CN106966986A - N benzyls heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof - Google Patents

Abstract

The invention relates to an N -benzyl nitroheterocyclic ketene ketone derivative, a synthesis method and an antitumor application. The structure of this compound is shown in formula (I): , formula (I); Wherein, X is fluorine, chlorine atom; Ar is phenyl, monofluorophenyl, monochlorophenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted benzene 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, methyl-substituted phenyl, methoxy-substituted phenyl, pyridyl, substituted pyridyl, thiophene group or substituted thienyl group. The compound of the present invention has excellent antitumor activity against human lung cancer (A549), human colon cancer (HT29), human gastric cancer (SGC7901) and human liver cancer (HepG2). The inhibitory activity of the invented compounds on human lung cancer (A549) is better than that of the reference drug cisplatin. The invention has broad application prospects in the preparation of antitumor drugs.

Description

N-benzyl nitroheterocyclic ketene ketone derivatives, synthesis method and antitumor application

technical field

The invention belongs to the technical field of medicinal chemistry, and specifically relates to an N-benzyl nitroheterocyclic ketene ketone derivative, a synthesis method and an antitumor application.

Background technique

Cancer is an important disease that seriously threatens human life and health in the world today, and it is becoming more and more rampant and killing more lives. The treatment and prevention of cancer has become a widespread concern of the whole society. According to the World Cancer Report released by the World Health Organization in 2014, cancer has become the leading cause of death in the world. Among them, lung cancer has become the world's largest killer, accounting for 19.4% of cancer mortality; the second liver cancer accounted for 9.1%. Chemotherapy is an important method for the treatment of lung cancer at present. Research and development of new anti-tumor drugs, especially anti-lung cancer drugs, has important practical significance for alleviating or treating the pain of lung cancer patients.

N-benzyl nitroketene amines are neonicotinoid analogues (such as imidacloprid, picloprid, etc.), wherein 6-Cl-PMNI in this class of compounds has better insecticidal activity; at the same time, N- Benzyl nitroketene ketenes are versatile synthetic building blocks for the synthesis of potentially bioactive nitrogen-containing heterocyclic compounds. Li Zhong's research group carried out a series of research work on neonicotinoid analogs, and synthesized many active compounds (Bao, H.; Shao, X.; Zhang, Y.; Deng, Y.; Xu, X.; Liu, Z. .; Li, Z. J. Agric. Food Chem. 2016, 64, 5148; L u, S.; Zhuang, Y.; .; Yuan, J.; Xu, X.J. Agri c. Food Chem. 2013, 61, 10858; Shao, X.; Xu, Z.; Zhao, X.; Xu, X.; Tao, L.; Li, Z .; Qiang, X. J. Agric. Food Chem. 2010, 58, 2690). So far, people generally pay attention to the insecticidal activity of N-benzyl nitroketene ketones, and there are few studies on other activities.

Halides play an important role in pharmaceutical research, especially anticancer compounds. For example, compounds such as anticancer drugs vandetanib, cediranib, lenvatinib, tivozanib, and cabozanib all contain halogen elements. Among halides, fluoride has attracted much attention. Because, on the one hand, due to the introduction of fluorine atoms, the volatility, diffusivity, compatibility and surface activity of the compound are increased, while the steric hindrance is reduced, so the fat-solubility of the organism can be fully exerted, and the various phase states of the organism, The characteristics of membrane and tissue penetration, that is, the "pseudo-pseudo effect" produced by fluorine atoms make fluorine-containing compounds often have very superior biological activity. On the other hand, fluorine-containing organics are recognized as environmentally friendly compounds. All kinds of halides synthesized with polyhalogenated isophthalonitrile as raw materials have good antitumor or antibacterial activity (Huang, C.; Yan, S.-J.; Zeng, X.-H.; Dai, X.-Y.; Zhang, Y.; Qing, C.; Lin, J. Eur. J. Med. Chem. 2011, 46, 1172～1180; Huang, C.; Yan, S.-J. ; Zeng, X.-H.; Sun, B.; La n, M.-B.; Xian Fan, Ji-Hong Zhang, Jun Lin.RSC Adv.2013, 3, 5563～5569; Sheng-Jiao Yan, Yong-Jiang Liu, Yu-Lan Chen, Lin Liu, JunLin.Bioorg.Med.Chem.Lett. 2010, 20, 5225-5228; Sheng-Jiao Yan, Han Zheng, Chao Huang, Yu-Yun Yan, Jun Lin. Bioorg. Med. Chem. Lett. 2010, 20, 4432-4435).

Therefore, the reaction of polyhalogenated isophthalonitrile and N-benzyl nitroketene ketene to synthesize N-benzyl nitroketene ketene derivatives is of great significance for the research and development of tumor drugs.

Contents of the invention

The purpose of the present invention is to provide a kind of N-benzyl nitroheterocyclic ketene ketone derivatives and its synthesis method and antitumor application in order to solve the deficiencies in the prior art; this type of compound has antitumor activity, especially antitumor Solid tumor activity, more precisely, it has very excellent activity against lung cancer, colon cancer, gastric cancer and liver cancer.

To achieve the above object, the technical scheme adopted in the present invention is as follows:

N-benzyl nitroheterocyclic ketene ketal derivatives, the structure of the compound is shown in formula (I):

In formula (I), X is a fluorine atom or a chlorine atom; Ar is phenyl, monofluorophenyl, monochlorophenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl , 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, methyl-substituted phenyl, methoxy-substituted phenyl, pyridyl, substituted pyridyl, thienyl Or substituted thienyl.

The present invention also provides a synthetic method for the above-mentioned N-benzyl nitroheterocyclic ketene ketone derivatives, which is characterized in that it comprises the following steps:

React the polyhalogenated isophthalonitrile with the structure of formula (II) and the nitroheterocyclic ketene amine of the structure of formula (III) under heating and grinding conditions or microwave heating conditions, TLC tracking, after the reaction is complete , adjust the pH _of the reaction solution to alkaline with _Na2CO3 or _NaHCO3 saturated aqueous solution, then extract with an organic solvent, take the organic phase, concentrate and separate through column chromatography to obtain the N-benzyl of the formula (I) structure nitro-heterocyclic ketene ketone derivatives;

In formula (II), X is a fluorine atom or a chlorine atom;

In formula (III), Ar is phenyl, monofluorophenyl, monochlorophenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, 2,4-difluoro Phenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, methyl-substituted phenyl, methoxy-substituted phenyl, pyridyl, substituted pyridyl, thienyl or substituted thienyl.

The function of saturated sodium bicarbonate aqueous solution or saturated sodium carbonate aqueous solution is to remove the acid produced in the reaction.

The degree of concentration is not particularly required, and concentration to no solvent is preferred.

Further, preferably, the heating temperature is 110-160° C., and the reaction time is 5-30 minutes.

Further, preferably, the solvent used in the column chromatographic separation is petroleum ether/ethyl acetate=1:1˜1:4, but not limited thereto.

Further, preferably, the molar ratio of the polyhalogenated isophthalonitrile with the structure of formula (II) to the nitroheterocyclic ketene ketal with the structure of formula (III) is 1:1-1.5.

The present invention also provides the application of the above-mentioned N-benzyl nitroheterocyclic ketene ketone derivatives as preparation of antitumor drugs.

Further, preferably, the anti-tumor drugs are anti-lung cancer, anti-colorectal cancer, anti-gastric cancer, anti-liver cancer drugs.

Compared with the prior art, the present invention has the beneficial effects of:

The present invention uses simple and easy-to-obtain raw materials such as the structure shown in formula (II) and the structure shown in formula (III), and obtains the target compound (I) through a one-pot method. The synthesis process of the invention is simple (one-step reaction is only required), the yield is high (66%-93%), the product is stable, no catalyst is needed, and the cost is saved.

The compounds of the present invention all have excellent antitumor activity, especially for solid tumors, such as human lung cancer (A549), human colon cancer (HT29), human gastric cancer (SGC7901) and human liver cancer (HepG2), all have excellent antitumor activity . Its anti-lung cancer (A549) activity of the compound of the present invention is all obviously better than positive control drug cisplatin (DPP); The compound of the present invention such as compound 1 and compound 14 carries out cytotoxicity test with L-02 (normal human liver cell) and shows that these two All compounds were non-toxic (CC50>40μmol/L).

The invention has broad application prospects in the preparation of antitumor drugs. The invention adopts solvent-free and catalyst-free one-step reaction to conveniently synthesize N-benzyl nitroheterocyclic ketene ketone derivative library.

Description of drawings

Figure 1 is the H NMR spectrum of compound 1.

Figure 2 is the high resolution mass spectrum of compound 1.

Fig. 3 is the proton nuclear magnetic resonance spectrum of compound 5.

FIG. 4 is a single crystal structure diagram of compound 24.

detailed description

The present invention will be further described in detail below in conjunction with the examples.

Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The materials, reagents or instruments used are not indicated by the manufacturer, but are all conventional products that can be purchased.

The method for synthesizing N-benzyl nitroheterocyclic enone ketene derivatives of the present invention is as follows:

React the polyhalogenated isophthalonitrile with the structure of formula (II) and the nitroheterocyclic ketene amine of the structure of formula (III) under heating and grinding conditions or microwave heating conditions, TLC tracking, after the reaction is complete Add appropriate amount of saturated aqueous sodium carbonate solution or saturated aqueous sodium bicarbonate solution to the reactant to adjust the pH of the reaction solution to alkalescence, then add an appropriate amount of organic solvent for extraction, get the organic phase, concentrate and separate and purify through column chromatography to obtain the formula (I ) structure of N-benzyl nitroheterocyclic ketene ketone derivatives, the specific reaction formula is as follows:

In formula (II), X is a fluorine atom or a chlorine atom;

In formula (III), Ar is phenyl, monofluorophenyl, monochlorophenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, cyano substituted phenyl, 2,4-difluoro Phenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, methyl-substituted phenyl, methoxy-substituted phenyl, pyridyl, substituted pyridyl, thienyl or substituted thienyl.

During the reaction, the reaction temperature is not specified, but is usually 110-160°C; the reaction time is not specified, and is generally 5-30 minutes.

The reaction process was tracked by TLC, and the heating was stopped after the reaction was complete. First transfer the reactant to a beaker with an appropriate amount of saturated sodium bicarbonate or sodium carbonate aqueous solution, then wash the reaction tube or mortar with a little acetone and combine the acetone solution into the beaker, and pour the solution in the beaker into a separatory funnel After that, add an appropriate amount of ethyl acetate for extraction. After the extraction, transfer the organic layer to a round bottom flask and add an appropriate amount of desiccant (anhydrous sodium sulfate) to dry for 1 hour. Remove the desiccant by suction filtration. After the organic layer is concentrated and dried, After adding an appropriate amount of acetone to dissolve, add an appropriate amount of silica gel to mix the sample, and then separate it by column chromatography. The eluent of column chromatography is not specified in detail, and it is usually a mixed solvent of ethyl acetate/petroleum ether.

The purpose of washing with acetone again is to transfer the reactants remaining on the reaction tube or mortar to the beaker, so that the yield can be calculated more accurately.

The solvent used for column chromatography is preferably a mixed solvent of petroleum ether/ethyl acetate=1:1～1:4.

In the reaction, for 1 mole of the compound of the formula (III), the dosage of the compound of the formula (II) is 1-1.5 moles. The yield of the reaction is generally 64-93%.

Compounds of formula (II) are well known and commercially available.

Compounds of formula (III) are known or can be prepared according to known methods.

The present invention starts from polyhalogenated isophthalonitrile (II) and easy-to-obtain raw material nitroheterocyclic ketene ketone compound (III), and synthesizes a series of new N-benzyl nitro compounds by grinding method or microwave method. Heterocyclic ketene ketone derivatives (I).

The compound of the present invention was tested on human tumor cell line: A549 (lung cancer). Cells were incubated with compounds for 144 hours, and then cytotoxicity was measured by MTT assay (test method references: J.Med.Chem.2001,44,1594; Cancer Res.1987,47,936; Immunol.Methods 1983,65,55 ; Bioorg. Med. Chem. Lett. 2010, 20, 48).

The obtained data prove that the compounds of the present invention have obvious activity on the solid tumor lung cancer, and the anti-lung cancer activities of most of the inventive compounds are better than the positive control drug cisplatin. It shows that the invented compound will have good prospect of antitumor drug.

The daily dosage of the compound of the present invention is 0.01 mg-10 mg/kg. A preferred daily dosage is about 0.2 mg to 2 mg/kg body weight, with a single dose of about 14 mg to about 140 mg of active substance administered in 24 hours for a patient weighing about 70 kg. This dosage range can be adjusted for better therapeutic effect. The active compound of the present invention can be administered orally, intravenously, intramuscularly, subcutaneously and the like.

The compounds of the present invention may be administered in combination with other agents used to induce tumor regression to synergistically increase the antitumor effect of the compounds. The compounds that can be used in the present invention can be used with different anticancer drugs, such as: cisplatin, oxaliplatin, 5-fluorouracil, doxorubicin, gemcitabine, paclitaxel, vincristine, hydroxycamptothecin, topotecan , Combination administration of irinotecan (combination administration ratio 1:10～10:1)

The pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the invention in a pharmaceutically acceptable mixture.

Oral compositions comprise capsules, tablets, pills, suspensions or syrups suitable for oral administration.

For the preparation of pharmaceutical compositions for parenteral administration, the active ingredient can be incorporated into a solution or suspension.

The present invention will be described in detail below in conjunction with some specific embodiments. These examples are only for illustrating the present invention, and are not intended to limit the scope of the present invention. The preparation schemes in the examples are only preferred schemes, but the present invention is not limited to the preferred preparation schemes.

The present invention will be described in detail below in conjunction with some specific embodiments.

Synthesis of the first part of the compound of the present invention

Example 1: (E)-1-((6-chloropyridin-3-yl)methyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro Synthesis of (1)methylene)imidazolidine (Compound 1): Tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 2-chloro-5-((2-(nitrosophthalonitrile) were added in a mortar Methyl)imidazolidin-1-yl)methyl)pyridine (1 mmol, 0.254g), fully grind evenly, place on a magnetic stirrer while heating while grinding, heat to reaction temperature 110°C and keep this temperature for 30 minutes Rear. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 50 ml of saturated aqueous sodium bicarbonate solution, then the reaction tube or mortar was washed with 3 ml of acetone and the acetone solution was combined into the beaker, and the beaker After the solution was poured into a separatory funnel, 50 ml of ethyl acetate was added for extraction. After extraction, the organic layer was transferred to a round-bottomed flask, and an appropriate amount of desiccant (anhydrous sodium sulfate) was added to dry for 1 hour, and the desiccant was removed by suction filtration. , after the organic layer was concentrated and dried, 4 milliliters of acetone was added to dissolve it, and then an appropriate amount of silica gel was added to mix the sample and then separated by column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent=1:4) to obtain a yellow solid product with a yield of 80 %. Melting point: 149.9–151.9°C.

As shown in Figure 1, proton nuclear magnetic resonance spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.45 (br, 1H, NH), 8.26 (d, J=2.2Hz, 1H, ArH), 7.74 (dd,J ₁ =8.3Hz,J ₂ =2.4Hz,1H,ArH),7.44–7.54(d,J=8.3Hz,1H,ArH),4.31(s,2H,NCH ₂ ),3.75–3.88( m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ＝161.5, 159.3, 154.7–154.9(m), 152.8(d, J＝6.3Hz), 150.6, 149.5, 145.1(dd, J ₁ = 247.5Hz, J2 = 11.3Hz), 139.4, 134.1 (d, J = _15.0Hz ), 131.6, 125.0, 111.4, 108.6, 100.8 (d, J = 15.0Hz), 97.8, 92.8–93.1 (m) , 51.1, 50.1, 43.0.

As shown in Figure 2, the high-resolution mass spectrum C ₁₈ H ₉ ClF ₃ N ₆ O ₂ [MH] ^- , the theoretical value is 433.0433; the measured value is 433.0430.

Example 2: (E)-1-benzyl-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 2) Synthesis: After adding tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 1-benzyl-2-(nitromethylene) imidazolidinidine (1.2 mmol, 0.26 g) in a mortar , Grind fully and evenly, put it on a magnetic stirrer and grind while heating, heat to 120°C and keep it for 15 minutes, then stop heating, and use the residual heat to complete the reaction. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 40 ml of saturated aqueous sodium bicarbonate solution, and then the reaction tube or mortar was washed with 2 ml of acetone and the acetone solution was combined into the beaker. After the solution was poured into a separatory funnel, 40 ml of ethyl acetate was added for extraction. After the extraction, the organic layer was transferred to a round-bottomed flask, and an appropriate amount of desiccant (anhydrous sodium sulfate) was added to dry for 1 hour, and the desiccant was removed by suction filtration. , after the organic layer was concentrated and dried, 4 milliliters of acetone was added to dissolve it, and then an appropriate amount of silica gel was added to mix the sample and then separated by column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent=1:1) to obtain a yellow solid product (E)- 1-Benzyl-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 2), the yield was 78%. Melting point: 178.5–180.5°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.52(br,1H,NH),7.26–7.35(m,3H,ArH,ArH,ArH),7.11–7.15(m, 2H, ArH, ArH), 4.20 (s, 2H, NCH ₂ ), 3.74–3.88 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=161.7, 160.2(d, J=263.8Hz), 153.7(d, J=277.5Hz), 145.1(dd, J ₁ =246.3 Hz, J2 = 10.0Hz ₎ , 136.3, 133.8 (d, J = 16.3Hz), 129.4, 128.5, 127.1, 111.4, 108.5, 101.2 (d, J = 15.0Hz), 97.7, 93.0–93.4 (m), 53.4, 51.4, 43.3.

High resolution mass spectrum C ₁₉ H ₁₁ F ₃ N ₅ O ₂ [MH] ^- , theoretical value 398.0870; measured value, 398.0868.

Example 3: (E)-1-((2-chlorothiazol-5-yl)methyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro Synthesis of tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 2-chloro-5-((2-(nitromethylene)imidazole Pyrinidin-1-yl)methyl)thiazole (1.3 mmol, 0.34 g) was added into a small mortar and thoroughly ground. Then the mixture was added into a 5 ml microwave reaction tube, heated to 130° C. by microwave for 10 minutes, and then the heating was stopped. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 50 ml of saturated aqueous sodium bicarbonate solution, and then the reaction tube or mortar was washed with 4 ml of acetone and the acetone solution was combined into the beaker. After the solution was poured into a separatory funnel, 60 ml of ethyl acetate was added for extraction. After extraction, the organic layer was transferred to a round-bottomed flask, and an appropriate amount of desiccant (anhydrous sodium sulfate) was added to dry for 1 hour, and the desiccant was removed by suction filtration. , after the organic layer was concentrated and dried, 5 milliliters of acetone was added to dissolve it, and then an appropriate amount of silica gel was added to mix the sample and then separated by column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent=1:2) to obtain a yellow solid product (E)- 1-((2-chlorothiazol-5-yl)methyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (Compound 3), the yield was 85%. Melting point: 180.7–182.7°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.39 (br, 1H, NH), 7.64 (s, 1H, ArH), 4.47 (s, 2H, NCH ₂ ), 3.70– 3.83 (m, 4H, NCH2, _{NCH2 )} .

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝160.8, 159.2 (d, J＝4.5Hz), 152.6–154.5 (m), 151.8, 143.9–145.7 (m), 141.8, 135.3, 133.8 (d, J=15.0Hz), 111.2, 108.3, 100.2 (d, J=13.5Hz), 97.4, 92.4–92.7 (m), 49.7, 45.7, 42.5.

High-resolution mass spectrum C ₁₆ H ₇ ClF ₃ N ₆ O ₂ S[MH] ^- , theoretical value 438.9997; measured value, 438.9999.

Example 4: (E)-1-(4-cyanobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene) Synthesis of imidazolidine (compound 4): Tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 1-(4-cyanobenzyl)-2-(nitromethylene) were added in a mortar After imidazolinidine (1.5 mmol, 0.37 g), it was fully ground evenly, placed on a magnetic stirrer while heating while grinding, heated to a reaction temperature of 160° C. and maintained at this temperature for 5 minutes. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 60 ml of saturated aqueous sodium bicarbonate solution, then the reaction tube or mortar was washed with 6 ml of acetone and the acetone solution was combined into the beaker, and the beaker After the solution was poured into a separatory funnel, 60 ml of ethyl acetate was added for extraction. After extraction, the organic layer was transferred to a round-bottomed flask, and an appropriate amount of desiccant (anhydrous sodium sulfate) was added to dry for 1 hour, and the desiccant was removed by suction filtration. , after the organic layer was concentrated and dried, 6 milliliters of acetone was added to dissolve it, and after adding an appropriate amount of silica gel to mix the sample, it was separated by column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent=1:3) to obtain a yellow solid product (E)- 1-(4-cyanobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 4), producing Rate 80%. Melting point: 186.3–188.3°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.53 (br, 1H, NH), 7.81–7.86 (m, 2H, ArH, ArH), 7.36–7.40 (m, 2H, ArH, ArH), 4.31 (s, 2H, NCH ₂ ), 3.80–3.89 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝161.2,159.0–160.8(m),152.3–154.3(m),143.8–145.5(m),141.8,133.0,132.8,127.9 , 119. 0, 111.0, 108.1, 100.8 (d, J=15.0Hz), 97.3, 92.7–92.9 (m), 52.6, 51.1, 42.8.

High-resolution mass spectrum C ₂₀ H ₁₀ F ₃ N ₆ O ₂ [MH] ^- , theoretical value 423.0823; measured value, 423.0824.

Example 5: (E)-1-(4-fluorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazole Synthesis of alkanes (compound 5): add tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 1-(4-fluorobenzyl)-2-(nitromethylene)imidazole in a microwave reaction tube Pyridine (1 mmol, 0.237 g) was well mixed and heated to the reaction temperature of 110° C. by microwave and kept at this temperature for 30 minutes. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 30 milliliters of saturated aqueous sodium carbonate solution, then the reaction tube or mortar was washed with 2 milliliters of acetone and the acetone solution was combined into the beaker, and the solution in the beaker After being poured into the separatory funnel, add 40 milliliters of ethyl acetates to extract again, the organic layer is transferred to the round-bottomed flask after extraction, adds appropriate desiccant (anhydrous sodium sulfate) after drying for 1 hour, removes desiccant by suction filtration, After the organic layer was concentrated and dried, 3 ml of acetone was added to dissolve it, then an appropriate amount of silica gel was added to mix the sample, and the sample was separated by column chromatography (eluent: petroleum ether/ethyl acetate mixed solvent = 1:1) to obtain a yellow solid product (E)-1 -(4-fluorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 5), yield 88 %. Melting point: 192.1–194.1°C.

As shown in Figure 3, H NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.48 (br, 1H, NH), 7.15–7.24 (m, 4H, ArH, ArH, ArH, ArH ), 4.19 (s, 2H, NCH ₂ ), 3.75–3.85 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=163.5, 161.5, 159.3, 152.6–154.9 (m), 145.1 (dd, J ₁ =247.5Hz, J ₂ =11.3Hz), 133.9(d, J=13.8Hz), 132.3(d, J=5.0Hz), 129.6(d, J=7.5Hz), 116.2(d, J=21.2Hz), 111.4, 108.6, 100.9(d, J= 13.8Hz), 97.7, 92.9–93.2(m), 52.4, 51.1, 43.1.

High-resolution mass spectrum C ₁₉ H ₁₀ F ₄ N ₅ O ₂ [MH] ^- , theoretical value 416.0776; measured value, 416.0778.

Example 6: (E)-1-(4-chlorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazole Synthesis of alkanes (compound 6): add tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 1-(4-chlorobenzyl)-2-(nitromethylene)imidazole in a microwave reaction tube Pyridine (1.2 mmol, 0.303 g) was well mixed and heated to the reaction temperature of 160° C. by microwave and kept at this temperature for 5 minutes. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 40 milliliters of saturated aqueous sodium carbonate solution, then the reaction tube or mortar was washed with 3 milliliters of acetone and the acetone solution was combined into the beaker, and the solution in the beaker After pouring into the separatory funnel, add 50 milliliters of ethyl acetates to extract again, after the extraction, the organic layer is transferred to a round bottom flask, and after adding an appropriate amount of desiccant (anhydrous sodium sulfate) to dry for 1 hour, the desiccant is removed by suction filtration. After the organic layer was concentrated and dried, 5 ml of acetone was added to dissolve it, then an appropriate amount of silica gel was added to mix the sample, and the sample was separated by column chromatography (eluent: petroleum ether/ethyl acetate mixed solvent = 1:4) to obtain a yellow solid product (E)-1 -(4-chlorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 6), yield 90 %. Melting point: 195.4–197.4°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.50 (br, 1H, NH), 7.36–7.42 (m, 2H, ArH, ArH), 7.16–7.22 (m, 2H, ArH, ArH), 4.20 (s, 2H, NCH ₂ ), 3.78–3.83 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝161.2, 159.9 (d, J = 264.0Hz), 152.3–154.3 (m), 144.7 (dd, J ₁ = 243.0Hz, J ₂ = 9.0Hz), 134.9, 133.4 (d, J = 16.5Hz), 132.8, 128.93, 128.91, 111.0, 108.1, 100.7 (d, J = 15.0Hz), 97.3, 92.6–92.9 (m), 52.2, 50.9 , 42.8.

High resolution mass spectrum C ₁₉ H ₁₀ ClF ₃ N ₅ O ₂ [MH] ^- , theoretical value 432.0481; measured value, 432.0485.

Example 7: (E)-1-(4-methylbenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene) Synthesis of imidazolidine (compound 7): Tetrafluoroisophthalonitrile (1 mmol, 0.2 g) and 1-(4-methylbenzyl)-2-(nitromethylene ) imidazolidinidine (1.5 mmol, 0.349 g) was well mixed and heated to a reaction temperature of 120° C. by microwave and kept at this temperature for 15 minutes. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 40 milliliters of saturated aqueous sodium carbonate solution, then the reaction tube or mortar was washed with 3 milliliters of acetone and the acetone solution was combined into the beaker, and the solution in the beaker After pouring into the separatory funnel, add 50 milliliters of ethyl acetates to extract again, after the extraction, the organic layer is transferred to a round bottom flask, and after adding an appropriate amount of desiccant (anhydrous sodium sulfate) to dry for 1 hour, the desiccant is removed by suction filtration. After the organic layer was concentrated and dried, 5 ml of acetone was added to dissolve it, then an appropriate amount of silica gel was added to mix the sample, and the sample was separated by column chromatography (eluent: petroleum ether/ethyl acetate mixed solvent = 1:2) to obtain a yellow solid product (E)-1 -(4-methylbenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 7), yield 70%. Melting point: 198.2–200.2°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.49 (br, 1H, NH), 7.10–7.15 (m, 2H, ArH, ArH), 6.96–7.02 (m, 2H, ArH, ArH), 4.14 (s, 2H, NCH ₂ ), 3.79–3.84 (m, 4H, NCH ₂ , NCH ₂ ), 2.29 (s, 3H, CH ₃ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=161.8, 160.2(d, J=262.5Hz), 152.5–154.7(m), 145.1(dd, J ₁ =245.0Hz, J ₂ = 8.8Hz), 137.8, 133.7(d, J = 13.8Hz), 133.2, 130.1, 127.1, 111.4, 108.5, 101.2 (d, J = 15.0Hz), 97.6, 93.0–93.3(m), 53.3, 51.4 , 43.3, 21.5.

High resolution mass spectrum C ₂₀ H ₁₃ F ₃ N ₅ O ₂ [MH] ^- , theoretical value 412.1027; measured value, 412.1028.

Example 8: (E)-1-(4-methoxybenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene ) Synthesis of imidazolidine (compound 8): replace 2-chloro-5-((2 -(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give light yellow solid (E)-1-(4-methoxybenzyl)-2-((2,4 -Dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 8), yield 72%. Melting point: 183.0–185.0°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.44 (br, 1H, NH), 7.02–7.08 (m, 2H, ArH, ArH), 6.85–6.91 (m, 2H, ArH, ArH), 4.11 (s, 2H, NCH ₂ ), 3.75–3.80 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ = 161.1, 159.9 (d, J = 264.0Hz), 159.3, 153.3 (dd, J ₁ = 261.0Hz, J ₂ = 14.3Hz) ,143.8–145.6(m),133.6(d,J=15.0Hz),128.4,127.5,114.4,111.1,108.2,100.6(d,J=13.5Hz),97.3,92.5–92.8(m),55.6,52.3 , 50.6, 42.7.

High-resolution mass spectrum C ₂₀ H ₁₃ F ₃ N ₅ O ₃ [MH] ^- , theoretical value 428.0976; measured value, 428.0977.

Example 9: (E)-1-(4-nitrobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene) Synthesis of imidazolidine (compound 9): replace 2-chloro-5-((2-( Nitromethylene) imidazolidin-1-yl) methyl) pyridine can be reacted to give light yellow solid (E)-1-(4-nitrobenzyl)-2-((2,4-dicyano yl-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (compound 9), the yield was 64%. Melting point: 193.8–195.8°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.53 (br, 1H, NH), 8.19–8.24 (m, 2H, ArH, ArH), 7.46–7.51 (m, 2H, ArH, ArH), 4.38 (s, 2H, NCH ₂ ), 3.81–3.90 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝161.3, 159.0–160.8(m), 159.0, 152.5–154.3(m), 147.4, 145.5(d, J＝9.0Hz), 144.0, 133.4 (d, J=15.0Hz), 128.4, 124, 111.0, 108.1, 100.7 (d, J=13.5Hz), 97.3, 92.6–92.9 (m), 52.4, 51.1, 42.8.

High-resolution mass spectrum C ₁₉ H ₁₀ F ₃ N ₆ O ₄ [MH] ^- , theoretical value 443.0721; measured value, 443.0722.

Example 10: (E)-1-(3-fluorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazole Synthesis of alkane (compound 10): replace 2-chloro-5-((2-(nitro) with 1-(3-fluorobenzyl)-2-(nitromethylene) imidazolinidine Methylene) imidazolidin-1-yl) methyl) pyridine can be reacted to give light yellow solid (E)-1-(3-fluorobenzyl)-2-((2,4-dicyano-3 ,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (Compound 10), the yield was 90%. Melting point: 181.4–183.4°C.

H NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.52(br,1H,NH),7.34–7.40(m,1H,ArH),7.10–7.15(m,1H,ArH) , 6.97–7.02 (m, 2H, ArH, ArH), 4.22 (s, 2H, NCH ₂ ), 3.78–3.89 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝162.7(d, J＝243.0Hz), 161.1, 159.8(d, J＝264.0Hz), 152.4–154.2(m), 144.7 (dd, J ₁ =247.5Hz, J ₂ =10.5Hz), 138.9 (d, J = 6.0Hz), 133.3 (d, J = 16.5Hz), 131.0 (d, J = 7.5Hz), 122.9, 114.8 ( d, J = 21.0 Hz), 113.8 (d, J = 6.0 Hz), 111.0, 108.1, 100.9 (d, J = 13.5 Hz), 97.3, 92.7–93.0 (m), 52.4, 51.2, 42.8.

High-resolution mass spectrum C ₁₉ H ₁₀ F ₄ N ₅ O ₂ [MH] ^- , theoretical value 416.0776; measured value, 416.0777.

Example 11: (E)-1-(3,5-difluorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene base) imidazolidine (compound 11): use 1-(3,5-difluorobenzyl)-2-(nitromethylene) imidazolidinidine instead of 2-chloro-5-( (2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give light yellow solid (E)-1-(3,5-difluorobenzyl)-2-(( 2,4-Dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (Compound 11), the yield was 81%. Melting point: 179.7–181.7°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.52 (br, 1H, NH), 7.14–7.20 (m, 1H, ArH), 6.91–6.96 (m, 2H, ArH, ArH), 4.24 (s, 2H, NCH ₂ ), 3.79–3.92 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ＝163.0(dd, J ₁ ＝246.3Hz, J ₂ ＝13.8Hz), 161.0, 158.8, 152.3–154.6(m), 143.7– 145.8(m), 140.7–140.9(m), 133.3(d, J=16.3Hz), 110.9, 110.3(d, J=6.3Hz), 110.1(d, J=6.3Hz), 108.0, 103.2–103.7( m), 100.9 (d, J = 15.0 Hz), 97.3, 92.7–93.0 (m), 52.1, 51.3, 42.8.

High-resolution mass spectrum C ₁₉ H ₉ F ₅ N ₅ O ₂ [MH] ^- , theoretical value 434.0682; measured value, 434.0683.

Example 12: (E)-1-(4-trifluoromethylbenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene base) imidazolidine (compound 12) synthesis: replace 2-chloro-5-( (2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-(4-trifluoromethylbenzyl)-2-((2 ,4-Dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (Compound 12), the yield was 92%. Melting point: 199.9–201.9°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.55 (br, 1H, NH), 7.65–7.71 (m, 2H, ArH, ArH), 7.35–7.40 (m, 2H, ArH, ArH), 4.31 (s, 2H, NCH ₂ ), 3.80–3.92 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=161.3, 159.8 (d, J=264.0Hz), 153.3 (dd, J ₁ =267.0Hz, J ₂ =18.0Hz), 143.9 –145.6(m), 140.9, 133.3(d, J=15.0Hz), 128.4–129.1(m), 127.5, 125.8, 124.6(d, J=271.5Hz), 110.9, 107.9, 110.0(d, J=15.0 Hz), 97.2, 92.7–93.0 (m), 52.7, 51.4, 42.9.

High-resolution mass spectrum C ₂₀ H ₁₀ F ₆ N ₅ O ₂ [MH] ^- , theoretical value 466.0744; measured value, 466.0742.

Example 13: (E)-1-(2,4-difluorobenzyl)-2-((2,4-dicyano-3,5,6-trifluorophenyl)(nitro)methylene base) imidazolidine (compound 13) synthesis: replace 2-chloro-5-( (2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give light yellow solid (E)-1-(2,4-difluorobenzyl)-2-(( 2,4-Dicyano-3,5,6-trifluorophenyl)(nitro)methylene)imidazolidine (Compound 13), the yield was 83%. Melting point: 187.4–189.4°C.

H NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.47(br,1H,NH),7.35–7.40(m,1H,ArH),7.23–7.29(m,1H,ArH) , 7.08–7.14 (m, 1H, ArH), 4.20 (s, 2H, NCH ₂ ), 3.72–3.80 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ＝162.6(dd, J ₁ ＝246.3Hz, J ₂ ＝12.5Hz), 161.1, 160.4(dd, J ₁ ＝246.3Hz, J ₂ = 12.5Hz), 158.9, 152.2–154.4(m), 144.7(dd, J ₁ =246.3Hz, J ₂ =9.4Hz), 133.6(d, J = 16.3Hz), 131.3–131.5(m), 112.0 –112.3(m), 110.9, 108.1, 104.3–104.7(m), 100.5(d, J=15.0Hz), 97.4, 92.5–92.8(m), 50.1, 46.5, 42.7.

High-resolution mass spectrum C ₁₉ H ₉ F ₅ N ₅ O ₂ [MH] ^- , theoretical value 434.0682; measured value, 434.0681.

Example 14: (E)-1-((6-chloropyridin-3-yl)methyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl) Synthesis of (nitro)methylene)imidazolidine (compound 14): 5-Chloro-2,4,6-trifluoroisophthalonitrile (1 mmol, 0.216 g) and 2- After chloro-5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine (1 mmol, 0.254 g), it was fully ground and evenly ground, and it was ground while heating on a magnetic stirrer. After maintaining 140°C for 10 minutes, the addition was stopped. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 40 ml of saturated aqueous sodium bicarbonate solution, and then the reaction tube or mortar was washed with 2 ml of acetone and the acetone solution was combined into the beaker. After the solution was poured into a separatory funnel, 50 ml of ethyl acetate was added for extraction. After extraction, the organic layer was transferred to a round bottom flask and an appropriate amount of desiccant (anhydrous sodium sulfate) was added. After drying for 1 hour, the desiccant was removed by suction filtration , after the organic layer was concentrated and dried, 3 milliliters of acetone was added to dissolve it, and then an appropriate amount of silica gel was added to mix the sample and then separated by column chromatography (eluent was petroleum ether/ethyl acetate mixed solvent=1:4) to obtain a yellow solid product yield of 83% . Melting point: 189.4–191.4°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.44(br,1H,NH),8.20(s,1H,ArH),7.66–7.70(m,1H,ArH),7.51 (d, J = 8.3 Hz, 1H, ArH), 4.20 (s, 2H, NCH2 ₎ , 3.75–3.86 (m, 2H, NCH2, _{NCH2 )} .

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝162.4(dd, J ₁ ＝214.5Hz, J ₂ ＝6.0Hz), 160.8, 160.7(dd, J ₁ ＝213.0Hz, J ₂ =6.0Hz),150.1,148.8,143.7,138.8,131.3,124.5,120.9(d,J=13.5Hz)),111.0,108.2,103.1(d,J=10.5Hz),101.5,93.2–93.5(m ), 50.8, 49.7, 42.7.

High resolution mass spectrum C ₁₈ H ₉ Cl ₂ F ₂ N ₆ O ₂ [MH] ^- , theoretical value 449.0138; measured value, 449.0135.

Example 15: (E)-1-((benzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazole Synthesis of alkane (compound 15): 5-Chloro-2,4,6-trifluoroisophthalonitrile (1 mmol, 0.216 g) and 1-benzyl-2-(nitromethanol) were added in a mortar Methyl)imidazoline (1 mmol, 0.22 g) was ground thoroughly and uniformly, placed on a magnetic stirrer while heating and grinding, and kept at 160°C for 5 minutes and then stopped heating. After cooling the reactant to room temperature, first use 50 ml Transfer the reactant to a beaker with saturated aqueous sodium bicarbonate solution, wash the reaction tube or mortar with 3 ml of acetone and combine the acetone solution into the beaker, pour the solution in the beaker into a separatory funnel, and then add 50 Milliliter of ethyl acetate for extraction, after extraction, transfer the organic layer to a round bottom flask, add an appropriate amount of desiccant (anhydrous sodium sulfate) to dry for 1 hour, remove the desiccant by suction filtration, and after the organic layer is concentrated and dried, add 4 ml of acetone After dissolving, add an appropriate amount of silica gel to mix the sample, and then separate by column chromatography (eluent: petroleum ether/ethyl acetate mixed solvent = 1:2) to obtain a yellow solid product with a yield of 80%. Melting point: 191.0–193.0°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.53(br,1H,NH),7.23–7.33(m,3H,ArH,ArH,ArH),7.02–7.07(m, 2H, ArH, ArH), 4.11 (s, 2H, NCH ₂ ), 3.76–3.84 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ＝162.9(dd, J ₁ ＝175.0Hz, J ₂ ＝5.0Hz), 161.6, 160.7(dd, J ₁ ＝172.5Hz, J ₂ = 6.3Hz), 144.0, 136.3, 129.3, 128.4, 126.8, 121.8–122.0(m), 111.4, 108.5, 103.6–103.7(m), 101.8, 93.6–94.0(m), 53.4, 51.7, 43.4.

High-resolution mass spectrum C ₁₉ H ₁₁ ClF ₂ N ₅ O ₂ [MH] ^- , theoretical value 414.0575; measured value, 414.0576.

Example 16: (E)-1-((2-chlorothiazol-5-yl)methyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl) Synthesis of (nitro)methylene)imidazolidine (compound 16): 5-chloro-2,4,6-trifluoroisophthalonitrile (1 mmol, 0.216 g) and 2-chloro-5- ((2-(Nitromethylene)imidazolidin-1-yl)methyl)thiazole (1 mmol, 0.26 g) was added into a small mortar and thoroughly ground. Then the mixture was added into a 5 ml microwave reaction tube, heated by microwave to 130° C. for 5-10 minutes and then stopped heating. After the reactant was cooled to room temperature, the reactant was transferred to the beaker with 30 milliliters of saturated aqueous sodium carbonate solution, then the reaction tube or mortar was washed with 3 milliliters of acetone and the acetone solution was combined into the beaker, and the solution in the beaker After pouring into the separatory funnel, add 60 milliliters of ethyl acetates to extract again, after the extraction, the organic layer is transferred to a round-bottomed flask, and after adding an appropriate amount of desiccant (anhydrous sodium sulfate) to dry for 1 hour, the desiccant is removed by suction filtration. After the organic layer was concentrated and dried, 5 ml of acetone was added to dissolve it, then an appropriate amount of silica gel was added to mix the sample, and the sample was separated by column chromatography ((eluent: petroleum ether/ethyl acetate mixed solvent = 1:1) to obtain a yellow solid (E)-1 -((2-chlorothiazol-5-yl)methyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazole Alkane (compound 16), yield 88%. Melting point: 185.4–187.4°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.35 (br, 1H, NH), 7.60 (s, 1H, ArH), 4.41 (s, 2H, NCH ₂ ), 3.67– 3.82 (m, 4H, NCH2, _{NCH2 )} .

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=162.6(dd, J ₁ =228.0Hz, J ₂ =6.0Hz), 160.9(dd, J ₁ =225.0Hz, J ₂ = 6.0Hz), 160.4, 151.7, 143.8, 141.6, 135.5, 120.7(d, J=13.5Hz), 111.1, 108.4, 103.0(d, J=13.5Hz), 101.4, 93.0–93.3(m), 49.8, 45.7 ,42.6.

High-resolution mass spectrum C ₁₆ H ₇ Cl ₂ F ₂ N ₆ O ₂ S[MH] ^- , theoretical value 454.9702; measured value, 454.9700.

Example 17: (E)-1-((4-cyanobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro) Synthesis of methyl)imidazolidine (compound 17): Add 5-chloro-2,4,6-trifluoroisophthalonitrile (1 mmol, 0.216 g) and 1-(4-cyano Benzyl benzyl)-2-(nitromethylene) imidazolidinidine (1.2 mmoles, 0.293 g) was thoroughly mixed, heated to the reaction temperature of 120 ° C by microwave and maintained at this temperature for 15 minutes. The reactant was cooled to After room temperature, first transfer the reactant to a beaker with 40 ml of saturated aqueous sodium bicarbonate solution, then wash the reaction tube or mortar with 5 ml of acetone and combine the acetone solution into the beaker, pour the solution in the beaker into the separatory After being placed in the funnel, add 70 ml of ethyl acetate for extraction. After extraction, transfer the organic layer to a round bottom flask and add an appropriate amount of desiccant (anhydrous sodium sulfate) to dry for 1 hour. Remove the desiccant by suction filtration, and the organic layer is concentrated. After drying, add 5 milliliters of acetone to dissolve, then add an appropriate amount of silica gel to mix the sample, and then separate by column chromatography (eluent is petroleum ether/ethyl acetate mixed solvent = 1:4) to obtain a yellow solid product (E)-1-((4 -cyanobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (compound 17), yield 81 %. Melting point: 195.4–197.4°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.54 (br, 1H, NH), 7.79–7.83 (m, 2H, ArH, ArH), 7.30–7.34 (m, 2H, ArH, ArH), 4.23 (s, 2H, NCH ₂ ), 3.80–3.88 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ＝162.9(dd, J ₁ ＝168.8Hz, J ₂ ＝5.0Hz), 161.3, 160.8(dd, J ₁ ＝166.3Hz, J ₂ =6.3Hz),143.9,142.3,133.2,128.1,121.7(d,J=15.0Hz),119.4,111.3,108.5,103.5–103.7(m),101.8,93.7–93.9(m),52.9,51.7, 43.3.

High-resolution mass spectrum C ₂₀ H ₁₀ ClF ₂ N ₆ O ₂ [MH] ^- , theoretical value 439.0527; measured value, 439.0530.

Example 18: (E)-1-((4-fluorobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene Base) the synthesis of imidazolidine (compound 18): replace the 2-chloro-5-((2- (Nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((4-fluorobenzyl)-2-((2,4-dicyano yl-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (compound 18), yield 89%. Melting point: 220.8–222.8°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.49 (br, 1H, NH), 7.14–7.19 (m, 4H, ArH, ArH, ArH, ArH), 4.10 (s, 2H, NCH ₂ ), 3.77–3.82 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ = 163.4, 162.9 (dd, J ₁ = 176.3Hz, J ₂ = 6.3Hz), 161.2, 160.8 (dd, J ₁ = 173.8Hz ,J ₂ =7.5Hz),144.0,132.5,129.3(d,J=8.8Hz),121.6(d,J=12.5Hz),116.2(d,J=22.5Hz),111.4,108.5,103.5–103.6( m), 101.9, 93.6–93.8 (m), 52.4, 51.3, 43.2.

High-resolution mass spectrum C ₁₉ H ₁₀ ClF ₃ N ₅ O ₂ [MH] ^- , theoretical value 432.0481; measured value, 432.0480.

Example 19: (E)-1-((4-chlorobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene Base) the synthesis of imidazolidine (compound 19): replace the 2-chloro-5-((2- (Nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((4-chlorobenzyl)-2-((2,4-dicyano yl-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (compound 19), yield 91%. Melting point: 197.2–199.2°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.50 (br, 1H, NH), 7.37–7.41 (m, 2H, ArH, ArH), 7.10–7.15 (m, 2H, ArH, ArH), 4.11 (s, 2H, NCH ₂ ), 3.79–3.83 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=162.3(d, J=202.5Hz), 161.0, 160.6(dd, J ₁ =207.0Hz, J ₂ =6.0Hz), 143.6 , 135.0, 132.8, 128.9, 128.6, 121.4 (d, J=16.5Hz), 111.0, 108.0, 103.2 (d, J=13.5Hz), 101.5 93.2–93.5 (m), 52.2, 51.1, 42.9.

High-resolution mass spectrum C ₁₉ H ₁₀ Cl ₂ F ₂ N ₅ O ₂ [MH] ^- , theoretical value 448.0185; measured value, 448.0187.

Example 20: (E)-1-((4-methylbenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro) Synthesis of methyl) imidazolidine (compound 20): replace 2-chloro-5-((( 2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((4-methylbenzyl)-2-((2,4 -Dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (Compound 20), 71% yield. Melting point: 223.2–225.2°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.51 (br, 1H, NH), 7.08–7.14 (m, 2H, ArH, ArH), 6.88–6.94 (m, 2H, ArH, ArH), 4.06 (s, 2H, NCH ₂ ), 3.78–3.86 (m, 4H, NCH ₂ , NCH ₂ ), 2.29 (s, 3H, CH ₃ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝162.8(dd, J ₁ ＝176.3Hz, J ₂ ＝6.3Hz), 161.8, 160.7(dd, J ₁ ＝173.8Hz, J ₂ =6.3Hz),144.0,137.7,133.3,129.8,126.7,122.0(d,J=16.3Hz),111.4,108.4,103.7(d,J=15.0Hz),101.8,93.5–93.9(m),53.4 , 51.8, 43.4, 21.5.

High-resolution mass spectrum C ₂₀ H ₁₃ ClF ₂ N ₅ O ₂ [MH] ^- , theoretical value 428.0731; measured value, 428.0730.

Example 21: (E)-1-((4-methoxybenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro) Synthesis of methylene) imidazolidine (compound 21): replace 2-chloro-5- ((2-(Nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((4-methoxybenzyl)-2-(( 2,4-Dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (Compound 21), 74% yield. Melting point: 207.5–209.5°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.45 (br, 1H, NH), 6.95–7.02 (m, 2H, ArH, ArH), 6.83–6.89 (m, 2H, ArH, ArH), 4.02 (s, 2H, NCH ₂ ), 3.76–3.80 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝162.3(dd, J ₁ ＝216.0Hz, J ₂ ＝6.0Hz), 161.0, 160.6(dd, J ₁ ＝214.5Hz, J ₂ =6.0Hz),159.3,143.7,128.1,127.6,121.3(d,J=15.0Hz),114.3,111.0,108.1,103.1(d,J=13.5Hz),101.5,93.2–9 3.5(m), 55.6, 52.4, 50.9, 42.9.

High resolution mass spectrum C ₂₀ H ₁₃ ClF ₂ N ₅ O ₃ [MH] ^- , theoretical value 444.0680; measured value, 444.0680.

Example 22: (E)-1-((4-nitrobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro) Synthesis of methyl) imidazolidine (compound 22): replace 2-chloro-5-((( 2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid-(E)-1-((4-nitrobenzyl)-2-((2, 4-Dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (Compound 22), 66% yield. Melting point: 171.6–173.6°C.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.52 (br, 1H, NH), 8.16–8.22 (m, 2H, ArH, ArH), 7.40–7.46 (m, 2H, ArH, ArH), 4.29 (s, 2H, NCH ₂ ), 3.81–3.88 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ＝162.5(dd, J ₁ ＝170.0Hz, J ₂ ＝6.3Hz), 161.0, 160.4(dd, J ₁ ＝168.8Hz, J ₂ =6.3Hz),147.3,144.1,143.5,128.1,124.0,121.2(d,J=18.8Hz),110.9,108.1,103.1–103.3(m),101.4,93.2–93.6(m),52.3,51.2, 42.9.

High resolution mass spectrum C ₁₉ H ₁₀ ClF ₂ N ₆ O ₄ [MH] ^- , theoretical value 459.0426; measured value, 459.0421.

Example 23: (E)-1-((3-fluorobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene base) imidazolidine (compound 23): use 1-(3-fluorobenzyl)-2-(nitromethylene) imidazolidinidine instead of 2-chloro-5-((2- (Nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((3-fluorobenzyl)-2-((2,4-dicyano yl-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (compound 23), yield 91%. Melting point: 174.7–176.7°C.

H NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.53(br,1H,NH),7.32–7.38(m,1H,ArH),7.08–7.14(m,1H,ArH) , 6.90–6.95 (m, 2H, ArH, ArH), 4.13 (s, 2H, NCH ₂ ), 3.78–3.88 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=162.7(d, J=242.5Hz), 162.5(dd, J ₁ =171.3Hz, J ₂ =6.3Hz), 160.9, 160.4 (dd, J ₁ =168.8Hz, J ₂ =6.3Hz), 143.5, 139.0, 131.0, 122.6, 121.3–121.6(m), 114.8(d, J=20.0Hz), 113.5(d, J=22.5Hz) , 110.9, 108.1, 103.2–103.4(m), 101.5, 93.2–93.6(m), 52.3, 51.4, 43.0.

High-resolution mass spectrum C ₁₉ H ₁₀ ClF ₃ N ₅ O ₂ [MH] ^- , theoretical value 432.0481; measured value, 432.0480.

Example 24: (E)-1-((3,5-difluorobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro ) Methylene) imidazolidine (compound 24) synthesis: replace 2-chloro- 5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((3,5-difluorobenzyl)-2 -((2,4-Dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (Compound 24), 83% yield. Melting point: 202.9–204.9°C The single crystal diagram is shown in Figure 4.

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.54 (br, 1H, NH), 7.13–7.19 (m, 1H, ArH), 6.84–6.90 (m, 2H, ArH, ArH), 4.15 (s, 2H, NCH ₂ ), 3.78–3.92 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=163.2(d, J=6.3Hz), 162.9(dd, J ₁ =245.0Hz, J ₂ =12.5Hz), 161.9, 160.6 ,160.4(dd,J ₁ =163.8Hz,J ₂ =6.3Hz),143.4,140.8–141.0(m),121.4(d,J=15.0Hz),110.9,110.0(d,J=6.3Hz),109.8 (d, J=6.3Hz), 108.0, 103.2–103.6(m), 101.5, 93.3–93.7(m), 51.9, 51.5, 42.9.

High-resolution mass spectrum C ₁₉ H ₉ ClF ₄ N ₅ O ₂ [MH] ^- , theoretical value 450.0386; measured value, 450.0384.

Example 25: (E)-1-((4-trifluoromethylbenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro ) (methylene) imidazolidine (compound 25) synthesis: replace 2-chloro- 5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((4-trifluoromethylbenzyl)-2 -((2,4-Dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (Compound 25), 93% yield. Melting point: 206.4–208.4°C .

Proton NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=9.55 (br, 1H, NH), 7.64–7.69 (m, 2H, ArH, ArH), 7.28–7.34 (m, 2H, ArH, ArH), 4.23 (s, 2H, NCH ₂ ), 3.80–3.90 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 600 instrument): δ=162.3 (dd, J ₁ =199.5Hz, J ₂ =6.0Hz), 161.2, 159.8 (d, J = 6.0Hz), 143.5 ,141.0,128.4–129.1(m),127.3,125.7,124.5(d,J=270.0Hz),121.5(d,J=12.0Hz),110.9,107.8,103.4(d,J=13.5Hz),101.4, 93.3–93.6(m), 52.7, 51.6, 43.1.

High resolution mass spectrum C ₂₀ H ₁₀ ClF ₅ N ₅ O ₂ [MH] ^- , theoretical value 482.0449; measured value, 482.0447.

Example 26: (E)-1-((2,4-difluorobenzyl)-2-((2,4-dicyano-3,5-difluoro-6-chlorophenyl)(nitro ) Synthesis of methylene) imidazolidine (compound 26): replace 2-chloro- 5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine can be reacted to give yellow solid (E)-1-((2,4-difluorobenzyl)-2 -((2,4-Dicyano-3,5-difluoro-6-chlorophenyl)(nitro)methylene)imidazolidine (Compound 26), 84% yield. Melting point: 191.7–193.7°C .

H NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=9.50(br,1H,NH),7.32–7.39(m,1H,ArH),7.21–7.28(m,1H,ArH) , 7.07–7.13 (m, 1H, ArH), 4.10 (s, 2H, NCH ₂ ), 3.72–3.80 (m, 4H, NCH ₂ , NCH ₂ ).

Carbon NMR spectrum (deuterated dimethyl sulfoxide, Bruker AM 500 instrument): δ=162.6(dd, J ₁ =180.0Hz, J ₂ =6.3Hz), 162.5(dd, J ₁ =246.3Hz, J ₂ = 12.5Hz), 161.0, 160.5(dd, J ₁ ＝245.0Hz, J ₂ ＝11.3Hz), 159.7(d, J＝6.3Hz), 143.7, 130.9–131.1(m), 121.4(d, J＝12.5Hz ),119.1–119.3(m),112.0–112.2(m),110.9,108.1,104.2–104.6(m),103.2(d,J＝13.8Hz),101.6,93.2–93.5(m),50.5,46.7, 42.9.

High-resolution mass spectrum C ₁₉ H ₉ ClF ₄ N ₅ O ₂ [MH] ^- , theoretical value 450.0386; measured value, 450.0385.

The antitumor effect of the second part of the compound of the present invention

The obtained data demonstrate that the compounds of the present invention have significant activity against the solid tumor lung cancer. _IC50 values of 26 compounds of the inventive practice.

The compounds of the present invention are tested against human tumor cell lines: human lung cancer (A549), human colon cancer (HT29), human gastric cancer (SGC7901), and human liver cancer (HepG2). The cell test was incubated with the compound for 144 hours, and then the cytotoxicity was measured by MTT assay (test method reference: J.Med.Chem.2001,44,1594; CancerRes.1987,47,936; Immunol.Methods 1983,65,55; Bioorg. Med. Chem. Lett. 2010, 20, 48). The IC ₅₀ of the compound against human lung cancer (A549) is 3.02-8.38, both of which are lower than that of the control group cisplatin (IC ₅₀ =47.51), which proves that the anti-human lung cancer cell activity in vitro is superior to cisplatin. According to the data in Table 1, it can be seen that for the compounds of the formula (I) structure involved in the present invention, when the substituents in the formula (I) have certain effects on the activity of human lung cancer (A549), but the effects are not large. As a result, the IC ₅₀ values of the 26 compounds implemented were all <10.0, and the anti-lung cancer activity of these compounds was better than that of the positive control drug cisplatin (IC ₅₀ =15.32). It shows that compounds 1-26 will have great medicinal prospects in anti-tumor methods, especially solid lung cancer. The compound of the present invention has excellent antitumor activity on human lung cancer (A549), human colon cancer (HT29), human gastric cancer (SGC7901) and human liver cancer (HepG2). Among them, the IC ₅₀ values of compounds 1, 3-12, 19-20 and 26 on the four kinds of cells are all smaller than the IC ₅₀ values of the positive control drug cisplatin, indicating that the 14 compounds have good activities on these four kinds of tumor cells in cisplatin.

Cytotoxic activity of representative compounds of the present invention to human tumor cell lines

Note: The unit of IC ₅₀ in the table is μg/mL.

Part III Cytotoxicity of Representative Compounds to Normal Cells

Application example

The compounds of the present invention were tested for cytotoxicity in normal human liver cell L-02. Cells were incubated with compounds for 144 hours, and then cytotoxicity was measured by MTT assay (test method references: J.Med.Chem.2001,44,1594; Cancer Res.1987,47,936; Immunol.Methods 1983,65,55 ; Bioorg. Med. Chem. Lett. 2010, 20, 48).

The proliferation of cells is quantitatively measured by the MTT method. Mitochondrial dehydrogenase in living cells can reduce MTT from yellow to blue formazan, and the yield is directly proportional to living cells. After the sample was dissolved in DMSO, the OD value could be detected with a microplate reader.

Table 2 Cytotoxicity of representative compounds to normal cells

The control group is: medium + L-02 (normal human liver cells); the solvent is dimethyl sulfoxide.

Test compound group: medium+L-02 (normal human hepatocytes)+test compound; solvent is dimethyl sulfoxide.

Enhancement/inhibition percentage = [(average OD of the tested sample - average OD of the control group)/average OD of the tested sample] x 100%; a negative sign before the percentage indicates that the sample has an inhibitory effect on the cells, and there is no negative sign before the percentage Indicates that this sample has a strengthening effect on cells.

CC ₅₀ : refers to the concentration of the compound required for the inhibition percentage to be 50%; when CC ₅₀ >40 μmol/L, the compound is usually considered non-toxic.

The above is that we selected compound 1 and compound 14 from the compounds of the present invention to test the cytotoxicity of normal human liver cell L-02. It can be seen from the above Table 2 that Compound 1 and Compound 14 of the present invention are non-toxic to normal human liver cells.

The basic principles, main features and advantages of the present invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above-mentioned embodiments. What are described in the above-mentioned embodiments and the description only illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will also have Variations and improvements are possible, which fall within the scope of the claimed invention. The protection scope of the present invention is defined by the appended claims and their equivalents.

Claims (7)

1.N- benzyl heterocyclic nitro ketene semiamine analog derivatives, it is characterised in that shown in the structure of the compound such as formula (I)：

In formula (I), X is fluorine atom or chlorine atom；Ar is phenyl, single difluorophenyl, mono-chlorosubstituted phenyl, trifluoromethyl substituted benzene Base, nitro substituted-phenyl, cyano group substituted-phenyl, 2,4 difluorobenzene base, 3,5- difluorophenyls, 2,6- difluorophenyls, methyl substitution Phenyl, methoxy substitution phenyl, pyridine radicals, substituted pyridinyl, thienyl or substituted thiophene base.

2. the synthetic method of the N- benzyl heterocyclic nitro ketene semiamine analog derivatives described in claim 1, it is characterised in that including Following steps：

By the polyhalo isophthalodinitrile of formula (II) structure and the heterocyclic nitro ketene semiamine of formula (III) structure in heating lapping stick Reacted under part or under microwave heating condition, TLC tracking after question response is complete, uses Na₂CO₃Or NaHCO₃Saturated aqueous solution The pH of reaction solution is adjusted to alkalescence, is extracted afterwards with organic solvent, takes organic phase, through pillar layer separation after concentration, obtains described The N- benzyl heterocyclic nitro ketene semiamine analog derivatives of formula (I) structure；

In formula (II), X is fluorine atom or chlorine atom；

In formula (III), Ar be phenyl, single difluorophenyl, mono-chlorosubstituted phenyl, trifluoromethyl substituted-phenyl, nitro substituted-phenyl, Cyano group substituted-phenyl, 2,4 difluorobenzene base, 3,5- difluorophenyls, 2,6- difluorophenyls, methyl substituted-phenyl, methoxy substitution benzene Base, pyridine radicals, substituted pyridinyl, thienyl or substituted thiophene base.

3. the synthetic method of N- benzyls heterocyclic nitro ketene semiamine analog derivative according to claim 2, it is characterised in that Heating-up temperature is 110-160 DEG C, and the reaction time is 5~30 minutes.

4. the synthetic method of N- benzyls heterocyclic nitro ketene semiamine analog derivative according to claim 2, it is characterised in that The solvent that described pillar layer separation is used for petrol ether/ethyl acetate mixed solvent=1:1~1:4.

5. the synthetic method of N- benzyls heterocyclic nitro ketene semiamine analog derivative according to claim 2, it is characterised in that The mol ratio of the polyhalo isophthalodinitrile of formula (II) structure and the heterocyclic nitro ketene semiamine of formula (III) structure is=1:1~ 1:1.5。

6. the N- benzyl heterocyclic nitro ketene semiamine analog derivatives described in claim 1 are used as the application for preparing antineoplastic.

7. N- benzyls heterocyclic nitro ketene semiamine analog derivative according to claim 6 as prepare antineoplastic should With, it is characterised in that described antineoplastic is anti-lung-cancer medicament or anti-colorectal cancer medicament.