CN1989136A

CN1989136A - 3-[4-(6-{4, 5-dihydroisoxazol -3-yl} pyridin-3-yl)- 3-phenyl]-5 -(1h-1, 2, 3-triazol -1-ylmethyl)-1, 3-oxazolidin- 2-ones as antibacterial agents

Info

Publication number: CN1989136A
Application number: CN 200580025055
Authority: CN
Inventors: D·R·卡卡纳古; M·B·格拉维斯托克
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2004-05-25
Filing date: 2005-05-24
Publication date: 2007-06-27
Also published as: ZA200609773B; GB0411594D0

Abstract

Compounds of the formula (I) or a pharmaceutically- acceptable salt or pro-drug thereof: wherein R<1> is selected for example from hydrogen, halogen, optionally substituted methyl; R<2> and R<3> are independently selected from hydrogen, fluoro, chloro and trifluoromethyl;R<4> and R<5> are independently selected, for example, from hydrogen, methyl, optionally substituted (2-4C)alkyl , C(O)R<6 >or R<4> and R<5> together with the nitrogen to which they are attached form an optionally substituted 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring or an optionally substituted imidazole ring. Methods for making the compounds of formula (I), compositions containing them and their use as antibacterial agents are also described.

Description

As the 3-[4-of antiseptic-germicide (6-{4, the 5-dihydro is different _ azoles-3-yl pyridin-3-yl)-the 3-phenyl]-5-(1H-1,2,3-triazol-1-yl-methyl)-1,3-_ azoles alkane-2-ketone

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

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

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

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

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

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

In this patent application, each comfortable 5-position of _ oxazolidone ring and different _ oxazoline ring has substituting group, described substituting group is selected from this area and it has been generally acknowledged that the substituting group that is suitable for described antiseptic-germicide, for example methylacetamide (referring to for example WO 93/09103), the heterocycle (referring to for example WO 00/21960) that is connected with methylamino and heterocyclyl methyl group (referring to for example WO 01/81350).

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

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

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

Wherein:

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

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

R ⁴And R ⁵Be independently selected from hydrogen, allyl group (optional on carbon-to-carbon double bond replaced), methyl, cyano methyl, carboxymethyl by 1,2 or 3 (1-4C) alkyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ²R ⁶,-S (O) ²NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NHR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶

Perhaps, R ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether or part is undersaturated and optionally contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can choose wantonly by-C (O)-replacement and wherein the sulphur atom in the ring can choose wantonly and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl;

Perhaps, R ⁴And R ⁵The nitrogen that is connected with them forms imidazole ring altogether, and described ring is chosen wantonly on available carbon by 1 or 2 methyl substituted;

R ⁶And R ⁷Be independently selected from hydrogen, methyl, cyclopropyl (optional), carboxymethyl by methyl substituted and (2-4C) alkyl (optionally replaced by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted);

Perhaps, R ⁶Or R ⁷The carbon that can form 4,5 or 6 yuan connects the saturated heterocyclic basic ring, and it contains 1 or 2 heteroatoms that is independently selected from O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced by 1 or 2 (1-4C) alkyl;

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

Condition is R ⁴And R ⁵Not hydrogen simultaneously.

Compound or its pharmaceutically useful salt or its prodrug of foregoing formula (I) are provided in another aspect of this invention, wherein:

R ⁴And R ⁵Be independently selected from hydrogen, allyl group (choose wantonly on carbon-to-carbon double bond and replaced), methyl, cyano methyl, carboxymethyl by 1,2 or 3 (1-4C) alkyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NHR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶

Perhaps, R ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether or part is undersaturated and optionally contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl.

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

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

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

In this manual, term " thiazolinyl " and " cycloalkenyl group " comprise all positional isomerss and geometrical isomer.

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

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

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

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

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

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

Wherein-CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Saturated or the part of group is undersaturated, and optional to contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S can be morpholine, piperazine suitably, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines, tetramethyleneimine, dihydropyridine, tetrahydropyridine, dihydro different _ azoles, imidazoles.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Special and aspect independently of the present invention has been represented in amino acid whose use with neutrality and/or basic side chain.Formula (I) but in the suitable body of compound the ester of hydrolysis as described below.For example, 1, the 2-glycol can circularize the pyrophosphate shown in cyclic ester shown in the accepted way of doing sth (PD1) or the formula (PD2), and 1, the 3-glycol can circularize the cyclic ester shown in the accepted way of doing sth (PD3),

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

If use the mixture of the epimer on _ oxazolidone chiral centre, then need bigger amount (ratio according to diastereomer decide) with the same effect that realizes and the pharmaceutical active enantiomorph of identical weight is realized.

In addition, compounds more of the present invention can have other chiral centre, for example in substituent R ⁴On.Be appreciated that the present invention includes all these has optical isomer and the diastereomer and the racemic mixture of anti-microbial activity.Known in this fieldly how to prepare optical activity form (for example synthetic by recrystallization, chirality, enzyme catalysis fractionation, bio-transformation or chromatographic separation technology split racemic form) and knownly how to determine anti-microbial activity as mentioned below.

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

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

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

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

Compound of the present invention is because the alkalescence and the R of amine side chain ⁴And R ⁵Substituent character and under physiological pH, generate ionization or partial ionization material, thus favourable solubleness and/or bioavailability had usually.

For example solubleness can be by any appropriate means measurement known in the art to be appreciated that each parameter.

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

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

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

On the other hand, R ¹Be hydrogen.

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

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

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

In one aspect, R ⁴Or R ⁵Be that hydrogen and another are selected from above or hereinafter about R ⁴And R ⁵Described any example.

In one aspect, R ⁴Or R ⁵Be that methyl and another are selected from above or hereinafter about R ⁴And R ⁵Described any example.

In one embodiment, R ⁴And R ⁵Be independently selected from hydrogen, allyl group (choose wantonly on carbon-to-carbon double bond and replaced), methyl, cyano methyl, carboxymethyl by 1,2 or 3 (1-4C) alkyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NHR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶, condition is R ⁴And R ⁵Not hydrogen simultaneously).

In one aspect, R ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NHR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶(condition is R ⁴And R ⁵Not hydrogen simultaneously).

In others, R ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶With-C (O) CH ₂NR ⁶R ⁷

In one aspect, R ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷(2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace], (condition is R ⁴And R ⁵Not hydrogen simultaneously).

On the other hand, R ⁴And R ⁵One of be hydrogen or methyl and another be selected from carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷(2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace].

On the other hand, R ⁴And R ⁵One of be hydrogen or methyl and another be selected from carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷(2-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace].

On the other hand, R ⁴And R ⁵One of be hydrogen or methyl and another be selected from carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷(2-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-NR ⁶R ^{7 Hes}-NHC (O) R ⁶Substituting group replace].

On the other hand, R ⁴And R ⁵One of be that hydrogen or methyl and another are selected from-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶

On the other hand, R ⁴And R ⁵One of be that hydrogen or methyl and another are selected from-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶With-C (O) NR ⁶R ⁷

On the other hand, R ⁴And R ⁵One of be that hydrogen or methyl and another are selected from-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷With-SO ₂NHR ⁶

On the other hand, R ⁴And R ⁵One of be that hydrogen or methyl and another are selected from-C (O) R ⁶With-C (O) CH ₂NR ⁶R ⁷

On the other hand, R ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶, (2-4C) alkyl [optional by 1 or 2 hydroxyl replace] ,-C (O) R ⁶With-C (O) CH ₂NR ⁶R ⁷Or

R ⁴And R ⁵The nitrogen that is connected with them forms morpholine, piperazine, N methyl piperazine altogether, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines and pyrrolidine ring.

On the other hand, R ⁴And R ⁵Be independently selected from hydrogen, allyl group (choose wantonly on carbon-to-carbon double bond and replaced), methyl, cyano methyl, carboxymethyl by 1,2 or 3 (1-4C) alkyl ,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶With-SO ₂NHR ⁶Condition is R ⁴And R ⁵Not hydrogen simultaneously or be not simultaneously-C (O) R ⁶And work as R ⁴Or R ⁵For-C (O) R ⁶The time R then ⁶Be selected from cyclopropyl (optional by methyl substituted), carboxymethyl and (2-4C) alkyl (optionally replaced by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted);

Perhaps, R ⁶Can form the saturated heterocyclic basic ring of 4,5 or 6 yuan carbon connection, it contains 1 or 2 and is independently selected from O, N and S heteroatoms, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced by 1 or 2 (1-4C) alkyl;

In others, R ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether or part is undersaturated and optionally contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl.

In others, R ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether and optionally contains 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl.Described optional substituting group suitably is 1 or 2 methyl.

Comprise R ⁴And R ⁵And the suitable example of this ring of the nitrogen that they connected be morpholine, piperazine, N methyl piperazine, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines, tetramethyleneimine and tetrahydropyridine.

Comprise R ⁴And R ⁵And other suitable examples of this ring of the nitrogen that they connected be morpholine, piperazine, N methyl piperazine, (and wherein sulphur is oxidized to S (O) or S (O) to thiomorpholine ₂The derivative of group), piperidines and tetramethyleneimine.

Comprise R ⁴And R ⁵And other suitable examples of this ring of the nitrogen that they connected is piperazine, N methyl piperazine, piperidines, tetramethyleneimine and tetrahydropyridine.

Comprise R ⁴And R ⁵And the further suitable examples of this ring of the nitrogen that they connected be thiomorpholine and wherein sulphur be oxidized to S (O) or S (O) ₂The derivative of group.Further suitable examples is a morpholine.

On the other hand, R ⁴And R ⁵The nitrogen that is connected with them forms 6 yuan unsaturated ring of list such as tetrahydropyridine altogether.

On the other hand, R ⁴And R ⁵The nitrogen that is connected with them forms imidazole ring altogether, and described ring is chosen wantonly on available carbon by 1 or 2 methyl substituted.

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

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, methyl, carboxymethyl and (2-4C) alkyl (optionally replaced by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

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

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, carboxymethyl and (2-4C) alkyl (replaced by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

On the other hand, R ⁶And R ⁷Be independently selected from hydrogen, carboxymethyl and (2-4C) alkyl (replaced by 1 or 2 substituting group that is independently selected from amino, methylamino, dimethylamino, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein methylamino or dimethylamino can be chosen wantonly on methyl by carboxyl substituted).

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

On the other hand, R ⁶Or R ⁷Formation contains the saturated heterocyclic basic ring that 1 or 2 heteroatomic 4,5 or 6 yuan carbon that is independently selected from O, N and S is connected, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced by 1 or 2 (1-4C) alkyl.Especially, work as R ⁴Be-C (O) R ⁶The time R ⁶Definition be suitable for.For R as described ring ⁶Or R ⁷Specific examples be azetidine, tetramethyleneimine and piperidines.For R as described ring ⁶Or R ⁷Other object lesson be azetidinone, pyrrolidone and piperidone.

In others, R ⁶And R ⁷The nitrogen that is connected with them forms optional 14, the 5 or 6 yuan of saturated heterocyclic basic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S that contains altogether, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and to be replaced by 1 or 2 (1-4C) alkyl that (condition is R ⁶And R ⁷The nitrogen that is connected is not thus by quaternized);

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

Comprising R ⁶And R ⁷And the optional substituent suitable example on the ring of the nitrogen that they connected is 1 or 2 methyl.

On the other hand, work as R ⁶Or R ⁷During for (2-4C) alkyl, then alkyl is selected from by 1 and above or aspect hereinafter any is replacing about the described substituting group of this group.In others, work as R ⁶Or R ⁷During for (2-4C) alkyl, then alkyl is selected from by 2 and above or aspect hereinafter any is replacing about the described substituting group of this group.

In one aspect, work as R ⁴Or R ⁵For-C (O) NHR ⁶Or-C (O) OR ⁶The time, R then ⁶Be selected from carboxymethyl and (2-4C) the alkyl substituting group of amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl and hydroxyl (be selected from replacement).

On the other hand, work as R ⁴Or R ⁵For-C (O) NR ⁶R ⁷The time, R then ⁶And R ⁷Can not form tetramethyleneimine, piperidines or morpholine ring with its nitrogen that is connected.

On the other hand, work as R ⁴Or R ⁵For-C (O) NR ⁶R ⁷The time, R then ⁶And R ⁷Can not form unsubstituted tetramethyleneimine, piperidines or morpholine ring with its nitrogen that is connected.

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

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

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NHR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶(condition is R ⁴And R ⁵Not hydrogen simultaneously);

R ⁶And R ⁷Be independently selected from hydrogen, methyl, carboxymethyl and (2-4C) alkyl (optionally be independently selected from amino by 1 or 2, (1-4C) substituting group of alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl replaces; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷(2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace], (condition is R ⁴And R ⁵Not hydrogen simultaneously);

R ⁶And R ⁷Be independently selected from hydrogen, methyl, carboxymethyl and (2-4C) alkyl (optionally replaced by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴And R ⁵One of be hydrogen or methyl and another be selected from carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷(2-4C) alkyl [by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace];

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴And R ⁵One of be that hydrogen or methyl and another are selected from-C (O) R ⁶,-C (O) CH ₂NR ⁶R ⁷,-C (O) OR ⁶,-C (O) NR ⁶R ⁷With-SO ₂NHR ⁶

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether or part is undersaturated and optionally contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl;

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁶And R ⁷The nitrogen that is connected with them form altogether azetidine, morpholine, piperazine, N methyl piperazine, thiomorpholine (or its wherein sulphur be oxidized to S (O) or S (O) ₂The derivative of group), piperidines or pyrrolidine ring; Optional by 1 or 2 methyl substituted.

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

R ²And R ³Be hydrogen or fluorine independently;

R ⁶And R ⁷The nitrogen that is connected with them form altogether azetidine, morpholine, piperazine, N methyl piperazine, thiomorpholine (or its wherein sulphur be oxidized to S (O) or S (O) ²The derivative of group), piperidines or pyrrolidine ring; Optional by 1 or 2 methyl substituted.

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

R ²And R ³Be hydrogen or fluorine independently;

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

R ²And R ³Be hydrogen or fluorine independently;

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

R ²And R ³Be hydrogen or fluorine independently;

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

The method part:

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

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

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

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

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

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

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

But the ester of hydrolysis can be by any known method preparation for preparing the chemofacies related compounds that is applicable in compound or pharmaceutically acceptable salt thereof of the present invention or the body.But described method is provided and sets forth in following exemplary embodiment as further feature of the present invention when being used to prepare the ester of hydrolysis in compound or pharmaceutically acceptable salt thereof of the present invention or the body.Necessary starting raw material can obtain (referring to for example Advanced OrganicChemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Organischen Chemie) by the organic chemistry standard method.The preparation of these starting raw materials is stated in non-limiting example subsequently.Perhaps, by can be in organic chemist's common sense as can be known the similar approach of the described method in the scope obtain necessary starting raw material.The information of starting raw material that relevant preparation is necessary or allied compound (its may through revising to form necessary starting raw material) can find in some patent application is open, and the content of the disclosed method part of described patent application is incorporated herein by reference: for example WO 94/13649; WO 98/54161; WO99/64416; WO 99/64417; WO 00/21960; WO 01/40222; WO 01/94342; WO 03/022824, JP2003335762 and WO 03/006440.

Especially, the inventor quotes PCT patent application WO 99/64417 and the WO00/21960 of oneself, has wherein provided the detailed instruction about the facilitated method of preparation _ oxazolidinone compounds.

Skilled organic chemist can use and be modified in the information that institute comprises and mentions among the embodiment of above-mentioned document and the embodiment that wherein encloses and this paper, to obtain necessary starting raw material and product.Term herein " can replace group ", " leavings group " and " displaceable group " is used interchangeably and can has the conventional sense of this area.The example of these groups is well known in the art and in the following suitable examples that provided.

Therefore, in others, the present invention also provides, but the ester of hydrolysis can pass through method (a) to (j) preparation in compound of the present invention and pharmacologically acceptable salt thereof and the body; And, afterwards, if necessary:

I) remove any protecting group;

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

Iii) form pharmacologically acceptable salt;

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

A) by using the substituting group in other compound of standard chemical process change the present invention or in other compound of the present invention, introducing substituting group (referring to for example, Comprehensive OrganicFunctional Group Transformations (Pergamon), Katritzky, Meth-Cohn﹠amp; Rees); For example: acyl amino or sulfo-acyl amino can be converted into other acyl amino or sulfo-acyl amino; Be converted into heterocyclic radical amino (choose wantonly on amino-nitrogen-atoms, be substituted or protected); By the heterocyclic radical (choose wantonly on the different carbon of the carbon adjacent and be substituted) that nitrogen connects, 1,2,3-triazoles-1-base that for example optional 4-position replaces with connecting nitrogen-atoms; This conversion of acyl amino is directly carried out or is carried out via the pilot process of one or more derivatives such as amino;

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

Amino can be converted into substituted-amino, for example passes through: alkylation (for example using alkylogen or other activating reagent such as sulphonate),

Reductive alkylation (for example by using carbonyl compound such as aldehyde and reductive agent such as sodium triacetoxy borohydride to handle),

Acylations (for example obtains acid amides with activated carboxylic acid derivatives such as chloride of acid or active ester reaction; obtain urea with the isocyanate derivates reaction; or obtain carbamate with chloro sulfonate derivatives reaction; perhaps amine can be converted into isocyanic ester; for example by at first being converted into carboxamides derivatives, handling with dehydrated reagent then; available then amine of the isocyanate derivates that obtains or alcohol are handled, and obtain urea or carbamate derivatives respectively), or

Alkylsulfonylization (for example obtaining sulphonamide) by using activation sulfonic acid such as SULPHURYL CHLORIDE to handle;

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

B) (wherein X is the leavings group that can be used in palladium [0] coupled reaction to a part of through type (II) compound, for example chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) with the partial reaction of Compound I Ia, described formula IIa also has leavings group X, and (wherein Y is an amine or as mentioned or hereinafter defined sulfonamide derivatives NR ⁴R ⁵, its synthetic precursor or its protected derivative (PG=protecting group)), make to replace phenyl-X and pyridyl-X key with pyridyl-phenyl key; These methods are known at present, for example referring to S.P.Stanforth, and Catalytic Cross-coupling Reactions in Biaryl Synthesis, Tetrahedron, 54,1998,263-303; J.K.Stille, Angew Chem.Int.Ed.Eng., 1986,25,509-524; N.Miyaura and A Suzuki, Chem.Rev., 1995,95,2457-2483; D.Baranano, G.Mann, and J.F.Hartwig, Current Org.Chem., 1997,1,287-305; S.P.Stanforth, Tetrahedron, 54 1998,263-303; P.R.Parry, C.Wang, A.S.Batsanov, M.R.Bryce; And B.Tarbit, J.Org.Chem., 2002,67,7541-7543;

Leavings group X in two molecules can be identical or different at (II) with (IIa), for example, shown in following diagram,

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

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

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

Wherein X is replaceable substituting group (as chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or a boric acid residue)

Compound reaction with formula V:

Wherein X ' is a replaceable substituting group (as chlorine, bromine, iodine, trifluoromethyl sulfonyloxy, trimethylammonium stannyl, trialkoxysilyl or boric acid residue) the and wherein definition of Y is the same; Wherein selecting substituent X and X ' is well known in the art being suitable for as right by the complementary substituting group of the complementary substrate of transition metal such as palladium (0) catalyzed coupling reaction;

E) make 3-pyridyl phenyl biaryl aldehyde derivatives (VI) reaction, thereby form different _ oxazoline ring (wherein the definition of Y is the same) in the position that does not form heteroaryl:

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

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

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

H) as follows, by making amino methyl _ oxazolidone and 1,1-dihalo ketone alkylsulfonyl hydrazone reaction (Sakai, Kunihazu; Hida, Nobuko; Kondo, Kiyosi; Bull.Chem.Soc.Jpn., 59,1986,179-183; Sakai, Kunikazu; Tsunemoto, Daiei; Kobori, Takeo; Kondo, Kiyoshi; Hido, Noboko EP 103840 A219840328), (wherein the definition of Y is the same);

I) as follows, by make azido methyl _ oxazolidone and vinyl halides base SULPHURYL CHLORIDE under the temperature between 0 ℃-100 ℃ solvent-free or in inert diluent such as chlorobenzene, chloroform or dioxane, react (wherein the definition of Y is the same);

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

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

J) the alternative route that obtains the preferred single epimer on different _ oxazoline ring is by the enantio-selectivity esterase hydrolyzed of the racemic mixture of ester, obtains hydroxyl in prochiral center, and this hydroxyl can be converted into the NR of this paper definition ⁴R ⁵Substituting group, but wherein unwanted isomer recirculation, for example, as shown in following diagram:

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

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

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

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

Perhaps, above-mentioned cyclization can use allylamine derivatives to carry out, and directly obtains sulfonamide derivatives, shown in following reaction sequence.In addition, be well known that the racemic mixture of amine can be by with chiral acid such as camphorsulfonic acid salify, crystallization splits then.Perhaps, can use the chirality phase chromatography to split isomer.

Reaction sequence that can be shown below is converted into NR with the hydroxyl in the above-mentioned intermediate ⁴R ⁵Substituting group.NR ⁴R ⁵Substituent alternative precursor is for example azido-, phthalimide-based, halogen [or other leavings group (LG) is as methanesulfonates or tosylate].

Be appreciated that, synthetic order shown in the following diagram can be used in any suitable stage in the described compound process of assembling, therefore, the pyridyl that can represent suitably to be replaced of the G in the following diagram, pyridyl-phenyl, pyridyl-phenyl-_ oxazolidone or pyridyl-phenyl-_ oxazolidone-methyl-triazole member ring systems;

Perhaps, shown in following diagram, can assemble wherein NR ⁴R ⁵Form the compound of ring together.Perhaps, cyclisation step can use intramolecularly reductive alkylation (if LG=aldehyde) to carry out.

Wherein X is that boric acid or ester and Y are NR ⁴R ⁵The compound of formula (IIa) be novelty and constituted the independent aspect of the present invention.The particular compound of this aspect of the present invention is R wherein ⁴And R ⁵As mentioned or the compound of of the present invention any aspect hereinafter described or the defined formula of scheme (IIa).Wherein X is that halogen and Y are OR ⁴The compound of formula (IIa) be novelty and constituted the independent aspect of the present invention.The particular compound of this aspect of the present invention is an intermediate 13,14,15,16,17,18,19,20,23,24,25,26 and 31.

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

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

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

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

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

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

BrO _3-+6H ⁺+5Br-→3Br ₂+3H ₂O

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Anti-microbial activity:

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

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

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

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

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

For example, obtained the following result of the compound of embodiment 3.

Organism MIC (μ g/ml)

Streptococcus aureus: MSQS 0.5

MRQR 0.5

Streptococcus pneumoniae 0.13

Hemophilus influenzae 8

Catarrhal catarrhalis 1

Linezolid resistance streptococcus pneumoniae 1

MSQS=methicillin-sensitivity and quinolone susceptibility

MRQR=methicillin resistance and quinolone resistance

The activity of the anti-MAO-A of The compounds of this invention is used as Biochem.Biophys.Res.Commun.1991, and 181,1084-1088 is described to be measured based on the standard in vitro tests with people's liver enzyme of yeast expression.When with above-mentioned test determination, the Ki value of the compound of embodiment 〉=5 μ M.The Ki value of embodiment 3＞22 μ M, by contrast, the Ki value of reference example 16 is 0.35 μ M.

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

Hereinafter described some intermediate and/or reference example place can have useful activity within the scope of the invention and/or also, and are provided as other aspect of the present invention.Specific embodiment is a reference example 16.

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

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

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

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

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

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

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

(vii) wherein can use following abbreviation:

DMF is N, dinethylformamide; DMA is a N,N-dimethylacetamide; TLC is a tlc; HPLC is a high pressure lipuid chromatography (HPLC); MPLC is the medium pressure liquid chromatography method; DMSO is a dimethyl sulfoxide (DMSO); CDCl ₃It is deuterochloroform; MS is a mass spectrum; ESP is an electrospray; EI is electron impact; CI is a chemi-ionization; APCI is the barometric point chemi-ionization; EtOAc is an ethyl acetate; MeOH is a methyl alcohol; Phosphoryl (phosphoryl) is (HO) ₂-P (O)-O-; Inferior phosphoryl (phosphiryl) is (HO) ₂-P-O-; SYNTHETIC OPTICAL WHITNER (Bleach) is " Clorox " 6.15% clorox; EDAC is 1-[3-(dimethylamino) propyl group]-the 3-ethyl carbodiimide; THF is a tetrahydrofuran (THF); TFA is a trifluoroacetic acid; RT is a room temperature; Ether is ether; CF.=relatively; HATU is O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea _ hexafluorophosphate

(viii) temperature is with a ℃ expression;

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

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

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), the dimethyl amine (solution of the THF of 2M, 6ml, 12mmol) and tetrabutylammonium iodide (2mg, catalytic amount) mix to open and in sealed vial, be warming to 100 ℃ and continue 5 days.Solution is through concentrating and by column chromatography purifying (silica gel, the methyl alcohol in methylene dichloride of 0-10%), obtain rough [(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl dimethyl amine, be waxy solid (225mg).With this material (220mg, 0.77mmol), (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 7,330mg, 0.85mmol), salt of wormwood (320mg, 2.3mmol) and four (triphenylphosphines) close palladium (0) (90mg 0.078mmol) be suspended in DMF (4ml) and the water (0.4ml).Mixture 80 ℃ heating and continuous 1 hour, directly mix then with a small amount of silica gel, behind the described silica gel of vacuum-drying, described material is directly carried out column chromatography separation [silica gel, the methyl alcohol in (20% in methylene dichloride acetonitrile) of 1-20%].Material and the methyl alcohol that obtains like this: ether (1: 10) grinds, and filters and use ether rinse then.So obtain title compound, be pale solid (205mg): fusing point: 212 ℃.

MS (electrospray):C ₂₃H ₂₄FN ₇O ₃Be 466 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.50(s，6H)；2.89(bm，2H)；3.29(dd，1H)；3.62(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.03(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)；8.83(s，1H)。

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

Under nitrogen, (5R)-3-(3-fluorophenyl)-5-hydroxymethyl _ azoles alkane-2-ketone (40g, 0.189mol is referring to Upjohn WO 94-13649) is suspended in the anhydrous methylene chloride (400ml) by stirring.Add triethylamine (21g, 0.208mol) and 4-dimethylaminopyridine (0.6g, 4.9mmol), (20.3g 0.199mol), and continues stirring 18 hours in envrionment temperature to drip diacetyl oxide then in 30 minutes.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):C ₁₂H ₁₂FNO ₄Be 254 (MH ⁺)

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

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

Under nitrogen with acetate (5R)-3-(3-fluoro-phenyl)-2-oxo-_ azoles alkane-5-base methyl esters (intermediate 1,15.2g 60mmol) are dissolved in the mixture of chloroform (100ml) and acetonitrile (100ml), and interpolation trifluoroacetic acid silver (16.96g, 77mmol).Portioning interpolation iodine in 30 minutes (18.07g, 71mmol) in the solution of vigorous stirring, and envrionment temperature continuation stirring 18 hours.Because reaction is not finished, add the trifluoroacetic acid silver (2.64g of part in addition, 12mmol) also continue to stir 18 hours, after the filtration, with mixture add to hypo solution (3%, 200ml) and in the methylene dichloride (200ml), separate organic layer, 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), and adds the ether of capacity and stir 1 hour simultaneously, filter and obtain required product (24.3g), be cream-colored solid to isolate brown impurity.

MS (ESP):C ₁₂H ₁₁FINO ₄Be 380 (MH ⁺)

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

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

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

MS (ESP):C ₁₀H ₉FINO ₃Be 338 (MH ⁺)

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

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

In methylene dichloride (250ml), stir (5R)-3-(3-fluoro-4-iodophenyl)-5-(hydroxymethyl)-1 at 0 ℃, and 3-_ azoles alkane-2-ketone (intermediate 3,25.0g, 74.2mmol).(10.5g, 104mmol), (11.2g, 89.0mmol), reaction is stirred and is spent the night the room temperature of slowly rising again to add methylsulfonyl chloride then to add triethylamine.Yellow solution dilutes with sodium bicarbonate, and (3 * 250ml) extract the gained compound with methylene dichloride.Dry organic layer (sal epsom) filters and concentrates and obtains required product, is light yellow solid (30.3g).

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

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

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

Will [(5R)-and 3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-_ azoles alkane-5-yl] (intermediate 4,6.14g 14.7mmol) are dissolved in N to the methylmethanesulfonate ester, dinethylformamide (50ml).(1.92g 29.6mmol), is reflected at 75 ℃ of stirrings and spends the night to add sodiumazide.Yellow mixture is poured in the half saturated sodium bicarbonate, uses ethyl acetate extraction.Organic layer washes with water three times, and dry (sal epsom), filter and concentrate and obtain title compound is yellow solid (4.72g).

MS (ESP):C ₁₀H ₈FIN ₄O ₂Be 363 (MH ⁺)

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

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

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

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

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

Intermediate 7:(5R)-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), two (tetramethyl ethylene ketone base) two boron (bis (pinacolato) diboron) (2.62g, 10.3mmol), potassium acetate (2.5g, 25.5mmol) and 1,1 '-(0.38g 0.52mmol) is suspended among the DMSO (15ml) [two (diphenylphosphine) ferrocene] dichloro palladium (II) methylene dichloride title complex.Mixture obtains transparent dark solution 80 ℃ of heating 40 minutes.Add ethyl acetate (150ml) then, mixture is by diatomite filtration, with the saturated brine washing (2 * 100ml), with dried over sodium sulfate and evaporation.Black residue obtains product by chromatography purification (silica gel, the ethyl acetate in hexane of 40-100% are the acetonitrile in ethyl acetate of 1-5% then), is brown crystalline solid, 1.97g (98%).(annotate-wash-out goes out the very heavy impurity of color before the product band, needs to prolong wash-out to obtain product).

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

Perhaps:

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

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

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

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

Annotate: it is a lachrymator.

Intermediate 8a:5-bromopyridine-2-formoxime

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

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

Intermediate 9: butyric acid [3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl esters

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

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

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

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

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

Intermediate 11:[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl alcohol

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

Intermediate 12:5-bromo-2-[(5S)-and 5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine

Will [(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] (intermediate 11,4g 16mmol) are dissolved in the methylene dichloride in (80ml) methyl alcohol.Add triphenylphosphine (7.0g, 26.7mmol) and tetracol phenixin (9ml, 93mmol), mixture was stirring at room 2 hours.Solution passes through concentrated and passes through hurried chromatography purification (silica gel, 7: 3 hexanes: methylene dichloride) obtain title product, be white solid (3.9g).

¹H-NMR(300MHz，CDCl ₃)δ：3.42-3.73(m，4H)；4.98-5.08(m，1H)；7.84(dd，1H)；7.90(d，1H)；8.65(d，1H)。

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

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.40g, 1.45mmol), methylamine (the THF solution of 2M, 8ml, 16mmol) and tetrabutylammonium iodide (2mg, catalytic amount) mix to be incorporated in and be warming to 100 ℃ in the sealed vial and continue 5 days.Solution is through concentrating and by column chromatography purifying (silica gel, the methyl alcohol in methylene dichloride of 0-10%), obtain rough [(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl methylamine, be waxy solid (160mg).With this material (155mg, 0.57mmol), (5R)-3-[3-fluorine 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 7,245mg, 0.63mmol), salt of wormwood (240mg, 1.74mmol) and four (triphenylphosphines) close palladium (0) (66mg 0.057mmol) be suspended in DMF (3ml) and the water (0.3ml).Mixture directly mixes with a small amount of silica gel then 80 ℃ of heating 1 hour, behind the described silica gel of vacuum-drying, described material is directly carried out column chromatography separate [silica gel, the methyl alcohol of 1-20% in (20% the acetonitrile in methylene dichloride)].Material and the methyl alcohol that obtains like this: ether (1: 10) grinds, and filters and use ether rinse then.So obtain title compound, be pale solid (75mg): fusing point: 215 ℃.

MS (electrospray):C ₂₂H ₂₂FN ₇O ₃Be 452 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.57(s，3H)；3.14(d，2H)；3.37(dd，1H)；3.67(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.05(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.01(d，1H)；8.08(d，1H)；8.18(s，1H)；8.24(bs，1H)；8.84(s，1H)。

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

With 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } morpholine (intermediate 13,325mg, 0.99mmol), (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 7,350mg, 0.90mmol), salt of wormwood (420mg, 3.04mmol) and four (triphenylphosphines) close palladium (0) (120mg 0.10mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 30 minutes, and cooling is also filtered.Solid acetonitrile rinsing, the evaporation of the filtrate of merging is dissolved in acetonitrile again and is adsorbed onto on the silica gel.Adsorbent is by column chromatography purifying [silica gel, the methyl alcohol in (20% the acetonitrile in methylene dichloride) of 1-10%], and so material that obtains and hot methanol (20ml) stir and with ether (20ml) dilution, filter and use ether rinse then.So obtain title compound, be pale solid (154mg): fusing point: 230 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄Be 508 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.47(bm，4H)；2.56(m，2H)；3.27(dd，1H)；3.54(dd，1H)；3.56(bm，4H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.94(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Embodiment 3a:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ Azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone, Hydrochloride

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 3 for 3-_ azoles alkane-2-ketone, 1g 1.97mmol) is dissolved in the mixture of acetonitrile (5ml), methyl alcohol (5ml), DMF (5ml) and methylene dichloride (15ml), is cooled to 0 ℃ then.(2mmol), clear solution obtains suspension with ether (30ml) dilution for the dioxane solution of 4M, 0.5ml to add hydrochloric acid.Collect solid, obtain title compound, be pale solid (909mg) fusing point: 242 ℃ with ether rinse and 50 ℃ of vacuum-dryings.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄Be 508 (M+1)

¹H-NMR(300MHz，DMSO-d ₆)δ：3.18(bm，2H)；3.33-3.55(bm，4H)；3.72-3.88(bm，4H)；3.95(m，3H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.37(bm，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.02(d，1H)；8.09(d，1H)；8.19(s，1H)；8.85(s，1H)；11.17(bs，1H)。

Embodiment 3b:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ Azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone, Hydrobromate

Under vigorous stirring to embodiment 3 (380mg, 7.5mmol) Virahol/methylene dichloride (1: 1,20mL) add in the solution in the acetate contain HBr (33%, 0.3mL).Solvent evaporated under reduced pressure, and the mixture of resistates and isopropanol (1: 1, twice of 2 * 5mL) condistillation.With resistates be dissolved in heat isopropanol (2: 1,20mL), be settled out product by adding cold isopropanol (20mL).By solid collected by filtration and at 48 ℃ of drying under reduced pressure, obtain the hydrobromate of the embodiment 3 of 367mg, be colorless solid, mp＞280 ℃ (decomposition).

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄508 (M+1)

¹H-NMR(300MHz，DMSO-d ₆)δ：3.20(bm，2H)；3.45-3.60(bm，4H)；3.70-3.84(bm，4H)；3.92-4.01(m，3H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.30(bm，1H)；7.43(dd，1H)；7.59(dd，1H)；7.70(t，1H)；7.77(s，1H)；8.03(d，1H)；8.10(d，1H)；8.19(s，1H)；8.85(s，1H)；10.13(bs，1H)。

Embodiment 3c:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ Azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone, Mesylate

Under thermal condition with (5R)-3-(3-fluoro-4-{6-[(5S)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 3 for 3-_ azoles alkane-2-ketone, 100mg 0.197mmol) is dissolved in 1: 1 acetonitrile: in the methyl alcohol (50ml).(0.2mmol), clear solution is concentrated to 10ml and obtains suspension with the ethyl acetate dilution for the methanol solution of 0.5M, 0.4ml to add methylsulfonic acid.Collect solid,, obtain title compound, be fusing point: 165-168 ℃ of pale solid (100mg) with the ethyl acetate rinsing and 50 ℃ of vacuum-dryings.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄Be 508 (M+1)

¹H-NMR(300MHz，DMSO-d ₆)δ：2.28(s，3H)；3.19(bm，2H)；3.40-3.59(bm，4H)；3.64-3.82(bm，4H)；3.92-4.02(m，3H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.28(bm，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.77(s，1H)；8.03(d，1H)；8.10(d，1H)；8.18(s，1H)；8.85(s，1H)；10.02(bs，1H)。

Intermediate 13:4-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Morpholine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (0.30g, 1.09mmol), morpholine (1g, 11.5mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and be warming to 115 ℃ and continue 16 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (345mg).

MS (electrospray):C ₁₃H ₁₆BrN ₃O ₂Be 327 (M+1).

Embodiment 4:(5R)-and 3-[3-fluoro-4-(6-{ (5S)-5-[(4-methylpiperazine-1-yl) methyl]-4,5- Dihydro is different _ azoles-3-yl } and pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1, the 3-_ azoles Alkane-2-ketone

With 1-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl }-4-methylpiperazine intermediate 14,360mg, 1.06mmol), (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 7,350mg, 0.90mmol), salt of wormwood (420mg, 3.04mmol) and four (triphenylphosphines) close palladium (0) (120mg 0.10mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 60 minutes, and cooling directly is adsorbed onto on the silica gel and vacuum-drying.Adsorbent is by column chromatography purifying [silica gel, 1-20% is at (20% the acetonitrile in methylene dichloride, contain 1% triethylamine) in methyl alcohol], so the material that obtains stirs with hot methanol (10ml) and dilutes with ether (60ml), filters and use ether rinse then.So obtain title compound, be pale solid (190mg): fusing point: 218 ℃.

MS (electrospray):C ₂₆H ₂₉FN ₈O ₃Be 521 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.22(bm，4H)；2.55(bm，7H)；3.25(dd，1H)；3.29(m，2H)；3.52(dd，1H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.92(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 14:1-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] first Base }-the 4-methylpiperazine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), 1-methylpiperazine (0.9ml, 10mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and are warming to 100 ℃ and continue 20 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (360mg).

MS (electrospray):C ₁₄H ₁₉BrN ₄O is 340 (M+1).

Embodiment 5:(5R)-and 3-{3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl) amino] methyl }-4,5- Dihydro is different _ azoles-3-yl) and pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1, the 3-_ azoles Alkane-2-ketone

With 2-([(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } amino) ethanol (intermediate 15,315mg, 1.05mmol), (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 7,350mg, 0.90mmol), salt of wormwood (420mg, 3.04mmol) and four (triphenylphosphines) close palladium (0) (120mg 0.10mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 60 minutes, and cooling directly is adsorbed onto on the silica gel and vacuum-drying.Adsorbent is by column chromatography purifying [silica gel, the methyl alcohol in (20% the acetonitrile in methylene dichloride contains 1% triethylamine) of 1-20%].So material that obtains and hot methanol (10ml) stir and with ether (60ml) dilution, filter and use ether rinse then.So obtain title compound, be pale solid (170mg): fusing point: 190 ℃.

MS (electrospray):C ₂₃H ₂₄FN ₇O ₄Be 482 (M+1).

¹H-NMR(400MHz，DMSO-d ₆)δ：2.64(t，2H)；2.78(d，2H)；3.29(dd，1H)；3.45(m，2H)；3.50(dd，1H)；3.96(dd，1H)；4.29(t，1H)；4.53(t，1H)；4.85(m，1H)；4.86(d，2H)；5.18(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1?H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 15:2-([(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Amino) ethanol

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), thanomin (0.6ml, 9.7mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and be warming to 100 ℃ and continue 20 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (315mg).

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

Embodiment 6:(5R)-and 3-[4-(6-{ (5S)-5-[(butyl amino) methyl]-4, the 5-dihydro is different _ azoles-3- Base } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

With N-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } butane-1-amine (intermediate 16,335mg, 1.07mmol), (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 7,350mg, 0.90mmol), salt of wormwood (420mg, 3.04mmol) and four (triphenylphosphines) close palladium (0) (120mg 0.10mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 60 minutes, and cooling directly is adsorbed onto on the silica gel and vacuum-drying.Adsorbent is by column chromatography purifying [silica gel, the methyl alcohol in (20% the acetonitrile in methylene dichloride) of 1-20%].So material that obtains and hot methanol (10ml) stir and with ether (60ml) dilution, filter and use ether rinse then.So obtain title compound, be pale solid (190mg): fusing point: 230 ℃.

MS (electrospray):C ₂₅H ₂₈FN ₇O ₃Be 494 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：0.88(t，3H)；1.31(m，2H)；1.52(m，2H)；2.81(t，2H)；3.06(d，2H)；3.35(dd，1H)；3.63(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；4.99(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.01(d，1H)；8.08(d，1H)；8.18(s，1H)；8.84(s，1H)。

Intermediate 16:N-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Butane-1-amine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), n-butylamine (1.0ml, 10mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and are warming to 100 ℃ and continue 20 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (335mg).

MS (electrospray):C ₁₃H ₁₈BrN ₃O is 313 (M+1).

Embodiment 7:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(thiomorpholine-4-ylmethyl)-4, the 5-dihydro Different _ azoles-the 3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2- Ketone

With 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } thiomorpholine (intermediate 17,280mg, 0.82mmol), (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 7,349mg, 0.90mmol), salt of wormwood (340mg, 2.46mmol) and four (triphenylphosphines) close palladium (0) (95mg 0.082mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 1 hour, and cooling is also filtered, and filtrate is mixed with silica gel and vacuum-drying.Adsorbent is by column chromatography purifying (silica gel, 1-10% methyl alcohol: methylene dichloride).So the material that obtains is dissolved in warm methyl alcohol (5ml) and methylene dichloride (5ml), and the solution heating is concentrated to 5ml, and cooling obtains throw out.Solid is through filtering and with methyl alcohol, water rinse, and once more with methyl alcohol then with ether rinse and vacuum-drying.So obtain title compound, be pale solid (150mg): fusing point: 222-225 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₃S is 524 (M+1).

¹H-NMR(400MHz，DMSO-d ₆)δ：2.58(bm，6H)；2.75(bm，4H)；3.24(dd，1H)；3.52(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；4.93(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.82(s，1H)。

Intermediate 17:4-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Thiomorpholine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,1g, 3.26mmol), thiomorpholine (3g, 29mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (3ml) mix and are warming to 110 ℃ and continue 16 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer dried over sodium sulfate that merges, evaporation is also passed through hurried chromatography purification (silica gel, the ethyl acetate in hexane of 10-50%), obtains title compound, is pale solid (635mg).

¹H-NMR(400MHz，DMSO-d ₆)δ：2.57(bm，6H)；2.72(bm，4H)；3.17(dd，1H)；3.46(dd，1H)；4.91(m，1H)；7.84(d，1H)；8.11(d，1H)；8.77(s，1H)。

Embodiment 8:(5R)-3-[3-fluoro-4-(6-{ (5S)-5-[(1-oxidation thiomorpholine-4-yl) methyl]- 4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- _ azoles alkane-2-ketone

With 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } thiomorpholine 1-oxide compound (intermediate 18,130mg, 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 7,155mg, 0.40mmol), salt of wormwood (150mg, 1.09mmol) and four (triphenylphosphines) close palladium (0) (42mg 0.036mmol) be suspended in DMF (3ml) and the water (0.5ml).Mixture was 80 ℃ of heating 1 hour, and cooling is also filtered.Filtrate is mixed with silica gel and vacuum-drying.Adsorbent is by column chromatography purifying (silica gel, the methyl alcohol in methylene dichloride of 1-15%).So the material that obtains is dissolved in warm methyl alcohol (5ml) and the methylene dichloride (5ml), and the solution heating is concentrated to 5ml, and cooling obtains throw out.Solid is through filtering and using methanol rinse, then with ether rinse and vacuum-drying.So obtain title compound, be pale solid (110mg): fusing point: 218-220 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄S is 540 (M+1).

¹H-NMR(400MHz，DMSO-d ₆)δ：2.64-2.78(m，6H)；2.87(bm，2H)；3.01(bq，2H)；3.26(dd，1H)；3.53(dd，1H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.94(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)；8.05(d，1H)；8.18(s，1H)；8.82(s，1H)。

Intermediate 18:4-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Thiomorpholine 1-oxide compound

With 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } (intermediate 17,150mg 0.44mmol) are dissolved in acetonitrile (4ml) and the water (1ml) and are cooled to 0 ℃ thiomorpholine, add solid Oxone ^_One persulfate compound [2KHSO ₅.KHSO ₄.K ₂SO ₄(160mg, 0.26mmol)], remove cooling bath.Mixture stirred 20 minutes, was suspended in acetonitrile: also filter in the methyl alcohol (1: 1).Filtrate is mixed with silica gel and vacuum-drying.Adsorbent obtains title compound by hurried chromatography purification (silica gel, the methyl alcohol in methylene dichloride of 1-50%), is pale solid (130mg).

MS (electrospray):C ₁₃H ₁₆N ₃O ₂S is 359 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.60-2.77(m，6H)；2.86(bm，2H)；3.00(bq，2H)；3.20(dd，1H)；3.48(dd，1H)；4.93(m，1H)；7.85(d，1H)；8.12(d，1H)；8.78(s，1H)。

Embodiment 9:(5R)-3-[4-(6-{ (5S)-5-[(1,1-titanium dioxide thiomorpholine-4-yl) methyl]- 4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)- 1,3-_ azoles alkane-2-ketone

With 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } thiomorpholine 1,1-dioxide (intermediate 19,185mg, 0.49mmol), (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 7,205mg, 0.53mmol), salt of wormwood (200mg, 1.45mmol) and four (triphenylphosphines) close palladium (0), and (60mg 0.051mmol) is suspended in DMF (3ml) and the water (0.5ml).Mixture was 80 ℃ of heating 1 hour, and cooling is also filtered, and filtrate is mixed with silica gel and vacuum-drying.Adsorbent is by column chromatography purifying (silica gel, the methyl alcohol in methylene dichloride of 1-10%).So the material that obtains is dissolved in warm ethanol (5ml) and the methylene dichloride (5ml), and the solution heating is concentrated to 5ml, and cooling obtains throw out.Solid is through filtering and with methyl alcohol, water rinse, once more with methyl alcohol then with ether rinse and vacuum-drying.So obtain title compound, be pale solid (125mg): fusing point: 200-203 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₅S is 556 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.79(m，2H)；3.06(m，8H)；3.26(dd，1H)；3.54(dd，1H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；4.94(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.06(d，1H)；8.18(s，1H)；8.82(s，1H)。

Intermediate 19:4-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Thiomorpholine 1, the 1-dioxide

With 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } (intermediate 17,200mg 0.56mmol) are dissolved in acetonitrile (5ml) and the water (2ml) and are cooled to 0 ℃ thiomorpholine.Add solid Oxone ^_One persulfate compound [2KHSO ₅.KHSO ₄.K ₂SO ₄(620mg, 1.01mmol)], remove cooling bath.Mixture stirred 16 hours, was suspended in acetonitrile: also filter in the methyl alcohol (1: 1).Filtrate is mixed with silica gel and vacuum-drying.Adsorbent obtains pale solid (215mg) by hurried chromatography purification (silica gel, the methyl alcohol in methylene dichloride of 4-20%).This material is through being accredited as the N-oxide compound of title compound:

MS (electrospray):C ₁₃H ₁₆N ₃O ₄S is 391 (M+1)

Following realization is to the conversion of title compound: the N-oxide compound that will as above prepare (205mg, 0.53mmol) with triphenylphosphine (250mg, 0.95mmol) among DMF (4ml), mix and be warming to 80 ℃ lasting 15 minutes.Mixture dilutes with ethyl acetate, washes with water.Water layer extracts with ethyl acetate and ethyl acetate: THF (1: 1).The organic layer that merges also evaporates with dried over sodium sulfate.Resistates is by hurried chromatography purification (silica gel, the ethyl acetate in hexane of 10-100%), obtain 4-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } thiomorpholine 1, the 1-dioxide is pale solid (190mg).

MS (electrospray):C ₁₃H ₁₆N ₃O ₃S is 375 (M+1)

¹H-NMR (400MHz, DMSO-d ₆) δ: 2.76 (m, 2H); 3.03 and 3.06 (2Xbm, 8H); 3.20 (dd, 1H); 3.49 (dd, 1H); 4.92 (m, 1H); 7.83 (d, 1H); 8.12 (d, 1H); 8.77 (s, 1H).

Embodiment 10:(5R)-and 3-{3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl) (methyl) amino] first Base }-4, the 5-dihydro is different _ azoles-3-yl) pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)- 1,3-_ azoles alkane-2-ketone

With 2-[{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } (methyl) amino] ethanol (intermediate 20,335mg, 1.07mmol), (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 7,420mg, 1.08mmol), salt of wormwood (450mg, 3.26mmol) and four (triphenylphosphines) close palladium (0) (125mg 0.108mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 40 minutes, and cooling directly is adsorbed onto on the silica gel and vacuum-drying.Adsorbent is by column chromatography purifying [silica gel, the methyl alcohol in (20% acetonitrile, 1% triethylamine is in methylene dichloride) of 0-20%].So the material that obtains is collected crystallization and is used ether rinse from methanol crystallization.So obtain title compound, be pale solid (70mg): fusing point: 153-156 ℃.

MS (electrospray):C ₂₄H ₂₆FN ₇O ₄Be 496 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.29(s，3H)；2.48(bm，2H)；2.63(bm，2H)；3.27(dd，1H)；3.47(bq，2H)；3.51(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.37(bm，1H)；4.86(d，2H)；4.89(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；7.99(d，1H)；8.05(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 20:2-[{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] first Base } (methyl) amino] ethanol

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridine (intermediate 12,0.30g, 1.09mmol), 2-(methylamino) ethanol (0.9ml, 11.2mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and be warming to 110 ℃ and continue 3.5 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is dense thick yellow oil (335mg).

MS (electrospray):C ₁₂H ₁₆BrN ₃O ₂Be 315 (M+1).

Embodiment 11:(5R)-and 3-(3-fluoro-4-{6-[(5R)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ Azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

With 4-{[(5R)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } morpholine (intermediate 23,320mg, 0.98mmol), (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 (400mg, 1.03mmol), salt of wormwood (intermediate 7,450mg, (120mg 0.10mmol) is suspended in DMF (5ml) and the water (0.5ml) 3.26mmol) to close palladium (0) with four (triphenylphosphines).Mixture was 80 ℃ of heating 60 minutes, and cooling is also filtered.Solid acetonitrile rinsing, the filtrate of merging is adsorbed onto on the silica gel, and adsorbent is by column chromatography purifying (silica gel, the methyl alcohol in methylene dichloride of 1-10%).The pale solid that so obtains (430mg) is dissolved in hot dioxane (30ml), and (the dioxane solution of 4M, 0.25ml 1mmol) handle, and obtain suspension, and it filters and use ether rinse then with ether (50ml) dilution with HCl.So obtain the hydrochloride of title compound, be pale solid (400mg): fusing point: 239-245 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄Be 508 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.18(bm，2H)；3.37(dd，1H)；3.49(bm，3H)；3.77(m，4H)；3.96(m，3H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.32(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.02(d，1H)；8.09(d，1H)；8.18(s，1H)；8.81(s，1H)；10.55(bs，1H)。

Embodiment 11a:(5R)-(3-fluoro-4-{6-{ (5R)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different for 3- _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2- Ketone, hydrochloride

With (5R)-3-(3-fluoro-4-{6-[(5R)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 11 for 3-_ azoles alkane-2-ketone, 430mg 0.85mmol) is dissolved in hot dioxane (30ml) also with HCl (the dioxane solution of 4M, 0.25ml, 1mmol) handle, obtain suspension, it filters and uses ether rinse then with ether (50ml) dilution.So obtain title compound, be pale solid (400mg): fusing point: 239-245 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₄Be 508 (M+1)

Intermediate 21:[(5R)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl alcohol

With (R, S)-[3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] (the hydrolysis preparation by intermediate 9 3.1g) is dissolved in hot methanol (25ml) to methyl alcohol, separate (Chiral PakAS), the Virahol wash-out in hexane by chiral column then with 30%.Wash-out lower banner compound [(-) isomer, 1.5g)] from the post at first, (second peak 1.18g) is collected together with (+) isomer for it.There is (+) isomer of＜2% in chirality HPLC analysis revealed.

[α] _D=-125 ° (c=0.0076g/ml is in methyl alcohol).

Alternative method for providing of intermediate 21

With racemic [3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methylbutyrate (intermediate 9,140mg 0.43mmol) is dissolved in the acetone (10ml), and adds 0.1M potassium phosphate buffer (pH～7) (10ml) obtain glassy yellow solution under vigorous stirring.Add PS-lipase (2mg, Sigma catalog number (Cat.No.) L-9156), mixture leniently stirred 5 hours at ambient temperature, and the HPLC analysis revealed has 40% transformation efficiency at that time.Solution with water is diluted to 40ml and (3 * 40ml) extract, and the organic phase of merging is also evaporated with dried over sodium sulfate with ethyl acetate.Resistates and 3: 1 hexanes: (2 * 20ml) grindings obtain title compound to ether, are white powder (35mg).There is (+) isomer of＜0.5% in chirality HPLC analysis revealed.

[α] _D=-140 ° (c=0.01g/ml is in methyl alcohol).

Intermediate 22:5-bromo-2-[(5R)-and 5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine

Will [(5R)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] (intermediate 21,0.274g 1.06mmol) are dissolved in the methylene dichloride in (5ml) methyl alcohol.Add triphenylphosphine (0.8g, 3.05mmol) and tetracol phenixin (0.6ml, 6.2mmol), mixture was stirring at room 2 hours.Add methyl alcohol (0.5ml), solution is white solid (280mg) through concentrating and obtaining title compound by hurried chromatography purification (silica gel, the ethyl acetate in hexane of 5-20%).

Intermediate 23:4-{[(5R)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } Morpholine

With 5-bromo-2-[(5R)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 22,0.276g, 1.0mmol), morpholine (0.9ml, 10.3mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (0.9ml) mix and be warming to 115 ℃ and continue 4 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (320mg).

MS (electrospray):C ₁₃H ₁₆BrN ₃O ₂Be 327 (M+1)

Embodiment 12:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(tetramethyleneimine-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

With 5-bromo-2-[(5S)-5-(tetramethyleneimine-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridine (intermediate 24,305mg, 0.98mmol), (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 7,380mg, 0.98mmol), salt of wormwood (400mg, 2.9mmol) and four (triphenylphosphines) close palladium (0) (114mg 0.099mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 40 minutes, and cooling is filtered and is adsorbed onto on the silica gel.Adsorbent is by column chromatography purifying [silica gel, (1-10% methyl alcohol, 0.025-0.5% triethylamine) is in methylene dichloride].So the material that obtains is dissolved in the methylene dichloride (10ml) and with ether (20ml) dilution, filters and use ether rinse then, obtains the free alkali (200mg) of title compound.This material is dissolved in methyl alcohol: in the methylene dichloride (1: 5), (the dioxane solution of 4M, 0.1ml), the suspension that obtains obtains throw out with the ether dilution to add HCl.The collection solid is used ether rinse, uses the ethyl acetate rinsing then, and vacuum-drying, obtains the hydrochloride of title compound, is pale solid (170mg): fusing point: 260-263 ℃.

MS (electrospray):C ₂₅H ₂₆FN ₇O ₃Be 492 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：1.90(bm，2H)；2.02(bm，2H)；3.10(bm，2H)；3.36(dd，1H)；3.49(bm，2H)；3.61(bm，2H)；3.74(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.19(m，2H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.02(d，1H)；8.09(d，1H)；8.18(s，1H)；8.85(s，1H)；9.93(bs，1H)。

Intermediate 24:5-bromo-2-[(5S)-and 5-(tetramethyleneimine-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] Pyridine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), tetramethyleneimine (1ml, 12mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and are warming to 85 ℃ and continue 16 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (305mg).

MS (electrospray):C ₁₃H ₁₆BrN ₃O is 311 (M+1).

Embodiment 13:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(piperidines-1-ylmethyl)-4, the 5-dihydro is different _ Azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

With 5-bromo-2-[(5S)-5-(piperidines-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridine (intermediate 25,325mg, 1.0mmol), (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 7,380mg, 0.98mmol), salt of wormwood (400mg, 2.9mmol) and four (triphenylphosphines) close palladium (0) (114mg 0.099mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 40 minutes, and cooling is filtered and is adsorbed onto on the silica gel.Adsorbent is by column chromatography purifying [silica gel, (1-10% methyl alcohol contains the 0.025-0.5% triethylamine) is in methylene dichloride].So the material that obtains is dissolved in the methylene dichloride (10ml) and with ether (20ml) dilution, filters and use ether rinse then, obtains the free alkali (200mg) of title compound.This material is dissolved in methyl alcohol: in the methylene dichloride (1: 5), (the dioxane solution of 4M 0.16ml), obtains throw out with the ether dilution then to add HCl.Collect solid, use ether rinse, use ethyl acetate rinsing and vacuum-drying then, obtain the hydrochloride of title compound, be pale solid (260mg): fusing point: 211-215 ℃.

MS (electrospray):C ₂₆H ₂₈FN ₇O ₃Be 506 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：1.17(t，2H)；1.65-1.87(bm，4H)；2.99(bm，1H)；3.08(m，1H)；3.36(dd，1H)；3.41(bt，1H)；3.51(bd，1H)；3.75(dd，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.30(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.02(d，1H)；8.09(d，1H)；8.18(s，1H)；8.85(s，1H)；9.83(bs，1H)。

Intermediate 25:5-bromo-2-[(5S)-and 5-(piperidines-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] Pyridine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), piperidines (1ml, 10.1mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and be warming to 85 ℃ and continue 16 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (325mg).

MS (electrospray):C ₁₄H ₁₈BrN ₃O is 325 (M+1)

Embodiment 14:(5R)-and 3-(4-{6-[(5S)-5-(3,6-dihydropyridine-1 (2H)-ylmethyl)-4,5- Dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3- _ azoles alkane-2-ketone

With 5-bromo-2-[(5S)-5-(3,6-dihydropyridine-1 (2H)-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridine (intermediate 26,330mg, 1.02mmol), (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 7,380mg, 0.98mmol), salt of wormwood (400mg, 2.9mmol) and four (triphenylphosphines) close palladium (0), and (114mg 0.099mmol) is suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 40 minutes, and cooling is filtered and is adsorbed onto on the silica gel.Adsorbent is by column chromatography purifying [silica gel, (1-10% methyl alcohol, 0.025-0.5% triethylamine) is in methylene dichloride].So the material that obtains is dissolved in the methylene dichloride (10ml) and with ether (20ml) dilution, filters and use ether rinse then, obtains the free alkali (200mg) of title compound.This material is dissolved in methyl alcohol: in the methylene dichloride (1: 5), (the dioxane solution of 4M 0.13ml), with the ether dilution, obtains throw out then to add HCl.Collect solid, use ether rinse, use ethyl acetate rinsing and vacuum-drying then, obtain the hydrochloride of title compound, be pale solid (230mg): fusing point: 250-255 ℃.

MS (electrospray):C ₂₆H ₂₆FN ₇O ₃Be 504 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.22(bm，1H)；3.34-3.62(m，6H)；3.74(bm，1H)；3.76(dd，1H)；3.88(bm，1H)；3.96(dd，1H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.31(m，1H)；5.74(m，1H)；5.93(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.02(d，1H)；8.10(d，1H)；8.18(s，1H)；8.85(s，1H)；10.11(bs，1H)。

Intermediate 26:5-bromo-2-[(5S)-and 5-(3,6-dihydropyridine-1 (2H)-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,0.30g, 1.09mmol), 1,2,3, the 6-tetrahydropyridine (1ml, 10.9mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (1ml) mix and be warming to 90 ℃ and continue 16 hours.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer that merges obtains rough title compound with dried over sodium sulfate and evaporation, is wax shape yellow solid (330mg).

MS (electrospray):C ₁₄H ₁₆BrN ₃O is 323 (M+1).

Embodiment 15:{[(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 } ammonia Base formic acid tertiary butyl ester

With { [3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } carboxylamine tertiary butyl ester (intermediate 30,408mg, 1.1mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (intermediate 7,427mg, 1.1mmol), salt of wormwood (456mg, 3.3mmol) and four (triphenylphosphines) close palladium (0) (64mg 0.06mmol) be suspended in DMF (7.2ml) and the water (0.72ml).Mixture heated 1 hour at 85 ℃ under nitrogen.Reaction mixture is through filtering, then by column chromatography purifying (silica gel, the acetonitrile in ethyl acetate of 100% ethyl acetate to 50%).So obtain title compound, be yellow crystal solid (227mg): fusing point: 228-230 ℃.

MS (electrospray):C ₂₆H ₂₈FN ₇O ₅Be 536 (M+1)

¹H-NMR(300MHz，DMSO-d ₆)δ：1.37(s，9H)；3.09-3.33(m，2H)；3.33(m，2H)3.45-3.55(m，1H)；3.91-3.96(m，1H)；4.264-4.32(m，1H)；4.71-4.83(m，1H)4.84-4.87(m，2H)；5.14-5.22(m，1H)；7.40-7.42(dd，1H)；7.56-7.60(dd，1H)；7.66-7.72(m，1H)；7.77(s，1H)；7.98-8.00(d，1H)；8.04-8.07(d，1H)；8.18(s，1H)；8.81(s，1H)。

Intermediate 27: methylsulfonic acid [(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] first Ester

Add [(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl alcohol (intermediate 11,3g, 11.7mmol) in anhydrous methylene chloride (15ml), add then triethylamine (2.27ml, 16.3mmol).Solution is cooled to 0 ℃, drip then methylsulfonyl chloride (1.08ml, 1.4mmol).Be reflected at 0 ℃ and stirred 2 hours, add sodium bicarbonate aqueous solution (20ml) then.(after 2 * 20ml) the further extractions, merging organic layer,, obtaining required product (4.8g) with methylene dichloride with dried over sodium sulfate and vacuum concentration.

¹H-NMR(DMSO-d ₆)δ：3.08(s，3H)；3.27(dd，1H)；3.47(dd，1H)；4.37(m，2H)；5.02(m，1H)；7.53(m，4H)。

Intermediate 28:2-[(5S)-and 5-(azido methyl)-4, the 5-dihydro is different _ azoles-3-yl]-the 5-bromopyridine

Add methylsulfonic acid [(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl esters (intermediate 27,1.5g, 4.6mmol) in dimethyl formamide (8ml), add then sodiumazide (0.6g, 9.0mmol).Mixture heating up to 75 ℃ continues 6 hours, is added to then in the sodium chloride aqueous solution (10ml), and (3 * 20ml) extract to use ethyl acetate then.Merge organic layer,, obtain required product (1.1g) with dried over sodium sulfate and vacuum concentration.

¹H-NMR(DMSO-d ₆)δ：3.25(dd，1H)；3.53(dd，1H)；3.61(m，2H)；4.96(m，1H)；7.65(d，2H)；7.71(d，2H)。

Intermediate 29:{[5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } amine

With 2-[(5S)-5-(azido methyl)-4, the 5-dihydro is different _ azoles-3-yl]-5-bromopyridine (intermediate 28,2g, 7.1mmol) be dissolved in methylene dichloride: methyl alcohol: in the water 3.5: 2: 1 (13ml), add the polystyrene resin that is combined with triphenylphosphine (the Argonaut Technologies of 8 grams then, Inc.Foster City, CA USA) (1.6mmol/g).Mixture is in stirring at room 16 hours and filtration.Resin washs with methylene dichloride (20ml) and methyl alcohol (10ml), and the vacuum concentration solvent obtains required product (1.45g) then.

¹H-NMR(DMSO-d ₆)δ：3.75(m，2H)；3.25(dd，1H)；3.44(dd，1H)；4.69(m，1H)；7.62(d，2H)；7.68(d，2H)。

Intermediate 30:{[3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } amino first The acid tertiary butyl ester

Will [(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } (400mg 1.56mmol) is dissolved in (4ml) in the methylene dichloride to amine.Add saturated sodium bicarbonate aqueous solution (4ml) in the reaction mixture that stirs, add then two carbonic acid, two-tertiary butyl ester (1g, 4.59mmol).Reaction mixture was stirring at room 16 hours.Adding methylene dichloride separates with water and with layer.The dichloromethane layer dried over sodium sulfate, evaporation is also passed through chromatography purification (silica gel, the ethyl acetate in hexane of 10-50%).Evaporation contains the fraction and the vacuum-drying of product, obtains title compound (408mg).

MS (electrospray):C ₁₄H ₁₈BrN ₃O ₃Be 301 (M+1).

Reference example 16:(5R)-and 3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] Pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone

Will [(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] and methyl } carboxylamine tertiary butyl ester (intermediate 15,150mg 0.29mmol) is dissolved in DMF/ dioxane (5ml), slowly adds the dioxane solution (2.4ml) of 4M HCl then and stirs 18 hours.Use acetonitrile/ether to make the product precipitation, and under nitrogen, filter.Use ether to grind yellow solid.So obtain title compound, be yellow crystal solid (120mg): fusing point: 11-9122 ℃.

MS (electrospray):C ₂₁H ₂₀FN ₇O ₃Be 438.2 (M+1)

¹H-NMR(300MHz，DMSO-d ₆)δ：2.91-3.32(m，2H)；3.33-3.45(m，1H)；3.56-3.71(m，2H)；4.26-4.32(m，1H)；4.84-4.87(m，2H)；5.06(m，1H)；5.14-5.22(m，1H)；7.40-7.42(dd，1H)；7.56-7.60(dd，1H)；7.66-7.72(m，1H)；7.77(s，1H)；7.95-8.01(d，1H)；8.04-8.07(d，1H)；8.36(s，1H)；8.85(s，1H)。

Embodiment 17:N ¹-{ [(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 }-N ², N ²-dimethyl glycyl amide hydrochloride

With N ¹-[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl }-N ², N ²-dimethyl G-NH2 (intermediate 31,450mg, 1.3mmol), (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 7,512mg, 1.3mmol), salt of wormwood (539mg, 3.9mmol) and four (triphenylphosphines) close palladium (0), and (65mg 0.05mmol) is suspended in DMF (8.1ml) and the water (0.81ml).Mixture heated 1 hour at 85 ℃ under nitrogen.After reaction is finished, with mixture cool to room temperature and filtration.The filter cake methanol wash.Concentrated filtrate also passes through column chromatography purifying (silica gel, the methyl alcohol in ethyl acetate of 100% ethyl acetate to 30%), obtains N ¹-{ [(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 }-N ², N ²-dimethyl G-NH2 (0.435g).

(0.250g 0.5mmol) is dissolved in DMF (3ml), methyl alcohol (10ml) methylene dichloride (5ml) and the acetonitrile (10ml), and (0.15ml is 0.6mmol) and stirring at room 25 minutes to add the dioxane solution of 4M HCl then with this material.Add ether (30ml) in reaction mixture.Filter from the solid process that ether sedimentation forms, obtain title compound, be hydrochloride, fusing point: 202-204 ℃.

MS (electrospray):C ₂₅H ₂₇FN ₈O ₄Be 523 (M+1)

¹H-NMR(300MHz，DMSO-d6)2.43-2.55(m，6H)；3.21-3.35(m，1H)；3.36-3.48(m，2H)；3.51-3.68(m，1H)；4.22(m，2H)，4.30-4.33(m.2H)，4.86(s，2H)；5.14-5.24(m，1H)；7.42-7.44(dd，1H)；7.57-7.62(dd，1H)；7.67-7.72(m，1H)；7.78(s，1H)；7.98-8.01(d，1H)；8.05-8.08(d，1H)；8.19(s，1H)；8.82(s，1H)；9.78-9.89(s，1H)。

Intermediate 31:N ¹-[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl }-N ², N ²-dimethyl G-NH2

Under nitrogen will [(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl (intermediate 29,410mg 1.6mmol) are dissolved in the dry DMF (5ml) amine.(0.836ml is 4.8mmol) in reaction mixture and in stirring at room to add diisopropyl ethyl amine.In independent flask, (670mg 1.8mmol) is dissolved in the dry DMF (2ml) with HATU.(165mg is 1.6mmol) in the reaction mixture that contains HATU and stirred 20 minutes to add N-methylsarcosine.The mixture that slowly adds amine and diisopropyl ethyl amine is in the mixture of HATU and N-methylsarcosine.Reaction mixture under nitrogen stirring at room 18 hours.Use methylene dichloride and water to the reactant aftertreatment.Organic layer washs with saturated sodium-chloride, uses dried over sodium sulfate, and evaporation is also passed through chromatography purification (silica gel, the methyl alcohol in ethyl acetate of 1-20%).Fraction and vacuum-drying that evaporation contains product obtain title compound, are solid (450mg).

MS (electrospray):C ₉H ₁₀BrN ₃O is 341.0 (M+1).

Embodiment 18:N-{[(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 5-dihydro is different _ azoles-5-yl] methyl }- The sarcosine tertiary butyl ester

With N-{[(5S)-3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl }-sarcosine tertiary butyl ester (intermediate 32,275mg, 0.72mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (intermediate 7,340mg, 0.88mmol), salt of wormwood (300mg, 2.2mmol) and four (triphenylphosphines) close palladium (0) (88mg 0.076mmol) be suspended in DMF (5ml) and the water (0.5ml).Mixture was 80 ℃ of heating 1 hour, and cooling is filtered and is adsorbed onto on the silica gel.Adsorbent is by column chromatography purifying (silica gel, the methyl alcohol in methylene dichloride of 0.5-5%), so the material that obtains is dissolved in hot methanol (3ml) and dilutes with ether (10ml), filter then and obtain title compound, be pale solid (254mg): fusing point: 180 ℃ with ether rinse.

MS (electrospray):For C ₂₈H ₃₂FN ₇O ₅Be 566 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：1.43(s，9H)；3.34(bm，6H)；3.59(bs，1H)；3.96(dd，1H)；4.29(t，1H)；4.86(d，2H)；5.19(m，2H)；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)。

Intermediate 32:N-{[(5S)-and 3-(5-bromopyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] first Base }-the sarcosine tertiary butyl ester

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridine (intermediate 12,0.40g, 1.45mmol), sarcosine tert-butyl ester hydrochloride (1.3g, 7.14mmol), diisopropyl ethyl amine (2.6ml, 14.9mmol), tetrabutylammonium iodide (2mg, catalytic amount) and DMSO (3ml) mix and be warming to 105 ℃ and continue 2 days.Solution with water dilution and with twice of ethyl acetate extraction.The organic layer dried over sodium sulfate that merges, evaporation is also passed through chromatography purification (silica gel, the ethyl acetate in hexane of 10-50%) and is obtained title compound, is dense thick oily matter (275mg).

MS (electrospray):C ₁₆H ₂₂BrN ₃O ₃Be 385 (M+1).

Embodiment 19:N-{[(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 5-dihydro is different _ azoles-5-yl] methyl }- Sarcosine

With N-{[(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] and methyl }-(embodiment 18 for the sarcosine tertiary butyl ester, 210mg 0.37mmol) is dissolved in acetate (6ml), Virahol (2ml) and the water (0.5ml).In this solution, add HCl (the dioxane solution of 4M, 1ml, 4mmol).Solution obtains the oily throw out stirring at room 2 hours.(0.5ml 6mmol) obtains clear solution, and it spends the night at the room temperature restir, obtains the oily throw out again to add dense HCl.Mixture is continued 3 hours 80 ℃ warm (obtaining clear solution), concentrate then and obtain dense thick yellow oil.In oily matter water-soluble (5ml), and by disposable C18 silica gel (2g) extraction column, further water, use the acetonitrile/water wash-out then.The elutriant that merges obtains yellow residue through concentrating, and it is from alcohol crystal.The solid that collection obtains with cold ethanol and ether rinse, obtains title compound 50 ℃ of vacuum-dryings then, is pale solid (155mg): fusing point: 212-218 ℃.

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

¹H-NMR(400MHz，DMSO-d ₆)δ：2.92(s，3H)；3.37(dd，1H)；3.47(bm，2H)；3.73(dd，1H)；3.96(dd，1H)；4.12(bm，2H)；4.30(t，1H)；4.86(d，2H)；5.19(m，1H)；5.26(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.69(t，1H)；7.76(s，1H)；8.01(d，1H)；8.09(d，1H)；8.18(s，1H)；8.84(s，1H)。

Embodiment 20:N-{[(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 5-dihydro is different _ azoles-5-yl] methyl }- L-prolineamide hydrochloride

Under nitrogen under agitation with (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,300mg 0.69mmol) is dissolved in the dry DMF (5ml).Add HATU (286mg, 0.75mmol) to reaction mixture, add then the BOC-L-proline(Pro) (147mg, 0.69mmol).(358ml 2.03mmol), and was reflected at stirring at room 2 hours to add diisopropyl ethyl amine.After reaction is finished, the white depositions that filtration forms in reaction process, obtain (2S)-2-[({[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } amino) carbonyl] tetramethyleneimine-1-carboxylic acid tertiary butyl ester (153mg detects purity for＞90% by LCMS).Filtrate is by chromatography purification (silica gel; The methanol-eluted fractions in ethyl acetate of the methyl alcohol to 45% in ethyl acetate of use 10%), obtain more (2S)-2-[({[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } amino) carbonyl] tetramethyleneimine-1-carboxylic acid tertiary butyl ester, be white solid (106mg), and in the interpolation precipitated solid, obtain 259mg, 0.41mmol.Solid is dissolved in DMF (1ml), has added the dioxane solution (4ml) of 4M HCl among the DMF.Reaction mixture is heated to 60 ℃ then and continues 1 hour stirring at room 18 hours, monitors by HPLC simultaneously.With the reaction mixture cool to room temperature, and use acetonitrile that product is precipitated out.Solid is yellow solid (100mg) through filtering and with the ether washing, after 32 hours, obtaining title product 40 ℃ of vacuum-dryings.

Fusing point: 246-249 ℃.

MS (electrospray):C ₂₆H ₂₇FN ₈O ₄Be 535.5 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：(1.58-1.80m，1H)；2.25(m，1H)；3.18-3.29(m，1H)；3.14-3.57(m，6H)；3.98(m，1H)，4.14(m，1H)，4.22(m，2H)，4.26-4.33(m.2H)，4.86(s，2H)；5.17-5.20(m，1H)；7.42-7.44(dd，1H)；7.57-7.72(m，1H)；7.76(s，1H)；7.98-8.08(m，1H)；8.19(s，1H)；8.43-8.59(m，1H)；8.82(m，2H)；9.77(s，1H)。

Embodiment 21:N ¹-{ [(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 }-D-valine amide hydrochloride

Under nitrogen under agitation with (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,300mg 0.69mmol) is dissolved in the dry DMF (5ml).Add HATU (286mg, 0.75mmol) in reaction mixture, add then the BOC-D-Xie Ansuan (150mg, 0.69mmol).(358ml 2.03mmol), will be reflected at stirring at room 2 hours to add diisopropyl ethyl amine.After reaction was finished, reaction mixture was by chromatography purification (silica gel; The methanol-eluted fractions in ethyl acetate of the methyl alcohol to 45% in ethyl acetate with 10%) obtain (1R)-1-[({[(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] and methyl } amino) carbonyl]-the 2-methyl-propyl } the carboxylamine tertiary butyl ester, for white solid (221mg, 0.35mmol).Solid is dissolved in DMF (1ml), has added the dioxane solution (4ml) of 4M HCl among the DMF.Reaction mixture is heated to 60 ℃ then and continues 1 hour stirring at room 18 hours, monitors by HPLC simultaneously.With the reaction mixture cool to room temperature, and use acetonitrile that product is precipitated out.Solid is yellow solid (132mg) through filtering and with the ether washing, after 32 hours, obtaining title product 40 ℃ of vacuum-dryings.

Fusing point: 130-134 ℃

MS (electrospray):C ₂₆H ₂₉FN ₈O ₄Be 537.6 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：0.93(m，6H)；2.07(m，1H)；2.25(m，1H)，2.71(s，1H)；2.85(s，1H)；3.23-3.45(m，1H)；3.45-3.60(m，1H)，3.98-3.98(m，1H)，4.22(m，2H)，4.26-4.33(m.2H)，4.86(s，2H)；5.17-5.20(m，1H)；7.42-7.44(dd，1H)；7.57-7.72(m，1H)；7.76(s，1H)；7.98-8.08(m，1H)；8.19(s，1H)；8.43-8.59(m，1H)；8.82(m，2H)。

Embodiment 22:N ¹-{ [(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 }-L-alanimamides hydrochloride

Under nitrogen under agitation with (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,300mg 0.69mmol) is dissolved in dry DMF (5ml).Add HATU (286mg, 0.75mmol) to reaction mixture, add then the BOC-L-L-Ala (130mg, 0.69mmol).(358ml 2.03mmol), will be reflected at stirring at room 2 hours to add diisopropyl ethyl amine.After reaction was finished, reaction mixture was by chromatography purification (silica gel; The methanol-eluted fractions in ethyl acetate of the methyl alcohol to 45% in ethyl acetate of use 10%) obtain [(1S)-2-([(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } amino)-1-methyl-2-oxoethyl] the carboxylamine tertiary butyl ester, for white solid (351mg, 0.58mmol).This solid is dissolved in DMF (1ml), has added the dioxane solution (4ml) of 4M HCl among the DMF.Reaction mixture is heated to 60 ℃ then and continues 1 hour stirring at room 18 hours, monitors by HPLC simultaneously.The reaction mixture cool to room temperature uses acetonitrile that product is precipitated out.Solid is yellow solid (163mg) through filtering and with the ether washing, after 32 hours, obtaining title compound 40 ℃ of vacuum-dryings.

Fusing point: 242-244 ℃

MS (electrospray):C ₂₄H ₂₅FN ₈O ₄Be 509.5 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：1.21(m.3H)；3.23-3.45(m，1H)；3.45-3.60(m，1H)，3.98-3.98(m，1H)，4.22(m，2H)，4.26-4.33(m.2H)，4.86(s，2H)；5.17-5.20(m，1H)；7.42-7.44(dd，1H)；7.57-7.72(m，1H)；7.76(s，1H)；7.98-8.08(m，1H)；8.19(s，1H)；8.43-8.59(m，1H)；8.82(m，2H)。

Embodiment 23:N ¹-{ [(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 }-N ¹, N ², N ²-trimethylammonium G-NH2

(285mg 0.75mmol) is dissolved in the dry DMF (5ml) with HATU.(103mg, 1mmol), and stirred suspension obtained clear solution in 60 minutes to add N-methylsarcosine.Add (5R)-3-[3-fluoro-4-(6-{ (5S)-5-[(methylamino) methyl]-4, the 5-dihydro is different _ azoles-3-yl } and pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone, (embodiment 2,0.225g, 0.50mmol) and diisopropyl ethyl amine (0.3ml, 1.73mmol), with reaction mixture stirring at room 3.5 hours.Reactant directly is adsorbed onto on the silica gel also by chromatography purification (silica gel, 0.5% methyl alcohol/0.05% triethylamine is to 10% methyl alcohol/1% triethylamine, in methylene dichloride).Fraction and vacuum-drying that evaporation contains product obtain crude product resistates (160mg).This material of a part (50mg) is further passed through preparation reversed-phase HPLC purifying (C18,5-95% acetonitrile/water contain 0.1% trifluoroacetic acid).Evaporation contains the fraction of product, is dissolved in the methyl alcohol (5ml), and (the dioxane solution of 0.2M, 0.6ml 0.12mmol) handle and concentrate with HCl.Sample is dissolved in methylene chloride, with the ethylacetate/ether dilution, obtains throw out then.The collecting precipitation thing with ether rinse and vacuum-drying, obtains the hydrochloride of title compound, is pale solid (27mg) fusing point: 122-132 ℃.

MS (electrospray):C ₂₆H ₂₉FN ₈O ₄Be 537 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：2.80(m，6H)；3.02(s，3H)；3.27(dd，1H)；3.52-3.68(m，4H)；3.96(dd，1H)；4.30(m，2H)；4.86(d，2H)；4.99(m，1H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.68(t，1H)；7.76(s，1H)；8.01(d，1H)；8.07(d，1H)；8.18(s，1H)；8.82(s，1H)；9.57(bs，1H)。

Embodiment 24:N-{2-[{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-hydrogen generation-5-(1H-1,2,3-triazole -1-ylmethyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] first Base } (methyl) amino]-the 2-oxoethyl }-sarcosine

With N-{2-[{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } (methyl) amino]-the 2-oxoethyl }-sarcosine tertiary butyl ester (intermediate 33,70mg) be dissolved in the trifluoroacetic acid (5ml), be warming to 55 ℃ then and continue 1 hour.Solution concentration to doing, is dissolved in methyl alcohol (1ml), adds ether (15ml) then, the suspension that obtains carries out supersound process.Collect solid,, obtain title compound, be pale solid (55mg) with ether rinse and vacuum-drying.

Fusing point 135-145 ℃

MS (electrospray):C ₂₇H ₂₉FN ₈O ₆Be 581 (MH ⁺)

¹H-NMR (400MHz, DMSO-d ₆) δ: 2.79 (bs, 3H); 2.99 and 3.03 (2xs, 3H); 3.19-3.33 (m, 2H); 3.52-3.69 (m, 3H); 3.94 (m, 3H); 4.21 (bs, 1H); 4.29 (t, 1H); 4.86 (d, 2H); 4.95-5.08 (m, 1H); 5.19 (m, 1H); 7.42 (d, 1H); 7.58 (d, 1H); 7.68 (t, 1H); 7.76 (s, 1H); 8.02 (t, 1H); 8.07 (m, 1H); 8.18 (s, 1H); 8.82 (2xs, 1H).

Intermediate 33:N-{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 5-dihydro is different _ azoles-5-yl] first Base } (methyl) amino]-the 2-oxoethyl }-the sarcosine tertiary butyl ester

With (5R)-3-[3-fluoro-4-(6-{ (5S)-5-[(methylamino) methyl]-4, the 5-dihydro is different _ azoles-3-yl } and pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 2 for 3-_ azoles alkane-2-ketone, 0.198g, 0.44mmol), N-(2-tert.-butoxy-2-oxoethyl)-sarcosine sodium salt (intermediate 33A, 0.200g, 0.89mmol), N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (0.200g, 1.04mmol), 4-dimethylaminopyridine (5mg, catalytic amount) and DMF (5ml) mixing obtain suspension.Mixture, washes with water with the ethyl acetate dilution stirring at room 2 hours, uses the salt water washing then, with dried over sodium sulfate and evaporation.Material is by column chromatography purifying (silica gel; 0.5-5%MeOH is in methylene dichloride) obtain title compound, be dense thick oily matter (70mg).

MS (electrospray):C ₃₁H ₃₇FN ₈O ₆Be 637 (MH ⁺).

Intermediate 33A:N-(2-tert.-butoxy-2-oxoethyl)-sarcosine sodium salt

(3.2g, 20.7mmol) (3.6ml 20.7mmol) mixes and is cooled to 0 ℃ with DMF (10ml) and diisopropyl ethyl amine with hydrochloride ethyl sarcosnate.(3ml 20.3mmol), obtains suspension behind 0 ℃ of stirring several minutes to add the bromoacetic acid tertiary butyl ester.After 20 minutes, remove cooling bath, mixture is stirring at room 1 hour, then with the saturated sodium bicarbonate dilution and use ethyl acetate extraction.Organic layer obtains rough N-(2-tert.-butoxy-2-oxoethyl)-sarcosine ethyl ester with dried over sodium sulfate and evaporation, is transparent light yellow liquid (2.76g).(1.08g 4.67mmol) is dissolved in ethanol (6ml) with rough ethyl ester.(5M, 1ml 5mmol), stirring at room 1 day, obtain suspension with mixture to add aqueous sodium hydroxide solution.Collect solid and vacuum-drying and obtain title compound, be white solid (260mg).

¹H-NMR(400MHz，CD ₃OD)δ：1.44(s，9H)；2.39(s，3H)；3.14(s，2H)；3.57(s，2H)。

Embodiment 25:N-[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 5-dihydro is different _ azoles-5-yl] first Base } amino)-the 2-oxoethyl] glycine

With N-(tert-butoxycarbonyl)-N-[2-([(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] and methyl } amino)-the 2-oxoethyl] glycine tertiary butyl ester (intermediate 34,157mg 0.22mmol) is dissolved in trifluoroacetic acid (8ml), is warming to 45 ℃ and lasting 1 hour then.Solution concentration is to doing, with resistates water-soluble (1ml).Product solution filters (the anti-phase silicon-dioxide of 2g C18, the 0-100% acetonitrile is in water), evaporation of eluate by short column.Add ethyl acetate (5ml) in resistates, supersound process obtains suspension then.Collect solid, obtain title compound, be pale solid (110mg) with ether rinse and vacuum-drying.

Fusing point 200-210 ℃

MS (electrospray):C ₂₅H ₂₅FN ₈O ₆Be 553 (MH ⁺)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.26(dd，1H)；3.43(m，2H)；3.55(dd，1H)；3.72(s，2H)；3.80(s，2H)；3.96(dd，1H)；4.29(t，1H)；4.84(m，2H)；4.86(d，2H)；5.19(m，1H)；7.42(dd，1H)；7.59(dd，1H)；7.68(t，1H)；7.76(s，1H)；8.00(d，1H)；8.07(d，1H)；8.18(s，1H)；8.70(t，1H)；8.82(s，1H)。

Intermediate 34:N-(tert-butoxycarbonyl)-N-[2-([(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxygen Generation-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4,5-two Hydrogen is different _ azoles-5-yl] and methyl } amino)-the 2-oxoethyl] the glycine tertiary butyl ester

With N-(tert-butoxycarbonyl)-N-(2-tert.-butoxy-2-oxoethyl) glycine [Tetrahedron Letters 1998,39,253] (250mg, 0.90mmol), (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,197mg, 0.45mmol), N-[3-(dimethylamino) propyl group]-N '-ethyl-carbodiimide hydrochloride (180mg, 0.94mmol), 4-dimethylaminopyridine (5mg, catalytic amount) and DMF (4ml) mix and were incorporated in stirring at room 30 minutes.Mixture dilutes with ethyl acetate, washes with water, then with the saturated sodium-chloride washing, with dried over sodium sulfate and evaporation.Described material is by column chromatography purifying (silica gel; 0.5-4%MeOH is in methylene dichloride) obtain rough title compound, be light yellow solid (157mg).

MS (electrospray):C ₃₄H ₄₁FN ₈O ₈Be 709 (MH ⁺).

Embodiment 26:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(1H-imidazoles-1-ylmethyl)-4, the 5-dihydro Different _ azoles-the 3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2- Ketone

With 5-bromo-2-[(5S)-5-(1H-imidazoles-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridine (intermediate 35,100mg, 0.33mmoles), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) phenyl]-[(1H-1,2, the 3-triazol-1-yl) methyl] _ azoles alkane-2-ketone (126mg, 0.33mmol), salt of wormwood (137mg, 1mmol) and four (triphenylphosphines) close palladium (0) (19mg, 0.017mmol) in DMF (1.8ml) and distilled water (0.18ml), mix, be heated to 80 ℃ then and continue 30 minutes.Reaction mixture directly is adsorbed onto on the silica gel, then by column chromatography purifying (silica gel; 0-50%MeOH is in methylene dichloride) obtain title compound, be pale solid (70mg). fusing point: 239-242 ℃.

MS (electrospray): C ₂₄H ₂₁FN ₈O ₃Be 489 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：3.19-3.22(m，2H)；3.53-3.63(m，1H)，3.98-3.98(m，1H)，4.18-4.35(m.2H)，4.85(s，2H)；5.04-5.10(m，1H)；5.17-5.22(m，1H)；6.88(s，1H)；7.22(s，1H)；7.56-7.76(m，4H)；7.74(s，1H)；7.94-8.06(m，2H)；8.18(s，1H)；8.8(s，1H)。

Intermediate 35:5-bromo-2-[(5S)-and 5-(1H-imidazoles-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3- Base] pyridine

With 5-bromo-2-[(5S)-5-(chloromethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridine (intermediate 12,300mg, 1.09mmol) and imidazoles (700mg, 10.3mmol), salt of wormwood (300mg, 2.17mmol), tetrabutylammonium iodide (5mg, catalytic amount) and DMF (1ml) mix.Mixture stirred 3 days at 80 ℃, with the ethyl acetate dilution, washed with water, with dried over sodium sulfate and evaporation.This material obtains title compound by hurried chromatography purification (silica gel, the methyl alcohol in methylene dichloride of 0.5-5%), is white solid (105mg).

MS (electrospray):C ₁₂H ₁₁BrN ₄O is 308 (M+1)

¹H-NMR(400MHz，DMSO-d ₆)δ：3.18(dd，1H)；3.52(dd，1H)；4.20(dd，1H)；4.27(dd，1H)；5.06(m，1H)；6.86(s，1H)；7.20(s，1H)；7.63(s，1H)；7.81(d，1H)；8.12(dd，1H)；8.77(s，1H)。

Embodiment 26a:(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(1H-imidazoles-1-ylmethyl)-4, the 5-dihydro Different _ azoles-the 3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2- Keto hydrochloride

With (5R)-3-(3-fluoro-4-{6-[(5S)-5-(1H-imidazoles-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1, (embodiment 26 for 3-_ azoles alkane-2-ketone, 60mg 0.13mmol) is dissolved in DMF: dioxane (1ml: 2ml).Room temperature add 4M HCl dioxane solution (0.035ml, 0.14mmol).Filtering precipitate also obtains title compound with ether (1ml) washing, is pale solid hydrochloride (40mg).

MS (electrospray): C ₂₄H ₂₁FN ₈O ₃Be 489 (MH ⁺)

¹H-NMR(300MHz，DMSO-d6)δ：3.37-3.48(m，1H)；3.57(s，1H)，3.66-3.75(m，1H)，3.95-4.00(m，1H)；4.28-4.34(m.1H)，4.43-4.58(m，2H)；4.88(m，4H)；5.24(m，2H)；7.40-7.43(m，1H)；7.56-7.76(m，3H)；7.95-8.10(m，2H)；8.13(s，1H)；8.81(s，1H)。

Embodiment 27:N-[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 5-dihydro is different _ azoles-5-yl] first Base } amino)-the 2-oxoethyl]-sarcosine

With methyliminodiacetic acid (800mg 5.4mmol) is dissolved in DMF (10ml) and the water (1ml), adds N-[3-(dimethylamino) propyl group then]-N '-ethyl carbodiimide? HCl (140mg, 0.73mmol).In independent phial, under nitrogen under agitation with (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,200mg, 0.46mmol) be dissolved in DMF (5ml), add then diisopropyl ethyl amine (0.2ml, 1.6mmol).Add the amine reaction mixture in the oxalic acid reaction mixture.The mixture that obtains was stirring at room 1 hour.Reaction mixture dilutes with ethyl acetate/water.The ethyl acetate layer drying is concentrated into dried then.The oily matter that obtains by silicagel column purifying (with 100% methylene dichloride to 100% methanol-eluted fractions) (130mg).Solid is further by reverse phase preparative chromatography purifying (the C18-0%-95% acetonitrile contains 0.1% trifluoroacetic acid in water).After 24 hours, obtain title compound 40 ℃ of vacuum-dryings, be yellow solid (73mg).

Fusing point: 185-188 ℃

MS (electrospray): C ₂₆H ₂₇FN ₈O ₆Be 567 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：2.50(m，3H)；3.33-3.46(m，10H)；3.47-3.69(m，4H)，3.93-3.99(m，1H)；4.22-4.33(m，1H)；4.86-4.87(m，2H)；5.17-5.22(m，1H)；7.41-7.43(dd，1H)；7.56-7.72(m，1H)；7.76(s，1H)；7.98-8.08(m，1H)；8.19(s，1H)；8.43(m，1H)；8.82(m，1H)。

Embodiment 28:N ¹-{ [(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 }-L-α-l-asparagine

With N ²-(tert-butoxycarbonyl)-N ¹-[(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] and methyl }-L-α-l-asparagine tertiary butyl ester (intermediate 36,371mg 0.52mmol) is dissolved in the trifluoroacetic acid (5ml) and stirring at room 1 hour.Solution concentration is dissolved in methyl alcohol (1ml) to doing, and adds ether (15ml) then.Collect solid, obtain title product, be pale solid (276mg) with ether rinse and vacuum-drying.

Fusing point 224-226 ℃

MS (electrospray): C ₂₅H ₂₅FN ₈O ₆Be 553 (M+1)

¹H-NMR(300MHz，DMSO-d6)δ：1.22-1.25(m，2H)；3.33-3.74(m，4H)；3.95(m，1H)，4.29(m，1H)；4.85(m，2H)；5.16(m，1H)；7.41-7.43(dd，1H)；7.54-7.74(m，2H)；7.76(s，1H)；7.98-8.08(m，3H)；8.19(s，1H)；8.32(m，1H)；8.82(m，1H)。

Intermediate 36:N ²-(tert-butoxycarbonyl)-N ¹-{ [(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 }-L-α-l-asparagine tertiary butyl ester

With (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,287mg, 0.66mmol), diisopropyl ethyl amine (0.345ml, 1.98mmol), the N-[(dimethylamino) (3H-[1,2,3] methylene radical triazolo [4,5-b] pyridin-3-yl oxygen base)]-N-methyl first ammonium hexafluorophosphate (300mg, 0.79mmol), N-tert-butoxycarbonyl-L-aspartic acid 4-tertiary butyl ester (190mg, 0.66mmol) and DMF (3ml) mix and to be incorporated in stirring at room 30 minutes.Reaction mixture is adsorbed onto on the silica gel also by silicagel column purifying (with the methanol-eluted fractions in methylene dichloride of 100% methylene dichloride to 10%).Obtain title product, after 24 hours, be yellow solid (371mg) 40 ℃ of vacuum-dryings.

MS (electrospray): C ₃₄H ₄₁FN ₈O ₈Be 709 (M+1).

Embodiment 29:N ¹-{ [(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 }-L-α-glutamine

With N ²-(tert-butoxycarbonyl)-N ¹-[(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] and methyl }-L-α-glutamine tertiary butyl ester (intermediate 37,500mg 0.69mmol) is dissolved in trifluoroacetic acid (5ml) and stirring at room 1 hour.Solution concentration is dissolved in methyl alcohol (1ml) to doing, and adds ether (15ml) then.Collect solid, obtain title product, be pale solid (276mg) with ether rinse and vacuum-drying.

Fusing point 215.0-217.0 ℃

MS (electrospray): C ₂₆H ₂₇FN ₈O ₆Be 567 (M+1)

¹H-NMR(300MHz，DMSO-d ₆)δ：1.22-1.25(m，3H)；3.33-3.74(m，8H)；3.95(m，1H)，4.29(m，1H)；4.85(m，3H)；5.16(m，1H)；7.41-7.43(dd，1H)；7.54-7.74(m，2H)；7.76(s，1H)；7.98-8.08(m，3H)；8.19(s，1H)；8.32(m，1H)；8.82(m，1H)。

Intermediate 37:N ²-(tert-butoxycarbonyl)-N ¹-{ [(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 }-L-α-glutamine tertiary butyl ester

With (5R)-3-(4-{6-[(5S)-5-(amino methyl)-4, the 5-dihydro is different _ azoles-3-yl] and pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone (reference example 16,287mg, 0.66mmol), diisopropyl ethyl amine (0.345ml, 1.98mmol), the N-[(dimethylamino) (3H-[1,2,3] methylene radical triazolo [4,5-b] pyridin-3-yl oxygen base)]-N-methyl first ammonium hexafluorophosphate (300mg, 0.79mmol), N-tert-butoxycarbonyl-L-glutamic acid gamma-tertiary butyl ester (200mg, 0.66mmol) and DMF (3ml) mix and to be incorporated in stirring at room 30 minutes.Reaction mixture is adsorbed onto on the silica gel also by silicagel column purifying (with the methanol-eluted fractions in methylene dichloride of 100% methylene dichloride to 10%).Obtaining title product (500mg), is yellow solid after 24 hours 40 ℃ of vacuum-dryings.

MS (electrospray): C ₃₅H ₄₃FN ₈O ₈Be 723 (M+1).

Claims

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

Wherein:

Perhaps, R ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether or part is undersaturated and optionally contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl;

Perhaps, R ⁶Or R ⁷Can form the saturated heterocyclic basic ring of 4,5 or 6 yuan carbon connection, it contains 1 or 2 heteroatoms that is independently selected from O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced by 1 or 2 (1-4C) alkyl;

Condition is R ⁴And R ⁵Not hydrogen simultaneously.

2. the compound or pharmaceutically acceptable salt thereof or the prodrug of formula (I):

Wherein:

Perhaps, R ⁶Or R ⁷Can form the saturated heterocyclic basic ring that 4,5 or 6 yuan of carbon connect, it contains 1 or 2 heteroatoms that is independently selected from O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced by 1 or 2 (1-4C) alkyl;

Condition is R ⁴And R ⁵Not hydrogen simultaneously.

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

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

5. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I), wherein R among the claim 1-4 ⁴And R ⁵Be independently selected from hydrogen, methyl, carboxymethyl ,-CH ₂C (O) OR ⁶,-CH ₂C (O) NR ⁶R ⁷, (2-4C) alkyl [optional by 1 or 2 be independently selected from hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, hydroxyl (2-4C) alkoxyl group, azido-, cyano group ,-C (O) OR ⁶,-OC (O) R ⁶, carboxyl ,-C (O) NR ⁶R ⁷,-S (O) ₂R ⁶,-S (O) ₂NR ⁶R ⁷,-NR ⁶R ⁷,-NHC (O) R ⁶With-NHS (O) ₂R ⁶Substituting group replace] ,-C (O) R ⁶With-C (O) CH ₂NR ⁶R ⁷

6. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I), wherein R among the claim 1-4 ⁴And R ⁵The nitrogen that is connected with them forms saturated altogether or part is undersaturated and optionally contain 1 or 25 or 6 yuan of heterocyclic ring that are independently selected from other heteroatoms (except being connected the N atom) of O, N and S, wherein-and CH ₂-group can be chosen wantonly can be chosen wantonly by the sulphur atom in-C (O)-replacement and the ring and be oxidized to S (O) or S (O) ₂Group; Described ring is chosen wantonly on available carbon or nitrogen-atoms and is replaced (condition is that described nitrogen is not thus by quaternized) by 1 or 2 (1-4C) alkyl.

7. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I), wherein R among the claim 1-6 ⁶And R ⁷Be independently selected from hydrogen, methyl, cyclopropyl (optional), carboxymethyl by methyl substituted and (2-4C) alkyl (optionally replaced by 1 or 2 substituting group that is independently selected from amino, (1-4C) alkylamino, two-(1-4C) alkylaminos, carboxyl, (1-4C) alkoxyl group and hydroxyl; Wherein (1-4C) alkylamino or two-(1-4C) alkylaminos can be chosen wantonly on (1-4C) alkyl chain by carboxyl substituted).

8. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I) among the claim 1-7, it is the diastereomer of formula (Ia),

9. the compound or pharmaceutically acceptable salt thereof or the prodrug of each described formula (I) among the claim 1-8, it is selected from:

(5R)-and 3-[4-(6-{ (5S)-5-[(dimethylamino) methyl]-4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-[3-fluoro-4-(6-{ (5S)-5-[(methylamino) methyl]-4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-[3-fluoro-4-(6-{ (5S)-5-[(4-methylpiperazine-1-yl) methyl]-4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-{3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl) amino] methyl }-4, the 5-dihydro is different _ azoles-3-yl) pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-[4-(6-{ (5S)-5-[(butyl amino) methyl]-4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(thiomorpholine-4-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-[3-fluoro-4-(6-{ (5S)-5-[(1-oxidation thiomorpholine-4-yl) methyl]-4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl) phenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-[4-(6-{ (5S)-5-[(1,1-titanium dioxide thiomorpholine-4-yl) methyl]-4, the 5-dihydro is different _ azoles-3-yl } pyridin-3-yl)-the 3-fluorophenyl]-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-{3-fluoro-4-[6-((5S)-5-{[(2-hydroxyethyl) (methyl) amino] methyl }-4, the 5-dihydro is different _ azoles-3-yl) pyridin-3-yl] phenyl }-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-(3-fluoro-4-{6-[(5R)-5-(morpholine-4-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(tetramethyleneimine-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(piperidines-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

(5R)-and 3-(4-{6-[(5S)-5-(3,6-dihydropyridine-1 (2H)-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl }-the 3-fluorophenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

{ [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } the carboxylamine tertiary butyl ester;

N ¹-{ [(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 }-N ², N ²-dimethyl G-NH2;

N-{[(5S)-and 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 }-the sarcosine tertiary butyl ester;

N-{[(5S)-and 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 }-sarcosine;

N-{[(5S)-and 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 }-the L-prolineamide;

N ¹-{ [(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 }-the D-valine amide;

N ¹-{ [(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 }-the L-alanimamides;

N ¹-{ [(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 }-N ¹, N ², N ²-trimethylammonium G-NH2;

N-{2-[{[(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } (methyl) amino]-the 2-oxoethyl }-sarcosine;

N-[2-({ [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } amino)-the 2-oxoethyl] glycine;

(5R)-and 3-(3-fluoro-4-{6-[(5S)-5-(1H-imidazoles-1-ylmethyl)-4, the 5-dihydro is different _ azoles-3-yl] pyridin-3-yl } phenyl)-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-2-ketone;

N-[2-({ [(5S)-3-(5-{2-fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-yl methyl)-1,3-_ azoles alkane-3-yl] phenyl } pyridine-2-yl)-4, the 5-dihydro is different _ azoles-5-yl] methyl } amino)-the 2-oxoethyl]-sarcosine;

N ¹-{ [(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 }-L-α-l-asparagine;

N ¹-{ [(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 }-L-α-glutamine.

10. method that in warm-blooded animal, produces antibacterial effect, but comprise and give ester with hydrolysis in each described compound or pharmaceutically acceptable salt thereof of the present invention among the claim 1-9 of significant quantity or the body to described animal.

But 11. the ester of hydrolysis in each described compound or pharmaceutically acceptable salt thereof of the present invention or the body among the claim 1-9, it is as medicine.

But 12. among the claim 1-9 in each described compound or pharmaceutically acceptable salt thereof of the present invention or the body ester of hydrolysis be used for producing application in the medicine of antibacterial effect in preparation warm-blooded animal.

13. a pharmaceutical composition, but it comprises ester and the acceptable diluents or the carrier of hydrolysis in each described compound or pharmaceutically acceptable salt thereof of the present invention among the claim 1-9 or the body.

14. the described pharmaceutical composition of claim 13, wherein said composition comprise the compound of formula (I) and effectively to the combination of the antiseptic-germicide of resisting gram-positive bacteria.

15. the described pharmaceutical composition of claim 14, wherein said composition comprise the compound of formula (I) and the effectively combination of the antiseptic-germicide of antagonism Gram-negative bacteria.

16. one kind prepare the described formula of claim 1 (I) but compound or pharmaceutically acceptable salt thereof or body in the method for ester of hydrolysis, this method comprises following method (a) to one of (j), and, after this if necessary:

I) remove any protecting group;

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

Iii) form pharmacologically acceptable salt;

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

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

B) make a part of formula (II) compound

Wherein X is the leavings group that can be used in palladium [0] coupled reaction,

With the partial reaction of Compound I Ia,

Wherein Y is as mentioned or hereinafter defined amine or sulfonamide derivatives NR ⁴R ⁵, its synthetic precursor or its protected derivative (PG=protecting group) and X be can with the identical or different leavings group of X in the compound (II);

C) make pyridyl-phenylcarbamate derivative (III)

Wherein Y is as hereinbefore defined amine or sulfonamide derivatives NR ⁴R ⁵,

With the reacting ethylene oxide shown in the following formula that is suitably replaced,

Thereby formation _ oxazolidone ring;

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

D) make the compound of formula (IV):

Wherein X is replaceable substituting group,

Compound reaction with formula V:

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

E) make the oxime of formula (VII),

With formula

Compound (wherein the definition of Y is the same) reaction form different _ oxazoline ring;

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

G) by the trinitride shown in the following formula,

With acetylene

Carry out cycloaddition;

H) by making the amino methyl _ oxazolidone shown in the following formula,

With suitable 1,1-dichloro-ketone alkylsulfonyl hydrazone reaction;

I) for R wherein ¹Be the compound of the formula (I) of halogen, by making the azido methyl _ oxazolidone shown in the following formula,

With suitable vinyl halides base SULPHURYL CHLORIDE reaction;

J) racemic mixture by the ester shown in the following formula carries out the enantio-selectivity esterase hydrolyzed at the prochiral center place and obtains hydroxyl, and this hydroxyl can be converted into NR ⁴R ⁵Substituting group,

17. the compound of formula (IIa),

Wherein, perhaps:

A) X is that boric acid or ester and Y are NR ⁴R ⁵, R wherein ⁴And R ⁵As in the claim 1 to the definition of formula (I); Perhaps

B) X is that halogen and Y are-OR ⁴, R wherein ⁴As in the claim 1 to the definition of formula (I).