to add the butyric acid allyl ester then for intermediate 8,46g for formyl radical chlorine to add 5-bromo-N-pyridone-2-imido.In 1 hour, drip then and contain triethylamine (30ml, EtOAc 215.8mmol) (100ml).0 ℃ of stirring reaction 1 hour, add EtOAc (1L) then then.By the vacuum filtration disgorging, vacuum concentrated filtrate obtains product (65g).

¹H-NMR(DMSO-d ₆)δ：0.81(t，3H)；1.43(m，2H)；2.24(t，2H)；3.21(dd，1H)；3.54(dd，1H)；4.13(dd，1H)；4.23(dd，1H)；5.01(m，1H)；7.85(dd，1H)；8.12(dd，1H)；8.81(d，1H)。

Intermediate 10: butyric acid (5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles-5 of 5-dihydro -yl] methyl esters

According to the comparison of p.1847 carrying out with Chem.Lett.1993, it is (5S) that (+) isomer is confirmed as.

(intermediate 9,80g 0.244mol) are dissolved in acetone (4L), add 0.1M potassium phosphate buffer (pH～7) (4L) under vigorous stirring, obtain glassy yellow solution with racemic butyric acid [3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl esters.Add PS-lipase (1.45g, Sigma catalog number (Cat.No.) L-9156), mixture at room temperature leniently stirred 42 hours.With solution be divided into equal-volume (～2.6L) three parts, every part with methylene dichloride (2 * 1L) extract, and the organic phase of merging is with dried over sodium sulfate and evaporation.Unreacted butyric acid [(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] (9: 1 hexanes: ethyl acetate) separation is glassy yellow oily matter, 36.4g (45.5%) to methyl esters by hurried column chromatography.

Intermediate 11:[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methyl alcohol

(intermediate 10,16.88g 0.051mol) are dissolved in methyl alcohol (110ml) to methyl esters with butyric acid [(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl].Add 50% aqueous sodium hydroxide solution (3.6ml, 0.068mol).Solution at room temperature stirred 15 minutes, added 1MHCl (75ml), was concentrated in vacuo to then～cumulative volume of 100ml.Interpolation water (～50ml), collect white depositions and also use water rinse.Filtrate merges organic layer with ethyl acetate extraction twice, with dried over sodium sulfate and evaporation, collect solid residue and with 10: 1 hexane: the ethyl acetate rinsing, with the merging of initial precipitation thing, vacuum-drying then, obtain title compound, be white crystalline solid, 12.3g (93%).There is (-) isomer of＜0.5% in chirality HPLC analysis revealed.[α] _D=+139 (c=0.01g/ml is in methyl alcohol).

Intermediate 12:{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methoxyl group } ra-butyl acetate

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11,200mg, 0.78mmol) and tetrabutylammonium iodide (2mg, catalytic amount) be dissolved among the THF (3ml), add sodium hydride (60% the dispersion liquid in mineral oil carefully, 65mg, 1.63mmol), stirred suspension 5 minutes is cooled to 0 ℃ then.(0.25ml, 1.69mmol), at room temperature stirred suspension is 5 hours to add tert-butylbromo acetate.Mixture is water and 1M HCl dilution carefully, uses ethyl acetate extraction.Organic layer washs with saturated sodium-chloride, uses dried over sodium sulfate, and evaporation is also passed through chromatography purification (silica gel, the 10-20% ethyl acetate in hexane).Evaporation contains the fraction of product, and vacuum-drying, obtain [(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ra-butyl acetate, be dense thick oily matter (179mg).

¹H-NMR(400MHz，DMSO-d ₆)δ：1.40(s，9H)；3.29(dd，1H)；3.47(dd，1H)；3.60(dd，1H)；3.65(dd，1H)；4.02(d，2H)；4.91(m，1H)；7.85(d，1H)；8.12(dd，1H)；8.77(d，1H)。

Reference example 2:(5R)-and 3-[4-(6-{ (5S)-5-[(allyl group oxygen base) methyl]-4,5-two The different  azoles of hydrogen-3-yl } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-2-ketone

2-{ (5S)-5-[(allyl group oxygen base) methyl]-4, the different  azoles of 5-dihydro-3-yl }-5-bromopyridine (intermediate 13,210mg, 0.71mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,302mg, 0.78mmol), salt of wormwood (293mg, 2.12mmol) and four (triphenylphosphines) close palladium (0) (82mg 0.071mmol) be suspended in DMF (4ml) and the water (0.4ml).Mixture is poured in the water 80 ℃ of heating 1 hour, uses ethyl acetate extraction, with dried over sodium sulfate and evaporation.Resistates is by column chromatography purifying (silica gel, the 1-5% methyl alcohol in methylene dichloride).So the material that obtains is with methylene dichloride: ether: hexane (1: 5: 5) grinds, and subsequent filtration is also used ether: hexane (1: 1) rinsing.So obtain title compound, be pale solid (160mg): fusing point: 162 ℃.

MS (electrospray):C ₂₄H ₂₃FN ₆O ₄Be 479 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.27(dd，1H)；3.48-3.60(m，3H)；3.96(dd，1H)；4.01(dt，2H)；4.29(t，1H)；4.86(d，2H)；4.93(m，1H)；5.14(dd，1H)；5.18(m，1H)；5.24(dd，1H)；5.87(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 13:2-{ (5S)-5-[(allyl group oxygen base) methyl]-4, the different  azoles-3-of 5-dihydro Base }-the 5-bromopyridine

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (200mg, 0.78mmol) and tetrabutylammonium iodide (2mg, catalytic amount) is dissolved in THF (3ml), add carefully sodium hydride (60% dispersion liquid in mineral oil, 65mg, 1.63mmol), stirred suspension 5 minutes is cooled to 0 ℃ then.(0.15ml, 1.74mmol), at room temperature stirred suspension is 5 hours to add allyl bromide 98.Mixture is water and 1M HCl dilution carefully, uses ethyl acetate extraction.Organic layer washs with saturated sodium-chloride, uses dried over sodium sulfate, and evaporation is also passed through chromatography purification (silica gel, the 10-20% ethyl acetate in hexane).Evaporation contains the fraction and the vacuum-drying of product, obtains 2-{ (5S)-5-[(allyl group oxygen base) methyl]-4, the different  azoles of 5-dihydro-3-yl }-the 5-bromopyridine, be dense thick oily matter (214mg).

¹H-NMR(400MHz，?DMSO-d ₆)δ：3.21(dd，1H)；3.52-3.58(m，3H)；3.99(dt，2H)；4.91(m，1H)；5.12(dt，1H)；5.22(dt，1H)；5.86(m，1H)；7.85(d，1H)；8.11(dd，1H)；8.77(d，1H)。

Embodiment 3:{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3 -triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4,5- The different  azoles of dihydro-5-yl] methoxyl group } acetate

[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ra-butyl acetate (prodrug embodiment 1,940mg 1.7mmol) mixes with trifluoroacetic acid (12ml) and stirs, and obtains transparent brown solution.Mixture at room temperature stirs and concentrated then in 45 minutes, obtains dense thick brown oil.This material and ether supersound process obtain solid residue, and decant falls ether, use ether to repeat this process, and use ether then: methylene dichloride (1: 1) repeats this process, solid vacuum-drying.So obtain title compound, be pale solid (840mg): fusing point: 190 ℃.

MS (electrospray):C ₂₃H ₂₁FN ₆O ₆Be 497 (M+1)

¹H-NMR(400?MHz，DMSO-d ₆)δ：3.35(dd，1H)；3.55(dd，1H)；3.66(m，2H)；3.96(dd，1H)；4.08(s，2H)；4.29(t，1H)；4.86(d，2H)；4.92(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.82(s，1H)。

Embodiment 4:2-{[(5S)-3-(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)- 4, the different  azoles of 5-dihydro-5-yl] methoxyl group }-the N-methylacetamide

[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } (embodiment 3,500mg for acetate, 1.0mmol), Pentafluorophenol (370mg, 2.0mmol), 4-(dimethylamino) pyridine (3mg, 0.025mmol) and DMF (1ml) mix, obtain clear solution.Add 1-[3-(dimethylamino) propyl group]-(390mg, 2.0mmol), solution at room temperature stirred 4 hours the 3-ethyl-carbodiimide hydrochloride, diluted with ethyl acetate.Mixture water and saturated sodium-chloride washing with dried over sodium sulfate and evaporation, obtain active pentafluorophenyl group ester, are rough sticky solid (662mg), and it need not further to characterize or purifying can directly use.

With the pentafluorophenyl group ester (331mg, 0.5mmol) with methylamine (2M THF solution, 3ml, 6mmol) and dioxane (3ml) mix.Mixture is warming to 60 ℃ and continues 1.5 hours, and evaporation is dissolved in the methyl alcohol again and is adsorbed onto on the silica gel.By hurried chromatography purification (silica gel, 0.5-5% ethanol/methylene), obtain solid, it grinds and vacuum-drying with ether, obtains title compound, is 153-156 ℃ of pale solid (135mg) .Mp.

MS (electrospray):C ₂₄H ₂₄FN ₇O ₅Be 510 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.61(d，3H)；3.35(dd，1H)；3.54(dd，1H)；3.64(d，2H)；3.92(s，2H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.96(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.65(bs，1H)；7.69(t，1H)；7.76(s，1H)；8.00(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H)。

Embodiment 5:2-{[(5S)-3-(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)- 4, the different  azoles of 5-dihydro-5-yl] methoxyl group }-N,N-dimethylacetamide

[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } (embodiment 3 for acetate, 500mg, 1.0mmol), Pentafluorophenol (370mg, 2.0mmol), 4-(dimethylamino) pyridine (3mg, 0.025mmol) and DMF (1ml) mix, obtain clear solution, add 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (390mg, 2.0mmol), solution at room temperature stirred 4 hours, diluted with ethyl acetate.Mixture water and saturated sodium-chloride washing with dried over sodium sulfate and evaporation, obtain active pentafluorophenyl group ester, are rough sticky solid (662mg), and it need not further to characterize or purifying can directly use.

With the pentafluorophenyl group ester (331mg, 0.5mmol) with dimethylamine (2M THF solution 3ml, 6mmol) and dioxane (3ml) mix, mixture is warming to 60 ℃ and continues 1.5 hours, evaporates, and is dissolved in the methyl alcohol again and is adsorbed onto on the silica gel.By hurried chromatography purification (silica gel, 0.5-5% ethanol/methylene), obtain solid, it grinds and vacuum-drying with ether, obtains title compound, is 166-168 ℃ of pale solid (155mg) .Mp.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₅Be 524 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.79(s，3H)；2.88(s，3H)；3.38(dd，1H)；3.52(dd，1H)；3.62(m，2H)；3.96(dd，1H)；4.20(s，2H)；4.29(t，1H)；4.86(d，2H)；4.92(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.82(s，1H)。

Embodiment 6:(5R)-3-{3-fluoro-4-[6-((5S)-5-{[2-(4-methylpiperazine-1 -yl)-and 2-oxo oxyethyl group] methyl }-4, the different  azoles of 5-dihydro-3-yl) pyridin-3-yl] Phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } (embodiment 3,200mg for acetate, 0.4mmol), Pentafluorophenol (150mg, 0.82mmol), 4-(dimethylamino) pyridine (3mg, 0.025mmol) and DMF (2ml) mix, obtain clear solution.Add 1-[3-(dimethylamino) propyl group]-(160mg, 0.83mmol), solution at room temperature stirred 45 minutes the 3-ethyl-carbodiimide hydrochloride, diluted with ethyl acetate.Mixture water and saturated sodium-chloride washing with dried over sodium sulfate and evaporation, obtain active pentafluorophenyl group ester, are rough sticky solid (265mg), and it need not further to characterize or purifying can directly use.

With pentafluorophenyl group ester and 1-methylpiperazine (0.25ml, 2.26mmol) and dioxane (4ml) mix.Mixture is warming to 60 ℃ and continues 20 minutes, and evaporation also by hurried chromatography purification (silica gel, 0.5-20% ethanol/methylene), obtains solid (135mg), and it is dissolved in the dioxane (10ml) under warm.(the dioxane solution of 0.4M, 0.68ml 0.272mmol) obtains throw out to add HCl.Suspension filters with ether (10ml) dilution, with ether rinse and vacuum-drying, obtains title compound, is .Mp165-175 ℃ of pale solid (140mg).

MS (electrospray):C ₂₈H ₃₁FN ₈O ₅Be 579 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.75(s，3H)；2.98(bs，2H)；3.36(bm，3H)；3.54(dd，1H)；3.56(s，2H)；3.64(bm，2H)；3.96(dd，2H)；4.23-4.38(m，4H)；4.86(d，2H)；4.95(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.68(t，1H)；7.76(s，1H)；7.99(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H)；10.40(bs，1H)。

Embodiment 7:(5R)-and 3-[3-fluoro-4-(6-{[5S)-5-[(3-hydroxyl propoxy-) methyl] -4, the different  azoles of 5-dihydro-3-yl } pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-2-ketone

3-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } propane-1-alcohol (intermediate 14,370mg, 1.17mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,457mg, 1.l8mmol), salt of wormwood (460mg, 3.33mmol) and four (triphenylphosphines) close palladium (0) (140mg 0.12mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture directly is adsorbed onto on the silica gel and vacuum-drying 80 ℃ of heating 35 minutes.By column chromatography purifying (silica gel, the 0.5-10% methyl alcohol in methylene dichloride), obtain pale solid.The material that will so obtain under warm is dissolved in the methyl alcohol (4ml) and makes its cooling, obtains throw out.Mixture dilutes with ether (20ml), and supersound process obtains thin solid, collects solid, with ether rinse and vacuum-drying, so obtains pure title compound, is pale solid (235mg): fusing point: 176 ℃.

MS (electrospray):C ₂₄H ₂₅FN ₆O ₅Be 497 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：1.63(p，2H)；3.25(dd，1H)；3.42(t，2H)；3.46-3.55(m，5H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.89(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.06(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 14:3-{[5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles-5 of 5-dioxy -yl] methoxyl group } propane-1-alcohol

2-{ (5S)-5-[(allyl group oxygen base) methyl]-4, the different  azoles of 5-dihydro-3-yl }-(1.18mmol) (7ml is 3.5mmol) 0 ℃ of mixing for BBN, the THF solution of 0.5M with assorted dicyclo [3.3.1] nonane of 9-boron for intermediate 12,350mg for the 5-bromopyridine.Remove cooling bath, solution at room temperature stirred 45 minutes.Solution is cooled to 0 ℃, add carefully then sodium hydroxide (50% aqueous solution, 1ml) and hydrogen peroxide (30% aqueous solution, 0.5ml).Remove cooling bath, mixture at room temperature stirred 1.5 hours.Mixture dilutes with ethyl acetate, washes with water, washs and use dried over sodium sulfate with saturated sodium-chloride then.Evaporation subsequently by the filtration of little silicagel pad, with 50% ethyl acetate rinsing in hexane, obtains 3-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } propane-1-alcohol, be dense thick yellow oil (370mg).

¹H-NMR(400MHz，DMSO-d ₆)δ：1.81(p，2H)；3.33(dd，1H)；3.49(dd，1H)；3.64(m，2H)；3.70(t，2H)；3.73(t，2H)；4.94(m，1H)；7.83(dd，1H)；7.89(d，1H)；8.64(d，1H)。

Embodiment 8:(5S)-and 3-[3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl)] methyl } -4, the different  azoles of 5-dihydro-3-yl) pyridin-3-yl] phenyl]-5-(1 H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-2-ketone

2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethanol (intermediate 15,0.302g, 0.84mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,313mg, 0.81mmol), salt of wormwood (223mg, 1.62mmol) and four (triphenylphosphines) close palladium (0) (0.049g 0.042mmol) be suspended in DMF (5.6ml) and the water (0.56ml).Mixture is 85 ℃ of heating 1 hour, with ethyl acetate and water extraction.Ethyl acetate layer also evaporates with dried over sodium sulfate.Resistates is by column chromatography purifying (silica gel, the methyl alcohol of 100% ethyl acetate to 30% in ethyl acetate).So obtain title compound, be pale solid (0.160g): fusing point: 162 ℃.

MS (electrospray):C ₂₃H ₂₃FN ₆O ₅Be 483.2 (M+1)

¹H-NMR (300MHz, and δ: the 2.08-2.01 of chloroform-D) (t, 1H); 3.52-3.36 (m, 1H), 3.44-3.61 (m, 1H); 3.64-3.76 (m, 6H); 3.98-4.03 (m, 1H); 4.18 (t, 1H); 4.81 (m, 1H); 4.83 (s, 1H); 4.94-5.03 (m, 1H); 5.07-5.15 (m, 1H); 7.20-7.24 (dd, 1H); 7.48 (dd, 1H); 7.75 (s, 1H); 7.79 (s, 1H); 7.85-7.88 (d, 1H); 8.05 (d, 1H); 8.18 (s, 1H); 8.74 (s, 1H).

Intermediate 15:{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methoxyl group } acetaldehyde

2-{ (5S)-5-[(allyl group oxygen base) methyl]-4, the different  azoles of 5-dihydro-3-yl }-the 5-bromopyridine (intermediate 13,0.500g 1.7mmol) are dissolved in/become slurry in THF: water (1: 1,8ml) in.The perosmic anhydride that adds catalytic amount is in the reaction mixture that stirs.The interpolation sodium periodate (1.80g, 8.4mmol), the reaction mixture vigorous stirring.Form a large amount of throw outs.Reaction is monitored by TLC, at room temperature stirs after 20 minutes and finishes.Reaction mixture distributes between methylene dichloride and water, and dichloromethane layer also evaporates with dried over mgso.Obtain title compound, be blackish oily matter (0.525g).

MS (electrospray):299.0 (M+1)

¹H-NMR (300MHz, and δ: the 3.31-3.53 of chloroform-D) (m, 2H); 3.70-3.71 (m, 2H); 4.89-4.98 (m, 1H); 5.23 (s, 2H); 7.76-7.85 (m, 2H); 8.59 (m, 1H); 9.64 (s, 1H)

Intermediate 16:2-{[(5S)-3-(5-bromopyridine-2-yl)-different  azoles-5 of 45-dihydro -yl] methoxyl group } ethanol

[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } (intermediate 15,0.525g 0.18mmol) are dissolved in MeOH (10ml) to acetaldehyde, use ice/water-bath to be cooled to 0 ℃ then.Add at leisure sodium borohydride (0.131g, 0.36mmol).After interpolation finished, stirring the mixture made its room temperature of rising again, and stirs then 30 minutes.Solution dilutes with ethyl acetate, washes twice with water, with dried over mgso and evaporation.By column chromatography purifying (silica gel, 100% hexane is to 100% ethyl acetate), obtain title compound (0.287g).

MS (electrospray):303.08 (M+1)

¹H-NMR (300MHz, and δ: the 3.29-3.55 of chloroform-D) (m, 2H): 3.63-3.71 (m, 6H); 4.89-5.01 (m, 1H); 7.81-7.91 (m, 2H); 8.64 (m, 1H)

Reference example 9:(5R)-and 3-[4-(6-{[5S)-5-[(2-azido-oxyethyl group) methyl]-4,5 The different  azoles of-dihydro-3-yl } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

2-{ (5S)-5-[(2-azido-oxyethyl group) methyl]-4, the different  azoles of 5-dihydro-3-yl }-5-bromopyridine (intermediate 17,360mg, 1.1mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,425mg, 1.1mmol), salt of wormwood (460mg, 3.33mmol) and four (triphenylphosphines) close palladium (0) (132mg 0.11mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture directly is adsorbed onto on the silica gel and vacuum-drying 80 ℃ of heating 40 minutes.By column chromatography purifying (silica gel, the 0.5-5% methyl alcohol in methylene dichloride), obtain dense thick oily matter.This oily matter is dissolved in methylene dichloride (4ml),, obtains thin solid, collect solid, with ether rinse and vacuum-drying with ether (20ml) dilution and supersound process.So obtain title compound, be pale solid (205mg): fusing point: 148 ℃.

MS (electrospray):C ₂₃H ₂₂FN ₉O ₄Be 508 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.29(dd，1H)；3.39(t，2H)；3.53(dd，1H)；3.62-3.68(m，4H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.93(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 17:2-{[5S)-and 5-[(2-azido-oxyethyl group) methyl]-4, the different  azoles of 5-dihydro -3-yl }-the 5-bromopyridine

2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group ethanol (intermediate 16,320mg, 1.06mmol) and triphenylphosphine (500mg 1.9mmol) is dissolved in the tetrahydrofuran (THF) (5ml) and is cooled to 0 ℃.Add diphenylphosphine acylazide thing (0.46ml, 2.1mmol), in 10 minutes, drip subsequently azo-2-carboxylic acid's diisopropyl ester (0.42ml, 2.1mmol).Remove cooling bath, solution at room temperature stirred 30 minutes.The solution of muddiness is cooled to 0 ℃, adds methyl alcohol (1ml) then.Remove cooling bath, mixture at room temperature stirred 1.5 hours.Solution stirring 5 minutes, vacuum concentration obtains dense thick oily matter then.By column chromatography purifying (silica gel, the 10-25% ethyl acetate in hexane), obtain title compound, be transparent oily matter (285mg).

¹H-NMR(400?MHz，CDCl ₃)δ：3.36(t，2H)；3.39(dd，1H)；3.52(dd，1H)；3.70(d，2H)；3.72(t，2H)；4.96(m，1H)；7.84(dd，1H)；7.90(d，1H)；8.65(d，1H)。

Embodiment 10:(5S)-3-[3-fluoro-4-(6-{ (5S)-5-[(2-morpholine-4-base ethoxy Base) methyl]-4, the different  azoles of 5-dihydro-3-yl } pyridin-3-yl) phenyl]-5-(1H- 1,2,3-triazoles-1-ylmethyl)-1,3- azoles alkane-2-ketone

4-(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group }-ethyl) morpholine (intermediate 18,405mg, 1.09mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,493mg, 1.3mmol), salt of wormwood (360mg, 2.6mmol) and four (triphenylphosphines) close palladium (0) (0.075g 0.065mmol) be suspended in DMF (8.9ml) and the water (0.89ml).Mixture heated 1 hour at 85 ℃ under nitrogen.After reaction was finished, reaction mixture was poured in the water.Filter the throw out that forms, wash with water.Wet cake is dissolved in 1: 1 methyl alcohol: acetonitrile, then by column chromatography purifying (silica gel, 1: 1 ethyl acetate: methyl alcohol).So obtain title compound, be cream-coloured crystalline solid (0.350g): fusing point: 171 ℃.

MS (electrospray):C ₂₇H ₃₀FN ₇O ₅Be 552.2 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：2.36(m，5H)；74-3.57(m，10H)；3.94-3.99(m，1H)；4.28-4.34(m，1H)；4.86-4.88(m，2H)；5.14-5.24(m，1H)；7.42-7.44(dd，1H)；7.57-7.62(dd，1H)；7.67-7.72(m，1H)；7.78(s，1H)；7.98-8.01(d，1H)；8.05-8.08(d，1H)；8.19(s，1H)；8.82(s，1H)。

Intermediate 18:4-(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro -5-yl] methoxyl group } ethyl) morpholine

Under nitrogen, incite somebody to action [(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } (intermediate 15,0.068g 0.23mmol) are dissolved in anhydrous methylene chloride (3ml) to acetaldehyde.Add morpholine (0.018g, 0.21mmol) in reaction mixture, add subsequently sodium triacetoxy borohydride (0.063g, 0.29mmol).Reaction was at room temperature stirred 18 hours.Add saturated sodium bicarbonate solution in reaction mixture.Add methylene dichloride, layering.Dichloromethane layer salt water washing is with dried over mgso and evaporation.Blackish oily matter is by chromatography purification (10% in ethyl acetate the ethane of ethane to 40% in ethyl acetate).Obtain title compound, be oily matter (0.030g).

MS (electrospray):372.0 (M+1)

¹H-NMR (300MHz, and δ: the 2.44-2.47 of chloroform-D) (m, 4H); 2.54-2.58 (m, 2H); 3.30-3.52 (m, 2H); 3.59-3.73 (m, 8H); 4.89-4.98 (m, 1H); 7.81-7.91 (m, 2H); (8.64 s, 1 H)

Reference example 11:(5S)-and 3-(4-{6-[(5S)-5-(ethoxyl methyl)-4, the different  of 5-dihydro Azoles-3-yl] pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl Methyl)-1,3- azoles alkane-2-ketone

5-bromo-2-[(5S)-5-(ethoxyl methyl)-4, the different  azoles of 5-dihydro-3-yl] pyridine) (intermediate 19,240mg, 0.84mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,310mg, 0.80mmol), salt of wormwood (350mg, 2.5mmol) and four (triphenylphosphines) close palladium (0), and (50mg 0.04mmol) is suspended in DMSO (4.3ml) and the water (0.43ml).Mixture heated 1 hour at 85 ℃ under nitrogen.After reaction was finished, the reaction mixture ethyl acetate extraction washed with water, with dried over sodium sulfate and evaporation.Resistates is by column chromatography purifying (silica gel, the methyl alcohol of 100% methylene dichloride to 10% in methylene dichloride).The solid of collecting is from methylene dichloride/ether crystallization.So obtain title compound, be cream-coloured crystalline solid (122mg): fusing point: 171 ℃.

MS (electrospray):C ₂₃H ₂₃FN ₆O ₄Be 467.2 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：1.07-1.12(t，3H)；3.19-3.28(m，2H)；3.42-3.56(m，5H)；3.93-3.98(m，1H)；4.26-4.32(m，1H)；4.84-4.87(m，2H)；5.14-5.22(m，1H)；7.40-7.42(dd，1H)；7.56-7.60(dd，1H)；7.66-7.72(m，1H)；7.77(s，1H)；7.98-8.00(d，1H)；8.04-8.07(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 19:5-bromo-2-[(5S)-and 5-(ethoxyl methyl)-4, the different  azoles-3 of 5-dihydro -yl] pyridine

Under nitrogen, incite somebody to action [(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] (intermediate 11,300mg 1.0mmol) are dissolved in anhydrous THF (4.5ml) to methyl alcohol.(100mg is 2.3mmol) in the reaction mixture that stirs to add sodium hydride (60% in mineral oil dispersion liquid).Reaction mixture is cooled to 0 ℃.Slowly add iodoethane (0.2ml, 2.3mmol).Make rise again room temperature and monitor of reaction by TLC.Be reflected in 18 hours and finish.Mixture methyl alcohol cancellation with the ethyl acetate dilution, washes with water.The ethyl acetate layer dried over sodium sulfate, evaporation is also passed through chromatography purification (silica gel, the 10-20% ethyl acetate in hexane).Evaporation contains the fraction and the vacuum-drying of product, obtains title compound, is dense thick oily matter (240mg).

¹H-NMR (300 MHz, and δ: the 1.17-1.21 of chloroform-D) (m, 3H); 3.29-3.50 (m, 2H); 3.52-3.62 (m, 4H); 4.89-4.98 (m, 1H); 7.81-7.92 (m, 2H); 8.64 (s, 1H)

Embodiment 12:(5S)-and 3-(4-{6-[(5S)-5-(ethoxyl methyl)-4, the different  of 5-dihydro Azoles-3-yl] pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl Methyl)-1,3- azoles alkane-2-ketone

5-bromo-2-{ (5S)-5-[(2-methoxy ethoxy) methyl]-4, the different  azoles of 5-dihydro-3-yl] pyridine (intermediate 20,375mg, 1.2mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,443mg, 1.14mmol), salt of wormwood (315mg, 2.3mmol), (69mg 0.06mmol) is suspended in DMF (6.75ml) and the water (0.68ml), and mixture heated 1 hour at 85 ℃ under nitrogen to close palladium (0) with four (triphenylphosphines).After reaction is finished, reaction mixture is poured in the water.The throw out that forms washes with water through filtering.Filter cake filters and washs with ether from methyl alcohol/acetonitrile crystallization.So obtain title compound, be cream-coloured crystalline solid (152mg): fusing point: 150.9 ℃.

MS (electrospray):C ₂₄H ₂₅FN ₆O ₅Be 497.2 (M+1)

¹H-NMR (300 MHz,, the δ of chloroform-D): 3.19 (s, 3H); (3.24-3.27 m 1H); 3.34-3.43 (m, 3H); 3.48-3.60 (m, 4H); 3.81-3.60 (m, 1H); 4.05 (m, 1H); 4.65 (m, 2H); 4.83 (m, 1H); 4.95 (m, 1H); 7.04-7.09 (s, 2H); 7.22-7.31 (d, 1H); 7.58-7.63 (d, 1H); 7.63-77 (d, 1H); 7.86-7.89 (d, 1H); 8.56 (s, 1H).

Intermediate 20:5-bromo-2-{ (5S)-5-[(2-methoxy ethoxy) methyl]-4, the 5-dihydro Different  azoles-3-yl] pyridine

Under nitrogen with 2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group (intermediate 16,393mg 1.3mmol) are dissolved in anhydrous THF (13ml) to ethanol.(91mg is 3.9mmol) in the reaction mixture that stirs to add sodium hydride (60% in mineral oil dispersion liquid).Reaction mixture is cooled to 0 ℃.Slowly add methyl iodide (0.163ml, 2.0mmol).Reaction mixture is monitored by TLC.Be reflected in 1 hour and finish, and make its ambient temperature overnight of rising again.Mixture methyl alcohol cancellation with the ethyl acetate dilution, washes with water.The ethyl acetate layer dried over sodium sulfate, evaporation.Obtain title compound, be dense thick oily matter (375mg).

¹H-NMR (300MHz, the δ of chloroform-D): 3.21 (s, 3H); 3.14-3.57 (m, 8H); 4.84-4.93 (m, 1H); 7.86 (d, 1H); 8.09 (d, 1H); 8.77 (s, 1H)

Embodiment 13:N-(2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2- Base)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl) Toluidrin

N-(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl) Toluidrin (intermediate 22,270mg, 0.71mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,280mg, 0.72mmol), salt of wormwood (300mg, 2.17mmol) and four (triphenylphosphines) close palladium (0) (100mg 0.087mmol) be suspended in DMF (4ml) and the water (0.5ml).Mixture directly is adsorbed onto on the silica gel and vacuum-drying 80 ℃ of heating 1 hour.By column chromatography purifying (silica gel, the 1-10% methyl alcohol in ethyl acetate), obtain pale solid.Solid is dissolved in methyl alcohol (4ml) under heating, cool to room temperature obtains throw out, with ether (10ml) dilution and supersound process, obtains thin solid, collects solid, with ether rinse and vacuum-drying.So obtain title compound, be pale solid (70mg): fusing point: 170 ℃.

MS (electrospray):C ₂₄H ₂₆FN ₇O ₆S is 560 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.88(s，3H)；3.11(q，2H)；3.29(dd，1H)；3.48-3.56(m，3H)；3.60(d，2H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.92(m，1H)；5.19(m，1H)；7.07(t，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.82(s，1?H)。

Intermediate 21:(2-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles-5 of 5-dihydro -yl] methoxyl group } ethyl) amine

With 2-{ (5S)-5-[(2-azido-oxyethyl group) methyl]-4, the different  azoles of 5-dihydro-3-yl }-(intermediate 17,630mg 1.93mmol) are dissolved in methylene dichloride (20ml) to the 5-bromopyridine, add methyl alcohol (6ml) and water (1.5ml), obtain two-phase mixture.(CAUSA) (5.02mmol), the suspension that obtains at room temperature stirred 3 days for 1.57mmol/g, 3.2g for Argonaut Technologies, Inc.Foster City to add the polystyrene resin that is combined with triphenylphosphine.Filter resin and use methyl alcohol: methylene dichloride (1: 3,200ml) rinsing.Concentrated filtrate obtains title compound, is dense thick yellow oil (575mg).This thick material need not to be further purified directly as intermediate.

MS (electrospray):C ₁₁H ₁₄BrN ₃O ₂Be 301 (M+1)

Intermediate 22:N-(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro -5-yl] methoxyl group } ethyl) Toluidrin

(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl) amine (intermediate 21,280mg, 0.93mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) be dissolved in methylene dichloride (2ml) and the pyridine (1ml), be cooled to 0 ℃ then.(0.37ml, 4.76mmol), solution stirred 1 hour at 0 ℃, with the methylene dichloride dilution, with 0.2M HCl washing, washed with saturated sodium-chloride then to drip methylsulfonyl chloride.The solution dried over sodium sulfate, evaporation, with ether: hexane (1: 1) grinds, and vacuum-drying, obtains rough title compound, is dense thick oily matter (275mg), and it need not to be further purified directly as intermediate.

MS (electrospray):C ₁₂H ₁₆BrN ₃O ₄S is 379 (M+1)

Embodiment 14:N-(2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2- Base)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl) ethanamide

N-(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl) ethanamide (intermediate 23,295mg, 0.86mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,340mg, 0.88mmol), salt of wormwood (360mg, 2.61mmol) and four (triphenylphosphines) close palladium (0) (120mg 0.104mmol) be suspended in DMF (4ml) and the water (0.5ml).Mixture directly is adsorbed onto on the silica gel and vacuum-drying 80 ℃ of heating 1 hour.By column chromatography purifying (silica gel, the 1-20% methyl alcohol in ethyl acetate), obtain pale solid.Under heating solid is dissolved in methyl alcohol (4ml), cool to room temperature obtains throw out, with ether (10ml) dilution and supersound process, obtains thin solid, collects solid, with ether rinse and vacuum-drying.So obtain title compound, be pale solid (200mg): fusing point: 134 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₅Be 524 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：1.77(s，3H)；3.18(q，2H)；3.27(dd，1H)；3.46(t，2H)；3.54(dd，1H)；3.57(d，2H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.91(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.88(bt，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 23:N-(2-{[5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro -5-yl] methoxyl group } ethyl) ethanamide

(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl) amine (intermediate 21,280mg, 0.93mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) be dissolved in methylene dichloride (2ml) and the pyridine (1ml), be cooled to 0 ℃ then.(0.45ml, 4.76mmol), solution stirred 1 hour at 0 ℃ then, with the methylene dichloride dilution, with 0.2M HCl washing, washed with saturated sodium-chloride then to drip the methylsulfonyl aceticanhydride.Solution obtains rough title compound with dried over sodium sulfate and evaporation, is pale solid (300mg), and it need not to be further purified directly as intermediate.

MS (electrospray):C ₁₃H ₁₆BrN ₃O ₃Be 343 (M+1)

Embodiment 15:{[(5S)-3-(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)- 4, the different  azoles of 5-dihydro-5-yl] methoxyl group } acetonitrile

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } acetonitrile (intermediate 24,165mg, 0.56mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,240mg, 0.62mmol), salt of wormwood (250mg, 1.81mmol) and four (triphenylphosphines) close palladium (0) (64mg 0.055mmol) be suspended in DMF (3ml) and the water (0.5ml).Mixture filters 80 ℃ of heating 30 minutes, and evaporation is also passed through column chromatography purifying (silica gel, the 0.5-5% methyl alcohol in methylene dichloride).So the material that obtains is from methyl alcohol: methylene dichloride (10: 1) crystallization, subsequent filtration is also used ether rinse.Obtain title compound, be pale solid (110mg): fusing point: 90-115 ℃.

MS (electrospray):C ₂₃H ₂₀FN ₇O ₄Be 478 (M+1)

¹H-NMR(400?MHz，DMSO-d ₆)δ：3.28(dd，1H)；3.56(dd，1H)；3.68(dd，1H)；3.74(dd，1H)；3.96(dd，1H)；4.29(t，1H)；4.54(s，2H)；4.86(d，2H)；4.97(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H)。

Intermediate 24:{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methoxyl group } acetonitrile

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11,325mg, 1.26mmol) and tetrabutylammonium iodide (2mg, catalytic amount) be dissolved in THF (5ml), carefully add sodium hydride (60% dispersion liquid in mineral oil, 110mg, 2.75mmol), suspension stirred 5 minutes, was cooled to 0 ℃ then.(0.20ml, 2.87mmol), suspension at room temperature stirred 6 hours to add the bromo acetonitrile.Mixture is water and 1M HCl dilution carefully, uses ethyl acetate extraction.Organic layer washs with saturated sodium-chloride, uses dried over sodium sulfate, and evaporation is also passed through chromatography purification (silica gel, the 10-30% ethyl acetate in hexane).Evaporation contains the fraction and the vacuum-drying of product, obtains title compound, is dense thick oily matter (169mg).

¹H-NMR(400?MHz，CDCl ₃)δ：3.36(dd，1H)；3.54(dd，1H)；3.77(dd，1H)；3.81(dd，1H)；4.35(s，2H)；4.98(m，1H)；7.85(dd，1H)；7.90(d，1H)；8.65(d，1H)。

Embodiment 16:(5R)-3-[3-fluoro-4-(6-{ (5S)-5-[(2-hydroxy-2-methyl Propoxy-) methyl]-4, the different  azoles of 5-dihydro-3-yl } pyridin-3-yl) phenyl]-5-(1H -1,2,3-triazoles-1-ylmethyl)-1,3- azoles alkane-2-ketone

1-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group }-2-methylpropane-2-alcohol (intermediate 26,235mg, 0.71mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,280mg, 0.72mmol), salt of wormwood (320mg, 2.32mmol) and four (triphenylphosphines) close palladium (0) (88mg 0.076mmol) be suspended in DMF (3ml) and the water (0.5ml).Mixture heated 60 minutes at 80 ℃, with acetonitrile (15ml) dilution, filtered, and evaporation is also passed through column chromatography purifying (silica gel, the 0.5-5% methyl alcohol in methylene dichloride).So the material that obtains is from methyl alcohol: ether (1: 1) crystallization, subsequent filtration is also used ether rinse.Obtain title compound, be pale solid (140mg): fusing point: 180-187 ℃.

MS (electrospray):C ₂₅H ₂₇FN ₆O ₅Be 511 (M+1)

¹H-NMR(400?MHz，DMSO-d ₆)δ：1.04(s，6H)；3.23(s，2H)；3.30(dd，1H)；3.52(dd，1H)；3.62(d，2H)；3.96(dd，1H)；4.30(m，2H)；4.86(d，2H)；4.92(m，1H)；5.19(m，1H)；7.43(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.06(d，1H)；8.19(s，1H)；8.82(s，1H)。

Intermediate 25:{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methoxyl group } ethyl acetate

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11,2.0g, 7.78mmol) be dissolved in THF (25ml) and be cooled to 0 ℃, add sodium hydride (60% dispersion liquid in mineral oil, 0.58g carefully, 14.5mmol), remove cooling bath, suspension stirred 30 minutes, and then was cooled to 0 ℃.(1.3ml, 11.7mmol), stirred suspension also makes its room temperature of slowly rising again continue 16 hours to add tetrabutylammonium iodide (10mg, catalytic amount) and bromoethyl acetate.Mixture is used 0.5M HCl (100ml) dilution carefully, with ethyl acetate extraction (100ml).Organic layer washs with saturated sodium-chloride, uses dried over sodium sulfate, evaporation and by chromatography purification (silica gel, 20% ethyl acetate in hexane).Evaporation contains the fraction of product, obtains dense thick oily matter, and itself and 10ml hexane merge and stir under cooling, obtain white solid.Decant falls hexane, solid is resuspended in the hexane, and decant and vacuum-drying, obtain [(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl acetate, be white solid (2.2g).

¹H-NMR(400MHz，CDCl ₃)δ：1.26(t，3H)；3.41-3.55(m，2H)；3.76(d，2H)；4.16(s，2H)；4.19(q，2H)；4.98(m，1H)；7.83(dd，1H)；7.89(d，1H)；8.64(s，1H)。

Intermediate 26:1-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles-5 of 5-dihydro -yl] methoxyl group }-2-methylpropane-2-alcohol

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl acetate (intermediate 25,255mg, 0.74mmol) be dissolved in THF (5ml) and be cooled to-70 ℃, in several minutes, drip methyl-magnesium-bromide (3M diethyl ether solution, 0.65ml, 1.95mmol), solution stirred 1.5 hours at-70 ℃, removes cooling bath, and mixture was at room temperature stirred other 1.25 hours.Mixture is poured among the 0.5M HCl (50ml), with ethyl acetate extraction (50ml).Organic layer washs with saturated sodium-chloride, with dried over sodium sulfate and evaporation, obtains title compound, is dense thick oily matter (239mg).

¹H-NMR(400MHz，CDCl ₃)δ：1.16(s，6H)；3.36(s，2H)；3.37(dd，1H)；3.51(dd，1H)；3.70(d，2H)；4.97(m，1H)；7.85(dd，1H)；7.90(d，1H)；8.65(s，1H)。

Embodiment 17:L-Isoleucine 2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxygen Generation-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyrrole Pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl ester

Under nitrogen under agitation with (5S)-3-[3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl)] methyl-4, the different  azoles of 5-dihydro-3-yl) pyridin-3-yl] phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-(embodiment 8 for 2-ketone, 400mg 0.83mmol) is dissolved in the dry DMF (8ml).Add the DMAP of catalytic amount.Interpolation BOC-L-Isoleucine (383mg 1.70mMol) in reaction mixture, adds 1-[3-(dimethylamino) propyl group subsequently]-the 3-ethyl-carbodiimide hydrochloride (336mg, 1.67mmol).Reaction was stirred 18 hours.After reaction is finished, reaction mixture ethyl acetate/water aftertreatment.Ethyl acetate layer also evaporates with dried over mgso.Resistates (blackish oily matter) is by column chromatography purifying (silica gel, the methyl alcohol of 100% ethyl acetate to 10% in ethyl acetate).The solid of collecting is from methylene dichloride/ether recrystallization.With solid, { (1S, 2S)-1-[(2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } oxyethyl group) methyl]-the 2-methyl butyl } the carboxylamine tertiary butyl ester, be dissolved in dioxane (anhydrous) (2ml) in, described dioxane has been added with dioxane (2.5ml) solution of 4M HCl.Reaction mixture stirs under nitrogen.The solid that filtering-depositing goes out washs with ether.Obtaining title compound (being its HCl salt), is solid (340mg) after 18 hours 80 ℃ of vacuum-dryings, fusing point: 119 ℃.

MS (electrospray):C ₂₉H ₃₄FN ₇O ₆Be 596.2 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：0.75-0.86(m，6H)；1.2-1.35(m，1H)；1.8-1.9(m，2H)，3.18-3.32(m，2H)，3.38-3.81(m，4H)，4.18-4.51(m.2H)，4.81-4.91(t，1H)；5.14-5.24(m，1H)；7.42-7.44(dd，1H)；7.57-7.62(dd，1H)；7.67-7.72(m，1H)；7.78(s，1H)；7.98-8.01(d，1H)；8.05-8.08(d，1H)；8.19(s，1H)；8.82(s，1H)。

Embodiment 18:N, N N-methylsarcosine 2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2 -oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] benzene Base } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } carbethoxy hydrochloride

Under nitrogen under agitation with (5S)-3-[3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl)] methyl-4, the different  azoles of 5-dihydro-3-yl) pyridin-3-yl] phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-(embodiment 8 for 2-ketone, 400mg 0.83mmol) is dissolved in dry DMF (8ml).The DMAP of interpolation catalytic amount (300mg, 2.8mmol).The interpolation N-methylsarcosine (206mg 2.0mmol) in reaction mixture, adds 1-[3-(dimethylamino) propyl group subsequently]-the 3-ethyl-carbodiimide hydrochloride (403mg, 2.0mmol).To react and stir 3 hours.After reaction is finished, reaction mixture ethyl acetate/water aftertreatment.Ethyl acetate layer also evaporates with dried over mgso.Resistates (oily matter) is by being purified from methylene dichloride/ether crystallization.With solid be dissolved in dioxane (anhydrous) (3ml) in, be added with dioxane (0.15ml, 0.6mmol) solution of 4M HCl in the described dioxane.Reaction mixture stirs under nitrogen.The solid that filtering-depositing goes out with the ether washing, obtains title compound, is solid (340mg) after 18 hours 40 ℃ of vacuum-dryings.

MS (electrospray):C ₂₇H ₃₀FN ₇O ₆Be 568.2 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：2.83(s，6H)；3.18-3.29(m，1H)；3.48-3.58(m，1H)；3.60-3.78(m，5H)，3.53-4.01(m，2H)，4.22(m，2H)，4.30-4.33(m.2H)，4.86(s，2H)；5.14-5.24(m，1H)；7.42-7.44(dd，1H)；7.57-7.62(dd，1H)；7.67-7.72(m，1H)；7.78(s，1H)；7.98-8.01(d，1H)；8.05-8.08(d，1H)；8.19(s，1H)；8.82(s，1H)；10.23-10.36(s，1H)。

Embodiment 19:((5R)-3-{4-[6-((5S)-5-{[3-(dimethylamino)-2-hydroxyl Propoxy-] methyl }-4, the different  azoles of 5-dihydro-3-yl) pyridin-3-yl]-the 3-fluorophenyl } -5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

1-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group }-3-(dimethylamino) propane-2-alcohol (intermediate 28,215mg, 0.60mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,285mg, 0.73mmol), salt of wormwood (250mg, 1.8mmol), (70mg 0.06mmol) is suspended in DMF (4ml) and the water (0.4ml) to close palladium (0) with four (triphenylphosphines).Mixture was 80 ℃ of heating 1 hour, and cooling is filtered and is adsorbed onto on the silica gel.Adsorbed material is by column chromatography purifying [silica gel, (1-10% methyl alcohol, 0.1-2% triethylamine) is in methylene dichloride], and so the material that obtains grinds with ether, and subsequent filtration is also used ether rinse, obtains the free alkali (180mg) of title compound.This material is dissolved in the warm dioxane (5ml), and (the dioxane solution of 4M 0.1ml), with the ether dilution, obtains throw out then to add HCl.Collect solid and use ether rinse, obtain the hydrochloride of title compound, be pale solid (170mg): fusing point: 110-115 ℃.

MS (electrospray):C ₂₆H ₃₀FN ₇O ₅Be 540 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.74(d，3H)；2.77(d，3H)；3.06(m，2H)；3.25-3.65(m，6H)；3.96(dd，1H)；4.02(m，1H)；4.29(t，1H)；4.86(d，2H)；5.19(m，1H)；5.72(bs，1H)；7.42(dd，1H)；7.59(dd，1H)；7.68(t，1H)；7.76(s，1H)；8.00(d，1H)；8.07(d，1H)；8.18(s，1H)；8.82(s，1H)；9.33(bs，1H)。

Intermediate 27:5-bromo-2-{ (5S)-5-[(oxyethane-2-ylmethoxy) methyl]-4,5 The different  azoles of-dihydro-3-yl } pyridine

2-{ (5S)-5-[(allyl group oxygen base) methyl]-4, the different  azoles of 5-dihydro-3-yl }-the 5-bromopyridine (intermediate 13,220mg is 0.74mmol) with 3-chlorine peroxybenzoic acid (70-75% aqueous slurries, 230mg, 0.93mmol) mixing was also at room temperature stirred 16 hours in methylene dichloride (2ml).Suspension dilutes with ethyl acetate, with moisture Sulfothiorine, 0.2M sodium hydroxide and saturated sodium-chloride washing.Organic solution obtains title compound with dried over sodium sulfate and by chromatography purification (silica gel, 10-100% ethyl acetate/hexane), is white solid (100mg). ¹H-NMR (400MHz, CDCl ₃) 2.59 (m, 1H); 2.78 (m, 1H); 3.14 (m, 1H); 3.38 and 3.33 (2 * dd, 1H); 3.43-3.53 (m, 2H); 3.67 (dd, 1H), 3.71-3.77 (m.1H), 3.88 and 3.85 (2 * t, 1H); 4.95 (m, 1H); 7.83 (dd, 1H); 7.90 (d, 1H); 8.65 (d, 1H).

Intermediate 28:1-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles-5 of 5-dihydro -yl] methoxyl group }-3-(dimethylamino) propane-2-alcohol

5-bromo-2-{ (5S)-5-[(oxyethane-2-ylmethoxy) methyl]-4, the different  azoles of 5-dihydro-3-yl } (intermediate 27,195mg 0.62mmol) are dissolved in THF (1ml) and the Virahol (2ml) pyridine.(the THF solution of 2M, 1ml 2mmol) add, and solution at room temperature stirred 1 day to add dimethylamine.Vacuum concentrated solution obtains title compound, is rough oily matter (215mg).

MS (electrospray):C ₁₄H ₂₀BrN ₃O ₃Be 359 (M+1)

Intermediate 29:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-two The different  azoles of hydrogen-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl Methyl)-1,3- azoles alkane-2-ketone

[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11,0.277g, 1.08mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 7,0.35g, 0.9mmol), salt of wormwood (0.622g, 4.5mmol) and four (triphenylphosphines) close palladium (0) (0.1g 0.09mmol) mix and is suspended in DMF (7ml) and the water (1ml).Mixture is poured in the cold water (30ml) then 75 ℃ of heating 2 hours.Collect the solid that forms, use water rinse, with methylene dichloride (2 * 10ml) washings, then solid is dissolved in the warm trifluoroethanol (2ml), further by the column chromatography purifying, with 8% methanol-eluted fractions in methylene dichloride, obtain title compound, be white solid (0.193g).

MS (ESP):C ₂₁H ₁₉FN ₆O ₄Be 439.22 (M+1)

NMR(300Mz)(DMSO-d ₆)δ：3.36-3.58(m，4H)；3.95(dd，1H)；4.29(t，1H)；4.78(m，1H)；4.86(d，2H)；5.02(t，1H)；5.18(m，1H)；7.41(dd，1H)；7.58(dd，1H)；7.69(t，1H)；7.77(s，1H)；7.98(d，1H)；8.05(dd，1H)；8.18(s，1H)；8.78(s，1H)。

Intermediate 30: carbonic acid [(5S)-3-(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)- 4, the different  azoles of 5-dihydro-5-yl] methyl 4-nitrophenyl ester

(5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (intermediate 29,200mg 0.46mmol) is dissolved in DMF (3ml) and the pyridine (0.5ml), is cooled to 0 ℃ then.(140mg, 0.70mmol), mixture stirred 2 hours at 0 ℃ to add chloroformic acid 4-nitrophenyl ester.The ammonia formic acid 4-nitrophenyl ester of the other part of interpolation (110mg, 0.55mmol).Mixture at room temperature stirred 2 hours, with the ethyl acetate dilution, with 0.2M HCl washing, then with the saturated sodium-chloride washing, with dried over sodium sulfate and evaporation.Resistates is suspended in methylene dichloride: in the ether (1: 1), cross filter solid and use methylene dichloride: ether (1: 1) rinsing, obtain title compound, and be pale solid (115mg).

MS (electrospray):C ₂₈H ₂₂FN ₇O ₈Be 604 (MH ⁺)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.40(dd，1H)；3.63(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.38(dd，1H)；4.49(dd，1H)；4.86(d，2H)；5.11(m，1H)；5.19(m，1H)；7.43(dd，1H)；7.55(d，2H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.06(d，1H)；8.18(s，1H)；8.26(d，2H)；8.83(s，1H)。

Embodiment 20:N-(2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2- Base)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl)-sarcosine

N-(2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl)-sarcosine tertiary butyl ester (intermediate 31,115mg 0.19mmol) is dissolved in the 15ml trifluoroacetic acid, is heated to 60 ℃ then and continues 6 hours.Solution concentration is extremely done, in resistates water-soluble (1ml).Product solution filters (the anti-phase silicon-dioxide of 2g C18, the acetonitrile of 0-20% in water) and evaporation of eluate by pillar.Resistates is dissolved in methyl alcohol: methylene dichloride (2: 1,3ml) in, add ether (20ml) then, collect solid and the vacuum-drying obtain, obtain title compound, be pale solid (75mg) mp 135-140 ℃.

MS (electrospray):C ₂₆H ₂₈FN ₇O ₆Be 554 (MH ⁺)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.71(s，3H)；3.17-3.39(m，4H)；3.54(dd，1H)；3.61(bm，2H)；3.74-3.85(2×bd，3H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.94(m，1H)；5.18(m，1H)；7.42(d，1H)；7.59(d，1H)；7.68(t，1H)；7.77(s，1H)；7.99(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H)。

Intermediate 31:N-(2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5- (1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2- Base)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl)-the sarcosine tertiary butyl Ester

N-(2-{[(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } ethyl)-sarcosine tertiary butyl ester (intermediate 32,0.19g, 0.44mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone (0.26g, 0.67mmol), salt of wormwood (0.20g, 1.45mmol), (0.051g 0.044mmol) mixes in DMF (3ml) and distilled water (0.3ml), is heated to 80 ℃ then and continues 30 minutes to close palladium (0) with four (triphenylphosphines).Reaction mixture directly is adsorbed onto on the silica gel then by column chromatography purifying (silica gel; The MeOH of 0.5-5% in methylene dichloride), obtain rough resistates, it is dissolved in the warm methyl alcohol (3ml), add ether (20ml) then, collect the solid that obtains and use ether rinse, obtain title compound, be pale solid (0.116g).

MS (electrospray):C ₃₀H ₃₆FN ₇O ₆Be 610 (MH ⁺)

Intermediate 32:N-(2-{[5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro -5-yl] methoxyl group } ethyl)-the sarcosine tertiary butyl ester

[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxyl group } (intermediate 15,170mg 0.57mmol) are dissolved in methyl alcohol (3ml) to acetaldehyde.(310mg, 1.70mmol), solution at room temperature stirred 15 minutes, was cooled to 0 ℃ then to add sarkosine-tert-butyl ester hydrochloride.(193mg 0.91mmol), removes cooling bath, and mixture stirred 2.5 hours, with the methylene dichloride dilution, with the saturated sodium bicarbonate washing, with dried over sodium sulfate and evaporation to add sodium triacetoxy borohydride.By the described material of hurried chromatography purification (silica gel, the 20-100% ethyl acetate in hexane), obtain title compound, be dense thick yellow oil (160mg).

MS (electrospray):C ₁₈H ₂₆BrN ₃O ₄Be 429 (M+1).

Claims

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

Wherein:

R ⁴Be selected from cyano methyl, carboxyl methyl ,-CH ₂C (O) NR ⁵R ⁶(2-4C) 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, cyano group ,-OC (O) R ⁵, carboxyl ,-C (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];

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 selected from the carboxyl methyl ,-CH ₂C (O) NR ⁵R ⁶(2-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group ,-NR ⁵R ⁶,-NHS (O) ₂R ⁵,-NHC (O) R ⁵With-OC (O) R ⁵Substituting 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, 1 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 and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted);

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

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

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

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

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

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

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

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

14. the preparation described formula of claim 1 (I) but compound or pharmaceutically acceptable salt thereof or body in the method for ester of hydrolysis, this method comprises following method (a) to one of (j), 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 (j) (wherein except as otherwise noted otherwise the definition of each variable with the definition of claim 1) as described below:

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

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

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

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

(d) make the compound of formula (IV):

Wherein X is replaceable substituting group,

Compound reaction with formula V:

Wherein X ' is a replaceable substituting group the and wherein definition of Y is the same; Wherein selecting substituent X and X ' is well known in the art being suitable for as right by the complementary substituting group of the complementary substrate of transition metal such as palladium (0) catalyzed coupling reaction;

E) make 3-pyridyl phenyl biaryl aldehyde derivatives (VI) reaction, form different  oxazoline ring in the position of unshaped heteroaryl;

Or by wherein not this method variant that obtains active intermediate (nitrile oxide VII ') of the oxidation by oxime (VII) carry out;

F) form triazole ring from the suitably functionalized intermediate of quilt that has wherein formed different  azoles-pyridyl-benzyl ring system;

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

H) make amino methyl  oxazolidone and 1,1-dichloro-ketone alkylsulfonyl hydrazone reaction;

I) for R ₁When being the 4-halogenic substituent, make the reaction of azido methyl  oxazolidone and vinyl halides base SULPHURYL CHLORIDE;

J) racemic mixture by ester carries out the enantio-selectivity esterase hydrolyzed at the prochiral center place, but wherein unwanted isomer recirculation