CN102617487A

CN102617487A - Multi-substituted pyrimidinones compounds as well as preparation method and application thereof

Info

Publication number: CN102617487A
Application number: CN2012100530899A
Authority: CN
Inventors: 胡利明; 胡杰; 章彬; 王雨捷; 曾程初; 王小利
Original assignee: Beijing University of Technology
Current assignee: Beijing University of Technology
Priority date: 2012-03-02
Filing date: 2012-03-02
Publication date: 2012-08-01
Anticipated expiration: 2032-03-02
Also published as: CN102617487B

Abstract

The invention relates to multi-substituted benzamides compounds as well as a preparation method and the application thereof, wherein, the multi-substituted benzamides compounds are expressed as N-((4-(1-methyl-2-substituted benzyl-5-methoxy-6-oxo-1,6-dihydropyrimidine-4-carbonyl) piperazidine-1-yl) alkyl) shown in the formula (I). In the formula (I), R1 represents -H or -Cl, R2 represents -H or -Cl or -F or -CH3 or -OH, R3 and R4 represent-OH, R5 represents -H or -OH, and n equals to 2 or 3. The method comprises the steps as follows: oxammonium hydrochloride and substituted phenylacetonitrile can synthesize N'-hydroxyl-2-substituted phenyl acetamidine compounds at first; then the N'-hydroxyl-2-substituted phenyl acetamidine compounds react with dimethyl acetylenedicarboxylate to synthesize 2-(1-amino substituted phenyl ethylidene amino) oxo butadiene diacid dimethyl compounds; 2-(1-amino substituted phenyl ethylidene amino) oxo butadiene diacid dimethyl compounds are processed through cyclization and methylation and then are processed through hydrolyzation and acidification so as to generate formate compounds; then formate compounds react with N-piperazinyl alkyl substituted benzamide to generate N-((4-(1-methyl-2-substituted benzyl-5-methoxy-6-oxo-1,6-dihydropyrimidine-4-carbonyl)piperazidine-1-yl)alkyl)-3,4-dimethoxy-5-substituted benzamide; and finally, demethylation is performed to generate the compounds shown in the formula (I). The multi-substituted benzamides compounds achieve a restraining effect on HIV-1 (Human immunodeficiency virus-1) integrase.

Description

The polysubstituted pyrimidine ketone compounds

Technical field

The present invention relates to the polysubstituted pyrimidine ketone compounds.Specifically, relate to polysubstituted benzamide compound of N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) and preparation method thereof and as the application of HIV-1 integrase inhibitor.

Background technology

(Acquired immunodeficiency syndrome is that (Human immunodeficiency virus-1 HIV-1) infects a kind of autoimmune disorder that causes by human immunodeficiency virus AIDS) to AIDS.Since this disease of reported first in 1981, it develops the great communicable disease that becomes serious threat human health and existence rapidly, is to cause one of dead main transmissible disease.Show that according to 2011 United Nations's AIDS data statistics the HIV the infected and the aids patient of whole world survival in 2010 have 3,400 ten thousand people approximately, wherein newly-increased number of the infected 2,700,000 in 2010 has 1,800,000 people to die from and AIDS-related diseases.

The anti-HIV-1 medicine is primarily aimed at the main phase through the AIDS mechanism of causing a disease, that is: intrusion, rt, integration and assembling.At present, the medicine of the treatment AIDS of FDA approval mainly contains following several types: NRTI (nucleoside reverse transcriptase inhibitors), non-nucleoside reverse transcriptase inhibitor (non-nucleoside reverse transcriptase inhibitors), proteinase inhibitor (protease inhibitors), fusion inhibitor (fusion inhibitors), accessory receptor suppressor factor (co-receptor inhibitors) and integrase inhibitor (integrase inhibitors).The use of these medicines can effectively prolong AIDS patient's life.So intergrase is considered to design a desirable target of HIV-1 medicine, therefore, development of new anti-HIV-1 integrase inhibitor just becomes one of focus of present research.

Intergrase is one of very significant target in the anti-HIV-1 research, and its basic role in the life circulation shows that virus relies on to integrate and keeps it effectively to duplicate and Infection Status.In recent years, people give intergrase and pay close attention to greatly.At first; Also there is not to find the analogue that has same structure and function with intergrase in the human body, so the integrase inhibitor of highly selective almost is free from side effects to human body, next; Because action target spot is different, integrase inhibitor does not receive at present chemical sproof influence the because of chemotherapy produced.Although coffee acyl derivatives class, ucleotides, vinylbenzene quinoline etc. show the effect of inhibition intergrase in active determination in vitro, the compound that has only part to contain two ketone acid structures all shows selectivity and inhibition activity preferably in live body and isolated activity mensuration.D64 and the interaction of the Mg2+ between D116 mediation by two ketone acid structures and IN; Diketone acid compound and " D, D-3-E " part combines to form the mixture sealing should the zone, though its combination can not change IN to 3 '-catalysis of p; But make 1; The 3-dicarbapentaborane combines with second Mg2+ between D64 and the E152, and this Mg2+ is the reaction site of ST, and this makes the alternative ST of inhibition of diketone acid compound process.

S-1360 was first integrase inhibitor that gets into clinical study, and this compound got into the II clinical trial phase in 2002.Clinical data shows; Metabolism is carried out through acellular cytochrome p 450 approach in vivo; Be prone to by the reduction of the carbonyl reductase in the human liver, the enol that links to each other with triazole in its structure is prone to be reduced, and this metabolism unstable is its reason that was terminated clinical study in 2003.

EP2161258 (A2) (open day: 2010.03.10) disclose a series of quinolinone acid derivative compound methods and integrase inhibiting activities.

WO 2009/089263 (A2) (open day: 2009.07.16) disclose a series of integrase inhibitor, wherein just comprised the quinoline keto-acid compound.

At " Investigating The Role of Metal Chelation In HIV-1 Integrase Strand Transfer Inhibitors " (J.Med.Chem.; 2011,54:8407-8420) reported in the literary composition that the coordination between HIV-1 intergrase chain transfer suppressor factor and metals ion concerns.

At " Design And Synthesis Of Novel N-Hydroxy-Dihydronaphththyridiones As Potent And Orally Bioavailable HIV-1 Integrase Inhibitors " (J.Med.Chem.; 2011,54:3393-3417) reported in the literary composition N-hydroxyl-dihydronaphthridine ketone as the design of the HIV-1 integrase inhibitor of efficient and bioavailability with synthesize.

Summary of the invention

The purpose of this invention is to provide polysubstituted benzamide compound of N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) and preparation method thereof and as the application of HIV-1 integrase inhibitor.

The invention provides the polysubstituted benzamide compound of N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) of formula (I) expression,

Wherein, R ¹Expression-H or-Cl, R ²Expression-H ,-Cl ,-F ,-CH ₃Or-OH, R ³, R ⁴Expression-OH, R ⁵Expression-H or-OH, n=2 or 3.

The present invention also provides N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) preparation method of polysubstituted benzamide compound, may further comprise the steps:

(a) oxammonium hydrochloride and Pottasium Hydroxide are reacted in anhydrous methanol, 0～30 ℃ of temperature of reaction is reacted after 1～2 hour; Filter and collect filtrating; Add benzyl cyanide and continue reaction, 10～70 ℃ of temperature of reaction, 5～10 hours reaction times; Obtain the N '-hydroxyl-2-substituted-phenyl ethanamidine compound of formula (II) expression

Wherein, R ¹Expression-H or-Cl, R ²Expression-H ,-Cl ,-F ,-CH ₃Or-OCH ₃

(b) formula (II) compound is dissolved in the trichloromethane; Add dimethyl butyn, reaction under the triethylamine effect, formula (II) compound is 1: 1～1.5 with the amount of substance ratio of dimethyl butyn; 10～70 ℃ of temperature of reaction; In 2～5 hours reaction times, obtain 2-(the amino substituted-phenyl ethylidene of 1-ammonia) the oxo divinyl two dimethyl phthalate compounds that formula (III) is represented

Wherein, R ¹, R ²The same step of group (a) of expression is said;

(c) formula (III) compound is reacted in YLENE, 100～150 ℃ of temperature of reaction, 10～20 hours reaction times, obtain 5 of formula (IV) expression, 6-dihydroxyl-2-substituted benzyl pyrimidine-4-methyl-formiate compound,

Wherein, R ¹, R ²The same step of group (a) of expression is said;

(d) formula (IV) compound is dissolved in N, in the dinethylformamide, adds salt of wormwood and methyl iodide; 10～40 ℃ of temperature of reaction; In 10～20 hours reaction times, obtain 1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate compound that formula V is represented

Wherein, R ¹, R ²The same step of group (a) of expression is said;

(e) formula V compound and Pottasium Hydroxide are reacted in ethanol; The formula V compound is 1: 1～4 with the amount of substance ratio of Pottasium Hydroxide; 10～40 ℃ of temperature of reaction were reacted after 0.5～2 hour, added acid to pH=2～4; Obtain the 1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid cpds of formula (VI) expression

Wherein, R ¹, R ²The same step of group (a) of expression is said;

(f) in methylene dichloride, react under the triethylamine existence condition with the substituted benzoyl chloride of formula (VII) expression with the hydrochloride of the chloro alkylamine of formula (VIII) expression; 0～40 ℃ of temperature of reaction; 10～20 hours reaction times; Obtain the N-chloro alkyl substituted benzamide compound of formula (IX) expression

Wherein, R ³, R ⁴Expression-OCH ₃, R ⁵Expression-H or-OCH ₃, n=2 or 3;

(g) with formula (IX) compound and piperazine reaction under salt of wormwood and the effect of catalyzer potassiumiodide in trichloromethane, 40～90 ℃ of temperature of reaction, 8～16 hours reaction times, obtain the N-piperazinyl alkyl substituted benzamide compound that formula (X) is represented,

Wherein, R ³, R ⁴, R ⁵The group of expression and the same step of value (f) of n are said;

(h) with formula (X) compound and formula (IV) compound in condensing agent N, under N '-carbonyl dimidazoles effect, at N; React in the dinethylformamide, the amount of substance ratio of formula (X) compound and formula (VI) compound is 1: 1～2,0～40 ℃ of temperature of reaction; In 8～16 hours reaction times, obtain the N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl)-3 that formula (XI) is represented; 4-dimethoxy-5-substituted benzamide compound

Wherein, R ¹, R ²The same step of group (a) of expression is said, R ³, R ⁴, R ⁵The group of expression and the same step of value (f) of n are said;

(i) with formula (XI) compound at N, in the dinethylformamide with the deprotecting regent boron tribromide reaction that is dissolved in methylene dichloride, 1～5 hour reaction times; 0～40 ℃ of temperature of reaction is hydrolyzed and sloughs alkyl, 0～40 ℃ of hydrolysis temperature; 2～10 hours reaction times; Obtain the polysubstituted benzamide compounds of N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) of formula (I) expression

Wherein, R ¹, R ², R ³, R ⁴, R ⁵The group of expression and the value of n are with the above.

Oxammonium hydrochloride described in the above-mentioned steps (a) is 1: 1～1.5 with the amount of substance ratio of Pottasium Hydroxide.

Formula (IV) compound described in the above-mentioned steps (d) is 1: 3～5 with the amount of substance ratio of potassiumiodide, and formula (IV) compound is 1: 3～5 with the amount of substance ratio of salt of wormwood.

Formula (IX) compound described in the above-mentioned steps (g) is 1: 3～7 with piperazine amount of substance ratio.

Formula (X) compound and condensing agent N described in the above-mentioned steps (h), the amount of substance ratio of N '-carbonyl dimidazoles is 1: 1～2.

Formula (XI) compound described in the above-mentioned steps (i) is 1: 2～15 with the amount of substance ratio of deprotecting regent boron tribromide.

Reaction formula in the above-mentioned building-up process is following:

The compounds of this invention all has the restraining effect to the HIV-1 intergrase, and wherein the inhibition effect of part of compounds is remarkable.

The inventive method uses industry to go up general agents and conventional working condition, and reaction conditions is gentle, and step is simple.

Embodiment

The preparation (1a) of embodiment 1:N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

(a) (Z)-preparation of N '-hydroxyl-2-phenyl ethanamidine

Under the room temperature with oxammonium hydrochloride (1.9g; 23.0mmol) add in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving, weighing KOH (1.29g; 23.0mmol) be dissolved in the 40mL anhydrous methanol; Pour into again in the constant pressure funnel of 60mL, and under condition of ice bath, slowly splash in the methanol solution of oxammonium hydrochloride, continue to be stirred to and dropwise.Remove ice bath, reaction system filter is collected filtrating, (2.42g, 20.7mmol) reflux finish to the TLC monitoring reaction to add benzyl cyanide.The decompression precipitation gets white solid, and products therefrom need not purifying, directly gets into step reaction down.

(b) preparation of 2-(1-aminophenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates

(2.5g 16.7mmol) adds in the 100mL round-bottomed flask, with 35mL trichloromethane stirring and dissolving with N '-hydroxyl-2-phenyl ethanamidine.(2.37g 16.7mmol) adds in the reaction system, and adds 10 triethylamine solutions, reflux to get dimethyl butyn.Reaction system becomes chocolate by scarlet, and the TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adding 60mL acetic acid ethyl dissolution, with 40mL * 3 washings, 20mL * 3 saturated common salts washing, anhydrous magnesium sulfate drying filters, and the decompression precipitation gets red oily liquids.Products therefrom need not purifying and directly descends the step reaction.

(c) 5, the preparation of 6-dihydroxyl-2-benzyl pyrimidines-4-methyl-formiate

Compound 2-(1-aminophenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates are added 60mL YLENE post-heating reflux, finish to the TLC monitoring reaction.After the cooling, there are a large amount of solids to separate out, suction filtration, the gained solid is with petroleum ether and dry.

Pure article are the gray solid powder, mp:212.4～214.6 ℃.

This three steps overall yield: 36.2%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：3.80(s，3H，-COOCH ₃)，3.81(s，2H，Ar-CH ₂-)，7.21-7.33(m，5H，Ar-H)，10.25(s，1H，-OH)，12.94(s，1H，-NH).

ESI-MS?m/z，258.6[M-H] ^-.

(d) preparation of 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

Get compound 5, (0.78g 3.0mmol) is dissolved among the 50mL DMF 6-dihydroxyl-2-benzyl pyrimidines-4-methyl-formiate, in reaction system, adds K again ₂CO ₃(1.24g, 9.0mmol) and CH ₃I (1.28g, 9.0mmol), stirred overnight at room temperature, the TLC monitoring reaction finishes.With 40mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, the decompression precipitation, residue is through column chromatography (eluent: petrol ether/ethyl acetate) purifying.

Pure article are reddish black liquid, yield: 30.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.36(s，3H，N-CH ₃)，3.92(s，3H，-COOCH ₃)，3.95(s，3H，O-CH ₃)，4.13(s，2H，Ar-CH ₂-)，7.15(d，2H，J＝7.2，Ar-H)，7.21(m，1H，Ar-H)，7.28(t，2H，J＝6.8，Ar-H).

ESI-MS?m/z，288.9[M+H] ⁺，310.9[M+Na] ⁺.

(e) preparation of 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid

With compound 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate (3.0g 10.4mmol) is dissolved in the 50mL anhydrous methanol, add again 0.5N KOH solution (1.66g, 41.6mmol), stirring at room 30min, the TLC monitoring reaction finishes.In reaction system, slowly drip 1N HCl solution to pH=2, with 30mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, decompression precipitation and vacuum-drying.

Pure article are the faint yellow solid powder, mp:184.4～186.1 ℃.

Yield: 95.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.47(s，3H，N-CH ₃)，4.14(s，3H，O-CH ₃)，4.16(s，2H，Ar-CH ₂-)，7.18(d，2H，J＝6.8，Ar-H)，7.30-7.38(m，3H，Ar-H).

ESI-MS?m/z，272.5[M-H] ^-，274.7[M+H] ⁺，296.6[M+Na] ⁺.

(f) N-3-chloropropyl-3,4, the preparation of 5-trimethoxy-benzamide

Three chloro propyl amine hydrochloric acid salts of 0.03mol are joined in the 100mL there-necked flask, add the methylene dichloride of crossing through drying treatment of 35mL then, drip the triethylamine solution of 10mL again to the dichloromethane solution of three chloro propyl amine hydrochloric acid salts; After stirring at room is reacted half a hour, with 3,4; The dichloromethane solution of 5-trimethoxy-benzoyl chloride is added drop-wise in the above-mentioned solution under condition of ice bath, after dropwising, removes ice bath; Stirred overnight at room temperature, TLC monitoring reaction process.Reaction system is used the saturated NaHCO in 30mL * 3 respectively ₃The 1molL of solution, 30mL * 3 ^-1Hydrochloric acid soln washing, use the saturated common salt solution washing of 30mL again, anhydrous magnesium sulfate drying, the decompression precipitation obtains N-3-chloropropyl-3,4, the pure article of 5-trimethoxy-benzamide.

Pure article are the white solid powder, yield: 60.4%.

¹H?NMR(CDCl ₃，400MHz，δppm)：2.14-2.17(m，2H，NH-CH ₂-CH ₂-CH ₂-)，2.62-2.70(m，4H，NH-CH ₂-CH ₂-CH ₂-)，3.90(s，3H，Ar-OCH ₃)，3.93(s，6H，Ar-OCH ₃)，7.00(s，2H，Ar-H).

(g) N-3-(piperazine-1-yl) propyl group-3,4, the preparation of 5-trimethoxy-benzamide

Under the room temperature to N-3-chloropropyl-3,4, the 5-trimethoxy-benzamide (9.8g, add in chloroform soln 0.034mol) piperazine (11.7g, 13.6mol), the potassiumiodide of catalytic amount, K ₂CO ₃(4.7g, 0.034mol), reflux, TLC monitoring reaction process.After reaction finishes reaction system is filtered, get the filtrate decompression precipitation, residue is through column chromatography purification.

Pure article are the yellow solid powder.mp：108.9～109.9℃。

Yield: 58.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.76-1.81(m，2H，-CH ₂-CH ₂-CH ₂-)，2.40-2.45(m，4H，-CH ₂-of?piperazidine)，2.48(t，2H，J＝6.4，-CH ₂-CH ₂-CH ₂-)，2.83(t，4H，J＝5.2，-CH ₂-of?piperazidine)，3.51(q，2H，J＝6.0，-CH ₂-CH ₂-CH ₂-)，3.84(s，3H，Ar-OCH ₃)，3.88(s，6H，Ar-OCH ₃)，7.02(s，2H，Ar-H)，7.69(s，1H，-NH-).

ESI-MS?m/z，335.8[M-H] ^-，337.8[M+H] ⁺.

(h) N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.Weighing compound 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid (0.5g; 1.83mmol) and it is dissolved among the dry DMF of 25mL; Under condition of ice bath, it slowly is added dropwise in the DMF solution of CDI, after dropwising then with constant pressure funnel; Remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3,4, (0.62g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions; With 40mL * 3 water washings to remove residual DMF, saturated common salt water washing, anhydrous magnesium sulfate drying; Filter, the decompression precipitation, residue is through column chromatography (elutriant: purifying ETHYLE ACETATE/ethanol).

Pure article are the white solid powder, mp:87.8～90.5 ℃.

Yield: 55.4%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.79-1.83(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.45(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，2.54(t，4H，J＝6.8，-CH ₂-of?piperazidine)，3.35(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.42(s，3H，N-CH ₃)，3.55(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.77(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，3.87(s，3H，Ar-OCH ₃)，3.89(s，6H，Ar-OCH ₃)，3.94(s，3H，-OCH ₃)，4.12(s，2H，Ar-CH ₂-)，7.00(s，2H，Ar-H)，7.10(br，1H，-NH-)，7.17(d，2H，J＝6.8，Ar-H)，7.26-7.28(m，1H，Ar-H)，7.30-7.34(m，2H，Ar-H).

ESI-MS?m/z：594.0[M+H] ⁺，615.9[M+Na] ⁺，631.8[M+K] ⁺.

(i) preparation of N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take by weighing compound N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.45g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature, TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

Pure article are white solid, mp:200.2～203.2 ℃.

Yield: 50.1%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：2.04-2.07(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.70-2.80(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.00-3.10(m，2H，-CH ₂-of?piperazidine)，3.15-3.30(m，2H，-CH ₂-of?piperazidine)，3.30-3.40(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.40-3.60(m，4H，-CH ₂-of?piperazidine)，3.52(s，3H，N-CH ₃)，3.90(s，3H，-OCH ₃)，4.20(s，2H，Ar-CH ₂-)，6.90(s，2H，Ar-H)，7.17(t，2H，J＝7.2，Ar-H)，7.24-7.28(m，3H，Ar-H).

ESI-MS?m/z：550.0[M-H] ^-，552.1[M+H] ⁺，574.0[M+Na] ⁺.

The preparation (1b) of embodiment 2:N-(3-(4-(1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

(a) (Z)-preparation of 2-rubigan-N '-hydroxyl acetamidine

(1.9g 23.0mmol) adds in the round-bottomed flask of 250mL, adds 40mL anhydrous methanol stirring and dissolving with oxammonium hydrochloride under the room temperature.(1.29g 23.0mmol) is dissolved in the 40mL anhydrous methanol to weighing KOH, pours in the constant pressure funnel of 60mL again; And under condition of ice bath, slowly splash in the methanol solution of oxammonium hydrochloride; Continue to be stirred to and dropwise, remove ice bath, reaction system is filtered collect filtrating.(2.42g, 20.7mmol) reflux finish to the TLC monitoring reaction to add p-chlorobenzyl cyanide.The decompression precipitation gets white solid.Products therefrom need not purifying, directly gets into step reaction down.

(2.5g 16.7mmol) adds in the 100mL round-bottomed flask, with 35mL trichloromethane stirring and dissolving with (Z)-2-rubigan-N '-hydroxyl acetamidine.Get dimethyl butyn (2.37g 16.7mmol) adds in the reaction system, and adds 10 triethylamine solutions, reflux, reaction system becomes chocolate by scarlet, the TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adding 60mL acetic acid ethyl dissolution, with 40mL * 3 washings, 20mL * 3 saturated common salts washing, anhydrous magnesium sulfate drying filters, and the decompression precipitation gets red oily liquids.Products therefrom need not purifying and directly descends the step reaction.

(c) 5, the preparation of 6-dihydroxyl-2-p-chlorobenzyl pyrimidine-4-methyl-formiate

Pure article are the gray solid powder, mp:214.3～216.3 ℃.

This three steps overall yield: 29.0%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：3.80(s，3H，-COOCH ₃)，3.81(s，2H，Ar-CH ₂-)，7.30(d，2H，J＝8.4，Ar-H)，7.37(m，2H，J＝7.2，Ar-H)，10.30(s，1H，-OH)，12.98(s，1H，-NH).

ESI-MS?m/z，292.6[M-H] ^-，316.8[M+Na] ⁺.

(d) preparation of 1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

Get compound 5, (0.78g 3.0mmol) is dissolved among the 50mL DMF 6-dihydroxyl-2-p-chlorobenzyl pyrimidine-4-methyl-formiate, in reaction system, adds K again ₂CO ₃(1.24g, 9.0mmol) and CH ₃I (1.28g, 9.0mmol), stirred overnight at room temperature.The TLC monitoring reaction finishes.With 40mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, the decompression precipitation, residue is through column chromatography (eluent: petrol ether/ethyl acetate) purifying.

Pure article are reddish black liquid, yield: 31.2%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.42(s，3H，N-CH ₃)，3.98(s，3H，-COOCH ₃)，4.01(s，3H，O-CH ₃)，4.15(s，2H，Ar-CH ₂-)，7.15(d，2H，J＝8.4，Ar-H)，7.32(d，2H，J＝6.4，Ar-H).

ESI-MS?m/z，322.9[M+H] ⁺，344.9[M+Na] ⁺.

(e) preparation of 1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid

With compound 1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate (3.0g 10.4mmol) is dissolved in the 50mL anhydrous methanol, add again 0.5N KOH solution (1.66g, 41.6mmol), stirring at room 30min.The TLC monitoring reaction finishes.In reaction system, slowly drip 1N HCl solution to pH=2, with 30mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, decompression precipitation and vacuum-drying.

Pure article are the faint yellow solid powder, mp:155.1～157.0 ℃.

Yield: 96.2%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.49(s，3H，N-CH ₃)，4.15(s，3H，O-CH ₃)，4.16(s，2H，Ar-CH ₂-)，7.16(d，2H，J＝8.4，Ar-H)，7.36(d，2H，J＝8.0，Ar-H).

ESI-MS?m/z，306.5[M-H] ^-，308.8[M+H] ⁺，330.7[M+Na] ⁺.

Step (f), (g) are with embodiment 1.

(h) N-(3-(4-(1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3,4, (0.62g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions; With 40mL * 3 water washings to remove residual DMF, saturated common salt water washing, anhydrous magnesium sulfate drying; Filter, the decompression precipitation, residue is through column chromatography (elutriant: purifying ETHYLE ACETATE/ethanol).

Pure article are the white solid powder, mp:85.2～88.7 ℃.

Yield: 53.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.81-1.84(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.43(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，2.54(t，4H，J＝6.4，-CH ₂-of?piperazidine)，3.34(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.44(s，3H，N-CH ₃)，3.55(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.77(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，3.87(s，3H，Ar-OCH ₃)，3.89(s，6H，Ar-OCH ₃)，3.94(s，3H，-OCH ₃)，4.08(s，2H，Ar-CH ₂-)，7.03(s，2H，Ar-H)，7.13(d，2H，J＝8.8，Ar-H)，7.21(br，1H，-NH-)，7.29-7.32(m，2H，Ar-H).

ESI-MS?m/z：628.0[M+H] ⁺，649.9[M+Na] ⁺，665.8[M+K] ⁺

(i) preparation of N-(3-(4-(1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take by weighing compound N-(3-(4-(1-methyl-2-p-chlorobenzyl-5-methoxyl group-6-oxo-1; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.45g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

Pure article are white solid, mp:179.8～181.9 ℃.

Yield: 55.0%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：1.55-1.75(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.10-2.45(m，4H，-CH ₂-of?piperazidine)，3.10-3.30(m，4H，-CH ₂-of?piperazidine)，3.30-3.40(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.50-3.70(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.43(s，3H，N-CH ₃)，3.77(s，3H，-OCH ₃)，4.16(s，2H，Ar-CH ₂-)，6.81(s，2H，Ar-H)，7.26(d，2H，J＝8.0，Ar-H)，7.39(d，2H，J＝8.0，Ar-H)，8.08(br，1H，-NH-)，8.61(s，1H，Ar-OH)，8.97(s，2H，Ar-OH).

ESI-MS?m/z：584.9[M-H] ^-，620.8[M+Cl] ^-.

The preparation (1c) of embodiment 3:N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

(a) 2-is to the preparation of fluorophenyl-N '-hydroxyl acetamidine

(1.9g 23.0mmol) adds in the round-bottomed flask of 250mL, adds 40mL anhydrous methanol stirring and dissolving with oxammonium hydrochloride under the room temperature.(1.29g 23.0mmol) is dissolved in the 40mL anhydrous methanol to weighing KOH, pours in the constant pressure funnel of 60mL again, and under condition of ice bath, slowly splashes in the methanol solution of oxammonium hydrochloride, continues to be stirred to dropwise.Remove ice bath, reaction system is filtered collect filtrating.(2.42g, 20.7mmol) reflux finish to the TLC monitoring reaction to fluorophenyl acetonitrile in adding.The decompression precipitation gets white solid.Products therefrom need not purifying, directly gets into step reaction down.

(b) preparation of 2-(1-amino is to fluorophenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates

(2.5g 16.7mmol) adds in the 100mL round-bottomed flask, with 35mL trichloromethane stirring and dissolving to fluorophenyl-N '-hydroxyl acetamidine with (Z)-2-.(2.37g 16.7mmol) adds in the reaction system, and adds 10 triethylamine solutions, reflux to get dimethyl butyn.Reaction system becomes chocolate by scarlet.The TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds the 60mL acetic acid ethyl dissolution, with 40mL * 3 washings, 20mL * 3 saturated common salts washing.Anhydrous magnesium sulfate drying filters, and the decompression precipitation gets red oily liquids.Products therefrom need not purifying and directly descends the step reaction.

(c) 5,6-dihydroxyl-2-is to the preparation of luorobenzyl pyrimidine-4-methyl-formiate

Compound 2-((1-amino is to fluorophenyl ethylidene ammonia)) oxo divinyl two dimethyl phthalates are added 60mL YLENE post-heating reflux, finish to the TLC monitoring reaction.After the cooling, there are a large amount of solids to separate out.Suction filtration, the gained solid is with petroleum ether and dry.

Pure article are the gray solid powder, mp:201.9～202.3 ℃.

This three steps overall yield: 25.2%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：3.79(s，3H，-COOCH ₃)，3.80(s，2H，Ar-CH ₂-)，7.14(m，2H，J＝8.8，Ar-H)，7.32(m，2H，J＝7.6，Ar-H)，10.25(s，1H，-OH)，12.93(s，1H，-NH).

(d) 1-methyl-2-is to the preparation of luorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

Get compound 5, (0.78g 3.0mmol) is dissolved among the 50mL DMF 6-dihydroxyl-2-, in reaction system, adds K again to luorobenzyl pyrimidine-4-methyl-formiate ₂CO ₃(1.24g, 9.0mmol) and CH ₃I (1.28g, 9.0mmol), stirred overnight at room temperature.The TLC monitoring reaction finishes.With 40mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, the decompression precipitation, residue is through column chromatography (eluent: petrol ether/ethyl acetate) purifying.

Pure article are reddish black liquid, yield: 31.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.42(s，3H，N-CH ₃)，3.97(s，3H，-COOCH ₃)，4.00(s，3H，O-CH ₃)，4.14(s，2H，Ar-CH ₂-)，7.05-7.05(m，2H，Ar-H)，7.17-7.28(m，2H，Ar-H).

ESI-MS?m/z，306.7[M+H] ⁺，328.7[M+Na] ⁺.

(e) 1-methyl-2-is to the preparation of luorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid

With compound 1-methyl-2-to luorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate (3.0g 10.4mmol) is dissolved in the 50mL anhydrous methanol, add again 0.5N KOH solution (1.66g, 41.6mmol), stirring at room 30min.The TLC monitoring reaction finishes.In reaction system, slowly drip 1N HCl solution to pH=2, with 30mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, decompression precipitation and vacuum-drying.

Pure article are the faint yellow solid powder, mp:136.7～138.0 ℃.

Yield: 93.1%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.50(s，3H，N-CH ₃)，4.15(s，3H，O-CH ₃)，4.15(s，2H，Ar-CH ₂-)，7.07(t，2H，J＝8.4，Ar-H)，7.19(dd，2H，J＝5.2and?8.4，Ar-H).

ESI-MS?m/z，290.5[M-H] ^-，292.7[M+H] ⁺，314.6[M+Na] ⁺.

IR(KBr)：3438，2951，2891，1735，1640，1698，1546，1509，1449，1229，739cm ^-1.

Step (f), (g) are with embodiment 1.

(h) N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then to luorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3,4, (0.62g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions; With 40mL * 3 water washings to remove residual DMF, saturated common salt water washing, anhydrous magnesium sulfate drying; Filter, the decompression precipitation, residue is through column chromatography (elutriant: purifying ETHYLE ACETATE/ethanol).

Pure article are the yellow solid powder, mp:89.7～91.4 ℃.

Yield: 57.4%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.77-1.80(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.40(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，2.51(t，4H，J＝6.8，-CH ₂-of?piperazidine)，3.34(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.41(s，3H，N-CH ₃)，3.51(t，2H，J＝6.4，-CH ₂-of?piperazidine)，3.74(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，3.84(s，3H，Ar-OCH ₃)，3.86(s，6H，Ar-OCH ₃)，3.91(s，3H，-OCH ₃)，4.06(s，2H，Ar-CH ₂-)，6.99(s，2H，Ar-H)，7.01(d，2H，J＝8.8，Ar-H)，7.14(d，2H，J＝8.4，Ar-H)，7.24(br，1H，-NH-).

ESI-MS?m/z：612.0[M+H] ⁺，634.0[M+Na] ⁺，649.9[M+K] ⁺.

(i) preparation of N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take by weighing that compound N-(((1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1 for 4-for 3-; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.45g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

Pure article are white solid, mp:187.2～190.2 ℃.

Yield: 52.4%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：2.05-2.08(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.80-2.90(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.00-3.15(m，2H，-CH ₂-of?piperazidine)，3.15-3.20(m，2H，-CH ₂-of?piperazidine)，3.30-3.35(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.40-3.55(m，4H，-CH ₂-of?piperazidine)，3.57(s，3H，N-CH ₃)，3.92(s，3H，-OCH ₃)，4.18(s，2H，Ar-CH ₂-)，6.89(s，2H，Ar-H)，7.08(t，2H，J＝8.4，Ar-H)，7.27(q，2H，J＝8.0，Ar-H).

ESI-MS?m/z：567.9[M-H] ^-，603.8[M+Cl] ^-.

The preparation (1d) of embodiment 4:N-(3-(4-(1-methyl-2-is to methyl-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

(a) preparation of 2-p-methylphenyl-N '-hydroxyl acetamidine

(1.9g 23.0mmol) adds in the round-bottomed flask of 250mL, adds 40mL anhydrous methanol stirring and dissolving with oxammonium hydrochloride under the room temperature.(1.29g 23.0mmol) is dissolved in the 40mL anhydrous methanol to weighing KOH, pours in the constant pressure funnel of 60mL again, and under condition of ice bath, slowly splashes in the methanol solution of oxammonium hydrochloride, continues to be stirred to dropwise.Remove ice bath, reaction system is filtered collect filtrating.(2.42g, 20.7mmol) reflux finish to the TLC monitoring reaction to the methylbenzene acetonitrile in adding.The decompression precipitation gets white solid.Products therefrom need not purifying, directly gets into step reaction down.

(b) preparation of 2-(the amino p-methylphenyl ethylidene of 1-ammonia) oxo divinyl two dimethyl phthalates

(2.5g 16.7mmol) adds in the 100mL round-bottomed flask, with 35mL trichloromethane stirring and dissolving with (Z)-2-p-methylphenyl-N '-hydroxyl acetamidine.(2.37g 16.7mmol) adds in the reaction system, and adds 10 triethylamine solutions, reflux to get dimethyl butyn.Reaction system becomes chocolate by scarlet.The TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds the 60mL acetic acid ethyl dissolution, with 40mL * 3 washings, 20mL * 3 saturated common salts washing.Anhydrous magnesium sulfate drying filters, and the decompression precipitation gets red oily liquids.Products therefrom need not purifying and directly descends the step reaction.

(c) 5,6-dihydroxyl-2-is to the preparation of methyl-benzyl pyrimidine-4-methyl-formiate

Compound 2-(1-amino p-methylphenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates are added 60mL YLENE post-heating reflux, finish to the TLC monitoring reaction.After the cooling, there are a large amount of solids to separate out.Suction filtration, the gained solid is with petroleum ether and dry.

Pure article are the gray solid powder, mp:194.8～196.2 ℃.

This three steps overall yield: 31.1%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：2.25(s，3H，Ar-CH ₃)，3.75(s，2H，Ar-CH ₂-)，3.80(s，3H，-COOCH ₃)，7.11(d，2H，J＝8.0，Ar-H)，7.17(m，2H，J＝8.0，Ar-H)，10.25(s，1H，-OH)，12.93(s，1H，-NH).

(d) 1-methyl-2-is to the preparation of methyl-benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

Get compound 5, (0.78g 3.0mmol) is dissolved among the 50mL DMF 6-dihydroxyl-2-, in reaction system, adds K again to methyl-benzyl pyrimidine-4-methyl-formiate ₂CO ₃(1.24g, 9.0mmol) and CH ₃I (1.28g, 9.0mmol), stirred overnight at room temperature.The TLC monitoring reaction finishes.With 40mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, the decompression precipitation, residue is through column chromatography (eluent: petrol ether/ethyl acetate) purifying.

Pure article are reddish black liquid, yield: 29.6%.

¹H?NMR(CDCl ₃，400MHz，δppm)：2.33(s，3H，Ar-CH ₃)，3.48(s，3H，N-CH ₃)，3.98(s，3H，-COOCH ₃)，4.00(s，3H，O-CH ₃)，4.14(s，2H，Ar-CH ₂-)，7.08(d，2H，J＝8.0，Ar-H)，7.14(d，2H，J＝8.0，Ar-H).

(e) 1-methyl-2-is to the preparation of methyl-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid

With compound 1-methyl-2-to methyl-benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate (3.0g 10.4mmol) is dissolved in the 50mL anhydrous methanol, add again 0.5N KOH solution (1.66g, 41.6mmol), stirring at room 30min.The TLC monitoring reaction finishes.In reaction system, slowly drip 1N HCl solution to pH=2, with 30mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, decompression precipitation and vacuum-drying.

Pure article are the faint yellow solid powder, mp:162.4～164.9 ℃.

Yield: 94.0%.

Step (f), (g) are with embodiment 1.

(h) N-(3-(4-(1-methyl-2-is to methyl-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then to methyl-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3,4, (0.62g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions; With 40mL * 3 water washings to remove residual DMF, saturated common salt water washing, anhydrous magnesium sulfate drying; Filter, the decompression precipitation, residue is through column chromatography (elutriant: purifying ETHYLE ACETATE/ethanol).

Pure article are the yellow solid powder, mp:85.9～88.3 ℃.

Yield: 55.2%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.81-1.85(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.33(s，3H，Ar-CH ₃)，2.47(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，2.56(t，4H，J＝6.4，-CH ₂-of?piperazidine)，3.37(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.43(s，3H，N-CH ₃)，3.57(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.79(t，2H，J＝4.8，-CH ₂-CH ₂-CH ₂-NH-)，3.88(s，3H，Ar-OCH ₃)，3.91(s，6H，Ar-OCH ₃)，3.94(s，3H，-OCH ₃)，4.09(s，2H，Ar-CH ₂-)，7.02(s，2H，Ar-H)，7.07(d，2H，J＝8.0，Ar-H)，7.13(d，2H，J＝8.0，Ar-H)，7.14(br，1H，-NH-).

ESI-MS?m/z：606.3095[M-H] ^-，608.3026[M+H] ⁺，630.2849[M+Na] ⁺.

(i) preparation of N-(3-(4-(1-methyl-2-is to methyl-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take by weighing that compound N-(((1-methyl-2-is to methyl-benzyl-5-methoxyl group-6-oxo-1 for 4-for 3-; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.45g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

Pure article are white solid, mp:252.5～255.3 ℃.

Yield: 51.0%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：2.05-2.08(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.29(s，3H，-CH ₃)，2.90-3.00(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.00-3.20(m，2H，-CH ₂-of?piperazidine)，3.20-3.25(m，2H，-CH ₂-of?piperazidine)，3.30-3.40(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.50-3.60(m，4H，-CH ₂-of?piperazidine)，3.50(s，3H，N-CH ₃)，3.90(s，3H，-OCH ₃)，4.15(s，2H，Ar-CH ₂-)，6.90(s，2H，Ar-H)，7.11(d，2H，J＝8.0，Ar-H)，7.15(d，2H，J＝8.0，Ar-H).

ESI-MS?m/z：563.9[M-H] ^-，599.9[M+Cl] ^-.

The preparation (1e) of embodiment 5:N-(3-(4-(1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

(a) preparation of 2-(3, the 4-dichlorophenyl)-N '-hydroxyl acetamidine

(1.9g 23.0mmol) adds in the round-bottomed flask of 250mL, adds 40mL anhydrous methanol stirring and dissolving with oxammonium hydrochloride under the room temperature.(1.29g 23.0mmol) is dissolved in the 40mL anhydrous methanol to weighing KOH, pours in the constant pressure funnel of 60mL again, and under condition of ice bath, slowly splashes in the methanol solution of oxammonium hydrochloride, continues to be stirred to dropwise.Remove ice bath, reaction system is filtered collect filtrating.Add 3, (2.42g, 20.7mmol) reflux finish to the TLC monitoring reaction 4-dichloro benzyl cyanide.The decompression precipitation gets white solid.Products therefrom need not purifying, directly gets into step reaction down.

(b) preparation of 2-(1-amino-(3, the 4-dichlorophenyl) ethylidene ammonia) oxo divinyl two dimethyl phthalates

(2.5g 16.7mmol) adds in the 100mL round-bottomed flask, with 35mL trichloromethane stirring and dissolving with (Z)-2-(3, the 4-dichlorophenyl)-N '-hydroxyl acetamidine.(2.37g 16.7mmol) adds in the reaction system, and adds 10 triethylamine solutions, reflux to get dimethyl butyn.Reaction system becomes chocolate by scarlet.The TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds the 60mL acetic acid ethyl dissolution, with 40mL * 3 washings, 20mL * 3 saturated common salts washing.Anhydrous magnesium sulfate drying filters, and the decompression precipitation gets red oily liquids.Products therefrom need not purifying and directly descends the step reaction.

(c) 5, the preparation of 6-dihydroxyl-2-(3, the 4-dichloro benzyl) pyrimidine-4-methyl-formiate

Compound 2-((1-amino-(3, the 4-dichlorophenyl) ethylidene ammonia)) oxo divinyl two dimethyl phthalates are added 60mL YLENE post-heating reflux, finish to the TLC monitoring reaction.After the cooling, there are a large amount of solids to separate out.Suction filtration, the gained solid is with petroleum ether and dry.

Pure article are the gray solid powder, mp:182.3～184.8 ℃.

This three steps overall yield: 23.0%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：3.80(s，3H，-COOCH ₃)，3.83(s，2H，Ar-CH ₂-)，7.26(dd，1H，J＝1.6and?8.4，Ar-H)，7.54-7.66(m，2H，Ar-H)，10.33(s，1H，-OH)，12.95(s，1H，-NH).

(d) preparation of 1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

Get compound 5, (0.78g 3.0mmol) is dissolved among the 50mL DMF 6-dihydroxyl-2-(3, the 4-dichloro benzyl) pyrimidine-4-methyl-formiate, in reaction system, adds K again ₂CO ₃(1.24g, 9.0mmol) and CH ₃I (1.28g, 9.0mmol), stirred overnight at room temperature.The TLC monitoring reaction finishes.With 40mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, the decompression precipitation, residue is through column chromatography (eluent: petrol ether/ethyl acetate) purifying.

Pure article are reddish black liquid, yield: 32.5%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.42(s，3H，N-CH ₃)，3.98(s，3H，-COOCH ₃)，4.01(s，3H，O-CH ₃)，4.15(s，2H，Ar-CH ₂-)，7.04(d，1H，J＝7.2，Ar-H)，7.30(s，1H，Ar-H).7.40(d，1H，J＝8.0，Ar-H).

(e) preparation of 1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo pyrimidine-4-formic acid

With compound 1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate (3.0g 10.4mmol) is dissolved in the 50mL anhydrous methanol, add again 0.5N KOH solution (1.66g, 41.6mmol), stirring at room 30min.The TLC monitoring reaction finishes.In reaction system, slowly drip 1N HCl solution to pH=2, with 30mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, decompression precipitation and vacuum-drying.

Pure article are the faint yellow solid powder, mp:180.3～182.0 ℃.

Yield: 95.2%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：3.41(s，3H，N-CH ₃)，3.77(s，3H，O-CH ₃)，4.18(s，2H，Ar-CH ₂-)，7.21(dd，1H，J＝2.0and?8.4，Ar-H)，7.54(s，1H，Ar-H)，7.58(d，1H，J＝8.4，Ar-H).

Step (f), (g) are with embodiment 1.

(h) N-(3-(4-(1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo pyrimidine-4-formic acid, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3,4, (0.62g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions; With 40mL * 3 water washings to remove residual DMF, saturated common salt water washing, anhydrous magnesium sulfate drying; Filter, the decompression precipitation, residue is through column chromatography (elutriant: purifying ETHYLE ACETATE/ethanol).

Pure article are the yellow solid powder, mp:99.0～101.0 ℃.

Yield: 59.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：2.46(t，2H，J＝4.8，-CH ₂-CH ₂-NH-)，2.60(t，2H，J＝4.8，-CH ₂-of?piperazidine)，2.66(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.35(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.49(s，3H，N-CH ₃)，3.58(q，2H，J＝6.4，-CH ₂-CH ₂-NH-)，3.79-3.81(m，2H，-CH ₂-of?piperazidine)，3.90(s，3H，Ar-OCH ₃)，3.92(s，6H，Ar-OCH ₃)，3.97(s，3H，-OCH ₃)，4.07(s，2H，Ar-CH ₂-)，6.59(br，1H，-NH-)，7.00(s，2H，Ar-H)，7.06(dd，2H，J＝2.0?and?8.0，Ar-H)，7.33(s，1H，Ar-H)，7.43(d，1H，J＝8.0，Ar-H).

¹³C?NMR(CDCl ₃，100MHz，δppm)：31.24，36.53，40.83，41.58，46.66，52.44，52.88，56.36，56.57，60.29，60.90，104.49，128.04，130.03，130.56，130.94，131.82，133.07，134.36，140.58，144.13，153.19，154.43，159.36，163.91，167.20.

ESI-MS?m/z：646.2019[M-H] ^-，648.1919[M+H] ⁺，670.1731[M+Na] ⁺

(i) preparation of N-(3-(4-(1-methyl-2-(3, the 4-dichloro benzyl)-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take by weighing compound N-(3-(4-(1-methyl-2-(3; The 4-dichloro benzyl)-and 5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3,4; 5-trimethoxy-benzamide (0.45g; 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed, under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

Pure article are white solid, mp:206.6～209.4 ℃.

Yield: 56.6%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：1.60-1.75(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.10-2.50(m，4H，-CH ₂-of?piperazidine)，3.10-3.25(m，4H，-CH ₂-of?piperazidine)，3.25-3.40(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.40-3.60(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.46(s，3H，N-CH ₃)，3.77(s，3H，-OCH ₃)，4.17(s，2H，Ar-CH ₂-)，6.81(s，2H，Ar-H)，7.23(d，1H，J＝8.0，Ar-H)，7.58(d，2H，J＝8.0，Ar-H)，8.06(br，1H，-NH-)，8.60(s，1H，Ar-OH)，8.97(s，2H，Ar-OH).

ESI-MS?m/z：617.9[M-H] ^-，653.7[M+Cl] ^-，699.6[M+Br] ^-.

The preparation (1f) of embodiment 6:N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

Step (a) and (b), (c), (d), (e) are with embodiment 1.

(f) N-2-chloroethyl-3,4, the preparation of 5-trimethoxy-benzamide

Two chloroethylamine hydrochlorides of 0.03mol are joined in the 100mL there-necked flask, add the methylene dichloride of crossing through drying treatment of 35mL then, drip the triethylamine solution of 10mL again to the dichloromethane solution of two chloroethylamine hydrochlorides; After stirring at room is reacted half a hour, with 3,4; The dichloromethane solution of 5-trimethoxy-benzoyl chloride is added drop-wise in the above-mentioned solution under condition of ice bath; After dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.Reaction system is used the saturated NaHCO in 30mL * 3 respectively ₃The 1molL of solution, 30mL * 3 ^-1Hydrochloric acid soln washing, use the saturated common salt solution washing of 30mL again, anhydrous magnesium sulfate drying, the decompression precipitation obtains N-2-chloroethyl-3,4, the pure article of 5-trimethoxy-benzamide.

Pure article are the white solid powder, yield: 70.5%.

(g) N-2-(piperazine-1-yl) ethyl-3,4, the preparation of 5-trimethoxy-benzamide

Under the room temperature to N-2-chloroethyl-3,4, the 5-trimethoxy-benzamide (9.3g, add in chloroform soln 0.034mol) piperazine (11.7g, 13.6mol), the potassiumiodide of catalytic amount, K ₂CO ₃(4.7g, 0.034mol), reflux.TLC monitoring reaction process.After reaction finishes reaction system is filtered, get the filtrate decompression precipitation, residue is through column chromatography purification.

Pure article are the yellow solid powder, mp:131.5～133.1 ℃.

Yield: 55.8%.

¹HNMR(CDCl ₃，400MHz，δppm)：2.46-2.51(m，4H，-CH ₂-of?piperazidine)，2.58(t，2H，J＝6.0，-CH ₂-CH ₂-)，2.89(t，4H，J＝4.8，-CH ₂-of?piperazidine)，3.52(q，2H，J＝6.4，-CH ₂-CH ₂-)，3.87(s，3H，Ar-OCH ₃)，3.90(s，6H，Ar-OCH ₃)，6.86(s，1H，-NH-)，7.01(s，2H，Ar-H).

(h) N-(2-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add N-2-(piperazine-1-yl) ethyl-3,4, (0.6g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions, with 40mL * 3 water washings removing residual DMF, the saturated common salt water washing, anhydrous magnesium sulfate drying, filtration, the precipitation that reduces pressure, residue is through column chromatography purification.

The yellow solid powder, mp:91.5～94.6 ℃.

Yield: 62.1%.

¹H?NMR(CDCl ₃，400MHz，δppm)：2.51(t，2H，J＝4.8，-CH ₂-CH ₂-NH-)，2.62(t，2H，J＝4.8，-CH ₂-of?piperazidine)，2.66(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.39(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.44(s，3H，N-CH ₃)，3.57(q，2H，J＝6.4，-CH ₂-CH ₂-NH-)，3.79-3.81(m，2H，-CH ₂-of?piperazidine)，3.89(s，3H，Ar-OCH ₃)，3.91(s，6H，Ar-OCH ₃)，3.95(s，3H，-OCH ₃)，4.11(s，2H，Ar-CH ₂-)，6.73(br，1H，-NH-)，7.01(s，2H，Ar-H)，7.19(d，2H，J＝7.2，Ar-H)，7.26-7.28(m，1H，Ar-H)，7.33(d，2H，J＝7.2，Ar-H).

ESI-MS?m/z：578.2[M-H] ^-，580.1[M+H] ⁺，602.0[M+Na] ⁺.

(i) preparation of N-(2-(4-(1-methyl-2-phenyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-gallamide

Take by weighing compound N-(2-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1; 6-dihydro-pyrimidin-4-carbonic acyl radical) ethyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.44g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography purification.

Obtain white solid, mp:193～194.5 ℃.

Yield: 55.7%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：3.10-3.20(m，2H，-CH ₂-CH ₂-NH-)，3.00-3.40(m，2H，-CH ₂-CH ₂NH-)，3.45-3.60(m，8H，-CH ₂-of?piperazidine)，3.50(s，3H，N-CH ₃)，3.91(s，3H，-OCH ₃)，4.22(s，2H，Ar-CH ₂-)，6.93(s，2H，Ar-H)，7.27(q，3H，J＝7.2，Ar-H)，7.35(t，2H，J＝7.2，Ar-H).

ESI-MS?m/z：535.9[M-H] ^-，571.8[M+Cl] ^-.

Embodiment 7:N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide (1g)

Step (a) and (b), (c), (d), (e) are with embodiment 3.

Step (f), (g) are with embodiment 6.

(h) N-(2-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.53g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing 1-methyl-2-, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then to luorobenzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add N-2-(piperazine-1-yl) ethyl-3,4, (0.6g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions, with 40mL * 3 water washings removing residual DMF, the saturated common salt water washing, anhydrous magnesium sulfate drying, filtration, the precipitation that reduces pressure, residue is through column chromatography purification.

The yellow solid powder, mp:91.6～94.1 ℃.

Yield: 65.7%.

¹HNMR(CDCl ₃，400MHz，δppm)：2.51(t，2H，J＝4.8，-CH ₂-CH ₂-NH-)，2.62(t，2H，J＝4.8，-CH ₂-of?piperazidine)，2.66(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.39(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.43(s，3H，N-CH ₃)，3.57(q，2H，J＝6.4，-CH ₂-CH ₂-NH-)，3.79-3.81(m，2H，-CH ₂-of?piperazidine)，3.89(s，3H，Ar-OCH ₃)，3.91(s，6H，Ar-OCH ₃)，3.95(s，3H，-OCH ₃)，4.11(s，2H，Ar-CH ₂-)，6.73(br，1H，-NH-)，7.01(s，2H，Ar-H)，7.19(d，2H，J＝7.2，Ar-H)，7.26-7.28(m，1H，Ar-H)，7.33(d，2H，J＝7.2，Ar-H).

ESI-MS?m/z：596.2696[M-H] ^-，598.2607[M+H] ⁺，620.2429[M+Na] ⁺.

(i) preparation of N-(2-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-gallamide

Take by weighing that compound N-(((1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1 for 4-for 2-; 6-dihydro-pyrimidin-4-carbonic acyl radical) ethyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.45g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography purification.

Obtain white solid, mp:210.0～213.3 ℃.

Yield: 52.8%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：3.15-3.25(m，2H，-CH ₂-CH ₂-NH-)，3.25-3.40(m，2H，-CH ₂-CH ₂NH-)，3.45-3.65(m，8H，-CH ₂-of?piperazidine)，3.48(s，3H，N-CH ₃)，3.90(s，3H，-OCH ₃)，4.19(s，2H，Ar-CH ₂-)，6.91(s，2H，Ar-H)，7.27(d，2H，J＝8.0，Ar-H)，7.35(d，2H，J＝8.0，Ar-H).

ESI-MS?m/z：553.9[M-H] ^-，589.8[M+Cl] ^-.

The preparation (1h) of embodiment 8:N-(3-(4-(1-methyl-2-is to acrinyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

(a) (Z)-2-p-methoxyphenyl-N '-hydroxyl acetamidine

(1.9g 23.0mmol) adds in the round-bottomed flask of 250mL, adds 40mL anhydrous methanol stirring and dissolving with oxammonium hydrochloride under the room temperature.(1.29g 23.0mmol) is dissolved in the 40mL anhydrous methanol to weighing KOH, pours in the constant pressure funnel of 60mL again, and under condition of ice bath, slowly splashes in the methanol solution of oxammonium hydrochloride, continues to be stirred to dropwise.Remove ice bath, reaction system is filtered collect filtrating.(3.04g, 20.7mmol) reflux finish to the TLC monitoring reaction to add PARA METHOXY PHENYL ACETONITRILE.The decompression precipitation gets white solid.Products therefrom need not purifying, directly gets into step reaction down.

(b) preparation of 2-(the amino p-methoxyphenyl ethylidene of 1-ammonia) oxo divinyl two dimethyl phthalates

(3.0g 16.7mmol) adds in the 100mL round-bottomed flask, with 35mL trichloromethane stirring and dissolving with (Z)-2-p-methoxyphenyl-N '-hydroxyl acetamidine.(2.37g 16.7mmol) adds in the reaction system, and adds 10 triethylamine solutions, reflux to get dimethyl butyn.Reaction system becomes chocolate by scarlet.The TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds the 60mL acetic acid ethyl dissolution, with 40mL * 3 washings, 20mL * 3 saturated common salts washing.Anhydrous magnesium sulfate drying filters, and the decompression precipitation gets red oily liquids.Products therefrom need not purifying and directly descends the step reaction.

(c) 5,6-dihydroxyl-2-is to the preparation of methoxybenzyl yl pyrimidines-4-methyl-formiate

Compound 2-(1-amino p-methoxyphenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates are added 60mL YLENE post-heating reflux, finish to the TLC monitoring reaction.After the cooling, there are a large amount of solids to separate out.Suction filtration, the gained solid is with petroleum ether and dry.

Brown solid, mp:202.3～204.2 ℃.

Yield 30.7%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：3.71(s，3H，Ar-OCH ₃)，3.73(s，2H，Ar-CH ₂-)，3.80(s，3H，-COOCH ₃)，6.88(d，1H，J＝8.4，Ar-H)，6.95(d，1H，J＝8.4，Ar-H)，7.21(d，2H，J＝8.0，Ar-H)，10.24(s，1H，-OH)，12.92(s，1H，-NH).

(d) 1-methyl-2-is to the preparation of methoxy-benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

Get compound 5, (0.87g 3.0mmol) is dissolved among the 50mL DMF 6-dihydroxyl-2-, in reaction system, adds K again to methoxybenzyl yl pyrimidines-4-methyl-formiate ₂CO ₃(1.24g, 9.0mmol) and CH ₃I (1.28g, 9.0mmol), stirred overnight at room temperature.The TLC monitoring reaction finishes.With 40mL * 3 ethyl acetate extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, the decompression precipitation, residue is through column chromatography purification.

Pure article are brown solid, yield 28.8%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.40(s，3H，N-CH ₃)，3.78(s，3H，-COOCH ₃)，3.96(s，3H，O-CH ₃)，3.98(s，3H，-ArOCH ₃)，4.10(s，2H，Ar-CH ₂-)，6.85(d，2H，J＝8.8，Ar-H)，7.13(d，2H，J＝8.4，Ar-H).

(e) 1-methyl-2-is to the preparation of methoxy-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid

Pure article are the faint yellow solid powder, mp:133.1-133.8 ℃.

Yield: 96.3%.

¹H?NMR(CDCl ₃，400MHz，δppm)：3.47(s，3H，N-CH ₃)，3.79(s，3H，Ar-OCH ₃)，4.09(s，3H，O-CH ₃)，4.10(s，2H，Ar-CH ₂-)，6.87(dd，2H，J＝2.0?and?6.8，Ar-H)，7.09(d，2H，J＝8.8，Ar-H). ¹³CNMR(CDCl ₃，100MHz，δppm)：31.64，40.98，61.14，116.07，116.28，129.24，129.27，130.05，130.13，145.88，154.03，159.98，160.97，163.43.

Step (f), (g) are with embodiment 6.

(h) N-(2-(4-(1-methyl-2-is to methoxy-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-3,4, the preparation of 5-trimethoxy-benzamide

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.56g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing 1-methyl-2-, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then to methoxy-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add N-2-(piperazine-1-yl) ethyl-3,4, (0.59g 1.83mmol), continues stirring at room to reaction and finishes the 5-trimethoxy-benzamide.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions, with 40mL * 3 water washings removing residual DMF, the saturated common salt water washing, anhydrous magnesium sulfate drying, filtration, the precipitation that reduces pressure, residue is through column chromatography purification.

Pure article are the faint yellow solid powder, mp:89.2～92.3 ℃.

Yield: 61.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：2.52(t，2H，J＝4.4，-CH ₂-CH ₂-NH-)，2.63(t，2H，J＝4.4，-CH ₂-of?piperazidine)，2.67(t，2H，J＝6.0，-CH ₂-of?piperazidine)，3.39(t，2H，J＝4.4，-CH ₂-of?piperazidine)，3.45(s，3H，N-CH ₃)，3.57(q，2H，J＝6.4，-CH ₂-CH ₂-NH-)，3.80(s，3H，Ar-OCH ₃)，3.80-3.82(m，2H，-CH ₂-of?piperazidine)，3.90(s，3H，Ar-OCH ₃)，3.92(s，6H，Ar-OCH ₃)，3.96(s，3H，-OCH ₃)，4.07(s，2H，Ar-CH ₂-)，6.64(br，1H，-NH-)，6.87(d，2H，J＝8.4，Ar-H)，7.01(s，2H，Ar-H)，7.11(d，2H，J＝8.4，Ar-H).

¹³C?NMR(CDCl ₃，100MHz，δppm)：30.90，31.24，36.48，41.38，41.55，46.66，52.46，52.92，55.31，56.40，56.53，60.30，60.91，104.52，114.53，125.96，129.41，130.03，140.29，141.10，144.48，153.24，156.09，158.97，159.62，164.18，167.17.

ESI-MS?m/z：608.2899[M-H] ^-，610.2806[M+H] ⁺，632.2628[M+Na] ⁺.

(i) N-(2-(4-(1-methyl-2-is to hydroxybenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-3,4, the preparation of 5-trimethoxy-benzamide

Take by weighing that compound N-(((1-methyl-2-is to methoxy-benzyl-5-methoxyl group-6-oxo-1 for 4-for 2-; 6-dihydro-pyrimidin-4-carbonic acyl radical) ethyl group piperazine-1-yl))-3; 4, the 5-trimethoxy-benzamide (0.46g, 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed; Under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography purification.

Obtain white solid, mp:145.1～147.9 ℃.

Yield: 55.0%.

¹H?NMR(DMSO-d ₆，400MHz，δppm)：2.80-3.00(m，2H，-CH ₂-CH ₂-NH-)，3.00-3.20(m，2H，-CH ₂-CH ₂NH-)，3.30-3.50(m，8H，-CH ₂-of?piperazidine)，3.29(s，3H，N-CH ₃)，3.80(s，3H，-OCH ₃)，4.01(s，2H，Ar-CH ₂-)，6.71(d，2H，J＝8.4，Ar-H)，6.84(s，2H，Ar-H)，7.01(d，2H，J＝8.4，Ar-H).

ESI-MS?m/z：551.9[M-H] ^-.

Embodiment 9:N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-3, the preparation of 4-dihydroxy benzoyl amine (1i)

Step (a) and (b), (c), (d), (e) are with embodiment 1.

(f) N-3-chloropropyl-3, the preparation of 4-dimethoxy BM

Three chloro propyl amine hydrochloric acid salts of 0.03mol are joined in the 100mL there-necked flask, add the methylene dichloride of crossing through drying treatment of 35mL then, drip the triethylamine solution of 10mL again to the dichloromethane solution of three chloro propyl amine hydrochloric acid salts; After stirring at room is reacted half a hour; With 3, the dichloromethane solution of 4-dimethoxy-benzoyl chloride is added drop-wise in the above-mentioned solution under condition of ice bath, after dropwising; Remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.Reaction system is used the saturated NaHCO in 30mL * 3 respectively ₃The 1molL of solution, 30mL * 3 ^-1Hydrochloric acid soln washing, use the saturated common salt solution washing of 30mL again, anhydrous magnesium sulfate drying, the decompression precipitation obtains N-3-chloropropyl-3, the pure article of the preparation of 4-dimethoxy BM.

Get white solid, yield 62.1%.

(g) N-3-(piperazine-1-yl) propyl group-3, the preparation of 4-dimethoxy BM

Under the room temperature to N-2-chloropropyl-3,4-dimethoxy BM (8.7g, add in chloroform soln 0.034mol) piperazine (11.7g, 13.6mol), the potassiumiodide of catalytic amount, K ₂CO ₃(4.7g, 0.034mol), reflux.TLC monitoring reaction process.After reaction finishes reaction system is filtered, get the filtrate decompression precipitation, residue is through column chromatography purification.

Yellow solid, mp:105.0～108.0 ℃.

Yield 57.6%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.59-1.65(m，2H，-CH ₂-CH ₂-CH ₂-)，2.20-2.30(m，4H，-CH ₂-of?piperazidine)，2.35(t，2H，J＝6.0，-CH ₂-CH ₂-CH ₂-)，2.74(t，4H，J＝4.8，-CH ₂-of?piperazidine)，3.38(q，2H，J＝6.0，-CH ₂-CH ₂-CH ₂-)，3.77(s，6H，Ar-OCH ₃)，6.71(d，1H，J＝8.4，Ar-H)，7.22(dd，1H，J＝1.6?and?8.4，Ar-H)，7.35(s，1H，Ar-H)，8.01(s，1H，-NH-).

(h) N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3, the preparation of 4-dimethoxy BM

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-2-(piperazine-1-yl) propyl group-3, (0.59g 1.83mmol), continues stirring at room to reaction and finishes 4-dimethoxy BM.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions, with 40mL * 3 water washings removing residual DMF, the saturated common salt water washing, anhydrous magnesium sulfate drying, filtration, the precipitation that reduces pressure, residue is through column chromatography purification.

Pure article are the yellow solid powder, mp:79.7～81.5 ℃.

Yield: 62.0%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.81-1.86(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.46(t，2H，J＝4.4，-CH ₂-CH ₂-CH ₂-NH-)，2.56-2.59(m，4H，-CH ₂-of?piperazidine)，3.35(t，2H，J＝4.8，-CH ₂-of?piperazidine)，3.45(s，3H，N-CH ₃)，3.57(q，2H，J＝6.4，-CH ₂-CH ₂-CH ₂-NH-)，3.80-3.82(m，2H，-CH ₂-of?piperazidine)，3.93(s，3H，Ar-OCH ₃)，3.95(s，3H，Ar-OCH ₃)，3.96(s，3H，-OCH ₃)，4.10(s，2H，Ar-CH ₂-)，，6.87(d，1H，J＝8.0，Ar-H)，7.13(t，2H，J＝8.4，Ar-H)，7.16-7.18(m，2H，Ar-H)，7.19(s，1H，Ar-H)，7.37(br，1H，-NH-)，7.48(s，1H，Ar-H).

¹³C?NMR(CDCl ₃，100MHz，δppm)：25.33，31.23，39.86，41.27，41.53，46.59，52.80，53.30，56.01，56.06，57.47，60.26，110.20，110.90，115.93，116.14，118.92，127.48，129.79，130.01，140.37，144.32，149.07，151.69，155.44，159.49，160.86，163.31，164.03，166.97.

ESI-MS?m/z：580.2735[M-H] ^-，582.2655[M+H] ⁺，604.2472[M+Na] ⁺.

(i) N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3, the preparation of 4-dihydroxy benzoyl amine

Take by weighing compound N-(3-(4-(1-methyl-2-benzyl-5-methoxyl group-6-oxo-1; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4-dimethoxy BM (0.43g; 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed, under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

Pure article are white solid, mp:162.1～164.9 ℃.

Yield: 57.5%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：2.00-2.10(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.80-3.90(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.00-3.15(m，2H，-CH ₂-of?piperazidine)，3.20-3.28(m，2H，-CH ₂-of?piperazidine)，3.30-3.45(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.45-3.60(m，4H，-CH ₂-of?piperazidine)，3.53(s，3H，N-CH ₃)，3.92(s，3H，-OCH ₃)，4.23(s，2H，Ar-CH ₂-)，6.81(d，1H，J＝8.0，Ar-H)，7.25-7.30(m，4H，Ar-H)，7.30-7.37(m，3H，Ar-H).

¹³C?NMR(MeOH-d ₄，100MHz，δppm)：22.83，25.27，29.33，30.62，37.35，40.10，40.93，45.24，51.87，52.37，55.34，59.44，114.40，114.51，119.30，125.40，126.98，128.50，128.63，134.75，140.41，143.38，144.96，148.87，156.92，159.90，164.65，169.04.

ESI-M?m/z：536.2[M+H] ⁺，558.1[M+Na] ⁺，533.9[M-H] ^-，569.9[M+Cl] ^-.

Embodiment 10:N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-3, the preparation of 4-dihydroxy benzoyl amine (1j)

Step (a) and (b), (c), (d), (e) are with embodiment 3.

Step (f), (g) are with embodiment 9.

(h) N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3, the preparation of 4-dimethoxy BM

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.5g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3, (0.56g 1.83mmol), continues stirring at room to reaction and finishes 4-dimethoxy BM.TLC detection reaction process.After reaction finishes,, merge organic phase with 30mL * 3 dichloromethane extractions, with 40mL * 3 water washings removing residual DMF, the saturated common salt water washing, anhydrous magnesium sulfate drying, filtration, the precipitation that reduces pressure, residue is through column chromatography purification.

Yellow solid, mp:79.7～81.5 ℃.

Yield 62.0%.

ESI-MS?m/z：580.2735[M-H] ^-，582.2655[M+H] ⁺，604.2472[M+Na] ⁺.

(i) N-(3-(4-(1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3, the preparation of 4-dihydroxy benzoyl amine

Take by weighing that compound N-(((1-methyl-2-is to luorobenzyl-5-methoxyl group-6-oxo-1 for 4-for 3-; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4-dimethoxy BM (0.44g; 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed, under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

White solid, mp:155.8～158.2 ℃.

Yield 53.0%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：2.07-2.12(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.75-2.95(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.05-3.15(m，2H，-CH ₂-of?piperazidine)，3.20-3.30(m，2H，-CH ₂-of?piperazidine)，3.30-3.40(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.50-3.65(m，4H，-CH ₂-of?piperazidine)，3.56(s，3H，N-CH ₃)，3.91(s，3H，-OCH ₃)，4.19(s，2H，Ar-CH ₂-)，6.80(d，1H，J＝8.0，Ar-H)，7.09(t，2H，J＝8.8，Ar-H)，7.25-7.33(m，4H，Ar-H).

¹³C?NMR(MeOH-d ₄，100MHz，δppm)：22.84，25.15，29.35，30.55，37.24，39.92，40.13，45.05，51.83，52.26，55.26，59.49，78.11，114.44，114.55，115.38，119.37，125.23，125.33，129.72，140.42，143.24，144.95，148.88，156.35，157.36，159.95，164.67，169.09.

ESI-MS?m/z：554.1[M+H] ⁺，576.1[M+Na] ⁺，551.9[M-H] ^-，587.8[M+Cl] ^-.

Embodiment 11:N-(3-(4-(1-methyl-2-is to hydroxybenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-3, the preparation of 4-dihydroxy benzoyl amine (1k)

Step (a) and (b), (c), (d), (e) are with embodiment 3.

Step (f), (g) are with embodiment 8.

(h) N-(3-(4-(1-methyl-2-is to methoxy-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3, the preparation of 4-dimethoxy BM

With N, (0.39g 2.38mmol) adds in the 100mL single port flask N '-carbonyl dimidazoles CDI, adds DMF and stirring and dissolving that 10mL crosses through drying treatment again.(0.52g 1.83mmol) and with it is dissolved among the dry DMF of 25mL weighing compound 1-methyl-2-benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid, under condition of ice bath, with constant pressure funnel it slowly is added dropwise in the DMF solution of CDI then.After dropwising, remove ice bath, stirring at room 1 hour.In reaction system, add compound N-3-(piperazine-1-yl) propyl group-3, (0.59g 1.83mmol), continues stirring at room to reaction and finishes in the preparation of 4-dimethoxy BM.TLC detection reaction process.After reaction finishes,, merge organic phase, wash removing residual DMF with 40mL * 3 water with 30mL * 3 dichloromethane extractions, the saturated common salt water washing, anhydrous magnesium sulfate drying, filtration, the precipitation that reduces pressure, residue is through column chromatography purification.

Yellow solid, mp:75.3～77.4 ℃.

Yield 65.3%.

¹H?NMR(CDCl ₃，400MHz，δppm)：1.81(m，2H，J＝6.0，-CH ₂-CH ₂-CH ₂-NH-)，2.48(t，2H，J＝4.4，-CH ₂-CH ₂-CH ₂-NH-)，2.54-2.57(m，4H，-CH ₂-of?piperazidine)，3.35(t，2H，J＝4.4，-CH ₂-of?piperazidine)，3.42(s，3H，N-CH ₃)，3.55(q，2H，J＝6.4，-CH ₂-CH ₂-CH ₂-NH-)，3.77(s，3H，Ar-OCH ₃)，3.78-3.79(m，2H，J＝4.8，-CH ₂-of?piperazidine)，3.91(s，6H，Ar-OCH ₃)，3.91(s，3H，-OCH ₃)，4.05(s，2H，Ar-CH ₂-)，，6.85(t，2H，J＝8.4，Ar-H)，7.09(d，2H，J＝8.4，Ar-H)，7.24-7.26(m，2H，Ar-H)，7.39(br，1H，-NH-)，7.46(s，1H，Ar-H).

¹³C?NMR(CDCl ₃，100MHz，δppm)：25.23，31.24，39.99，41.38，41.51，46.59，52.84，53.36，55.30，56.03，56.07，57.61，60.28，110.20，110.93，114.53，118.84，125.94，127.49，129.40，140.29，144.45，149.11，151.71，156.09，158.97，159.61，164.14，166.97.

(i) N-(3-(4-(1-methyl-2-is to methoxy-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-3, the preparation of 4-dihydroxy benzoyl amine

Take by weighing that compound N-(((1-methyl-2-is to methoxy-benzyl-5-methoxyl group-6-oxo-1 for 4-for 3-; 6-dihydro-pyrimidin-4-carbonic acyl radical) propyl group piperazine-1-yl))-3; 4-dimethoxy BM (0.45g; 0.76mmol) be dissolved in 20mL in the methylene dichloride that drying treatment is crossed, under the condition of ice bath, in above-mentioned solution, slowly be added dropwise to 12 times of excessive 1molL ^-1BBr ₃Dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitoring reaction process.After reaction finished, the anhydrous methanol that in ice bath downhill reaction system, slowly drips 30mL was in order to the unnecessary BBr of cancellation ₃, continued stirring at room 1 hour.The decompression precipitation, residue is through column chromatography (eluent: purifying methyl alcohol/chloroform).

White solid, mp:162.2～165.5 ℃.

Yield 53.6%.

¹H?NMR(MeOH-d ₄，400MHz，δppm)：2.05-2.10(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，2.70-2.90(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.00-3.10(m，2H，-CH ₂-of?piperazidine)，3.15-3.25(m，2H，-CH ₂-of?piperazidine)，3.30-3.40(m，2H，-CH ₂-CH ₂-CH ₂-NH-)，3.45-3.55(m，4H，-CH ₂-of?piperazidine)，3.49(s，3H，N-CH ₃)，3.89(s，3H，-OCH ₃)，4.09(s，2H，Ar-CH ₂-)，6.80(q，3H，J＝8.4，Ar-H)，7.07(d，2H，J＝8.4，Ar-H)，7.35(d，1H，J＝8.4，Ar-H)，7.33(s，1H，Ar-H).

¹³C?NMR(MeOH-d ₄，100MHz，δppm)：22.84，25.06，29.36，30.59，37.16，39.76，40.03，44.90，51.76，52.25，55.17，59.49，60.16，78.12，114.54，115.13，119.39，125.31，140.51，143.19，144.94，148.89，156.75，159.87，160.79，163.22，164.64，169.09.

ESI-MS?m/z：549.9[M-H] ^-.

Embodiment 12

It is following that the intergrase chain transfer reaction suppresses the determination of activity process:

The active inhibition of intergrase experimental procedure is following.Synthesize the donor substrate (donor DNA) of the double-stranded oligonucleotide of the 30bp that is similar to HIV-1 U5 LTR as enzyme reaction, the double-stranded oligonucleotide of the 20bp of synthetic 3 ' end mark digoxin (digoxin) is as target substrate (target DNA).

In 96 hole Sptting plates, add the intergrase (drug group adds medicine to be measured in addition again) of reaction buffer and reorganization, behind the incubated at room 10min, add donor DNA and target DNA again, 37 ℃ of reaction 1h.In reaction process, intergrase is exercised chain transfer activity, makes target DNA be connected to donor DNA, i.e. the chain transfer product.After adding the stop buffer termination reaction, reaction system is transferred to 96 pore chain affinity elements encapsulate plate, incubated at room 45min.Since the end mark of donor DNA vitamin H (biotin), the chain transfer product also can be incorporated into streptavidin and encapsulates plate.After washing plate, the used mark again SEAP of DigiTAb (Anti-Digoxin-Alkaline Phosphatase) Color Appearance System, detection reaction product.Through the comparison of drug group and positive controls OD value, can confirm medicine to the active restraining effect of intergrase, its determination of activity result sees table 1.

Table 1 compound suppresses intergrase determination of activity result

Annotate: MK-0518 (its English name is Raltegravir) is the medicine of target with HIV-1 for what gone on the market.

Claims

1. the polysubstituted benzamide compound of representing by formula (I) of N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl),

2. compound according to claim 1 is characterized in that R ¹Expression-H.

3. compound according to claim 1 is characterized in that R ⁵Expression-OH.

4. the preparation method of the described compound of claim 1 is characterized in that may further comprise the steps:

Wherein, R ¹Expression-H or-Cl, R ²Expression-H ,-Cl ,-F ,-CH ₃Or-OCH ₃

Wherein, R ¹, R ²The same step of group (a) of expression is said;

Wherein, R ¹, R ²The same step of group (a) of expression is said;

Wherein, R ¹, R ²The same step of group (a) of expression is said;

Wherein, R ¹, R ²The same step of group (a) of expression is said;

Wherein, R ³, R ⁴Expression-OCH ₃, R ⁵Expression-H or-OCH ₃, n=2 or 3;

Wherein, R ¹, R ², R ³, R ⁴, R ⁵The group of expression and the value of n are said with claim 1.

5. according to the method for claim 4, it is characterized in that the oxammonium hydrochloride described in the step (a) and the amount of substance ratio of Pottasium Hydroxide are 1: 1～1.5.

6. according to the method for claim 4, it is characterized in that formula (IV) compound described in the step (d) and the amount of substance ratio of methyl iodide are 1: 3～5, formula (IV) compound is 1: 3～5 with the amount of substance ratio of salt of wormwood.

7. according to the method for claim 4, it is characterized in that formula (IX) compound described in the step (g) is 1: 3～7 with piperazine amount of substance ratio.

8. according to the method for claim 4, it is characterized in that formula (X) compound and the condensing agent N described in the step (h), the amount of substance ratio of N '-carbonyl dimidazoles is 1: 1～2.

9. according to the method for claim 4, it is characterized in that formula (XI) compound described in the step (i) and the amount of substance ratio of deprotecting regent boron tribromide are 1: 2～15.

10. the application of the described compound of claim 1 in preparation HIV-1 integrase inhibitor.