CN102030700A

CN102030700A - Benzamide carboxylic acid compound as well as manufacturing method and medicinal application thereof

Info

Publication number: CN102030700A
Application number: CN2009102352841A
Authority: CN
Inventors: 肖志艳; 叶菲; 郭宗儒; 田金英; 刘军政; 张书恩; 聂菲璘; 陶荣亚; 张晓琳; 刘峻玚; 贺伊博; 马轶鸣
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Baoding Norway Technology Co., Ltd.
Priority date: 2009-09-30
Filing date: 2009-09-30
Publication date: 2011-04-27
Anticipated expiration: 2029-09-30
Also published as: CN102030700B

Abstract

The invention discloses a new benzamide carboxylic acid compound of formula I, an enantiomer, a racemate and physiologically acceptable salt, solvate and crystalline form thereof, a preparation method of the compound, a medicinal preparation containing the compound and an application of the compound in clinic treatment related to insulin resistance.

Description

Benzoylamino carboxylic acid compound and method for making thereof and pharmaceutical use

Technical field

The present invention relates to the new benzoylamino carboxylic acid compound of general formula I, and their steric isomer and physiologically acceptable salt.These compounds with the syndromic therapeutic processes of metabolism such as diabetes in purposes, also relate to the method that it is used for the treatment of, and the pharmaceutical composition that contains described compound.

Background technology

Diabetes are a kind of common metabolism disorder diseases, and in recent years, the sickness rate of diabetes is in rising trend in the world, and human life's health has been constituted serious threat.Diabetes mainly are divided into amphitypy, type 1 diabetes and diabetes B.(insulin-dependent diabetes mellitus is to cause the low hyperglycemia that causes of insulin secretion level owing to the beta Cell of islet function is impaired IDDM) to type 1 diabetes, accounts for diabetics's 10%.Diabetes B (non insulin dependent diabetes, NIDDM) in the diabetic subject, account for about 90%, it is because peripheral tissues's (liver, muscle and fatty tissue) produces opposing to Regular Insulin, causes the generation of hyperglycemia level, and then causes cardiovascular disordeies such as blood fat disorder, hypertension.Improve body and can treat diabetes B the medicine of insulin sensitivity.

(Protein tyrosine phosphatase, PTP) 1B is the novel targets of treatment diabetes B to Protein-tyrosine-phosphatase.Suppress PTP 1B and not only produce significant insulin-sensitizing effect, and increase susceptibility, can regulate body weight and metabolism of fat leptin protein.Therefore, suppress PTP 1B metabolism syndromes such as diabetes B are had combined therapy effect, may have the potential advantages (Zhang Sand Zhang Z-Y, Drug Discov.Today, 2007,12,373) that are better than existing treatment means.

The research of small molecules PTP 1B inhibitor is one of focus of current anti-diabetes B new drug development.Because blood sugar reducing function reaches and optionally realizes becoming the critical bottleneck that restriction PTP 1B inhibitor develops into antidiabetic medicine in the positive polarity and the structure conservative property feature of PTP 1B enzyme binding cavity, body.Many aromatic rings-monocarboxylic acid class inhibitor the Ertiprotafib of Wyeth company development has entered clinical trial, though owing to liver toxicity stops, but prove that the rational and effective molecular designing is to obtain novel safely and efficiently PTP 1B inhibitor, and then research and develop feasible way (the Liu G of anti-diabetes B original new drug, Curr.Med.Chem., 2003,10,1407).

The present invention is intended to design synthetic novel PTP 1B inhibitor with antidiabetic effect.According to the interaction pattern of known PTP 1B inhibitor and enzyme, the pharmacophore that sums up inhibitor should comprise two aryl and a carboxyl at least.In view of the above, adopt pharmacophore to move the layout strategy that combines more, make up virtual compound library with skeleton, through AutoDock program virtual screening, from virtual data base, optimize potent in theory bonded compound, and these compounds are synthesized, estimate its activity.

Summary of the invention

The object of the present invention is to provide the new benzamides yl carboxylic acid compounds shown in a kind of formula I.

Another object of the present invention is to provide the benzoylamino carboxylic acid compound shown in a kind of preparation formula I and the method for analogue thereof.

Another purpose of the present invention is to provide the purposes of the compound shown in the formula I in arrestin tyrosine-phosphatase 1B (PTP 1B), and the purposes in treatment and the PTP 1B diseases associated.

In order to finish purpose of the present invention, the present invention adopts following technical scheme:

The present invention relates to have new benzamides yl carboxylic acid compounds and the steric isomer and the physiologically acceptable salt of general formula I,

Wherein, Ar1, Ar2 independently are selected from and replace or unsubstituted phenyl, replacement or unsubstituted naphthyl, replacement or unsubstituted furyl, replacement or unsubstituted benzothiazolyl;

M1, M2, X and Y are independently selected from methylene radical-CH2-or saturated covalent linkage; As M1, when M2 is saturated covalent linkage, Ar1 and Ar2 isolate each other or connect into ring at the ortho position that N-replaces through covalent linkage;

R1 be selected from replace or unsubstituted C1-6 straight or branched alkyl, C3-6 cycloalkyl ,-(CH2) n-R (n=0～4), R is selected from alkyl or alkenyl, C1-6 alkoxyl group, C1-6 alkylamino or C1-6 alkylthio, replacement or unsubstituted phenyl, replacement or unsubstituted thienyl, replacement or unsubstituted imidazolyl, replacement or unsubstituted furyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or the unsubstituted naphthyl of C1-6; R1 and the carbon atom that is attached thereto also can with adjacent five yuan of N atomic buildings, hexa-member heterocycle, or formation and phenyl ring is thick and five yuan, hexa-member heterocycle;

R2, R3 are independently selected from hydrogen, halogen, C1-6 alkoxyl group;

Above-mentioned substituting group is selected from hydroxyl, amino, halogen, the straight or branched alkyl of C1-6, C3-6 cycloalkyl, C1-6 alkoxyl group, C1-6 alkylamino, the C1-6 alkylthio contains 1～3 heteroatomic five yuan, hexa-atomic or seven-membered ring alkyl, carboxyl, phenyl, phenoxy group, anilino, nitro, cyano group, methylene-dioxy.

Preferred Ar1, Ar2 is the phenyl of replacement or the naphthyl of replacement;

Preferred L 2 and X are methylene radical-CH2-;

Preferred L 1 and Y are saturated covalent linkage;

Preferred R1 is the phenyl that replaces, the indyl of replacement, the naphthyl of replacement;

Preferred R2, R3 are hydrogen or methyl.

Preferred formula (I) compound, including but not limited to, compound shown in the general formula (IA) and steric isomer thereof and physiologically acceptable salt:

Substituting group is selected from hydroxyl, amino, halogen, the straight or branched alkyl of C1-6, C3-6 cycloalkyl, C1-6 alkoxyl group, the C1-6 alkylamino, the C1-6 alkylthio contains 1～3 heteroatomic five yuan, hexa-atomic or seven-membered ring alkyl, carboxyl, phenyl, phenoxy group, anilino, nitro, cyano group, methylene-dioxy.

Preferred formula (IA) compound, including but not limited to, compound shown in the general formula (IAa) and steric isomer thereof and physiologically acceptable salt:

Substituting group is selected from hydroxyl, amino, halogen, the straight or branched alkyl of C1-6, C3-6 cycloalkyl, C1-6 alkoxyl group, the C1-6 alkylamino, the C1-6 alkylthio contains 1～3 heteroatomic five yuan, hexa-atomic or seven-membered ring alkyl, carboxyl, phenyl, phenoxy group, anilino, cyano group, methylene-dioxy.

Preferred formula (IA) compound, including but not limited to, compound shown in the general formula (IAb) and steric isomer thereof and physiologically acceptable salt:

Wherein, Ar2 is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted naphthyl, replacement or unsubstituted furyl;

Substituting group is selected from hydroxyl, halogen, C1-6 alkoxyl group, nitro.

Preferred formula (IAb) compound, including but not limited to, compound shown in the general formula (IAb1) and steric isomer thereof and physiologically acceptable salt:

Wherein, R1 be selected from replace or unsubstituted C1-6 straight or branched alkyl, C3-6 cycloalkyl ,-(CH2) n-R (n=0～4), R is selected from alkyl or alkenyl, C1-6 alkoxyl group, C1-6 alkylamino or C1-6 alkylthio, replacement or unsubstituted phenyl, replacement or unsubstituted thienyl, replacement or unsubstituted imidazolyl, replacement or unsubstituted furyl, replacement or unsubstituted indyl, replacement or unsubstituted benzofuryl, replacement or the unsubstituted naphthyl of C1-6; R1 and the carbon atom that is attached thereto also can with adjacent five yuan of N atomic buildings, hexa-member heterocycle, or formation and phenyl ring is thick and five yuan, hexa-member heterocycle;

Preferred formula (IA) compound, including but not limited to, compound shown in the general formula (IAc) and steric isomer thereof and physiologically acceptable salt:

Wherein, Ar1 is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted benzothiazolyl;

Preferred formula (IAc) compound, including but not limited to, compound shown in the general formula (IAc1) and steric isomer thereof and physiologically acceptable salt:

Wherein, R1 is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted naphthyl;

Preferred formula (IAc) compound, including but not limited to, compound shown in the general formula (IAc2) and steric isomer thereof and physiologically acceptable salt:

Wherein, R1 is selected from and replaces or unsubstituted phenyl, replacement or unsubstituted indyl;

Preferred formula (I) compound, including but not limited to, compound shown in the general formula (IB) and steric isomer thereof and physiologically acceptable salt:

Preferred formula (I) compound, including but not limited to, compound shown in the general formula (IC) and steric isomer thereof and physiologically acceptable salt:

Wherein, Ar1, Ar2 are independently selected from and replace or unsubstituted phenyl, replacement or unsubstituted naphthyl, replacement or unsubstituted furyl, replacement or unsubstituted benzothiazolyl; Ar1 and Ar2 isolate each other or connect into ring at the ortho position that N-replaces through covalent linkage;

Most preferred is selected from following group:

The invention also discloses the method for preparing The compounds of this invention, may further comprise the steps:

Formula II compound and formula III compound reaction production IV compound, formula IV compound hydrolysis production IV ', IV ' generate compound shown in the general formula I with the amino acid reaction that replaces again:

Wherein, Ar ₁, Ar ₂, M ₁, M ₂, X, Y, R ₁, R ₂, R ₃Definition the same identical;

W represents-Br or-CH ₂Br; R ' is methyl or ethyl.

According to the present invention, the form that The compounds of this invention can isomer exists, and described usually " The compounds of this invention " comprises the isomer of this compound.

Can there be the cis-trans-isomer of two keys in The compounds of this invention, and asymmetric center has S configuration or R configuration, the present invention includes all possible steric isomer and two or more mixture of isomers.If there is suitable/trans isomer, the present invention relates to the mixture of cis form and trans forms and these forms, single if desired foreign body object can separate according to conventional methods or prepare by three-dimensional selection is synthetic.

In order to make medicament, compound of Formula I can be pressed currently known methods mixes with known method with suitable pharmacy carrier substance, perfume compound, seasonings and pigment, and be made into the tablet of tablet or dressing, perhaps itself and other additional substances is suspended or be dissolved in water or the oil.

The invention still further relates to a kind of pharmaceutical composition that contains medicine effective dose as described compound of general formula I and pharmaceutically acceptable carrier.

Pharmaceutical research shows that compound of Formula I of the present invention has the activity that suppresses PTP 1B, and for the diabetes B that causes because of insulin resistant, this compound can improve body to insulin sensitivity, thereby reaches the purpose of treatment.

In addition, along with further research, find PTP 1B inhibitor to tumour, especially disease such as mammary cancer also has treatment, and therefore, PTP 1B inhibitor can be treated other disease relevant with PTP 1B.

Further aspect of the present invention also relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be by the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, make any formulation that is suitable for human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.

The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.

Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.

The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.

For The compounds of this invention is made tablet, can be extensive use of various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.

Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.

For capsule is made in the administration unit, the effective constituent The compounds of this invention can be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also the effective constituent The compounds of this invention particle or micropill be can be made with thinner, tamanori, disintegrating agent earlier, hard capsule or soft capsule placed again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.

For The compounds of this invention is made injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.

In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.

For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.

The dosage of The compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the suitable dose scope of the every day of The compounds of this invention is the 0.01-300mg/Kg body weight, is preferably the 0.1-200mg/Kg body weight, and more preferably the 10-150mg/Kg body weight most preferably is the 25-100mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.

Compound of the present invention or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.

Embodiment

Below in conjunction with embodiment invention is further described, but these embodiment do not limit the scope of the invention.

The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS) or high resolution mass spectrum (HRMS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.M.p. be that temperature is correction up not with a ℃ fusing point that provides.Column chromatography generally uses 200～300 order silica gel to be carrier.It is to use INOVA-500 that NMR measures, and the mensuration solvent is CDCl ₃, DMSO-D ₆, in be designated as TMS, chemical shift is to provide as unit with ppm.The mensuration of MS VG-ZAB-2F 200C mass spectrograph.

Abbreviation:

TLC: thin-layer chromatography;

DMSO: dimethyl sulfoxide (DMSO);

CDCl3: deuterochloroform;

DMF:N, dinethylformamide;

Min: minute;

H: hour.

Embodiment 1:ZSE-1-24

a)

(4.506g 30mmol) is dissolved in 15mL CCl with methyl p-methyl benzoate ₄In, add in turn NBS (5.696g, 32mmol) and benzoyl peroxide (0.500g, 2.1mmol), reflux 6h, TLC monitoring, raw material point disappears, and filters, and steams except that CCl ₄, get faint yellow thick thing.

b)

Above-mentioned thick thing is dissolved in the 20mL acetone, add in turn carbazole (3.340g, 20mmol) and K ₂CO ₃(4.140g 30mmol), stirs reflux 72h down, the TLC monitoring, and the point of carbazole disappears substantially, filtering K ₂CO ₃, steaming desolventizes, and ethyl alcohol recrystallization gets colourless crystallization a 3.345g, yield 54.8%.

c)

(0.800g 20mmol) is dissolved in the 30mL water, adds a, stirs 12h under 40 ℃ temperature, and dilute hydrochloric acid acidifying (to Ph=3-4) is filtered, and clear water washs, and drying gets white solid b 3.211g, yield 97.0% with NaOH.

d)

With b (0.301g, 1mmol) CH that handled at 10mL of mixing ₂Cl ₂In, (0.152g 1.2mmol) drips with DMF1, and stirring at room 3h is spin-dried for solvent, takes out 1h with vacuum pump and gets c to add oxalyl chloride.

e)

With phenylalanine (0.165g 1mmol) is dissolved in 10mL water: in the mixing solutions of acetone=1: 1, add NaOH (0.040g 1mmol), slowly is added drop-wise to this solution among the c then, stirred overnight at room temperature, the TLC monitoring, the raw material overwhelming majority reacts completely.Stopped reaction is spin-dried for acetone, uses the dilute hydrochloric acid acidifying, filters drying.Column chromatography for separation, eluent are PE: EA=2: 1+2%HAc, get white solid 0.271g, yield 60.5%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?8.19-7.12(m，18H，ArH，NH)，5.70(s，2H，NCH ₂)，4.90-4.83(dt，1H，J＝5.1Hz，J＝13.5Hz，CHCOOH)，3.33-3.26(dd，1H，J＝5.4Hz，J＝14.1Hz，PhCH ₂)，3.14-3.06(dd，1H，J＝9.3Hz，J＝14.1Hz，PhCH ₂).FAB-MS(positive，m/z)：449(M+H ⁺)

Embodiment 2:ZSE-4-5-p1

a)

Methyl 4 methylbenzoate (8mmol) and NBS (8.8mmol) are placed single neck bottle, add the 15mL tetracol phenixin, nitrogen protection, reflux 4h under the illumination, stopped reaction filters, and steams and removes tetracol phenixin, gets oily matter a, does not deal with and continues following reaction.

b)

Phenyl aldehyde (10mmol) and 4-fluoroaniline (10mmol) are dissolved in the 20mL dehydrated alcohol, stir reflux 8h down, be cooled to room temperature, add NaBH ₄(10mmol), continue to stir 6h, steam and remove ethanol, add 15mL water, ether (15mL*3) extraction merges organic phase, the saturated common salt washing, and anhydrous sodium sulfate drying filters, and steams and removes ether, and 95% ethyl alcohol recrystallization gets compound b.

c)

B (7mmol) is joined among a, and (1380mg, 10mmol) with 15mL DMF, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merging organic phase, saturated aqueous common salt cleaning, anhydrous sodium sulfate drying to add Anhydrous potassium carbonate in turn.Be spin-dried for ether, column chromatography for separation gets compound c, yield 71%.

d)

(160mg 4mmol) is dissolved in the 25mL water, joins among the c (2mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filters, and drying gets compound d, yield 96% with NaOH.

e)

D (1.6mmol) is placed 50mL single port bottle, stir and drip oxalyl chloride solution (2mmol in 20mLCH down ₂Cl ₂), in 30 minutes, drip off, drip Bi Jixu and stir 2.5h, be spin-dried for solvent and get e, do not deal with and continue following reaction.

f)

With phenylalanine (1.6mmol) and NaOH (130mg 3.2mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the e, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 78%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.76-6.65(m，18H，ArH)，4.84(dt，1H，J＝3.6Hz，J＝11.7Hz，CHCOOH)，4.67(s，2H，NCH ₂)，4.65(s，2H，NCH ₂)，3.35-3.29(dd，1H，J＝5.1Hz，J＝14.1Hz，CH ₂)，3.19-3.11(dd，1H，J＝8.7Hz，J＝14.7Hz，CH ₂).ESI-TOF-MS(positive，m/z)：483(M+H ⁺)

Embodiment 3:ZSE-4-5-p2

a)

4-tolyl aldehyde (10mmol) and 4-fluoroaniline (10mmol) are dissolved in the 20mL dehydrated alcohol, stir reflux 8h down, be cooled to room temperature, add NaBH ₄(10mmol), continue to stir 6h, steam and remove ethanol, add 15mL water, ether (15mL*3) extraction merges organic phase, and saturated aqueous common salt cleans, and anhydrous sodium sulfate drying filters, and steams and removes ether, and 95% ethyl alcohol recrystallization gets a.

b)

A (7mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated aqueous common salt cleans, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 73%.

c)

(160mg 4mmol) is dissolved in the 25mL water, joins among the b (2mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filter, dry c, the yield 93% of getting with NaOH.

d)

C (1.6mmol) is placed 50mL single port bottle, stir and drip oxalyl chloride solution (2mmol in 20mLCH down ₂Cl ₂), in 30 minutes, drip off, drip Bi Jixu and stir 2.5h, be spin-dried for solvent and get d, do not deal with and continue following reaction.

e)

With phenylalanine (1.6mmol) and NaOH (130mg 3.2mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 73%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.76-6.66(m，17H，ArH)，4.85-4.78(m，1H，CHCOOH)，4.66(s，2H，NCH ₂)，4.61(s，2H，NCH ₂)，3.46-3.11(m，2H，CH ₂)，2.28(s，3H，CH ₃).

ESI-TOF-MS(positive，m/z)：497(M+H ⁺)

Embodiment 4:ZSE-4-5-p3

a)

4-methoxybenzaldehyde (10mmol) and 4-fluoroaniline (10mmol) are dissolved in the 20mL dehydrated alcohol, stir reflux 8h down, be cooled to room temperature, add NaBH ₄(10mmol), continue to stir 6h, steam and remove ethanol, add 15mL water, ether (15mL*3) extraction merges organic phase, and saturated aqueous common salt cleans, and anhydrous sodium sulfate drying filters, and steams and removes ether, and 95% ethyl alcohol recrystallization gets a.

b)

A (7mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 70%.

c)

(160mg 4mmol) is dissolved in the 25mL water, joins among the b (2mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filter, dry c, the yield 95% of getting with NaOH.

d)

e)

With phenylalanine (1.6mmol) and NaOH (130mg 3.2mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 76%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.80-6.66(m，17H，ArH)，4.82(dt，1H，J＝Hz，J＝Hz，CHCOOH)，4.61(s，2H，NCH ₂)，4.55(s，2H，NCH ₂)，3.74(s，3H，CH ₃)，3.35-3.29(dd，1H，J＝4.5Hz，J＝14.5Hz，CH ₂)，3.19-3.11(dd，1H，J＝8.7Hz，J＝13.2Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：513(M+H ⁺)

Embodiment 5:ZSE-4-5-p4

a)

4-cyanobenzaldehyde (10mmol) and 4-fluoroaniline (10mmol) are dissolved in the 20mL dehydrated alcohol, stir reflux 8h down, be cooled to room temperature, add NaBH ₄(10mmol), continue to stir 6h, steam and remove ethanol, add 15mL water, ether (15mL*3) extraction merges organic phase, the saturated common salt washing, and anhydrous sodium sulfate drying filters, and steams and removes ether, and 95% ethyl alcohol recrystallization gets a.

b)

A (7mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated aqueous common salt cleans, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 63%.

c)

(160mg 4mmol) is dissolved in the 25mL water, joins among the b (2mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filter, dry c, the yield 91% of getting with NaOH.

d)

e)

With phenylalanine (1.6mmol) and NaOH (130mg 3.2mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 53%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.79-6.68(m，17H，ArH)，(dt，1H，J＝Hz，J＝Hz，CHCOOH)，4.80(s，2H，NCH ₂)，4.76(s，2H，NCH ₂)，3.36-3.30(dd，1H，J＝5.1Hz，J＝Hz，CH ₂)，3.19-3.11(dd，1H，J＝9.3Hz，J＝Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：508(M+H ⁺)

Embodiment 6:ZSE-4-17

With NaOH (44mg 1.1mmol) is dissolved in the 10mL water, add ZSE-4-5-p4 (254mg 0.5mmol), stirs 12h under 50 ℃ of temperature, 5% dilute hydrochloric acid is regulated pH to 3-4, filter, drying, column chromatography for separation, white solid 223mg, yield 85%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.90-6.67(m，17H，ArH)，4.89(dt，1H，J＝4.8Hz，J＝13.5Hz，CHCOOH)，4.64(s，4H，NCH ₂)，3.36-3.30(dd，1H，J＝5.1Hz，J＝14.1Hz，CH ₂)，3.19-3.11(dd，1H，J＝9.0Hz，J＝13.8Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：526(M ⁺)

Embodiment 7:ZSE-4-2-p1

a)

Piperonylaldehyde (10mmol) and 4-fluoroaniline (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH ₄(10mmol), continue to stir 4h.Be spin-dried for ethanol, add 20mL water,, merge organic phase with ether (20mL*3) extraction, the saturated common salt washing, anhydrous sodium sulfate drying filters, and is spin-dried for ether, and 95% ethyl alcohol recrystallization gets a, yield 83%.

b)

A (8mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 81%.

c)

(240mg 6mmol) is dissolved in the 25mL water, joins among the b (3mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filter, dry c, the yield 96% of getting with NaOH.

d)

C (2mmol) is placed 50mL single port bottle, stir and drip oxalyl chloride solution (2.4mmol in 20mLCH down ₂Cl ₂), in 30 minutes, drip off, drip Bi Jixu and stir 2.5h, be spin-dried for solvent and get d, do not deal with and continue following reaction.

f)

With phenylalanine (2mmol) and NaOH (160mg 4mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 67%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm11.21(br.s，1H，COOH)，7.78-6.70(m，17H，ArH，NH)，5.95(s，2H，OCH ₂)，4.90(m，1H，CHCOOH)，4.68(s，2H，NCH ₂)，4.58(s，2H，NCH ₂)，3.38-3.10(m，2H，CH ₂).

ESI-TOF-MS(positive，m/z)：527(M+H ⁺)

Embodiment 8:ZSE-4-2-p2

a)

Piperonylaldehyde (10mmol) and aniline (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH ₄(10mmol), continue to stir 4h.Be spin-dried for ethanol, add 20mL water, ether (20mL*3) extraction merges organic phase, the saturated common salt washing, and anhydrous sodium sulfate drying filters, and is spin-dried for ether, and 95% ethyl alcohol recrystallization gets a, yield 79%.

b)

A (8mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 86%.

c)

(240mg 6mmol) is dissolved in the 25mL water, joins among the b (3mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filter, dry c, the yield 97% of getting with NaOH.

d)

e)

With phenylalanine (2mmol) and NaOH (160mg 4mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 78%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm11.21(br.s，1H，COOH)，7.78-6.59(m，18H，ArH，NH)，5.95(s，2H，OCH ₂)，4.90(dt，1H，J＝4.8Hz，J＝13.2Hz，CHCOOH)，4.72(s，2H，NCH ₂)，4.62(s，2H，NCH ₂)，3.36-3.30(dd，1H，J＝5.1Hz，J＝14.1Hz，CH ₂)，3.18-3.12(dd，1H，J＝9.3Hz，J＝13.8Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：509(M+H ⁺)

Embodiment 9:ZSE-4-2-p3

a)

Piperonylaldehyde (10mmol) and 4-monomethylaniline (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH ₄(10mmol), continue to stir 4h.Be spin-dried for ethanol, add 20mL water,, merge organic phase with ether (20mL*3) extraction, the saturated common salt washing, anhydrous sodium sulfate drying filters, and is spin-dried for ether, and 95% ethyl alcohol recrystallization gets a, yield 74%.

b)

A (8mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 79%.

c)

(240mg 6mmol) is dissolved in the 25mL water, joins among the b (3mmol), and stirring at room 8h, 5% dilute hydrochloric acid regulate the pH value to 3-4, filter, dry c, the yield 93% of getting with NaOH.

d)

e)

With phenylalanine (2mmol) and NaOH (160mg 4mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 69%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm11.21(br.s，1H，COOH)，7.77-6.62(m，17H，ArH，NH)，5.94(s，2H，OCH ₂)，(dt，1H，J＝Hz，J＝Hz，CHCOOH)，4.66(s，2H，NCH ₂)，4.57(s，2H，NCH ₂)，(dd，1H，J＝Hz，J＝Hz，CH ₂)，(dd，1H，J＝Hz，J＝Hz，CH ₂)，2.14(s，3H，CH ₃).

ESI-TOF-MS(positive，m/z)：523(M+H ⁺)

Embodiment 10:ZXK-2-27

a)

Piperonylaldehyde (10mmol) and 4-anisidine (10mmol) are dissolved in the 25mL ethanol, and reflux 5h is cooled to room temperature, adds NaBH ₄(10mmol), continue to stir 4h.Be spin-dried for ethanol, add 20mL water,, merge organic phase with ether (20mL*3) extraction, the saturated common salt washing, anhydrous sodium sulfate drying filters, and is spin-dried for ether, and 95% ethyl alcohol recrystallization gets a, yield 78%.

b)

A (8mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, and (1380mg is 10mmol) with 15mL DMF to add Anhydrous potassium carbonate in turn, stirring at room 12h adds 20mL water, ether (20mL*3) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets b, yield 60%.

c)

(240mg 6mmol) is dissolved in the 25mL water, joins among the b (3mmol), and stirring at room 8h regulates the pH value to 3-4, filters, dry c, the yield 90% of getting with NaOH.

d)

e)

With phenylalanine (2mmol) and NaOH (160mg 4mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 42%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.77-6.71(m，17H，ArH，NH)，5.93(s，2H，OCH ₂)，4.95-4.75(m，1H，CH)，4.57(s，2H，CH ₂N)，4.48(s，2H，CH ₂N)，3.65(s，3H，OCH ₃)，3.36-3.30(dd，1H，J＝4.8Hz，J＝14.1Hz，CH ₂)，3.19-3.11(dd，1H，J＝9.6Hz，J＝14.1Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：539(M+H ⁺)

Embodiment 11:ZXK-1-20

a)

b)

c)

d)

e)

With 2-amino-3-(4-hydroxyphenyl) propionic acid (2mmol) and NaOH (160mg 4mmol) is dissolved in the 20mL water, stir down to be added drop-wise among the d, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filtration, drying, column chromatography for separation, yield 45.9%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?8.15(br.s，1H，OH)，7.79-6.71(m，15H，ArH，NH)，5.95(s，2H，OCH ₂)，4.83(dt，1H，J＝4.8Hz，J＝10.2Hz，CH)，4.70(s，2H，CH ₂N)，4.60(s，2H，CH ₂N)，3.25-3.19(dd，1H，J＝5.1Hz，J＝13.8Hz，CH ₂)，3.09-3.01(dd，1H，J＝8.7Hz，J＝13.8Hz，CH ₂).

ESI-Q-MS(negative，m/z)541(M-H ⁺)

Embodiment 12:ZSE-4-15

a)

(1310mg, 10mmol) (1230mg 10mmol) is dissolved in the 25mL dehydrated alcohol, stirs reflux 6h down, is cooled to room temperature, adds NaBH with the 4-anisidine with the 4-cyanobenzaldehyde ₄(378mg 10mmol), finishes room temperature and continues to stir 4h, steams and removes ethanol, adds 10mL water, ether (10mL * 3) extraction merges organic phase, the saturated common salt washing, and anhydrous sodium sulfate drying filters, be spin-dried for solvent, 95% ethyl alcohol recrystallization gets brown needle crystal a 4880mg, yield 79%.

b)

(1666mg 7mmol) joins in the 4-bromomethyl-benzoic acid methyl ester, and (1104mg is 8mmol) with the 20mL acetonitrile to add Anhydrous potassium carbonate with a, stir reflux 12h down, filter, be spin-dried for solvent, column chromatography for separation (PE: EA=4: 1), get faint yellow thickness b 1756mg, yield 65%.

c)

With b (1756mg 4.55mmol) is dissolved in the 10mL methyl alcohol, add NaOH (240mg, 6mmol) and 5mL water, stirring at room 8h steams and removes methyl alcohol, adds 10mL water, 5% dilute hydrochloric acid is regulated pH to 4-6, filter, drying, white solid c 1574mg, yield 93%.

d)

(1574mg 4.2mmol) is dissolved in the 20mL methylene dichloride, and (762mg 6mmol), finishes and continues to stir 3h, and steaming removes methylene dichloride and gets d, does not deal with, and continues following reaction slowly to drip oxalyl chloride under the ice bath with c.

e)

With NaOH (400mg, 10mmol) and phenylalanine (693mg 4.2mmol) is dissolved in the 20mL water, joins among the d, stirring at room 8h, 5% dilute hydrochloric acid is regulated pH to 4-6, filters drying, column chromatography for separation (PE: EA=1: 1+1%HAc), get white solid 1137mg, yield 52.2%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.78-6.70(m，17H，ArH)，4.92-4.85(m，1H，CHCOOH)，4.69(s，2H，NCH ₂)，4.66(s，2H，NCH ₂)，3.66(s，3H，OCH ₃)，3.33-3.10(m，2H，CH ₂).

ESI-TOF-MS(positive，m/z)：520(M+H ⁺)

Embodiment 13:ZSE-4-16

With NaOH (48mg 1.2mmol) is dissolved in the 10mL water, add ZSE-4-15 (260mg, 0.5mmol), stir 12h under 60 ℃ of conditions, 5% dilute hydrochloric acid is regulated pH to 4-6, filters drying, column chromatography for separation (PE: EA=1: 2+1%HAc), get white solid 193mg, yield 72%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.88-6.71(m，17H，ArH)，4.89(m，1H，CHCOOH)，4.64(s，4H，NCH ₂)，3.65(s，3H，OCH ₃)，3.36-3.30(dd，1H，J＝4.8Hz，J＝13.8Hz，CH ₂)，3.18-3.11(dd，1H，J＝9.0Hz，J＝13.5Hz，CH ₂)，2.83(br.s，1H，NH).ESI-TOF-MS(positive，m/z)：538(M)

Embodiment 14:ZXK-2-25

a)

Dibenzylamine (8mmol) is joined in the 4-bromomethyl-benzoic acid methyl ester, add in turn Anhydrous potassium carbonate (1380mg, 10mmol) and the 15mL acetonitrile, reflux 12h, be spin-dried for acetonitrile, add 20mL water, ether (20mL*3) extraction, merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Be spin-dried for ether, column chromatography for separation gets a.

b)

NaOH (16mmol) is dissolved in the 15mL water, joins among the b (8mmol) stirring at room 6h, alkaline condition cleans with ether (5mL*3) down, 5% dilute hydrochloric acid is regulated pH to 5-6, and ethyl acetate (15mL*3) extraction merges organic phase, the saturated common salt washing, anhydrous sodium sulfate drying filters, and is spin-dried for solvent, get white solid b, yield 21%.

c)

B (1.5mmol) is dissolved in the 15mL methylene dichloride, slowly drips oxalyl chloride (3mmol) under the ice bath, finish and continue to stir 3h, steaming removes methylene dichloride and gets c, does not deal with, and continues following reaction.

d)

Phenylalanine (1.5mmol) and NaOH (3mmol) are dissolved in the 10mL water, are added drop-wise among the c under stirring, stirred overnight at room temperature, dilute hydrochloric acid is regulated pH to 3-4, filters, drying, column chromatography for separation gets white solid, yield 53%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.81-7.19(m，20H，ArH，NH)，4.90(m，1H，CHCOOH)，3.59(s，2H，NCH ₂)，3.55(s，4H，NCH ₂)，3.37-3.31(dd，1H，J＝8.1Hz，J＝14.1Hz，CH ₂)，3.20-3.13(dd，1H，J＝9.3Hz，J＝14.1Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：479(M+H ⁺)

Embodiment 15:ZSE-4-11

a)

The 4-bromomethyl-benzoic acid methyl ester is dissolved in the 15mL acetonitrile, add pentanoic (855mg, 4.5mmol) and Anhydrous potassium carbonate (690mg, 5mmol), reflux 12h filters, and is spin-dried for solvent, column chromatography for separation must yellow oil a 513mg, yield 37%.

b)

With NaOH (140mg 3.5mmol) is dissolved in the 15mL water, add a (513mg, 1.74mmol), stirring at room 8h, the dilute hydrochloric acid acidifying is filtered, drying, white solid b 485mg, yield 92%.

c)

(485mg 1.6mmol) is dissolved in the 10mL methylene dichloride, slowly drips oxalyl chloride (3mmol) under the ice bath, finishes to continue to stir 3h, and steaming removes methylene dichloride and gets c, does not deal with, and continues following reaction with b.

d)

With NaOH (128mg, 3.2mmol) and phenylalanine (262mg, 1.6mmol) be dissolved in the 10mL water, slowly be added drop-wise among the c, finish and continue to stir 5h, dilute hydrochloric acid is regulated the pH value to 4-6, filter drying, column chromatography for separation (PE: EA=3: 1+1%HAc), get white solid 107mg, yield 14.9%.

¹H?NMR(300Hz，CD ₃COCD ₃)δppm?7.76-6.69(m，19H，ArH)，5.04(s，2H，NCH ₂)，4.84-4.80(m，1H，CHCOOH)，3.36-3.30(dd，1H，J＝4.8Hz，J＝13.8Hz，CH ₂)，3.19-3.12(dd，1H，J＝8.7Hz，J＝14.1Hz，CH ₂).

ESI-TOF-MS(positive，m/z)：451(M+H ⁺)

Embodiment's 16 to embodiment 25 is synthetic similar with ZSE-4-5-p3.Phenylalanine in the final step is replaced with corresponding amino acid.

Embodiment 16:NFL-1-24-2

Chromatographic system P.E: EtOAc=1: 1+0.25%HOAc collects product.Get 325mg.Yield: 29.2%.

1H?NMR(300Mz，Acetone-d6)δ11.38(s，1H，COOH)，8.17-6.69(m，16H，ArH)，7.88(d，1H，J＝8.1Hz，NH)，5.04-4.97(ddd，1H，J＝3.9Hz，J＝5.1Hz，J＝9.6Hz，CH)，4.66(s，2H，CH2N)，4.59(s，2H，CH2N)，3.75(s，3H，CH3O)，3.53-3.47(dd，1H，J＝5.1Hz，J＝14.1Hz，CH2a)，3.36-3.28(dd，1H，J＝9.3Hz，J＝13.5Hz，CH2b).ESI-TOF-MS(m/z，positive)：558.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C31H29N3O6F+558.2034，found?558.2015(-3.57ppm).

Embodiment 17:NFL-1-24-3

Chromatographic system P.E: EtOAc=1: 1+0.25%HOAc collects product.Get 300mg.Yield: 28.4%.

1H?NMR(300Mz，Acetone-d6)δ11.20(s，1H，COOH)，8.14(s，1H，OH)，7.79-6.69(m，16H，ArH)，7.62(d，1H，J＝8.1Hz，NH)，4.86-4.79(m，1H，CH)，4.67(s，2H，CH2N)，4.60(s，2H，CH2N)，3.76(s，3H，CH3O)，3.25-3.19(dd，1H，J＝5.1Hz，J＝13.8Hz，CH2a)，3.09-3.01(dd，1H，J＝9.0Hz，J＝14.4Hz，CH2b).

ESI-TOF-MS(m/z，positive)：529.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C31H30N2O5F+529.2133，found?529.2130(-0.62ppm).

Embodiment 18:NFL-1-25-1

Chromatographic system P.E: EtOAc=2: 1+0.25%HOAc collects product.Get 553mg.Yield: 57.8%.

1H?NMR(300Mz，CDCl3)δ7.75-6.69(m，12H，ArH)，6.44(d，1H，J＝8.1Hz，NH)，4.81-4.78(m，1H，CH)，4.58(s，2H，CH2N)，4.53(s，2H，CH2N)，3.79(s，3H，CH3O)，1.88-1.71(m，3H，CHCH2)，1.00(s，3H，CH3)，0.98(s，3H，CH3).

ESI-TOF-MS(m/z，positive)：479.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C28H32N2O4F+479.2340，found?479.2342(0.29ppm).

Embodiment 19:NFL-1-25-2

Chromatographic system P.E: EtOAc=2: 1+0.25%HOAc collects product.Get 658mg.Yield: 68.8%.

1H?NMR(300Mz，CDCl3)δ7.76-6.61(m，13H，ArH，NH)，4.85-4.80(dd，1H，J＝4.8Hz，J＝7.8Hz，CHCO)，4.57(s，2H，CH2N)，4.52(s，2H，CH2N)，3.79(s，3H，CH3O)，2.07-2.04(m，1H，CH)，1.60-1.54(m，1H，CH2a)，1.33-1.21(m，1H，CH2b)，1.02-0.95(m，6H，CH3).

ESI-TOF-MS(m/z，positive)：479.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C28H32N2O4F+479.2340，found?479.2328(-2.63ppm).

Embodiment 20:NFL-1-25-3

Chromatographic system P.E: EtOAc=1: 1+0.25%HOAc collects product.Get 663mg.Yield: 71.7%.

1H?NMR(300Mz，CDCl3)δ7.52-6.69(m，12H，ArH)，4.80-4.76(dd，1H，J＝4.8Hz，J＝8.1Hz，CHCO)，4.58(s，2H，CH2N)，4.53(s，2H，CH2N)，3.79(s，3H，CH3O)，3.64-3.52(m，2H，CH2CH2N)，2.53-1.88(m，4H，CH2CH2).

ESI-TOF-MS(m/z，positive)：463.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C27H28N2O4F+463.2027，found?463.2024(-0.78ppm).

Embodiment 21:NFL-1-25-4

Chromatographic system P.E: EtOAc=1: 1+0.25%HOAc collects product.Get 412mg.Yield: 31.5%.

1H?NMR(300Mz，CDCl3)δ7.78-6.61(m，13H，ArH，NH)，4.94-4.88(ddd，1H，J＝5.1Hz，J＝7.2Hz，J＝12.3Hz，CHCO)，4.57(s，2H，CH2N)，4.52(s，2H，CH2N)，3.79(s，3H，CH3O)，2.65(t，2H，J＝6.6Hz，CH2CH)，2.36-2.13(m，2H，SCH2)，2.12(s，3H，CH3S).

ESI-TOF-MS(m/z，positive)：497.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C27H30N2O4FS+497.1904，found?497.1902(-0.57ppm).

Embodiment 22:NFL-1-26-1

Chromatographic system P.E: EtOAc=2: 1+0.25%HOAc collects product.Get 690mg.Yield: 69.3%.

1H?NMR(300Mz，Acetone-d6)δ11.38(s，1H，COOH)，8.10(d，1H，J＝6.9Hz，NH)，7.92-6.70(m，17H，ArH)，5.75(d，1H，J＝4.5Hz，CH)，4.68(s，2H，CH2N)，4.60(s，2H，CH2N)，3.75(s，3H，CH3O).

ESI-TOF-MS(m/z，positive)：499.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C30H28N2O4F+422.2027，found?499.2023(-0.93ppm).

Embodiment 23:NFL-1-26-2

Chromatographic system P.E: EtOAc=2: 1+0.25%HOAc collects product.Get 818mg.Yield: 74.2%.

1H?NMR(300Mz，Acetone-d6)δ11.20(s，1H，COOH)，10.05(s，1H，phNH)，7.78-6.69(m，18H，ArH，NH)，5.00-4.94(dt，1H，J＝5.1Hz，J＝7.8Hz，CH)，4.66(s，2H，CH2N)，4.59(s，2H，CH2N)，3.75(s，3H，CH3O)，3.51-3.44(dd，1H，J＝4.8Hz，J＝14.7Hz，CH2a)，3.38-3.30(dd，1H，J＝8.1Hz，J＝14.7Hz，CH2b).

ESI-TOF-MS(m/z，positive)：552.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C33H31N3O4F+552.2293，found?552.2290(-0.56ppm).

Embodiment 24:NFL-1-26-3

Filter.Get 545mg.Yield: 54.3%.

1H?NMR(300Mz，DMSO-d6)δ8.67(d，1H，NH)，7.77-6.60(m，14H，ArH)，4.66(s，2H，CH2N)，4.59-4.54(m，3H，CH2N，CH)，3.71(s，3H，CH3O)，3.02(d，2H，J＝6.6Hz，CH2).

ESI-TOF-MS(m/z，positive)：503.1(M+H ⁺).

HRMS(m/z，positive)：calc.for?C28H28N4O4F+503.2094，found?503.2096(0.28ppm).

Embodiment 25:NFL-1-26-4

Chromatographic system P.E: EtOAc=2: 1+0.25%HOAc collects product.Get 650mg.Yield: 62.0%.

1H?NMR(300Mz，Acetone-d6)δ7.45-6.76(m，16H，ArH)，5.61(m，1H，CH)，4.85-4.62(m，6H，CH2N)，3.76(s，3H，CH3O)，3.28(s，2H，CH2).

ESI-TOF-MS(m/z，positive)：525.2(M+H ⁺).

HRMS(m/z，positive)：calc.for?C32H30N2O4F+525.2184，found?525.2186(0.36ppm).

Embodiment 26:LJZ-1-32

a)

2120mg (20mmol) phenyl aldehyde, 1860mg (20mmol) aniline are dissolved in an amount of ethanol, and reflux 9h stops heating, be cooled to room temperature, add sodium borohydride 760mg (20mmol), stirring at room, reaction 6h, stopped reaction removes ethanol under reduced pressure, add water, the dilute hydrochloric acid regulator solution is weakly alkaline, ethyl acetate extraction, dried over sodium sulfate, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), get white crystal a 2g, productive rate=55%.

b)

1830mg (10mmol) a, 1380mg (10mmol) Anhydrous potassium carbonate are dissolved among an amount of DMF, add the DMF solution of 2290mg (10mmol), stirring at room, reaction 24h to bromomethyl-benzoic acid methyl ester, stopped reaction, filter, concentrate ethyl acetate extraction, dried over sodium sulfate, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), get white solid b 1416mg, productive rate=43%.

c)

331mg (1mmol) b is dissolved in the 10mL ethanol, the small amount of acetone hydrotropy, the aqueous solution of adding potassium hydroxide (112mg), stirring at room 6h, stopped reaction, concentrate, dilute hydrochloric acid transfers the pH value of solution value to be about 3, separates out a large amount of white solids, filter, drying gets white powder solid c 298mg, yield=94%.

d)

600mg (1.89mmol) c is dissolved in the methylene dichloride, drips 2 DMF, fully stirring, ice bath drips oxalyl chloride 0.2mL (2mmol) down, and drip and finish, stirring at room 10min, steaming desolventizes, and gets yellow solid.This yellow solid is dissolved in the tetrahydrofuran (THF) of new steaming, be added drop-wise in sodium hydroxide (80mg) solution of phenylalanine (297mg) stirring at room 30min, stopped reaction, it is 3-4 that dilute hydrochloric acid is transferred the pH value of solution value, separate out a large amount of solids, filter drying, column chromatography for separation [(sherwood oil: ethyl acetate=3: 1)+1%HAc], drying gets pale yellow powder shape solid 210mg, yield=24%.

1H?NMR(300MHz，acetone-d6)δppm?7.79-6.59(m，19H)，4.88(m，1H)，4.74(s，2H)，4.72(s，2H)，3.33(dd，J＝5.0，13.8Hz，1H)，3.15(dd，J＝9.2，13.8Hz，1H)

ESI-TOF-MS(positive，m/z)：465.2(M+H ⁺)

HRMS(m/z，positive)：calc.for?C30H29N2O3+465.2172，found?465.2172(-0.15ppm).

Embodiment 27:LJZ-2-16

a)

1.66mL (20mmol) furfural, 1.91mL (20mmol) para-fluoroaniline are dissolved in the 20mL benzene, and reflux 3h stops heating, steam and remove benzene, gained reddish-brown oily matter is dissolved in the anhydrous methanol, add sodium borohydride 950mg (25mmol), stirring at room, reaction 3h, stopped reaction, remove methyl alcohol under reduced pressure, add water, it is neutral that the dilute hydrochloric acid regulator solution is, ethyl acetate extraction, dried over sodium sulfate, column chromatography for separation (sherwood oil: ethyl acetate=4: 1), get red oil.

b)

2.74g (18mmol) 4-fluoro-N-(furfuryl) aniline and 4-bromomethyl-benzoic acid methyl ester (etc. amount) are dissolved among the DMF, add 2.9g (21mmol) Anhydrous potassium carbonate, stirring at room, reaction 4h, stopped reaction filters, concentrate, be dissolved in water ethyl acetate extraction, anhydrous sodium sulfate drying.Column chromatography for separation (sherwood oil: ethyl acetate=30: 1), get colorless oil 3.12g, yield=51%.(LJZ-2-8) is dissolved in the small amount of acetone with this oily matter, adds ethanol 60mL, slowly drips the aqueous solution of KOH, drips and finishes stirring at room.Reaction 4h, raw material is several to react completely.Steaming removes organic solvent, and resistates adds the less water dilution, and dilute hydrochloric acid is transferred pH value of solution value to 3～4, separates out a large amount of light yellow solids, filters, and drying gets pale yellow powder a 2.98g.The total recovery of four-step reaction is 50.9%.

c)

A 650mg (2mmol) is dissolved among the DCM of new system, drips 1d DMF, ice bath drips oxalyl chloride 0.24mL (2.4mmol), room temperature reaction 5h, stopped reaction, solvent evaporated down.322mg (1.8mmol) phenylalanine is dissolved in the aqueous solution of 300mg (7.5mmol) sodium hydroxide, is added drop-wise in the acyl chlorides solid of gained, stirring at room, reaction 1h, stopped reaction, the pH value of dilute hydrochloric acid regulator solution is 3～4, separates out a large amount of white solids.Ethyl acetate extraction, drying, column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get pale yellow powder 291mg, productive rate=34.3%.

1H?NMR(300MHz，acetone-d6)δppm?7.76-6.27(m，16H)，4.81(m，1H)，4.62(s，2H)，4.58(s，2H)，3.32(dd，J＝4.9，13.5Hz，1H)，3.17(dd，J＝8.7，13.5Hz，1H)，2.98(s，1H)

ESI-TOF-MS(positive，m/z)：473.2(M+H ⁺)

HRMS(m/z，positive)：calc.for?C28H26N2O4F+473.1879，found?473.1871(1.66ppm).

Embodiment's 28 to embodiment 31 is synthetic similar with ZSE-4-5-p3.Phenylalanine in the final step is replaced with corresponding amino acid.

Embodiment 28:LJZ-2-26

Get pale yellow powder 480mg, yield=65%.

1H?NMR(300MHz，acetone-d6)δppm?7.78-6.69(m，16H)，4.88(m，1H)，4.67(s，2H)，4.60(s，2H)，3.76(s，3H)，3.32(dd，J＝4.8，13.8Hz，1H)，3.15(dd，J＝9.3，14.1Hz，1H)

ESI-TOF-MS(positive，m/z)：531.2(M+H ⁺)

HRMS(m/z，positive)：calc.for?C31H29N2O4F2+531.2092，found?531.2090(0.39ppm).

Embodiment 29:LJZ-2-27-1

Get white powder 388mg, yield=49%.

1H?NMR(300MHz，acetone-d6)δppm?7.85-6.68(m，19H)，5.01(m，1H)，4.65(s，2H)，4.58(s，2H)，3.75(s，3H)，3.51(dd，J＝5.1，13.8Hz，1H)，3.34(dd，J＝9.3，13.8Hz，1H)

ESI-TOF-MS(positive，m/z)：563.2(M+H ⁺)

HRMS(m/z，positive)：calc.for?C35H32N2O4F+563.2360，found?563.2341(3.44ppm).

Embodiment 30:LJZ-2-27-2

Get white powder 210mg, yield=29%.

1H?NMR(300MHz，acetone-d6)δppm?7.85-6.71(m，15H)，5.89(m，1H)，4.67(s，2H)，4.60(s，2H)，3.75(s，3H)，3.07(m，2H)

ESI-TOF-MS(positive，m/z)：519.2(M+H ⁺)

HRMS(m/z，positive)：calc.for?C29H28N2O4FS+519.1746，found?519.1748(-0.23ppm).

Embodiment 31:LJZ-2-27-4

Get white powder 385mg, yield=55%.

1H?NMR(300MHz，acetone-d6)δppm?7.90-6.70(m，12H)，5.86(s，1H)，5.67(q，2H)，5.09(t，1H)，

4.68(s，2H)，4.61(s，2H)，3.76(s，3H)，2.76(m，4H)

HRMS(m/z，positive)：calc.for?C30H30N2O4F+501.2204，found?501.2184(3.97ppm).

Embodiment 32:LJZ-2-28

a)

With 4-cyclohexyl aniline 1.05g (6mmol) and etc. the aubepine of amount be dissolved in the 40mL methyl alcohol heating reflux reaction 5h, stopped reaction, be chilled to room temperature, to wherein adding 6mmol sodium borohydride, stirring at room 1h, stopped reaction removes methyl alcohol under reduced pressure, is dissolved in water, extracted with diethyl ether, drying removes ether under reduced pressure, gained oily matter 95% ethyl alcohol recrystallization, get silvery white crystal 1.05g, yield=59%.

b)

With 4-cyclohexyl-N-(4-methoxy-benzyl) aniline (885mg, 4mmol), bromo methyl p toluate 4mmol, salt of wormwood 552mg (4mmol) are dissolved among the DMF, stirring at room 8h, stopped reaction filters, and concentrates, ethyl acetate extraction, drying, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), get yellow oil.The faint yellow oily thing of gained is dissolved in the small amount of acetone, adds 40mL ethanol, and the aqueous solution of sodium hydroxide, stirring at room, reaction 8h steams and removes organic solvent, and it is 3～4 that dilute hydrochloric acid is transferred the pH value of solution value, ethyl acetate extraction, drying, and column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1%HAc), drying, get pale yellow powder 850mg, yield=66%.

c)

(511mg 1.4mmol) is dissolved in the methylene dichloride of new system, drips 1 DMF, and ice bath drips oxalyl chloride 1.5mmol, room temperature reaction 3h, stopped reaction, solvent evaporated down with 4-(((4-cyclohexyl phenyl) (4-methoxy-benzyl) amino) methyl) phenylformic acid.308mg (1.4mmol) P-fluoropnenylalanine hydrochloride is dissolved in the aqueous solution of 224mg (5.6mmol) sodium hydroxide, is added drop-wise in the acyl chlorides solid of gained stirring at room, reaction 3h, stopped reaction, the pH value of dilute hydrochloric acid regulator solution is 3～4, separates out a large amount of solids.Filter drying, column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get pale yellow powder 480mg, productive rate=65%.

1H?NMR(300MHz，acetone-d6)δppm?7.58-6.62(m，17H)，4.77(m，1H)，4.63(s，2H)，4.57(s，2H)，3.75(s，3H)，3.31(dd，J＝5.0，13.5Hz，1H)，3.18(dd，J＝7.8，13.5Hz，1H)，2.33(m，1H)，1.72(m，5H)，1.34(m，5H)

ESI-TOF-MS(positive，m/z)：577.3(M+H ⁺)

HRMS(m/z，positive)：calc.for?C37H41N2O4+577.3063，found?577.3061(0.37ppm).

Embodiment 33:LJZ-2-29

a)

2-aminobenzothiazole 1.2g (8mmol) and etc. the aubepine of amount be dissolved in the benzene, add the tosic acid of catalytic amount, reflux, fraction water device water-dividing.Reaction 12h, stopped reaction concentrates, and gets yellow oil.It is dissolved in the methyl alcohol, adds 304mg (8mmol) sodium borohydride, stirring at room 10min produces a large amount of white solids, filters, and recrystallization in the acetone gets colourless acicular crystal 1.66g, yield=77%.

b)

The described method of the same LJZ-2-28 of operation steps (b), column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get white solid 618mg, yield=38%.

c)

The described method of the same LJZ-2-28 of operation steps (c) gets pale yellow powder 160mg, yield=42%.

1H?NMR(300MHz，acetone-d6)δppm?7.79-6.87(m，17H)，4.84(s，1H)，4.81(s，2H)，4.73(s，2H)，3.76(s，3H)，3.32(dd，J＝4.5，13.8Hz，1H)，3.17(dd，J＝8.4，13.8Hz，1H)

ESI-TOF-MS(positive，m/z)：552.2(M+H ⁺)

HRMS(m/z，positive)：calc.for?C32H30N3O4S+552.1951，found?552.1952(-0.10ppm).

Embodiment 34:LJZ-2-35

a)

890mg (5mmol) 4-morpholinyl aniline and etc. the aubepine of amount be dissolved in the dehydrated alcohol, drips 3 piperidines, reflux 4h,, stopped reaction, it is solid to produce a large amount of reddish-brown sheets, cooling, filtration.Filter cake is dissolved in the methyl alcohol of heat, adds the 5mmol sodium borohydride, and holding temperature fully stirs, reaction 30min, stopped reaction, dilute hydrochloric acid regulator solution pH value are neutral, dichloromethane extraction, drying, concentrate, ethyl alcohol recrystallization gets light coffee color tabular crystal 840mg, yield=56%.

b)

The described method of the same LJZ-2-28 of operation steps (b), column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get light green solid 789mg, yield=62%.

c)

The described method of the same LJZ-2-28 of operation steps (c), column chromatography for separation (methyl alcohol: methylene dichloride=1: 40+1% acetic acid), get pale solid 154mg, yield=15%.

1H?NMR(300MHz，acetone-d6)δppm?7.96-6.62(m，18H)，4.67(s，1H)，4.53(s，2H)，4.48(s，2H)，3.74(s，3H)，3.69(t，3H)，3.30(m，1H)，3.23(m，1H)，2.91(t，3H)

ESI-TOF-MS(positive，m/z)：580.3(M+H ⁺)

HRMS(m/z，positive)：calc.for?C35H38N3O5+580.2804，found?580.2806(-0.34ppm).

Embodiment 35:LJZ-2-36

a)

1.11g (6mmol) 4-benzene oxygen aniline and etc. the aubepine of amount be dissolved in the methyl alcohol reflux 6h, cool overnight, separate out a large amount of silvery white tabular crystals, filter, filter cake is dissolved in the methyl alcohol of heat, add the 6mmol sodium borohydride, 50 ℃ are fully stirred, reaction 30min, stopped reaction, evaporate to dryness methyl alcohol, dilute hydrochloric acid regulator solution pH value is neutral, extracted with diethyl ether, drying concentrates, get khaki color solid 1.368g, yield=75%.

b)

The described method of the same LJZ-2-28 of operation steps (b) gets pale yellow powder 930mg, yield=59%.

c)

The described method of the same LJZ-2-28 of operation steps (c), column chromatography for separation (ethyl acetate: sherwood oil=1: 5+1% acetic acid), get yellow solid 700mg, yield=57%.

1H?NMR(300MHz，acetone-d6)：δppm?7.96-6.69(m，22H)，4.72(m，1H)，4.60(s，2H)，4.54(s，2H)，3.73(s，3H)，3.31(dd，J＝4.5，13.5Hz，1H)，3.18(dd，J＝8.0，13.5Hz，1H)

ESI-TOF-MS(positive，m/z)：587.3(M+H ⁺)

HRMS(m/z，positive)：calc.for?C37H35N2O5+587.2538，found?587.2540(-0.42ppm).

Embodiment 36:LJZ-2-48

A) 4-(4-fluoroaniline methyl)-methyl benzoate

P formylbenzoic acid methyl esters 3.28g (20mmol) is dissolved in the methyl alcohol; drip the para-fluoroaniline of equivalent, separate out a large amount of white crystals immediately, back flow reaction 2h; cooling is approximately to 50 ℃; add sodium borohydride 760mg (20mmol), keep this temperature and stir 30min, separate out a large amount of white plates crystal; filter; drying gets white flakey crystal 3 .428g, yield=66%.

b)

4-(4-fluoroaniline methyl)-methyl benzoate 777mg (3mmol), 442mg (3.2mmol) salt of wormwood are dissolved in the acetonitrile, the sodium iodide that adds catalytic amount, Dropwise 5 30mg (3mmol) 1 chloromethyl naphthalene, stirred overnight at room temperature, heating reflux reaction 5h, stopped reaction, filter, concentrate column chromatography for separation (ethyl acetate: sherwood oil=25: 1), get white powder.It is dissolved in the small amount of acetone alcohol dilution, the aqueous solution of adding 3.6mmol potassium hydroxide, stirring at room 8h, stopped reaction concentrates, and dilute hydrochloric acid regulator solution pH value is 1-2, separates out a large amount of white solids, filter, drying gets white solid a 1.03g, yield=89%.

c)

A (770mg 2mmol) is dissolved in the methylene dichloride of new system, drips 2 DMF, and ice bath drips the 3mmol oxalyl chloride down, stirring at room, and reaction 3h, stopped reaction concentrates, and gets yellow solid.330mg (2mmol) phenylalanine is dissolved in the aqueous solution of 5mmol sodium hydroxide, join in the above-mentioned gained yellow solid, stirred overnight at room temperature, stopped reaction, dilute hydrochloric acid regulator solution pH value is 2-3, ethyl acetate extraction, dry, column chromatography for separation (ethyl acetate: sherwood oil=4: the 1+1% Glacial acetic acid), get yellow solid 734mg, yield=69%.

1H?NMR(300MHz，acetone-d6)δppm?8.09-6.66(m，20H)，5.16(s，2H)，4.82(m，1H)，4.76(s，2H)，3.33(dd，J＝5.1，13.8Hz，1H)，3.18(dd，J＝8.1，13.8Hz，1H)

HRMS(m/z，positive)：calc.for?C34H30N2O3F+533.2236，found?533.2235(0.19ppm).

Embodiment 37:LJZ-3-10

a)

b)

4-cyclohexyl-N-(4-methoxy-benzyl) aniline 885mg (4mmol), bromo methyl p toluate 4mmol, salt of wormwood 552mg (4mmol) are dissolved among the DMF, stirring at room 8h, stopped reaction, filter, concentrate ethyl acetate extraction, drying, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), get yellow oil.The faint yellow oily thing of gained is dissolved in the small amount of acetone, adds 40mL ethanol, and the aqueous solution of sodium hydroxide, stirring at room, reaction 8h steams and removes organic solvent, and it is 3～4 that dilute hydrochloric acid is transferred the pH value of solution value, ethyl acetate extraction, drying, and column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1%HAc), drying, get pale yellow powder 850mg, yield=66%.

c)

4-(((4-cyclohexyl phenyl) (4-methoxy-benzyl) amino) methyl) phenylformic acid 410mg (0.96mmol) is dissolved in the methylene dichloride of new system, drips 1 DMF, ice bath drips oxalyl chloride 1mmol, room temperature reaction 3h, stopped reaction, solvent evaporated down.238mg (0.95mmol) β-naphthylalanine hydrochloride is dissolved in the aqueous solution of 160mg (4mmol) sodium hydroxide, is added drop-wise in the acyl chlorides solid of gained stirring at room, reaction 3h, stopped reaction, the pH value of dilute hydrochloric acid regulator solution is 3～4, separates out a large amount of solids.Filter drying, column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get khaki color powder 300mg, yield=50%.

1H?NMR(300MHz，DMSO-d6)：δppm?7.82-6.54(m，20H)，4.61(s，2H)，4.55(s，2H)，4.21(m，1H)，3.71(s，3H)，3.37(dd，J＝5.1，13.0Hz，1H)，3.22(dd，J＝5.8，13.0Hz，1H)，2.29(m，1H)，1.70(m，5H)，1.27(m，5H)

ESI-TOF-MS(positive，m/z)：627.3(M+H+)

Embodiment 38:LJZ-4-9

a)

3.7g (20mmol) 4-benzene oxygen aniline and etc. the aubepine of amount be dissolved in the methyl alcohol reflux 6h, cool overnight, separate out a large amount of silvery white tabular crystals, filter, filter cake is dissolved in the methyl alcohol of heat, add the 25mmol sodium borohydride, 50 ℃ are fully stirred, reaction 30min, stopped reaction, evaporate to dryness methyl alcohol, dilute hydrochloric acid regulator solution pH value is neutral, extracted with diethyl ether, drying concentrates, get khaki color solid 3.9g, yield=64%.

b)

With N-(4-methoxy-benzyl)-4-benzene oxygen aniline (3.9g, 12.8mmol), bromo methyl p toluate 13mmol, salt of wormwood 2.07g (15mmol) be dissolved among the DMF, stirring at room 8h, stopped reaction filters, and concentrates, ethyl acetate extraction, drying, column chromatography for separation (sherwood oil: ethyl acetate=20: 1), get yellow oil.The faint yellow oily thing of gained is dissolved in the small amount of acetone, adds 40mL ethanol, and the aqueous solution of sodium hydroxide, stirring at room, reaction 8h steams and removes organic solvent, and it is 3～4 that dilute hydrochloric acid is transferred the pH value of solution value, ethyl acetate extraction, drying, and column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1%HAc), drying, get pale yellow powder 3.05g, yield=54.3%.

c)

(439mg 1mmol) is dissolved in the methylene dichloride of new system, drips 1 DMF, and ice bath drips oxalyl chloride 1.2mmol, room temperature reaction 3h, stopped reaction, solvent evaporated down with 4-(((4-methoxy-benzyl) (4-phenoxy phenyl) amino) methyl) phenylformic acid.220mg (1mmol) P-fluoropnenylalanine hydrochloride is dissolved in the aqueous solution of 160mg (4mmol) sodium hydroxide, is added drop-wise in the acyl chlorides solid of gained, stirring at room, reaction 3h, stopped reaction, the pH value of dilute hydrochloric acid regulator solution is 3～4, separates out a large amount of solids.Filter drying, column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get white powder 285mg, productive rate=47%.

1H?NMR(300MHz，acetone-d6)：δ7.98-6.74(m，21H)，4.82(m，1H)，4.67(s，2H)，4.61(s，2H)，3.75(s，3H)，3.32(dd，J＝5.1，13.5Hz，1H)，3.16(dd，J＝8.4，13.5Hz，1H)

HRMS(m/z，positive)：calc.for?C37H34N2O5F+605.24462，found?605.2447(0.12ppm).

Embodiment 39:LJZ-4-10

a)

b)

c)

(439mg 1mmol) is dissolved in the methylene dichloride of new system, drips 1 DMF, and ice bath drips oxalyl chloride 1.2mmol, room temperature reaction 3h, stopped reaction, solvent evaporated down with 4-(((4-methoxy-benzyl) (4-phenoxy phenyl) amino) methyl) phenylformic acid.204mg (1mmol) tryptophane is dissolved in the aqueous solution of 80mg (2mmol) sodium hydroxide, is added drop-wise in the acyl chlorides solid of gained, stirring at room, reaction 3h, stopped reaction, the pH value of dilute hydrochloric acid regulator solution is 3～4, separates out a large amount of solids.Filter drying, column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get white powder 240mg, productive rate=38%.

1H?NMR(300MHz，acetone-d6)：δ7.70-6.65(m，22H)，4.81(s，1H)，4.52(s，2H)，4.49(s，2H)，3.72(s，3H)，3.50(dd，J＝7.8，13.5Hz，1H)，3.35(dd，J＝5.7，13.5Hz，1H)HRMS(m/z，positive)：calc.for?C37H34N2O5F+626.26494，found?626.2638(-1.83ppm).

Embodiment 40:LJZ-4-17

a)

b)

c)

(429mg 1mmol) is dissolved in the methylene dichloride of new system, drips 1 DMF, and ice bath drips oxalyl chloride 1.2mmol, room temperature reaction 3h, stopped reaction, solvent evaporated down with 4-(((4-cyclohexyl phenyl) (4-methoxy-benzyl) amino) methyl) phenylformic acid.220mg (1mmol) P-fluoropnenylalanine hydrochloride is dissolved in the aqueous solution of 200mg (5mmol) sodium hydroxide, is added drop-wise in the acyl chlorides solid of gained, stirring at room, reaction 3h, stopped reaction, the pH value of dilute hydrochloric acid regulator solution is 3～4, separates out a large amount of solids.Filter drying, column chromatography for separation (sherwood oil: ethyl acetate=3: 1+1% acetic acid), get white powder 476mg, productive rate=80%.

1H?NMR(300MHz，acetone-d6)：δ7.92-6.63(m，16H)，4.75(m，1H)，4.63(s，2H)，4.57(s，2H)，3.75(s，3H)，3.30(dd，J＝5.1，13.8Hz，1H)，3.16(dd，J＝8.1，13.8Hz，1H)，2.34(m，1H)，1.77-1.66(m，5H)，1.41-1.17(m，5H)

HRMS(m/z，positive)：calc.for?C37H40N2O4F+595.29721，found?595.2978(0.99ppm).

Pharmacological evaluation

Experimental example 1: compound of the present invention is to the recombinate restraining effect of PTP 1B enzyme of people

Method:

Utilize the BL21E.Coli intestinal bacteria to prepare the people PTP1B engineering bacteria of gene recombination, and use GST affinitive layer purification albumen, obtain PTP1B albumen.With nitro phosphoric acid salt is substrate, carries out the zymetology reaction of PTP1B, and the observation in vitro medicine is to the influence of PTP1B protein-active.

The result:

Having measured above-claimed cpd respectively is 10 at final concentration ^-4M, 10 ^-5During M to the inhibiting rate of the people PTP1B of gene recombination; Measure and calculate several The compounds of this invention.The result is as shown in table 1.

Table v1. test-compound is to the restraining effect of gene recombinant human PTP1B enzyme

Experimental example 2: compound of the present invention is to the growth-inhibiting effect of tumor cell line

Method:

Adopt of the growth-inhibiting effect of SRB (Sulforhodamine B) method assessing compound to lung cancer cell line A549, prostate cancer cell strain DU145, breast cancer cell line mcf-7, squamous cell carcinoma strain KB and persister KBvin thereof.After continuing medication 3 days, calculate GI by dose-effect curve ₅₀Value.

The result:

Measure and calculate the GI of several The compounds of this invention respectively ₅₀Value.The result is as shown in table 2.

Table 2. test-compound is to the growth-inhibiting effect of tumor cell line

ND：Not?Determined；

NA：Not?active(Percentage?inhibition?less?than?50％at?20μg/mL)

Claims

1. benzoylamino carboxylic acid compound and steric isomer and physiologically acceptable salt by following general formula (I) expression,

R2, R3 are independently selected from hydrogen, halogen, C1-6 alkoxyl group;

2. the compound of stating according to claim 1 is characterized in that, described compound is the compound shown in the general formula (IA) and steric isomer and physiologically acceptable salt:

Wherein, Ar ₁, Ar ₂Independently be selected from and replace or unsubstituted phenyl, replacement or unsubstituted naphthyl, replacement or unsubstituted furyl, replacement or unsubstituted benzothiazolyl;

3. according to the described compound of claim 2, it is characterized in that described compound is the compound shown in the general formula (IAa) and steric isomer and physiologically acceptable salt:

4. compound according to claim 2 is characterized in that, described compound is the compound shown in the general formula (IAb) and steric isomer and physiologically acceptable salt:

5. compound according to claim 4 is characterized in that, described compound is the compound shown in the general formula (IAb1) and steric isomer and physiologically acceptable salt:

6. compound according to claim 2 is characterized in that, described compound is the compound shown in the general formula (IAc) and steric isomer and physiologically acceptable salt:

7. compound according to claim 6 is characterized in that, described compound is the compound shown in the general formula (IAc1) and steric isomer and physiologically acceptable salt:

(IAc1)

8. compound according to claim 6 is characterized in that, described compound is the compound shown in the general formula (IAc2) and steric isomer and physiologically acceptable salt:

9. the compound of stating according to claim 1 is characterized in that, described compound is the compound shown in the general formula (IB) and steric isomer and physiologically acceptable salt:

10. the compound of stating according to claim 1 is characterized in that, described compound is the compound shown in the general formula (IC) and steric isomer and physiologically acceptable salt:

11., it is characterized in that described compound is selected from according to each described compound among the claim 1-10:

12. the preparation method of each described compound is characterized in that in the claim 1～11, may further comprise the steps:

Wherein, Ar ₁, Ar ₂, M ₁, M ₂, X, Y, R ₁, R ₂, R ₃Definition with each is identical among the claim 1-11;

W represents-Br or-CH ₂Br; R ' is methyl or ethyl.

13. the composition of a medicine, contain effective dose as each described arbitrary compound in the claim 1～11 with at pharmaceutically acceptable carrier.

14. pharmaceutical composition according to claim 13 is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation or various particulate delivery system.

15. as the purposes of each described compound of claim 1～11 as protein-tyrosine-phosphatase 1 1B inhibitor.

16. be used for preparing the application that prevents or treat the medicine of protein-tyrosine-phosphatase 1 1B relative disease as each described compound of claim 1～11.

17. according to the application of claim 16, described disease is selected from malignant tumours such as metabolism syndrome diseases such as diabetes, hypertension, obesity, hyperlipidemia and mammary cancer.