Synthesis method and application of benzimidazole borneol derivative

Abstract

The invention relates to the technical field of biological medicine, in particular to a synthetic method and application of a benzimidazole borneol derivative, and the synthetic method comprises the following steps: by taking a benzimidazole compound, borneol, phenylboronic acid with different substitutions and acetophenone as raw materials, carrying out a substitution reaction, a Suzuki coupling reaction, a condensation reaction and other multi-step reactions to obtain 21 target compounds; the structure of the compound is characterized by 1H NMR, 13C NMR and HRMS, and glioblastoma U87 and U251 cells are used as research objects. The benzimidazole disclosed by the invention can play an anti-cancer role in various modes, and the structure similar to purine can effectively enhance the capabilities of inhibition on protein and nucleic acid, microtubule degeneration, cell apoptosis, DNA breakage, electrostatic interaction between hydrogen bonds and topoisomerase complexes, embedding with DNA and the like. Meanwhile, natural bicyclic terpene borneol has high fat solubility and has a certain promoting effect on permeability of BBB, the bicyclic terpene borneol is widely applied to an auxiliary agent of central drugs so as to improve drug delivery to the brain, and the bicyclic terpene borneol is novel in product structure and high in yield.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a synthesis method and application of a benzimidazole borneol derivative. Background Art

[0002] GBM is a common primary central nervous system tumor, accounting for approximately 50% of gliomas. It is characterized by rapid invasion and persistent infiltration and spread. Its etiology may be related to genetic factors, ionizing radiation, environmental pollution, infection, and other factors. Furthermore, GBM often causes clinical symptoms such as headache, vomiting, tumor compression, and brain tissue invasion. Despite significant advances in GBM treatment in recent years (including surgery, chemotherapy, radiotherapy, and systemic therapy), overall survival remains short.

[0003] Benzimidazole compounds possess a variety of biological activities, including antitumor, antibacterial, and anti-inflammatory. Studies have shown that the benzimidazole skeleton plays a crucial role in antitumor activity due to its structural similarity to purine, which enhances the inhibition of tumor cell proteins and nucleic acids, microtubule degeneration, apoptosis, DNA breakage, hydrogen bonding, electrostatic interactions with topoisomerase complexes, and intercalation into DNA, exerting potent antitumor activity. Modification of the benzimidazole ring has become a hot topic in the development of anticancer drugs.

[0004] Furthermore, considering that borneol is a highly lipid-soluble bicyclic terpenoid compound that promotes BBB (blood-brain barrier) permeability, it is widely used as an adjuvant for central nervous system drugs to improve drug delivery to the brain. Therefore, modifying borneol structural fragments onto a benzimidazole core to develop new anti-GBM small molecule chemotherapy drugs has broad application prospects.

[0005] Despite significant advances in medical technology in recent years, the diagnosis and treatment of GBM remain largely ineffective. Furthermore, the blood-brain barrier (BBB) ​​prevents chemotherapy drugs from entering the central nervous system, leading to low drug bioavailability, high toxicity, and a high GBM recurrence rate. Therefore, the development of novel GBM therapeutics is urgently needed.

[0006] To solve the above technical problems, the present application modified borneol onto the benzimidazole core, designed and synthesized a series of borneol-modified benzimidazole derivatives, and studied their anti-GBM activity and mechanism. Summary of the Invention

[0007] The purpose of the present invention is to solve the shortcomings of the prior art and propose a synthesis method and application of a benzimidazole borneol derivative. The compounds of the present invention have good inhibitory activity against GBM, among which compound S has the best activity and IC50 0.73 μM and 0.35 μM respectively.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] A method for synthesizing a benzimidazole-borneol derivative comprises the following steps:

[0010] Through literature research, the preliminary structure-activity relationship of benzimidazole derivatives showed that the benzimidazole ring as a fused system in the structure has important significance for tumor inhibition activity, among which the benzene ring connected to the benzimidazole is particularly important (I1, I2 and I3, Figure 1 ). Therefore, based on this, the present invention modified borneol to the structure of coupling benzimidazole with different substituted benzene rings, and designed and synthesized the target compound AL, a total of 12 compounds ( Figure 1 , Table 1).

[0011] Table 1 Structure of Compound AL

[0012]

[0013] Chalcone compounds have been widely studied for their various physiological activities, such as anticancer, antioxidant, anti-inflammatory, and anti-infective activities. In addition, studies have shown that natural or synthetic chalcone derivatives (I4, I5, and I6, Figure 2 ) not only has good tumor inhibitory activity, but is also relatively safe to healthy tissues. Therefore, the present invention retains the active skeleton of chalcone, replaces the aromatic ring with a benzimidazole ring, and further introduces a lipophilic borneol group to design and synthesize a series of target compounds MU containing chalcone structure, a total of 9 compounds ( Figure 2 , Table 2).

[0014] Table 2 Structure of compound MU

[0015]

[0016] Preferably, the specific steps are as follows:

[0017] Synthesis route of compound AL

[0018] like Figure 3As shown, the raw material (+)-borneol (1) is dissolved in anhydrous dichloromethane, and then 4-dimethylaminopyridine (DMAP) and triethylamine are added. Chloroacetyl chloride (2) is slowly added under ice bath. After the addition is complete, the mixture is returned to room temperature and the reaction is continued for 12 hours to obtain the intermediate bornyl ester 3. Pd(PPh3)4 is then dissolved in a mixed solution of toluene, ethanol and water, K2CO3 is added, and then the compound imidazole 4 and different substituted phenylboronic acids (5a-5l) are added. The mixture is reacted at 120°C for 12 hours to obtain benzimidazole 6a-6l. Finally, benzimidazole 6a-6l and borneol derivative 3 are dissolved in acetone, K2CO3 is added, and the mixture is reacted at 60°C for 8 hours to obtain the target compound AL.

[0019] like Figure 4 As shown, imidazole aldehyde 8 and various substituted acetophenones (9a-9i) were dissolved in methanol, followed by the addition of NaOH and reaction at room temperature for 0.5 h to yield intermediate imidazole benzenes 10a-10i. Finally, imidazole benzenes 10a-10i and bornyl ester derivative 3 were dissolved in acetone, K₂CO₃ was added, and reaction was continued at 60°C for 8 h to yield the target compound MU.

[0020] The present invention also provides a use of the benzimidazole borneol derivative obtained by the above synthesis method in the preparation of anti-glioma drugs.

[0021] By adopting the above-mentioned technical scheme, the present invention's synthetic route uses benzimidazole compounds, borneol, variously substituted phenylboronic acids, and acetophenone as raw materials. Through multiple steps including substitution, Suzuki coupling, and condensation reactions, 21 target compounds with novel structures were obtained. The structures and related activities of all compounds have not been reported in the literature. Their structures were characterized by 1H NMR, 13CNMR, and HRMS. The in vitro anti-GBM activity and mechanism of action of the target compounds were evaluated in glioblastoma U87 and U251 cells, providing excellent leads and new therapeutic strategies for the subsequent development of anti-GBM chemotherapeutic drugs.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The application adopts the substrate benzimidazole which has good anti-proliferation effect on malignant cells, can play the anti-cancer effect through various ways, and the structure similar to purine can effectively enhance the inhibition on protein and nucleic acid, microtubule denaturation, cell apoptosis, DNA rupture, hydrogen bond, and electrostatic interaction with topoisomerase complex, embedding with DNA, etc. The natural bicyclic terpene borneol has high fat solubility, has certain promoting effect on the permeability of BBB, is widely used as an auxiliary agent of central drugs to improve the drug delivery to the brain. Therefore, the borneol is modified on the benzimidazole nucleus, a series of borneol modified benzimidazole derivatives are designed and synthesized, and the anti-GBM activity is studied. The series of products are novel in structure, high in yield, simple in separation and purification operation, and part of the products such as compound S has shown good biological activity. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The synthesis route of the target compounds A-L of the application is shown in the figure;

[0025] Figure 2 The synthesis route of the target compounds M-U of the application is shown in the figure;

[0026] Figure 3 The specific synthesis route of the target compounds A-L of the application is shown in the figure;

[0027] Figure 4 The specific synthesis route of the target compounds M-U of the application is shown in the figure;

[0028] Figure 5 The nuclear magnetic resonance hydrogen spectrum of the benzimidazole borneol derivative A in example 1 of the application is shown in the figure 1 H-NMR;

[0029] Figure 6 The nuclear magnetic resonance carbon spectrum of the benzimidazole borneol derivative A in example 1 of the application is shown in the figure 13 C-NMR;

[0030] Figure 7 The high resolution mass spectrum HRMS of the benzimidazole borneol derivative A in example 1 of the application is shown in the figure

[0031] Figure 8 The nuclear magnetic resonance hydrogen spectrum of the benzimidazole borneol derivative B in example 2 of the application is shown in the figure 1 H-NMR;

[0032] Figure 9 The nuclear magnetic resonance carbon spectrum of the benzimidazole borneol derivative B in example 2 of the application is shown in the figure 13 C-NMR;

[0033] Figure 10 The high resolution mass spectrum HRMS of the benzimidazole borneol derivative B in example 2 of the application is shown in the figure

[0034] Figure 11 This is the H NMR spectrum of the benzimidazole borneol derivative C of Example 3 of the present invention. 1 H-NMR;

[0035] Figure 12 This is the carbon NMR spectrum of the benzimidazole borneol derivative C of Example 3 of the present invention. 13 C-NMR;

[0036] Figure 13 This is the H NMR spectrum of the benzimidazole borneol derivative D of Example 4 of the present invention. 1 H-NMR;

[0037] Figure 14 This is the carbon NMR spectrum of the benzimidazole borneol derivative D of Example 4 of the present invention. 13 C-NMR;

[0038] Figure 15 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative D of Example 4 of the present invention;

[0039] Figure 16 This is the H NMR spectrum of the benzimidazole borneol derivative E of Example 5 of the present invention 1 H-NMR;

[0040] Figure 17 This is the carbon NMR spectrum of the benzimidazole borneol derivative E of Example 5 of the present invention. 13 C-NMR;

[0041] Figure 18 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative E of Example 5 of the present invention;

[0042] Figure 19 This is the H NMR spectrum of the benzimidazole borneol derivative F of Example 6 of the present invention. 1 H-NMR;

[0043] Figure 20 This is the carbon NMR spectrum of the benzimidazole borneol derivative F of Example 6 of the present invention. 13 C-NMR;

[0044] Figure 21 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative F of Example 6 of the present invention;

[0045] Figure 22 This is the H NMR spectrum of the benzimidazole borneol derivative G of Example 7 of the present invention. 1 H-NMR;

[0046] Figure 23This is the carbon NMR spectrum of the benzimidazole borneol derivative G of Example 7 of the present invention. 13 C-NMR;

[0047] Figure 24 This is the H NMR spectrum of the benzimidazole borneol derivative H of Example 8 of the present invention 1 H-NMR;

[0048] Figure 25 This is the carbon NMR spectrum of the benzimidazole borneol derivative H of Example 8 of the present invention 13 C-NMR;

[0049] Figure 26 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative H of Example 8 of the present invention;

[0050] Figure 27 This is the H NMR spectrum of the benzimidazole borneol derivative I of Example 9 of the present invention 1 H-NMR;

[0051] Figure 28 This is the carbon NMR spectrum of the benzimidazole borneol derivative I of Example 9 of the present invention 13 C-NMR;

[0052] Figure 29 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative I of Example 9 of the present invention;

[0053] Figure 30 This is the H NMR spectrum of the benzimidazole borneol derivative J of Example 10 of the present invention. 1 H-NMR;

[0054] Figure 31 This is the carbon NMR spectrum of the benzimidazole borneol derivative J of Example 10 of the present invention. 13 C-NMR;

[0055] Figure 32 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative J of Example 10 of the present invention;

[0056] Figure 33 This is the nuclear magnetic resonance hydrogen spectrum of the benzimidazole borneol derivative K of Example 11 of the present invention 1 H-NMR;

[0057] Figure 34 This is the carbon NMR spectrum of the benzimidazole borneol derivative K of Example 11 of the present invention. 13 C-NMR;

[0058] Figure 35 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative K of Example 11 of the present invention;

[0059] Figure 36 This is the nuclear magnetic resonance hydrogen spectrum of the benzimidazole borneol derivative L of Example 12 of the present invention 1 H-NMR;

[0060] Figure 37 This is the carbon NMR spectrum of the benzimidazole borneol derivative L of Example 12 of the present invention. 13 C-NMR;

[0061] Figure 38 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative L of Example 12 of the present invention;

[0062] Figure 39 This is the H NMR spectrum of the benzimidazole borneol derivative M of Example 13 of the present invention. 1 H-NMR;

[0063] Figure 40 This is the carbon NMR spectrum of the benzimidazole borneol derivative M of Example 13 of the present invention. 13 C-NMR;

[0064] Figure 41 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative M of Example 13 of the present invention;

[0065] Figure 42 This is the H NMR spectrum of the benzimidazole borneol derivative N of Example 14 of the present invention. 1 H-NMR;

[0066] Figure 43 This is the carbon NMR spectrum of the benzimidazole borneol derivative N of Example 14 of the present invention. 13 C-NMR;

[0067] Figure 44 This is the nuclear magnetic resonance hydrogen spectrum of the benzimidazole borneol derivative O of Example 15 of the present invention 1 H-NMR;

[0068] Figure 45 This is the carbon NMR spectrum of the benzimidazole borneol derivative O of Example 15 of the present invention 13 C-NMR;

[0069] Figure 46 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative O of Example 15 of the present invention;

[0070] Figure 47 This is the H NMR spectrum of the benzimidazole borneol derivative P of Example 16 of the present invention. 1 H-NMR;

[0071] Figure 48H-NMR of the benzimidazole borneol derivative P of Example 16 of the present invention 13 C-NMR;

[0072] Figure 49 HRMS of the benzimidazole borneol derivative P of Example 16 of the present invention

[0073] Figure 50 H-NMR of the benzimidazole borneol derivative Q of Example 17 of the present invention 1 H-NMR;

[0074] Figure 51 C-NMR of the benzimidazole borneol derivative Q of Example 17 of the present invention 13 C-NMR;

[0075] Figure 52 HRMS of the benzimidazole borneol derivative Q of Example 17 of the present invention

[0076] Figure 53 H-NMR of the benzimidazole borneol derivative R of Example 18 of the present invention 1 H-NMR;

[0077] Figure 54 C-NMR of the benzimidazole borneol derivative R of Example 18 of the present invention 13 C-NMR;

[0078] Figure 55 H-NMR of the benzimidazole borneol derivative S of Example 19 of the present invention 1 H-NMR;

[0079] Figure 56 HRMS of the benzimidazole borneol derivative S of Example 19 of the present invention

[0080] Figure 57 H-NMR of the benzimidazole borneol derivative T of Example 20 of the present invention 1 H-NMR;

[0081] Figure 58 C-NMR of the benzimidazole borneol derivative T of Example 20 of the present invention 13 C-NMR;

[0082] Figure 59 HRMS of the benzimidazole borneol derivative T of Example 20 of the present invention

[0083] Figure 60 H-NMR of the benzimidazole borneol derivative U of Example 21 of the present invention 1 H-NMR;

[0084] Figure 61 This is the carbon NMR spectrum of the benzimidazole borneol derivative U of Example 21 of the present invention 13 C-NMR;

[0085] Figure 62 This is the high resolution mass spectrometry HRMS of the benzimidazole borneol derivative U of Example 21 of the present invention;

[0086] Figure 63 Imaging of 3D cell tumor spheroids treated with compound S of the present invention under A) inverted microscope and B) confocal microscope. DETAILED DESCRIPTION

[0087] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings so that those skilled in the art can better understand the advantages and features of the present invention and thus more clearly define the scope of protection of the present invention. The embodiments described in the present invention are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative work shall fall within the scope of protection of the present invention.

[0088] Unless otherwise stated, all reagents and solvents were purchased commercially and used without further purification. Distilled water was used in all experiments. Thin layer chromatography (TLC, UV 254 nm) on silica gel plates (0.25 mm, China Co., Ltd.) was used to verify subsequent responses. Melting points were determined using an Optimelt-MPA100 melting point instrument. Data were recorded on a Bruker AV-500 MHz spectrometer. 1 H NMR (400 MHz) and 13 C NMR spectra (100 MHz) were recorded using solutions and tetramethylsilane as an internal standard. Chemical shifts are expressed in ppm, and coupling constants (J) are expressed in Hertz (Hz). High-resolution mass spectrometric data were acquired on a QSTAR Elite high-resolution liquid tandem mass spectrometer.

[0089] A method for synthesizing benzimidazole-borneol derivatives. According to the synthesis route, the benzimidazole-borneol derivatives are synthesized in three steps, including the following steps:

[0090] Chloroacetate 3 was synthesized in 70% yield via the condensation reaction between borneol and chloroacetyl chloride, promoted by triethylamine.

[0091] Subsequently, the imidazole reacted with substituted phenylboronic acid via Suzuki coupling to afford the benzimidazole derivative 6a-l;

[0092] Chloroacetate 3 and benzimidazole derivative 6a-1 were condensed to give the target product AL.

[0093] Chloroacetate 3 and chalcone derivatives 10a-i were condensed to give the target product MU.

[0094] The synthesis of all new compounds is described in detail in the Examples section. 1 H NMR and 13 Each compound was thoroughly characterized by C NMR spectroscopy and HRMS.

[0095] Example: Benzimidazole-borneol derivatives

[0096] 1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl-2-chloroacetate

[0097] (+)-Borneolum 1 (5 g, 1 mmol) was dissolved in 100 mL of anhydrous DCM, followed by the addition of DMAP (795 mg, 0.2 mmol) and TEA (9 mL, 2 mmol). Chloroacetyl chloride 2 (7.8 mL, 3 mmol) was slowly added under an ice bath. After the addition was complete, the mixture was returned to room temperature and the reaction continued for 12 h. After completion of the reaction, 50 mL of water was added to the reaction flask, and the mixture was extracted with DCM (50 mL x 3). The organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated by column chromatography (V(EA):V(PE) = 1:100) to afford compound 3 as a pale yellow oil in a 70% yield.

[0098] Synthesis of intermediate benzimidazole 6a-1

[0099] Pd(PPh3)4 (40 mg, 0.01 mmol) was dissolved in a mixture of 6 mL of toluene, 2 mL of ethanol, and 2 mL of water. K2CO3 (905 mg, 2 mmol) was added, followed by compound 4 (500 mg, 1 mmol) and various substituted phenylboronic acids 5a-1 (600 mg, 1.2 mmol). The mixture was reacted at 120°C for 12 h. After completion of the reaction, 50 mL of water was added to the reaction flask, and the mixture was extracted with EA (50 mL x 3). The organic phase was washed with saturated NaCl solution (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and separated by column chromatography (V(EA):V(PE) = 1:8) to afford intermediate 6a-1 in 88%-92% yields.

[0100] Example 1: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(4-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)acetate (A)

[0101] Intermediate 6a (224.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound A (313.9 mg) as a white solid in a 75% yield. 1 H NMR (400MHz, DMSO-d6) δ7.74-7.65(m,3H),7.64-7.53(m,1H),7.32-7.21(m,2H),7.11(d,J=8.8Hz,2H),5.25(s,2H),4.79-4.71(m,1H),3.84(s, 3H),2.24-2.12(m,1H),1.65-1.53(m,2H),1.26(d,J=11.6Hz,2H),1.09- 1.01(m,1H),0.78(d,J=10.3Hz,6H),0.72(d,J=3.4Hz,1H),0.58(s,3H); 13 C NMR(101MHz,DMSO-d6)δ168.7,160.9,153.8,142.9,136.9,130.9,122.9,122.6,122.5,119.4,11 4.7,110.9,80.8,55.8,48.8,47.8,46.8,44.5,36.4,27.8,26.7,19.8,19.0,13.5; HRMS(ESI)m / z calcd for C 26 H 31 N2O3 419.2334; found,419.2234[M+H] + .

[0102] Example 2: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(3-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)acetate (B)

[0103] Intermediate 6b (224.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound B (322.8 mg) as a white solid in a 77% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.69 (m, 1H), 7.69 - 7.61 (m, 1H), 7.51 - 7.44 (m, 1H), 7.36 - 7.21 (m, 4H), 7.18 - 7.09 (m, 1H), 5.29 (s, 2H), 4.80 - 4.70 (m, 1H), 3.82 (s, 3H), 2.26 - 2.10 (m, 1H), 1.66 - 1.50 (m, 2H), 1.40 - 1.32 (m, 1H), 1.12 - 1.01 (m, 1H), 0.98 - 0.80 (m, 2H), 0.78 (d, J = 10.0 Hz, 6H), 0.59 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 168.7, 159.8, 153.5, 142.8, 136.9, 131.6, 130.5, 123.2, 122.8, 121.5, 119.7, 116.2, 114.7, 111.1, 80.9, 55.7, 48.8, 47.9, 46.8, 44.5, 36.4, 27.8, 26.7, 19.9, 19.0, 13.5; HRMS (ESI) m / z calcd for C 26 H 31 N2O3 419.2334; found, 419.2239 [M+H] + .

[0104] Example 3: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-(3,4- dimethoxyphenyl)-1H-benzo[d]imidazol-1-yl)acetate (C)

[0105] Intermediate 6c (254.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, K2CO3 (900 mg, 2 mmol) was added, and the reaction was carried out at 60 °C for 8 h. After the reaction was completed, it was concentrated under reduced pressure, and column chromatography was used for separation [V(PE):V(DCM) = 1:1], to obtain compound C (336.5 mg) as a white solid, with a yield of 75%. 1H NMR(400MHz,DMSO-d6)δ7.76-7.66(m,1H),7.65-7.56(m,1H),7.31-7.23(m,4 H),7.12(d,J=8.4Hz,1H),5.28(s,2H),4.80-4.71(m,1H),3.83(d,J=7.6Hz,6H ),2.28-2.08(m,1H),1.62-1.52(m,2H),1.40-1.30(m,1H),1.09-1.01(m,1H), 0.93-0.87(m,1H),0.78(d,J=11.0Hz,6H),0.72(d,J=3.4Hz,1H),0.59(s,3H); 13 C NMR (101MHz, DMSO-d6) δ168.8,153.8,150.6,149.2,142.9,136.9,122.9,122.7,122.6,122.0,119. 4,112.8,112.1,110.9,80.8,56.1,56.0,48.8,47.8,46.9,44.5,36.4,27.8,26.7,19.8,19.0,13.5.

[0106] Example 4: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(m-tolyl)-1H-benzo[d]imidazol-1-yl)acetate (D)

[0107] Intermediate 6d (208.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound D (314.5 mg) as a white solid in a 78% yield. 1 H NMR(400MHz,DMSO-d6)δ7.74-7.68(m,1H),7.66-7.60(m,1H),7.58-7.49(m,2H) ,7.48-7.42(m,1H),7.37(d,J=7.6Hz,1H),7.33-7.22(m,2H),5.27(s,2H),4.82 -4.73(m,1H),2.40(s,3H),2.24-2.14(m,1H),1.64-1.54(m,2H),1.41-1.32(m, 1H),1.10-1.01(m,1H),0.96-0.83(m,2H),0.78(d,J=10.2Hz,6H),0.58(s,3H);13 C NMR(101MHz,DMSO-d6)δ168.7,153.9,142.9,138.6,136.9,131.0,130.3,130.0,129.2,126.5,123.1,12 2.7,119.6,111.1,80.8,48.8,47.9,46.8,44.5,36.4,27.8,26.8,21.5,19.9,19.0,13.5; HRMS(ESI)m / z calcd for C 26 H 31 N2O2 403.2385; found,403.2394[M+H] + .

[0108] Example 5: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(o-tolyl)-1H-benzo[d]imidazol-1-yl)acetate (E)

[0109] Intermediate 6e (208.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound E (286.3 mg) as a white solid in a 71% yield. 1 H NMR(400MHz,DMSO-d6)δ7.72(d,J=7.4Hz,1H),7.65-7.59(m,1H),7.49-7.4 0(m,2H),7.35(d,J=4.1Hz,2H),7.33-7.24(m,2H),4.99(s,2H),4.77-4.70( m,1H),2.22(s,3H),2.21-2.11(m,1H),1.62-1.53(m,2H),1.37-1.29(m,1H) ,1.08-1.00(m,1H),0.97-0.81(m,2H),0.78(d,J=10.8Hz,6H),0.60(s,3H); 13CNMR(101MHz,DMSO-d6)δ166.9,166.9,151.2,139.5,139.4,133.9,132.0,132.0,131.9,130.9,127.8,127.5,127.4,120.2,120.2,114.6,114 .1,82.1,82.0,49.1,49.0,48.0,48.0,47.5,44.5,44.4,36.2,36.2,33.4,27.8,26.8,26.8,19.9,19.3,19.0,13.7,13.6; HRMS(ESI)m / zcalcd for C 26 H 31 N2O2 403.2385; found,403.2394[M+H] + .

[0110] Example 6: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-(3,4-dimethylphenyl)-1H-benzo[d]imidazol-1-yl)acetate (F)

[0111] Intermediate 6f (212.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound F (304.6 mg) as a white solid in a 73% yield. 1 H NMR(400MHz,DMSO-d6)δ7.72-7.67(m,1H),7.64-7.58(m,1H),7.51(s,1H) ),7.46-7.41(m,1H),7.33-7.23(m,3H),5.25(s,2H),4.79-4.74(m,1H), 2.30(s,6H),2.23-2.15(m,1H),1.63-1.55(m,2H),1.41-1.33(m,1H),1. 10-1.01(m,1H),0.97-0.82(m,2H),0.78(d,J=10.5Hz,6H),0.58(s,3H); 13C NMR (101MHz, DMSO-d6) δ168.8,154.0,142.9,138.9,137.3,136.9,130.4,130.3,127.8,126.7,123.0,122. 6,119.5,111.0,80.8,48.8,47.9,46.8,44.5,36.4,27.8,26.7,19.9,19.9,19.8,19.0,13.5; HRMS(ESI)m / z calcd for C 27 H 33 N2O2 417.2542; found,417.2549[M+H] + .

[0112] Example 7: (1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(2-fluoro-4-methoxyphenyl)-1H-benzo[d]imidazol-1-yl)acetate (G)

[0113] Intermediate 6g (242.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound G (313.9 mg) as a white solid in a 75% yield. 1 H NMR(400MHz,DMSO-d6)δ7.75-7.67(m,1H),7.62-7.58(m,1H),7.57-7.49(m, 1H),7.32-7.23(m,2H),7.09-7.04(m,1H),7.01-6.96(m,1H),5.14-4.92(m, 2H),4.58-4.43(m,1H),3.86(s,3H),1.70-1.62(m,1H),1.62-1.58(m,1H),1 .58-1.37(m,3H),1.07-0.95(m,2H),0.67(s,3H),0.52(s,3H),0.45(s,3H); 13 C NMR(101MHz,DMSO-d6)δ167.6,162.9,162.8,159.6,149.0,143.1,136.3,133.3,123.2,122.6,119.5 ,111.4,110.1,110.0,102.6,102.3,82.1,56.5,48.6,46.8,46.2,44.7,38.4,26.9,20.2,19.5,11.5.

[0114] Example 8: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-(4-fluorophenyl)-1H-benzo[d]imidazol-1-yl)acetate (H)

[0115] Intermediate 6h (208.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound H (313.5 mg) as a white solid in a 77% yield. 1 H NMR(400MHz,DMSO-d6)δ7.85-7.76(m,2H),7.75-7.68(m,1H),7.67-7.60(m ,1H),7.47-7.38(m,2H),7.34-7.24(m,2H),5.30(s,2H),4.79-4.69(m,1H) ,2.23-2.12(m,1H),1.65-1.54(m,2H),1.40-1.31(m,1H),1.10-1.01(m,1H ),0.92-0.87(m,1H),0.77(d,J=8.2Hz,6H),0.74-0.69(m,1H),0.57(s,3H); 13 CNMR(101MHz,DMSO-d6)δ168.6,164.7,162.2,152.9,142.8,136.9,131.9,131.8,126.9,126.9,123.3,122.8 ,119.6,116.5,116.3,111.1,80.9,48.8,47.8,46.7,44.5,36.4,27.8,26.7,19.8,19.0,13.5; HRMS(ESI)m / z calcd for C 25 H 28 FN2O2 407.2135; found,407.2138[M+H] + .

[0116] Example 9: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(4-fluoro-2-methylphenyl)-1H-benzo[d]imidazol-1-yl)acetate (I)

[0117] Intermediate 6i (227.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound I (303.3 mg) as a white solid in a 72% yield. 1 H NMR(400MHz,DMSO-d6)δ7.75-7.68(m,1H),7.66-7.58(m,1H),7.45-7.39(m, 1H),7.34-7.24(m,3H),7.24-7.18(m,1H),5.02(d,J=2.4Hz,2H),4.77-4.67 (m,1H),2.22(s,3H),1.63-1.54(m,2H),1.41-1.32(m,1H),1.10-1.02(m,1H ),0.99-0.82(m,2H),0.78(d,J=9.3Hz,6H),0.76-0.72(m,1H),0.60(s,3H); 13 CNMR(101MHz,DMSO-d6)δ168.6,164.4,162.0,152.4,142.8,141.9,141.8,135.8,132.4,132.3,126.3,126.2,123.1,122.6,1 19.6,117.9,117.7,113.4,113.1,111.1,80.9,48.8,47.9,46.0,44.5,36.3,27.8,26.7,19.9,19.9,19.0,13.6; HRMS(ESI)m / z calcd forC 26 H 30 FN2O2 421.2291; found,421.2303[M+H] + .

[0118] Example 10: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-(4-methoxy-2-methylphenyl)-1H-benzo[d]imidazol-1-yl)acetate (J)

[0119] Intermediate 6j (238.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound J (320.6 mg) as a white solid in a 74% yield. 1H NMR(400MHz,DMSO-d6)δ7.73-7.66(m,1H),7.62-7.54(m,1H),7.31-7.21(m ,3H),6.98(d,J=2.6Hz,1H),6.94-6.87(m,1H),4.98(s,2H),4.76-4.70(m,1 H),3.81(s,3H),2.20(s,3H),1.62-1.52(m,J=3.8Hz,2H),1.47-1.12(m,2H) ,1.08-0.99(m,1H),0.96-0.84(m,2H),0.78(d,J=10.7Hz,6H),0.60(s,3H); 13 C NMR (101MHz, DMSO-d6) δ168.6,160.6,153.4,142.9,140.2,135.8,131.5,122.8,122.4,121.9,119.5,116. 4,111.7,111.0,80.9,55.7,48.8,47.9,46.1,44.5,36.3,27.8,26.7,20.2,19.9,19.0,13.6; HRMS(ESI)m / z calcd for C 27 H 33 N2O3 433.2491; found,433.2497[M+H] + .

[0120] Example 11: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-phenyl-1H-benzo[d]imidazol-1-yl)acetate (K)

[0121] Intermediate 6k (194.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound K (272.4 mg) as a white solid in a 70% yield. 1H NMR (400MHz, DMSO-d6) δ7.78-7.70(m,3H),7.67-7.62(m,1H),7.61-7.53(m,3H),7.34-7.24(m,2H),5.29(s,2H),4.79-4.71(m,1H),2.24-2. 12(m,1H),1.64-1.53(m,2H),1.41-1.32(m,1H),1.10-1.00(m,1H),0. 94-0.88(m,1H),0.77(d,J=9.3Hz,6H),0.75-0.70(m,1H),0.58(s,3H); 13 C NMR(101MHz,DMSO-d6)δ168.7,153.8,142.9,136.9,130.4,130.3,129.4,129.3,123.2,122.8 ,119.7,111.1,80.8,48.8,47.9,46.8,44.5,36.4,27.8,26.7,19.9,19.0,13.5; HRMS(ESI)m / z calcd forC 25 H 29 N2O2 389.2229; found,389.2229[M+H] + .

[0122] Example 12: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl-2-(2-(p-tolyl)-1H-benzo[d]imidazol-1-yl)acetate (L)

[0123] Intermediate 61 (208.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound L (322.6 mg) as a white solid in 80% yield. 1H NMR (400MHz, DMSO-d6) δ7.66-7.61(m,1H),7.60-7.48(m,3H),7.30(d,J=7.9Hz,2H),7.26-7.16(m,2H),5.19(s,2H),4.73-4.63(m,1H),2.3 3(s,3H),2.16-2.06(m,1H),1.57-1.46(m,2H),1.33-1.25(m,1H),1.0 3-0.94(m,1H),0.89-0.75(m,2H),0.71(d,J=9.4Hz,6H),0.51(s,3H); 13 C NMR(101MHz,DMSO-d6)δ168.7,153.9,142.9,140.1,136.9,129.9,129.3,127.5,123.1,122.7,11 9.5,111.0,80.8,48.8,47.9,46.8,44.5,36.4,27.8,26.7,21.4,19.9,19.0,13.5; HRMS(ESI)m / z calcd forC 26 H 31 N2O2 403.2385; found,403.2384[M+H] + .

[0124] Synthesis of Benzimidazole Chalcone Borneol Derivative MU

[0125] Synthesis of intermediate 10a-i

[0126] Compound 8 (500 mg, 1 mmol) and various substituted acetophenones 9a-i (500 mg, 1.1 mmol) were dissolved in 10 mL of methanol. NaOH (273 mg, 2 mmol) was added and allowed to react at room temperature for 0.5 h. After completion of the reaction, the reaction solution was added dropwise to 20 mL of ice water to precipitate a yellow solid. The filter cake was then dried in a vacuum dryer to afford yellow solids 10a-i in 72%-77% yields.

[0127] Example 13: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-oxo-3-phenylprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (M)

[0128] Intermediate 10a (248.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound M (248.2 mg) as a yellow solid in a 56% yield. 1 H NMR(400MHz, CDCl3)δ8.34(d,J=14.9Hz,1H),8.13-8.02(m,2H),7.81-7.75(m,1H),7.71 (d,J=14.9Hz,1H),7.58-7.53(m,1H),7.48-7.43(m,2H),7.31-7.24(m,3H),5.01(s,2H) ,4.87-4.82(m,1H),2.31-2.17(m,1H),1.58-1.50(m,2H),1.38-1.30(m,1H),1.15-0.97 (m,1H),0.96-0.87(m,1H),0.75(s,3H),0.74(d,J=1.0Hz,1H),0.72(s,3H),0.60(s,3H); 13 C NMR (101MHz, CDCl3) δ188.9,167.0,148.7,143.1,137.3,135.9,133.5,128.8,128.8,128.5,127.4,124 .6,123.9,120.5,109.4,82.5,48.8,47.8,45.3,44.7,36.6,27.8,26.8,19.6,18.7,13.3; HRMS(ESI)m / z calcd forC 28 H 32 N2O3 443.2334; found,443.2329[M+H] + .

[0129] Example 14: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-oxo-3-(o-tolyl)prop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (N)

[0130] Intermediate 10b (262.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound N (256.0 mg) as a yellow solid in a 56% yield. 1 H NMR(400MHz,DMSO-d6)δ7.84(d,J=15.3Hz,1H),7.76-7.71(m,2H),7.69-7.66(m,1H),7 .62(d,J=15.3Hz,1H),7.54-7.45(m,1H),7.42-7.25(m,4H),5.56(s,2H),4.86-4.78(m, 1H),2.44(s,3H),2.28-2.19(m,1H),1.65-1.55(m,2H),1.49-1.41(m,1H),1.13-1.05( m,1H),0.99-0.92(m,1H),0.85(d,J=2.1Hz,1H),0.81(s,3H),0.78(s,3H),0.63(s,3H); 13 C NMR(101MHz,DMSO-d6)δ193.8,168.6,149.2,143.0,138.2,137.6,136.7,132.1,132.0,131.7,129.5,129.2 ,126.5,124.4,123.7,120.1,111.2,80.9,53.1,48.9,47.9,44.5,36.5,27.8,26.8,20.7,19.9,19.0,13.6.

[0131] Example 15: (1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (O)

[0132] Intermediate 10c (278.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound O (260.3 mg) as a yellow solid in a 55% yield. 1H NMR(400MHz, DMSO-d6)δ8.29(d,J=15.0Hz,1H),8.20-8.10(m,2H),7.83-7.73(m,2H) ,7.72-7.64(m,1H),7.38-7.28(m,2H),7.18-7.08(m,2H),5.60(s,2H),4.87-4.78(m ,1H),3.89(s,3H),2.29-2.18(m,1H),1.65-1.54(m,2H),1.51-1.43(m,1H),1.14-1. 04(m,1H),1.00-0.92(m,1H),0.88-0.84(m,1H),0.78(d,J=12.4Hz,6H),0.64(s,3H); 13 C NMR(101MHz,DMSO-d6)δ187.2,168.7,164.1,149.5,143.0,136.6,131.5,130.3,128.6,128.3,124.3,123.6,1 20.0,114.8,111.2,80.9,56.1,48.9,47.9,45.2,44.5,36.5,27.8,26.8,19.9,19.0,13.6; HRMS(ESI)m / zcalcd for C 29 H 33 N2O4473.2440; found,473.2446[M+H] + .

[0133] Example 16: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (P)

[0134] Intermediate 10d (266.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound P (267.5 mg) as a yellow solid in a 58% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 14.9 Hz, 1H), 8.26 - 8.19 (m, 2H), 7.83 (d, J = 15.0 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.45 - 7.29 (m, 4H), 5.61 (s, 2H), 4.86 - 4.80 (m, 1H), 2.29 - 2.19 (m, 1H), 1.64 - 1.55 (m, 2H), 1.53 - 1.45 (m, 1H), 1.14 - 1.05 (m, 1H), 1.00 - 0.93 (m, 1H), 0.84 (d, J = 2.8 Hz, 1H), 0.79 (d, J = 12.2 Hz, 6H), 0.64 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ 187.7, 168.7, 167.0, 164.5, 149.3, 143.0, 136.7, 134.2, 134.1, 132.2, 132.1, 129.5, 128.0, 124.4, 123.7, 120.1, 116.7, 116.5, 111.3, 80.9, 48.9, 47.9, 45.2, 44.5, 36.5, 27.8, 26.8, 19.9, 19.0, 13.6; HRMS (ESI) m / z calcd for C 28 H 30 FN2O3461.2240; found, 461.2243 [M+H] + .

[0135] Example 17: (1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-oxo-3-(m-tolyl)prop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (Q)

[0136] Intermediate 10e (262.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, K2CO3 (900 mg, 2 mmol) was added, and the reaction was carried out at 60 °C for 8 h. After the reaction was completed, it was concentrated under reduced pressure, and column chromatography was used for separation [V(PE):V(DCM) = 1:1] to obtain compound M (260.6 mg) as a yellow solid with a yield of 57%. 1H NMR(400MHz, DMSO-d6)δ8.28(d,J=15.1Hz,1H),8.01-7.89(m,2H),7.83(d,J=15.0Hz, 1H),7.78-7.66(m,2H),7.56-7.46(m,2H),7.38-7.28(m,2H),5.61(s,2H),4.87-4.77 (m,1H),2.44(s,3H),2.28-2.19(m,1H),1.64-1.54(m,2H),1.52-1.43(m,1H),1.14-1 .04(m,1H),1.00-0.93(m,1H),0.88-0.84(m,1H),0.78(d,J=12.4Hz,6H),0.64(s,3H); 13 C NMR(101MHz,DMSO-d6)δ189.1,168.7,149.3,143.0,139.0,137.5,136.7,134.8,129.4,129.4,129.2,128.3,126.2 ,124.4,123.7,120.1,111.2,80.9,48.9,47.9,45.2,44.5,36.5,27.8,26.8,21.3,19.9,19.0,13.6; HRMS(ESI)m / z calcd for C 29 H 33 N2O3 457.2491; found,457.2496[M+H] + .

[0137] Example 18: (1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-(3-methoxyphenyl)-3-oxoprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (R)

[0138] Intermediate 10f (278.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound R (283.9 mg) as a yellow solid in a 60% yield. 1H NMR(400MHz,DMSO-d6)δ8.25(d,J=15.0Hz,1H),7.82(d,J=15.1Hz,1H),7.78-7.72(m,2H), 7.71-7.65(m,1H),7.57-7.50(m,2H),7.37-7.31(m,2H),7.31-7.28(m,1H),5.61(s,2H),4 .86-4.79(m,1H),3.87(s,3H),2.27-2.19(m,1H),1.63-1.55(m,2H),1.51-1.43(m,1H),1. 13-1.05(m,1H),1.00-0.93(m,1H),0.86-0.84(m,1H),0.79(d,J=12.4Hz,6H),0.64(s,3H); 13 C NMR(101MHz,DMSO-d6)δ188.9,168.7,160.1,149.3,143.0,138.9,136.7,130.7,129.4,128.3,124.4,123.7 ,121.7,120.4,120.1,113.0,111.2,80.9,55.9,48.9,47.9,45.2,44.5,36.5,27.8,26.8,19.9,19.0,13.6.

[0139] Example 19: (1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-(2-fluoro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (S)

[0140] Intermediate 10g (296.3mg, 1mmol) and intermediate 3 (1g, 3mmol) were dissolved in 6mL of acetone, and KCO (900mg, 2mmol) was added. The mixture was reacted at 60°C for 8h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to obtain compound S (319.3mg) as a yellow solid in a 65% yield. 1H NMR(400MHz,DMSO-d6)δ8.06-7.76(m,2H),7.73-7.57(m,3H),7.31-7.19(m,2H),7. 06-6.72(m,2H),5.50(d,J=9.6Hz,2H),4.83-4.64(m,1H),3.84(d,J=16.3Hz,3H),2 .21-2.12(m,1H),1.57-1.46(m,2H),1.42-1.35(m,1H),1.06-0.98(m,1H),0.93-0. 86(m,1H),0.77(d,J=3.1Hz,1H),0.72(d,J=13.2Hz,6H),0.57(s,3H); HRMS(ESI)m / z calcd for C 29 H 32 FN2O4 491.2346; found,491.2347[M+H] + .

[0141] Example 20: (1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-(3,4-dimethoxyphenyl)-3-oxoprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (T)

[0142] Intermediate 10h (308.3 mg, 1 mmol) and Intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, and KCO (900 mg, 2 mmol) was added. The mixture was reacted at 60°C for 8 h. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by column chromatography (V(PE):V(DCM) = 1:1) to afford Compound T (291.9 mg) as a yellow solid in a 58% yield. 1 H NMR(400MHz,DMSO-d6)δ8.23(d,J=14.9Hz,1H),7.83-7.77(m,1H),7.74

[0143] -7.66(m,2H),7.64-7.57(m,1H),7.52(d,J=2.1Hz,1H),7.31-7.21(m,2H),7.11

[0144] -7.02 (m, 1H), 5.52 (s, 2H), 4.80-4.72 (m, 1H), 3.81 (d, J = 4.9 Hz, 6H), 2.21-2.12 (m, 1H), 1.56-1.48 (m, 2H), 1.43-1.36 (m, 1H), 1.06-0.98 (m, 1H), 0.93-0.86 (m, 1H), 0.82-0.77 (m, 1H), 0.72 (d, J = 12.5 Hz, 6H), 0.57 (s, 3H); 13 C NMR (101 MHz, DMSO-de) δ 187.2, 168.7, 154.1, 149.5, 149.4, 143.0, 136.6, 130.4, 128.4, 128.4, 124.3, 124.1, 123.6, 120.0, 111.5, 111.2, 110.9, 80.9, 56.3, 56.0, 48.9, 47.9, 45.2, 44.5, 36.5, 27.8, 26.8, 19.9, 19.0, 13.6; HRMS (ESI) m / z calcd for C 30 H 35 N2O5 503.2546; found, 503.2549 [M+H] + .

[0145] Example 21: (1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-2-(2-((E)-3-(3,4- dimethylphenyl)-3-oxoprop-1-en-1-yl)-1H-benzo[d]imidazol-1-yl)acetate (U)

[0146] Intermediate 10i (276.3 mg, 1 mmol) and intermediate 3 (1 g, 3 mmol) were dissolved in 6 mL of acetone, K2CO3 (900 mg, 2 mmol) was added, and the reaction was carried out at 60 °C for 8 h. After the reaction was completed, it was concentrated under reduced pressure, and column chromatography was performed [V(PE):V(DCM) = 1:1] to separate and obtain compound U (282.8 mg) as a yellow solid in a yield of 60%. 1H NMR(400MHz, DMSO-d6)δ8.21(d,J=15.0Hz,1H),7.86-7.83(m,1H),7.82-7.78(m,1H),7.73(d, J=15.1Hz,1H),7.70-7.66(m,1H),7.63-7.57(m,1H),7.31-7.22(m,3H),5.52(s,2H),4.78-4.7 3(m,1H),2.26(d,J=6.5Hz,6H),2.20-2.10(m,1H),1.55-1.47(m,2H),1.44-1.33(m,1H),1.06 -0.98(m,1H),0.92-0.85(m,1H),0.77(d,J=2.8Hz,1H),0.73(s,3H),0.70(s,3H),0.56(s,3H); 13 CNMR(101MHz,DMSO-d6)δ188.6,168.6,149.4,143.6,143.0,137.7,136.6,135.3,130.6,129.9,128.9,128.4,126.8,1 24.3,123.7,120.0,111.2,80.9,48.9,47.9,45.2,44.5,36.5,27.8,26.8,20.2,19.8,19.8,19.0,13.6; HRMS(ESI)m / z calcd for C 30 H 35 N2O3 471.2647; found,471.2647[M+H] + .

[0147] In order to evaluate the in vitro antitumor activity of the target compound, the present invention used a cell proliferation detection kit (CCK-8) to determine the half-maximal inhibitory concentration (IC) of the target compound on human brain glioblastoma U87 cells and human glioma U251 cells. 50 Compound S has the strongest inhibitory effect on both glioma cells, with IC 50 The values ​​were 0.73±0.41μM and 0.35±0.25μM, respectively, which were stronger than the positive control drug temozolomide (IC 50 The value was 19.59±0.33μM).

[0148] Three-dimensional cell culture technology (also known as 3D cell culture) refers to a technology of culturing a carrier material with different three-dimensional structures and various different types of cells together in vitro, so that the cells can migrate and grow in the three-dimensional space structure of the carrier to form a three-dimensional cell-carrier composite. Studies have shown that in a 3D culture system, a complex aggregated cell population can better reflect the interaction between cells and matrix than a simple 2D cell monolayer, and can provide a microenvironment closer to the in-vivo living conditions for the cells. Therefore, in the experiment, the scaffold-free 3D cell culture technology is used to evaluate the proliferation and killing ability of the compound S on tumor spheres. After the 3D cell tumor spheres constructed by U251 cells are treated with the compound S for 3 days, the prepared Calcein-AM / PI staining solution is added, and the reaction is carried out in the dark for 30 minutes. The growth of the tumor spheres is recorded by a microscope and a confocal every day. Figure 63 As shown in A, with the increase of the treatment time of the compound, the tumor spheres gradually collapse; in addition, with the increase of the concentration of the compound, the tumor spheres also gradually disintegrate. In addition, with the increase of the concentration of the compound S, the red fluorescence in the 3D cell tumor spheres gradually increases, and the number of dead cells obviously increases, which further proves that the compound S has good anti-glioma proliferation activity (as shown in B). Figure 63

[0149] In summary, a series of benzimidazole borneol derivatives are synthesized in the present application, and the half inhibitory concentration IC 50 of the compound S on human brain astrocytoma U87 cells and human glioma U251 cells shows very good biological activity, and the 3D cell culture further confirms the anti-tumor effect. In general, the compound S represents a new type of benzimidazole borneol derivative inhibitor with strong anti-glioma effect.

[0150] The description and practice disclosed in the present application are easy to think and understand for ordinary skilled persons in the technical field, and some improvements and refinements can be made without departing from the principles of the present application. Therefore, the modifications or improvements made without departing from the spirit of the present application should also be regarded as the protection scope of the present application.​

Claims

1. A method for synthesizing a benzimidazole borneol derivative, characterized in that: The steps include: Chloroacetate 3 was synthesized in 70% yield by the condensation reaction of borneol and chloroacetyl chloride under the promotion of triethylamine. Subsequently, the imidazole was reacted with a substituted phenylboronic acid via Suzuki coupling to afford the benzimidazole derivative 6a-l; The target product AL was obtained by condensing chloroacetate 3 and benzimidazole derivative 6a-1.

2. The method for synthesizing a benzimidazole borneol derivative according to claim 1, wherein: The specific steps are as follows: The raw material (+)-borneol 1 was dissolved in anhydrous dichloromethane, and then 4-dimethylaminopyridine DMAP and triethylamine were added. Chloroacetyl chloride 2 was slowly added under ice bath. After the addition, the mixture was returned to room temperature and the reaction was continued for 12 hours to obtain the intermediate borneol ester 3; then Pd(PPh3)4 was dissolved in a mixed solution of toluene, ethanol and water, K2CO3 was added, and then the compound imidazole 4 and differently substituted phenylboronic acids 5a-5l were added, and the mixture was reacted at 120°C for 12 hours to obtain benzimidazole 6a-6l; finally, benzimidazole 6a-6l and borneol derivative 3 were dissolved in acetone, K2CO3 was added, and the mixture was reacted at 60°C for 8 hours to obtain the target compound AL.

3. The method for synthesizing a benzimidazole borneol derivative according to claim 1, wherein: The target product MU was obtained by condensing chloroacetate 3 with chalcone derivatives of benzimidazole 10a-i.

4. The method for synthesizing a benzimidazole borneol derivative according to claim 3, wherein: The specific steps are as follows: The compound imidazole aldehyde 8 and differently substituted acetophenones 9a-9i are dissolved in methanol, and then NaOH is added and reacted at room temperature for 0.5 h to obtain the intermediate imidazole benzene 10a-10i; finally, the compound imidazole benzene 10a-10i and the bornyl ester derivative 3 are dissolved in acetone, K2CO3 is added, and the reaction is carried out at 60°C for 8 h to obtain the target compound MU.

5. Use of a benzimidazole borneol derivative obtained by the synthesis method according to any one of claims 1 to 4 in the preparation of an anti-glioma drug.

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