2-arylbenzimidazole compound, and preparation method therefor and use thereof

Abstract

The present application relates to the technical field of biological medicines. Specially, disclosed are a 2-arylbenzimidazole compound, and a preparation method therefor and the use thereof. The 2-arylbenzimidazole compound provided by the present application is a compound as shown in general formula I, or a pharmaceutically acceptable salt, isomer, solvate, hydrate, prodrug or isotope derivative thereof. The general formula I has a structural formula as follows: in the general formula I, R represents 1, 2, 3 or 4 identical or different substituents present on a benzene ring, and R is independently selected from the following groups: hydrogen, halogen, cyano, hydroxyl, optionally substituted C1-6 alkoxy, optionally substituted amino, optionally substituted formyl, optionally substituted sulfonyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. The 2-arylbenzimidazole compound of the present application exhibits an excellent inhibitory activity against BCR-ABL kinase, and is expected to be developed into a drug for treating and / or preventing BCR-ABL-related diseases.

Description

A 2-arylbenzimidazole compound, its preparation method and application Technical Field

[0001] This application relates to the field of biomedical technology, specifically to a 2-arylbenzimidazole compound and its preparation method and application. Background Technology

[0002] ABL1 is a protein encoded by the ABL1 gene located on chromosome 9 in the human body. It is widely distributed in the cell nucleus and cytoplasm, belonging to the tyrosine kinase family, and is mainly involved in cell differentiation, adhesion, division, and stress responses. The activity of ABL1 protein is self-inhibited by its SH3 domain. The loss of the SH3 domain will cause ABL1 to transform into a proto-oncogene, and the continuous activation of ABL1 protein will lead to cell carcinogenesis. Related studies have shown that the hallmark of chronic myeloid leukemia (CML) is the Philadelphia chromosome, formed by the t(9;22) translocation that causes the expression of the BCR-ABL tyrosine kinase fusion gene. This fusion gene encodes a chimeric BCR-ABL protein, resulting in the loss of the SH3 domain's self-regulation in ABL1 protein. Therefore, the standard treatment for CML patients is the use of a tyrosine kinase inhibitor (TKI) targeting the BCR-ABL protein.

[0003] For the treatment of CML, tyrosine kinase inhibitors, such as imatinib, have been developed. These inhibitors inhibit the tyrosine kinase activity of BCR-ABL through an ATP-competitive mechanism. However, clinical results show that this tyrosine kinase inhibitor has poor resistance, and long-term use is unlikely to achieve ideal results. In recent years, a pharmaceutical company has developed an ABL1 kinase allosteric inhibitor, ABL001, which inactivates ABL1 by targeting the myristoyl pocket of the allosteric site, exhibiting good therapeutic effects. Moreover, when this allosteric inhibitor ABL001 is used in combination with an ATP-competitive BCR-ABL tyrosine kinase inhibitor (nilotinib), it can effectively prevent the development of resistance to ATP-competitive inhibitors and / or allosteric inhibitors, achieving a radical cure for CML.

[0004] Currently, although ABL001, as an allosteric inhibitor of ABL1 kinase, is effective in treating conditions such as CML, discovering compounds with novel structures that can treat CML and other conditions remains a challenging task. Therefore, there is still a need in this field to continue developing compounds with novel structures and inhibitory activity against BCR-ABL kinase.

[0005] Summary of the Invention

[0006] In order to obtain a novel compound with inhibitory activity against BCR-ABL kinase, thereby achieving effective treatment of CML, this application provides a 2-arylbenzimidazole compound, its preparation method and application.

[0007] Firstly, the 2-arylbenzimidazole compounds provided in this application adopt the following technical solution:

[0008] A 2-arylbenzimidazole compound, wherein the 2-arylbenzimidazole compound is a compound represented by general formula I or a pharmaceutically acceptable salt, isomer, solvate, hydrate, prodrug, or isotope derivative thereof; the structural formula of general formula I is:

[0009] In the general formula I, R represents 1, 2, 3 or 4 identical or different substituents present on the benzene ring;

[0010] R is independently selected from the following groups: hydrogen, halogen, cyano, hydroxyl, and optionally substituted C. 1-6 Alkoxy, optionally substituted amino, optionally substituted formyl, optionally substituted sulfonyl, optionally substituted heterocyclic alkyl, optionally substituted aryl, optionally substituted heteroaryl.

[0011] Optionally, the 2-arylbenzimidazole compound has the structural formula shown in Formula II or Formula III:

[0012] In Formula II or Formula III, R1 is hydrogen, an optionally substituted amino group, an optionally substituted formyl group, an optionally substituted sulfonyl group, or an optionally substituted C group. 3-7 Heterocyclic alkyl, optionally substituted C 3-7 Mixed aromatics;

[0013] R2 is hydrogen, halogen, optionally substituted amino group, optionally substituted formyl group, or optionally substituted C group. 3-7 Heterocyclic alkyl groups;

[0014] R3 is hydrogen, halogen, or C. 1-6 Alkyl group.

[0015] Optionally, the 2-arylbenzimidazole compounds are selected from compounds 1 to 30 in Table 1.

[0016] Table 1. Structural formulas of some compounds in this application.

[0017] Secondly, this application provides the use of the 2-arylbenzimidazole compound in the preparation of a medicament for treating and / or preventing tumor diseases.

[0018] Thirdly, this application provides a medicament for treating and / or preventing tumor diseases, comprising the 2-arylbenzimidazole compound.

[0019] Fourthly, this application provides a BCR-ABL inhibitor comprising the 2-arylbenzimidazole compound.

[0020] Fifthly, this application provides a pharmaceutical composition comprising the 2-arylbenzimidazole compound and a pharmaceutically acceptable carrier and / or excipient.

[0021] In a sixth aspect, this application provides a medicament for treating and / or preventing BCR-ABL-related diseases, comprising the 2-arylbenzimidazole compound and a pharmaceutically acceptable carrier and / or excipient.

[0022] Optionally, the BCR-ABL-related diseases are selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, invasive carcinoma, viral infection, or CNS disorder.

[0023] In this application, for the purpose of more clearly describing the content of this application, the terms used are explained as follows. Those skilled in the art can understand the following terms in conjunction with relevant technologies:

[0024] The term "cyano" refers to -CN. The term "hydroxyl" refers to -OH. The term "amino" refers to -NH2. The term "formyl" refers to -CHO. The term "sulfonyl" refers to RS(=O)2-.

[0025] Term "C" 1-6 "Alkoxy" alone or in combination represents the C group. 1-6 Alkyl-O-. "C" 1-6 "Alkoxy" includes (but is not limited to) methoxy (-OCH3), ethoxy (-OCH2CH3), n-propoxy (-OCH2CH2CH3), isopropoxy (-OCH(CH3)2), n-butoxy (-OCH2CH2CH2CH3), sec-butoxy (-OCH(CH3)CH2CH3), isobutoxy (-OCH2CH(CH3)2), tert-butoxy (-OC(CH3)3), n-pentoxy (-OCH2CH2CH2CH2CH3), neopentoxy (-OCH2C(CH3)3), etc.

[0026] The term "heterocyclic alkyl" refers to a cycloalkyl group, either alone or in combination, containing multiple carbon atoms and heteroatoms. The term "C"... 3-7 "Heterocyclic alkyl" refers to cycloalkyl groups containing 3-7 carbon atoms and heteroatoms, either alone or in combination, including aziridine, aziridine, oxocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazine, etc.

[0027] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with a conjugated π-electron system, including phenyl, naphthyl, anthracene, and 1,2,3,4-tetrahydronaphthalene, etc.

[0028] The term "heteroaryl" alone or in combination refers to one or more rings having 5 to 20 atoms, wherein at least one atom in one ring is a heteroatom selected from nitrogen, oxygen, and sulfur, and the at least one ring containing the heteroatom is further aromatic. In heteroaryls comprising two or more fused rings, the ring containing the non-heteroatom may be a carbocyclic ring.

[0029] The term "optionally substituted" refers to the group that is unsubstituted or has at least one substituent, including hydroxyl, alkyl, substituted alkyl, alkoxy, mercapto, halogen, cyano, nitro, amino, substituted amino, amide, acyl, oxyacyl, heterocycle, substituted heterocycle, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, etc.

[0030] The term "pharmaceutically acceptable salt" indicates that the compounds of this application exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. In this application, a pharmaceutically acceptable non-toxic acid addition salt refers to a salt formed by the compounds of this application with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, homosine, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. A pharmaceutically acceptable non-toxic base addition salt refers to a salt formed by the compounds of this application with an organic or inorganic base, including but not limited to alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic base salts, such as base salts formed by reacting with an organic base containing an N group or N... + (C 1-6 Alkyl)4 salt; the organic or inorganic base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, tetrabutylammonium hydroxide, etc. "Pharmaceutically acceptable salts" can be synthesized by common chemical methods.

[0031] In this application, the term "pharmaceuticalally acceptable carrier" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceuticalally acceptable carrier" includes buffers compatible with drug administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption delay agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of compatibility with other components in the formulation and harmlessness to the patient. The carriers include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn... Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0032] The term "isomer" encompasses all isomeric forms, including enantiomers, diastereomers, tautomers, and geometric isomers, including cis-trans isomers. Therefore, any single stereochemical isomer of the compound designed in this application, or a mixture of its enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), is within the scope of this application.

[0033] The term "solvent" refers to an association formed by one or more solvent molecules with the compound in this application. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0034] The term "hydrate" refers to a complex formed by water and the compound described in this application.

[0035] The term "prodrug" refers to a chemical derivative of the compound of this application, which is converted into the compound represented by general formula I in vivo through a chemical reaction.

[0036] The term "isotope derivative" refers to isotope derivatives obtained by replacing hydrogen atoms in general formula I with 1-6 deuterium atoms, and isotope derivatives obtained by replacing carbon atoms in general formula I with 1-3 carbon-14 atoms.

[0037] In summary, this application has the following beneficial effects:

[0038] This application provides a 2-arylbenzimidazole compound that exhibits good inhibitory activity against BCR-ABL-WT transfected Ba / F3 cells. Therefore, this 2-arylbenzimidazole compound can be used as a BCR-ABL inhibitor and is expected to be developed into a drug for the treatment and / or prevention of BCR-ABL-related diseases. Detailed Implementation

[0039] All raw materials, reagents, solvents, etc. involved in this application can be obtained commercially. The abbreviations of each raw material are shown in Table 2 below.

[0040] Table 2. Chinese names and abbreviations of the raw materials involved in this application.

[0041] The following describes the general experimental conditions in the embodiments of this application.

[0042] First, unless otherwise specified, all reactions in the embodiments of this application are carried out under nitrogen protection.

[0043] In the embodiments of this application, the intermediates and final products were separated and purified using thin-layer chromatography silica gel plates (Qingdao Bangkai), a rapid preparative liquid chromatography system (Biotage Isolera Flash), and a preparative high-performance liquid chromatography system (Agilent 1290 Infinity II LC System, equipped with a Welch Xtimate C18 reversed-phase column). Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters ACQUITYArc equipped with a QDa Detector. Mass spectrometry (MS) used an ESI source, indicating only the molecular weight M of the parent molecule, typically reporting [M+H]. + The injection volume is determined by the sample concentration: the flow rate is 1.0 mL / min.

[0044] In the embodiments of this application, the peak values ​​of high-performance liquid chromatography (Pre-HPLC) are recorded and read using UV Vis wavelengths at 220 nm and 254 nm. The elution conditions of the mobile phase gradient elution method are shown in Table 3 below:

[0045] Table 3 Gradient elution conditions

[0046] In the embodiments of this application, nuclear magnetic resonance (NMR) spectra were detected using a 400 MHz NMR spectrometer, with CDCl3 or DMSO-d6 as the solvent, and chemical shifts (δ) reported in ppm (parts per million). The various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet). Coupling constants are expressed in Hz (Hertz).

[0047] The present application will be further described in detail below with reference to embodiments and performance testing.

[0048] Example 1

[0049] Example 1 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazole (compound 1) with the following structural formula:

[0050] The preparation method of compound 1 includes the following steps:

[0051] (1) Preparation of intermediate 1-2: 4-(chlorodifluoromethoxy)aniline (100 g, 516.6 mmol) was dissolved in 500 mL of 3N hydrochloric acid. 50 mL of an aqueous solution of sodium nitrite (35.6 g, 516.6 mmol) was added dropwise to the solution under ice bath conditions, and the mixture was stirred for 1 h under ice bath conditions. Subsequently, 100 mL of an aqueous solution of potassium iodide (111.5 g, 671.6 mmol) was added dropwise to the solution, and the reaction was allowed to proceed for 1 h. After the reaction was complete, EA was added for extraction and separation. The organic phase was dried and concentrated. The crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a white solid 1-2 (120 g, yield: 76.30%). The reaction formula is as follows:

[0052] (2) Preparation of intermediate 1-3: Compound 1-2 (100 g, 328.5 mmol) was dissolved in 500 mL THF, cooled to -20 °C, and 60.6 mL of 1.3 M tetrahydrofuran solution of isopropyl magnesium chloride-lithium chloride was slowly added dropwise. The mixture was stirred at -20 °C for 1 h, then slowly heated to 10 °C, and 25.2 mL of LDM was added dropwise. The mixture was stirred at this temperature for 1 h. After the reaction was complete, EA was added for extraction and separation. The organic phase was dried and concentrated. The crude product was purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow oily substance 1-3 (16 g, yield: 23.58%). The reaction formula is as follows:

[0053] (3) Preparation of compound 1: Compounds 1-3 (500 mg, 2.42 mmol) were dissolved in 5 mL of DMF, and p-toluenesulfonic acid monohydrate (46.02 mg, 0.24 mmol) and o-phenylenediamine (261.70 mg, 2.42 mmol) were added. The reaction system was replaced with oxygen and reacted overnight at 85 °C. After the reaction was completed, 30 mL of water and 60 mL of EA were added, the mixture was separated, the organic phase was dried and concentrated, and purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a white solid compound 1 (32.35 mg, yield: 26.87%).

[0054] Compound 1 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 295.1 [M+H] + The NMR spectrum of compound 1 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ13.06 (s, 1H), 8.30 (d, J = 8.0Hz, 2H), 7.62-7.55 (m, 4H), 7.24-7.21 (m, 2H).

[0055] Example 2

[0056] Example 2 provides methyl 2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazolium-5-carboxylate (compound 2), with the following structural formula:

[0057] The preparation method of compound 2 includes the following steps: Compounds 1-3 (2 g, 9.68 mmol) were dissolved in 20 mL of DMF, and p-toluenesulfonic acid monohydrate (180 mg, 0.968 mmol) and methyl 3,4-diamine benzoate (1.61 g, 9.68 mmol) were added. The reaction system was replaced with oxygen, and the reaction was carried out overnight at 85 °C. After the reaction was completed, 40 mL of water and 80 mL of EA were added, the mixture was separated, the organic phase was dried and concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 2 (1.9 g, yield: 38.95%).

[0058] Compound 2 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 353.0 [M+H] + The NMR spectrum of compound 2 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1H NMR (DMSO-d6, 400MHz): δ13.38 (s, 1H), 8.33 (d, J=8.0Hz, 2H), 8.23 ​​(s, 1H), 7. 87 (d, J=8.0Hz, 1H), 7.71 (d, J=8.0Hz, 1H), 7.59 (d, J=8.0Hz, 2H), 3.89 (s, 3H).

[0059] Example 3

[0060] Example 3 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-carboxylic acid (compound 3), with the following structural formula:

[0061] The preparation method of compound 3 includes the following steps: compound 2 (5.8 g, 16.44 mmol) was dissolved in a mixed solvent of 20 mL THF and 25 mL MeOH, and lithium hydroxide monohydrate (1.38 g, 32.87 mmol) was added. The reaction was carried out overnight at 50 °C under nitrogen protection. After the reaction was completed, 40 mL of water and 80 mL of EA were added, the mixture was separated, the organic phase was dried and concentrated, and purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 3 (1.9 g, yield: 38.95%).

[0062] Compound 3 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 339.0 [M+H] + The NMR spectrum of compound 3 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ 13.32 (s, 1H), 8.33 (d, J=8.0Hz, 2H), 8.20 (s, 1H), 7.86 (d, J=8.0Hz, 1H), 7.68 (s, 1H), 7.58 (d, J=12.0Hz, 2H).

[0063] Example 4

[0064] Example 4 provides a 2-{2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-yl}thiazole (compound 4), with the following structural formula:

[0065] The preparation method of compound 4 includes the following steps:

[0066] (1) Preparation of intermediate 4-1: Compound 1-3 (1 g, 4.84 mmol) was dissolved in 10 mL of DMF, and p-toluenesulfonic acid monohydrate (90 mg, 0.484 mmol) and 4-bromo-o-phenylenediamine (0.91 g, 4.84 mmol) were added. The reaction system was replaced with oxygen, and the reaction was carried out overnight at 85 °C. After the reaction was completed, 20 mL of water and 40 mL of EA were added, the mixture was separated, the organic phase was dried and concentrated, and the crude product was purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 4-1 (760 mg, yield: 64.18%). The reaction formula is as follows:

[0067] (2) Preparation of intermediate 4-2: Compound 4-1 (322 mg, 0.862 mmol) was dissolved in 10 mL of dioxane. Dipicolinate (218.88 mg, 0.862 mmol) and potassium acetate (104.80 mg, 1.068 mmol) were added to the solution, and after stirring and mixing, Pd(dppf)Cl2 (62.55 mg, 0.086 mmol) was added. The mixture was then heated to 110 °C and reacted for 16 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a colorless oily substance 4-2 (310 mg, yield: 83.79%). The reaction formula is as follows:

[0068] (3) Preparation of compound 4: Intermediate 4-2 (120 mg, 0.285 mmol) was dissolved in a mixed solvent of 5 mL dioxane and 1 mL water. 2-bromothiazole (46.79 mg, 0.285 mmol) and cesium carbonate (24 mg, 0.174 mmol) were added, and the mixture was stirred. Pd(dppf)Cl2 (6.5 mg, 0.01 mmol) was then added, and the mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed, 20 mL of water and 40 mL of EA were added. The mixture was separated, and the organic phase was dried and concentrated. The organic phase was purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 4 (30 mg, yield: 87.00%).

[0069] Compound 4 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 378.0 [M+H] + The NMR spectrum of compound 4 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ 8.33 (d, J=8.0Hz, 2H), 8.18 (s, 1H), 7.92 (d, J=4.0Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 7.76-7.72 (m, 2H), 7.60 (d, J=8.0Hz, 2H).

[0070] Example 5

[0071] Example 5 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-5-(1H-imidazol-2-yl)-1H-benzo[d]imidazolium (compound 5), with the following structural formula:

[0072] The preparation method of compound 5 includes the following steps: intermediate 4-2 (80 mg, 0.190 mmol) was dissolved in a mixed solvent of 5 mL dioxane and 1 mL water, 2-bromoimidazole (27.92 mg, 0.190 mmol) and cesium carbonate (15.76 mg, 0.114 mmol) were added, and after stirring and mixing, Pd(dppf)Cl2 (4.33 mg, 0.06 mmol) was added, and then the mixture was heated to 90 °C and reacted for 16 h. After the reaction was completed, 20 mL of water and 40 mL of EA were added, the mixture was separated, the organic phase was dried and concentrated, and purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 5 (53.28 mg, yield: 73.92%).

[0073] Compound 5 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 361.0 [M+H] + The NMR spectrum of compound 5 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.36 (s, 1H), 8.22 (d, J=8.0Hz, 2H), 8.14 (s, 1H), 7.8 1 (d, J=8.0Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.49 (d, J=8.0Hz, 2H), 7.30 (s, 2H).

[0074] Example 6

[0075] Example 6 provides a 2-{2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-yl}-5-cyclopropyl-1,3,4-oxadiazole (compound 6), with the following structural formula:

[0076] The preparation method of compound 6 includes the following steps:

[0077] (1) Preparation of intermediate 6-1: Compound 3 (1 g, 2.95 mmol) was dissolved in 30 mL of DMF, and DIEA (760 mg, 5.90 mmol) and HATU (1.23 g, 3.25 mmol) were added. After stirring and mixing, anhydrous hydrazine (90 mg, 2.95 mmol) was added, and the mixture was reacted at room temperature for 30 min. After the reaction was completed, 40 mL of EA was added for extraction, the organic phase was dried and concentrated, and the crude product was purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a white solid 6-1 (600 mg, yield: 57.61%). The reaction formula is as follows:

[0078] (2) Preparation of intermediate 6-2: Compound 6-1 (500 mg, 1.60 mmol) was dissolved in 30 mL of DCM, and TEA (327 mg, 3.20 mmol) and cyclopropylformyl chloride (169 mg, 1.60 mmol) were added. The mixture was reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a white solid 6-2 (610 mg, yield: 90.60%). The reaction formula is as follows:

[0079] (3) Preparation of compound 6: Compound 6-2 (610 mg, 1.45 mmol) was dissolved in 30 mL of THF, and triphenylphosphine (760.63 mg, 2.90 mmol) and tetrachloromethane (223.04 mg, 1.45 mmol) were added. The mixture was reacted at 75 °C for 2 h. After the reaction was completed, the reaction solution was concentrated, dichloromethane and water were added, the mixture was extracted and separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain white solid 6 (474.25 mg, yield: 81.20%).

[0080] Compound 6 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 403.1 [M+H] + The NMR spectrum of compound 6 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.32 (d, J=12.0Hz, 2H), 8.18 (s, 1H), 7.86 (d, J=4.0Hz, 1H) , 7.80 (d, J=4.0Hz, 1H), 7.60 (d, J=8.0Hz, 2H), 2.52-2.50 (m, 1H), 1.20-1.14 (m, 4H).

[0081] Example 7

[0082] Example 7 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-carboxamide (compound 7), with the following structural formula:

[0083] The preparation method of compound 7 includes the following steps: compound 3 (58 mg, 0.17 mmol) was dissolved in 5 mL of DCM, and DCC (53 mg, 0.26 mmol), DMAP (32 mg, 0.26 mmol), and ammonium chloride (28.89 mg, 0.54 mmol) were added. The mixture was reacted overnight at room temperature. After the reaction was completed, DCM and water were added to the reaction solution, the mixture was extracted and separated, the organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a white solid 7 (20.20 mg, yield: 23%).

[0084] Compound 7 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 338.1 [M+H] + The NMR spectrum of compound 7 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ13.28 (s, 1H), 8.32 (s, 2H), 8.10 (d, J=8.0Hz, 2H), 7.81 (d, J=8.0Hz, 1H), 7.260-7.58 (m, 3H), 7.30 (d, J=16.0Hz, 1H).

[0085] Example 8

[0086] Example 8 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-cyclopropyl-1H-benzo[d]imidazol-5-carboxamide (compound 8), with the following structural formula:

[0087] The preparation method of the above compound 8 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and cyclopropane (8.57 mg, 0.15 mmol) as raw materials, it is prepared according to a method similar to step (1) of Example 6 to obtain yellow solid compound 8 (26.18 mg, yield: 46.20%).

[0088] Compound 8 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 378.1 [M+H] + The NMR spectrum of compound 8 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1H NMR (MeOD, 400MHz): δ8.21 (d, J=8.0Hz, 2H), 8.12 (s, 1H), 7.78 (d, J=8.0Hz, 1H), 7.66 (d, J=8 .0Hz, 1H), 7.50 (d, J=12.0Hz, 2H), 2.90-2.88 (m, 1H), 0.84-0.83 (m, 2H), 0.69-0.67 (m, 2H).

[0089] Example 9

[0090] Example 9 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-methyl-1H-benzo[d]imidazolium-5-carboxamide (compound 9), with the following structural formula:

[0091] The preparation method of the above compound 9 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and methylamine hydrochloride (10.08 mg, 0.15 mmol) as raw materials, it is prepared in a manner similar to step (1) of Example 6 to obtain yellow solid compound 9 (22.74 mg, yield: 43.10%).

[0092] Compound 9 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 352.1 [M+H] + The NMR spectrum of compound 9 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.47 (s, 1H), 8.33 (d, J=8.0Hz, 2H), 8.14 (s, 1H), 7.79 (d, J=8.0Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 7.59 (d, J=8.0Hz, 2H), 2.83 (d, J=4.0Hz, 3H).

[0093] Example 10

[0094] Example 10 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N,N-dimethyl-1H-benzo[d]imidazol-5-carboxamide (compound 10), with the following structural formula:

[0095] The preparation method of the above compound 10 includes the following steps: using a THF solution of compound 3 (50 mg, 0.15 mmol) and 2M dimethylamine (75 μL, 0.15 mmol) as raw materials, the compound 10 is prepared in a manner similar to step (1) of Example 6 to obtain a yellow solid compound 10 (23.32 mg, yield: 42.50%).

[0096] Compound 10 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 366.1 [M+H] + The NMR spectrum of compound 10 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.34 (d, J=12.0Hz, 2H), 7.69-7.67 (m, 2H), 7.60 (d, J=8.0Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 3.01 (s, 6H).

[0097] Example 11

[0098] Example 11 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-cyclopentyl-1H-benzo[d]imidazolium-5-carboxamide (compound 11), with the following structural formula:

[0099] The preparation method of the above compound 11 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and cyclopentylamine (12.78 mg, 0.15 mmol) as raw materials, it is prepared according to a method similar to step (1) of Example 6 to obtain yellow solid compound 11 (24.72 mg, yield: 40.60%).

[0100] Compound 11 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 406.1 [M+H] + The NMR spectrum of compound 11 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (CDCl3, 400MHz): δ8.38-8.34 (m, 3H), 7.67 (d, J=8.0Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.32 (d, J=8.0Hz, 2H), 6 .42 (d, J=8.0Hz, 1H), 4.48 (dd, J=8.0Hz, 1H), 2.11 (dt, J=4.0Hz, 2H), 1.81-1.66 (m, 4H), 1.59 (dt, J=4.0Hz, 2H).

[0101] Example 12

[0102] Example 12 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-isopropyl-1H-benzo[d]imidazol-5-carboxamide (compound 12), with the following structural formula:

[0103] The preparation method of the above compound 12 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and 2-aminopropane (8.87 mg, 0.15 mmol) as raw materials, it is prepared according to a method similar to step (1) of Example 6 to obtain yellow solid compound 12 (25.69 mg, yield: 45.10%).

[0104] Compound 12 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 380.1 [M+H] + The NMR spectrum of compound 12 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.32 (d, J=8.0Hz, 2H), 8.25 (d, J=8.0Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.0H z, 1H), 7.65 (d, J=8.0Hz, 1H), 7.59 (d, J=8.0Hz, 2H), 4.14 (tt, J=8.0Hz, 1H), 1.20 (d, J=8.0Hz, 6H).

[0105] Example 13

[0106] Example 13 provides a {2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-yl}(morpholinyl) methyl ketone (compound 13), with the following structural formula:

[0107] The preparation method of the above compound 13 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and morpholine (13.07 mg, 0.15 mmol) as raw materials, it is prepared according to a method similar to step (1) of Example 6 to obtain yellow solid compound 13 (27.10 mg, yield: 44.30%).

[0108] Compound 13 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 408.1 [M+H] + The NMR spectrum of compound 13 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.34 (d, J=12.0Hz, 2H), 7.69-7.67 (m, 2H), 7.60 (d, J= 8.0Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 3.94 (t, J=4.0Hz, 4H), 3.45 (t, J=4.0Hz, 4H).

[0109] Example 14

[0110] Example 14 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-cyclopropyl-1H-benzo[d]imidazol-5-carboxamide (compound 8), with the following structural formula:

[0111] The preparation method of the above compound 14 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and 4-fluoroaniline (16.67 mg, 0.15 mmol) as raw materials, it is prepared in a manner similar to step (1) of Example 6 to obtain yellow solid compound 14 (26.10 mg, yield: 40.30%).

[0112] Compound 14 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 432.1 [M+H] + The NMR spectrum of compound 14 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ10.36 (s, 1H), 8.35 (d, J=8.0Hz, 2H), 8.30 (s, 1H), 7.91 (d, J=8.0Hz, 1H), 7.86-7.83 (m, 2H), 7.75 (d, J=8.0Hz, 1H), 7.62 (d, J=8.0Hz, 2H), 7.21 (t, J=8.0Hz, 2H).

[0113] Example 15

[0114] Example 15 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-(1H-pyrazol-4-yl)-1H-benzo[d]imidazol-5-carboxamide (compound 15), with the following structural formula:

[0115] The preparation method of the above compound 15 includes the following steps:

[0116] (1) Preparation of intermediate 15-1: Using compound 3 (50 mg, 0.15 mmol) and tert-butyl 4-amino-1H-pyrazole-1-carboxylate (27.48 mg, 0.15 mmol) as starting materials, intermediate 15-1 was prepared by a method similar to step (1) in Example 6, yielding a yellow solid 15-1 (31.97 mg, yield: 42.30%). The reaction formula is as follows:

[0117] (2) Preparation of compound 15: Compound 15-1 (31.97 mg, 0.06 mmol) was dissolved in 1 mL of 1,4-dioxane solution in 4 M hydrochloric acid and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum, the filter cake was collected, purified by preparative high performance liquid chromatography (Pre-HPLC), the eluent was concentrated, and freeze-dried to obtain a yellow solid compound 15 (13.08 mg, yield: 54%).

[0118] Compound 15 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 404.1 [M+H] + The NMR spectrum of compound 15 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (MeOD, 400MHz): δ 8.25-8.23 (m, 3H), 7.92-7.89 (m, 3H), 7.73 (s, 1H), 7.51 (d, J=8.0Hz, 2H).

[0119] Example 16

[0120] Example 16 provides a cyclopropyl 2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazolium-5-carboxylic acid compound 16, with the following structural formula:

[0121] The preparation method of the above compound 16 includes the following steps: using compound 3 (50 mg, 0.15 mmol) and cyclopropyl-1-ol (17.42 mg, 0.30 mmol) as raw materials, the compound 16 is prepared in a manner similar to that in Example 7 to obtain a white solid compound 16 (13.75 mg, yield: 24.20%).

[0122] Compound 16 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 379.1 [M+H] + The NMR spectrum of compound 16 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ13.44 (s, 1H), 8.32 (d, J=12.0Hz, 2H), 8.18 (s, 1H), 7.82 (d, J=4 .0Hz, 1H), 7.70 (d, J=12.0Hz, 1H), 7.59 (d, J=8.0Hz, 2H), 4.36-4.31 (m, 1H), 0.82 (m, 4H).

[0123] Example 17

[0124] Example 17 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-cyclopropyl-1H-benzo[d]imidazolium-5-sulfonamide (compound 17), with the following structural formula:

[0125] The preparation method of the above compound 17 includes the following steps:

[0126] (1) Preparation of intermediate 17-2: 4-fluoro-3-nitrobenzenesulfonyl chloride (5 g, 20.87 mmol) and cyclopropane (6 g, 104.35 mmol) were dissolved in 5 mL of THF and reacted in an ice bath for 1 h. After the reaction was complete, 10 mL of EA and 5 mL of water were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted three times with 5 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 17-2 (2.31 g, yield: 42.55%). The reaction formula is as follows:

[0127] (2) Preparation of intermediate 17-3: Compound 17-2 (2.31 g, 8.88 mmol) was dissolved in 20 mL of ACN, and PMBNH2 (1.34 g, 9.77 mmol) and potassium carbonate (2.45 g, 17.76 mmol) were added. The reaction was carried out at 80 °C for 16 h. After the reaction was completed, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 17-3 (2.10 g, yield: 62.66%). The reaction formula is as follows:

[0128] (3) Preparation of intermediate 17-4: Compound 17-3 (2.00 g, 5.30 mmol) was dissolved in 6.4 mL of methanol and 6.4 mL of THF. An aqueous solution of ammonium chloride (1.42 g, 26.5 mmol) was added, and zinc (1.74 g, 26.5 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 16 h. After the reaction was complete, the reaction solution was filtered and concentrated. The pH was adjusted to 9 by adding an aqueous sodium carbonate solution. 30 mL of EA and 20 mL of water were added, and the mixture was extracted and separated. The aqueous phase was extracted three times with 30 mL of EA. The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 17-4 (887.54 mg, yield: 48.20%). The reaction formula is as follows:

[0129] (4) Preparation of intermediate 17-5: Using compound 17-4 (800 mg, 2.30 mmol) and compound 1-3 (475.11 mg, 2.30 mmol) as raw materials, intermediate 17-5 was prepared by a method similar to step (1) in Example 4, yielding a yellow solid 17-5 (764.27 mg, yield: 62.23%). The reaction formula is as follows:

[0130] (5) Preparation of compound 17: Compound 17-5 (760 mg, 1.42 mmol) was dissolved in 2 mL of DCM, and 5 mL of TFA was added. The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 17 (236.11 mg, yield: 40.18%).

[0131] Compound 17 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 414.1 [M+H] + The NMR spectrum of compound 17 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.18 (d, J=12.0Hz, 2H), 8.12 (s, 1H), 7.85-7.81 (m, 2H), 7.57 (d, J=8.0Hz, 2H), 7.30-7.32(m, 2H), 3.88-3.87(m, 1H), 1.15-1.14(m, 2H), 0.67-0.69(m, 2H).

[0132] Example 18

[0133] Example 18 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-amine (compound 18), with the following structural formula:

[0134] The preparation method of the above compound 18 includes the following steps:

[0135] (1) Preparation of intermediate 18-1: Using compound 1-3 (500 mg, 2.42 mmol) and 4-nitro-o-phenylenediamine (370.60 mg, 2.42 mmol) as raw materials, intermediate 18-1 was prepared by a method similar to step (1) in Example 4, yielding a brown solid 18-1 (427.45 mg, yield: 50.20%). The reaction formula is as follows:

[0136] (2) Preparation of compound 18: Compound 18-1 (200 mg, 0.59 mmol) was dissolved in 1 mL of methanol, and then 5% palladium on carbon (136 mg) was added under nitrogen protection. Hydrogen was replaced three times and the reaction was carried out for 161 h. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain brown solid 18 (177.5 mg, yield: 97.14%).

[0137] Compound 18 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 310.1 [M+H] + The NMR spectrum of compound 18 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (MeOD, 400 MHz): δ 8.12 (d, J = 8.0 Hz, 2H), 7.46-7.40 (m, 3H), 6.96 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H).

[0138] Example 19

[0139] Example 19 provides an N-{2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-yl}cyclopropaneformamide (compound 19), with the following structural formula:

[0140] The preparation method of the above compound 19 includes the following steps:

[0141] Using compound 18 (50 mg, 0.16 mmol) and cyclopropylformyl chloride (16.73 mg, 0.16 mmol) as raw materials, compound 19 (48.36 mg, yield: 80%) was prepared by a method similar to step (2) of Example 6.

[0142] Compound 19 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 378.1 [M+H] + The NMR spectrum of compound 19 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ12.90 (s, 1H), 10.25 (s, 1H), 8.26 (d, J=4.0Hz, 2H), 8.23 (s, 1H), 7.59-7.53 (m, 3H), 7.23 (d, J=8.0Hz, 1H), 1.23 (m, 1H), 0.83-0.79 (m, 4H).

[0143] Example 20

[0144] Example 20 provides an N-[2-(4-(chlorodifluoromethoxy)phenyl)-1H-benzo[d]imidazol-5-yl)acetamide (compound 20), with the following structural formula:

[0145] The preparation method of the above compound 20 includes the following steps:

[0146] (1) Preparation of intermediate 20-1: Compound 18-1 (200 mg, 0.59 mmol) was dissolved in 5 mL of DMF, and sodium hydride (15.57 mg, 0.65 mmol) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 1 h. Then, SEMCl (108.85 mg, 0.65 mmol) was added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed, water and EtOAc were added, the mixture was extracted and separated, the organic phases were combined, and the mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain brown solid 20-1 (230 mg, yield: 82.95%). The reaction formula is as follows:

[0147] (2) Preparation of intermediate 20-2: Using compound 20-1 (100 mg, 0.22 mmol) as a starting material, intermediate 20-2 was prepared according to a method similar to step (2) of Example 18, yielding a brown solid 20-2 (92.60 mg, yield 95.67%). The reaction formula is as follows:

[0148] (3) Preparation of intermediate 20-3: Compound 20-2 (50 mg, 0.11 mmol) was dissolved in 1 mL of DCM, and triethylamine (11.13 mg, 0.11 mmol) and acetic anhydride (11.23 mg, 0.11 mmol) were added. The mixture was reacted at 90 °C for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a white solid 20-3 (42.68 mg, yield: 80.50%). The reaction formula is as follows:

[0149] (4) Preparation of compound 20: Compound 20-3 (40 mg, 0.08 mmol) was dissolved in 1 mL of DCM, and 3 mL of TFA was added. The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a white solid compound 20 (11.4 mg, yield: 40.50%).

[0150] Compound 20 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 352.1 [M+H] +The NMR spectrum of compound 20 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (MeOD, 400MHz): δ 8.18 (d, J=4.0Hz, 2H), 8.09 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.47 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 1H), 2.16 (s, 3H).

[0151] Example 21

[0152] Example 21 provides a 7-chloro-2-[4-(chlorodifluoromethoxy)phenyl]-N-cyclopropyl-1H-benzo[d]imidazolium-6-carboxamide (compound 21), with the following structural formula:

[0153] The preparation method of the above compound 21 includes the following steps:

[0154] (1) Preparation of intermediate 21-2: Using methyl 4-amino-2-chlorobenzoate (10 g, 53.88 mmol) and acetic anhydride (5.5 g, 53.88 mmol) as raw materials, intermediate 21-2 was prepared by a method similar to step (3) of Example 20, yielding a yellow solid 21-2 (10.10 g, yield: 82.32%). The reaction formula is as follows:

[0155] (2) Preparation of intermediates 21-3A and 21-3B: Compound 21-2 (10 g, 43.93 mmol) was dissolved in 25 mL of concentrated sulfuric acid. Fuming nitric acid (3.8 mL, 90 mmol) was slowly added dropwise to the reaction solution under ice bath conditions, and the reaction was carried out for 1 h under ice bath conditions. After the reaction was completed, the reaction solution was quenched in ice water, extracted with DCM, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain brown solids 21-3A (2.67 g, yield: 22.30%) and 21-3B (2.41 g, yield: 20.10%). The reaction formula is as follows:

[0156] (3) Preparation of intermediate 21-4: Compound 21-3A (2.5 g, 9.70 mmol) was dissolved in 10 mL THF, and 20 mL of 10% potassium hydroxide was added. The reaction was refluxed overnight. After the reaction was completed, the reaction solution was washed with saturated brine, filtered and concentrated. The crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain brown solid 21-4 (974 mg, yield: 43.56%). The reaction formula is as follows:

[0157] (4) Preparation of intermediate 21-5: Compound 21-4 (950 mg, 4.12 mmol) and ammonium chloride (242.42 mg, 4.53 mmol) were dissolved in 20 mL of ethanol solution, and iron filings (1.15 g, 20.6 mmol) were added. The reaction was carried out at 78 °C for 1 h. After the reaction was completed, the reaction solution was concentrated under vacuum and azeotropically reacted with benzene twice to obtain brown solid 21-5 (662.90 mg, yield 80.20%). The reaction formula is as follows:

[0158] (5) Preparation of intermediate 21-6: Using compounds 1-3 (617.64 mg, 2.99 mmol) and 21-5 (600 mg, 2.99 mmol) as raw materials, intermediate 21-6 was prepared by a method similar to step (1) in Example 4, yielding a yellow solid 21-6 (604.85 mg, yield: 52.25%). The reaction formula is as follows:

[0159] (6) Preparation of intermediate 21-7: Using compound 21-6 (600 mg, 1.55 mmol) as a starting material, intermediate 21-7 was prepared according to a method similar to that in Example 3, yielding a yellow solid 21-7 (228.80 mg, yield 39.56%). The reaction formula is as follows:

[0160] (7) Preparation of compound 21: Using compound 21-7 (200 mg, 0.54 mmol) and cyclopropane (30.83 mg, 0.54 mmol) as raw materials, compound 21 was prepared by a method similar to step (1) of Example 6, to obtain a yellow solid compound 21 (89.31 mg, yield: 40.12%).

[0161] Compound 21 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 412.1 [M+H] + The NMR spectrum of compound 21 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.42 (d, J=4.0Hz, 1H), 8.36 (d, J=8.0Hz, 2H), 7.60-7.56 (m, 3H), 7.26 (d , J=8.0Hz, 1H), 2.88-2.84(m, 1H), 0.74-0.69(m, 2H), 0.58-0.54(m, 2H).

[0162] Example 22

[0163] Example 22 provides a 6-chloro-2-[4-(chlorodifluoromethoxy)phenyl]-N-cyclopropyl-1H-benzo[d]imidazolium-5-carboxamide (compound 22), with the following structural formula:

[0164] The preparation method of the above compound 22 includes the following steps:

[0165] Using compound 21-3B (2.0 g, 7.34 mmol) as the starting material, compound 22 was prepared by a method similar to steps (3)-(7) of Example 21 to obtain a yellow solid compound 22 (88.59 mg, yield: 39.80%).

[0166] Compound 22 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 412.1 [M+H] + The NMR spectrum of compound 22 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.44 (d, J=4.0Hz, 1H), 8.30 (d, J=12.0Hz, 2H), 7.71 (s, 1H), 7.6 0 (d, J=4.0Hz, 2H), 7.58 (s, 1H), 2.87-2.83 (m, 1H), 0.73-0.68 (m, 2H), 0.58-0.54 (m, 2H).

[0167] Example 23

[0168] Example 23 provides an N-{2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-5-yl}cyclopropanesulfonamide (compound 23), with the following structural formula:

[0169] The preparation method of the above compound 23 includes the following steps: using compound 18 (50 mg, 0.16 mmol) and cyclopropylsulfonyl chloride (22.49 mg, 0.16 mmol) as raw materials, it is prepared according to a method similar to that of Example 19 to obtain yellow solid compound 23 (52.23 mg, yield 78.89%).

[0170] Compound 23 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 414.1 [M+H] + The NMR spectrum of compound 23 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1H NMR (MeOD, 400MHz): δ8.18 (d, 8.0Hz, 2H), 7.62-7.58 (m, 2H), 7.49 (d, J=8.0Hz, 2H ), 7.25 (d, J=8.0Hz, 1H), 2.55-2.51 (m, 1H), 1.03-1.00 (m, 2H), 0.94-0.91 (m, 2H).

[0171] Example 24

[0172] Example 24 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-6-methoxy-N-methyl-1H-benzo[d]imidazol-5-carboxamide (compound 24), with the following structural formula:

[0173] The preparation method of the above compound 24 includes the following steps:

[0174] (1) Preparation of intermediate 24-2: Using methyl 2-bromo-4-nitrobenzoate (10 g, 38.46 mmol) as a raw material, it was prepared according to a method similar to step (4) of Example 21 to obtain brown solid 24-2 (6.98 g, yield 78.89%). The reaction formula is as follows:

[0175] (2) Preparation of intermediate 24-3: Using compound 24-2 (6.90 g, 30 mmol) as a starting material, intermediate 24-3 was prepared according to a method similar to steps (1)-(5) of Example 21, yielding a brown solid 24-3 (517.94 mg, yield: 48.89%). The reaction formula is as follows:

[0176] (3) Preparation of intermediate 24-4: Compound 24-3 (500 mg, 1.16 mmol) was dissolved in 10 mL of DMF. Cesium carbonate (755.90 mg, 2.32 mmol), cuprous iodide (243.78 mg, 1.28 mmol), methanol (74.33 mg, 2.32 mmol), and 1,10-o-phenanthroline (416.74 mg, 2.32 mmol) were added under argon protection. The reaction was carried out at 120 °C for 1 h. After the reaction was complete, water and EA were added to the reaction solution for extraction and separation. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 24-4 (160 mg, yield: 36%). The reaction formula is as follows:

[0177] (4) Preparation of intermediate 24-5: Using compound 24-4 (160 mg, 0.42 mmol) as a starting material, intermediate 24-5 was prepared according to a method similar to that in Example 3, yielding a yellow solid 24-5 (66.90 mg, yield 43.20%). The reaction formula is as follows:

[0178] (5) Preparation of compound 24: Using compound 24-5 (66.90 mg, 0.18 mmol) and methylamine hydrochloride (12.10 mg, 0.18 mmol) as raw materials, compound 24 was prepared by a method similar to step (1) of Example 6, to obtain a yellow solid compound 24 (27.49 mg, yield: 40%).

[0179] Compound 24 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 382.1 [M+H] + The NMR spectrum of compound 24 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ8.28 (d, J=8.0Hz, 2H), 8.23 ​​(d, J=8.0Hz, 1H), 8.05 (s , 1H), 7.60 (d, J=8.0Hz, 2H), 7.25 (s, 1H), 3.96 (s, 3H), 2.84 (d, J=4.0Hz, 3H).

[0180] Example 25

[0181] Example 25 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-carboxamide (compound 25), with the following structural formula:

[0182] The preparation method of the above compound 25 includes the following steps:

[0183] (1) Preparation of intermediate 25-1: Using compound 1-3 (621.52 mg, 3.01 mmol) and methyl 3,4-diaminobenzoate (500 mg, 3.01 mmol) as raw materials, intermediate 25-1 was prepared by a method similar to step (1) in Example 4, yielding a yellow solid 25-1 (397 mg, yield: 37.37%). The reaction formula is as follows:

[0184] (2) Preparation of intermediate 25-2: Using compound 25-1 (350 mg, 0.99 mmol) as a starting material, intermediate 25-2 was prepared according to a method similar to that in Example 3, yielding a yellow solid 25-2 (230 mg, yield: 68.59%). The reaction formula is as follows:

[0185] (3) Preparation of intermediate 25-3: Using compound 25-2 (200 mg, 0.59 mmol) and 2-(tert-butyldimethylsiloxy)ethyl-1-amine (113.80 mg, 0.65 mmol) as raw materials, intermediate 25-3 was prepared by a method similar to step (1) in Example 6, yielding a yellow solid 25-3 (247 mg, yield: 84.40%). The reaction formula is as follows:

[0186] (4) Preparation of compound 25: Compound 25-3 (200 mg, 0.40 mmol) was dissolved in 10 mL of 1,4-dioxane solution in 4 M hydrochloric acid and stirred for 1 h. After the reaction was completed, the reaction solution was filtered and concentrated, and purified by preparative high performance liquid chromatography (Pre-HPLC) to obtain a yellow solid compound 25 (73.30 mg, yield: 48%).

[0187] Compound 25 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 382.1 [M+H] + The NMR spectrum of compound 25 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (MeOD, 400MHz): δ8.22 (d, J=8.0Hz, 2H), 8.17 (s, 1H), 7.81 (d, J=8.0Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.50 (d, J=8.0Hz, 2H), 3.75 (t, J=8.0Hz, 3H), 3.55 (t, J=8.0Hz, 2H).

[0188] Example 26

[0189] Example 26 provides (R)-1-{2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-6-yl}pyrrolidine-3-ol (compound 26), with the following structural formula:

[0190] The preparation method of the above compound 26 includes the following steps:

[0191] (1) Preparation of intermediate 26-2: 5-fluoro-2-nitroaniline (1 g, 6.41 mmol) and (R)-3-hydroxypyrrolidine (558.44 mg, 6.41 mmol) were dissolved in 20 mL of DMSO, and potassium carbonate (1.77 g, 12.82 mmol) was added. The reaction was carried out at 100 °C for 16 h. After the reaction was complete, the concentrated reaction solution was filtered and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain brown solid 26-2 (1.2 g, yield: 83.86%). The reaction formula is as follows:

[0192] (2) Preparation of intermediate 26-3: Using compound 26-2 (1.2 g, 5.38 mmol) as a starting material, intermediate 26-3 was prepared according to a method similar to step (2) of Example 18, yielding a brown solid 26-3 (900 mg, yield: 86.56%). The reaction formula is as follows:

[0193] (3) Preparation of compound 26: Using compound 1-3 (535.02 mg, 2.59 mmol) and compound 26-3 (500 mg, 2.59 mmol) as raw materials, compound 26 was prepared by a method similar to step (1) of Example 4, to obtain yellow solid compound 26 (340.05 mg, yield 34.57%).

[0194] Compound 26 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 380.1 [M+H] + The NMR spectrum of compound 26 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (MeOD, 400MHz): δ8.11 (d, J=8.0Hz, 2H), (7.48-7.43 (m, 3H), 6.72-6.65 (m, 2H), 4.57-4.5(m, 1H), 3.58-3.49(m, 2H), 3.41-3.23(m, 2H), 2.22-2.03(m, 2H).

[0195] Example 27

[0196] Example 27 provides a 5-{2-[4-(chlorodifluoromethoxy)phenyl]-6-[(R)-3-hydroxypyrrolidone-1-yl]-1H-benzo[d]imidazol-7-yl}imidazolidine-2,4-dione (compound 27), with the following structural formula:

[0197] The preparation method of the above compound 27 includes the following steps:

[0198] (1) Preparation of intermediate 27-2: 2-Bromo-3-fluoro-6-nitroaniline (15 g, 21.276 mmol) was dissolved in 90 mL of DMSO, and DIEA (5.4 g, 41.5 mmol) and (R)-pyrrolidine-3-ol (5.55 g, 21.756 mmol) were added. The mixture was heated to 80 °C and reacted for 12 h. After the reaction was complete, the reaction solution was added to ice water, filtered, and concentrated to obtain a yellow solid 27-2 (18 g, yield: 95%). The reaction formula is as follows:

[0199] (2) Preparation of intermediate 27-3: Compound 27-2 (18 g, 59.6 mmol) was dissolved in 500 mL of methanol and 62.5 mL of THF. Ammonium chloride (64 g, 1200 mmol) and zinc powder (39 g, 596 mmol) were added. The reaction was carried out at 50 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered through a diatomaceous earth-lined sand core funnel. The organic phase was concentrated and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 27-3 (9.8 g, yield: 61%). The reaction formula is as follows:

[0200] (3) Preparation of intermediate 27-4: Using compound 27-3 (4.9 g, 18.2 mmol) and compound 1-3 (3.75 g, 18.2 mmol) as raw materials, intermediate 27-4 was prepared by a method similar to step (1) in Example 4, yielding a yellow solid 27-4 (5.8 g, yield: 92%). The reaction formula is as follows:

[0201] (4) Preparation of intermediate 27-5: Compound 27-4 (3.5 g, 7.6 mmol) was dissolved in 30 mL of DMF, and imidazole (777 mg, 11.438 mmol), DMAP (93 mg, 0.76 mmol), and TBSCl (1.7 g, 11.438 mmol) were added at room temperature. The reaction was allowed to proceed for 5 h at room temperature. After the reaction was completed, 300 mL of 1 mol citric acid aqueous solution and 200 mL of ethyl acetate were added to the reaction solution for extraction three times. The organic phase was washed three times with 200 mL of saturated brine, dried, concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 27-5 (4.1 g, yield: 93%). The reaction formula is as follows:

[0202] (5) Preparation of intermediate 27-6: Compound 27-5 (4.1 g, 7.18 mmol) was dissolved in 50 mL of DMF. NaH (431 mg, 10.77 mmol) was added under ice bath conditions. After the addition was complete, the mixture was stirred at this temperature for 0.5 h. SEMCl (1.32 g, 7.9 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 h. After the reaction was complete, the mixture was extracted three times with 300 mL of aqueous solution and 200 mL of ethyl acetate. The organic phase was washed three times with 200 mL of saturated brine, dried, and concentrated. The solution was purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 27-6 (4.5 g, yield: 90%). The reaction formula is as follows:

[0203] (6) Preparation of intermediate 27-7: Compound 27-6 (1 g, 1.42 mmol) was dissolved in 10 mL of 1,4-dioxane, and 4,4,5,5-tetramethyl-2-vinyl-1,3-dioxane (1.42 g, 222 mmol), cesium carbonate (926 mg, 2.84 mmol), and Pd(dppf)Cl2 (104 mg, 0.142 mmol) were added. The reaction was carried out at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the mixture was filtered and concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 27-7 (318 mg, yield: 40%). The reaction formula is as follows:

[0204] (7) Preparation of intermediate 27-8: Compound 27-7 (1.28 g, 1.97 mmol) was dissolved in 8 mL THF and 1 mL water, and sodium periodate (1.9 g, 8.871 mmol) and potassium osmium tetroxide (1.3 mg, 0.004 mmol) were added. The reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the mixture was extracted three times with 100 mL water and 10 mL ethyl acetate. The organic phase was washed three times with 15 mL saturated brine, dried and concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow oily substance 27-8 (300 mg, yield: 23.4%). The reaction formula is as follows:

[0205] (8) Preparation of intermediate 27-9: Compound 27-8 (900 mg, 1.38 mmol) was dissolved in 50 mL of MeOH, and potassium cyanide (180 mg, 2.76 mmol) and ammonium carbonate (535 mg, 5.52 mmol) were added. The mixture was reacted at 40 °C for 48 h. After the reaction was completed, the mixture was extracted three times with 100 mL of water and 10 mL of ethyl acetate. The organic phase was washed three times with 15 mL of saturated brine, dried, concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 27-9 (148 mg, yield: 15%). The reaction formula is as follows:

[0206] (9) Preparation of intermediate 27-10: Compound 27-9 (140 mg, 0.194 mmol) was dissolved in 5 mL of THF, and TBAF (0.4 mL, 1 mmol / L) was added. The mixture was reacted at room temperature for 2 h. After the reaction was completed, the mixture was extracted three times with 100 mL of water and 10 mL of ethyl acetate. The organic phase was washed three times with 15 mL of saturated brine, dried, concentrated, and purified by preparative high-performance liquid chromatography (Pre-HPLC) to obtain a yellow solid 27-10 (65 mg, yield: 55%). The reaction formula is as follows:

[0207] (10) Preparation of compound 27: Compound 27-10 (65 mg 0.11 mmol) was dissolved in 0.5 mL LTA and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated, dissolved in DMF and sent to prepare a light yellow solid compound 27 (7.5 mg, yield: 14.7%).

[0208] Compound 27 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 478.1 [M+H] + The NMR spectrum of compound 27 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (MeOD, 400MHz): δ8.25 (d, J=8.0Hz, 2H), 7.73 (d, J=8.0Hz, 2H), 7.59-7.55 (m, 3H), 5 .83(s, 1H), 4.51-4.49(m, 1H), 3.49-2.86(m, 4H), 2.88-2.20(m, 1H), 1.90-1.86(m, 1H).

[0209] Example 28

[0210] Example 28 provides a 4-{2-[4-(chlorodifluoromethoxy)phenyl]-6-[(R)-3-hydroxypyrrolidone-1-yl]-1H-benzo[d]imidazol-7-yl}imidazolidine-2-one (compound 28), with the following structural formula:

[0211] The preparation method of the above compound 28 includes the following steps:

[0212] Compound 27 (28 mg, 0.06 mmol) was dissolved in 1 mL of THF, and 2 mL of 1 mol / L BH3 in THF solution was added. The reaction was carried out at 50 °C for 2 h. After the reaction was completed, the solution was concentrated to dryness and dissolved in DMF to prepare a white solid compound 28 (1.4 mg, yield: 5%).

[0213] Compound 28 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 464.1 [M+H] + The NMR spectrum of compound 28 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1H NMR (MeOD, 400MHz): δ8.22 (d, J=8.0Hz, 2H), 7.47-7.45 (m, 3H), 7.30 (d, J=8.0Hz, 1H), 5.79-5.77 (m, 1H), 4.50-4.48(m, 2H), 4.01-3.00(m, 1H), 3.50-3.48(m, 2H), 3.04-3.01(m, 2H), 2.03-1.92(m, 2H).

[0214] Example 29

[0215] Example 29 provides a 2-[4-(chlorodifluoromethoxy)phenyl]-N-methyl-1H-benzo[d]imidazolium-7-carboxamide (compound 29), with the following structural formula:

[0216] The preparation method of the above compound 29 includes the following steps:

[0217] (1) Preparation of intermediate 29-2: Using methyl 2,3-diaminobenzoate (500 mg, 3.01 mmol) and compound 1-3 (621.52 mg, 3.01 mmol) as raw materials, intermediate 29-2 was prepared by a method similar to step (1) in Example 4, yielding a yellow solid 29-2 (532 mg, yield: 50.11%). The reaction formula is as follows:

[0218] (2) Preparation of intermediate 29-3: Using compound 29-2 (500 mg, 1.42 mmol) as a starting material, intermediate 29-3 was prepared according to a method similar to that in Example 3, yielding a yellow solid 29-3 (320 mg, yield: 66.54%). The reaction formula is as follows:

[0219] (3) Preparation of compound 29: Using compound 29-3 (150 mg, 0.47 mmol) and methylamine hydrochloride (31.59 mg, 0.47 mmol) as raw materials, compound 29 was prepared by a method similar to step (1) of Example 6, to obtain a yellow solid compound 29 (70.26 mg, yield: 42.50%).

[0220] Compound 29 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 352.1 [M+H]+. The NMR spectrum of compound 29 was detected by a 400MHz nuclear magnetic resonance spectrometer, and the results are as follows: 1H NMR (DMSO-d6, 400MHz): δ13.52 (s, 1H), 9.73 (s, 1H), 8.43 (d, J = 8.0Hz, 2H), 7.89 (d, J = 8.0Hz, 1 H), 7.75 (d, J=8.0Hz, 1H), 7.60 (d, J=8.0Hz, 2H), 7.37 (t, J=8.0Hz, 1H), 3.02 (d, J=4.0Hz, 3H).

[0221] Example 30

[0222] Example 30 provides an N-{2-[4-(chlorodifluoromethoxy)phenyl]-1H-benzo[d]imidazol-7-yl}cyclopropaneformamide (compound 30), with the following structural formula:

[0223] The preparation method of the above compound 30 includes the following steps: using compound 29-3 (150 mg, 0.47 mmol) and cyclopropane (26.85 mg, 0.47 mmol) as raw materials, it is prepared in a manner similar to step (1) of Example 6 to obtain yellow solid compound 30 (82.03 mg, yield: 46.20%).

[0224] Compound 30 was detected by LC-MS (Liquid-Mass Chromatography-Mass Spectrometry), and its MS (ESI) m / z = 378.1 [M+H] + The NMR spectrum of compound 30 was detected using a 400MHz nuclear magnetic resonance spectrometer. The results are as follows: 1 H NMR (DMSO-d6, 400MHz): δ 8.27-8.23 (m, 2H), 7.65 (d, J=8.0Hz, 2H), 7.60-7.52 (m, 3H), 2.00-1.97 (m, 1H), 1.11-1.09 (m, 2H), 1.01-0.99 (m, 2H).

[0225] Inhibition activity test

[0226] The inhibitory activity of some of the 2-arylbenzimidazole compounds provided in the embodiments of this application was tested. The results are shown in Table 4 below.

[0227] The following experiments investigated the inhibitory effects of compounds 2, 8, 9, 11, 12, 16, and 22 on the proliferation of BCR-ABL-WT transfected Ba / F3 cells. The specific procedures are as follows:

[0228] (1) First, prepare complete culture medium (RPMI-1640 + 10% FBS + 1% P / S) to revive Ba / F3-BCR-ABL-WT cells (purchased from Hefei Prestige). After passage for about two generations, centrifuge to collect cells in the logarithmic growth phase and count them. Resuspend the cells to a suitable concentration and seed the cell suspension into a 96-well plate. Add 95 μL of cell suspension to each well, and the seeding density is 2000 cells / well.

[0229] (2) The test compound was prepared into a stock solution using DMSO, and serially diluted with DMSO. The test compound was diluted 50-fold with culture medium, and 5 μL of each solution was added to a 96-well cell plate containing 95 μL of cells. Cell-free culture medium was added to the Min control wells, and 5 μL of DMSO-cell culture medium mixture was added to the Max control wells. The mixture was incubated at 37°C and 5% CO2 for 72 h. 50 μL / well CellTiter Glo was added to stop the reaction, and the mixture was incubated at room temperature in the dark for 30 min. After gentle shaking, the fluorescence value (RLU) was measured in SpectraMax Paradigm.

[0230] (3) Calculate the cell proliferation inhibition rate (Inh%) according to the following formula: Cell proliferation inhibition rate = 100 - (RLUDrug - RLUMin) / (RLUMax - RLUMin) × 100%. Calculate the inhibition rate corresponding to different concentrations of the compound in EXCEL, and use GraphPadPrism software to plot the inhibition rate curve to obtain the half-maximum inhibitory concentration (IC50). 50 value.

[0231] Note: IC 50 A value <5000 nM is considered to indicate that the compound has an inhibitory effect on the proliferation of BCR-ABL-WT transfected Ba / F3 cells, and the IC50 value is <5000 nM. 50 The smaller the value, the stronger the inhibitory effect of the compound.

[0232] Table 4. Results of the inhibitory effects of the compounds on the proliferation of BCR-ABL-WT transfected Ba / F3 cells.

[0233] According to the activity test results in Table 4, the compounds provided in this application showed good inhibitory activity against BCR-ABL-WT transfected Ba / F3 cells, indicating that the 2-arylbenzimidazole compounds provided in this application can be used as BCR-ABL inhibitors and are expected to be developed into drugs for the treatment and / or prevention of BCR-ABL-related diseases.

[0234] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A 2-arylbenzimidazole compound, characterized in that, The 2-arylbenzimidazole compounds are compounds represented by general formula I or pharmaceutically acceptable salts, isomers, solvates, hydrates, prodrugs, or isotope derivatives thereof; the structural formula of general formula I is: In the general formula I, R represents 1, 2, 3 or 4 identical or different substituents present on the benzene ring; R is independently selected from the following groups: hydrogen, halogen, cyano, hydroxyl, and optionally substituted C. 1-6 Alkoxy, optionally substituted amino, optionally substituted formyl, optionally substituted sulfonyl, optionally substituted heterocyclic alkyl, optionally substituted aryl, optionally substituted heteroaryl.

2. The 2-arylbenzimidazole compound according to claim 1, characterized in that, The structural formula of the 2-arylbenzimidazole compounds is shown in Formula II or Formula III: In Formula II or Formula III, R1 is hydrogen, an optionally substituted amino group, an optionally substituted formyl group, an optionally substituted sulfonyl group, or an optionally substituted C group. 3-7 Heterocyclic alkyl, optionally substituted C 3-7 Mixed aromatics; R2 is hydrogen, halogen, optionally substituted amino group, optionally substituted formyl group, or optionally substituted C group. 3-7 Heterocyclic alkyl groups; R3 is hydrogen, halogen, or C. 1-6 Alkyl group.

3. The 2-arylbenzimidazole compound according to claim 1, characterized in that, The 2-arylbenzimidazole compounds are selected from:

4. The use of any 2-arylbenzimidazole compound as described in any one of claims 1-3 in the preparation of medicaments for the treatment and / or prevention of tumor diseases.

5. A medicament for treating and / or preventing tumor diseases, characterized in that, The compound comprising any one of claims 1-3.

6. A BCR-ABL inhibitor, characterized in that, The compound comprising any one of claims 1-3.

7. A pharmaceutical composition, characterized in that, It comprises any one of the 2-arylbenzimidazole compounds according to claims 1-3, and a pharmaceutically acceptable carrier and / or excipient.

8. A medicament for treating and / or preventing BCR-ABL-related diseases, characterized in that, It comprises any one of the 2-arylbenzimidazole compounds according to claims 1-3, and a pharmaceutically acceptable carrier and / or excipient.

9. The medicament according to claim 8, characterized in that, The BCR-ABL-related diseases are selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, invasive carcinoma, viral infection, or CNS disorder.

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