Anti-tumor compound as well as preparation method and application thereof

Abstract

The invention discloses an anti-tumor compound as well as a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to a compound with an anti-tumor activity and a specific chemical structure. The compound is a 6 '-phenyl-2' H-spiro [cyclohexane-1, 1 '-isoquinoline]-3' (4 'H)-ketone compound, the structure of the compound is shown as a general formula (I) or (II), or R is a hydrogen atom, a chlorine atom, a methoxyl group or a fluorine atom monosubstituted at different positions on a benzene ring. According to a tumor cell line test, namely human diffuse large B lymphoma cells, it is proved that the compound has the effect of inhibiting tumor activity. The raw materials of the compound are easy to obtain, and experiments prove that the compound has a good anti-cancer effect and has a good application prospect in the field of design, research and development of anti-tumor 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 "aggressive" or "high-grade malignant" lymphoma in clinical practice. 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 effects, they also have problems such as drug resistance, poor selectivity, and large toxic and side effects. Therefore, many researchers at home and abroad try 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: An anti-tumor compound, the compound is a 6'-phenyl-2'H-spiro [cyclohexane-1,1'-isoquinoline]-3'(4'H)-ketone compound, and the structure is as shown in general formula (I) or (II): Or Wherein R is a hydrogen atom, a chlorine atom, a methoxy group or a fluorine atom for single substitution at different positions of a benzene ring.

[0005] The structure of the general formula compound 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.

[0006] 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); N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-2); 4-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-3); 3-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-4); 2-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-5); N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-6); N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-7); N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-8); N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-fluoro-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-9); N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l, -isoquinoline]-6'-yl)benzamide (J-10); 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 (J-11); 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'-isoquinolin]-6'-yl)benzamide (J-12); 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'-isoquinolin]-6'-yl)benzamide (J-13); 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'-isoquinolin]-6'-yl)benzamide (J-14); 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'-isoquinolin]-6'-yl)benzamide (J-15); 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'-isoquinolin]-6'-yl)benzamide (J-16); 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'-isoquinolin]-6'-yl)benzamide (J-17).

[0007] A method for preparing an antitumor compound, comprising the steps of: (1) adding 2-(3-bromophenyl)acetamide, polyphosphoric acid (PPA) and cyclohexanone into a container, and heating to react to obtain an intermediate A: 6'-bromo-2'H-spiro[cyclohexane-1,1'- isoquinolin]-3'(4'-H)-one; (2) In a container, 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one, benzoic acid with different positions of R group substitution and boronic acid substitution, and appropriate N,N-dimethylformamide DMF as a solvent were added, 1-hydroxybenzotriazole HOBt, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride EDCI and N-methylmorpholine NMM were added, acylation reaction was carried out, and intermediate B was obtained; (3) In a container, the intermediate B obtained in step (2) above, intermediate A and tetrakis(triphenylphosphine)palladium were added and dissolved with DMF, coupling reaction was carried out, and the target compound was obtained.

[0008] Use of an antitumor compound for preparing an antitumor drug for inhibiting human diffuse large B-cell lymphoma cell WSU-DLCL2.

[0009] An antitumor drug for inhibiting human diffuse large B-cell lymphoma cell WSU-DLCL2, comprising the antitumor compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0010] Further, the pharmaceutical composition comprises the antitumor compound, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0011] In addition, the present application also includes prodrugs of the derivatives of the present application. The prodrugs of the derivatives of the present application are derivatives of the general formula, which may have weak activity or even no activity themselves, but are converted into the corresponding biologically active forms under physiological conditions (for example, by metabolism, solvolysis or other means) after administration.

[0012] The present application can contain 6'-phenyl-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'H)-one compounds of general formula I and general formula II and pharmaceutically acceptable salts and solvates thereof as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare pharmaceutical compositions, and prepared into clinically acceptable dosage forms. The above-mentioned pharmaceutically acceptable excipients refer to any diluents, adjuvants and / or carriers that can be used in the pharmaceutical field. The derivatives of the present application can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions.

[0013] The pharmaceutical composition of the present application can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. As described above, several dosage forms can be used in the form of injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, ointment, etc.

[0014] The carriers used for the pharmaceutical composition of the present application are the common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non- pigments, flavoring agents, preservatives, solubilizers and substrates, etc.

[0015] Advantages: The compound of the present application has significant effect in the in vitro anti-tumor activity test. In the design process of the present application, 6'-phenyl-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'H)-one compounds are designed and synthesized, the anti-tumor effect is improved, and it is found that the human diffuse large B-cell lymphoma cells (WSU-DLCL2) have good anti-proliferation ability. In the synthesis process, the synthesis steps are optimized, which provides the possibility for future industrial production. DETAILED DESCRIPTION

[0016] The technical solutions of the present application are further described below in combination with specific examples, but are not limited thereto.

[0017] Example 1 Intermediate A: 6'-Bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one synthesis: In a 500 ml tomato flask, 2-(3-bromophenyl)acetamide (45.0 g, 210 mmol), cyclohexanone (31.0 g, 315 mmol) and 450 ml PPA were added. The reaction 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 water was added, and the pH value of the solution was adjusted to 9-10, extracted, dried, and rotary evaporated. Finally, 6'-bromo-2'H-spiro[cyclohexane-1,1'-isoquinoline]-3'(4'-H)-one was obtained by column chromatography, white solid, yield: 75.1%.

[0018] 1 H 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). The preparation methods of the intermediates in the subsequent examples are the same as those in Example 1.

[0019] Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo- 3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinolin]-6'-yl)benzamide (J-1): a. In a 100 mL round bottom flask, add 3-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (687.89 mg, 4.52 mmol) in appropriate amount of DMF, add HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol) and NMM (1.98 g, 19.59 mmol), and allow the reaction to proceed for 3 h at room temperature. Monitor the progress of the reaction by TLC. After completion, pour the reaction mixture into ice-cold water and allow the product to precipitate. Filter the solid and dry to obtain the intermediate (3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This process does not require purification and the intermediate is used as such for the next step.

[0020] b. In a 100 mL round bottom flask, add the above obtained intermediate (3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,l'-isoquinolin]-3'(4'-H)-one (459.07 mg, 1.53 mmol) in 50.00 mL DMF. Add tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as a catalyst. Allow the reaction to proceed for 5 h at 90 °C under a nitrogen atmosphere. Monitor the progress of the reaction by TLC. After completion, pour the reaction mixture into ice-cold water and allow the product to precipitate. Filter the solid and dry. Purify the final product by column chromatography to obtain N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinolin]-6'-yl)benzamide (J-1) as a white solid in 77.1% yield.

[0021] 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) δ 166.37, 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. Example 2 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): a. In a 100 mL flask, add 4-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (687.89 mg, 4.52 mmol) in appropriate amount of DMF, add HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol) and NMM (1.98 g, 19.59 mmol), and react at room temperature for 3 hours. Monitor the reaction progress by TLC. After completion, add ice-cold water and precipitate, filter to get the intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This process does not require purification and is used directly for the next step.

[0022] b. In a 100 mL flask, add the above obtained intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,l'-isoquinolin]-3'(4'-H)-one (459.07 mg, 1.53 mmol) and react. Dissolve in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. React at 90 °C under nitrogen atmosphere for 5 hours. Monitor the reaction progress by TLC. After completion, add ice-cold water and precipitate, filter. Finally purify by column chromatography to get N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinolin]-6'- yl)benzamide (J-2) as a white solid with 73.4% yield.

[0023] 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. Example 3 Synthesis of 4-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'- oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinolin]-6'-yl)benzamide (J-3): a. Into a 100 mL round bottom flask was added 4-chloro-3-carboxyphenylboronic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (569.65 mg, 3.74 mmol) in appropriate amount of DMF as solvent, HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol) and NMM (1.64 g, 16.22 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and the precipitate was filtered to obtain the intermediate (2-chloro-5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This was used as such for the next step without further purification.

[0024] b. Into a 100 mL round bottom flask, was added the above obtained intermediate (2-chloro-5-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r-isoquinoline]-3'(4'-H)-one (511.75 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was carried out under nitrogen at 90 °C for 5 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, ice water was added to precipitate the product, which was then filtered. The final product, 4-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide (J-3), was obtained as a white solid in a yield of 77.8% after purification by column chromatography.

[0025] 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) δ192.83, 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. Example 4 3-Chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r -isoquinoline]-6'-yl)benzamide (J-4) synthesis: a. Into a 100 mL round bottom flask was added 3-carboxy-5-chlorobenzoic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (569.65 mg, 3.74 mmol) in appropriate amount of DMF, HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol) and NMM (1.64 g, 16.22 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice cold water and the precipitate was filtered to obtain the intermediate (3-chloro-5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This was used as such for the next step without further purification.

[0026] b. In a 100 mL round bottom flask, add the above obtained intermediate (3-chloro-5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r-isoquinoline]-3'(4'-H)-one (511.75 mg, 1.53 mmol) react. Dissolve with 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. React at 90 °C under nitrogen protection for 5 hours, monitor the reaction progress by thin layer chromatography. After the reaction is completed, add ice water to precipitate, and filter. Finally, purify by column chromatography to obtain 3-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide (J-4), white solid, yield: 72.6%.

[0027] 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) δ170.08, 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. Example 5 2-Chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r -isoquinoline]-6'-yl)benzamide (J-5) synthesis: a. Into a 100 mL pear-shaped flask was added 5-carboxy-2-chlorobenzoic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (569.65 mg, 3.74 mmol) in appropriate amount of DMF as solvent, HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol) and NMM (1.64 g, 16.22 mmol), and the reaction was allowed to proceed at room temperature for 3 hours, with TLC monitoring. After the reaction was completed, ice water was added to precipitate the product, which was filtered to give the intermediate (4-chloro-3-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This process was used without purification in the next step.

[0028] b. Into a 100 mL round bottom flask, was added the above obtained intermediate (4-chloro-3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)amino- carbonyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r- isoquinolin]-3'(4'-H)-one (511.75 mg, 1.53 mmol). 50.00 mL DMF was used to dissolve the reactants with tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. The reaction was carried out under nitrogen protection at 90 °C for 5 hours. The reaction progress was monitored by thin layer chromatography. After the reaction was completed, ice water was added to precipitate the product, which was then filtered. The final product, 2-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r-isoquinolin]-6'-yl)benzamide (J-5), was obtained as a white solid with a yield of 77.2%.

[0029] 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. Example 6 Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-fluoro-3-(3'- oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinoline]-6'-yl)benzamide (J-6): a. Into a 100 mL round bottom flask was added 4-fluoro-3-carboxyphenylboronic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (620.61 mg, 4.08 mmol) in appropriate amount of DMF, HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol) and NMM (1.79 g, 17.67 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice cold water and the precipitate was filtered to obtain the intermediate (5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2- fluorophenyl)boronic acid. This was used as such for the next step without further purification.

[0030] b. In a 100 mL round bottom flask, add the above obtained intermediate (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'-isoquinolin]-3'(4'-H)-one (486.59 mg, 1.53 mmol) react. Dissolve with 50.00 mL DMF with tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. React at 90 °C under nitrogen protection for 5 hours, monitor the reaction progress by thin layer chromatography. After the reaction is completed, add ice water to precipitate, and filter. Finally, purify 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'-isoquinolin]-6'-yl)benzamide (J-6), white solid, yield: 70.2%.

[0031] 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. Example 7 Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-fluoro-3-(3'- oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinoline]-6'-yl)benzamide (J-7): a. Into a 100 mL round bottom flask was added 3-carboxy-5-fluoro-benzoic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (620.61 mg, 4.08 mmol) in appropriate amount of DMF, HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol) and NMM (1.79 g, 17.67 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice cold water and the precipitate was filtered to obtain the intermediate (3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5- fluorophenyl)boronic acid. This was used for the next step without further purification.

[0032] b. In a 100 mL round bottom flask, add the above obtained intermediate (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'-isoquinolin]-3'(4'-H)-one (486.59 mg, 1.53 mmol) react. Dissolve with 50.00 mL DMF, using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. React at 90 °C under nitrogen protection for 5 hours, monitor the reaction progress by thin layer chromatography. After the reaction is completed, add ice water to precipitate, and filter. Finally, purify 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'-isoquinolin]-6'-yl)benzamide (J-7), white solid, yield: 76.2%.

[0033] 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. Example 8 Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'- oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinoline]-6'-yl)benzamide (J-8): a. Into a 100 mL round bottom flask, 5-carboxy-2-fluorobenzoic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (620.61 mg, 4.08 mmol) were added in a suitable amount of DMF as solvent, followed by the addition of HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol) and NMM (1.79 g, 17.67 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and the precipitate was filtered to obtain the intermediate (3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-4- fluorophenyl)boronic acid. This was used as such for the next step without further purification.

[0034] b. Into a 100 mL round bottom flask, was added the intermediate from Step 1 (3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-4- fluorophenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r- isoquinolin]-3'(4'-H)-one (486.59 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was heated at 90 °C under nitrogen for 5 hours and monitored by thin layer chromatography. After the reaction was complete, the reaction was diluted with ice water and the precipitate was collected by filtration. The product, N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-fluoro-3-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r-isoquinolin]-6'-yl)benzamide (J-8), was obtained as a white solid after purification by column chromatography in 78.6% yield.

[0035] 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. Example 9 Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-fluoro-4-(3'- oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-isoquinoline]-6'-yl)benzamide (J-9): a. Into a 100 mL round bottom flask, 3-fluoro-4-carboxyphenylboronic acid (500 mg, 2.72 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (620.61 mg, 4.08 mmol) were added in a suitable amount of DMF as solvent, followed by the addition of HOBt (440.80 mg, 3.26 mmol), EDCI (625.36 mg, 3.26 mmol) and NMM (1.79 g, 17.67 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and the precipitate was filtered to obtain the intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2- fluorophenyl)boronic acid. This was used for the next step without further purification.

[0036] b. In a 100 mL round bottom flask, add the above obtained intermediate (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'-isoquinolin]-3'(4'-H)-one (486.59 mg, 1.53 mmol) react. Dissolve with 50.00 mL DMF, using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. React at 90 °C under nitrogen protection for 5 hours, monitor the reaction progress by thin layer chromatography. After the reaction is completed, add ice water to precipitate, and filter. Finally, purify 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'-isoquinolin]-6'-yl)benzamide (J-9), white solid, yield: 75.1%.

[0037] 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. Example 10 Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'- oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinoline]-6'-yl)benzamide (J-10): a. Into a 100 mL round bottom flask was added 2-fluoro-4-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (687.89 mg, 4.52 mmol) in appropriate amount of DMF, HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol) and NMM (1.98 g, 19.59 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and the precipitate was filtered to obtain the intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-3- fluorophenyl)boronic acid. This was used for the next step without further purification.

[0038] b. Into a 100 mL round bottom flask, was added the intermediate from Step 1 (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-3- fluorophenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r- isoquinolin]-3'(4'-H)-one (459.07 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was carried out under nitrogen at 90 °C for 5 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, ice water was added to precipitate the product, which was then filtered. The final product, N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-fluoro-4-(3'-oxo-3',4'- dihydro-2'H-spiro[cyclohexane-l,r-isoquinolin]-6'-yl)benzamide (J-10), was obtained as a white solid in 73.2% yield after purification by column chromatography.

[0039] 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. Example 11 3-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 (J-11) synthesis: a. Into a 100 mL round bottom flask was added 3-chloro-4-carboxyphenylboronic acid (500 mg, 3.01 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (687.89 mg, 4.52 mmol) in appropriate amount of DMF, HOBt (488.59 mg, 3.62 mmol), EDCI (693.16 mg, 3.62 mmol) and NMM (1.98 g, 19.59 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice cold water and the precipitate was filtered to obtain the intermediate (2-chloro-4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This was used as such for the next step without further purification.

[0040] b. Into a 100 mL round bottom flask, was added the intermediate from step 1 (2-chloro-4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,l'-isoquinolin]-3'(4'-H)-one (459.07 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was heated at 90 °C under nitrogen for 5 h, and monitored by TLC. After the reaction was completed, ice water was added to the reaction mixture to precipitate the product, which was collected by filtration. The product was purified by column chromatography to give 3-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinolin]-6'-yl)benzamide (J-11) as a white solid in 79.2% yield.

[0041] 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. Example 12 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 (J-12) synthesis: a. Into a 100 mL round bottom flask was added 2-chloro-4-carboxyphenylboronic acid (500 mg, 2.50 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (569.65 mg, 3.74 mmol) in appropriate amount of DMF, HOBt (404.61 mg, 2.99 mmol), EDCI (574.02 mg, 2.99 mmol) and NMM (1.64 g, 16.22 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice cold water and the precipitate was filtered to obtain the intermediate (3-chloro-4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid. This was used as such for the next step without further purification.

[0042] b. Into a 100 mL round bottom flask, was added the intermediate from Step 1 (3-chloro-4-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)phenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,l'-isoquinolin]-3'(4'-H)-one (511.75 mg, 1.53 mmol) and dissolved in 50.00 mL DMF with tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. The reaction was heated at 90 °C under nitrogen for 5 hours, and monitored by thin layer chromatography. After the reaction was completed, ice water was added to precipitate the product, which was then filtered. The product was purified by column chromatography to give 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,l'-isoquinolin]-6'-yl)benzamide (J-12) as a white solid in 78.4% yield.

[0043] 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. Example 13 Synthesis of 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,l'-isoquinoline]-6'-yl)benzamide (J-13): a. Into a 100 mL round bottom flask was added 4-methoxy-3-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (582.49 mg, 3.83 mmol) in appropriate amount of DMF, HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol) and NMM (1.68 g, 16.58 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and the precipitate was filtered to obtain the intermediate (5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2- methoxyphenyl)boronic acid. This was used for the next step without further purification.

[0044] b. Into a 100 mL round bottom flask, was added the intermediate from Step 1 (5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2- methoxyphenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r- isoquinolin]-3'(4'-H)-one (505.00 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was heated at 90 °C under nitrogen for 5 hours and monitored by thin layer chromatography. After the reaction was complete, the reaction was diluted with ice water and the precipitate was collected by filtration. The product, 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-isoquinolin]-6'-yl)benzamide (J-13), was obtained as a white solid after purification by column chromatography in 71.4% yield.

[0045] 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. Example 14 Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-isoquinolin]-6'- yl)benzamide (J-14): a. Into a 100 mL round bottom flask was added 5-methoxy-3-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (582.49 mg, 3.83 mmol) in appropriate amount of DMF, HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol) and NMM (1.68 g, 16.58 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. After completion, the reaction mixture was diluted with ice cold water and the precipitate was filtered to give the intermediate (5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-3- methoxyphenyl)boronic acid. This was used in the next step without further purification.

[0046] b. Into a 100 mL round bottom flask, was added the intermediate from Step 1 (5-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-3- methoxyphenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r- isoquinolin]-3'(4'-H)-one (505.00 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was run under nitrogen at 90 °C for 5 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was complete, the reaction was diluted with ice water and the precipitate was collected by suction filtration. The product, N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- methoxy-3-(3'-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-isoquinolin]-6'-yl)benzamide (J-14), was obtained as a white solid after purification by column chromatography in 75.7% yield.

[0047] 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. Example 15 Synthesis of 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,l'-isoquinolin]-6'-yl)benzamide (J-15): a. In a 100 mL round bottom flask, add 5-carboxy-2-methoxybenzoic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (582.49 mg, 3.83 mmol) in appropriate amount of DMF, add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol) and NMM (1.68 g, 16.58 mmol), and stir at room temperature for 3 h. Monitor the reaction progress by TLC. After completion, add ice cold water and the precipitate obtained was filtered to get the intermediate (3-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-4- methoxyphenyl)boronic acid. This process was used as such for the next step without purification.

[0048] b. In a 100 mL round bottom flask, add the intermediate (3-((((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-4-methoxyphenyl)boronic acid (300 mg, 1.02 mmol) obtained in step-a and 6'-bromo-2'H-spiro[cyclohexane-l,l'-isoquinolin]-3'(4'-H)-one (505.00 mg, 1.53 mmol) in 50.00 mL DMF. Stir at 90 °C under nitrogen atmosphere for 5 h. Monitor the reaction progress by TLC. After completion, add ice cold water and the precipitate obtained was filtered. Finally, the product was purified by column chromatography to get 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,l'-isoquinolin]-6'-yl)benzamide (J-15) as a white solid in 73.4% yield.

[0049] 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. Example 16 Synthesis of 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,l'-isoquinolin]-6'-yl)benzamide (J-16): a. In a 100 mL flask, add 3-methoxy-4-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (582.49 mg, 3.83 mmol) in appropriate amount of DMF, add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol) and NMM (1.68 g, 16.58 mmol), and react at room temperature for 3 hours. Monitor the reaction progress by TLC. After completion, add ice water and precipitate, filter, and obtain the intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methoxyphenyl)boronic acid. No purification is required, and directly use in the next step.

[0050] b. In a 100 mL flask, add the intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methoxyphenyl)boronic acid (300 mg, 1.02 mmol) obtained in the first step and 6'-bromo-2'H-spiro[cyclohexane-l,l'-isoquinolin]-3'(4'-H)-one (505.00 mg, 1.53 mmol) and dissolve in 50.00 mL DMF using tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) as catalyst. React at 90°C under nitrogen for 5 hours. Monitor the reaction progress by TLC. After completion, add ice water and precipitate, filter, and purify by column chromatography to obtain 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,l'-isoquinolin]-6'-yl)benzamide (J-16) as a white solid with a yield of 76.7%.

[0051] 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. Example 17 Synthesis of 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,l'-isoquinolin]-6'-yl)benzamide (J-17): a. In a 100 mL flask, add 2-methoxy-4-carboxyphenylboronic acid (500 mg, 2.55 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(lH)-one (582.49 mg, 3.83 mmol) in appropriate amount of DMF, add HOBt (413.72 mg, 3.06 mmol), EDCI (586.95 mg, 3.06 mmol) and NMM (1.68 g, 16.58 mmol), and react at room temperature for 3 hours. Monitor the reaction progress by TLC. After the reaction is completed, add ice water to precipitate the product, and filter to obtain the intermediate (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-3- methoxyphenyl)boronic acid. This process does not require purification and is directly used in the next step.

[0052] b. Into a 100 mL round bottom flask, was added the intermediate from Step 1 (4-((((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-3- methoxyphenyl)boronic acid (300 mg, 1.02 mmol) and 6'-bromo-2'H-spiro[cyclohexane-l,r- isoquinolin]-3'(4'-H)-one (505.00 mg, 1.53 mmol). The reaction was catalyzed by tetrakis(triphenylphosphine)palladium (117.84 mg, 101.97 μmol) and dissolved in 50.00 mL DMF. The reaction was heated at 90 °C under nitrogen for 5 hours and monitored by thin layer chromatography. After the reaction was complete, the reaction was diluted with ice water and the precipitate was collected by filtration. The product, 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-isoquinolin]-6'-yl)benzamide (J-17), was obtained as a white solid after purification by column chromatography in 77.3% yield.

[0053] 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. Inhibition of tumor cell proliferation experiment The tumor cell proliferation inhibition experiment was carried out on the compound of the present application, and the test method used the conventional CCK-8 method.

[0054] Cell culture: The cell strain WSU-DLCL2 (human diffuse large B-cell lymphoma cells) was selected and diluted with DMEM high glucose medium, and the above cells were resuspended with DMEM high glucose nutrient solution. Finally, the cells were cultured in a 37°C incubator containing 5% CO2 and saturated humidity.

[0055] 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 with phosphate buffered saline (PBS). The above cells were inoculated in a 96-well plate at a concentration of 5×10 3 cells per well, and cultured in a 37°C incubator containing 5% CO2. After the cells adhered, the nutrient solution was discarded, and 100 μL of serum-free medium containing different concentrations of compounds was added to the cells. After the compounds were incubated with the cells for 24 hours, hypersensitive CCK-8 solution (5 μL) was added to each well. Next, it was incubated at 37°C for 4 hours, and then the optical density value (OD) was analyzed at 490 nm. The compound concentration that caused 50% inhibition was taken as the IC 50 value. The experimental results are shown in Table 1.

[0056] Table 1 In vitro proliferation inhibition activity IC 50 value of samples on human tumor cells The above experimental data show that some of the compounds in the present application have good in vitro anti-tumor activity, and are more valuable for further research and development of new anti-tumor drugs, and also provide a broader approach for new drug development.

[0057] It should be noted that the above-mentioned embodiments only illustrate some but not all of the preferred ways for implementing the present application. Obviously, based on the above-mentioned embodiments of the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work should belong to the protection scope of the present application.

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 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 method comprises the following steps:

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

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