An antitumor compound, its preparation method and uses

Abstract

This invention discloses an antitumor compound, its preparation method, and its uses, belonging to the field of pharmaceutical technology, and specifically relating to a class of compounds with specific chemical structures possessing antitumor activity. The compound is a 6'-phenyl-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'H)-one compound, with the structure shown in general formula (I) or (II): or, where R is a monosubstituted hydrogen atom, chlorine atom, methoxy atom, or fluorine atom at different positions on the benzene ring. This invention demonstrates the compound's tumor-inhibiting activity based on tumor cell line testing, specifically human diffuse large B-cell lymphoma cells. The compound provided by this invention uses readily available raw materials, and experiments have shown it to have good anticancer effects, demonstrating promising application prospects in the design and development of antitumor drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to an anti-tumor compound and a preparation method and application thereof. BACKGROUND

[0002] Diffuse large B-cell lymphoma is the most common type of NHL, accounting for almost 1 / 3 of all cases. This type of lymphoma accounts for most cases of clinically "aggressive" or "highly malignant" lymphoma. Diffuse large B-cell lymphoma can be primary lymph node or primary extranodal lesion. In recent years, the incidence and mortality of diffuse large B-cell lymphoma have increased year by year, and the lethal age is lower than that of other solid tumors. Therefore, the synthesis of effective new anti-diffuse large B-cell lymphoma drugs is one of the most important goals of modern pharmaceutical chemistry. At present, the main way of treating cancer in clinical practice is to use chemical drugs. Although the current anti-tumor drugs have certain efficacy, they also have problems such as drug resistance, poor selectivity, and large toxic and side effects. Therefore, many researchers at home and abroad have tried to explore anti-diffuse large B-cell lymphoma compounds with new structures in order to obtain a new compound with better anti-tumor effect. SUMMARY

[0003] The present application provides a kind of 6'-phenyl-2'H-spiro [cyclohexane-1,1'-isoquinoline]-3'(4'H)-ketone class of anti-tumor compounds and preparation method thereof, the prepared compound shows good results in vitro anti-tumor activity test.

[0004] To achieve the above technical purpose, the technical scheme adopted by the present application is:

[0005] An anti-tumor compound, the compound is a 6'-phenyl-2'H-spiro [cyclohexane-1,1'-isoquinoline]-3'(4'H)-ketone compound, the structure is as shown in general formula (I) or (II):

[0006] Or Wherein R is a hydrogen atom, a chlorine atom, a methoxy group or a fluorine atom which is monosubstituted on different positions of a benzene ring.

[0007] The structure of the compound of the general formula is selected from any of the following, but is not limited to the following compounds, as long as the compound structure meets the general formula, it is within the scope of the present application.

[0008] N-((4,6-dimethyl-2-oxo-1,2-dihydro-pyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro [cyclohexane-1,1'-isoquinoline]-6'-yl) benzamide (J-1);

[0009] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-2);

[0010] 4-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-3);

[0011] 3-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-4);

[0012] 2-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-5);

[0013] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-6);

[0014] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-7);

[0015] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-8);

[0016] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-9);

[0017] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-10);

[0018] 3-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-11);

[0019] 2-Chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-12);

[0020] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-13);

[0021] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-14);

[0022] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-15);

[0023] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-16);

[0024] N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methoxy-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-17).

[0025] A method for preparing an antitumor compound, comprising the following steps:

[0026] (1) Add 2-(3-bromophenyl)acetamide, polyphosphate PPA and cyclohexanone to a container and react under heating to obtain intermediate A: 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one;

[0027] (2) Add 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one, benzoic acid with R-group substitution at different positions and boric acid substitution to a container, and an appropriate amount of N,N-dimethylformamide DMF as solvent. Add 1-hydroxybenzotriazole HOBt, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride EDCI and N-methylmorpholine NMM. After acylation reaction, intermediate B is obtained.

[0028] (3) Add intermediate B, intermediate A and tetra(triphenylphosphine)palladium obtained in step (2) above to a container, dissolve in DMF, and obtain the target compound through a coupling reaction.

[0029] Use of an antitumor compound in the preparation of an antitumor drug that inhibits human diffuse large B-cell lymphoma cells WSU-DLCL2.

[0030] An antitumor drug that inhibits human diffuse large B-cell lymphoma cells WSU-DLCL2, comprising the said antitumor compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0031] Furthermore, the pharmaceutical composition comprises the antitumor compound of this application, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0032] Furthermore, the present invention also includes prodrugs derived from the present invention. These prodrugs are derivatives of a general formula, which may themselves have weak or no activity, but are converted into their corresponding biologically active forms under physiological conditions (e.g., through metabolism, solvation, or other means) after administration.

[0033] This invention can prepare pharmaceutical compositions by mixing 6'-phenyl-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'H)-one compounds of general formulas I and II, as well as their pharmaceutically acceptable salts and solvates, with pharmaceutically acceptable carriers or excipients, and then prepare them into clinically acceptable dosage forms. The aforementioned pharmaceutically acceptable excipients refer to any diluent, adjuvant, and / or carrier that can be used in the pharmaceutical field. The derivatives of this invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

[0034] The pharmaceutical compositions of the present invention can be formulated into several dosage forms, containing some commonly used excipients in the pharmaceutical field. The dosage forms described above can be injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, ointments, and other dosage forms.

[0035] The carriers used in the pharmaceutical compositions of this invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavoring agents, preservatives, solvents, and matrices, etc.

[0036] Beneficial effects:

[0037] The compounds of this invention exhibit significant antitumor activity in in vitro assays. During the design process of this invention, 6'-phenyl-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'H)-one compounds were designed and synthesized, which enhanced the antitumor effect and showed good anti-proliferative activity against human diffuse large B-cell lymphoma (WSU-DLCL2) cells. The synthetic steps were optimized, providing possibilities for future industrial production. Detailed Implementation

[0038] The technical solution of the present invention will be further described below with reference to specific embodiments, but it is not limited thereto.

[0039] Example 1

[0040] Synthesis of intermediate A: 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one:

[0041] 2-(3-bromophenyl)acetamide (45.0 g, 210 mmol), cyclohexanone (31.0 g, 315 mmol), and 450 ml of PPA were added to a 500 ml round-bottom flask. The reaction mixture was stirred at 100 °C for 48 hours, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, 500 ml of water was added, and the pH of the solution was adjusted to 9-10. The mixture was extracted, dried, and then evaporated to dryness. Finally, the solution was purified by column chromatography to obtain 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one, a white solid, in 75.1% yield.

[0042] 1H NMR: (400 MHz, CHLOROFORM-d) δ 7.40 (d, J = 8.4 Hz, 1H), 7.31 (s,1H), 7.21 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 3.62 (s, 2H), 1.90 - 1.73 (m,7H), 1.68 - 1.46 (m, 2H), 1.41 - 1.21 (m, 1H).

[0043] The preparation methods of the intermediates in subsequent embodiments are the same as those in Example 1.

[0044] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-1):

[0045] a. In a 100 mL round-bottom flask, add 3-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (687.89 mg, 4.52 mmol), and an appropriate amount of DMF as solvent. Add HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol), and NMM (1.98 g, 19.59 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0046] b. Add the intermediate obtained above (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (459.07 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, and filter. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-1), a white solid, in 77.1% yield.

[0047] 1 H NMR (600 MHz, DMSO- d 6) δ 11.49 (s, 1H), 8.51 (t, J = 4.9 Hz, 1H), 8.10(d, J = 2.3 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.52 (q, J = 7.9 Hz, 3H), 7.27 – 7.16 (m, 1H), 5.87 (d, J =5.7 Hz, 1H), 4.34 (d, J = 4.9 Hz, 2H), 3.63 (s, 2H), 2.18 (d, J = 13.2 Hz, 3H), 2.12 (s, 3H), 1.89 – 1.71 (m, 6H), 1.68 (m, 1H), 1.59 (dd, J = 12.5, 5.0 Hz,2H), 1.32 – 1.21 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ166.37, 150.14, 143.27, 141.17, 140.02, 138.75, 135.58, 133.28, 129.59, 129.31, 127.01, 126.58, 125.88, 125.62, 124.56, 122.08, 118.12, 114.73, 107.97, 57.42, 37.27, 37.06, 35.88, 25.17, 21.32, 19.41, 18.66.

[0048] Example 2

[0049] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-2):

[0050] a. In a 100 mL round-bottom flask, add 4-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (687.89 mg, 4.52 mmol), and an appropriate amount of DMF as solvent. Add HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol), and NMM (1.98 g, 19.59 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0051] b. Add the intermediate obtained above (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (459.07 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, and filter. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-2), a white solid, in 73.4% yield.

[0052] 1 H NMR (600 MHz, DMSO- d 6) δ 11.50 (s, 1H), 8.42 (s, 1H), 7.93 (s, 2H), 7.76 (d, J = 8.3 Hz, 3H), 7.57 (d, J = 3.0 Hz, 3H), 5.88 (s, 1H), 4.33 (s, 2H), 4.14 (s, 2H), 3.63 (s, 3H), 3.17 (s, 3H), 2.16 (d, J = 9.3 Hz, 6H), 1.93 – 1.49 (m, 3H), 1.39 – 1.11 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 166.11, 150.07, 143.26, 142.38, 141.47, 138.24, 133.76, 133.38, 128.42, 126.73, 126.58, 125.52, 124.63, 122.10, 107.99, 57.43, 55.38, 49.05, 37.25, 37.00, 35.88, 25.17, 21.30, 19.39, 18.66.

[0053] Example 3

[0054] Synthesis of 4-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-3):

[0055] a. In a 100 mL round-bottom flask, add 4-chloro-3-carboxyphenylboronic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (569.65 mg, 3.74 mmol), and an appropriate amount of DMF as solvent. Add HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol), and NMM (1.64 g, 16.22 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (2-chloro-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This precipitate does not require purification and can be used directly in the next step.

[0056] b. Add the intermediate obtained above (2-chloro-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (511.75 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, and filter. Finally, the product was purified by column chromatography to obtain 4-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-3), a white solid, in yield of 77.8%.

[0057] 1 H NMR (600 MHz, DMSO- d 6) δ 11.47 (s, 1H), 8.52 (s, 1H), 7.89 (d, J = 2.1Hz, 1H), 7.85 (dd, J= 8.4, 2.3 Hz, 1H), 7.81 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 5.85 (s, 1H), 4.28 (dd, J = 14.9, 4.8 Hz, 2H), 3.61 (s, 2H), 2.16 (d, J = 5.3 Hz, 3H), 2.11 (d, J = 7.0 Hz, 3H), 1.94 – 1.73 (m, 5H), 1.68 (d, J = 13.1 Hz, 1H), 1.65 – 1.56 (m, 2H), 1.42 – 1.18 (m, 2H). 3 C NMR (151 MHz, DMSO- d 6) δ 192.83, 180.64, 172.49, 130.64, 130.25, 128.08, 123.84, 123.29, 119.27, 113.67, 111.44, 111.27, 108.64, 106.63, 104.51, 104.00, 98.32, 97.16, 95.41, 93.51, 57.48, 37.17, 35.87, 25.17, 21.33, 19.38, 18.65.

[0058] Example 4

[0059] Synthesis of 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-4):

[0060] a. In a 100 mL round-bottom flask, add 3-carboxy-5-chlorophenylboronic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (569.65 mg, 3.74 mmol), and an appropriate amount of DMF as solvent. Add HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol), and NMM (1.64 g, 16.22 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (3-chloro-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0061] b. Add the intermediate obtained above (3-chloro-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (511.75 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, and filter. Finally, the product was purified by column chromatography to obtain 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-4), a white solid, in yield of 72.6%.

[0062] 1 H NMR (600 MHz, DMSO- d 6) δ 11.52 (s, 1H), 8.67 (t, J = 4.8 Hz, 1H), 8.09(s, 1H), 7.88 – 7.85 (m, 2H), 7.82 (s, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.59 (s,1H), 7.54 (d, J = 8.2 Hz, 1H), 5.88 (s, 1H), 4.33 (d, J= 4.8 Hz, 2H), 3.64 (s,2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.90 – 1.72 (m, 6H), 1.68 (m, 1H), 1.59 (d, J = 11.6 Hz, 2H), 1.39 – 1.20 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 170.08, 164.97, 163.50, 150.35, 143.39, 142.14, 141.83, 137.30, 137.20, 134.24, 133.45, 129.07, 126.75, 126.63, 125.74, 124.65, 121.81, 107.95, 57.44, 37.21, 36.98, 35.97, 25.15, 21.29, 19.41, 18.66.

[0063] Example 5

[0064] Synthesis of 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-5):

[0065] a. In a 100 mL round-bottom flask, add 5-carboxy-2-chlorophenylboronic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (569.65 mg, 3.74 mmol), and an appropriate amount of DMF as solvent. Add HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol), and NMM (1.64 g, 16.22 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (4-chloro-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0066] b. Add the intermediate obtained above (4-chloro-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (511.75 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, and filter. Finally, the product was purified by column chromatography to obtain 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-5), a white solid, in yield of 77.2%.

[0067] 1 H NMR (600 MHz, DMSO- d 6) δ 11.52 (s, 1H), 8.44 (t, J = 5.1 Hz, 1H), 7.81(s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 7.7 Hz, 3H), 5.87 (s, 1H), 4.32 (d, J = 5.0 Hz, 2H), 3.62 (s,2H), 2.22 (s, 3H), 2.12 (s, 3H), 1.91 – 1.70 (m, 6H), 1.67 (d, J = 13.0 Hz, 1H), 1.58 (d, J = 10.8 Hz, 2H), 1.36 – 1.20 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ170.12, 166.24, 163.49, 150.28, 143.41, 141.45, 138.63, 137.59, 137.45, 133.43, 130.54, 129.73, 128.95, 127.49, 126.42, 125.38, 124.67, 121.73, 107.91, 57.43, 37.25, 36.96, 35.39, 25.16, 21.30, 19.45, 18.67.

[0068] Example 6

[0069] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-6):

[0070] a. In a 100 mL round-bottom flask, add 4-fluoro-3-carboxyphenylboronic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (620.61 mg, 4.08 mmol), and an appropriate amount of DMF as solvent. Add HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol), and NMM (1.79 g, 17.67 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-fluorophenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0071] b. Add the intermediate obtained above (5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-fluorophenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (486.59 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-6), a white solid, in yield of 70.2%.

[0072] 1 H NMR (600 MHz, DMSO- d 6) δ 11.48 (s, 1H), 8.49 (d, J = 5.7 Hz, 1H), 8.01(d, J = 7.3 Hz, 1H), 7.92 – 7.87 (m, 1H), 7.80 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.43 – 7.34 (m, 2H), 5.86 (s, 1H), 4.32 – 4.29 (m,2H), 3.62 (s, 2H), 2.17 (d, J = 2.3 Hz, 3H), 2.11 (s, 3H), 1.81 (m, 6H), 1.68(d, J = 12.8 Hz, 1H), 1.59 (d, J = 12.3 Hz, 2H), 1.36 – 1.19 (m, 1H). 13 C NMR (151MHz, DMSO- d 6) δ165.32, 160.21, 154.05, 133.72, 133.07, 130.47, 128.55, 127.69, 124.27, 121.98, 119.49, 118.02, 116.62, 116.45, 112.82, 109.84, 107.95, 57.47, 55.39, 49.04, 37.19, 36.97, 35.87, 25.16, 21.31, 19.39, 18.65.

[0073] Example 7

[0074] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-7):

[0075] a. In a 100 mL round-bottom flask, add 3-carboxy-5-fluoro-phenylboronic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (620.61 mg, 4.08 mmol), and an appropriate amount of DMF as solvent. Add HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol), and NMM (1.79 g, 17.67 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-fluorophenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0076] b. Add the intermediate obtained above (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-fluorophenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (486.59 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, and filter. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-7), a white solid, in yield of 76.2%.

[0077] 1 H NMR (600 MHz, DMSO- d 6) δ 11.49 (s, 1H), 8.63 – 8.60 (m, 1H), 8.00 (s,1H), 7.80 (s, 1H), 7.69 – 7.60 (m, 3H), 7.58 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 5.87 (s, 1H), 4.33 (d, J = 4.7 Hz, 2H), 3.63 (s, 2H), 2.19 (s, 3H), 2.12 (s,3H), 1.91 – 1.72 (m, 6H), 1.68 (d, J = 13.1 Hz, 1H), 1.59 (d, J = 12.4 Hz, 2H),1.36 – 1.20 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ170.06, 165.07, 163.73, 163.51, 162.11, 150.30, 142.50, 142.45, 141.83, 137.72, 137.68, 137.39, 133.42, 126.73, 125.74, 124.63, 121.98, 121.86, 116.35, 116.20, 113.69, 113.54, 107.93, 57.44, 55.38, 37.21, 37.03, 35.97, 25.15, 21.29, 19.41, 18.66.

[0078] Example 8

[0079] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-8):

[0080] a. In a 100 mL round-bottom flask, add 5-carboxy-2-fluorophenylboronic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (620.61 mg, 4.08 mmol), and an appropriate amount of DMF as solvent. Add HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol), and NMM (1.79 g, 17.67 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-fluorophenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0081] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-fluorophenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (486.59 mg, 1.53 mmol). Dissolve in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-8), a white solid, in yield of 78.6%.

[0082] 1 H NMR (600 MHz, DMSO- d 6) δ 11.57 (s, 1H), 8.38 (q, J = 4.7 Hz, 1H), 7.87(d, J = 6.6 Hz, 1H), 7.82 (s, 1H), 7.78 (dt, J = 7.0, 3.0 Hz, 1H), 7.60 – 7.48(m, 3H), 7.34 (t, J = 9.4 Hz, 1H), 5.88 (s, 1H), 4.35 (d, J = 5.1 Hz, 2H), 3.63(s, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.89 – 1.71 (m, 6H), 1.67 (d, J = 12.8 Hz, 1H), 1.58 (d, J = 10.5 Hz, 2H), 1.35 – 1.22 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ170.15, 163.60, 163.45, 160.25, 158.60, 149.84, 143.44, 141.13, 137.65, 136.34, 136.31, 133.37, 130.83, 130.78, 128.69, 128.67, 126.42, 125.37, 124.62, 124.42, 124.33, 121.87, 117.22, 117.07, 107.99, 57.41, 55.38, 37.27, 36.97, 35.81, 25.17, 21.31, 19.33, 18.66.

[0083] Example 9

[0084] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-9):

[0085] a. In a 100 mL round-bottom flask, add 3-fluoro-4-carboxyphenylboronic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (620.61 mg, 4.08 mmol), and an appropriate amount of DMF as solvent. Add HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol), and NMM (1.79 g, 17.67 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-fluorophenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0086] b. Add the intermediate obtained above (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-fluorophenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (486.59 mg, 1.53 mmol) to a 100 mL round-bottom flask. Dissolve the precipitate in 50.00 mL DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-9), a white solid, in yield of 75.1%.

[0087] 1 H NMR (600 MHz, DMSO- d 6) δ 11.54 (s, 1H), 8.57 (t, J = 4.9 Hz, 1H), 7.86(s, 1H), 7.84 – 7.73 (m, 2H), 7.61 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.47 (dt, J = 8.2, 1.9 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 5.88 (s, 1H), 4.32 (d, J = 4.8 Hz, 2H), 3.63 (s, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.80 (m, 6H), 1.68(d, J = 12.9 Hz, 1H), 1.61 – 1.56 (m, 2H), 1.32 – 1.21 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ164.82, 160.03, 158.39, 150.28, 143.36, 141.82, 136.00, 135.95, 133.42, 133.15, 131.02, 128.51, 128.49, 127.59, 127.56, 124.32, 124.28, 121.84, 115.58, 115.42, 107.96, 57.47, 37.16, 36.93, 35.93, 25.16, 21.28, 19.40, 18.67.

[0088] Example 10

[0089] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-10):

[0090] a. In a 100 mL round-bottom flask, add 2-fluoro-4-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (687.89 mg, 4.52 mmol), and an appropriate amount of DMF as solvent. Add HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol), and NMM (1.98 g, 19.59 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-fluorophenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0091] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (300 mg, 1.02 mmol) of 4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-fluorophenyl)boronic acid and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (459.07 mg, 1.53 mmol). Dissolve the precipitate in 50.00 mL of DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-10), a white solid, in yield of 73.2%.

[0092] 1 H NMR (600 MHz, DMSO- d 6) δ 11.52 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 7.85(d, J = 12.0 Hz, 1H), 7.76 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 8.1 Hz,1H), 7.58 – 7.51 (m, 2H), 7.44 (d, J = 7.9 Hz, 1H), 5.88 (s, 1H), 4.30 (d, J =5.0 Hz, 2H), 3.63 (s, 2H), 2.21 (s, 3H), 2.12 (s, 3H), 1.88 – 1.71 (m, 6H), 1.67 (d, J = 12.6 Hz, 1H), 1.58 (d, J = 12.3 Hz, 2H), 1.27 (m, 1H). 13 C NMR (151MHz, DMSO- d 6) δ170.12, 166.24, 163.46, 150.24, 143.39, 142.20, 141.86, 136.97, 136.04, 133.55, 131.10, 130.06, 127.68, 126.59, 125.51, 125.41, 124.72, 121.73, 107.88, 57.43, 37.18, 36.96, 35.32, 25.15, 21.28, 19.43, 18.68.

[0093] Example 11

[0094] Synthesis of 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-11):

[0095] a. In a 100 mL round-bottom flask, add 3-chloro-4-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (687.89 mg, 4.52 mmol), and an appropriate amount of DMF as solvent. Add HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol), and NMM (1.98 g, 19.59 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (2-chloro-4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0096] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (2-chloro-4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (459.07 mg, 1.53 mmol). Dissolve the precipitate in 50.00 mL of DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-11), a white solid, in yield of 79.2%.

[0097] 1 H NMR (600 MHz, DMSO- d 6) δ 11.57 (s, 1H), 8.63 (t, J = 4.9 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.92 – 7.87 (m, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.48 (d, J =8.0 Hz, 1H), 7.36 (dd, J = 8.1, 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 5.89 (s,1H), 4.33 (d, J = 4.8 Hz, 2H), 3.62 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.88 –1.74 (m, 6H), 1.70 – 1.65 (m, 1H), 1.62 – 1.57 (m, 2H), 1.35 – 1.21 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ170.18, 164.77, 163.53, 150.33, 143.37, 141.97, 141.59, 137.10, 135.45, 132.77, 131.85, 131.69, 129.11, 128.83, 127.93, 126.90, 123.85, 121.81, 107.99, 57.48, 37.15, 36.94, 35.94, 25.17, 21.31, 19.40, 18.67.

[0098] Example 12

[0099] Synthesis of 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-12):

[0100] a. In a 100 mL round-bottom flask, add 2-chloro-4-carboxyphenylboronic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (569.65 mg, 3.74 mmol), and an appropriate amount of DMF as solvent. Add HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol), and NMM (1.64 g, 16.22 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (3-chloro-4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0101] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (3-chloro-4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (511.75 mg, 1.53 mmol). Dissolve the precipitate in 50.00 mL of DMF using tetra(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-12), a white solid, in yield of 78.4%.

[0102] 1 H NMR (600 MHz, DMSO- d 6) δ 11.57 (s, 1H), 8.32 (q, J = 5.0 Hz, 1H), 7.85(s, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.67 – 7.58 (m, 3H), 7.55 (d, J = 8.3 Hz, 1H), 5.89 (s, 1H), 4.33 (d, J = 5.2 Hz, 2H), 3.63 (s, 2H), 2.21 (s, 3H), 2.12 (s,3H), 1.88 – 1.71 (m, 5H), 1.67 (d, J = 12.9 Hz, 1H), 1.59 (dd, J = 9.7, 5.9 Hz,2H), 1.34 – 1.21 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ163.24, 161.06, 159.42, 149.71, 142.08, 136.84, 133.53, 131.43, 126.66, 125.57, 124.71, 122.82, 122.80, 122.50, 122.41, 121.90, 114.40, 114.24, 107.98, 57.45, 37.16, 36.98, 35.79, 25.15, 21.27, 19.34, 18.67.

[0103] Example 13

[0104] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-13):

[0105] a. In a 100 mL round-bottom flask, add 4-methoxy-3-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (582.49 mg, 3.83 mmol), and an appropriate amount of DMF as solvent. Add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol), and NMM (1.68 g, 16.58 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methoxyphenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0106] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methoxyphenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (505.00 mg, 1.53 mmol). Dissolve in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-13), a white solid, in yield of 71.4%.

[0107] 1 H NMR (600 MHz, DMSO- d 6) δ 11.51 (s, 1H), 8.33 (t, J = 4.9 Hz, 1H), 7.90– 7.86 (m, 1H), 7.86 – 7.79 (m, 1H), 7.69 – 7.60 (m, 2H), 7.37 (dd, J = 8.0, 1.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 5.86 (s, 1H), 4.29 (d, J = 4.8 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 2H), 2.16 (s, 3H), 2.11 (s,3H), 1.87 – 1.70 (m, 6H), 1.68 (d, J = 12.5 Hz, 1H), 1.61 – 1.55 (m, 2H), 1.31 – 1.22 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ165.87, 163.57, 158.70, 150.11, 145.61, 143.19, 140.54, 136.81, 132.29, 129.99, 129.11, 129.08, 128.91, 128.17, 127.19, 123.57, 122.19, 111.58, 107.96, 57.41, 56.22, 37.22, 35.73, 25.20, 21.34, 21.19, 19.39, 18.65.

[0108] Example 14

[0109] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-14):

[0110] a. In a 100 mL round-bottom flask, add 5-methoxy-3-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (582.49 mg, 3.83 mmol), and an appropriate amount of DMF as solvent. Add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol), and NMM (1.68 g, 16.58 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methoxyphenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0111] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methoxyphenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (505.00 mg, 1.53 mmol). Dissolve in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-14), a white solid, in yield of 75.7%.

[0112] 1 H NMR (600 MHz, DMSO- d 6) δ 11.51 (s, 1H), 8.53 (s, 1H), 7.56 (m, 7H), 5.87 (d, J = 7.3 Hz, 1H), 4.33 (s, 2H), 3.86 (s, 3H), 3.63 (s, 2H), 2.16 (d, J =4.4 Hz, 6H), 1.88 – 1.66 (m, 6H), 1.59 (s, 2H), 1.27 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 170.55, 166.12, 163.58, 160.13, 150.64, 147.21, 141.31, 138.64, 136.30, 133.24, 126.68, 125.72, 124.49, 121.64, 118.43, 115.53, 112.10, 108.00, 57.41, 55.92, 55.40, 37.24, 37.05, 35.91, 25.17, 21.30, 19.42, 18.66.

[0113] Example 15

[0114] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-15):

[0115] a. In a 100 mL round-bottom flask, add 5-carboxy-2-methoxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (582.49 mg, 3.83 mmol), and an appropriate amount of DMF as solvent. Add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol), and NMM (1.68 g, 16.58 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methoxyphenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0116] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methoxyphenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one (505.00 mg, 1.53 mmol). Dissolve in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-15), a white solid, in yield of 73.4%.

[0117] 1 H NMR (600 MHz, DMSO- d 6) δ 11.66 (s, 1H), 8.84 (t, J = 5.6 Hz, 1H), 8.17(d, J= 2.5 Hz, 1H), 7.85 (s, 1H), 7.78 (dd, J = 8.6, 2.6 Hz, 1H), 7.57 – 7.48(m, 2H), 7.46 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 5.88 (s, 1H), 4.37(d, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.64 (s, 2H), 2.25 (s, 3H), 2.13 (s, 3H),1.86 – 1.77 (m, 4H), 1.73 (d, J = 8.9 Hz, 2H), 1.70 – 1.65 (m, 1H), 1.63 – 1.56 (m, 2H), 1.26 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 170.24, 164.19, 163.83, 157.18, 148.77, 143.29, 140.53, 138.20, 133.29, 132.38, 130.88, 129.28, 125.88, 124.89, 124.58, 122.70, 122.58, 113.34, 107.99, 57.36, 56.70, 37.29, 36.98, 35.80, 25.18, 21.31, 19.33, 18.64.

[0118] Example 16

[0119] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-16):

[0120] a. In a 100 mL round-bottom flask, add 3-methoxy-4-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (582.49 mg, 3.83 mmol), and an appropriate amount of DMF as solvent. Add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol), and NMM (1.68 g, 16.58 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methoxyphenyl)boronic acid. This step is optional and requires no purification; the product can be used directly in the next step.

[0121] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (300 mg, 1.02 mmol) of 4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methoxyphenyl)boronic acid and 505.00 mg, 1.53 mmol) of 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one. Dissolve the precipitate in 50.00 mL of DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methoxy-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-16), a white solid, in yield of 76.7%.

[0122] 1 H NMR (600 MHz, DMSO- d 6) δ 11.54 (s, 1H), 8.49 (t, J = 5.0 Hz, 1H), 7.82(s, 1H), 7.55 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.29 (s, 1H), 5.89 (s, 1H), 4.33(d, J = 4.8 Hz, 2H), 3.81 (s, 3H), 3.58 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H),1.87 – 1.72 (m, 6H), 1.68 (d, J = 12.7 Hz, 1H), 1.59 (d, J = 13.1 Hz, 2H), 1.26 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 166.00, 156.39, 150.16, 145.48, 140.73, 136.54, 135.35, 132.36, 132.18, 130.54, 128.84, 128.04, 123.63, 122.10, 120.30, 115.83, 110.98, 108.01, 57.42, 56.16, 49.04, 37.23, 37.01, 35.88, 25.19, 21.34, 19.41, 18.66.

[0123] Example 17

[0124] Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methoxy-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-17):

[0125] a. In a 100 mL round-bottom flask, add 2-methoxy-4-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (582.49 mg, 3.83 mmol), and an appropriate amount of DMF as solvent. Add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol), and NMM (1.68 g, 16.58 mmol). React at room temperature for 3 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, filter, and obtain the intermediate (4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methoxyphenyl)boronic acid. This step does not require purification and can be used directly in the next step.

[0126] b. In a 100 mL round-bottom flask, add the intermediate obtained in step one (300 mg, 1.02 mmol) of 4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-3-methoxyphenyl)boronic acid and 505.00 mg, 1.53 mmol) of 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one. Dissolve the precipitate in 50.00 mL of DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. React at 90 °C under nitrogen protection for 5 hours, monitoring the reaction progress by thin-layer chromatography. After the reaction is complete, add ice water to precipitate the precipitate, which is then filtered. Finally, the product was purified by column chromatography to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methoxy-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-1,1'-isoquinoline]-6'-yl)benzamide (J-17), a white solid, in yield of 77.3%.

[0127] 1 H NMR (600 MHz, DMSO- d 6) δ 11.62 (s, 1H), 8.82 (t, J = 5.7 Hz, 1H), 7.97(d, J = 8.1 Hz, 1H), 7.83 (s, 1H), 7.63 (dd, J = 8.2, 2.0 Hz, 1H), 7.59 (d, J = 1.9Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.38 – 7.32 (m, 2H), 5.88 (s, 1H), 4.35 (d, J = 5.6 Hz, 2H), 4.00 (s, 3H), 3.64 (s, 2H), 2.24 (s, 3H), 2.12 (s, 3H), 1.89 –1.71 (m, 6H), 1.70 – 1.65 (m, 1H), 1.60 – 1.53 (m, 2H), 1.35 – 1.22 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ170.15, 164.05, 158.00, 148.66, 144.29, 143.27, 141.69, 138.23, 133.34, 132.05, 126.79, 125.73, 124.53, 122.65, 121.13, 119.31, 110.85, 107.97, 57.43, 56.65, 55.40, 37.20, 37.03, 35.74, 25.16, 21.29, 19.34, 18.65.

[0128] Experiments to inhibit tumor cell proliferation

[0129] The compounds of the present invention were subjected to tumor cell proliferation inhibition experiments using the conventional CCK-8 assay.

[0130] Cell culture: The cell line used was WSU-DLCL2 (human diffuse large B-cell lymphoma), diluted with DMEM high-glucose medium, and resuspended in DMEM high-glucose nutrient solution. Finally, the cells were cultured in an incubator at 37°C with 5% CO2 and saturated humidity.

[0131] After culturing the cells 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 cells were then cultured in 96-well plates at a density of 5 × 10⁶ cells per well. 3 Cells were seeded at a concentration of [specific concentration] and cultured in an incubator at 37°C with 5% CO2. Once 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 incubation with the compound for 24 hours, 5 µL of ultrasensitive CCK-8 solution was added to each well. The cells were then incubated at 37°C for 4 hours, and the optical density (OD) was analyzed at 490 nm. The concentration of the compound that caused 50% inhibition was defined as the IC50 concentration. 50 Values. Experimental results are shown in Table 1.

[0132] Table 1. In vitro inhibitory activity (IC50) of the samples against human tumor cells. 50 value

[0133]

[0134] The experimental data above show that some of the compounds in this invention have good in vitro antitumor activity, and are of great value for further research and development of new antitumor drugs, and also provide a broader perspective for new drug development.

[0135] It should be noted that the above embodiments are merely some preferred embodiments of the present invention, and not all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

Claims

1. An antitumor compound, characterized in that, The compound is a 6'-phenyl-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'H)-one compound, and its structure is shown in general formula (I) or (II): or wherein R is a hydrogen atom, a chlorine atom, a methoxy group or a fluorine atom monosubstituted in different positions on the benzene ring.

2. The antitumor compound according to claim 1, characterized in that, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; 4-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-fluoro-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide; 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-1,1'-isoquinolin]-6'-yl)benzamide;2-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide; N-((4,6-dimethyl-2- oxo-l,2-dihydropyridin-3-yl)methyl)-4-methoxy-3-(3'-oxo-3',4'-dihydro-2'H- spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-3-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane- 1,1 '-isoquinoline]-6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-2-methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]- 6'-yl)benzamide; N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-methoxy-4- (3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide; N- ((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-methoxy-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide.

3. A method for preparing the antitumor compound according to claim 1 or 2, characterized by, The method comprises the following steps: (1) adding 2-(3-bromophenyl)acetamide, polyphosphoric acid (PPA) and cyclohexanone into a container, and heating to obtain an intermediate A: 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one; (2) adding 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one, a benzene carboxylic acid substituted with different positions R groups and a boronic acid into a container, adding an appropriate amount of N,N-dimethylformamide (DMF) as a solvent, adding 1-hydroxybenzotriazole (HOBt), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and N-methylmorpholine (NMM), and performing acylation reaction to obtain an intermediate B; (3) adding the intermediate B obtained in the step (2), the intermediate A and tetrakis(triphenylphosphine)palladium into a container, dissolving with DMF, and performing coupling reaction to obtain the target compound.

4. Use of the antitumor compound of claim 1 or 2 for preparing an antitumor drug for inhibiting human diffuse large B-cell lymphoma cell WSU-DLCL2.

5. An antitumor drug for inhibiting human diffuse large B-cell lymphoma cells WSU-DLCL2, characterized by, The antitumor compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

6. The antitumor agent according to claim 5, wherein The pharmaceutical composition comprises the antitumor compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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