Benzo [4, 5] imidazo [2, 1-a] isoquinoline compound as well as preparation method and application thereof

Abstract

The invention discloses benzo [4, 5] imidazo [2, 1-a] isoquinoline compounds as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The benzo [4, 5] imidazo [2, 1-a] isoquinoline compound can be used for preparing anti-tumor (human breast cancer) drugs, the structure of the benzo [4, 5] imidazo [2, 1-a] isoquinoline compound is shown in the specification, in the formula, R1 is any one or two of hydrogen, halogen, alkyl, alkoxy, fused ring and aryl; r2 is any one of hydrogen, halogen, alkyl and alkoxy; and R3 is any one or two of hydrogen, halogen, alkyl and alkoxy. The preparation method of the compound comprises the following steps: by taking palladium acetate and norbornene as catalysts, tris (4-chlorphenyl) phosphine and the like as ligands, potassium carbonate and the like as alkali and 1, 4-dioxane as a solvent, carrying out one-pot synthesis on a 1-(2-bromo-1-phenyl vinyl) benzimidazole compound and an iodobenzene compound in an argon atmosphere. Structure of compound: # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a class of compounds and preparation methods and applications thereof, in particular to benzo[4,5]imidazo[2,1-a]isoquinoline compounds and preparation methods thereof and applications thereof as anti-tumor drugs, belonging to the technical field of biomedicine. Background Art

[0002] A large number of studies have shown that the benzimidazole skeleton and the isoquinoline skeleton are two important active skeletons, which are widely present in many natural products and drug molecules and have multiple biological activities. In fact, they are also the building blocks of many drugs (for example: omeprazole, telmisartan, codeine phosphate and berberine hydrochloride, etc.). The study of the pharmacological activity of benzimidazole and isoquinoline compounds provides an important basis for the subsequent splicing research of these two skeletons. The benzimidazole and isoquinoline compounds spliced ​​together by the benzimidazole skeleton and the isoquinoline skeleton have pharmacological activities such as anticonvulsant, antibacterial, antimalarial, antiviral and anticancer. Isoquinoline and benzimidazole can be combined by functional group / bond fusion. Studies have shown that the interconnection of these heterocyclic rings can produce a new heterocyclic compound with good physiological activity. Therefore, scientists have successively developed a series of synthetic methods for benzimidazole derivatives and isoquinoline derivatives, but the synthetic research on the four-membered core skeleton of benzimidazole and isoquinoline is very rare, and there is a lack of drug activity evaluation results. Therefore, it is of great significance to develop efficient synthetic methods to construct benzimidazole-isoquinoline skeletons and evaluate their pharmaceutical activity.

[0003] Since the benzimidazoloisoquinoline core structure has good pharmacological activity, its synthesis method has attracted widespread attention from organic chemists and medicinal chemists.

[0004] Wang reported a synthetic method for the formation of benzimidazoloisoquinolines by the reaction of o-bromophenyl-substituted benzimidazoles with substituted 1,3-diketones. This reaction was carried out by copper-catalyzed coupling followed by deacylation. The use of copper(I) iodide as a catalyst in the presence of cesium carbonate resulted in a yield of 69-85%. The reaction equation is shown below:

[0005]

[0006] Li reported a two-step synthesis of benzimidazoloisoquinolines using phenylbenzimidazole and bromoacetylene derivatives. The method is based on the nucleophilic addition of 2-arylbenzimidazole to alkynyl bromide followed by palladium-catalyzed intramolecular CH vinylation. This synthetic method effectively generates a molecular bond between the benzimidazole and the phenyl group. The reaction equation for the reaction is shown below:

[0007]

[0008] Zhu synthesized benzimidazoloisoquinoline using N-phenyl-1-aminoisoquinoline via a metal-free reaction. This CH ring amination reaction was catalyzed by the hypervalent iodine (III) generated by the reaction of iodobenzene and peracetic acid. The reaction was carried out at room temperature with a yield of 77%. The reaction equation is shown below:

[0009]

[0010] The method of using two pre-installed halogens to construct two rings, imidazole ring and pyridine ring, greatly improves the efficiency of the synthesis of benzimidazole isoquinoline skeleton. Nickel ligands are powerful tools for activating these halogens and terminal alkynes. Xiao and Deng reported the synthesis of benzimidazole isoquinoline compounds by cyclization reaction of 2-chloro-N-(2-halogenophenyl)benzimidazole with terminal alkynes under nickel catalysis under anhydrous conditions and high temperature of 140°C. The yield of the product depends on the halogen in the starting material. Compared with the chloroaryl reactant (X=Cl; 42-59% yield), the reverse yield of the fluoroaryl reactant (X=F; 60-86% yield) is increased. The reaction equation of the reaction is shown below:

[0011]

[0012] Zhong developed a one-pot synthesis of iodine-functionalized benzimidazoloisoquinolines. 2-ethynylbenzaldehyde and o-phenylenediamine were catalyzed by copper (I) iodide in the presence of iodine to synthesize 5-iodine-substituted benzimidazoloisoquinolines in good yields (35-72%). The reaction equation is shown below:

[0013]

[0014] There are many routes to synthesize the benzimidazoloisoquinoline nucleus, but most of them have the problems of long steps, low yield and poor compound structure diversity. Even if some steps are short and the yield is high, the starting materials are not easy to obtain. Therefore, it is particularly important to develop a method with cheap and easy-to-obtain raw materials and fewer reaction steps to directly synthesize the benzimidazoloisoquinoline nucleus structure. After establishing a simple and practical synthetic methodology, a series of benzimidazoloisoquinoline nucleus derivatives with different structures are synthesized, which can provide an important material basis for subsequent pharmacological activity screening. Summary of the invention

[0015] The first object of the present invention is to provide a class of benzo[4,5]imidazo[2,1-a]isoquinoline compounds with anti-tumor activity. The second object is to provide a method for preparing the benzo[4,5]imidazo[2,1-a]isoquinoline compounds, which has readily available raw materials, mild reaction conditions, and is simple and practical. The third object is to provide the use of the benzo[4,5]imidazo[2,1-a]isoquinoline compounds in the preparation of anti-tumor drugs.

[0016] In order to achieve the above object, the present invention adopts the following technical solution:

[0017] Benzo[4,5]imidazo[2,1-a]isoquinoline compounds, the structure of which is shown below:

[0018]

[0019] Among them, R 1 is any one or two of hydrogen, halogen, alkyl, alkoxy, cyclopentane and aryl; R 2 is any one of hydrogen, halogen, alkyl and alkoxy; R 3 It is any one or two of hydrogen, halogen, alkyl and alkoxy.

[0020] The preparation method of the aforementioned benzo[4,5]imidazo[2,1-a]isoquinoline compounds, using palladium acetate and norbornene as catalysts, tri(4-chlorophenyl)phosphine, triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-methylphenyl)phosphine, tri(4-fluorophenyl)phosphine, tricyclohexylphosphine or tri(2-furyl)phosphine) as ligands, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide or lithium tert-butoxide as bases, 1,4-dioxane as solvent, 1-(2-bromo-1-phenylvinyl)benzimidazole compounds and iodobenzene compounds are synthesized in one pot in an argon atmosphere to synthesize the benzo[4,5]imidazo[2,1-a]isoquinoline compounds according to claim 1, the reaction formula is as follows:

[0021]

[0022] Preferably, the norbornene is any one of NBE1, NBE2, NBE3, NBE4, NBE5, NBE6 and NBE7, and the structural formula is as follows:

[0023]

[0024] Preferably, the molar ratio of the 1-(2-bromo-1-phenylvinyl)benzimidazole compound, the iodobenzene compound and the base is 1:1.0~1.5:2.0~6.0; more preferably, the molar ratio of the 1-(2-bromo-1-phenylvinyl)benzimidazole compound, the iodobenzene compound and the base is 1:1.5:5.0.

[0025] Preferably, the specific steps of the preparation method are:

[0026] (1) adding an iodobenzene compound, a 1-(2-bromo-1-phenylvinyl)benzimidazole compound, palladium acetate, a ligand, a base and norbornene to a reaction container in sequence;

[0027] (2) evacuate and exchange with argon three times, and add solvent under argon atmosphere;

[0028] (3) Stirring in an oil pan at 100°C to 130°C to react until the reaction is complete;

[0029] (4) The product is post-treated to obtain a white solid.

[0030] More preferably, in step (1), the iodobenzene compound is any one of 1-iodonaphthalene, 2-iodonaphthalene, 2,4-dimethyl-1-iodobenzene, 2-isopropyliodobenzene, 2-methoxyiodobenzene, 2-fluoroiodobenzene, 3-fluoro-2-iodotoluene, 4-iododibenzothiophene, 1-iodo-4-methoxynaphthalene and 2-iodobiphenyl.

[0031] More preferably, in step (1), the 1-(2-bromo-1-phenylvinyl)benzimidazole compound is 1-(2-bromo-1-phenylvinyl)benzimidazole, 1-(2-bromo-1-(4-methoxyphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-ethoxyphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-propylphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-butylphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(3-chlorophenyl)benzimidazole, Any one of 1-(2-bromo-1-(4-bromophenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-fluorophenyl)vinyl)benzimidazole, 1-(2-bromo-1-phenylvinyl)-5-methyl-benzimidazole, 1-(2-bromo-1-phenylvinyl)-5,6-dimethyl-benzimidazole, 1-(2-bromo-1-phenylvinyl)-5-methoxy-benzimidazole and 1-(2-bromo-1-phenylvinyl)-5-chloro-benzimidazole.

[0032] The use of the aforementioned benzo[4,5]imidazo[2,1-a]isoquinoline compounds in the preparation of anti-tumor drugs, wherein the tumor is human breast cancer.

[0033] Preferably, the benzo[4,5]imidazo[2,1-a]isoquinoline compound is:

[0034]

[0035] The present invention is beneficial in that:

[0036] (1) The benzo[4,5]imidazo[2,1-a]isoquinoline compounds provided by the present invention have good anti-tumor activity and can be used for the screening and preparation of anti-tumor drugs;

[0037] (2) In the screening of anti-tumor drugs, the benzo[4,5]imidazo[2,1-a]isoquinoline compounds provided by the present invention showed good growth inhibition activity on human breast cancer cells MCF-7, providing a good material basis for the research and development of new drugs. In particular, the compounds prepared in Example 26, Example 37 and Example 41 showed strong inhibitory effects on the proliferation of human breast cancer cells MCF-7, and had potential application value as drug lead compounds for subsequent preparation and development of anti-tumor drugs;

[0038] (3) The preparation method of the above-mentioned benzo[4,5]imidazo[2,1-a]isoquinoline compounds provided by the present invention adopts the strategy of directing group CH activation under Catellani reaction, takes cheap and readily available 1-(2-bromo-1-phenylvinyl)benzimidazole compounds and iodobenzene compounds as starting materials, and integrates multiple steps of reaction into one pot through the synergistic catalysis of palladium acetate and norbornene under argon conditions, and finally synthesizes benzo[4,5]imidazo[2,1-a]isoquinoline compounds through oxidative addition, reductive elimination and intramolecular Heck coupling. This method provides a new preparation idea for synthesizing benzo[4,5]imidazo[2,1-a]isoquinoline compounds modified with different substituents. Compared with the existing methods, the present invention uses a cross-coupling reaction strategy to synthesize the target product in one pot, and has mild reaction conditions, simple operation, good safety, high reaction efficiency, cheap and readily available raw materials, and rich product types. DETAILED DESCRIPTION

[0039] The present invention is described in detail below with reference to specific embodiments.

[0040] 1. Structure of Compounds

[0041] The structure of the benzo[4,5]imidazo[2,1-a]isoquinoline compound provided by the present invention is as follows:

[0042]

[0043] Among them, R 1is any one or two of hydrogen, halogen (e.g., fluorine), alkyl (e.g., methyl, isopropyl), alkoxy (e.g., methoxy), cyclic (e.g., benzene, benzothiophene) and aryl (e.g., phenyl); R 2 is any one of hydrogen, halogen (e.g., fluorine, chlorine, bromine), alkyl (e.g., propyl, butyl) and alkoxy (e.g., methoxy, ethoxy); R 3 It is any one or two of hydrogen, halogen (eg, chlorine), alkyl (eg, methyl), and alkoxy (eg, methoxy).

[0044] 2. Preparation Methods of Compounds

[0045] The present invention uses palladium acetate (Pd(OAc) 2 ) and norbornene (NBE) as catalysts, tri(4-chlorophenyl)phosphine (or triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-methylphenyl)phosphine, tri(4-fluorophenyl)phosphine, tricyclohexylphosphine, tri(2-furyl)phosphine) as ligands, potassium carbonate (or sodium carbonate, potassium phosphate, potassium tert-butoxide, lithium tert-butoxide) as base, 1,4-dioxane as solvent, 1-(2-bromo-1-phenylvinyl)benzimidazole Compounds of this class (e.g., 1-(2-bromo-1-phenylvinyl)benzimidazole, 1-(2-bromo-1-(4-methoxyphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-ethoxyphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-propylphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-butylphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(3-chlorophenyl)vinyl)benzimidazole, benzimidazole, 1-(2-bromo-1-(4-bromophenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-fluorophenyl)vinyl)benzimidazole, 1-(2-bromo-1-phenylvinyl)-5-methyl-benzimidazole, 1-(2-bromo-1-phenylvinyl)-5,6-dimethyl-benzimidazole, 1-(2-bromo-1-phenylvinyl)-5-methoxy-benzimidazole, 1-(2-bromo-1 -phenylvinyl)-5-chloro-benzimidazole) and iodobenzene compounds (for example: 1-iodonaphthalene, 2-iodonaphthalene, 2,4-dimethyl-1-iodobenzene, 2-isopropyliodobenzene, 2-methoxyiodobenzene, 2-fluoroiodobenzene, 3-fluoro-2-iodotoluene, 4-iododibenzothiophene, 1-iodo-4-methoxynaphthalene, 2-iodobiphenyl) were used to synthesize the above-mentioned benzo[4,5]imidazo[2,1-a]isoquinoline compounds in one pot in an argon atmosphere. The reaction formula is shown below:

[0046]

[0047] Wherein, norbornene (NBE) is any one of NBE1, NBE2, NBE3, NBE4, NBE5, NBE6 and NBE7, and the structural formula is as follows:

[0048]

[0049] The molar ratio of 1-(2-bromo-1-phenylvinyl)benzimidazole compounds, iodobenzene compounds and potassium carbonate (or cesium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, lithium tert-butoxide) is 1:1.0-1.5:2.0-6.0, and the optimal molar ratio is 1:1.5:5.0.

[0050] Example 1

[0051] The compound structure is:

[0052]

[0053] The reaction formula is:

[0054]

[0055] The specific preparation method is:

[0056] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.12 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), triphenylphosphine (PPh 3 , 0.02mmol), Cs 2 CO 3 (0.5mmol) and NBE7 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 100℃ oil pan and stir for 10h, monitor with TLC plate, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid in a yield of 19%.

[0057] The identification data of the obtained product are as follows:

[0058] 1 H NMR (500 MHz, CDCl 3)δ10.98 (d, J=8.7Hz, 1H), 8.13 (d, J=8.2Hz, 1H), 8.07 (d, J=8.5Hz, 1H), 8.03 (d, J=8.1Hz, 1H), 7.96 (t, J=7.8Hz, 1H), 7 .76-7.70 (m, 2H), 7.67-7.62 (m, 5H), 7.46 (t, J=7.4Hz, 1H), 7.10 (s, 1H), 7.04 (t, J=7.8Hz, 1H), 6.59 (d, J=8.4Hz, 1H);

[0059] 13 C NMR (126 MHz, CDCl 3 )δ148.44, 144.70, 138.14, 134.74, 132.85, 131.75, 131.28, 130.21, 129.90, 129.42, 129.33, 12 9.05, 128.76, 128.36, 128.27, 126.65, 124.90, 124.37, 121.03, 120.00, 117.92, 114.26, 113.39;

[0060] HR-MS(ESI): m / z[M+H] + C 25 H 16 N 2 : Calculated value of molecular weight: 345.1392; theoretical value: 345.1382.

[0061] Embodiment 2 to Embodiment 7

[0062] The preparation methods of Examples 2 to 7 are basically the same as those of Example 1, with the only difference being that the types of ligands are different.

[0063] Table 1 Effect of ligand type on product yield

[0064] Example Ligand Yield 2 <![CDATA[Tris(4-methylphenyl)phosphine, abbreviated as P(p-MeC 6 H 4 ) 3 > 12％ 3 <![CDATA[Tris(4-methoxyphenyl)phosphine, abbreviated as P(p-OMeC 6 H 4 ) 3 > 16％ 4 <![CDATA[Tris(4-chlorophenyl)phosphine, abbreviated as P(p-ClC 6 H 4 ) 3 > 27％ 5 <![CDATA[Tris(4-fluorophenyl)phosphine, abbreviated as P(p-FC 6 H 4 ) 3 > 13％ 6 <![CDATA[Tricyclohexylphosphine, abbreviated as PCy 3 > Trace 7 Tri(2-furyl)phosphine, abbreviated as TFP 30％

[0065] Embodiment 8 to Embodiment 12

[0066] The preparation methods of Examples 8 to 12 are basically the same as those of Example 4, with the only difference being the type of base.

[0067] Table 2 Effect of base type on product yield

[0068]

[0069]

[0070] Example 13 to Example 18

[0071] The preparation methods of Examples 13 to 18 are basically the same as those of Example 9, with the only difference being that the types of norbornene are different.

[0072] Table 3 Effect of norbornene type on product yield

[0073] Example Norbornene Yield 13 NBE1 43％ 14 NBE2 32％ 15 NBE3 69％ 16 NBE4 12％ 17 NBE5 22％ 18 NBE6 21％

[0074] Example 19 to Example 22

[0075] The preparation methods of Examples 19 to 22 are basically the same as those of Example 15, with the only difference being: the reaction temperature is different.

[0076] Table 4 Effect of reaction temperature on product yield

[0077] Example temperature Yield 19 110℃ 65％ 20 120℃ 67％ 21 130℃ 78％ 22 140℃ 60％

[0078] Example 23 to Example 25

[0079] The preparation methods of Examples 23 to 25 are substantially the same as those of Example 21, except that the amount of 1-iodonaphthalene used is different.

[0080] Table 5 Effect of the amount of 1-iodonaphthalene on product yield

[0081] Example Dosage of 1-iodonaphthalene Yield (%) 23 0.15mmol(1.5eq.) 88％ 24 0.18mmol(1.8eq.) 70％ 25 0.20mmol(2.0eq.) 65％

[0082] It can be seen from Examples 1 to 25 that the type of ligand, the type of base, the type of norbornene, the reaction temperature and the amount of 1-iodonaphthalene used will have a significant effect on the yield of the product. 6 H 4 ) 3 As ligand, K 2 CO 3 When NBE3 is used as a base, 1-iodonaphthalene is used as a catalyst, the amount of 1.5 eq, and the reaction temperature is 130°C, the yield of the product obtained by the reaction is the highest (Example 23, 88%).

[0083] Embodiment 26

[0084] The compound structure is:

[0085]

[0086] The reaction formula is:

[0087]

[0088] The specific preparation method is:

[0089] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-methoxyphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 63%.

[0090] The identification data of the obtained product are as follows:

[0091] 1 H NMR (500 MHz, CDCl 3 )δ10.98 (d, J=8.7Hz, 1H), 8.12 (d, J=8.1Hz, 1H), 8.07 (d, J=8.5Hz, 1H), 8.02 (d, J=6.7Hz, 1H), 7.95 (t, J=7.8Hz, 1H), 7.76-7.70 ( m, 2H), 7.57 (d, J=8.7Hz, 2H), 7.46 (t, J=7.6Hz, 1H), 7.14 (d, J=8.7Hz, 2H), 7.09-7.05 (m, 2H), 6.70 (d, J=8.5Hz, 1H), 3.98 (s, 3H);

[0092] 13 C NMR (126 MHz, CDCl 3 )δ160.74, 148.54, 144.71, 138.08, 132.80, 131.85, 131.23, 130.66, 130.24, 129.52, 128.74, 12 8.34, 128.24, 127.11, 126.58, 124.89, 124.33, 120.99, 119.97, 117.81, 114.37, 113.47, 55.49;

[0093] HR-MS(ESI): m / z[M+H] + C 26 H 18 N 2 Calculated value of O molecular weight: 375.1497; theoretical value: 375.1493.

[0094] Embodiment 27

[0095] The compound structure is:

[0096]

[0097] The reaction formula is:

[0098]

[0099] The specific preparation method is:

[0100] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-ethoxyphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid with a yield of 56%.

[0101] The identification data of the obtained product are as follows:

[0102] 1 H NMR (500 MHz, CDCl 3)δ10.97 (d, J=8.7Hz, 1H), 8.12 (d, J=8.1Hz, 1H), 8.07 (d, J=8.5Hz, 1H), 8.02 (d, J=7.9Hz, 1H), 7.98-7.91 (m, 1H), 7.77-7.68 (m, 2H), 7.58- 7.53 (m, 2H), 7.49-7.42 (m, 1H), 7.12 (d, J=8.7Hz, 2H), 7.08-7.04 (m, 2H), 6.71 (d, J=8.4Hz, 1H), 4.24-4.17 (m, 2H), 1.54 (t, J=6.9Hz, 3H);

[0103] 13 C NMR (126 MHz, CDCl 3 )δ160.16, 148.53, 138.18, 132.80, 131.90, 131.25, 130.65, 130.25, 129.54, 128.74, 128.35, 128.2 6, 126.93, 126.58, 124.90, 124.34, 120.99, 119.95, 117.78, 114.85, 114.42, 113.47, 63.74, 14.83;

[0104] HR-MS(ESI): m / z[M+H] + C 27 H 20 N 2 Calculated value of molecular weight O: 389.1654; theoretical value: 389.1646.

[0105] Embodiment 28

[0106] The compound structure is:

[0107]

[0108] The reaction formula is:

[0109]

[0110] The specific preparation method is:

[0111] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-propylphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid with a yield of 72%.

[0112] The identification data of the obtained product are as follows:

[0113] 1 H NMR (500 MHz, CDCl 3 )δ10.98 (d, J=8.7Hz, 1H), 8.12 (d, J=8.2Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8. 03 (d, J=8.1Hz, 1H), 7.95 (t, J=7.0Hz, 1H), 7.77-7.70 (m, 2H), 7.55 (d, J=8 .1Hz, 2H), 7.47-7.42(m, 3H), 7.10(s, 1H), 7.08-7.01(m, 1H), 6.62(d, J=8 .4Hz, 1H), 2.80 (t, J=7.6Hz, 2H), 1.86-1.76 (m, 2H), 1.06 (t, J=7.3Hz, 3H);

[0114] 13 C NMR (126 MHz, CDCl 3 )δ148.49, 144.71, 144.69, 138.36, 132.80, 132.06, 131.83, 131.21, 130.24, 129.48, 129.17, 129.08, 128.76, 1 28.74, 128.33, 128.22, 126.57, 124.90, 124.30, 120.91, 119.94, 117.82, 114.37, 113.30, 37.95, 24.47, 13.79;

[0115] HR-MS(ESI): m / z[M+H] + C 28 H 22 N 2 Calculated molecular weight: 387.1861; theoretical value: 387.1853.

[0116] Embodiment 29

[0117] The compound structure is:

[0118]

[0119] The reaction formula is:

[0120]

[0121] The specific preparation method is:

[0122] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-butylphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 68%.

[0123] The identification data of the obtained product are as follows:

[0124] 1 H NMR (400 MHz, CDCl 3 )δ10.99 (d, J=8.5Hz, 1H), 8.13 (d, J=8.1Hz, 1H), 8.06 (d, J=8.4Hz, 1H), 8.02 (d, J=8.1Hz, 1H), 7.98-7.93 (m, 1H), 7.75-7.69 (m, 2H), 7.54 (d, J=8.1Hz, 2H) , 7.48-7.41 (m, 3H), 7.08 (s, 1H), 7.07-7.02 (m, 1H), 6.62 (d, J=8.4Hz, 1H), 2. 84-2.79 (m, 2H), 1.81-1.72 (m, 2H), 1.52-1.43 (m, 2H), 1.03 (t, J=7.4Hz, 3H);

[0125] 13 C NMR (101 MHz, CDCl 3 )δ148.49, 144.96, 144.71, 138.38, 132.81, 132.02, 131.85, 131.22, 130.25, 129.49, 129.19, 129.04, 128.76, 128.33, 128.23, 126.58, 124.90, 124.31, 120.93, 119.95, 117.82, 114.39, 113.32, 35.61, 33.52, 22.37, 13.99;

[0126] HR-MS(ESI): m / z[M+H] + C 29 H 24 N 2 Calculated molecular weight: 401.2018; theoretical value: 401.2011.

[0127] Embodiment 30

[0128] The compound structure is:

[0129]

[0130] The reaction formula is:

[0131]

[0132] The specific preparation method is:

[0133] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(3-chlorophenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 78%.

[0134] The identification data of the obtained product are as follows:

[0135] 1 H NMR (400 MHz, CDCl 3 )δ10.97 (d, J=7.6Hz, 1H), 8.14 (d, J=8.1Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8.02 (d, J=8.1Hz, 1H), 7.98-7.93 (m, 1H), 7. 76-7.71 (m, 2H), 7.70-7.63 (m, 2H), 7.59-7.53 (m, 2H), 7.50-7.45 (m, 1H), 7.12-7.07 (m, 2H), 6.67 (d, J=8.5Hz, 1H);

[0136] 13 C NMR (101 MHz, CDCl 3 )δ148.32, 144.71, 136.49, 136.35, 135.08, 132.98, 131.48, 131.43, 130.32, 130.15, 130.10, 129.43, 12 9.20, 128.82, 128.39, 128.36, 127.59, 126.84, 124.84, 124.53, 121.31, 120.22, 118.20, 113.99, 113.77;

[0137] HR-MS(ESI): m / z[M+H] + C 25 H 15 C1N 2 Calculated molecular weight: 379.1002; theoretical value: 379.0996.

[0138] Embodiment 31

[0139] The compound structure is:

[0140]

[0141] The reaction formula is:

[0142]

[0143] The specific preparation method is:

[0144] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-bromophenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 45%.

[0145] The identification data of the obtained product are as follows:

[0146] 1 H NMR (500 MHz, CDCl 3 )δ10.97 (d, J=8.7Hz, 1H), 8.13 (d, J=8.1Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8.03 (d, J=7.9Hz, 1H), 7.97-7.94 (m, 1H), 7.78 (d, J=2.0Hz, 1H), 7.77 (d, J=2.0Hz , 1H), 7.74 (dd, J=8.3, 2.5Hz, 2H), 7.55 (d, J=2.0Hz, 1H), 7.54 (d, J=2.0Hz, 1 H), 7.50-7.46 (m, 1H), 7.12-7.09 (m, 1H), 7.07 (s, 1H), 6.70 (d, J=8.4Hz, 1H);

[0147] 13 C NMR (126 MHz, CDCl 3 )δ144.73, 136.85, 133.64, 132.96, 132.36, 131.55, 131.43, 130.96, 130.17, 129.26, 12 8.81, 128.37, 126.83, 124.85, 124.55, 124.28, 121.28, 120.22, 118.13, 114.06, 113.75;

[0148] HR-MS(ESI): m / z[M+H] + C 25 H 15 Bn 2 Calculated molecular weight: 423.0497; theoretical value: 423.0492.

[0149] Embodiment 32

[0150] The compound structure is:

[0151]

[0152] The reaction formula is:

[0153]

[0154] The specific preparation method is:

[0155] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-fluorophenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 70%.

[0156] The identification data of the obtained product are as follows:

[0157] 1 H NMR (400 MHz, CDCl 3)δ10.98 (d, J=8.5Hz, 1H), 8.13 (d, J=7.1Hz, 1H), 8.07 (d, J=5.4Hz, 1H), 8.02 (d, J=8.1Hz, 1H), 7.98-7.92 (m, 1H), 7.7 3(d, J=8.4Hz, 2H), 7.66-7.61(m, 2H), 7.47(t, J=8.2Hz, 1H), 7.36-7.30(m, 2H), 7.10-7.04(m, 2H), 6.63-6.59(m, 1H);

[0158] 13 C NMR (101 MHz, CDCl 3 )δ163.61(d,J CF =251Hz, 1 J CF ), 148.41, 144.72, 137.01, 132.91, 131.61, 131.39, 131.36, 131.31, 130.87, 130.83, 130.18, 129.33, 128.79, 128.35 (d, J CF =5.9Hz, 3 J CF ), 126.75, 124.82, 124.46, 121.16, 120.16, 116.25 (d, J CF =22Hz, 2 J CF ), 114.01, 113.70;

[0159] HR-MS(ESI): m / z[M+H] + C 25 H 15 FN 2 Calculated molecular weight: 363.1297; theoretical value: 363.1290.

[0160] Embodiment 33

[0161] The compound structure is:

[0162]

[0163] The reaction formula is:

[0164]

[0165] The specific preparation method is:

[0166] To a 25 mL dry end pressure tube equipped with a stirrer, 2-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid with a yield of 52%.

[0167] The identification data of the obtained product are as follows:

[0168] 1 H NMR (400 MHz, CDCl 3 )δ8.03-7.99(m, 1H), 7.65-7.61(m, 1H), 7.59(d, J=4.7Hz, 4H), 7.57-7.54(m, 2H), 7.53-7.48( m, 1H), 7.41-7.35 (m, 1H), 7.03-6.98 (m, 1H), 6.88 (s, 1H), 6.47 (d, J=9.3Hz, 1H), 3.35 (s, 3H);

[0169] 13 C NMR (101 MHz, CDCl 3 )δ148.86, 144.22, 138.76, 137.09, 134.88, 132.85, 130.44, 129.76, 129.71, 129.3 5, 129.14, 128.95, 124.64, 123.68, 121.92, 121.15, 120.02, 113.92, 113.37, 24.52;

[0170] HR-MS(ESI): m / z[M+H] + C 22 H 16 N 2Calculated molecular weight: 309.1392; theoretical value: 309.1384.

[0171] Embodiment 34

[0172] The compound structure is:

[0173]

[0174] The reaction formula is:

[0175]

[0176] The specific preparation method is:

[0177] 2,4-Dimethyl-1-iodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added to a 25 mL dry pressure tube equipped with a stirrer. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 52%.

[0178] The identification data of the obtained product are as follows:

[0179] 1 H NMR (400 MHz, CDCl 3 )δ7.99(d, J=8.1Hz, 1H), 7.66-7.56(m, 5H), 7.38-7.32(m, 3H), 7.00-6.95(m, 1H), 6.81(s, 1H), 6.46-6.43(m, 1H), 3.30(s, 3H), 2.51(s, 3H);

[0180] 13 C NMR (101 MHz, CDCl 3)δ144.27, 139.34, 138.56, 137.10, 134.99, 133.08, 132.01, 129.77, 129.67, 1 29.37, 128.93, 124.59, 123.60, 120.93, 119.85, 113.86, 113.26, 24.30, 21.47;

[0181] HR-MS(ESI): m / z[M+H] + C 23 H 18 N 2 Calculated molecular weight: 323.1548; theoretical value: 323.1524.

[0182] Embodiment 35

[0183] The compound structure is:

[0184]

[0185] The reaction formula is:

[0186]

[0187] The specific preparation method is:

[0188] To a 25 mL dry end pressure tube equipped with a stirrer, 2-isopropyl iodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 42%.

[0189] The identification data of the obtained product are as follows:

[0190] 1 H NMR (400 MHz, CDCl3 )δ7.99 (d, J=8.1Hz, 1H), 7.71 (dd, J=7.6, 1.5Hz, 1H), 7.66-7.58 (m, 6H), 7.55 (dd, J=7.7, 1.5Hz, 1H), 7.39-7.35 (m , 1H), 7.02-6.97 (m, 1H), 6.88 (s, 1H), 6.46 (d, J=8.4Hz, 1H), 5.74-5.67 (m, 1H), 1.57 (s, 1H), 1.49 (d, J=6.7Hz, 6H);

[0191] 13 C NMR (101 MHz, CDCl 3 )δ149.93, 148.17, 144.12, 136.85, 134.93, 132.96, 129.68, 129.45, 129.36, 128.94, 1 25.24, 124.73, 123.62, 121.11, 120.74, 120.00, 119.36, 113.90, 113.62, 29.35, 23.99;

[0192] HR-MS(ESI): m / z[M+H] + C 24 H 20 N 2 Calculated molecular weight: 337.1705; theoretical value: 337.1680.

[0193] Embodiment 36

[0194] The compound structure is:

[0195]

[0196] The reaction formula is:

[0197]

[0198] The specific preparation method is:

[0199] 2-Methoxyiodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added to a 25 mL dry pressure tube equipped with a stirrer. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3(0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid in a yield of 56%.

[0200] The identification data of the obtained product are as follows:

[0201] 1 H NMR (400 MHz, CDCl 3 )δ8.07 (d, J=8.2Hz, 1H), 7.66-7.56 (m, 6H), 7.38-7.31 (m, 2H), 7.18 (d, J=8 .2Hz, 1H), 7.01-6.96(m, 1H), 6.88(s, 1H), 6.45-6.42(m, 1H), 4.25(s, 3H);

[0202] 13 C NMR (101 MHz, CDCl 3 )δ158.20, 146.59, 144.47, 137.86, 134.66, 134.10, 130.55, 129.83, 129.47, 129.3 2, 128.96, 123.74, 121.26, 120.52, 119.02, 113.70, 112.93, 112.82, 109.06, 56.62;

[0203] HR-MS(ESI): m / z[M+H] + C 22 H 16 N 2 Calculated value of molecular weight O: 325.1341; theoretical value: 325.1332.

[0204] Embodiment 37

[0205] The compound structure is:

[0206]

[0207] The reaction formula is:

[0208]

[0209] The specific preparation method is:

[0210] 2-Fluoroiodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added to a 25 mL dry pressure tube equipped with a stirrer. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 64%.

[0211] The identification data of the obtained product are as follows:

[0212] 1 H NMR (400 MHz, CDCl 3 )δ8.09 (d, J=8.2Hz, 1H), 7.68-7.58 (m, 6H), 7.52 (d, J=6.7Hz, 1H), 7.43-7. 37 (m, 2H), 7.05-7.00 (m, 1H), 6.91 (d, J = 1.9Hz, 1H), 6.45 (d, J = 8.5Hz, 1H);

[0213] 13 C NMR (101 MHz, CDCl 3 )δ160.15(d,J CF =262Hz, 1 J CF ), 144.71, 144.57, 138.48, 134.31, 133.99, 130.51 (d, J CF =8.7Hz, 3 J CF ), 130.05, 129.67, 129.26, 129.06, 124.24, 122.40 (d, J CF =3.9Hz, 3 J CF), 121.80, 120.52, 114.48 (d, J CF =21Hz, 2 J CF ), 113.88, 112.30(d, J CF =11Hz, 2 J CF ), 112.06;

[0214] HR-MS(ESI): m / z[M+H] + C 21 H 13 FN 2 Calculated molecular weight: 313.1141; theoretical value: 313.1122.

[0215] Embodiment 38

[0216] The compound structure is:

[0217]

[0218] The reaction formula is:

[0219]

[0220] The specific preparation method is:

[0221] 3-Fluoro-2-iodotoluene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added to a 25 mL dry pressure tube equipped with a stirrer. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then evacuate and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid in a yield of 54%.

[0222] The identification data of the obtained product are as follows:

[0223] 1H NMR (400 MHz, CDCl 3 )δ8.01 (d, J=8.2Hz, 1H), 7.66-7.60 (m, 1H), 7.60-7.57 (m, 4H), 7.54 (dd, J=8.5, 5.4Hz, 1H), 7.41-7.36 (m, 2H), 7.04-6.99 (m, 1H), 6.85 (s, 1H), 6.49-6.46 (m, 1H), 3.28 (d, J=2.9Hz, 3H);

[0224] 13 C NMR (101 MHz, CDCl 3 )δ160.3(d,J CF =244Hz, 1 J CF ), 136.4, 134.6, 129.8, 129.4(d, J CF =41Hz, 2 J CF ), 129.4, 129.0, 125.7 (d, J=9.8Hz, 3 J CF ), 124.4(d, J = 17 Hz, 3 J CF ), 124.0, 121.6, 120.1, 117.6 (d, J CF =17Hz, 2 J CF ), 114.0, 112.9, 13.89 (d, J=6.6Hz, 3 J CF );

[0225] HR-MS(ESI): m / z[M+H] + C 22 H 15 FN 2 Calculated molecular weight: 327.1298; theoretical value: 327.1279.

[0226] Embodiment 39

[0227] The compound structure is:

[0228]

[0229] The reaction formula is:

[0230]

[0231] The specific preparation method is:

[0232] 4-Iodinated dibenzothiophene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added to a 25 mL dry pressure tube equipped with a stirrer. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid with a yield of 58%.

[0233] The identification data of the obtained product are as follows:

[0234] 1 H NMR (400 MHz, CDCl 3 )δ8.48 (d, J=8.4Hz, 1H), 8.35-8.30 (m, 1H), 8.19 (d, J=8.1Hz, 1H), 8.15-8.10 (m, 1H), 7.84 (d, J=8.2Hz, 1H), 7 .68-7.62(m, 5H), 7.59-7.56(m, 2H), 7.48-7.43(m, 1H), 7.12(s, 1H), 7.09-7.04(m, 1H), 6.60(d, J=8.4Hz, 1H);

[0235] 13 C NMR (101 MHz, CDCl 3 )δ147.05, 144.70, 142.05, 137.45, 134.92, 134.82, 134.62, 130.96, 130.34, 129.95, 129.44 , 129.03, 126.70, 124.51, 124.25, 123.04, 122.99, 121.47, 121.43, 120.40, 114.12, 112.84;

[0236] HR-MS(ESI): m / z[M+H] + C 27 H16 N 2 Calculated value of S molecular weight: 401.1112; theoretical value: 401.1093.

[0237] Embodiment 40

[0238] The compound structure is:

[0239]

[0240] The reaction formula is:

[0241]

[0242] The specific preparation method is:

[0243] In a 25 mL dry end pressure tube equipped with a stirrer, 1-iodo-4-methoxynaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 61%.

[0244] The identification data of the obtained product are as follows:

[0245] 1 H NMR (400 MHz, CDCl 3 )δ10.94 (d, J=8.7Hz, 1H), 8.49 (dd, J=8.2, 1.0Hz, 1H), 8.08 (d, J=8.1Hz, 1H), 7.99-7.94 (m, 1H), 7.74-7 .70 (m, 1H), 7.67-7.60 (m, 5H), 7.44-7.40 (m, 1H), 7.04-6.97 (m, 3H), 6.55 (d, J=8.4Hz, 1H), 4.15 (s, 3H);

[0246] 13 C NMR (101 MHz, CDCl 3 )δ177.48, 174.10, 157.16, 144.75, 134.84, 133.19, 129.86, 129.40, 129.34, 129.03, 128.77, 12 8.59, 126.25, 126.07, 124.25, 121.97, 120.55, 119.64, 118.55, 114.08, 113.40, 101.51, 55.73;

[0247] HR-MS(ESI): m / z[M+H] + C 26 H 18 N 2 Calculated value of molecular weight O: 375.1497; theoretical value: 375.1487.

[0248] Embodiment 41

[0249] The compound structure is:

[0250]

[0251] The reaction formula is:

[0252]

[0253] The specific preparation method is:

[0254] 2-Iodobiphenyl (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc) were added to a 25 mL dry pressure tube equipped with a stirrer. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid in a yield of 55%.

[0255] The identification data of the obtained product are as follows:

[0256] 1 H NMR (400 MHz, CDCl 3 )δ7.72(dd, J=7.8, 1.5Hz, 1H), 7.69-7.65(m, 1H), 7.64-7.59(m, 6H), 7.58-7.55(m , 2H), 7.54-7.48(m, 4H), 7.26-7.21(m, 1H), 6.95-6.90(m, 2H), 6.44-6.41(m, 1H);

[0257] 13 C NMR (101 MHz, CDCl 3 )δ147.46, 143.77, 142.75, 141.76, 137.60, 134.78, 132.83, 131.23, 129.81, 129.76, 129.69, 12 9.29, 128.96, 128.93, 127.51, 126.93, 126.27, 123.49, 121.12, 120.55, 120.51, 113.63, 112.89;

[0258] HR-MS(ESI): m / z[M+H] + C 27 H 18 N 2 Calculated molecular weight: 371.1548; theoretical value: 371.1529.

[0259] Embodiment 42

[0260] The compound structure is:

[0261]

[0262] The reaction formula is:

[0263]

[0264] The specific preparation method is:

[0265] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5-methyl-benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 71%.

[0266] The identification data of the obtained product are as follows:

[0267] 1 H NMR (400 MHz, CDCl 3 )δ10.99-10.97(m, 1H), 10.97-10.95(m, 1H), 8.05(d, J=9.1Hz, 2H), 8.01( dd, J=8.2, 2.5Hz, 3H), 7.97-7.90(m, 3H), 7.74-7.68(m, 4H), 7.68-7.59(m , 10H), 7.28 (dd, J=8.3, 2.0Hz, 1H), 7.06 (d, J=2.2Hz, 2H), 6.86 (dd, J=8.6 , 1.9Hz, 1H), 6.46 (d, J=8.7Hz, 1H), 6.33 (s, 1H), 2.53 (s, 3H), 2.28 (s, 3H);

[0268] 13 C NMR (101 MHz, CDCl 3 )δ148.46, 148.13, 145.10, 142.83, 138.11, 138.05, 134.85, 134.81, 134.27, 132.8 3, 131.65, 131.49, 131.08, 131.01, 130.77, 130.21, 130.17, 129.83, 129.79, 129.5 4, 129.37, 129.32, 129.00, 128.92, 128.82, 128.77, 128.31, 128.18, 126.57, 126.02, 124.91, 122.70, 119.61, 119.45, 114.19, 113.73, 113.15, 113.08, 22.00, 21.64;

[0269] HR-MS(ESI): m / z[M+H]+ C 26 H 18 N 2 Calculated molecular weight: 359.1548; theoretical value: 359.1540.

[0270] Embodiment 43

[0271] The compound structure is:

[0272]

[0273] The reaction formula is:

[0274]

[0275] The specific preparation method is:

[0276] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5,6-dimethyl-benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid with a yield of 72%.

[0277] The identification data of the obtained product are as follows:

[0278] 1 H NMR (400 MHz, CDCl 3 )δ10.96 (d, J=7.4Hz, 1H), 8.03 (dd, J=14.4, 8.2Hz, 2H), 7.96-7.91 (m, 1H), 7.88 (s, 1H), 7. 74(d, J=8.4Hz, 1H), 7.71-7.60(m, 6H), 7.06(s, 1H), 6.30(s, 1H), 2.42(s, 3H), 2.16(s, 3H);

[0279] 13 C NMR (101 MHz, CDCl 3 )δ147.88, 143.45, 138.07, 134.92, 133.60, 132.81, 131.42, 130.84, 130.19, 130.12, 129.75, 12 9.40, 128.91, 128.82, 128.28, 128.13, 127.88, 126.52, 124.95, 119.81, 118.00, 114.37, 112.83;

[0280] HR-MS(ESI): m / z[M+H] + C 27 H 20 N 2 Calculated molecular weight: 373.1705; theoretical value: 373.1694.

[0281] Embodiment 44

[0282] The compound structure is:

[0283]

[0284] The reaction formula is:

[0285]

[0286] The specific preparation method is:

[0287] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5-methoxy-benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=20:1, v / v) to obtain a white solid with a yield of 69%.

[0288] The identification data of the obtained product are as follows:

[0289] 1 H NMR (400 MHz, CDCl 3 )δ10.97-10.91(m, 2H), 8.07-7.98(m, 5H), 7.97-7.91(m, 2H), 7.76-7.69(m, 4H), 7.68-7.62(m, 10H), 7.56(d, J=2.3Hz, 1H ), 7.11-7.06 (m, 3H), 6.68 (dd, J=9.1, 2.5Hz, 1H), 6.45 (d, J=9.1Hz, 1H), 6.00 (d, J=2.3Hz, 1H), 3.93 (s, 3H), 3.49 (s, 3H);

[0290] 13 C NMR (101 MHz, CDCl 3 )δ157.52, 154.73, 148.77, 145.95, 139.29, 137.84, 132.88, 132.83, 131.52, 1 31.10, 131.03, 130.80, 130.16, 130.02, 129.92, 129.81, 129.74, 129.60, 129. 32, 129.09, 128.89, 128.73, 128.33, 128.17, 126.60, 124.95, 123.97, 120.43, 118.27, 117.67, 114.75, 114.65, 113.12, 111.69, 100.95, 97.25, 55.66, 55.20;

[0291] HR-MS(ESI): m / z[M+H] + C 26 H 18 N 2 Calculated value of molecular weight O: 375.1497; theoretical value: 375.1485.

[0292] Embodiment 45

[0293] The compound structure is:

[0294]

[0295] The reaction formula is:

[0296]

[0297] The specific preparation method is:

[0298] To a 25 mL dry end pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5-chloro-benzimidazole (0.1 mmol), Pd(OAc) were added in sequence. 2 (0.01mmol), P(p-ClC 6 H 4 ) 3 (0.02mmol), K 2 CO 3 (0.5mmol) and NBE3 (0.1mmol), then vacuum and exchange with argon three times, add 1,4-dioxane (2mL) under argon atmosphere, finally place the mixed solution in a 130℃ oil pan and stir for 10h, after the reaction is complete, add 10mL water to the organic residue, extract with dichloromethane three times (3×50mL), collect all the organic phases and wash with anhydrous Na 2 SO 4 The residue was dried and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate=25:1, v / v) to obtain a white solid with a yield of 61%.

[0299] The identification data of the obtained product are as follows:

[0300] 1 H NMR (400 MHz, CDCl 3 )δ10.89 (d, J=7.6Hz, 2H), 8.10-8.06 (m, 3H), 8.01 (dd, J=8.3, 3.9Hz, 3H), 7.97-7.92 (m, 2H), 7.75-7.61 (m, 14H), 7.41 ( dd, J=8.7, 2.0Hz, 1H), 7.11 (d, J=1.6Hz, 2H), 6.98 (dd, J=8.9, 2.1Hz, 1H), 6.50 (d, J=1.5Hz, 1H), 6.46 (d, J=8.9Hz, 1H);

[0301] 13 C NMR (101 MHz, CDCl 3)δ149.37, 145.53, 143.18, 137.89, 134.37, 134.15, 132.91, 131.98, 131.8 5, 131.67, 131.61, 130.25, 130.11, 130.04, 129.75, 129.29, 129.24, 129.20 , 128.68, 128.62, 128.43, 128.38, 128.01, 126.82, 126.40, 125.06, 124.87, 124.84, 121.43, 120.68, 119.46, 177.89, 117.78, 114.95, 114.31, 113.79;

[0302] HR-MS(ESI): m / z[M+H] + C 25 H 15 C1N 2 Calculated molecular weight: 379.1002; theoretical value: 379.0983.

[0303] 3. Antitumor activity of the compounds

[0304] Human breast cancer MCF-7 cells in the logarithmic growth phase were digested with trypsin digestion solution (0.25% trypsin + 0.02% EDTA), and then a single-cell suspension with a concentration of 30,000 cells / mL was prepared and inoculated into a 96-well plate at 100 μL / well and incubated at 37°C with 5% CO 2 Culture in the incubator for 24 hours. Add 100 μL of the test compound (etoposide, the compound prepared in Example 1, and the compound prepared in Example 26 to Example 45) at a concentration of 10 μM to each well of the experimental group, and add 100 μL of complete culture medium to each well of the control group. Set up 3 parallel wells in each group and continue to culture in the incubator for 72 hours. Afterwards, add 20 μL of 5 mg / mL tetramethylthiazolyl blue (MTT) solution to each well, continue to culture in the incubator for 3 hours, discard the supernatant, add 150 μL of DMSO to each well to dissolve the formazan crystals, oscillate and mix with a micro-oscillator, and use a microplate reader (reference wavelength 450 nm, detection wavelength 570 nm) to measure the optical density (OD) of each well. Calculate the inhibition rate of each test compound on human breast cancer cells MCF-7 according to the following formula:

[0305] Cell inhibition rate (%) = (1-average OD value of experimental group / average OD value of control group) × 100%

[0306] The calculation results of the inhibition rate of each test compound on human breast cancer cell MCF-7 are shown in Table 6.

[0307] Table 6 Inhibition rate of each test compound on human breast cancer cell MCF-7

[0308] Example Cell inhibition rate (%) Example Cell inhibition rate (%) Etoposide 71.7 35 56.2 1 64.1 36 52.4 26 72.1 37 68.5 27 53.4 38 52.0 28 55.7 39 61.3 29 32.0 40 5.0 30 53.4 41 73.3 31 2.0 42 53.7 32 55.0 43 11.3 33 17.5 44 44.4 34 53.3 45 8.0

[0309] As can be seen from Table 6, the compounds prepared in Example 1 and the compounds prepared in Examples 26 to 45 all showed a certain inhibitory effect on the proliferation of human breast cancer cells MCF-7. Among them, the compounds prepared in Examples 26, 37 and 41 had a strong inhibitory effect on human breast cancer cells MCF-7, and can be used as drug lead compounds for the preparation and development of subsequent anti-tumor drugs. Except for the above three compounds, the inhibitory activity of the remaining compounds on human breast cancer cells MCF-7 was not strong, but they also showed a certain inhibitory activity, which can provide a quantitative effect on the compound for future new drug development.

[0310] It should be noted that the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the embodiments here. Any obvious changes or modifications derived from the technical solution of the present invention are still within the scope of protection of the present invention.

Claims

1. A benzo[4,5]imidazo[2,1-a]isoquinoline compound, characterized in that: The structure is as follows: Among them, R 1 is any one or two of hydrogen, halogen, alkyl, alkoxy, cyclopentane and aryl; R 2 is any one of hydrogen, halogen, alkyl and alkoxy; R 3 It is any one or two of hydrogen, halogen, alkyl and alkoxy.

2. The method for preparing the benzo[4,5]imidazo[2,1-a]isoquinoline compound according to claim 1, characterized in that: Using palladium acetate and norbornene as catalysts, tri(4-chlorophenyl)phosphine, triphenylphosphine, tri(4-methoxyphenyl)phosphine, tri(4-methylphenyl)phosphine, tri(4-fluorophenyl)phosphine, tricyclohexylphosphine or tri(2-furyl)phosphine) as ligands, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide or lithium tert-butoxide as bases, and 1,4-dioxane as solvent, 1-(2-bromo-1-phenylvinyl)benzimidazole compounds and iodobenzene compounds are reacted in an argon atmosphere in one pot to synthesize the benzo[4,5]imidazo[2,1-a]isoquinoline compounds according to claim 1, and the reaction formula is as follows:

3. The preparation method according to claim 2, characterized in that: The norbornene is any one of NBE1, NBE2, NBE3, NBE4, NBE5, NBE6 and NBE7, and the structural formula is as follows:

4. The preparation method according to claim 2, characterized in that: The molar ratio of the 1-(2-bromo-1-phenylvinyl)benzimidazole compound, the iodobenzene compound and the base is 1:1.0-1.5:2.0-6.

0.

5. The preparation method according to claim 4, characterized in that: The molar ratio of the 1-(2-bromo-1-phenylvinyl)benzimidazole compound, the iodobenzene compound and the base is 1:1.5:5.

0.

6. The preparation method according to claim 2, characterized in that: The specific steps are: (1) adding an iodobenzene compound, a 1-(2-bromo-1-phenylvinyl)benzimidazole compound, palladium acetate, a ligand, a base and norbornene to a reaction container in sequence; (2) evacuate and exchange with argon three times, and add solvent under argon atmosphere; (3) Stirring in an oil pan at 100°C to 130°C to react until the reaction is complete; (4) The product is post-treated to obtain a white solid.

7. The preparation method according to claim 6, characterized in that: The iodobenzene compound is any one of 1-iodonaphthalene, 2-iodonaphthalene, 2,4-dimethyl-1-iodobenzene, 2-isopropyliodobenzene, 2-methoxyiodobenzene, 2-fluoroiodobenzene, 3-fluoro-2-iodotoluene, 4-iododibenzothiophene, 1-iodo-4-methoxynaphthalene and 2-iodobiphenyl.

8. The preparation method according to claim 6, characterized in that: The 1-(2-bromo-1-phenylvinyl)benzimidazole compound is 1-(2-bromo-1-phenylvinyl)benzimidazole, 1-(2-bromo-1-(4-methoxyphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-ethoxyphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-propylphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-butylphenyl)vinyl)benzimidazole, 1-(2-bromo-1-(3-chlorophenyl)vinyl)benzimidazole, )benzimidazole, 1-(2-bromo-1-(4-bromophenyl)vinyl)benzimidazole, 1-(2-bromo-1-(4-fluorophenyl)vinyl)benzimidazole, 1-(2-bromo-1-phenylvinyl)-5-methyl-benzimidazole, 1-(2-bromo-1-phenylvinyl)-5,6-dimethyl-benzimidazole, 1-(2-bromo-1-phenylvinyl)-5-methoxy-benzimidazole and 1-(2-bromo-1-phenylvinyl)-5-chloro-benzimidazole.

9. Use of the benzo[4,5]imidazo[2,1-a]isoquinoline compound of claim 1 in the preparation of an anti-tumor drug, wherein the tumor is human breast cancer.

10. The use according to claim 9, characterized in that: The benzo[4,5]imidazo[2,1-a]isoquinoline compound is:

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