Benzimidazole compound and application thereof

Abstract

The invention discloses a benzimidazole compound and an application thereof. The compounds have strong affinity with Snail protein, can effectively inhibit the activity of Snail, can significantly reduce the generation of in vivo atherosclerotic plaques, and also have pharmacokinetic properties beneficial to patent medicines. And # imgabs0 # I is adopted.

Description

Technical Field

[0001] The invention relates to a benzimidazole compound and application thereof, in particular to a benzimidazole compound with Snail inhibitory activity and application thereof. Background Art

[0002] Snail protein is a regulatory zinc finger transcription factor that contains four zinc finger structures. Its function and sequence are highly conserved in different species. Snail binds to downstream target gene promoters through the zinc finger structure in the protein structure, participates in downstream gene transcription, inhibits chromatin structure formation, and maintains normal biological functions of the body.

[0003] Studies have shown that Snail has the effect of promoting cell migration, inhibiting the secretion of epithelial cell adhesion molecules, and leading to the occurrence of epithelial-mesenchymal transition (EMT). During the EMT process, the gene expression of epithelial cells in some parts of the body changes dramatically, the key cell adhesion molecule protein E-cadherin is downregulated, the peripheral components of the cells are transformed and degraded, and the connection between cells is lost, thereby increasing the migration characteristics of the cells and enabling the cells to migrate to other parts. At the same time, low shear stress can induce endothelial cell dedifferentiation through EMT, and this process depends on the regulation of Snail protein. Gene silencing found that Snail can positively regulate the expression of EMT markers in endothelial cells under low shear stress, and can also enhance the permeability of monolayer endothelial cells to macromolecules by promoting endothelial cell proliferation and migration. In addition, Snail is also expressed in endothelial cells on coronary atherosclerotic plaques in patients with ischemic heart disease, indicating that Snail also plays a role in human arterial disease and is an important driver of EMT.

[0004] CN115433167 discloses a type of benzoheterocyclic compound. Although these compounds have a certain affinity with Snail protein, their pharmacokinetic properties and oral bioavailability are still far from being druggable. Summary of the invention

[0005] Objectives of the invention: The first objective of the present invention is to provide a benzimidazole compound having Snail inhibitory activity, and the second objective is to provide a pharmaceutical application of the compound.

[0006] Technical solution: The benzimidazole compound or a pharmaceutically acceptable salt thereof of the present invention, wherein the compound has a structure of Formula I: I, In the structure described: X is selected from substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 N, O, S ring heteroatoms, substituted or unsubstituted 5-10 membered heterocyclyl containing 1-4 N, O, S ring heteroatoms, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted C1-C6 straight chain or branched alkyl thioether, monosubstituted or disubstituted C1-C6 straight chain or branched alkyl substituted amino; Y is selected from CH or nitrogen; R 1 Selected from hydrogen, halogen, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 straight chain or branched alkynyl, phenyl, hydroxyl, aldehyde, carboxyl, -OC(O)-(C1-C6 straight chain or branched alkyl), amino, -NHCO-(C1-C6 straight chain or branched alkyl); The substituent is selected from the group consisting of hydrogen, halogen, unsubstituted or halogen substituted or C3-C6 cycloalkyl substituted C1-C6 straight or branched alkyl, C1-C4 straight or branched alkoxy, C3-C6 cycloalkyl, C1-C4 straight or branched alkyl substituted amino, hydroxyl, cyano, nitro, =O, carboxyl, thiol, -OSO 2 -(C1-C6 straight or branched alkyl), unsubstituted or 1-3 halogen-substituted or hydroxy-substituted C5-C10 aryl, unsubstituted or halogen-substituted 5-7 membered heterocyclic group containing 1-4 N, O, S ring heteroatoms, unsubstituted or halogen-substituted C2-C6 straight or branched acyl, C1-C6 straight or branched hydroxyalkyl.

[0007] Preferably, in the structure: X is selected from substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 N, O, S ring heteroatoms, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-3 N, O, S ring heteroatoms, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted C1-C6 straight chain or branched alkyl thioether, monosubstituted or disubstituted C1-C6 straight chain or branched alkyl substituted amino; Y is selected from CH or nitrogen; The substituent is selected from hydrogen, halogen, unsubstituted or halogen substituted or C3-C6 cycloalkyl substituted C1-C6 straight or branched alkyl, C1-C4 straight or branched alkoxy, C3-C6 cycloalkyl, C1-C4 straight or branched alkyl substituted amino, hydroxyl, cyano, nitro, =O, carboxyl, thiol, -OS(O) 2-(C1-C6 straight chain or branched alkyl), unsubstituted or 1-3 halogen-substituted or hydroxy-substituted C5-C10 aryl, unsubstituted or halogen-substituted 5-7 membered heterocyclyl containing 1-4 N, O, S ring heteroatoms, unsubstituted or halogen-substituted C2-C6 straight chain or branched acyl, C1-C6 straight chain or branched hydroxyalkyl.

[0008] Preferably, in the structure: R 1 Selected from hydrogen, halogen, C1-C4 straight chain or branched alkyl, C1-C4 straight chain or branched alkoxy, hydroxyl, carboxyl, and amino.

[0009] Preferably, in the structure: X is selected from substituted or unsubstituted 5-6 membered heteroaryl containing 1-2 N, O, S ring heteroatoms, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-2 N, O, S ring heteroatoms, substituted or unsubstituted C1-C4 straight chain or branched alkoxy, monosubstituted or disubstituted C1-C4 straight chain or branched alkyl substituted amino; The substituent is selected from hydrogen, halogen, unsubstituted or halogen substituted or C3-C6 cycloalkyl substituted C1-C6 straight or branched alkyl, C1-C4 straight or branched alkoxy, C3-C6 cycloalkyl, C1-C4 straight or branched alkyl substituted amino, hydroxyl, cyano, nitro, =O, carboxyl, thiol, -OS(O) 2 -(C1-C6 straight chain or branched alkyl), unsubstituted or 1-3 halogen-substituted or hydroxy-substituted C5-C10 aryl, unsubstituted or halogen-substituted 5-7 membered heterocycle containing 1-4 N, O, S ring heteroatoms, unsubstituted or halogen-substituted C2-C6 straight chain or branched acyl, C1-C6 straight chain or branched hydroxyalkyl.

[0010] Preferably, in the structure, X is selected from any one of the following chemical structures: , , , , , , , , , , , , , , , , , , , , .

[0011] Preferably, in the structure: R 1 Selected from hydrogen, fluorine, methyl, methoxy, hydroxy, carboxyl, and amino.

[0012] Preferably, the compound of the present invention is selected from any one of the following compounds:

[0013]

[0014] .

[0015] Wherein, the pharmaceutically acceptable salt is a salt formed by the benzimidazole compound and any one of the following acids: hydrochloric acid, carbonic acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

[0016] The benzimidazole compounds of the present invention, when R 1 When it is methyl or hydrogen, its preparation method is selected from any one of the following methods: Method 1: .

[0017] Specifically, step a: dissolving the raw material 4-bromo-2-nitroaniline 1-1 in acetone, adding sodium hydroxide and benzyl bromide, and reacting at room temperature to obtain intermediate 1-2; step b: CN coupling or CC coupling of intermediate 1-2 with compound XH to obtain intermediate 1-3; step c: dissolving intermediate 1-3 in methanol, 2 Step d: dissolving the intermediate 1-4 in ethanol, and then adding CS 2 and KOH at 70°C to obtain intermediate 1-5; step e: dissolving intermediate 1-5 in acetonitrile, adding NaOH and raw material 1-6, and reacting at room temperature to obtain the compound shown in formula I.

[0018] Method 2: .

[0019] Specifically, step a: dissolve the raw material 3,4-dinitrofluorobenzene 2-1 in DMF, add compounds XH and K 2 CO 3 , react at 90 °C to obtain intermediate 2-2; step b: dissolve intermediate 2-2 in methanol and 2Step c: dissolving the intermediate 2-3 in ethanol, and then adding CS 2 and KOH at 70°C to obtain intermediate 2-4; step d: dissolve intermediate 2-4 in acetonitrile, add NaOH and raw material 1-6, and react at room temperature to obtain the compound shown in formula I.

[0020] Wherein, the definitions of X and Y are as described above.

[0021] The pharmaceutically acceptable salt of the present invention is obtained by reacting the compound I prepared by the above method with a pharmaceutically acceptable acid. Generally, the salt is prepared by reacting the compound in the form of a free base with a stoichiometric amount of an acid in water or an organic solvent or a mixture of the two.

[0022] The pharmaceutical composition of the present invention comprises the benzimidazole compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0023] The pharmaceutically acceptable carrier can be an adjuvant widely used in the field of drug production. The adjuvant is mainly used to provide a safe, stable and functional pharmaceutical composition, so that the active ingredient dissolves at a desired rate after the subject receives the administration, or promotes the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical adjuvant can be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical adjuvant can include one or more of the following adjuvants: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, sweeteners.

[0024] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art, for example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding, and freeze-drying.

[0025] The pharmaceutical composition of the present invention can be administered in any form, including mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical, parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or sustained release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, hard capsules, caplets, soft capsules, tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, emulsions for injection. Examples of other preparation forms include, but are not limited to, eye drops, other ophthalmic preparations; aerosols, such as nasal sprays, inhalants; suppositories and lozenges suitable for parenteral administration.

[0026] The benzimidazole compound or its pharmaceutically acceptable salt or its pharmaceutical composition described in the present invention is used in preparing a drug for treating atherosclerosis.

[0027] Preferably, the drug is a Snail inhibitor drug.

[0028] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: The compound designed by the present invention has significant anti-atherosclerotic activity by forming a good binding effect with Snail protein (affinity reaches micromolar concentration level), and the pharmacokinetic property is conducive to salt formation, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The figures are the comparison results of the atherosclerotic plaque volumes before and after administration of the compound of the present invention. DETAILED DESCRIPTION

[0030] The technical solution of the present invention is further described below in conjunction with embodiments.

[0031] Example 1: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(tetrahydro-1 H -pyrrol-1-yl)-1 H -Benzo[ d ] Imidazole (1)

[0032] Refer to synthesis method 1: Step a: N -Benzyl-4-bromo-2-nitroaniline (1-2) 4-Bromo-2-nitroaniline (5.00 g, 0.020 mol) was dissolved in acetone (25 mL), sodium hydroxide (1.80 g, 0.460 mol) was added, stirred for 10 min, and finally benzyl bromide (4.70 g, 0.030 mol) was added. The reaction was carried out at room temperature for 4 h. TLC was monitored until the reaction was complete. The solvent was evaporated, and the mixture was slurried with petroleum ether. The yellow solid (6.0 g) was obtained by suction filtration. The yield was 84.79%. 1 HNMR (400 MHz, CDCl 3 ) d 8.30 (d, J = 1.5 Hz, 1H), 7.61 (dd, J = 7.5, 1.5 Hz,1H), 7.40-7.29 (m, 5H), 7.28-7.21 (m, 1H), 6.74 (d, J = 7.5 Hz, 1H), 4.43(dt, J = 7.7, 1.0 Hz, 2H); ESI-MS m / z: 312.1 calcd for C 22 H 20 N 2 [M+H] + 313.1.

[0033] Step b: 1-[4-(Benzylamino)-3-nitrophenyl]tetrahydropyrrole (1-3) The intermediate 1-2 (3.00 g, 0.010 mol) was dissolved in redistilled toluene, and tetrahydropyrrole (1.02 g, 0.011 mol), cesium carbonate (6.42 g, 0.011 mol), tris(dibenzylideneacetone)dipalladium (0.92 g, 0.001 mol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.64 g, 0.001 mol) were added. The reaction was carried out at 100 °C for 18 h. TLC was used to monitor the reaction until it was complete. After the reaction was completed, diatomaceous earth was used for filtration, and the filtrate was evaporated to dry the solvent. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was allowed to stand, the solvent was evaporated to dryness, and column chromatography was performed to obtain 1.9 g of a purple solid with a yield of 62.08%. 1 H NMR (400 MHz, CDCl 3 ) d 7.96 (d, J = 1.5 Hz, 1H), 7.37(ddt, J= 7.2, 1.7, 0.9 Hz, 2H), 7.38-7.29 (m, 2H), 7.28-7.21 (m, 1H), 7.19(dd, J = 7.5, 1.5 Hz, 1H), 6.76 (t, J = 7.7 Hz, 1H), 6.68 (d, J = 7.4 Hz,1H), 4.43 (dt, J = 7.7, 1.0 Hz, 2H), 3.55-3.44 (m, 4H), 2.06-1.95 (m, 4H).

[0034] Step c: 4-(tetrahydro-1 H -pyrrol-1-yl)benzene-1,2-diamine (1-4) The intermediate 1-3 (1.00 g, 0.003 mol) was dissolved in methanol (25 mL), and palladium carbon (0.15 g, 0.005 mol) was added. The reaction was carried out at room temperature under hydrogen for 18 h. The reaction was monitored by TLC until it was complete. After the reaction, the reaction solution was filtered through diatomaceous earth, the filtrate was evaporated to dryness, and the obtained solid was washed with solvent (petroleum ether: ethyl acetate = 4:1) to obtain 500 mg of black solid. The yield was 83.88%. 1 H NMR (400 MHz, CDCl 3 ) d 6.30 (d, J = 7.5 Hz, 1H), 6.24 (dd, J =7.5, 1.5 Hz, 1H), 5.95 (d, J = 1.5 Hz, 1H), 4.93 (d, J = 7.3 Hz, 1H), 4.80(d, J = 7.5 Hz, 1H), 4.57 (d, J = 7.3 Hz, 1H), 4.47 (d, J = 7.5 Hz, 1H), 3.51-3.42 (m, 2H), 3.42-3.33 (m, 2H), 2.07-1.97 (m, 4H).

[0035] Step d: 5-(tetrahydro-1 H -pyrrol-1-yl)-1 H -Benzo[ d ]Imidazole-2-thiophenol (1-5) Compound 1-4 (0.50 g, 0.003 mol) was dissolved in anhydrous ethanol, potassium hydroxide (0.32 g, 0.005 mol) and carbon disulfide (0.26 g, 0.004 mol) were added, and the mixture was reacted at 90 °C for 12 h. The reaction was monitored by TLC until completion. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain 420 mg of a yellow solid. The yield was 67.89%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.29 (d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 6.91 (d, J = 1.5 Hz, 1H), 6.28 (s, 1H), 3.51 – 3.42 (m, 2H), 3.39-3.30 (m, 2H), 2.08-1.97 (m, 5H).

[0036] Step e: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(tetrahydro-1 H -pyrrol-1-yl)-1 H -Benzo[ d ] Imidazole (1) Compound 1-5 (0.20 g, 0.001 mol) was dissolved in acetonitrile (10 mL), and sodium hydroxide (0.07 g, 0.002 mol) and 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride (0.29 g, 0.001 mol) were added. The mixture was reacted at room temperature for 4 h and monitored by TLC until the reaction was complete. After the reaction, the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, allowed to stand, concentrated, and subjected to column chromatography to obtain 265 mg of a light yellow solid with a yield of 70.43%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.4Hz, 1H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 6.95 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.35 (s, 1H), 4.09 (t,J = 7.1 Hz, 2H), 3.55-3.47 (m, 6H), 3.18 (s, 2H), 2.25 (s, 2H), 2.11-1.97 (m, 6H); ESI-MS m / z: 412.2 calcd forC 22 H 28 N 4 O 2 S [M+H] + 413.2.

[0037] Example 2: 5-(isoxazol-4-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (13)

[0038] The intermediate 1-2 (1.00 g, 0.010 mol) was dissolved in 1,4-dioxane, and isoxazole-4-boric acid (1.32 g, 0.011 mol), potassium carbonate (2.70 g, 0.019 mol), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (0.74 g, 0.001 mol) were added. The reaction was carried out at 100 °C for 18 h. The reaction was monitored by TLC until the reaction was complete. After the reaction was completed, the filtrate was filtered with diatomaceous earth, the solvent was evaporated, water was added to the residue, and it was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was allowed to stand, the solvent was evaporated, and column chromatography was performed to obtain 1.8 g of the intermediate 4-[4-(benzylamino)-3-nitrophenyl]isoxazole as an orange-red solid with a yield of 62.41%. 1 H NMR (400 MHz, CDCl 3 ) d 8.90 (d, J = 1.5 Hz, 1H), 8.43(d, J = 1.5 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 7.5, 1.5 Hz,1H), 7.41 (t, J = 7.7 Hz, 1H), 7.37 (ddt, J = 7.2, 1.7, 1.0 Hz, 2H), 7.36-7.29 (m, 2H), 7.28-7.21 (m, 1H), 7.17 (d, J= 7.5 Hz, 1H), 4.45 (dt, J = 7.7,1.0 Hz, 2H).

[0039] Compound 13 can be obtained by treating 4-[4-(benzylamino)-3-nitrophenyl]isoxazole according to the procedures of steps c to d in Example 1. The yield is 63.51%. 1 H NMR (400 MHz, DMSO) d 12.57 (s, 1H),8.51 (d, J =1.4 Hz, 1H), 8.43 (d, J = 1.4 Hz, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.88 (dd, J = 7.5, 1.5 Hz, 1H), 7.76-7.69 (m, 2H), 6.87 (d, J = 7.5 Hz, 1H), 4.36 (s,2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.25(s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 410.2 calcd for C 21 H 22 N 4 O 3 S [M+H] + 411.2.

[0040] Example 3: 5-(dimethylamino)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (10)

[0041] Refer to synthesis method 2: Step a: (3,4-Dinitrophenyl)dimethylamine (2-2) Dissolve 4-fluoro-1,2-dinitrobenzene (0.50 g, 0.003 mol) in DMF (15 mL), add potassium carbonate (0.74 g, 0.005 mol) and dimethylamine (0.18 mg, 0.004 mol), react at 100 °C for 6 h, monitor the reaction by TLC until the reaction is complete, add water after the reaction is complete, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, stand, evaporate the solvent, and perform column chromatography to obtain 455 mg of a yellow solid with a yield of 80.19%. 1 H NMR (400 MHz, CDCl 3 ) δ8.26 (d, J = 1.4 Hz, 1H), 8.06 (d, J = 7.5 Hz, 1H), 7.19 (dd, J = 7.5, 1.5Hz, 1H), 2.96 (s, 6H).

[0042] Step b: 4-(Dimethylamino)benzene-1,2-diamine (2-3) The intermediate 2-2 (0.45 g, 0.002 mol) was dissolved in methanol (10 mL), and palladium carbon (0.09 g, 0.001 mol) was added. The reaction was carried out at room temperature under hydrogen for 8 h. The reaction was monitored by TLC until it was complete. After the reaction was completed, the reaction solution was filtered with diatomaceous earth, and the solvent was evaporated to dryness to obtain 260 mg of black solid. The yield was 79.80%. 1 H NMR (400 MHz, DMSO) d 6.41(dd, J = 7.5, 1.5 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 5.95 (d, J = 1.5 Hz,1H), 4.81 (dd, J = 7.3, 6.6 Hz, 2H), 4.65 (d, J = 7.5 Hz, 1H), 4.60 (d, J =7.1 Hz, 1H), 2.96 (s, 6H).

[0043] Step c: 5-(dimethylamino)-1 H -Benzo[ d ]Imidazole-2-thiophenol (2-4) Compound 2-3 (0.26 g, 0.002 mol) was dissolved in anhydrous ethanol, potassium hydroxide (0.19 g, 0.003 mol) and carbon disulfide (0.16 g, 0.002 mol) were added, and the mixture was reacted at 90 °C for 12 h. The reaction was monitored by TLC until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain 185 mg of a yellow solid. The yield was 55.67%. 1 H NMR (400 MHz, CDCl 3 ) d 7.01 (s,1H), 7.31 (d, J = 7.5 Hz, 1H), 7.01 (dd, J = 7.5, 1.5 Hz, 1H), 6.97 (d, J =1.6 Hz, 1H), 5.58 (s, 1H), 2.98 (s, 6H).

[0044] Step d: 5-(dimethylamino)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (10) Compound 2-4 (0.10 mg, 0.500 mmol) was dissolved in acetonitrile (10 mL), and sodium hydroxide (0.04 mg, 0.600 mmol) and 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride (0.17 g, 0.001 mol) were added. The mixture was reacted at room temperature for 4 h and monitored by TLC until the reaction was complete. After the reaction, the solvent was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, allowed to stand, concentrated, and subjected to column chromatography to obtain 115 mg of a light yellow solid with a yield of 55.67%. 1 H NMR (400 MHz, DMSO) d 12.70 (s, 1H), 8.40 (d, J = 7.5 Hz,2H), 7.40 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 1.5 Hz, 1H), 6.87 (d, J = 7.5 Hz,1H), 4.39 (s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.53 (t, J= 7.1 Hz, 2H), 3.19(s, 3H), 2.98 (s, 6H), 2.24 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z:386.2 calcd for C 20 H 26 N 4 O 2 S [M+H] + 387.2.

[0045] Example 4: 5-(Hexahydropyridin-1-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (2)

[0046] In this example, tetrahydropyrrole was replaced with piperidine, and the product (135 mg) was obtained according to the operation of Example 1, with a yield of 62.38%. 1 H NMR (400 MHz, DMSO) d 12.50 (s, 1H), 8.36 (d, J = 7.5 Hz, 1H), 7.43(d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.5, 1.6 Hz, 1H), 6.96 (d, J = 1.5 Hz,1H), 6.87 (d, J = 7.5 Hz, 1H), 4.35 (s, 2H), 4.10 (t, J = 7.1 Hz, 3H), 3.52(t, J = 7.1 Hz, 3H), 3.42 (t, J = 7.0 Hz, 5H), 3.19 (s, 3H), 2.23 (s, 3H), 2.08 (p, J = 7.1 Hz, 3H), 1.67 (pd, J = 7.0, 1.0 Hz, 6H), 1.63-1.57 (m, 3H);ESI-MS m / z: 426.2 calcd for C 23 H 30 N 4 O2 S [M+H] + 427.2.

[0047] Example 5: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(1,4-oxazacyclohexane-4-yl)-1 H -Benzo[ d ] Imidazole (3)

[0048] In this example, tetrahydropyrrole was replaced with morpholine, and the procedure of Example 1 was followed to obtain 142 mg of the product with a yield of 64.27%. 1 H NMR (400 MHz, DMSO) d 12.20 (s, 1H), 8.36 (d, J = 7.5 Hz, 1H), 7.41(d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 6.95 (d, J = 1.5 Hz,1H), 6.87 (d, J = 7.5 Hz, 1H), 4.35 (s, 2H), 4.10 (t, J = 7.1 Hz, 2H), 3.80(t, J = 7.1 Hz, 4H), 3.52 (t, J = 7.1 Hz, 2H), 3.28 (t, J = 7.1 Hz, 4H), 3.19(s, 3H), 2.23 (s, 3H), 2.08 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 428.2 calcd forC 22 H 28 N 4 O 3 S [M+H] + 429.2.

[0049] Example 6: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(piperazin-1-yl)-1 H -Benzo[ d ] Imidazole (4)

[0050] In this embodiment, tetrahydropyrrole is replaced by N -Boc-piperazine, according to the operation of Example 1, finally using trifluoroacetic acid (65 mg, 0.5 mmol) and dichloromethane (10 mL), reacting at room temperature for 4 h to obtain 125 mg of the product, with a yield of 52.14%. 1 H NMR (400 MHz, DMSO) d 12.82 (s, 1H), 8.36 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.01 (dd, J = 7.5, 1.5 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H), 6.87(d, J = 7.5 Hz, 1H), 4.35 (s, 2H), 4.10 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1Hz, 2H), 3.31 (t, J = 7.0 Hz, 4H), 3.19 (s, 3H), 3.07 (td, J = 7.1, 5.0 Hz,4H), 2.23 (s, 3H), 2.08 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 427.2 calcd forC 22 H 29 N 5 O 2 S [M+H] + 428.2.

[0051] Example 7: 5-(Imidazol-1-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (5)

[0052] In this example, tetrahydropyrrole was replaced with imidazole, and the operation according to Example 1 was followed to obtain 133 mg of the product with a yield of 65.15%. 1 H NMR (400 MHz, DMSO) d12.52 (s, 1H), 8.41-8.36 (m, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.23 (dd, J = 7.5, 1.6 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 4.39(s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 409.2 calcd for C 21 H 23 N 5 O 2 S[M+H] + 410.2.

[0053] Example 8: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(pyrazol-1-yl)-1 H -Benzo[ d ] Imidazole (6)

[0054] In this example, tetrahydropyrrole was replaced with pyrazole, and the procedure of Example 1 was followed to obtain 148 mg of the product with a yield of 63.56%. 1 H NMR (400 MHz, DMSO) d 12.32 (s, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.96-7.90 (m, 2H), 7.73 (dd, J = 7.5, 1.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.49(dd, J = 7.5, 1.5 Hz, 1H), 6.87 (d, J= 7.5 Hz, 1H), 6.49 (t, J = 7.5 Hz,1H), 4.39 (s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18(s, 3H), 2.25 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 409.2 calcd forC 21 H 23 N 5 O 2 S [M+H] + 410.2.

[0055] Example 9: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(pyrrol-1-yl)-1 H -Benzo[ d ] Imidazole (7)

[0056] In this example, tetrahydropyrrole was replaced with pyrrole, and the product (152 mg) was obtained according to the operation of Example 1, with a yield of 68.72%. 1 H NMR (400 MHz, DMSO) d 12.70 (s, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.64(d, J = 1.6 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.29 (dd, J = 7.5, 1.5 Hz,1H), 7.01 (dd, J = 5.6, 3.5 Hz, 2H), 6.87 (d, J = 7.5 Hz, 1H), 6.21 (dd, J =5.5, 3.4 Hz, 2H), 4.39 (s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1Hz, 2H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J= 7.1 Hz, 2H); ESI-MS m / z:408.1 calcd for C 22 H 24 N 4 O 2 S [M+H] + 409.1.

[0057] Example 10: 5-(2,5-dimethylpyrrol-1-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (8)

[0058] In this example, tetrahydropyrrole was replaced with 2,5-dimethylpyrrole, and the product (125 mg) was obtained according to the operation of Example 1, with a yield of 62.15%. 1 H NMR (400 MHz, DMSO) d 12.54 (s, 1H), 8.37 (d, J = 7.5 Hz,1H), 7.60 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 7.5,1.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 5.65 (s, 2H), 4.35 (s, 2H), 4.11 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.19 (s, 3H), 2.23 (s, 3H), 2.19 (s,6H), 2.08 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 436.2 calcd for C 24 H 28 N 4 O 2 S [M+H] + 437.2.

[0059] Example 11: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(3-methylpyrrol-1-yl)-1 H -Benzo[d ] Imidazole (9)

[0060] In this example, tetrahydropyrrole was replaced with 3-methylpyrrole, and the product (134 mg) was obtained according to the operation of Example 1, with a yield of 63.74%. 1 H NMR (400 MHz, DMSO) d 12.64 (s, 1H), 8.36 (d, J = 7.5 Hz, 1H),7.67 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.28 (dd, J = 7.5, 1.5Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.91 (t, J = 1.2 Hz, 1H), 6.87 (d, J = 7.5Hz, 1H), 6.13 (ddq, J = 7.5, 1.5, 0.8 Hz, 1H), 4.35 (s, 2H), 4.10 (t, J = 7.1Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.31 (d, J = 0.8 Hz, 3H),2.24 (s, 3H), 2.08 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 422.2 calcd for C 23 H 26 N 4 O 2 S[M+H] + 423.2.

[0061] Example 12: 5-(Diethylamino)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (11)

[0062] In this example, dimethylamine was replaced with diethylamine, and the operation according to Example 3 was followed to obtain 157 mg of the product with a yield of 58.45%. 1 H NMR (400 MHz, DMSO) d 12.74 (s, 1H), 8.36 (d, J = 7.5 Hz, 1H), 7.37(d, J = 7.6 Hz, 1H), 7.04 (dd, J = 7.5, 1.5 Hz, 1H), 6.98 (d, J = 1.5 Hz,1H), 6.85 (d, J = 7.5 Hz, 1H), 4.35 (s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.57-3.42 (m, 6H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H), 1.17 (t, J = 8.0 Hz, 6H); ESI-MS m / z: 414.2 calcd for C 22 H 30 N 4 O 2 S [M+H] + 415.2.

[0063] Example 13: 5-(Dipropylamino)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (12)

[0064] In this example, dimethylamine was replaced with di-n-propylamine, and the operation according to Example 3 was followed to obtain 172 mg of the product with a yield of 60.54%. 1 H NMR (400 MHz, DMSO) d 12.54 (s, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.44(d, J = 7.6 Hz, 1H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 6.98 (d, J= 1.6 Hz,1H), 6.87 (d, J = 7.5 Hz, 1H), 4.35 (s, 2H), 4.10 (t, J = 7.1 Hz, 2H), 3.52(t, J = 7.1 Hz, 2H), 3.26 (t, J = 7.1 Hz, 4H), 3.18 (s, 3H), 2.23 (s, 3H), 2.08 (p, J = 7.1 Hz, 2H), 1.61 (dtd, J = 15.1, 7.9, 7.1 Hz, 4H), 0.93 (t, J =8.0 Hz, 6H); ESI-MS m / z: 442.2 calcd for C 24 H 34 N 4 O 2 S [M+H] + 443.2.

[0065] Example 14: 5-(1 H -pyrazol-3-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1- H -Benzo[ d ] Imidazole (14)

[0066] In this example, isoxazole-4-boronic acid is replaced by 1 H -pyrazole-3-boronic acid, according to the operation of Example 2, the product 90 mg was obtained, with a yield of 50.34%, 1 H NMR (400 MHz, DMSO) d 12.84 (s, 1H), 11.25 (s, 1H), δ8.38 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 1.4 Hz, 1H), 7.81 (dd, J = 7.5, 1.5Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.45 (dd, J = 7.5, 4.8 Hz, 1H), 6.87 (d, J= 7.5 Hz, 1H), 6.65 (d, J = 7.5 Hz, 1H), 4.39 (s, 2H), 4.09 (t, J = 7.1 Hz,2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J = 7.1Hz, 2H); ESI-MS m / z: 409.2 calcd for C 21 H 23 N 5 O 2 S [M+H] + 410.2.

[0067] Example 15: 5-(Furan-3-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (15)

[0068] In this example, isoxazole-4-boric acid was replaced with furan-3-boric acid, and the procedure of Example 2 was followed to obtain 120 mg of the product with a yield of 65.44%. 1 H NMR (400 MHz, DMSO) d 12.61 (s, 1H), 8.38 (d, J = 7.5 Hz,1H), 7.92-7.83 (m, 2H), 7.73-7.64 (m, 3H), 6.90-6.80 (m, 2H), 4.39 (s, 2H),4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.25 (s,3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 409.1 calcd for C 22 H 23 N 3 O 3 S [M+H] + 410.1.

[0069] Example 16: 5-(isothiazol-4-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (16)

[0070] In this example, isoxazole-4-boric acid was replaced with isothiazole-4-boric acid, and the procedure of Example 2 was followed to obtain 135 mg of the product with a yield of 62.14%. 1 H NMR (400 MHz, DMSO) d 12.61 (s, 1H), 8.94 (d, J = 1.4Hz, 1H), 8.64 (d, J = 1.4 Hz, 1H), 8.36 (d, J = 7.5 Hz, 1H), 7.87 (dd, J =7.5, 1.5 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.67 (d, J = 7.5 Hz, 1H), 6.85(d, J = 7.5 Hz, 1H), 4.36 (s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1Hz, 2H), 3.19 (s, 3H), 2.24 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z:426.1 calcd for C 21 H 22 N 4 O 2 S 2 [M+H] + 427.1.

[0071] Example 17: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(thiophen-3-yl)-1 H -Benzo[ d ] Imidazole (17)

[0072] In this example, isoxazole-4-boric acid was replaced with thiophene-3-boric acid, and the procedure of Example 2 was followed to obtain 142 mg of the product with a yield of 67.25%. 1 H NMR (400 MHz, DMSO) d 12.67 (s, 1H), 8.36 (d, J = 7.5 Hz,1H), 7.84 (dd, J = 7.5, 1.5 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.61 (d, J =7.5 Hz, 1H), 7.47 (dd, J = 2.8, 1.6 Hz, 1H), 7.44 (dd, J = 7.4, 2.8 Hz, 1H),7.31 (dd, J = 7.4, 1.5 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.36 (s, 2H), 4.09(t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.19 (s, 3H), 2.24 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 425.1 calcd for C 22 H 23 N 3 O 2 S 2 [M+H] + 426.1.

[0073] Example 18: 5-(1 H -pyrrol-3-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1- H -Benzo[ d ] Imidazole (18)

[0074] In this example, isoxazole-4-boric acid was replaced with pyrrole-3-boric acid, and the procedure of Example 2 was followed to obtain 98 mg of the product with a yield of 52.45%. 1 H NMR (400 MHz, DMSO) d12.85 (s, 1H), 9.62-9.50 (m, 1H), 8.38 (d, J = 7.5 Hz, 1H), 7.84 (dd, J = 7.5, 1.5 Hz, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.16 (ddd, J = 8.4, 2.2, 1.5 Hz, 1H),6.89-6.80 (m, 2H), 6.30 (dd, J = 7.5, 1.5 Hz, 1H), 4.39 (s, 2H), 4.09 (t, J =7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H); ESI-MS m / z: 408.2 calcd for C 22 H 24 N 4 O 2 S [M+H] + 409.2.

[0075] Example 19: 5-(3 H -imidazol-5-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1- H -Benzo[ d ] Imidazole (19)

[0076] In this example, isoxazole-4-boronic acid is replaced by 1 H -imidazole-4-boronic acid, according to the operation of Example 2, the product 102 mg was obtained, the yield: 55.45%, 1 H NMR (400 MHz, DMSO) d 12.35 (s, 1H), 8.38 (d, J = 7.5Hz, 1H), 7.90 (dd, J = 7.3, 2.0 Hz, 1H), 7.86 (d, J= 1.5 Hz, 1H), 7.82 (dd, J = 6.7, 2.1 Hz, 1H), 7.79 (dd, J = 7.5, 1.5 Hz, 1H), 7.75 (d, J = 7.5 Hz,1H), 6.87 (d, J = 7.5 Hz, 1H), 4.39 (s, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52(t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J = 7.1 Hz, 2H);ESI-MS m / z: 409.2 calcd for C 21 H 23 N 5 O 2 S [M+H] + 410.2.

[0077] Example 20: 5-(3,5-dimethylisoxazol-4-yl)-2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-1 H -Benzo[ d ] Imidazole (20)

[0078] In this example, isoxazole-4-boric acid was replaced with 3,5-dimethylisoxazole-4-boric acid, and the procedure of Example 2 was followed to obtain 132 mg of the product with a yield of 64.58%. 1 H NMR (400 MHz, DMSO) d 12.75 (s, 1H), 8.37 (d, J = 7.5 Hz, 1H), 7.86 (dd, J = 7.5, 1.5 Hz, 1H), 7.7-7.65 (m, 2H), 6.87 (d, J =7.5 Hz, 1H), 4.36 (s, 2H), 4.11 (t, J = 7.1 Hz, 2H), 3.52 (t, J= 7.1 Hz,2H), 3.19 (s, 3H), 2.59 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H), 2.08 (p, J = 7.1Hz, 2H); ESI-MS m / z: 438.2 calcd for C 23 H 26 N 4 O 3 S [M+H] + 439.2.

[0079] Example 21: 2-[({3-[(3-methoxypropyl)oxy]-2-methylphenyl}methyl)thio]-5-(pyrrol-1-yl)-1 H -Benzo[ d ] Imidazole (21)

[0080] In this example, 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride was replaced with 1-(chloromethyl)-3-[(3-methoxypropyl)oxy]-2-methylbenzene, and the procedure of Example 1 was followed to obtain 145 mg of the product with a yield of 68.57%. 1 HNMR (400 MHz, DMSO) d 12.65 (s, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.53 (d, J =7.5 Hz, 1H), 7.29 (dd, J = 7.5, 1.5 Hz, 1H), 7.14-7.08 (m, 2H), 7.01 (dd, J =5.6, 3.5 Hz, 2H), 6.70 (dd, J = 6.9, 2.1 Hz, 1H), 6.21 (dd, J = 5.5, 3.4 Hz,2H), 4.38 (d, J = 1.0 Hz, 2H), 4.09 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz,2H), 3.18 (s, 3H), 2.25 (s, 3H), 2.06 (p, J= 7.1 Hz, 2H); ESI-MS m / z: 407.2calcd for C 23 H 25 N 3 O 2 S [M+H] + 408.2.

[0081] Example 22: 2-[({3-[(3-methoxypropyl)oxy]phenyl}methyl)thio]-5-(pyrrol-1-yl)-1 H -Benzo[ d ] Imidazole (22)

[0082] In this example, 2-chloromethyl-3-methyl-4-(3-methoxypropoxy)pyridine hydrochloride was replaced with 1-(chloromethyl)-3-[(3-methoxypropyl)oxy]benzene, and the procedure of Example 1 was followed to obtain 153 mg of the product with a yield of 72.54%. 1 H NMR (400 MHz, DMSO) d 12.72 (s, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 7.5Hz, 1H), 7.31 (dd, J = 7.5, 1.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.14-7.09(m, 1H), 7.01 (dd, J = 5.6, 3.5 Hz, 2H), 6.89 (dt, J = 7.5, 1.6 Hz, 1H), 6.80(t, J = 1.3 Hz, 1H), 6.21 (dd, J = 5.5, 3.4 Hz, 2H), 4.49-4.38 (m, 2H), 4.03(t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.06 (p, J = 7.1Hz, 2H); ESI-MS m / z: 393.2 calcd for C 22 H 23 N 3 O 2S [M+H] + 394.2.

[0083] Example 23: 2-[({4-[(3-methoxypropyl)oxy]-3-methylpyridin-2-yl}methyl)thio]-5-(pyridin-2-yl)-1 H -Benzo[ d ] Imidazole (23)

[0084] In this example, isoxazole-4-boric acid was replaced with pyridine-2-boric acid, and the product (125 mg) was obtained according to the procedure of Example 2, with a yield of 63.72%. 1 H NMR (400 MHz, DMSO) d 12.68 (s, 1H), 8.79 (dd, J = 7.5, 1.4Hz, 1H), 8.36 (d, J = 7.5 Hz, 1H), 8.24 (d, J = 1.5 Hz, 1H), 7.82 (dd, J =7.5, 1.5 Hz, 1H), 7.74-7.70 (m, 1H), 7.70-7.69 (m, 1H), 7.68 (d, J = 1.1 Hz,1H), 7.23 (td, J = 7.3, 1.9 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 4.36 (s, 2H), 4.10 (t, J = 7.1 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H), 3.18 (s, 3H), 2.24 (s,3H), 2.08 (p, J = 7.1 Hz, 2H).

[0085] Example 24: Evaluation of the affinity of compounds to Snail protein (MST molecular interaction) 1. Experimental methods According to the requirements in the MST detection kit manual, dilute the GFP-labeled Snail recombinant protein to the required concentration. Then use GFP fusion expression receptor protein to perform instrument pre-scan to determine that the fluorescence signal value of the receptor protein at a certain concentration can be distributed between 600 and 1600, which is a reasonable range. Set the machine temperature and room temperature to 25 °C. Fluorescence intensity measurement is automatic. Prepare the compound prepared in the example into a 2.5 mM DMSO mother solution, take 4 μL and add it to 100 μL PBS, observe its dissolution, and ensure that it can be dissolved at the highest concentration; prepare a 4% DMSO PBS solution, dilute the compound mother solution step by step, and mix well; add an equal volume of Snail protein and centrifuge, let it stand for 10 minutes; operate the machine and measure twice in a row.

[0086] 2. Experimental results Table 1 Affinity of compounds for Snail protein (μM)

[0087] As shown in Table 1, the compounds designed in the present invention have a strong affinity with the Snail protein, reaching a micromolar concentration level.

[0088] Example 25: Pharmacokinetic Evaluation of Compounds 1. Experimental methods SD rats, 3 in each group, were administered intravenously or orally, and the injection volume was calculated for each mouse individually. Plasma samples were taken at 5, 15, 30, 60, 120, 240, 360, 480, 600 and 1440 min after administration (150-200 μL of blood at each time point), and the concentrations of compounds 5, 7, and 13 in plasma were determined by LC-MS. The compounds and internal standard compounds were effectively separated on HPLC, and the column temperature was 40 °C. The mobile phase consisted of a mixture of solvent A (acetonitrile) and solvent B (formic acid / ultrapure water, 1:1000, v / v). The linear gradient program of the mobile phase was as follows: based on the volume fraction of solvent A, 0 min: 10% A, 0.5 min: 30% A, 1 min: 95% A, 2 min: 95% A, 2.3 min: 10% A; the flow rate of the mobile phase was 0.4 mL / min, and the injection volume was 2 μL. Quantification was performed by multiple reaction monitoring (MRM) mode using a triple quadrupole mass spectrometer (ESI ion source).

[0089] 2. Experimental results Table 2 PK parameters of compound 5

[0090] a The average of three animals, b35 mg / kg was administered orally. c 5 mg / kg was administered by intravenous injection, and the same applies below.

[0091] Table 3 PK parameters of compound 7

[0092] Table 4 PK parameters of compound 13

[0093] Table 5 PK parameters of compound 17 in CN115433167

[0094] As shown in Tables 2 to 5, the compounds designed in the present invention have pharmacokinetic properties that are more conducive to drug development.

[0095] Example 26: In vivo efficacy evaluation of compounds 1. Experimental methods 8-week-old male ApoE - / - Mice were subjected to carotid artery ligation surgery to establish an atherosclerosis model, and after surgery, 50 mg / kg of compound 5, 7, 13 or vehicle was intraperitoneally injected for 3 weeks. After 3 weeks, the mice were killed and carotid artery plaque samples were taken for analysis.

[0096] 2. Experimental results like Figure 1 As shown, compared with the model group, the plaque area of ​​the groups treated with the compounds of the present invention was significantly reduced, and the plaque area of ​​the group treated with compound 7 was reduced to less than 40% (*** P <0.001).

[0097] Example 27: Preparation of tablets 1. Tablet prescription

[0098] 2. Preparation method (1) According to the above prescription, the prescribed amount of compound 13, hydroxypropyl methylcellulose E5 and microcrystalline cellulose MCC120 were mixed evenly, and 8% povidone K30 solution was added to granulate; (2) Dry the wet granules at 50-60 °C and then sieve through a 20-mesh screen; (3) Add the prescribed amount of magnesium stearate to the granules after granulation and mix evenly to obtain final mixed granules; (4) The final mixed granules are compressed into tablets to obtain tablets of compound 13.

Claims

1. A benzimidazole compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure of Formula I: I， in: X is selected from substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 N, O, S ring heteroatoms, substituted or unsubstituted 5-10 membered heterocyclyl containing 1-4 N, O, S ring heteroatoms, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted C1-C6 straight chain or branched alkyl thioether, monosubstituted or disubstituted C1-C6 straight chain or branched alkyl substituted amino; Y is selected from CH or nitrogen; R1 is selected from hydrogen, halogen, substituted or unsubstituted C1-C6 straight chain or branched alkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted C2-C6 straight chain or branched alkenyl, substituted or unsubstituted C2-C6 straight chain or branched alkynyl, phenyl, hydroxyl, aldehyde, carboxyl, -OC(O)-(C1-C6 straight chain or branched alkyl), amino, -NHC(O)-(C1-C6 straight chain or branched alkyl); The substituents are selected from hydrogen, halogen, unsubstituted or halogen-substituted or C3-C6 cycloalkyl-substituted C1-C6 straight or branched alkyl, C1-C4 straight or branched alkoxy, C3-C6 cycloalkyl, C1-C4 straight or branched alkyl-substituted amino, hydroxyl, cyano, nitro, =O, carboxyl, mercapto, -OS(O)2-(C1-C6 straight or branched alkyl), unsubstituted or 1-3 halogen-substituted or hydroxyl-substituted C5-C10 aryl, unsubstituted or halogen-substituted 5-7 membered heterocyclyl containing 1-4 N, O, S ring heteroatoms, unsubstituted or halogen-substituted C2-C6 straight or branched acyl, C1-C6 straight or branched hydroxyalkyl.

2. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structure described: X is selected from substituted or unsubstituted 5-6 membered heteroaryl containing 1-3 N, O, S ring heteroatoms, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-3 N, O, S ring heteroatoms, substituted or unsubstituted 3-7 membered cycloalkyl, substituted or unsubstituted C1-C6 straight chain or branched alkoxy, substituted or unsubstituted C1-C6 straight chain or branched alkyl thioether, monosubstituted or disubstituted C1-C6 straight chain or branched alkyl substituted amino; Y is selected from CH or nitrogen; The substituents are selected from hydrogen, halogen, unsubstituted or halogen-substituted or C3-C6 cycloalkyl-substituted C1-C6 straight or branched alkyl, C1-C4 straight or branched alkoxy, C3-C6 cycloalkyl, C1-C4 straight or branched alkyl-substituted amino, hydroxyl, cyano, nitro, =O, carboxyl, mercapto, -OS(O)2-(C1-C6 straight or branched alkyl), unsubstituted or 1-3 halogen-substituted or hydroxyl-substituted C5-C10 aryl, unsubstituted or halogen-substituted 5-7 membered heterocyclyl containing 1-4 N, O, S ring heteroatoms, unsubstituted or halogen-substituted C2-C6 straight or branched acyl, C1-C6 straight or branched hydroxyalkyl.

3. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structure described: R1 is selected from hydrogen, halogen, C1-C4 straight chain or branched alkyl, C1-C4 straight chain or branched alkoxy, hydroxyl, carboxyl, and amino.

4. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structure described: X is selected from substituted or unsubstituted 5-6 membered heteroaryl containing 1-2 N, O, S ring heteroatoms, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-2 N, O, S ring heteroatoms, substituted or unsubstituted C1-C4 straight chain or branched alkoxy, monosubstituted or disubstituted C1-C4 straight chain or branched alkyl substituted amino; The substituents are selected from hydrogen, halogen, unsubstituted or halogen-substituted or C3-C6 cycloalkyl-substituted C1-C6 straight or branched alkyl, C1-C4 straight or branched alkoxy, C3-C6 cycloalkyl, C1-C4 straight or branched alkyl-substituted amino, hydroxyl, cyano, nitro, =O, carboxyl, mercapto, -OS(O)2-(C1-C6 straight or branched alkyl), unsubstituted or 1-3 halogen-substituted or hydroxyl-substituted C5-C10 aryl, unsubstituted or halogen-substituted 5-7 membered heterocyclyl containing 1-4 N, O, S ring heteroatoms, unsubstituted or halogen-substituted C2-C6 straight or branched acyl, C1-C6 straight or branched hydroxyalkyl.

5. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structure, X is selected from any one of the following chemical structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In the structure described: R1 is selected from hydrogen, fluorine, methyl, methoxy, hydroxy, carboxyl, and amino.

7. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound is selected from any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by the benzimidazole compound and any one of the following acids: hydrochloric acid, carbonic acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

9. Use of the benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating atherosclerosis.

10. The use according to claim 9, characterized in that: The drug is a Snail inhibitor drug.

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