Antitumor compounds, methods of making and using the same

Abstract

This invention discloses an antitumor compound, its preparation method, and its application, relating to the field of antitumor compound technology; it has the structure described in general formula I; the antitumor compound provided by this invention has good antitumor activity, and while maintaining highly efficient killing activity against tumor cells, its toxicity to normal cells is significantly reduced, resulting in a wider therapeutic window and potential clinical safety advantages.

Description

Technical Field

[0001] This invention relates to the field of antitumor compound technology, and in particular to an antitumor compound, its preparation method, and its application. Background Technology

[0002] Cancer, as a malignant disease that seriously threatens human health, is harmful not only in the structural destruction of normal tissues and organs by abnormally proliferating cancer cells, but also in the multiple organ failure caused by its invasive and metastatic characteristics, ultimately leading to patient death. Current clinical treatment mainly employs a comprehensive strategy including surgical resection, radiotherapy, chemotherapy, and emerging targeted therapies and immunotherapies. Among these, chemotherapy, as a systemic treatment, remains the core treatment for most mid-to-late-stage cancers. However, traditional chemotherapy drugs, due to their non-specific mechanisms of action, indiscriminately attack normal dividing cells while killing cancer cells, leading to serious toxic side effects such as bone marrow suppression causing anemia and infection risks, severe vomiting due to gastrointestinal mucosal damage, and hair loss due to damage to hair follicle cells. Furthermore, long-term use easily induces drug resistance, resulting in diminished efficacy. Therefore, developing novel drugs with precise targeting characteristics, selectively killing tumor cells, and reducing systemic toxicity has become an urgent need to improve the safety and effectiveness of cancer treatment. Summary of the Invention

[0003] In view of this, the main objective of the present invention is to provide an antitumor compound, its preparation method and application. The antitumor compound provided by the present invention has good antitumor activity, and while maintaining highly efficient killing activity against tumor cells, its toxicity to normal cells is significantly reduced, resulting in a wider therapeutic window and potential clinical safety advantages.

[0004] To achieve the above objectives, the technical solution of the present invention is as follows:

[0005] In a first aspect, the present invention provides an antitumor compound, characterized in that it has the structure described in general formula I:

[0006]

[0007] In Formula I, R1 is selected from hydrogen and methoxy; R2 is selected from hydrogen and chlorine; R3 is selected from 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl, 2-(pyrrolidine-1-yl)ethyl, 2-(pyrrolidine-1-yl)propyl, 2-(piperidin-1-yl)ethyl, 2-(piperidin-1-yl)propyl, 2-(4-methylpiperazin-1-yl)propyl, 3-(dimethylamino)-2-hydroxypropyl, 3-cyclopentyl-2-hydroxypropyl, 3-cyclohexyl-2-hydroxypropyl, 2-hydroxy-3-(pyrrolidine-1-yl)propyl, 2-hydroxy-3-(piperidin-1-yl)propyl, and 2-hydroxy-3-(4-methylpiperazin-1-yl)propyl.

[0008] Furthermore, the compound is selected from any one of the following formulas: 7A-7F, 8A-8H, and 10A-10K.

[0009]

[0010] Furthermore, in the aforementioned structure, R1 is hydrogen, R2 is chlorine, and R3 is 3-(pyrrolidine-1-yl)propyl.

[0011] In a second aspect, the present invention provides an intermediate having the structure described in general formula II:

[0012]

[0013] In Formula II, R1 is selected from hydrogen and methoxy; R2 is selected from hydrogen and chlorine;

[0014] The intermediate is used in the synthesis of the compound described in Formula I above.

[0015] In a third aspect, the present invention provides a method for preparing the aforementioned intermediate, comprising the following preparation route:

[0016] Further, the preparation method of compound 3 is as follows: compound 1, compound 2, NaOH and EtOH are mixed and the reactants are stirred at 100°C for 3-5 hours. After the reaction is completed, the mixture is cooled to room temperature, and concentrated sulfuric acid is added dropwise to the reaction solution to make the pH between 6 and 8. The solid is precipitated, filtered, washed with water, and dried to obtain compound 3.

[0017] The preparation method of compound 4 is as follows: compound 3, toluene, DMF and POCl3 are mixed and stirred at 100°C for 20-40 min. After the reaction is completed, the solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 4.

[0018] The preparation method of compound 5 is as follows: compound 4, anhydrous ethanol and aniline are mixed and reacted at 80°C for 40-80 min, cooled to room temperature, solvent is removed under reduced pressure, and purified by silica gel column chromatography to obtain compound 5;

[0019] The preparation method of compound 6 is as follows: compound 5, DCE and trifluoromethanesulfonic acid are mixed and reacted at 85°C for 40-80 min. After the reaction is completed, water is added while stirring to precipitate solid. The reaction system is distilled to distill out DCE. Then, the mixture is refluxed at 100°C for 7-9 h, cooled to room temperature, filtered, and the solid is washed with saturated sodium bicarbonate solution to obtain compound 6.

[0020] Furthermore, when synthesizing compound 3, the molar ratio of compound 1, compound 2, and NaOH is 1:1:1; the mass-to-volume ratio of compound 1 to EtOH is 1g:150ml~200ml;

[0021] When synthesizing compound 4, the molar ratio of compound 3 to POCl3 was 1:3; the mass-to-volume ratio of compound 3 to toluene was 1g:40ml-50ml; and the volume ratio of N,N-dimethylformamide (DMF) to toluene was 1:50-100.

[0022] When synthesizing compound 5, the molar ratio of compound 4 to aniline was 1:1.5 to 2.5; the mass-to-volume ratio of compound 4 to anhydrous ethanol was 1 g:30 ml to 45 ml.

[0023] When synthesizing compound 6, the mass-to-volume ratio of compound 5 to trifluoromethanesulfonic acid was 1 g: 10 ml to 20 ml.

[0024] In a fourth aspect, the present invention provides the use of any of the compounds described above in the preparation of tumor treatment products.

[0025] Furthermore, the tumors include: squamous cell carcinoma of the tongue, rhabdomyosarcoma, osteosarcoma, bladder cancer, and melanoma.

[0026] The beneficial effects of this invention include at least the following:

[0027] The antitumor compounds provided by this invention have good antitumor activity, and while maintaining high efficiency in killing tumor cells, they significantly reduce toxicity to normal cells, thus having a wider therapeutic window and potential clinical safety advantages. Attached Figure Description

[0028] Figure 1 This is the NMR spectrum of compound 7A.

[0029] Figure 2 This is the NMR spectrum of compound 7B.

[0030] Figure 3 This is the NMR spectrum of compound 7C.

[0031] Figure 4 This is the NMR spectrum of compound 7D.

[0032] Figure 5 This is the NMR spectrum of compound 7E.

[0033] Figure 6 This is the NMR spectrum of compound 7F.

[0034] Figure 7 This is the NMR spectrum of compound 8A.

[0035] Figure 8 This is the NMR spectrum of compound 8B.

[0036] Figure 9 This is the NMR spectrum of compound 8C.

[0037] Figure 10 This is the NMR spectrum of compound 8D.

[0038] Figure 11 This is the NMR spectrum of compound 8E.

[0039] Figure 12 This is the NMR spectrum of compound 8F.

[0040] Figure 13 This is the NMR spectrum of compound 8G.

[0041] Figure 14 This is the NMR spectrum of compound 8H.

[0042] Figure 15 The image shows the NMR spectrum of compound 10A.

[0043] Figure 16 This is the NMR spectrum of compound 10B.

[0044] Figure 17 This is the NMR spectrum of compound 10C.

[0045] Figure 18 This is the NMR spectrum of compound 10D.

[0046] Figure 19 The NMR spectrum of compound 10E is shown.

[0047] Figure 20 This is the NMR spectrum of compound 10F.

[0048] Figure 21 The image shows the NMR spectrum of compound 10G.

[0049] Figure 22 This is the NMR spectrum of compound 10H.

[0050] Figure 23 The image shows the NMR spectrum of compound 10I.

[0051] Figure 24 The image shows the NMR spectrum of compound 10J.

[0052] Figure 25 This is the NMR spectrum of compound 10K.

[0053] Figure 26 The image shows the HRMS spectrum of compound 7A.

[0054] Figure 27 The image shows the HRMS spectrum of compound 7B.

[0055] Figure 28 This is the HRMS spectrum of compound 7C.

[0056] Figure 29 The image shows the HRMS spectrum of compound 7D.

[0057] Figure 30 The image shows the HRMS spectrum of compound 7E.

[0058] Figure 31 The image shows the HRMS spectrum of compound 7F.

[0059] Figure 32 The image shows the HRMS spectrum of compound 8A.

[0060] Figure 33 This is the HRMS spectrum of compound 8B.

[0061] Figure 34 This is the HRMS spectrum of compound 8C.

[0062] Figure 35 The image shows the HRMS spectrum of compound 8D.

[0063] Figure 36 The image shows the HRMS spectrum of compound 8E.

[0064] Figure 37 The image shows the HRMS spectrum of compound 8F.

[0065] Figure 38 The image shows the HRMS spectrum of compound 8G.

[0066] Figure 39 This is the HRMS spectrum of compound 8H.

[0067] Figure 40 The image shows the HRMS spectrum of compound 10A.

[0068] Figure 41 The image shows the HRMS spectrum of compound 10B.

[0069] Figure 42 This is the HRMS spectrum of compound 10C.

[0070] Figure 43 The image shows the HRMS spectrum of compound 10D.

[0071] Figure 44 The image shows the HRMS spectrum of compound 10E.

[0072] Figure 45 The image shows the HRMS spectrum of compound 10F.

[0073] Figure 46 The image shows the HRMS spectrum of compound 10G.

[0074] Figure 47 The image shows the HRMS spectrum of compound 10H.

[0075] Figure 48 The image shows the HRMS spectrum of compound 10I.

[0076] Figure 49 The image shows the HRMS spectrum of compound 10J.

[0077] Figure 50 The image shows the HRMS spectrum of compound 10K. Detailed Implementation

[0078] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0079] Furthermore, the technical solutions of the various embodiments of the present invention can be combined with each other, but only if they are based on the ability of those skilled in the art to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such combination of technical solutions does not exist and is not within the scope of protection claimed by the present invention.

[0080] The following specific embodiments illustrate the solution proposed in this invention:

[0081] Example 1: Preparation of the compound

[0082] 1. Synthesis of Compound 3

[0083] Under electromagnetic stirring, benzoamidine hydrochloride 1 (324 mg, 2.7 mmol), ethyl 2-cyano-3-ethoxyacrylate 2 (456 mg, 2.7 mmol), NaOH (108 mg, 2.7 mmol), and EtOH (60 mL) were added sequentially to a 100 mL round-bottom flask. The reaction mixture was stirred at 100 °C for 4 h (TLC was used to monitor the reaction progress, with the developing solvent being VEA:VPE = 1:2). After the reaction was completed, the flask was cooled to room temperature, and concentrated sulfuric acid (0.2 mL) was added dropwise to the reaction solution to maintain the pH between 6 and 8, thereby neutralizing most of the NaOH. A large amount of solid precipitated, which was filtered, washed with water (3 × 10 mL), and dried to obtain 335 mg of a light yellow solid of compound 3, with a yield of 62%.

[0084] 2. Synthesis of Compound 4

[0085] Under electromagnetic stirring, compound 3 (335 mg, 1.7 mmol), toluene (15 mL), N,N-dimethylformamide (DMF) (0.2 mL), and POCl3 (0.5 mL, 5.1 mmol) were sequentially added to a 50 mL round-bottom flask. The mixture was stirred at 100 °C for 0.5 h (TLC was used to monitor the reaction progress, with VEA:VPE as the eluent: 1:1). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: VEA:VPE = 1:30) to give 258 mg of a white solid of compound 4, with a yield of 69%.

[0086] 3. Synthesis of Compound 5

[0087] Compound 4 (258 mg, 1.3 mmol), anhydrous ethanol (10 mL), and aniline (177 mg, 1.9 mmol) were added sequentially to a 50 mL round-bottom flask under electromagnetic stirring. The reaction was carried out at 80 °C for 1 h (TLC was used to monitor the reaction progress, with the developing solvent being VEA:VPE = 1:4). After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: VEA:VPE = 1:30) to give 350 mg of compound 5 as a white solid, with a yield of 99%.

[0088] 4. Synthesis of Compound 6

[0089] Under electromagnetic stirring, compound 5 (350 mg, 1.3 mmol), DCE (8 mL), and trifluoromethanesulfonic acid (5 mL) were added sequentially to a 50 mL round-bottom flask and reacted at 85 °C for 1 h (TLC monitoring of reaction progress, developing solvent: VEA:VPE = 1:40). The reaction solution was transferred to a 250 mL round-bottom flask, and 50 mL of water was added while stirring, resulting in the precipitation of a large amount of bright yellow solid. The reaction apparatus was then changed to a distillation apparatus, and DCE was distilled off at 90 °C, followed by reflux at 100 °C for 8 h. At this point, the bright yellow solid turned into a pale yellow solid. After cooling to room temperature, the solid was filtered and washed with saturated sodium bicarbonate solution (2 × 10 mL) to obtain 246 mg of compound 6 as a pale yellow solid, with a yield of 70%.

[0090] 5. Synthesis of compound 7 (taking the synthesis of 7A and 7B as examples)

[0091] Under electromagnetic stirring, compound 6 (246 mg, 0.9 mmol), DMF (8 mL), 2-chloroethyldimethylamine hydrochloride (193 mg, 1.2 mmol), and anhydrous potassium carbonate (993 mg, 7.2 mmol) were sequentially added to a 50 mL round-bottom flask and reacted at 100 °C for 12 h (TLC monitoring of reaction progress, eluent: VEA:VPE = 1:4). After cooling to room temperature, 30 mL of water was added, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with water (3 × 10 mL), dried, and purified by silica gel column chromatography (eluent: VEA:VPE = 1:30) to give 267 mg of compound 7A as a white solid, with a yield of 99%.

[0092] Under electromagnetic stirring, compound 6 (275 mg, 1 mmol), DMF (9 mL), N-(2-chloroethyl)pyrrolidine hydrochloride (221 mg, 1.3 mmol), and anhydrous potassium carbonate (1103 mg, 8 mmol) were sequentially added to a 50 mL round-bottom flask and reacted at 100 °C for 12 h (TLC monitoring of reaction progress, eluent: VEA:VPE = 1:4). After cooling to room temperature, 30 mL of water was added, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was washed with water (3 × 10 mL), dried, and purified by silica gel column chromatography (eluent: VEA:VPE = 1:30) to give 353 mg of compound 7B as a yellow solid, with a yield of 95%.

[0093] (7A-7F) and (8A-8H) can be prepared using the same method.

[0094] 6. Synthesis of Compound 9

[0095] Compound 6 (246 mg, 0.9 mmol) and epichlorohydrin (4 mL) were added sequentially to a 50 mL round-bottom flask under electromagnetic stirring. The mixture was heated to reflux under a heating mantle and reacted for 4 h (TLC monitoring of the reaction progress, developing solvent:VEA:VPE = 1:4). After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: DCM) to give 220 mg of compound 9 as a white solid, with a yield of 83%.

[0096] 7. Synthesis of Compound 10 (taking the synthesis of 10A and 10B as examples)

[0097] Under electromagnetic stirring, dimethylamine (55 mg, 0.86 mmol), anhydrous potassium carbonate (338 mg, 1.72 mmol), and acetonitrile (4 mL) were sequentially added to a 50 mL round-bottom flask. After stirring at 80 °C for 30 min, compound 9 (220 mg, 0.43 mmol) was added, and the reaction was allowed to proceed for 4 h (TLC monitoring of the reaction progress, eluent: VDCM:VEA:VMeOH = 9:3:1). After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: VDCM:VEA:VMeOH = 9:3:1) to give 60 mg of compound 10A as a yellow solid, with a yield of 35%.

[0098] Under electromagnetic stirring, tetrahydropyrrole (mg, 0.78 mmol), anhydrous potassium carbonate (307 mg, 1.56 mmol), and acetonitrile (4 mL) were sequentially added to a 50 mL round-bottom flask. After stirring at 80 °C for 30 min, compound 9 (200 mg, 0.39 mmol) was added, and the reaction was allowed to proceed for 4 h (TLC monitoring of the reaction progress, eluent: VDCM:VEA:VMeOH = 9:3:1). After cooling to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography (eluent: VDCM:VEA:VMeOH = 9:3:1) to give 57 mg of compound 10B as a yellow solid, with a yield of 37%.

[0099] The same method can be used to prepare 10A-10K.

[0100] Characterization of the compound in Example 2

[0101] The characterization data of compounds (7A-7F) and (8A-8H) are shown below:

[0102] Compound 7A:

[0103] 10-(2-Dimethylaminoethyl)-2-phenylpyrido[4,5-b]quinoline-5(10H)-one (7A), pale yellow solid, yield 74%, melting point 205-207℃. 1 H NMR(400MHz, CDCl3)δ9.67(s,1H),8.62–8.57(m,2H),8.56–8.51(m,1H),7.84–7.78(m,1H),7.70–7.6 5(m,1H),7.57–7.50(m,3H),7.43–7.37(m,1H),4.99–4.89(m,2H),2.79(t,J=7.9Hz,2H),2.47(s,6H). 13C NMR (100MHz, CDCl3) δ177.5,166.1,159.1,155.0,141.6,137.1,135.0,13 1.9,129.1,128.7,128.0,124.7,123.2,115.7,112.2,56.0,46.1,41.7.C 21 H 21 [M+H] of N4O + The theoretical calculated value of HRMS(ESI) m / z for the ion is 345.1710, and the actual detected value is 345.1710.

[0104] Compound 7B:

[0105] 2-Phenylon-10-(2-pyrrolidinylethyl)pyrido[4,5-b]quinoline-5(10H)-one (7B), pale yellow solid, 71% yield, melting point 179–181 °C. 1 H NMR(400MHz, CDCl3)δ9.65(s,1H),8.61–8.56(m,2H),8.51(dd,J=8.0,1.6Hz,1H),7.82–7.77(m,1H),7.71–7.67(m,1H) ,7.55–7.50(m,3H),7.40–7.35(m,1H),5.02–4.88(m,2H),2.95(t,J=8.1Hz,2H),2.80–2.73(m,4H),1.91–1.84(m,4H). 13 C NMR (100MHz, CDCl3) δ177.4,166.1,159.1,154.9,141.6,137.0,135.0,131. 8,129.1,128.7,127.9,124.7,123.2,115.8,112.1,54.7,52.7,42.5,23.6.C 23 H 23 N4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 371.1866, while the actual detected value is 371.1864.

[0106] Compound 7C:

[0107] 2-Phenylacetyl-10-(2-piperidinylethyl)pyrimido[4,5-b]quinoline-5(10H)-one (7C), pale yellow solid, 99% yield, melting point 150–152 °C. 1H NMR (400MHz, CDCl3) δ9.67(s,1H),8.62–8.57(m,2H),8.53(dd,J=8.0,1.5Hz,1H),7.83–7.78(m,1H),7.73–7.68(m,1H),7.57–7. 50(m,3H),7.42–7.36(m,1H),5.05–4.88(m,2H),2.80(t,J=7.7Hz,2H),2.70–2.56(m,4H),1.66–1.58(m,4H),1.52–1.43(m,2H). 13 C NMR (100MHz, CDCl3) δ177.4,166.0,159.1,155.0,141.7,137.1,134.9,131.8,1 29.1,128.6,127.8,124.6,123.1,115.8,112.1,55.7,55.2,41.2,26.0,24.2.C 24 H 25 N4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 385.2023, and the actual detected value is also 385.2023.

[0108] Compound 7D:

[0109] 2-(4-Chlorophenyl)-10-(2-dimethylaminoethyl)pyrimidino[4,5-b]quinoline-5(10H)-one (7D), pale yellow solid, 96% yield, melting point 237–239 °C. 1 H NMR(400MHz, CDCl3)δ9.63(s,1H),8.54–8.49(m,3H),7.85–7.80(m,1H),7.71–7.66(m,1H), 7.51–7.47(m,2H),7.40(t,J=7.3Hz,1H),5.00–4.86(m,2H),2.80–2.73(m,2H),2.46(s,6H). 13 C NMR (100MHz, CDCl3) δ177.4,165.1,159.1,154.8,141.4),138.2,135.4,1 35.2,130.3,129.0,127.9,124.6,123.4,115.6,112.1,55.7,45.9,41.3.C 20 H 21 ClN4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 379.1320, while the actual detected value is 379.1326.

[0110] Compound 7E:

[0111] 2-(4-Chlorophenyl)-10-(2-pyrrolidinylethyl)pyrimido[4,5-b]quinoline-5(10H)-one (7E), pale yellow solid, 72% yield, melting point 182–184 °C. 1 H NMR(400MHz, CDCl3)δ9.62(s,1H),8.55–8.47(m,3H),7.84–7.78(m,1H),7.77–7.68(m,1H),7.52–7.46(m ,2H),7.42–7.36(m,1H),5.05–4.87(m,2H),2.97(t,J=8.0Hz,2H),2.89–2.68(m,4H),1.97–1.85(m,4H). 13 C NMR (100MHz, CDCl3) δ177.3,165.1,159.1,154.8,141.4,138.2,135.5,135. 1,130.3,128.9,127.9,124.6,123.3,115.8,112.1,54.6,52.6,42.2,23.6.C 23 H 22 ClN4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 405.1477, while the actual detected value is 405.1476.

[0112] Compound 7F:

[0113] 2-(4-Chlorophenyl)-10-(2-piperidinylethyl)pyrimido[4,5-b]quinoline-5(10H)-one (7F), pale yellow solid, yield 57%, melting point 190–192 °C. 1 H NMR(400MHz, CDCl3)δ9.64(s,1H),8.55–8.49(m,3H),7.84–7.78(m,1H),7.73–7.68(m,1H),7.52–7.47(m,2H),7.4 2–7.36(m,1H),5.02–4.82(m,2H),2.79(t,J=7.7Hz,2H),2.72–2.52(m,4H),1.65–1.59(m,4H),1.52–1.43(m,2H). 13CNMR (100MHz, CDCl3) δ177.3,165.0,159.1,154.9,141.6,138.1,135.5,135.0, 130.3,128.9,127.8,124.6,123.,115.9,112.1,55.6,55.2,41.2,25.9,24.1.C 24 H 24 ClN4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 419.1633, while the actual detected value is 419.1631.

[0114] Compound 8A:

[0115] 10-(3-Dimethylaminopropyl)-2-phenylpyrimidino[4,5-b]quinoline-5(10H)-one (8A), pale yellow solid, 84% yield, melting point 236–238 °C. 1 H NMR (400MHz, CDCl3) δ9.67 (s, 1H), 8.65–8.56 (m, 2H), 8.52 (dd, J = 8.0, 1.5Hz, 1H), 7.84–7.72 (m, 2H), 7.58 –7.49(m,3H),7.41–7.35(m,1H),5.05–4.69(m,2H),2.50(t,J=6.7Hz,2H),2.29(s,6H),2.13–2.00(m,2H). 13 C NMR (100MHz, CDCl3) δ177.5,165.9,159.1,154.8,141.7,137.1,134.8,131. 8,129.1,128.6,127.8,124.6,123.0,115.9,112.1,57.0,45.6,41.7,25.8.C 22 H 23 N4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 359.1866, while the actual detected value is 359.1868.

[0116] Compound 8B:

[0117] 2-Phenylacetyl-10-(3-pyrrolidinylpropyl)pyrimido[4,5-b]quinoline-5(10H)-one (8B), pale yellow solid, yield 61%, melting point 238–240 °C. 1H NMR(400MHz, CDCl3)δ9.54(s,1H),8.53–8.44(m,2H),8.44–8.37(m,1H),7.86–7.79(m,1H),7.78–7.72(m,1H),7.55–7.46 (m,3H),7.38–7.31(m,1H),5.13–5.87(m,2H),3.30–3.24(m,2H),3.10–2.81(m,4H),2.52–2.37(m,2H),2.12–1.92(m,4H). 13 C NMR (100MHz, CDCl3) δ177.3,166.0,159.0,154.8,141.0,136.6,135.6,132.0,1 28.9,128.8,127.7,124.3,123.6,115.8,111.9,53.8,53.0,40.3,24.5,23.1.C 24 H 25 N4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 385.2023, and the actual detected value is also 385.2023.

[0118] Compound 8C:

[0119] Phenyl-10-(3-piperidinylpropyl)pyrimido[4,5-b]quinoline-5(10H)-one (8C), pale yellow solid, yield 59%, melting point 222–224 °C. 1 H NMR(400MHz, CDCl3)δ9.56(s,1H),8.51–8.44(m,2H),8.44–8.39(m,1H),7.88–7.76(m,2H),7.54–7.45(m,3H),7.36(t,J=7.3Hz,1H),4. 95(s,2H),3.67–3.30(m,2H),3.28–3.14(m,2H),3.06–2.94(m,2H),2.69–2.49(s,2H),2.20–1.66(d,J=106.3Hz,5H),1.45–1.23(s,1H). 13 C NMR (100MHz, CDCl3) δ177.4,166.0,159.0,154.7,141.0,136.6,135.7,132.0,128 .9,128.8,127.6,124.3,123.7,116.0,111.9,54.9,53.3,40.4,22.6,22.5,21.8.C 25 H 27N4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 399.2179, while the actual detected value is 399.2178.

[0120] Compound 8D:

[0121] 10-(3-(4-methylpiperazin-1-yl)propyl)-2-phenylpyrimidino[4,5-b]quinoline-5(10H)-one (8D), pale yellow solid, 91% yield, melting point 139–141 °C. 1 H NMR (400MHz, CDCl3) δ9.68(s,1H),8.64–8.57(m,2H),8.56–8.51(m,1H),7.83–7.76(m,2H),7.59–7. 52(m,3H),7.43–7.36(m,1H),5.06–4.77(m,2H),2.65–2.36(m,8H),2.32(s,3H),2.18–1.85(m,4H). 13 C NMR (100MHz, CDCl3) δ177.5,165.9,159.1,155.0,141.7,137.1,134.8,131.8,129 .1,128.7,127.8,124.7,123.1,116.0,112.2,55.6,55.1,53.2,46.0,41.7,24.8.C 25 H 28 N5O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 414.2288, while the actual detected value is 414.2286.

[0122] Compound 8E:

[0123] 2-(4-Chlorophenyl)-10-(3-dimethylaminopropyl)pyrimidino[4,5-b]quinoline-5(10H)-one (8E), pale yellow solid, yield 62%, melting point 160–162 °C. 1 H NMR(400MHz, CDCl3)δ9.63(s,1H),8.58–8.47(m,3H),7.83–7.77(m,1H),7.76–7.70(m,1H),7.53–7.4 4(m,2H),7.43–.34(m,1H),5.01–4.68(m,2H),2.49(t,J=6.6Hz,2H),2.29(s,6H),2.10–2.01(m,2H). 13C NMR (100MHz, CDCl3) δ177.4,165.0,159.1,154.9,141.7,138.1,135.6,135. 0,130.4,128.9,127.8,124.7,123.2,117.0,112.2,57.0,45.7,41.7,25.8.C 22 H 22 ClN4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 393.1477, while the actual detected value is 393.1448.

[0124] Compound 8F:

[0125] 2-(4-Chlorophenyl)-10-(3-pyrrolidinylpropyl)pyrimido[4,5-b]quinoline-5(10H)-one (8F), pale yellow solid, 48% yield, melting point 158–160 °C. 1 H NMR(600MHz, CDCl3)δ9.63(s,1H),8.56–8.44(m,3H),7.83–7.78(m,1H),7.75–7.70(m,1H),7.52–7.45(m,2H),7.4 1–7.37(m,1H),5.03–4.72(m,2H),2.69(t,J=7.1Hz,2H),2.61–2.49(m,4H),2.17–2.10(m,2H),1.85–1.77(m,4H). 13 CNMR (150MHz, CDCl3) δ177.5,165.0,159.1,154.8,141.5,138.1,135.5,135.1, 130.4,128.9,127.8,124.5,123.3,116.0,112.1,54.2,53.6,41.6,26.8,23.4.C 24 H 24 ClN4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 419.1633, while the actual detected value is 419.1636.

[0126] Compound 8G:

[0127] 2-(4-Chlorophenyl)-10-(3-piperidinylpropyl)pyrimido[4,5-b]quinoline-5(10H)-one (8G), pale yellow solid, 84% yield, melting point 154–156 °C. 1H NMR(400MHz, CDCl3)δ9.62(s,1H),8.53–8.48(m,3H),7.81–7.76(m,2H),7.50–7.46(m,2H),7.40–7.35(m,1H),4.9 8–4.70(m,2H),2.53(t,J=6.7Hz,2H),2.50–4.22(m,4H),2.13–2.05(m,2H),1.66–1.58(m,4H),1.52–1.42(m,2H). 13 CNMR (100MHz, CDCl3) δ177.4,164.9,159.1,154.8,141.6,138.1,135.5,134.9,130 .3,128.9,127.7,124.6,123.2,116.1,112.1,56.3,54.7,41.8,25.9,24.8,24.3.C 25 H 25 ClN4O[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 433.1790, while the actual detected value is 433.1785.

[0128] Compound 8H:

[0129] 2-(4-Chlorophenyl)-10-(3-(4-methylpiperazin-1-yl)propyl)pyrimido[4,5-b]quinoline-5(10H)-one (8H), pale yellow solid, 94% yield, melting point 226–228 °C. 1 H NMR(400MHz, CDCl3)δ9.63(s,1H),8.57–8.44(m,3H),7.85–7.70(m,2H),7.56–7.43(m,2H),7.43–7. 35(m,1H),5.05–4.69(m,2H),2.59–2.42(m,6H),2.31(s,3H),2.12–2.05(m,2H),1.86–1.35(s,2H). 13 C NMR (100MHz, CDCl3) δ177.5,164.9,159.1,154.9,141.6,138.2,135.5,134.9,130 .3,128.9,127.8,124.6,123.3,116.0,112.2,55.6,55.0,52.9,45.8,41.7,24.7.C 25 H 26 ClN5O[M+H] +The theoretical calculated value of the HRMS (ESI) m / z for the ion is 448.1899, while the actual detected value is 448.1894.

[0130] The characterization data of compound 10A-10K are shown below:

[0131] Compound 10A:

[0132] 10-(3-(dimethylamino)-2-hydroxypropyl)-2-phenylpyrido[4,b]quinoline-5(10H)-one (10A), pale yellow solid, yield 35%, melting point 232-234℃. 1 H NMR(600MHz, CDCl3)δ9.59(s,1H),8.53–8.50(m,2H),8.45–8.41(m,1H),7.97–7.94(m,1H),7.80–7.77(m,1H),7.53–7.49(m,3H), 7.35(t,J=7.5Hz,1H),5.13–5.02(m,1H),4.68–4.57(m,1H),4.34–4.29(m,1H),2.74–2.69(m,1H),2.56–2.52(m,1H),2.32(s,6H). 13 C NMR (150MHz, CDCl3) δ177.5,165.7,159.0,155.3,142.4,136.7,134.9,131. 9,128.9,128.7,127.3,124.3,123.4,117.1,112.0,66.9,63.5,47.8,45.6.C 22 H 23 N4O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 375.1816, while the actual detected value is 375.1820.

[0133] Compound 10B:

[0134] 10-(2-hydroxy-3-(pyrrolidone-1-yl)propyl)-2-phenylpyrido[4,b]quinoline-5(10H)-one (10B), pale yellow solid, yield 33%, melting point 181-182 °C. 1H NMR(400MHz, CDCl3)δ9.64(s,1H),8.61–8.51(m,2H),8.51–8.43(m,1H),7. 99–7.92(m,1H),7.84–7.77(m,1H),7.58–7.48(m,3H),7.42–7.36(m,1H),5 .16–5.06(m,1H),4.74–4.63(m,1H),4.40–4.32(m,1H),3.02–2.94(m,1H), 2.80–2.67(m,3H),2.65–2.56(m,2H),1.85–1.73(m,4H),1.28–1.18(s,1H). 13 CNMR(100MHz,DMSO-d6)δ176.5,164.6,158.2,155.2,142.4,136.6,134.7,132.0 ,128.8,128.7,126.2,123.9,123.1,118.1,111.9,66.4,60.1,54.3,47.4,23.0.C 24 H 25 N4O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 401.1972, while the actual detected value is 401.1979.

[0135] Compound 10C:

[0136] 2-(4-chlorophenyl)-10-(2-hydroxy-3-(piperidin-1-yl)propyl)pyrido[4,b]quinoline-5(10H)-one (10C), pale yellow solid, 85% yield, melting point 185–187 °C. 1 H NMR(400MHz, CDCl3)δ9.63(s,1H),8.56–8.43(m,3H),8.07–7.95(m,1H),7.84–7.78(m,1H),7.55–7.47(m,2H),7.43–7.36(m,1H),5.18–4.97 (m,1H),4.78–4.58(m,1H),4.38–4.24(m,1H),2.70–2.55(m,4H),2.51 –2.36(m,2H),1.65–1.54(m,4H),1.51–1.41(m,2H),1.30–1.22(m,1H). 13C NMR (100MHz, CDCl3) δ177.4,164.8,159.2,155.5,142.4,138.3,135.4,134.9,130 .3,129.1,127.5,124.6,123.5,117.1,112.3,66.3,62.8,54.9,47.9,25.9,24.0.C 25 H 27 N4O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 415.2129, while the actual detected value is 415.2135.

[0137] Compound 10D:

[0138] 10-(2-hydroxy-3-(4-methylpiperazin-1-yl)propyl)-2-phenylpyrido[4,b]quinoline-5(10H)-one (10D), pale yellow solid, 70% yield, melting point 180–182 °C. 1 H NMR(400MHz, CDCl3)δ9.64(s,1H),8.56–8.51(m,2H),8.50–8.46(m,1H),8 .02–7.96(m,1H),7.82–7.77(m,1H),7.57–7.50(m,3H),7.38(t,J=7.4Hz,1 H),5.15–4.99(m,1H),4.79–4.62(m,1H),4.39–4.29(m,1H),4.11–3.82(m, 1H),2.75–2.63(m,4H),2.60–2.36(m,5H),2.29(s,3H),1.95–1.83(m,1H). 13 C NMR(100MHz,DMSO-d6)δ176.5,164.5,158.2,155.3,142.34,136.6,134.7,132.0,12 8.8,128.7,126.3,123.9,123.0,118.0,111.9,64.9,62.9,54.56,53.5,47.8,45.7.C 25 H 28 N5O2[M+H] + The theoretical calculated value of HRMS (ESI) m / z for the ion is 430.2238, while the actual detected value is 430.2244.

[0139] Compound 10E:

[0140] 2-(4-Chlorophenyl)-10-(3-(dimethylamino)-2-hydroxypropyl)pyrido[4,b]quinoline-5(10H)-one (10E), pale yellow solid, 48% yield, melting point 175–178 °C. 1 H NMR(400MHz, DMSO-d6)δ9.46(s,1H),8.56–8.50(m,2H),8.32–8.27(m,1H),8.11–8.01(m,1H),7.90–7.84(m,1H),7.66–7.60( m,2H),7.42(t,J=7.5Hz,1H),5.28–4.36(m,3H),4.21–4.07(m,1H),2.66–2.57(m,1H),2.49–2.42(m,1H),2.30–2.18(m,6H). 13 C NMR(100MHz,DMSO-d6)δ176.4,163.6,158.3,155.0,142.5,136.9,135.4,134 .7,130.4,128.9,126.2,123.9,123.1,118.3,111.9,66.5,63.9,47.9,46.1.C 22 H 22 ClN4O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 409.1426, while the actual detected value is 409.1431.

[0141] Compound 10F:

[0142] 2-(4-chlorophenyl)-10-(2-hydroxy-3-(pyrrolidine-1-yl)propyl)pyrido[4,b]quinoline-5(10H)-one (10F), pale yellow solid, yield 62%, melting point 228–230 °C. 1 H NMR(600MHz,DMSO-d6)δ9.48(s,1H),8.60–8.54(m,2H),8.35–8.30(m,1H),8.12–8.07(m,1H),7.92–7.87(m,1H),7.66–7.61( m,2H),7.45(t,J=7.4Hz,1H),5.23–4.64(m,2H),4.52–4.37(m,1H),3.40–3.30(m,4H),3.14–2.98(m,2H),1.91–1.75(m,4H). 13C NMR(100MHz,DMSO-d6)δ176.5,163.6,158.3,155.3,136.9,135.5,134.8,130 .4,129.0,126.3,124.0,123.2,118.1,112.0,54.2,31.0,23.0,22.1,14.0.C 24 H 24 ClN4O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 435.1582, while the actual detected value is 435.1579.

[0143] Compound 10g:

[0144] 2-(4-chlorophenyl)-10-(2-hydroxy-3-(piperidin-1-yl)propyl)pyrido[4,b]quinoline-5(10H)-one (10G), pale yellow solid, 71% yield, melting point 204–206 °C. 1 H NMR(400MHz, CDCl3)δ9.63(s,1H),8.57–8.43(m,3H),8.07–7.95(m,1H),7.84–7.77(m,1H),7.56–7.46(m,2H),7.40(t,J=7.5Hz,1H),5.18–4.9 7(m,1H),4.78–4.58(m,1H),4.38–4.24(m,1H),2.70–2.54(m,4H),2.51 –2.35(m,2H),1.65–1.54(m,4H),1.51–1.41(m,2H),1.30–1.22(m,1H). 13 C NMR (100MHz, CDCl3) δ177.4,164.8,159.2,155.5,142.4,138.3,135.4,134.9,130 .3,129.1,127.5,124.6,123.5,117.1,112.3,66.3,62.8,54.9,47.9,25.9,24.0.C 25 H 26 ClN4O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 449.1739, while the actual detected value is 449.1741.

[0145] Compound 10H:

[0146] 2-(4-Chlorophenyl)-10-(2-hydroxy-3-(4-methylpiperazin-1-yl)propyl)pyrido[4,b]quinoline-5(10H)-one (10H), pale yellow solid, 35% yield, melting point 208–210 °C. 1 H NMR(400MHz, CDCl3)δ9.58(s,1H),8.47–8.41(m,3H),7.95–7.89(m,1H),7.82–7.75(m,1H),7.50–7.44(m,2H),7.37(t,J =7.5Hz,1H),5.06–4.94(m,1H),4.75–4.61(m,1H),4.35–4.25(m,1H),2.72–2.59(m,5H),2.51–2.35(s,5H),2.28(s,3H). 13 C NMR(100MHz,DMSO-d6)δ176.4,163.5,158.2,155.2,142.2,136.9,135.4,134.7,13 0.3,129.0,126.3,123.9,123.1,117.9,118.0,64.9,62.8,54.5,53.4,47.7,45.6.C 25 H 27 ClN5O2[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 464.1848, while the actual detected value is 464.1854.

[0147] Compound 10I:

[0148] 10-(3-(dimethylamino)-2-hydroxypropyl)-7-methoxy-2-phenylpyrido[4,b]quinoline-5(10H)-one (10I), pale yellow solid, yield 52%, melting point 205-207℃. 1 H NMR(600MHz, CDCl3)δ9.60(s,1H),8.54–8.51(m,2H),7.94–7.91(m,1H),7.85–7.79(m,1H),7.54–7.50(m,3H),7.43–7.39(m, 1H),5.15–5.06(m,1H),4.68–4.57(m,1H),4.37–4.31(m,1H),3.89(s,3H),2.78–2.72(m,1H),2.61–2.56(m,1H),2.36(s,6H). 13C NMR (150MHz, CDCl3) δ177.0,165.4,159.2,155.8,154.4,136.8,131.87,128 .9,128.7,125.3,125.0,118.8,111.3,106.7,66.9,63.4,55.8,47.8,45.5.C 23 H 25 N4O3[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 405.1921, while the actual detected value is 405.1927.

[0149] Compound 10J:

[0150] 10-(2-hydroxy-3-(pyrrolidone-1-yl)propyl)-7-methoxy-2-phenylpyrido[4,b]quinoline-5(10H)-one (10J), pale yellow solid, yield 47%, melting point 217-219℃. 1 H NMR(600MHz, CDCl3)δ9.62(s,1H),8.53–8.49(m,2H),7.93–7.90(m,1H),7.86–7.82(m,1H),7.54–7.50(m,3H),7.44–7.40(m,1H) ,5.16–5.08(m,1H),4.72–4.61(m,1H),4.45–4.39(m,1H),3.90(s,3H),2.83–2.77(m,4H),2.73–2.71(m,2H),1.84–1.80(m,4H). 13 C NMR (150MHz, CDCl3) δ177.1,165.5,159.3,155.9,154.4,136.7,136.7,131.9,128 .9,128.7,125.3,125.1,118.8,111.3,106.8,67.5,60.1,55.8,54.5,47.6,23.3.C 25 H 27 N4O3[M+H] + The theoretical calculated value of HRMS (ESI) m / z for the ion is 431.2078, while the actual detected value is 431.2084.

[0151] Compound 10K:

[0152] 10-(2-hydroxy-3-(piperidin-1-yl)propyl)-7-methoxy-2-phenylpyrido[4,b]quinoline-5(10H)-one (10K), pale yellow solid, yield 53%, melting point 188-190℃. 1H NMR(600MHz, CDCl3)δ9.59(s,1H),8.53–8.47(m,2H),7.96–7.91(m,1H),7 .85–7.79(m,1H),7.55–7.48(m,3H),7.43–7.38(m,1H),5.18–4.99(m,1H) ,4.80–4.54(m,1H),4.47–4.33(m,1H),3.88(s,3H),2.80–2.72(m,3H),2. 70–2.59(m,3H),2.58–2.46(m,2H),1.67–1.56(m,4H),1.49–1.36(m,2H). 13 C NMR (151MHz, CDCl3) δ177.08,165.42,159.22,155.87,154.32,136.72,136.70,131.88,128.88,12 8.70,125.25,125.01,118.85,111.25,106.74,66.05,62.68,55.72,54.82,47.72,25.11,23.42.C 26 H 29 N4O3[M+H] + The theoretical calculated value of the HRMS (ESI) m / z for the ion is 445.2229, while the actual detected value is 445.2228.

[0153] Example 3: Compounds on IC50 in different cells 50 Research

[0154] To test whether the synthesized target compounds possess good antitumor activity, this embodiment selected five human tumor cell lines—Cal27 (human tongue squamous cell carcinoma cells), A673 (human rhabdomyosarcoma cells), 143B (human osteosarcoma cells), T24 (human bladder transitional cell carcinoma cells), and A375 (human malignant melanoma cells)—as well as one normal cell line, HaCaT (human immortalized epidermal cells), to test the toxicity of the compounds. Doxorubicin (DOX) was used as a positive control, and the antitumor activity of the target compounds 7A–7F, 8A–8H, and 10A–10K was determined using the MTT assay. The results are shown in Tables 1 and 2.

[0155] Table 1 shows the IC50 values ​​of the compounds for different cell lines. 50 value

[0156]

[0157]

[0158] a: Represented as three independent mean ± SD (standard deviation); b: DOX: Doxorubicin.

[0159] Table 2 shows the IC50 values ​​of the compounds for different cell lines. 50 value

[0160]

[0161] a: Represented as three independent mean ± SD (standard deviation); b: DOX: Doxorubicin.

[0162] The results showed that compound 8E exhibited significantly superior targeting properties compared to the positive control drug DOX in in vitro cytotoxicity selectivity index (SI) evaluation. Specifically, its IC50 value against human malignant melanoma A375 cells was 6.15 ± 0.30 μM, while its IC50 value against normal skin cells (Hacat) was 1.49 ± 0.56 μM, resulting in an calculated SI value of 4.13, which was 9-fold higher than that of the positive control drug (SI = 0.43). This result indicates that compound 8E maintains highly efficient tumor cell killing activity while significantly reducing toxicity to normal cells, suggesting a wider therapeutic window and potential clinical safety advantages.

[0163] The sequence numbers of the above embodiments of the present invention are for descriptive purposes only and do not represent the superiority or inferiority of the embodiments.

[0164] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. An antitumor compound, characterized in that, It has the structure described in general formula I: ； In Formula I, R1 is selected from hydrogen and methoxy; R2 is selected from hydrogen and chlorine; R3 is selected from 2-(dimethylamino)ethyl, 2-(dimethylamino)propyl, 2-(pyrrolidine-1-yl)ethyl, 2-(pyrrolidine-1-yl)propyl, 2-(piperidin-1-yl)ethyl, 2-(piperidin-1-yl)propyl, 2-(4-methylpiperazin-1-yl)propyl, 3-(dimethylamino)-2-hydroxypropyl, 3-cyclopentyl-2-hydroxypropyl, 3-cyclohexyl-2-hydroxypropyl, 2-hydroxy-3-(pyrrolidine-1-yl)propyl, 2-hydroxy-3-(piperidin-1-yl)propyl, and 2-hydroxy-3-(4-methylpiperazin-1-yl)propyl.

2. The antitumor compound according to claim 1, characterized in that, The compound is selected from any one of the following formulas: 7A-7F, 8A-8H, and 10A-10K. 。 3. The compound according to claim 1, characterized in that, In the structure described, R1 is hydrogen, R2 is chlorine, and R3 is 2-(pyrrolidone-1-yl)propyl.

4. An intermediate, characterized in that, It has the structure described in Formula II: ； In Formula II, R1 is selected from hydrogen; R2 is selected from hydrogen and chlorine; The intermediate is used in the synthesis of the compound of claim 1.

5. A method for preparing the intermediate according to claim 4, characterized in that, The preparation should be carried out according to the following route: 。 6. The preparation method according to claim 5, characterized in that, The preparation method of compound 3 is as follows: compound 1, compound 2, NaOH and EtOH are mixed and the reactants are stirred at 100°C for 3-5 hours. After the reaction is completed, the mixture is cooled to room temperature. Concentrated sulfuric acid is added dropwise to the reaction solution to make the pH between 6 and 8. The solid is precipitated, filtered, washed with water, and dried to obtain compound 3. The preparation method of compound 4 is as follows: compound 3, toluene, DMF and POCl3 are mixed and stirred at 100°C for 20-40 min. After the reaction is completed, the solvent is removed under reduced pressure, and the residue is purified by silica gel column chromatography to obtain compound 4. The preparation method of compound 5 is as follows: compound 4, anhydrous ethanol and aniline are mixed and reacted at 80°C for 40-80 min, cooled to room temperature, solvent is removed under reduced pressure, and purified by silica gel column chromatography to obtain compound 5; The preparation method of compound 6 is as follows: compound 5, DCE and trifluoromethanesulfonic acid are mixed and reacted at 85°C for 40-80 min. After the reaction is completed, water is added while stirring to precipitate solid. The reaction system is distilled to distill out DCE. Then, the mixture is refluxed at 100°C for 7-9 h, cooled to room temperature, filtered, and the solid is washed with saturated sodium bicarbonate solution to obtain compound 6.

7. The preparation method according to claim 6, characterized in that, When synthesizing compound 3, the molar ratio of compound 1, compound 2, and NaOH is 1:1:1; the mass-volume ratio of compound 1 to EtOH is 1g:150ml~200ml. When synthesizing compound 4, the molar ratio of compound 3 to POCl3 was 1:3; the mass-to-volume ratio of compound 3 to toluene was 1g:40ml~50ml; and the volume ratio of N,N-dimethylformamide (DMF) to toluene was 1:50~100. When synthesizing compound 5, the molar ratio of compound 4 to aniline is 1:1.5~2.5; the mass-to-volume ratio of compound 4 to anhydrous ethanol is 1g:30ml~45ml. When synthesizing compound 6, the mass-to-volume ratio of compound 5 to trifluoromethanesulfonic acid was 1 g: 10 ml to 20 ml.

8. The use of any one of the compounds according to claims 1 to 3 in the preparation of tumor treatment products.

9. The application according to claim 8, characterized in that, The tumors include: squamous cell carcinoma of the tongue, rhabdomyosarcoma, osteosarcoma, bladder cancer, and melanoma.

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