CN102617487B - Multi-substituted pyrimidinones compounds as well as preparation method and application thereof - Google Patents

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

Polysubstituted pyrimidine ketone compounds and its preparation method and application

Technical field

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

Background technology

Acquired immune deficiency syndrome (AIDS) (Acquired immunodeficiency syndrome, AIDS) is to infect by human immunodeficiency virus (Human immunodeficiency virus-1, HIV-1) a kind of autoimmune disorder causing.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 Infectious Diseases.According to 2011 United Nations's acquired immune deficiency syndrome (AIDS) data statistics, show, HIV the infected and the aids patient of whole world survival in 2010 approximately have 3,400 ten thousand people, and wherein newly-increased number of the infected 2,700,000 in 2010, has 1,800,000 people to die from and AIDS-related diseases.

Anti-HIV-1 medicines is mainly for passing through the main phase of acquired immune deficiency syndrome (AIDS) mechanism of causing a disease, that is: intrusion, reverse transcription, integration and assembling.At present, the medicine of the treatment acquired immune deficiency syndrome (AIDS) of FDA approval mainly contains following several types: nucleoside reverse transcriptase inhibitor (nucleoside reverse transcriptase inhibitors), non-nucleoside reverse transcriptase inhibitor (non-nucleoside reverse transcriptase inhibitors), proteinase inhibitor (protease inhibitors), fusion inhibitor (fusion inhibitors), accessory receptor inhibitor (co-receptor inhibitors) and integrase inhibitor (integrase inhibitors).The use of these medicines can effectively extend 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 current research.

Intergrase is one of very significant target in anti-HIV-1 research, and its basic role in Life Cycles shows, virus relies on to integrate and keeps it effectively to copy and Infection Status.In recent years, people give intergrase and pay close attention to greatly.First, in human body, also there is no to find to have with intergrase the analogue of same structure and function, so the integrase inhibitor of highly selective is almost free from side effects to human body, secondly, because action target spot is different, integrase inhibitor is not subject at present the impact of the resistance that produces because of chemotherapy.Although coffee acyl derivatives class, ucleotides, vinylbenzene quinoline etc. show the effect that suppresses intergrase in determination of activity in vitro, only have part all to show good selectivity and suppress active in live body and isolated activity mensuration containing the compound of two ketone acid structures.D64 and the interaction of the Mg2+ between D116 mediation by two ketone acid structures and IN, diketoacids seals this region with " D; D-3-E " part in conjunction with forming mixture, although it is in conjunction with not changing the catalysis of IN to 3 '-p, but make 1, second Mg2+ of 3-dicarbapentaborane between D64 and E152 is combined, and this Mg2+ is the reaction site of ST, and this makes the alternative ST of inhibition of diketoacids process.

S-1360 was first integrase inhibitor that enters clinical study, and this compound entered II clinical trial phase in 2002.Clinical data shows, metabolism is carried out through acellular cytochrome p 450 approach in vivo, easily by the carbonyl reductase in human liver, reduced, the enol being connected with triazole in its structure is easily reduced, and this metabolism unstable is that it was terminated the reason of clinical study in 2003.

EP2161258 (A2) (open day: 2010.03.10) disclose a series of Quinolone acid derivative synthesizing process and integrase inhibiting activities.

WO 2009/089263 (A2) (open day: 2009.07.16) disclose a series of integrase inhibitor, wherein just comprised Quinolone acid compounds.

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

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) in a literary composition, reported N-hydroxyl-dihydronaphthridine ketone as the design of the HIV-1 integrase inhibitor of efficient and bioavailability with synthesize.

Summary of the invention

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

The invention 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) the Multi substituted benzenes Carbox amide that formula (I) represents,

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, the 6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) preparation method of Multi substituted benzenes Carbox amide, comprises the following steps:

(a) oxammonium hydrochloride is reacted in anhydrous methanol with potassium hydroxide, 0～30 ℃ of temperature of reaction, react after 1～2 hour, filter and collect filtrate, add benzyl cyanide to continue reaction, 10～70 ℃ of temperature of reaction, 5～10 hours reaction times, obtain N '-hydroxyl-2-substituted-phenyl ethanamidine compound that formula (II) represents

Wherein, R ¹expression-H or-Cl, R ²expression-H ,-Cl ,-F ,-CH ₃or-OCH ₃;

(b) formula (II) compound is dissolved in trichloromethane, add dimethyl butyn, under triethylamine effect, react, 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) represents

Wherein, R ¹, R ²described in the same step of group (a) representing;

(c) formula (III) compound is reacted in dimethylbenzene, 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 ²described in the same step of group (a) representing;

(d) formula (IV) compound is dissolved in DMF, 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) represents

Wherein, R ¹, R ²described in the same step of group (a) representing;

(e) formula (V) compound is reacted in ethanol with potassium hydroxide, formula (V) compound is 1: 1～4 with the amount of substance ratio of potassium hydroxide, 10～40 ℃ of temperature of reaction, react after 0.5～2 hour, acid adding is to pH=2～4, obtain 1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid cpds that formula (VI) represents

Wherein, R ¹, R ²described in the same step of group (a) representing;

(f) hydrochloride of the substituted benzoyl chloride representing with formula (VII) and the chloro alkylamine that represents with formula (VIII) reacts under triethylamine existence condition in methylene dichloride, 0～40 ℃ of temperature of reaction, 10～20 hours reaction times, obtain the N-chloro alkyl substituted benzamide compound that formula (IX) represents

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

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

Wherein, R ³, R ⁴, R ⁵described in the group representing and the same step of value (f) of n;

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

Wherein, R ¹, R ²described in the same step of group (a) representing, R ³, R ⁴, R ⁵described in the group representing and the same step of value (f) of n;

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

Wherein, R ¹, R ², R ³, R ⁴, R ⁵the group representing and the value of n are same as above.

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

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

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

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

Chemical equation in above-mentioned building-up process is as follows:

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

The inventive method is used industrial common reagent 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) preparation of (Z)-N '-hydroxyl-2-phenylacetamidino

Under room temperature by oxammonium hydrochloride (1.9g, 23.0mmol) add in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving, weigh KOH (1.29g, 23.0mmol) be dissolved in 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 is filtered and collected filtrate, add benzyl cyanide (2.42g, 20.7mmol) reflux, to TLC monitoring reaction end.Decompression precipitation, obtains white solid, and products therefrom, without purifying, directly enters the next step.

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

N '-hydroxyl-2-phenylacetamidino (2.5g, 16.7mmol) is added in 100mL round-bottomed flask, by 35mL trichloromethane stirring and dissolving.Get dimethyl butyn (2.37g, 16.7mmol) and add in reaction system, and add 10 triethylamine solutions, reflux.Reaction system becomes chocolate by scarlet, and TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds 60mL acetic acid ethyl dissolution, and with 40mL * 3 washing, the washing of 20mL * 3 saturated common salt, anhydrous magnesium sulfate drying, filters, and decompression precipitation, obtains red oily liquids.Products therefrom directly carries out the next step without purifying.

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

Add 60mL dimethylbenzene post-heating to reflux compound 2-(1-aminophenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates, to TLC monitoring reaction end.After cooling, there are a large amount of solids to separate out, suction filtration, petroleum ether dry for gained solid.

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

Sterling is 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

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

Sterling is 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, the preparation of 4,5-trimethoxy-benzamide

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

Sterling is 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, the preparation of 4,5-trimethoxy-benzamide

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

Sterling is 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

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

Sterling is 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 compound 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; 5-trimethoxy-benzamide (0.45g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature, TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

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

Under room temperature, oxammonium hydrochloride (1.9g, 23.0mmol) is added in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving.Weigh KOH (1.29g, 23.0mmol) and be dissolved in 40mL anhydrous methanol, then pour 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 is filtered and collected filtrate.Add p-chlorobenzyl cyanide (2.42g, 20.7mmol) reflux, to TLC monitoring reaction end.Decompression precipitation, obtains white solid.Products therefrom, without purifying, directly enters the next step.

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

(Z)-2-rubigan-N '-hydroxyl acetamidine (2.5g, 16.7mmol) is added in 100mL round-bottomed flask, by 35mL trichloromethane stirring and dissolving.Get dimethyl butyn (2.37g, 16.7mmol) and add in reaction system, and add 10 triethylamine solutions, reflux, reaction system becomes chocolate by scarlet, and TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds 60mL acetic acid ethyl dissolution, and with 40mL * 3 washing, the washing of 20mL * 3 saturated common salt, anhydrous magnesium sulfate drying, filters, and decompression precipitation, obtains red oily liquids.Products therefrom directly carries out the next step without purifying.

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

Add 60mL dimethylbenzene post-heating to reflux compound 2-(1-aminophenyl ethylidene ammonia) oxo divinyl two dimethyl phthalates, to TLC monitoring reaction end.After cooling, there are a large amount of solids to separate out, suction filtration, petroleum ether dry for gained solid.

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

Sterling is 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

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

Sterling is 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

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

Sterling is 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 compound 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; 5-trimethoxy-benzamide (0.45g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Sterling is 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-to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

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

Under room temperature, oxammonium hydrochloride (1.9g, 23.0mmol) is added in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving.Weighing KOH (1.29g, 23.0mmol) is dissolved in 40mL anhydrous methanol, then pours in the constant pressure funnel of 60mL, 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 and collected filtrate.Add fluorophenyl acetonitrile (2.42g, 20.7mmol) reflux, to TLC monitoring reaction end.Decompression precipitation, obtains white solid.Products therefrom, without purifying, directly enters the next step.

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

(Z)-2-is added in 100mL round-bottomed flask fluorophenyl-N '-hydroxyl acetamidine (2.5g, 16.7mmol), by 35mL trichloromethane stirring and dissolving.Get dimethyl butyn (2.37g, 16.7mmol) and add in reaction system, and add 10 triethylamine solutions, reflux.Reaction system becomes chocolate by scarlet.TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds 60mL acetic acid ethyl dissolution, with 40mL * 3 washing, the washing of 20mL * 3 saturated common salt.Anhydrous magnesium sulfate drying, filters, and decompression precipitation, obtains red oily liquids.Products therefrom directly carries out the next step without purifying.

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

Add 60mL dimethylbenzene post-heating to reflux compound 2-((1-amino is to fluorophenyl ethylidene ammonia)) oxo divinyl two dimethyl phthalates, to TLC monitoring reaction end.After cooling, there are a large amount of solids to separate out.Suction filtration, petroleum ether dry for gained solid.

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

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

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

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

Sterling is 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-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

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

Sterling is 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-to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take 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) piperazine-1-yl) propyl group)-3; 4; 5-trimethoxy-benzamide (0.45g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Sterling is 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-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

Under room temperature, oxammonium hydrochloride (1.9g, 23.0mmol) is added in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving.Weighing KOH (1.29g, 23.0mmol) is dissolved in 40mL anhydrous methanol, then pours in the constant pressure funnel of 60mL, 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 and collected filtrate.Add methylbenzene acetonitrile (2.42g, 20.7mmol) reflux, to TLC monitoring reaction end.Decompression precipitation, obtains white solid.Products therefrom, without purifying, directly enters the next step.

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

(Z)-2-p-methylphenyl-N '-hydroxyl acetamidine (2.5g, 16.7mmol) is added in 100mL round-bottomed flask, by 35mL trichloromethane stirring and dissolving.Get dimethyl butyn (2.37g, 16.7mmol) and add in reaction system, and add 10 triethylamine solutions, reflux.Reaction system becomes chocolate by scarlet.TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds 60mL acetic acid ethyl dissolution, with 40mL * 3 washing, the washing of 20mL * 3 saturated common salt.Anhydrous magnesium sulfate drying, filters, and decompression precipitation, obtains red oily liquids.Products therefrom directly carries out the next step without purifying.

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

Add 60mL dimethylbenzene post-heating to reflux compound 2-(the amino p-methylphenyl ethylidene of 1-ammonia) oxo divinyl two dimethyl phthalates, to TLC monitoring reaction end.After cooling, there are a large amount of solids to separate out.Suction filtration, petroleum ether dry for gained solid.

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

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

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

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

Sterling is faint yellow solid powder, mp:162.4～164.9 ℃.

Yield: 94.0%.

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).

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

(h) N-(3-(4-(1-methyl-2-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

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

Sterling is 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-to methyl-benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take 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) piperazine-1-yl) propyl group)-3; 4; 5-trimethoxy-benzamide (0.45g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Sterling is 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-(3,4-dichloro benzyl)-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide

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

Under room temperature, oxammonium hydrochloride (1.9g, 23.0mmol) is added in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving.Weighing KOH (1.29g, 23.0mmol) is dissolved in 40mL anhydrous methanol, then pours in the constant pressure funnel of 60mL, 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 and collected filtrate.Add 3,4-dichloro benzyl cyanide (2.42g, 20.7mmol) reflux, to TLC monitoring reaction end.Decompression precipitation, obtains white solid.Products therefrom, without purifying, directly enters the next step.

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

(Z)-2-(3,4-dichlorophenyl)-N '-hydroxyl acetamidine (2.5g, 16.7mmol) is added in 100mL round-bottomed flask, by 35mL trichloromethane stirring and dissolving.Get dimethyl butyn (2.37g, 16.7mmol) and add in reaction system, and add 10 triethylamine solutions, reflux.Reaction system becomes chocolate by scarlet.TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds 60mL acetic acid ethyl dissolution, with 40mL * 3 washing, the washing of 20mL * 3 saturated common salt.Anhydrous magnesium sulfate drying, filters, and decompression precipitation, obtains red oily liquids.Products therefrom directly carries out the next step without purifying.

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

Add 60mL dimethylbenzene post-heating to reflux compound 2-((1-amino-(3,4-dichlorophenyl) ethylidene ammonia)) oxo divinyl two dimethyl phthalates, to TLC monitoring reaction end.After cooling, there are a large amount of solids to separate out.Suction filtration, petroleum ether dry for gained solid.

Sterling is 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-(3,4-dichloro benzyl)-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

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

Sterling is 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-(3,4-dichloro benzyl)-5-methoxyl group-6-oxo pyrimidine-4-formic acid

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

Sterling is 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-(3,4-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

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

Sterling is 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-(3,4-dichloro benzyl)-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl group)-gallamide

Take compound N-(3-(4-(1-methyl-2-(3; 4-dichloro benzyl)-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 the methylene dichloride that the drying of 20mL processed, under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Sterling is 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), (b), (c), (d), (e) are with embodiment 1.

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

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

Sterling is white solid powder, yield: 70.5%.

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

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

Sterling is 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

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

Obtain 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 compound 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; 5-trimethoxy-benzamide (0.44g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.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-to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) propyl)-gallamide (1g)

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

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

(h) N-(2-(4-(1-methyl-2-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

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

Obtain 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-to luorobenzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) ethyl group)-gallamide

Take 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) piperazine-1-yl) ethyl group)-3; 4; 5-trimethoxy-benzamide (0.45g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.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-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

Under room temperature, oxammonium hydrochloride (1.9g, 23.0mmol) is added in the round-bottomed flask of 250mL, add 40mL anhydrous methanol stirring and dissolving.Weighing KOH (1.29g, 23.0mmol) is dissolved in 40mL anhydrous methanol, then pours in the constant pressure funnel of 60mL, 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 and collected filtrate.Add PARA METHOXY PHENYL ACETONITRILE (3.04g, 20.7mmol) reflux, to TLC monitoring reaction end.Decompression precipitation, obtains white solid.Products therefrom, without purifying, directly enters the next step.

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

(Z)-2-p-methoxyphenyl-N '-hydroxyl acetamidine (3.0g, 16.7mmol) is added in 100mL round-bottomed flask, by 35mL trichloromethane stirring and dissolving.Get dimethyl butyn (2.37g, 16.7mmol) and add in reaction system, and add 10 triethylamine solutions, reflux.Reaction system becomes chocolate by scarlet.TLC monitoring reaction finishes.Removal of solvent under reduced pressure, residue adds 60mL acetic acid ethyl dissolution, with 40mL * 3 washing, the washing of 20mL * 3 saturated common salt.Anhydrous magnesium sulfate drying, filters, and decompression precipitation, obtains red oily liquids.Products therefrom directly carries out the next step without purifying.

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

Add 60mL dimethylbenzene post-heating to reflux compound 2-(the amino p-methoxyphenyl ethylidene of 1-ammonia) oxo divinyl two dimethyl phthalates, to TLC monitoring reaction end.After cooling, there are a large amount of solids to separate out.Suction filtration, petroleum ether dry for gained solid.

Obtain 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) preparation of 1-methyl-2-to methoxy-benzyl-5-methoxyl group-6-oxo pyrimidine-4-methyl-formiate

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

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

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

Sterling is 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-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

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

Sterling is 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-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 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) piperazine-1-yl) ethyl group)-3; 4; 5-trimethoxy-benzamide (0.46g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.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), (b), (c), (d), (e) are with embodiment 1.

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

Three chloro propyl amine hydrochloric acid salts of 0.03mol are joined in 100mL there-necked flask, then the methylene dichloride that adds the drying of 35mL to process, to the dichloromethane solution of three chloro propyl amine hydrochloric acid salts, drip again the triethylamine solution of 10mL, stirring at room was reacted after half an hour, the dichloromethane solution of 3,4-dimethoxy-benzoyl chloride is added drop-wise in above-mentioned solution, after dropwising under condition of ice bath, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.Reaction system is used respectively the saturated NaHCO in 30mL * 3 ₃the 1molL of solution, 30mL * 3 ^-1hydrochloric acid soln washing, then use the saturated common salt solution washing of 30mL, anhydrous magnesium sulfate drying, decompression precipitation obtains N-3-chloropropyl-3, the sterling of the preparation of 4-dimethoxy benzamide.

Obtain white solid, yield 62.1%.

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

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

Obtain 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 benzamide

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

Sterling is 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 compound 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-dimethoxy benzamide (0.43g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Sterling is 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-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), (b), (c), (d), (e) are with embodiment 3.

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

(h) N-(3-(4-(1-methyl-2-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 benzamide

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

Obtain yellow solid, 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-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 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) piperazine-1-yl) propyl group)-3; 4-dimethoxy benzamide (0.44g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Obtain 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-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), (b), (c), (d), (e) are with embodiment 3.

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

(h) N-(3-(4-(1-methyl-2-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 benzamide

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

Obtain 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-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 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) piperazine-1-yl) propyl group)-3; 4-dimethoxy benzamide (0.45g; 0.76mmol) be dissolved in the methylene dichloride that the drying of 20mL processed; under condition of ice bath, in above-mentioned solution, be slowly added dropwise to 12 times of excessive 1molL ^-1bBr ₃dichloromethane solution, after dropwising, remove ice bath, stirred overnight at room temperature.TLC monitors reaction process.After reaction finishes, in ice bath downhill reaction system, slowly drip the anhydrous methanol of 30mL in order to the unnecessary BBr of cancellation ₃, continue stirring at room 1 hour.Decompression precipitation, residue is through column chromatography (eluent: methyl alcohol/chloroform) purifying.

Obtain 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 as follows that intergrase chain transfer reaction suppresses determination of activity process:

Integrate inhibition of enzyme activity experimental procedure as follows.Synthesize the double-stranded oligonucleotide of the 30bp that is similar to HIV-1 U5 LTR as the donor substrate (donor DNA) of 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 (medicine group adds medicine to be measured in addition again) of reaction buffer and restructuring, after incubated at room 10min, then add donor DNA and target DNA, 37 ℃ of reaction 1h.In reaction process, intergrase is exercised chain transfer activity, makes target DNA be connected to donor DNA, i.e. chain transfer product.Add after stop buffer termination reaction, reaction system is transferred to the coated plate of 96 hole streptavidins, incubated at room 45min.Due to an end mark of donor DNA vitamin H (biotin), chain transfer product also can be incorporated into the coated plate of streptavidin.Wash after plate, then the used mark alkaline phosphatase of DigiTAb (Anti-Digoxin-Alkaline Phosphatase) Color Appearance System, detection reaction product.By the comparison of medicine group and positive controls OD value, can determine the restraining effect of medicine to intergrase activity, its determination of activity the results are shown in Table 1.

Table 1 compound suppresses intergrase determination of activity result

The take medicine that HIV-1 be target of note: MK-0518 (its English name is Raltegravir) for having gone on the market.

Claims (10)

1. N-((4-(1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo-1,6-dihydro-pyrimidin-4-carbonic acyl radical) piperazine-1-yl) alkyl) the Multi substituted benzenes Carbox amide being represented by formula (I),

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.

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 compound claimed in claim 1, is characterized in that comprising the following steps:

(a) oxammonium hydrochloride is reacted in anhydrous methanol with potassium hydroxide, 0～30 ℃ of temperature of reaction, react after 1～2 hour, filter and collect filtrate, add benzyl cyanide to continue reaction, 10～70 ℃ of temperature of reaction, 5～10 hours reaction times, obtain N'-hydroxyl-2-substituted-phenyl ethanamidine compound that formula (II) represents

Wherein, R ¹expression-H or-Cl, R ²expression-H ,-Cl ,-F ,-CH ₃or-OCH ₃;

(b) formula (II) compound is dissolved in trichloromethane, add dimethyl butyn, under triethylamine effect, react, 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) represents

Wherein, R ¹, R ²described in the same step of group (a) representing;

(c) formula (III) compound is reacted in dimethylbenzene, 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 ²described in the same step of group (a) representing;

(d) formula (IV) compound is dissolved in DMF, 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) represents

Wherein, R ¹, R ²described in the same step of group (a) representing;

(e) formula (V) compound is reacted in ethanol with potassium hydroxide, formula (V) compound is 1:1～4 with the amount of substance ratio of potassium hydroxide, 10～40 ℃ of temperature of reaction, react after 0.5～2 hour, acid adding is to pH=2～4, obtain 1-methyl-2-substituted benzyl-5-methoxyl group-6-oxo pyrimidine-4-formic acid cpds that formula (VI) represents

Wherein, R ¹, R ²described in the same step of group (a) representing;

(f) hydrochloride of the substituted benzoyl chloride representing with formula (VII) and the chloro alkylamine that represents with formula (VIII) reacts under triethylamine existence condition in methylene dichloride, 0～40 ℃ of temperature of reaction, 10～20 hours reaction times, obtain the N-chloro alkyl substituted benzamide compound that formula (IX) represents

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

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

Wherein, R ³, R ⁴, R ⁵described in the group representing and the same step of value (f) of n;

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

Wherein, R ¹, R ²described in the same step of group (a) representing, R ³, R ⁴, R ⁵described in the group representing and the same step of value (f) of n;

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

Wherein, R ¹, R ², R ³, R ⁴, R ⁵the group representing and the value of n are with described in claim 1.

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

6. according to the method for claim 4, it is characterized in that the amount of substance ratio of formula (IV) compound described in step (d) and methyl iodide is 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 step (g) and piperazine amount of substance ratio are 1:3～7.

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

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

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