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

Abstract

The application discloses a benzopentaheterocyclic carboxamide compound or a pharmaceutically acceptable salt thereof and an application thereof, and belongs to the field of medicinal chemistry, and specifically discloses a compound with poly (ADP-ribose) polymerase (PARP) and microtubule protein polymerization double inhibition activity, a structure of the compound is shown as general formula (I). In view of the problems of limited efficacy of existing single-target anti-tumor drugs and drug interaction risks of combined drug use, the compound simultaneously realizes inhibition of PARP and microtubule protein in a single molecule. In-vitro tests show that the compound has good anti-proliferation activity on various tumor cells, and has low toxicity on normal cells; in-vivo xenograft tumor model tests show that the anti-tumor activity of the compound is better than that of a single drug group and a combined drug administration group, meanwhile, the compound does not cause damage to main organs, has good safety, and shows great potential for clinical development as an anti-tumor drug.

Description

Technical Field

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

[0002] Traditional cancer treatments (surgery, chemotherapy, radiotherapy) have limitations such as numerous adverse reactions and high recurrence rates; while molecular targeted therapy improves selectivity, tumor heterogeneity and acquired drug resistance still limit its clinical efficacy.

[0003] Microtubules are dynamic polymers composed of α- and β-tubulin dimers, crucial for cell mitosis and intracellular transport. Inhibitors targeting the colchicine binding site (CBS) offer advantages such as ease of synthesis, low susceptibility to P-glycoprotein-mediated resistance, and anti-angiogenic effects; however, due to the toxic side effects often associated with their clinical application, no such drugs have yet been approved for marketing. Poly(ADP-ribose) polymerases (PARPs, such as PARP1 and PARP2) are key enzymes for repairing DNA single-strand breaks. PARP inhibitors (such as olaparib and veliparib) can exert their effects through synthetic lethal mechanisms in tumors with homologous recombination repair defects (such as BRCA1 / 2 mutations), but their efficacy is limited in individuals without specific gene mutations, and resistance issues exist.

[0004] Recent studies have shown that the combined use of microtubule-targeting agents and PARP inhibitors has synergistic potential: on the one hand, microtubule-targeting agents can interfere with the intracellular transport of DNA damage repair proteins, prolonging the DNA damage induced by PARP inhibitors; on the other hand, PARP inhibitors can prevent tumor cells from escaping mitotic catastrophe induced by microtubule-targeting agents by interfering with mitotic checkpoint proteins. Clinical studies have shown that olaparib or veliparib combined with the microtubule-targeting agent paclitaxel has a synergistic therapeutic effect on triple-negative breast cancer and ovarian cancer (Abraham JE, et al. Nat. Commun. 2025, 16, 4269; Appleman LJ, et al.). Cancer Chemother. Pharmacol. (2019, 84, 1289-1301), but combination dosing regimens have practical problems such as complex dosage, drug interactions, and unpredictable pharmacokinetics. In contrast, single-molecule dual-target drugs can avoid these drawbacks.

[0005] Currently, although some PARP / CBS dual-target inhibitors such as AMXI-5001 and TP-3 have entered preclinical or clinical trial stages, research in this field remains relatively limited. Therefore, there is still a lack of dual inhibitors of PARP and tubulin polymerization that are structurally diverse, have high safety profiles, and exhibit excellent in vitro and in vivo activity. Summary of the Invention

[0006] Purpose of the invention: The purpose of this invention is to provide a benzo[a]pentacyclic heterocyclic formamide compound with dual inhibitory activity against poly(ADP-ribose) polymerase (PARP) and tubulin polymerization, and its applications.

[0007] Technical solution: The present invention relates to benzo[a]pentacyclic heterocyclic formamide compounds or pharmaceutically acceptable salts thereof, wherein the structure of the compounds 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, hydroxyl, C1-C3 alkyl or C1-C3 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 –C(=O)–, –C(=CH2)–, –CH(OH)– or –CH2–; Y is selected from –N=, Z is selected from –NH–; or Y is selected from –O–, Z is selected from –CH=.

[0008] Furthermore, R 1 R 3 For H; R 2 R 4 It is a methoxy group; or R 1 For H, R 3 It is a methoxy group, R 2 R 4 Each is independently selected from H, F, Cl, hydroxyl, methyl, or methoxy.

[0009] Furthermore, R 5 R 7 R 8 For H, R 6 Selected from H, F, Cl, hydroxyl, methyl, or methoxy; or R 5 R 6 R 8 For H, R 7Selected from H, F, Cl, trifluoromethyl, trifluoromethoxy, methyl or methoxy.

[0010] Furthermore, R 5 R 7 R 8 For H, R 6 Selected from H or F; or R 5 , R 6 , R 8 For H, R 7 Selected from H, F, Cl, methyl or methoxy.

[0011] Furthermore, X is selected from –C(=O)–; Y is selected from –N=; Z is selected from –NH–.

[0012] The benzopentacyclic heterocyclic formamide compounds or their pharmaceutically acceptable salts described in this invention have structures as shown in Formulas 1 to 40: .

[0013] The use of the benzo[a]pentacyclic heterocyclic formamide compounds or pharmaceutically acceptable salts thereof described in this invention in the preparation of poly(adenosine diphosphate ribose) polymerase and / or microtubule polymerization inhibitors.

[0014] The use of the benzopentacyclic heterocyclic formamide compounds or their pharmaceutically acceptable salts 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 the above-mentioned benzopentacyclic heterocyclic formamide 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 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 single-drug and combination therapy groups, 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 28 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-(3,4,5-trimethoxybenzyltoluyl)-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) δ 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. 1H NMR (500 MHz, DMSO- d 6) δ 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-(3,4,5-trimethoxybenzoyl)benzaldehyde In a sealed tube, 3,4,5-trimethoxyphenylboronic acid (1.2 mmol), 3-iodobenzaldehyde (1.0 mmol), potassium carbonate (3.0 mmol), palladium acetate (0.05 mmol), triphenylphosphine (0.1 mmol), formic acid (3.0 mmol), triethylamine (4.0 mmol), and acetic anhydride (3.0 mmol) were added sequentially, followed by toluene (3 mL). The tube was sealed and reacted in an oil bath at 100 °C for 12 hours. After the reaction, the mixture was cooled to room temperature and filtered. The filtrate was diluted with water (10 mL) 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 = 5 / 1) to give a white solid compound in 69% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 10.10 (s, 1H), 8.25 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.04 (s, 2H), 3.79 (s, 6H), 3.77 (s, 3H). Step IV: 2-(3-(3,4,5-trimethoxybenzyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide 2,3-Diaminobenzamide (0.2 mmol) and 3-(3,4,5-trimethoxybenzoyl)benzaldehyde (0.2 mmol) were dissolved in methanol, and sodium bisulfite (0.3 mmol) was added with stirring. The resulting mixture was heated to reflux for 5 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 91% yield. 1 H NMR (500 MHz, DMSO- d 6) δ 13.60 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.77 (dd, J = 14.2, 7.6 Hz, 3H), 7.36 (t, J = 7.8 Hz, 1H), 7.13 (s, 2H), 3.82 (s, 6H), 3.81 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.65, 172.40, 166.63, 153.21, 151.49,142.31, 138.54, 132.12, 132.02, 131.23, 129.96, 127.83, 123.61, 123.09,115.74, 108.11, 60.72, 56.58. HRMS (ESI) m / z : calcd for C 24 H 22 N3O5 [M+H] + ,432.1554; found, 432.1558. Example 2: 2-(3-(2,3,4-trimethoxybenzyltoluyl)-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 pale yellow solid with a yield of 44%. 1 H NMR (500 MHz, DMSO-d 6) δ 13.60 (s, 1H), 9.28 (s,1H), 8.57 (s, 1H), 8.53 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.80(d, J = 8.0 Hz, 2H), 7.74 (t, J = 9.0 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.23(d, J = 8.6 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.63 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.71, 166.55, 156.89, 152.60,151.48, 141.90, 141.80, 139.51, 135.87, 131.75, 131.52, 129.90, 129.84,127.17, 125.67, 125.50, 123.62, 123.11, 123.06, 115.66, 108.19, 61.85, 60.99,56.61. HRMS (ESI) m / z : calcd for C 24 H 22 N3O5 [M+H] + , 432.1554; found, 432.1559. Example 3: 2-(3-(2,4-dimethoxybenzyltoluyl)-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 60%. 1 H NMR (500 MHz, DMSO- d6) δ 13.61 (s, 1H), 9.27 (s,1H), 8.61 (s, 1H), 8.57 (d, J = 7.8 Hz, 1H), 7.90 – 7.88 (dd, J = 7.8, 3.4Hz, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.8Hz, 1H), 6.90 (s, 2H), 6.86 (s, 1H), 3.81 (s, 6H). 13 C NMR (126 MHz, DMSO- d 6)δ 195.37, 166.53, 160.92, 151.40, 141.81, 139.14, 138.30, 135.88, 132.10,131.44, 129.97, 127.77, 123.66, 123.14, 115.70, 108.04, 105.28, 56.06. HRMS(ESI) m / z : calcd for C 23 H 20 N3O4 [M+H] + , 402.1448; found, 402.1455. Example 4: 2-(3-(2,3-dimethoxybenzyl)-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 44%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.59 (s, 1H), 9.30 (s, 1H), 8.55 (s, 1H), 8.54 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.85 (d, J= 7.4 Hz, 1H), 7.78 – 7.74 (m, 3H), 7.48 – 7.45 (m, 1H), 7.40 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 8.2 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.43, 166.57, 153.72,151.54, 149.28, 141.84, 139.20, 135.87, 131.67, 130.75, 129.83, 129.49,127.64, 125.79, 123.62, 123.09, 115.68, 112.38, 111.30, 56.32, 56.05. HRMS(ESI) m / z : calcd for C 23 H 18 N3O4 [MH] − , 400.1303; found, 400.1313. Example 5: 2-(3-(3-hydroxy-4-methoxybenzoyl)phenyl)-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 white solid with a yield of 68%. 1 H NMR (500 MHz, DMSO- d 6) δ 9.12 (s, 1H), 8.53 (d, J =9.4 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.80 – 7.76(m, 3H), 7.41 (t, J = 7.9 Hz, 1H), 7.34 (d, J= 2.2 Hz, 1H), 7.29 (dd, J =8.5, 2.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.32, 166.75, 152.89, 151.17, 147.07, 139.34, 135.21, 132.44,131.46, 129.73, 129.52, 128.66, 127.49, 124.24, 124.21, 123.93, 122.53,116.72, 116.68, 111.84, 56.26. HRMS (ESI) m / z : calcd for C 22 H 16 N3O4 [MH] − ,386.1146; found, 386.1156. Example 6: 2-(3-(4-methoxy-3-methylbenzoyl)phenyl)-1H-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 55%. 1 H NMR (500 MHz, DMSO) δ 13.57 (s, 1H), 9.29 (s, 1H), 8.53 (d, J = 6.6 Hz, 2H), 7.89 (t, J = 6.7 Hz, 1H), 7.83 (t, J = 7.1 Hz, 1H),7.78 – 7.73 (m, 3H), 7.70 (d, J = 6.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.13(d, J = 7.8 Hz, 1H), 3.92 (s, 3H), 2.23 (s, 3H). 13 C NMR (126 MHz, DMSO-d 6) δ194.58, 166.57, 161.96, 151.53, 141.84, 139.32, 135.88, 132.52, 131.64,131.16, 130.68, 129.83, 129.16, 127.61, 126.69, 123.64, 123.11, 115.64,110.46, 56.27, 16.46. HRMS (ESI) m / z : calcd for C 23 H 18 N3O3 [MH] − , 384.1354;found, 384.1359. Example 7: 2-(3-(3-fluoro-4-methoxybenzoyl)phenyl)-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 pale yellow solid with a yield of 81%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.58 (s, 1H), 9.29 (s,1H), 8.56 (s, 1H), 8.55 (d, J = 7.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.86(d, J = 7.5 Hz, 1H), 7.82 – 7.73 (m, 3H), 7.70 (d, J = 12.3 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.39 – 7.35 (m, 2H), 3.97 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6)δ 193.60, 166.55, 151.91 (d, J = 10.2 Hz), 151.60 (d, J= 247.0 Hz), 151.42,141.82, 138.55, 135.86, 131.74, 131.05, 129.94, 129.76 (d, J = 5.3 Hz),128.69, 127.68, 123.65, 123.13, 117.34 (d, J = 19.2 Hz), 115.66, 113.82,56.91. HRMS (ESI) m / z : calcd for C 22 H 15 FN3O3 [MH] − , 388.1103; found, 388.1109. Example 8: 2-(3-(3-chloro-4-methoxybenzoyl)phenyl)-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 88%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.55 (s, 1H), 9.30 (s,1H), 8.56 (s, 1H), 8.54 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.87(s, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.80 – 7.71 (m, 4H), 7.37 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 3.98 (s, 3H). 13 C NMR (126 MHz, DMSO- d6) δ193.44, 166.57, 158.79, 151.40, 141.83, 138.50, 135.86, 131.71, 131.07,130.32, 129.97, 129.91, 127.70, 123.65, 123.13, 122.11, 115.64, 112.90,57.17. HRMS (ESI) m / z : calcd for C 22 H 17 ClN3O3 [M+H] + , 406.0953; found, 406.0955. Example 9: 2-(3-(4-methoxybenzoyl)phenyl)-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 70%. 1 H NMR (500 MHz, DMSO) δ 13.58 (s, 1H), 9.29 (s, 1H), 8.54 (s, 1H), 8.53 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.86 – 7.83 (m,3H), 7.79 (s, 1H), 7.76 (t, J = 8.1 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.14(d, J = 8.7 Hz (2H), 3.89 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.38,166.64, 163.72, 151.50, 141.83, 139.13, 135.86, 132.84, 131.64, 130.73,129.82, 129.53, 127.59, 123.65, 123.12, 123.04, 115.67, 114.50, 56.06. HRMS(ESI) m / z : calcd for C 22 H 16 N3O3 [MH] − , 372.1343; found, 372.1352. Example 10: 2-(3-(2,3-dihydrobenzofuran-5-carbonyl)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 80%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.57 (s, 1H), 9.30 (s, 1H), 8.53 (s, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.83 – 7.74 (m, 5H), 7.66 (d, J = 8.5 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.68 (t, J = 8.3 Hz, 2H), 3.28 (t, J = 9.1 Hz, 2H). 13 C NMR (126 MHz, DMSO- d 6)δ 194.31, 166.58, 164.61, 151.52, 141.83, 139.46, 135.86, 132.54, 131.54,130.57, 129.79, 128.90, 127.84, 127.54, 123.62, 123.09, 115.64, 109.37,72.75, 28.86. HRMS (ESI) m / z : calcd for C 23 H 16 N3O3 [MH] − , 382.1197; found, 382.1211. Example 11: 2-(3-(benzo[d [1,3]dioxacyclopentane-5-carbonyl)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 white solid with a yield of 71%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.57 (s, 1H), 9.30 (s, 1H), 8.54 (s, 1H), 8.53 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.79 – 7.74 (m, 3H), 7.40 – 7.35 (m, 3H), 7.09 (d, J = 7.9 Hz, 1H), 6.19 (s, 2H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.10, 166.56,152.13, 151.48, 148.37, 141.82, 139.02, 135.86, 131.64, 131.36, 130.83,129.84, 127.62, 127.45, 123.63, 123.10, 115.66, 109.43, 108.55, 102.70. HRMS(ESI) m / z : calcd for C 22 H 14 N3O4 [MH] − , 384.0990; found, 384.0999. Example 12: 2-(3-(2,3-dihydrobenzo[ b [1,4]dioxane-6-carbonyl)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 white solid with a yield of 51%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.57 (s, 1H), 9.29 (s, 1H), 8.54 (s, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H),7.79 – 7.74 (m, 3H), 7.40 – 7.33 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 4.37 (s, 2H), 4.32 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 194.10, 166.72, 151.36,148.55, 143.74, 138.88, 135.91, 132.02, 131.23, 130.19, 129.81, 128.86,128.11, 124.72, 123.85, 123.55, 122.68, 119.23, 117.71, 116.39, 65.09, 64.47.HRMS (ESI) m / z : calcd for C 23 H 16 N3O4 [MH] − , 398.1146; found, 398.1155. Example 13: 2-(3-benzoylphenyl)-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 pale yellow solid with a yield of 64%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.60 (s, 1H), 9.28 (s, 1H), 8.60 (s,1H), 8.57 (d, J = 7.3 Hz, 1H), 7.88 (t,J = 8.3 Hz, 2H), 7.84 (d, J = 7.1 Hz,2H), 7.81 –7.72 (m, 4H), 7.64 – 7.59 (m, 2H), 7.38 (dt, J = 7.7, 3.1 Hz, 1H). 13 C NMR (126 MHz, DMSO- d 6) δ 195.84, 166.67, 151.48, 138.40, 137.15, 133.53,132.00, 131.33, 130.29, 130.02, 129.94, 129.20, 127.92, 123.58, 123.06,115.94. HRMS (ESI) m / z : calcd for C 21 H 14 N3O2 [MH] − , 340.1092; found, 340.1098. Example 14: 2-(4-(3,4,5-trimethoxybenzoyl)phenyl)-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 pale yellow solid with a yield of 67%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.45 (s, 1H), 9.38 (s, 1H), 8.31 (d, J =8.1 Hz, 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 (126 MHz, DMSO- d6) δ 194.52, 166.52, 153.16,151.23, 142.13, 141.92, 138.91, 135.94, 132.93, 132.29, 130.91, 127.37,123.79, 123.38, 123.23, 115.78, 107.90, 60.68, 56.52. HRMS (ESI) m / z : calcdfor C 24 H 20 N3O5[MH] − , 430.1408; found, 430.1414. Example 15: 2-(2-(3,4,5-trimethoxybenzoyl)phenyl)-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 54%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.64 (s, 1H), 9.31 (s, 1H), 8.62 (s, 1H), 8.58 (d, J = 7.9 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H),7.85 (s, 1H), 7.81 – 7.74 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.12 (s, 2H), 3.82 (s, 6H), 3.80 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 194.66, 166.64,153.18, 151.50, 142.16, 141.76, 138.48, 135.95, 132.10, 131.28, 129.98,129.90, 127.84, 123.57, 123.05, 115.74, 107.98, 60.69, 56.51. HRMS (ESI) m / z :calcd for C 24 H 20 N3O5[MH] − , 430.1408; found, 430.1419. Example 16: 2-(2-methyl-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0036] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 3-iodo-2-methylbenzaldehyde to obtain a pale yellow solid with a yield of 75%. 1 H NMR (400 MHz, DMSO- d 6) δ 13.29 (s, 1H), 9.26 (d, J = 3.5 Hz, 1H), 7.94 (d, J = 6.7 Hz, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.79 – 7.74 (m, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.51 (d, J = 6.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.07 (s, 2H), 3.78 (s, 9H), 2.44 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 193.26,165.13, 151.67, 150.10, 140.62, 138.19, 137.06, 134.40, 130.98, 130.68,130.22, 128.24, 123.76, 122.02, 121.48, 114.24, 106.48, 59.19, 55.01, 19.85.HRMS (ESI) m / z : calcd for C 25 H 22 N3O5[MH] − , 444.1565; found, 444.1562. Example 17: 2-(4-methyl-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0037] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 3-iodo-4-methylbenzaldehyde to obtain a pale yellow solid with a yield of 51%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.42 (s, 1H), 9.28 (d, J = 3.4 Hz, 1H), 8.36 (dd, J = 8.0, 2.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.87 (d, J =7.6 Hz, 1H), 7.75 (d, J = 3.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.61 (d, J =8.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.10 (s, 2H), 3.80 (s, 3H), 3.78 (s, 6H), 2.34 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 196.23, 166.57, 153.40,151.62, 143.07, 141.83, 139.43, 138.98, 135.77, 132.31, 132.15, 129.05,126.87, 126.22, 123.50, 122.91, 115.49, 107.89, 60.73, 56.54, 19.92. HRMS(ESI) m / z : calcd for C 25 H 22 N3O5[MH] − , 444.1565; found, 444.1562. Example 18: 2-(3-methyl-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H-benzo[ d Preparation of imidazole-4-carboxamide

[0038] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 3-iodo-5-methylbenzaldehyde to obtain a pale yellow solid with a yield of 74%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.55 (s, 1H), 9.29 (s, 1H), 8.40 (s, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.73(s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.12 (s, 2H), 3.82 (s, 6H), 3.81 (s, 3H), 2.53 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.7, 166.5, 153.1, 151.5, 142.2,141.8, 139.6, 138.6, 135.8, 132.4, 132.1, 131.6, 129.6, 125.2, 123.5, 123.0,123.0, 115.6, 108.0, 60.6, 56.5, 21.3. HRMS (ESI) m / z : calcd for C 25 H 24 N3O5[M+H] + , 446.1710; found, 446.1711. Example 19: 2-(2-methyl-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0039] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-2-methylbenzaldehyde to obtain a light brown solid with a yield of 52%. 1 H NMR (500 MHz, DMSO- d6) δ 8.79 (s, 1H), 8.21 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 7.9 Hz, 2H), 7.84 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.07 (s, 2H), 3.82 (s, 6H), 3.77 (s, 3H), 2.64(s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 194.02, 166.76, 153.16, 150.71, 143.33,142.02, 135.23, 133.74, 133.06, 132.88, 132.19, 131.72, 125.22, 124.74,121.90, 117.52, 107.78, 60.65, 56.58, 20.84. HRMS (ESI) m / z : calcd forC 25 H 22 N3O5[MH] − , 444.1565; found, 444.1562. Example 20: 2-(4-methoxy-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0040] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 3-iodo-4-methoxybenzaldehyde to obtain a white solid with a yield of 57%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.33 (s, 1H), 9.31 (s, 1H), 8.43 (d, J = 6.6 Hz, 1H), 8.18 (s, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.43 (d, J= 8.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.07 (s, 2H), 3.83(s, 3H), 3.78 (s, 3H), 3.77 (s, 6H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.08,166.64, 158.81, 153.28, 151.74, 142.98, 141.97, 135.81, 132.32, 131.13,129.26, 127.71, 123.34, 122.73, 122.61, 122.04, 115.28, 113.27, 107.54,60.71, 56.53. HRMS (ESI) m / z : calcd for C 25 H 22 N3O6[MH] − , 460.1514; found, 460.1515. Example 21: 2-(3-methoxy-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0041] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 3-iodo-5-methoxybenzaldehyde to obtain a white solid with a yield of 90%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.59 (s, 1H), 9.26 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.79 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.42 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.14 (s, 2H), 3.95 (s, 3H), 3.82 (s, 6H), 3.80 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 194.28, 166.51,160.15, 153.19, 151.26, 142.27, 141.70, 139.98, 135.81, 131.96, 131.02,123.68, 123.21, 123.06, 120.45, 116.79, 116.71, 115.72, 108.03, 60.71, 56.55,56.31. HRMS (ESI) m / z : calcd for C 25 H 22 N3O6[MH] − , 460.1514; found, 460.1512. Example 22: 2-(2-methoxy-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0042] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-2-methoxybenzaldehyde to obtain a white solid with a yield of 84%. 1 H NMR (500 MHz, DMSO- d 6) δ 12.70 (s, 1H), 9.24 (s, 1H), 8.80 (s,1H), 7.98 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.83 (d, J = 7.7 Hz,1H), 7.79 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.09(s, 2H), 4.16 (s, 3H), 3.83 (s, 6H), 3.80 (s, 3H). 13 C NMR (126 MHz, DMSO- d6)δ 193.38, 166.68, 160.59, 153.14, 149.13, 141.90, 140.84, 135.64, 134.51,132.69, 132.31, 130.35, 123.58, 122.75, 122.69, 117.76, 116.23, 112.78,107.85, 60.73, 57.05, 56.59. HRMS (ESI) m / z : calcd for C 25 H 22 N3O6[MH] − ,460.1514; found, 460.1519. Example 23: 2-(4-hydroxy-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0043] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 4-hydroxy-3-iodobenzaldehyde to obtain a pale yellow solid with a yield of 38%. 1 H NMR (500 MHz, DMSO- d 6) δ 11.11 (s, 1H), 8.86 (s, 1H), 8.37 (d, J = 8.7 Hz, 1H), 8.32 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 8.1 Hz,1H), 7.78 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.10 (s, 2H), 3.79 (s, 6H), 3.78 (s, 3H). 13 C NMR (126 MHz, DMSO- d6) δ 194.61,166.89, 160.00, 153.24, 151.15, 142.83, 134.07, 132.97, 132.50, 130.70,127.13, 124.64, 124.34, 121.95, 117.73, 116.59, 107.70, 60.72, 56.59. HRMS(ESI) m / z : calcd for C 24 H 20 N3O6[MH] − , 446.1358; found, 446.1363. Example 24: 2-(2-hydroxy-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0044] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 2-hydroxy-5-iodobenzaldehyde to obtain a white solid with a yield of 56%. 1 H NMR (500 MHz, DMSO- d 6) δ 12.88 (brs, 2H), 8.82 (brs, 2H), 7.85 –7.81 (m, 3H), 7.72 (s, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 8.6 Hz,1H), 7.08 (s, 2H), 3.83 (s, 6H), 3.80 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ193.44, 167.49, 161.23, 153.12, 150.92, 141.64, 137.20, 134.26, 133.08,131.48, 128.93, 123.16, 122.64, 117.63, 114.49, 107.78, 60.68, 56.57. HRMS(ESI) m / z : calcd for C 24 H 20 N3O6[MH] −, 446.1358; found, 446.1359. Example 25: 2-(4-hydroxy-3-methoxy-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0045] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 4-hydroxy-3-iodo-5-methoxybenzaldehyde to obtain a white solid with a yield of 42%. 1 H NMR (500 MHz, DMSO- d 6) δ 10.39 (s, 1H), 8.83 (s, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 7.10 (s, 2H), 4.03 (s, 3H), 3.79 (s, 6H), 3.78 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 195.07, 166.85, 153.23, 151.93,148.88, 148.64, 142.73, 135.84, 132.63, 126.64, 123.49, 123.03, 122.27,121.15, 115.91, 113.23, 107.72, 60.71, 56.96, 56.59. HRMS (ESI) m / z : calcdfor C 25 H 22 N3O7[MH] − , 476.1463; found, 476.1463. Example 26: 2-(2-fluoro-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0046] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 2-fluoro-3-carboxyphenylboronic acid, yielding a pale yellow solid with a yield of 61%. 1 H NMR (500MHz, DMSO- d 6) δ 13.17 (s, 1H), 9.27 (s, 1H), 8.56 (s, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.83 – 7.74 (m, 3H), 7.58 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.8 Hz,1H), 7.14 (s, 2H), 3.80 (s, 6H), 3.79 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ191.48, 166.49, 157.16 (d, J = 256.3 Hz), 153.40, 146.85, 143.27, 141.06,135.87, 133.76, 132.83, 132.17, 128.16 (d, J = 15.8 Hz), 125.79, 123.85,123.34, 123.10, 118.48 (d, J = 12.3 Hz), 116.23, 107.75, 60.75, 56.62. HRMS(ESI) m / z : calcd for C 24 H 21 FN3O5[M+H] + , 450.1460; found, 450.1467. Example 27: 2-(4-fluoro-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0047] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 2-fluoro-5-carboxyphenylboronic acid, yielding a light brown solid with a yield of 97%.1 H NMR (500MHz, DMSO- d 6) δ 13.54 (s, 1H), 9.26 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.89(d, J = 7.5 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.64 (t, J = 9.1 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.15 (s, 2H), 3.80 (s, 9H). 13 C NMR (126 MHz, DMSO- d 6) δ191.28, 166.52, 160.87 (d, J = 253.5 Hz), 153.40, 150.73, 143.32, 141.78,135.86, 132.52, 131.95, 129.13, 127.64 (d, J = 16.1 Hz), 126.35, 123.65,123.10, 123.06, 118.01 (d, J = 22.0 Hz), 115.63, 107.82, 60.76, 56.62. HRMS(ESI) m / z : calcd for C 24 H 21 FN3O5[M+H] + , 450.1460; found, 450.1466. Example 28: 2-(3-fluoro-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0048] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 3-fluoro-5-carboxyphenylboronic acid, yielding a pale yellow solid with a yield of 89%. 1 H NMR (500MHz, DMSO- d6) δ 13.67 (s, 1H), 9.21 (s, 1H), 8.44 (s, 1H), 8.42 (d, J = 9.5Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.72 (d, J = 8.3Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.16 (s, 2H), 3.84 (s, 6H), 3.82 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 193.34, 166.43, 162.66 (d, J = 246.1 Hz), 153.25,150.31, 142.56, 141.66, 141.56, 140.86 (d, J = 6.6 Hz), 135.90, 132.16 (d, J = 6.7 Hz), 131.55, 123.89, 123.35, 118.33 (d, J = 25.8 Hz), 117.85 (d, J =25.3 Hz), 115.92, 108.18, 60.71, 56.59. HRMS (ESI) m / z : calcd for C 24 H 21 FN3O5[M+H] + , 450.1460; found, 450.1461. Example 29: 2-(2-fluoro-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0049] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 4-fluoro-3-carboxyphenylboronic acid, yielding a white solid with a yield of 72%. 1H NMR (500 MHz, DMSO- d 6) δ 13.29 (s, 1H), 9.20 (s, 1H), 8.66 (d, J = 6.9 Hz, 1H), 7.99 (s,1H), 7.91 (d, J = 7.5 Hz, 1H), 7.81 (s, 2H), 7.66 (t, J = 9.7 Hz, 1H), 7.40 (s, 1H), 7.12 (s, 2H), 3.83 (s, 6H), 3.80 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6)δ 193.32, 166.43, 161.23, 153.17, 146.71, 142.29, 141.16, 135.74, 134.75,134.42, 132.17, 131.97, 123.81, 123.41, 123.15, 117.76, 116.18, 108.03,60.69, 56.58. HRMS (ESI) m / z : calcd for C 24 H 19 FN3O5[MH] − , 448.1314; found, 448.1326. Example 30: 2-(4-chloro-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0050] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 2-chloro-5-carboxyphenylboronic acid, yielding a white solid with a yield of 91%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.54 (s, 1H), 9.23 (s, 1H), 8.45 (d, J = 7.1 Hz, 1H), 8.34 (s,1H), 7.89 (d, J = 7.4 Hz, 1H), 7.85 (d,J = 8.2 Hz, 1H), 7.76 – 7.73 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.10 (s, 2H), 3.79 (s, 6H), 3.78 (s, 3H). 13 C NMR (126 MHz, DMSO-) d 6) δ 193.08, 166.69, 153.51, 150.66, 143.61, 139.02, 132.28,131.30, 131.12, 130.33, 128.72, 127.49, 123.69, 123.19, 119.79, 115.96,107.91, 60.77, 56.62. HRMS (ESI) m / z : calcd for C 24 H 21 ClN3O5[M+H] + , 466.1164;found, 466.1171. Example 31: 2-(3-chloro-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0051] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 3-chloro-5-carboxyphenylboronic acid, yielding a white solid with a yield of 76%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.70 (s, 1H), 9.22 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 7.90 (s,2H), 7.78 (d, J = 8.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.15 (s, 2H), 3.83 (s, 6H), 3.82 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 193.29, 166.38, 153.25,150.04, 142.52, 141.60, 140.50, 135.84, 134.82, 131.69, 131.48, 131.06,130.40, 126.32, 123.89, 123.50, 123.25, 115.85, 108.16, 60.72, 56.59. HRMS(ESI) m / z : calcd for C 24 H 19 ClN3O5[MH] − , 464.1019; found, 464.1016. Example 32: 2-(3-trifluoromethoxy-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0052] Following the synthesis method of Example 1, 3-iodobenzaldehyde was replaced with 5-iodo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxyphenylboronic acid was replaced with 3-formyl-5-trifluoromethoxyphenylboronic acid, yielding a white solid with a yield of 61%. 1 H NMR (400 MHz, DMSO-) d 6) δ 13.78 (s, 1H), 9.23 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.86 – 7.78 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 7.16(s, 2H), 3.83 (s, 6H), 3.81 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 193.03,166.38, 153.27, 149.99, 149.10, 142.65, 140.69, 135.94, 132.26, 131.37,126.77, 123.84, 123.54, 123.40, 120.58 (q, J= 258.1 Hz), 115.92, 108.23,60.73, 56.55. HRMS (ESI) m / z : calcd for C 25 H 19 F3N3O6[MH] − ,514.1231; found,514.1230. Example 33: 2-(3-trifluoromethyl-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0053] Step I: Preparation of 2-(3-bromo-5-trifluoromethylphenyl)-1,3-dioxocyclopentane 3-Bromo-5-trifluoromethylbenzaldehyde (1.0 mmol), ethylene glycol (5.0 mmol), and p-toluenesulfonic acid (0.1 mmol) were dissolved in toluene (4 mL), and the mixture was heated to reflux for 2 hours. After the reaction was complete, the mixture was cooled to room temperature. The reaction solution was added to saturated sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed successively with saturated sodium bicarbonate solution (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a colorless liquid in 84% yield. 1 H NMR (500MHz, CDCl3) δ 7.84 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 5.85 (s, 1H), 4.16 –4.11 (m, 2H), 4.10 – 4.06 (m, 2H). Step II: Preparation of (3-(1,3-dioxocyclopentan-2-yl)-5-trifluoromethylphenyl)(3,4,5-trimethoxyphenyl)methanol 2-(3-bromo-5-trifluoromethylphenyl)-1,3-dioxocyclopentane (0.8 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and cooled to -78 °C. Under nitrogen protection, a 2.5 M n-butyllithium solution in n-hexane (0.88 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour after the addition was complete. Subsequently, a 3,4,5-trimethoxybenzaldehyde solution in anhydrous tetrahydrofuran (0.88 mmol) was slowly added dropwise, and the reaction was continued at -78 °C for 1 hour after the addition was complete. After the reaction was completed, a saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was heated to room temperature. The mixture was extracted with ethyl acetate (3 × 10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a white solid in 53% yield. 1 H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 6.57 (s, 2H), 5.83 – 5.81 (m, 2H), 4.15 – 4.10 (m, 2H), 4.09 –4.04 (m, 2H), 3.84 (s, 9H), 2.37 (s, 1H). Step III: Preparation of 3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-5-trifluoromethylbenzaldehyde (3-(1,3-dioxocyclopentan-2-yl)-5-trifluoromethylphenyl)(3,4,5-trimethoxyphenyl)methanol (0.4 mmol) was dissolved in tetrahydrofuran (2 mL), and 1.2 M hydrochloric acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution (3 mL) was added to neutralize the solution. The mixture was extracted with ethyl acetate (3 × 10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a white solid product in 95% yield. 1 H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 6.60 (s, 2H), 5.90 (s, 1H), 3.86 (s, 9H), 2.49 (s, 1H). Step IV: Preparation of 3-trifluoromethyl-5-(3,4,5-trimethoxybenzoyl)benzaldehyde 0.3 mmol of 3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-5-trifluoromethylbenzaldehyde was dissolved in 2 mL of anhydrous dichloromethane. Under ice bath conditions, 0.45 mmol of Desmond reagent was added, and the mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was placed back under ice bath conditions, and the reaction was quenched by adding 5 mL of saturated sodium thiosulfate solution and 5 mL of saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed successively with 15 mL of saturated sodium bicarbonate solution and 15 mL of saturated brine. 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 = 1 / 1) to give a white solid product in 90% yield. 1 H NMR (500 MHz, CDCl3) δ 10.18 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.06 (s, 2H), 4.00 (s, 3H), 3.90 (s, 6H). Step V: 2-(3-trifluoromethyl-5-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide Following the synthesis method of Example 1, 3-(3,4,5-trimethoxybenzoyl)benzaldehyde was replaced with 3-trifluoromethyl-5-(3,4,5-trimethoxybenzoyl)benzaldehyde, yielding a white solid with a yield of 60%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.81 (s, 1H), 9.19 (s, 1H), 8.88 (d, J = 5.2 Hz, 2H), 8.18 (s,1H), 7.93 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.8 Hz,1H), 7.18 (s, 2H), 3.83 (s, 6H), 3.83 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ193.27, 166.36, 153.27, 149.99, 142.59, 141.59, 139.71, 135.89, 131.40,131.33, 131.10, 130.74 (q, J = 31.7 Hz), 127.87, 127.09, 124.06 (q, J = 273.5Hz), 123.97, 123.61, 123.32, 115.94, 108.24, 60.73, 56.57. HRMS (ESI) m / z :calcd for C 25 H 19 F3N3O5[MH] − , 498.1282; found, 498.1286. Example 34: 2-(2,4-difluoro-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0054] Following the synthesis method of Example 33, 3-bromo-5-trifluoromethylbenzaldehyde was replaced with 3-bromo-2,4-difluorobenzaldehyde to obtain a white solid with a yield of 80%. 1 H NMR (400 MHz, DMSO- d 6) δ 13.20 (s, 1H), 9.25 (s,1H), 8.64 – 8.57 (m, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 3.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 8.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.21 (s, 2H), 3.82 (s, 6H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 187.25,166.45, 160.26 (dd, J= 252.9, 7.2 Hz), 156.87 (dd, J = 255.1, 7.6 Hz),153.67, 146.30 (d, J = 2.4 Hz), 144.04, 141.01, 135.77, 133.99 (dd, J = 9.9,2.8 Hz), 131.73, 123.83, 123.34, 123.06, 117.47 (t, J = 22.6 Hz), 116.17,115.22 (dd, J = 12.7, 2.5 Hz), 113.93 (dd, J = 22.0, 2.1 Hz), 107.42, 60.79,56.67. HRMS (ESI) m / z : calcd for C 24 H 18 F2N3O5[MH] − , 466.1220; found, 466.1215. Example 35: 2-(2,4-difluoro-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0055] Following the synthesis method of Example 33, 3-bromo-5-trifluoromethylbenzaldehyde was replaced with 3-bromo-2,5-difluorobenzaldehyde to obtain a white solid with a yield of 79%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.23 (s, 1H), 9.21 (s,1H), 8.45 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 6.6 Hz, 2H), 7.70(s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.18 (s, 2H), 3.82 (s, 6H), 3.80 (s, 3H). 13 C NMR (126 MHz, DMSO- d6) δ 190.19, 166.55, 158.22 (d, J = 242.8 Hz), 153.45,153.32 (d, J = 251.8 Hz), 145.89, 143.53, 131.66, 129.86 (d, J = 7.1 Hz), 129.70 (d, J = 7.7 Hz), 123.97, 123.53, 120.22 (d, J = 9.4 Hz), 120.10 (d, J = 8.9 Hz), 119.66, 119.44, 119.20, 118.97, 107.85, 60.74, 56.68. HRMS (ESI) m / z : calcd for C 24 H 18 F2N3O5[MH] − , 466.1220; found, 466.1216. Example 36: 2-(2,6-difluoro-3-(3,4,5-trimethoxybenzoyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0056] Following the synthesis method of Example 33, 3-bromo-5-trifluoromethylbenzaldehyde was replaced with 3-bromo-2,6-difluorobenzaldehyde, yielding a white solid with a yield of 58%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.48 (s, 1H), 9.19 (s, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.91 – 7.86 (m, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 9.1 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.14 (s, 2H), 3.83 (s, 6H), 3.79 (s, 3H). 13 C NMR (126 MHz, DMSO- d6) δ 190.56, 166.76, 161.98 (dd, J = 256.9, 6.3 Hz), 158.21 (dd, J = 258.8, 6.8 Hz), 153.36, 143.26, 141.90,133.86 (d, J = 6.7 Hz), 133.77 (d, J = 6.4 Hz), 132.02, 124.20 (d, J = 14.8Hz), 123.59, 123.29, 113.33, 113.15, 109.54 (t, J = 18.2 Hz), 107.85, 60.73,56.64. HRMS (ESI) m / z : calcd for C 24 H 18 F2N3O5[MH] − , 466.1220; found, 466.1222. Example 37: 2-(3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0057] Step I: Preparation of 2-(3-iodophenyl)-1,3-dioxocyclopentane Following the synthesis method of Example 33, 3-bromo-5-trifluoromethylbenzaldehyde was replaced with 3-iodobenzaldehyde to obtain a colorless liquid with a yield of 88%. 1 H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 5.75 (s, 1H), 4.14 –4.08 (m, 2H), 4.07 – 4.00 (m, 2H). Step II: Preparation of (3-(1,3-dioxocyclopentan-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanol Following the synthesis method of Example 33, 2-(3-bromo-5-trifluoromethylphenyl)-1,3-dioxocyclopentane was replaced with 2-(3-iodophenyl)-1,3-dioxocyclopentane to obtain a white solid with a yield of 70%. 1 H NMR (500 MHz, CDCl3) δ7.53 (s, 1H), 7.42 (t, J = 4.6 Hz, 1H), 7.37 (d, J = 4.7 Hz, 2H), 6.60 (s,2H), 5.80 (s, 1H), 5.79 (d, J = 3.1 Hz, 1H), 4.15 – 4.10 (m, 2H), 4.07 – 4.02(m, 2H), 3.83 (s, 9H), 2.21 (d, J = 3.5 Hz, 1H). Step III: Preparation of 3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)benzaldehyde Referring to the synthesis method of Example 33, (3-(1,3-dioxocyclopentan-2-yl)-5-trifluoromethylphenyl)(3,4,5-trimethoxyphenyl)methanol was replaced with (3-(1,3-dioxocyclopentan-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanol, yielding a white solid with a yield of 93%. 1 H NMR (500 MHz, CDCl3) δ 10.02 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 7.6Hz, 1H), 6.60 (s, 2H), 5.85 (s, 1H), 3.84 (s, 9H), 2.32 (s, 1 Hz). Step IV: 2-(3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide Following the synthesis method of Example 1, 3-(3,4,5-trimethoxybenzoyl)benzaldehyde was replaced with 3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)benzaldehyde, yielding a pale yellow solid with a yield of 94%. 1 H NMR (500 MHz, DMSO- d6) δ 13.44 (s, 1H), 9.36 (s, 1H), 8.36 (s, 1H), 8.08 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H),7.54 – 7.50 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.78 (s, 2H), 6.10 (d, J = 3.8Hz, 1H), 5.76 (d, J = 3.9 Hz, 1H), 3.75 (s, 6H), 3.61 (s, 3H). 13 C NMR (126MHz, DMSO- d 6) δ 166.69, 153.23, 152.50, 147.10, 141.94, 141.52, 136.86,135.82, 129.41, 129.35, 129.01, 125.85, 124.98, 123.40, 122.87, 122.80,115.50, 104.01, 74.57, 60.43, 56.37. HRMS (ESI) m / z : calcd for C 24 H 22 N3O5[MH] − , 432.1565; found, 432.1567. Example 38: 2-(3-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0058] Step I: Preparation of (3-(1,3-dioxolane-2-yl)phenyl)(3,4,5-trimethoxyphenyl) ketone Following the synthesis method of Example 33, 3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-5-trifluoromethylbenzaldehyde was replaced with the intermediate (3-(1,3-dioxocyclopent-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanol) of the compound of Example 37, yielding a white solid of 89%. 1 H NMR (500 MHz, DMSO- d 6) δ 7.82 (t, J = 1.7 Hz, 1H), 7.79 (dt, J = 7.6, 1.5 Hz, 1H), 7.73 (dt, J = 7.7, 1.5 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.03 (s, 2H), 5.85 (s, 1H), 4.10 – 4.03 (m, 2H), 4.02 – 3.95 (m, 2H), 3.81 (s, 6H), 3.79 (s, 3H). Step II: Preparation of 2-(3-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)-1,3-dioxocyclopentane Methyltriphenylphosphine bromide (0.4 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Under nitrogen protection and an ice bath, a 2.5 M n-butyllithium solution in n-hexane (0.48 mmol) was slowly added dropwise, followed by stirring for 0.5 hours. Subsequently, an anhydrous tetrahydrofuran solution of (3-(1,3-dioxolane-2-yl)phenyl)(3,4,5-trimethoxyphenyl) methyl ketone (0.4 mmol) (1 mL) was added dropwise, followed by stirring in an ice bath for 2 hours. After the reaction was complete, a saturated ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was brought to room temperature. 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), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) to give a white solid product in 83% yield. 1 H NMR (500 MHz, CDCl3) δ 7.51(s, 1H), 7.45 (dt, J = 6.8, 2.0 Hz, 1H), 7.38 – 7.32 (m, 2H), 6.54 (s, 2H), 5.80 (s, 1H), 5.45 (d, J = 1.2 Hz, 1H), 5.44 (d,J = 1.2 Hz, 1H), 4.16 – 4.11(m, 2H), 4.07 – 4.02 (m, 2H), 3.88 (s, 3H), 3.80 (s, 6H). Step III: Preparation of 3-(1-(3,4,5-trimethoxyphenyl)vinyl)benzaldehyde Following the synthesis method of Example 33, (3-(1,3-dioxocyclopentan-2-yl)-5-trifluoromethylphenyl)(3,4,5-trimethoxyphenyl)methanol was replaced with 2-(3-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)-1,3-dioxocyclopentane to obtain a white solid in 86% yield. 1 H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.89 (s, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.6Hz, 1H), 6.51 (s, 2H), 5.51 (s, 2H), 3.89 (s, 3H), 3.81 (s, 6H). Step IV: 2-(3-(1-(3,4,5-trimethoxyphenyl)vinyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide Following the synthesis method of Example 1, 3-(3,4,5-trimethoxybenzoyl)benzaldehyde was replaced with 3-(1-(3,4,5-trimethoxyphenyl)vinyl)benzaldehyde, yielding a white solid with a yield of 72%. 1 H NMR (500 MHz, DMSO- d 6) δ 13.44 (s, 1H), 9.32 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.24 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.35 (t,J = 7.7 Hz, 1H), 6.63 (s,2H), 5.67 (s, 1H), 5.61 (s, 1H), 3.74 (s, 6H), 3.70 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 166.60, 153.25, 152.18, 149.02, 142.08, 141.89, 138.13, 136.37,135.81, 130.75, 129.73, 129.71, 127.13, 126.49, 123.47, 122.97, 122.89,115.97, 115.52, 105.96, 60.55, 56.41. HRMS (ESI) m / z : calcd for C 25 H 22 N3O4[MH] − , 428.1616; found, 428.1626. Example 39: 2-(3-(3,4,5-trimethoxyphenyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide

[0059] Step I: Preparation of 2-(3-(3,4,5-trimethoxyphenyl)phenyl)-1,3-dioxocyclopentane (3-(1,3-dioxolane-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methyl ketone (0.5 mmol) was added to diethylene glycol (5 mL) containing 85% hydrazine hydrate (5.0 mmol), and the mixture was heated to 120 °C for 2 hours. After cooling to room temperature, potassium hydroxide (1.5 mmol) was added, and the mixture was heated to 190 °C and maintained at this temperature for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (10 mL), and the pH was adjusted to neutral with dilute hydrochloric acid (2 M). The mixture was extracted with ethyl acetate (3 × 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give a white solid in 81% yield. 1 H NMR (500 MHz, CDCl3) δ 7.38 – 7.31(m, 3H), 7.20 (d, J= 7.2 Hz, 1H), 6.42 (s, 2H), 5.80 (s, 1H), 4.17 – 4.12(m, 2H), 4.07 – 4.03 (m, 2H), 3.96 (s, 2H), 3.84 (s, 3H), 3.82 (s, 6H). Step II: Preparation of 3-(3,4,5-trimethoxybenzyl)benzaldehyde Following the synthesis method of Example 33, (3-(1,3-dioxocyclopentan-2-yl)-5-trifluoromethylphenyl)(3,4,5-trimethoxyphenyl)methanol was replaced with 2-(3-(3,4,5-trimethoxyphenyl)phenyl)-1,3-dioxocyclopentane to obtain a white solid in 84% yield. 1 H NMR (500 MHz, CDCl3) δ 10.00 (s, 1H), 7.74 (t, J =4.1 Hz, 1H), 7.73 (s, 1H), 7.47 (d, J = 3.7 Hz, 2H), 6.39 (s, 2H), 4.00 (s, 2H), 3.83 (s, 3H), 3.81 (s, 6H). Step III: 2-(3-(3,4,5-trimethoxyphenyl)phenyl)-1 H -benzo[ d Preparation of imidazole-4-carboxamide Following the synthesis method of Example 1, 3-(3,4,5-trimethoxybenzoyl)benzaldehyde was replaced with 3-(3,4,5-trimethoxybenzyl)benzaldehyde to obtain a white solid with a yield of 47%. 1 H NMR (400 MHz, DMSO- d 6) δ 13.39(s, 1H), 9.34 (s, 1H), 8.17 (s, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.87 (d, J =7.5 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.35 (t, J= 7.8 Hz, 1H), 6.62 (s, 2H), 4.00 (s, 2H), 3.74 (s, 6H), 3.61 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 166.67,153.37, 152.44, 142.69, 141.93, 136.98, 136.38, 135.78, 131.41, 129.71,129.67, 127.57, 125.19, 123.41, 122.89, 122.81, 115.48, 106.58, 60.44, 56.34,41.73. HRMS (ESI) m / z : calcd for C 24 H 22 N3O4[MH] − , 416.1616; found, 416.1625. Example 40: Preparation of 2-(3-(3,4,5-trimethoxybenzoyl)phenyl)benzofuran-7-carboxamide

[0060] Step I: Preparation of (3-iodophenyl)(3,4,5-trimethoxyphenyl)methanol Following the synthesis method of Example 33, 2-(3-bromo-5-trifluoromethylphenyl)-1,3-dioxocyclopentane was replaced with 5-bromo-1,2,3-trimethoxybenzene, and 3,4,5-trimethoxybenzaldehyde was replaced with 3-iodobenzaldehyde, yielding a white solid with a yield of 42%. 1 H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.33(d, J = 7.7 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.57 (s, 2H), 5.71 (s, 1H), 3.84 (s, 6H), 3.84 (s, 3H), 2.24 (s, 1H). Step II: Preparation of (3-iodophenyl)(3,4,5-trimethoxyphenyl) methyl ketone Following the synthesis method of Example 33, 3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-5-trifluoromethylbenzaldehyde was replaced with (3-iodophenyl)(3,4,5-trimethoxyphenyl)methanol to obtain a white solid with a yield of 92%. 1 H NMR (500 MHz, CDCl3) δ 8.16 (t, J = 1.7 Hz, 1H), 7.94 (dt, J = 8.1, 1.5 Hz, 1H), 7.76 (dt, J = 7.7, 1.3 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.06 (s, 2H), 3.97 (s, 3H), 3.90 (s, 6H). Step III: Preparation of 2-(3-(3,4,5-trimethoxybenzoyl)phenyl)benzofuran-7-nitrile In a sealed tube, (3-iodophenyl)(3,4,5-trimethoxyphenyl) ketone (0.4 mmol), (7-cyanobenzofuran-2-yl)boronic acid (0.44 mmol, Cas No: 1392502-90-7), tetrakis(triphenylphosphine)palladium (0.04 mmol), sodium carbonate (0.8 mmol), and a toluene / water mixture (4:1, 2.5 mL) were added sequentially. After sealing, the tube was heated in an oil bath at 100 °C for 14 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, 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 white solid in 64% yield. 1 H NMR (500 MHz, CDCl3) δ 8.29 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.34 (t, J= 7.7 Hz, 1H), 7.18 (s, 1H), 7.13(s, 2H), 3.97 (s, 3H), 3.90 (s, 6H). Step IV: Preparation of 2-(3-(3,4,5-trimethoxybenzoyl)phenyl)benzofuran-7-carboxamide 0.2 mmol of 2-(3-(3,4,5-trimethoxybenzoyl)phenyl)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 2 hours. After the reaction was complete, the solution was diluted with 10 mL of water, and a white solid precipitated. The solid was filtered, dried, and the yield was 85%. 1 H NMR (500 MHz, DMSO- d 6) δ 8.35 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.85 – 7.81 (m, 3H), 7.78(d, J = 7.7 Hz, 1H), 7.76 – 7.72 (m, 2H), 7.70 (s, 1H), 7.37 (t, J = 7.6 Hz,1H), 7.12 (s, 2H), 3.83 (s, 6H), 3.81 (s, 3H). 13 C NMR (126 MHz, DMSO- d 6) δ 194.69, 165.74, 155.30, 153.19, 151.82, 142.31, 138.58, 132.11, 130.50,130.19, 129.72, 129.22, 126.00, 125.79, 124.84, 123.76, 119.78, 108.04,103.59, 60.70, 56.55. HRMS(ESI):calcd for C 25 H 20 NO6 [MH] − ,430.1296; found,430.1299. Example 41 Preparation of tablets

[0061] Take the above formula and prepare it into tablets using conventional methods.

[0062] 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.

[0063] 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).

[0064] 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).

[0065] 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.

[0066] 1.2. Experimental Methods Collect test cells in the logarithmic growth phase, digest with trypsin, count the cells, and resuspend them in a culture medium containing 10% fetal bovine serum at a density of 2-5 × 10⁶ cells per well. 3100 μL of cells per well were seeded into 96-well plates, with blank control wells containing no cells (culture medium only). The plates were pre-cultured at 37°C and 5% CO2 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 (Veliparib, Olaparib, Phenstatin, Bio-Pharmaceutical) were also included. The plates were cultured for another 72 hours. After the culture period, 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%. The inhibition rates at each concentration were then used to calculate the IC50 using GraphPad Prism 8.0 software. 50 value.

[0067] 1.3. Experimental Results Table 1. Antiproliferative activity of compounds in Examples 1-40 against MDA-MB-231 cells

[0068] As shown in Table 1, most of the compounds in the examples exhibited potent anti-proliferative activity against human breast cancer MDA-MB-231 cells, with an IC50 value of [missing information]. 50 The values ​​were significantly lower than those of the positive control PARP inhibitors Veliparib (>100 μM) and Olaparib (41.91 μM), and the compounds in Example 1 (0.006 μM) and Example 28 (0.004 μM) had a stronger inhibitory effect on MDA-MB-231 cells than the positive control microtubule polymerization inhibitor Phenstatin (0.033 μM).

[0069] Table 2. Antiproliferative activity of some of the compounds in the examples against MCF-10A cells.

[0070] As shown in Table 2, the selected compounds exhibited low cytotoxicity against normal human breast epithelial cells MCF-10A, while demonstrating potent inhibitory activity against human breast cancer MDA-MB-231 cells, exhibiting high selectivity. For example, the compound in Example 28 had a selectivity index (SI) of 104.8, significantly higher than the positive control PARP inhibitor Olaparib (SI = 1.2) and the microtubule polymerization inhibitor Phenstatin (SI = 1.7).

[0071] Table 3. In vitro antiproliferative activity of some of the compounds in the examples against various human tumor cell lines.

[0072] As shown in Table 3, the compounds in the selected examples exhibited potent anti-proliferative activity against various human tumor cell lines, with IC50 values ​​of [missing information]. 50 The value was significantly lower than that of the positive control PARP inhibitor Olaparib and the microtubule polymerization inhibitor Phenstatin.

[0073] 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, MedChemExpress, HY-P74652) or PARP2 enzyme (0.5μg / mL, MedChemExpress, HY-P702585), and set up solvent control wells (DMSO), positive control wells (Veliparib), and background control wells (without PARP enzyme), pre-incubate at room temperature for 15 minutes; then add 35μL of NAD⁺ (final concentration 50-100μM, Bio-Pharmaceutical, BD126917), 37 Incubate at ℃ for 30 minutes; discard the reaction solution and wash three times with PBST; add 100 μL of pADPr antibody (1:2000, Santa Cruz, sc-56198) to each well and incubate at room temperature for 1 hour; discard the primary antibody and wash three times with PBST; add 100 μL of goat anti-mouse IgG horseradish peroxidase (1:3000, Proteintech, RGAM001) to each well and incubate at room temperature for 30 minutes; discard the secondary antibody and wash four times with PBST; add 100 μL of TMB chromogenic solution (Biosharp, BL728A) to each well and incubate at room temperature in the dark for 10-15 minutes, then add 50 μL of 2M H2SO4 to terminate the reaction. Read the absorbance (OD value) at 450 nm using a multi-functional microplate reader (Tecan, USA). Enzyme activity percentage (%) = (OD of drug wells – OD background) / (OD of control wells – OD background) × 100%. Substitute the percentage of enzyme activity at each concentration into GraphPad Prism 8.0 to calculate IC50. 50 value.

[0074] 2.2 Test Results Table 4. In vitro inhibitory activity of some of the compounds in the examples against PARP1 / 2 enzymes.

[0075] As shown in Table 4, the selected compound examples exhibited good inhibitory activity against PARP1 and PARP2, comparable to the activity of the positive control PARP inhibitor Veliparib.

[0076] 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 (Combretastatin A-4, Shanghai Dibai Biotechnology Co., Ltd.), and a background control group were prepared in 384-well clear flat-bottom plates. 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. Finally, the volume was brought to 50 μL with pre-chilled polymerization buffer. After rapid mixing, the plate was placed in a microplate reader (Tecan, USA) preheated 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 wells representing 100% polymerization and background correction), the inhibition rate (%) was calculated as (1 - (OD sample - OD background) / (OD control - OD background)) × 100%. The IC50 was calculated using GraphPad Prism 8.0 software. 50 value.

[0077] 3.2 Test Results Table 5. In vitro inhibitory activity of some of the compounds in the examples against tubulin polymerization.

[0078] As shown in Table 5, the selected compounds in the examples exhibited potent inhibitory activity against tubulin polymerization, with an IC50 value of [missing information]. 50 The value was similar to that of the positive control microtubule polymerization inhibitor Combretastatin A-4.

[0079] 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 19-21 g were used. MDA-MB-231 human breast cancer cells in the logarithmic growth phase were subcutaneously inoculated into the right axilla of each mouse. Each mouse was inoculated with 0.1 mL of cell suspension (cell concentration 1.0 × 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 of 5 mice each using a randomized block design: model group (equal volume of solvent, solvent composition: 5% DMSO + 50% PEG300 + 5% Tween80 + 40% saline), Phenstatin monotherapy group (Phe, 20 mg / kg), Veliparib monotherapy group (Vel, 100 mg / kg), combination therapy group (Phe 20 mg / kg + Vel 100 mg / kg), low-dose group of compound from Example 28 (10 mg / kg), and high-dose group of compound from Example 28 (20 mg / kg). All drugs were administered intraperitoneally once daily for 21 consecutive days. Mice were then sacrificed by cervical dislocation, and tumor tissue was removed and weighed. Tumor growth inhibition rate (%) = (mean tumor weight of model group – mean tumor weight of drug-treated 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.

[0080] 4.2 Test Results Table 6. In vivo antitumor activity of the compound from Example 28 against MDA-MB-231 tumor-bearing mice.

[0081] As shown in Table 6, the compound of Example 28 exhibited excellent in vivo antitumor activity in a dose-dependent manner. At a low dose of 10 mg / kg, its tumor growth inhibition rate was 62.2%, significantly higher than that of the positive control Phe group (46.4%), the Vel group (32.8%), and the combined treatment group (54.7%); when the dose was increased to 20 mg / kg, the tumor growth inhibition rate further increased to 72.3%. In addition, this compound did not cause a decrease in body weight in mice during treatment, demonstrating good safety.

[0082] like Figure 1 As shown, the compound in Example 28 did not cause damage to major organs such as the heart, liver, spleen, lungs, and kidneys even at high doses (20 mg / kg), further demonstrating its good safety profile.

[0083] 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 benzo[5]-heterocyclic formamide 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, hydroxyl, C1-C3 alkyl or C1-C3 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 –C(=O)–, –C(=CH2)–, –CH(OH)– or –CH2–; Y is selected from –N=, Z is selected from –NH–; or Y is selected from –O–, Z is selected from –CH=.

2. The benzopentacyclic formamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 1 R 3 For H; R 2 R 4 It is a methoxy group; or R 1 For H, R 3 It is a methoxy group, R 2 R 4 Each is independently selected from H, F, Cl, hydroxyl, methyl, or methoxy.

3. The benzopentacyclic heterocyclic formamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 5 R 7 R 8 For H, R 6 Selected from H, F, Cl, hydroxyl, methyl, or methoxy; or R 5 R 6 R 8 For H, R 7 Selected from H, F, Cl, trifluoromethyl, trifluoromethoxy, methyl or methoxy.

4. The benzopentacyclic heterocyclic formamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R 5 R 7 R 8 For H, R 6 Selected from H or F; or R 5 , R 6 , R 8 For H, R 7 Selected from H, F, Cl, methyl or methoxy.

5. The benzopentacyclic heterocyclic formamide compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, X is selected from –C(=O)–; Y is selected from –N=; Z is selected from –NH–.

6. A benzo[5]-heterocyclic formamide compound or a pharmaceutically acceptable salt thereof, characterized in that, The structures of the compounds are shown in Formulas 1 to 40: 。 7. The use of the benzopentacyclic heterocyclic formamide compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6 in the preparation of poly(ADP-ribose) polymerase (PARP) and / or microtubule polymerization inhibitors.

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

9. The application according to claim 7, 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 benzopentacyclic heterocyclic formamide compound as described in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

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