Anti-tumor compound, preparation method, pharmaceutical composition containing anti-tumor compound and application

Abstract

The invention discloses an anti-tumor compound, a preparation method, a pharmaceutical composition containing the compound and application, and belongs to the technical field of biological medicine. The compound disclosed by the invention has a remarkable effect in an in-vitro anti-tumor activity test. In the design process, the N3-((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl)-N3 '-(R)-[1, 1'-biphenyl]-3, 3 '-dicarboxamide compound is designed and synthesized, the anti-tumor effect is improved, and it is found that the N3-((4, 6-dimethyl-2-oxo-1, 2-dihydropyridine-3-yl) methyl)-N3'-(R)-[1, 1 '-biphenyl]-3, 3'-dicarboxamide compound has good anti-proliferation capacity on human melanoma cells A375. In the synthesis process, the synthesis steps are optimized, and possibility is provided for future industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an anti-tumor compound, a preparation method, and a pharmaceutical composition and application containing the compound. Background Art

[0002] Melanoma is a highly malignant tumor derived from melanocytes. It mostly occurs in the skin, but can also be seen in mucous membranes and internal organs. In recent years, the incidence and mortality of malignant melanoma have increased year by year, and its age of death is lower than that of other solid tumors. In addition to early surgical resection, malignant melanoma lacks specific treatment and has a poor prognosis. Therefore, the synthesis of effective new anti-melanoma drugs is one of the most important goals of modern medicinal chemistry. At present, the main way to treat cancer clinically is to use chemical drugs. Although current anti-tumor drugs have certain therapeutic effects, they also have problems such as drug resistance, poor selectivity, and large toxic side effects. Therefore, many researchers at home and abroad have tried to explore anti-melanoma compounds with new structures in order to obtain a new compound with better anti-tumor effects. Summary of the invention

[0003] The present invention aims at the problems existing in the prior art and provides an anti-tumor compound, a preparation method, a pharmaceutical composition comprising the compound and its application. The compound has good anti-proliferation ability against human melanoma cells (A375).

[0004] In order to achieve the above technical objectives, the technical solution adopted by the present invention is:

[0005] An antitumor compound, the compound is: N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(R)-[1,1'-biphenyl]-3,3'-dicarboxamide compounds, whose structure is shown in the general formula (I) or the stereoisomers, geometric isomers, tautomers, prodrugs, crystal forms, metabolites, pharmaceutically acceptable salts, hydrates or solvates of the compounds shown in the formula (I):

[0006] The R group is one or more of 2-fluoro-9H-purine-6-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, 7H-purine-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl and 3-methyl-3H-purine-6-yl.

[0007] The compounds, isomers and pharmaceutically acceptable salts, hydrates or prodrugs of the general formula of the present invention are particularly preferred as follows, but these compounds do not imply any limitation on the present invention:

[0008] N3 -(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(2-Fluoro-9H-purin-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-1);

[0009] N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-2);

[0010] N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(7H-purin-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-3);

[0011] N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-4);

[0012] N 3 -(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(3-methyl-3H-purin-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-5).

[0013] A method for preparing an antitumor compound comprises the following steps:

[0014] (1) 3-bromobenzoic acid, 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one, 1-hydroxybenzotriazole HOBt, carbodiimide EDCI and 4-methylmorpholine are added to a container, dissolved in an organic solvent a, and subjected to an acylation reaction to obtain a key intermediate 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide;

[0015] (2) adding 3-carboxyphenylboronic acid, the key intermediate 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide and tetrakis(triphenylphosphine)palladium into a container, and adding into an organic solvent b to obtain a mixed solution A; then dissolving potassium carbonate into a solvent c to obtain a mixed solution B; mixing the mixed solutions A and B, and subjecting the mixed solutions A and B to a Suzuki reaction under nitrogen protection to obtain a key intermediate 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid;

[0016] (3) The key intermediate 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid, a substituent component, 1-hydroxybenzotriazole HOBt, carbodiimide EDCI and 4-methylmorpholine are added to a container and dissolved in an organic solvent d. After an acylation reaction, the target compound is obtained.

[0017] The different amounts of the raw materials used in the present invention only affect the yield of the final product, and do not affect the structure and synthesis of the product.

[0018] Furthermore, the organic solvent a in step (1), the organic solvent b in step (2), and the organic solvent d in step (3) are all N,N-dimethylformamide DMF, the volume of solvent c is 1 / 5 of that of organic solvent b, and solvent c is water.

[0019] Furthermore, the substituent component in step (3) is one or more of 2-fluoro-9H-purine-6-amine, 7H-pyrrolo[2,3-d]pyrimidine-4-amine, 7H-purine-6-amine, 1H-pyrazolo[3,4-d]pyrimidine-4-amine, and 3-methyl-3H-purine-6-amine.

[0020] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the general formula (I) of the present application, or a stereoisomer, geometric isomer, tautomer, prodrug, crystal form, metabolite, pharmaceutically acceptable salt, hydrate or solvate.

[0021] In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of the general formula, which themselves may have weak activity or even no activity, but after administration, are converted into the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or other means).

[0022] The present invention may contain N of the general formula 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3'-(R)-[1,1'-biphenyl]-3,3'-dicarboxamide compounds, and pharmaceutically acceptable salts and solvates thereof as active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare pharmaceutical compositions and clinically acceptable dosage forms. The pharmaceutically acceptable excipients are any diluents, adjuvants and / or carriers that can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

[0023] The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. The above-mentioned several dosage forms can be injections, tablets, capsules, aerosols, suppositories, films, pills, external liniments, ointments and other dosage forms.

[0024] The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, preservatives, solubilizers and bases, etc.

[0025] An application of an anti-tumor compound, the compound of the invention is used for preparing an anti-tumor drug.

[0026] Furthermore, the compounds of the present invention are used to prepare anti-melanoma drugs.

[0027] Beneficial effects:

[0028] The compounds of the present invention have significant effects in in vitro anti-tumor activity tests. 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(R)-[1,1'-biphenyl]-3,3'-dicarboxamide compounds have improved anti-tumor effects and have been found to have good anti-proliferation ability against human melanoma cells (A375). During the synthesis process, the synthesis steps were optimized, providing possibilities for future industrial production. DETAILED DESCRIPTION

[0029] The technical solution of the present invention is further described below in conjunction with specific embodiments, but is not limited thereto.

[0030] Example 1

[0031] N 3 -(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 Preparation method of '-(2-fluoro-9H-purine-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-1):

[0032] a. Preparation of 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide:

[0033] 3-bromobenzoic acid (5g, 24.87mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (5.68g, 37.31mmol), HOBt (4.03g, 29.85mmol), EDCI (5.72g, 29.85mmol) and 4-methylmorpholine (16.35g, 161.68mmol) were added to a 250mL eggplant-shaped bottle and dissolved in an appropriate amount of DMF. The mixture was stirred at room temperature for 30 minutes and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, ice water was added to precipitate a white precipitate, which was filtered and dried to obtain the product 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide as a white solid with a yield of 87.9%.

[0034] b. Preparation of 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid:

[0035] 3-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide (2g, 5.97mmol), 3-carboxyphenylboronic acid (1.49g, 8.95mmol) and tetrakis(triphenylphosphine)palladium (689.49mg, 596.66μmol) were added to a 100mL eggplant-shaped bottle and dissolved in 100mL DMF. Potassium carbonate (3.30g, 23.87mmol) was dissolved in 20mL water, the two were mixed, replaced with nitrogen three times, and reacted at 90℃ for 8 hours under nitrogen protection, and the reaction progress was monitored by thin layer chromatography. After the reaction is completed, the palladium salt is filtered off, and the filtrate is added with ice water to precipitate a white precipitate, which is filtered off and dried to obtain the product 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid as a purple-black solid with a yield of 89.7%.

[0036] cN 3 -(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 Preparation of '-(2-fluoro-9H-purine-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide:

[0037] 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid (300 mg, 797.00 μmol), 2-fluoro-9H-purine-6-amine (183.06 mg, 1.20 mmol), HOBt (129.23 mg, 956.40 μmol), EDCI (183.34 mg, 956.40 μmol) and 4-methylmorpholine (524.00 mg, 5.18 mmol) were added to a 100 mL eggplant-shaped bottle and dissolved in an appropriate amount of DMF. The mixture was stirred at room temperature for 2 hours and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, ice water was added to precipitate the precipitate, which was filtered with suction. The filter cake was purified by column chromatography to obtain the product N 3 -(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(2-Fluoro-9H-purin-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-1), yellow solid, yield: 82.08%.

[0038] Product A-1: 1 H NMR (600MHz, DMSO-d6) δ11.56(s,1H),8.63(t,J=5.0Hz,1H),8.15(d,J=1.9Hz,1H),7.88(d,J=7.6Hz,1H),7.85–7.79(m,2H),7. 78–7.74(m,1H),7.55(dt,J=10.5,7.7Hz,2H),7.44–7.38(m,1H),5.88(s,1H),4.35(d,J=4.8Hz,2H),2.20(s,3H),2.13(s,3H). 13 C NMR(151MHz,DMSO-d6)δ170.41,166.31,150.26,143.31,140.12,139.74,137.76,135.61,129.79 ,129.45,129.42,128.18,127.46,126.55,125.94,125.69,122.06,108.01,35.84,19.42,18.66.

[0039] Example 2

[0040] N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)

[0041] Preparation method of -[1,1'-biphenyl]-3,3'-dicarboxamide (A-2):

[0042] The preparation of 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide was as in Example 1a, and the preparation of 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid was as in Example 1b. 7H-pyrrolo[2,3-d]pyrimidin-4-amine was used as a raw material, and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide was prepared according to the steps of Example 1c. 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-2), yellow solid, yield: 83.76%.

[0043] Product A-2: 1 H NMR (600MHz, DMSO-d6) δ11.55(s,1H),8.65–8.62(m,1H),8.26(s,1H),8.17(s,1H),8.01(m,2H),7.90(d,J=7.7Hz,1H),7.84(d,J=7.7Hz ,1H),7.65(t,J=8.0Hz,1H),7.57(t,J=7.7Hz,1H),7.42(d,J=8.1Hz,1H),5.88(s,1H),4.35(d,J=5.0Hz,2H),2.20(s,3H),2.13(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.62,166.24,163.56,150.25,143.31,140.64,139.41,135.66,132.25,13 0.83,130.00,129.84,129.54,128.82,127.74,126.05,122.05,107.99,52.77,35.84,19.42,18.66.

[0044] Example 3

[0045] N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 Preparation method of '-(7H-purine-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-3):

[0046] The preparation of 4-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide was as in Example 1a, and the preparation of 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid was as in Example 1b. Using 7H-purin-6-amine as the starting material, N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(7H-Purin-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-3), yellow solid, yield: 82.05%.

[0047] Product A-3: 1 H NMR (600MHz, DMSO-d6) δ11.56(s,1H),8.65–8.62(m,1H),8.26(s,1H),8.17(s,1H),8.01(m,2H),7.90(d,J=7.8Hz,1H),7.84(d,J=7.6Hz, 1H),7.65(t,J=7.7Hz,1H),7.60–7.50(m,1H),7.41(t,J=7.6Hz,1H),5.88(s,1H),4.35(d,J=4.8Hz,2H),2.22–2.19(s,3H),2.13(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.62,166.24,150.25,143.31,140.64,139.42,135.66,132.25,130.8 4,130.00,129.84,129.55,128.83,127.74,126.05,122.05,108.00,52.77,35.84,19.42,18.66.

[0048] Example 4

[0049] Preparation method of N3-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N3'-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-4):

[0050] The preparation of 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide was as in Example 1a, and the preparation of 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid was as in Example 1b. 1H-pyrazolo[3,4-d]pyrimidin-4-amine was used as the raw material, and N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide was prepared according to the steps of Example 1c. 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-4), yellow solid, 83.88%.

[0051] Product A-4: 1 H NMR(600MHz,DMSO-d6)δ8.65(q,J=5.2Hz,1H),8.27(dt,J=7.4,1.8Hz,1H),8.18(q ,J=1.7Hz,1H),8.00–7.97(m,2H),7.91(ddt,J=7.7,4.8,1.4Hz,1H),7.84(dt,J=7. 7,1.4Hz,1H),7.74(d,J=8.4Hz,1H),7.64(dt,J=13.6,7.7Hz,1H),7.59–7.53(m,2H ),7.45–7.40(m,1H),5.88(s,1H),4.37(d,J=4.8Hz,2H),2.21(s,3H),2.13(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.66,162.54,149.22,142.26,134.62,131.19,130.95,130.76,129.7 9,128.94,128.75,127.78,127.31,126.91,126.70,121.02,106.97,51.72,34.81,18.38,17.61.

[0052] Example 5

[0053] Preparation method of N3-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N3'-(3-methyl-3H-purine-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-5):

[0054] The preparation of 4-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide was as in Example 1a, and the preparation of 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid was as in Example 1b. Using 3-methyl-3H-purin-6-amine as a raw material, N 3 -(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(3-methyl-3H-purin-6-yl)-[1,1'-biphenyl]-3,3'-dicarboxamide (A-5), white solid, 84.2%.

[0055] Product A-5: 1 H NMR (600MHz, DMSO-d6) δ11.54(s,1H),8.62(t,J=5.0Hz,1H),8.26(t,J=1.9Hz,1H),8 .17(d,J=1.9Hz,1H),8.02(dt,J=7.8,1.5Hz,1H),7.98(dt,J=7.8,1.4Hz,1H),7.90(d t,J=7.8,1.4Hz,1H),7.84(dt,J=7.8,1.4Hz,1H),7.65(t,J=7.7Hz,1H),7.57(t,J=7 .7Hz,1H),5.88(s,1H),4.36(d,J=4.8Hz,2H),3.91(s,3H),2.21(s,3H),2.13(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.61,166.24,150.23,143.30,140.64,139.42,135.68,132.23,130.84,12 9.99,129.83,129.53,128.82,127.74,127.59,126.06,122.06,108.00,52.76,35.85,19.42,18.66.

[0056] Tumor cell proliferation inhibition assay

[0057] The compounds of the present invention were subjected to a tumor cell proliferation inhibition experiment, and the experimental method adopted the conventional CCK8 method.

[0058] Cell culture: A375 (human melanoma cells) were selected as the cell line, diluted with DMEM high-glucose medium, and resuspended in DMEM high-glucose nutrient solution. Finally, the cells were cultured at 37°C in an incubator containing 5% CO2 and saturated humidity.

[0059] After the cells were cultured according to the manufacturer's instructions, they were digested with 0.25% trypsin and finally diluted to a single cell suspension using phosphate buffered saline (PBS). The above cells were plated in a 96-well plate at 5 × 10 3 The cells were inoculated at a concentration of 100 cells and cultured in an incubator at 37°C with 5% CO2. When the cells adhered, the nutrient solution was discarded and 100 μL of serum-free medium containing different concentrations of the compound was added to the cells. After the compound was incubated with the cells for 24 hours, the ultrasensitive CCK-8 solution (5 μL) was added to each well. Next, it was incubated at 37°C for 4 hours, and its optical density (OD) was analyzed at 490 nm. The concentration of the compound that caused a 50% inhibition rate was taken as the IC 50 value.

[0060] The experimental results are shown in Table 1:

[0061] Table 1 In vitro proliferation inhibition activity IC of samples on human tumor cells 50 value

[0062]

[0063]

[0064] The above experimental data show that the compounds of the present invention have relatively good in vitro antitumor activity, are valuable for in-depth research and development of new antitumor drugs, and also provide a broader idea for the research and development of new drugs.

[0065] It should be noted that the above embodiments are only partial embodiments of the preferred methods of implementing the present invention, rather than all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

Claims

1. An antitumor compound, characterized in that: The compound is: N 3 -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-N 3 '-(R)-[1,1'-biphenyl]-3,3'-dicarboxamide compounds, whose structure is shown in the general formula (I) or the stereoisomers, geometric isomers, tautomers, prodrugs, crystal forms, metabolites, pharmaceutically acceptable salts, hydrates or solvates of the compounds shown in the formula (I): The R group is one or more of 2-fluoro-9H-purine-6-yl, 7H-pyrrolo[2,3-d]pyrimidin-4-yl, 7H-purine-6-yl, 1H-pyrazolo[3,4-d]pyrimidin-4-yl and 3-methyl-3H-purine-6-yl.

2. A method for preparing the antitumor compound according to claim 1, characterized in that: The following steps are involved: (1) 3-bromobenzoic acid, 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one, 1-hydroxybenzotriazole HOBt, carbodiimide EDCI and 4-methylmorpholine are added to a container, dissolved in an organic solvent a, and subjected to an acylation reaction to obtain a key intermediate 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide; (2) adding 3-carboxyphenylboronic acid, the key intermediate 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide and tetrakis(triphenylphosphine)palladium into a container, and then adding organic solvent b to obtain a mixed solution A; then dissolving potassium carbonate in solvent c to obtain a mixed solution B; mixing the mixed solutions A and B, and subjecting the mixed solutions A and B to Suzuki reaction under nitrogen protection to obtain the key intermediate 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid; (3) The key intermediate 3'-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-[1,1'-biphenyl]-3-carboxylic acid, a substituent component, 1-hydroxybenzotriazole HOBt, carbodiimide EDCI and 4-methylmorpholine are added to a container and dissolved in an organic solvent d. After an acylation reaction, the target compound is obtained.

3. The method for preparing the antitumor compound according to claim 2, characterized in that: The organic solvent a in step (1), the organic solvent b in step (2), and the organic solvent d in step (3) are all N,N-dimethylformamide DMF, the volume of solvent c is 1 / 5 of that of organic solvent b, and solvent c is water.

4. The method for preparing the antitumor compound according to claim 2, characterized in that: The substituent component in step (3) is one or more of 2-fluoro-9H-purine-6-amine, 7H-pyrrolo[2,3-d]pyrimidine-4-amine, 7H-purine-6-amine, 1H-pyrazolo[3,4-d]pyrimidine-4-amine, and 3-methyl-3H-purine-6-amine.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of claims 1 to 4, or its geometric isomers, tautomers, stereoisomers, prodrugs, crystal forms, metabolites, pharmaceutically acceptable salts, hydrates or solvates.

6. Use of the antitumor compound according to any one of claims 1 to 4, characterized in that: The compound is used for preparing anti-tumor drugs.

7. The use of the antitumor compound according to claim 6, characterized in that: The compound is used for preparing anti-melanoma drugs.

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