Benzimidazoloisoquinolines, processes for their preparation and uses thereof

Abstract

The application discloses a benzo[4,5]imidazo[2,1-a]isoquinoline compound and 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 an anti-tumor (human breast cancer) drug, and has the structure as shown in the following formula, wherein R 1 is any one or two of hydrogen, halogen, alkyl, alkoxy, annelated ring and aryl; R 2 is any one of hydrogen, halogen, alkyl and alkoxy; R 3 is any one or two of hydrogen, halogen, alkyl and alkoxy. The preparation method of the compound is as follows: 1-(2-bromo-1-phenylvinyl)benzimidazole compounds and iodobenzene compounds are one-pot synthesized in an argon atmosphere by taking palladium acetate and norbornene as a catalyst, taking tris(4-chlorophenyl)phosphine as a ligand, taking potassium carbonate as a base, and taking 1,4-dioxane as a solvent. The structure of the compound is as shown in the following formula:

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of compound and its preparation method and application, specifically to benz [4, 5] imidazo [2, 1-a] isoquinoline compound and its preparation method and as anti-tumor drug application, belong to biological medicine technical field. BACKGROUND

[0002] A large number of studies show that benzimidazole skeleton and isoquinoline skeleton are two important active skeletons, widely exist in many natural products and drug molecules, have a variety of biological activities. In fact, they are also the building blocks of numerous drugs (for example: omeprazole, telmisartan, codeine phosphate and berberine hydrochloride, etc.). The research on the pharmacological activity of benzimidazole and isoquinoline compounds provides an important basis for the subsequent study of the combination of the two skeletons. Benzimidazole and isoquinoline skeleton combined into benzimidazole isoquinoline compounds have anticonvulsant, antibacterial, antimalarial, antiviral and anticancer pharmacological activities. Isoquinoline and benzimidazole can be combined by functional group / bond fusion, and research has proved that the mutual connection of these heterocycles can produce a new heterocyclic compound and have good physiological activity. Therefore, scientists have developed a series of synthesis methods for benzimidazole derivatives and isoquinoline derivatives, but the synthesis of benzimidazole isoquinoline four-membered core skeleton is very rare, and there is a lack of drug activity evaluation results. Therefore, it is of great significance to develop an efficient synthesis method for constructing benzimidazole isoquinoline skeleton and to evaluate its drug activity.

[0003] Due to the good pharmacological activity of benzimidazole isoquinoline mother nucleus structure, the synthesis method thereof has attracted widespread attention of organic chemists and medicinal chemists.

[0004] Wang reported a synthesis method of benzimidazole isoquinoline by reacting ortho-bromophenyl-substituted benzimidazole with substituted 1,3-diketone. The reaction is carried out by copper-catalyzed coupling, followed by deacylation. Using copper (I) iodide as catalyst in the presence of cesium carbonate, the yield of this reaction reaches 69-85%. The reaction formula of the reaction is as follows:

[0005]

[0006] Li reported a two-step synthesis method of benzimidazole isoquinoline using phenyl benzimidazole and bromoacetylene derivatives. The method is based on the nucleophilic addition of 2-aryl benzimidazole to alkynyl bromide, followed by palladium-catalyzed intramolecular C-H vinylization. This synthesis method effectively produces molecular bonds between benzimidazole and phenyl. The reaction formula of the reaction is as follows:

[0007]

[0008] Zhu synthesized benzimidazoisoquinolines via metal-free reaction using N-phenyl-1-aminoisoquinoline. This C-H annulation reaction was catalyzed by hypervalent iodine (III) generated from iodobenzene and peracetic acid. The reaction was carried out at room temperature with 77% yield. The reaction scheme is shown as follows:

[0009]

[0010] The method of using two pre-installed halogens to construct the imidazole ring and the pyridine ring two rings greatly improves the efficiency of the synthesis of benzimidazoisoquinoline skeleton. And the nickel ligand is a powerful tool to activate these halogens and terminal alkynes. Xiao, Deng reported that under anhydrous conditions and high temperature of 140℃, 2-chloro-N-(2-halogenophenyl) benzimidazole was used to synthesize benzimidazoisoquinoline compounds with terminal alkyne under nickel catalysis. The yield of the product depends on the halogen in the starting material. Compared with the chloroaryl reactant (X = Cl; 42-59% yield), the fluorine aryl reactant (X = F; 60-86% yield) has increased reaction yield. The reaction scheme is shown as follows:

[0011]

[0012] Zhong developed a one-pot synthesis of iodine-functionalized benzimidazoisoquinolines. In the presence of iodine, 2-ethynylbenzaldehyde and o-phenylenediamine were synthesized into 5-iodo-substituted benzimidazoisoquinolines with good yield (35-72%) using copper (I) iodide catalyst. The reaction scheme is shown as follows:

[0013]

[0014] There are many routes to synthesize benzimidazoisoquinoline 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 benzimidazoisoquinoline nucleus structure. After establishing a simple and practical synthetic method, a series of structurally different benzimidazoisoquinoline nucleus derivatives can be synthesized, which can provide important material basis for subsequent pharmacological activity screening. SUMMARY

[0015] The first object of the present application is to provide a kind of benz [4, 5] imidazo [2, 1-a] isoquinoline compounds with anti-tumor activity, the second object is to provide a kind of raw material, the preparation method of benz [4, 5] imidazo [2, 1-a] isoquinoline compound is simple and practical, and the reaction condition is mild, the third object is to provide the application of the benz [4, 5] imidazo [2, 1-a] isoquinoline compound in the preparation of antitumor drugs.

[0016] In order to realize the above object, the technical scheme adopted by the present application is as follows:

[0017] Benz [4, 5] imidazo [2, 1-a] isoquinoline compound, structure as follows:

[0018]

[0019] Wherein, R 1 is any one or two of hydrogen, halogen, alkyl, alkoxy, annelated and aryl;R 2 is any one of hydrogen, halogen, alkyl and alkoxy;R 3 is any one or two of hydrogen, halogen, alkyl and alkoxy.

[0020] The preparation method of the foregoing benz [4, 5] imidazo [2, 1-a] isoquinoline compound is that, with palladium acetate and norbornene as catalyst, with tris (4-chlorophenyl) phosphine, triphenylphosphine, tris (4-methoxyphenyl) phosphine, tris (4-methylphenyl) phosphine, tris (4-fluorophenyl) phosphine, tricyclohexylphosphine or tris (2-furyl) phosphine) As ligand, with potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide or lithium tert-butoxide as base, with 1, 4-dioxane as solvent, 1-(2-bromo-1-phenylvinyl) benzimidazole compound and iodobenzene compound are one pot synthesized in argon atmosphere benz [4, 5] imidazo [2, 1-a] isoquinoline compound of claim 1, 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 as follows:

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

[0027] (2) vacuumizing and exchanging with argon for three times, and adding a solvent under argon atmosphere;

[0028] (3) stirring and reacting in an oil bath at 100-130°C until the reaction is completed;

[0029] (4) post-treating the product 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-isopropyl iodobenzene, 2-methoxy iodobenzene, 2-fluoro iodobenzene, 3-fluoro-2-iodotoluene, 4-iodobis thiophene, 1-iodo-4-methoxynaphthalene and 2-iodobiphenyl.

[0031] More preferably, in step (1), the 1-(2-bromo-1-phenylvinyl)benzimidazole compound is any one of 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, 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] Use of the aforementioned benz[4,5]imidazo[2,1-a]isoquinoline compound in the preparation of an antitumor drug, wherein the tumor is human breast cancer.

[0033] Preferably, the benzo[4,5]imidazo[2,1-a]isoquinoline compounds are as follows:

[0034]

[0035] The present application has the advantages of:

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

[0037] (2) In the screening of antitumor drugs, the benzo[4,5]imidazo[2,1-a]isoquinoline compounds provided by the present application show good growth inhibition activity on human breast cancer cells MCF-7, providing a good material basis for the development of new drugs, especially the compounds prepared by example 26, example 37 and example 41, which all show strong inhibition effect on the proliferation of human breast cancer cells MCF-7, and have potential application value as lead compounds for subsequent preparation and development of antitumor drugs.

[0038] (3) The preparation method of the above-mentioned benzo[4,5]imidazo[2,1-a]isoquinoline compounds provided by the present application adopts a strategy of directing group C-H activation under Catellani reaction, uses cheap and easily available 1-(2-bromo-1-phenylvinyl) benzimidazole compounds and iodobenzene compounds as starting materials, integrates multiple reactions into one pot through synergistic catalysis of palladium acetate and norbornene under argon, 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 with different substituent modifications. Compared with existing methods, the present application uses cross-coupling reaction strategy to synthesize target products in one pot, and has the advantages of mild reaction conditions, simple operation, good safety, high reaction efficiency, cheap and easily available raw materials, and rich product types. DETAILED DESCRIPTION

[0039] The present application will be specifically described below in combination with specific examples.

[0040] I. Structure of the compound

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

[0042]

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

[0044] II. Preparation method of the compound

[0045] The present application uses palladium acetate (Pd(OAc)2) and norbornene (NBE) as catalyst, tris(4-chlorophenyl)phosphine (or triphenylphosphine, tris(4-methoxyphenyl)phosphine, tris(4-methylphenyl)phosphine, tris(4-fluorophenyl)phosphine, tricyclohexylphosphine, tris(2-furyl)phosphine) as ligand, 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 (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, 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 (e.g. 1-iodonaphthalene, 2-iodonaphthalene, 2,4-dimethyl-1-iodobenzene, 2-isopropyl iodobenzene, 2-methoxy iodobenzene, 2-fluoro iodobenzene, 3-fluoro-2-iodotoluene, 4-iodobenzothiophene, 1-iodo-4-methoxynaphthalene, 2-iodobiphenyl) are one-pot synthesized into the above-mentioned benz[4,5]imidazo[2,1-a]isoquinoline compounds in an argon atmosphere. The reaction formula is as follows:

[0046]

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

[0048]

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

[0050] Example 1

[0051] The structure of the compound is:

[0052]

[0053] The reaction formula is:

[0054]

[0055] The specific preparation method is:

[0056] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 1-iodonaphthalene (0.12 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), triphenylphosphine (PPh3, 0.02 mmol), Cs2CO3(0.5 mmol) and NBE7 (0.1 mmol) were sequentially added, then vacuumized and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 100°C for stirring for 10 h, monitored by TLC plate, after the reaction was completed, 10 mL of water was added to the organic residue, then extracted with dichloromethane for three times (3x50 mL), all the organic phases were collected and dried with anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to obtain a white solid with a yield of 19%.

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

[0058] 1H NMR (500 MHz, CDCI3) δ 10.98 (d, J = 8.7 Hz, 1 H), 8.13 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 7.96 (t, J = 7.8 Hz, 1 H), 7.76-7.70 (m, 2 H), 7.67-7.62 (m, 5 H), 7.46 (t, J = 7.4 Hz, 1 H), 7.10 (s, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 6.59 (d, J = 8.4 Hz, 1 H);

[0059] 13 C NMR (126 MHz, CDCI3) δ 148.44, 144.70, 138.14, 134.74, 132.85, 131.75, 131.28, 130.21, 129.90, 129.42, 129.33, 129.05, 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 N2: Calculated molecular weight: 345.1392; Found: 345.1382.

[0061] Examples 2-7

[0062] Examples 2-7 were prepared in the same manner as Example 1, except that the ligand type was different.

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

[0064] Example Ligand Yield 2 tris(4-methylphenyl)phosphine, abbreviated as P(p-MeC6H4)3 12％ 3 tris(4-methoxyphenyl)phosphine, abbreviated as P(p-OMeC6H4)3 16％ 4 tris(4-chlorophenyl)phosphine, abbreviated as P(p-ClC6H4)3 27％ 5 tris(4-fluorophenyl)phosphine, abbreviated as P(p-FC6H4)3 13％ 6 tricyclohexylphosphine, abbreviated as PCy3 Trace 7 Tris(2-furyl)phosphine, abbreviated as TFP 30％

[0065] Examples 8-12

[0066] Examples 8-12 were prepared in the same manner as Example 4, except that the base type was different.

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

[0068]

[0069]

[0070] Examples 13-18

[0071] The preparation method of Examples 13 to 18 is basically the same as that of Example 9, except that the norbornene species is different.

[0072] Table 3. Effect of norbornene species 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] Examples 19 to 22

[0075] The preparation method of Examples 19 to 22 is basically the same as that of Example 15, except that 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] Examples 23 to 25

[0079] The preparation method of Examples 23 to 25 is basically the same as that of Example 21, except that the amount of 1-iodonaphthalene is different.

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

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

[0082] From Examples 1 to 25, it can be seen that the ligand species, the base species, the norbornene species, the reaction temperature, and the amount of 1-iodonaphthalene all have a significant effect on the yield of the product. Among them, when P(p-ClC6H4)3 is used as the ligand, K2CO3 is used as the base, NBE3 is used as the catalyst, the amount of 1-iodonaphthalene is 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] Example 26

[0084] The compound structure is:

[0085]

[0086] The reaction formula is:

[0087]

[0088] The specific preparation method is:

[0089] Into a 25 mL dry round-bottom pressure tube equipped with a stir bar was added 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-methoxyphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol), and NBE3(0.1 mmol) sequentially, then vacuumed and flushed with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and the mixture was stirred in an oil bath at 130 °C for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, which was extracted with dichloromethane (3 x 50 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 25:1, v / v) to give a white solid in 63% yield.

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

[0091] 1 H NMR (500 MHz, CDC13) δ 10.98 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 6.7 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.76-7.70 (m, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.09-7.05 (m, 2H), 6.70 (d, J = 8.5 Hz, 1H), 3.98 (s, 3H);

[0092] 13 C NMR (126 MHz, CDC13) δ 160.74, 148.54, 144.71, 138.08, 132.80, 131.85, 131.23, 130.66, 130.24, 129.52, 128.74, 128.34, 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 Calculated molecular weight of N2O: 375.1497; Found: 375.1493.

[0094] Example 27

[0095] The structure of the compound is:

[0096]

[0097] The reaction formula is:

[0098]

[0099] The specific preparation method is:

[0100] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-ethoxyphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were sequentially added, then vacuumized and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL), and all the organic phases were collected and dried with anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained, which was subjected to 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, CDCl3) δ 10.97 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 7.9 Hz, 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 = 8.7 Hz, 2H), 7.08-7.04 (m, 2H), 6.71 (d, J = 8.4 Hz, 1H), 4.24-4.17 (m, 2H), 1.54 (t, J = 6.9 Hz, 3H);

[0103] 13C NMR (126 MHz, CDC13) δ 160.16, 148.53, 138.18, 132.80, 131.90, 131.25, 130.65, 130.25, 129.54, 128.74, 128.35, 128.26, 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 N2O Molecular weight calculated: 389.1654; found: 389.1646.

[0105] Example 28

[0106] The structure of the compound is:

[0107]

[0108] The reaction formula is:

[0109]

[0110] The specific preparation method is:

[0111] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-propylphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were sequentially added, then vacuumized and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL), and all the organic phases were collected and dried with anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained, which was subjected to 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] 1H NMR (500 MHz, CDC13) δ 10.98 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.95 (t, J = 7.0 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.47 - 7.42 (m, 3H), 7.10 (s, 1H), 7.08 - 7.01 (m, 1H), 6.62 (d, J = 8.4 Hz, 1H), 2.80 (t, J = 7.6 Hz, 2H), 1.86 - 1.76 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H);

[0114] 13 C NMR (126 MHz, CDC13) δ 148.49, 144.71, 144.69, 138.36, 132.80, 132.06, 131.83, 131.21, 130.24, 129.48, 129.17, 129.08, 128.76, 128.74, 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 N2Calcd: 387.1861; Found: 387.1853.

[0116] Example 29

[0117] The structure of the compound is:

[0118]

[0119] The reaction scheme is:

[0120]

[0121] The specific preparation method is:

[0122] Into a 25 mL dry round-bottomed pressure tube equipped with a stir bar was added 1-iodonaphthalene (0.15 mmol), 1-(2-bromine-1-(4-butylphenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol), and NBE3(0.1 mmol) sequentially, then vacuumed and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixture was stirred in an oil bath at 130 °C for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane three times (3 x 50 mL). All the organic phases were collected and dried over anhydrous Na2SO4. After being concentrated under reduced pressure, the crude product was obtained. The crude product 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 were as follows:

[0124] 1 H NMR (400 MHz, CDC13) δ 10.99 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.98-7.93 (m, 1H), 7.75-7.69 (m, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.48-7.41 (m, 3H), 7.08 (s, 1H), 7.07-7.02 (m, 1H), 6.62 (d, J = 8.4 Hz, 1H), 2.84-2.79 (m, 2H), 1.81-1.72 (m, 2H), 1.52-1.43 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H);

[0125] 13 C NMR (101 MHz, CDC13) δ 148.49, 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 24Calculated mass of N2: 401.2018; Found: 401.2011.

[0127] Example 30

[0128] The structure of the compound is:

[0129]

[0130] The reaction formula is:

[0131]

[0132] The specific preparation method is:

[0133] Into a 25 mL dry branch pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(3-chlorophenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were added in turn, then vacuumed and replaced with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane three times (3×50 mL), and all the organic phases were collected and dried with anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained, which was subjected to 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, CDCl3) δ 10.97 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 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 = 8.5 Hz, 1H);

[0136] 13C NMR (101 MHz, CDC13) δ 148.32, 144.71, 136.49, 136.35, 135.08, 132.98, 131.48, 131.43, 130.32, 130.15, 130.10, 129.43, 129.20, 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 ClN2Molecular Weight Calcd: 379.1002; Found: 379.0996.

[0138] Example 31

[0139] The structure of the compound is:

[0140]

[0141] The reaction formula is:

[0142]

[0143] The specific preparation method is:

[0144] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-bromophenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were sequentially added, then vacuumized and replaced with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL), and all the organic phases were collected and dried with anhydrous Na2SO4. After being concentrated under reduced pressure, the crude product was obtained, which was subjected to 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] 1H NMR (500 MHz, CDC13) δ 10.97 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.97 - 7.94 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 8.3, 2.5 Hz, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.12 - 7.09 (m, 1H), 7.07 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H);

[0147] 13 C NMR (126 MHz, CDC13) δ 144.73, 136.85, 133.64, 132.96, 132.36, 131.55, 131.43, 130.96, 130.17, 129.26, 128.81, 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 BrN2Molecular weight calculated: 423.0497; found: 423.0492.

[0149] Example 32

[0150] The structure of the compound is:

[0151]

[0152] The reaction formula is:

[0153]

[0154] The specific preparation method is:

[0155] Into a 25 mL dry round-bottomed pressure tube equipped with a stir bar was added 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-(4-fluorophenyl)vinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol), and NBE3(0.1 mmol) sequentially, then vacuumed and flushed with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and the mixture was stirred in an oil bath at 130 °C for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, which was extracted with dichloromethane (3 x 50 mL). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to give a white solid in 70% yield.

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

[0157] 1 H NMR (400 MHz, CDC13) δ 10.98 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 7.1 Hz, 1H), 8.07 (d, J = 5.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.66 - 7.61 (m, 2H), 7.47 (t, J = 8.2 Hz, 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, CDC13) δ 163.61 (d, J = 251 Hz, 1C), 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 = 5.9 Hz, 2C), 126.75, 124.82, 124.46, 121.16, 120.16, 116.25 (d, J = 22 Hz, 1C), 114.01, 113.70; CF 1 J CF CF 3 CF CF 2 CF ​​​​​​​​

[0159] HR-MS (ESI): m / z [M+H] + C 25 H 15 FN2 calculated: 363.1297; found: 363.1290.

[0160] Example 33

[0161] The structure of the compound is:

[0162]

[0163] The reaction formula is:

[0164]

[0165] The specific preparation method is:

[0166] Into a 25 mL dry branch pressure tube equipped with a stirrer, 2-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were added in turn, then vacuumed and exchanged with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C and stirred for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane three times (3×50 mL), and all the organic phases were collected and dried over anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained, which was subjected to 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, CDCl3) δ 8.03-7.99 (m, 1H), 7.65-7.61 (m, 1H), 7.59 (d, J = 4.7 Hz, 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 = 9.3 Hz, 1H), 3.35 (s, 3H);

[0169] 13C NMR (101 MHz, CDC13) δ 148.86, 144.22, 138.76, 137.09, 134.88, 132.85, 130.44, 129.76, 129.71, 129.35, 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 N2Molecular weight calculated: 309.1392; found: 309.1384.

[0171] Example 34

[0172] The structure of the compound is:

[0173]

[0174] The reaction formula is:

[0175]

[0176] The specific preparation method is:

[0177] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 2,4-dimethyl-1-iodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were sequentially added, then vacuumized and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL). All the organic phases were collected and dried with anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude product, which was subjected to 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] 1H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) δ144.27, 139.34, 138.56, 137.10, 134.99, 133.08, 132.01, 129.77, 129.67, 129.37, 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 Calculated value of N2 molecular weight: 323.1548; theoretical value: 323.1524.

[0182] Example 35

[0183] The compound structure is as follows:

[0184]

[0185] The reaction formula is:

[0186]

[0187] The specific preparation method is as follows:

[0188] 2-Isopropyliodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2 (0.01 mmol), P(p-ClC6H4)3 (0.02 mmol), K2CO3 (0.5 mmol), and NBE3 (0.1 mmol) were added sequentially to a 25 mL dry pressure tube equipped with a stir bar. The mixture was then evacuated and exchanged with argon three times. 1,4-Dioxane (2 mL) was added under argon atmosphere. Finally, the mixture was placed in an oil pan at 130 °C and stirred for 10 h. After the reaction was complete, 10 mL of water was added to the organic residue, and the mixture was extracted three times with dichloromethane (3 × 50 mL). All organic phases were collected and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and then subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to obtain a white solid with a yield of 42%.

[0189] The product was identified by the following data:

[0190] 1 H NMR (400 MHz, CDC13) δ 7.99 (d, J = 8.1 Hz, 1H), 7.71 (dd, J = 7.6, 1.5 Hz, 1H), 7.66 - 7.58 (m, 6H), 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.02 - 6.97 (m, 1H), 6.88 (s, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.74 - 5.67 (m, 1H), 1.57 (s, 1H), 1.49 (d, J = 6.7 Hz, 6H);

[0191] 13 C NMR (101 MHz, CDC13) δ 149.93, 148.17, 144.12, 136.85, 134.93, 132.96, 129.68, 129.45, 129.36, 128.94, 125.24, 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] calcd for C2H2iN4O2, 337.1705; found: 337.1680. + C 24 H 20 N2Molecular weight calculated: 337.1705; found: 337.1680.

[0193] Example 36

[0194] The structure of the compound is:

[0195]

[0196] The reaction formula is:

[0197]

[0198] The specific preparation method is:

[0199] Into a 25 mL dry round-bottomed pressure tube equipped with a stir bar was added 2-methoxyiodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol), and NBE3(0.1 mmol) sequentially, then vacuumed and flushed with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, finally the mixture was stirred at 130 °C for 10 h in an oil bath. After the reaction was completed, 10 mL water was added to the organic residue, then extracted with dichloromethane three times (3 x 50 mL), all the organic phases were collected and dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to give a white solid in 56% yield.

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

[0201] 1 H NMR (400 MHz, CDC13) δ 8.07 (d, J = 8.2 Hz, 1H), 7.66-7.56 (m, 6H), 7.38-7.31 (m, 2H), 7.18 (d, J = 8.2 Hz, 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, CDC13) δ 158.20, 146.59, 144.47, 137.86, 134.66, 134.10, 130.55, 129.83, 129.47, 129.32, 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 Calcd for N2O: 325.1341; Found: 325.1332.

[0204] Example 37

[0205] The structure of the compound is:

[0206]

[0207] The reaction scheme is:

[0208]

[0209] The specific preparation method is as follows:

[0210] 2-Fluoroiodobenzene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2 (0.01 mmol), P(p-ClC6H4)3 (0.02 mmol), K2CO3 (0.5 mmol), and NBE3 (0.1 mmol) were added sequentially to a 25 mL dry pressure tube equipped with a stir bar. The mixture was then evacuated and exchanged with argon three times. 1,4-Dioxane (2 mL) was added under an argon atmosphere. Finally, the mixture was placed in an oil pan at 130 °C and stirred for 10 h. After the reaction was complete, 10 mL of water was added to the organic residue, and the mixture was extracted three times with dichloromethane (3 × 50 mL). All organic phases were collected and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and then subjected to 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 results of the obtained products are as follows:

[0212] 1 H NMR (400MHz, CDCl3) 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 (101MHz, CDCl3) 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 Calculated value of FN2 molecular weight: 313.1141; theoretical value: 313.1122.

[0215] Example 38

[0216] The compound structure is as follows:

[0217]

[0218] The reaction formula is:

[0219]

[0220] The specific preparation method is as follows:

[0221] 3-Fluoro-2-iodotoluene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2 (0.01 mmol), P(p-ClC6H4)3 (0.02 mmol), K2CO3 (0.5 mmol), and NBE3 (0.1 mmol) were added sequentially to a 25 mL dry pressure tube equipped with a stir bar. The mixture was then evacuated and exchanged with argon three times. 1,4-Dioxane (2 mL) was added under an argon atmosphere. The mixture was then placed in an oil pan at 130 °C and stirred for 10 h. After the reaction was complete, 10 mL of water was added to the organic residue, and the mixture was extracted three times with dichloromethane (3 × 50 mL). All organic phases were collected and dried over anhydrous Na2SO4. The crude product was concentrated under reduced pressure and subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to obtain a white solid with a yield of 54%.

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

[0223] 1 H NMR (400MHz, CDCl3) 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, CDC13) δ 160.3 (d, J = 244 Hz, CF = 244 Hz, 1 J CF ), 136.4, 134.6, 129.8, 129.4 (d, J = 41 Hz, CF = 41 Hz, 2 J CF ), 129.4, 129.0, 125.7 (d, J = 9.8 Hz, 3 J CF ), 124.4 (d, J = 17 Hz, 3 J CF ), 124.0, 121.6, 120.1, 117.6 (d, J = 17 Hz, CF = 17 Hz, 2 J CF ), 114.0, 112.9, 13.89 (d, J = 6.6 Hz, 3 J CF );

[0225] HR-MS (ESI): m / z [M + H] + C 22 H 15 FN2 calculated for C2H12FN2: 327.1298; found: 327.1279.

[0226] Example 39

[0227] The structure of the compound is:

[0228]

[0229] The reaction scheme is:

[0230]

[0231] The specific preparation method is:

[0232] Into a 25 mL dry round-bottomed pressure tube equipped with a stir bar was added 4-iododibenzothiophene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol), and NBE3(0.1 mmol) sequentially, then vacuumed and flushed with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and the mixture was stirred in an oil bath at 130 °C for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, which was extracted with dichloromethane three times (3 x 50 mL). All the organic phases were collected and dried over anhydrous Na2SO4. After being concentrated under reduced pressure, the crude product was obtained and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to give a white solid with a yield of 58%.

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

[0234] 1 H NMR (400 MHz, CDC13) δ 8.48 (d, J = 8.4 Hz, 1H), 8.35-8.30 (m, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.15-8.10 (m, 1H), 7.84 (d, J = 8.2 Hz, 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 = 8.4 Hz, 1H);

[0235] 13 C NMR (101 MHz, CDC13) δ 147.05, 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 H 16 Calcd. for N2S: 401.1112; Found: 401.1093.

[0237] Example 40

[0238] The structure of the compound is:

[0239]

[0240] The reaction formula is:

[0241]

[0242] The specific preparation method is:

[0243] Into a 25 mL dry round-bottom pressure tube equipped with a stir bar was added 1-iodo-4-methoxynaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) successively, then vacuumed and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, finally the above mixture solution was placed in an oil bath at 130 °C for stirring for 10 h, after the reaction was completed, 10 mL water was added to the organic residue, then extracted with dichloromethane for three times (3 x 50 mL), all the organic phases were collected and dried with anhydrous Na2SO4, concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 25:1, v / v) to obtain a white solid, yield 61%.

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

[0245] 1 H NMR (400 MHz, CDCl3) δ 10.94 (d, J = 8.7 Hz, 1H), 8.49 (dd, J = 8.2, 1.0 Hz, 1H), 8.08 (d, J = 8.1 Hz, 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 = 8.4 Hz, 1H), 4.15 (s, 3H);

[0246] 13 C NMR (101 MHz, CDCl3) δ 177.48, 174.10, 157.16, 144.75, 134.84, 133.19, 129.86, 129.40, 129.34, 129.03, 128.77, 128.59, 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 Calcd for N2O: 375.1497; Found: 375.1487.

[0248] Example 41

[0249] The structure of the compound is:

[0250]

[0251] The reaction scheme is:

[0252]

[0253] The specific preparation method is:

[0254] Into a 25 mL dry round-bottom pressure tube equipped with a stir bar was added 2-iodobiphenyl (0.15 mmol), 1-(2-bromo-1-phenylvinyl)benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) successively, then vacuumed and exchanged with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, finally the above mixture solution was placed in an oil bath at 130 °C for stirring for 10 h, after the reaction was completed, 10 mL water was added to the organic residue, then extracted with dichloromethane for three times (3 x 50 mL), all the organic phases were collected and dried with anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, which was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to obtain a white solid with a yield of 55%.

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

[0256] 1 H NMR (400 MHz, CDC13) δ 7.72 (dd, J = 7.8, 1.5 Hz, 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] 13C NMR (101 MHz, CDC13) δ 147.46, 143.77, 142.75, 141.76, 137.60, 134.78, 132.83, 131.23, 129.81, 129.76, 129.69, 129.29, 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 N2Molecular weight calculated: 371.1548; found: 371.1529.

[0259] Example 42

[0260] The structure of the compound is:

[0261]

[0262] The reaction formula is:

[0263]

[0264] The specific preparation method is:

[0265] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5-methyl-benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were added in turn, then vacuumed and replaced with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130°C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL), and all the organic phases were collected and dried with anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained, which was subjected to 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] 1H NMR (400 MHz, CDC13) δ 10.99 - 10.97 (m, 1H), 10.97 - 10.95 (m, 1H), 8.05 (d, J = 9.1 Hz, 2H), 8.01 (dd, J = 8.2, 2.5 Hz, 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, 2.0 Hz, 1H), 7.06 (d, J = 2.2 Hz, 2H), 6.86 (dd, J = 8.6, 1.9 Hz, 1H), 6.46 (d, J = 8.7 Hz, 1H), 6.33 (s, 1H), 2.53 (s, 3H), 2.28 (s, 3H);

[0268] 13 C NMR (101 MHz, CDC13) δ 148.46, 148.13, 145.10, 142.83, 138.11, 138.05, 134.85, 134.81, 134.27, 132.83, 131.65, 131.49, 131.08, 131.01, 130.77, 130.21, 130.17, 129.83, 129.79, 129.54, 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 N2Calcd: 359.1548; Found: 359.1540.

[0270] Example 43

[0271] The structure of the compound is:

[0272]

[0273] The reaction scheme is:

[0274]

[0275] The specific preparation method is:

[0276] Into a 25 mL dry round-bottomed pressure tube equipped with a stir bar was added 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5,6-dimethyl- benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol), and NBE3(0.1 mmol) sequentially, then vacuumed and flushed with argon three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and the mixture was stirred in an oil bath at 130 °C for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, which was extracted with dichloromethane (3 x 50 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1, v / v) to give a white solid in 72% yield.

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

[0278] 1 H NMR (400 MHz, CDC13) δ 10.96 (d, J = 7.4 Hz, 1H), 8.03 (dd, J = 14.4, 8.2 Hz, 2H), 7.96-7.91 (m, 1H), 7.88 (s, 1H), 7.74 (d, J = 8.4 Hz, 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, CDC13) δ 147.88, 143.45, 138.07, 134.92, 133.60, 132.81, 131.42, 130.84, 130.19, 130.12, 129.75, 129.40, 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 Calcd for N2: 373.1705; Found: 373.1694.

[0281] Example 44

[0282] The structure of the compound is:

[0283]

[0284] The reaction is as follows:

[0285]

[0286] The specific preparation method is as follows:

[0287] Into a 25 mL dry round-bottom pressure tube equipped with a stir bar was added 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5-methoxy-benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) successively, then vacuumed and replaced with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, finally the above mixture was stirred in an oil bath at 130 °C for 10 h. After the reaction was completed, 10 mL water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL). All the organic phases were collected and dried over anhydrous Na2SO4. After being concentrated under reduced pressure, the crude product was obtained. The crude product 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, CDC13) δ 10.97-10.91 (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 = 2.3 Hz, 1H), 7.11-7.06 (m, 3H), 6.68 (dd, J = 9.1, 2.5 Hz, 1H), 6.45 (d, J = 9.1 Hz, 1H), 6.00 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H), 3.49 (s, 3H);

[0290] 13C NMR (101 MHz, CDC13) δ 157.52, 154.73, 148.77, 145.95, 139.29, 137.84, 132.88, 132.83, 131.52, 131.10, 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 Calcd for N2O: 375.1497; Found: 375.1485.

[0292] Example 45

[0293] The structure of the compound is:

[0294]

[0295] The reaction formula is:

[0296]

[0297] The specific preparation method is:

[0298] Into a 25 mL dry-mouth pressure tube equipped with a stirrer, 1-iodonaphthalene (0.15 mmol), 1-(2-bromo-1-phenylvinyl)-5-chloro-benzimidazole (0.1 mmol), Pd(OAc)2(0.01 mmol), P(p-ClC6H4)3(0.02 mmol), K2CO3(0.5 mmol) and NBE3(0.1 mmol) were added in turn, then vacuumed and replaced with argon for three times, 1,4-dioxane (2 mL) was added under argon atmosphere, and finally the above mixed solution was placed in an oil bath at 130 °C for stirring for 10 h. After the reaction was completed, 10 mL of water was added to the organic residue, followed by extraction with dichloromethane for three times (3 x 50 mL). All the organic phases were collected and dried over anhydrous Na2SO4. After concentration under reduced pressure, the crude product was obtained. The crude product was subjected to 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, CDC13) δ 10.89 (d, J = 7.6 Hz, 2H), 8.10 - 8.06 (m, 3H), 8.01 (dd, J = 8.3, 3.9 Hz, 3H), 7.97 - 7.92 (m, 2H), 7.75 - 7.61 (m, 14H), 7.41 (dd, J = 8.7, 2.0 Hz, 1H), 7.11 (d, J = 1.6 Hz, 2H), 6.98 (dd, J = 8.9, 2.1 Hz, 1H), 6.50 (d, J = 1.5 Hz, 1H), 6.46 (d, J = 8.9 Hz, 1H);

[0301] 13 C NMR (101 MHz, CDC13) δ 149.37, 145.53, 143.18, 137.89, 134.37, 134.15, 132.91, 131.98, 131.85, 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 ClN2Calcd: 379.1002; Found: 379.0983.

[0303] III. Anti-tumor activity of the compounds

[0304] Logarithmic growth phase human breast cancer cells MCF-7 were digested with trypsin solution (0.25% trypsin + 0.02% EDTA), and then a single cell suspension with a concentration of 30000 / mL was prepared, 100 μL per well was inoculated in a 96-well plate, and cultured in a 37°C 5% CO2 incubator for 24 h. 100 μL of the test compound (etoposide, the compound prepared in Example 1, the compounds prepared in Examples 26-45) with a concentration of 10 μM was added to each well of the experimental group, 100 μL of complete culture medium was added to each well of the control group, and 3 parallel holes were set in each group, and the incubator was continued to be cultured for 72 h. Then, 20 μL of tetramethyl benzidine (MTT) solution with a concentration of 5 mg / mL was added to each well, the incubator was continued to be cultured for 3 h, the supernatant was discarded, 150 μL of DMSO was added to dissolve the MTT crystals, and the micro-vibration oscillator was vibrated to mix, and the optical density value (OD) of each well was determined by an enzyme-labeled instrument (reference wavelength 450 nm, detection wavelength 570 nm). The inhibition rate of each test compound on human breast cancer cells MCF-7 was calculated according to the following formula:

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

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

[0307] Table 6 Inhibition rate of each test compound on human breast cancer cells 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 compound prepared in Example 1 and the compounds prepared in Examples 26-45 all exhibit certain inhibition effect on the proliferation of human breast cancer cells MCF-7, wherein the compounds prepared in Examples 26, 37 and 41 have strong inhibition effect on human breast cancer cells MCF-7, and can be used as a lead compound for the preparation and research and development of subsequent antitumor drugs. In addition to the above three compounds, the remaining compounds do not have strong inhibition activity on human breast cancer cells MCF-7, but also exhibit certain inhibition activity, which can provide the role of a large number of compounds for the subsequent new drug research and development.

[0310] It should be noted that the above examples are only examples for clearly illustrating the present application, and are not intended to limit the embodiments of the present application. Based on the above description, other different forms of changes or variations can also be made by those skilled in the art. Here, all the embodiments cannot be exhausted. Any obvious changes or variations derived from the technical scheme of the present application still fall within the protection scope of the present application.

Claims

1. Benzo[4,5]imidazo[2,1- a Isoquinoline compounds, characterized in that, The structure is shown as follows: 、 。 2. The benzo[4,5]imidazo[2,1- c]isoquinoline compounds as claimed in claim 1, characterized by a ] isoquinolines, characterized in that The benz[4,5]imidazo[2,1- ]isoquinoline compound of claim 1 is synthesized by one pot reaction of 1-(2-bromo-1-phenylvinyl)benzimidazole and iodobenzene in an argon atmosphere, using palladium acetate and norbornene NBE3 as catalyst, tris(4-chlorophenyl)phosphine as ligand, potassium carbonate as base, and 1,4-dioxane as solvent, wherein the 1-(2-bromo-1-phenylvinyl)benzimidazole is 1-(2-bromo-1-(4-methoxyphenyl)vinyl)benzimidazole or 1-(2-bromo-1-phenylvinyl)benzimidazole, and the iodobenzene is 1-iodonaphthalene or 2-iodobiphenyl, as shown in the following reaction formula: a ] 。 3. 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 1:1.5:5.

0.

4. The production method according to claim 2, characterized by, The specific steps are: (1) adding the iodobenzene compound, the 1-(2-bromo-1-phenylvinyl)benzimidazole compound, the palladium acetate, the ligand, the base and the norbornene into the reaction container in sequence; (2) vacuumizing and exchanging with argon for three times, and adding the solvent under the argon atmosphere; (3) stirring in the oil bath at 130℃ to carry out the reaction until the reaction is completed; (4) carrying out the post-treatment on the product to obtain the white solid.

5. Use of a benzo[4,5]imidazo[2,1- b]isoquinoline compound as claimed in claim 1 for the preparation of an antitumor medicament, said tumor being human breast cancer. a ]isoquinoline compounds for the preparation of an antitumor medicament, said tumor being human breast cancer.

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