A biphenyl benzopentaheterocyclic compound or a pharmaceutically acceptable salt thereof and use thereof

Abstract

The application discloses a kind of biphenyl benzo five-membered heterocyclic compound or its pharmaceutically acceptable salt and application thereof, belong to the field of medicinal chemistry, specifically discloses a kind of compound with polyadenylate ribose polymerase (PARP) and microtubule protein polymerization dual inhibition activity, its structure is as shown in general formula (I).In view of the limited efficacy of existing single-target anti-tumor drugs and the risk of drug interaction of combined drug, the compound simultaneously realizes the inhibition of PARP and microtubule protein in a single molecule.The in vitro test shows that the compound has good antiproliferative activity on a variety of tumor cells, and has low toxicity to normal cells;The xenograft tumor model test in vivo shows that its antitumor activity is better than PARP inhibitor Olaparib and microtubule protein polymerization inhibitor Combretastatin A-4, and does not cause major organ damage, has good safety, and shows great potential for clinical development as an antitumor drug.

Description

Technical Field

[0001] This invention relates to a biphenylbenzo5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof and its applications, belonging to the field of medicinal chemistry. Background Technology

[0002] In the field of anti-tumor treatment, traditional therapies (such as surgery, radiotherapy, and chemotherapy) are often accompanied by severe toxic side effects and have a very high risk of recurrence. Although molecularly targeted drugs have improved treatment selectivity, their clinical application is still not ideal due to tumor heterogeneity and acquired drug resistance.

[0003] Microtubules are dynamic, reversible polymers composed of α / β-tubulin dimers, involved in regulating cell mitosis and intracellular transport. Tubulin polymerization inhibitors acting on the colchicine site (CBS) are readily synthesized and have specific effects on... P Glycoprotein-mediated drug resistance and anti-angiogenic properties are advantageous; however, due to the strong toxic side effects often caused in vivo, no drugs targeting this site have been approved for marketing to date. On the other hand, poly(ADP-ribose) polymerases (such as PARP1 and PARP2) are key enzymes responsible for DNA single-strand break repair. Although PARP inhibitors can selectively kill BRCA1 / 2-mutated tumor cells through a "synthetic lethality" mechanism, their efficacy is limited in patients without such gene defects, and drug resistance is becoming increasingly prominent.

[0004] Existing research suggests that combining microtubule-targeting drugs with PARP inhibitors can have a synergistic effect: the former can block the normal intracellular transport of DNA damage repair proteins, thus perpetuating the DNA damage caused by PARP inhibitors; the latter can interfere with the function of mitotic checkpoint proteins, preventing tumor cells from escaping mitotic collapse induced by microtubule-targeting agents. Clinical evidence shows that the combination of the PARP inhibitor olaparib or veliparib with the microtubule-targeting agent paclitaxel has synergistic therapeutic value in triple-negative breast cancer and ovarian cancer (Abraham JE, et al.). Nat. Commun. 2025, 16 , 4269;ApplemanLJ, et al. Cancer Chemother. Pharmacol. 2019, 84 (1289-1301). However, this combination therapy strategy faces practical difficulties such as cumbersome dosing regimens, difficulty in controlling drug interactions, and uncertain pharmacokinetic behavior. In contrast, the strategy of using a single molecule to simultaneously inhibit two targets can effectively avoid these problems.

[0005] Currently, although several PARP and tubulin dual-target small molecule inhibitors (such as AMXI-5001 and TP-3) are in preclinical research and have shown promise for anti-tumor treatment, especially AMXI-5001 which has been advanced to clinical trials, research in this area is still insufficient overall. The structural types of dual-target compounds are relatively limited, and the dual-target activities of some compounds are low and severely unbalanced. Therefore, there is an urgent need to develop PARP and tubulin polymerization dual inhibitors with novel structures, good safety profiles, and potent inhibitory activity both in vitro and in vivo, to enrich the library of dual-target molecules in this field and thus obtain more promising anti-tumor small molecule drugs. Summary of the Invention

[0006] Purpose of the invention: The purpose of this invention is to provide a biphenylbenzo five-membered heterocyclic compound with dual inhibitory activities against PARP and tubulin polymerization, and its applications.

[0007] Technical solution: The present invention relates to a biphenyl benzo-five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof, the structure of which is shown in general formula (I):

[0008] Among them, R 1 It is H or methoxy; R 2 R 3 R 4 Each is independently selected from H, halogen, trifluoromethoxy, hydroxyl, C1-C3 alkyl or C1-C6 alkoxy; or R 2 With R 3 Together with the carbon atoms of the benzene ring to which it is attached, it forms a cyclic structure selected from –OCH2O–, –CH2CH2O– or –OCH2CH2O–; R 5 R 6 R 7 R 8 Each is independently selected from H, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C1~C3 alkyl or C1~C3 alkoxy; X is selected from –N=, Y is selected from –NH–; or X is selected from –O–, Y is selected from –CH=.

[0009] Furthermore, R 1 For H, R 3 It is methyl, trifluoromethoxy, or C1~C3 alkoxy, R 2 R 4 Each is independently selected from H, F, Cl, hydroxyl, methyl, or methoxy; or R 1 R 4 For H, R 2 With R3 Together with the carbon atoms of the benzene ring to which it is attached, it forms a cyclic structure selected from –CH2CH2O–.

[0010] Furthermore, R 1 For H, R 3 It is methyl or methoxy, R 2 R 4 Each is independently selected from H or F.

[0011] Furthermore, R 5 R 6 R 7 R 8 Each is independently selected from H, F, Cl, hydroxyl, trifluoromethyl, trifluoromethoxy, methyl or methoxy; Furthermore, X is selected from –N=; Y is selected from –NH–.

[0012] The biphenylbenzo-5-membered heterocyclic compounds or their pharmaceutically acceptable salts described in this invention have structures as shown in Formulas 1 to 41: .

[0013] The use of the biphenylbenzo five-membered heterocyclic compound or its pharmaceutically acceptable salt described in this invention in the preparation of poly(adenosine diphosphate ribose) polymerase and / or microtubule polymerization inhibitors.

[0014] The use of the biphenylbenzopentacyclic heterocyclic compound or its pharmaceutically acceptable salt described in this invention in the preparation of drugs for the prevention and / or treatment of tumors.

[0015] Furthermore, the tumor is selected from breast cancer, ovarian cancer, liver cancer, lung cancer, colorectal cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, leukemia, or lymphoma.

[0016] The antitumor pharmaceutical composition of the present invention comprises an antitumor active ingredient being a biphenylbenzopentacyclic compound or a pharmaceutically acceptable salt thereof.

[0017] Beneficial Effects: Compared with existing technologies, this invention has the following significant advantages: This invention provides a novel class of PARP / tubulin dual inhibitors. Compared to single-target drugs, the dual-target compounds of this invention exhibit potent anti-proliferative activity against various tumor cell types in vitro, with low toxicity to normal cells, potentially broadening the therapeutic window. These compounds simultaneously achieve highly efficient dual inhibition of PARP and tubulin polymerization in a single molecule, avoiding the complexity of combination therapy and potentially overcoming pharmacokinetic problems caused by drug interactions. In vivo pharmacodynamic studies further confirm that the compounds of this invention exhibit superior antitumor activity in xenograft tumor models compared to the positive control group, and demonstrate good safety, showcasing great potential for clinical development as antitumor drugs. Attached Figure Description

[0018] Figure 1 The effects of the compound prepared in Example 36 on the morphology of major organ tissues in mice. Detailed Implementation

[0019] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0020] Example 1: 2-(3',4',5'-trimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0021] Step I: Preparation of 2-amino-3-nitrobenzamide 10.0 mmol of 2-amino-3-nitrobenzoic acid was dissolved in 30 mL of thionyl chloride and heated under reflux for 3 hours. After the reaction was complete, excess thionyl chloride was removed by vacuum distillation, and the residue was dissolved in 20 mL of tetrahydrofuran. The resulting solution was cooled to 0 °C, and 20 mL of ammonia solution (25%) was slowly added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 1 hour. The reaction solution was filtered, and the orange solid was collected, dried, and the target product was obtained in 89% yield. 1 H NMR (500 MHz, DMSO- d 6) d 8.47 (s, 2H), 8.18 (d, J =8.5 Hz, 1H), 8.16 (s, 1H), 7.94 (d, J = 6.8 Hz, 1H), 7.63 (s, 1H), 6.68 (t, J = 8.0 Hz, 1H). Step II: Preparation of 2,3-diaminobenzamide 2-Amino-3-nitrobenzamide (8.0 mmol) was dissolved in ethanol / water (4:1, 30 mL), and iron powder (50.0 mmol) and ammonium chloride (50.0 mmol) were added sequentially with stirring. The resulting mixture was heated to reflux and stirred for 5 hours. After the reaction was complete, the mixture was filtered while hot, and the filter cake was washed with ethanol (3 × 10 mL). The filtrates were combined and concentrated under reduced pressure to remove most of the ethanol. The residue was extracted with ethyl acetate (3 × 20 mL), and the organic phase was washed sequentially with saturated sodium bicarbonate solution (2 × 20 mL) and saturated brine (2 × 20 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give a pale yellow solid in 76% yield. 1 H NMR (500 MHz, DMSO- d 6) d 7.57(s, 1H), 6.94 (s, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 6.31 (t, J = 7.7 Hz, 1H), 6.04 (s, 2H), 4.57 (s, 2H). Step III: Preparation of 3',4',5'-trimethoxy-[1,1'-biphenyl]-3-carboxaldehyde 3,4,5-Trimethoxyphenylboronic acid (1.1 mmol), 3-iodobenzaldehyde (0.5 mmol), tetrakis(triphenylphosphine)palladium (0.1 mmol), and sodium carbonate (2.0 mmol) were added sequentially to a sealed tube, followed by a 2:1 mixture of ethylene glycol dimethyl ether and water (3 mL). The tube was sealed and the mixture was placed in an oil bath at 90 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was diluted with 10 mL of water and then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed sequentially with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid compound in 71% yield. 1 H NMR (500 MHz, DMSO- d 6) d 10.10 (s, 1H), 8.22 (s, 1H), 8.05 (d, J= 7.8 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.00 (s, 2H), 3.88 (s, 6H), 3.71 (s, 3H). Step IV: 2-(3',4',5'-trimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide 2,3-Diaminobenzamide (0.2 mmol) and 3',4',5'-trimethoxy-[1,1'-biphenyl]-3-carboxaldehyde (0.2 mmol) were dissolved in methanol (2 mL), and sodium bisulfite (0.3 mmol) was added with stirring. The resulting mixture was heated to reflux for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was collected and dried to give a white solid in 90% yield. 1 HNMR (500 MHz, DMSO- d 6) d 13.46 (s, 1H), 9.38 (s, 1H), 8.46 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz,1H), 7.04 (s, 2H), 3.91 (s, 6H), 3.73 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 172.29, 166.78, 153.81, 152.41, 141.69, 138.12, 135.84, 130.10, 130.08,129.46, 126.48, 125.59, 123.43, 122.86, 115.89, 105.13, 60.61, 56.64. HRMS(ESI) m / z: calcd for C 23 H 20 N3O4[MH] - , 402.1459; found, 402.1461. Example 2: 2-(2',3',4'-trimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0022] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 2,3,4-trimethoxyphenylboronic acid to obtain a white solid with a yield of 78%. 1 H NMR (500 MHz, DMSO- d 6) d 13.43 (s, 1H), 9.37 (s,1H), 8.31 (s, 1H), 8.23 ​​– 8.17 (m, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.76 – 7.73(m, 2H), 7.63 (d, J = 5.0 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.6Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.66 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.65, 153.84, 152.40, 151.28, 142.61, 141.94,139.17, 135.83, 131.54, 129.54, 129.47, 127.70, 127.42, 125.76, 125.15,123.44, 122.93, 122.85, 115.51, 108.81, 61.32, 60.99, 56.43. HRMS (ESI) m / z :calcd for C 23 H 20 N3O4[MH] -, 402.1459; found, 402.1454. Example 3: 2-(3',5'-dimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0023] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 2,4-dimethoxyphenylboronic acid to obtain a light brown solid with a yield of 85%. 1 H NMR (500 MHz, DMSO- d 6) d 13.46 (s, 1H), 9.37 (s,1H), 8.48 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.94 (s, 2H), 6.59 (s, 1H), 3.85 (s, 6H). 13 C NMR (126 MHz, DMSO- d 6) d 166.63, 161.48, 152.28, 142.06, 141.94, 141.35, 135.80, 130.16,130.12, 129.39, 126.84, 125.53, 123.49, 123.02, 122.92, 115.49, 105.71,99.98, 55.85. HRMS (ESI) m / z : calcd for C 22 H 18 N3O3[MH] - , 372.1354; found, 372.1357. Example 4: 2-(3',4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0024] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 3,4-dimethoxyphenylboronic acid to obtain a white solid with a yield of 88%. 1 H NMR (500 MHz, DMSO- d 6) d 13.45 (s, 1H), 9.37 (s, 1H), 8.46 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.79 – 7.74 (m, 2H), 7.65 (t, J = 7.9 Hz, 1H), 7.39 – 7.33 (m,3H), 7.12 (d, J = 8.1 Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.64, 152.42, 149.65, 149.44, 141.95, 141.45, 135.79, 132.66,130.14, 130.09, 129.04, 125.93, 125.10, 123.48, 122.99, 122.90, 119.68,115.49, 112.75, 111.22, 56.23, 56.10. HRMS (ESI) m / z : calcd for C 22 H 18 N3O3[MH] - , 372.1354; found, 372.1354. Example 5: 2-(3'-hydroxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0025] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 3-hydroxy-4-methoxyphenylboronic acid to obtain a pale yellow solid with a yield of 84%.1 H NMR (500 MHz, DMSO- d 6) d 13.49 (s, 1H), 9.38 (d, J = 3.4 Hz, 1H), 9.16 (s, 1H), 8.43 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.90(d, J = 7.5 Hz, 1H), 7.80 – 7.73 (m, 3H), 7.64 (t, J = 7.7 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.25 – 7.19 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 166.78, 152.47, 148.30, 147.37, 141.93, 141.39,135.85, 132.76, 130.15, 130.08, 128.70, 125.80, 124.91, 123.45, 122.93,122.87, 118.22, 115.55, 114.52, 113.05, 56.18. HRMS (ESI) m / z : calcd forC 21 H 18 N3O3[M+H] + , 360.1343; found, 360.1343. Example 6: 2-(4'-methoxy-3'-methyl-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0026] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxy-3-methylphenylboronic acid to obtain a white solid with a yield of 79%. 1 H NMR (500 MHz, DMSO- d 6) d13.45 (s, 1H), 9.37 (s,1H), 8.45 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.81 –7.74 (m, 3H), 7.66 – 7.59 (m, 3H), 7.37 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 9.3 Hz,1H), 3.86 (s, 3H), 2.27 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 166.67, 157.88,152.44, 141.96, 141.31, 135.80, 131.78, 130.14, 130.08, 129.32, 128.75,126.63, 125.90, 125.74, 124.83, 123.47, 122.98, 122.88, 115.48, 111.19,55.84, 16.70. HRMS (ESI) m / z : calcd for C 22 H 18 N3O2[MH] - , 356.1405; found, 356.1410. Example 7: 2-(3'-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0027] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 3-fluoro-4-methoxyphenylboronic acid to obtain a light brown solid with a yield of 82%. 1 H NMR (500 MHz, DMSO- d 6) d 13.45 (s, 1H), 9.36 (s,1H), 8.49 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.85(d, J= 7.8 Hz, 1H), 7.79 – 7.70 (m, 3H), 7.68 – 7.61 (m, 2H), 7.39 – 7.30 (m, 2H), 3.92 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.64, 152.32 (d, J =243.9 Hz), 152.25, 147.51 (d, J = 10.6 Hz), 141.94, 139.87, 135.77, 132.75(d, J = 6.3 Hz), 130.26, 130.20, 128.80, 126.34, 124.99, 123.51, 123.42 (d, J = 3.2 Hz), 123.00 (d, J = 10.9 Hz), 115.49, 114.77, 114.62, 56.58. HRMS (ESI) m / z : calcd for C 21 H 15 FN3O2 [MH] - , 360.1154; found, 360.1161. Example 8: 2-(3'-chloro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0028] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 3-chloro-4-methoxyphenylboronic acid to obtain a white solid with a yield of 90%. 1 H NMR (500 MHz, DMSO- d 6) d 13.47 (s, 1H), 9.35 (d, J = 3.3 Hz, 1H), 8.47 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.89 (dd,J = 7.6, 1.2 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.79 – 7.75(m, 3H), 7.66 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.7Hz, 1H), 3.93 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.64, 154.87, 152.24,141.94, 139.69, 135.77, 133.17, 130.29, 130.21, 128.83, 128.44, 127.12,126.41, 124.91, 123.51, 123.01, 122.93, 122.21, 115.50, 113.72, 56.72. HRMS(ESI) m / z : calcd for C 21 H 15 ClN3O2 [MH] - , 376.0858; found, 376.0861. Example 9: 2-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0029] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid to obtain a light brown solid with a yield of 87%. 1 H NMR (500 MHz, DMSO- d 6) d 13.46 (s, 1H), 9.37 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.82 – 7.72(m, 5H), 7.65 (t, J= 7.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.6Hz, 2H), 3.83 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.67, 159.76, 152.40,141.95, 141.11, 135.80, 132.21, 130.20, 130.13, 128.73, 128.44, 125.81,124.88, 123.49, 122.98, 122.90, 115.50, 114.94, 55.69. HRMS (ESI) m / z : calcdfor C 21 H 16 N3O2 [MH] - , 342.1248; found, 342.1257. Example 10: 2-(3-(2,3-dihydrobenzofuran-5-yl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0030] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 2,3-dihydro-1-benzofuran-5-ylboronic acid to obtain a white solid with a yield of 78%. 1 H NMR (500 MHz, DMSO- d 6) d 13.45 (s, 1H),9.36 (s, 1H), 8.44 (s, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.5 Hz,1H), 7.79 – 7.74 (m, 3H), 7.69 (s, 1H), 7.63 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 6.92 (d, J= 8.3 Hz, 1H), 4.61 (t, J = 8.7 Hz, 2H), 3.29 (t, J = 8.8 Hz, 2H). 13 C NMR (126 MHz, DMSO- d 6) d 166.65,160.32, 152.43, 141.95, 141.62, 135.79, 132.37, 130.16, 130.08, 128.81,128.76, 127.17, 125.66, 124.86, 124.11, 123.46, 122.97, 122.88, 115.47,109.77, 71.74, 29.56. HRMS (ESI) m / z : calcd for C 22 H 16 N3O2 [MH] - , 354.1248;found, 354.1255. Example 11: 2-(3-(benzo[ d [1,3]dioxolane-5-yl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0031] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 3,4-(methylenedioxy)phenylboronic acid to obtain a light brown solid with a yield of 88%. 1 H NMR (500 MHz, DMSO- d 6) d 13.44 (s, 1H), 9.36 (s, 1H), 8.45 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H),7.81 – 7.74 (m, 3H), 7.64 (t, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.37 (t, J = 7.7Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.08 (d,J = 8.0 Hz, 1H), 6.11 (s, 2H). 13 CNMR (126 MHz, DMSO- d 6) d 166.64, 152.32, 148.59, 147.72, 141.94, 141.12,135.77, 134.11, 130.18, 130.09, 128.94, 126.06, 125.14, 123.48, 122.99,122.91, 120.98, 115.48, 109.22, 107.69, 101.78. HRMS (ESI) m / z : calcd forC 21 H 14 N3O3 [MH] - , 356.1041; found, 356.1041. Example 12: 2-(3-(2,3-dihydrobenzo[ b [1,4]dioxane-6-yl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0032] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with benzo-1,4-dioxane-6-boronic acid to obtain a pale yellow solid with a yield of 81%. 1 H NMR (500 MHz, DMSO- d 6) d 9.17 (s, 1H), 8.47 (s, 1H), 8.21 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 – 7.75 (m,3H), 7.65 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.4, 2.3 Hz, 1H), 7.02 (d, J= 8.4 Hz, 1H), 4.31 (s, 4H). 13 C NMR (126 MHz, DMSO- d 6) d 166.82, 151.98, 144.27, 144.08, 140.79, 135.21,132.83, 130.18, 129.58, 127.96, 126.68, 125.88, 124.04, 123.92, 122.50,120.20, 118.08, 116.46, 115.82, 64.70, 64.64. HRMS (ESI) m / z : calcd forC 22 H 16 N3O3 [MH] - , 370.1197; found, 370.1200. Example 13: 2-([1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0033] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with phenylboronic acid to obtain a light brown solid with a yield of 86%. 1 H NMR (500 MHz, DMSO- d 6) d 13.50 (s, 1H), 9.37 (d, J = 3.4 Hz,1H), 8.52 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 7.5, 1.1 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.83 – 7.76 (m, 4H), 7.70 (t, J = 7.8 Hz, 1H), 7.56(t, J = 7.8 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H). 13CNMR (101 MHz, DMSO- d 6) d 166.63, 152.27, 141.92, 141.47, 139.92, 135.79,130.32, 130.20, 129.54, 129.28, 128.44, 127.36, 126.54, 125.45, 123.51,122.98, 122.95, 115.54. HRMS (ESI) m / z : calcd for C 20 H 14 N3O [MH] - , 312.1142;found, 312.1151. Example 14: 2-(3',4',5'-trimethoxy-[1,1'-biphenyl]-4-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0034] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 4-iodobenzaldehyde to obtain a white solid with a yield of 83%. 1 H NMR (500 MHz, DMSO- d 6) d 13.45 (s, 1H), 9.38 (s, 1H), 8.31 (d, J = 8.1Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.03 (s, 2H), 3.90 (s, 6H), 3.71 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d166.55, 153.16, 152.88,141.64, 141.47, 137.22, 135.75, 135.11, 131.16, 130.78, 130.70, 129.64,127.95, 123.07, 122.78, 122.58, 115.41, 106.76, 60.51, 56.00. HRMS (ESI) m / z :calcd for C 23 H 20 N3O4 [MH] - , 402.1459; found, 402.1464. Example 15: 2-(3',4',5'-trimethoxy-[1,1'-biphenyl]-2-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0035] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 2-iodobenzaldehyde to obtain a white solid with a yield of 69%. 1 H NMR (500 MHz, DMSO- d 6) d 12.73 (s, 1H), 9.02 (d, J = 3.5 Hz, 1H), 7.82(d, J = 7.4 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 4.3 Hz, 2H), 7.60(d, J = 8.0 Hz, 1H), 7.59 – 7.54 (m, 2H), 7.29 (t, J = 7.8 Hz, 1H), 6.47 (s, 2H), 3.61 (s, 3H), 3.47 (s, 6H). 13 C NMR (126 MHz, DMSO- d 6) d166.57, 153.16,152.91, 141.66, 141.50, 137.38, 135.78, 135.14, 131.12, 130.70, 129.66,127.93, 123.07, 122.83, 122.54, 115.38, 106.90, 60.52, 56.08. HRMS (ESI) m / z :calcd for C 23 H 20 N3O4 [MH] - , 402.1459; found, 402.1462. Example 16: Preparation of 2-(3',4',5'-trimethoxy-[1,1'-biphenyl]-3-yl)benzofuran-7-carboxamide

[0036] Step I: Preparation of 3',4',5'-trimethoxy-[1,1'-biphenyl]-3-amine Palladium acetate (0.2 mmol), Xantphos (0.2 mmol), 3,4,5-trimethoxyphenylboronic acid (4.4 mmol), 3-iodoaniline (4 mmol), and potassium phosphate (12 mmol) were added sequentially to a sealed tube. After purging with nitrogen, a 1,4-dioxane / water mixed solvent (3:1, 4 mL) was injected. The tube was sealed and reacted at 100 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed sequentially with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give a grayish-white solid in 89% yield. 1 H NMR (500 MHz, CDCl3) d 7.24 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.89 (t, J = 2.0 Hz, 1H), 6.78(s, 2H), 6.71 (dd, J = 7.9, 1.5 Hz, 1H), 3.94 (s, 6H), 3.91 (s, 3H), 3.79 (s, 2H). Step II: Preparation of 3'-iodo-3,4,5-trimethoxy-1,1'-biphenyl 3',4',5'-trimethoxy-[1,1'-biphenyl]-3-amine (2 mmol) was dissolved in acetonitrile (3 mL), and p-toluenesulfonic acid (6 mmol) was added and stirred until dissolved. Under ice bath conditions, an aqueous solution of sodium nitrite (2.4 mmol) (1 mL) was slowly added dropwise. After the addition was complete, stirring continued for 30 minutes. Then, an aqueous solution of potassium iodide (2.4 mmol) (1 mL) was slowly added dropwise. After the addition was complete, stirring continued for 30 minutes. The reaction was then allowed to proceed to room temperature for 3 hours. After the reaction was complete, saturated sodium thiosulfate solution was added dropwise until the brown color completely disappeared, and then saturated sodium bicarbonate solution was added to adjust the pH to 7-8. The mixture was extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined and washed successively with saturated brine (2 × 10 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a pale yellow solid in 81% yield. 1 H NMR (500MHz, CDCl3) d 7.91 (t, J = 1.8 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.7, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.74 (s, 2H), 3.95 (s, 6H), 3.92 (s, 3H). Step III: Preparation of 2-(3',4',5'-trimethoxy-[1,1'-diphenyl]-3-yl)benzofuran-7-nitrile Following the synthetic method for 3',4',5'-trimethoxy-[1,1'-biphenyl]-3-amine, 3,4,5-trimethoxyphenylboronic acid was replaced with (7-cyanobenzofuran-2-yl)boronic acid (Cas No: 1392502-90-7), and 3-iodoaniline was replaced with 3'-iodo-3,4,5-trimethoxy-1,1'-biphenyl, yielding a white solid in 83% yield. 1 H NMR (500 MHz, CDCl3) d 8.07 (s, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.62 (d, J= 7.7Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.18 (s, 1H), 6.85 (s, 2H), 3.99 (s, 6H), 3.94 (s, 3H). Step IV: Preparation of 2-(3',4',5'-trimethoxy-[1,1'-diphenyl]-3-yl)benzofuran-7-carboxamide 0.2 mmol of 2-(3',4',5'-trimethoxy-[1,1'-diphenyl]-3-yl)benzofuran-7-onitrile was dissolved in 2 mL of DMSO, followed by the addition of 0.3 mmol of K₂CO₃ and 0.2 mL of 30% H₂O₂. The mixture was stirred in an ice bath for 3 hours. After the reaction was complete, the solution was diluted with 10 mL of water, and a solid precipitated. The solid was filtered, dried, and a white solid was obtained in 77% yield. 1 H NMR (500 MHz, DMSO-) d 6) d 8.26 (s, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.86 – 7.81 (m,3H), 7.77 – 7.73 (m, 2H), 7.68 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.03 (s, 2H), 3.90 (s, 6H), 3.72 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 165.60, 156.19, 153.76, 151.66, 141.58, 137.94, 135.88, 130.26,129.93, 128.05, 125.72, 124.73, 124.38, 123.96, 123.73, 119.48, 104.95,102.93, 60.56, 56.56. HRMS (ESI) m / z : calcd for C 24 H 21 NaNO5 [M+Na] +, 426.1312;found, 426.1315. Example 17: 2-(4'-ethoxy-[1,1'-diphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0037] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-ethoxyphenylboronic acid to obtain a light brown solid with a yield of 78%. 1 H NMR (500 MHz, DMSO- d 6) d 13.47 (s, 1H), 9.36 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.82 – 7.72(m, 5H), 7.64 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 8.7Hz, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.68, 159.03, 152.41, 141.97, 141.12, 135.80, 132.05, 130.19,130.13, 128.68, 128.41, 125.78, 124.84, 123.49, 122.99, 122.89, 115.48,115.39, 63.62, 15.10. HRMS (ESI) m / z : calcd for C 22 H 18 N3O2 [MH] - , 356.1405;found, 356.1417. Example 18: 2-(4'-isopropoxy-[1,1'-diphenyl]-3-yl)-1H -benzo[ d Preparation of imidazole-4-carboxamide

[0038] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-isopropoxyphenylboronic acid to obtain a pale yellow solid with a yield of 76%. 1 H NMR (400 MHz, DMSO- d 6) d 13.49 (s, 1H), 9.38 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J = 3.1 Hz, 1H), 7.76 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 7.8Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 4.70 (hept, J = 6.0Hz, 1H), 1.30 (d, J = 5.7 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) d 166.64, 157.94,152.40, 141.93, 141.10, 135.79, 131.89, 130.22, 130.11, 128.67, 128.49,125.79, 124.82, 123.45, 122.91, 116.48, 115.52, 69.66, 22.29. HRMS (ESI) m / z :calcd for C 23 H 20 N3O2[MH] - , 370.1561; found, 370.1565. Example 19: 2-(4'-methyl-[1,1'-diphenyl]-3-yl)-1 H -benzo[d Preparation of imidazole-4-carboxamide

[0039] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methylphenylboronic acid to obtain a pale yellow solid with a yield of 67%. 1 H NMR (500 MHz, DMSO- d 6) d 13.50 (s, 1H), 9.37 (d, J = 3.4 Hz,1H), 8.50 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.84 (d, J =7.6 Hz, 1H), 7.80 – 7.75 (m, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.7 Hz,1H), 7.39 – 7.33 (m, 3H), 2.38 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.65,152.34, 141.95, 141.34, 137.81, 136.99, 135.81, 130.24, 130.17, 130.11,128.98, 127.12, 126.25, 125.13, 123.49, 123.01, 122.91, 115.50, 21.18. HRMS(ESI) m / z : calcd for C 21 H 16 N3O [MH] - , 326.1299; found, 326.1309. Example 20: 2-(4'-hydroxy-[1,1'-diphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0040] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-hydroxyphenylboronic acid to obtain a white solid with a yield of 65%. 1 H NMR (500 MHz, DMSO- d 6) d 13.44 (s, 1H), 9.66 (s, 1H), 9.40 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.79 –7.73 (m, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7Hz, 1H), 6.93 (d, J = 8.3 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) d 166.71, 158.03,152.55, 141.97, 141.45, 135.89, 130.63, 130.13, 128.45, 125.53, 124.70,124.03, 123.37, 122.79, 116.31, 115.57. HRMS (ESI) m / z : calcd for C 20 H 14 N3O2 [MH] - , 328.1092; found, 328.1086. Example 21: 2-(4'-trifluoromethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0041] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-trifluoromethoxyphenylboronic acid, yielding a white solid with a yield of 84%. 1 H NMR (500 MHz, DMSO- d 6) d13.51 (s, 1H), 9.36 (s, 1H), 8.54 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.89 (t, J = 8.3Hz, 2H), 7.79 (d, J = 7.2 Hz, 2H), 7.72 (t, J = 7.7 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) d 166.60, 152.12,148.66, 141.90, 140.06, 139.30, 135.78, 130.41, 130.30, 129.40, 129.33,126.91, 125.65, 123.53, 123.01, 122.10, 120.61 (q, J = 256.4 Hz), 115.54. HRMS(ESI) m / z : calcd for C 21 H 13 F3N3O2[MH] - , 396.0965; found, 396.0975. Example 22: Preparation of 2-(4'-fluoro-[1,1'-biphenyl]-3-yl)-1H-benzo[d]imidazol-4-carboxamide

[0042] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-fluorophenylboronic acid to obtain a white solid with a yield of 72%. 1 H NMR (400 MHz, DMSO- d 6) d 13.51 (s, 1H), 9.36 (s, 1H), 8.50 (s,1H), 8.27 (d, J = 7.8 Hz, 1H), 7.91 – 7.80 (m, 5H), 7.78 (d, J= 7.9 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.42 – 7.34 (m, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.64, 162.65 (d, J = 245.1 Hz), 152.22, 141.93, 140.44, 136.41 (d, J = 3.2Hz), 135.79, 130.31, 130.24, 129.37 (d, J = 8.3 Hz), 129.20, 126.49, 125.39,123.52, 123.02, 122.95, 116.33 (d, J = 21.5 Hz), 115.51. HRMS (ESI) m / z :calcd for C 20 H 13 FN3O [MH] - , 330.1048; found, 330.1055. Example 23: 2-(4'-chloro-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0043] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-chlorophenylboronic acid to obtain a light brown solid with a yield of 81%. 1 H NMR (400 MHz, DMSO- d 6) d 13.59 (s, 1H), 9.43 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 7.98 – 7.87 (m, 5H), 7.85 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.44 (t,J = 7.7 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) d 166.70, 152.21, 141.87, 140.04, 138.70,135.84, 133.33, 130.36, 129.49, 129.35, 129.13, 129.10, 128.80, 126.91,125.38, 123.45, 122.90, 115.60. HRMS (ESI) m / z : calcd for C 20 H 13 ClN3O [MH] - ,346.0753; found, 346.0761. Example 24: 2-(4'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0044] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-bromo-2-methylbenzaldehyde, yielding a pale yellow solid with a yield of 52%. 1 H NMR (500 MHz, DMSO- d 6) d 13.19 (s, 1H), 9.32 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.77 –7.70 (m, 3H), 7.46 (t, J = 7.6 Hz, 1H), 7.40 – 7.35 (m, 2H), 7.33 (d, J = 8.6Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H), 2.41 (s, 3H). 13 C NMR (101MHz, DMSO- d 6) d166.71, 158.92, 153.44, 143.28, 141.70, 135.14, 134.98,133.73, 131.92, 130.98, 130.82, 129.41, 126.35, 123.17, 122.92, 122.70,115.55, 114.22, 55.57, 19.13. HRMS (ESI) m / z : calcd for C 22 H 19 N3O2[M+H] + ,358.1550; found, 358.1554. Example 25: 2-(4'-methoxy-6-methyl-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0045] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-iodo-4-methylbenzaldehyde, resulting in a white solid with a yield of 69%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.35 (s, 1H), 9.36 (d, J = 3.4 Hz, 1H), 8.13 (dd, J = 7.9, 2.0 Hz, 1H), 8.06(d, J = 2.0 Hz, 1H), 7.87 (dd, J = 7.5, 1.1 Hz, 1H), 7.74 – 7.69 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 3.84 (s, 3H), 2.33 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 166.71, 159.03, 152.38, 142.16, 141.99, 138.31, 135.78, 133.23, 131.62,130.67, 128.35, 127.27, 125.90, 123.34, 122.79, 122.68, 115.35, 114.25,55.61, 20.75. HRMS (ESI) m / z : calcd for C 22 H 20 N3O2[M+H] + , 358.1550; found, 358.1551. Example 26: 2-(4'-methoxy-5-methyl-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0046] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-iodo-5-methylbenzaldehyde, yielding a white solid with a yield of 71%. 1 H NMR (500 MHz, DMSO- d 6) δ13.41 (s, 1H), 9.37 (s, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 7.88 (d, J = 7.4 Hz,1H), 7.77 – 7.72 (m, 4H), 7.63 (s, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 3.83 (s, 3H), 2.50 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ166.67, 159.69, 152.50, 141.95, 141.08, 139.55, 135.76, 132.32, 130.03,129.50, 128.42, 126.27, 123.42, 122.93, 122.82, 122.24, 115.43, 114.89,55.69, 21.60. HRMS (ESI) m / z : calcd for C 22 H 18 N3O2[MH] - , 356.1405; found, 356.1410. Example 27: 2-(4'-methoxy-4-methyl-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0047] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 5-iodo-2-methylbenzaldehyde, yielding a white solid with a yield of 43%. 1 H NMR (500 MHz, DMSO- d 6) d 13.26 (s, 1H), 9.35 (s, 1H), 8.11 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.80 –7.73 (m, 4H), 7.71 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.70 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) d 166.72, 159.53, 153.01, 141.88, 138.26, 136.08, 135.08,132.77, 132.07, 129.56, 128.21, 127.91, 127.56, 123.19, 122.94, 122.81,115.47, 114.87, 55.67, 21.45. HRMS (ESI) m / z : calcd for C 22 H 20 N3O2[M+H] + ,358.1550; found, 358.1551. Example 28: 2-(4',6-dimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0048] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-iodo-4-methoxybenzaldehyde, yielding a light brown solid with a yield of 76%. 1 H NMR (500 MHz, DMSO- d 6) d 13.26 (s, 1H), 9.37 (s, 1H), 8.21 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.71 – 7.68 (m, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.33– 7.28 (m, 2H), 7.04 (d, J = 8.2 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 3H). 13 C NMR (126 MHz, DMSO-) d 6) d 166.77, 159.10, 158.50, 152.50, 142.13, 135.82, 130.97,130.55, 130.11, 129.20, 127.86, 123.19, 122.60, 122.39, 122.11, 115.14,114.07, 112.70, 56.29, 55.62. HRMS (ESI) m / z : calcd for C 22 H 18 N3O3[MH] - ,372.1354; found, 372.1351. Example 29: 2-(4',5-dimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0049] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-iodo-5-methoxybenzaldehyde (Cas No. 152734-38-8), yielding a white solid with a yield of 66%. 1 HNMR (500 MHz, DMSO- d 6) d 13.45 (s, 1H), 9.34 (d, J = 3.3 Hz, 1H), 8.08 (t, J = 1.6 Hz, 1H), 7.90 (dd, J = 7.6, 1.1 Hz, 1H), 7.79 – 7.73 (m, 5H), 7.38 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 2.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 2H), 3.95 (s, 3H), 3.84 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 166.65, 160.69, 159.82,152.26, 142.61, 141.86, 135.74, 132.15, 131.22, 128.55, 123.52, 122.98,122.95, 117.59, 115.49, 114.85, 114.50, 110.87, 55.96, 55.68. HRMS (ESI) m / z :calcd for C 22 H 20 N3O3[M+H] + , 374.1499; found, 374.1501. Example 30: 2-(4,4'-dimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0050] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 5-iodo-2-methoxybenzaldehyde, yielding a light brown solid with a yield of 63%. 1 H NMR (500 MHz, DMSO- d 6) d 12.61 (s, 1H), 9.37 (s, 1H), 8.53 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 7.67 (s, 1H), 7.64(d, J = 8.3 Hz, 2H), 7.38 – 7.32 (m, 2H), 7.06 (d, J = 8.6 Hz, 2H), 4.09 (s, 3H), 3.81 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 167.11, 159.23, 156.63,150.03, 133.44, 132.14, 130.28, 127.97, 127.76, 123.15, 122.44, 117.71,114.93, 113.45, 56.69, 55.65. HRMS (ESI) m / z : calcd for C 22 H 18 N3O3[MH] - ,372.1354; found, 372.1350. Example 31: 2-(6-hydroxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0051] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 4-hydroxy-3-iodobenzaldehyde, yielding a white solid with a yield of 79%. 1 H NMR (500 MHz, DMSO-d 6) d 10.59 (s, 1H), 8.85 (s, 1H), 8.23 ​​(s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 3.82 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.99, 159.45, 159.06,151.65, 133.57, 131.71, 130.87, 129.81, 129.54, 128.67, 124.98, 124.49,121.78, 117.16, 116.68, 114.02, 55.65. HRMS (ESI) m / z : calcd for C 21 H 18 N3O3[M+H] + , 360.1343; found, 360.1347. Example 32: 2-(4-hydroxy-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0052] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 2-hydroxy-5-iodobenzaldehyde, yielding a light brown solid with a yield of 70%. 1 H NMR (500 MHz, DMSO- d 6) d 8.62 (d, J= 2.3 Hz, 1H), 8.57 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.83 (dd, J = 8.7, 2.3 Hz, 1H), 7.73 (d, J =8.6 Hz, 2H), 7.58 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.07 (d, J =8.6 Hz, 2H), 3.82 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 167.27, 159.27,156.94, 148.89, 133.03, 132.90, 132.31, 131.26, 127.84, 126.89, 125.70,124.58, 119.96, 118.39, 117.68, 114.80, 109.74, 55.66. HRMS (ESI) m / z : calcdfor C 21 H 16 N3O3[MH] - , 358.1197; found, 358.1203. Example 33: 2-(6-hydroxy5-dimethoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0053] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 4-hydroxy-3-iodo-5-methoxybenzaldehyde, yielding a white solid with a yield of 67%. 1 H NMR (500 MHz, DMSO- d 6) d 13.18 (s, 1H), 9.37 (s, 1H), 9.27 (s, 1H), 7.84 (d, J= 7.5 Hz,1H), 7.79 (s, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 3.99 (s, 3H), 3.81 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.79, 158.93, 152.99, 148.72,146.33, 142.15, 135.81, 130.81, 130.39, 128.53, 123.12, 122.49, 122.27,121.69, 120.44, 115.00, 114.01, 109.22, 56.70, 55.61. HRMS (ESI) m / z : calcdfor C 22 H 18 N3O4[MH] - , 388.1303; found, 388.1302. Example 34: 2-(2-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0054] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 2-fluoro-3-iodobenzaldehyde, resulting in a white solid with a yield of 79%. 1 H NMR (400 MHz, DMSO- d 6) d 13.14 (s, 1H), 9.33 (d, J = 2.8 Hz, 1H), 8.25 (td, J = 7.6, 1.7 Hz, 1H), 7.92(d, J = 7.4 Hz, 1H), 7.84 – 7.77 (m, 2H), 7.66 (td,J = 7.6, 1.8 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 166.57, 159.75, 156.99 (d, J = 252.6 Hz), 147.72, 141.18, 135.79, 133.22 (d, J = 3.2Hz), 130.73, 130.70, 129.80, 129.69, 127.09, 125.77 (d, J = 3.8 Hz), 123.67, 123.07 (d, J = 11.7 Hz), 118.35 (d, J = 12.5 Hz), 116.10, 114.63, 55.70. HRMS(ESI) m / z : calcd for C 21 H 15 FN3O2[MH] - , 360.1154; found, 360.1163. Example 35: 2-(6-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0055] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 4-fluoro-3-iodobenzaldehyde, resulting in a white solid with a yield of 83%. 1 H NMR (500 MHz, DMSO- d 6) d 13.44 (s, 1H), 9.31 (s, 1H), 8.36 (d, J= 5.8 Hz, 1H), 8.26 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.52 (t, J =9.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.65, 160.74 (d, J = 250.2 Hz), 159.83,151.55, 141.95, 135.90, 130.64, 130.61, 129.52, 129.14 (d, J = 13.7 Hz), 128.24 (d, J = 8.0 Hz), 127.06, 126.53 (d, J = 3.7 Hz), 123.45, 122.84,117.58 (d, J = 23.6 Hz), 115.48, 114.70, 55.73. HRMS (ESI) m / z : calcd forC 21 H 15 FN3O2[MH] - , 360.1154; found, 360.1163. Example 36: 2-(5-fluoro-4'-methoxy-[1,1'-diphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0056] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-fluoro-5-iodobenzaldehyde, yielding a pale yellow solid with a yield of 75%. 1 H NMR (500 MHz, DMSO- d 6) d13.20 (s, 1H), 9.32 (s, 1H), 8.43 (dd, J = 7.1, 2.5 Hz, 1H), 7.91 (d, J = 7.5Hz, 1H), 7.87 – 7.80 (m, 2H), 7.75 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.54 (dd, J = 11.0, 8.6 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 166.55, 163.48 (d, J = 243.5Hz), 160.18, 151.19, 143.53 (d, J = 8.3 Hz), 141.73, 135.75, 132.17 (d, J =7.1 Hz), 130.90, 128.63, 123.70, 123.21, 120.87, 115.63, 115.15 (d, J = 23.4Hz), 114.95, 114.84, 112.20 (d, J = 23.9 Hz), 55.74. HRMS (ESI) m / z : calcdfor C 21 H 15 FN3O2[MH] - , 360.1154; found, 360.1159. Example 37: 2-(4-fluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0057] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 2-fluoro-5-iodobenzaldehyde, yielding a light brown solid with a yield of 73%.1 H NMR (500 MHz, DMSO- d 6) d 13.18 (s, 1H), 9.32 (s, 1H), 8.42 (dd, J = 7.1, 2.5 Hz, 1H), 7.91 (d, J = 7.5Hz, 1H), 7.85 – 7.79 (m, 2H), 7.75 – 7.69 (m, 3H), 7.53 (t, J = 9.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H). 13 C NMR (126MHz, DMSO- d 6) d 166.55, 159.69, 159.34 (d, J = 251.8 Hz), 147.69, 141.36,137.46 (d, J = 2.7 Hz), 135.72, 131.36, 130.59 (d, J = 6.8 Hz), 128.45,128.10, 123.67, 123.15, 117.96 (d, J = 11.5 Hz), 117.71 (d, J = 22.2 Hz),116.02, 114.98, 55.70. HRMS (ESI) m / z : calcd for C 21 H 15 FN3O2[MH] - , 360.1154;found, 360.1158. Example 38: 2-(6-chloro-4'-methoxy-[1,1'-diphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0058] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 4-chloro-3-iodobenzaldehyde, yielding a light brown solid with a yield of 81%. 1 H NMR (500 MHz, DMSO- d 6) d 13.48 (s, 1H), 9.28 (s, 1H), 8.25 (s, 1H), 8.24 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.78 – 7.71 (m, 3H), 7.50 (d, J = 8.6 Hz, 2H), 7.36 (t, J =7.7 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) d 166.54, 159.64, 151.19, 141.84, 140.66, 135.82, 134.01, 131.19, 131.05,130.81, 129.96, 128.76, 127.48, 123.61, 123.08, 123.05, 115.56, 114.26,55.71. HRMS (ESI) m / z : calcd for C 21 H 15 ClN3O2 [MH] - , 376.0858; found, 376.0868. Example 39: 2-(5-chloro-4'-methoxy-[1,1'-diphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0059] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-chloro-5-iodobenzaldehyde, resulting in a white solid with a yield of 68%. 1 H NMR (500 MHz, DMSO- d 6) d 13.58 (s, 1H), 9.28 (d, J = 3.3 Hz, 1H), 8.45 (t, J = 1.7 Hz, 1H), 8.25 (t, J = 1.7 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.83 –7.77 (m, 3H), 7.75 (d, J = 2.6 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 166.49, 160.20,150.90, 143.13, 141.73, 135.77, 135.02, 131.94, 130.71, 128.68, 127.98,125.06, 123.73, 123.44, 123.26, 123.20, 115.65, 114.99, 55.75. HRMS (ESI) m / z : calcd for C 21 H 17 ClN3O2[M+H] + , 378.1004; found, 378.1008. Example 40: 2-(4'-methoxy-5-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0060] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-bromo-5-(trifluoromethoxy)benzaldehyde, yielding a white solid with a yield of 61%. 1 H NMR (500 MHz, DMSO- d 6) d13.64 (s, 1H), 9.26 (s, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.86 – 7.78 (m, 4H), 7.77 (s, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) d 166.50,160.31, 150.82, 149.93, 143.46, 141.70, 135.80, 132.18, 130.55, 128.73,123.78, 123.32, 123.25, 120.76, 120.65 (q, J = 256.9 Hz), 117.65, 115.71,115.02, 55.74. HRMS (ESI) m / z : calcd for C 21 H 17 F3N3O3[M+H] + , 428.1217; found,428.1217. Example 41: 2-(4'-methoxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0061] Following the synthesis method of Example 1, 3,4,5-trimethoxyphenylboronic acid was replaced with 4-methoxyphenylboronic acid, and 3-iodobenzaldehyde was replaced with 3-bromo-5-(trifluoromethyl)benzaldehyde, yielding a white solid with a yield of 56%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.69 (s, 1H), 9.28 (s, 1H), 8.77 (s, 1H), 8.52 (s, 1H), 8.10 (s,1H), 7.92 (d, J = 7.5 Hz, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.82 (d, J = 7.8 Hz,1H), 7.76 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 3.86 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 166.47, 160.32, 150.80, 142.35, 141.72,135.81, 131.26, 131.16 (d, J = 32.0 Hz), 130.61, 128.84, 128.48, 124.57 (d, J = 4.0 Hz), 124.46 (q, J = 273.8 Hz), 123.82, 123.36, 123.28, 121.87 (d, J =4.1 Hz), 115.72, 115.05, 55.75. HRMS (ESI) m / z : calcd for C 22 H 17 F3N3O2[M+H] + ,412.1267; found, 412.1271. Example 42 Preparation of tablets

[0062] Take the above formula and prepare it into tablets using conventional methods.

[0063] The pharmacodynamic tests and results of the compounds of this invention are as follows. The chemical structures of the compounds used in the tests are given in the examples above.

[0064] 1. In vitro antitumor activity test 1.1. Experimental Equipment and Reagents Instruments: Clean bench (Suzhou Aikelin Purification Equipment Co., Ltd.), constant temperature CO2 incubator (SANYO, Japan), multifunctional microplate reader (Tecan, USA), inverted biological microscope (OLYMPUS, Japan).

[0065] Reagents: Fetal bovine serum (Jiangsu Kaiji Biotechnology Co., Ltd., KGL3002-50), DMEM medium (Jiangsu Kaiji Biotechnology Co., Ltd., KGL1206-500), RPMI-1640 medium (Jiangsu Kaiji Biotechnology Co., Ltd., KGL1501-500), trypsin digestion solution (BIOSHARP, BL512A), PBS (Servicebio, G4202), DMSO (Servicebio, BL165B), CCK-8 (GLPBIO, GK10001).

[0066] Cell lines (Jiangsu Kaiji Biotechnology Co., Ltd.): Human breast cancer cells MDA-MB-231, MDA-MB-468, MCF-7, human liver cancer cells HepG2, human lung cancer cells A549, human colon cancer cells HCT-116, human leukemia cells MV-4-11, and human normal breast epithelial cells MCF-10A.

[0067] 1.2. Experimental Methods Test cells in the logarithmic growth phase were digested with trypsin, counted, and then resuspended in a culture medium containing 10% fetal bovine serum at a density of 2-5 × 10⁶ cells per well. 3 100 μL of cells were seeded into each well of a 96-well plate, with a blank control well containing no cells (culture medium only). The plates were pre-cultured at 37°C in a 5% CO2 incubator for 24 hours to allow cell adhesion. After pre-culture, the old culture medium was discarded, and 100 μL of fresh culture medium containing different concentrations of the test drug was added to each well. A solvent control group (DMSO) and a positive control group were set up {PARP inhibitor NU-1085 (Cas No. 188106-83-4), Olaparib (Biode Pharmaceuticals); microtubule polymerization inhibitor Combretastatin A-4 (CA-4, Shanghai Dibai Biotechnology Co., Ltd.), XA (Cas No. 566915-58-0)}. The plates were then cultured for another 72 hours. After culture, 20 μL of CCK-8 solution was added to each well, and the plates were incubated at 37°C for 1–4 hours. The absorbance (OD value) of each well was measured at 450 nm using a microplate reader. Cell proliferation inhibition rate (%) = [1 – (OD drug group – OD blank) / (OD solvent control group – OD blank)] × 100%. Substitute the inhibition rates at each concentration into GraphPad Prism 8.0 software to calculate the IC50. 50 value.

[0068] 1.3. Experimental Results Table 1. Antiproliferative activity of compounds from Examples 1-41 against MDA-MB-231 cells

[0069] As shown in Table 1, most of the compound examples showed IC50 activity against human breast cancer MDA-MB-231 cells. 50 The value was lower than that of the positive controls NU-1085 (87.21 μM), Olaparib (39.42 μM) and XA (15.04 μM), indicating better anti-proliferative activity.

[0070] Table 2. Antiproliferative activity of some of the compounds in the examples against MCF-10A cells.

[0071] As shown in Table 2, the selected compounds exhibited low cytotoxicity against normal human breast epithelial cells MCF-10A, but stronger inhibitory activity against human breast cancer MDA-MB-231 cells, demonstrating high selectivity. For example, the compound in Example 36 had a selectivity index (SI) of 57.9, significantly higher than the positive controls NU-1085 (SI = 1.8), Olaparib (SI = 1.6), XA (SI = 1.1), and CA-4 (SI = 2.7).

[0072] Table 3. In vitro antiproliferative activity of some of the compounds in the examples against various human tumor cell lines.

[0073] As shown in Table 3, the compounds in the selected examples all exhibited strong anti-proliferative activity against various human tumor cell lines, with IC50 values ​​of [missing information]. 50 The values ​​were mostly lower than those of the positive controls NU-1085 and XA.

[0074] 2. In vitro PARP enzyme inhibitory activity test 2.1 Experimental Methods Coat 96-well microplates with 100 μL of PBS solution containing 5 μg / mL histone (Shanghai Yuanye, S27586) per well and incubate overnight at 4°C. Discard the coating solution and wash three times with PBST. Add 200 μL of PBS solution containing 3% bovine serum albumin (Suzhou Xinsaimei, WB6504) and block at room temperature for 2 hours. Discard the blocking solution and wash three times with PBST. Then, immerse the plates in PARP buffer (50 mM Tris-HCl). pWash once with H8.0, 50mM KCl, 10mM MgCl2, 1mM DTT, 0.05% NP-40; add 35μL of activated DNA (125μg / mL, sequence CGGAATTCCG, GenScript) to each well, then add 10μL of DMSO solution containing different concentrations of the test compound, 20μL of PARP1 (0.5μg / mL, MCE, HY-P74652) or PARP2 enzyme (0.5μg / mL, MCE, HY-P702585), and set up solvent control wells (DMSO), positive control wells (NU-1085), and background control wells (without PARP2 enzyme), pre-incubate at room temperature for 15 minutes; then add 35μL of NAD⁺ (final concentration 50-100μM, Bio-Pharmaceutical, BD126917), react at 37℃ for 30 minutes; discard the reaction solution, wash 3 times with PBST; add 100μL of PBST to each well. pADPr antibody (1:2000, Santa Cruz, sc-56198) was incubated at room temperature for 1 hour; the primary antibody was discarded, and the sample was washed three times with PBST; 100 μL of goat anti-mouse IgG horseradish peroxidase (1:3000, Proteintech, RGAM001) was added to each well, and the sample was incubated at room temperature for 30 minutes; the secondary antibody was discarded, and the sample was washed four times with PBST; 100 μL of TMB chromogenic buffer (Biosharp, BL728A) was added to each well, and the sample was incubated at room temperature in the dark for 10-15 minutes, followed by the addition of 50 μL of 2M H2SO4 to terminate the reaction. The absorbance (OD value) at 450 nm was read using a multi-functional microplate reader (Tecan, USA). Enzyme activity percentage (%) = (OD of drug wells – OD background) / (OD of control wells – OD background) × 100%. The enzyme activity percentage at each concentration was substituted into GraphPad Prism 8.0 to calculate the IC50. 50 value.

[0075] 2.2 Test Results Table 4. In vitro inhibitory activity of some of the compounds in the examples against PARP1 / 2 enzymes.

[0076] As shown in Table 4, the selected compounds in the examples all showed good inhibitory activity against PARP1 and PARP2, with the activity of the compound in Example 36 being comparable to that of the positive control PARP inhibitor NU-1085.

[0077] 3. In vitro microtubule polymerization inhibitory activity test 3.1 Experimental Methods Formulated with 80 mM PIPES pPolymerization buffer containing H 6.8 (Biosharp, BL2176A), 2.0 mM MgCl2, and 0.5 mM EGTA (Biosharp, BS153) was prepared and kept on ice. A solvent control group (DMSO), a positive control group (CA-4, Shanghai Dibai Biotechnology Co., Ltd.), and a background control group were prepared in 384-well clear plate. Then, 10 μL of different concentrations of the compound, 2.5 μL of glycerol (Biosharp, BS154), 10 μL of 10 mg / mL tubulin (Cytoskeleton, CSK-T240-B), and 2 μL of 25 mM GTP (Shanghai Beyotime, D7380) were added sequentially. The volume was then brought to 50 μL with pre-chilled polymerization buffer. After rapid mixing, the plate was placed in a microplate reader (Tecan, USA) pre-warmed to 37 ℃, and the absorbance (OD value) was read every 10 seconds at 340 nm in kinetic mode for 55 minutes. Based on the inhibition rate of each compound concentration on the maximum polymerization degree of tubulin (with the solvent control well representing 100% polymerization and background correction), the inhibition rate (%) is calculated as (1 - (OD sample - OD background) / (OD control - OD background)) × 100%. The IC50 value was calculated using GraphPad Prism 8.0 software. 50 value.

[0078] 3.2 Test Results Table 5. In vitro inhibitory activity of some of the compounds in the examples against tubulin polymerization.

[0079] As shown in Table 5, the selected compounds in the examples exhibit high inhibitory activity against tubulin polymerization, with the compound in Example 36 showing the highest IC50 value. 50 The value was comparable to that of the positive control microtubule polymerization inhibitor CA-4.

[0080] 4. In vivo antitumor activity test 4.1 Experimental Methods Thirty female BALB / c nude mice (Changzhou Cavens Laboratory Animal Co., Ltd.) aged 4-6 weeks and weighing 18-20 g were subcutaneously inoculated with MDA-MB-231 human breast cancer cells in the logarithmic growth phase in the right axilla. Each mouse was inoculated with 0.1 mL of cell suspension (cell concentration of 1×10⁻⁶). 7 (Inoculate at a rate of 1 / mL, store on ice, and gently mix before inoculation). Wait until the average tumor volume grows to approximately 85 mm. 3Mice were randomly divided into 6 groups (n=5 per group) using a randomized block design: model group (equal volume of solvent, solvent composition: 5% DMSO + 30% PEG300 + 5% Tween80 + 60% saline), CA-4 group (20 mg / kg), Olaparib group (20 mg / kg), low-dose group of compound 36 (20 mg / kg), and high-dose group of compound 36 (40 mg / kg). The model group, CA-4 group, and Olaparib group were administered the compound via intraperitoneal injection, while the low-dose and high-dose groups of compound 36 were administered the compound via gavage, once daily for 21 consecutive days. Afterwards, mice were euthanized by cervical dislocation, and tumor tissue was dissected and weighed. Tumor growth inhibition rate (%) = (mean tumor weight of model group – mean tumor weight of administered group) / mean tumor weight of model group × 100%. Simultaneously, major organs (heart, liver, spleen, lung, and kidney) were isolated and stained with hematoxylin and eosin to assess the effects of the drug on tissue morphology.

[0081] 4.2 Test Results Table 6. In vivo antitumor activity of the compound in Example 36 against MDA-MB-231 tumor-bearing mice.

[0082] As shown in Table 6, the compound of Example 36 exhibited excellent in vivo antitumor activity in a dose-dependent manner. At a low dose of 20 mg / kg, its tumor growth inhibition rate was 51.9%, significantly higher than that of the positive control Olaparib group (36.4%) and CA-4 group (44.2%) at the same dose; when the dose was increased to 40 mg / kg, the tumor growth inhibition rate further increased to 69.2%. In addition, this compound did not cause a decrease in body weight in mice during treatment, demonstrating good safety.

[0083] like Figure 1 As shown, even at high doses (40 mg / kg), the compound in Example 36 did not cause damage to major organs such as the heart, liver, spleen, lungs, and kidneys, further demonstrating its good safety profile.

[0084] The above embodiments are for illustrative purposes only, and the scope of the invention is not limited thereto. Modifications will be readily apparent to those skilled in the art, and the invention is limited only by the scope of the appended claims.

Claims

1. A biphenylbenzo-5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the compound is shown in general formula (I): ； Among them, R 1 It is H or methoxy; R 2 R 3 R 4 Each is independently selected from H, halogen, trifluoromethoxy, hydroxyl, C1-C3 alkyl or C1-C6 alkoxy; or R 2 With R 3 Together with the carbon atoms of the benzene ring to which it is attached, it forms a cyclic structure selected from –OCH2O–, –CH2CH2O– or –OCH2CH2O–; R 5 R 6 R 7 R 8 Each is independently selected from H, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, C1~C3 alkyl or C1~C3 alkoxy; X is selected from –N=, Y is selected from –NH–; or X is selected from –O–, Y is selected from –CH=.

2. The biphenylbenzo-5-membered heterocyclic compound or its pharmaceutically acceptable salt according to claim 1, characterized in that, R 1 For H, R 3 It is methyl, trifluoromethoxy, or C1~C3 alkoxy, R 2 R 4 Each is independently selected from H, F, Cl, hydroxyl, methyl, or methoxy; or R 1 R 4 For H, R 2 With R 3 Together with the carbon atoms of the benzene ring to which it is attached, it forms a cyclic structure selected from –CH2CH2O–.

3. The biphenylbenzo-5-membered heterocyclic compound or its pharmaceutically acceptable salt according to claim 2, characterized in that, R 1 For H, R 3 It is methyl or methoxy, R 2 R 4 Each is independently selected from H or F.

4. The biphenylbenzo-5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 5 R 6 R 7 R 8 Each is independently selected from H, F, Cl, hydroxyl, trifluoromethyl, trifluoromethoxy, methyl or methoxy.

5. The biphenylbenzo-five-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, X is selected from –N=; Y is selected from –NH–.

6. A biphenylbenzo-5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof, characterized in that, The structures of the compounds are shown in Formulas 1 to 41:

7. The use of the biphenylbenzo five-membered heterocyclic compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of poly(ADP-ribose) polymerase (PARP) and / or microtubule polymerization inhibitors.

8. The use of the biphenylbenzopentacyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6 in the preparation of medicaments for the prevention and / or treatment of tumors.

9. The application according to claim 8, characterized in that, The tumor is selected from breast cancer, ovarian cancer, liver cancer, lung cancer, colorectal cancer, pancreatic cancer, stomach cancer, cervical cancer, prostate cancer, leukemia, or lymphoma.

10. An antitumor drug composition, characterized in that, The antitumor active ingredient in the pharmaceutical composition is a biphenylbenzo5-membered heterocyclic compound as described in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

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