CN100390169C

CN100390169C - Hydroxymethyl substituted dihydroisoxazole derivatives useful as antibiotic agents

Info

Publication number: CN100390169C
Application number: CNB2004800054237A
Authority: CN
Inventors: M·B·格雷维斯托克; N·J·哈尔斯; D·R·卡卡纳格
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-03-01
Filing date: 2004-02-24
Publication date: 2008-05-28
Anticipated expiration: 2024-02-24
Also published as: ZA200506789B; GB0304723D0; CN1753888A

Abstract

Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, (I) R1a is NH(C=W)R5 or (a); W is O or S; R2 and R3 are for example H or F; R1 is for example hydrogen, or halogen; R5 is selected from hydrogen, (2-6C)alkyl (optionally substituted); R6 and R7 are independently selected from hydrogen, and (1-4C)alkyl (optionally substituted); wherein R4 is either a hydroxymethyl substituent on C-4' of the isoxazoline ring; or R4 is a hydroxymethyl substituent on C-5' of the isoxazoline ring and the stereochemistry at C-5' of the isoxazoline ring and at C-5 of the oxazolidinone ring is selected, such that the compound of formula (I) is a single diastereomer; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

Description

Be used as the dihydro Isoxazolo derivatives of the methylol replacement of antibiotic medicine

The present invention relates to Antibiotique composition and particularly contain the Antibiotique composition that replaces  oxazolidone and isoxazoline ring.The invention still further relates to they the preparation method, be used for their preparations intermediate, they are as the purposes of medicine and contain their medicinal compositions.

Drug-fast development can cause invalid continuation of present commercially available antimicrobial drug to express serious concern to strains in world microbiology group.Generally speaking, bacterial pathogens can be divided into Gram-positive or gram-negative pathogens.It has been generally acknowledged that Gram-positive and all effective Antibiotique composition of gram-negative pathogens are had broad spectrum antibiotic activity.The compounds of this invention is all effective to Gram-positive and some gram-negative pathogens.

Because in a single day it produce the development of endurance strain, not only be difficult to treatment but also be difficult to from hospital environment, eradicate, so Gram-positive pathogenic agent particularly important, for example staphylococcus (Staphylococci), faecalis (Enterococci), suis (Streptococci) and mycobacterium (mycobacteria).The example of this kind bacterial strain have methicillin-resistant staphylococcus (staphylococcus) (MRSA), methicillin resistant coagulase negative staphylococcus (staphylococci) (MRCNS), the faecium (Enterococcus faecium) of penicillin resistant streptococcus pneumoniae (Streptococcuspneumoniae) and multi-drug resistant.The microbiotic of effectively treating this resistance Gram-positive pathogenic agent clinically is mainly vancomycin.Vancomycin is a glycopeptide and relevant with the multiple toxicity that comprises renal toxicity.In addition, and the most serious be antimicrobial drug resistance also to have occurred to vancomycin and other glycopeptides.This resistance makes these medicines more and more invalid to treatment Gram-positive pathogenic agent just with stable speed increment.The beta-lactam, quinolone and the macrolides compound that for example are used for the treatment of upper respiratory tract infection and are caused infection by some gram negative strain that comprises Haemophilus influenzae (H.influenzae) and morazella catarrhalis (M.catarrhalis) growth also appearred, in the other drug resistance now.

Some antimicrobial compounds that contains  oxazolidone ring describe in this area (for example WalterA.Gregory etc. is at J.Med.Chem.1990,33,2569-2578 and 1989,32 (8), 1673-81; Chung-Ho Park etc. are at J.Med.Chem.1992, and 35,1156-1165 describes).Known antimicrobial drug is produced the differentiation that chemical sproof bacterium for example can result from active combining site on (i) bacterium, make previous activated pharmacophore validity reduce or unnecessary, and/or (ii) chemically make the development of the means of given pharmacophore inactivation and/or the (iii) variation of outflow path.Therefore, to the new antimicrobial drug of finding to have favourable pharmacology feature, particularly the compound that contains new more effective pharmacophore is still had continuous demand.

In addition, some antimicrobial compounds that contains  oxazolidone ring has anti-monoamine oxidase (MAO) activity, for example has the compound of amido methyl or methylol side chain on the C-5 position of  oxazolidone ring.This may cause unwanted characteristic, makes elevation of blood pressure when for example giving the patient, maybe may cause drug-drug interactions.Therefore, to finding that the new  (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides antimicrobial drug with more favourable anti-MAO feature still has continuous demand.

We find that a class contains the potential pair of pharmacophore Antibiotique composition that replaces  oxazolidone ring and substituted isoxazoles quinoline ring, it has the effectively anti-Gram-positive pathogenic agent activity that comprises MRSA and MRCNS, particularly, anti-various demonstrations are to vancomycin and/or Linezolid has chemical sproof bacterial strain and resist the β-Nei Xiananleikangshengsu to aminoglycoside and use clinically to produce chemical sproof faecium (E.faecium) bacterial strain, and also anti-fastidious Gram-negative bacteria, for example Haemophilus influenzae (H.influenzae), morazella catarrhalis (M.catarrhalis), Mycoplasma (mycoplasma spp.) and chlamydiaceae (chlamydial) strain.The compounds of this invention also demonstrates and can be derived from the stereochemical MAO activity favourable, that reduce of isoxazoline substitution in ring base.

We use term " two pharmacophore " but represent to replace the  oxazolidone and are bonded to similar or different pharmacophore combining sites with isoxazoline pharmacophore independent structure, this similar or different position can be simultaneously in the single creature body or not occupied simultaneously certificate, or can not change between the generic organism at two kinds the relative importance of the different combining forms of similar or different sites.The illustrative example that is bonded to mutually different two positions is that a kind of pharmacophore is bonded to the position that causes anti-microbial activity, and other pharmacophores are bonded to the position that makes the active rising of MAO.

Therefore the invention provides a kind of formula (I) compound or its pharmacy acceptable salt or prodrug,

Wherein:

R ₁A is-NH (C=W) R ₅Or

W is O or S;

R ₂And R ₃Independently be selected from H, F, Cl, CF ₃, OMe, SMe, Me and Et;

R ₁Be selected from hydrogen, halogen, cyano group, (1-4C) alkyl, cyano group (1-4C) alkyl, halo (1-4C) alkyl, dihalo (1-4C) alkyl, three halos (1-4C) alkyl, amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, (1-4C) alkylthio, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkyl, (2-4C) alkene oxygen base, (2-4C) thiazolinyl, (2-4C) alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl group and (1-4C) carbalkoxy;

And wherein at the R that contains alkyl, thiazolinyl, alkynyl, cycloalkyl or cycloalkenyl group part ₁When substituting group occurs at every turn, each this class partly choose wantonly on the available carbon atom by one, two, three or more independently is selected from substituting group replacement of F, Cl, Br, OH and CN;

R ₅Be selected from hydrogen, (2-6C) alkyl (optional replaced), methyl (optional replaced), 5-halogen-2-thienyl by 1,2 or 3 substituting group that independently is selected from methyl, chlorine, bromine, fluorine, methoxyl group, methylthio group, hydroxyl, benzyloxy, ethynyl, (1-4C) carbalkoxy, azido-and cyano group by 1,2 or 3 substituting group that independently is selected from methyl, chlorine, bromine, fluorine, methoxyl group, methylthio group, azido-and cyano group ,-N (R ₆) (R ₇) ,-OR ₆,-SR ₆, (2-4C) thiazolinyl ,-(1-8C) alkylaryl, perhalogeno (1-8C) alkyl, wherein p be 0,1 or 2-(CH ₂) p (3-6C) cycloalkyl and-(CH ₂) p (3-6C) cycloalkenyl group;

R ₆And R ₇Independently be selected from hydrogen and (1-4C) alkyl (optional replaced) by one, two, three or more halogen atom;

R wherein ₄Be the methylol substituting group on isoxazoline ring C-4 ' position; Or R ₄Be the methylol substituting group on isoxazoline ring C-5 ' position, and select the stereochemistry of isoxazoline ring C-5 ' position and  oxazolidone ring C-5 position so that formula (I) compound is single diastereomer.

Can understand: the R that wherein contains alkyl, thiazolinyl, alkynyl, cycloalkyl or cycloalkenyl group part ₁Substituting group is replaced by one, two, three or more substituting group that independently is selected from F, Cl, Br, OH and CN on the available carbon atom, then should replace to form chemically stable compound.For example, R ₁Substituting group can allow to contain trifluoromethyl and can not contain trishydroxymethyl.When definition examples of such optional substituting group, use identical convention.

In this manual, term " alkyl " comprises straight chain and branched structure.For example, (1-4C) alkyl comprises propyl group and sec.-propyl.Yet, relate to indivedual alkyl and only refer in particular to linear form as " propyl group ", only refer in particular to the side chain form and relate to indivedual branched-chain alkyls as " sec.-propyl ".In this manual, term " thiazolinyl " and " cycloalkenyl group " comprise all positional isomerss and geometrical isomer.In this manual, term " aryl " is unsubstituted isocyclic aryl, particularly phenyl, 1-and 2-naphthyl.

Enumerate some substituting group and the special and suitable value of group mentioned in this specification sheets below.These values can suitably be used in disclosed definition and embodiment in any context.For avoiding feeling uncertain, each kind of being stated represent the present invention specifically with aspect independently.

(1-4C) example of alkyl comprises methyl, ethyl, propyl group and sec.-propyl; (2-6C) example of alkyl comprises ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, amyl group and hexyl; The example of hydroxyl (1-4C) alkyl comprises methylol, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl; The example of cyano group (1-4C) alkyl comprises cyano methyl, 2-cyano ethyl, 1-cyano group propyl group, 2-cyano group propyl group and 3-cyano group propyl group; The example of halo (1-4C) alkyl comprises methyl fluoride, chloromethyl, brooethyl, 1-fluoro ethyl and 2-chloroethyl; The example of dihalo (1-4C) alkyl comprises difluoromethyl and dichloromethyl; The example of three halos (1-4C) alkyl comprises trifluoromethyl; (2-4C) example of thiazolinyl comprises vinyl, propenyl, allyl group, butenyl; (2-4C) example of alkene oxygen base comprises vinyloxy group, third-2-alkene oxygen base, but-2-ene oxygen base and fourth-3-alkene oxygen base; (2-4C) example of alkynyl comprises ethynyl, Propargyl, fourth-2-alkynyl and fourth-3-alkynyl; (1-4C) example of carbalkoxy comprises methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl and penta oxygen carbonyl; (1-4C) example of alkoxyl group comprises methoxyl group, oxyethyl group and propoxy-; (1-4C) example of alkoxyl group (1-4C) alkyl comprises methoxymethyl, ethoxyl methyl and propoxy-ethyl; (1-4C) example of alkylamino comprises methylamino-, ethylamino and third amino; The example of two-(1-4C) alkylaminos comprises dimethylamino, methylethyl amino and ethyl propyl amino; (1-4C) example of alkylthio comprises methylthio group and ethylmercapto group; (3-6C) example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (3-6C) example of cycloalkenyl group comprises cyclobutene base, cyclopentenyl and cyclohexenyl; The example of halogen group comprises fluorine, chlorine and bromine;-(1-8C) example of alkylaryl comprises benzyl;-(CH ₂) example of p (3-6C) cycloalkyl (p is 0,1 or 2) comprises (3-6C) cycloalkyl, methyl cyclopropyl, ethyl cyclopropyl and methyl cyclobutyl;-(CH2) example of p (3-6C) cycloalkenyl group (p is 0,1 or 2) comprises (3-6C) cycloalkenyl group, methylcyclopropene base, ethyl cyclopropenyl radical and methyl cyclobutene base.

Suitable pharmacy acceptable salt comprises acid salt, for example mesylate, esilate, fumarate, succinate, hydrochloride, Citrate trianion, maleate, tartrate and (less preferred) hydrobromate.Suitable salt also comprises the salt that is formed by phosphoric acid and sulfuric acid.On the other hand, suitable salt is alkali salt, for example an alkali metal salt such as sodium salt, alkaline earth salt such as calcium salt or magnesium salts, the salt of organic amine salt such as following organic amine: triethylamine, morpholine, N-methyl piperidine, N-ethylpiperidine, PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N, N-dibenzyl ethamine, three-(2-hydroxyethyl) amine, N-methyl d-glycosamine and amino acid such as Methionin.Have more than a positively charged ion or negatively charged ion, this depends on quantity and the positively charged ion or the anionic valency of electrically charged functional group.The salt of preferred pharmaceutical compositions is sodium salt.

Yet,, can preferably in selected solvent, dissolve less salt, no matter and whether be pharmacy acceptable salt for the ease of separated salt in preparation process.

Can understand: some compound of the present invention can exist by solvate, and for example hydrate, and non-solvent compound form exists.Can understand and the present invention includes all this type of has the solvate forms of claimed pharmaceutical activity.

The compounds of this invention can prodrug form administration, prodrug decomposes in human body or in the animal body and obtains The compounds of this invention.Prodrug can be used for changing or improving the physics and/or the pharmacokinetics feature of parent compound, but and can form prodrug when parent compound contains when derivatize forms the proper group of prodrug or substituting group.The example of prodrug comprises the interior hydrolyzable ester of the body of The compounds of this invention and pharmaceutically-acceptable salts thereof.

Be known in the art various forms of prodrugs, for example can referring to:

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

B) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard edit, the 5th chapter " Design and Application of Prodrugs (design of prodrug and application) ", H.Bundgaard be (1991) work 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 pyridine or the prodrug of triazole derivative comprise for example halogenide of acyloxy picoline or triazolium salt; For example prodrug as:

(referring to: 42 Interscience Conference of T.Yamazaki grade in an imperial examination onAntimicrobial Agents and Chemotherapy, San Diego, 2002; AbstractF820).

The suitable prodrug of hydroxyl is a glycosides, α-or β-glucoside for example, D-or L-configuration, for example β of embodiment 40-D glucoside.

The further suitable prodrug of hydroxyl is the acyl ester of acetal-carbonic ether of formula RCOOC (R, R ') OCO-, and wherein R is (1-4C) alkyl, and R ' is (1-4C) alkyl or H.Further suitable prodrug has carbonic ether and carbamate RCOO-and RNHCOO-.

This paper embodiment 6 and embodiment 7 provide the example of the suitable hydroxyl prodrug of indefiniteness, and this also is the prodrug example of embodiment 1.Embodiment 6-55 provides more examples of prodrug.These prodrugs in most of the cases are the example of hydrolyzable ester prodrugs in the body.Each example disclosed herein and the respectively of the present invention and independent aspects of each independent compounds represented.

Containing formula (I) compound of carboxyl or hydroxyl or the interior hydrolyzable ester of body of its pharmaceutically-acceptable salts is that for example hydrolysis produces parent acid or pure pharmaceutically acceptable ester in human body or in the animal body.

The pharmaceutically acceptable ester that carboxyl is suitable comprises for example methoxymethyl ester, (1-6C) alkanoyloxymethyl ester oxy acid methyl neopentyl ester, 2-benzo [C] furanonyl ester, (3-8C) cyclo alkoxy carbonyl oxygen base (1-6C) alkyl ester 1-cyclohexyl-carbonyl oxygen base ethyl ester for example for example of (1-6C) alkoxy methyl ester; 1,3-dioxolane-2-base (onyl) methyl ester 5-methyl isophthalic acid for example, 3-dioxolane-2-ylmethyl ester; And (1-6C) alkoxy-carbonyl oxy ethyl ester 1-methoxycarbonyl oxygen base ethyl ester for example, and can on any carboxyl of The compounds of this invention, form.

Contain that hydrolyzable ester comprises inorganic ester in the body of the The compounds of this invention of a hydroxyl or a plurality of hydroxyls or its pharmaceutically-acceptable salts, for example phosphoric acid ester (comprising the phosphamide cyclic ester) and alpha-acyloxy alkyl ester with ester in vivo hydrolysis decompose the relevant compound of result that obtains parent hydroxy.The example of alpha-acyloxy alkyl ester comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.For hydroxyl, the selection of hydrolyzable ester formation group comprises benzoyl and phenylacetyl, (1-10C) alkoxy carbonyl (obtaining alkyl carbonate), two-(1-4C) alkyl-carbamoyls and N-(two-(1-4C) alkylamino ethyls)-N-(1-4C) alkyl-carbamoyl (obtaining carbamate), two-(1-4C) alkylamino ethanoyl, carboxyl (2-5C) alkyl-carbonyl and the carboxyl ethanoyl of (1-10C) alkyloyl, benzoyl, phenylacetyl and replacement in the body.The example of ring substituents comprises chloromethyl or amino methyl, (1-4C) alkylamino methyl and two-((1-4C) alkyl) amino methyl and morpholino or piperazine-1-base (piperazino) on phenyl acetyl and the benzoyl, is connected to the 3-position or the 4-position of benzoyl basic ring by the methylene radical linking group from theheterocyclic nitrogen atom.Hydrolyzable ester comprises in other interested bodies, for example R ^AC (O) O (1-6C) alkyl-CO-(R wherein ^ABe for example optional benzyloxy that replaces-(1-4C) alkyl or the optional phenyl that replaces; Suitable substituents comprises on the phenyl of this type of ester, for example the alkyl of alkyl of the alkyl of 4-(1-4C) piperazine-1-base-(1-4C), piperazine-1-base-(1-4C) and morpholino-(1-4C).

Hydrolyzable ester is that those are by amino acids formed ester in the further suitable body.The ester that forms by the hydroxyl and the amino acid whose carboxylic acid reaction of compound for example.Term " amino acid " refers to any α-or other amino acid that replace herein, natural existence or otherwise be that non-natural exists, and those derivatives of for example forming of derivative by substitution reaction (for example by the azane glycosylation reaction on the amino).Special and the independent aspects of the present invention is represented in use natural or alpha-non-natural amino acid.The suitable a-amino acid and the example of derivative thereof have Xie Ansuan, leucine, Isoleucine, N-methyl Isoleucine, 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.Embodiment 26,41,42,46 and 55 provides the example of hydrolyzable ester in this type of amino acid derived body.

Concrete and the independent aspects of the present invention is represented in amino acid whose use with neutrality and/or basic side chain.

Further hydrolyzable ester comprises phosphoramidate in the body, comprises that also wherein any free hydroxyl group independently forms the The compounds of this invention of formula (PD4) phosphoryl (npd is 1) or phosphorous acid base (phosphiryl) (npd is 0) ester:

For avoiding feeling uncertain, phosphono is-P (O) is (OH) ₂(1-4C) alkoxyl group (hydroxyl)-phosphoryl be-O-P (O) (OH) ₂Single-(1-4C) alkoxy derivative; And two-(1-4C) alkoxy phosphoryls are-O-P (O) is (OH) ₂Two-(1-4C) alkoxy derivative.

The useful intermediates for preparing this type of ester comprises the compound of the group that contains formula (PD4), wherein in (PD4) arbitrary or two-OH group independently by the alkyl of (1-4C) alkyl (this compounds itself also is a compound of interest), phenyl or phenyl-(1-4C) (this type of phenyl optional by 1 or 2 independently is selected from (1-4C) alkyl, nitro, halogen and (1-4C) group of alkoxyl group replace) protection.

Therefore, contain can be by containing suitable hydroxyl just like the prodrug of (PD4) group The compounds of this invention and phosphoryl reagent (for example containing chlorine or dialkyl amido leavings group) reaction, the then oxidation (if necessary) and the deprotection preparation of due care.

Other suitable prodrugs comprise phosphonato methyl ether and salt thereof, for example the prodrug of R-OH as:

When The compounds of this invention contained a plurality of free hydroxyl group, those were not converted to the group of prodrug functional group can to protect (for example using the tertiary butyl-dimetylsilyl), and later deprotection.Also can use enzyme process selectivity phosphorylation or dephosphorylation alcohol functional group.

When the pharmacy acceptable salt of hydrolyzable ester in the organizer, can realize by routine techniques.Therefore, for example contain the compound ionizable (partly or entirely) of formula (PD4) group and the gegenion formation salt of proper amt.Therefore, by embodiment,, four HO-P-functional groups are arranged in whole molecule if the prodrug of hydrolyzable ester contains two (PD4) groups in the The compounds of this invention body, they can form separately suitable salt (be that whole molecule can form, for example single-, two-, three-or four-sodium salt).Embodiment 20 and 26 provides the non-limiting example of the pharmacy acceptable salt of formula (I) compound prodrug.

On the one hand, the suitable prodrug of the present invention is that the interior hydrolyzable ester of body is as (1-4C) alkyl ester; (1-4C) alkyl ester by following group replacement: (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 (therefore containing quaternised nitrogen-atoms), aminocarboxyl, carbamate, acid amides or heterocyclic radical are (for example by R ⁴Hydroxyl and methoxyacetic acid, methoxypropionic acid, hexanodioic acid monomethyl (momethyl) 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, 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-formic acid (for example pyrimidine-5-formic acid), the ester that pyrazine-formic acid (for example pyrazine-2-formic acid) or piperidines-reaction of 4-formic acid forms); (3-6C) cycloalkyl ester (optional) by (1-4C) alkoxy carbonyl, alkoxyl group or carboxyl substituted; Amino this type of carbonic ether that replaces of carbonic ether (for example (1-4C) alkyl carbonate reaches by (1-4C) alkoxyl group or two (1-4C) alkyl)); Sulfuric ester; Phosphoric acid ester and phosphate ester; And carbamate (seeing for example embodiment 10); And pharmacy acceptable salt.

Further suitable prodrug has the R of passing through ⁴Hydroxyl and carbonate reaction those prodrugs, particularly alkoxyl group of the forming alkyl carbonate such as the methoxy-propyl carbonic ether that replace, as embodiment 29.

Further suitable prodrug has the R of passing through ⁴Hydroxyl and the ester that forms of following acid-respons: methoxyacetic acid, methoxypropionic acid, hexanodioic acid monomethyl (momethyl) 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-5-formic acid, pyrazine-2-formic acid or piperidines-4-formic acid, 2-carboxyl-hexanaphthene-1-formic acid; And pharmacy acceptable salt.

Particular compound of the present invention is by hydrolyzable ester and pharmacy acceptable salt thereof in the amino acids formed body.

Further particular compound of the present invention has by 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, hydrolyzable ester in the body that N-N-methylsarcosine, L-Ala, sarkosine, glutamine, l-asparagine, proline(Pro), phenylalanine form; And pharmacy acceptable salt.

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

Further particular compound of the present invention has by Isoleucine, N-methyl Isoleucine, the N-tertiary butyl-Isoleucine, Methionin, glycine, N, hydrolyzable ester in the body that N-N-methylsarcosine, L-Ala, sarkosine and proline(Pro) form; And pharmacy acceptable salt.

Further particular compound of the present invention has by Isoleucine, N-methyl Isoleucine, Methionin, glycine, N, hydrolyzable ester in the body that N-N-methylsarcosine, L-Ala, sarkosine and proline(Pro) form; And pharmacy acceptable salt.

Further particular compound of the present invention has by Isoleucine, glycine, N, hydrolyzable ester in the body that N-N-methylsarcosine, L-Ala and sarkosine form; And pharmacy acceptable salt.

Further particular compound of the present invention has by Isoleucine, N, hydrolyzable ester in the body that N-N-methylsarcosine, L-Ala and sarkosine form; And pharmacy acceptable salt.

Most preferred is interior hydrolyzable ester of the body of embodiment 1 and pharmacy acceptable salt thereof; Particularly by reacting the ester that forms with any amino acid whose hydroxy-acid group as described above.

Particularly, most preferred be by with Isoleucine, leucine, N, hydrolyzable ester and pharmacy acceptable salt thereof in the body of the reaction of the hydroxy-acid group of N-N-methylsarcosine, L-Ala, phenylalanine, proline(Pro) (praline), Xie Ansuan or sarkosine and the embodiment 1 that forms.

In one embodiment, most preferred is hydrolyzable ester and pharmacy acceptable salt thereof in the body that reacts the embodiment 1 that forms by the hydroxy-acid group with Isoleucine.

Particularly, most preferred be by with N, hydrolyzable ester and pharmacy acceptable salt thereof in the body of the reaction of the hydroxy-acid group of N-N-methylsarcosine and the embodiment 1 that forms.

Particularly, most preferred is hydrolyzable ester and pharmacy acceptable salt thereof in the body that reacts the embodiment 1 that forms by the hydroxy-acid group with L-Ala.

Particularly, most preferred is hydrolyzable ester and pharmacy acceptable salt thereof in the body that reacts the embodiment 1 that forms by the hydroxy-acid group with sarkosine.

In another embodiment, preferred compound is the interior hydrolyzable ester of body that the hydroxy-acid group reaction of through type (I) compound and nicotinic acid forms; And pharmacy acceptable salt.

Particularly, preferred compound is hydrolyzable ester and pharmacy acceptable salt thereof in the body that reacts the embodiment 1 that forms by the hydroxy-acid group with nicotinic acid.

In another embodiment, preferred compound is the interior hydrolyzable ester of body that through type (I) compound and phosphoric acid ester reaction form; And pharmacy acceptable salt.

Particularly, preferred compound is for by hydrolyzable ester in the body among the embodiment 1 that forms with phosphoric acid or the reaction of its ester, and pharmacy acceptable salt.

In another embodiment, preferred compound is hydrolyzable ester and pharmacy acceptable salt thereof in the body that forms by embodiment 1 compound and nicotinic acid derivates reaction.

The compounds of this invention has chiral centre in the C-5 position of  oxazolidone ring, the C-4 or the C-5 position of isoxazoline ring.The pharmaceutical active diastereomer is formula (IA):

Preferred diastereomer is formula (IB):

Work as R ₁When a was N-connection-1,2,3-triazoles, (IB) Dai Biao pure diastereomer had (5R) configuration on  oxazolidone ring.Work as R ₁A is-NH (C=O) R ₅The time, (IB) Dai Biao pure diastereomer has (5S) configuration on  oxazolidone ring.Above-mentioned diastereomer (IB) (R ₄Be methylol) on the isoxazoline ring, have (5 ' S) configurations.Work as R ₄Be positioned at C-4 ' time, similarly convention is applied to the substituting group on the above-mentioned C-5 '.

If use the mixture of any epimer of  oxazolidone chiral centre, will need greater amount (ratio that depends on diastereomer) to reach the effect same with the pharmaceutical active enantiomer of identical weight.

In addition, some compound of the present invention can contain other chiral centres, for example at R ₁A.Can understand: the present invention includes all optics and diastereomer and racemic mixture with anti-microbial activity.Know in the art and how to prepare optical activity form (for example pass through recrystallization technology resolution of racemic form, synthesize, split, separate) and how to press hereinafter described method mensuration anti-microbial activity by bio-transformation or by chromatography by enzyme process by chirality.

Can understand in the present invention: formula (I) compound or its salt tautomerism can occur and formula figure in this manual can only represent a kind of possible tautomeric form.Can understand and the present invention includes any tautomeric form and be not only limited to employed tautomeric form among any formula figure with anti-microbial activity.

As described above, preferred diastereomer is formula (IB).Formula (IB) compound is compared with C-5 ' epimer usually and is demonstrated more favourable MAO feature.Hereinafter provide the active example of MAO of preferred compound of the present invention, compare with its C-5 ' epimer, (5 ' S) epimers have higher Ki value (rendeing a service lower).

Also can understand some compound of the present invention can solvate and the existence of non-solvent compound form, for example hydrated form.Can understand and the present invention includes this type of solvate forms that all have anti-microbial activity.

Also can understand some compound of the present invention and can have heteromorphism, and the present invention includes this type of form that all have anti-microbial activity.

As preceding statement, we have found a series ofly have anti-wide spectrum Gram-positive pathogenic agent and comprise the known anti-excellent active compound that the most generally uses antibiotic organism, it has anti-fastidious gram-negative pathogens activity simultaneously, as Haemophilus influenzae (H.influenzae), morazella catarrhalis (M.catarrhalis), mycoplasma (Mycoplasma) and chlamydozoan (Chlamydia) strain.Following compounds has preferred pharmacy and/or physics and/or pharmacokinetic property.Particularly, following compounds has MAO effectiveness favourable, that reduce.

The particularly preferred compound of the present invention comprises hydrolyzable ester, wherein substituent R in The compounds of this invention or its pharmacy acceptable salt or the body ₁A, R ₁, R ₂, R ₃And R ₄Have above disclosed value, or any down train value (its can be in context disclosed any definition and embodiment in suitably use).

Formula (I) compound is provided on the one hand.The pharmacy acceptable salt of formula (I) compound is provided on the other hand.The prodrug of formula (I) compound is provided on the other hand.The interior hydrolyzable ester of body of formula (I) compound is provided on the other hand.The pharmacy acceptable salt of the interior hydrolyzable ester of body of formula (I) compound is provided on the one hand again.

On the one hand, R ₂And R ₃Independently be selected from hydrogen and fluorine.In one embodiment, R ₂And R ₃Be hydrogen.In another embodiment, R ₂Be hydrogen, R ₃Be fluorine.

One side R ₁A is

Be that the 4-position is by R ₁The 1,2,3-triazoles that the N-that replaces connects.

R on the other hand ₁A is-NH (C=W) R ₅

W is an oxygen on the one hand.On the other hand, W is a sulphur.

In one embodiment, R ₁Be selected from hydrogen, halogen, cyano group, (1-4C) alkyl, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

In another embodiment, R ₁Be selected from halogen, cyano group, (1-4C) alkyl, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

In another embodiment, R ₁Be selected from hydrogen, halogen, cyano group, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

In another embodiment, R ₁Be selected from halogen, cyano group, (2-4C) alkyl, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

In another embodiment, R ₁Be selected from halogen, cyano group, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

R ₁Desired value be hydrogen, chlorine, bromine, fluorine, methyl, methyl fluoride, chloromethyl, brooethyl, difluoromethyl and dichloromethyl, ethynyl and proyl.

R ₁Further suitable value is chlorine, bromine, fluorine, methyl fluoride, chloromethyl, brooethyl, difluoromethyl and dichloromethyl, ethynyl and proyl.

R ₁Further suitable value is hydrogen, chlorine, bromine, methyl and methyl fluoride.

R ₁Further suitable value is hydrogen, chlorine, bromine and methyl fluoride.

R ₁Further suitable value is chlorine, bromine, methyl and methyl fluoride.

R ₁Further suitable value is chlorine, bromine and methyl fluoride.

When W is O, R ₅Be fit to be selected from methyl, ethyl, dichloromethyl and cyclopropyl.When W is O, R ₅Suitable ethyl, dichloromethyl and the cyclopropyl of being selected from.

When W is S, R ₅Be fit to be selected from (1-4C) alkyl (optional replaced) by 1,2 or 3 substituting group that independently is selected from methyl, chlorine, bromine, fluorine and methoxyl group ,-N (R ₆) (R ₇) and-OR ₆When W is S, R ₅Be more suitable for being selected from-NH ₂,-NHMe ,-OMe ,-SMe and methyl.

One side R ₄Be the substituting group on the C-4 '.R on the other hand ₄Be the substituting group on the C-5 '.

Work as R ₄During for the substituting group on the C-4 ', the isoxazoline ring is (4 ' S) configurations on the one hand.On the other hand, work as R ₄During for the substituting group on the C-4 ', the isoxazoline ring is (4 ' R) configurations.

Work as R ₄During for the substituting group on the C-5 ', the isoxazoline ring is (5 ' S) configurations on the one hand.On the other hand, work as R ₄During for the substituting group on the C-5 ', the isoxazoline ring is (5 ' R) configurations.Preferred isoxazoline ring is (5 ' S) configurations.

On the one hand, R ₆And R ₇Independently be selected from hydrogen and methyl.

Hydrolyzable ester in a kind of formula (IC) compound or its pharmacy acceptable salt or the body is provided in one embodiment:

Wherein

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from hydrogen, halogen, cyano group, (1-4C) alkyl, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IC) compound or its pharmacy acceptable salt or the body, wherein

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from halogen, cyano group, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from hydrogen, chlorine, bromine, fluorine, methyl, methyl fluoride, chloromethyl, brooethyl, difluoromethyl, dichloromethyl, ethynyl and proyl.

R ₂And R ₃Independently be selected from hydrogen and fluorine;

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

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from chlorine, bromine and methyl fluoride.

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from hydrogen and methyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (ID) compound or its pharmacy acceptable salt or the body,

Wherein

W is O;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₅Be selected from methyl, ethyl, dichloromethyl and cyclopropyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (ID) compound or its pharmacy acceptable salt or the body, wherein

W is O;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₅Be selected from ethyl, dichloromethyl and cyclopropyl.

W is S;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₅Be selected from (1-4C) alkyl (optional replaced) by 1,2 or 3 substituting group that independently is selected from methyl, chlorine, bromine, fluorine and methoxyl group ,-N (R ₆) (R ₇) and-OR ₆

R ₆And R ₇Independently be selected from hydrogen and methyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IE) compound or its pharmacy acceptable salt or the body,

Wherein

R ₂And R ₃Independently be selected from hydrogen and fluorine;

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IE) compound or its pharmacy acceptable salt or the body, wherein

R ₂And R ₃Independently be selected from hydrogen and fluorine;

Wherein

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from hydrogen, (1-4C) alkyl, halo (1-4C) alkyl and hydrogen, halogen, (1-4C) alkyl, halo (1-4C) alkyl, dihalo (1-4C) alkyl and (2-4C) alkynyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IF) compound or its pharmacy acceptable salt or the body, wherein

R ₂And R ₃Independently be selected from hydrogen and fluorine;

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IG) compound or its pharmacy acceptable salt or the body,

Wherein

W is O;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₅Be selected from methyl, ethyl, dichloromethyl and cyclopropyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IG) compound or its pharmacy acceptable salt or the body, wherein

W is S;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₆And R ₇Independently be selected from hydrogen and methyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IH) compound or its pharmacy acceptable salt or the body,

Wherein

W is O;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₅Be selected from methyl, ethyl, dichloromethyl and cyclopropyl.

Further aspect of the present invention provides hydrolyzable ester in a kind of formula (IH) compound or its pharmacy acceptable salt or the body, wherein

W is S;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₆And R ₇Independently be selected from hydrogen and methyl.

The particularly preferred compound of the present invention is included in the compound of describing in the following example, and each in them provides the present invention an independent aspects.Therefore, the present invention also is provided at the compound of describing in arbitrary the following example, or hydrolyzable ester (and particularly compound and salt thereof) in its pharmacy acceptable salt, solvate or the body; And as the purposes (as described herein) of medicine.

The method part:

Further aspect of the present invention provides a kind of method for preparing hydrolyzable ester in The compounds of this invention or its pharmacy acceptable salt or the body.Can recognize that in following some method some substituting group may need protection to prevent that it from unwanted reaction taking place.When skilled chemical technology personnel needs the protection of this class if will recognizing, how to connect this class blocking group and how to remove subsequently.

The example of blocking group can be referring to one of common teaching material of many relevant these themes, and for example ' Protective Groups in Organic Synthesis ', Theodora Greene and Peter Wuts edit (publisher: John Wiley﹠amp; Sons).Blocking group can be removed by any method or skilled known method of sloughing the blocking group of discussing that is applicable to of chemical technology personnel of making things convenient for of describing in the document, and selects these class methods to finish the deprotection group and to the minimum that influences of other groups in the molecule.

Therefore, if comprise for example amino, carboxyl or hydroxyl in the reactant, may in some reaction that this paper mentions, protect this group.

The suitable amino or the protecting group of alkylamino are for example acyl group, as alkyloyl ethanoyl for example; Carbalkoxy, for example methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl; Aryl methoxy carbonyl, for example benzyloxycarbonyl; Or aroyl, for example benzoyl.The deprotection condition of above-mentioned blocking group is along with the selection of blocking group changes necessarily.Therefore, for example acyl group such as alkyloyl or alkoxy carbonyl or aroyl for example can be by with suitable alkali alkali metal hydroxides for example, and for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps acyl group such as tert-butoxycarbonyl for example can be sloughed by handling with suitable sour example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid; and aryl methoxy carbonyl such as benzyloxycarbonyl for example can be by with removing as the catalyzer hydrogenation of palladium carbon, or by with Louis (Lewis) acid for example the processing of three (trifluoroacetic acid) boron slough.The alternative blocking group that primary amino is suitable has for example phthaloyl, and its available alkylamine is dimethylamino propylamine or handle with hydrazine and to slough for example.

The protecting group that hydroxyl is suitable has for example acyl group, for example alkyloyl such as ethanoyl, and aroyl is benzoyl for example; Or arylmethyl, for example benzyl.The deprotection condition of above-mentioned blocking group will change necessarily along with the selection of blocking group.Therefore, for example acyl group such as alkyloyl or aroyl for example can be by with suitable alkali alkali metal hydroxides for example, and for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps arylmethyl such as benzyl for example can be removed as the catalyzer hydrogenation of palladium carbon by using.

The protecting group that carboxyl is suitable has for example esterified group such as methyl or ethyl, and it for example can be removed as the basic hydrolysis of sodium hydroxide by using; Or the tertiary butyl for example, its for example can by with acid as organic acid for example the trifluoroacetic acid processing slough; Or benzyl for example, it for example can be by with sloughing as the catalyzer hydrogenation of palladium carbon.Resin also can be used as blocking group.

Blocking group can be in synthetic any stage easily, the routine techniques known in chemical field slough.

Hydrolyzable ester in The compounds of this invention or its pharmacy acceptable salt or the body can be by any known chemically method preparation of related compound that can be applicable to prepare.When being used to prepare in The compounds of this invention or its pharmacy acceptable salt or the body hydrolyzable ester, these class methods are provided and illustrate by following representational embodiment with further aspect of the present invention.Necessary starting raw material can by vitochemical standard method (referring to, AdvancedOrganic Chemistry (Wiley-Interscience) for example, Jerry March) acquisition.The preparation of these starting raw materials is followed in indefiniteness embodiment and is described.Perhaps, Bi Yao starting raw material can obtain by those similar approach of describing in the general skill of technique of organic chemistry personnel.The information for preparing necessary starting raw material or related compound (it can be used for forming necessary starting raw material) also can obtain in some patent application publication, so the content of its methods involving part is attached to herein by reference; WO 94-13649 for example; WO 98-54161; WO 99-64416; WO 99-64417; WO 00-21960; WO 01-40222.

Skilled technique of organic chemistry personnel can use and adopt the information that comprises and quote in the embodiment of above-mentioned reference and the embodiment that wherein encloses and this paper, to obtain necessary starting raw material and product.

Therefore, the present invention also provides in The compounds of this invention and pharmacy acceptable salt thereof and the body hydrolyzable ester to prepare by following method (a)-(i) (unless regulation in addition, otherwise wherein variable is as defined above):

A) by use standard chemical process (referring to for example, Comprehensive OrganicFunctional Group Transformations (Pergamon), Katritzky, Meth-Cohn﹠amp; Rees) modify its substituting group, or substituting group is introduced in another The compounds of this invention; For example:

Hydroxyl can be changed into amido or thio acylamino, for example acetamido (amido-nitrogen-atoms take up an official post choose the generation or the protection); Change into acyloxy, for example acetoxyl group; By the heterocyclic radical (carbon the carbon atom that connects the azo-cycle atom except that vicinity is taken up an official post and chosen generation) that nitrogen connects, 1,2,3-triazoles-1-base that for example optional 4-replaces; This class of hydroxyl transforms intermediate product (intermediacy) generation that (for example by acylation reaction or Mitsunobu reaction) can directly take place or pass through one or more derivatives (for example methanesulfonates or trinitride); Acyloxy can be changed into hydroxyl or change into the group that can obtain from hydroxyl (perhaps directly or the intermediate product by hydroxyl);

Amido or thio acylamino can be changed into another amido or thio acylamino; Change into heterocyclic radical amino (choose wantonly and on amino-nitrogen-atoms, replace or protection); By the heterocyclic radical (carbon the carbon that connects nitrogen-atoms except that vicinity is taken up an official post and chosen generation) that nitrogen connects, 1,2,3-triazoles-1-base that for example optional 4-replaces; This class of amido transforms and can directly take place or take place by for example amino intermediate product of one or more derivatives;

The heterocyclic radical that can connect by nitrogen (choosing generation taking up an official post) except that the contiguous carbon of carbon atom that connects the azo-cycle atom by introduce new ring substituents or by to existing ring substituents functionalized again change into another heterocyclic radical that connects by nitrogen (the carbon except that the contiguous carbon atom that connects the azo-cycle atom take up an official post choose for), for example by modifying 1 of 4-replacement, 2, the 4-substituting group of 3-triazol-1-yl.

B) (wherein X is for being used for the leavings group of palladium [0] coupling by the part with formula (II) compound, for example muriate, bromide, iodide, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or borate) with a part (it also the has leavings group X) reaction of Compound I Ia so that pyridyl-phenyl key is replaced phenyl-X and pyridyl-X key; These methods are now known, referring to for example S.P.Stanforth, and Catalytic Cross-CouplingReactions in Biaryl Synthesis (the catalysis cross-coupling reaction during two aryl are synthetic), Tetrahedron, 54,1998,263-303; J.K.Stille, Angew Chem.Int.Ed.Eng., 1986,25,509-524; N.Miyaura and A Suzuki, Chem.Rev., 1995,95,2457-2483; D.Baranano, G.Mann, and J.F.Hartwig, Current Org.Chem., 1997,1,287-305; S.P.Stanforth, Tetrahedron, 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 is at (II) and (IIa) can be identical or different in two molecules; For example:

C) form  oxazolidone ring by pyridyl-phenylcarbamate derivative (III) and the reacting ethylene oxide that suitably replaces;

The variation of this method also is well-known in the art, wherein carbamate replace by isocyanic ester or by amine replace or/and wherein oxyethane by being equal to reagent X-CH ₂CH (the optional protection of O-) CH ₂R ₁A replaces, and wherein X is interchangeable group, for example

D) through type (IV) compound:

Wherein X is muriate, bromide, iodide, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or the borate of replaceable substituting group-for example, with following formula

(V) reaction of compound:

Wherein X ' is replaceable substituting group (for example muriate, bromide, iodide, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or a borate); Wherein selecting substituent X and X ' is that complementary pair substituting group as known in the art is to be suitable as the complementary substrate by transition metal such as the reaction of palladium (O) catalyzed coupling;

E) form the isoxazoline ring on the undeveloped heteroaryl position by being reflected at of 3-pyridyl phenyl dibenzyl aldehyde derivatives (VI);

The variation of this method is well-known in the art, and wherein reaction intermediate (itrile oxides VII ') does not obtain by oxidation oxime (VII);

F) work as R ₁When a was the 1,2,3-triazoles of N-connection, by forming triazole ring from suitable functionalized intermediate, wherein different  azoles-pyridyl-benzyl ring system formed, shown in following flow process:

G) work as R ₁A is a 1,2,3-triazoles, formula (I) compound can be by triazo-compound and acetylene cycloaddition preparation, for example by azido-methyl  oxazolidone and terminal alkynes in aqueous alcohol solutions for example, under the envrionment temperature, usefulness Cu (I) catalyzed reaction, generate the 1,2,3-triazoles (V.V.Rostovtsev that 4-replaces, L.G.Green, V.V.Fokin, and K.B.Sharpless, Angew.Chem.Int.Ed., 2002,41,2596-2599):

H) work as R ₁A is the 1,2,3-triazoles that 4-replaces, and formula (I) compound can be by making amino methyl  oxazolidone and 1, the preparation of 1-dihalo-ketone sulphonyl 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 EP103840 A2 19840328);

I) work as R ₁A is a 4-halo 1,2,3-triazole, formula (I) compound also can be by making azido-methyl  oxazolidone and vinyl halides base SULPHURYL CHLORIDE under the temperature between 0 ℃ and 100 ℃, in prepared in reaction under the solvent-free condition or in inert diluent such as chlorobenzene, chloroform or dioxane (dioxan);

Halogen is under the situation of bromine in vinyl SULPHURYL CHLORIDE reagent as implied above, sees C.S.Rondestvedt, Jr.and P.K.Chang, J.Amer.Chem.Soc., 77,1955,6532-6540; By C.S.Rondestvedt, Jr., J.Amer.Chem.Soc., 76,1954,1926-1929) method prepares 1-bromo-1-ethene SULPHURYL CHLORIDE;

The cycloaddition reaction of 1-chloro-1-ethene SULPHURYL CHLORIDE and azido derivant forms wherein R in following method ₁A is formula (I) compound of 4-chloro-1,2,3-triazoles: temperature is carried out between 0 ℃ and 100 ℃, preferably at room temperature carry out, and preferred chlorobenzene, chloroform or dioxane in inert solvent, or more preferably solvent-free.

J) work as R ₁A is NHCOCH ₃, formula (I) compound also can be by the ordinary method preparation of describing in the prior art (referring to for example Upjohn patent application WO 97/37980); Or for example as follows:

K) work as R ₄On C ' 4, can use suitable dibasic alkene, wherein Y is the regioselectivity directing group in the cycloaddition reaction, it removes (Si (R) for example subsequently in final step ₃); For example work as R ₄Be the alkoxy methyl residue, can use Z-or E-formula alkene, shown in following Z formula:

L) the single hydroxyalkyl R of preferred C4 ' or C5 ' position ₄Another of epimer route wherein can utilize unwanted isomer again for by the racemic mixture of enantioselectivity esterase at the prochiral center ester hydrolysis, for example:

And then if necessary:

I) remove any blocking group;

Ii) form prodrug (for example hydrolyzable ester in the body); And/or

Iii) form pharmacy acceptable salt.

As above-mentioned b) middle formula (II) and (IIa) formation of using of compound:

Wherein each X is independently for being used for the leavings group of palladium [0] coupling, for example muriate, bromide, iodide, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or borate can be undertaken by any method that is used to assemble the type compound known in the art.

For example work as R ₁A is a triazole ring, and 3 loop systems of formula (II) compound can various mode be assembled, as following not method shown in the substituted triazole.Similarly method can be used for substituted triazole and R ₁Other values of a.To recognize that the X in the following flow process formula shown (II) can be identical in the assembling process of 3 loop systems, or can change in suitable site before with the coupling of formula (IIa) compound; For example wherein X is that formula (II) compound of I or Br can be converted into the compound that X is boric acid or ester or trimethylammonium stannyl derivative, uses suitable substituents X for example Br or I and the coupling of formula (IIa) compound then.Perhaps, wherein X is that formula (IIa) compound of boric acid or ester or trimethylammonium stannyl derivative can be formula (II) the compound reaction of suitable halogen derivative such as I or Br with X wherein.

Formula (IIa) compound can be derived from the pyridine derivate of oxime replacement as follows, and wherein X is Br or I.9 oxime derivate itself can be by aldehyde-haloperidid derived from simple halogen-pyridine derivate.Chiral centre on the different  azoles ring can be introduced by any method known in the art, for example by the fractionation of ester group, for example realizes selectivity with enzyme such as lipase.This method is illustrated by following butyl ester, yet will recognize and can use other alkyl or alkenyl esters, and fractionation and hydrolysis can be finished by one step of enzymatic selectivity ester hydrolysis.To recognize that the X in the formula shown in the following flow process (IIa) can be identical in the assembling process of 2 loop systems, or can change in appropriate site before with the coupling of formula (II) compound:

Wherein X is that formula (II) compound of boric acid or ester is new compound and forms independently aspect of the present invention.The present invention's particular compound in this respect is formula (II) compound, wherein R ₂And R ₃Independently be selected from H and F, R ₁A is

And R ₁Be selected from hydrogen, halogen and (1-4C) alkyl; R more particularly ₁Be selected from hydrogen and (1-4C) alkyl.

Wherein X is that formula (IIa) compound of boric acid or ester is new compound and forms independently aspect of the present invention.The present invention's particular compound in this respect is formula (IIa) compound, wherein R ₄Be the methylol substituting group on isoxazoline ring C-4 ' or the C-5 ' position, more particularly R ₄Be the substituting group on C-5 ' position, even more particularly its Chinese style (IIa) compound is a single stereoisomers.

Can understand " X is boric acid or ester " and refer to that X is-B (OR ^A) (OR ^B) group, wherein R ^AAnd R ^BIndependently be selected from hydrogen and (1-4C) alkyl (for example methyl, ethyl and sec.-propyl), or R ^AAnd R ^BBetween the Sauerstoffatom of two connection boron atoms, form 2 or 3 carbon bridges together and encircle (wherein 2 or 3 carbon bridges are optional by 1-4 methyl substituted, for example form 1,1,2,2-tetramethyl-ethylene bridge) to form 5-or 6-unit respectively, or R ^AAnd R ^BForm 1 together, 2-phenyl (therefore obtaining the catechu phenolic ester).

Standard technique is used in the formation of hydrolyzable ester or other prodrugs in the formation of the sloughing of any blocking group, pharmaceutically-acceptable salts and/or the body, all in common technique of organic chemistry personnel's skill.In addition, the details of these steps, for example the preparation of hydrolyzable ester prodrug provides in for example part of above-mentioned relevant this type of ester in the body.

When needs The compounds of this invention optical activity form, can obtain (for example by in suitable reactions steps, forming) by using the optical activity starting raw material to carry out one of aforesaid method through asymmetric induction, or pass through to use standard method to split the racemic form of compound or intermediate, or obtain by the chromatography separation of diastereomer (when producing).Zymotechnic also can be used for the preparation of optically active compound and/or intermediate.

Similarly, when the pure The compounds of this invention regional isomer of needs, can obtain by using pure regional isomer carry out one of aforesaid method, or obtain by the mixture that uses standard method to split regional isomer or intermediate as starting raw material.

According to a further general feature of the present invention, provide hydrolyzable ester in The compounds of this invention or its pharmacy acceptable salt or the body be used for the treatment of human body or animal body methods of treatment.

According to a further general feature of the present invention, the method that provides a kind of warm-blooded animal in this treatment of needs for example to produce anti-microbial effect among the people, this method comprise hydrolyzable ester in the The compounds of this invention that gives described animal effective dose or its pharmacy acceptable salt or the body.

The present invention also provides the purposes of the interior hydrolyzable ester of The compounds of this invention or its pharmacy acceptable salt or body as medicine; And in The compounds of this invention or its pharmacy acceptable salt or the body hydrolyzable ester preparation be used for warm-blooded animal for example the people produce purposes in the medicine of anti-microbial effect.

In order to use hydrolyzable ester in The compounds of this invention, its body or pharmacy acceptable salt to comprise the pharmacy acceptable salt of hydrolyzable ester in the body, (hereinafter relating to medicinal compositions " The compounds of this invention " in this part) treats the Mammals that (comprising prevention) comprises the people, particularly treatment is infected, and is mixed with usually with standard pharmaceutical and puts into practice corresponding to medicinal compositions.

Therefore, another aspect of the present invention provides a kind of and comprises the pharmacy acceptable salt that The compounds of this invention, the interior hydrolyzable ester of its body or pharmacy acceptable salt comprise hydrolyzable ester in the body, and the medicinal compositions of pharmaceutically acceptable diluent or carrier.

The present composition can be and is applicable to that the form that orally uses (for example is tablet, lozenge, hard or soft capsule, water-based or oiliness suspensoid, (lipid) emulsion, can disperse powder or granule, syrup or elixir), be applicable to that the local form of using (for example is ointment, ointment, gelifying agent or water-based or oily solution agent or suspensoid), be applicable to the form (for example being micro mist powder or liquid aerosol) of inhalation, be applicable to the form (for example being micro mist powder) that is blown into (insufflation) administration or be applicable to that the form of administered parenterally (for example is sterile aqueous or oiliness intravenously, subcutaneous, intramuscular or intramuscular administration solution or be rectal administration suppository).

The present composition can obtain with the method for routine by using conventional pharmaceutical excipient well-known in the art.Therefore, the composition that orally uses can be contained for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

The pharmaceutically acceptable vehicle that is applicable to tablet formulation 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 alginic acid (algenic acid); Tackiness agent such as starch; Lubricant such as Magnesium Stearate, stearic acid or talcum powder; Sanitas such as ethyl p-hydroxybenzoate or propyl ester, and antioxidant such as xitix.Tablet formulation not dressing or dressing with change its disintegration properties and subsequently activeconstituents or improve its stability and/or outward appearance in GI absorption, in arbitrary situation, use conventional Drug coating well known in the art and method.

The composition that orally uses can be the hard gelatin capsule form, wherein for example lime carbonate, calcium phosphate or kaolin mix activeconstituents with inert solid diluent, or be the soft gelatin capsule form, wherein activeconstituents and water or oil are as peanut oil, whiteruss or mixed with olive oil.

Aqueous suspension contains activeconstituents and one or more suspension agents of micro mist form, for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth and gum arabic usually; The condensation product of dispersion agent or wetting agent such as Yelkin TTS or oxirane and lipid acid (for example polyoxyethylene stearic acid ester), or the condensation product of oxyethane and long chain aliphatic alcohol, heptadecyl ethyleneoxy group hexadecanol (heptadecaethyleneoxycetanol) for example, or oxyethane and derived from the condensation product of the part ester of lipid acid and hexitol, as the polyoxyethylene sorbitol monoleate, or the condensation product of oxyethane and long chain aliphatic alcohol, heptadecyl ethyleneoxy group hexadecanol (heptadecaethyleneoxycetanol) for example, or oxyethane and derived from the condensation product of the part ester of lipid acid and hexitol polyoxyethylene sorbitol monoleate for example, or oxyethane and derived from the condensation product of the part ester of lipid acid and hexitan, for example polyethylene dehydrated sorbitol mono-fatty acid ester.Aqueous suspension also can contain one or more sanitass (for example ethyl p-hydroxybenzoate or propyl ester, antioxidant (for example xitix), tinting material, seasonings and/or sweeting agent (for example sucrose, asccharin or aspartame).

The oiliness suspensoid can be by being suspended in activeconstituents preparation in vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois) or the mineral oil (for example whiteruss).The oiliness suspensoid also can contain thickening material such as beeswax, paraffinum durum or hexadecanol.Can add aforesaid those sweeting agents and seasonings so that good to eat oral preparations to be provided.These compositions can be preserved by adding antioxidant such as xitix.

Be applicable to by adding disperseed powder and the granule that entry prepares aqueous suspension and contain activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass usually.Suitable dispersion agent or wetting agent and suspension agent exemplify in above-mentioned those vehicle of mentioning.Also can use other vehicle such as sweeting agent, seasonings and tinting material.

Medicinal compositions of the present invention also can be the oil-in-water emulsion form.Oil phase can be vegetables oil, for example sweet oil or peanut oil, or be for example any mixture of whiteruss or these oil of mineral oil.Suitable emulsifying agent is for example naturally occurring glue such as gum arabic or tragacanth, naturally occurring phosphatide as soybean, Yelkin TTS, derived from the ester of lipid acid and hexitan or part ester (for example dehydrated sorbitol mono-fatty acid ester) and as described in the condensation product such as the polyoxyethylene sorbitan monoleate of part ester and oxyethane.Emulsion also can contain sweeting agent, seasonings and sanitas.

Available sweeting agent such as glycerine, propylene glycol, Sorbitol Powder, aspartame or agent of sucrose obtain syrup and elixir, and also can contain negative catalyst, sanitas, seasonings and/or tinting material.

Medicinal compositions also can be aseptic injection water-based or oiliness suspensoid, and it can be according to currently known methods, with the suitable dispersion agent of having mentioned above one or more or wetting agent and suspension agent preparation.Aseptic injection preparation also can be at nontoxic, parenteral acceptable diluent or solvent aseptic injectable solution agent or the suspensoid in the 1,3 butylene glycol solution for example.

The medicinal compositions of intravenous administration preferably can contain (for example for improving stability) suitable sterilant, antioxidant or reductive agent, or suitable sequestrant.

The inhalation composition can be conventional pressurised aerosol form, distributes activeconstituents with the aerosol that contains micro mist solid or drop.Can use conventional aerosol propellant such as volatile hydrofluoric ether or hydrocarbon and the aerosol device activeconstituents of distribution and computation easily.

The reader can consult Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial BoaRd), the 5th volume of Pergamon press 1990, the 25.2nd chapter are to obtain the information of further preparation aspect.

The amount that produces the activeconstituents of single formulation with one or more excipient composition will change necessarily, and this depends on the host that treated and the concrete approach of administration.The preparation that for example will be used for the human oral administration will contain usually the promoting agent of 1mg-1g for example with suitably and the combination of sufficient quantity vehicle, the amount of vehicle is in the variation in about 5% to about 98% in composition total weight.Dosage unit form will contain the activeconstituents of 100mg to about 1g of having an appointment usually.The reader can consult Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman ofEditorial Board), the 5th volume of Pergamon press 1990, the 25.3rd chapter are to obtain the information of further route of administration and dosage aspect.

The suitable medicinal compositions of the present invention is a kind of medicinal compositions that is applicable to oral administration, is unit dosage, for example contains at the The compounds of this invention between 1mg and the 1g, the preferably tablet of compound or capsule between 100mg and 1g.Especially preferably contain at the The compounds of this invention between 50mg and the 800mg, particularly tablet in the 100mg-500mg scope or capsule.

On the other hand, medicinal compositions of the present invention is a kind of medicinal compositions that is applicable to intravenous injection, subcutaneous injection or intramuscularly, for example contains the injection at the The compounds of this invention of (between 1mg/ml and 500mg/ml) between 0.1%w/v and the 50%w/v.

Every patient for example can accept intravenously every day, subcutaneous or intramuscular administration dosage is 0.5mgkg ^-1To 20mgkg ^-1The compounds of this invention, said composition administration every day 1-4 time.In another embodiment, the per daily dose of The compounds of this invention administration is 5mgkg ^-1To 20mgkg ^-1Intravenously, subcutaneous and intramuscular administration dosage can the dense notes of disposable large vol (bolus) mode give.Perhaps intravenous administration dosage can the continuous infusion mode give in for some time.Perhaps every patient can accept about day oral dosage that equates with day administered parenterally dosage, said composition administration every day 1-4 time.

Except that The compounds of this invention, medicinal compositions of the present invention also can contain (promptly by associating-preparation (co-formulation)) one or more known drugs or with one or more known drug Combined Preparation (simultaneously, sequential or distinguish administration), known drug is selected from antimicrobial drug (for example beta-lactam, Macrolide, quinolones or aminoglycoside) and/or other anti-infectives (for example antifungal triazole or amphotericin) of other clinical uses.For enlarging result of treatment, these known drugs can comprise carbapenems, for example meropenem or imipenum.The compounds of this invention also can strengthen albumen (BPT) product or efflux pump inhibitor co-formulated or Combined Preparation with bactericidal, to improve the activity of anti-Gram-negative bacteria and anti-antibiotic property of medicine bacterium.The compounds of this invention also can with VITAMIN for example vitamins B such as Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid co-formulated or Combined Preparation.The compounds of this invention also can be prepared or Combined Preparation with cyclooxygenase (COX) inhibitor, particularly cox 2 inhibitor.

In one aspect of the invention, The compounds of this invention with have an active antimicrobial drug co-formulated of resisting gram-positive bacteria.

In another aspect of this invention, The compounds of this invention with have an active antimicrobial drug co-formulated of anti-Gram-negative bacteria.

In another aspect of this invention, The compounds of this invention with have an active antimicrobial drug Combined Preparation of resisting gram-positive bacteria.

In another aspect of this invention, The compounds of this invention with have an active antimicrobial drug Combined Preparation of anti-Gram-negative bacteria.

Above-mentioned other, in medicinal compositions, process, method, purposes and the medication preparation feature, also use the available and embodiment preferred of The compounds of this invention described herein.

Anti-microbial activity:

The pharmaceutically acceptable compound of the present invention is for having the bioactive effective antimicrobial drug of anti-standard Gram-positive in the wide spectrum body, and this biology is used to screen anti-pathogenic activity.Especially, the pharmaceutically acceptable compound exhibits of the present invention goes out the activity of anti-faecalis (enterococci), pneumococcus (pneumococci), methicillin-resistant strain golden look staphylococcus (S.aureus) and coagulase negative staphylococcus (staphylococci) and hemophilus (haemophilus) and moraxella (moraxella) bacterial strain.The antimicrobial spectrum of particular compound and effectiveness can be determined by the standard testing system.

(antibiotic) characteristic of The compounds of this invention also can and be estimated by routine test proof in the body, for example by using standard technique to give warm-blooded mammals with compound per os and/or intravenously.

Following result is obtained by the standard body automatic checkout system.Active in being 10 by inoculating big or small (size) ⁴The minimum inhibition concentration (MIC) that the agar dilution technology of CFU/ point (spot) is determined is described.Typically, compound is effective in 0.01-256 μ g/ml scope.

Staphylococcus (Staphylococci) is tested on agar, adopts 10 ⁴Inoculation that CFU/ is ordered and heated culture temperature are 37 ℃, the standard test condition that 24 hours-methicillin resistance of incubation is expressed.

Suis (Streptococci) and faecalis (Enterococci) are tested on agar, replenish 5% defibrinated horse blood, inoculation 10 ⁴CFU/ point and heated culture temperature are 37 ℃, the growth needs blood of 48 hours-some biological subject of incubation in 5% carbon dioxide atmosphere.Fastidious gram-negative biological is tested in the Mueller-Hinton broth culture, replenishes protohemine and NAD, in 37C grow aerobically 24 hours, and inoculates 5 * 10 ⁴The CFU/ hole.

For example, classify the result of the compound acquisition of embodiment 1 down as:

Biological MIC (μ g/ml)

Streptococcus aureus MSQS 0.25

(Staphylococcus?aureus)

MRQR 0.5

Streptococcus pneumoniae 0.02

(Streptococcus?pneumoniae)

Haemophilus influenzae 4

(Haemophilus?influenzae)

Morazella catarrhalis 0.5

(Moraxella?catarrhalis)

MSQS=methicillin-sensitivity and quinolone sensitivity

MRQR=methicillin resistance and quinolone resistance

The anti-MAO-A activity of The compounds of this invention is used based on experimental test outside the standard body of people's liver enzyme of expressing in yeast, as Biochem.Biophys.Res.Commum.1991, and 181, describe among the 1084-1088.When Ki value during with above-mentioned test determination, embodiment 1 demonstrates the Ki value of 20 μ M.

Hereinafter some intermediate of Miao Shuing and/or reference example and also can have useful activity within the scope of the invention, and provide as further feature of the present invention.

Now, the present invention illustrates by the following example, but not limited by it, unless otherwise indicated otherwise wherein:

(i) evaporation adopts the rotary evaporation vacuum to carry out, and last handling process carries out after removing by filter residual solids;

(ii) operation is carried out at ambient temperature, typically in 18-26 ℃ of scope, unless and unless otherwise indicated or those of skill in the art under inert atmosphere, operate otherwise excluding air not;

(iii) column chromatography (passing through fast method) is used for purifying compounds, and unless otherwise indicated otherwise on Merck Kieselgel silicon-dioxide (Art.9385), carry out;

(iv) given output is only for illustrating, and needn't be the available output of maximum;

(v) [proton magnetic resonance (PMR) spectrum is usually at DMSO-d by NMR and mass-spectrometric technique conclusive evidence usually for the structure of end product of the present invention ₆Middle mensuration unless otherwise indicated, operated under intensity of field 500MHz in operation under the intensity of field 300MHz or with Bruker DRX-500 spectrograph with Bruker DRX-300 spectrograph; Chemical shift is with part per million rate report, and tetramethylsilane is interior mark (a δ scale), is positioned at low, and the peak multiplicity 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; Fast atom bombardment(FAB) (FAB) mass-spectrometric data uses desk-top spectrograph (being provided by Micromass) to obtain usually, and if electron spray ionisation is and suitable positive ion data or the anion number certificate of collecting]; Specific rotation in the 7.6mM methanol solution, is measured with Perkin ElmerPolarimeter 341 under 589nm, 20 ℃;

(vi) each intermediate of purifying is to the desired standard of follow-up phase, and enough at length characterizes to confirm that specified structure is correct; Purity is measured by HPLC, TLC or NMR, and constitutional features is suitably determined by infrared spectra (IR), mass spectrum or NMR spectrum;

(vii) wherein can use following abbreviation :-

DMF is N, dinethylformamide; DMA is a N,N-dimethylacetamide; TLC is a thin-layer chromatography; HPLC is a high pressure liquid chromatography; MPLC is a medium pressure liquid chromatography; DMSO is a dimethyl sulfoxide (DMSO); CDCl ₃Be deuterochloroform; MS is a mass spectrum; ESP is an electron spray(ES); EI is electron impact; CI is a chemi-ionization; APCI is an atmospheric chemical ionization; EtOAc is an ethyl acetate; Et ₂O is an ether; MeOH is a methyl alcohol; Phosphoryl is (HO) ₂-P (O)-O-; The phosphorous acid base is (HO) ₂-P-O-; SYNTHETIC OPTICAL WHITNER is " clorox " 6.15% clorox;

(viii) temperature is ℃ to provide.

Embodiment

Embodiment 1:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles-3-of 5-dihydro Base] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

Will [(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).In 75 ℃ of heating this mixtures 2 hours, then in the impouring cold water (30ml).Collect formed solid, water washes and (2 * 10ml) washings are dissolved in solid in the warm trifluoroethanol (2ml) then, and further use column chromatography purification with methylene dichloride, with 8% ethanol/methylene wash-out, obtain white solid title compound (0.193g).

MS(ESP]：439.22(M+1)C ₂₁H ₁₉FN ₆O ₄

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 1: acetate (5R)-3-(3-fluoro-phenyl)-2-oxo- azoles alkane-5-ylmethyl ester

Under the nitrogen, (5R)-3-(3-fluorophenyl)-5-methylol  azoles alkane-2-ketone (40g, 0.189mol see Upjohn WO 94-13649) is suspended in the anhydrous methylene chloride (400ml) that is stirring.Add triethylamine (21g, 0.208mol) and 4-dimethylaminopyridine (0.6g, 4.9mmol), then in 30 minutes, drip diacetyl oxide (20.3g, 0.199mol), in envrionment temperature continuation stirring 18 hours.Add saturated sodium bicarbonate aqueous solution (250ml), separate organic phase, with the washing of 2% SODIUM PHOSPHATE, MONOBASIC, dry (sal epsom), filtration and evaporation obtain required product (49.6g), are oily matter.

MS(ESP)：254(MH ⁺)C ₁₂H ₁₂FNO ₄

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-ylmethyl Ester

Under nitrogen with acetate (5R)-3-(3-fluoro-phenyl)-2-oxo- azoles alkane-5-ylmethyl ester (intermediate 1,15.2g 60mmol) are dissolved in the mixture of chloroform (100ml) and acetonitrile (100ml), and add trifluoroacetic acid silver (16.96g, 77mmol).Gradation adds iodine (18.07g 71mmol), continues to stir 18 hours in envrionment temperature in the solution of vigorous stirring in 30 minutes.(2.64g 12mmol) also continues to stir 18 hours because reaction not exclusively, adds trifluoroacetic acid silver again.After the filtration, with mixture add 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.Crude product is suspended in the isohexane (100ml), adds the capacity ether to dissolve brown impurity and to stir 1 hour.Filtration obtains required product (24.3g), is Off-white solid.

MS(ESP)：380(MH ⁺)C ₁₂H ₁₁FINO ₄

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-methylol  azoles alkane-2-ketone

In envrionment temperature salt of wormwood (16.4g, 0.119mmol) in the mixture of methyl alcohol (800ml) and methylene dichloride (240ml), handle acetate (5R)-3-(3-fluoro-4-iodophenyl)-2-oxo- azoles alkane-5-ylmethyl ester (intermediate 2,30g, 79mmol) 25 minutes, add the neutralization of acetate (10ml) and water (500ml) then immediately.With sedimentation and filtration, wash with water, and be dissolved in the methylene dichloride (1.2L), wash this solution with saturated sodium bicarbonate, and dry (sal epsom).Filter and evaporate and obtain required product (23g).

MS(ESP)：338(MH ⁺)C ₁₀H ₉FINO ₃

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- Base] methyl ester

In 0 ℃, in methylene dichloride (250ml), stir (5R)-3-(3-fluoro-4-iodophenyl)-5-(methylol)-1,3- azoles alkane-2-ketone (intermediate 3,25.0g, 74.2mmol).(10.5g, 104mmol), (11.2g 89.0mmol) and stir this reaction and spend the night, slowly is warming up to room temperature then to add methylsulfonyl chloride to add triethylamine.Dilute this yellow solution and use methylene dichloride (3 * 250ml) extract compounds with sodium bicarbonate.With organic layer drying (sal epsom), filter and concentrate, obtain required product (30.3g), be light yellow solid.

MS(ESP)：416(MH ⁺)C ₁₁H ₁₁FINO ₅S

¹ H-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 ester, in the dinethylformamide (50ml) with methylsulfonic acid [(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3- azoles alkane-5-yl].(1.92g 29.6mmol) and in 75 ℃ of these reactions of stirring spends the night to add sodiumazide.With in the half saturated sodium bicarbonate of yellow mixture impouring and use ethyl acetate extraction.Organic layer washes with water three times, and dry (sal epsom) filters, and the concentrated yellow solid title compound (4.72g) that obtains.

MS(ESP)：363(MH ⁺)C ₁₀H ₈FIN ₄O ₂

¹ H-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-triazol-1-yl methyl)- 1,3- azoles alkane-2-ketone

1, stir (5R)-5-(azido methyl)-3-(3-fluoro-4-iodophenyl)-1 in the 4-dioxane, 3- azoles alkane-2-ketone (intermediate 5,30.3g, 72.9mmol).Add dicyclo [2.2.1] heptan-2, (40.3g 437mmol) also will react on 100 ℃ of heated overnight to the 5-diene.The gained brown mixture is filtered, obtain required product (14.8g), be the light brown solid.

MS(ESP)：389(MH ⁺)C ₁₂H ₁₀FIN ₄O ₂

¹ H-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 heterocycle pentanes -2-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

With (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), hypoboric acid two (tetramethyl ethylene ketone) ester (bis (pinacolato) diboron) 2.62g (10.3mmol), potassium acetate 2.5g (25.5mmol) and 1,1 '-[two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride mixture (dichoromethane complex) 0.38g (0.52mmol) is suspended among the DMSO 15ml.Mixture in 80 ℃ of heating 40 minutes, is obtained clarifying dark solution.Add ethyl acetate (150ml) then and mixture is passed through diatomite filtration, with saturated NaCl (2 * 100ml) washings, dried over sodium sulfate and evaporation.With chromatography (silica gel, 40-100% ethyl acetate/hexane, then 1-5% acetonitrile/ethyl acetate) this black residue of purifying, obtain crystalline brown solid product 1.97g (98%).(the very dark impurity wash-out before the product colour band of notes-color goes out, and obtains product and need prolong elution time).

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), tetramethyl ethylene ketone borine (pinacolborane) 2.9ml (20mmol), triethylamine 5.4ml (39mmol) and trans-dichloride two (triphenylphosphinyl) palladium (II) 0.92g (1.3mmol) be dissolved among the dioxane 70ml.This mixture in 100 ℃ of heating 90 minutes, is obtained dark solution,, be dissolved in the ethyl acetate, use the salt water washing, dried over sodium sulfate and evaporation this solution concentration.With this residue of purification by chromatography (silica gel, 0-5% ethanol/methylene contain 1% triethylamine), obtain light brown solid product 3.1g.

Intermediate 8:5-bromo-N-pyridone-2-carbon imido acyl chloride (carboximdoyl Chloride)

With 5-bromopyridine-2-formoxime (49.5g 246.3mmol) is dissolved in DMF (150ml), then add N-chloro-succinimide (39.5g, 295.5mmol).Bubbling feeding HCl gas stirred it 1 hour to cause this reaction in 20 seconds then in solution then.With in the reactant impouring distilled water (1L) and the vacuum filtration collecting precipitation.(2 * 500ml) washings in 60 ℃ of (30 inches (inches) Hg) dried overnight in vacuum drying oven, obtain white powder product (55g) to filter cake then with distilled water.

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

Annotate: lacrymator

Intermediate 8a:5-bromopyridine-2-formoxime

With 5-bromo-pyridine-2-formaldehyde (X.Wang etc., Tetrahedron Letters 41 (2000), 4335-4338) (60g 322mmol) is added in the methyl alcohol (700ml), adds entry (700ml) then, then add oxammonium hydrochloride (28g, 403mmol).(20.5g, (200ml) solution of water 193.2mmol) also stirs this reaction 30 minutes to add yellow soda ash.Add entry (500ml) then and with sedimentation and filtration, (2 * 300ml) washings obtain required product (60g) to 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] methyl ester

(intermediate 8,46g 195.7mmol) join among the EtOAc (200ml), and (145ml 1020.4mmol) also is cooled to 0 ℃ with this solution then to add the butyric acid allyl ester with 5-bromo-N-pyridone-2-carbon imido acyl chloride.In 1 hour, drip triethylamine (30ml, EtOAc 215.8mmol) (100ml) solution then.Then this is reacted on 0 ℃ and stirred 1 hour, add EtOAc (1L) then.Precipitation and this filtrate of vacuum concentration are removed in vacuum filtration, obtain product (65g).

¹ H-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 of 5-dihydro-5-yl] first The base ester

Based on the comparison of Chem.Lett.1993p.1847, be classified as (+) isomer of (5S).With racemize butyric acid [3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] (intermediate 9,80g 0.244mol) are dissolved in acetone (4L) to methyl ester, under vigorous stirring, add 0.1M potassium phosphate buffer (pH～7) (4L), obtain clarifying yellow solution.Add PS-lipase (1.45g, Sigma cat no L-9156) and mixture was stirred 42 hours gently in envrionment temperature.This solution is divided into～(2 * 1L) extractions, the organic phase of merging is with dried over sodium sulfate and evaporation for 3 parts of the 2.6L volume and each personal methylene dichloride.Unreacted butyric acid [(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl ester is separated (9: 1 hexanes: ethyl acetate), be clarified yellow oil, 36.4g (45.5%) by rapid 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 ester 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).In this solution of stirring at room 15 minutes, add 1M HCl (75ml), then vacuum concentration to cumulative volume is～100ml.Add entry (～50ml), collect the flushing of white precipitate and water.With this filtrate twice of ethyl acetate extraction, merge organic layer, dried over sodium sulfate and evaporation.Collect solid residue also with 10: 1 hexanes: ethyl acetate rinse, with initial precipitation merging, vacuum-drying then obtains white crystalline solid title compound 12.3g (93%).Chirality HPLC analyzes (-) isomer that shows existence＜0.5%.[α] _D=+139 (c=0.01g/ml, methanol solutions).

Embodiment 2:(5R)-and 3-(3-fluoro-4-{6-[(5R)-5-(methylol)-4, the different  azoles-3-of 5-dihydro Base] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-2-ketone

Will [(5R)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 12,0.139g, 0.54mmol), (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 7,0.2g, 0.514mmol), salt of wormwood (0.355g, 2.57mmol) and four (triphenylphosphines) close palladium (0) (0.059g 0.05mmol) mix and is suspended in DMF (7ml) and the water (1ml).In 75 ℃ of heating this mixtures 2 hours, then in the impouring cold water (30ml).Collect formed solid, water flushing and with methylene dichloride (2 * 10ml) washings, and solid further uses column chromatography purification, usefulness 5%DMF/ methylene dichloride wash-out obtains white solid title compound (0.125g).

MS(ESP)：439.22(M+1)C ₂₁H ₁₉FN ₆O ₄

¹ H-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 12:[(5R)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol

With (R, S)-[3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] (9 preparations of hydrolysis intermediate 3.1g) are dissolved in hot methanol (25ml) to methyl alcohol, use chiral column (Chiral Pak AS) to separate then, with 30% isopropanol/hexane wash-out.Collect the title compound [(-) isomer, 1.5g] that at first wash-out goes out from post, collect then (+) isomer (second peak, 1.18g).Chirality HPLC analyzes (+) isomer that shows existence＜2%.[α] _D=-125 ° (c=0.0076g/ml, methanol solution).

Embodiment 3:N-{[(5S)-and 3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro -3-yl] pyridin-3-yl } phenyl)-2-oxo-1,3- azoles alkane-5-yl] methyl } ethanamide

Will [(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11,0.5g, 1.95mmol), salt of wormwood (0.622g, 4.5mmol), N-((5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-2-oxo-1,3- azoles alkane-5-yl } methyl) ethanamide (intermediate 13,0.736g, 1.95mmol) and four (triphenylphosphines) close palladium (0) (0.225g 0.195mmol) mix and is suspended in DMF (7ml) and the water (1ml).In 75 ℃ of heating this mixtures 2 hours, then in the impouring cold water (30ml).Collect formed solid, washed with dichloromethane is also used in the water flushing, and vacuum-drying and collection obtain title compound (0.407g).

MS(ESP)：429.31(M+1)C ₂₁H ₂₁FN ₄O ₅

NMR(300Mz)(DMSO-d ₆ )δ：1.82(s，3H)；3.3(m，2H)；3.41(m，2H)；3.55(m，2H)；3.80(dd，1H)；4.21(t，1H)；4.78(m，2H)；5.02(t，1H)；7.43(dd，1H)；7.61(dd，1H)；7.69(t，1H)；7.98(d，1H)；8.05(dd，1H)；8.21(t，1H)；8.78(s，1H).

The starting raw material of embodiment 3 prepares as follows:

Intermediate 13:N-((5S)-and 3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycles Pentane-2-yl) phenyl]-2-oxo-1,3- azoles alkane-5-yl } methyl) ethanamide

With N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3- azoles alkane-5-yl] methyl } ethanamide (intermediate 14,1.0g, 2.65mmol), hypoboric acid two (tetramethyl ethylene ketone) ester (1.68g, 6.6mmol), potassium acetate (0.9g, 9.27mmol) and 1,1 '-(0.194g 0.265mmol) is suspended among the DMSO (10ml) [two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride mixture.Mixture was obtained clarifying dark solution in 90 minutes in 80 ℃ of heating.After being cooled to room temperature, adding ethyl acetate (150ml) and mixture is passed through diatomite filtration, (2 * 100ml) washings, dried over sodium sulfate also is concentrated into dried with saturated NaCl.Black residue is dissolved in methylene dichloride (5ml), then slowly adds hexane (20ml), with the gained sedimentation and filtration and with the washing of 5% dichloromethane/hexane, collect required product (0.99g), this product is not further purified directly and uses as intermediate.

Intermediate 14:N-{[(5S)-and 3-(3-fluoro-4-iodophenyl)-2-oxo-1,3- azoles alkane-5-yl] first Base } ethanamide

With (5R)-5-(azido methyl)-3-(3-fluoro-4-iodophenyl)-1, (intermediate 5,5.00g 0.014mol) are suspended in the thioacetic acid (10ml) 3- azoles alkane-2-ketone, and under nitrogen, room temperature, stir the about 16h of this solution.Vacuum concentration gained suspension.Crude product is crystallization in methanol/acetone, is further purified with silica gel column chromatography then, and the methylene dichloride wash-out obtains 3.71g white solid title product.

MS(ESP)：379(MH ⁺)C ₁₂H ₁₂FIN ₂O ₃

¹ H-NMR(500MHz)(DMSO-d ₆ )：1.86(s，3H)；3.45(t，2H)；3.76(dd，1H)；4.14(t，1H)；4.78(m，1H)；7.22(dd，1H)；7.58(dd，1H)；7.87(t，1H)；8.28(t，1H).

Embodiment 4:N-{[(5S)-and 3-(3-fluoro-4-{6-[(5R)-5-(methylol)-4, the different  azoles of 5-dihydro -3-yl] pyridin-3-yl } phenyl)-2-oxo-1,3- azoles alkane-5-yl] methyl } ethanamide

Will [(5R)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 12,0.5g, 1.95mmol), (0.35g, 0.9mmol), salt of wormwood (0.622g, 4.5mmol), N-((5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-2-oxo-1,3- azoles alkane-5-yl } methyl) ethanamide (intermediate 13,0.736g, 1.95mmol) and four (triphenylphosphines) close palladium (O) (0.225g 0.195mmol) mix and is suspended in DMF (7ml) and the water (1ml).In 75 ℃ of heating this mixtures 2 hours, then in the impouring cold water (30ml).Collect formed solid, the water flushing is also used washed with dichloromethane, and vacuum-drying is also collected title compound (0.42g).

MS(ESP)：429.31(M+1)C ₂₁H ₂₁FN ₄O ₅

¹ H-NMR(300Mz)(DMSO-d ₆ )δ：1.82(s，3H)；3.3(m，2H)；3.41(m，2H)；3.55(m，2H)；3.80(dd，1H)；4.21(t，1H)；4.78(m，2H)；5.02(t，1H)；7.43(dd，1H)；7.61(dd，1H)；7.69(t，1H)；7.98(d，1H)；8.05(dd，1H)；8.21(t，1H)；8.78(s，1H).

Embodiment 5:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles-3-of 5-dihydro Base] pyridin-3-yl } phenyl)-5-{[4-(methyl fluoride)-1H-1,2, the 3-triazol-1-yl] methyl }-1,3- azoles Alkane-2-ketone

Will [(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11,1.075g, 4.18mmol), (5R)-5-{[4-(methyl fluoride)-1H-1,2, the 3-triazol-1-yl] methyl }-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-1,3- azoles alkane-2-ketone (intermediate 15,1.6g, 3.80mmol), salt of wormwood (2.6g, 19mmol) and four (triphenylphosphines) close palladium (0) (0.44g 0.38mmol) be suspended in DMF (25ml) and the water (2.5ml).In 80 ℃ of heating this mixtures 2 hours, then in the impouring cold water (100ml).Collect formed solid, water washes and (2 * 10ml) washings are dissolved in then in the warm trifluoroethanol (6ml), and use column chromatography purification, with 8% ethanol/methylene wash-out, obtain white solid title compound (1.36g) with methylene dichloride.

MS(ESP)：471.15(M+1)C ₂₂H ₂₀F ₂N ₆O ₄

NMR(300Mz)(DMSO-d ₆ )δ：3.40(m，2H)；3.53(m，2H)；3.95(dd，1H)；4.29(t，1H)；4.78(m，1H)；4.86(d，2H)；5.02(t，1H)；5.18(m，1H)；5.50(d，2H)；7.41(dd，1H)；7.58(dd，1H)；7.69(t，1H)；8.0(overlapping?m，2H)；8.41(s，br，1H)；8.85(s，1H).

The starting raw material of embodiment 5 prepares as follows:

Intermediate 15:(5R)-and 5-{[4-(methyl fluoride)-1H-1,2, the 3-triazol-1-yl] methyl }-the 3-[3-fluoro- 4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-1,3- azoles alkane-2-ketone

With (5R)-3-(3-fluoro-4-iodophenyl)-5-{[4-(methyl fluoride)-1H-1,2, the 3-triazol-1-yl] methyl }-1,3- azoles alkane-2-ketone (intermediate 16,4.0g, 9.5mmol), hypoboric acid two (tetramethyl ethylene ketone) ester (6.0g, 23.75mmol), potassium acetate (3.24g, 33.25mmol) and 1,1 '-(0.695g 0.95mmol) is suspended among the DMSO (25ml) [two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride mixture.Mixture was obtained clarifying dark solution in 90 minutes in 80 ℃ of heating.After being cooled to room temperature, adding ethyl acetate (250ml) and mixture is passed through diatomite filtration, (2 * 100ml) washings, dried over sodium sulfate also is concentrated into dried with saturated NaCl.Black residue is dissolved in methylene dichloride (30ml), then slowly adds hexane (100ml), with the gained sedimentation and filtration and with the washing of 5% dichloromethane/hexane, obtain required product (2.73g), this product is not further purified directly and uses as intermediate.

Intermediate 16:(5R)-and 3-(3-fluorine 4-iodophenyl)-5-[(4-methyl fluoride-1H-1,2,3-triazole-1- Base) methyl]  azoles alkane-2-ketone

With (5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-brooethyl-1H-1,2,3-triazol-1-yl) methyl] (intermediate 17,6.94g 14.4mmol) dissolve/are suspended in acetonitrile (250mL) and the water (1.5mL)  azoles alkane-2-ketone.(4.19g 72.1mmol), then adds 1-butyl-3-methyl imidazolium tetrafluoroborate (18.4mL), and this solution is heated to 90 ℃ spends the night to add Potassium monofluoride.With the ethyl acetate dilution, water washing is also used dried over mgso.Silica gel column chromatography, eluent ethyl acetate obtain 2.7g (45%) pale solid title compound.

MS(ESP)：421.34(MH ⁺)C ₁₃H ₁₁F ₂IN ₄O ₂

¹ H-NMR(DMSO-d ₆ )δ：3.88(dd，1H)；4.23(dd，1H)；4.84(m，2H)；5.14(m，1H)；5.45(d，2H，J _H，F?52Hz)；7.14(m，1H)；7.49(m，1H)；7.81(m，1H)；8.34(d，1H).

Intermediate 17:(5R)-and 3-(3-fluoro-4-iodophenyl)-5-[(4-brooethyl-1H-1,2,3-triazole-1- Base) methyl]  azoles alkane-2-ketone

With 5R)-3-(3-fluorine 4-iodophenyl)-5-[(4-methylol-1H-1,2, the 3-triazol-1-yl) methyl] (intermediate 18,14.7g 35.1mmol) are suspended in the methylene dichloride (1L)  azoles alkane-2-ketone.Add carbon tetrabromide (1216g, 36.7mmol), be cooled to 0 ℃ and add triphenylphosphine (12.34g, 61.2mmol).Stirred this mixture 30 minutes in 0 ℃, then in stirred overnight at room temperature.During aftertreatment this reaction mixture placed on the silicagel column and use hexane/ethyl acetate (1: 1), ethyl acetate/methanol (95: 5) wash-out successively.Merging contains product stream part and uses re-crystallizing in ethyl acetate, obtains 14g colorless solid title compound.

MS(ESP)：482.69(MH ⁺?Br ⁸¹)C ₁₃H ₁₁BrFIN ₄O ₂

¹ H-NMR(DMSO-d ₆ )δ：3.87(dd，1H)；4.23(dd，1H)；4.74(s，2H)；4.81(m，2H)；5.12(m，1H)；7.14(m，1H)；7.49(m，1H)；7.81(m，1H)；8.22(d，1H).

Intermediate 18:(5R)-and 3-(3-fluorine 4-iodophenyl)-5-[(4-methylol-1H-1,2,3-triazole-1- Base) methyl]  azoles alkane-2-ketone

With (5R)-5-(azido methyl)-3-(3-fluoro-4-iodophenyl)-1, (intermediate 5,10g 28mmol) are dissolved in the acetonitrile (80mL) 3- azoles alkane-2-ketone.(3.2mL, 56mmol), (526mg, 2.8mmol) also stirring is spent the night to add CuI then to add propargyl alcohol.Extract this curing reaction mixture with ethylacetate/acetonitrile, wash and use dried over mgso with water.Vacuum evaporating solvent obtains 12.3g crude product (quantitatively).

MS(ESP)：419.13(MH ⁺)C ₁₃H ₁₂FIN ₄O ₃

¹ H-NMR(DMSO-d ₆ )δ：3.88(dd，1H)；4.23(dd，1H)；4.51(d，2H)；4.80(m，2H)；5.14(m，1H)；5.22(dd，1H)；7.16(m，1H)；7.51(m，1H)；7.83(m，1H)；8.01(d，1H).

Embodiment 6: and hexanodioic acid [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first Base ester ethyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1,0.25g, 0.57mmol), monoethyl adipatee (0.25g, 1.44mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride mixes in DMF (4ml).This suspension in stirring at room 1 hour, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-10% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white powder title compound (0.275g), fusing point: 88 ℃.

MS(ESP)：595(MH ⁺)C ₂₉H ₃₁FN ₆O ₇

¹ H-NMR(300MHz)(DMSO-d ₆ )δ：1.13(t，3H)；1.48(m，4H)；2.20(bt，2H)；2.31(bt，2H)；3.28(m，2H)；3.58(dd，1H)；3.96(dd，1H)；4.01(q，2H)；4.15(dd，1H)；4.25(dd，1H)；4.32(d，1H)；4.86(d，2H)；5.00(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.58(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 6 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 7: nicotinic acid [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2, the 3-triazole- The 1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first The base ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4,5, the different  azoles of-dihydro-3-yl] pyridin-3-yl } phenyl)-4-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-(embodiment 1 for 2-ketone, 200mg, 0.46mM), the nicotinoyl chlorine hydrochloride (175mg, 0.98mM), 4-(dimethylamino) pyridine (DMAP, 20mg 0.17mM) places flask.Add anhydrous dimethyl formamide (2mL) and anhydrous pyridine (2mL) and stirred this suspension 16 hours, this suspension becomes settled solution therebetween.Add 500mg silica gel and evaporating solvent.With the residue silica gel column chromatography,, obtain title compound (120mg, 48%) with ethanol/methylene gradient elution (1-20%).

MS(APCI)：544(M+1)C ₂₇H ₂₂N ₇O ₅F

NMR(DMSO-d ₆ )δ：3.51(dd，1H)；3.68(dd，1H)；3.95(dd，1H)；4.34(t，1H)；4.49(dd，1H)；4.55(dd，1H)；4.87(d，2H)；5.20(m，2H)；7.43(d?d，1H)；7.65(m，2H)；7.71(t，1H)；7.78(s，1H)；8.02(d，1H)；8.08(d，1H)；8.20(s，1H)；8.32(dd，1H)；8.81(m，2H)；9.06(s，1H)

Embodiment 7 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 8: and Beta-alanine [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles-5-of 5-dihydro Base] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 0.25g, 0.57mmol), N-(tert-butoxycarbonyl)-Beta-alanine (0.27g, 1.43mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-(0.25g 1.30mmol) mixes in DMF (4ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 1 hour, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 1% ethanol/methylene).Evaporation contains product stream part and uses hexane: methylene dichloride (5: 1) grinds the gained solid, obtains the tert-butoxycarbonyl derivative of title compound, is wax shape pale solid (0.34g).Should be dissolved in methylene dichloride (5ml) and add trifluoroacetic acid (10ml) by protected derivative.In stirring at room gained pale yellow solution 1 hour, vacuum concentration then.Residue is suspended in the dioxane (20ml), and with dioxane (2ml) solution-treated of 4M HCl.Stirring the thick suspension of gained 10 minutes, and with the ether dilution, and filtered and obtain title compound hydrochloride (0.30g), is the easy yellow solid of moisture absorption, mp 68-75 ℃.

MS(ESP)：510(MH ⁺)C ₂₄H ₂₄FN ₇O ₅

¹ H-NMR(300MHz，DMSO-d ₆ )δ：2.59(m，2H)；2.69(m，2H)；2.98(m，3H)；3.30-3.40(m，1H)；3.62(m，1H)；3.95(dd，1H)；4.19(dd，1H)；4.30(m，1H)；4.86(d，2H)；5.04(m，1H)；5.18(m，1H)；7.42(d，1H)；7.58(d，1H)；7.69(t，1H)；7.76(s，1H)；8.01(d，1H)；8.08(d，1H)；8.18(s，1H)；8.83(s，1H).

Embodiment 8 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 9:4-(dimethylamino) butyric acid [(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 5-dihydro Different  azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 0.25g, 0.57mmol), 4-(dimethylamino) butyrates hydrochlorate (0.24g, 1.43mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-(0.25g 1.30mmol) mixes in DMF (4ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 1 hour, is obtained clear soln.This mixture of vacuum concentration is suspended in ethyl acetate: acetonitrile (1: 1) and filtration then.This solid is dissolved in the minimum methyl alcohol, and directly uses purification by chromatography (silica gel, 1-20% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white solid title compound (0.195g), fusing point: 148 ℃.

MS(ESP)：552(MH ⁺)C ₂₇H ₃₀FN ₇O ₅

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.80(m，2H)；2.40(t，2H)；2.54(s，6H)；2.80(m，2H)；3.59(dd，1H)；3.96(dd，1H)；4.17(dd，1H)；4.30(m，2H)；4.86(d，2H)；5.02(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.58(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.07(dd，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 9 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 10:5-[(methoxycarbonyl) amino] and valeric acid [(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] methyl ester

With 5-aminovaleric acid hydrochloride (2g, 13mmol) and salt of wormwood (13g 94mmol) in water-soluble (30ml) and the dioxane (10ml), is cooled to 0 ℃ then.(5ml 65mmol), stirred this mixture 2.5 hours in 0 ℃ then to add methyl-chloroformate in 30 seconds.Add dense HCl and become acidity, then this mixture of dilute with water and extract with ether up to this mixture.The organic layer dried over mgso, evaporation and vacuum-drying obtain white powder 5-[(methoxycarbonyl) amino] valeric acid (1.5g).

Urethylane (0.25g with above-mentioned preparation, 1.43mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 0.25g, 0.57mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-(0.25g 1.30mmol) mixes in DMF (4ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 1 hour, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-10% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white powder title compound (0.33g), fusing point: 90 ℃.

MS(ESP)：596(MH ⁺)C ₂₈H ₃₀FN ₇O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.35(m，2H)；1.47(m，2H)；2.30(t，2H)；2.90(m，2H)；3.48(s，3H)；3.58(dd，1H)；3.95(dd，1H)；4.14(dd，1H)；4.29(m，2H)；4.86(d，2H)；5.01(m，1H)；5.19(m，1H)；7.07(bt，1H)；7.42(dd，1H)；7.58(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.06(dd，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 10 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 11:N, and N-diethyl-Beta-alanine [(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-two The different  azoles of hydrogen-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 0.25g, 0.57mmol), N, N-diethyl-Beta-alanine hydrochloride (0.24g, 1.43mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-(0.25g 1.30mmol) mixes in DMF (4ml) the 3-ethyl-carbodiimide hydrochloride.With this suspension in stirring at room 1 hour.Use acetonitrile then: ether (1: 1) dilutes this mixture and filters.This solid is dissolved in the minimum methyl alcohol also with purification by chromatography (silica gel, 5-20% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white solid title compound (70mg), fusing point: 167 ℃.

MS(ESP)：566(MH ⁺)C ₂₈H ₃₂FN ₇O ₅

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.13(bt，6H)；2.82(bm，2H)；3.08(bm，2H)；3.60(dd，1H)；3.96(dd，1H)；4.15-4.35(m，4H)；4.86(d，2H)；5.02(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.58(dd，1H)；7.68(t，1H)；7.76(s，1H)；8.00(d，1H)；8.07(d，1H)；8.18(s，1H)；8.83(s，1H).

Embodiment 11 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 12: and methoxyacetic 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  of 5-dihydro Azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1,0.25g for 2-ketone, 0.57mmol), methoxyacetic acid (0.15ml, 1.96mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-(0.25g 1.30mmol) mixes in DMF (4ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 1 hour, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-5% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white solid title compound (0.25g), fusing point: 170 ℃.

MS(ESP)：511(MH ⁺)C ₂₄H ₂₃FN ₆O ₆

¹ H-NMR(300MHz，DMSO-d ₆ )δ：3.29(s，3H)；3.60(dd，1H)；3.96(dd，1H)；4.06(s，2H)；4.19-4.35(m，4H)；4.86(d，2H)；5.02(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.58(dd，1H)；7.69(t，1H)；7.77(s，1H)；7.99(d，1H)；8.07(bd，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 12 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 13:3-methoxypropionic 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  of 5-dihydro Azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1,0.25g for 2-ketone, 0.57mmol), 3-methoxypropionic acid (0.15ml, 1.6mmol), 4-dimethylaminopyridine (0.02g, 0.16mmol) and 1-[3-(dimethylamino) propyl group]-(0.25g 1.30mmol) mixes in DMF (4ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 1 hour, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-5% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white solid title compound (0.255g), fusing point: 149 ℃.

MS(ESP)：525(MH ⁺)C ₂₅H ₂₅FN ₆O ₆

¹ H-NMR(300MHz，DMSO-d ₆ )δ：2.53(t，2H)；3.14(s，3H)；3.49(t，2H)；3.58(dd，1H)；3.96(dd，1H)；4.15-4.33(m，4H)；4.86(d，2H)；5.00(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.58(dd，1H)；7.69(t，1H)；777(s，1H)；7.99(d，1H)；8.07(bd，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 13 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 14: and carbonic acid [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first The base ester methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 0.2g, 0.46mmol) be dissolved in DMF (4ml) and the pyridine (1ml), be cooled to 0 ℃ then.(0.2ml 2.57mmol) and in 0 ℃ stirred this mixture 45 minutes to add methyl-chloroformate.Add a methyl-chloroformate (0.2ml) again, this mixture of restir 2 hours 15 minutes adds the 3rd part of methyl-chloroformate (0.2ml) then.After the 3rd part of methyl-chloroformate added, in this mixture of 0 ℃ of restir 1 hour, dilute with water with ethyl acetate extraction twice, and was used dried over sodium sulfate then.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0-10% acetonitrile/ethyl acetate).Evaporation contains product stream part and grinds the gained solid with ether, obtains white solid title compound (0.125g), fusing point: 205 ℃.

MS(ESP)：497(MH ⁺)C ₂₃H ₂₁FN ₆O ₆

¹ H-NMR(300MHz，DMSO-d ₆ )δ：3.59(dd，1H)；3.70(s，3H)；3.96(dd，1H)；4.22(dd，1H)；4.28-4.33(m，2H)；4.86(d，2H)；5.02(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.06(d，1H)；8.18(s，1H)；8.83(s，1H).

Embodiment 14 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 15: and carbonic acid [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first Base ester 2-methoxy ethyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 0.2g, 0.46mmol) be dissolved in DMF (4ml) and the pyridine (0.5ml), be cooled to 0 ℃ then.(0.2ml 1.73mmol), stirred this mixture 45 minutes in 0 ℃, then added second part of chloroformic acid 2-methoxy ethyl ester to add chloroformic acid 2-methoxy ethyl ester.In this mixture of 0 ℃ of restir 1 hour, dilute with water then was with twice of ethyl acetate extraction and use dried over sodium sulfate.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0-10% acetonitrile/ethyl acetate).Evaporation contains product stream part and grinds the gained solid with ether, obtains white solid title compound (0.20g), fusing point: 112 ℃.

MS(ESP)：541(MH ⁺)C ₂₅H ₂₅FN ₆O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ：3.51(m，2H)；3.60(dd，1H)；3.96(dd，1H)；4.19-4.24(m，3H)；4.28-4.33(m，2H)；4.86(d，2H)；5.02(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.07(d，1H)；8.18(s，1H)；8.83(s，1H).

Embodiment 15 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 16: pentanedioic acid [(5S)-and 3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-three Azoles-1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl }-the 2-pyridyl)-4, the different  azoles of 5-dihydro-5-base] The methyl ester methyl esters

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-base]-the 3-pyridyl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 1, and 60mg 0.13mmol) is suspended in the 2mL anhydrous dimethyl formamide for 3- azoles alkane-2-ketone.Add anhydrous pyridine (1ml, 12mmol), 4-dimethylaminopyridine (DMAP) (10mg, 0.08mmol) and Pyroglutaric acid (75mg, 0.55mmol), and in this solution of stirring at room 16 hours, this mixture became settled solution therebetween.With this reaction of 1mL methyl alcohol quencher and use by at diazomethane producer (Aldrich, catalog number Z41, the diazomethane that 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) produces 173-6) cleans (purged), is judged by LCMS up to all products all to change into its methyl ester and this solution becomes yellow.Remove and desolvate, product silica gel column chromatography purifying, 0-10% ethanol/methylene gradient elution obtains white solid title compound 31mg (40%).

MS(APCI)：567(M+1)C ₂₇H ₂₇N ₆O ₇F

NMR(300MHZ)(DMSO-d ₆ )δ：1.97(m，2H)；2.44(m，1H)；3.42(dd，1H)；3.70(m，4H)；4.05(dd，1H)；4.30(m，3H)；4.88(m，2H)；5.07(m，1H)；5.19(m，1H)；7.34(d，1H)；7.56(m，2H)；7.79(s，1H)；7.88(s，1H)；7.98(d，1H)；8.12(d，1H)；8.83(s，1H) ¹⁹ F-NMR(300MHZ)(DMSO-d ₆ )δ：-112.79

Embodiment 16 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 17:4-methoxyl group butyric 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  of 5-dihydro Azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1,0.125g for 2-ketone, 0.29mmol), 3-methoxypropionic acid (0.13g, 1.1mmol), 4-dimethylaminopyridine (0.003g, 0.025mmol) and 1-[3-(dimethylamino) propyl group]-(0.125g 0.65mmol) mixes in DMF (2ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 1.5 hours, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate gained residue methylene dichloride: ether (1: 5) solution supersound process, collect gained solid and vacuum-drying.Obtain white solid title compound (0.15g), fusing point: 154 ℃.

MS(ESP)：539(MH ⁺)C ₂₆H ₂₇FN ₆O ₆

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.66-1.75(m，2H)；2.33(t，2H)；3.15(s，3H)；3.26(t，2H)；3.58(dd，1H)；3.95(dd，1H)；4.12-4.18(m，2H)；4.24-4.33(m，2H)；4.86(d，2H)；5.00(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)；8.06(bd，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 17 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 18: and acetate [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl }-the 2-pyridyl)-4, the different  azoles of 5-dihydro-5-base] first The base ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-base]-the 3-pyridyl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 1, and 200mg 0.46mmol) is suspended in the 2mL anhydrous dimethyl formamide for 3- azoles alkane-2-ketone.Add anhydrous pyridine (2ml, 24mmol), 4-dimethylaminopyridine (DMAP) (20mg, 0.17mmol) and two-O-ethanoyl-L-winestone acid anhydrides (210mg, 0.97mmol), and in this solution of stirring at room 16 hours, this mixture became black therebetween.Should react with the quencher of 1mL methyl alcohol, vacuum evaporating solvent, product separates with quick silica gel column chromatography, and 0-5% ethanol/methylene gradient elution obtains pale solid title compound 50mg (25%).

MS(APCI)：481(M+1)C ₂₃H ₂₁N ₆O ₅F

NMR(300MHZ)(CDCL ₃ )δ：2.09(s，3H)；3.40(dd，1H)；3.63(dd，1H)；4.02(dd，1H)；4.21(m，3H)；4.82(d，2H)；5.07(m，2H)；7.21(d，1H)；7.43(m，2H)；7.77(d，2H)；7.89(d，1H)；8.09(d，1H)；8.74(s，1H)

¹⁹ F-NMR?(300MHZ)(CDCl ₃ )δ：-114.26

Embodiment 18 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 19:1, and the 2-cyclohexane cyclohexanedimethanodibasic [(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 }-the 2-pyridyl)-4, the 5-dihydro- The different  azoles of 5-base] the methyl ester methyl esters

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-base]-the 3-pyridyl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 1, and 60mg 0.13mmol) is suspended in the 2mL anhydrous dimethyl formamide for 3- azoles alkane-2-ketone.Add anhydrous pyridine (1ml, 12mmol), 4-dimethylaminopyridine (DMAP) (10mg, 0.08mmol) and cis-hexahydrophthalic anhydride (85mg, 0.55mmol), and in this solution of stirring at room 16 hours, this mixture became settled solution therebetween.With this reaction of 1mL methyl alcohol quencher and use by at diazomethane producer (Aldrich, catalog number Z41, the diazomethane that 1-methyl-3-nitro 173-6)-1-nitrosoguanidine (MNNG) produces cleans, all change into its methyl ester up to all products by the LCMS judgement, and this solution is become yellow by excessive diazomethane.Remove and desolvate, product silica gel column chromatography purifying, 0-20% ethanol/methylene gradient elution obtains pale solid title compound 40mg (48%).

MS(APCI)：607(M+1)C ₃₀H3 ₁N ₆O ₇F

NMR(300MHZ)(CDCL ₃ )δ：1.38(m，4H)；1.70(m，2H)；1.94(m，2H)；2.81(m.2H)；3.31(dd，1H)；3.55(m，1H)；3.65(d，3H)；4.00(dd，1H)；4.21(m，3H)；4.82(d，2H)；5.01(m，1H)；5.10(m，1H)；7.21(dd，1H)；7.40(m，2H)；7.77(d，2H)；7.89(d，1H)；8.09(d，1H)；8.74(s，1H).

¹⁹ F-NMR(300MHZ)(CDCl ₃ )δ：-114.46

Embodiment 19 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 20: and phosphoric acid [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first Base ester di-ammonium salts

With the di(2-ethylhexyl)phosphate tertiary butyl ester [(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] (intermediate 19,6.07g 9.63mmol) join MeO H: CH to methyl ester ₂Cl ₂In 1: 1 (100ml).Dioxane (15ml) solution that adds 4N HCl then, and this was reacted on stirring at room 2 hours.Then this solution is poured into Et ₂Among the O (800ml), and the vacuum filtration collecting precipitation.Precipitation Et ₂(3 * 100ml) washings, vacuum-drying is 1 hour then for O.The gained solid is dissolved in the mixture of distilled water (60ml) and strong aqua (5ml) then.Then that this aqueous solution is freezing and placed lyophilizer 2 days with dry ice/acetone in round-bottomed flask.Then with this solid suspension in MeOH (60ml) and Et ₂Also filter in the mixture of O (200ml).Solid is used Et again ₂(2 * 100ml) washings place then that round-bottomed flask spends the night under the vacuum to O, obtain product (5.262g).

MS(ESP)：519.28(MH ⁺)C ₂₁H ₂₀FN ₆O ₇P

¹ H-NMR 500MHz (D ₂ O)δ: 3.28 (m, 1H); 3.44 (dd, 1H); 3.92 (m, 3H); 4.18 (m, 1H); 4.70 (the water peak, 2H); 4.81 (dd, 1H); 4.89 (m, 1H); 5.03 (bs, 1H); 5.11 (bs, 1H); 6.98 (d, 1H); 7.12 (d, 1H); 7.24 (t, 1H); 7.61 (bs, 1H); 7.69 (bs, 1H); 7.75 (s, 1H); 8.04 (s, 1H); 8.39 (s, 1H).

Embodiment 20 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Intermediate 19: the di(2-ethylhexyl)phosphate tertiary butyl ester [(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 5-dihydro is different  azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1,8g for 2-ketone, 18.3mmol) the thick material of water precipitation [in the Suzuki reaction by] be suspended in the toluene (250ml), and be concentrated near doing, and heat then and stir and be dissolved among the DMF (120ml), be cooled to 0 ℃.In this settled solution, add two-tertiary butyl-diethyl phosphoramidite (phosphoramidite) (12ml, 40.2mmol), subsequently in about 10 minutes gradation add the 0.34M tetrazolium acetonitrile solution (107ml, 36mmol).Stirred this solution 1 hour in 0 ℃, and then add two-tertiary butyl-diethyl phosphoramidite (2.7ml, 9.04mmol) and the acetonitrile solution of 0.34M tetrazolium (27ml, 9.18mmol).After 30 minutes, this solution is cooled to-70 ℃ with dry ice-isopropanol bath in 0 ℃ of restir.Preparation 3-chlorine peroxybenzoic acid (70%, 9.04g, methylene dichloride 37mmol) (125ml) solution is also used dried over sodium sulfate, is added in the reaction mixture in about 10 minutes then.In cryostat, stir this settled solution 10 minutes, add 0.5M Sulfothiorine (400ml) then.This mixture is shifted out from cryostat and vigorous stirring 5 minutes.Add ethyl acetate, layering is also used the ethyl acetate extraction water layer.The organic layer that use saturated sodium bicarbonate earlier, merges then with the saturated sodium-chloride washing, dried over sodium sulfate and evaporation.Residue column chromatography purification (0.5-5% ethanol/methylene).This product dissolves in methylene dichloride, is insoluble in ethyl acetate.Obtain oyster white spumescence title compound 6.6g (58%).If necessary this raw material can be used ethyl acetate: the hexane crystallization.The purity of this sample is enough carried out deprotection reaction.

¹ H-NMR?300MHz(DMSO-d ₆ )δ：1.36(s，9H)；1.39(s，9H)；3.33(dd，1H)；3.58(dd，1H)；4.01(m，3H)；4.29(t，1H)；4.86(d，2H)；4.99(bm，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(d，1H)；7.99(d，1H)；8.06(d，1H)；8.18(d，1H)；8.82(bs，1H).

Embodiment 21: hydrosulphuric acid [(5S)-and 3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-three Azoles-1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 200mg, 0.46mmol) and sulfur trioxide pyridine complex (300mg 1.89mmol) joins among pyridine (2ml) and the DMSO (2ml).This is reacted on stirring at room 2 hours and vacuum is removed pyridine.With this residue of reversed-phase HPLC purifying, moving phase 0-50%ACN/H ₂O 0.1%TFA 15 minutes, obtains yellow mobile powdered compounds (117mg).

MS(ESP)：519.21(MH ⁺)C ₂₁H ₁₉FN ₆O ₇S

¹ H-NMR?500MHz(DMSO-d ₆ )δ：3.68(dd，1H)；3.53(dd，1H)；3.87(m，2H)；3.98(m，1H)；4.33(t，1H)；4.88(d，2H)；4.98(m，1H)；5.21(m，1H)；5.69(s，3H)；7.44(dd，1H)；7.62(dd，1H)；7.73(t，1H)；7.79(s，1H)；8.03(d，1H)；8.10(d，1H)；8.21(s，1H)；8.85(s，1H).

Embodiment 21 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 22: and piperidines-4-formic 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  of 5-dihydro Azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 250mg, 0.57mmol), butoxy carbonyl (Boc)-piperidines-4-formic acid (196mg, 0.86mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (219mg, 1.14mmol) and 4-dimethylaminopyridine (17.4mg 0.14mmol) joins among the DMF (3ml).This was reacted on stirring at room 3 hours.Join this reaction mixture in the distilled water (50ml) and filter collecting precipitation.Then should precipitation column chromatography purification, 0-5%MeOH/CH ₂Cl ₂Wash-out obtains white powder (271mg).(250mg) is added to CH with products therefrom ₂Cl ₂(20ml), add dioxane (3ml) solution of 4N HCl then, and should react and stir 3 hours.Add Et then ₂O (20ml) also filters collecting precipitation under nitrogen, obtain yellow solid product (250mg).

MS(ESP)：550.30(MH ⁺)C ₂₇H ₂₈FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：1.67(m，2H)；1.88(m，2H)；2.66(m，1H)；2.81(m，2H)；3.10(m，2H)；3.29(dd，1H)；3.55(dd，1H)；3.91(dd，1H)；4.14(dd，1H)；4.24(m，2H)；4.80(d，1H)；4.97(m，1H)；5.13(m，1H)；7.36(dd，1H)；7.54(dd，1H)；7.64(dd，1H)；7.71(s，1H)；7.95(d，1H)；8.02(d，1H)；8.14(s，1H)；8.77(s，2H)；9.01(s，1H).

Embodiment 22 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 23:4-(dimethylamino) valeric acid [(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 5-dihydro Different  azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 1 for 2-ketone, 150mg, 0.342mmol), 4-(dimethylamino) valeric acid (63.6mg, 0.514mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (131.5mg, 0.69mmol) and 4-dimethylaminopyridine (10.5mg 0.09mmol) joins among the DMF (3ml).This is reacted on stirred overnight at room temperature, then join among the EtOAc (40ml).Filter collecting precipitation, use column chromatography purification then, 0-5%MeOH/CH ₂Cl ₂Wash-out obtains white powder (100mg).

MS(ESP)：566.32(MH ⁺)C ₂₈H ₃₂FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：1.34(m，3H)；2.17(t，2H)；2.29(s，4H)；2.73(m，2H)；3.11(m，4H)；3.39(dd，1H)；3.75(dd，1H)；3.96(dd，1H)；4.09(m，1H)；4.65(d，2H)；4.81(m，1H)；4.98(m，1H)；7.21(d，1H)；7.38(d，1H)；7.49(t，1H)；7.56(s，1H)；7.82(dd，2H)；7.98(s，1H)；8.60(s，1H)；9.75(s，1H).

Embodiment 23 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 24:4-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole-1- Ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxy Base }-the 4-ketobutyric acid

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:150mg, 0.342mmol), dihydrofuran-2,5-diketone (83mg, 0.83mmol) and 4-dimethylaminopyridine (10.5mg 0.09mmol) joins in DMF (2.5ml) and the pyridine (0.5ml).This is reacted on stirred overnight at room temperature, then join Et ₂O (100ml).Filter collecting precipitation, and use Et again ₂O (2 * 20ml) washings.Precipitation is suspended in CH ₂Cl ₂(20ml), filter collecting precipitation, and then use CH ₂Cl ₂(2 * 20ml) washings obtain white solid product (131mg).

MS(ESP)：539.37(MH ⁺)C ₂₅H ₂₃FN ₆O ₇

¹ H-NMR?300MHz(DMSO-d ₆ )δ：2.54(m，2H)；3.35(m，3H)；3.62(dd，1H)；3.99(dd，1H)；4.28(m，3H)；4.86(d，2H)；5.06(m，1H)；5.26(m，1H)；7.47(d，1H)；7.81(d，1H)；7.87(t，1H)；7.91(s，1H)；8.07(t，2H)；8.24(s，1H)；8.84(s，1H)；12.26(s，1H).

Embodiment 24 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 25: and nicotinic acid [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first Base ester-1-oxide compound

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3- azoles alkane-2-ketone (embodiment 1:130mg, 0.30mMol), nicotinic acid-1-oxide compound (100mg, 0.72mMol), 1, the 3-DIC (290mg, 2.3mMol) and 4-dimethylaminopyridine (5mg 0.04mMol) is suspended among the 2ml DMF in room temperature.Stirred this mixture one day, and, stirred 5 minutes, further use ether (20ml) dilution then, obtain suspension with methyl alcohol (2ml) dilution.Collect solid and with the ether flushing, be suspended in acetonitrile then: methyl alcohol (1: 1,150ml) in, with this mixture heating up and stir several minutes, then with its cooling.Be concentrated into 10ml with this suspension filtered and with filtrate, obtain suspension.Collect solid,, obtain pale solid title compound (90mg), fusing point: 255 ℃ with acetonitrile, then with ether flushing and vacuum-drying.

MS (electron spray(ES)): 560 (MH ⁺) C ₂₇H ₂₂FN ₇O ₆

¹ H-NMR(500MHz，DMSO-d ₆ )δ：3.48(dd，1H)；3.67(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.45(dd，1H)；4.53(dd，1H)；4.86(d，2H)；5.19(m，2H)；7.42(dd，1H)；7.52(t，1H)；7.59(dd，1H)；7.69(d，1H)；7.73(d，1H)；7.77(s，1H)；8.01(d，1H)；8.07(d，1H)；8.18(s，1H)；8.42(d，1H)；8.45(s，1H)；8.88(s，1H).

Embodiment 25 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 26:N, N-N-methylsarcosine [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  of 5-dihydro Azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:250mg, 0.57mMol), N, N-N-methylsarcosine (150mg, 1.46mMol), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (300mg, 1.56mMol) and 4-dimethylaminopyridine (5mg 0.04mMol) is suspended among the 5ml DMF in room temperature.Stir this mixture overnight and concentrated.Residue chromatography (silica gel; 1-10% ethanol/methylene wash-out) purifying obtains the free alkali (250mg) of white solid title compound.Mp?185-198℃。

A part of sample heating is dissolved in ethyl acetate: acetonitrile (1: 1,12ml), be diluted to 100ml with dioxane solution (1ml) processing of 4M HCl and with ether.Collect solid and with the ether flushing, vacuum-drying obtains the hydrochloride (250mg) of title compound, is the easy light yellow solid of moisture absorption.Mp?175-180℃。

MS (electron spray(ES)): 524 (M+1) C ₂₅H ₂₆FN ₇O ₅

¹ H-NMR (300MHz, DMSO-d ₆ ) [HCl salt]δ: 2.82 (s, 6H); 3.38 (dd, 1H); 3.63 (dd, 1H); 3.96 (dd, 1H); 4.24-4.36 (m, 4H); 4.44 (dd, 1H); 4.86 (d, 2H); 5.07 (m, 1H); 5.19 (m, 1H); 7.42 (dd, 1H); 7.58 (dd, 1H); 7.69 (t, 1H); 7.76 (s, 1H); 8.01 (d, 1H); 8.07 (d, 1H); 8.18 (s, 1H); 8.83 (s, 1H); 10.15 (bs, 1H)

Embodiment 26 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 27:5-[(ethoxy carbonyl) amino] and valeric 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 ester

With 5-aminovaleric acid hydrochloride (1g, 6.5mmol) and salt of wormwood (6.5g 47mmol) in water-soluble (15ml) and the dioxane (5ml), is cooled to 0 ℃ then.(3ml 31.5mmol), stirred this mixture 4 hours in 0 ℃ then to add Vinyl chloroformate in 30 seconds.Add dense HCl and become acidity, then this mixture of dilute with water and extract with ether up to this mixture.The organic layer dried over mgso, evaporation and vacuum-drying obtain white powder 5-[(methoxycarbonyl) amino] valeric acid (1.07g).

Urethanum (0.175g with above-mentioned preparation, 0.93mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:0.25g, 0.57mmol), 4-dimethylaminopyridine (0.01g, 0.08mmol) and 1-[3-(dimethylamino) propyl group]-(0.19g 0.99mmol) mixes in DMF (2ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 3.5 hours, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-10% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white powder title compound (0.25g), fusing point: 183 ℃.

MS (electron spray(ES)): 610 (MH ⁺) C ₂₉H ₃₂FN ₇O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.12(t，3H)；1.35(m，2H)；1.47(m，2H)；2.30(t，2H)；2.90(m，2H)；3.30(dd，1H)；3.58(dd，1H)；3.91-3.98(m，3H)；4.15(dd，1H)；4.25(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.00(m，1H)；5.19(m，1H)；7.02(bt，1H)；7.42(dd，1H)；7.59(dd，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 27 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 28:2-{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole-1- Ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methoxy Base }-N, N, N-trimethylammonium-2 oxo second ammonium muriate

With N, N-N-methylsarcosine [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] (embodiment 26:100mg, 0.19mMol) heating is dissolved among the 1ml DMF methyl ester, is cooled to room temperature then.(0.15ml 2.4mmol) and stirred this mixture 45 minutes, uses ether (15ml) dilution then to add methyl-iodide.With oily suspension supersound process, grinding and decant obtain residue, and (5ml) grinds this residue with ethyl acetate.The gained solid is dissolved in 2: 1 acetonitriles: water (6ml) also passes through 2g C-18 reverse phase silica gel post, uses 1: 1 acetonitrile subsequently: water (15ml) flushing.(chlorion type ion exchange resin 5g), stirs this suspension number minute, filters then to add Dowex 1X2-100 in the filtrate that merges.Filtrate with acetonitrile flushing resin bed and evaporation merging.With this residue and 10: 1 ethyl acetate: acetonitrile (11ml) mixes, and supersound process is also ground and obtained solid, collects this solid and uses ethyl acetate rinse.With this material vacuum-drying, obtain white solid title compound (100mg).Mp?188℃。

¹ H-NMR(400MHz，DMSO-d ₆ )δ：3.22(s，9H)；3.39(dd，1H)；3.63(dd，1H)；3.96(dd，1H)；4.27-4.36(m，2H)；4.44(dd，1H)；4.48(s，2H)；4.86(d，2H)；5.08(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.00(d，1H)；8.08(d，1H)；8.18(s，1H)；8.83(s，1H).

Embodiment 28 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 29: carbonic acid (5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2, the 3-triazole- The 1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first Base ester 3-methoxy-propyl ester

(155mg 1.72mMol) is dissolved in the methylene dichloride (3ml), is cooled to 0 ℃ with 3-methoxyl group-1-propyl alcohol.(20% toluene solution: 1.5ml 2.8mMol), and slowly arrives this solution in ambient temperature overnight to add phosgene.This solution of vacuum concentration obtains clarifying oily chloro-formic ester intermediate, and it is dissolved in the methylene dichloride (2ml).This chloro-formic ester solution is joined ice-cooled (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:200mg, 0.46mMol), (0.4ml is 4.96mMol) in the solution for DMF (5ml) and pyridine.This mixture was reached room temperature within 10 minutes, and then stirred 2 hours.Add ethyl acetate, then with saturated NaCl washing.Organic layer is with dried over sodium sulfate, evaporation and with purification by chromatography (silica gel; 1-10% ethanol/methylene wash-out).Merge and contain product stream part, evaporation is dissolved in the minimum methylene dichloride and with ether and precipitates.Filter is collected solid and is washed with ether.Obtain white solid title compound 133mg, Mp142 ℃.

MS (electron spray(ES)): 555 (M+1) C ₂₆H ₂₇FN ₆O ₇

¹ H-NMR(400MHz，DMSO-d ₆ )δ：1.80(p，2H)；3.19(s，3H)；3.33(m，2H)；3.59(dd，1H)；3.96(dd，1H)；4.12(t，2H)；4.22(dd，1H)；4.30(m，3H)；4.86(d，2H)；5.02(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，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 29 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 30: and pyrazine-2-formic 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  of 5-dihydro Azoles-5-yl] methyl ester

With pyrazine-2-formic acid (118mg, 0.95mMol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3- azoles alkane-2-ketone (embodiment 1:200mg, 0.46mMol), 4-(dimethylamino) pyridine (5mg, 0.041mmol) and DMF (2ml) mixing, and heating obtains clear soln.This solution is cooled to room temperature, add then DIC (0.15ml, 0.96mmol).Stirred this mixture 18 hours, and added ethyl acetate, then with saturated NaCl washing.Organic layer is with dried over sodium sulfate, evaporation, and with 1: 5 ether: hexane grinds, and is dissolved in 1: 1 acetonitrile: methyl alcohol was adsorbed on the silica gel and usefulness purification by chromatography (silica gel; With 1-10% ethanol/methylene wash-out).Merge and contain part also evaporation of product stream, obtain white solid title compound 159mg.

Mp?205-226℃。

MS (electron spray(ES)): 545 (M+1) C ₂₆H ₂₁FN ₈0 ₅

¹ H-NMR(400MHz，DMSO-d ₆ )δ：3.48(dd，1H)；3.67(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.49(dd，1H)；4.59(dd，1H)；4.86(d，2H)；5.18(m，2H)；7.42(dd，1H)；7.59(dd，1H)；7.70(t，1H)；7.77(s，1H)；8.00(d，1H)；8.07(dm，1H)；8.18(s，1H)；8.82(dm，2H)；8.88(d，1H)；9.14(d，1H).

Embodiment 30 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 31:[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl Methyl)-1,3- azoles alkane

With pyrimidine-5-formic acid (113mg, 0.91mMol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:200mg, 0.46mMol), 4-(dimethylamino) pyridine (5mg, 0.041mmol) and DMF (2ml) mixes and heating obtains clear soln.This solution is cooled to room temperature, add then DIC (0.15ml, 0.96mmol).Stir this mixture and obtained suspension in 18 hours, dilute this suspension with ether (50ml) and hexane (25ml).Collect solid, with the ether flushing, be dissolved in 1: 1 acetonitrile: methyl alcohol is adsorbed on the silica gel also with purification by chromatography (silica gel; With 1-10% methyl alcohol/methylene fluoride wash-out).Merge and contain part also evaporation of product stream, obtain white solid title compound 160mg.

Mp?253-264℃。

MS (electron spray(ES)): 545 (M+1) C ₂₆H ₂₁FN ₈O ₅

¹ H-NMR(400MHz，DMSO-d ₆ )δ：3.52(dd，1H)；3.68(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.47(dd，1H)；4.58(dd，1H)；4.86(d，2H)；5.18(m，2H)；7.42(dd，1H)；7.59(dd，1H)；7.70(t，1H)；7.77(s，1H)；8.01(d，1H)；8.08(dm，1H)；8.18(s，1H)；8.83(s，1H)；9.17(s，2H)；9.39(s，1H).

Embodiment 31 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 32:2-[({[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] first The oxygen base } carbonyl) the oxygen base]-N, N, N-trimethylammonium second ammonium muriate

With choline chloride 60 (2g 14.3mmol) is suspended among the THF (100ml), and add phosgene (toluene solution of 1.93M, 28ml, 54.04mmol).This suspension of vigorous stirring 40 hours then filters, and with hexane wash and vacuum-drying, obtains the thick chloroformic acid cholinesterase of white solid (2.66g).

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:0.20g, 0.46mmol) heating be dissolved in DMF (5ml) and the pyridine (0.4ml), be cooled to 0 ℃ then.(460mg 2.28mmol), stirs this suspension and it slowly was warming up to room temperature within 2 hour, and 50 ℃ were heated 4 hours then to add thick chloroformic acid cholinesterase.(460mg 2.28mmol) also continues heating 12 hours to add second part of thick chloroformic acid cholinesterase.Dilute this mixture with methyl alcohol and obtain clear soln, stirred for several minute, vacuum concentration then.This material is with anti-phase preparation HPLC (C8 stationary phase: 0.1%TFA, 5-50% acetonitrile/water gradient) purifying.Evaporation contains product stream part to doing, be dissolved in the methyl alcohol and also pass through～5g Dowex 1X2-100 (chlorion type ion exchange resin) bed, filtrate with washed with methanol resin and evaporation merge obtains the spumescence yellow solid, is dissolved in it in minimum methyl alcohol and adds ether precipitating.The thick oily matter of supersound process gained and with 1: 1 acetonitrile: the water grinding obtains solid, collects this solid and washes with ether.With this material vacuum-drying, obtain pale solid title compound (110mg), fusing point: 180-190 ℃.

MS (electron spray(ES)): 569 (MH ⁺) C ₂₇H ₃₁FN ₇O ₆

¹ H-NMR(400MHz，DMSO-d ₆ )δ：3.09(s，9H)；3.34(dd，1H)；3.61(dd，1H)；3.69(bm，2H)；3.96(dd，1H)；4.24-4.32(m，2H)；4.37(dd，1H)；4.54(bm，2H)；4.86(d，2H)；5.04(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.00(d，1H)；8.07(d，1H)；8.18(s，1H)；8.83(s，1H).

Embodiment 32 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 33:5-[(methoxycarbonyl) (methyl) amino] and valeric acid [(5S)-3-(5-{2-fluoro-4- [(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine- The 2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl ester

With 1-methyl-2-piperidone (5ml, 44.1mmol) with hydrated barta (3.8g, 26.95mmol) and water (55ml) mixing.This suspension in 110 ℃ of heating 6 hours, is cooled off in ice bath then.The carbon dioxide bubbling was fed this solution 20 minutes.This suspension filters by Celite pad and concentrated filtrate is extremely done.Grind residue with acetonitrile, collect,, obtain white solid 5-(methylamino) valeric acid (2.95g) with ether flushing and vacuum-drying.With 5-(methylamino) valeric acid (2g, 15.3mmol) and salt of wormwood (13g 94mmol) is suspended in water (30ml) and the dioxane (10ml), is cooled to 0 ℃ then.(5ml 65mmol), stirs this mixture then and it slowly is warming up to room temperature, keeps 16 hours to add methyl-chloroformate in 30 seconds.Add dense HCl (20ml), then this mixture of dilute with water and use ethyl acetate extraction.Organic layer dried over mgso, evaporation, and vacuum-drying obtain the 5-[(methoxycarbonyl) (methyl) amino] the clarifying thick oily matter of valeric acid (2.56g).

Carbamate (0.175g with above-mentioned preparation, 0.93mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:0.25g, 0.57mmol), 4-dimethylaminopyridine (0.01g, 0.08mmol) and 1-[3-(dimethylamino) propyl group]-(0.19g 0.99mmol) mixes in DMF (2ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 3.5 hours, is obtained clear soln.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-10% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains white powder title compound (0.18g), fusing point: 82 ℃.

MS (electron spray(ES)): 610 (MH ⁺) C ₂₉H ₃₂FN ₇O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ；1.42(bm，4H)；2.32(bm，2H)；2.75(s，3H)；3.11(bm，2H)；3.28(m，1H)；3.53(s，3H)；3.58(dd，1H)；3.96(dd，1H)；4.16(dd，1H)；4.26(dd，1H)；4.29(t，1H)；4.86(d，2H)；5.01(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 33 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 34:5-[(tert-butoxycarbonyl) (methyl) amino] and valeric acid [(5S)-3-(5-{2-fluoro- 4-[(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine -2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl ester

With 1-methyl-2-piperidone (5ml, 44.1mmol) with hydrated barta (3.8g, 26.95mmol) and water (55ml) mixing.This suspension in 110 ℃ of heating 6 hours, is cooled off in ice bath then.The carbon dioxide bubbling was fed this solution 20 minutes.This suspension filters by Celite pad and concentrated filtrate is extremely done.Grind residue with acetonitrile, collect,, obtain white solid 5-(methylamino) valeric acid (2.95g) with ether flushing and vacuum-drying.With 5-(methylamino) valeric acid (5g, 38mmol) and sodium hydroxide (50% aqueous solution, 6.6g 82mmol) are suspended in water (30ml) and the dioxane (20ml).Add two dimethyl dicarbonate butyl esters (11g, 50mmol), then in this mixture of stirring at room 16 hours.This mixture of dilute with water is acidified to about pH5 and uses dichloromethane extraction with dense HCl.The organic layer dried over mgso, evaporation, and vacuum-drying obtain thick 5-[(tert-butoxycarbonyl) (methyl) amino] the clarifying thick oily matter of valeric acid (14g).

Thick carbamate (2g with above-mentioned preparation, 8.6mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3- azoles alkane-2-ketone (embodiment 1:1g, 2.28mmol), 4-dimethylaminopyridine (0.05g, 0.4mmol) and 1-[3-(dimethylamino) propyl group]-(1.28g 6.67mmol) mixes in DMF (10ml) the 3-ethyl-carbodiimide hydrochloride.This suspension in stirring at room 16 hours, with the ethyl acetate dilution, is washed with water, and uses dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-5% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains pale solid title compound (1.28g), fusing point: 121 ℃.

MS (electron spray(ES)): 652 (MH ⁺) C ₃₂H ₃₈FN ₇O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.35(s，9H)；1.41(bs，4H)；2.33(bt，2H)；2.69(bs，3H)；3.08(bt，2H)；3.29(dd，1H)；3.58(dd，lH)；3.96(d?d，1H)；4.16(dd，1H)；4.26(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.00(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).

Embodiment 34 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 35:4-[(methoxycarbonyl) (methyl) amino] and butyric acid [(5S)-3-(5-{2-fluoro-4- [(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine- The 2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl ester

With 4-(methylamino) butyrates hydrochlorate (5g, 32.5mmol) and salt of wormwood (18g 130mmol) is suspended in water (50ml) and the dioxane (25ml), is cooled to 0 ℃ then.(13ml 168mmol), stirs this mixture then and it slowly is warming up to room temperature, keeps 16 hours to add methyl-chloroformate in 1 minute.Add dense HCl (20ml) and this mixture of dilute with water, use ethyl acetate extraction.The organic layer dried over mgso, evaporation, and vacuum-drying obtain the 4-[(methoxycarbonyl) (methyl) amino] the clarifying thick oily matter of butyric acid (9.7g).

Carbamate (0.32g with above-mentioned preparation, 1.83mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:0.2g, 0.46mmol), 4-dimethylaminopyridine (0.01g, 0.08mmol) and 1-[3-(dimethylamino) propyl group]-(0.19g 0.99mmol) mixes in DMF (2ml) the 3-ethyl-carbodiimide hydrochloride.With this suspension in stirring at room 2 hours.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-10% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains pale solid title compound (0.23g), fusing point: 135 ℃.

MS (electron spray(ES)): 596 (MH ⁺) C ₂₈H ₃₀FN ₇O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.67(p，2H)；2.27(t，2H)；2.73(s，3H)；3.16(t，2H)；3.31(dd，1H)；3.53(s，3H)；3.59(dd，1H)；3.96(dd，1H)；4.15(dd，1H)；4.26(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.01(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)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 35 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 36:6-[(methoxycarbonyl) (methyl) amino] and caproic acid [(5S)-3-(5-{2-fluoro-4- [(5R)-and 2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine- The 2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl ester

With N-methyl-hexanolactam (15g, 118mmol) with hydrated barta (10.1g, 72mmol) and water (150ml) mixing.This suspension in 110 ℃ of heating 18 hours, is cooled off in ice bath then.The carbon dioxide bubbling was fed this solution 20 minutes.This suspension filters by Celite pad and concentrated filtrate is extremely done.Grind residue with acetonitrile, collect,, obtain white solid 6-(methylamino) caproic acid (10.7g) with ether flushing and vacuum-drying.With 6-(methylamino) caproic acid (5g, 34.5mmol) and salt of wormwood (18g 130mmol) is suspended in water (50ml) and the dioxane (25ml), is cooled to 0 ℃ then.(13ml 168mmol), stirs this mixture then and it slowly is warming up to room temperature, keeps 16 hours to add methyl-chloroformate in 1 minute.Add dense HCl (20ml) and this mixture of dilute with water, use ethyl acetate extraction.The organic layer dried over mgso, evaporation, and vacuum-drying obtain the 6-[(methoxycarbonyl) (methyl) amino] the clarifying thick oily matter of caproic acid (5.7g).

Carbamate (0.37g with above-mentioned preparation, 1.82mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:0.2g, 0.46mmol), 4-dimethylaminopyridine (0.01g, 0.08mmol) and 1-[3-(dimethylamino) propyl group]-(0.19g 0.99mmol) mixes in DMF (2ml) the 3-ethyl-carbodiimide hydrochloride.This suspension was obtained clear soln in 3.5 hours in stirring at room.Dilute this mixture with ethyl acetate then, wash with water, and use dried over mgso.After filtration and evaporate the gained residue with purification by chromatography (silica gel, 0.5-10% ethanol/methylene).Evaporation contains product stream part and grinds the gained solid with ether, obtains pale powder shape title compound (0.225g), fusing point: 103 ℃.

MS (electron spray(ES)): 624 (MH ⁺) C ₃₀H ₃₄FN ₇O ₇

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.16(p，2H)；1.36(p，2H)；1.48(p，2H)；2.29(t，2H)；2.74(s，3H)；3.10(t，2H)；3.29(dd，1H)；3.53(s，3H)；3.58(dd，1H)；3.96(dd，1H)；4.16(dd，1H)；4.26(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.00(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.68(t，1H)；7.76(s，1H)；8.00(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H).

Embodiment 36 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 37:5-(methylamino) valeric acid [(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 5-dihydro Different  azoles-5-yl] methyl ester

With the 5-[(tert-butoxycarbonyl) (methyl) amino] valeric acid [(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] methyl ester (embodiment 34:0.5g, 0.77mmol) and acetate (15ml) and hydrochloric acid (dioxane solution of 4M, 1ml, 4mmol) mixing.In about 80 ℃ of heating this suspension 2 minutes to dissolve most suspended matter.This mixture is in room temperature restir 15 minutes, concentrating under reduced pressure then.With residual solids water-soluble (40ml), use twice of ethyl acetate extraction (20ml) then.The evaporation water layer, then drying under reduced pressure is dissolved in methyl alcohol (1ml) with the solid that obtains, and (10ml) precipitation that adds diethyl ether.With solution incline and repeat the precipitation.The thick oil of gained in 50 ℃ of vacuum-dryings, is obtained the hydrochloride (0.46g) of title compound, be the solid of the easy moisture absorption, fusing point: 184 ℃.

MS (electron spray(ES)): 552 (MH ⁺) C ₂₇H ₃₀FN ₇O ₅

¹ H-NMR(300MHz，DMSO-d ₆ )δ：1.55(bm，4H)；2.36(t，2H)；2.49(s，3H)；2.82(m，2H)；3.31(dd，1H)；3.60(dd，1H)；3.96(dd，1H)；4.16(dd，1H)；4.27(dd，1H)；4.31(d，1H)；4.86(d，2H)；5.01(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.00(d，1H)；8.07(d，1H)；8.18(s，1H)；8.54(bs，2H)；8.83(s，1H).

Embodiment 37 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 38; 5-[(N, N-dimethyl glycyl) (methyl) amino] valeric acid [(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] methyl ester

With 5-(methylamino) valeric acid [(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] methyl ester (embodiment 37:134mg, 0.23nMol), N, the N-N-methylsarcosine (140mg, 1.36mMol), 1,3-DIC (121mg, 0.96mMol) and 4-dimethylaminopyridine (5mg 0.04mMol) is suspended among the 2ml DMF in room temperature.Stirred this mixture one day, with the ethyl acetate dilution, with saturated sodium bicarbonate aqueous solution washing, dried over sodium sulfate and evaporation.Residue purification by chromatography (silica gel; 1-10% ethanol/methylene wash-out), obtain the free alkali of title compound.This sample is dissolved in methylene dichloride (0.5ml), and (the 4M dioxane solution 0.05ml) is handled and is diluted with ether (10ml) with HCl.With this suspension supersound process and grinding, solution is inclined to from solid, the solid resuspending is in ether, and then supersound process is filtered then again.Solid vacuum-drying obtains the hydrochloride (95mg) of title compound, is light yellow solid, fusing point: 133 ℃.

MS (electron spray(ES)): 673 (MH ⁺) C ₃₁H ₃₇FN ₈O ₆

¹ H-NMR(300MHz.DMSO-d ₆ )δ：1.42-1.53(bm，4H)；2.36(m，2H)；2.78(s，6H)；2.85(s，3H)；3.27-3.36(m，3H)；3.60(dd，1H)；3.96(dd，1H)；4.13-4.32(m，5H)；4.86(d，2H)；5.00(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.00(d，1H).

Embodiment 38 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 39:(5R)-3-{3-fluoro-4-[6-((5S)-5-{[(2-methoxy ethoxy) methoxyl group] Methyl }-4, the different  azoles of 5-dihydro-3-yl) pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl first Base)-1,3- azoles alkane-2-ketone

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:250mg, 0.57mmol), diisopropylethylamine (238 μ L, 1.37mmol) and 2-methoxy ethoxy methyl chloride (MEMCl) (78 μ L, 0.68mmol) in dry DMF (5mL), mix, and in stirred overnight at room temperature.Add again diisopropylethylamine (250 μ L, 1.44mmol) and MEMCl (100 μ L, 0.88mmol), and restir 6 hours.(90 μ L, 0.79mmol) also stirring is spent the night to add MEMCl again.Solvent evaporated under reduced pressure.With 3: 1 silica gel column chromatographies of acetone/hexane, and, obtain pale solid product (261mg) with the dichloromethane/hexane precipitation.

MS(ESP)：527.57(MH ⁺)C ₂₅H ₂₇FN ₆O ₆

¹ H-NMR?300MHz(DMSO-d ₆ )δ：3.23(s，3H)；3.26-3.70(m，8H)；3.96(dd，1H)；4.29(dd，1H)；4.66(s，2H)；4.86(d，2H)；4.93(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.58(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.81(s，1H).

Embodiment 39 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 40:[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazole-1- Ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl β-D-glycopyranoside

Will [(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl β-D-glycopyranoside (intermediate 20,0.150g, 0.36mmol), (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 7,0.153g, 0.39mmol), yellow soda ash (0.152g, 1.43mmol) and four (triphenylphosphines) close palladium (0) (0.041g, 0.036mmol) under nitrogen in DMF/ water (10: 1, mix in 5mL), and bathe temperature heating 4 hours in 70 ℃.Solvent evaporated under reduced pressure.With 5: 1 silica gel column chromatographies of methylene chloride, then use alcohol crystal, obtain colorless solid product (83mg).

MS(ESP)：601.06(MH ⁺)C ₂₇H ₂₉FN ₆O ₉

¹ H-NMR?300MHz(MeOD-d ₆ )δ：3.17-3.60(m，7H)；3.75-3.90(m，2H)；4.00-4.10(m，2H)；4.28-4.39(m，2H)；4.85-4.95(m，2H)；5.03(m，1H)；5.19(m，1H)；7.35(dd，1H)；7.53-7.60(m，2H)；7.76(s，1H)；8.00(m，2H)；8.09(s，1H)；8.74(s，1H).

Embodiment 40 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Intermediate 20:[(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl β- The D-glycopyranoside

In-20 ℃, to [(5S)-and 3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl alcohol (intermediate 11; 0.369g; 1.43mmol) and 2,3,4; 6-four-O-ethanoyl-1-O-(2; 2,2-trichlorine acetimidoyl (ethanimidoyl))-α-D-Glucopyranose (R.R.Schmidt and J.Michel, Angew.Chem.Int.Ed.Engl.19 (1980); molecular sieve (pearl 731-732)

) drip in exsiccant methylene dichloride (20mL) solution trifluoromethanesulfonic acid trimethyl silyl ester dichloromethane solution (0.02M, 10mL).This reaction mixture was reached room temperature in 2 hours, add the placement of catalyst solution (5mL) and room temperature again and spend the night.Adding triethylamine (3) quencher should react, and filtered and removal of solvent under reduced pressure.With 2: 1 silica gel column chromatographies of hexane/acetone, obtain thick [(5S)-3-(5-bromopyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl 2,3,4,6-four-O-ethanoyl-β-D-glycopyranoside, for the mixture of intermediate 11.In anhydrous methanol (5mL) solution of this mixture, add salt of wormwood (20mg), and in room temperature vigorous stirring 4 hours.With AmberliteCG-50-II (H ⁺-type) this reaction mixture that neutralizes filters and removal of solvent under reduced pressure.With 8: 1 silica gel column chromatographies of methylene chloride, obtain colorless solid product (157mg).

MS(ESP)：419/421(MH ⁺)C ₁₅H ₁₉BrN ₂O ₇

¹ H-NMR?300MHz(DMSO-d ₆ +D ₂ O)δ：2.90-3.16(m，4H)；3.25(dd，1H)；3.37-3.48(m，2H)；3.59-3.65(m，2H)；3.89(dd，1H)；4.18(d，1H，JH1，H2?7.7Hz，H-1)；4.92(m，1H)；7.82(d，1H)；8.08(dd，1H)；8.71(brs，1H).

Embodiment 41:N-methylglycine [(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  of 5-dihydro Azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:200mg, 0.46mmol), diisopropylethylamine (122mg, 0.94mmol), phosphofluoric acid O-(7-azepine benzo triazol-1-yl-N, N, N ', N '-tetramethyl-urea (HATU) (188mg, 0.49mmol), I-hydroxybenzotriazole (HOBT) (64mg, 0.47mmol) and N-(tertbutyloxycarbonyl) glycine (98mg 0.52mmol) mixes in dry DMF (4mL), and in stirred overnight at room temperature.Add again HATU (94mg, 0.25mmol) and restir 24 hours.Add ethyl acetate (10mL), water (2 5mL) washs and uses dried over mgso.Solvent evaporated under reduced pressure.With 3% ethanol/methylene silica gel column chromatography, obtain BOC-protection intermediate, be colorless solid; This solid is dissolved in anhydrous 1,4-dioxane (2mL), add HCl dioxane solution (4M, 4mL), and in stirring at room mixture 10 minutes.Filter and collect the gained precipitation,, and, obtain the HCl salt (173mg) of product, be colorless solid in 60 ℃ of drying under reduced pressure with the anhydrous diethyl ether washing.

MS(ESP)：510.54(MH ⁺)C ₂₄H ₂₄FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：2.60(s，3H)；3.35(dd，1H)；3.60(dd，1H)；3.95(m，3H)；4.29(dd，2H)；4.40(m，1H)；4.86(d，2H)；5.05(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.81(s，1H)；9.21(brs，2H).

Embodiment 41 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 42:L-L-Ala [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles-5-of 5-dihydro Base] methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-L-L-Ala (98mg, 0.52mmol) outside, press the method that embodiment 41 describes and prepare.Obtain the HCl salt of product, be colorless solid (175mg).

MS(ESP)：510.58(MH ⁺)C ₂₄H ₂₄FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：1.35(d，3H)；2.70(d，2H)；3.35(dd，1H)；3.65(dd，1H)；3.95(m，1H)；4.29(dd，1H)；4.40(m，1H)；4.86(d，2H)；5.05(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.75(s，1H)；7.97-8.07(m，2H)；8.18(8，1H)；8.45(br8，2H)；8.85(s，1H).

Embodiment 42 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 43:L-Xie Ansuan [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles-5-of 5-dihydro Base] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:200mg, 0.46mmol) and N-(tert-butoxycarbonyl)-L-Xie Ansuan (113mg, 0.52mmol) reaction, except using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC) (175mg, 0.91mmol) replacement HATU/HOBt, and (14mg 0.11mmol) replaces outside the diisopropylethylamine, is undertaken by the method that embodiment 41 describes to use 4-dimethylaminopyridine (DMAP).Obtain the HCl salt of product, be colorless solid (200mg).

MS(ESP)：538.56(MH ⁺)C ₂₆H ₂₈FN ₇O ₅

¹ H-NMR300MHz(DMSO-d ₆ )δ：0.91(2xd，6H)；2.12(m，1H)；3.35(dd，1H)；3.60(dd，1H)；3.95(m，2H)；4.29(dd，2H)；4.40(m，1H)；4.86(d，2H)；5.05(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(8，1H)；8.61(brs，1H)；8.81(s，1H).

Embodiment 43 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 44:L-leucine [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles-5-of 5-dihydro Base] methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-L-leucine (208mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.Obtain the HCl salt of product, be colorless solid (161mg).

MS(ESP)：552.60(MH ⁺)C ₂₇H ₃₀FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：δ：0.71(2xd，6H)；1.5(dd，2H)；1.65(m，1H)；3.35(dd，1H)；3.60(m，1H)；3.95(m，2H)；4.31(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.51(brs，2H)；8.81(s，1H).

Embodiment 44 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 45: glycine [(5S)-and 3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-three Azoles-1-ylmethyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] Methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-glycine (158mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.Obtain the HCl salt of product, be colorless solid (140mg).

MS(ESP)：496.52(MH ⁺)C ₂₃H ₂₂FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：3.35(dd，1H)；3.60(m，1H)；3.95(m，3H)；4.31(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.31(brs，2H)；8.81(s，1H).

Embodiment 45 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 46:L-Isoleucine [(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  of 5-dihydro Azoles-5-yl] methyl ester

In dry DMF (10m1), press the method that embodiment 43 describes, make (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:2000mg, 4.6mmo1) with N-(tert-butoxycarbonyl)-L-Isoleucine (2.1g, 9.13mmo1), EDC (1.84g, 9.13mmo1) and DMAP (150mg, 1.23mmol) reaction.Obtain the HCl salt of product, be pale solid (2.0g).

MS(ESP)：552.17(MH ⁺)C ₂₇H ₃₀FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：0.71(t，3H)；0.87(d，3H)；1.20(m，1H)；1.40(m，1H)；1.85(m，1H)；3.35(dd，1H)；3.65(m，1H)；3.95(m，2H)；4.31(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(t，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.55(br，2H)；8.81(s，1H).

Embodiment 46 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 47:L-glutamine (glutaminate) [(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] methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-L-glutaminate (222mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.Obtain the HCl salt of product, be colorless solid (200mg).

MS(ESP)：496.52(MH ⁺)C ₂₆H ₂₇FN ₈O ₆

¹ H-NMR?300MHz(DMSO-d ₆ )δ：2.00(m，2H)；2.26(m，2H)；3.40(dd，1H)；3.60(m，1H)；3.95(m，2H)；4.31(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；6.98(brs，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.71(brs，2H)；8.81(s，1H).

Embodiment 47 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 48:L-aspartic acid 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  of 5-dihydro Azoles-5-yl] methyl ester

Except using amino acid to make up fragment N-(tert-butoxycarbonyl)-L-aspartic acid-4-tertiary butyl ester, two hexamethylene ammonium salts (423mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.The thick HCl salt of this product is further used the reversed-phase HPLC purifying, uses 5%～95% acetonitrile/water, obtains colorless solid product (98mg).

MS(ESP)：552.57(M-H ^-)C ₂₅H ₂₄FN ₇O ₇

¹ H-NMR?300MHz(DMSO-d ₆ )δ：2.82(dd，2H)；3.35(dd，1H)；3.60(m，1H)；3.95(m，1H)；4.31(m，4H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.41(brs，2H)；8.81(s，1H)；13.00(brs，1H).

Embodiment 48 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 49:L-aspartic acid 4-[(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  of 5-dihydro Azoles-5-yl] methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-L-aspartic acid-1-tertiary butyl ester (266mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.The thick HCl salt of this product is further used the reversed-phase HPLC purifying, and 5%～95% acetonitrile-water is a moving phase, obtains colorless solid product (98mg).

MS(ESP)：554.56(MH ⁺)C ₂₅H ₂₄FN ₇O ₇

¹ H-NMR?300MHz(DMSO-d ₆ )δ：2.85(m，2H)；3.35(m，1H)；3.60(m，1H)；3.95(m，2H)；4.15-4.35(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.42(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.76(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.82(s，1H).

Embodiment 49 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 50:L-Methionin [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles-5-of 5-dihydro Base] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 (embodiment 1:375mg, 0.86mmol), EDC (345mg, 1.28mmol), DMAP (25mg, 0.20mmol) and N ², N ⁶(444mg 0.52mmol) mixes in dry DMF (6ml)-two (tert-butoxycarbonyl)-L-Methionins, and presses the method reaction that embodiment 43 describes.Two HCl salt of this product are colorless solid (400mg).

MS(ESP)：567.48(MH ⁺)C ₂₇H ₃₁FN ₈O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：1.45(m，4H)；1.76(m，2H)；2.70(m，2H)；3.35(dd，1H)；3.60(dd，1H)；4.0(m，2H)；4.29(dd，1H)；4.40(d，2H)；4.86(d，2H)；5.05(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.90-8.10(m，4H)；8.18(s，1H)；8.55(m，2H)；8.81(s，1H).

Embodiment 50 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 51:L-phenylalanine [(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  of 5-dihydro Azoles-5-yl] methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-L-phenylalanine (244mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.Obtain the HCl salt of product, be colorless solid (255mg).

MS(ESP)：586.12(MH ⁺)C ₃₀H ₂₈FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：3.35(dd，1H)；3.45(dd，2H)；3.60(dd，1H)；4.0(dd，1H)；4.31(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.21(m，5H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.51(brs，2H)；8.81(s，1H).

Embodiment 51 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 52:L-proline(Pro) [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3- The triazol-1-yl methyl)-1,3- azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the different  azoles-5-of 5-dihydro Base] methyl ester

Except use amino acid make up fragment N-(tert-butoxycarbonyl)-L-proline(Pro) (198mg, 0.9mmol) outside, press the method that embodiment 43 describes and prepare.Obtain the HCl salt of product, be colorless solid (290mg).

MS(ESP)：636.19(MH ⁺)C ₂₆H ₂₆FN ₇O ₅

¹ H-NMR 300MHz (DMSO-d ₆ ) (HCl salt)δ: 1.95 (m, 3H); 2.16 (m, 1H); 3.18 (m, 2H); 3.35 (dd, 1H); 3.60 (dd, 1H); 4.0 (dd, 1H); 4.31 (m, 2H); 4.4 (m, 2H); 4.86 (d, 2H); 5.08 (m, 1H); 5.18 (m, 1H); 7.41 (dd, 1H); 7.60 (dd, 1H); 7.68 (dd, 1H); 7.77 (s, 1H); 7.97-8.07 (m, 2H); 8.18 (s, 1H); 8.81 (s, 1H); 9.05 (brs, 1H); 10.12 (brs, 1H).

Embodiment 52 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Embodiment 53:{2-[(methoxycarbonyl) (methyl) amino] oxyethyl 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] benzene Base } pyridine-2-yl)-4, the different  azoles of 5-dihydro-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3- azoles alkane-2-ketone (embodiment 1:250mg, 0.57mmol), EDC (200mg, 1.0mmol), DMAP (20mg, 0.16mmol) and intermediate 21 (100mg 0.52mmol) mixes in dry DMF (4ml), and in stirred overnight at room temperature.Add ethyl acetate (10ml) and wash the gained mixture with water, use dried over mgso.With 3% ethanol/methylene silica gel column chromatography, obtain colorless solid product (110mg).

MS(ESP)：612.14(MH ⁺)C ₂₈H ₃₀FN ₇O ₈

¹ H-NMR?300MHz(CDCl ₃ )δ：2.95(s，3H)；3.35(dd，1H)；3.45(m，2H)；3.60-3.67(m，3H)；3.70(s，3H)；4.0(dd，1H)；4.12(s，2H)；4.25(dd，1H)；4.36(m，2H)；4.82(d，2H)；5.0～5.2(m，2H)；7.21(dd，1H)；7.41(m，2H)；7.75(s，1H)；7.79(s，1H)；7.87(dd，1H)；8.05(dd，1H)；8.78(s，1H).

Embodiment 53 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Intermediate 21:{2-[(methoxycarbonyl) (methyl) amino] oxyethyl group } acetate

With [2-(methylamino) oxyethyl group] acetate (Bull.Soc.Chim.; 1956,1210) (130mg, 0.98mmol) (0.56mL 4mmol) mixes in dry DMF (2mL) with triethylamine.(185mg is 1.95mmol) and in this mixture of stirring at room 20 minutes, water quencher then to add methyl-chloroformate.Add hydrochloric acid (2M) and regulate pH to～2.The product ethyl acetate extraction, organic phase obtains oily crude product (100mg) with dried over mgso and concentrating under reduced pressure, and this product is not further purified and uses.

MS(ESP)：190.2(M-H ^-)C ₇H ₁₃NO ₅

Embodiment 54:[2-(methylamino) oxyethyl group] and 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] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3- azoles alkane-2-ketone (embodiment 1:200mg, 0.46mmol), EDC (175mg, 0.91mmol), DMAP (14mg, 0.11mmol) and intermediate 22 (229mg 0.98mmol) mixes in dry DMF (4ml), and in stirred overnight at room temperature.Add ethyl acetate (10ml), wash with water, use dried over mgso.Chromatography and take off the BOC group and undertaken by the method that embodiment 21 describes obtains the HCl salt of product, is colorless solid 200mg).

MS(ESP)：554.05(MH ⁺)C ₂₆H ₂₈FN ₇O ₆

¹ H-NMR?300MHz(CDCl ₃ )δ：2.50(s，3H)；2.55(t，2H)；3.07(m，2H)；3.35(dd，1H)；3.55(m，2H)；3.95(dd，1H)；4.23(s，2H)；4.30(m，2H)；4.82(d，2H)；5.05(m，1H)；5.20(m，1H)；7.45(dd，1H)；7.60(dd，1H)；7.70(dd，1H)；7.77(s，1H)；7.95-8.10(m，2H)；8.20(s，1H)；8.85(brs，2H).

Embodiment 54 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Intermediate 22:{2-[(tert-butoxycarbonyl) (methyl) amino] oxyethyl group } acetate

With [2-(methylamino) oxyethyl group] acetate (Bull.Soc.Chim.; 1956,1210) (130mg, 0.98mmol) and triethylamine (0.56mL, 4.0mmol) and two carbonic acid, two-tertiary butyl ester (647mg, 3.0mmol) mix, such as intermediate 21 reaction in dry DMF (5mL) the description, obtain oily crude product (229mg), this product is not further purified and uses.

MS(ESP)：232.22(M-H ^-)C ₁₀H ₁₉NO ₅

Embodiment 55:N-methyl-L-Isoleucine [(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 5-dihydro Different  azoles-5-yl] methyl ester

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-4, the different  azoles of 5-dihydro-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, and 3- azoles alkane-2-ketone (embodiment 1:250mg, 0.57mmol), EDC (230mg, 1.14mmol), DMAP (20mg, 0.16mmol) and N-(tert-butoxycarbonyl)-N-methyl-L-Isoleucine (280mg, 1.14mmol) mixing in dry DMF (2ml), and press embodiment 43 described methods reactions.Obtain the HCl salt (150mg) of product, be colorless solid.

MS(ESP)：566.45(MH ⁺)C ₂₈H ₃₂FN ₇O ₅

¹ H-NMR?300MHz(DMSO-d ₆ )δ：0.71(t，3H)；0.87(d，3H)；1.20(m，1H)；1.40(m，1H)；1.85(m，1H)；2.57(s，3H)；3.35(dd，1H)；3.65(m，1H)；3.95(m，2H)；4.31(m，3H)；4.86(d，2H)；5.08(m，1H)；5.18(m，1H)；7.41(dd，1H)；7.60(dd，1H)；7.68(dd，1H)；7.77(s，1H)；7.97-8.07(m，2H)；8.18(s，1H)；8.81(s，1H)；9.20(brs，1H)；9.50(brs，1H).

Embodiment 55 is the non-limiting example of the suitable prodrug of The compounds of this invention, and is the suitable prodrug of embodiment 1.

Claims

1. formula (I) compound or its pharmacy acceptable salt,

Wherein:

R ₁A is-NH (C=W) R ₅Or

W is O or S;

R ₂And R ₃Independently be selected from H and F;

R ₁Be selected from hydrogen and methyl;

R ₅Be methyl;

R ₄Be the methylol substituting group on isoxazoline ring C-5 ' position, so that formula (I) compound is single diastereomer.

2. the formula of claim 1 (I) compound or its pharmacy acceptable salt, described compound is formula (IC) compound:

Wherein:

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₁Be selected from hydrogen and methyl.

3. the formula of claim 1 (I) compound or its pharmacy acceptable salt, described compound is formula (ID) compound,

Wherein:

W is O;

R ₂And R ₃Independently be selected from hydrogen and fluorine;

R ₅Be selected from methyl.

4. (5R)-3-(3-fluoro-4-{6-[(5S)-5-(methylol)-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 or its pharmacy acceptable salt.

5. each compound or its pharmacy acceptable salt are used for producing purposes in the medicine of anti-microbial effect warm-blooded animal in preparation among the claim 1-4.

6. medicinal compositions, described composition comprise among the claim 1-4 each compound or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.

7. one kind prepares among the claim 1-4 each formula (I) compound or the method for its pharmacy acceptable salt, and described method is:

B) by the part with formula (II) compound, wherein X is 1,3,2-two oxa-boron heterocycle pentane-2-bases, with the part reaction of the Compound I Ia that also has leavings group X, so that pyridyl-phenyl key is replaced phenyl-X and pyridyl-X key, wherein the leavings group X of Compound I Ia is a bromine;