CN110156763A - A kind of posaconazole derivative, pharmaceutical composition with and application thereof - Google Patents

Abstract

The present invention provides a kind of posaconazole derivative as shown in general formula (I) or its pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotopic label or isomers, and the present invention also provides the pharmaceutical composition comprising it and the purposes of the derivative, pharmaceutical composition.Posaconazole derivative provided by the invention and its pharmaceutical composition can be effectively improved the water solubility problems of posaconazole, solubility can greatly improve, aqueous solution has good stability, and also has excellent oral administration biaavailability and pharmacokinetic property, and be also equipped with excellent antibacterial activity.

Description

A kind of posaconazole derivative, pharmaceutical composition with and application thereof

Technical field

The present invention relates to field of medicaments, and in particular to a kind of posaconazole derivative includes the posaconazole derivative Pharmaceutical composition and the posaconazole derivative, pharmaceutical composition purposes.

Background technique

In past 20 years, the total incidence of invasive fungal infection climbs up and up, with chemotherapy, transplanting, HIV/ The compromised immunes patient populations' such as AIDS infection or diabetes increases, especially for the patient for receiving long-term treatment, very The high-incidence danger of bacterium infection makes antifungal therapy drug receive more and more extensive concern.

Posaconazole is a kind of novel triazole type broad-spectrum antifungal drug, and anti-fungus spectra is wide, and antibacterial efficacy is strong, is taken orally Suspension and the successive list marketing of injection.However, oral suspensions are to powder due to the characteristic of posaconazole poorly water-soluble Granularity has a very harsh requirement, and the degree of absorption of suspension is highly prone to the influence such as food, gastrointestinal function, causes between individual Pharmacokinetic parameter variability is larger.Its injection type is in order to improve posaconazole defect not soluble in water, 300 milligrams of drugs Joined 6.68 grams sulfobutyl ether-beta-cyclodextrin carry out hydrotropy, and such cosolvent exist in clinical application it is biggish not Good reaction, mainly concentrates on renal toxicity and hemolytic, be not suitable in, the impaired renal patient of severe, moreover, intravenous formulations It need to be configured to the reagent of pH2.6, peripheral vein administration has apparent blood vessel irritation.

To overcome water-soluble defect, researcher develops the ester prodrug of a variety of posaconazoles, such as amino-acid ester, two Peptide ester, phosphate etc., in these prodrugs, amino-acid ester, dipeptides esters are limited to the raising of solubility, and dipeptides esters in vivo can There are multiple metabolites；And phosphoric acid ester, because containing phosphate, although solubility is preferable, metabolic rate is very fast, cell membrane Permeability is poor, and the concentration for causing to reach drug after target is lower, is less suitable for being used as oral preparation, and this kind of drug is in water Stability in solution is not so good, needs to be made into freeze-dried powder.

Based on this, there is an urgent need to develop further types of posaconazole derivatives, to improve its water-soluble, pharmacokinetics Property, and reduce the adverse reaction of clinical application.

Summary of the invention

It is an object of the present invention to provide a kind of novel posaconazole derivatives or its pharmaceutically acceptable salt, molten Agent compound, active metabolite, polymorph, isotopic label or isomers have excellent bioactivity, and have good Good water solubility and pharmacokinetic property.

It is a further object of the present invention to provide a kind of pharmaceutical compositions.

It is a further object of the present invention to provide the posaconazole derivative or its pharmaceutically acceptable salts, solvation The purposes of object, active metabolite, polymorph, isotopic label or isomers and described pharmaceutical composition.

The present invention provides a kind of posaconazole derivative as shown in general formula (I) or its pharmaceutically acceptable salts, molten Agent compound, active metabolite, polymorph, isotopic label or isomers,

Wherein,

X independently indicates F, Cl or Br；

A indicates C or the hetero atom selected from one of O, N, S；

R ' indicates H, C_1~4Alkyl is not present；

A indicate hetero atom when, R indicate be substituted or be unsubstituted with one of flowering structure :-(CH₂)_nN(R₂)₂, contain There are at least one heteroatomic 5~8 unit monocycle heterocycle ,-(CH₂)_nO(CO)-R₁Or R and A is formed and is contained at least one hetero atom 5~12 unit monocycles or bicyclic heterocyclic radical；Substituent group is selected from C_1~6Alkyl, C_1~6Alkyl amino, C_1~6Halogenated alkyl, C_1~6Alcoxyl Base or C_3~6Naphthenic base；

N indicates 2~6 integer；

R₁Indicate C_1~6Alkoxy, C_1~6Alkyl amino contains at least one heteroatomic 5~8 unit monocycle heterocycle；

R₂Indicate hydrogen, C_1~4Alkyl or-N (R₂)₂It is formed and contains at least one heteroatomic 5~8 unit monocycle heterocycle；

When A indicates C, what R and A formation was substituted or was unsubstituted contains at least one heteroatomic 5~8 circle heterocyclic ring base； Substituent group is selected from C_1~6Alkyl, C_1~6Alkyl amino, C_1~6Halogenated alkyl, C_1~6Alkoxy or C_3~6Naphthenic base；

The hetero atom is selected from one of O, N, S.

In one embodiment according to the present invention, the pharmaceutically acceptable salt can be pharmaceutically acceptable Acid salt.In a preferred embodiment according to the present invention, the pharmaceutically acceptable salt can be that can pharmaceutically connect The hydrochloride received.

In one embodiment according to the present invention, the substituent group X can independently indicate F or Cl.According to this In one preferred embodiment of invention, the substituent group X can indicate F simultaneously.

In one embodiment according to the present invention, the group A can indicate that O or N, the group R can be indicated through taking Generation or be unsubstituted-(CH₂)_nN(R₂)₂, n can indicate 2~5 integer (integer that can indicate 2,3,4 or 5) ,-(CH₂)_n- It can indicate straight chain or the alkylidene containing branch, R₂It can indicate C_1~4Alkyl or-N (R₂)₂Formed containing at least one heteroatomic 5 ~7 unit monocycle heterocycles, substituent group can be C_1~4Alkyl.In a preferred embodiment according to the present invention, monocyclic heterocycles Base may further be 5~6 unit monocycle heterocycles.In another preferred embodiment according to the present invention, monocyclic heterocycles base contains There is-N (the R₂)₂N hetero atom in group, also containing one or more hetero atoms in optional O, N, S.As an example, R₂ The including but not limited to groups such as methyl, ethyl, propyl, isopropyl, normal-butyl, monocyclic heterocycles base include but is not limited to piperidyl, The groups such as pyrrolidinyl, morpholinyl, piperazinyl, triazine radical.

In one embodiment according to the present invention, the group A can indicate that C, the group R can be formed with group A 5~6 unit monocycle heterocycles containing at least one N atom for being substituted or being unsubstituted, substituent group can be C_1~4Alkyl or C_1~6Alkyl amino, and connect with the N atom.In a preferred embodiment according to the present invention, substituent group can for- (CH₂)_mN(R₃)₂Shown in C_1~6Alkyl amino, R₃Each independently represent H or C_1~3Alkyl, m indicate 1~6 integer.As Example, substituent group include but is not limited to methyl, ethyl, propyl, isopropyl, normal-butyl ,-CH₂NH₂、-CH₂N(CH₃)₂、- CH₂CH₂NH₂、-CH₂CH₂N(CH₃)₂Equal groups, monocyclic heterocycles base includes but is not limited to piperidyl, pyrrolidinyl, piperazinyl, three The groups such as piperazine base.

In one embodiment according to the present invention, the group A can indicate O, the R can indicate to be substituted or without 5~6 unit monocycle heterocycles containing at least one N atom replaced, substituent group can be C_1~4Alkyl and with the N atom connect It connects.As an example, substituent group includes but is not limited to the groups such as methyl, ethyl, propyl, isopropyl, normal-butyl, monocyclic heterocycles Ji Bao Include but be not limited to the groups such as piperidyl, pyrrolidinyl, piperazinyl, triazine radical.

In one embodiment according to the present invention, the group A can indicate O, the R can indicate to be substituted or without Replace-(CH₂)_nO(CO)-R₁, n can indicate 2~5 integer (integer that can indicate 2,3,4 or 5) ,-(CH₂)_nIt can indicate Straight chain or alkylidene containing branch, R₁It can indicate C_1~4Alkoxy, C_1~4Alkyl amino or containing at least one N atom 5~6 Unit monocycle heterocycle, substituent group can be selected from C_1~4Alkyl.As an example, R₁Including but not limited to methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, methylamino, ethylamino, propylcarbamic, isopropylamino, n-butylamino, isobutylamino, piperidyl, The groups such as pyrrolidinyl, piperazinyl, triazine radical.

In one embodiment according to the present invention, the group A can indicate N, the R can be formed with A be substituted or Be unsubstituted containing comprising heteroatomic 5~12 unit monocycle of at least one N or bicyclic heterocyclic radical including A, substituent group can be with For C_1~4Alkyl.In a preferred embodiment according to the present invention, contain in 5~12 unit monocycle or bicyclic heterocyclic radical Include at least two N hetero atoms including A.As an example, monocyclic heterocycles base includes but is not limited to piperidyl, pyrrolidinyl, piperazine The groups such as piperazine base, triazine radical, bicyclic heterocyclic radical include but is not limited to the pyrrolidines of the piperidyl of piperidyl substitution, piperidyl substitution The piperazine of pyrrolidinyl, naphthenic base substitution that base, the piperazinyl of piperidyl substitution, the piperidyl of naphthenic base substitution, naphthenic base replace The groups such as the piperazinyl that pyrrolidinyl, the piperazinyl of piperidyl, piperazinyl substitution that piperazine base, piperazinyl replace replace.

Derivative provided by the invention or its pharmaceutically acceptable salt, solvate, active metabolite, polymorph, Isotopic label or isomers are more preferably selected from flowering structure:

The present invention also provides a kind of pharmaceutical compositions, and it includes the described in any item posaconazoles of above technical scheme to spread out Biology or its pharmaceutically acceptable salt, solvate, active metabolite, polymorph, isotopic label or isomers, with And pharmaceutically acceptable carrier.

In an embodiment of pharmaceutical composition according to the present invention, pharmaceutical composition can be peroral dosage form or note Penetrate dosage form.

In an embodiment of pharmaceutical composition according to the present invention, pharmaceutical composition can also include other activity Ingredient or drug, with the posaconazole derivative or its pharmaceutically acceptable salt, solvate, active metabolite, more Crystal form object, isotopic label or isomers drug combination.

The present invention also provides above-mentioned posaconazole derivative or its pharmaceutically acceptable salt, solvate, active generations Thank to the use of object, polymorph, isotopic label or isomers and above-mentioned pharmaceutical composition in preparation antibacterials On the way.

In an embodiment in accordance with the purpose of the invention, antibacterials can be antifungal drug.

The water solubility that posaconazole derivative provided by the invention and its pharmaceutical composition can be effectively improved posaconazole is asked Topic, solubility in water can be significantly improved.For not needing that the cosolvents such as cyclodextrin additionally are added when injection type, disappear In addition to potential nephrotoxic risks and other possible side effects, the target user of drug is expanded, so that the kidney of middle severe damages Hurting patient can also use, and can also reduce the ingredient in prescription；Again because stability in aqueous solution is preferable, injection type can be with It is made into liquid drugs injection, is not required to be made into freeze drying powder injection, reduces preparation cost.Bioavilability is significantly improved for peroral dosage form Height, bioavilability is improved without adding cyclodextrin solubilising, and the absorption of drug is not easily susceptible to the influence of food, gastrointestinal function. In short, posaconazole derivative provided by the invention and its pharmaceutical composition are avoided using the ring of genotoxic potential can be brought to paste Essence significantly improves bioavilability in aqueous solution, is both suitble to drug administration by injection, it can also be used to be administered orally.

In addition, posaconazole derivative provided by the invention and its pharmaceutical composition also have excellent pharmacokinetics After matter, vein or oral administration, posaconazole derivative more equably slowly releases posaconazole raw medicine in vivo, and 8 It is hour substantially all to be converted into posaconazole, have the characteristics that sustained release, more mitigated up to peak in vivo, reduces instantaneously high blood medicine The problems such as concentration bring genotoxic potential, avoidable phlebitis, concentration decline slowly, thus can improve drug after drug reaches peak Action time and drug effect, make it preferably play a role.

Third, posaconazole derivative provided by the invention and its pharmaceutical composition are also equipped with excellent antibacterial functions, especially It is in terms of antifungal activity.

It is described in detail

Unless otherwise defined, the connotation that all scientific and technical terminologies have herein and claim theme fields technology The normally understood connotation of personnel is identical.Unless otherwise indicated, all patents, patent application, the public material being cited in full text herein It is integrally incorporated by reference herein.When herein presented trade name, it is intended that refer to its corresponding commodity or its activity at Point.

It should be understood that above-mentioned summary and being specified as exemplary and being only used for explaining hereafter, without being done to this paper subject matter Any restrictions.In this application, it has to be noted that, unless clear explanation, otherwise in specification and claims Singular used in book includes the plural form of referents.It shall yet further be noted that unless otherwise stated, "or" used, "or" indicates "and/or".In addition, term " includes " used and other forms, such as "comprising", " containing " and " containing " are not It is restricted.

The definition of standard chemistry terms can be found in reference works, " the Advanced including Carey and Sundberg Organic Chemistry 4^thEd,Vol A(2000)and B(2001),Plenum Press,New York.Unless otherwise Illustrate, otherwise using the conventional method within the scope of art technology, as mass spectrum, NMR, HPLC, protein chemistry, biochemistry, Recombinant DNA technology and pharmacological method.Unless propose be specifically defined, otherwise herein analytical chemistry, Synthetic Organic Chemistry and The relevant name chemically such as medicine and pharmaceutical chemistry and laboratory operation and technology, are known to the skilled in the art. Standard technique can be used for chemical synthesis, chemical analysis, medicine preparation, and preparation passs medicine and the treatment of patient.Standard technique can be with For recombinant DNA, oligonucleotide synthesis and tissue cultures and conversion (such as electroporation, lipid infect method).For example, The kit that the specification provided with raw manufacturer is provided, perhaps according to method well known in the art or according to this hair The method of bright statement, to implement reaction and purification technique.In general, aforementioned techniques and step can pass through this field many institute's weeks The sum known conventional method described in various general literatures or more specific document is implemented, these documents are drawn in the present invention With and discuss.

When the conventional chemical formulas by writing from left to right describes substituent group, which similarly includes from right to left Write obtained equivalent substituent group in chemistry when structural formula.For example, CH₂O is equal to OCH₂。

Term " being substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, as long as specific Compound after the valence state of atom is normal and substitution is stable.When substituent group is oxo (i.e.=O), meaning Two hydrogen atoms be substituted, oxo does not occur on aromatic radical.

When any variable (such as R) occurs more than once in the composition of compound or structure, in every case Under definition be all independent.Thus, for example, the group can be optionally if a group is replaced 0-2 R At most replaced two R, and R in each case has independent option.In addition, the group of substituent group and/or its variant Conjunction is only just allowed in the case where such group of credit union generates stable compound.

C used herein_M~nReferring to has m~n carbon atom in the part.For example, the described " C_1~6" group refers to the portion There is 1-6 carbon atom, i.e. group includes 1 carbon atom, 2 carbon atoms, 3 carbon atoms ..., 6 carbon atoms in point.Cause This, for example " C_1~6Alkyl " refers to the alkyl containing 1-6 carbon atom, i.e., the described alkyl is selected from methyl, ethyl, propyl, different Propyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl ... etc..Digital scope herein, such as " 1-6 " refer to given range In each integer, such as " 1-6 carbon atom " refer to that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 A carbon atom, 5 carbon atoms or 6 carbon atoms.

Term " alkyl " refers to the saturated aliphatic hydrocarbons group of the straight chain optionally replaced or the branch optionally replaced, passes through The connection of the rest part of singly-bound and molecule." alkyl " of this paper can have about 6 carbon atoms of 1-, such as 1-4 carbon atom or 1-3 A carbon atom." alkyl " embodiment of this paper include but is not limited to methyl, ethyl, n-propyl, isopropyl, 2- methyl-l- propyl, 2- methyl-2-propyl, 2-methyl-1-butene base, 3- methyl-l- butyl, 2- methyl -3- butyl, 2,2- dimethyl -1- propyl, 2- Methyl-1-pentene base, 3- methyl-1-pentene base, 4- methyl-l- amyl, 2- methyl -2- amyl, 3- methyl -2- amyl, 4- methyl -2- Amyl, 2,2- dimethyl-l- butyl, 3,3- dimethyl -1- butyl, 2- ethyl -1- butyl, normal-butyl, isobutyl group, sec-butyl, Tert-butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl etc. and longer alkyl group, such as heptyl and octyl. Group defined herein, when such as there is digital scope in " alkyl ", such as " C_1~6Alkyl " refers to can be by 1 carbon atom, 2 carbon originals The alkyl that son, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms are constituted, for another example " C_1~4Alkyl " refers to can be by The alkyl that 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms are constituted.The alkyl of this paper also includes not specified number The case where range.

Term " naphthenic base " refers to non-aromatic containing carbocyclic ring, including saturated carbon ring (such as naphthenic base) or unsaturated carbocyclic are (such as Cycloalkenyl).Carbocyclic ring includes monocyclic carbocyclic ring (having a ring), such as can be monocyclic cycloalkyl；Bicyclic carbocyclic ring (there are two rings for tool), example It such as can be bicyclic cycloalkyl；More carbocyclic rings (there are more than two rings).It can be bridge conjunction or loop coil between ring.Carbocyclic ring (such as ring Alkyl or cycloalkenyl) it can have 3 to 8 carbon atoms, such as with about 6 ring carbons of 3- or 3- about 5 at ring carbon original Son.

Term " heterocycle " refers to nonaromatic heterocycles comprising saturated heterocyclic or unsaturated heterocycle (containing unsaturated bond), no π-electron system with total conjugated can be divided into monocycle, fused polycycle, bridged ring or the spiro ring system of no armaticity.Wherein one The atom of a or multiple (such as 1-4,1-3,1-2) cyclization is hetero atom, such as oxygen, nitrogen or sulphur atom.Heterocycle can wrap Include single heterocycle (with a ring) or double heterocycles (there are two the rings that bridge closes for tool) or more heterocycles (ring that there are more than two bridges to close)； It also include loop coil.Heterocycle can have 3 to about 20, about such as 3- about 10,3- about 8,4-8,4-7,5- about 8 or 5- 6 ring member nitrogen atoms.The non-limiting example of heterocycle includes Oxyranyle, thiirane base, azirane base, azetidine Base dislikes fourth ring group, thiophene fourth ring group, tetrahydrofuran base, pyrrolidinyl, oxazolidinyl, tetrahydro-pyrazole base, pyrrolinyl, dihydro furan It mutters base, dihydrothiophene, piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, morpholinyl, piperazinyl, dihydropyridine base, tetrahydro pyrrole Piperidinyl, dihydro pyranyl, THP trtrahydropyranyl, dihydro thiapyran base, nitrogen heterocyclic heptyl, oxepane alkyl, thia cycloheptyl alkyl, Bicyclic [2.2.1] heptyl of oxazepine and azaspiro [3.3] heptyl etc..

Term " alkoxy " refers to that alkylether radicals (O- alkyl), the nonlimiting examples of alkoxy include methoxyl group, second Oxygroup, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy etc..

Term " amino " refers to-NH₂Group ,-NH (C_1~6Alkyl) group or-N (C_1~6Alkyl)₂Group.The concrete example of amino Son includes but is not limited to-NH₂、-NHCH₃、-N(CH₃)₂、-NHC₂H₅、-N(C₂H₅)₂、-N(C₃H₇)₂、-N(CH₃)C₂H₅Deng.

Term " member " refers to the number for constituting the skeletal atom of ring.Such as pyridine is hexatomic ring, pyrroles is five-membered ring.

Term " pharmaceutically acceptable " be for those compounds, material, composition and/or dosage form, they Within the scope of reliable medical judgment, use is contacted suitable for the tissue with human and animal, without excessive toxicity, thorn Swash property, allergic reaction or other problems or complication, matches with reasonable interests/Hazard ratio.

Term " pharmaceutical composition ", which refers to, optional is mixed at least one pharmaceutically acceptable chemical component or reagent Bioactive compound, the pharmaceutically acceptable chemical component or reagent are " carrier ", are facilitated compound It is introduced into cell or tissue, including but not limited to stabilizer, diluent, suspending agent, thickener and/or excipient.

Term " pharmaceutically acceptable salt " refers to the biopotency of the free acid and free alkali that remain appointed compound, And the not no salt of ill-effect on biologically or otherwise.In addition to special instructions, the salt in the present invention can be mentioned that gold Belong to salt, ammonium salt, the salt formed with the salt of organic base formation and inorganic acid, the salt and alkaline or acid ammonia formed with organic acid The salt etc. that base acid is formed.The non-limiting example of metal salt includes but is not limited to salt of alkali metal, such as sodium salt, sylvite etc.；Alkali Salt of earth metal, such as calcium salt, magnesium salts, barium salt etc.；Aluminium salt etc..The non-limiting example of the salt formed with organic base includes but not It is limited to and trimethylamine, triethylamine, pyridine, picoline, 2,6- lutidines, ethanol amine, diethanol amine, triethanolamine, ring The salt of the formation such as hexylamine, dicyclohexylamine.With inorganic acid formed salt non-limiting example include but is not limited to and hydrochloric acid, hydrogen The salt of the formation such as bromic acid, nitric acid, sulfuric acid, phosphoric acid.With organic acid formed salt non-limiting example include but is not limited to and first Acid, acetic acid, trifluoroacetic acid, lactic acid, fumaric acid, tussol, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, The salt of the formation such as methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid.With basic amino acid formed salt non-limiting example include but It is not limited to and the salt of the formation such as arginine, lysine, ornithine.The non-limiting example of salt formed with acidic amino acid includes But it is not limited to and the salt of the formation such as aspartic acid, glutamic acid.

Pharmaceutically acceptable salt can be synthesized by the parent compound containing acid group or base by conventional chemical processes.One As in the case of, the preparation method of such salt is: in the mixture of water or organic solvent or both, via free acid or alkali shape These compounds of formula react to prepare with the alkali appropriate of stoichiometry or acid.It is generally preferable that ether, ethyl acetate, ethyl alcohol, The non-aqueous medias such as isopropanol or acetonitrile.

Term " solvate " refers to a compound in the present invention and the physics of one or more solvent molecule formation Aggregation, this physical agglomeration include the different degrees of and covalent bond of ion, such as hydrogen bond.Having proven to this solvate can To be separated, for example, when being mixed with one or more solvent molecules in the lattice of crystal." solvate " includes solvent phase and can Isolated solvate two parts.Corresponding solvate example has very much, including alcohol solvent compound, Methanol Solvate Deng." hydrate " is one kind with water (H₂O) molecule is the solvate of solvent.One or more compounds in the present invention all may be used Arbitrarily to prepare solvate.Preparing for solvate is well-known.Such as M.Caira et al, J.Pharmaceutical Sci., 93 (3) describe the system of the solvate of antifungal Fluconazole in 601-611 (2004) It is standby, i.e., it is prepared with ethyl acetate and water.E.C.van Tonder et al,AAPS PharmSciTech.,5(1),article 12(2004)；Solvate, water are also illustrated in A.L.Bingham et al, Chem.Commun., 603-604 (2001) Close the similar preparation method of object.A kind of typical, unrestricted preparation process is when being higher than the temperature of room temperature by invention Compound is dissolved in the ideal solvent of requirement (organic solvent or water or their mixed solvent), and crystallization is placed in cooling, Then choose crystal with the method separation of standard.It can be confirmed to form solvate in crystallization with I.R. spectroscopy analysis technology The presence of the solvent (water) of (hydrate).

Term " active metabolite " refers to the active derivative of the compound formed in compound metabolism.

Term " polymorph " refers to the compounds of this invention existing for different form crystal lattices.

Term " isotopic label " refers to the compounds of this invention for having isotope labelling.Such as in the compound of the present invention Isotope may include H, C, N, O, P, the various isotopes of the elements such as F, S, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁸O,¹⁷O,³¹P,³²P ,³⁵S,¹⁸F and³⁶S。

Term " isomers " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule.The present invention Compound contains the structures such as asymmetric or chiral centre, double bond, therefore, the compound of the present invention may include optical isomer, It is the various isomeric forms such as geometric isomer, tautomer, atropisomer, these isomers and its individual isomer, outer Raceme etc. is included within the scope of the present invention.For example, for optical isomer, can by chiral resolution, Chirality synthesis or chiral reagent or other routine techniques prepare optically active (R)-and (S)-isomers and D and L isomery Body.For example, can be by being non-with optically active substance appropriate (such as chiral alcohol or Mosher`s Mohs acyl chlorides) reaction conversions Enantiomter is isolated and converts (as hydrolyzed) as corresponding single isomers.For another example can also pass through chromatographic column It is separated.

" pharmaceutical composition " of this paper can be prepared by mode well known in pharmaceutical arts, and can give through a variety of ways or Them are applied, this depends on whether the region locally or systemically treated He treated.Can it is local (for example, transdermal, skin, Eye and mucous membrane include that intranasal, vagina and rectum pass medicine), lung (for example, by sucking or being blown into powder or aerosol, including passes through Sprayer；Intratracheally, intranasally), oral and extra-parenteral administration.Parenteral administration includes intravenously, in intra-arterial, subcutaneous, peritonaeum Or intramuscular injection or infusion；Or encephalic is for example intrathecal or intracerebroventricular administration.Can be by single-bolus high-dose form parenteral administration, or it can It pumps and is administered for example, by continuous pouring.The pharmaceutical composition of this paper includes but is not limited to following form: tablet, pill, powder, ingot It is agent, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (solid or being dissolved in liquid vehicle), soft Paste, soft hard gelatin capsule, suppository, aseptic injectable solution and aseptic packaging powder etc..

The pharmaceutical composition of this paper can be prepared by unit dosage forms, and every dose can contain about 0.1~1000mg, normally about 5~ 1000mg active constituent, more typically from about 100~500mg active constituent.Term " unit dosage forms " refers to physically separated suitable As the single dose unit for human patient and other mammals, constituent parts contain the warp mixed with the pharmaceutical carrier for being suitable for Calculate the active material that can produce the predetermined amount of required curative effect.

Detailed description of the invention

The posaconazole prototype that Fig. 1 is metabolized out for (1mg/kg) after 21 compound water solution intravenously administrable of the embodiment of the present invention The drug-time curve of medicine；

Fig. 2 is the drug-time curve of 21 compound of (1mg/kg) embodiment after 21 compound intravenously administrable of the embodiment of the present invention；

Fig. 3 be posaconazole HP- β-CD solution intravenously administrable after (20mg/kg) drug-time curve.

Specific embodiment

To make the object, technical solutions and advantages of the present invention clearer, it will be further described below example of the invention The technical solution of property embodiment.

The present invention can prepare compound of the present invention by following methods.Following methods and embodiment are to say These bright methods.These processes and embodiment are not construed in any way as limitation of the present invention.Ability can also be used Standard synthetic techniques known to field technique personnel synthesize compound as described herein, or be applied in combination means known in the art and Methods described herein.

The chemical reaction of the embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the present invention Chemical change and its required reagent and material.In order to obtain the compound of the present invention, it is sometimes desirable to those skilled in the art Synthesis step or reaction process are modified or selected on the basis of existing embodiment.

An important consideration factor in any synthetic route planning of this field be for reactive functional groups (in the present invention Amino) the suitable protecting group of selection.For trained practitioner, (the Protective of Greene and Wuts Groups In Organic Synthesis, Wiley and Sons, 1991) be this respect authority.The institute that the present invention quotes There is bibliography incorporated herein on the whole.

Reaction described herein can be monitored according to any suitable method as known in the art.For example, can be by wide Spectral method such as NMR spectrum (such as¹H or¹³C), infrared spectroscopy, spectrophotometry (such as UV- visible light), mass spectrum Deng, or product is monitored by chromatography such as high performance liquid chromatography (HPLC) or thin-layer chromatography (TLC) and is formed.

Embodiment 1 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base-ethane -1,2- diyl-two carbonic ester of isopropyl

Step A:2- hydroxyethyl-butylperoxyisopropyl carbonate

By 3g (24.05mmol, 1.0eq) isopropyl chlorocarbonate be slowly added dropwise under ice bath into 4.1mL (72.9mmol, 3.0eq) in the 30mL dichloromethane solution of ethylene glycol, 8mL (72.9mmol, 3.0eq) pyridine, reaction is warmed to room temperature after adding 2h, TLC monitor end of reaction.Reaction solution is poured slowly into water, water phase is extracted with dichloromethane.Merge organic phase, it will be organic It is mutually successively washed with water and saturated sodium bicarbonate, organic phase is dry by anhydrous sodium sulfate, and evaporated under reduced pressure, residue passes through column Chromatograph to obtain product (1.5g, yield=41%).

Step B:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- base -1- hydrogen-imidazoles -1- methyl esters

4.0g (5.7mmol, 1.0eq) posaconazole and 3.9g (22.8mmol, 4.0eq) carbonyl dimidazoles are dissolved in In 100mL methylene chloride, it is heated to back flow reaction 2 hours, TLC monitors end of reaction.Reaction solution is poured slowly into water, with two Chloromethanes aqueous phase extracted.Merge organic phase, organic phase washed with water and saturated sodium bicarbonate are washed, organic phase is passed through anhydrous Sodium sulphate is dry, evaporated under reduced pressure, and residue is directly used in next step (5.1g, yield=100%).

Step C:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- base-ethane -1,2- diyl-two carbonic ester of isopropyl

At room temperature by 150mg (0.188mmol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H- 1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) benzene Base) -5- oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base -1- hydrogen-imidazoles -1- methyl esters 50mg (0.282mol, 1.5eq), 2- hydroxyethyl-butylperoxyisopropyl carbonate, are dissolved in 50mg (0.282mol, 1.5eq) potassium carbonate In 25mL methylene chloride, TLC monitors end of reaction.Reaction solution is poured slowly into water, water phase is extracted with dichloromethane.It is associated with Machine phase washs organic phase washed with water and saturated sodium bicarbonate, organic phase is dried by anhydrous sodium sulfate, evaporated under reduced pressure, Residue chromatographs to obtain product (114mg, yield=70%) by column.

¹H NMR (400MHz, CDCl3): δ 8.14 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.45 (d, J=8Hz, 2H), 7.40 (t, J=8Hz, 1H), 7.05 (d, J=8Hz, 2H), 6.95 (d, J=8Hz, 2H), 6.83-6.91 (m, 2H), 6.79 (d, J=8Hz, 1H), 5.09-5.15 (m, 1H), 4.87-4.91 (m, 1H), 4.67 (d, J=16Hz, 1H), 4.54 (d, J =16Hz, 1H), 4.28-4.35 (m, 5H), 4.13 (t, J=8Hz, 1H), 3.71-3.82 (m, 2H), 3.65 (t, J=8Hz, 1H),3.34-3.43(m,4H),3.21-3.28(m,4H),2.54-2.67(m,2H),1.91-2.13(m,3H),1.78-1.87 (m, 1H), 1.38 (d, J=8Hz, 3H), 1.28-1.33 (m, 8H), 0.92 (t, J=8Hz, 3H) .LC-MS:m/z=875 [M+ H]⁺.

2 2- of embodiment (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) Methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-glycine ester hydrochloride

Step A:2- ((t-Butyldimethylsilyl) oxygroup) ethane -1- alcohol

10g (0.066mol, 1.0eq) tert-butyl chloro-silicane is slowly added dropwise under ice bath into 24.7g (0.4mol, 6.0eq) ethylene glycol, 40.3g (0.4mol, 6.0eq) triethylamine 200mL methylene chloride in, keep ice after adding Bath reaction 10min, TLC monitor end of reaction.Reaction solution is poured slowly into water, water phase is extracted with dichloromethane.Merge organic Phase washs organic phase washed with water and saturated sodium bicarbonate, and organic phase is dry by anhydrous sodium sulfate, and evaporated under reduced pressure is residual Excess chromatographs to obtain product (11.7g, yield=100%) by column.

Step B:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- base-(2- ((t-Butyldimethylsilyl) oxygroup) ethyl) carbonic ester

The step C referring to described in embodiment 1 comes prepare compound (500mg, yield=98%).

Step C:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- base-(2- ethoxy) carbonic ester

By 350mg (0.39mmol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- Triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- Oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base-(2- ((t-Butyldimethylsilyl) oxygroup) ethyl) carbon Acid esters, 1.05g (3.9mmol, 10.0eq) tetrabutyl ammonium fluoride are dissolved in 10mL methylene chloride, react at room temperature 3h, TLC monitoring End of reaction.Reaction solution is poured slowly into water, water phase is extracted with dichloromethane.Merge organic phase, by organic phase washed with water It is washed with saturated sodium bicarbonate, organic phase is dry by anhydrous sodium sulfate, and evaporated under reduced pressure, residue chromatographs to obtain product by column (182mg, yield=60%).

Step D:2- (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) first Base) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-t-butoxycarbonyl glycine ester

By 182mg (0.23mmol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- Triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- Oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base-(2- ethoxy) carbonic ester, 80mg (0.46mmol, 2.0eq) t-butoxycarbonyl glycine, 116mg (1.15mmol, 5.0eq) triethylamine are dissolved in 5mL methylene chloride.It is added 175mg EDCI (0.92mmol, 4.0eq) adds back flow reaction and stays overnight, and TLC monitors end of reaction.Reaction solution is poured slowly into In water, water phase is extracted with dichloromethane.Merge organic phase, organic phase washed with water and saturated sodium bicarbonate are washed, it will be organic Mutually dry by anhydrous sodium sulfate, evaporated under reduced pressure, residue chromatographs to obtain product (134mg, yield=58%) by column.

Step E:2- (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) first Base) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-glycine ester hydrochloride

By 68mg (0.072mmol, 1.0eq) 2- (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H- 1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) benzene Base) -5- oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-tertbutyloxycarbonyl is sweet Propylhomoserin ester is dissolved in 3mL ethyl acetate, and hydrogen chloride gas is passed through under ice bath, is reacted at room temperature 1 hour, and TLC monitors end of reaction.It will be anti- Liquid evaporated under reduced pressure is answered, residue is target product (60mg, yield=95%).

¹H NMR(400MHz,DMSO-d6):δ8.50(s,1H),8.46(s,1H),8.40-8.35(m,3H),7.89(s, 1H), 7.76 (brs, 2H), 7.61 (d, J=8Hz, 1H), 7.33 (d, J=8Hz, 2H), 7.22 (d, J=8Hz, 2H), 7.06 (d, J=8Hz, 2H), 7.04-6.98 (m, 1H), 5.23 (t, J=8Hz, 1H), 4.63 (q, J=8Hz, 2H), 4.20-4.02 (m,4H),3.95-3.50(m,9H),3.46-3.36(m,4H),2.65-2.45(m,2H),2.25-1.70(m,3H),1.34- 1.22 (m, 4H), 1.15-1.05 (m, 4H), 0.80 (t, J=8Hz, 3H) .LC-MS:m/z=846 [M+H]⁺.

3 2- of embodiment (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) Methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-glycinate

By 30mg (0.066mol, 1.0eq) 2- (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1, 2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) benzene Base) -5- oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-glycinate hydrochloric acid Salt is dissolved in 20.0ml (2N) sodium carbonate liquor, is added and is stirred at room temperature 15 minutes, and TLC monitors end of reaction.Reaction solution is used Methylene chloride extraction.It is dry to merge organic phase, anhydrous sodium sulfate, evaporated under reduced pressure, residue by column chromatograph product (25mg, Yield=86%).LC-MS:m/z=846 [M+H]⁺.

4 2- of embodiment (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) Methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-Valine ester hydrochloride

The step of referring to described in embodiment 2, t-butoxycarbonyl glycine is replaced with into tertbutyloxycarbonyl-Valine, For preparing target compound (67mg, 95%).LC-MS:m/z=888 [M+H]⁺.

5 2- of embodiment (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) Methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-Valine ester

Target compound (66mg, 94%) is prepared referring to embodiment 3.LC-MS:m/z=888 [M+H]⁺.

6 2- of embodiment (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) Methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-piperidin -4- formic acid ester hydrochloride

The step of referring to described in embodiment 2, t-butoxycarbonyl glycine is replaced with into 1- (tertbutyloxycarbonyl) piperidines -4- Formic acid, for preparing target compound (80mg, 95%).LC-MS:m/z=900 [M+H]⁺.

7 2- of embodiment (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) Methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) oxygen) carbonyl) oxygen) ethyl-piperidin -4- formic acid esters

Target compound (57mg, 95%) is prepared referring to embodiment 3.LC-MS:m/z=900 [M+H]⁺.

Embodiment 8 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base-piperidines -4- formic acid ester hydrochloride

Step A:4- ((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) first Base) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- two Hydrogen -1H-1,2,4- triazol-1-yl) pentane -2- base) -1- t-butoxycarbonylpiperidin -4- formic acid esters

By 110mg (0.16mmol, 1.0eq) posaconazole, 91mg (0.39mmol, 2.5eq) 1- t-butoxycarbonylpiperidin- 4- formic acid, 52.8mg (0.48mmol, 3.0eq) triethylamine are dissolved in 5mL methylene chloride.75mg EDCI is added (0.39mmol, 2.5eq) adds back flow reaction and stays overnight, and TLC monitors end of reaction.Reaction solution is poured slowly into water, dichloro is used Methane aqueous phase extracted.Merge organic phase, organic phase washed with water and saturated sodium bicarbonate are washed, organic phase is passed through into anhydrous sulphur Sour sodium is dry, and evaporated under reduced pressure, residue chromatographs to obtain product (114mg, yield=80%) by column.

Step B:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- base-piperidines -4- formic acid ester hydrochloride

By 78mg (0.072mmol, 1.0eq) 4- ((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2, 4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) - 5- oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base) -1- t-butoxycarbonylpiperidin -4- formic acid esters is dissolved in In 3mL ethyl acetate, it is passed through hydrogen chloride gas under ice bath, reacts at room temperature 1 hour, TLC monitors end of reaction.Reaction solution is depressurized and is steamed Dry, residue is target product (65mg, yield=94%).

¹H-NMR(400MHz,DMSO-d6)δ9.20(brs,1H),8.92(brs,1H),8.61(s,1H),8.44(s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.0Hz, 2H), 7.59 (d, J=8.0Hz, 2H), 7.32 (t, J=8.0Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.07 (d, J=8.0Hz, 2H), 6.79 (d, J=8.0Hz, 1H), 4.70-4.58 (m, 4H), 4.17-4.00(m,4H),3.87-3.63(m,11H),3.21-3.13(m,1H),3.08-2.98(m,1H),2.93-2.80(m, 2H), 2.63-2.56 (m, 2H), 2.46-2.38 (m, 1H), 2.17 (dd, J=13.2,7.9Hz, 1H), 1.82-1.65 (m, 3H), 1.29 (d, J=8.0Hz, 3H), 0.79 (t, J=8.0Hz, 3H) .LC-MS:m/z=812 [M+H]⁺.

Embodiment 9 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base-piperidines -4- formic acid esters

Target compound (59mg, 93%) is prepared referring to embodiment 3.LC-MS:m/z=812 [M+H]⁺.

Embodiment 10 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base -1- methyl piperidine -4- formic acid ester hydrochloride

The step A referring to described in embodiment 8, replaces with 1- methyl piperidine -4- for 1- t-butoxycarbonylpiperidin -4- formic acid Formic acid prepares target compound (80mg, 95%).LC-MS:m/z=826 [M+H]⁺.

Embodiment 11 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base -1- methyl piperidine -4- formic acid ester hydrochloride

By 68mg (0.082mmol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- Triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- Oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base -1- methyl piperidine -4- formic acid esters is dissolved in 3mL acetic acid second In ester, it is passed through hydrogen chloride gas at room temperature, reacts at room temperature 1 hour, TLC monitors end of reaction.By reaction solution evaporated under reduced pressure, residue is For target product (68mg, yield=95%).LC-MS:m/z=826 [M+H]⁺.

Embodiment 12 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base -1- (2- (dimethylamine) ethyl) piperidines -4- formic acid esters

Step A: ethyl -1- (2- dimethylamino-ethyl) piperidines -4- formic acid esters

At room temperature by 157mg (1mmol, 1.0eq) 4- piperidine ethyl formate, 288mg (2mol, 2.0eq) dimethylamino chlorine Ethane hydrochloric acid, 318mg (3mol, 3.0eq) sodium carbonate are dissolved in 5mL toluene, and it is anti-to be heated to back flow reaction TLC monitoring in 16 hours It should finish.Filtering, filtrate decompression is concentrated, residue chromatographs to obtain product (84mg, yield=36%) by column.

Step B:1- (2- dimethylamino-ethyl) piperidines -4- formic acid

At room temperature by 330mg (1.44mmol, 1.0eq) ethyl -1- (2- dimethylamino-ethyl) piperidines -4- formic acid esters, 819mg (2.6mol, 1.8eq) barium hydroxide is dissolved in the mixed solution of ethyl alcohol (5mL) and water (4mL), is heated to flowing back Reaction 2.5 hours.It is concentrated under reduced pressure, adds water 30ml, 730mg (7.44mmol) ammonium carbonate is added portionwise and reacts at room temperature 2 hours.It takes out Filter, by filtrate decompression be concentrated to get yellow solid 1- (2- dimethylamino-ethyl) piperidines -4- formic acid (250mg, yield= 86%).

Step C:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- base -1- (2- dimethylamine-ethyl) piperidines -4- formic acid esters

The step A referring to described in embodiment 8, replaces with 1- (2- diformazan ammonia for 1- t-butoxycarbonylpiperidin -4- formic acid Base-ethyl) piperidines -4- formic acid, for preparing target compound.LC-MS:m/z=883 [M+H]⁺.

Embodiment 13 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base -1- (2- (dimethylamine) ethyl) piperidines -4- formic acid ester hydrochloride

Target compound is prepared referring to embodiment 11.LC-MS:m/z=883 [M+H]⁺.

Embodiment 14 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base (1- methyl piperidine -4- base) carbonic ester

290mg (2.52mmol, 2.0eq) 1- methyl -4- piperidine alcohols are dissolved in 30mL anhydrous tetrahydro furan, under ice bath It is slowly added to 60% sodium hydride of 100mg (2.52mmol, 2.0eq) in batches, finishes and ice bath stirring is kept to react 10 minutes.Ice bath Upper disposable addition 1.0g (1.26mol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- Triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- Oxo -4,5- dihydro -1H-1,2,4- triazol-1-yls) pentane -2- base -1- hydrogen-imidazoles -1- methyl esters, finish holding ice bath stirring 80mL saturated aqueous ammonium chloride quenching reaction is added in reaction 10 minutes, and water phase is extracted with dichloromethane, and merges organic phase, will Organic phase is dry with anhydrous sodium sulfate.Evaporated under reduced pressure solvent, residue by silica gel column chromatography obtain product 655mg (yield= 62%).

¹H-NMR(400MHz,CDCl₃) δ 8.16 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.46 (d, J=9.0Hz, 2H), 7.44-7.38 (m, 1H), 7.07 (d, J=9.1Hz, 2H), 6.97 (d, J=9.1Hz, 2H), 6.92-6.84 (m, 2H), 6.82 (d, J=9.0Hz, 2H), 5.18-5.06 (m, 1H), 4.69 (d, J=14.4Hz, 2H), 4.56 (d, J=14.3Hz, 1H), 4.29 (s, 1H), 4.19-4.12 (m, 1H), 3.86-3.79 (m, 1H), 3.74 (dd, J=9.1,5.7Hz, 1H), 3.69- 3.62(m,1H),3.43-3.36(m,4H),3.29-3.24(m,4H),2.85-2.42(m,6H),2.37(s,3H),2.15- 1.97 (m, 4H), 1.87 (d, J=7.5Hz, 3H), 1.41 (d, J=6.4Hz, 3H), 0.94 (t, J=7.3Hz, 3H) .LC-MS: M/z=842 [M+H]⁺.

Embodiment 15 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base (1- methyl piperidine -4- base) carbonate salt hydrochlorate

By 300mg (0.36mol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- tri- Azoles -1- base) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxygen Generation -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base (1- methyl piperidine -4- base) carbonic ester is dissolved in 20mL acetic acid In ethyl ester, it is slowly introducing dry HCl gas at room temperature 30 minutes, logical finish is stirred at room temperature 20 minutes, and evaporated under reduced pressure solvent must produce Object 310mg (yield=99%).

¹H-NMR (400MHz, DMSO-d6) δ 11.08 (s, 1H), 8.67 (s, 1H), 8.46 (d, J=15.7Hz, 1H), 8.00 (s, 1H), 7.88 (d, J=8.5Hz, 2H), 7.59 (dd, J=13.2,9.0Hz, 2H), 7.35-7.26 (m, 2H), 7.23 (dd, J=9.1,2.6Hz, 2H), 7.08 (d, J=9.1Hz, 2H), 7.01 (td, J=8.5,2.3Hz, 1H), 5.05-4.54 (m,3H),4.18-3.65(m,13H),3.42-2.83(m,4H),2.75-2.65(m,4H),2.65-2.54(m,1H),2.47- 2.38(m,1H),2.23-2.13(m,2H),2.00(s,3H),1.79-1.71(m,2H),1.34-1.20(m,3H),0.80(t, J=7.2Hz, 3H) .LC-MS:m/z=842 [M+H]⁺.

Embodiment 16 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- phenylpiperidines -4- base carbonate salt hydrochlorate

Step A: tert-butyl 4- (((((2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazole - 1- yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo - 4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- base) oxo) carbonyl) oxo) piperidines -1- carbonic ester

The step of referring to described in embodiment 14, comes prepare compound (350mg, yield=54%).

Step B:(2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1, 2,4- triazol-1-yl) pentane -2- phenylpiperidines -4- base carbonate salt hydrochlorate

The step of referring to described in embodiment 15, comes prepare compound (260mg, yield=99%).

LC-MS:m/z=828 [M+H]⁺.

Embodiment 17 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- phenylpiperidines -4- base carbonic ester

By 200mg (0.24mmol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- Triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- Oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- phenylpiperidines -4- base carbonate salt hydrochlorate is dissolved in 20mL water In, pH to 8-9 is adjusted with 2M aqueous sodium carbonate, water phase is extracted with dichloromethane, merges organic phase, organic phase passes through anhydrous sulphur Sour sodium is dry, and evaporated under reduced pressure obtains product (196mg, yield=100%).

LC-MS:m/z=828 [M+H]⁺.

Embodiment 18 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base [bis- piperidines of 1,4'-] -1'- carbonic ester

By 215mg (1.26mmol, 2.0eq) 4- piperidinyl piperidine, 500mg (0.63mmol, 1.0eq) (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) -5- (2,4 difluorobenzene base) tetrahydrofuran - 3- yl) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H-1,2,4- triazol-1-yl) pentane -2- Base -1- hydrogen-imidazoles -1- methyl esters and 410mg (3.2mmol, 5.0eq) N, N- diisopropyl ethyl amine are miscible in 30mL tetrahydrofuran In.Reaction system is warming up to back flow reaction 3 days.100mL aqueous solution quenching reaction is added, water phase is extracted with dichloromethane, closes And organic phase, organic phase is dry with anhydrous sodium sulfate.Evaporated under reduced pressure solvent, residue obtain product by silica gel column chromatography 130mg (yield=23%).

¹H-NMR(400MHz,CDCl₃)δ8.15(s,1H),7.84(s,1H),7.72(s,1H),7.55-7.37(m,3H), 7.07 (d, J=8.7Hz, 2H), 6.96 (d, J=9.0Hz, 2H), 6.93-6.85 (m, 2H), 6.81 (d, J=9.1Hz, 2H), 5.18-5.03 (m, 1H), 4.69 (d, J=14.4Hz, 1H), 4.56 (d, J=14.3Hz, 1H), 4.41-4.14 (m, 4H), 3.85-3.79(m,1H),3.76-3.71(m,1H),3.68-3.62(m,1H),3.45-3.37(m,4H),3.30-3.21(m, 4H), 3.19-3.09 (m, 4H), 2.78-2.54 (m, 5H), 2.16-1.41 (m, 13H), 1.36 (d, J=6.4Hz, 3H), 0.94 (t, J=7.2Hz, 3H) .LC-MS:m/z=895 [M+H]⁺.

Embodiment 19 (2S, 3S) -3- (4- (4- (4- (4- (((3R, 5R) -5- ((1H-1,2,4- triazol-1-yl) methyl) - 5- (2,4 difluorobenzene base) tetrahydrofuran -3- base) methoxyl group) phenyl) piperazine -1- base) phenyl) -5- oxo -4,5- dihydro -1H- 1,2,4- triazol-1-yl) pentane -2- base [bis- piperidines of 1,4'-] -1'- carbonate salt hydrochlorate

The step of referring to described in embodiment 15, comes prepare compound (73mg, yield=100%).

¹H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.60-8.39(m,2H),7.97-7.52(m,5H), 7.35-7.25 (m, 2H), 7.20 (d, J=7.1Hz, 2H), 7.10-6.95 (s, 3H), 4.90-4.80 (m, 1H), 4.70-4.52 (m,2H),4.13-3.51(m,18H),3.29-2.96(m,2H),2.60-2.50(m,1H),2.44-2.40(m,1H),2.22- 2.10(m,1H),1.86-1.63(m,6H),1.31-1.19(m,8H),1.18-1.14(m,3H),0.84-0.76(m,3H) .LC-MS:m/z=895 [M+H]⁺.

Following embodiment is prepared by similar approach:

Recruitment evaluation

1. solubility experiment

Test sample precision is weighed into appropriate rear addition 1mL water, places in 25 DEG C of environment, was shaken 30 seconds every 5 minutes, continued 30 minutes, observe dissolved state, detect each compound solubility through HPLC external standard correction method, the hydrochloride of embodiment compound with The solubility comparing result of posaconazole is shown in Table 1.

1. solubility test result of table

Table 1 the result shows that, solubility of the compound of the present invention in pure water is much better than posaconazole, effectively improves The water solubility of posaconazole.

2. stability experiment

Each test sample aqueous solution of 30mg/mL is placed in cillin bottle, sealing of jumping a queue, is 40 DEG C ± 2 DEG C, relatively in temperature It places 90 days in the stability test case that humidity is 60% ± 2%, is detected through HPLC, investigate test sample aqueous solution before and after placement Total miscellaneous changes of contents.It the results are shown in Table 2.

2. aqueous stability test result of table

Table 2 the result shows that, the compounds of this invention placed in pure water 90 days after have good stability.

3. pharmacokinetic studies

Male SD rat is grouped, every group 3, test compound sample clear aqueous solution is given in vein/stomach-filling respectively.It is dynamic Object overnight fasting before experiment, fasting time is from administration first 10 hours to 4 hours after administration.0.083 after the administration of vein group, 0.25, it takes a blood sample within 0.5,1,2,4,8 and 24 hour, takes a blood sample within 0.25,0.5,1,2,4,8,12 and 24 hour after the administration of stomach-filling group.It uses Toy Anesthesia machine takes 0.3mL whole blood by eyeground vein clump after isoflurane is anaesthetized, and is put in anticoagulant heparin pipe, sample in 4 DEG C, 4000rpm centrifugation 5min, blood plasma is transferred in centrifuge tube, and is put in -80 DEG C and is saved until analysis.Sample uses in blood plasma Precipitation of protein extraction, extract liquor analyze the content of untested compound and posaconazole by LC/MS/MS.Pharmacokinetics Experimental result is as shown in table 3, and drug-time curve (repeats three groups of experimental results) as shown in Figure 1, 2, 3.

3. intravenously administrable pharmacokinetic parameter of table

By table 3, Fig. 1 and Fig. 3 result it is found that 21 compound of the embodiment of the present invention can after water dissolves intravenously administrable, It avoids slightly solubility posaconazole and uses potential renal toxicity problem brought by cyclodextrin for hydrotropy.Moreover, embodiment 21 is changed It closes object and slowly resolves into posaconazole in blood, the internal instantaneous drug concentration after significantly reducing Cmax and administration makes medicine Object is steadily discharged, and is reduced toxicity problem brought by high drug concentration itself and is made because instantaneous drug concentration is excessively high Phlebitis problem caused by drug is precipitated, extends pharmaceutically-active half-life period, and the drug concentration after administration 24 hours still maintains The 51% of Cmax, the action time of drug in vivo is increased.As shown in Figure 2,21 combound itself of embodiment is in blood plasma Concentration gradually reduce, the 8th hour concentration close to disappear, in this process, the posaconazole being metabolized out by slowly uniformly It releases, this feature enables such compound to play the effect of sustained release.

Pharmacokinetic parameter is administered orally in table 4.

As shown in Table 4, the aqueous solution of 21 compound of the embodiment of the present invention makes posaconazole peak time under oral administration 6 hours are delayed, sustained release is played the role of.After using cyclodextrin solubilising, bioavilability can be only achieved posaconazole 66%, and bioavilability reaches 85% to embodiment 21 in aqueous solution, higher than effect of the posaconazole after cyclodextrin solubilising.

Bioavilability is also significantly improved other compounds in aqueous solution, as shown in table 5.

Bioavilability is administered orally in table 5.

4. drug effect in anti-fungal infection body

It takes male ICR mouse (18-22g), mouse tail vein injection (0.1mL/ is only) contains Candida albicans (1.5x10⁸CFU/mL infection liquid) causes mouse system fungal infection, and mouse is grouped at random, every group 10, respectively moors Saperconazole (HP- β-CD) group, test-compound group and solvent group, posaconazole are dissolved using HP- β-CD, other test-compounds With physiological saline solution, ultrasound is to after clarifying for being administered.After mouse tail vein injection candida albicans infection liquid 2h, respectively give Medicine group difference tail vein or gastric infusion 20mg/kg, administered volume 0.1ml/10g, solvent group give 0.9% sodium chloride solution 0.1ml/10g, once a day, successive administration 5 days.Dead mouse situation is observed, the time-to-live is recorded, altogether observation 7 days, as a result such as Shown in table 6,7.

6. systemic fungal infection intravenously administrable mouse survival rate (%) of table

Mouse survival rate (%) is administered orally in 7 systemic fungal infection of table

In terms of table 6,7 results, the mouse survival rate of the compounds of this invention administration is apparently higher than solvent group, and mouse is deposited within the 7th day Motility rate is higher than posaconazole group.

Although the preferred embodiments of the invention, those skilled in the art has been disclosed in order to illustrate the present invention Member can be the present invention it should be appreciated that in the case where not departing from present inventive concept defined by claims and range Various modifications, addition and replacement out.

Claims (10)

1. a kind of posaconazole derivative as shown in general formula (I) or its pharmaceutically acceptable salt, solvate, active metabolism Object, polymorph, isotopic label or isomers,

Wherein,

X independently indicates F, Cl or Br；

A indicates C or the hetero atom selected from one of O, N, S；

R ' indicates H, C_1~4Alkyl is not present；

A indicate hetero atom when, R indicate be substituted or be unsubstituted with one of flowering structure :-(CH₂)_nN(R₂)₂, containing extremely Few heteroatomic 5~8 unit monocycle heterocycle ,-(a CH₂)_nO(CO)-R₁Or R and A formed containing at least one heteroatomic 5 ~12 unit monocycles or bicyclic heterocyclic radical；Substituent group is selected from C_1~6Alkyl, C_1~6Alkyl amino, C_1~6Halogenated alkyl, C_1~6Alkoxy or C_3~6Naphthenic base；

N indicates 2~6 integer；

R₁Indicate C_1~6Alkoxy, C_1~6Alkyl amino contains at least one heteroatomic 5~8 unit monocycle heterocycle；

R₂Indicate hydrogen, C_1~4Alkyl or-N (R₂)₂It is formed and contains at least one heteroatomic 5~8 unit monocycle heterocycle；

When A indicates C, what R and A formation was substituted or was unsubstituted contains at least one heteroatomic 5~8 circle heterocyclic ring base；Replace Base is selected from C_1~6Alkyl, C_1~6Alkyl amino, C_1~6Halogenated alkyl, C_1~6Alkoxy or C_3~6Naphthenic base；

The hetero atom is selected from one of O, N, S.

2. posaconazole derivative according to claim 1 or its pharmaceutically acceptable salt, solvate, active metabolism Object, polymorph, isotopic label or isomers, wherein the pharmaceutically acceptable salt is pharmaceutically acceptable salt Hydrochlorate.

3. posaconazole derivative according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate, activity Metabolin, polymorph, isotopic label or isomers, wherein the A indicates O or N, the R expression be substituted or without Replace-(CH₂)_nN(R₂)₂, the integer of n expression 2~5, R₂Indicate C_1~4Alkyl or-N (R₂)₂It is formed and contains at least one miscellaneous original 5~7 unit monocycle heterocycles of son, substituent group are selected from C_1~4Alkyl；Preferably, the monocyclic heterocycles base contains the-N (R₂)₂Base One or more hetero atoms in N hetero atom in group, and optional O, N, S.

4. posaconazole derivative according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate, activity Metabolin, polymorph, isotopic label or isomers, wherein the A indicates O, and the R expression is substituted or without taking 5~6 unit monocycle heterocycles containing at least one N atom in generation, substituent group are selected from C_1~4It alkyl and is connect with the N atom.

5. posaconazole derivative according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate, activity Metabolin, polymorph, isotopic label or isomers, wherein the A indicates O, and the R expression is substituted or without taking Generation-(CH₂)_nO(CO)-R₁, the integer of n expression 2~5, R₁Indicate C_1~4Alkoxy, C_1~4Alkyl amino contains at least one N 5~6 unit monocycle heterocycles of atom, substituent group are selected from C_1~4Alkyl.

6. posaconazole derivative according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate, activity Metabolin, polymorph, isotopic label or isomers, wherein the A indicate N, the R and A formed be substituted or without What is replaced contains comprising heteroatomic 5~12 unit monocycle of at least one N or bicyclic heterocyclic radical including A, and substituent group is selected from C_1~4Alkane Base.

7. posaconazole derivative according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate, activity Metabolin, polymorph, isotopic label or isomers, wherein the A indicate C, the R and A formed be substituted or without 5~6 unit monocycle heterocycles containing at least one N atom replaced, substituent group are selected from C_1~4Alkyl or C_1~6Alkyl amino, and It is connect with the N atom.

8. posaconazole derivative according to claim 1 or its pharmaceutically acceptable salt, solvate, active metabolism Object, polymorph, isotopic label or isomers, wherein selected from flowering structure:

9. a kind of pharmaceutical composition, it includes the described in any item posaconazole derivatives of claim 1-8 or its pharmaceutically may be used Salt, solvate, active metabolite, polymorph, isotopic label or the isomers of receiving and pharmaceutically acceptable load Body.

10. the described in any item posaconazole derivatives of claim 1-8 or its pharmaceutically acceptable salt, solvate, work Property metabolin, polymorph, isotopic label or isomers and pharmaceutical composition as claimed in claim 9 it is anti-in preparation Bacterium drug, the purposes especially in antifungal drug.