A uracilcarbazole derivative, preparation method and application

Abstract

The application belongs to the technical field of organic synthesis chemistry and medicinal chemistry, and particularly relates to a uracil and carbazole derivative, a preparation method and application. 1 selected from hydrogen, methyl, methoxy, halogen, trifluoromethyl or cyano; R 2 selected from hydrogen, C1-6 alkyl or phenyl; R 3 selected from C1-6 alkyl or benzyl; R 4 selected from hydrogen,, naphthyl, 1,2-methylenedioxyphenyl, thienyl or cyclopropyl; R 5 is hydrogen, methyl, methoxy or halogen; the compound has excellent antitumor activity, some of the compounds present broad-spectrum inhibition characteristics, has low toxicity to normal liver cells L02, the preparation method is efficient, and the yield is relatively high.

Description

Technical Field

[0001] This invention belongs to the fields of organic synthetic chemistry and medicinal chemistry, specifically relating to a uracil-carbazole derivative, its preparation method, and its application. Background Technology

[0002] Carbazole is an important nitrogen-containing heterocyclic skeleton widely found in natural products and drug molecules. Carbazole derivatives exhibit a variety of biological activities, including antitumor, antibacterial, anti-inflammatory, neuroprotective, and hypoglycemic effects, attracting widespread attention in the field of medicinal chemistry. In recent years, numerous studies have shown that carbazole compounds exert their antitumor effects through multiple mechanisms, such as inducing cell cycle arrest, promoting apoptosis, inhibiting angiogenesis, and interfering with cell migration.

[0003] Ellipticine, a naturally derived carbazole alkaloid, exerts its antitumor effects by intercalating into the DNA double helix and inhibiting topoisomerase II activity. Its derivative, 2-methyl-9-hydroxyellipticine acetate (Celiptium), has shown success in the treatment of advanced breast cancer. Indole-carbazole compounds (such as staurosporine, rebeccamycin, and their derivatives) exhibit broad antitumor activity through multiple mechanisms, including inhibiting protein kinases and targeting topoisomerase I; some of these compounds have entered clinical trials. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a uracil-carbazole derivative, its preparation method and application. The compounds of the present invention have excellent antitumor activity and some compounds exhibit broad-spectrum inhibitory characteristics. They have low LO2 toxicity to normal hepatocytes. The preparation method is efficient and has a high yield.

[0005] This invention provides a uracil-carbazole derivative, the structural formula of which is:

[0006] in: R 1 Selected from hydrogen, methyl, methoxy, halogen, trifluoromethyl, or cyano; R 2 Selected from hydrogen, C1-6 alkyl, or phenyl; R 3 Selected from C1-6 alkyl or benzyl groups; R 4 Selected from hydrogen, Naphthyl, 1,2-methylenedioxyphenyl, thienyl or cyclopropyl; R 5 It can be hydrogen, methyl, methoxy, or halogen.

[0007] Preferred, R 1 Selected from hydrogen, methyl, Cl, F or trifluoromethyl; R 2 Selected from hydrogen or methyl; R 3 Selected from methyl or benzyl; R 4 It is selected from phenyl, naphthyl, 1,2-methylenedioxyphenyl or thiophene.

[0008] Preferred, R 1 Selected from hydrogen, methyl, Cl, or F; R 2 Selected from hydrogen or methyl; R 3 Selected from methyl; R 4 Selected from phenyl.

[0009] Preferred, R 1 Selected from hydrogen, methyl, or Cl; R 2 Selected from hydrogen or methyl; R 3 Selected from methyl; R 4 Selected from phenyl.

[0010] Preferred, R 1 Selected from hydrogen; R 2 Selected from hydrogen; R 3 Selected from methyl; R 4 Selected from phenyl.

[0011] This invention provides a method for preparing the uracil-carbazole derivative, wherein a 6-vinyluracil compound and an indole compound are heated and stirred under reaction conditions of a catalyst, an oxidant, and an organic solvent. The general structural formula of the 6-vinyluracil compounds is as follows: ; Among them, R 3 Selected from C1-6 alkyl or benzyl; R 4 Selected from hydrogen, Naphthyl, 1,2-methylenedioxyphenyl, thienyl, or cyclopropyl; R 5 It can be hydrogen, methyl, methoxy, or halogen; The general structural formula of the indole compounds is as follows: ; Where: R 1 Selected from hydrogen, methyl, methoxy, halogen, trifluoromethyl, or cyano; R 2 Selected from hydrogen, C1-6 alkyl, or phenyl; The catalyst is at least one of elemental iodine, KI, NaI, HI, NaIO4, NH4I, tetrabutylammonium iodide, NIS, or IBr; The oxidant is at least one of DDQ, DMSO, tert-butyl hydroperoxide, di-tert-butyl peroxide, K2S2O8, and p-benzoquinone.

[0012] Preferably, the organic solvent is selected from at least one of chlorobenzene, toluene, trifluorotoluene, p-xylene, 1,4-dioxane, acetonitrile, cyclohexane, pyridine, ethylbenzene, anisole, and ethyl acetate.

[0013] Preferably, the molar ratio of the 6-vinyluracil compound, indole compound, catalyst, and oxidant is 1.0:1.0-2.0:0.05-0.5:0-2.0; the reaction temperature is 100-140℃; and the reaction atmosphere is air, oxygen, or argon.

[0014] This invention provides an application of the uracil-carbazole derivative, which is used to prepare substances that fight tumor cells.

[0015] Preferably, the tumor is colorectal cancer, pancreatic cancer, breast cancer, or liver cancer.

[0016] The beneficial effects of this invention are that its synthetic method is innovative, efficient, and environmentally friendly. This invention, for the first time, uses 6-vinyluracil compounds and indole compounds as raw materials, and in the presence of an iodine catalyst and an oxidant, constructs a uracil-carbazole fused-ring skeleton in one step through a [4+2] cycloaddition-dehydrogenation tandem reaction. Compared with the shortcomings of existing technologies, such as reliance on multi-step synthesis, transition metal (e.g., copper, palladium) catalysis, strong acid and strong base conditions, and highly functionalized substrates, this invention has outstanding advantages such as short reaction steps, high atom economy, no need for transition metals, mild reaction conditions (100-140 °C), and simple operation. The method of this invention has broad substrate applicability, achieving high yields for substrates with various substituents. For example, the yield in Example 1 is as high as 90%, in Example 2 it is 79%, and in Example 17 it is 69%, providing a new route for the efficient preparation of this type of fused-ring compound.

[0017] This invention presents novel and diverse molecular structures. By introducing uracil structural fragments into the carbazole backbone, a new class of uracil-carbazole fused-ring molecules is constructed. This is achieved through the manipulation of R¹-R... 5 Systematic substitution modification at multiple sites yielded a rich and diverse library of compounds, which not only expanded the π-conjugated system but also regulated the electronic and spatial effects of molecules. This provides novel and diverse molecular entities for the discovery of antitumor lead compounds, effectively solving the problem of single molecular structure and lack of drug screening basis in existing technologies.

[0018] The compounds of this invention exhibit excellent antitumor activity, and some compounds show broad-spectrum inhibitory characteristics. In vitro MTT assay screening results for antitumor activity show that the compounds of this invention exhibit excellent inhibitory activity against various human tumor cell lines. For example, the compound in Example 7 showed good broad-spectrum inhibitory activity against colon cancer, pancreatic cancer, breast cancer, and liver cancer; the compound in Example 10 showed extremely strong inhibitory activity against colon cancer, with an IC50 value of [missing value]. 50 The concentration reached 6.89 ± 0.84 μM; the compound in Example 1 showed selective and efficient inhibitory activity against pancreatic cancer cells; the compounds in Examples 8 and 12 also showed good inhibitory activity against colon cancer.

[0019] This invention exhibits low toxicity to normal cells, a wide safety window, and significant drug development potential. Unlike most antitumor compounds that lack selectivity, some compounds in this invention demonstrate good tumor selectivity while effectively inhibiting tumor cells and exhibiting low toxicity to normal hepatocytes. For example, the compound in Example 1 shows an IC50 value against normal hepatocyte LO2. 50 Greater than 100 μM, while the IC50 against pancreatic cancer cells PANC-1... 50 The selectivity index was 17.71 μM, indicating a high selectivity index; the IC50 of the compound in Example 7 against LO2 was... 50 The concentration was 62.31 ± 1.78 μM, significantly higher than its IC50 for most cancer cells. 50 The value indicates that the compound has a good safety window.

[0020] In summary, this invention not only provides a novel, efficient, green, and universally applicable method for synthesizing uracil-carbazole compounds, but also yields a class of novel fused-ring compounds with excellent antitumor activity and good selectivity. These compounds can serve as antitumor lead compounds, particularly as candidate drug molecules for colon cancer, pancreatic cancer, breast cancer, and liver cancer, possessing significant value in drug development and promising clinical applications. Detailed Implementation

[0021] Example 1 2,4,11-Trimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0022] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 90% yield.

[0023] 1 H NMR (500 MHz, CDCl3) δ 7.57 (s, 5H), 7.51 (d, J = 8.2 Hz, 1H), 7.43(t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.90 (s, 1H), 4.12 (s, 3H), 3.70 (s, 3H), 3.58 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ160.8, 151.5, 144.2, 144.1, 141.5, 140.4, 140.0, 128.8, 128.7, 128.6, 125.8,122.1, 121.4, 120.3, 118.6, 110.3, 107.0, 100.3, 37.0, 32.0, 28.8.

[0024] Example 2 2,4,7,11-Tetramethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0025] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.3 mmol of 1,4-dimethyl-1H-indole, and 0.05 mmol of elemental iodine. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 79% yield.

[0026] 1 H NMR (500 MHz, CDCl3) δ 7.49 – 7.45 (m, 5H), 7.39 – 7.34 (m, 2H), 6.91 (d, J = 6.6 Hz, 1H), 6.83 (s, 1H), 4.05 (s, 3H), 3.68 (s, 3H), 3.57 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.6, 151.5, 145.0, 144.1, 143.6, 142.5,139.6, 132.9, 129.2, 128.3, 128.06, 125.8, 123.9, 121.3, 119.4, 107.6, 107.6,99.2, 37.4, 31.8, 28.7, 22.3.

[0027] Example 3 8-Methoxy-2,4,11-trimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0028] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.35 mmol of 5-methoxy-1-methyl-1H-indole, and 0.02 mmol of elemental iodine. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 64% yield.

[0029] 1 H NMR (500 MHz, CDCl3) δ 7.58 – 7.56 (m, 5H), 7.39 (d, J = 8.9 Hz, 1H), 7.04 (dd, J = 8.9, 2.6 Hz, 1H), 6.88 (s, 1H), 6.62 (d, J = 2.5 Hz, 1H), 4.09 (s, 3H), 3.70 (s, 3H), 3.57 (d, J = 1.4 Hz, 6H). 13 C NMR (125 MHz, CDCl3) δ160.8, 154.1, 151.4, 144.0, 141.8, 140.5, 139.8, 139.1, 128.8, 128.6, 128.6,122.5, 118.5, 114.6, 110.9, 106.4, 104.3, 100.2, 55.4, 37.0, 32.0, 28.8.

[0030] Example 4 8-Chloro-2,4,11-trimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0031] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 5-chloro-1-methyl-1H-indole, and 0.01 mmol of elemental iodine. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 2 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 52% yield.

[0032] 1 H NMR (500 MHz, CDCl3) δ 7.60 – 7.57 (m, 3H), 7.54 (dd, J = 6.7, 3.0Hz, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.36 (dd, J = 8.7, 2.0 Hz, 1H), 7.12 (d, J =2.0 Hz, 1H), 6.91 (s, 1H), 4.09 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H). 13 C NMR(125 MHz, CDCl3) δ 160.6, 151.3, 144.3, 142.4, 141.8, 140.9, 139.3, 128.9,128.9, 128.5, 125.8, 123.2, 120.9, 117.6, 111.2, 107.4, 100.3, 37.1, 32.0,28.8.

[0033] Example 5 2,4,11-Trimethyl-1,3-dione-6-phenyl-2,3,4-11-tetrahydro-1H-pyrimidino[5,4-a]carbazole-9-nitrile, with the following structural formula: .

[0034] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole-6-onitrile, and 0.1 mmol of KI. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 4 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 35% yield.

[0035] 1 H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.61 – 7.58 (m, 3H), 7.55 –7.52 (m, 2H), 7.25 (d, J = 9.1 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 4.15 (s, 3H), 3.72 (s, 3H), 3.58 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.5,151.3, 145.0, 143.0, 142.7, 141.9, 139.2, 129.0, 129.0, 128.5, 125.7, 123.5,121.9, 119.8, 117.5, 114.3, 108.2, 108.1, 100.5, 37.2, 32.1, 28.8.

[0036] Example 6 2,4,10,11-Tetramethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0037] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1,7-dimethyl-1H-indole, and 0.1 mmol of NaI, without solvent, and add a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 6 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 26% yield.

[0038] 1 H NMR (500 MHz, CDCl3) δ 7.55 (s, 5H), 7.16 (d, J = 7.2 Hz, 1H), 7.01(d, J = 7.9 Hz, 1H), 6.92 – 6.87 (m, 2H), 4.01 (s, 3H), 3.70 (s, 3H), 3.58 (s, 3H), 2.82 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.4, 151.5, 145.2, 144.5,143.9, 140.4, 139.9, 128.9, 128.7, 128.7, 128.5, 123.6, 122.4, 120.9, 119.3,119.2, 107.6, 100.4, 41.1, 31.9, 28.7, 20.1.

[0039] Example 7 2,4-Dimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0040] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1H-indole, and 0.1 mmol of HI. Add 0.5 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 9 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 79% yield.

[0041] 1 H NMR (500 MHz, CDCl3) δ 10.65 (s, 1H), 7.64 (dd, J = 7.6, 1.8 Hz,2H), 7.59 – 7.56 (m, 3H), 7.52 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.84 (s, 1H), 3.68 (s, 3H), 3.57 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 163.0, 151.4, 144.6, 139.9, 139.8,139.4, 138.8, 128.8, 128.7, 128.6, 125.7, 121.8, 121.6, 120.1, 116.5, 111.2,105.9, 97.9, 31.5, 28.1.

[0042] Example 8 7-Fluoro-2,4-dimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0043] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 4-fluoro-1H-indole, and 0.05 mmol of NaIO4. Add 0.8 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 10 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 74% yield.

[0044] 1 H NMR (500 MHz, CDCl3) δ 10.85 (s, 1H), 7.50 (s, 5H), 7.35 – 7.29 (m,2H), 6.87 (s, 1H), 6.76 (dd, J = 14.3, 5.4 Hz, 1H), 3.67 (s, 3H), 3.58 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 163.0, 156.9 (d, J = 252.7 Hz), 151.3, 145.5,142.2 (d, J = 9.8 Hz), 141.7 (d, J = 4.1 Hz), 139.3, 138.8, 128.8 (d, J = 3.6Hz), 128.0, 127.6, 126.6 (d, J = 8.4 Hz), 115.1 (d, J = 4.0 Hz), 110.2 (d, J =20.1 Hz), 107.2, 107.0 (d, J = 3.8 Hz), 106.9 (d, J = 21.5 Hz), 97.5, 31.5, 28.1. 19 F NMR (471 MHz, CDCl3) δ -105.36.

[0045] Example 9 2,4,8-Trimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: 。

[0046] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 5-methyl-1H-indole, and 0.1 mmol of NH4I. Add 0.3 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 13 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 38% yield.

[0047] 1 H NMR (500 MHz, CDCl3) δ 10.55 (s, 1H), 7.66 – 7.63 (m, 2H), 7.59 –7.56 (m, 3H), 7.41 (d, J = 8.9 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 6.81 (s, 1H), 3.67 (s, 3H), 3.56 (s, 3H), 2.32 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 163.0,151.4, 144.5, 140.0, 139.6, 138.7, 138.01, 129.4, 128.8, 128.6, 127.0, 121.9,121.6, 121.5, 116.3, 110.9, 105.7, 97.8, 31.5, 28.1, 21.5.

[0048] Example 10 8-Chloro-2,4-dimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0049] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 5-methyl-1H-indole, and 0.1 mmol of tetrabutylammonium iodide. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 15 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 52% yield.

[0050] 1 H NMR (500 MHz, CDCl3) δ 10.65 (s, 1H), 7.65 (dd, J = 7.6, 2.0 Hz,2H), 7.60 – 7.56 (m, 3H), 7.53 (d, J = 8.1 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.05(t, J = 7.5 Hz, 1H), 6.85 (s, 1H), 3.68 (s, 3H), 3.58 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 163.1, 151.4, 144.6, 139.9, 139.8, 139.4, 138.9, 128.8, 128.7,128.6, 125.7, 121.8, 121.6, 120.1, 116.5, 111.2, 105.9, 97.9, 31.5, 28.1.

[0051] Example 11 2,4-Dimethyl-6-phenyl-9-(trifluoromethyl)-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0052] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.3 mmol of 6-trifluoromethyl-1H-indole, and 0.1 mmol of NIS. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 16 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 73% yield.

[0053] 1 H NMR (500 MHz, CDCl3) δ 10.83 (s, 1H), 7.80 (s, 1H), 7.64 – 7.59 (m,5H), 7.48 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H), 3.71 (s, 3H), 3.59 (s, 3H). 13 C NMR (125 MHz, CDCl3)δ 162.9, 151.3, 145.3, 140.4, 139.8, 139.4, 138.9, 129.0, 128.9, 128.7, 127.4 (q, J = 31.9 Hz), 124.6 (q, J =270.4 Hz), 124.5, 121.8, 116.8 (q, J = 3.5 Hz), 115.65, 108.5 (q, J = 4.2Hz), 106.8, 98.1, 31.6, 28.2. 19 F NMR (471 MHz, CDCl3) δ -61.23.

[0054] Example 12 2,4,10-Trimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0055] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 6-trifluoromethyl-1H-indole, and 0.05 mmol of IBr. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 100°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 50% yield. 1 H NMR (500MHz, CDCl3) δ 10.55 (s, 1H), 7.65 – 7.63 (m, 2H), 7.58 – 7.55 (m, 3H), 7.27(t, J = 3.8 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.85(s, 1H), 3.68 (s, 3H), 3.58 (s, 3H), 2.62 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ163.2, 151.4, 144.7, 139.9, 139.2, 139.2, 138.7, 128.8, 128.7, 128.6, 126.3,121.4, 120.5, 120.2, 119.2, 117.0, 106.0, 97.9, 31.5, 28.1, 16.9. Example 13 11-Ethyl-2,4-dimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0056] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-ethyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of chlorobenzene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 110 °C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 35% yield.

[0057] 1 H NMR (500 MHz, CDCl3) δ 7.57 (s, 6H), 7.41 (t, J = 7.7 Hz, 1H), 7.14(d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.91 (s, 1H), 4.86 (q, J = 7.0Hz, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 1.47 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDCl3) δ 161.0, 151.3, 144.1, 143.0, 140.4, 140.0, 140.0, 128.7, 128.7,128.5, 125.6, 122.5, 121.4, 120.2, 119.0, 110.6, 107.2, 100.8, 43.2, 32.1,28.9, 14.7.

[0058] Example 14 11-Ethyl-2,4-dimethyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0059] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-phenyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of trifluorotoluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 43% yield.

[0060] 1 H NMR (500 MHz, CDCl3) δ 7.65 – 7.58 (m, 5H), 7.52 (t, J = 7.7 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 7.9 Hz, 1H), 7.05 – 7.01 (m, 1H), 7.00 (s, 1H), 3.70 (s, 3H), 3.25 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 159.3, 151.5, 144.2, 144.2,144.0, 142.2, 140.3, 140.0, 129.0, 128.8, 128.7, 128.6, 127.1, 125.8, 125.8,122.3, 121.3, 121.0, 119.4, 111.5, 108.1, 100.6, 31.9, 28.5.

[0061] Example 15 2,4-Dimethyl-6-phenyl-11,12-dihydro-10H-pyrido[3,2,1-jk]pyrimido[5,4-a]carbazole-1,3(2H,4H)-dione, with the following structural formula: .

[0062] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, and 0.1 mmol of elemental iodine. Add 1 mL of p-xylene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 130 °C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 36% yield.

[0063] 1 H NMR (500 MHz, CDCl3) δ 7.60 – 7.55 (m, 5H), 7.13 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.89 (s, 1H), 4.80 (t, J = 6.0 Hz, 2H), 3.70 (s, 3H), 3.57 (s, 3H), 3.05 (t, J = 6.0 Hz, 2H), 2.19(p, J = 6.0 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 161.0, 151.4, 144.3, 140.2,140.1, 139.5, 139.3, 128.7, 128.6, 128.5, 123.2, 123.2, 120.3, 120.0, 119.0,118.5, 106.4, 100.2, 48.9, 32.0, 28.7, 25.4, 24.0.

[0064] Example 16 2,4,11-Trimethyl-6-(p-Tolyl)-4,11-Dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0065] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-(4-methylstyryl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of 1,4-dioxane as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 140°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 44% yield.

[0066] 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.88 (s, 1H), 4.11 (s, 3H), 3.69 (s, 3H), 3.57(s, 3H), 2.52 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.8, 151.4, 144.2, 144.1,141.4, 140.4, 138.4, 137.0, 129.4, 128.6, 125.7, 122.2, 121.4, 120.2, 118.6,110.2, 107.1, 100.0, 36.9, 31.9, 28.7, 21.4.

[0067] Example 17 6-(4-methoxyphenyl)-2,4,11-trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0068] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 6-(4-methoxystyryl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of acetonitrile as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 69% yield.

[0069] 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.6 Hz, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.04 (t, J = 7.5 Hz,1H), 6.87 (s, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H). 13 CNMR (125 MHz, CDCl3) δ 160.8, 159.9, 151.5, 144.1, 143.9, 141.5, 140.4,132.2, 130.0, 125.7, 122.2, 121.4, 120.2, 118.7, 114.1, 110.2, 107.1, 100.0, 55.4, 37.0, 32.0, 28.8.

[0070] Example 18 6-(4-chlorophenyl)-2,4,11-trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0071] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 6-(4-chlorostyryl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of cyclohexane as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 79% yield.

[0072] 1 H NMR (500 MHz, CDCl3) δ 7.56 – 7.51 (m, 5H), 7.45 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.85 (s, 1H), 4.12 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.7, 151.4,144.2, 142.6, 141.5, 140.4, 138.4, 134.7, 130.1, 129.0, 125.9, 121.9, 121.2,120.4, 118.4, 110.3, 106.9, 100.4, 37.0, 32.0, 28.8.

[0073] Example 19 6-(3-methoxyphenyl)-2,4,11-trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0074] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 6-(3-methoxystyryl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of pyridine as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 71%.

[0075] 1 H NMR (500 MHz, CDCl3) δ 7.51 – 7.46 (m, 2H), 7.43 (t, J = 8.2 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 10.5 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 4.12 (s, 3H), 3.86 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.7, 159.7, 151.3, 144.0,143.7, 141.3, 141.2, 140.3, 129.7, 125.7, 122.0, 121.4, 121.0, 120.2, 118.4,114.1, 114.1, 110.1, 106.8, 100.2, 55.3, 36.9, 31.9, 28.7.

[0076] Example 20 6-(3-chlorophenyl)-2,4,11-trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0077] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 6-(3-chlorostyryl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of ethylbenzene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 62%.

[0078] 1 H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.55 – 7.42 (m, 5H), 7.20 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.85 (s, 1H), 4.11 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.6, 151.3, 144.1, 142.1,141.6, 141.3, 140.3, 134.6, 129.9, 128.7, 128.6, 127.0, 125.9, 121.7, 121.1,120.4, 118.3, 110.3, 106.7, 100.4, 36.9, 32.0, 28.7.

[0079] Example 21 2,4,11-Trimethyl-6-(o-tolyl)-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0080] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-(2-methylstyryl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of anisole as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 47% yield.

[0081] 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.5 Hz,1H), 7.44 – 7.36 (m, 3H), 7.31 (d, J = 7.4 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.15 (s, 3H), 3.70 (s, 3H), 3.59 (s, 3H), 2.07 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.9, 151.4, 144.0, 143.4,141.0, 140.5, 139.4, 135.9, 130.2, 128.6, 128.57, 126.2, 125.7, 122.3, 120.7,120.6, 119.1, 110.1, 106.5, 100.3, 36.9, 32.0, 28.7, 19.6. Example 22 6-(2-fluorophenyl)-2,4,11-trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0082] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 6-(2-fluorostyryl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine. Add 1 mL of ethyl acetate as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 58% yield.

[0083] 1 H NMR (500 MHz, CDCl3) δ 7.58 – 7.54 (m, 1H), 7.51 – 7.47 (m, 2H),7.43 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 9.0 Hz, 1H), 7.09 – 7.03 (m, 2H), 6.95 (s, 1H), 4.12 (s, 3H), 3.70 (s, 3H), 3.58 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.7, 159.6 (d, J = 247.8 Hz), 151.3, 144.1,141.2, 140.3, 136.9, 130.6 (d, J = 7.9 Hz), 130.6 (d, J = 7.9 Hz), 127.4,127.3, 125.9, 124.5 (d, J = 3.6 Hz), 122.0, 120.6 (d, J = 26.2 Hz), 119.2, 116.1 (d, J = 21.6 Hz), 110.2, 107.3, 100.8, 36.9, 32.0, 28.7. 19 F NMR (471 MHz, CDCl3) δ -114.68.

[0084] Example 23 2,4,11-Trimethyl-6-(naphth-1-yl)-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0085] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-(2-(naphth-1-yl)vinyl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, 0.1 mmol of elemental iodine, and 0.2 mmol of DDQ. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then purge with argon gas, repeating this process three times to ensure an argon atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 36% yield.

[0086] 1 H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.2 Hz,1H), 7.66 (t, 1H), 7.56 (d, J = 5.6 Hz, 1H), 7.52 – 7.46 (m, 3H), 7.34 (t, J =7.5 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.03 (s, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 4.18 (s, 3H), 3.68 (s, 3H), 3.61 (s, 3H). 13 C NMR (125MHz, CDCl3) δ 160.9, 151.4, 144.1, 142.1, 141.1, 140.4, 137.5, 133.5, 131.4,128.8, 128.3, 126.7, 126.3, 126.3, 125.7, 125.5, 121.9, 121.3, 120.4, 120.0, 110.0, 107.7, 100.6, 36.9, 32.1, 28.8.

[0087] Example 24 6-(benzo[d][1,3]dioxacyclopenten-4-yl)-2,4,11-trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0088] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 6-(2-(benzo[d][1,3]dioxo-4-yl)vinyl)-1,3-dimethylpyrimidin-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, 0.1 mmol of elemental iodine, and 0.4 mmol of DMSO. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then purge with argon gas, repeating this process three times to ensure an argon atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 57%. 1 H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 8.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H),7.05 – 7.01 (m, 3H), 7.00 (s, 1H), 5.95 (d, J = 22.5 Hz, 2H), 4.12 (s, 3H), 3.71 (s, 3H), 3.57 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.7, 151.4, 147.8,145.0, 144.1, 141.4, 140.4, 137.3, 125.9, 122.7, 122.1, 122.0, 121.4, 121.2,120.4, 118.8, 110.2, 108.9, 107.1, 101.1, 100.7, 37.0, 32.0, 28.8.

[0089] Example 25 2,4,11-Trimethyl-6-(thiophen-2-yl)-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0090] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-(2-(thiophen-2-yl)vinyl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, 0.1 mmol of elemental iodine, and 0.3 mmol of tert-butyl hydroperoxide. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then purge with argon gas, repeating this process three times to ensure an argon atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 35% yield.

[0091] 1 H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 3.9 Hz, 1H), 7.50 (t, J = 3.9 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.26 (t, J = 4.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.01 (s, 1H), 4.10 (s, 3H), 3.70 (s, 3H), 3.56(s, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.6, 151.3, 144.1, 141.4, 140.3, 140.1,136.2, 127.6, 127.5, 126.7, 126.0, 121.9, 121.3, 120.4, 119.3, 110.3, 108.2,100.7, 37.0, 32.0, 28.8.

[0092] Example 26 6-Cyclopropyl-2,4,11-trimethyl-4,6b,10a,11-tetrahydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0093] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dimethyl-6-(2-(thiophen-2-yl)vinyl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, 0.1 mmol of elemental iodine, and 0.3 mmol of di-tert-butyl peroxide. Add 1 mL of toluene as a solvent and add a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then purge with argon gas. Repeat this process three times to ensure an argon atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 48%.

[0094] 1 H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 7.8 Hz, 1H), 7.56 – 7.51 (m,2H), 7.34 (t, J = 7.3 Hz, 1H), 6.77 (s, 1H), 4.10 (s, 3H), 3.70 (s, 3H), 3.54(s, 3H), 2.68 – 2.61 (m, 1H), 1.28 – 1.26 (m, 2H), 0.95 (q, J = 5.6 Hz, 2H). 13 CNMR (125 MHz, CDCl3) δ 160.7, 151.4, 145.3, 143.9, 141.0, 140.7, 125.4,122.6, 122.2, 120.5, 120.5, 110.2, 103.5, 99.6, 36.9, 31.9, 28.7, 15.7, 7.5.

[0095] Example 27 2,4-Diethyl-11-methyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0096] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-diethyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, 0.1 mmol of elemental iodine, and 0.1 mmol of K₂S₂O₈. Add 1 mL of toluene as solvent, and add a magnetic stir bar under air atmosphere. Finally, seal the pressure-resistant tube and react it in an oil bath at 120 °C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 65% yield.

[0097] 1 H NMR (500 MHz, CDCl3) δ 7.56 (s, 5H), 7.48 (d, J = 8.3 Hz, 1H), 7.40(t, J = 7.7 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.89(s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 1.39(t, J = 7.1 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, CDCl3) δ 160.3,150.4, 144.1, 143.9, 141.6, 140.0, 139.5, 128.7, 128.5, 125.6, 122.1, 121.2,120.2, 118.3, 110.2, 106.7, 100.6, 39.79, 37.1, 37.0, 13.2, 12.8.

[0098] Example 28 2,4-Dibenzyl-6-phenyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0099] The preparation method is as follows: In a 15 mL pressure-resistant tube, accurately weigh 0.2 mmol of 1,3-dibenzyl-6-styrylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1H-indole, 0.1 mmol of elemental iodine, and 0.4 mmol of p-benzoquinone. Add 1 mL of toluene as solvent, and add a magnetic stir bar under air atmosphere. Finally, seal the pressure-resistant tube and react it in an oil bath at 120 °C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid in 45% yield.

[0100] 13 C NMR (125 MHz, CDCl3) δ 162.9, 151.7, 144.6, 139.8, 139.8, 139.6,138.4, 137.1, 135.9, 128.9, 128.7, 128.6, 128.6, 128.4, 127.6, 127.6, 126.6,125.7, 123.1, 121.8, 121.6, 120.9, 120.8, 120.1, 116.6, 111.2, 111.2, 106.9,98.2, 47.9, 44.8.

[0101] Example 29 2,4,11-Trimethyl-4,11-dihydro-1H-pyrimidino[5,4-a]carbazole-1,3(2H)-dione, with the following structural formula: .

[0102] The preparation method is as follows: Method 1: Accurately weigh 0.2 mmol of 6-(2-(dimethylamino)vinyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine into a 15 mL pressure-resistant tube. Add 1 mL of toluene as solvent and a magnetic stir bar under air atmosphere. Finally, seal the pressure-resistant tube and react it in an oil bath at 120°C for 8 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 32%.

[0103] Method 2: Accurately weigh 0.2 mmol of 1,3-dimethyl-6-(2-(morpholinyl)vinyl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine into a 15 mL pressure-resistant tube. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 10 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter under vacuum, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 22%.

[0104] Method 3: Accurately weigh 0.2 mmol of 1,3-dimethyl-6-(2-(piperidin-1-yl)vinyl)pyrimidine-2,4(1H,3H)-dione, 0.4 mmol of 1-methyl-1H-indole, and 0.1 mmol of elemental iodine into a 15 mL pressure-resistant tube. Add 1 mL of toluene as solvent and a magnetic stir bar. Then, evacuate the reaction tube using an oil pump, and then introduce oxygen, repeating this process three times to ensure an oxygen-rich reaction atmosphere. Finally, seal the pressure-resistant tube and place it in an oil bath at 120°C for 12 hours. After the reaction is complete, cool to room temperature, open the lid, add an appropriate amount of ethyl acetate, filter, distill under reduced pressure, and separate by column chromatography to obtain a yellow solid with a yield of 15%.

[0105] 1 H NMR (500 MHz, CDCl3) δ 8.27 (d, J = 8.6 Hz, 1H), 8.02 (d, 1H), 7.53– 7.49 (m, 2H), 7.34 – 7.29 (m, 1H), 7.04 (d, J = 8.6 Hz, 1H), 4.14 (s, 3H), 3.71 (s, 3H), 3.55 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 161.0, 151.3, 143.8,140.8, 126.5, 126.0, 122.3, 120.6, 119.1, 110.4, 105.1, 101.7, 36.7, 32.1,28.7.

[0106] Test Example 1 MTT assay was used to determine the growth inhibition rate of certain compounds on colon cancer cells. Test Method: HCT-116 colon cancer cells were cultured in RPMI 1640 or MEM medium containing 10% fetal bovine serum at 37°C and 5% CO2 in a cell culture incubator. When the cells reached the logarithmic growth phase, 5000–8000 cells per well were seeded into 96-well plates. After 24 hours of culture, the old medium was removed, and medium containing the test sample was added (100 mmol / L DMSO stock solution was prepared to experimental concentrations of 100, 50, 25, 12.5, 6.25, and 3.125 mmol / L). Each experimental concentration was tested in triplicate, and a blank control group was also included. After 72 hours of cell culture, 10 μL of MTT solution was added, and after 4 hours of incubation, the supernatant in the 96-well plates was aspirated, and 150 μL of DMSO was added to each well. The plates were then shaken for 20 minutes. The absorbance (OD value) of each well in the 96-well plate was measured at 570 nm using a microplate reader. The cell proliferation inhibition rate (IR) was calculated as follows: Cell proliferation inhibition rate (%) = (1 - average absorbance value of experimental group / average absorbance value of control group) × 100%. The half-maximal inhibitory concentration (IC50) was calculated using GraphPad Prism 7.00. 50 Values ​​(means ± SD, n = 3), detailed data are shown in Table 1. Data are calculated as the mean ± standard deviation of 3 independent experiments.

[0107] Table 1. Antiproliferative activity of some compounds against HCT-116 colon cancer cells.

[0108] Test Example 2 MTT assay was used to determine the growth inhibition rate of certain compounds on different cancer cells and normal hepatocytes. Test Method: Colon cancer cells (HCT-116), pancreatic cancer cells (PANC-1, BXPC-3), breast cancer cells (MDA-MB-231), liver cancer cells (HepG2), and normal hepatocytes (LO2) were cultured in a cell culture incubator at 37°C and 5% CO2 using RPMI 1640 or MEM medium containing 10% fetal bovine serum. When the cells reached the logarithmic growth phase, 5000-8000 cells per well were seeded into 96-well plates. After culturing for 24 hours, the old medium was removed, and medium containing the test sample was added (100 mmol / L of the target compound DMSO stock solution was prepared to experimental concentrations of 100, 50, 25, 12.5, 6.25, and 3.125 mmol / L). Each experimental concentration was tested in triplicate, and a blank control group was also included. After culturing the experimental cells for 72 hours, 10 μL of MTT solution was added, and after incubation for 4 hours, the supernatant in the 96-well plate was aspirated, and 150 μL of DMSO was added to each well. The plates were then shaken for 20 minutes. The absorbance (OD value) of each well in the 96-well plate was measured at 570 nm using a microplate reader, and the cell proliferation inhibition rate (IR) was calculated. The cell proliferation inhibition rate (%) was calculated as (1 - average absorbance value of experimental group / average absorbance value of control group) × 100%. The half-maximal inhibitory concentration (IC50) (means ± SD, n = 3) was calculated using GraphPad Prism 7.00. Specific data are shown in Table 2. The data are calculated as the mean ± standard deviation of three independent experiments.

[0109] Table 2. Antiproliferative activities of some compounds against different cancer cells and normal hepatocytes.

[0110] As can be seen from Tables 1 and 2, some compounds of the present invention have good inhibitory effects on HCT-116 colon cancer cells, and Example 1 has specific inhibitory effects on pancreatic cancer cell lines (PANC-1, BxPC-3). Example 7 has good inhibitory effects on multiple cancer cells such as HCT-116, PANC-1, BxPC-3, MDA-MB-231, and HepG2. In addition, some compounds have low toxicity to normal hepatocytes (LO2).

[0111] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; under the concept of this application, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of different aspects of one or more embodiments of this application as described above, which are not provided in detail for the sake of brevity.

[0112] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of one or more embodiments in this application should be included within the protection scope of this application.

Claims

1. A uracil-carbazole derivative, characterized in that, The structural formula of the uracil-carbazole derivative is: in: R 1 Selected from hydrogen, methyl, methoxy, halogen, trifluoromethyl, or cyano; R 2 Selected from hydrogen, C1-6 alkyl, or phenyl; R 3 Selected from C1-6 alkyl or benzyl groups; R 4 Selected from hydrogen, Naphthyl, 1,2-methylenedioxyphenyl, thienyl or cyclopropyl; R 5 It can be hydrogen, methyl, methoxy, or halogen.

2. The uracil-carbazole derivative as described in claim 1, characterized in that, R 1 Selected from hydrogen, methyl, Cl, F or trifluoromethyl; R 2 Selected from hydrogen or methyl; R 3 Selected from methyl or benzyl; R 4 It is selected from phenyl, naphthyl, 1,2-methylenedioxyphenyl or thiophene.

3. The uracil-carbazole derivative as described in claim 2, characterized in that, R 1 Selected from hydrogen, methyl, Cl, or F; R 2 Selected from hydrogen or methyl; R 3 Selected from methyl; R 4 Selected from phenyl.

4. The uracil-carbazole derivative as described in claim 3, characterized in that, R 1 Selected from hydrogen, methyl, or Cl; R 2 Selected from hydrogen or methyl; R 3 Selected from methyl; R 4 Selected from phenyl.

5. The uracil-carbazole derivative as described in claim 4, characterized in that, R 1 Selected from hydrogen; R 2 Selected from hydrogen; R 3 Selected from methyl; R 4 Selected from phenyl.

6. A method for preparing a uracil-carbazole derivative as described in any one of claims 1-5, characterized in that, The product is obtained by heating and stirring 6-vinyluracil compounds and indole compounds under reaction conditions of catalyst, oxidant and organic solvent; The general structural formula of the 6-vinyluracil compounds is as follows: ； Among them, R 3 Selected from C1-6 alkyl or benzyl; R 4 Selected from hydrogen, Naphthyl, 1,2-methylenedioxyphenyl, thienyl, or cyclopropyl; R 5 It can be hydrogen, methyl, methoxy, or halogen; The general structural formula of the indole compounds is as follows: ； Where: R 1 Selected from hydrogen, methyl, methoxy, halogen, trifluoromethyl, or cyano; R 2 Selected from hydrogen, C1-6 alkyl, or phenyl; The catalyst is at least one of elemental iodine, KI, NaI, HI, NaIO4, NH4I, tetrabutylammonium iodide, NIS, or IBr; The oxidant is at least one of DDQ, DMSO, tert-butyl hydroperoxide, di-tert-butyl peroxide, K2S2O8, and p-benzoquinone.

7. The preparation method according to claim 6, characterized in that, The organic solvent is selected from at least one of chlorobenzene, toluene, trifluorotoluene, p-xylene, 1,4-dioxane, acetonitrile, cyclohexane, pyridine, ethylbenzene, anisole, and ethyl acetate.

8. The preparation method according to claim 6, characterized in that, The molar ratio of the 6-vinyluracil compound, indole compound, catalyst, and oxidant is 1.0:1.0-2.0:0.05-0.5:0-2.0; the reaction temperature is 100-140℃; and the reaction atmosphere is air, oxygen, or argon.

9. An application of a uracil-carbazole derivative as described in any one of claims 1-5, characterized in that, The uracil-carbazole derivative is used to prepare substances that fight tumor cells.

10. The application as described in claim 9, characterized in that, The tumor is colorectal cancer, pancreatic cancer, breast cancer, or liver cancer.

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