Carbazole-benzimidazole conjugate compounds and their applications

Abstract

The present invention discloses a carbazole-benzimidazole conjugate compound, and the general formula of the compound is (I): #imgabs0#In the formula, R1, R2, and R3 are the same or different and are each independently selected from hydrogen, a straight-chain, branched-chain or cyclic alkyl group of C 1～20 a straight-chain, branched-chain or cyclic alkyl group of, a C 1～20 a straight-chain, branched-chain or cyclic alkyl group of, a C 1～25 a straight-chain, branched-chain or cyclic alkyl group of, a C 2～20 a heterocyclic group containing N, O or S of, a C 6～20 aryl group, an alkyl-substituted amino group, a C-6 alkyl disubstituted amino group, an amino group, a cyano group, a hydroxyl group, a carboxyl group, an ester group, an amide, a formamido group, a methyl ester group or an isopropyl group; X represents C, N, O or S. The carbazole-benzimidazole conjugate compound provided by the present invention has the advantages of strong anti-tumor activity and low toxicity, etc.

Description

Technical Field

[0001] The present invention relates to the technical field of conjugate compounds. More specifically, the present invention relates to a carbazole-benzimidazole conjugate compound and its application. Background Art

[0002] Cancer, namely malignant tumor, is a class of complex systemic malignant diseases that seriously threaten human life and has a very great impact on social development, economic development and people's health. According to the latest statistical data of the International Agency for Research on Cancer (IARC), there were approximately 19.3 million newly diagnosed cancer patients and nearly 10 million cancer patients died globally in 2020. Lung cancer, gastric cancer, liver cancer, colon cancer, breast cancer, cervical cancer, thyroid cancer, esophageal cancer, pancreatic cancer, and brain cancer are the top 10 cancers with the highest incidence in our country, accounting for about 76.70% of the total incidence of all malignant tumors. Among them, lung cancer ranks first in male incidence, and breast cancer ranks first in female incidence. Although great progress has been made in cancer treatment and prevention with the advancement of science and technology, cancer is still one of the main causes of death. Despite some traditional types of cancer treatment methods, such as surgery, chemotherapy, etc., due to poor efficacy, large toxic and side effects, and unpleasant experiences, the successful treatment of cancer remains a huge challenge, and the development of new anti-cancer agents and treatment strategies is highly needed and necessary.

[0003] With the progress of molecular biology, tumor-targeted therapy has become a research hotspot in tumor treatment in recent years, and a number of targeted drugs have been approved for clinical application. Therefore, the development of anti-tumor drugs with low toxicity and high activity is currently a hot topic and a difficult point. Summary of the Invention

[0004] An object of the present invention is to solve at least the above problems and provide at least the advantages described hereinafter.

[0005] To achieve these objects and other advantages in accordance with the present invention, there is provided a carbazole-benzimidazole conjugate compound, and the general formula of this compound is (I):

[0006]

[0007]

[0008] In the formula, R1, R2, and R3 are the same or different and are each independently selected from hydrogen, a straight-chain, branched-chain or cyclic alkyl group of C 1～20 a straight-chain, branched-chain or cyclic alkyl group of C containing N, O, S or halogen, a straight-chain, branched-chain or cyclic alkyl group of C containing N, O, S or halogen, C 1～20 a straight-chain, branched-chain or cyclic alkyl group of C containing N, O, S or halogen, a straight-chain, branched-chain or cyclic alkyl group of C containing N, O, S or halogen, C 1～25A linear, branched or cyclic alkyl group, a C with substituents 2～20 A heterocyclic group containing N, O or S, a C with substituents 6～20 One of an aryl group, an alkyl-substituted amino group, a C-6 alkyl disubstituted amino group, an amino group, a cyano group, a hydroxyl group, a carboxyl group, an ester group, an amide, a formamido group, a methyl ester group or an isopropyl group;

[0009] X represents C, N, O or S.

[0010] Preferably, for the carbazole-benzimidazole conjugate compound, R1 represents hydrogen, C 1～20 A linear, branched or cyclic alkyl group, a C containing N, O, S or halogen 1～20 One of a linear, branched or cyclic alkyl group;

[0011] R2 represents hydrogen, a cyano group, a carboxyl group, an ester group, an amide, a C containing N, O, S or halogen 1～25 A linear, branched or cyclic alkyl group, a C with substituents 2～20 A heterocyclic group containing N, O or S, a C with substituents 6～20 One of an aryl group;

[0012] R3 represents hydrogen, a C containing N, O, S or halogen 1～25 A linear, branched or cyclic alkyl group, a C with substituents 2～20 A heterocyclic group containing N, O or S, a C with substituents 6～20 One of an aryl group.

[0013] The present invention also provides an application of a carbazole-benzimidazole conjugate compound in the preparation of a drug for treating tumors.

[0014] The present invention also provides an application of a carbazole-benzimidazole conjugate compound in the preparation of a drug for treating liver cancer.

[0015] Preferably, for the above application, the drug includes a pharmaceutically acceptable salt of the carbazole-benzimidazole conjugate compound and a pharmaceutically acceptable excipient.

[0016] The present invention at least includes the following beneficial effects:

[0017] The present invention provides a small molecule organic compound with selective toxicity to tumor cells and normal cells. According to the embodiments of the present invention, this type of anti-tumor small molecule contains the carbazole-benzimidazole conjugate compound described above. Therefore, this type of compound has the advantages of strong anti-tumor activity and low toxicity. The purpose of the present invention is to provide the use of a carbazole-benzimidazole conjugate compound in the preparation of a drug for treating chronic liver diseases.

[0018] Other advantages, objects and features of the present invention will be partly reflected by the following description, and partly will be understood by those skilled in the art through the research and practice of the present invention. Description of the Drawings

[0019] Figure 1 It is the test result of the effects of compounds DP-9 and DP-18 on the colony formation of human hepatocellular carcinoma HepG2 cells in Test Example 2 of the present invention;

[0020] Figure 2 It is the test result of the effects of compounds DP-9 and DP-18 on the migration of human hepatocellular carcinoma HepG2 cells (100x) in Test Example 3 of the present invention;

[0021] Figure 3 It is the test result of the effects of compounds DP-9 and DP-18 on the apoptosis of human hepatocellular carcinoma HepG2 cells (100x) in Test Example 4 of the present invention;

[0022] Figure 4 It is the test result of the in vivo antitumor activity of compounds DP-9 and DP-18 in Test Example 8 of the present invention. Detailed Embodiments

[0023] The present invention will be further described in detail below with reference to the drawings and embodiments, so that those skilled in the art can implement it according to the description in the specification.

[0024] It should be understood that the terms such as "having", "comprising" and "including" used herein do not exclude the existence or addition of one or more other elements or their combinations.

[0025] It should be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0026] In the description of the present invention, the orientation or positional relationship indicated by terms such as "transverse", "longitudinal", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc. is based on the orientation or positional relationship shown in the drawings. It is only for the convenience of describing the present invention and simplifying the description, and does not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation to the present invention.

[0027] <Example 1>

[0028] Synthesis of compound 2-hydroxyethyl 2-(6-methyl-9-(3-morpholinopropyl))-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 1):

[0029] (1) NaH (60%, 0.7 g, 17 mmol) was slowly added to a DMF solution of 3-methyl-9H-carbazole (15 mmol) within 10 minutes with vigorous stirring. After dehydrogenation, 4-(3-iodopropyl)morpholine hydrochloride (16 mmol) was added to the reaction system. After continuing the reaction for 1 hour, the reaction system was poured into water, and the precipitate was filtered. The obtained off-white solid was recrystallized with petroleum ether to obtain needle-like white crystals. By the Vilsmeier–Haack method, using N,N-dimethylformamide (DMF) as the solvent, the obtained needle-like white crystals were subjected to formylation reaction with POCl3 under the reaction conditions of 110 °C for 8 h. After drying the crude product, it was purified by silica gel column chromatography with ethyl acetate:methanol as the eluent to obtain compound A1 (6-methyl-9-(3-morpholinopropyl)-9H-carbazole-3-carbaldehyde) with a yield of 86%. The structural formula of compound A1 is as follows:

[0030]

[0031] The 1H NMR data of compound A1 are as follows:

[0032] 1 H NMR (500 MHz, CDCl3) δ 8.56–8.52 (m, 1H), 7.97 (dd, J = 7.5, 1.5 Hz, 1H), 7.69–7.65 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.11 (ddd, J = 7.5, 1.5, 0.8 Hz, 1H), 4.09 (t, J = 7.1 Hz, 2H), 3.64 (t, J = 7.1 Hz, 4H), 2.56 (t, J = 7.1 Hz, 2H), 2.52–2.46 (m, 7H), 1.81 (p, J = 7.1 Hz, 2H).

[0033] (2) 3,4-Diaminobenzoic acid was mixed with excess ethylene glycol and reacted at 110 °C for 24 hours under the catalysis of concentrated sulfuric acid. Ethylene glycol was removed under reduced pressure. 1M NaOH solution was added, and it was extracted 3 times with dichloromethane. The organic layer was neutralized with HCl (0.05M), washed with saturated sodium bicarbonate solution and deionized water until clear, and washed 3 times with saturated sodium chloride solution, dried over sodium sulfate. After evaporation of the solvent, a high-viscosity solution was obtained. The crude product was purified by silica gel column chromatography to obtain the product compound B1 with a yield of 75%. The structural formula of compound B1 is as follows:

[0034]

[0035] The 1H NMR data of compound B1 are as follows:

[0036] 1 1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 7.5, 1.6 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 5.08 (d, J = 7.3 Hz, 1H), 4.88 (d, J = 7.3 Hz, 1H), 4.83 (d, J = 7.5 Hz, 1H), 4.70 (d, J = 7.5 Hz, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3.84 (q, J = 7.2 Hz, 2H), 3.50 (t, J = 7.5 Hz, 1H).

[0037] (3) 1.12 g of compound A1 and 0.504 g of compound B1 were dissolved in 50 ml of absolute ethanol. After the reaction system started to reflux, 0.97 g of sodium metabisulfite (dissolved in an appropriate amount of water) was added as a catalyst, and the reaction was carried out under reflux at 85 °C for 8 h. After drying the crude product, it was separated and purified by column chromatography. Elution conditions: dichloromethane / petroleum ether. After drying, the target compound was obtained as a white solid with a yield of 91%. The 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of compound 1 are as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J = 1.4 Hz, 1H), 7.92 (dt, J = 7.5, 1.6 Hz, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.70–7.64 (m, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.10 (dq, J = 7.5, 0.8 Hz, 1H), 4.37 (t, J = 7.1 Hz, 2H), 4.07 (t, J = 7.1 Hz, 2H), 3.83 (q, J = 7.2 Hz, 2H), 3.67 (t, J = 7.1 Hz, 4H), 2.82–2.76 (m, 1H), 2.58 (t, J = 7.1 Hz, 2H), 2.51 (t, J = 7.1 Hz, 4H), 2.47 (d, J = 0.7 Hz, 3H), 1.79 (p, J = 7.1 Hz, 2H). 1313C NMR (125 MHz, DMSO-d6) δ 167.50, 153.14, 141.33, 141.04, 140.69, 139.27, 131.88, 126.67, 125.53, 125.38, 124.79, 123.89, 123.50, 123.26, 122.00, 120.47, 119.11, 114.26, 109.13, 107.87, 67.07, 64.40, 61.15, 54.05, 53.94, 43.22, 26.55, 21.24. HRMS (EI-TOF) m / z 512.2459, which is in agreement with the calculated C 31H32 N4O4 512.2424.

[0038] <Example 2>

[0039] Synthesis of 2-(2-hydroxyethyl)-2-(6-methyl-9-(3-(piperazin-1-yl)propyl)-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 2-DP-15):

[0040] (1) Step (1) was the same as in Example 1, except that an equimolar amount of 1-(3-iodopropyl)piperazine was used instead of 4-(3-iodopropyl)morpholine to obtain a colorless solid compound A2 with a yield of 77%. The structural formula of compound A2 is as follows:

[0041]

[0042] The 1H NMR data of compound A2 are as follows:

[0043] 1 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J = 1.4 Hz, 1H), 7.97 (dd, J = 7.5, 1.5 Hz, 1H), 7.69–7.65 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.11 (ddd, J = 7.5, 1.6, 0.9 Hz, 1H), 4.10 (t, J = 7.1 Hz, 2H), 2.78 (dd, J = 7.4, 6.8 Hz, 4H), 2.63–2.48 (m, 9H), 2.07 (p, J = 5.2 Hz, 1H), 1.84 (p, J = 7.1 Hz, 2H);

[0044] (2) Step (2) was the same as in Example 1;

[0045] (3) Step (3) is the same as in Example 1, except that compound A2 is used instead of compound A1 to obtain compound 2 (DP-15) with a yield of 63%. The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 2 are as follows:

[0046] 1 H NMR(500MHz,DMSO-d6)δ8.11(d,J=1.5Hz,1H),7.92(dt,J=7.5,1.6Hz,2H),7.83(d,J=1.9Hz,1H),7.70–7.64(m,2H),7.43(d,J=7.5Hz,1H),7.38(d,J=7.5Hz,1H),7.12–7.07(m,1H),4.37(t,J=7.0Hz,2H),4.09(t,J=7.1Hz,2H),3.83(q,J=7.2Hz,2H),2.82–2.73(m,5H),2.62(ddd,J=7.3,6.7,5.2Hz,2H),2.60–2.51(m,4H),2.46(s,3H),2.02(p,J=5.2Hz,1H),1.82(p,J=7.1Hz,2H). 13 C NMR(125MHz,DMSO-d6)δ167.50,153.14,141.33,141.04,140.69,139.27,131.88,126.67,125.53,125.38,124.79,123.89,123.50,123.26,122.00,120.47,119.11,114.26,109.13,107.87,67.07,61.15,53.58,52.63,44.33,43.22,26.63,21.24.HRMS(EI-TOF)M 511.2559, which is consistent with the calculated C 31H33 N5O3 511.2583.

[0047] <Example 3>

[0048] Synthesis of 2-(2-methoxyethyl)-2-(6-methyl-9-(3-(piperazin-1-yl)propyl)-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 3 - DP-16):

[0049] (1) Step (1) is the same as in Example 2;

[0050] (2) Step (2) is the same as that in Example 1, except that an equimolar amount of ethylene glycol monomethyl ether is used instead of ethylene glycol to obtain a colorless solid compound B2 with a yield of 80%. The structural formula of compound B2 is as follows:

[0051]

[0052] The 1H NMR data of compound B2 are as follows:

[0053] 1 H NMR(500MHz,CDCl3)δ7.37(dd,J=7.4,1.5Hz,1H),7.14(d,J=1.6Hz,1H),6.56(d,J=7.5Hz,1H),4.88(s,2H),4.83(d,J=7.5Hz,1H),4.70(d,J=7.5Hz,1H),4.46(t,J=7.1Hz,2H),3.61(t,J=7.1Hz,2H),3.38(s,3H).

[0054] (3) Step (3) is the same as that in Example 2, except that an equimolar amount of compound B2 is used instead of compound B1 to obtain compound 3 (DP-16) with a yield of 62%; the 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 3 are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.11(d,J=1.4Hz,1H),7.92(ddd,J=7.3,2.6,1.5Hz,2H),7.83(d,J=1.8Hz,1H),7.70–7.64(m,2H),7.42(d,J=7.6Hz,1H),7.38(d,J=7.5Hz,1H),7.10(dq,J=7.5,0.9Hz,1H),4.39(t,J=7.1Hz,2H),4.09(t,J=7.1Hz,2H),3.60(t,J=7.1Hz,2H),3.37(s,2H),2.77–2.71(m,4H),2.62(ddd,J=7.4,6.6,5.2Hz,2H),2.59–2.51(m,4H),2.46(d,J=0.9Hz,2H),2.02(p,J=5.2Hz,1H),1.82(p,J=7.1Hz,2H). 1313C NMR (125 MHz, DMSO-d6) δ 167.26, 153.14, 141.33, 141.04, 140.69, 139.27, 132.01, 126.67, 125.53, 125.37, 124.79, 124.07, 123.50, 123.26, 122.00, 120.43, 119.00, 114.26, 109.17, 107.86, 70.76, 64.12, 59.00, 53.18, 52.49, 44.33, 43.22, 26.56, 21.24. HRMS (EI-TOF) m / z 525.2759, which is consistent with the calculated C 31 H 35 N5O3 525.2740.

[0055] <Example 4>

[0056] Synthesis of 2-(2-methoxyethoxy)ethyl 2-(6-methyl-9-(3-(piperazin-1-yl)propyl)-9H-carbazol-3-yl)-1H-benzoimidazole-5-carboxylate (Compound 4-DP-17):

[0057] (1) Step (1) is the same as in Example 2;

[0058] (2) Step (2) is the same as in Example 1, except that equimolar amount of methyldiglycol is used instead of ethylene glycol to obtain colorless solid Compound B3 in 81% yield. The structural formula of Compound B3 is as follows:

[0059]

[0060] The 1H NMR data of Compound B3 are as follows:

[0061] 1 1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 7.5, 1.5 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 4.91 (s, 2H), 4.85 (d, J = 7.5 Hz, 1H), 4.66–4.59 (m, 3H), 3.72 (t, J = 7.1 Hz, 2H), 3.66–3.54 (m, 4H), 3.38 (s, 3H);

[0062] (3) Step (3) is the same as in Example 2, except that Compound B3 is used instead of Compound B1 to obtain Compound 4 (DP-17) in 62% yield; the 1H NMR and high resolution mass spectrometry (HRMS (EI-TOF)) data of Compound 4 are as follows: 1HNMR(500 MHz, DMSO-d6) δ 8.11 (d, J = 1.6 Hz, 1H), 7.90 (ddd, J = 13.0, 7.5, 1.5 Hz, 2H), 7.82 (d, J = 1.8 Hz, 1H), 7.70–7.64 (m, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.11–7.06 (m, 1H), 4.56 (t, J = 7.1 Hz, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.74 (t, J = 7.1 Hz, 2H), 3.67–3.60 (m, 2H), 3.60–3.54 (m, 2H), 3.38 (s, 2H), 2.77–2.71 (m, 4H), 2.65–2.50 (m, 6H), 2.47 (d, J = 0.9 Hz, 2H), 2.02 (p, J = 5.2 Hz, 1H), 1.82 (p, J = 7.1 Hz, 2H). 13 C NMR(125 MHz, DMSO-d6) δ 167.18, 153.10, 141.75, 140.75, 139.78, 139.25, 132.09, 126.37, 125.57, 125.37, 124.71, 124.12, 123.50, 123.26, 121.91, 120.43, 119.07, 114.28, 109.01, 107.93, 71.70, 70.50, 68.89, 64.82, 59.02, 53.44, 52.49, 44.33, 43.24, 26.56, 21.24. HRMS(EI-TOF) M 569.3059, consistent with the calculated C 33 H 39 N5O4 569.3002.

[0063] <Example 5>

[0064] Synthesis of 2-(2-Hydroxyethoxy)ethyl 2-(6-methyl-9-(3-(piperazin-1-yl)propyl)-9H-carbazol-3-yl)-1H-benzimidazole-5-carboxylate (Compound 5-DP-18):

[0065] (1) Step (1) is the same as in Example 2;

[0066] (2) Step (2) is the same as in Example 1, except that equimolar amount of diethylene glycol is used instead of ethylene glycol to obtain a colorless solid compound B4 with a yield of 85%. The structural formula of compound B4 is as follows:

[0067]

[0068] The 1H NMR data of compound B4 are as follows:

[0069] 1 H NMR(500MHz,CDCl3)δ7.38(dd,J=7.5,1.6Hz,1H),7.14(d,J=1.6Hz,1H),6.56(d,J=7.5Hz,1H),4.91(s,2H),4.85(d,J=7.5Hz,1H),4.66–4.59(m,3H),4.29(t,J=7.4Hz,1H),3.71(t,J=7.1Hz,2H),3.68–3.62(m,2H),3.56(td,J=7.0,1.0Hz,2H).

[0070] (3) Step (3) is the same as that in Example 2, except that an equimolar amount of compound B3 is used instead of compound B1 to obtain compound 5 (DP-18) with a yield of 62%. The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 5 are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.11(d,J=1.6Hz,1H),7.91(ddd,J=15.4,7.5,1.6Hz,2H),7.84(d,J=1.6Hz,1H),7.70–7.65(m,2H),7.42(d,J=7.5Hz,1H),7.37(d,J=7.5Hz,1H),7.12–7.07(m,1H),4.56(t,J=7.1Hz,2H),4.09(t,J=7.1Hz,2H),3.94–3.87(m,1H),3.77–3.71(m,2H),3.69–3.61(m,2H),3.54(td,J=7.0,0.8Hz,2H),2.77–2.71(m,4H),2.62(ddd,J=7.4,6.6,5.2Hz,2H),2.59–2.50(m,4H),2.47(d,J=0.9Hz,3H),2.02(p,J=5.2Hz,1H),1.82(p,J=7.1Hz,2H). 1313C NMR (125 MHz, DMSO-d6) δ 167.20, 153.10, 141.65, 141.04, 140.75, 139.25, 132.09, 126.54, 125.57, 125.37, 124.73, 124.12, 123.50, 123.26, 121.91, 120.43, 119.07, 114.26, 109.10, 107.94, 72.89, 69.08, 64.82, 61.53, 53.44, 52.49, 44.33, 43.42, 26.56, 21.24. HRMS (EI-TOF) m / z calcd for C 32 H 37 N5O4 555.2846, found 555.2859.

[0071] <Example 6>

[0072] Synthesis of methyl 2-(6-methyl-9-(3-(piperazin-1-yl)propyl)-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 6):

[0073] (1) Step (1) was the same as in Example 2;

[0074] (2) Methyl 3,4-diaminobenzoate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0075] (3) Step (3) was the same as in Example 2, except that an equimolar amount of methyl 3,4-diaminobenzoate was used instead of Compound B1 to give Compound 6 in a yield of 82%. The 1H NMR and high resolution mass spectrometry (HRMS (EI-TOF)) data of Compound 6 are as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 1.5 Hz, 1H), 7.94 (ddd, J = 11.3, 7.5, 1.5 Hz, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.70–7.64 (m, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.10 (dt, J = 7.7, 1.2 Hz, 1H), 4.09 (t, J = 7.1 Hz, 2H), 3.94 (s, 2H), 2.81–2.74 (m, 4H), 2.65–2.57 (m, 4H), 2.54 (t, J = 7.1 Hz, 2H), 2.46 (s, 2H), 2.02 (p, J = 5.2 Hz, 1H), 1.82 (p, J = 7.1 Hz, 2H). 1313C NMR (125 MHz, DMSO-d6) δ 166.95, 153.14, 141.33, 141.04, 140.78, 139.13, 131.88, 126.67, 125.74, 125.71, 124.90, 123.75, 123.50, 123.23, 122.00, 120.47, 119.02, 113.78, 109.13, 107.85, 53.58, 52.63, 52.17, 44.33, 43.05, 26.39, 21.19. HRMS (EI-TOF) m / z calcd for C 29 H 31 N5O2 481.2478, found 481.2478.

[0076] <Example 7>

[0077] Synthesis of ethyl 2-(6-methyl-9-(3-(piperazin-1-yl)propyl)-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 7):

[0078] (1) Step (1) was the same as in Example 2;

[0079] (2) Ethyl 3,4-diaminobenzoate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0080] (3) Step (3) was the same as in Example 2, except that an equimolar amount of ethyl 3,4-diaminobenzoate was used instead of Compound B1 to obtain Compound 7, with a yield of 82%; the 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of Compound 7 are as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J = 1.5 Hz, 1H), 7.93 (ddd, J = 7.5, 2.2, 1.5 Hz, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.70–7.64 (m, 2H), 7.43 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.12–7.07 (m, 1H), 4.35 (q, J = 8.0 Hz, 2H), 4.09 (t, J = 7.1 Hz, 2H), 2.79–2.73 (m, 4H), 2.62 (ddd, J = 7.4, 6.8, 5.2 Hz, 2H), 2.60–2.51 (m, 4H), 2.46 (s, 3H), 2.02 (p, J = 5.2 Hz, 1H), 1.82 (p, J = 7.1 Hz, 2H), 1.39 (t, J = 8.0 Hz, 3H). 1313C NMR (125 MHz, DMSO-d6) δ 166.73, 153.14, 141.33, 141.04, 140.69, 139.17, 131.88, 126.67, 125.78, 125.35, 124.87, 123.89, 123.50, 123.26, 122.00, 120.47, 119.11, 114.26, 109.13, 107.87, 60.88, 53.58, 52.63, 44.33, 43.22, 26.55, 21.19, 14.30. HRMS (EI-TOF) m / z 495.2414, which is in agreement with the calculated value of C 31H33 N5O2 495.2634.

[0081] <Example 8>

[0082] Synthesis of 2-(2-hydroxyethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 8-DP-1):

[0083] (1) Step (1) was the same as in Example 1, except that an equimolar amount of iodoethane was used instead of 4-(3-iodopropyl)morpholine to obtain a colorless solid compound A3 in a yield of 85%; the structural formula of compound A3 is as follows:

[0084]

[0085] The 1H NMR data of compound A3 are as follows: 1 1H NMR (500 MHz, CDCl3) δ 8.61–8.57 (m, 1H), 7.95 (dd, J = 7.5, 1.4 Hz, 1H), 7.93–7.85 (m, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.43–7.38 (m, 1H), 7.37–7.29 (m, 2H), 4.35 (q, J = 8.0 Hz, 2H), 1.41 (t, J = 8.0 Hz, 3H);

[0086] (2) Step (2) was the same as in Example 1;

[0087] (3) Step (3) was the same as in Example 1, except that compound A3 was used instead of compound A1 to obtain compound 8 (DP-1) in a yield of 61%; the 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of compound 8 are as follows: 11H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.22–8.14 (m, 1H), 8.00 (dd, J = 8.4, 2.4 Hz, 1H), 7.97–7.90 (m, 1H), 7.86 (dd, J = 8.4, 2.2 Hz, 1H), 7.68 (dd, J = 8.5, 7.1 Hz, 2H), 7.40–7.31 (m, 2H), 4.47–4.36 (m, 4H), 3.81 (dt, J = 7.3, 6.5 Hz, 2H), 2.84 (t, J = 7.3 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 167.60, 152.72, 141.04, 140.85, 139.87, 139.69, 127.87, 125.91, 125.58, 124.87, 124.03, 123.83, 122.23, 121.08, 120.25, 119.46, 119.25, 113.48, 109.55, 107.64, 66.73, 61.11, 39.92, 13.34. HRMS (EI-TOF) M 399.1595, consistent with the calculated C 24 H 21 N3O3 399.1583.

[0088] <Example 9>

[0089] Synthesis of 2-(2-methoxyethyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 9-DP-2):

[0090] (1) Step (1) is the same as in Example 8;

[0091] (2) Step (2) is the same as in Example 3;

[0092] (3) Step (3) is the same as in Example 8, except that Compound B2 is used instead of Compound B1 to obtain Compound 9 (DP-2), yield: 68%; The 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of Compound 9 are as follows: 11H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 8.22–8.14 (m, 1H), 8.02 (dd, J = 8.4, 2.4 Hz, 1H), 7.97–7.89 (m, 1H), 7.87 (dd, J = 8.4, 2.4 Hz, 1H), 7.68 (dd, J = 8.4, 2.5 Hz, 2H), 7.40–7.31 (m, 2H), 4.46–4.38 (m, 4H), 3.67 (t, J = 6.2 Hz, 2H), 3.39 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 167.37, 152.72, 141.04, 140.85, 139.84, 139.63, 127.79, 125.91, 125.60, 124.79, 124.05, 123.85, 122.23, 121.08, 120.25, 119.45, 119.25, 113.49, 109.47, 107.72, 70.68, 64.35, 58.99, 39.94, 13.34. HRMS (EI-TOF) M 413.4959, which is consistent with the calculated C 25 H 23 N3O3 413.1739.

[0093] <Example 10>

[0094] Synthesis of 3-(diethylamino)propyl 2-(9-ethyl-6-methyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 10-DP-3): (1) Step (1) is the same as in Example 1, except that 6-methylcarbazole is used instead of carbazole to obtain Compound A4, yield: 58%; the structure of Compound A4 is:

[0095]

[0096] The 1H NMR data of Compound A4 are as follows: 1 1H NMR (500 MHz, CDCl3) δ 8.61–8.57 (m, 1H), 7.95 (dd, J = 7.5, 1.4 Hz, 1H), 7.93–7.85 (m, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.43–7.38 (m, 1H), 7.37–7.29 (m, 2H), 4.35 (q, J = 8.0 Hz, 2H), 1.41 (t, J = 8.0 Hz, 3H).

[0097] (2) Step (2) is the same as that in Example 1. The difference is that 2-(diethylamino)ethan-1-ol is used instead of ethylene glycol to obtain a colorless solid compound B5 with a yield of 54%; the structural formula of compound B5 is as follows:

[0098]

[0099] The 1H NMR data of compound B5 are as follows: 1 H NMR(500MHz,Chloroform-d)δ7.36(dd,J=7.5,1.5Hz,1H),7.14(d,J=1.6Hz,1H),6.56(d,J=7.5Hz,1H),4.91(s,2H),4.85(d,J=7.5Hz,1H),4.62(d,J=7.5Hz,1H),4.33(t,J=7.1Hz,2H),2.83(t,J=7.0Hz,2H),2.64(q,J=8.0Hz,4H),1.06(t,J=8.0Hz,6H);

[0100] (3) Step (3) is the same as that in Example 1. The difference is that compound A4 is used instead of compound A1, and B5 is used instead of compound B1 to obtain compound 10 (DP-3) with a yield of 68%; the 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 10 are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.22(dd,J=19.0,2.5Hz,2H),7.99(dd,J=8.4,2.4Hz,1H),7.91–7.84(m,2H),7.66(dd,J=23.3,8.4Hz,2H),7.50(d,J=8.4Hz,1H),7.13–7.06(m,1H),4.40(q,J=7.1Hz,2H),4.22(t,J=6.1Hz,2H),2.69–2.58(m,6H),2.49(t,J=0.6Hz,3H),1.96(p,J=6.2Hz,2H),1.38(t,J=7.0Hz,3H),1.02(t,J=7.2Hz,6H). 1313C NMR (125 MHz, DMSO-d6) δ 167.30, 152.72, 140.96, 140.83, 139.94, 138.69, 132.58, 126.18, 125.64, 125.55, 124.40, 124.35, 124.15, 124.02, 122.37, 119.53, 119.27, 113.49, 108.37, 107.67, 64.10, 51.63, 46.95, 40.49, 26.67, 21.16, 13.36, 11.30. HRMS (EI-TOF) m / z 482.2686, found for C 31 H 34 N4O2 482.2682.

[0101] <Example 11>

[0102] Synthesis of 2-(piperazin-1-yl)ethyl 2-(9-ethyl-6-methyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 11-DP-4):

[0103] (1) Step (1) is the same as in Example 10;

[0104] (2) Step (2) is the same as in Example 1, except that equimolar amount of N-hydroxyethylpiperazine is used instead of ethylene glycol to obtain colorless solid Compound B6 in 54% yield; The structural formula of Compound B6 is as follows:

[0105]

[0106] The 1H NMR data of Compound B6 are as follows: 1 1H NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 7.4, 1.5 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 4.89 (s, 2H), 4.79 (d, J = 7.5 Hz, 1H), 4.57 (d, J = 7.5 Hz, 1H), 4.33 (t, J = 7.1 Hz, 2H), 2.90 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.1 Hz, 4H), 2.53 (td, J = 7.0, 5.2 Hz, 4H), 2.06 (p, J = 5.2 Hz, 1H):

[0107] (3) Step (3) is the same as in Example 10, except that equimolar amount of Compound B6 is used instead of Compound B5 to obtain Compound 11 (DP-4) in 68% yield; The 1H NMR and high resolution mass spectrometry (HRMS (EI-TOF)) data of Compound 11 are as follows:1 1H NMR (500 MHz, DMSO-d6) δ 8.22 (dd, J = 19.1, 2.3 Hz, 2H), 7.99 (dd, J = 8.4, 2.4 Hz, 1H), 7.91–7.84 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.09 (dq, J = 8.5, 1.0 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 4.31 (t, J = 6.5 Hz, 2H), 2.90–2.70 (m, 6H), 2.63–2.50 (m, 5H), 2.49 (s, 3H), 1.41–1.34 (m, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 167.28, 152.72, 140.96, 140.83, 139.94, 138.69, 132.58, 126.18, 125.73, 125.56, 124.40, 124.35, 124.15, 124.02, 122.37, 119.53, 119.27, 113.49, 108.37, 107.66, 62.69, 54.73, 53.13, 44.26, 40.49, 21.16, 13.36. HRMS (EI-TOF) M 481.2424, consistent with the calculated C 29 H 31 N5O2 481.2478.

[0108] <Example 12>

[0109] Synthesis of 2-morpholinoethyl 2-(9-ethyl-6-methyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 12-DP-5):

[0110] (1) Step (1) is the same as in Example 10;

[0111] (2) Step (2) is the same as in Example 1, except that equimolar amount of N-hydroxyethylmorpholine is used instead of ethylene glycol to obtain colorless solid Compound B7 with a yield of 61%; The structural formula of Compound B7 is as follows:

[0112]

[0113] The 1H NMR data of Compound B7 are as follows: 11H NMR (500 MHz, CDCl3) δ 7.38 (dd, J = 7.5, 1.5 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 4.89 (s, 2H), 4.79 (d, J = 7.5 Hz, 1H), 4.57 (d, J = 7.5 Hz, 1H), 4.33 (t, J = 7.1 Hz, 2H), 3.71 (t, J = 7.1 Hz, 4H), 2.91 (t, J = 7.1 Hz, 2H), 2.59 (t, J = 7.1 Hz, 4H);

[0114] (3) Step (3) is the same as in Example 10, except that compound B7 is used instead of compound B5 to obtain compound 12 (DP-5), yield: 68%; The 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of compound 12 are as follows: 1 1H NMR (500 MHz, DMSO-d6) δ 8.22 (dd, J = 17.1, 2.2 Hz, 2H), 7.99 (dd, J = 8.4, 2.4 Hz, 1H), 7.91–7.84 (m, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.12–7.05 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.31 (t, J = 6.5 Hz, 2H), 3.72–3.59 (m, 4H), 2.86 (t, J = 6.4 Hz, 2H), 2.62–2.47 (m, 7H), 1.41–1.34 (m, 3H). 13 13C NMR (125 MHz, DMSO-d6) δ 167.28, 152.72, 140.96, 140.83, 139.94, 138.69, 132.58, 126.18, 125.73, 125.56, 124.40, 124.35, 124.15, 124.02, 122.37, 119.53, 119.27, 113.49, 108.37, 107.66, 65.91, 62.67, 54.78, 53.53, 40.49, 21.16, 13.36. HRMS (EI-TOF) M 482.2359, consistent with the calculated C 29 H 30 N4O3 482.2318.

[0115] <Example 13>

[0116] Synthesis of 3-(5,6-difluoro-substituted derivative 1H-benzo[d]imidazol-2-yl)-9-ethyl-9H-carbazole (Compound 13-DP-6):

[0117] (1) Step (1) is the same as in Example 8;

[0118] (2) Compound 3,5-difluorobenzene-1,2-diamine was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0119] (3) Step (3) is the same as in Example 8, except that an equimolar amount of compound 3,5-difluorobenzene-1,2-diamine was used instead of compound B1 to obtain compound 13 (DP-6) with a yield of 51%; The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 13 are as follows: 1 H NMR(500MHz, DMSO-d6)δ8.22–8.17(m, 1H), 7.92(dd, J = 7.5, 1.5Hz, 1H), 7.87(d, J = 1.4Hz, 1H), 7.62(d, J = 7.5Hz, 1H), 7.47(dd, J = 8.0, 5.0Hz, 1H), 7.44–7.27(m, 4H), 4.41(q, J = 8.0Hz, 2H), 1.38(t, J = 8.0Hz, 3H). 13 C NMR(125MHz, DMSO-d6)δ152.68, 148.62, 147.09, 146.93, 146.60, 141.57, 139.74, 138.87, 138.80, 135.58, 135.56, 127.35, 124.68, 123.54, 123.47, 122.46, 121.06, 120.57, 120.08, 110.00, 107.53, 105.03, 104.87, 100.51, 100.44, 40.10, 13.66.HRMS(EI-TOF)M 347.1225, consistent with the calculated C 21 H 15 F2N3 347.1234.

[0120] <Example 14>

[0121] Synthesis of 9-ethyl-3-(6-(2-(4-methylpiperazin-1-yl))ethoxy)-1H-benzo[D]imidazol-2-yl)-9H-carbazole (Compound 14-DP-7):

[0122] (1) Step (1) is the same as in Example 8;

[0123] (2) Purchase compound 4-(4-methylpiperazin-1-yl)-1,2-benzenediamine from Wuhan Zhenbang Biotechnology Co., Ltd.;

[0124] (3) Step (2) is the same as in Example 8, except that an equimolar amount of compound 4-(4-methylpiperazin-1-yl)-1,2-benzenediamine is used instead of compound B1 to obtain compound 14 (DP-7), yield: 68%; The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 14 are as follows: 1 H NMR(500MHz, DMSO-d6)δ8.17–8.12(m, 1H), 7.92(dd, J = 7.5, 1.5Hz, 1H), 7.86–7.82(m, 1H), 7.58(dd, J = 7.5, 2.2Hz, 2H), 7.45–7.39(m, 1H), 7.39–7.34(m, 1H), 7.26(td, J = 7.4, 1.7Hz, 1H), 7.06(d, J = 1.5Hz, 1H), 6.99(dd, J = 7.5, 1.5Hz, 1H), 4.34(q, J = 8.0Hz, 2H), 4.10(t, J = 7.1Hz, 2H), 2.81(t, J = 7.1Hz, 2H), 2.63–2.54(m, 8H), 2.32(s, 3H), 1.40(t, J = 8.0Hz, 3H). 13 C NMR(125MHz, DMSO-d6)δ157.78, 151.57, 141.67, 139.68, 139.65, 137.57, 128.06, 124.93, 123.48, 123.43, 122.44, 121.06, 120.36, 120.31, 119.76, 113.33, 110.00, 107.41, 99.15, 65.66, 55.14, 53.99, 53.27, 44.92, 39.95, 13.62.HRMS(EI-TOF)M 453.2524, in accordance with the calculated C 28 H 31 N5O 453.2529.

[0125] <Example 15>

[0126] Synthesis of 3-(6-bromo-1H-benzo[d]imidazol-2-yl)-9-ethyl-9H-carbazole (Compound 15-DP-8):

[0127] (1) Step (1) is the same as in Example 8;

[0128] (2) Purchase compound 4-bromobenzene-1,2-diamine from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0129] (3) Step (3) is the same as in Example 8, except that compound 4-bromophenyl-o-phenylenediamine is used instead of compound B1 to obtain compound 15 (DP-8), yield: 53%. The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 15 are as follows: 1 H NMR(600MHz,DMSO-d6)δ8.98(d,J=1.4Hz,1H),8.36–8.18(m,1H),7.72(dd,J=74.7,8.4Hz,1H),7.60–7.47(m,1H),7.40–7.24(m,1H),4.50(d,J=7.2Hz,2H),1.37(t,J=7.2Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ153.74,140.56,140.10,126.26,124.45,122.38,122.11,120.32,120.16,119.40,118.97,113.76,109.44,37.11,13.57.HRMS(EI-TOF)[M-I] + 390.0434, which is consistent with the calculated value of C 21 H 16 BrN3 390.2889.

[0130] <Example 16>:

[0131] Synthesis of 2-(9-ethyl-9H-carbazol-3-yl)-1H-naphtho[2,3-d]imidazole (Compound 16-DP-9):

[0132] (1) Step (1) is the same as in Example 8;

[0133] (2) Compound 2,3-diaminonaphthalene was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0134] (3) Step (3) is the same as in Example 8, except that an equimolar amount of compound 2,3-diaminonaphthalene is used instead of compound B1 to obtain compound 16 (DP-9), yield: 56%. The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 16 are as follows: 11H NMR (600 MHz, DMSO-d6) δ 12.90 (s, 1H), 9.10 (d, J = 1.2 Hz, 1H), 8.41 (dd, J = 8.6, 1.5 Hz, 1H), 8.28 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 8.00 (dd, J = 16.7, 7.2 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.41–7.27 (m, 2H), 4.54 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 154.53, 141.05, 140.62, 126.84, 126.47, 125.00, 122.92, 122.66, 122.34, 120.93, 119.97, 119.51, 110.02, 40.52, 40.33, 40.12, 39.98, 39.80, 39.64, 14.30. HRMS (EI-TOF) [M-I] + 362.1654, consistent with the calculated C 25 H 19 N3 361.1689.

[0135] <Example 17>

[0136] Synthesis of 3-(5,6-dibromo-1H-benzo[d]imidazol-2-yl)-9-ethyl-9H-carbazole (Compound 17-DP-10):

[0137] (1) Step (1) is the same as in Example 8;

[0138] (2) Compound 4,5-dibromo-o-phenylenediamine was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0139] (3) Step (3) is the same as in Example 8, except that an equimolar amount of compound 4,5-dibromo-o-phenylenediamine was used instead of compound B1 to obtain compound 17 (DP-10), yield: 68%; The 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of compound 17 are as follows: 11H NMR (600 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.97 (d, J = 0.8 Hz, 1H), 8.31–8.21 (m, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 4.49 (q, J = 7.1 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 154.00 (s, 1H), 142.89, 140.99, 140.62, 126.83, 125.00, 122.91, 122.68, 120.99, 120.64, 119.95, 119.45, 110.04, 40.49, 40.41, 40.14, 39.96, 39.86, 39.68, 39.58, 37.66 (s, 2H), 14.19. HRMS (EI-TOF) [M-I] + 466.9695, which is consistent with the calculated C 21 H 15 Br2N3 467.9538.

[0140] <Example 18>

[0141] Synthesis of 2-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-6-carbonitrile (Compound 18-DP-11):

[0142] (1) Step (1) is the same as in Example 8;

[0143] (2) Compound 3,4-diaminobenzonitrile was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0144] (3) Step (3) is the same as in Example 8, except that an equimolar amount of compound 3,4-diaminobenzonitrile was used instead of compound B1 to obtain compound 18, yield: 65%. The 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of compound 18 (DP-11) are as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.03 (d, J = 13.1 Hz, 1H), 8.37–8.00 (m, 3H), 7.84–7.66 (m, 3H), 7.61–7.51 (m, 2H), 7.29 (t, J = 7.4 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 141.32, 140.65, 126.94, 125.86, 125.21, 122.96, 122.62, 120.98, 120.70, 120.30, 120.00, 110.11, 40.39, 40.18, 40.08–40.08, 39.97, 39.83, 39.69, 39.56, 37.69, 14.22. HRMS (EI-TOF) [M-I] + 337.1448, which is consistent with the calculated C 22 H 16 N4 336.1409.

[0145] <Example 19>

[0146] Synthesis of 3-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-9-ethyl-9H-carbazole (Compound 19-DP-12):

[0147] (1) Step (1) is the same as in Example 8;

[0148] (2) Compound 4,5-dimethyl-1,2-phenylenediamine was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0149] (3) Step (3) is the same as in Example 8, except that compound 4,5-dimethyl-1,2-phenylenediamine is used instead of compound B1 to obtain compound 19 (DP-12), yield: 55%; the 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of compound 19 are as follows: 1 1H NMR (600 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.93 (d, J = 1.4 Hz, 1H), 8.30–8.20 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.53–7.49 (m, 1H), 7.36 (s, 2H), 7.27 (t, J = 7.4 Hz, 1H), 4.50 (d, J = 7.2 Hz, 2H), 2.34 (s, 6H), 1.35 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 152.21, 140.62, 130.43, 126.69, 124.78, 122.85, 122.71, 121.85, 120.89, 119.82, 118.99, 109.91, 40.04, 39.85, 39.84, 20.52, 14.21. HRMS (EI-TOF) [M-I] +340.1809, which is consistent with the calculated C 23 H 21 N3 339.1778

[0150] <Example 20>

[0151] Synthesis of methyl 3-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 20-DP-13):

[0152] (1) Step (1) is the same as in Example 8;

[0153] (2) Methyl 3,4-diaminobenzoate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0154] (3) Step (3) is the same as in Example 8, except that an equimolar amount of methyl 3,4-diaminobenzoate was used instead of Compound B1 to obtain Compound 20 (DP-13) with a yield of 52%; the 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of Compound 20 (DP-13) are as follows: 1 H NMR(600MHz,DMSO-d6)δ13.22(s,1H),9.02(d,J=1.1Hz,1H),8.35–8.16(m,1H),7.87–7.78(m,1H),7.67(dd,J=19.0,8.2Hz,1H),7.51(dd,J=11.6,4.3Hz,1H),7.29(t,J=7.4Hz,1H),4.49(q,J=7.1Hz,2H),3.89(s,3H),1.34(t,J=7.2Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ167.34,141.19,140.64,126.87,125.15,123.49,122.94(s,1H),122.65,120.98,120.72,120.02,119.71,110.05,52.42,40.31,40.10,40.07–40.02,39.96,39.82,39.68,39.54,37.67,14.21.HRMS(EI-TOF)[M-I] +

[0155] 368.1404, which is consistent with the calculated C 23 H 19 N3O2 369.1509

[0156] <Example 21>

[0157] Synthesis of ethyl 2-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxylate (Compound 21-DP-14):

[0158] (1) Step (1) is the same as in Example 8;

[0159] (2) Ethyl 3,4-diaminobenzoate was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0160] (3) Step (3) is the same as in Example 8, except that an equimolar amount of ethyl 3,4-diaminobenzoate was used instead of Compound B1 to obtain Compound 21 (DP-14), yield: 60%; The 1H NMR and high-resolution mass spectrometry (HRMS (EI-TOF)) data of Compound 21 are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 13.16 (s, 1H), 9.00 (s, 1H), 8.46–7.97 (m, 1H), 7.83 (dd, J = 18.5, 8.8 Hz, 1H), 7.71–7.49 (m, 2H), 7.30 (t, J = 7.4 Hz, 1H), 4.51 (d, J = 7.2 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (td, J = 7.1, 2.5 Hz, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 125.13, 120.99, 120.05, 110.10, 60.93, 40.42, 40.22, 40.08, 39.98, 39.87, 39.67, 39.53, 37.69, 14.76, 14.23. HRMS (EI-TOF) [M-I] + 382.1560, which is consistent with the calculated C 24 H 21 N3O2 383.1687.

[0161] <Example 22>

[0162] Synthesis of 2-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-sulfonic acid (Compound 22):

[0163] (1) Step (1) is the same as in Example 8;

[0164] (2) 3,4-Diaminobenzenesulfonic acid was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0165] (3) Step (3) is the same as in Example 8, except that compound 3,4-diaminobenzenesulfonic acid is used instead of compound B1 to obtain compound 22, yield: 47%. The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 22 are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.00(s,1H),8.37–8.18(m,1H),7.92(s,1H),7.81–7.47(m,3H),7.27(t,J=7.4Hz,1H),4.48(q,J=7.0Hz,2H),1.33(t,J=7.1Hz,2H). 13 CNMR(151MHz,DMSO-d6)δ155.48,141.23,140.64,126.91,125.14,122.92,122.61,120.98,120.34,120.05,119.76,116.17,110.08,40.70–40.21,40.04,39.96,39.94,39.84,39.70,39.56,37.68,14.22.HRMS(EI-TOF)[M-I] + 390.0919, consistent with the calculated C 21 H 17 N3O3S391.1079.

[0166] <Example 23>

[0167] Synthesis of N-(3-(dimethylamino)propyl)-2-(9-ethyl-9H-carbazol-3-yl)-1H-benzo[d]imidazole-5-carboxamide (Compound 23):

[0168] (1) Step (1) is the same as in Example 8;

[0169] (2) Purchase compound 3,4-diamino-N-(3-(dimethylamino)propyl)benzamide from Beijing Ximeijie Technology Co., Ltd.

[0170] (3) Step (3) is the same as in Example 8, except that compound 3,4-diamino-N-(3-(dimethylamino)propyl)benzamide is used instead of compound B1 to obtain compound 23, yield: 69%; The 1H NMR and high-resolution mass spectrometry (HRMS(EI-TOF)) data of compound 23 are as follows: 11H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J = 1.8 Hz, 2H), 8.35 (t, J = 6.8 Hz, 2H), 8.21–8.13 (m, 4H), 7.94 (dd, J = 7.5, 1.6 Hz, 2H), 7.79 (dd, J = 7.5, 1.5 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 1.6 Hz, 1H), 7.41–7.34 (m, 3H), 7.27 (td, J = 7.4, 1.7 Hz, 2H), 4.36 (q, J = 8.0 Hz, 4H), 3.38 (q, J = 7.0 Hz, 4H), 2.82 (t, J = 7.1 Hz, 4H), 2.38 (s, 12H), 1.81 (p, J = 7.1 Hz, 4H), 1.38 (t, J = 8.0 Hz, 6H). 13 13C NMR (125 MHz, DMSO-d6) δ 167.33, 153.14, 141.68, 140.32, 139.87, 138.20, 131.24, 128.03, 124.82, 124.21, 123.55, 123.34, 122.46, 121.06, 120.31, 120.30, 117.54, 113.99, 110.00, 107.42, 56.73, 44.69, 40.02, 38.72, 26.55, 13.59. HRMS (EI-TOF) M 439.2369, consistent with the calculated C 27 H 29 N5O 439.2372.

[0171] The structural formulas of Compounds 1 - 23 are shown as follows:

[0172]

[0173]

[0174] Select DP-1 - DP-18 from the above compounds for experimental analysis and research:

[0175] Compound 8-DP-1, Compound 9-DP-2, Compound 10-DP-3, Compound 11-DP-4, Compound 12-DP-5, Compound 13-DP-6, Compound 14-DP-7, Compound 15-DP-8, Compound 16-DP-9, Compound 17-DP-10, Compound 18-DP-11, Compound 19-DP-12, Compound 20-DP-13, Compound 21-DP-14, Compound 2-DP-15, Compound 3-DP-16, Compound 4-DP-17, Compound 5-DP-18.

[0176] <Test Example 1> Cytotoxicity Experiment

[0177] The cytotoxicity of the squaric acid dye compounds prepared in the above examples was detected using HCT-116 (human colon cancer cells), MCF-7 (breast cancer cells), A2780 (human ovarian cancer cells), A549 (non-small cell lung cancer cells), Hep G2 (human liver cancer cells), Bel-7402 (human liver cancer cells), SMMC-7721 (human liver cancer cells), and HCS-T6 (rat hepatic stellate) cells, as well as three normal cell lines: L02 (human normal liver cells), HK-2 (human renal cortical proximal tubular epithelial cells), and HEK-293 (human embryonic kidney cells). All of the above cells were incubated in DMEM (Hyclone) cell culture medium containing 10% fetal bovine serum (FBS, Gibco) and 1% penicillin-streptomycin. The cells were routinely cultured in an incubator at 37°C under 5% CO2 conditions.

[0178] In each 96-well plate, 6,000 cells (cell lines are MCF-7, HCT-116, A2780, A549, HepG2, Bel-7402, SMMC-7721, HCS-T6, L02, HK-2, and HEK-293) were seeded per well, and the volume of the culture medium containing the cells was 100 μL per well. After the 96-well plate seeded with cells was placed in an incubator at 37 °C for 24 hours, different volumes of the stock solutions of each compound (DP-1 to DP-18) were added to each well, controlling the final concentration in the well to be a fixed value. Each concentration was replicated three times in parallel. 1 μL of DMSO was added to the blank control, and the zero-adjustment well (without cells) could be left without addition or added with an equal volume of the culture medium, and then continued to be cultured. After the 96-well plate was placed in the cell culture incubator for 24 h to allow the cells to adhere, the old culture medium was aspirated with a pipette, and according to the grouping design, complete medium without drugs, stock solutions of drugs with different concentrations, and the positive drug camptothecin solution were added, 200 μL per well. The 96-well plate was placed in the incubator for 48 h. The culture medium containing the drugs was discarded, and washed twice with PBS buffer at pH 7.4, 110 μL of MTT solution (5 mg / mL) was added to each well, and after continued incubation for 4 h, the MTT solution was discarded, 150 μL of DMSO was added to each well, and placed on a shaker and shaken horizontally for 10 minutes. The OD value at a wavelength of 490 nm was detected with an enzyme-linked immunosorbent assay (ELISA) reader within 15 min, and the cell growth inhibition rate was calculated according to the formula. The experiment was repeated in parallel three times. The experimental results are shown in Table 1, and all compounds have good inhibitory activity against tumor cells. While DP-15, DP-16, DP-17, and DP-18 have basically no cytotoxicity to normal cells, showing excellent cell selectivity toxicity. They have the potential to be developed into highly effective and low-toxic drugs.

[0179] Table 1 Results of cytotoxicity experiments

[0180]

[0181] <Test Example 2> Cell colony formation experiment

[0182] Human liver cancer HepG2 cells in the logarithmic growth phase were digested with 0.25% trypsin and resuspended in complete medium to prepare a single-cell suspension with a density of 500 cells / mL. The cell suspension was inoculated into a 6-well plate at 1 mL per well and incubated overnight in an incubator at 37°C and 5% CO2. The medium was discarded, and a control group and treatment groups with different concentrations were established. The control group received 1 mL of complete medium per well, and the treatment groups received 1 mL of medium containing different drug concentrations per well. Each group had 3 replicate wells. After incubation in an incubator at 37°C and 5% CO2 for 24 h, the medium was discarded, and the cells were carefully washed with 2 mL of PBS to remove the drug-containing medium. Then, 2 mL of complete medium was added, and the medium was changed every 3 days. When the number of single-cell clones exceeded 50 cells, the culture was terminated, the medium was discarded, and the cells were carefully washed twice with PBS. The cells were fixed with 4% paraformaldehyde solution for 20 min, the fixing solution was discarded, and the cells were gently washed twice with PBS. Then, 0.1% crystal violet solution was added for staining for 10 - 20 min. The cells were observed under a microscope, and the number of cell colonies was counted. A cell cluster composed of 50 or more cells was counted as 1 colony. The experiment was repeated 3 times. Colony inhibition rate (%) = (1 - (colony formation rate of experimental group / colony formation rate of control group)) × 100%. The experimental results showed (as Figure 1 shown), after treatment of HepG2 cells with DP-9 (2.5, 5, 10 μM) and DP-18 (0.9, 1.89, 3.78 μM) drug solutions, the formation of cell colonies was significantly inhibited; it was obvious that with the increase in concentration, the inhibition rate of cell colony formation gradually increased, showing a statistically significant difference compared with the control group (P < 0.05), and it was concentration-dependent.

[0183] <Test Example 3> Cell Scratch Assay

[0184] HepG2 cells were digested and counted, and the cells were seeded at 5×10 4Inoculate at a density of 4×10⁵ cells / mL into 6-well plates for plating. For the HepG2 cell line, set up a blank control group and two drug administration groups (DP-9 and DP-18), a total of 3 groups, and place them in an incubator at 37°C and 5% CO₂ for culture. The next day, take out the 6-well plates and observe under a microscope whether the cells are completely adherent. An appropriate cell density is about 80%. Use a 10 μL sterilized pipette tip to make a cell scratch along the culture plate in a laminar flow hood, paying attention to applying force evenly. After the scratch is made, discard the original culture medium in the wells, slowly add 1 mL of PBS buffer and wash twice, then add 2 mL of prepared complete medium and the drug administration group solution along the well wall to each well. Take a photo of the scratch under a microscope. At this time, record the time as 0 h, and then take photos under a microscope at 24 h and 48 h after the scratch, and record the growth and migration of the cells. Use Image J software to calculate the cell scratch area, compare the cell healing situation, and calculate the wound healing degree (%), and the formula is as follows: Wound healing degree (%) = (Initial scratch area - Scratch area healed at a certain time point) / Initial scratch area × 100%

[0185] By tracking and observing the cell morphology at different time periods (0 h, 24 h, 48 h) (as Figure 2 shown), there have been great changes in the healing degree and the healing ability of the drug on the cells. As time increases, the HepG2 cells have migrated to varying degrees, the scratched area of the cells is slowly healing, and the cell scratch area gradually shrinks. The healing degree of the blank control group of HepG2 cells after 48 h is 36.89%, and the healing degrees of the drug administration groups are 11.38% and 7.98% respectively (P < 0.5). The results show that the compound can significantly inhibit the healing of HepG2 cells and effectively inhibit cell migration.

[0186] <Experimental Example 4> Hoechst 33258 Staining Experiment

[0187] Take human liver cancer HepG2 cells in the logarithmic growth phase, digest them with 0.25% trypsin, and resuspend them in a medium containing 10% fetal bovine serum to make a single-cell suspension with a density of 4×10⁵ 5 cells / mL. Inoculate 1.5 mL of the cell suspension into each well of a 6-well plate and incubate overnight in an incubator at 37°C and 5% CO₂. Discard the culture medium, set up a control group and different concentration drug administration groups (DP-9 and DP-18). Add 1.5 mL of complete medium to each well in the control group, and add 1.5 mL of medium containing different drug concentrations to each well in the drug administration groups. Set 3 replicates for each group. After incubating for 24 h in an incubator at 37°C and 5% CO₂, discard the culture medium, carefully wash the cells 2 times with 2 mL of PBS, add 1 mL of Hoechst 33258 staining working solution to each well and stain for 5 min, carefully wash the cells 1 time with 2 mL of PBS, add 1 mL of PBS to each well, and observe and take photos under a fluorescence microscope.

[0188] The results showed that the cells in the control group (as Figure 3 shown) (Control group) were round or approximately square, the nuclear morphology was clear and complete, showing a regular round shape, with uniform staining and pale blue fluorescence; after acting on the cells, as the concentration gradually increased, the nuclear staining changed from blue fluorescence to bright blue fluorescence, and the apoptotic cells gradually increased; it could be observed that the cell morphology changed from round to spindle-shaped or irregular, and obvious nuclear morphological changes occurred, such as nuclear distortion, pyknosis, chromatin condensation and marginal aggregation, nuclear content overflow, and the formation of apoptotic bodies and other apoptotic characteristics.

[0189] <Experimental Example 5> Cell Cycle Inhibition Experiment

[0190] Human hepatoma HepG2 cells in the logarithmic growth phase were digested with 0.25% trypsin, and the cells were resuspended in complete medium to prepare a single-cell suspension with a density of 3×10 5 cells / mL. Then, 2 mL of it was inoculated into each culture dish and cultured overnight in an incubator at 37°C and 5% CO2. After the cells were completely adherent, the culture medium was changed, and the prepared DP-9 (5 μM) and DP-18 (1.89 μM) drug-containing media were added to the wells respectively, and the drug-free medium was set as the blank control group, with three replicate wells in each group. The cells floating in the supernatant were collected, the cells were digested with trypsin without EDTA, centrifuged at 1200 rpm for 5 min in a centrifuge, the supernatant was discarded, and 75% pre-cooled ethanol was added to each tube and quickly mixed evenly, then fixed overnight in a -20°C refrigerator. Centrifuged at 1200 rpm for 5 min in a low-temperature centrifuge, the supernatant was discarded, and the cells were washed once with 1 mL of PBS, and the supernatant was discarded after centrifugation. 500 μL of PI / RNase dye was added to each sample, incubated at room temperature in the dark for 15 min, and the cell cycle was measured with a flow cytometer within 0.5 h. The experimental results showed (as shown in Table 2) that compared with the control group, the proportions of HepG2 cells blocked in the G1 phase in the drug-administered groups were 56.85% and 56.18% respectively, the proportions of HepG2 cells blocked in the G2 phase in the drug-administered groups were 16.46% and 15.23% respectively, and the proportions of cells in the S phase in the drug-administered groups were 26.69% and 28.58% respectively, and there were statistically significant differences between the drug-administered groups and the control group (P<0.05). It indicated that DP-9 and DP-18 could promote the cell cycle arrest of HepG2 cells.

[0191] Table 2 Effects of Compounds on the Cell Cycle of Human Hepatoma HepG2 Cells ( n = 3, three parallel experiments were set for each group)

[0192]

[0193] Note: Compared with the control group, *P<0.05, **P<0.01, ***P<0.001

[0194] <Experimental Example 6> Acute Toxicity Experiment

[0195] Experimental animals: SPF-grade Kunming mice, half male and half female, weighing (18 - 22 g), of appropriate age and healthy, provided by the Experimental Animal Center of Guangxi Medical University. Acute toxicity pre-experiment of mice: Take the mice after fasting for 12 h before the experiment, half male and half female, randomly divided by body weight into: high, medium, and low dose groups of drug DP-18 (0.5, 2.5, and 5 g·kg -1 mouse weight per day) groups, with 5 mice in each group. The water control group was gavaged with an equal volume of water. The LD 100 value (100% death dose), LD0 value (0% mortality rate), and the corresponding dose group interval r value were found respectively to measure the LD 50 value. No deaths occurred in all four groups, and it was difficult to measure the LD 50 . The results showed that the toxicity of this type of compound by oral administration to Kunming mice was low and the safety was high. Therefore, we then conducted the maximum tolerated dose experiment.

[0196] <Experimental Example 7>: Maximum Tolerated Dose

[0197] Formal experiment of acute toxicity MTD of mice: Take 60 of the above mice, 30 in each group, randomly divided into the administration group and the water control group according to body weight and gender. After fasting but not water-depriving for 12 h before the experiment, the administration group was gavaged with DP-18 multiple times at 5 g·kg -1 mouse weight, calculate the dosage within 1 day, and the water control group was gavaged with an equal volume of water for acute toxicity experiment observation. No deaths occurred, and then they were fed for 14 days, and all mice grew normally. There was no significant difference in the body weight of the mice in the administration group and the normal group. The in vivo experimental results showed that the compound had basically no toxicity to mice and had the potential for further development.

[0198] <Experimental Example 8>: Anti-tumor Activity in Vivo

[0199] Experimental animals: The experimental animals used in this experiment were BALB / C (nu / nu) nude mice, weighing 15 - 20 g, 4 - 5 weeks old, provided by the Experimental Animal Center of Guangxi Medical University. Cell line: The hepatocellular carcinoma HepG2 cell line was purchased from the Shanghai Institute of Cell Biology, Chinese Academy of Sciences, and was routinely cultured in DMEM medium containing 10% fetal bovine serum under the conditions of 37°C and complete saturated humidity. Cells in the logarithmic growth phase were taken for the experiment. Preparation of transplanted tumor tissue: HepG2 hepatocellular carcinoma cells, observed under the microscope to be round, with distinct outlines, and some visible cell nuclei. When the cells grew to more than 90%, the cells were collected after digestion, and the survival rate stained with trypan blue was >95%. The cell concentration was adjusted to 1×10 7 / ml; 0.2 ml per mouse was injected subcutaneously at the blank area of the right axilla of nude mice for transplantation. After subcutaneous transplantation of tumor sources, when the tumor diameter reached 0.3 - 0.5 cm, 50 tumor-bearing nude mice were divided into a liver cancer model group (without any treatment, allowing them to eat freely, n = 10, given an equal volume of 0.3% CMC-Na solution), a positive drug group (sorafenib, n = 10, gavaged with a suspension prepared with 20 mg / kg of 0.3% CMC-Na), a drug administration group (DP-9, n = 10, gavaged with a suspension prepared with 40 mg / kg of 0.3% CMC-Na), and a drug administration group (DP-18, n = 10, gavaged with a suspension prepared with 40 mg / kg of 0.3% CMC-Na), once a day for 27 consecutive days. After 24 h of drug withdrawal, the nude mice were sacrificed by cervical dislocation. After soaking in 75% ethanol, the skin at the axilla was cut open, the tumor mass was dissected, and the non-tumor tissues on the surface of the tumor mass were removed, and the tumor weight was weighed; during drug administration, the long diameter (a) and short diameter (b) of the tumor mass were measured with a vernier caliper every 2 days. The experimental results are as Figure 4 shown. It can be seen that compared with the model group, the tumor volumes of the positive drug group and the drug administration groups were significantly reduced; compared with the positive drug group, the tumor volume of the drug administration groups was also significantly reduced. In vivo experiments showed that this type of compound had good therapeutic effects on liver cancer in vivo and low toxicity. It had the characteristics of being developed into a targeted drug and was worthy of further development and research.

[0200] The number of devices and the processing scale described here are used to simplify the description of the present invention. Applications, modifications, and variations of the present invention will be apparent to those skilled in the art.

[0201] Although the embodiments of the present invention have been disclosed as above, it is not limited to the applications listed in the specification and the embodiments. It can be fully applied to various fields suitable for the present invention. For those familiar with the field, additional modifications can be easily made. Therefore, without departing from the general concept defined by the claims and the equivalent scope, the present invention is not limited to specific details and the illustrated and described examples here.

Claims

1. Carbazole-benzimidazole conjugate compounds, characterized in that, The structural formula of the compound is shown as follows: 。 2. Use of the carbazole-benzimidazole conjugate compound according to claim 1 in the preparation of a medicament for treating tumors.

3. Use of the carbazole-benzimidazole conjugate compound according to claim 1 in the preparation of a medicament for treating liver cancer.

4. The application according to any one of claims 2 to 3, characterized in that, The medicament includes a pharmaceutically acceptable salt of the carbazole-benzimidazole conjugate compound, and a pharmaceutically acceptable excipient.

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