CN103554025B - 3-arsenic triazole carboxylic acid's amides compound, its preparation method and preparation as the application in CB1 acceptor inhibitor medicine - Google Patents

Abstract

The present invention relates to a kind of 3 arsenic triazole carboxylic acid's amides compounds, its preparation method and its preparation as the application in CB1 acceptor inhibitor medicine, belong to pharmaceutical chemistry technical field.Wherein, the chemical structure of general formula of this compound is as shown in (I):Wherein, R1 is 1,5 disubstituted phenyl 4 R9 pyrazoles 3 bases, and its chemical structure of general formula is as shown in (II):Technical points is the R in logical formula (I)₃Corresponding to various alpha amino acidsSubstituent group beyond amino and carboxyl in molecule；R₆And R₇It is H simultaneously, or is O jointly.Compound of the present invention has the external activity the most suitable with profit, and toxicity Billy the most substantially reduces.

Description

3-arsenic triazole carboxylic acid's amides compound, its preparation method and preparation be subject to as CB1 Application in body inhibitor medicaments

The application is the divisional application of an application for a patent for invention.The filing date of original application on 05 12nd, 2011, Shen Please number be 201110122819.1, invention and created name be " 3-arsenic triazole carboxylic acid's amides compound, its preparation method and in system Standby as the application in CB1 acceptor inhibitor medicine ".

Technical field

The present invention relates to a kind of 3-arsenic triazole carboxylic acid's amides compound, its preparation method and its be subject to as CB1 in preparation Application in body inhibitor medicaments, is specifically related to it and is preparing anti-additive medicament, slimming medicine as CB1 acceptor inhibitor and controlling Treat the application in diabetes medicament, belong to pharmaceutical chemistry technical field.

Background technology

Since the product profit of Sanofi-Aventis company of France is the most just like that because of the toxic and side effects for central nervous system And withdraw from the market, the many enterprises such as U.S., method, print, Korea Spro, Hungary find the CB1 acceptor inhibitor that they are studied, although each other Between structure quite different, the most all show same toxicity.Within one not long period, a lot of pharmacy men were once suspected, this Plant toxic and side effects and be probably what CB1 acceptor inhibitor was difficult to avoid that.But in the near future, pharmacy men are i.e. devoted to research and make it The strategy that toxicity separates with drug effect.Even it is believed that the real beginning of research " the most just CB1 acceptor inhibitor " [¹]。

Summary of the invention

It is an object of the invention to, for the CB1 acceptor inhibitor that the toxicity of prior art is stronger, it is provided that Yi Zhongxin Hypotoxic CB1 acceptor inhibitor, and the application in preparing anti-additive medicament of this hypotoxic CB1 acceptor inhibitor, Application in preparing slimming medicine, and the application in preparation treatment diabetes medicament.CB1 receptor of the present invention presses down Preparation can be used for preparing anti-additive medicament, slimming medicine and treatment diabetes medicament, has the external activity the most suitable with profit, And toxicity (especially for the toxicity of central nervous system) Billy the most substantially reduces, it is expected to overcome the CB1 of prior art The Side effect that acceptor inhibitor is shown.

In order to realize the technical purpose of the present invention, technical scheme is as follows.

One, a kind of 3-arsenic triazole carboxylic acid's amides compound, its chemical structure of general formula is as shown in (I):

Wherein, R₁For 1,5-disubstituted phenyl-4-R₉-pyrazole-3-yl, as shown in structure formula (II):

In structure formula (II):

A₂, A₃, A₄, A₅, A₆；B₂, B₃, B₄, B₅, B₆It is same to each other or different to each other, for H, F, Cl, Br, or I atom, C1-C3 Alkyl, C1-C3 alkoxyl, trifluoromethyl or nitro；B₄Or phenyl；

In structure formula (II), A₂, A₃, A₄, A₅, A₆；B₂, B₃, B₄, B₅, B₆In these substituent groups, at least one is chlorine Atom or methyl；B₄Especially chlorine or bromine；A₂And A₄Especially chlorine；

Substituent R on pyrazole ring 4 in structure formula (II)₉For hydrogen or C1-C5 alkyl, especially methyl or ethyl；Alkane Base can be straight or branched；

In structure formula (II), the substituent group that pyrazole ring is 3 is corresponding to the amide in structure formula (I), and this part is amino Acid, or the recessive carboxyl of the ester of the multi-form of aminoacid carboxyl, amide or heterocyclic forms；Or amino acid whose carboxyl quilt The produced alcohol of reduction；And the derivant of this alcohol, such as ether or various forms of ester；

In structure formula (I), R₂It is the alkyl of H, C1-C5 straight or branched, it is also possible to be acyl group；

In structure formula (I), R₄And R₅It it is the alkyl of H or C1 to C10 straight or branched；Any one carbon in alkyl On can be replaced, substituted group can be halogen, hydroxyl, sulfydryl or sulfonic group；R₄With R₅Can mutually the same or Different；

In structure formula (I), n can be equal to 0(zero), 1,2,3,4 or 5；

In structure formula (I), R₆And R₇It is H simultaneously, or is O jointly；

Wherein the first situation is to work as R₆And R₇When being H simultaneously, R₃It may be that but be not limited only to H, CH₃、CH₂CH₃、 CH₂CH₂CH₃、CH(CH₃)₂、CH₂SH、CH(OH)CH₃、CH₂COOH、CH₂CH₂COOH、CH₂C₆H₅、CH₂C₆H₄(2-Cl)、CH₂C₆H₄ (3-Cl)、CH₂C₆H₄(4-Cl)、CH₂C₆H₃(2,4-bis-Cl), CH₂C₆H₃(3,4-bis-Cl), CH₂C₆H₄(4-OH)、CH₂C₆H₄(2- OCH₃)、CH₂C₆H₄(4-OCH₃)、CH₂C₆H₃(2,4-bis-OCH₃)、CH(CH₃)CH₂CH₃、CH₂CH₂CH₂CH₂NHCOR₁、CH₂CH (CH₃)₂、CH₂CONH₂、CH₂CH₂CONH₂、 CH₂C₆H₄(4-OCF₃)、CH₂CH₂SCH₃, orOr CH₂C₆H₄(4-OR₁₀), R₁₀It is defined as follows and states.

Further, R is worked as₃When being not equal to H, the amino acid whose absolute configuration of amide moieties can be R, can be S, it is also possible to be Racemic mixture both this；

Work as R₆And R₇When being H simultaneously, R₈It is OR₁₀；

Wherein, R₁₀Can be H, (C1-C16) straight chain, side chain or ring-type alkyl, as cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, trifluoromethyl；R₁₀Can also is that the acyl group of the saturated of various C1-C16 or undersaturated fatty acid, these acyl groups can With the substituent group with halogen, amino, alkoxyl etc, such as acetyl group, ChloroacetYl, acrylic acid acyl group, beta-methoxy carbonyl Base propiono, β-carboxypropanoyl, γ-maloyl group etc.；R₁₀Can also is that various aromatic acyl group, such as benzoyl Base, substituted benzoyl etc.；Or even various aliphatic or aromatic amino acid whose acyl group, the such as acyl of alanine Base, the acyl group of phenylalanine, pantonine-(2-thiazolyl)-alanine acyl group etc.；Amino acid whose configuration can be R, it is possible to To be S, it is also possible to be their racemic mixture；

The second situation, in structure formula (I), works as R₆And R₇When being O jointly, R₃It is CH₂CH₂SCH₃、Or Person CH₂C₆H₄(4-OCF₃)；

Now, R₈It is OR₁₀Or NR₁₁R₁₂；

Wherein, R₁₀Can be H, (C1-C16) straight chain, side chain or ring-type alkyl, as cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl；

At NR₁₁R₁₂In, R₁₁With R₁₂Can be H, C1-C6 straight chain, side chain or ring-type alkyl；At same intramolecular, R₁₁ With R₁₂Can be identical or different；

Work as R₁₀During equal to H, the present invention includes possibly as medicinal, this acid react with cation and the salt that produces, all Such as sodium, potassium, magnesium, calcium, or the salt that various quaternary ammonium cations is formed；

In structure formula (I),Can also be itrile group CN, can be the heterocycle derived by carboxylic acid, including R in formula₁₃For hydrogen or C₁-C₆Straight chain, side chain or Ring-type alkyl.

Compound described herein (I) also includes other various possible salts, other described possible salt bags Include, but be not limited to hydrochlorate, hydrogen bromide salt, sulfate, sulfur hydrogen salt, dihydrogen orthophosphate, mesylate, methyl sulfate salt, Maleate, fumarate, oxalates, naphthalene-2-sulfonic acid salt, gluconate, citrate, hydroxyethylsulfonic acid. Salt, tosilate, or 3,5-dimethyl-benzyl sulfonate and and alkyl halide, particularly C₁-C₁₀The chloride of alkyl, bromine The quaternary ammonium salt that compound or iodide are formed.

CB1 acceptor inhibitor representated by structure formula (I) also includes: by its corresponding free acid of certain ester therein or The complex that the salt of person's acid is formed；Or the complex formed with other compound meeting structure formula (I) is for treating The illness relevant to CB1 receptor.The ratio of each composition in complex, can give adjustment according to the emphasis for the treatment of.

In a word, compared with the various CB1 acceptor inhibitors that countries in the world have been delivered, as a part for molecule, this Bright structure is had aminoacid primitive that is that introduced by esterification, amidatioon or alternate manner, natural or that synthesize.

Hypotoxic CB1 acceptor inhibitor of the present invention, except the compound itself required represented by structure formula (I) Outward, their solvate is also required.

The prioritization scheme that the application recommends, i.e. should be top-priority: A₂, A₄, and B₄These three substituent group is chlorine atom Or the compound of bromine atoms.

Two, the preparation method of 3-arsenic triazole carboxylic acid's amides compound of the present invention:

First by aminoacid by thionyl chloride and methanol esterification, obtain the hydrochlorate of amino acid methyl ester, then with 5-(4- Halogenophenyl)-1-(2,4-Dichlorobenzene base)-4-alkyl-1H-pyrazoles-3-carboxylic acid chloride (II) condensation, i.e. obtain product methyl ester (III)；Ester obtains corresponding free acid (IV) through basic hydrolysis.Under the catalysis of EDC.HCl, HOBT, this acid and alcohol react To ester (V)；Or react with amine, obtain amide (VI).As shown in reaction equation 1:

In order to prepare the ester (V) of other form, it is also possible to first react to be converted into corresponding alcohol by aminoacid and expected Amino-acid ester (VII), then with above-mentioned acyl chlorides (II) be condensed, as shown in reaction equation 2.The preparation method of intermediate (VII) can With identical with methyl ester；Water knockout drum can be utilized to add with corresponding alcohol in aminoacid under acid (such as p-methyl benzenesulfonic acid hydrate) catalysis Hot reflux, dehydration esterification.Can also from N-Boc aminoacid, EDC hydrochlorate, HOBT, DMAP catalysis under be condensed with alcohol After slough protection group Boc again.

As by aforesaid amino acid methyl ester (I) in addition ammonolysis, produced amino acid amide (VIII) contracts with acyl chlorides (II) Close, then obtain the amide (IX) of unsubstituted on nitrogen, such as reaction equation 3:

The amide obtained is processed with phosphorus oxychloride and just produces nitrile, such as reaction equation 4:

By condensation substance methyl ester with lithium boron hydrogen reduction, just obtain corresponding alcohol；Make this alcohol and various aliphatic or aromatic series Carboxylic acid, the aminoacid of protection be condensed under the effect of catalyst, or with the acyl chlorides direct polycondensation of above-mentioned various acid, just obtain Corresponding various ester, such as reaction equation 5:

R in formula₁₀For various aliphatic or aromatic carboxylic acid or amino acid whose acyl group.

Inventor is in patent application before^[2]In once mentioned tyrosine condensation substance (compounds X III, IC₅₀227.4nM)；Finding later, once by the HM on its phenyl ring, the inhibitory activity for CB1 receptor just improves A lot (compound ZH-313-SM, IC₅₀26.3nM).In this application, for pursuing higher activity, inventor is by this hydroxyl three Fluoromethylation obtains (XIV)；Reply as after methyl ester (XV), be then reduced into alcohol (XVI), with various different acyl chlorides or acid therewith React and form ester (XVII), such as reaction equation 6:

Or, if first protecting the hydroxyl on tyrosine condensation substance (XIII) to provide intermediate (XVIII), reduction produces Alcohol (XIX), trifluoromethylation obtains (XX), then sloughs protection group and just obtain compound (XXI), finally with various different acyl chlorides Or acid reacts and is formed for another class ester (XXII), such as reaction equation 7:

Three, 3-arsenic triazole carboxylic acid's amides compound of the present invention is being prepared as in CB1 acceptor inhibitor medicine Application.

Wherein, described application refers to its application in preparing anti-additive medicament, stop smoking medicine or Temperance medicine.

Described application refers to its application in preparing slimming medicine.

Described application refers to that it is in the application in preparation treatment diabetes medicament.

The action principle of the present invention and having the beneficial effects that:

The reality being eliminated because toxicity is too high in view of existing CB1 acceptor inhibitor Rimonabant, the strategy of the present invention, It is that the drug effect seeking this type of medicine separates with its toxicity；With the highest druggability, rather than the highest activity is for pursuing a goal.Very The IC of many marketed drug₅₀Numerical value is to represent with μM (1,000nM), and according to the experiment value of inventor, the IC of Rimonabant₅₀ For 11.2nm, it is seen that its activity is the highest.In order to pursue the reduction of toxicity, the highest activity, one can be tolerated completely Determine the sacrifice of degree.First part of related application applicant^[2]In, the IC of compound ZH-303-SA₅₀Numerical value is up to 3, 500nM, under the concentration of 10 μMs, the most just corresponding to the suppression ratio of CB1 receptor 9 5%.True based on this, it has been recognised by the inventors that just For CB1 acceptor inhibitor, every IC₅₀Numerical value be less than 5,000nM(5 μM) compound, as long as toxicity is the lowest, it is possible to become Good clinical medicine.To this end, various aminoacid are introduced molecule with the form of ester by inventor, after being hydrolyzed into free carboxy acid, then from Carboxylic acid derives the recessive carboxyl of the ester of multi-form, amide or heterocyclic forms, or is reduced into alcohol, and is further converted to Various different esters, thus improve the hydrophilic of compound, increase donor and/or the acceptor number of hydrogen bond simultaneously.Applicant's Previous patent application^[2]In, inventors herein propose the condensation substance of phenylalanine etc. and arsenic triazole carboxylic acid, the most all show powerful work Property, and toxicity is the lowest.Inventor in the research of polypeptide drug it is found that, when with pantonine-(2-thienyl)-the third During acid substituted benzene alanine, the activity of product is the most powerful.In view of this, inventor synthesized the last stage research and on Once apply for^[2]In the condensation substance of pantonine-(2-thienyl)-propanoic acid of not related to and arsenic triazole carboxylic acid；In view of fluorine atom Specific action, inventor have studied the condensation substance of pantonine-(4-trifluoromethyl-phenyl)-propanoic acid；And for previous specially It has been already mentioned that but the methionine condensation substance do not furtherd investigate has made further exploitation in profit application.

It is, in general, that hydrophilic group inherently may make drug toxicity decline；It the most necessarily drops low molecular blood brain barrier Penetration ration, makes medicine less entrance central nervous system.These factors should weaken the side effect causing depression.Moreover, because Inhibitor is for the pharmacological action of CB1 receptor in peripheral nervous and central nervous system incomplete same, the chemical combination of the present invention Thing may act on periphery stomach function regulating enteric nervous system more, will show certain characteristic, may show the most exactly more preferably Fat-reducing effect.

Free acid relatively low from blood brain barrier Penetration ration for ester higher for blood brain barrier Penetration ration is combined in different ratios Use, particularly by this compounds and applicant's earlier patent application^[2,3,4]In apllied compound merge use, then have Optionally may act on cental system or peripheral nervous system by emphasis, thus produce different pharmacological effects.

As a rule, asymmetric center is the most just introduced the while of introducing amino acid whose.Since it has been recognised by the inventors that life Inherently chirality, the molecule with chirality more will may have single-minded drug effect, it is also possible to make toxicity reduce.

Make a general survey of the high activity CB1 acceptor inhibitor found so far, it can be seen that any one portion in this quasi-molecule Position they can replaced or modify all do not have the strongest specificity, close molecule itself is likely to be this One of common trait of quasi-molecule.By introducing different aminoacid, " compactness " or the profile of molecule are adjusted by inventor Joint, inventor expects that this also will assist in and facilitates drug effect to separate with toxic and side effects.

Amino acid whose introducing is also possible to improve the bioavailability of compound.

It practice, the toxicity of CB1 acceptor inhibitor can separate with its drug effect, inventor's preliminary study goes out aminoacid Compound and two classifications of 3-hydroxylpiperidine compounds^[2,3,4], they all show the most powerful, even with Rimonabant phase Same external activity, and toxicity is the lowest；The apllied a lot of compounds of this patent are also such.

This patent research finds again, and the methyl ester of amino condensation compound still shows the strongest work through the produced alcohol of reduction Property, representational compound is listed in table 4 below；Hypotoxicity, highly active esters can be derived again further from this alcohol, Such as above-mentioned reaction equation 5, shown in 6,7；Table 5 that part of compounds is listed below and table 6.

Applicant and with regard to this propose a kind of new theory: " single composite medicine ".Hereby with the ZH-303-SAL-13 in table 5 As a example by be explained, such as reaction equation 8:

Compound ZH-303-SAL-13 is the compound of a kind of " single ", but once enters human body, is being partly absorbed While, certainly will partly be hydrolyzed into ZH-303-SAL-00 and 2,4-dichlorobenzoic acid.The latter is inactive , safety by-product；The former is but activated (IC₅₀198.1nM), it is also absorbed by health.So " single " changes Compound ZH-303-SAL-13 once enters human body, has reformed into " the dual composite medicine " of this prototype and its both hydrolyzate, Thus produce comprehensive effect.Prototype compound ZH-303-SAL-13, as a kind of ester, is easier to through blood brain barrier；And water Hydrolysis products ZH-303-SAL-00 is relatively strong, by less entrance cental system due to hydrophilic.The ratio of the two reactive compound, The ratio the most just being absorbed equal to prototype compound and being hydrolyzed；And this ratio can regulate；The method of regulation, just It is to change ester group.The actually Penetration ration of the blood brain barrier of prototype ester itself can also regulate, and the mode of regulation is still that change The blood brain barrier Penetration ration of ester group: ZH-303-SAL-01 is clearly different from ZH-303-SAL-13.

List of references:

[1]F.J.Bermudez-Silva,d,M.P.Viverosb,J.M.McPartland c,F.Rodriguez de Fonseca a；“The endocannabinoid system,eating behavior and energy homeostasis: The end or a new beginning?”；Pharmacology,Biochemistry and Behavior;95(2010) 375-382.

[2] Fan Rulin；Chinese patent application 201010187654.1.

[3] Fan Rulin, Chen Zhiyuan；Chinese patent application 201110027174.3.

[4] Fan Rulin；Chinese patent application 201110092998.9.

Accompanying drawing explanation

Fig. 1 is the testing result (first group) determining product external activity by measuring the suppression ratio of CB1 receptor；

Fig. 2 determines the testing result (second group) of product external activity by measuring the suppression ratio of CB1 receptor.

The external activity of product

5-(4-halogenophenyl)-1-(2,4 dichloro benzene base)-4-alkyl-1H-pyrazoles-3-carboxylic acid synthesized by the present invention or Its acyl chlorides and amino acid whose condensation substance and the carboxylic acid derivates of these condensation substances, including methyl ester, the ester of other form, amide, Free acid, the recessive carboxyl compound of heterocyclic forms and reduzate alcohol or the esters derived further by this alcohol, In vitro in screening active ingredients, majority all shows the highest or high inhibitory activity, relevant IC to CB1 receptor₅₀Data according to The classification of compound lists table 2 below in respectively to table 5.IC₅₀Data system is measured by two kinds of methods:

First method, is measured by U.S.'s associated mechanisms, experimental procedure:

First radioactivity [3H]-Li Mo is dissolved in the combination based on HEPES containing 0.25%BSA (pH7.4) just like that Buffer, concentration is 2～5nM；Put into 3 μ g in 96 The Small Wells on test board and express the Chinese hamster ovary celI film egg of CB1 receptor In vain；Sample is dissolved in DMSO with the ratio of 1:100 and is incorporated in these The Small Wells.Test board is allowed at room temperature to hatch 1.5 little Time；With a Packard cell harvestor, reactant mixture being proceeded to GF/B filter plate makes association reaction terminate.Washing filter plate, plate On material with Packard scintillation counter (Packard TopCount Scintillation Counter) calculate；Add The inactive profit of excess 1000 times measures non-specific connection the most just like that；Deduct non-specific connection from sum and be special company Connect.Based on total and non-specific connection, CPM is scaled inhibition percentage；IC50 value is calculated with suppression data and curve.

Second method, is measured by Zhejiang University's school of life and health sciences bio-technology department.With once surveying according to first method 3 compounds determined as internal standard, (ginseng table 1), experimental procedure:

1. cell is cultivated and stable expression cell strain builds: the cell strain for this project is mainly HEK293 cell.This Planting cell uses DMEM culture medium to add 10%FBS.Cell transfecting or cotransfection receptor expression vector and reporter gene expression carrier are used Lipofectamine-2000.After transfecting 24 hours, adding G418, HEK293 cell is 800 μ g/mL, within three-four days, changes and once contains G418 fresh culture.After two weeks, it is seen that significantly population of cells, after choosing 20-30 population of cells's expansion, use functional experiment Or flow cytometry recipient cell surface expression and the effect of reporter gene, good to overexpression cell line or functional test Cell strain is frozen after expanding, and tests for drug screening, functional activity and combines the experiments such as active testing.

2. the detection of intracellular cAMP concentration: at cannabinoid CB 1 receptor and CRE-Luciferase stable expression cell strain Cell adds serum-free DMEM, the preincubate 15min containing variable concentrations compound, adds CB1 agonist win55212-2 Make final concentration of 1 μM, after stimulating 4-5h, detect cAMP activity.

3. the mensuration of luciferase activity: cellular level high flux screening model uses cAMP response element (CRE) to control Under luciferase expression vector detection cAMP, final use detection luciferase activity to determine_cAMP activity.Luciferase Activity test method: first suck the culture medium containing part, every hole adds 100 μ L lysates, after shaking table hatches 15min, inhales The 20 μ L detection liquid taking 20 μ L lysate sample and prepare mix, and put into rapidly in F12 detector, read 5 seconds interior average Luminous intensity, with luminous intensity reflection luciferase expression number.Thus convert the suppression ratio for CB1 receptor.

The result of the mensuration of this patent compound is respectively in table 2 to table 6；The measurement result of second method also sees accompanying drawing 1 and accompanying drawing 2.

Table 1, two kinds of results analyzing method: for the IC of CB1 receptor₅₀Numerical value and the reference of inhibition percentage

Table 2, the ester of amino acid condensation and the external activity of acid, for the IC of CB1 receptor₅₀Numerical value or suppression ratio

Table 3, the amide of amino acid condensation and the external activity of nitrile, for the IC of CB1 receptor₅₀Numerical value or suppression ratio

Table 4, the external activity of the alcohol of amino acid condensation, for the IC of CB1 receptor₅₀Numerical value or suppression ratio

Table 5, the ester of amino acid condensation alcohol or the external activity of ether, for the IC of CB1 receptor₅₀Numerical value

Table 6, the external activity of the amino-acid ester of amino acid condensation alcohol, for the IC of CB1 receptor₅₀Numerical value

The compounds of this invention is for the acute toxicity of mice

In the compounds of this invention, the toxicity of some compound is the lowest, the ZH-303-in the most above-mentioned tabular compound SAL-13 poison almost completely free for mice.

Compound ZH-303-SAL-13 acute toxicity test:

Animal: body weight 18～22g mice, male and female half and half.Exploration 0 and the dosage range of 100% mortality rate.

Method: take each 9 of male and female mice, be respectively divided into 3 groups, ZH-303-SAL-13 Yu 1%CMC is configured to 5,000mg/ Kg, 1,670mg/Kg, 557mg/Kg Three doses (9:3:1), be administered to respectively three groups of mouse stomaches.

Rimonabant is made into same solution, 3 groups of mices are made parallel controlled trial.Separately take each 3 of male and female mice, use 1%CMC gavage (blank group).Breeding observing 7 days.ZH-303-SAL-13 group is without dead mouse.And as the profit compareed the most just like that Group, 5, under the dosage of 000mg/Kg, mice is the most dead in 5 days, and 1,670mg/Kg dosage lower part is dead.

The synthesis of compound

Embodiment 1:2-(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid methyl (ZH-301-SM) and corresponding acid (ZH-301-SA) thereof.

A) L-Methionine methyl ester hydrochloride

Under ice-salt bath cools down, the SOCl that will newly distill₂7.2mL(98.7mmol) it is slowly dropped to 100mL CH₃In OH, Temperature controls below-10 DEG C, drips complete follow-up continuous stirring 1 hour；It is added thereto to L-Methionine 8.19g (54.9mmol), temperature rising reflux 1 hour；Remove solvent under reduced pressure to dry；Add the CH of 50mL2M HCl₃OH solution, backflow 1 is little Shi Hou, concentrating under reduced pressure, vacuum drying, obtain 8.5g white solid.Yield 77.6%, mp, 147.9～148.2 DEG C.¹H-NMR (400MHz, D₂O) δ: 2.05 (s, 3H)；2.2(m,2H)；2.62(m,2H);3.80(s,3H);4.25(dd,1H).B)2-(S)- [5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide groups]-4-first mercaptobutyric acid methyl (ZH- 301SM).

Under nitrogen protection, by 5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acyloxy Chlorine (2.0g, 5mmol, 1eq.) is dissolved in 20mLCH₂Cl₂, it is cooled to 0 DEG C；It is slowly added dropwise L-Methionine methyl ester hydrochloride wherein (1.20g, 6mmol) and Et₃N(1.52g, 15mmol) at 20mLCH₂Cl₂In solution, control reaction temperature at about 0 DEG C.Drip Add complete i.e. end to react；Successively with water and the washing of saturated NaCl solution；With anhydrous Na₂SO₄It is dried, is evaporated to oily, very Empty dry.2.11g solid, yield 80.2%, mp, 79.1～81.0 DEG C are obtained through column chromatography purification (eluant: EA:Hex=1:4)；¹H-NMR(400MHz, CDCl₃) δ: 2.10 (m, 1H)；2.13(s,3H)；2.28(m,1H)；2.38(s,3H)；2.62(m,2H)； 3.80(s,3H)；4.95(m,1H)；7.07-7.46(m,7H).

C) 2-(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide groups]-4-first Mercaptobutyric acid (ZH-301SA)

By 2-(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide groups]-4-first The KOH/methanol solution (3.9mL, 7.8mmol) of mercaptobutyric acid methyl (ZH-301SM) (1.35g, 2.6mmol) and 2M joins 50mLCH₃In OH, after stirring 2 hours under room temperature, remove solvent under reduced pressure.40mLH is added in residue₂O, with 2 × 40mLEtOAc washs, and aqueous phase 6M HCl is acidified to pH2；Stir under room temperature 2 hours, then extract with 5 × 10mLEA, extract Liquid is through anhydrous Na₂SO₄It is dried, is evaporated to oily；Be vacuum dried to obtain solid 1.13g, yield 86.26%, mp, 103.1～ 104.6℃；¹H-NMR(400MHz, CDCl₃) δ: 2.15 (s, 3H)；2.16(m,1H)；2.32(m,1H)；2.35(s,3H)；2.66 (m,2H)；4.91(m,1H)；7.07-7.51(m,8H).

Embodiment 2:(S) and-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid ring pentyl ester-

(ZH-301-SAE-3)

A) L-Methionine ring pentyl ester trifluoroacetate

N-Boc-L-methionine 0.8g (3.2mmol) is dissolved in 10mL dichloromethane, and ice bath is cooled to 0 DEG C, adds wherein Enter cyclopentanol 0.34mL (3.74mmol), EDC.HCl1.19g(6.2mmol) and DMAP38mg (0.31mmol), add three second Amine 1.2mL (9mmol).Reactant liquor is allowed to be slowly increased to room temperature and to continue to stir 12 hours；Add 30mL dichloromethane after completion of the reaction Alkane dilutes, sequentially with appropriate 1N HCl, 1N NaHCO₃Wash with saturated aqueous common salt.Organic layer is dried through anhydrous magnesium sulfate；Concentrate Gained crude product is quick crosses column purification, obtains the N-Boc-L-methionine ring pentyl ester of 0.7g oily, yield 69%.¹H-NMR(CDCl₃): δ: 1.45 (s, 9H);1.61-1.93(m,10H);2.11(s,3H);2.52-2.54(m,2H);4.34-4.35(m,1H); 5.14-5.22(m,1H)

This ring pentyl ester 0.7g (2.20mmol) is dissolved in TFA/DCM (v/v=1/1) 30mL, is stirred at room temperature 3 hours, decompression The trifluoroacetate of aminoacid ring pentyl ester is obtained after concentration.

B) (ZH-301-SAE-3)

By 5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid chloride 202mg (0.5mmol) it is dissolved in 5mLDCM, under ice-water bath, is slowly added to the trifluoroacetate dissolved with 200mg above-mentioned aminoacid ring pentyl ester (0.6mmol) and the DCM solution 3mL of 0.21mL triethylamine；Stirring 10 minutes under room temperature, TLC display reaction is complete；Reduce pressure dense After contracting, through column chromatography purification, obtain 190mg, yield 55%；Mp, 52-52.8 DEG C；¹H-NMR(CDCl₃): δ: 1.62-1.89 (m, 8H)；2.05-2.09(m,1H);2.13(s,3H);2.23-2.26(m,1H);2.37(s,3H)；2.54-2.62(m,2H)； 4.85-4.87(m,1H)；5.24-5.26(m,1H)；7.07-7.49(7H).

Embodiment 3:2-(S)-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid methyl (ZH-401-SM) and corresponding acid (ZH-401-SA) thereof

Under nitrogen protection, by 5-(4-bromophenyl)-1-(2,4-Dichlorobenzene base)-4-ethyl-1H-pyrazoles-3-carboxylic acyloxy Chlorine 2.0g(4.36mmol) it is dissolved in 20mLCH₂Cl₂, it is cooled to 0 DEG C；It is slowly added dropwise L-Methionine methyl ester hydrochloride wherein (1.20g, 6mmol) and Et₃N(1.52g, 15mmol) at 20mLCH₂Cl₂In solution, control reaction temperature at about 0 DEG C.Drip Add complete i.e. end to react；Successively with water and the washing of saturated NaCl solution；With anhydrous Na₂SO₄It is dried, is evaporated to oily, very Empty dry.2.5g solid, yield 84%, mp, 47.0-47.6 DEG C is obtained through column chromatography purification (eluant: EA:Hex=1:4)；¹H- NMR(400MHz, CDCl₃) δ: 1.18-1.22 (m, 3H)；2.07-2.08(m,1H);2.13(s,3H)；2.26-2.31(m, 1H)；2.60-2.64(m,2H)；2.77-2.83(m,2H)；3.80(s,3H)；4.92-4.94(m,1H)；7.02-7.48(m, 8H).According to the preparation procedure of ZH-301-SA, ZH-401-SM hydrolysis is just obtained corresponding acid ZH-401-SA.

Embodiment 4:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid ring pentyl ester

(ZH-401-SAE-3)

The preparation procedure of operation same (ZH-301-SAE-3), yield, 82%；Mp, 72.5-83.1 DEG C；¹H-NMR(CDCl₃): δ: 1.18-1.24 (t, 3H);1.62-1.88(m,8H)；2.07-2.09(m,1H);2.13(s,3H);2.23-2.27(m,1H); 2.60-2.64(m,2H)；2.77-2.78(m,2H)；4.85-4.87(m,1H)；5.24-5.26(m,1H)；7.02-7.48 (m, 8H)。

Embodiment 5:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide Base]-3-(4-benzyl oxy phenyl) methyl propionate (ZH-302B-SM)

By (S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide groups]-3- (4-hydroxy phenyl) methyl propionate (ZH-302-SM)^[2]5g (9.0mmol) is dissolved in DMF50ml, adds Anhydrous potassium carbonate 4.2g (30mmol), benzyl bromine 1.85g(10.8mmol)；Heating reflux reaction 4 hours；Pour into after cooling in frozen water and obtain white suspendible Liquid；Extracting three times by ethyl acetate 50mL, merge organic facies, wash with saturated aqueous common salt, anhydrous sodium sulfate is dried, mistake after concentration Column purification obtains expected benzyl derivative 2.63g；Yield 45.1%.¹H-NMR(400MHz, CDCl₃): δ: 2.38 (s, 3H); 3.16(m,2H);3.75(s,3H);5.03(m,1H);5.23(s,2H);6.72(d,2H);7.05-7.45 (m, 14H).

Embodiment 6:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide Base]-3-(thiophene-2-base) methyl propionate (ZH-314-SM) and corresponding acid (ZH-314-SA) thereof

Operate identical with the preparation procedure of (ZH-301-SM) and (ZH-301-SA).(ZH-301-SM) yield 69%;Mp, 57.5-58.0℃；¹H-NMR(400MHz, CDCl₃) δ: 2.39 (s, 3H)；3.49-3.50(m,2H)；3.77(s,3H)；5.08- 5.09(m,1H)；6.88-7.54(m,10H).

(ZH-314-SA) yield 80%；Mp, 74.5-75.0 DEG C；¹H-NMR(400MHz, CDCl₃) δ: 2.36 (s, 3H)； 3.45-3.56(m,2H)；5.07-5.08(m,1H)；6.90-7.64(m,10H).

Embodiment 7:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide Base]-3-(thiophene-2-base) propanoic acid ring pentyl ester ZH-314-SAE-3

A) N-Boc-(S)-2-amino-3-(thiophene-2-base) propanoic acid

By thienyl aminoacid 0.5g(2.92mmol in 25mL round-bottomed flask) it is dissolved in 5mL dichloromethane, under room temperature Add Boc anhydride 0.67g(3.07mmol) and 0.95mL triethylamine, reaction is overnight.642mg is obtained after removing solvent under reduced pressure； Yield 81%, directly carries out next step reaction.

Aminoacid 257mg(0.95mmol by above-mentioned Boc protection), EDC.HCl384mg (2.00mmol) is at 25mL circle End flask is dissolved in 6mL dichloromethane, adds cyclopentanol 0.11mL(1.21mmol), triethylamine 0.42mL(3.24mmol) And 12mg DMAP, normal-temperature reaction 16h, TLC display reaction is completely.Add 1mL saturated ammonium chloride cancellation reaction, ethyl acetate 30mL extracts three times, then washs successively with saturated ammonium chloride, saline solution, and anhydrous sodium sulfate is dried.Concentrating under reduced pressure, column chromatography purify After obtain ring pentyl ester 154mg, yield 47%.

B) (S)-2-amino-3-(thiophene-2-base) propanoic acid ring pentyl ester trifluoroacetate

N-Boc-(S)-2-amino-3-(thiophene-2-base) propanoic acid 157mg (0.58mmol) is dissolved in 5mL dichloromethane, ice Bath be cooled to 0 DEG C, be added thereto to cyclopentanol 0.111mL (1.22mmol), EDC.HCl0.384g (2.0mmol) and DMAP12mg (0.01mmol), adds triethylamine 0.417mL (3.14mmol).Reactant liquor is allowed to be slowly increased to room temperature and to continue to stir Mix 12 hours；Add 30mL dchloromethane after completion of the reaction, sequentially with appropriate 1N HCl, 1N NaHCO₃And saturated common salt Water washs.Organic layer is dried through anhydrous magnesium sulfate；Concentrate gained crude product, quick column purification excessively, obtain the BOC-ammonia of 150mg oily Base acid ring pentyl ester, yield 48%.¹H-NMR(CDCl₃): δ:¹H-NMR(CDCl₃): δ: 1.46 (s, 9H);1.60-1.87(m,8H)； 2.34-2.35(m,2H);4.32-4.35(m,1H)；5.15-5.21(m,1H)；6.82(s,1H);6.94(d,1H);7.18(s, 1H)。

This ring pentyl ester 0.15g (0.44mmol) is dissolved in TFA/DCM (v/v=1/1) 30mL, is stirred at room temperature 3 hours, subtracts Pressure obtains the trifluoroacetate of aminoacid ring pentyl ester after concentrating, direct plunge into next step reaction.

C) (S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide groups]-3- (thiophene-2-base) propanoic acid ring pentyl ester (ZH-314-SAE-3)

By 5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acid chloride 200mg (0.50mmol) it is dissolved in 5mLDCM, is slowly added to dissolved with made by 150mg N-Boc-aminoacid ring pentyl ester under ice-water bath cooling The trifluoroacetate (0.44mmol) become and 0.21mL triethylamine solution in dichloromethane 3mL；Stir 10 minutes under room temperature, TLC display reaction is complete；After concentrating under reduced pressure, through column chromatography purification, obtain 0.25g；Yield 94%；Mp, 61.2-61.7 DEG C；¹H-NMR (CDCl₃): δ: 1.58-1.84 (m, 8H)；2.39(s,3H);3.47-3.48(m,2H)；5.01-5.03(m,1H)；5.21- 5.23(m,1H)；6.88-7.59(m,10H).

Embodiment 8:(S)-2-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-arsenic azoles-3-amide Base]-3-(thiophene-2-base) methyl propionate ZH-414-SM

Operation is with the preparation of (ZH-314-SM), only with 5-(4-bromophenyl)-1-(2,4-Dichlorobenzene base)-4-ethyl-1-H- Arsenic azoles-3-carboxylic acid chloride replaces 5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-carboxylic acid chloride, Yield 81%；Mp, 65.2-66.0 DEG C；¹H-NMR(400MHz, CDCl₃) δ: 1.20-1.23 (t, 3H);2.77-2.80(m,2H)； 3.49-3.50(m,2H)；3.77(s,3H)；5.08-5.09(m,1H)；6.88-7.55(m,10H).

Embodiment 9:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide Base]-3-(4-(trifluoromethoxy) phenyl) methyl propionate (ZH-315-SM) and corresponding acid (ZH-315-SA) thereof

A) trifluoromethylation, the preparation of (ZH-315-SA)

Condensation substance (ZH-302-SM sees document 2) 1.2g(2.15mmol by Rimonabant parent nucleus Yu TYR methyl ester) Put into 50mL round-bottomed bottle, dissolve with DMF10mL, add 60% sodium hydride 172mg(4.3mmol), start stirring；By in balloon About 3g bromotrifluoromethane imports reaction bulb and seals bottleneck.Under high voltage mercury lamp radiation, in room temperature reaction overnight；TLC shows Pour in 30mL frozen water after remaining without raw material；With 6N salt acid for adjusting pH；It is extracted with ethyl acetate three times, each 20mL, is associated with Machine phase, is dried；Column chromatography purification.Due to methyl ester hydrolysis while trifluoromethylation, product is (ZH-315-SA), 783mg；Yield 59.5%；¹H-NMR(400MHz, CDCl₃) δ: 2.26 (3H, s)；3.06(2H,dd)；4.92(1H,d)；7.45- 6.66(11H,m)；9.8(1H,bs).

B) the methylating of (ZH-315-SA), the preparation of (ZH-315-SM)

By (ZH-315-SA) 700mg(1.14mmol) it is dissolved in 10mL ethyl acetate；The diazonium of brand-new is dripped in this solution Methane diethyl ether solution 4mL, after stirring half an hour, raw material disappears, and column chromatography purification obtains white solid 600mg；Yield 84%；¹H-NMR (400MHz, CDCl₃) δ: 2.33(3H, s);3.15(2H, dd);3.68(3H, s);5.01(1H,d)；7.49-6.71 (12H, m)。¹⁹F-NMR(400MHz, CDCl₃) δ :-62.03 (3F, s)

Embodiment 10:2-(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid Methanamide (ZH-301-SAA-2)

Under nitrogen protection, by 2-(S)-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4-methyl isophthalic acid H-pyrazoles-3- Amide groups]-4-first mercaptobutyric acid (350mg, 0.68mmol), it is dissolved in 5mL DCM and is added thereto to EDC.HCl0.20mg (1.04mmol), HOBt0.14g(1.04mmol) and triethylamine 0.28mL(2.15mmol)；Add methylamine hydrochloride 55mg (0.81mmol), it is stirred overnight under room temperature；Pour in 15mL frozen water, filter separate out white solid, washing, after drying obtain pure Product 220mg, yield: 62%；Mp, 89.0-90.0 DEG C;¹H-NMR(400MHz, CDCl₃) δ: 2.06-2.08 (m, 1H)；2.13 (s,3H)；2.25-2.30(m,1H)；2.37(s,3H)；2.59-2.64(m,2H)；2.84(s,3H)；4.77-4.80(m,1H)； 6.59-7.50(m,7H)。

Embodiment 11:2-(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid diformamide (ZH-301-SAA-3)

Method is with the preparation procedure of (ZH-301-SAA-2), and difference is to replace methylamine hydrochloric acid with dimethylamine hydrochloride Salt, yield 60%；Mp, 81.1-81.8 DEG C；¹H-NMR(400MHz, CDCl₃) δ: 1.97-2.10 (m, 2H)；2.13(s,3H)； 2.36(s,3H)；2.59-2.65(m,2H)；2.99(s,3H)；3.20(s,3H)；5.33(m,1H)；7.05-7.41(m, 7H)； 7.68(d,1H)。

Embodiment 12:2-(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid cyclopropyl amide (ZH-301-SAA-4)

Method is with the preparation procedure of (ZH-301-SAA-3), and difference is to replace dimethylamine hydrochloride with cyclopropylamine, Yield 82%；Mp, 80.6-81.4 DEG C；¹H-NMR(400MHz, CDCl₃) δ: 0.54-0.79 (m, 4H)；2.03-2.06(m,1H); 2.12(s,3H)；2.22-2.25(m,1H)；2.37(s,3H)；2.57-2.64(m,2H);2.73-2.75(m,1H)；4.71- 4.73(m,1H);7.06-7.46(m,7H)。

Embodiment 13:2-(S)-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide Base]-4-first mercaptobutyric acid cyclopropyl amide (ZH-401-SAA-4)

Operation, with (ZH-301-SAA-2), replaces methylamine hydrochloride with cyclopropylamine, with 2-(S)-[5-(4-bromophenyl)-1- (2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide groups]-4-first mercaptobutyric acid replacement 2-(S)-[5-(4-chlorphenyl)- 1-(2,4-Dichlorobenzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide groups]-4-first mercaptobutyric acid, yield 84%；Mp, 98.0-99.0 ℃；¹H-NMR(400MHz, CDCl₃) δ: 0.50-0.79 (m, 4H)；1.18-1.21(m,3H);2.02-2.05(m,1H);2.12 (s,3H)；2.28(m, 1H)；2.55-2.65(m,2H)；2.74-2.97(m,3H);4.69-4.71(m,1H)；7.01-7.48 (m,7H)；8.03(s, 1H).

Embodiment 14:(S)-5-(4-chlorphenyl)-N-[1-(cyclopropyl-amino)-1-oxygen-3-(thiophene-2-base) acrylate-2- Base]-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide (ZH-314-SAA-4)

The same ZH-314-SAE-3 of operation of tert-butoxy carbonyl protected amino acid

Boc protected amino acid 514mg (1.89mmol) is dissolved in 5mL dichloromethane, adds the EDC.HCl of 576mg (3.00mmol), HOBt405mg (3.00mmol) and triethylamine 0.84mL (6.49mmol), addition 0.16mL after being sufficiently stirred for Cyclopropylamine (2.30mmol), reaction is overnight.After 24h, reaction is completely, adds the extraction of 50mL dichloromethane, successively with water, ammonium chloride Solution, brine It；It is dried with anhydrous sodium sulfate, filters；Column chromatography after concentrating under reduced pressure, obtains N-Boc-ring propionic acid amide. 320mg, Yield 55%.¹H-NMR(CDCl₃): δ: 0.41-0.42 (m, 2H);0.72-0.74(m,2H);1.44(s,9H);2.65-2.66 (m,1H)；2.64-2.65(m,1H);3.24-3.33(m,2H)；4.82-4.83(m,1H)；6.85(s,1H);6.94(d,1H); 7.18(s,1H)

The amino acid amide of above-mentioned protection is dissolved in the TFA/DCM(1:3 of 4mL) in mixed solution, after reaction half an hour, instead Should be complete, concentration is drained, and obtains 300mg, is directly used in the next step.

Under nitrogen protection, by 5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4-methyl isophthalic acid H-pyrazoles-3-carboxylic acyloxy Chlorine 195mg(2.05mmol) it is dissolved in 5mLCH₂Cl₂, it is cooled to 0 DEG C；It is slowly added dropwise thienyl amides trifluoroacetate wherein 150mg(0.46mmol) and Et₃N0.2mL(1.54mmol) at 5mLCH₂Cl₂In solution, control reaction temperature at about 0 DEG C. Drip complete i.e. end to react；Successively with water and the washing of saturated NaCl solution；With anhydrous Na₂SO₄It is dried, is evaporated to oily, Vacuum drying.Through column chromatography purified product.Yield；Mp, 92.5-93.0 DEG C；¹H-NMR(CDCl₃): δ: 0.42-0.45 (m, 2H); 0.71-0.73(m,2H);2.36(s,3H);2.66-2.67(m,1H)；3.39-3.43(m,2H);4.78-4.80(m,1H)； 6.92-7.44(s,10H)。

Embodiment 15:(S)-5-(4-chlorphenyl)-N-[1-cyano group-2-(thiophene-2-base) ethyl]-1-(2,4 dichloro benzene Base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide (ZH-314-SAC-1)

By (S)-3-(2-thienyl)-2 alanine 200mg(1.17mmol) it is dissolved in 2mL toluene, it is added thereto to 28% ammonia 2mL (33mmol);Being stirred vigorously 16 hours under room temperature, concentrating under reduced pressure obtains white solid 3-(2-thienyl)-2 ammonia Base propionic acid amide., directly carries out the next step.

Take above-mentioned propionic acid amide. 85mg(0.50mmol), it is dissolved in 3mL dichloromethane, adds 0.2mL triethylamine, the most slowly add Enter 1-(2,4 dichloro benzene base)-4-methyl-5-(4-chlorphenyl)-1H-3-pyrazol formyl chloride 200mg(0.50mmol)；Continue to stir Mix 10 minutes, be concentrated to give crude product, obtain 491mg, yield 92% after purification through column chromatography.¹H-NMR(CDCl₃): δ 2.33 (s, 3H);3.43(m,2H);4.91-4.95(m,1H);5.90(s,1H);6.41(s,1H);6.94-7.55(m,10H)。

Take above-mentioned condensation substance amide 0.230mg(0.43mmol), add by pyridine 1.25mL and dichloromethane 0.25mL group In the solution become, it is cooled to-10 DEG C, is slowly added to phosphorus oxychloride 0.06mL(0.64mmol), continue stirring one at this temperature Hour；Reactant liquor is poured in frozen water, be extracted with ethyl acetate；Organic layer concentrates after drying through anhydrous sodium sulfate, crosses column purification Obtain the product that 160mg is expected, yield 72%, mp:49.3-50.0 DEG C;1H-NMR (CDCl3): δ 2.39 (s, 3H);3.44 (m,2H);5.32(m.1H);7.02-7.47(m,10H)。

Embodiment 16:(S)-5-(4-bromophenyl)-N-[1-(cyclopropyl-amino)-1-oxygen-3-(thiophene-2-base) acrylate-2- Base]-1-(2,4 dichloro benzene base)-4-ethyl-1-H-arsenic azoles-3-amide (ZH-414-SAA-4)

Operation, with the preparation of (ZH-314-SAA-4), makes (S)-amino-N-cyclopropyl-3-(thiophene-2-base)-propionic acid amide. exist In the presence of triethylamine, the acyl chlorides with 5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1-H-arsenic azoles-3-carboxylic acid contracts Close, yield 75%；Mp, 87.8-88.4 DEG C；¹H-NMR(CDCl₃): δ: 0.41-0.44 (m, 2H);0.71-0.73(m,2H); 1.18-1.19(t,3H);2.66-2.67(m,2H);2.75-2.77(m,1H)；3.39-3.42(m,2H);4.76-4.78(m, 1H)；6.92-7.48(s,10H).

Embodiment 17:2-(S)-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4-methyl isophthalic acid H-pyrazoles-3-amide Base]-4-first Mercaptobutanol. (ZH-301-SAL-00)

Under nitrogen protection, 10mL round-bottomed flask makes 2-(S)-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4- Methyl isophthalic acid H-pyrazoles-3-amide groups]-4-first mercaptobutyric acid methyl (ZH-301SM) (280mg, 0.53mmol) is dissolved in 3mLTHF； Ice-water bath cooling is lower adds 50mg LiBH₄Solution 2.4mL (0.55mmol) in 10mLTHF, reaction adds full after half an hour Reacting with ammonium chloride 1mL cancellation, extract with 3 × 10mLEA, extracting solution is successively with water and the washing of saturated NaCl solution；With anhydrous Na₂SO₄Being dried, concentrating under reduced pressure, column chromatography purification (eluent EA:Hex=1:3) obtains 190mg solid, yield 71%, mp, 64.8- 65.5℃；¹H-NMR(400MHz, CDCl₃) δ: 1.90-1.98 (m, 2H)；2.13(s,3H)；2.38(s,3H)；2.61-2.66 (m,2H)；3.76-3.87(m,2H)；4.23-4.26(bs,1H)；7.07-7.45(m,7H).

Embodiment 18:2-(S)-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-4-ethyl-1H-pyrazoles-3-amide Base]-4-first Mercaptobutanol. (ZH-401-SAL-00)

With 2-(S)-[5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-ethyl-1H-pyrazoles-3-amide groups]-4-first Mercaptobutyric acid methyl (ZH-401SM) is raw material, and preparation procedure is with (ZH-301-SAL-00, yield: 83%；Mp, 61.0-61.5 ℃;¹H-NMR(400MHz, CDCl₃) δ: 1.19-1.23 (t, 3H)；1.94-1.99(m,2H);2.14(s,3H)；2.61-2.64 (m,2H)；2.76-2.80(m,2H)；3.76-3.85(m,2H)；4.23-4.25(bs,1H)；7.02-7.49(m,7H).

Embodiment 19:(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-benzyl oxy phenyl)- Acrylate-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-302B-SAL-00)

By benzyl compounds (S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amido]-3-(4-benzyl oxy phenyl) methyl propionate (ZH-302B-SM) 2.5g(3.9mmol) it is dissolved in THF50mL, the most under room temperature Secondary addition lithium borohydride 0.175g (8mmol)；Continuing stirring reaction 2 hours after adding, add water 1mL stopped reaction；Filter precipitation Solid, the dried concentrated post of solution, obtain reduzate (ZH-302B-SAL-00) 2.16g, yield 89%；¹H-NMR (400MHz, CDCl₃) δ: 2.37(s, 3H)；2.95 (bs, 1H)；2.97(m, 2H)；3.70(m, 1H)；3.80(m, 1H)；4.36 (bs, 1H)；7.06-7.54(m, 16H).

Embodiment 20:(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-phenyl-propyl-2- Base]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-303-SAL-00)

The same ZH-301-SAL-1 of preparation procedure, with LiBH4 to (S)-2-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)- 4-methyl isophthalic acid-H-arsenic azoles-3-amide groups]-3-phenyl) methyl propionate reduces, yield 81%；Mp, 70.0-71.5 DEG C；¹H- NMR(400MHz, CDCl₃) δ: 2.37 (s, 3H)；2.95 (bs, 1H)；2.99 (m, 2H)；3.69 (m, 1H)；3.79 (m, 1H)； 4.36 (bs, 1H)；7.06-7.45(m,12H).

Embodiment 21:(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(thiophene-2-base) Acrylate-2-yl]-4-methyl isophthalic acid-H-arsenic azoles-3-amide (ZH-314-SAL-00)

With lithium boron hydrogen, ZH-314-SM is reduced, operate the preparation with ZH-301-SAL-00；Yield 85%；Mp, 79.0-80.0℃；¹H-NMR(400MHz, CDCl₃) δ: 2.38 (s, 3H)；3.22-3.24(m,2H)；3.76-3.83(m,2H)； 4.35(bs,1H)；6.93-7.45(m,10H).

Embodiment 22:(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-trifluoromethyl- Phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-315-SAL-00)

By (S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide groups]-3- (4-trifluoromethyl-phenyl)-methyl propionate (ZH-315-SM) 0.5g(0.8mMol) it is dissolved in THF5mL, add lithium borohydride 52mg (2.4mMol), is stirred at room temperature 48 hours.Adding 0.5mL makes water reaction stop；After filtering the solid of precipitation reactant liquor is dense Contracting, crosses column purification, reclaims unreacted raw material 231mg, obtain reduzate 187mg, yield 72.6%；¹H-NMR(400MHz, CDCl₃) δ: 2.37 (s, 3H)；2.91(m,2H)；3.67-3.81(m,2H)；4.30(bs,1H)；6.76-7.46(m,11H).

Embodiment 23:(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-trifluoromethoxy-3-(4-benzyloxy Phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-316-SAL-31) and (S)-[5-(4-chlorphenyl)-1-(2, 4-Dichlorobenzene base)-N-1-(4-hydroxy-pheny)-3-(trifluoromethoxy)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-316-SAL-00)

A) by (S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-benzyl oxy phenyl)-propyl-2- Base]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-302B-SAL-00) 1.28g(2.06mmol) and DMF10mL devote 50mL not Rust steel voltage-resistant reactor, adds solid potassium hydroxide 100mg(2.5mmL), crown ether 18-C-610mg, leads under cryosel bath cooling Enter CF3I900mg(4.6mmL)；Put into after stirring bar magnet airtight；Under agitation react 4 hours in 80 DEG C.Cool down with cryosel bath, Carefully open reactor, be gradually increased to room temperature.Reactant is poured into 30mL frozen water；It is extracted with ethyl acetate three times, each 20mL, Merge organic facies；It is dried, concentrates, obtain intermediate (S)-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)-N-[1-fluoroform Epoxide-3-(4-benzyl oxy phenyl)-propyl-2-yl] the crude product 1.01g of-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-316-SAL-00). Do not refine, be directly used in next step hydrogenation debenzylation reaction.

B) obtained crude product 1.01g is dissolved in ethyl acetate 50mL, adds 5%Pd/C300mg, in the pressure of balloon hydrogen Under power, in 50 DEG C of stirring reactions overnight.Raw material reaction is complete；Filter；Concentrate；Column chromatography purification, obtains expected product 523mg；Yield 42.4% for benzyl oxy phenyl raw material；¹H-NMR(400MHz, CDCl₃) δ: 2.38 (s, 3H)；2.95(m,1H)； 3.00(m,1H)；3.89(m,1H)；3.99(m,1H)；4.61(bs,1H)；6.71-7.51(m,11H).

Embodiment 24:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-phenyl propyl acetate (ZH-303-SAL-01)

By (S)-5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-(1-hydroxyl-3-phenyl-propyl-2-yl)-4-methyl- 1-H-arsenic azoles-3-amide (ZH-313-SAL-00) 515mg (1mmol) is dissolved in the DCM that 15mL is dried, and adds 1.5mL Et₃N (10mmol), CH is added under cooling₃COCl0.26mL (3.6mmol), reacts 0.5h, TLC and shows that reaction is completely under room temperature.It is evaporated off Solvent, adds the ethyl acetate of 80mL；Wash twice with 2 × 20mL water, then washed once with saturated aqueous common salt 20mL.Anhydrous Na₂SO₄Steam after drying to 1mL；Directly through silica column purification, with petroleum ether: ethyl acetate (2:1) eluting, obtain 320mg chemical combination Thing, yield 57.5%.

¹H-NMR(CDCl₃, 300MHZ): δ, 2.10 (s, 3H)；(2.38 s, 3H)；2.95 (m, 1H)；3.05 (m, 1H)； 4.15 (m, 2H)；4.64 (bs, 1H)；7.07-7.12 (m, 3H)；7.26-7.31 (m, 8H)；7.46(1H,s).

Embodiment 25:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-phenyl propyl propylene propionic ester (ZH-303-SAL-02)

Preparation procedure, with (ZH-303-SAL-01), replaces chloroacetic chloride, yield 52.7% with the acyl chlorides of allyl acid.

¹H-NMR(CDCl₃, 300MHZ): δ, 2.38 (s, 3H)；2.93-3.09 (m, 2H)；4.24 (m, 2H)；4.69 (m, 1H)；5.87(d,1H)；6.20 (dd, 1H)；(6.47 dd, 1H)；7.07-7.08 (m, 3H)；7.46 (s, 1H)；7.28-7.32 (m, 8H).

Embodiment 26:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-phenyl propyl chloracetic acid ester (ZH-303-SAL-03)

Preparation procedure, with (ZH-303-SAL-01), replaces chloroacetic chloride, yield 49.0% with chloracetyl chloride.¹H-NMR(CDCl₃, 300MHZ): δ, 2.38 (s, 3H)；2.95 (m, 1H)；3.06 (m, 1H)；4.10 (bs, 2H)；4.23 (d, 1H)；4.32 (d, 1H)； 4.69 (m, 1H)；7.07-7.09 (m, 3H)；7.28-7.32 (m, 8H)；7.47 (s, 1H).

Embodiment 27:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-amide Base]-3-phenyl propyl succinic acid methyl ester (ZH-303-SAL-04M) and (S)-2-[5-(4-chlorphenyl)-1-(2,4-dichloro Phenyl)-N-(4-methoxyl group-4-oxygen-bytyry)-4-methyl isophthalic acid-H-arsenic azoles-3-amide groups]-3-phenyl propyl succinic acid methyl Ester (ZH-303-SAL-04MM)

Preparation procedure, with (ZH-303-SAL-01), replaces chloroacetic chloride with the acyl chlorides of beta-methoxycarbonyl group propanoic acid, obtains yellowish Color product, yield 31.8%；¹H-NMR (400MHz, CDCl₃): δ, 2.38 (s, 3H)；(2.66-2.69 m, 4H), 2.90-3.06 (m, 2H)；3.68 (s, 3H)；4.18 (m, 2H)；4.64(bs,1H)；7.07-7.12 (m, 3H)；(7.24-7.31 m, 8H)； 7.46 (s, 1H).

While obtaining expected product ZH-303-SAL-04M, the acylate ZH-being also obtained on amide nitrogen 303-SAL-04MM, yield 18.2%；¹H-NMR (400MHz, CDCl₃): δ, 2.37 (s, 3H)；(2.52-2.68 m, 3H)； (2.80-3.20 m, 7H)；3.66 (s, 3H)；3.68 (s, 3H)；4.23 (d, 1H)；(4.32 d, 1H)；4.66 (bs, 1H)； 7.07-7.08 (d, 2H)；(7.45 s, 1H)；7.26-7.31 (m, 9H).

Embodiment 28:(S)-4{2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amido]-3-phenyl-propoxy }-4-oxygen-butanoic acid (ZH-303-SAL-04A)

By (S)-5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-(1-hydroxyl-3-phenyl-propyl-2-yl)-4-methyl- 1-H-arsenic azoles-3-amide (ZH-313-SAL-00) 515mg (1mmol) is dissolved in L acetone 50m, adds succinic anhydride 400mg (4mmol) and DMAP25mg, the lower backflow of stirring 12 hours.Solvent is evaporated off, adds dichloromethane 50mL and 10mL water；After layering, Water layer dichloromethane 50mL extracts once again；Merge organic layer, wash twice with saturated aqueous common salt 30mL.Organic layer is through anhydrous Sodium sulfate is evaporated after drying.Residue by silicagel column purification, obtains faint yellow product 415mg；Yield 67.9%.¹H-NMR (400MHz, CDCl₃): δ, 2.35 (s, 3H), 2.67 (m, 4H), 2.90-3.04 (m, 2H), 4.18 (dd, 2H), 4.64 (bs, 1H), 7.06-7.8 (m, 3H), 7.22-7.30 (m, 8H), 7.44 (s, 1H).

Embodiment 29:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-phenyl propyl 2,4 dichloro benzene formic acid esters (ZH-303-SAL-13)

A) preparation of 2,4 dichlorobenzyl chloride

By 2,4-dichlorobenzoic acid 286mg (1.5mmol) is dissolved in dry DCM, drips (COCl)₂0.22mL and 1 DMF, reacts 0.5-1 hour under room temperature；Solvent evaporated, adds 2mLDCM；Again it is evaporated, obtains faint yellow 2,4-dichloro-benzoyl Chlorine crude product, is directly used in next step reaction.

B) preparation procedure is with (ZH-303-SAL-01), and with 2,4-dichlorobenzoyl chloride replaces chloroacetic chloride.Yield 42.2%；¹H-NMR (400MHz, CDCl₃): δ, 2.39 (s, 3H)；2.99-3.04(m,1H)；3.11-3.15 (m, 1H)；4.41 (m, 2H)； 4.78 (bs, 1H)；7.07-7.08 (m, 2H)；7.28-7.30 (m, 10H)；7.47 (m, 2H)；7.84 (d, 1H).

Embodiment 30:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-phenyl propyl benzoate (ZH-303-SAL-16)

Preparation procedure, with (ZH-303-SAL-01), replaces chloroacetic chloride, yield 54.9% with Benzenecarbonyl chloride..

¹H-NMR (400MHz, CDCl₃): δ, 2.39 (s, 3H)；3.01-3.18 (m, 2H)；4.40(m,2H)；4.79(m, 1H)；7.06-7.09 (m, 3H)；(7.21-7.33 m, 8H)；7.43-7.47 (m, 3H)；7.58(dd,1H),8.07(d,2H).

Embodiment 31:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-(2-thienyl)-propyl group acetate (ZH-314-SAL-01)

Under nitrogen protection, by amino acid whose condensation substance alcohol (ZH-314-SAL-00) 185mg(0.36mmol), it is dissolved in 5mL Dichloromethane, adds triethylamine 0.10mL (0.8mmol), is cooled to 0 DEG C；The most slowly drip chloroacetic chloride 0.032mL (about 0.4mmol), reaction temperature is controlled at about 0 DEG C.Drip complete i.e. end to react；Successively with water and the washing of saturated NaCl solution； With anhydrous Na₂SO₄It is dried, is evaporated to oily, through column chromatography purification, obtains product 200mg, yield 99%, mp:42.5- 43.5℃。¹H-NMR(CDCl₃): δ 2.11 (s, 3H);2.39(s,3H);3.32(m,2H);4.19(m,2H);4.65(m.1H); 6.91-7.46(m,10H)

Embodiment 32:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-(4-trifluoromethoxy-phenyl)-propyl group acetate (ZH-315-SAL-01)

By (S)-5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl- 2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-315-SAL-00) 45mg(0.075mMol) it is dissolved in dichloromethane 8mL, add Triethylamine 15mg(0.15mMol), chloroacetic chloride 69mg (0.08mmol), after half an hour is stirred at room temperature, concentrated column purification, obtains acetyl Change product 38mg, yield 79.1%；¹H-NMR(CDCl₃): δ 2.10 (s, 3H);2.38(s,3H);2.91-3.01(dm, 2H)； 4.17(bs, 2H)；4.63(bs, 1H)；7.03-7.05(m, 3H)；7.29-7.31(m, 7H)；7.46(bs, 1H).

Embodiment 33:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-(4-trifluoromethoxy-phenyl)-propyl group acid allyl ester (ZH-315-SAL-02)

By (S)-5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl- 2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-315-SAL-00) is by reduzate 47mg(0.075mMol) it is dissolved in dichloromethane Alkane 8mL, adds triethylamine 18mg(0.15mMol), acryloyl chloride 7mg (0.08mmol), concentrated after half an hour is stirred at room temperature Column purification, obtains allyl acylate 43mg, yield 87.9%；¹H-NMR(CDCl₃): δ, 2.38 (s, 3H)；2.95-3.08 (m, 2H)；4.27 (bs, 2H)；4.68 (bs, 1H)；5.95(d, 1H)；6.20(m, 1H)；6.45(d, 1H)；7.09-7.46(m, 11H).

Embodiment 34:(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3-acyl Amine]-3-(4-trifluoromethoxy-phenyl)-propyl group-(the chloro-benzoate of 2-) (ZH-315-SAL-14)

By (S)-5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl- 2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-315-SAL-00) 44mg(0.075mMol) it is dissolved in dichloromethane 8mL, then add Enter triethylamine 16mg(0.15mMol), o-chlorobenzoyl chloride 14mg (0.08mmol), concentrate after half an hour is stirred at room temperature, cross post pure Change, obtain expected product 48mg, yield 86.8%；¹H-NMR(CDCl₃): δ, 2.39 (s, 3H)；3.09-3.14 (m, 2H)； 4.47(bs,2H)；4.79(bs,1H)；7.09-7.54 (m, 15H)；8.05(bs, 1H).

Embodiment 35:(S)-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-N-1-(4-acetoxyl group-phenyl)-3- (trifluoromethoxy)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-316-SAL-01)

Preparation procedure is with the preparation of (ZH-315-SAL-01), with ZH-316-SAL-00 as raw material.Yield 69.5%.

¹H-NMR(400MHz, CDCl₃) δ: 2.18 (s, 3H)；2.38(s,3H)；2.96(m,1H)；3.00(m,1H)；3.90 (m,1H)；4.00(m,1H)；4.60(bs,1H)；7.24-7.55(m,11H).

Embodiment 36:(S)-(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3- Amide groups]-3-phenyl propyl] 2-amino-propionic acid ester (ZH-303-SAL-21)

By raw alcohol (ZH-303-SAL-00) 515mg (1mmol), EDC.HCl288mg (1.5mmol), DAMP50mg, and (S)-N-Boc-L-alanine 327mg (1.73mmol) puts into the single port bottle of 50mL, evacuation 0.5 hour, is filled with after nitrogen again Evacuation 0.5 hour；Dry dichloromethane 10mL is injected in bottle, react 24 hours under room temperature；TLC shows to show reactive group This is completely.Solvent is evaporated off；The solid that obtains is the most purified directly carries out next step reaction, sloughs Boc protection group.

Being dissolved in dichloromethane 6mL by obtained solid, add TFA3mL, react 2 hours, raw material disappears substantially.? Major part solvent is evaporated off at 30 DEG C.Ethyl acetate 50mL is added in residue；Use saturated NaHCO₃Solution washing is to neutral；Again Through anhydrous Na₂SO₄Steam to 1mL after drying, directly through silica column purification, with petroleum ether: ethyl acetate (2:1) eluting, obtain The compound that 205mg is expected, yield 35.0%.

¹H-NMR(CDCl₃,300MHz):δ1.35(d,3H)；2.37 (bs, 3H), 2.91 (d, 1H), 3.05 (d, 1H)； 3.57(d,1H)；4.15(d,1H)；4.22(d,1H)；4.68(bs,1H)；7.06-7.10(m, 3H)；7.25-7.31(m, 8H)； 7.46 (s, 1H).

Embodiment 37:(S)-(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3- Amide groups]-3-phenyl propyl] 2-amino-3-phenylpropionic acid ester (ZH-303-SAL-22)

N-Boc-L-phenylalanine is used to replace N-Boc-L-alanine, according to the same program system of ZH-303-SAL-21 Standby.Obtain light yellow solid, yield 39.3%.¹H-NMR(CDCl₃): δ, 2.38(bs, 3H)；2.82-2.89(m, 2H)；2.98 (m, 1H)；3.10(m, 1H)；3.77(bs, 1H)；4.15(d, 1H)；4.25(d, 1H)；4.66(bs, 1H)；7.05-7.09(m, 3H)；7.24-7.31(m, 13H)；7.44(s, 1H).

Embodiment 38:(S)-(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3- Amide groups]-3-(2-thienyl)-propyl group] 2-amino-propionic acid ester (ZH-314-SAL-21)

Under nitrogen protection, by alcohol (ZH-314-SAL-00) 155mg(0.30mmol of amino condensation compound) it is dissolved in In DMF5mL, add triethylamine 0.10mL(0.8mmol), EDC hydrochlorate 192mg(1.0mmol), and DMAP16mg (0.13mmol), and N-Boc-alanine 91mg(0.48mmol), normal-temperature reaction overnight, uses water and saturated NaCl solution successively Washing；With anhydrous Na₂SO₄It is dried, is evaporated to oily, through column chromatography purified product 160mg, yield 77%.¹H-NMR (CDCl₃): δ 1.11 (m, 3H);1.49(s,9H);2.38(s,3H);3.22(m,2H);4.25-4.37(m,2H);4.67(m, 1H);5.06(m.1H);6.92-7.33(m,10H)

Above-mentioned condensation substance is dissolved in TFA/DCM(volume ratio 1/2) in mixed liquor 3mL, to stir half an hour, reaction is completely, dense It is reduced to oily.Dichloromethane dissolves this product, and after being passed through a small amount of ammonia, column chromatography obtains product 130mg, productivity 95%;mp:51.0- 52.0℃。¹H-NMR(CDCl₃): δ 1.38-1.39 (m, 3H);2.38(s,3H);3.16-3.22(m,2H);3.65-3.67(m, 1H);4.23-4.29(m,2H);4.67(m.1H);6.91-7.33(m,10H)

Embodiment 39:(S)-(S)-2-[5-(4-chlorphenyl)-1-(2,4 dichloro benzene base)-4-methyl isophthalic acid-H-arsenic azoles-3- Amide groups]-3-(4-trifluoromethoxy-phenyl) propyl group] 2-amino-propionic acid ester (ZH-315-SAL-21)

Preparation procedure with the preparation of (ZH-303-SAL-21), with (S)-[5-(4-chlorphenyl)-1-(2,4-Dichlorobenzene base)- N-[1-hydroxyl-3-(4-trifluoromethyl-phenyl)-propyl-2-yl]-4-methyl isophthalic acid H-arsenic azoles-3-amide (ZH-315-SAL-00) takes In generation (ZH-303-SAL-00), is condensed with (S)-N-Boc-L-alanine；Intermediate product does not refines, and with TFA process, sloughs protection Base；Expected product is obtained through column chromatography purification.Yield 33%；¹H-NMR(CDCl₃, 300MHz): δ, 1.35 (d, 3H)；2.37 (bs, 3H)；2.84 (d, 1H), 2.99 (d, 1H)；3.57(d,1H)；4.13(d,1H)；4.22(d,1H)；4.68(bs,1H)； 6.99-7.03(m, 2H)；7.09-7.47(m, 9H).

Claims (3)

1. a 3-arsenic triazole carboxylic acid amides compound, it is the compound of following chemical structural formula:

2. the 3-arsenic triazole carboxylic acid's amides compound described in claim 1 is being prepared as answering in CB1 acceptor inhibitor medicine With.

3-arsenic triazole carboxylic acid's amides compound the most according to claim 2 is being prepared as in CB1 acceptor inhibitor medicine Application, it is characterised in that preparing anti-additive medicament, stop smoking medicine, Temperance medicine, slimming medicine or treatment diabetes medicament In application.