A benzimidazole derivative and its application

Abstract

The present invention provides a benzimidazole derivative and its application. This compound is a completely new type of compound, having targeted MAO-B inhibitory activity and potential therapeutic effects on diseases with overexpression of MAO-B, including Alzheimer's disease and Parkinson's disease. The compounds in Patent WO2017068090 are predicted by admet.scbdd.com to be unable to penetrate the blood-brain barrier; the compounds provided by the present invention have blood-brain barrier permeability and can act on central nervous system diseases including Alzheimer's disease and Parkinson's disease.

Description

Technical Field

[0001] The present invention provides a benzimidazole derivative, its pharmaceutically acceptable salt, a preparation method thereof, and its use as a drug, especially as a monoamine oxidase B inhibitor, more particularly for use in the preparation of a drug for preventing or treating diseases caused by overexpression of monoamine oxidase B, such as Alzheimer's disease and Parkinson's disease. Background Art

[0002] Monoamine oxidases (MAOs) belong to the family of flavin adenine dinucleotide (FAD)-dependent enzymes and are located on the outer mitochondrial membrane. MAOs can catalyze the oxidation of various exogenous amines and endogenous neurotransmitters to regulate their levels in the peripheral and central nervous systems. There are two subtypes of MAOs, namely monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They have 70% sequence similarity, but differ in substrate specificity, tissue distribution, and inhibitor selectivity. The catalytic mechanism of MAOs is that the deprotonated form of the monoamine substrate binds to the active site of the enzyme, is reduced to the hydroquinone form by 8α-s-cysteine, and the amine is oxidized to the imine. Then, the reduced FAD cofactor can react with O2 to produce the oxidized form of FAD and hydrogen peroxide, and the latter further produces highly toxic hydroxyl radicals, leading to neuronal damage and death.

[0003] With the increase of age, the expression level of MAO-B in nerve tissues, especially in glial cells, increases by 4 times, resulting in an increase in dopamine metabolism level and an increase in toxic by-products. Studies have shown that overexpression of MAO-B plays an important role in the pathology of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. MAO-B inhibitors can inhibit the catalytic activity of the enzyme and reduce the metabolism of monoamine neurotransmitters. Therefore, MAO-B inhibitors are considered as therapeutic drugs for diseases related to MAO-B overexpression. In addition, MAO-B inhibitors can also reduce the production of toxic by-products such as hydrogen peroxide, toxic aldehydes, and hydroxyl radicals by blocking the monoamine oxidation process, thereby preventing damage to neurons. Therefore, MAO-B inhibitors are also considered as potential neuroprotective agents. Summary of the Invention

[0004] To solve the above problems, the present invention designed and synthesized a benzimidazole derivative with potential MAO-B inhibitory activity based on computer-aided drug design, druggability prediction, blood-brain barrier permeability experiments, etc., provided a preparation method of the benzimidazole derivative and its pharmaceutically acceptable salt, and prevented or treated diseases related to MAO-B overexpression, including Alzheimer's disease and Parkinson's disease, by inhibiting MAO-B activity.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] In a first aspect, the present invention provides a benzimidazole derivative represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] In formula (I):

[0009] R 1 and R 2 are each independently H, halogen, a C1-C5 straight or branched alkyl, or a C1-C5 straight or branched alkoxy group;

[0010] m is 0, 1 or 2; when m is 0, the carbonyl group is directly connected to the C on the imidazole.

[0011] In formula (II):

[0012] R 3 and R 4 are each independently H, halogen, a C1-C5 haloalkyl, a C1-C5 straight or branched alkyl, or a C1-C5 straight or branched alkoxy group;

[0013] n is 0, 1 or 2. When n is 0, the carbonyl group is directly connected to the C on the imidazole.

[0014] Preferably, in formula (I), R 1 and R 2 are each independently H, F, Cl, CH3 or OCH3; m is 1.

[0015] Preferably, in formula (II), R 3 and R 4 are each independently H, F, Cl, CF3, CH3 or OCH3; n is 1.

[0016] Specifically, the benzimidazole derivative represented by formula (I) or formula (II) is one of the following compounds:

[0017]

[0018] In a second aspect, the present invention provides the use of the benzimidazole derivative represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing diseases caused by overexpression of MAO-B.

[0019] Furthermore, the diseases caused by overexpression of MAO-B are Parkinson's disease or Alzheimer's disease.

[0020] Preferably, the benzimidazole derivative represented by formula (I) or formula (II) is the compound represented by formula b2, b3, b5, b6, b8 or b12, and particularly preferably the compound represented by b3.

[0021] In a third aspect, the present invention also provides a method for preparing the benzimidazole derivative represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0022] I. A method for preparing the benzimidazole derivative represented by formula (I), the method comprising the following steps:

[0023] (1) Dissolve the compound represented by formula 2 in organic solvent A, successively add basic substance A and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), stir evenly at room temperature, then add the aniline compound represented by formula 9, and stir at room temperature for 3 - 18 h (8 h in one embodiment of the present invention). The obtained reaction solution A is subjected to post-treatment A to obtain the compound represented by formula 3; the molar ratio of the compound represented by formula 2, basic substance A, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) to the aniline compound represented by formula 9 is 1:1 - 3:1 - 1.5:0.5 - 1.5 (preferably 1:2:1.1:1); the basic substance A is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, and triethylamine (preferably triethylamine);

[0024]

[0025] (2) The compound represented by formula 3 in step (1) reacts in concentrated hydrochloric acid at 40 °C for 35 - 50 min. The obtained reaction solution B is subjected to post-treatment B to obtain the benzimidazole derivative represented by formula (I);

[0026]

[0027] Furthermore, in step (1), the organic solvent A is one or a mixture of two or more of acetonitrile, N,N-dimethylformamide (DMF), methanol, ethanol, acetonitrile, and dichloromethane (DCM), preferably N,N-dimethylformamide (DMF).

[0028] Furthermore, in step (1), the volume of the organic solvent A is 1 - 2 mL / mmol based on the amount of substance of the compound represented by formula 2.

[0029] Furthermore, in step (1), the post-treatment A is: add saturated brine, extract with dichloromethane (DCM), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, perform column chromatography separation using a mixed solution of dichloromethane and methanol with a volume ratio of 30:1 as the eluent, collect the eluate containing the target intermediate, concentrate, and dry to obtain the compound represented by formula 3.

[0030] Further, in step (2), the volume of the concentrated hydrochloric acid is 2 - 4 mL / mmol based on the amount of substance of the compound shown in Formula 3.

[0031] Further, in step (2), the post-treatment B is as follows: adjusting the pH of the reaction solution B to neutral with saturated sodium bicarbonate solution, precipitating a solid, performing suction filtration, subjecting the obtained filter cake to column chromatography separation using a mixed solution of dichloromethane and methanol with a volume ratio of 20:1 as the eluent, collecting the eluent containing the target compound, concentrating, and drying to obtain the benzimidazole derivative shown in Formula (I).

[0032] II. A preparation method of the benzimidazole derivative shown in Formula (II), the method comprising the following steps:

[0033] S1: Dissolve the compound shown in Formula 5 in solvent D, add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and base D, stir at room temperature for 5 min, and then add cyanoacetic acid; stir at room temperature for 5 - 10 h, and subject the obtained reaction solution D to post-treatment D to obtain the compound shown in Formula 6; the molar ratio of the compound shown in Formula 5, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), base D, and cyanoacetic acid is 1:1 - 2:1.5 - 2.5:1 - 1.5 (preferably 1:1.1:2:1.1);

[0034]

[0035] S2: Dissolve the compound shown in Formula 6 obtained in step S1 in a mixed solvent E, sequentially add Zn powder and NH4Cl, stir and react at 50 °C for 10 min, and subject the obtained reaction solution E to post-treatment E to obtain the compound shown in Formula 7; the molar ratio of the compound shown in Formula 6, Zn powder, and NH4Cl is 1:5 - 10:5 - 10 (preferably 1:8:8);

[0036]

[0037] S3: Dissolve the compound shown in Formula 7 obtained in step S2 in acetic acid, reflux and react for 2 h, and subject the obtained reaction solution G to post-treatment G to obtain the compound shown in Formula 8;

[0038]

[0039] S4: Dissolve the compound shown in Formula 8 described in Step S3 in Solvent Q, sequentially add hydrogen peroxide with a mass fraction of 30% and Basic Substance Q, stir at 25 °C for 3 - 8 h, and subject the obtained Reaction Solution Q to Post-treatment Q to obtain the benzimidazole derivative shown in Formula (II); the molar ratio of the compound shown in Formula 8, hydrogen peroxide in the hydrogen peroxide, and Basic Substance Q is 1:5 - 12:0.2 - 0.5 (preferably 1:8:0.2);

[0040]

[0041] R in Formulas 1 - 9 1 -R 4 has the same range as described above.

[0042] Furthermore, in Step S1, the Solvent D is one or a mixture of two or more of water, toluene, acetonitrile, dichloromethane (DCM), methanol, ethanol, and N,N-dimethylformamide (DMF), preferably dichloromethane (DCM).

[0043] Furthermore, in Step S1, the volume of the Solvent D is 1 - 3 mL / mmol based on the amount of substance of the compound shown in Formula 5.

[0044] Furthermore, in Step S1, the Basic Substance D is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, N,N-diisopropylethylamine (DIPEA), and triethylamine, preferably N,N-diisopropylethylamine (DIPEA).

[0045] Furthermore, in Step S1, the Post-treatment D is: distill off part of the solvent from the Reaction Solution D under reduced pressure, perform suction filtration, wash the obtained Filter Cake A with methanol, slurry the obtained Filter Cake B with methanol, perform suction filtration, and dry the obtained Filter Cake C to obtain the compound shown in Formula 6.

[0046] Furthermore, in Step S2, the Mixed Solvent E is a mixed solvent of water and Organic Solvent E, and the Organic Solvent E is one or a mixture of two or more of toluene, acetonitrile, dichloromethane (DCM), methanol, ethanol, and N,N-dimethylformamide (DMF), preferably a mixed solvent of ethanol, water, and acetonitrile with a volume ratio of 2:1:1.

[0047] Furthermore, in Step S2, the volume of the Mixed Solvent E is 8 - 12 mL / mmol based on the amount of substance of the compound shown in Formula 6.

[0048] Further, in step S2, the post-treatment E is as follows: The reaction solution E is suction filtered, and after the obtained filtrate is distilled under reduced pressure, it is extracted with dichloromethane (DCM) and saturated brine. The obtained organic phase is dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain the compound shown in Formula 7.

[0049] Further, in step S3, the volume of acetic acid is 5 - 8 mL / mmol based on the amount of substance of the compound shown in Formula 7.

[0050] Further, in step S3, the post-treatment G is as follows: The reaction solution G is extracted with ethyl acetate (EA) and saturated brine. The obtained organic phase is dried with anhydrous sodium sulfate and then distilled under reduced pressure to obtain the compound shown in Formula 8.

[0051] Further, in step S4, the solvent Q is one or a mixture of two or more of water, methanol, acetonitrile, dichloromethane (DCM), ethanol, dimethyl sulfoxide (DMSO), and N,N-dimethylformamide (DMF), and is preferably dimethyl sulfoxide (DMSO).

[0052] Further, in step S4, the volume of the solvent Q is 1 - 3 mL / mmol based on the amount of substance of the compound shown in Formula 8.

[0053] Further, in step S4, the basic substance Q is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, and sodium hydroxide, and is preferably potassium carbonate.

[0054] Further, in step S4, the post-treatment Q is as follows: Water is added to the reaction solution Q to precipitate a solid, and then suction filtration is carried out. The obtained filter cake is purified by column chromatography using a mixed solution of DCM and methanol with a volume ratio of 20:1 as the eluent. The eluent containing the target compound is collected, concentrated, and dried to obtain the benzimidazole derivative shown in (II).

[0055] The present invention also provides a method for preparing the compound shown in Formula 2:

[0056] The compound shown in Formula 1 is dissolved in an organic solvent C, ethyl cyanoacetate is added, and the mixture is refluxed for 2 h. The obtained reaction solution C is subjected to post-treatment C to obtain the compound shown in Formula 2; the molar ratio of the compound shown in Formula 1 to ethyl cyanoacetate is 1:1 - 5 (preferably 1:3);

[0057]

[0058] Further, the organic solvent C is one or a mixture of two or more of toluene, acetonitrile, dichloromethane (DCM), methanol, ethanol, and N,N-dimethylformamide (DMF), and is preferably DMF.

[0059] Furthermore, the volume of the organic solvent C is 1 - 2 mL / mmol based on the amount of substance of the compound of Formula 1.

[0060] Furthermore, the post-treatment C is as follows: saturated brine is added to the reaction solution C, and extraction is carried out with ethyl acetate (EA). The organic phases are combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized with a mixed solvent of methanol, ethyl acetate (EA) and petroleum ether (PE) with a volume ratio of 1:5:20, followed by suction filtration. The obtained filter cake is dried to obtain the compound shown in Formula 2.

[0061] Furthermore, more specifically, the compound shown in Formula 5 of the present invention is prepared according to the following method:

[0062] The compound shown in Formula 4 is dissolved in the mixed solvent H, and an alkaline substance I and tetrabutylammonium bromide (TBAB) are added in sequence, and finally the benzyl bromide compound shown in Formula 10 is added. The mixture is stirred at room temperature for 2 h to obtain the reaction solution J, and after post-treatment J, the compound shown in Formula 5 is obtained; the molar ratio of the compound shown in Formula 4, benzyl bromide with different substituents, TBAB and the alkaline substance is 1:1 - 2:0.1 - 0.5:1 - 3 (preferably 1:1.4:0.1:2);

[0063]

[0064] Furthermore, the mixed solvent H is a mixed solvent of water and an organic solvent H, and the organic solvent H is one or a mixture of two or more of toluene, acetonitrile, DCM, methanol, ethanol, and DMF, preferably a mixed solvent of DCM and water with a volume ratio of 1:1.

[0065] Furthermore, the volume of the mixed solvent H is 4 - 8 mL / mmol based on the amount of substance of the compound of Formula 4.

[0066] Furthermore, the alkaline substance I is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide or triethylamine, preferably potassium hydroxide.

[0067] Furthermore, the post-treatment J is as follows: the solvent of the reaction solution J is removed by distillation under reduced pressure, saturated brine is added, and extraction is carried out with ethyl acetate (EA); the organic phases are combined and dried with anhydrous sodium sulfate; the solvent is concentrated by distillation under reduced pressure, and column chromatography separation is carried out using a mixed solvent of PE and DCM with a volume ratio of 1:1 as the eluent. The eluate containing the target compound is collected, concentrated, and dried to obtain the compound shown in Formula 5.

[0068] All the above letters are for distinguishing different reaction stages or various substances in different stages for convenient description and have no other special meanings.

[0069] Compared with the prior art, the beneficial effects of the present invention are as follows: The compounds provided by the present invention are a novel class of compounds with targeted MAO-B inhibitory activity and have potential therapeutic effects on diseases with overexpression of MAO-B, including Alzheimer's disease and Parkinson's disease. The series of compounds in Patent WO2017068090 are predicted by admet.scbdd.com to be unable to cross the blood-brain barrier; the compounds provided by the present invention have blood-brain barrier permeability and can act on central nervous system diseases, including Alzheimer's disease and Parkinson's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 are the results of pharmacokinetic experiments. DETAILED IMPLEMENTATION METHODS

[0071] The present invention will be further described below with specific examples, but the present invention is not limited to the following examples.

[0072] Preparation method of Example 1 a1

[0073] Add 3,4-diaminobenzoic acid (1.522 g, 10 mmol), DMF (12 mL), and ethyl cyanoacetate (3.394 g, 30 mmol) to a single-necked flask, and heat to 160 °C for reaction for 2 h; monitor by TLC, and stop the reaction when the raw materials are completely reacted; add saturated brine (200 mL), and extract with EA (100 mL); combine the organic phases, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and recrystallize with a mixed solvent of methanol, EA, and PE (v / v / v = 1:5:20), filter by suction, collect the filter cake, and dry. 1.368 g of crude 2-cyanomethyl-5-carboxy-1H-benzimidazole was obtained as a brown solid. The yield was 68%.

[0074] Add the obtained 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol), DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) to a round-bottomed flask, stir evenly at room temperature, then add o-fluoroaniline (0.444 g, 4 mmol), and continue to stir for 8 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.259 g of a red-brown intermediate. The yield was 22%.

[0075] Add the red-brown intermediate obtained from the above reaction (0.259 g, 0.88 mmol) to a round-bottom flask, add 3 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 35 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain white solid a1 (0.107 g). The yield is 39%. m.p. = 259.1 - 260.8 °C; 1 H NMR (600 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.05 (s, 1H), 8.20 (s, 1H), 7.83 (dd, J = 8.4, 1.8 Hz, 1H), 7.75 (s, 1H), 7.65–7.57 (m, 2H), 7.32–7.18 (m, 4H), 3.79 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 166.82, 164.88, 158.72 (q, 2 J C-F = 37.8 Hz, TFA), 158.08 (d, 1 J C-F = 245.5 Hz), 151.00, 133.20, 131.66, 130.87, 127.41, 127.40, 127.30 (d, 3 J C-F = 7.6 Hz), 125.82 (d, 2 J C-F = 12.2 Hz), 125.57, 124.50 (d, 4 J C-F = 3.5 Hz), 116.03 (d, 2 J C-F = 19.7 Hz), 114.41 (q, 1 J C-F = 287.1 Hz, TFA), 114.17 (d, 3 J C-F = 11.0 Hz), 33.60. HRMS (ESI): m / z calcd for C 16 H 14 FN4O2 [M + H] + 313.1095, found 313.1097; HPLC purity: 100%.

[0076] Preparation method of Example 2 a2

[0077] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add m-fluoroaniline (0.444 g, 4 mmol), and continue stirring for 8 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM:methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.283 g of a red-brown intermediate. The yield is 24%.

[0078] Add the red-brown intermediate (0.283 g, 0.96 mmol) obtained from the above reaction into a round-bottom flask, add 3 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 35 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM:methanol v / v = 20:1), collect the intermediate containing the target compound, concentrate, and dry to obtain 0.120 g of a khaki solid a2. The yield is 40%. m.p. = 141.8 - 156.1 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (d, J = 28.8 Hz, 1H), 10.36 (s, 1H), 8.18 (d, J = 64.8 Hz, 1H), 7.81 (m, 2H), 7.72 (s, 1H), 7.68–7.51 (m, 2H), 7.38 (q, J = 7.9 Hz, 1H), 7.19 (s, 1H), 6.91 (td, J = 8.4, 2.8 Hz, 1H), 3.79 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 166.90, 165.22, 162.37 (d, 1 J C-F = 239.7 Hz), 158.80 (q, 2 J C-F = 37.8 Hz, TFA), 151.09, 141.04 (d, 3 J C-F = 11.0 Hz), 133.20, 132.37, 130.88, 130.47 (d, 3 J C-F = 9.3 Hz), 125.57, 116.40 (d, 4 J C-F = 2.5 Hz), 115.46 (q, 1 JC-F = 287.0 Hz, TFA), 114.23, 114.15, 110.57 (d, 2 J C-F = 21.0 Hz), 107.40 (d, 2 J C-F = 26.1 Hz), 33.64. HRMS(ESI): m / z calcd for C 16 H 14 FN4O2 [M+H] + 313.1095, found 313.1088; HPLC purity: 100%.

[0079] Preparation method of Example 3 a3

[0080] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add p-fluoroaniline (0.444 g, 4 mmol), and continue stirring for 9 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, and separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.353 g of a red-brown intermediate. The yield is 30%.

[0081] Add the red-brown intermediate (0.353 g, 1.2 mmol) obtained from the above reaction into a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.146 g of off-white solid a3. The yield is 39%. m.p. = 132.0 - 139.5 °C; 1 H NMR(400 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.24 (s, 1H), 8.17 (d, J = 59.6 Hz, 1H), 7.82 (m, 3H), 7.71 (s, 1H), 7.59 (d, J = 20.8 Hz, 1H), 7.23–7.13 (m, 3H), 3.78 (s, 2H). 13 C NMR(100 MHz, DMSO-d6, TFA) δ 166.92, 164.88, 158.82 (q,2 J C-F =38.0Hz,TFA),158.80(d, 1 J C-F =239.2Hz),151.01,135.62(d, 4 J C-F =2.6Hz),133.11,132.63,130.91,125.56,122.78(d, 3 J C-F =7.8Hz),115.47(q, 1 J C-F =286.9Hz,TFA),115.43(d, 2 J C-F =22.1Hz),114.13,114.10,33.66.HRMS(ESI):m / zcalcd for C 16 H 14 FN4O2[M+H] + 313.1095, found 313.1090; HPLC purity: 99.84%.

[0082] Preparation method of Example 4a4

[0083] To a round-bottom flask were added 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol), prepared according to Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol). After stirring at room temperature, aniline (0.373 g, 4 mmol) was added and stirring continued for 5 h. After completion of the reaction, saturated brine (200 mL) was added and the mixture was extracted with DCM (120 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography (DCM:methanol v / v = 30:1). The eluate containing the target intermediate was collected, concentrated, and dried to obtain 0.287 g of a reddish-brown intermediate in a 26% yield.

[0084] The reddish-brown intermediate (0.287 g, 1.04 mmol) obtained in the above reaction was added to a round-bottom flask, along with 4 mL of concentrated hydrochloric acid (w / v = 36%). The mixture was reacted at 40°C for 40 min. After completion of the reaction, the pH was adjusted to neutral with saturated sodium bicarbonate solution to precipitate a solid. The filter cake was collected by suction and separated by column chromatography (DCM:methanol v / v = 20:1). The eluate containing the target compound was collected, concentrated, and dried to afford an off-white solid a4 (0.125 g). Yield: 41%. mp = 150.5-153.2°C. 11H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.21 (s, 1H), 8.22 (s, 1H), 7.88–7.69 (m, 4H), 7.59 (s, 1H), 7.35 (t, J = 7.6 Hz, 2H), 7.22 (s, 1H), 7.09 (t, J = 7.2 Hz, 1H), 3.78 (s, 2H). 13 13C NMR (100 MHz, DMSO-d6, TFA) δ 167.02, 165.05, 158.93 (q, 2 J C-F = 38.0 Hz, TFA), 151.05, 139.37, 133.14, 132.89, 130.96, 128.95, 125.69, 124.25, 120.99, 115.53 (q, 1 J C-F = 286.8 Hz, TFA), 114.23, 114.15, 33.72. HRMS (ESI): m / z calcd for C 16 H 15 N4O2 [M + H] + 295.1190, found 295.1195; HPLC purity: 100%.

[0085] Preparation method of Example 5a5

[0086] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add m-chloroaniline (0.510 g, 4 mmol), and continue stirring for 10 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.286 g of a red-brown intermediate. The yield is 23%.

[0087] Add the red-brown intermediate obtained from the above reaction (0.286 g, 0.92 mmol) to a round-bottom flask, add 3.5 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 45 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM:methanol v / v = 20:1), collect the intermediate containing the target compound, concentrate, and dry to obtain off-white solid a5 (0.118 g). Yield 39%. m.p. = 227.8 - 231.1 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (m, 1H), 10.34 (s, 1H), 8.18 (d, J = 52.4 Hz, 1H), 8.01 (m, 1H), 7.87–7.67 (m, 3H), 7.60 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.25–7.01 (m, 2H), 3.78 (s, 2H). 13 C NMR (150 MHz, DMSO-d6, TFA) δ 166.94, 165.23, 158.87 (q, 2 J C-F = 37.5 Hz, TFA), 151.10, 140.77, 133.33, 133.27, 132.33, 130.95, 130.54, 125.59, 123.85, 120.27, 119.11, 115.55 (q, 1 J C-F = 287.1 Hz, TFA), 114.25, 114.18, 33.67. HRMS (ESI): m / z calcd for C 16 H 14 ClN4O2 [M+H] + 329.0800, found 329.0806; HPLC purity: 100%.

[0088] [[ID=2#1]]Preparation method of Example 6a6

[0089] Add 2-cyanomethyl-5-carboxy-1H-benzoimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add p-chloroaniline (0.510 g, 4 mmol), and continue stirring for 8 h. After the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate. Distill off the solvent under reduced pressure, separate by column chromatography (DCM:methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.298 g of a reddish-brown intermediate. The yield is 24%.

[0090] Add the reddish-brown intermediate obtained from the above reaction (0.298 g, 0.96 mmol) into a round-bottom flask, add 3.5 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 50 min. After the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM:methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.126 g of white solid a6. The yield is 40%. m.p. = 251.3 - 254.7 °C; 1 H NMR (600 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.33 (s, 1H), 8.18 (s, 1H), 7.89–7.83 (m, 2H), 7.80 (dd, J = 8.4, 1.8 Hz, 1H), 7.74 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.43–7.38 (m, 2H), 7.20 (s, 1H), 3.78 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 166.88, 165.02, 158.79 (q, 2 J C-F = 38.0 Hz, TFA), 151.04, 138.25, 133.15, 132.48, 130.89, 128.77, 127.88, 125.57, 122.33, 115.45 (q, 1 J C-F = 287.0 Hz, TFA), 114.19, 114.10, 33.64. HRMS (ESI): m / z calcd for C 16 H 14 ClN4O2 [M + H] + 329.0800, found 329.0796; HPLC purity: 100%.

[0091] Preparation method of Example 7a7

[0092] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add o-toluidine (0.429 g, 4 mmol), and continue stirring for 4 h. After the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate. Distill off the solvent under reduced pressure, and separate by column chromatography (DCM:methanol v / v = 30:1). Collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.372 g of a red-brown intermediate. The yield is 32%.

[0093] Add the red-brown intermediate (0.372 g, 1.28 mmol) obtained from the above reaction into a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min. After the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM:methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.162 g of off-white solid a7. The yield is 41%. m.p. = 232.9 - 236.4 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 9.30 (s, 1H), 8.15 (s, 1H), 7.87 (dd, J = 7.6, 1.6 Hz, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.23–7.12 (m, 2H), 7.10 (m, 1H), 6.97 (td, J = 7.6, 1.6 Hz, 1H), 3.86 (s, 3H), 3.78 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.01, 164.66, 158.95 (q, 2 J C-F = 37.3 Hz, TFA), 152.24, 150.99, 133.15, 132.27, 130.99, 126.80, 126.50, 125.41, 120.48, 115.66 (q, 1 J C-F= 286.1 Hz, TFA), 114.23, 114.20, 114.08, 111.68, 55.85, 33.64. HRMS(ESI): m / z calcd for C 17 H 17 N4O2 [M + H] + 309.1346, found 309.1359; HPLC purity: 100%.

[0094] Preparation method of Example 8a8

[0095] In a round-bottom flask, add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), HATU (1.673 g, 4.4 mmol). After stirring evenly at room temperature, add m-toluidine (0.429 g, 4 mmol) and continue stirring for 4.5 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry the organic phase with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.383 g of a red-brown intermediate. The yield is 33%.

[0096] Add the red-brown intermediate (0.383 g, 1.32 mmol) obtained from the above reaction to a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.155 g of white solid a8. The yield is 38%. m.p. = 187.2 - 195.3 °C; 1 H NMR(400 MHz, DMSO-d6) δ 12.57(s, 1H), 10.13(s, 1H), 8.18(s, 1H), 7.80(dd, J = 8.8, 2.0 Hz, 1H), 7.74(s, 1H), 7.65(m, 1H), 7.59(m, 2H), 7.22(m, 2H), 6.91(d, J = 7.2 Hz, 1H), 3.78(s, 2H), 2.31(s, 3H). 13 C NMR(100 MHz, DMSO-d6, TFA) δ 166.97, 164.90, 158.88(q, 2 J C-F= 37.9 Hz, TFA), 150.99, 139.22, 138.16, 133.08, 132.84, 130.87, 128.75, 125.61, 124.90, 121.47, 118.11, 115.52 (q, 1 J C-F = 287.0 Hz, TFA), 114.13, 114.09, 33.68, 21.35. HRMS(ESI): m / z calcd for C 17 H 17 N4O2 [M+H] + 309.1346, found 309.1344;HPLC purity: 100%.

[0097] Preparation method of Example 9a9

[0098] In a round-bottom flask, add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), HATU (1.673 g, 4.4 mmol). After stirring evenly at room temperature, add p-toluidine (0.429 g, 4 mmol) and continue stirring for 4 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, and separate by column chromatography (DCM: methanol v / v = 30:1). Collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.372 g of a red-brown intermediate. The yield is 32%.

[0099] Add the red-brown intermediate (0.372 g, 1.28 mmol) obtained from the above reaction to a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.162 g of off-white solid a9. The yield is 41%.

[0100] m.p. = 235.7 - 238.9 °C; 1 H NMR(400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.10 (s, 1H), 8.22 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.74–7.63 (m, 3H), 7.58 (s, 1H), 7.16 (m, 3H), 3.78 (s, 2H), 2.28 (s, 3H). 1313C NMR (100 MHz, DMSO-d6, TFA) δ 167.06, 164.85, 159.00 (q, 2 J C-F = 38.0 Hz, TFA), 150.97, 136.81, 133.39, 133.11, 132.97, 130.99, 129.34, 125.66, 121.08, 115.58 (q, 1 J C-F = 286.6 Hz, TFA), 114.15, 114.10, 33.72, 20.64. HRMS (ESI): m / z calcd for C 17 H 17 N4O2 [M+H] + 309.1346, found 309.1360; HPLC purity: 100%.

[0101] Preparation method of Example 10a10

[0102] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add o-anisidine (0.493 g, 4 mmol), and continue stirring for 6 h; after the reaction is completed, add saturated brine (200 mL), extract with dichloromethane (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.343 g of a red-brown intermediate. The yield is 28%.

[0103] Add the red-brown intermediate (0.343 g, 1.12 mmol) obtained from the above reaction into a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the intermediate containing the target compound, concentrate, and dry to obtain 0.127 g of off-white solid a10. The yield is 35%. m.p. = 226.2 - 229.9 °C; 11H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.79 (s, 1H), 8.19 (s, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (dd, J = 7.6, 2.0 Hz, 1H), 7.19 (m, 3H), 3.78 (s, 2H), 2.26 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6, TFA) δ 166.98, 164.87, 158.90 (q, 2 J C-F = 37.8 Hz, TFA), 150.97, 136.57, 134.25, 133.13, 132.38, 131.00, 130.67, 127.07, 126.54, 126.36, 125.57, 115.55 (q, 1 J C-F = 287.1 Hz, TFA), 114.11, 33.68, 18.12. HRMS (ESI): m / z calcd for C 17 H 17 N4O3 [M + H] + 325.1295, found 325.1300; HPLC purity: 100%.

[0104] Preparation method of Example 11a11

[0105] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add m-methoxyaniline (0.493 g, 4 mmol), and continue stirring for 6 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.343 g of a reddish-brown intermediate. The yield is 28%.

[0106] Add the red-brown intermediate obtained from the above reaction (0.343 g, 1.12 mmol) to a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min; after the reaction, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain off-white solid a11 (0.141 g). The yield is 39%. m.p. = 140.0 - 141.4 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.18 (s, 1H), 8.17 (s, 1H), 7.84–7.77 (m, 1H), 7.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.52 (m, 1H), 7.44–7.37 (m, 1H), 7.28–7.17 (m, 2H), 6.67 (dd, J = 8.0, 2.4 Hz, 1H), 3.78 (s, 2H), 3.76 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 166.95, 165.00, 159.72, 158.86 (q, 2 J C-F =37.4 Hz, TFA), 151.00, 140.45, 133.10, 132.68, 130.89, 129.69, 125.53, 115.58 (q, 1 J C-F =287.6 Hz, TFA) 114.08, 113.00, 109.61, 106.49, 55.21, 33.64. HRMS (ESI): m / z calcd for C 17 H 17 N4O3[M+H] + 325.1295, found 325.1294; HPLC purity: 100%.

[0107] Preparation method of Example 12 a12

[0108] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) to a round-bottom flask. After stirring evenly at room temperature, add p-methoxyaniline (0.493 g, 4 mmol), and continue stirring for 6 h. After the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry the organic phase with anhydrous sodium sulfate. Distill off the solvent under reduced pressure, separate by column chromatography (DCM:methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.306 g of a reddish-brown intermediate. The yield is 25%.

[0109] Add the reddish-brown intermediate (0.306 g, 1 mmol) obtained from the above reaction to a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min. After the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM:methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.156 g of a pale yellow solid a12. The yield is 48%. m.p. = 230.3 - 244.1 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.08 (s, 1H), 8.16 (s, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (m, 3H), 7.58 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.97–6.88 (m, 2H), 3.77 (s, 2H), 3.75 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.12, 164.68, 159.00 (q, 2 J C-F = 37.2 Hz, TFA), 156.19, 151.12, 133.22, 132.96, 132.47, 131.15, 125.61, 122.66, 115.83 (q, 1 J C-F = 287.9 Hz, TFA), 114.24, 114.21, 114.16, 55.58, 33.85. HRMS (ESI): m / z calcd for C 17 H 17 N4O3 [M+H] +325.1295, found 325.1294; HPLC purity: 100%.

[0110] Preparation method of Example 13a13

[0111] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add 2,3-dimethylaniline (0.485 g, 4 mmol) and continue stirring for 6 h. After the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate. Distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.341 g of a red-brown intermediate. The yield is 28%.

[0112] Add the red-brown intermediate (0.341 g, 1.12 mmol) obtained from the above reaction into a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min. After the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate the solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.141 g of off-white solid a13. The yield is 39%. m.p. = 218.5 - 223.8 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.90 (s, 1H), 8.19 (s, 1H), 7.82 (dd, J = 8.4, 1.6 Hz, 1H), 7.76 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.20–7.00 (m, 3H), 3.78 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.13, 165.10, 159,04 (q, 2 J C-F = 38.0 Hz, TFA), 151.06, 137.60, 136.55, 133.35, 133.21, 132.54, 131.11, 128.20, 125.74, 125.71, 125.25, 115.61 (q, 1 J C-F= 286.7 Hz, TFA), 114.26, 114.20, 33.78, 20.37, 14.56. HRMS(ESI): m / z calcd for C 18 H 19 N4O2[M + H] + 323.1503, found 323.1509; HPLC purity: 100%.

[0113] Preparation method of Example 14a14

[0114] Add 2-cyanomethyl-5-carboxy-1H-benzimidazole (0.805 g, 4 mmol) prepared according to the operation of Example 1, DMF (5 mL), triethylamine (0.810 g, 8 mmol), and HATU (1.673 g, 4.4 mmol) into a round-bottom flask. After stirring evenly at room temperature, add 3,4-dimethylaniline (0.485 g, 4 mmol), and continue stirring for 6 h; after the reaction is completed, add saturated brine (200 mL), extract with DCM (120 mL), combine the organic phases, and dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, separate by column chromatography (DCM: methanol v / v = 30:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 0.317 g of a red-brown intermediate. The yield is 26%.

[0115] Add the red-brown intermediate (0.317 g, 1.04 mmol) obtained from the above reaction into a round-bottom flask, add 4 mL of concentrated hydrochloric acid (w / v = 36%), and react at 40 °C for 40 min; after the reaction is completed, adjust the pH to neutral with saturated sodium bicarbonate solution, precipitate a solid, filter by suction, collect the filter cake, separate by column chromatography (DCM: methanol v / v = 20:1), collect the eluate containing the target compound, concentrate, and dry to obtain 0.127 g of off-white solid a14. The yield is 38%. m.p. = 252.1 - 254.8 °C; 1 H NMR(400 MHz, DMSO-d6) δ 12.59(s, 1H), 10.07(s, 1H), 8.17(s, 1H), 7.83–7.74(m, 2H), 7.58(m, 2H), 7.52(dd, J = 8.0, 2.0 Hz, 1H), 7.25(s, 1H), 7.09(d, J = 8.4 Hz, 1H), 3.78(s, 2H), 2.22(s, 3H), 2.19(s, 3H). 13 C NMR(100 MHz, DMSO-d6, TFA) δ 167.13, 164.80, 159.05(q, 2 J C-F= 37.9 Hz, TFA), 151.05, 137.11, 136.69, 133.13, 133.03, 132.21, 131.02, 129.89, 125.72, 122.32, 118.64, 115.62 (q, 1 J C-F = 286.7 Hz, TFA), 114.16, 33.78, 19.86, 19.07. HRMS(ESI): m / z calcd for C 18 H 19 N4O2 [M + H] + 323.1503, found 323.1507; HPLC purity: 100%.

[0116] Preparation method of Example 15b1

[0117] Add 3-amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 2-fluorobenzyl bromide (2.117 g, 11.2 mmol) into a round-bottom flask in sequence, and stir at room temperature for 2 h; after the reaction is completed, distill off DCM under reduced pressure, add saturated brine (200 mL), and extract with EA (80 mL); combine the organic phases, dry over anhydrous sodium sulfate; concentrate the solvent by distillation under reduced pressure, and then separate by column chromatography (PE:DCM v / v = 1:1), collect the eluate containing the target intermediate, concentrate, and dry to obtain 1.930 g of an orange solid intermediate shown in Formula 5. The yield is 92%.

[0118] Add the obtained orange solid intermediate (1.834 g, 7 mmol) into DCM (15 mL) in a round-bottom flask, then add DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol), stir at room temperature for 5 min, then add cyanoacetic acid (0.595 g, 7 mmol), and continue to stir for 8 h; after the reaction is completed, an orange solid precipitates, distill off part of the solvent under reduced pressure, filter by suction, collect the filter cake, wash the filter cake with methanol and then slurry, filter by suction, and dry to obtain 1.175 g of a yellow solid intermediate shown in Formula 6. The yield is 51%.

[0119] The above yellow solid intermediate (0.988 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, filtration was carried out by suction, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.790 g of a off-white solid intermediate shown in Formula 7. The yield was 88%.

[0120] The above white solid intermediate (0.748 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (30 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.640 g of a red-brown solid intermediate shown in Formula 8. The yield was 91%.

[0121] The above red-brown solid intermediate (0.563 g, 2 mmol) was dissolved in DMSO (6 mL), 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added in sequence, and the reaction was carried out at 25 °C for 5 h; after the reaction was completed, water (20 mL) was added to precipitate a pink solid, filtration was carried out by suction, the filter cake was collected, the filter cake was purified by column chromatography (DCM:methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain white solid b1 (0.293 g). The yield was 49%. m.p. = 194.7 - 199.3 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.71 (s, 1H), 7.57 (td, J = 7.6, 1.6 Hz, 1H), 7.46–7.33 (m, 2H), 7.29–7.15 (m, 3H), 7.11 (s, 1H), 6.87–6.79 (m, 1H), 5.14 (s, 2H), 3.67 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.22, 160.82 (d, 1 J C-F =244.7 Hz), 158.93 (q, 2 J C-F =37.9 Hz, TFA), 156.99, 148.41, 132.03, 131.06 (d, 3 J C-F =3.9 Hz), 130.84 (d, 3 J C-F= 8.2 Hz), 125.63, 124.85 (d, 4 J C-F = 3.4 Hz), 123.71 (d, 2 J C-F = 14.4 Hz), 116.21, 115.73 (d, 2 J C-F = 20.9 Hz), 115.53 (q, 1 J C-F = 286.8 Hz, TFA), 115.15, 97.97, 64.69 (d, 3 J C-F = 3.5 Hz), 33.44. HRMS(ESI): m / z calcd for C 16 H 15 FN3O2 [M + H] + 300.1143, found 300.1141; HPLC purity: 100%.

[0122] Preparation method of Example 16b2

[0123] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 3-fluorobenzyl bromide (2.117 g, 11.2 mmol) were successively added to a round-bottom flask and stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and extraction was carried out with EA (80 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), and the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.888 g of an orange solid intermediate shown in Formula 5. The yield was 90%.

[0124] The above-obtained orange solid intermediate (1.834 g, 7 mmol) was added to DCM (15 mL) in a round-bottom flask, and then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added. After stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 8 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and then slurried, suction filtration was carried out, and drying was carried out to obtain 1.314 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 57%.

[0125] The above orange-yellow solid intermediate (0.988 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, suction filtration was carried out, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.763 g of a off-white solid intermediate shown in Formula 7. The yield was 85%.

[0126] The above white solid intermediate (0.748 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (30 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 0.675 g of a red-brown solid intermediate shown in Formula 8. The yield was 96%.

[0127] The above red-brown solid intermediate (0.563 g, 2 mmol) was dissolved in DMSO (6 mL), 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added in sequence, and the reaction was carried out at 25 °C for 5 h; after the reaction was completed, water (20 mL) was added to precipitate a pink solid, suction filtration was carried out, and the filter cake was collected. The filter cake was purified by column chromatography (DCM:methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain a slightly yellow solid b2 (0.323 g). The yield was 54%. m.p. = 181.8 - 182.6 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 7.68 (s, 1H), 7.47–7.35 (m, 2H), 7.35–7.25 (m, 2H), 7.20–7.10 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 5.14 (s, 2H), 3.67 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.27, 162.69 (d, 1 J C-F =242.4 Hz), 158.97 (q, 2 J C-F =38.0 Hz, TFA), 156.98, 148.41, 139.93 (d, 3 J C-F =7.4 Hz), 132.06, 130.84 (d, 3 JC-F = 8.3 Hz), 125.63, 123.85 (d, 4 J C-F = 2.7 Hz), 116.34, 115.54 (q, 1 J C-F = 286.6 Hz, TFA), 115.18, 115.04 (d, 2 J C-F = 20.9 Hz), 114.64 (d, 2 J C-F = 21.8 Hz), 98.09, 69.50 (d, 4 J C-F = 1.2 Hz), 33.48. HRMS(ESI): m / z calcd for C 16 H 15 FN3O2 [M + H] + 300.1143, found 300.1145; HPLC purity: 100%.

[0128] Preparation method of Example 17b3

[0129] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 4-fluorobenzyl bromide (2.117 g, 11.2 mmol) were successively added to a round-bottom flask and stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and extraction was carried out with EA (80 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 2.014 g of an orange solid intermediate shown in Formula 5. The yield was 96%.

[0130] The above-obtained orange solid intermediate (1.834 g, 7 mmol) was added to a round-bottom flask in DCM (15 mL) solvent, then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added, and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 8 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and then slurried, suction filtration was carried out, and drying was carried out to obtain 1.267 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 55%.

[0131] Dissolve the above orange-yellow solid intermediate (0.988 g, 3 mmol) in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), add ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol), and stir vigorously at 50 °C for 10 min; after the reaction is completed, filter by suction and collect the filtrate; after distilling the filtrate under reduced pressure, extract with DCM (300 mL) and saturated brine (400 mL), collect the organic phase, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain 0.826 g of the off-white solid intermediate shown in Formula 7. The yield is 92%.

[0132] Dissolve the above white solid intermediate (0.748 g, 2.5 mmol) in glacial acetic acid (20 mL), and reflux at heating for 2 h; after the reaction is completed, extract with EA (30 mL) and saturated brine (80 mL), collect the organic phase, dry over anhydrous sodium sulfate and then distill under reduced pressure to obtain 0.633 g of the reddish-brown solid intermediate shown in Formula 8. The yield is 90%.

[0133] Dissolve the above reddish-brown solid intermediate (0.563 g, 2 mmol) in DMSO (6 mL), successively add 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol), and react at 25 °C for 5 h; after the reaction is completed, add water (20 mL) to precipitate a pink solid, filter by suction, collect the filter cake, purify the filter cake by column chromatography (DCM:methanol v / v = 20:1), collect the eluate containing the target compound, concentrate and dry to obtain off-white solid b3 (0.377 g). The yield is 63%. m.p. = 213.9 - 217.0 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.68 (s, 1H), 7.55–7.46 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.24–7.18 (m, 2H), 7.16 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 5.09 (s, 2H), 3.66 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.14, 162.17 (d, 1 J C-F =242.5 Hz), 158.85 (q, 2 J C-F =37.6 Hz, TFA), 156.98, 148.26, 133.04 (d, 4 J C-F =3.0 Hz), 131.96, 130.28 (d,3 J C-F = 8.3 Hz), 125.45, 116.21, 115.54 (d, 2 J C-F = 21.2 Hz), 115.52 (q, 1 J C-F = 287.2 Hz, TFA), 115.03, 97.94, 69.57, 33.37. HRMS(ESI): m / z calcd for C 16 H 15 FN3O2 [M+H] + 300.1143, found 300.1145; HPLC purity: 100%.

[0134] Preparation method of Example 18b4

[0135] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 2-chlorobenzyl bromide (2.301 g, 11.2 mmol) were successively added to a round-bottom flask and stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (80 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.984 g of an orange solid intermediate shown in Formula 5. The yield was 89%.

[0136] The above-obtained orange solid intermediate (1.834 g, 7 mmol) was added to a round-bottom flask in DCM (15 mL) solvent, then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added, and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 8 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and then slurried, suction filtration was carried out, and drying was carried out to obtain 1.355 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 56%.

[0137] The above orange-yellow solid intermediate (0.988 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, filtration was carried out under suction, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.890 g of the off-white solid intermediate shown in Formula 7. The yield was 95%.

[0138] The above white solid intermediate (0.748 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (50 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 0.670 g of the red-brown solid intermediate shown in Formula 8. The yield was 90%.

[0139] The above red-brown solid intermediate (0.563 g, 2 mmol) was dissolved in DMSO (6 mL), 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added in sequence, and the reaction was carried out at 25 °C for 5 h; after the reaction was completed, water (20 mL) was added to precipitate a pink solid, filtration was carried out under suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM:methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain white solid b4 (0.360 g). The yield was 57%. m.p. = 204.9 - 220.2 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.69 (s, 1H), 7.64–7.58 (m, 1H), 7.55–7.48 (m, 1H), 7.43–7.33 (m, 3H), 7.17 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H), 5.17 (s, 2H), 3.67 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.29, 159.00 (q, 2 J C-F = 38.1 Hz, TFA), 157.10, 148.49, 134.31, 133.17, 132.13, 130.51, 130.32, 129.83, 127.73, 125.77, 116.27, 115.56 (q, 1 J C-F= 286.5 Hz, TFA), 115.24, 98.15, 68.12, 33.51. HRMS (ESI): m / z calcd for C 16 H 15 ClN3O2 [M+H] + 316.0847, found 316.0841; HPLC purity: 100%.

[0140] Preparation method of Example 19b5

[0141] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 3-chlorobenzyl bromide (2.301 g, 11.2 mmol) were successively added to a round-bottom flask and stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (80 mL); the organic phases were combined and dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), and the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.984 g of an orange solid intermediate shown in Formula 5. The yield was 89%.

[0142] The above-obtained orange solid intermediate (1.834 g, 7 mmol) was added to DCM (15 mL) solvent in a round-bottom flask, and then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added. After stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 7 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and then slurried, suction filtration was carried out, and drying was carried out to obtain 1.306 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 54%.

[0143] The above orange-yellow solid intermediate (0.988 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, suction filtration was carried out to collect the filtrate; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.853 g of an off-white solid intermediate shown in Formula 7. The yield was 90%.

[0144] The above-mentioned white solid intermediate (0.748 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (50 mL) and saturated brine (90 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 0.670 g of the red-brown solid intermediate shown in Formula 8. The yield was 90%.

[0145] The above-mentioned red-brown solid intermediate (0.563 g, 2 mmol) was dissolved in DMSO (6 mL), 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added successively, and the reaction was carried out at 25 °C for 5 h; after the reaction was completed, water (20 mL) was added to precipitate a pink solid, which was filtered by suction, the filter cake was collected, and the filter cake was purified by column chromatography (DCM: methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain white solid b5 (0.398 g). The yield was 63%. m.p. = 215.7 - 217.5 °C; 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.69 (s, 1H), 7.55–7.52 (m, 1H), 7.44–7.36 (m, 4H), 7.17 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.4, 2.4 Hz, 1H), 5.14 (s, 2H), 3.67 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.23, 158,93 (q, 2 J C-F =38.2 Hz, TFA), 156.94, 148.41, 139.56, 133.66, 132.04, 130.68, 128.22, 127.72, 126.48, 125.63, 116.30, 115.52 (q, 1 J C-F =286.6 Hz, TFA), 115.18, 98.10, 69.43, 33.47. HRMS (ESI): m / z calcd for C 16 H 15 ClN3O2 [M + H] + 3l6.0847, found 316.0849; HPLC purity: 100%.

[0146] Preparation method of Example 20b6

[0147] In a round-bottom flask, 3-amino-4-nitrophenol shown in Formula 4 (1.233 g, 8 mmol), a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 4-chlorobenzyl bromide (2.301 g, 11.2 mmol) were added in sequence, and the mixture was stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (70 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 2.118 g of an orange solid intermediate shown in Formula 5. The yield was 95%.

[0148] The orange solid intermediate obtained above (1.834 g, 7 mmol) was added to a DCM (15 mL) solvent in a round-bottom flask, then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added, and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 8 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and slurried, filtered, and dried to obtain 1.331 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 55%.

[0149] The orange-yellow solid intermediate above (0.988 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, filtration was carried out, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.843 g of an off-white solid intermediate shown in Formula 7. The yield was 89%.

[0150] The white solid intermediate above (0.748 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated to reflux for 2 h; after the reaction was completed, it was extracted with EA (50 mL) and saturated brine (90 mL), the organic phase was collected, dried over anhydrous sodium sulfate and then distilled under reduced pressure to obtain 0.670 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 90%.

[0151] The above-mentioned reddish-brown solid intermediate (0.563 g, 2 mmol) was dissolved in DMSO (6 mL), and 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added successively. The reaction was carried out at 25 °C for 5 h. After the reaction was completed, water (20 mL) was added to precipitate a pink solid, which was filtered by suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM:methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain white solid b6 (0.278 g). The yield was 44%. m.p. = 230.2 - 238.4 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.70 (s, 1H), 7.52–7.42 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 5.11 (s, 2H), 3.66 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.13, 158.85 (q, 2 J C-F = 37.9 Hz, TFA), 156.93, 148.29, 135.91, 132.94, 131.98, 129.78, 128.76, 125.53, 116.25, 115.50 (q, 1 J C-F = 286.9 Hz, TFA), 115.07, 98.07, 69.50, 33.39. HRMS (ESI): m / z calcd for C 16 H 15 ClN3O2 [M+H] + 316.0847, found 316.0846; HPLC purity: 100%. Preparation method of Example 21 b7

[0152] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol), and 2-methylbenzyl bromide (2.072 g, 11.2 mmol) were successively added to a round-bottom flask, and the mixture was stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (50 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.900 g of an orange solid intermediate shown in Formula 5. The yield was 92%.

[0153] The above-obtained orange solid intermediate (1.834 g, 7 mmol) was added to a DCM (15 mL) solvent in a round-bottom flask, followed by the addition of DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol), and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and the mixture was stirred for an additional 9 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and slurried, suction filtered, and dried to obtain 1.161 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 51%.

[0154] The above orange-yellow solid intermediate (0.988 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, suction filtration was carried out, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (350 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.780 g of an off-white solid intermediate shown in Formula 7. The yield was 88%.

[0155] The above white solid intermediate (0.748 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (50 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 0.631 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 91%.

[0156] The above-mentioned reddish-brown solid intermediate (0.563 g, 2 mmol) was dissolved in DMSO (6 mL). 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added successively, and the reaction was carried out at 25 °C for 4 h. After the reaction was completed, water (20 mL) was added to precipitate a pink solid. The solid was filtered by suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM: methanol v / v / v = 20:1), and the eluate containing the target compound was collected, concentrated, and dried to obtain white solid b7 (0.289 g). The yield was 49%. m.p. = 225.7 - 233.7 °C; 1 H NMR (600 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.68 (s, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26–7.17 (m, 3H), 7.15 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 9.0, 2.4 Hz, 1H), 5.08 (s, 2H), 3.68 (s, 2H), 2.34 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.12, 158.85 (q, 2 J C-F = 37.7 Hz, TFA), 157.24, 148.20, 137.01, 134.72, 132.01, 130.47, 128.94, 128.49, 126.06, 125.46, 116.17, 115.54 (q, 1 J C-F = 287.0 Hz, TFA), 115.02, 97.94, 69.12, 33.38, 18.65. HRMS (ESI): m / z calcd for C 17 H 18 N3O2 [M + H] + 296.1394, found 296.1395; HPLC purity: 100%.

[0157] Preparation method of Example 22 b8

[0158] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 3-methylbenzyl bromide (2.072 g, 11.2 mmol) were successively added to a round-bottom flask, and stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and extracted with EA (70 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.942 g of an orange solid intermediate shown in Formula 5. The yield was 94%.

[0159] The orange solid intermediate obtained above (1.808 g, 7 mmol) was added to DCM (15 mL) in a round-bottom flask, then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added, and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 8 h; after the reaction was completed, an orange solid precipitated out, part of the solvent was removed by distillation under reduced pressure, filtered by suction, the filter cake was collected, washed with methanol and slurried, filtered by suction, and dried to obtain 1.344 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 59%.

[0160] The orange-yellow solid intermediate above (0.976 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and stirred vigorously at 50 °C for 10 min; after the reaction was completed, filtered by suction, and the filtrate was collected; after the filtrate was distilled under reduced pressure, extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.824 g of an off-white solid intermediate shown in Formula 7. The yield was 93%.

[0161] The white solid intermediate above (0.738 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and heated under reflux for 2 h; after the reaction was completed, extracted with EA (50 mL) and saturated brine (100 mL), the organic phase was collected, dried over anhydrous sodium sulfate and then distilled under reduced pressure to obtain 0.631 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 91%.

[0162] Dissolve the above-mentioned reddish-brown solid intermediate (0.555 g, 2 mmol) in DMSO (6 mL). Sequentially add 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol), and react at 25 °C for 4 h. After the reaction is completed, add water (20 mL) to precipitate a pink solid. Filter by suction, collect the filter cake, and purify the filter cake by column chromatography (DCM: methanol v / v = 20:1). Collect the eluate containing the target compound, concentrate it, and dry it to obtain off-white solid b8 (0.295 g). The yield is 50%. m.p. = 223.1 - 227.5 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.70 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.30–7.23 (m, 3H), 7.18 (s, 1H), 7.12 (d, J = 6.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 5.06 (s, 2H), 3.66 (s, 2H), 2.31 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.19, 158.91 (q, 2 J C-F = 38.0 Hz, TFA), 157.16, 148.23, 138.04, 136.81, 132.01, 128.90, 128.68, 128.61, 125.42, 125.13, 116.27, 115.54 (q, 1 J C-F = 287.0 Hz, TFA), 115.05, 97.87, 70.33, 33.40, 21.15. HRMS (ESI): m / z calcd for C 17 H 18 N3O2 [M+H] + 296.1394, found 296.1399; HPLC purity: 99.32%.

[0163] Preparation method of Example 23 b9

[0164] In a round-bottom flask, 3-amino-4-nitrophenol shown in Formula 4 (1.233 g, 8 mmol), a mixed solvent (DCM:H2O v / v = 1:1) in a total of 40 mL, potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 4-methylbenzyl bromide (2.072 g, 11.2 mmol) were successively added, and the mixture was stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (40 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.922 g of an orange solid intermediate shown in Formula 5. The yield was 93%.

[0165] The above-obtained orange solid intermediate (1.808 g, 7 mmol) was added to a DCM (15 mL) solvent in a round-bottom flask, and then DIPEA (1.809 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added. After stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and the mixture was stirred at room temperature for 8 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and slurried, filtered, and dried to obtain 1.230 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 54%.

[0166] The above orange-yellow solid intermediate (0.976 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, filtration was carried out, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (450 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.842 g of an off-white solid intermediate shown in Formula 7. The yield was 95%.

[0167] The above white solid intermediate (0.738 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (30 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 0.645 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 93%.

[0168] Dissolve the above-mentioned reddish-brown solid intermediate (0.555 g, 2 mmol) in DMSO (6 mL). Sequentially add 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol), and react at 25 °C for 5 h. After the reaction is completed, add water (20 mL) to precipitate a pink solid. Filter by suction, collect the filter cake, and purify the filter cake by column chromatography (DCM: methanol v / v = 20:1). Collect the eluate containing the target compound, concentrate it, and dry it to obtain off-white solid b9 (0.354 g). The yield is 60%. m.p. = 208.4 - 213.9 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.69 (s, 1H), 7.45–7.28 (m, 3H), 7.18 (d, J = 8.0 Hz, 3H), 7.06 (d, J = 2.0 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 5.05 (s, 2H), 3.66 (s, 2H), 2.30 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.10, 158.81 (q, 2 J C-F = 37.7 Hz, TFA), 157.06, 148.14, 137.54, 133.76, 131.93, 129.26, 128.09, 125.33, 116.25, 115.52 (q, 1 J C-F = 287.3 Hz, TFA), 114.96, 97.88, 70.16, 33.33, 20.88. HRMS (ESI): m / z calcd for C 17 H 18 N3O2 [M + H] + 296.1394, found 296.1391; HPLC purity: 100%.

[0169] Preparation method of Example 24 b10

[0170] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 3-methoxybenzyl bromide (2.251 g, 11.2 mmol) were successively added to a round-bottom flask, and the mixture was stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (80 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 2.018 g of an orange solid intermediate shown in Formula 5. The yield was 92%.

[0171] The above-obtained orange solid intermediate (1.808 g, 7 mmol) was added to a DCM (15 mL) solvent in a round-bottom flask, followed by addition of DIPEA (1.920 g, 14 mmol) and HATU (2.927 g, 7.7 mmol), and the mixture was stirred at room temperature for 5 min, then cyanoacetic acid (0.654 g, 7.7 mmol) was added, and stirring was continued for 8 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was washed with methanol and then slurried, suction filtered, and dried to obtain 1.219 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 51%.

[0172] The above orange-yellow solid intermediate (1.024 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, suction filtration was carried out, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.778 g of an off-white solid intermediate shown in Formula 7. The yield was 88%.

[0173] The above white solid intermediate (0.778 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and the mixture was heated to reflux for 2 h; after the reaction was completed, it was extracted with EA (60 mL) and saturated brine (90 mL), the organic phase was collected, dried over anhydrous sodium sulfate and then distilled under reduced pressure to obtain 0.660 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 90%.

[0174] The above-mentioned reddish-brown solid intermediate (0.587 g, 2 mmol) was dissolved in DMSO (6 mL). 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added successively, and the reaction was carried out at 25 °C for 4 h. After the reaction was completed, water (20 mL) was added to precipitate a pink solid. The solid was filtered by suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM: methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain off-white solid b10 (0.324 g). The yield was 52%. m.p. = 197.7 - 198.9 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 7.69 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.04–7.00 (m, 2H), 6.88 (ddd, J = 8.0, 2.4, 1.2 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 5.08 (s, 2H), 3.75 (s, 3H), 3.66 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.29, 159.93, 159.03 (q, 2 J C-F = 38.1 Hz, TFA), 157.30, 148.28, 138.62, 132.17, 130.03, 125.63, 120.12, 116.51, 115.63 (q, 1 J C-F = 286.7 Hz, TFA), 115.14, 113.72, 113.63, 98.18, 70.37, 55.32, 33.53. HRMS (ESI): m / z calcd for C 17 H 18 N3O3 [M + H] + 312.1343, found 312.1345; HPLC purity: 100%.

[0175] Preparation method of Example 25 b11

[0176] 3-Amino-4-nitrophenol (1.233 g, 8 mmol) shown in Formula 4, a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol), and benzyl bromide (1.915 g, 11.2 mmol) were successively added to a round-bottom flask, and the mixture was stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (60 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (petroleum ether:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 1.798 g of an orange solid intermediate shown in Formula 5. The yield was 92%.

[0177] The orange solid intermediate obtained above (1.709 g, 7 mmol) was added to a DCM (15 mL) solvent in a round-bottom flask, then DIPEA (1.920 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added, and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and the mixture was stirred at room temperature for 7 h; after the reaction was completed, an orange solid precipitated, part of the solvent was removed by distillation under reduced pressure, suction filtration was carried out, the filter cake was collected, the filter cake was slurried with methanol, suction filtration was carried out, and dried to obtain 1.264 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 58%.

[0178] The orange-yellow solid intermediate above (0.934 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, suction filtration was carried out, and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (400 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.768 g of an off-white solid intermediate shown in Formula 7. The yield was 91%.

[0179] The white solid intermediate above (0.703 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (40 mL) and saturated brine (90 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to obtain 0.592 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 90%.

[0180] Dissolve the above-mentioned reddish-brown solid intermediate (0.526 g, 2 mmol) in DMSO (6 mL), and successively add 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol). React at 25 °C for 4 h. After the reaction, add water (20 mL) to precipitate a pink solid. Filter by suction, collect the filter cake, and purify the filter cake by column chromatography (DCM: methanol v / v = 20:1). Collect the eluate containing the target compound, concentrate it, and dry it to obtain white solid b11 (0.366 g). The yield is 65%. m.p. = 202.2 - 2?4.8 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 7.70 (s, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 8.0 Hz, 3H), 7.32 (m, 1H), 7.18 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 5.11 (s, 2H), 3.66 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.12, 158.92 (q, 2 J C-F = 36.8 Hz, TFA), 156.99, 148.18, 136.80, 131.96, 128.70, 128.19, 127.99, 125.40, 116.16, 115.73 (q, 1 J C-F = 288.2 Hz, TFA), 114.99, 97.84, 70.20, 33.32. HRMS (ESI): m / z calcd for C 16 H 16 N3O2 [M + H] + 282.1237, found 282.1235; HPLC purity: 100%.

[0181] Preparation method of Example 26 b12

[0182] In a round-bottom flask, 3-amino-4-nitrophenol shown in Formula 4 (1.233 g, 8 mmol), a total of 40 mL of a mixed solvent (DCM:H2O v / v = 1:1), potassium hydroxide (0.898 g, 16 mmol), TBAB (0.258 g, 0.8 mmol) and 4-(trifluoromethyl)benzyl bromide (2.677 g, 11.2 mmol) were successively added, and the mixture was stirred at room temperature for 2 h; after the reaction was completed, DCM was removed by distillation under reduced pressure, saturated brine (200 mL) was added, and the mixture was extracted with EA (80 mL); the organic phases were combined, dried over anhydrous sodium sulfate; the solvent was concentrated by distillation under reduced pressure, and then separated by column chromatography (PE:DCM v / v = 1:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 2.198 g of an orange solid intermediate shown in Formula 5. The yield was 88%.

[0183] The above-obtained orange solid intermediate (2.185 g, 7 mmol) was added to a DCM (15 mL) solvent in a round-bottom flask, then DIPEA (1.920 g, 14 mmol) and HATU (2.927 g, 7.7 mmol) were added, and after stirring at room temperature for 5 min, cyanoacetic acid (0.654 g, 7.7 mmol) was added, and the mixture was stirred for another 8 h; after the reaction was completed, an orange solid precipitated out, part of the solvent was removed by distillation under reduced pressure, filtered, the filter cake was collected, the filter cake was washed with methanol and then slurried, filtered, and dried to obtain 1.513 g of an orange-yellow solid intermediate shown in Formula 6. The yield was 57%.

[0184] The above orange-yellow solid intermediate (1.138 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, filtered, the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (300 mL) and saturated brine (400 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.891 g of an off-white solid intermediate shown in Formula 7. The yield was 85%.

[0185] The above white solid intermediate (0.873 g, 2.5 mmol) was dissolved in glacial acetic acid (20 mL), and heated to reflux for 2 h; after the reaction was completed, it was extracted with EA (30 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate and then distilled under reduced pressure to obtain 0.779 g of a reddish-brown solid intermediate shown in Formula 8. The yield was 94%.

[0186] The above-mentioned reddish-brown solid intermediate (0.663 g, 2 mmol) was dissolved in DMSO (6 mL). 30% hydrogen peroxide (1.812 g containing 16 mmol H2O2) and potassium carbonate (0.056 g, 0.4 mmol) were added successively, and the reaction was carried out at 25 °C for 6 h. After the reaction was completed, water (20 mL) was added to precipitate a pink solid, which was filtered by suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM: methanol v / v = 20:1), the eluent containing the target compound was collected, concentrated, and dried to obtain a pale yellow solid b12 (0.426 g). The yield was 61%. m.p. = 210.7 - 211.8 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.0 Hz, 3H), 7.39 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 8.8, 2.8 Hz, 1H), 5.24 (s, 2H), 3.67 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.30, 159.03 (q, 2 J C-F = 38.2 Hz, TFA), 157.05, 148.48, 141.85, 132.17, 129.18 (q, 2 J C-F = 31.9 Hz), 128.37, 125.80, 125.70 (q, 3 J C-F = 3.9 Hz), 124.59 (q, 1 J C-F = 270.1 Hz), 116.38, 115.60 (q, 1 J C-F = 286.5 Hz, TFA), 115.25, 98.29, 69.62, 33.54. HRMS (ESI): m / z calcd for C 17 H 15 F3N3O2 [M + H] + 350.1111, found 350.1110; HPLC purity: 100%.

[0187] Preparation method of Example 27 b13

[0188]

[0189] 4-Methoxyo-phenylenediamine (0.691 g, 5 mmol) and ethyl cyanoacetate (1.696 g, 15 mmol) were successively added to a sealed tube and stirred at 210 °C for 1.5 h. After the reaction was completed, the reaction solution was purified by column chromatography (DCM:methanol v / v = 50:1), the eluate containing the target compound was collected, concentrated, and dried to obtain 0.271 g of a red-brown solid intermediate of 2-(5-methoxy-1H-benzo[d]imidazol-2-yl)acetonitrile. The yield was 29%.

[0190] The above red-brown solid intermediate (0.234 g, 1.25 mmol) was dissolved in DMSO (3 mL), 30% hydrogen peroxide (1.133 g containing 10 mmol H2O2) and potassium carbonate (0.034 g, 0.25 mmol) were successively added, and the reaction was carried out at 25 °C for 3 h. After the reaction was completed, water (15 mL) was added to precipitate a pink solid, which was filtered by suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM:methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain 0.154 g of white solid b13. The yield was 60%. m.p. = 191.7 - 194.5 °C; 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.69 (s, 1H), 7.40–7.31 (m, 1H), 7.17 (s, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 2H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 167.05, 158.80 (q, 2 J C-F = 37.5 Hz, TFA), 158.15, 148.02, 132.56, 125.24, 115.58, 115.56 (q, 1 J C-F = 287.6 Hz, TFA), 114.86, 96.55, 55.98, 33.31. HRMS (ESI): m / z calcd for C 10 H 12 N3O2 [M+H] + 206.0924, found 206.0920; HPLC purity: 100%.

[0191] Preparation method of Example 28 b14

[0192]

[0193] 4-Fluoro-o-phenylenediamine (0.630 g, 5 mmol) and ethyl cyanoacetate (1.696 g, 15 mmol) were successively added into a sealed tube, and stirred at 210 °C for 1.5 h; after the reaction was completed, the reaction solution was purified by column chromatography (DCM: methanol v / v = 50:1), the eluate containing the target intermediate was collected, concentrated, and dried to obtain 0.280 g of a red-brown solid intermediate of 2-(5-fluoro-1H-benzo[d]imidazol-2-yl)acetonitrile. The yield was 32%.

[0194] The above red-brown solid intermediate (0.219 g, 1.25 mmol) was dissolved in DMSO (3 mL), 30% hydrogen peroxide (0.850 g containing 7.5 mmol H2O2) and potassium carbonate (0.034 g, 0.25 mmol) were successively added, and the reaction was carried out at 25 °C for 3 h; after the reaction was completed, water (15 mL) was added to precipitate a pink solid, which was filtered by suction, and the filter cake was collected. The filter cake was purified by column chromatography (DCM: methanol v / v = 20:1), the eluate containing the target compound was collected, concentrated, and dried to obtain 0.133 g of a off-white solid b14. The yield was 55%. m.p. = 203.3 - 206.1 °C; ESI-HRMS m / z calc for C9H9FN3O [M+H] + 194.0724, found 194.0721; 1 HNMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 7.55 (s, 1H), 7.41 (dd, J = 8.7, 2.0 Hz, 1H), 6.97 (s, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.7, 2.4 Hz, 1H), 3.44 (d, J = 2.9 Hz, 2H).

[0195] Preparation method of Example 29 b15

[0196]

[0197] The orange solid intermediate of formula 5 prepared according to Example 17 (1.311 g, 5 mmol) was added to DCM (15 mL) solvent in a round-bottom flask, and then acetyl chloride (0.589 g, 7.5 mmol) was slowly added dropwise; after the addition was completed, the reaction was carried out overnight at room temperature; after the reaction was completed, it was filtered by suction, and the filtrate was collected; the filtrate was concentrated under reduced pressure, slurried with methanol, and dried to obtain 1.111 g of an orange-yellow solid intermediate of N-(4-((3-fluorobenzyl)oxy)-2-nitrophenyl)acetamide. The yield was 73%.

[0198] The above orange-yellow solid intermediate (0.913 g, 3 mmol) was dissolved in 32 mL of a mixed solvent (ethanol:acetonitrile:water v / v / v = 2:1:1), ammonium chloride (1.284 g, 24 mmol) and zinc powder (1.569 g, 24 mmol) were added, and the mixture was vigorously stirred at 50 °C for 10 min; after the reaction was completed, filtration was carried out under suction and the filtrate was collected; after the filtrate was distilled under reduced pressure, it was extracted with DCM (100 mL) and saturated brine (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 0.667 g of the off-white solid intermediate shown in Formula 7. The yield was 81%.

[0199] The above white solid intermediate (0.549 g, 2 mmol) was dissolved in glacial acetic acid (10 mL), and the mixture was heated under reflux for 2 h; after the reaction was completed, it was extracted with EA (30 mL) and saturated brine (80 mL), the organic phase was collected, dried over anhydrous sodium sulfate and then distilled under reduced pressure, and dried to obtain light pink solid b15 (0.492 g). The yield was 96%. m.p. = 145.8 - 149.6 °C; 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 8.8 Hz, 1H), 7.48–7.40 (m, 1H), 7.36–7.28 (m, 2H), 7.27 (d, J = 2.4 Hz, 1H), 7.20–7.11 (m, 2H), 5.22 (s, 2H), 2.73 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, TFA) δ 162.39 (d, 1 J C-F = 242.3 Hz), 158.56 (q, 2 J C-F = 37.9 Hz, TFA), 156.49, 150.73, 139.76 (d, 3 J C-F = 7.3 Hz), 131.76, 130.63 (d, 3 J C-F = 8.4 Hz), 125.33, 123.65 (d, 4 J C-F = 2.7 Hz), 115.59, 115.30 (q, 1 J C-F = 286.8 Hz, TFA), 114.80 (d, 2 J C-F = 20.8 Hz), 114.54, 114.40 (d, 2 J C-F = 21.8 Hz), 97.71, 69.25 (d, 4 JC-F = 2.0 Hz), 12.26 HRMS (ESI): m / z calcd for C 15 H 14 FN2O [M+H] + 257.1085, found 257.1083; HPLC purity: 100%.

[0200] Pharmacological experimental data of some compounds in Example 30

[0201] 1. Determination of the inhibitory activity of compounds against MAO-B

[0202] Experimental method:

[0203] The MAO-B inhibitor screening kit (MAK296) used in this experiment was purchased from Sigma and stored at -20 °C for later use. Before the experiment, the enzyme, buffer, substrate, chromogenic agent, etc. in the kit were transferred to room temperature to thaw, and the enzyme and substrate solutions were prepared according to the instructions. The sample was dissolved in DMSO solution to prepare a stock solution, and then gradually diluted with buffer solution to the required concentrations (50 μM, 25 μM, 3.125 μM, 0.781 μM, 0.390 μM, 0.195 μM, 0.098 μM, 0.049 μM, 0.012 μM). Take 10 μL of the compound or positive drugs Pargyline and Safinamide to be tested and mix with 50 μL of the enzyme solution, then add them to a 9-six-well black flat bottom plate and incubate with shaking at 37 °C for 10 minutes. Then add 40 μL of the substrate solution (containing 1 μL of substrate tyrosine, 1 μL of chromogenic agent, 1 μL of horseradish peroxidase and 37 μL of buffer), and continuously detect the fluorescence value within 40 minutes (excitation: 535 nm; emission: 587 nm).

[0204] The results showed that the compounds prepared in Examples 1-29 of the present invention had good inhibitory effects on MAO-B. When the drug concentration was 1 μM, the inhibitory activity could reach up to 78.74%, significantly higher than that of the positive drug Pargyline; the IC 50 value of the best compound b3 was 67.3 nM, significantly better than the positive control drug Pargyline and comparable to the only clinically available reversible MAO-B inhibitor Safinamide.

[0205] Table 1. Inhibitory rate of Examples 1-29 against MAO-B at 1 μM

[0206]

[0207] Table 2. IC 50 value

[0208]

[0209]

[0210] Through the IC 50 value determination, it can be known that Example b2 (IC 50 = 125.5 ± 7.1 nM), Example b3 (IC 50 = 67.3 ± 1.5 nM) perform the best among all compounds.

[0211] 2. Parallel artificial membrane permeability test

[0212] Dissolve the test compounds b2 and b3 in DMSO at a concentration of 5 mg / mL, and then gradually dilute them with phosphate buffer solution (PBS) (pH = 7.4) to 25 μg / mL for testing. Dissolve an appropriate amount of porcine polar brain lipid (PBL, purchased from Avanti Polar Lipids, Inc) directly in dodecane at a concentration of 20 mg / mL. After the pretreatment of the entire filter membrane (area = 0.28 cm 2 ), add the prepared PBL solution to the surface of the filter membrane on the donor plate (4 μL per well), then add the test compound solution (V d ) to the donor plate (150 μL), and add 300 μL of PBS buffer solution (V a ) to the receiving well. After adding the solutions, carefully place the donor plate on the receptor plate so that the membrane contacts the upper and lower liquid surfaces. Cover the lid and let it stand in the dark at 25 °C for 6 hours, in parallel eight times. Measure the absorbance with a microplate reader. According to the Pe equation, calculate the concentration and permeability of the compound in the well. A is the filtration area, t is the permeation time, drug acceptor is the absorbance obtained in the receptor well, and drug equilibrium is the theoretical equilibrium absorbance.

[0213] Pe = -ln(1 – drug acceptor / drug equilibrium ) / [At(V d + V a ) / V d V a

[0214] Table 3. IC 50 values of inhibitory activities of some examples

[0215]

[0216] Pe ≥ 4, high BBB permeability; Pe ≤ 2, low BBB permeability; 2 < Pe < 4, uncertain BBB permeability. ​

[0217] It can be known from the parallel artificial membrane permeability experiment that both Example b2 and b3 can penetrate the blood-brain barrier.

[0218] 3. Pharmacokinetic experiment

[0219] Pharmacokinetic studies were performed on compound b3. All rats (190 ± 10 g) were divided into three groups (blank group, b3 gavage group, b3 intravenous injection group), and were strictly raised according to the requirements of the experimental animal operation procedures, at a temperature of (22 ± 2°C), with a 12-hour day-night cycle in a fixed environment. 12 hours before the experiment, the rats were fasted but could drink water freely. At each time point of 0.083, 0.25, 0.50, 0.70, 1.0, 4.0, 6.0, 6.0, 1.0, 1.0, 10, and 24 hours after administration, retro-orbital blood samples (0.3 mL) were taken from each rat into polyethylene tubes soaked in EDTA. The collected blood samples were centrifuged at 4000 rpm for 10 minutes at 4°C, 100 μL of the supernatant was taken, and it was stored in a -80°C refrigerator before use. Chromatographic separation experiments of biological samples were carried out on a 1260 HPLC system (Agilent, California, USA), which was equipped with a Triple Quad 4500 system (SCIEX, Bremen, Germany), using combined electrospray ionization (ESI) in the positive ion mode. Separation was carried out on a BEH C18 column (50 × 2.1 mm, 1.8 μm, Waters, Milford, MA, USA), and the column temperature was maintained at 35°C. The samples were eluted by isocratic elution with 30% A (0.2% formic acid aqueous solution) and 70% B (0.3% formic acid methanol) at a flow rate of 0.2 mL / min. The total running time of each sample was 5 minutes. The injection volume of the solution was 5 μL. The mass spectrometer was operated in the positive ion mode, and the multiple reaction monitoring (MRM) mode was selected for all analytes. The precursor-product ion pair for Y-3 was m / z 300.1 → 191.0 (DP 114.6 eV, CE 35.5 eV). The optimized MS parameter settings were as follows: collision gas (CAD) at 9 psi, curtain gas (CUR) at 30 psi, nebulizer gas (GS1) at 45 psi, N2 gas (GS2) heating at 40 psi, ion spray voltage at 5500 V, and temperature at 500°C. The results are as Figure 1 shown in Table 4.

[0220] Table 4. Pharmacokinetic parameters of rats (n = 4, mean ± SD)

[0221]

[0222] Analysis of the pharmacokinetic data showed that compound b3 exhibited good pharmacokinetic properties. It had a wide absorption distribution, was not easily accumulated in the body, and had a high bioavailability.

[0223] 4. In Vivo Blood-Brain Barrier Permeability Test

[0224] Prepare b3 into a clear PBS solution containing 0.2% DMSO and 10% cyclodextrin, and study the blood-brain barrier permeability of compound b3 in SD rats. Administer the compound to rats by gavage (17.5 mg / kg) and tail vein injection (4 mg / kg) respectively. According to the pharmacokinetic data, take out the brain tissue at 0.75 h (i.v. group) and 4 h (p.o. group), wash it with physiological saline until there is no blood stain, and dry the surface moisture with filter paper; then weigh the brain tissue. After homogenizing the brain tissue, add 0.5 mL of the homogenate to 1.5 mL of acetonitrile for protein precipitation, and then centrifuge twice at 4°C and 12,000 rpm for 10 min each time. Take the supernatant for injection. Detect the content of b3 in the brain tissue by the method 3 in Example 29. The results are shown in Table 5.

[0225] Table 5. Blood-Brain Barrier Permeability of Compound b3 in Rats (Mean ± SD)

[0226]

[0227] Analyze the content and find that compound b3 has good blood-brain barrier permeability in the rat brain.

Claims

1. A benzimidazole derivative represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof: In formula (I): R 1 、R 2 are each independently H, a halogen, a C1-C5 straight or branched alkyl, or a C1-C5 straight or branched alkoxy group; m is 0, 1 or 2; In formula (II): R 3 、R 4 each independently represents H, a halogen, a C1-C5 haloalkyl group, a C1-C5 straight-chain or branched alkyl group, or a C1-C5 straight-chain or branched alkoxy group; n is 0, 1 or 2.

2. The benzimidazole derivative represented by formula (I) or formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: In formula (I), R 1 , R 2 are each independently H, F, Cl, CH3 or OCH3; m is 1; in formula (II), R 3 , R 4 are each independently H, F, Cl, CF3, CH3 or OCH3; n is 1.

3. The benzimidazole derivative represented by formula (I) or formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The benzimidazole derivative represented by formula (I) or formula (II) is one of the following compounds:

4. Use of the benzimidazole derivative represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 3 in the preparation of a drug for treating or preventing diseases caused by overexpression of MAO - B.

5. The application according to claim 4, characterized in that: The diseases caused by overexpression of MAO - B are Parkinson's disease or Alzheimer's disease.

6. The application according to claim 4, characterized in that: The benzimidazole derivative represented by formula (I) or formula (II) is the compound represented by formula b2, b3, b5, b6, b8 or b12; 7. A method for preparing the benzimidazole derivative represented by formula (I), characterized in that The method comprises the following steps: (1) Dissolve 2 - cyanomethyl - 5 - carboxy - 1H - benzimidazole represented by formula 2 in organic solvent A, successively add basic substance A and 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, stir evenly at room temperature, then add aniline compound represented by formula 9, and stir at room temperature for 3 - 18 h. The obtained reaction solution A is subjected to post - treatment A to obtain the compound represented by formula 3; the molar ratio of 2 - cyanomethyl - 5 - carboxy - 1H - benzimidazole represented by formula 2, basic substance A, 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate to aniline compound represented by formula 9 is 1:1 - 3:1 - 1.5:0.5 - 1.5; the basic substance A is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, triethylamine; the organic solvent A is one or a mixture of two or more of acetonitrile, N,N - dimethylformamide (DMF), methanol, ethanol, acetonitrile, dichloromethane, and the volume of the organic solvent A based on the molar amount of the compound represented by formula 2 is 1 - 2 mL / mmol; (2) The compound represented by formula 3 in step (1) reacts in concentrated hydrochloric acid at 40 °C for 35 - 50 min. The obtained reaction solution B is subjected to post - treatment B to obtain the benzimidazole derivative represented by formula (I); In Formulae 9, 3, (I), R 1 , R 2 are each independently H, halogen, a C1-C5 straight or branched alkyl, or a C1-C5 straight or branched alkoxy; m is 0, 1 or 2.

8. The preparation method of the benzimidazole derivative represented by formula (I) according to claim 7, characterized in that: In step (1), the organic solvent A is one or a mixture of two or more of acetonitrile, N,N - dimethylformamide, methanol, ethanol, acetonitrile, dichloromethane; the volume of the organic solvent A based on the molar amount of the compound represented by formula 2 is 1 - 2 mL / mmol; the post - treatment A is: add saturated brine, extract with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate; distill off the solvent under reduced pressure, perform column chromatography separation using a mixed solution of dichloromethane and methanol with a volume ratio of 30:1 as the eluent, collect the eluate containing the target intermediate, concentrate, and dry to obtain the compound represented by formula 3; In step (2), the volume of the concentrated hydrochloric acid is 2 - 4 mL / mmol based on the amount of substance of the compound shown in Formula 3; the post-treatment B is as follows: adjusting the pH of the reaction solution B to neutral with saturated sodium bicarbonate solution, precipitating a solid, performing suction filtration, subjecting the obtained filter cake to column chromatography separation using a mixed solution of dichloromethane and methanol with a volume ratio of 20:1 as the eluent, collecting the eluent containing the target compound, concentrating, and drying to obtain the benzimidazole derivative shown in Formula (I).

9. A method for preparing a benzimidazole derivative represented by formula (II), characterized in that The method comprises the following steps: S1: Dissolve the compound shown in Formula 5 in solvent D, add 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and base D, stir at room temperature for 5 min, and then add cyanoacetic acid; stir at room temperature for 5 - 10 h, and subject the obtained reaction solution D to post-treatment D to obtain the compound shown in Formula 6; the molar ratio of the compound shown in Formula 5, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, base D, and cyanoacetic acid is 1:1 - 2:1.5 - 2.5:1 - 1.5; the solvent D is one or a mixture of two or more of water, toluene, acetonitrile, dichloromethane (DCM), methanol, ethanol, and N,N-dimethylformamide (DMF); the volume of the solvent D is 1 - 3 mL / mmol based on the amount of substance of the compound shown in Formula 5; S2: Dissolve the compound shown in Formula 6 obtained in step S1 in a mixed solvent E, successively add Zn powder and NH4Cl, stir and react at 50 °C for 10 min, and subject the obtained reaction solution E to post-treatment E to obtain the compound shown in Formula 7; the molar ratio of the compound shown in Formula 6, Zn powder, and NH4Cl is 1:5 - 10:5 - 10; S3: Dissolve the compound shown in Formula 7 obtained in step S2 in acetic acid, reflux and react for 2 h, and subject the obtained reaction solution G to post-treatment G to obtain the compound shown in Formula 8; S4: Dissolve the compound shown in Formula 8 obtained in step S3 in solvent Q, successively add 30% hydrogen peroxide by mass and base Q, stir at 25 °C for 3 - 8 h, and subject the obtained reaction solution Q to post-treatment Q to obtain the benzimidazole derivative shown in Formula (II); the molar ratio of the compound shown in Formula 8, hydrogen peroxide contained in hydrogen peroxide, and base Q is 1:5 - 12:0.2 - 0.5; In Formulas 5, 6, 7, 8, and (II), R 3 , R 4 are each independently H, halogen, C1-C5 haloalkyl, C1-C5 straight or branched alkyl, or C1-C5 straight or branched alkoxy; and n is 0, 1, or 2.

10. The preparation method of the benzimidazole derivative represented by formula (II) as described in claim 9, characterized in that: In step S1, the solvent D is one or a mixture of two or more of water, toluene, acetonitrile, dichloromethane, methanol, ethanol, and N,N-dimethylformamide; the volume of the solvent D is 1 - 3 mL / mmol based on the amount of substance of the compound shown in Formula 5; the base D is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine; the post-treatment D is as follows: distilling off part of the solvent from the reaction solution D under reduced pressure, performing suction filtration, washing the obtained filter cake A with methanol, slurrying the obtained filter cake B with methanol, performing suction filtration, and drying the obtained filter cake C to obtain the compound shown in Formula 6; In step S2, the mixed solvent E is a mixed solvent of water and organic solvent E. The organic solvent E is one or a mixture of two or more of toluene, acetonitrile, dichloromethane, methanol, ethanol, and N,N-dimethylformamide. The volume of the mixed solvent E is 8-12 mL / mmol based on the amount of substance of the compound shown in Formula 6. The post-treatment E is as follows: The reaction solution E is suction filtered, and the obtained filtrate is distilled under reduced pressure, then extracted with dichloromethane and saturated brine. The obtained organic phase is dried with anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound shown in Formula 7. In step S3, the volume of acetic acid is 5-8 mL / mmol based on the amount of substance of the compound shown in Formula 7. The post-treatment G is as follows: The reaction solution G is extracted with ethyl acetate and saturated brine. The obtained organic phase is dried with anhydrous sodium sulfate and distilled under reduced pressure to obtain the compound shown in Formula 8. In step S4, the solvent Q is one or a mixture of two or more of water, methanol, acetonitrile, dichloromethane, ethanol, dimethyl sulfoxide, and N,N-dimethylformamide. The volume of the solvent Q is 1-3 mL / mmol based on the amount of substance of the compound shown in Formula 8. The basic substance Q is one or a mixture of two or more of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, and sodium hydroxide. The post-treatment Q is as follows: Water is added to the reaction solution Q to precipitate a solid, and then suction filtered. The obtained filter cake is purified by column chromatography using a mixed solution of dichloromethane and methanol with a volume ratio of 20:1 as the eluent. The eluate containing the target compound is collected, concentrated, and dried to obtain the benzimidazole derivative shown in (II).

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