A 1-phenyl-1h-benzo[d]imidazole compound as an FLT3 kinase inhibitor, preparation method, pharmaceutical composition and application

Abstract

Disclosed in the present application is a 1-phenyl-1 H -benzo[ d ]imidazole compound as an FLT3 kinase inhibitor, a preparation method, a pharmaceutical composition and an application. H -benzo[ d ]imidazole compound as shown in structural formula (I) or a pharmaceutically acceptable salt thereof: the 1-phenyl-1 H -benzo[ d ]imidazole compound has obvious proliferation inhibition effect on leukemia cells, especially human acute myeloid leukemia cells MOLM-13 and MV4-11, blocks the cell cycle at G0 / G1 phase, induces cell apoptosis, has good safety and significantly inhibits tumor growth in a MOLM-13 nude mouse xenograft model, has potential to be prepared into a new antitumor drug, and has good market prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a 1-phenyl-1-ethylhexyl group as an FLT3 kinase inhibitor. H -benzo[ d Imidazole compounds, preparation methods, pharmaceutical compositions and applications. Background Technology

[0002] Acute myeloid leukemia (AML), the most common acute leukemia in adults, poses a serious challenge to global health systems due to its high mortality, significant economic burden, and cross-age mortality. AML progresses rapidly, with a median survival of only 8 weeks for untreated patients. Even with intensive chemotherapy, the 5-year overall survival rate remains below 30% (<10% for elderly patients, approximately 40%-50% for younger patients). In 2024, there were over 120,000 new cases and 110,000 deaths worldwide (WHO data), ranking among the top three causes of cancer death in young adults aged 15-39.

[0003] In AML patients, the incidence of FLT3 gene mutations is as high as 25%–30%. Numerous clinical studies have shown that AML patients carrying FLT3-ITD mutations typically exhibit leukocytosis, high relapse rates, significant cardiotoxicity, and significantly shortened overall survival. Normal cells do not have FLT3 mutations. Therefore, FLT3 mutations have been considered a poor prognostic factor and a crucial breakthrough for targeted therapy. Currently, several FLT3 inhibitors (such as the first-generation midotulin and the second-generation giglitinib) have been approved for clinical use, significantly improving the survival of some patients. FLT3 mutations lead to abnormal activation of signaling pathways, causing cell cycle and / or apoptosis dysregulation, which in turn leads to the disordered growth and proliferation of tumor cells. Therefore, targeted inhibition of FLT3 can inhibit the cell cycle of tumor cells, induce apoptosis, and thus inhibit the growth and proliferation of AML cells, achieving a highly effective and low-toxicity anti-tumor effect. Summary of the Invention

[0004] In view of this, the present invention aims to propose a 1-phenyl-1-yl group as an FLT3 kinase inhibitor. H -benzo[ d Imidazole compounds, preparation methods, pharmaceutical compositions, and applications are provided to solve at least one technical problem in the background art.

[0005] To achieve the above objectives, the technical solution of the present invention is implemented as follows: A 1-phenyl-1-yl group that acts as an FLT3 kinase inhibitor H -benzo[ d Imidazole compounds, such as 1-phenyl-1-yldioxane as shown in structural formula (I), H -benzo[ d Imidazole compounds or their pharmaceutically acceptable salts: (I); in, R1 is selected from one of -C(O)NH-, SO2, C(O), and -C(S)NH-; R2, R3 and R4 are independently selected from one of hydrogen atom, C1-6 alkyl group, halogen, CF3, -OCH3; R5 is selected from one of halogens, phenols, and phenyl m-tolylcarbamate.

[0006] Furthermore, R1 is -C(O)NH-, R2, R3 and R4 are selected from one of hydrogen atom, methyl, -OCH3, CF3 and chlorine atom, and R2, R3 and R4 may be the same or different; R5 is selected from one of phenol, bromine atom and m-tolylcarbamate. Alternatively, R1 may be SO2, R2, R3, and R4 may be selected from hydrogen atoms, -OCH3, and chlorine atoms, and R2, R3, and R4 may be the same or different; R5 may be selected from phenol and bromine atoms. Alternatively, R1 may be C(O), R2, R3, and R4 may be selected from hydrogen atoms, -OCH3, and chlorine atoms, and R2, R3, and R4 may be the same or different; R5 may be selected from phenol atoms and bromine atoms. Alternatively, R1 can be -C(S)NH-, R2, R3 and R4 can be selected from hydrogen atoms, -OCH3 and chlorine atoms, and R2, R3 and R4 can be the same or different; R5 can be a bromine atom.

[0007] Further, it is any one of the following compounds: Compound 1: N-(3-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide, with the structural formula shown in (1): (1); Compound 2: N-(3-(5-bromo-1) H -benzo[ d [Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, with the structural formula shown in (2); (2); Compound 3: N-(4-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide, with the structural formula shown in (3); (3); Compound 4: N-(4-(5-bromo-1) H -benzo[ d[Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, with the structural formula shown in (4); (4); Compound 5: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)thiourea, with the structural formula shown in (5); (5); Compound 6: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea, with the structural formula shown in (6); (6); Compound 7: 1-(4-(5-bromo-1) H -benzo[ d [Imidazol-1-yl)phenyl)-3-(3-chlorophenyl)thiourea, with the structural formula shown in (7); (7); Compound 8: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea, with the structural formula shown in (8); (8); Compound 9: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea, with the structural formula shown in (9); (9); Compound 10: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, with the structural formula shown in (10); (10); Compound 11: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea, with the structural formula shown in (11); (11); Compound 12: 1-[3-(5-bromo-1-] H -benzo[ d[Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, with the structural formula shown in (12); (12); Compound 13: 1-(3-(5-bromo-1) H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, with the structural formula shown in (13); (13); Compound 14: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea, with the structural formula shown in (14); (14); Compound 15: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, with the structural formula shown in (15); (15); Compound 16: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea, with the structural formula shown in (16); (16); Compound 17: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, with the structural formula shown in (17); (17); Compound 18: N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-4-methoxybenzamide, with the structural formula shown in (18); (18); Compound 19: N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzamide, with the structural formula shown in Figure 19; (19); Compound 20: 3-chloro-N-(3-(5-(4-hydroxyphenyl)-1H -benzo[ d [Imidazol-1-yl)phenyl)benzenesulfonamide, with the structural formula shown in (20); (20); Compound 21: N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, with the structural formula shown in (21); (twenty one); Compound 22: 3-chloro-N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)benzenesulfonamide, with the structural formula shown in (22); (twenty two); Compound 23: N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, with the structural formula shown in (23); (twenty three); Compound 24: 1-(3-chlorophenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)urea, with the structural formula shown in (24); (twenty four); Compound 25: 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-3-(m-tolyl)urea, with the structural formula shown in (25); (25); Compound 26: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)urea, with the structural formula shown in (26); (26); Compound 27: 1-(4-chloro-2-methylphenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)urea, with the structural formula shown in (27); (27); Compound 28: 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, with the structural formula shown in (28); (28); Compound 29: 1-(3-chlorophenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)urea, with the structural formula shown in (29); (29); Compound 30: 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-3-(m-tolyl)urea, with the structural formula shown in (30); (30); Compound 31: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)urea, with the structural formula shown in (31); (31); Compound 32: 1-(4-chloro-2-methylphenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)urea, with the structural formula shown in (32); (32); Compound 33: 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, with the structural formula shown in (33); (33); Compound 34: 4-(1-(3-(3-(m-tolyl)ureo)phenyl)-1 H -benzo[ d Imidazol-5-yl)phenyl-m-tolyl carbamate; (34); Furthermore, compounds 1, 2, 3, and 4 are the first compound; The preparation method of the first compound includes the following steps: dissolving a benzenesulfonamide compound in pyridine, cooling in an ice bath, adding a benzenesulfonyl chloride derivative; raising the reaction mixture to room temperature and stirring, concentrating the reaction solution under reduced pressure, pouring it into ice water, filtering, washing the filter cake, and drying to obtain the first compound; Benzenesulfonamide compounds are selected from 3-(5-bromo-1-yl) H -benzo[ d Imidazol-1-yl)aniline, 4-(5-bromo-1-yl)aniline H -benzo[ d One of imidazole-1-yl)aniline; The benzenesulfonyl chloride derivative is selected from one of 4-methoxybenzenesulfonyl chloride or 3-chlorobenzenesulfonyl chloride; Compounds 20, 21, 22, and 23 are second compounds; The preparation method of the second compound includes the following steps: Benzenesulfonamide derivatives and pinacol 4-hydrophenylboronic acid were dissolved in dioxane aqueous solution, nitrogen gas was introduced, and then Pd(PPh3)4 and potassium carbonate were added. The mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, filtered, the filter cake was washed, and dried to obtain the second compound. Benzenesulfonamide derivatives are selected from N-(3-(5-bromo-1-) H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide, N-(3-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, N-(4-(5-bromo-1) H -benzo[ d One of imidazole-1-yl)phenyl)-3-chlorobenzenesulfonamides.

[0008] Furthermore, compounds 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17 are third compounds; The preparation method of the above-mentioned third compound includes the following steps: Aromatic amine compounds are dissolved in anhydrous N,N-dimethylformamide or anhydrous dichloromethane, and the corresponding aryl isothiocyanate derivatives are slowly added. After the addition is complete, the reaction mixture is stirred at room temperature. The reaction solution is concentrated under reduced pressure, poured into ice water, filtered, the filter cake is washed, and dried to obtain the third compound. Aromatic amine compounds are selected from 3-(5-bromo-1-methyl)-2-methyl ... H -benzo[ d Imidazol-1-yl)aniline, 4-(5-bromo-1-yl)aniline H-benzo[ d One of imidazole-1-yl)aniline; The aryl isothiocyanate derivatives are 3-chloroaryl isothiocyanate and 4-methoxyaryl isothiocyanate; the aryl isocyanate derivatives are selected from one of 3-chloroaryl isocyanate, 3-methylaryl isocyanate, 4-chloro-3-trifluoromethylaryl isocyanate, 4-chloro-2-methylaryl isocyanate, and 4-methoxyaryl isocyanate.

[0009] Furthermore, compounds 18 and 19 are fourth compounds; The preparation method of the above-mentioned fourth compound includes the following steps: Aromatic amine compounds were dissolved in pyridine, and acyl chloride derivatives were added. The reaction mixture was stirred at room temperature, filtered, and washed to obtain an intermediate. The intermediate and 4-hydrophenylboronic acid pinacol ester were dissolved in dioxane aqueous solution, nitrogen gas was introduced, Pd(PPh3)4 and potassium carbonate were added, and the mixture was heated under reflux for 2-4 hours. The reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography to obtain the fourth compound.

[0010] Aromatic amine compounds are selected from 3-(5-bromo-1-methyl)-2-methyl ... H -benzo[ d Imidazol-1-yl)aniline, 4-(5-bromo-1-yl)aniline H -benzo[ d One of imidazole-1-yl)aniline; The acyl chloride derivative is 4-methoxybenzoyl chloride.

[0011] Furthermore, compounds 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33 are the fifth compounds; The preparation of the fifth compound mentioned above includes the following steps: Urea derivatives and 4-hydrophenylboronic acid pinacol ester were dissolved in dioxane aqueous solution, nitrogen gas was introduced, Pd(PPh3)4 and potassium carbonate were added, and the mixture was heated under reflux for 2-4 hours. Urea derivatives are selected from 1-(4-(5-bromo-1-) H -benzo[ d [Imidazol-1-yl)phenyl)-3-(3-chlorophenyl)urea, 1-[3-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, 1-[3-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea, 1-[3-(5-bromo-1] H -benzo[d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, 1-(3-(5-bromo ... H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, 1-(4-(5-bromo ... H -benzo[ d One of the imidazole-1-yl)phenyl)-3-(4-methoxyphenyl)urea.

[0012] Furthermore, compound 13 is the sixth compound. The preparation method of the sixth compound mentioned above includes the following steps: dissolving 1,1'-carbonyldiimidazole in anhydrous DCM and cooling it in an ice bath; then adding triethylamine, and under a nitrogen atmosphere, adding anhydrous DCM solution of p-methoxyaniline dropwise to the above-mentioned cooled solution, and continuing to stir the reaction in an ice bath for 1-3 hours to obtain a reaction solution; 3-(5-bromo-1- H -benzo[ d A solution of imidazole-1-yl)aniline was added dropwise to the above reaction solution. The reaction system was then raised to room temperature and stirred continuously. The reaction solution was concentrated under reduced pressure, filtered, washed, dried, and purified by rapid column chromatography to obtain the sixth compound. Compound 34 is the seventh compound; The preparation method of the seventh compound includes the following steps: 4-(1-(3-aminophenyl)-1 H -benzo[ d Imidazol-5-yl)phenol was slowly added to a solution in anhydrous DCM with the corresponding aryl isocyanate derivative. The mixture was stirred at room temperature, filtered, washed with diethyl ether, dried, and purified by column chromatography to give compound VII.

[0013] A pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, preferably, the dosage form of the pharmaceutical composition being an oral formulation or an injection. The carrier includes pharmaceutical excipients, the selection of which varies depending on the route of administration and characteristics of action, and is typically a filler, diluent, binder, wetting agent, disintegrant, lubricant, emulsifier, or suspending agent.

[0014] The pharmaceutical composition may be prepared using any method known to those skilled in the art, as disclosed, such as conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0015] The above-mentioned 1-phenyl-1-ylgenide as an FLT3 kinase inhibitor H -benzo[ d The use of imidazole compounds or one of the above-mentioned pharmaceutical compositions as active ingredients in the preparation of antitumor drugs, preferably as active ingredients in the preparation of antitumor drugs with inhibitory activity against human acute myeloid leukemia cell lines MOLM-13 and MV4-11.

[0016] Furthermore, 1-phenyl-1, as shown in general formula (I), H -benzo[ d The imidazole FLT3 inhibitor or a pharmaceutically acceptable salt thereof constitutes 0.1% to 99.9% by mass in the pharmaceutical composition, wherein the mass percentage refers to the 1-phenyl-1-methyl-2-ethylhexylene oxide as shown in formula (I). H -benzo[ d The percentage of imidazole FLT3 inhibitors or their pharmaceutically acceptable salts by mass in the total pharmaceutical composition. The 1-phenyl-1-yl group as shown in formula (I) is... H -benzo[ d The sum of the mass fractions of imidazole compounds or their pharmaceutically acceptable salts and pharmaceutical excipients is 100%.

[0017] The pharmaceutical compositions of the present invention can be administered orally, by injection (intravenous, intramuscular, subcutaneous, and intracoronary), sublingually, buccally, rectally, urethra, vaginally, nasally, by inhalation, or topically.

[0018] Compared to existing technologies, the present invention describes a 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor. H -benzo[ d Imidazole compounds, their preparation methods, pharmaceutical compositions, and applications have the following advantages: The compound provided by this invention contains 1-phenyl-1 H -benzo[ dThis invention relates to an imidazole-based FLT3 inhibitor, a type of FLT3 inhibitor whose potential applications have not been previously reported. Our experimental results show that the compounds of this invention have significant inhibitory effects on the proliferation of human acute myeloid leukemia cells MOLM-13 and MV4-11, demonstrating the potential to be developed into novel antitumor drugs and possessing good market prospects. Attached Figure Description

[0019] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings: Figure 1 The graph shows the effect of compounds 1-34 on FLT3 kinase phosphorylation in acute myeloid leukemia cells (A shows the effect of compounds 1-17 on FLT3 kinase phosphorylation, and B shows the effect of compounds 18-34 on FLT3 kinase phosphorylation). Figure 2 The graph shows the effect of compound 1-34 on the proliferation of acute myeloid leukemia cells MOLM-13 and MV4-11 (A shows the effect of compound 1-34 on the proliferation of MOLM-13 cells, and B shows the effect of compound 1-34 on the proliferation of MV4-11 cells). Figure 3 The effect of compound 31 on FLT3 kinase activity is shown in the figure. Figure 4 The following graphs show the effects of compound 31 on the proliferation of solid tumor cells HCT116, PC3, MKN28, A549, and MDA-MB-231 (A shows the effect of compound 31 on the proliferation of HCT116 cells, B shows the effect of compound 31 on the proliferation of PC3 cells, C shows the effect of compound 31 on the proliferation of MKN28 cells, D shows the effect of compound 31 on the proliferation of A549 cells, and E shows the effect of compound 31 on the proliferation of MDA-MB-231 cells). Figure 5 The diagram shows the effect of compound 31 on the cell cycle of MOLM-13 and MV4-11 cells (A shows the effect of compound 31 on the cell cycle of MOLM-13 cells, and B shows the effect of compound 31 on the cell cycle of MV4-11 cells). Figure 6 The diagram shows the effect of compound 31 on apoptosis of MOLM-13 and MV4-11 cells (A shows the effect of compound 31 on apoptosis of MOLM-13 cells, and B shows the effect of compound 31 on apoptosis of MV4-11 cells). Figure 7The diagram shows the effect of compound 31 on FLT3 and its downstream molecules in MOM-13 and MV4-11 cells (A shows the effect of compound 31 on FLT3 and its downstream molecules in MOM-13 cells, and B shows the effect of compound 31 on FLT3 and its downstream molecules in MV4-11 cells). Figure 8 The results of the in vivo anti-MOLM-13 tumor assay of compound 31 are shown in the figure (A is a comparison of tumor size in each group of mice, B is a curve of tumor volume change in each group of mice, C is a comparison of tumor weight in each group of mice, and D is a curve of body weight change in each group of mice). Detailed Implementation

[0020] It should be noted that, unless otherwise specified, the embodiments and features described in the present invention can be combined with each other.

[0021] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0022] Unless otherwise specified, all descriptions in the following examples are in units of mass (grams), and room temperature refers to 20°C to 30°C.

[0023] The present invention will now be described in detail with reference to the embodiments and accompanying drawings.

[0024] Example 1 N-(3-(5-bromo-1) H -benzo[ d Preparation of imidazole-1-yl)phenyl)-3-chlorobenzenesulfonamide Using 4-fluoro-3-nitrobromobenzene as a starting material, it was reacted with 3-aminoacetanilide in K2CO3 / DMF at 80–90°C for 16 hours. After reduction of the nitro group by SnCl2·2H2O, formic acid was added at 120°C to cyclize and form a benzimidazole ring. Finally, the target product 3-(5-bromo-1-nitrobromobenzene) was obtained by reflux with concentrated hydrochloric acid for 1 hour to deacetylate. H -benzo[ d Imidazol-1-yl)aniline, 3-(5-bromo-1 H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in pyridine (10 mL) and cooled in an ice bath. The corresponding 3-chlorobenzenesulfonyl chloride (1.248 mmol, 1.2 equiv) was slowly added. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hours. After the reaction was complete as monitored by thin-layer chromatography (TLC), the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water and diethyl ether. After drying, a gray solid N-(3-(5-bromo-1-yl)aniline was obtained. H -benzo[ dImidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide, yield 97.64%.

[0025] The obtained target product was tested, and the test results are as follows: 1 HNMR (400MHz, DMSO-) d6 )δ10.79(s,1H),8.58(s,1H),8.00(s,1H),7.85(s,1H),7.81–7.76(m,2H),7.65(t, J =7.9Hz,1H),7.56–7.48(m,2H),7.41–7.38(m,1H),7.34(d, J =2.1Hz, 1H), 7.29(d, J =8.6Hz, 1H), 7.24(dd, J =8.1, 2.1 Hz, 1H).

[0026] Example 2 N-(3-(5-bromo-1) H -benzo[ d Preparation of imidazole-1-yl)phenyl)-4-methoxybenzenesulfonamide: The 3-(5-bromo-1-dimethylamine) prepared in Example 1 will be used as a reference. H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in pyridine (10 mL) and cooled in an ice bath. The corresponding 4-methoxybenzenesulfonyl chloride (1.248 mmol, 1.2 equiv) was slowly added. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water and diethyl ether. After drying, a gray solid N-(3-(5-bromo-1-yl)aniline was obtained. H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, yield 98.82%.

[0027] The obtained target product was tested, and the test results are as follows: 1 HNMR (400MHz, DMSO-) d6 )δ10.56(s,1H),8.56(s,1H),7.99(s,1H),7.78(d, J =8.5Hz,2H),7.49(t, J =9.5Hz,2H),7.32(q, J =8.4, 7.8 Hz, 3H), 7.22 (d,J =8.3Hz, 1H), 7.12(d, J =8.6Hz,2H),3.81(s,3H).

[0028] Example 3 N-(4-(5-bromo-1) H -benzo[ d Preparation of imidazole-1-yl)phenyl)-3-chlorobenzenesulfonamide The reaction was carried out using 4-fluoro-3-nitrobromobenzene as a starting material, which was reacted with 4-aminoacetanilide in K2CO3 / DMF at 80–90°C for 16 hours. The intermediate was then subjected to nitro reduction via SnCl2·2H2O, followed by cyclization with formic acid at 120°C to form a benzimidazole ring. Finally, the product was deacetylated by reflux with concentrated hydrochloric acid for 1 hour to obtain the target product 4-(5-bromo-1-nitrobromobenzene). H -benzo[ d Imidazol-1-yl)aniline; 4-(5-bromo-1 H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in pyridine (10 mL) and cooled in an ice bath. The corresponding 3-chlorobenzenesulfonyl chloride (1.248 mmol, 1.2 equiv) was slowly added. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water and diethyl ether. After drying, a gray solid N-(4-(5-bromo-1-yl)aniline was obtained. H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide, yield 95.2%.

[0029] The obtained target product was tested, and the test results are as follows: 1 HNMR (400MHz, DMSO-) d 6)δ10.76(s,1H),8.54(s,1H),7.96(s,1H),7.85(s,1H),7.77(dd, J =15.4, 7.5 Hz, 2H), 7.65 (d, J =7.9Hz, 1H), 7.59(d, J =8.4Hz, 2H), 7.50(d, J =8.6Hz, 1H), 7.44(d, J =8.7Hz, 1H), 7.33(d, J =8.2Hz, 2H).

[0030] Example 4 N-(4-(5-bromo-1) H -benzo[ d Preparation of imidazole-1-yl)phenyl)-4-methoxybenzenesulfonamide The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in pyridine (10 mL) and cooled in an ice bath. The corresponding 4-methoxybenzenesulfonyl chloride (1.248 mmol, 1.2 equiv) was slowly added. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water and diethyl ether. After drying, a gray solid N-(4-(5-bromo-1-yl)aniline was obtained. H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, yield 85.28%.

[0031] The obtained target product was tested, and the test results are as follows: 1 HNMR (400MHz, DMSO-) d 6)δ10.52(s,1H),8.52(s,1H),7.96(s,1H),7.78(d, J =8.3Hz,2H),7.56(d, J =8.3Hz,2H),7.51–7.41(m,2H),7.31(d, J =8.4Hz,2H),7.11(d, J =8.5Hz,2H),3.81(s,3H).

[0032] Example 5 1-[3-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(3-chlorophenyl)thiourea The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H -benzo[ dImidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous N,N-dimethylformamide (DMF) (10 mL), and the corresponding 3-chloroaryl isothiocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water, n-hexane, and diethyl ether. After drying, a gray solid 1-[3-(5-bromo-1-yl)aniline was obtained. H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)thiourea, yield 80.76%.

[0033] 1 HNMR (400MHz, DMSO-) d 6)δ10.59(s,2H),8.64(s,1H),8.31(s,1H),8.07(s,1H),7.99(s,1H),7.81–7.70(m,2H),7.62–7.53(m,2H),7.50–7.44(m,2H),7.36(td, J =8.0, 2.7 Hz, 1H), 7.18 (d, J =7.7Hz, 1H).

[0034] Example 6 1-[3-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DMF (10 mL), and the corresponding 4-methoxyaryl isothiocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water, n-hexane, and diethyl ether. After drying, a gray solid 1-[3-(5-bromo-1-yl)aniline was obtained. H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea, yield 95.22%.

[0035] 1 HNMR (400MHz, DMSO-) d6)δ9.90(s,1H),9.86(s,1H),8.63(s,1H),8.02–7.97(m,2H),7.74(d, J =8.7Hz,1H),7.60–7.52(m,2H),7.49(dd, J =8.7, 1.9 Hz, 1H), 7.42 (dd, J =7.2, 2.1 Hz, 1H), 7.35 (d, J =8.8Hz,2H),6.93(d, J =8.9Hz,2H),3.76(s,3H).

[0036] Example 7 1-(4-(5-bromo-1) H -benzo[ d Preparation of imidazol-1-yl)phenyl)-3-(3-chlorophenyl)thiourea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DMF (10 mL), and the corresponding 3-chloroaryl isothiocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water, n-hexane, and diethyl ether. After drying, a gray solid 1-(4-(5-bromo-1-yl)aniline was obtained. H -benzo[ d Imidazol-1-yl)phenyl)-3-(3-chlorophenyl)thiourea, yield 75.5%.

[0037] 1 HNMR (400MHz, DMSO-) d 6)δ10.20(s,2H),8.59(s,1H),7.93(s,1H),7.80–7.72(m,3H),7.68–7.63(m,2H),7.58(d, J =8.7Hz,1H),7.50–7.42(m,2H),7.37(t, J =7.7Hz, 1H), 7.22(s, 1H).

[0038] Example 8 1-[4-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DMF (10 mL), and the corresponding 4-methoxyaryl isothiocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure, poured into ice water, filtered, and the filter cake was washed successively with water, n-hexane, and diethyl ether. After drying, a gray solid 1-[4-(5-bromo-1-yl)aniline was obtained. H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea, yield 62.15%.

[0039] 1 HNMR (400MHz, DMSO-) d 6)δ9.80(d, J =28.8Hz,1H),8.59(s,1H),7.97(s,1H),7.74(d, J =8.1Hz,2H),7.68–7.39(m,5H),7.35(d, J =8.5Hz,2H),6.91(d, J =8.3Hz,2H),3.75(s,3H).

[0040] Example 9 1-[3-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (DCM, 10 mL), and the corresponding 3-chloroaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a pale yellow solid 1-[3-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea, yield 84.86%.

[0041] 1HNMR (400MHz, DMSO-) d 6)δ9.10(s,1H),9.03(s,1H),8.63(s,1H),8.00(d, J =1.9Hz, 1H), 7.89(t, J =2.2Hz, 1H), 7.72(d, J =2.3Hz, 1H), 7.62(d, J =8.6Hz,1H),7.57–7.48(m,3H),7.33–7.26(m,3H),7.04(dq, J =5.9, 3.5, 2.3 Hz, 1H).

[0042] MSm / z: 441.01123 (M+1).

[0043] Example 10 1-[3-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(m-tolyl)urea The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (DCM, 10 mL), and the corresponding 3-methylaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a pale yellow solid 1-[3-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, yield 86.2%.

[0044] 1 HNMR (400MHz, DMSO-) d 6))δ9.01(s,1H),8.74(s,1H),8.63(s,1H),8.01(d, J =1.9Hz, 1H), 7.90(t, J =2.1Hz, 1H), 7.62(d, J =8.7Hz,1H),7.55–7.45(m,3H),7.31(s,1H),7.25(dd, J =10.2,7.6Hz,2H),7.17(t,J =7.7Hz, 1H), 6.81(d, J =7.4Hz, 1H), 2.28(s, 3H).

[0045] MSm / z: 421.06585 (M+1).

[0046] Example 11 1-[3-(5-bromo-1-] H -benzo[ d Preparation of [imidazol-1-yl)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (DCM, 10 mL), and the corresponding 4-chloro-3-trifluoromethyl aryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-[3-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea, yield 62.15%.

[0047] 1 HNMR (400MHz, DMSO-) d 6)δ9.38(s,1H),9.26(s,1H),8.63(s,1H),8.10(d, J =2.5Hz, 1H), 8.00(d, J =1.9Hz, 1H), 7.88(d, J =2.1Hz, 1H), 7.68(dd, J =8.8, 2.5Hz, 1H), 7.63(d, J =3.2Hz, 1H), 7.61(d, J =3.0Hz,1H),7.57–7.49(m,3H),7.30(dt, J =7.4, 1.9 Hz, 1H).

[0048] MSm / z: 508.99861 (M+1).

[0049] Example 12 1-[3-(5-bromo-1-]H -benzo[ d Preparation of [imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (DCM, 10 mL), and the corresponding 4-chloro-2-methylaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-[3-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, yield 86.5%.

[0050] 1 HNMR (400MHz, DMSO-) d 6)δ9.46(s,1H),8.63(s,1H),8.17(s,1H),8.00(d, J =1.9Hz, 1H), 7.90(t, J =2.1Hz, 1H), 7.86(d, J =8.7Hz, 1H), 7.62(d, J =8.6Hz, 1H), 7.50(ddd, J =12.6,10.7,7.9Hz,3H),7.27(dd, J =7.4, 2.3Hz, 2H), 7.20(dd, J =8.7,2.6Hz,1H),2.26(s,3H).

[0051] MSm / z: 455.02688 (M+1).

[0052] Example 13 1-(3-(5-bromo-1) H -benzo[ d Preparation of imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea 1,1'-carbonyldiimidazole (CDI) (0.5 g, 3.17 mmol, 1.3 eqiv) was dissolved in anhydrous DCM (5 mL) and cooled in an ice bath. Triethylamine (TEA) (0.44 mL, 3.17 mmol, 1.3 eqiv) was then added. Under a nitrogen atmosphere, a solution of p-methoxyanisidine (0.3 g, 2.44 mmol, 1 eqiv) in anhydrous DCM (5 mL) was added dropwise over 30 minutes to the cooled solution. After the addition was complete, the reaction was stirred in an ice bath for 2 hours. After the reaction was complete as monitored by TLC, 3-(5-bromo-1-diimidazole) was added... H -benzo[ d A solution of imidazole-1-yl)aniline (0.265 g, 0.920 mmol, 1 eqiv) was added dropwise to the above reaction mixture. The reaction system was then brought to room temperature and stirred for 24 hours. After confirming the completion of the reaction by TLC, the reaction solution was concentrated under reduced pressure, filtered, washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-(3-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, yield 54.44%.

[0053] 1 HNMR (400MHz, DMSO-) d 6)δ8.93(s,1H),8.62(s,1H),8.60(s,1H),8.00(s,1H),7.89(s,1H),7.62(d, J =8.7Hz,1H),7.55–7.44(m,3H),7.37(d, J =8.5Hz,2H),7.25(d, J =7.7Hz, 1H), 6.88(d, J =8.4Hz,2H),3.72(s,3H).

[0054] MSm / z: 437.06312 (M+1).

[0055] Example 14 1-[4-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ dImidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DCM (10 mL), and the corresponding 3-chloroaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-[4-(5-bromo-1-yl)aniline. H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea, yield 64.979%.

[0056] 1 HNMR (400MHz, DMSO-) d 6)δ9.06(s,1H),8.99(s,1H),8.56(s,1H),7.98(s,1H),7.75–7.67(m,3H),7.63–7.52(m,3H),7.47(d, J =8.8Hz, 1H), 7.32(d, J =4.9Hz,2H),7.08–7.01(m,1H).

[0057] MSm / z: 441.01123 (M+1).

[0058] Example 15 1-[4-(5-bromo-1-] H -benzo[ d Preparation of imidazol-1-yl)phenyl]-3-(m-tolyl)urea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DCM (10 mL), and the corresponding 3-methylaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-[4-(5-bromo-1-yl)aniline. H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, yield 68.13%.

[0059] 1 HNMR (400MHz, DMSO-) d6)δ8.94(s,1H),8.67(s,1H),8.56(s,1H),7.98(d, J =1.8Hz,1H),7.72–7.68(m,2H),7.60–7.52(m,3H),7.47(dd, J =8.7, 1.9 Hz, 1H), 7.32 (d, J =2.2Hz, 1H), 7.26(d, J =8.3Hz, 1H), 7.18(t, J =7.7Hz, 1H), 6.82(d, J =7.4Hz, 1H), 2.30(s, 3H).

[0060] MSm / z: 421.06585 (M+1).

[0061] Example 16 1-[4-(5-bromo-1-] H -benzo[ d Preparation of [imidazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DCM (10 mL), and the corresponding 4-chloro-3-trifluoromethyl aryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-[4-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea, yield 86.64%.

[0062] 1 HNMR (400MHz, DMSO-) d 6) δ10.08(s,1H),9.87(s,1H),8.55(s,1H),8.13(s,1H),7.96(s,1H),7.73(d, J =8.5Hz, 3H), 7.68(s, 1H), 7.59(t, J =7.9Hz,3H),7.53(d, J =8.5Hz, 1H), 7.44(d,J =8.7Hz, 1H).

[0063] Example 17 1-[4-(5-bromo-1-] H -benzo[ d Preparation of [imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous DCM (10 mL), and the corresponding 4-chloro-2-methylaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give a white solid 1-[4-(5-bromo-1-yl)aniline. H -benzo[ d Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, yield 81.47%.

[0064] 1 HNMR (400MHz, DMSO-) d 6)δ9.39(s,1H),8.56(s,1H),8.17(d, J =28.0Hz, 1H), 7.98(d, J =1.8Hz, 1H), 7.89(dd, J =8.8, 2.3 Hz, 1H), 7.71 (d, J =8.4Hz, 2H), 7.58(d, J =8.4Hz, 2H), 7.54(d, J =8.6Hz, 1H), 7.47(d, J =8.6Hz, 1H), 7.29(d, J =2.5Hz, 1H), 7.22(d, J =8.7Hz, 1H), 2.27(s, 3H).

[0065] Example 18 N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)-4-methoxybenzamide The 3-(5-bromo-1-dimethylamine) prepared in Example 1 was used... H-benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in pyridine (10 mL), and 4-methoxybenzoyl chloride (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours, monitored by TLC, filtered, and washed to obtain N-(3-(5-bromo-1-yl)aniline. H -benzimidazol-1-yl)phenyl)-4-methoxybenzamide intermediate. The intermediate (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL) under nitrogen purging. Then Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed by TLC monitoring, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a pale yellow solid N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-4-methoxybenzamide, yield 50.97%.

[0066] 1 HNMR (400MHz, DMSO-) d 6) δ 10.40 (s, 1H), 9.53 (d, J =2.8Hz, 1H), 8.59(s, 1H), 8.21(d, J =2.4Hz, 1H), 8.00(d, J =8.5Hz, 2H), 7.94(s, 1H), 7.88(d, J =8.2Hz, 1H), 7.75(d, J =8.5Hz, 1H), 7.61(t, J =7.9Hz,2H),7.56(d, J =8.2Hz,2H),7.42(dd, J =7.8, 2.1 Hz, 1H), 7.09 (d, J =8.6Hz,2H),6.87(d, J =8.3Hz,2H),3.85(s,3H).

[0067] MSm / z: 436.16557 (M+1).

[0068] Example 19 N-(4-(5-(4-hydroxyphenyl)-1 H-benzo[ d Preparation of imidazole-1-yl)phenyl)-4-methoxybenzamide The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in pyridine (10 mL), and 4-methoxybenzoyl chloride (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours, monitored by TLC, filtered, and washed to obtain N-(4-(5-bromo-1-yl)aniline. H -benzimidazol-1-yl)phenyl)-4-methoxybenzamide intermediate. The intermediate (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL) under nitrogen purging. Then Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed by TLC monitoring, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a pale yellow solid N-(4-(5-(4-hydroxyphenyl)-1-yl)-4-methoxybenzamide. H -benzo[ d [Imidazol-1-yl)phenyl)-4-methoxybenzamide, yield 36.64%.

[0069] 1 HNMR (400MHz, DMSO-) d 6)δ10.34(s,1H),9.50(s,1H),8.55(s,1H),8.05(s,1H),8.03(d, J =2.3Hz,2H),8.00(d, J =2.0Hz, 1H), 7.93(s, 1H), 7.68(d, J =8.8Hz,2H),7.65(d, J =8.5Hz,1H),7.58–7.52(m,3H),7.12–7.08(m,2H),6.87(d, J =8.5Hz,2H),3.86(s,3H).

[0070] MSm / z: 436.16557 (M+1).

[0071] Example 20 3-Chloro-N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ dPreparation of imidazole-1-yl)phenyl)benzenesulfonamide The product obtained in Example 1 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) and nitrogen gas was introduced. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a pale yellow solid 3-chloro-N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)benzenesulfonamide, yield 24.39%.

[0072] 1 HNMR (400MHz, DMSO-) d 6)δ10.81(s,1H),9.53(s,1H),8.54(s,1H),7.93(s,1H),7.87(d, J =2.0Hz, 1H), 7.80(dd, J =7.8, 2.0 Hz, 2H), 7.67 (d, J =7.7Hz, 1H), 7.55 (dd, J =12.2,8.2Hz,4H),7.43–7.33(m,3H),7.22(dd, J =8.0, 2.1Hz, 1H), 6.88(d, J =8.2Hz, 2H).

[0073] MSm / z: 476.08302 (M+1).

[0074] Example 21 N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)-4-methoxybenzenesulfonamide The product obtained in Example 2 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to obtain a pale yellow solid N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, yield 16.1%.

[0075] 1 HNMR (400MHz, DMSO-) d 6)δ9.55(s,1H),8.50(s,1H),7.92(s,1H),7.78(d, J =8.6Hz,2H),7.56(d, J =7.4Hz,2H),7.49(d, J =8.0Hz,3H),7.35(t, J =4.3Hz,3H),7.20(d, J =8.2Hz, 1H), 7.13(d, J =8.6Hz,2H),6.88(d, J =8.2Hz,2H),3.81(s,3H).

[0076] MSm / z: 472.13255 (M+1).

[0077] Example 22 3-Chloro-N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)benzenesulfonamide The product obtained in Example 3 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a white solid 3-chloro-N-(4-(5-(4-hydroxyphenyl)-1H -benzo[ d Imidazol-1-yl)phenyl)benzenesulfonamide, yield 61.983%.

[0078] 1 HNMR (400MHz, DMSO-) d 6)δ9.52(s,1H),8.49(s,1H),7.90(s,1H),7.85(s,1H),7.80(d, J =7.8Hz, 1H), 7.75(d, J =7.9Hz, 1H), 7.63(dd, J =13.0,8.2Hz,3H),7.54(dd, J =7.6, 3.3 Hz, 5H), 7.34 (d, J =8.3Hz,2H),6.86(d, J =8.1Hz, 2H).

[0079] MSm / z: 476.08302 (M+1).

[0080] Example 23 N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)-4-methoxybenzenesulfonamide The product obtained in Example 4 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) and nitrogen gas was introduced. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a pale yellow solid N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, yield 58.25%.

[0081] 1 HNMR (400MHz, DMSO-) d 6)δ10.50(s,1H),9.50(s,1H),8.46(s,1H),7.90(s,1H),7.79(d, J =8.5Hz,2H),7.58(d, J=8.7Hz,2H),7.53(d, J =8.3Hz,4H),7.33(d, J =8.5Hz,2H),7.11(d, J =8.6Hz,2H),6.86(d, J =8.2Hz,2H),3.81(s,3H).

[0082] MSm / z: 472.13255 (M+1).

[0083] Example 24 1-(3-chlorophenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)urea The prepared product 3-(5-bromo-1 H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (DCM, 10 mL), and the corresponding 3-chloroaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give 1-[3-(5-bromo-1-yl)aniline. H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea (Example 9). 1-(3-(5-bromo-1H-benzo[d]imidazol-1-yl)phenyl)-3-(3-chlorophenyl)urea (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL) and purged with nitrogen. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was complete as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a pale yellow solid 1-(3-chlorophenyl)-3-(3-(5-(4-hydroxyphenyl)-1-yl)phenyl]-3-(3-chlorophenyl)-3-(5-(4-hydroxyphenyl) ...(5-(4-hydroxyphenyl)-3-(5-(4-hydroxyphenyl)-3-(5 H -benzo[ d Imidazol-1-yl)phenyl)urea, yield 37.576%.

[0084] 1 HNMR (400MHz, DMSO-) d6)δ9.62(s,1H),9.55(s,2H),8.58(s,1H),7.95(d, J =10.0Hz,2H),7.75–7.68(m,2H),7.61–7.50(m,5H),7.35–7.28(m,3H),7.03(d, J =7.3Hz, 1H), 6.87(d, J =8.2Hz, 2H).

[0085] MSm / z: 455.12693 (M+1).

[0086] Example 25 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazol-1-yl)phenyl)-3-(m-tolyl)urea The product obtained in Example 10 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a white solid 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-3-(m-tolyl)urea, yield 63.1067%.

[0087] 1 HNMR (400MHz, DMSO-) d 6)δ9.51(s,1H),8.99(s,1H),8.72(s,1H),8.57(s,1H),7.94(d, J =4.1Hz,2H),7.69(d, J =8.5Hz, 1H), 7.56(q, J =8.1, 6.5 Hz, 4H), 7.45 (d, J =8.3Hz,1H),7.33–7.23(m,3H),7.17(t, J =7.7Hz, 1H), 6.87(d, J =8.2Hz,2H),6.81(d, J =7.4Hz, 1H), 2.28(s, 3H).

[0088] MSm / z: 435.18155 (M+1).

[0089] Example 26 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)urea The product obtained in Example 11 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated to reflux for 3 hours. After the reaction was complete as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a white solid 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(5-(4-hydroxyphenyl)-1- H -benzo[ d Imidazol-1-yl)phenyl)urea, yield 41.42%.

[0090] 1 HNMR (400MHz, DMSO-) d 6)δ9.52(s,1H),9.37(s,1H),9.25(s,1H),8.58(s,1H),8.11(s,1H),7.98–7.90(m,2H),7.69–7.53(m,8H),7.32(d, J =10.3Hz,1H),6.92–6.84(m,2H).

[0091] MSm / z: 523.11431 (M+1).

[0092] Example 27 1-(4-chloro-2-methylphenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)urea The product obtained in Example 12 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated to reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a milky white solid 1-(4-chloro-2-methylphenyl)-3-(3-(5-(4-hydroxyphenyl)-1- H -benzo[ d Imidazol-1-yl)phenyl)urea, yield 40.976%.

[0093] 1 HNMR (400MHz, DMSO-) d 6)δ9.53(s,1H),9.42(s,1H),8.59(s,1H),8.14(s,1H),7.95(s,2H),7.87(d, J =8.6Hz, 1H), 7.70(d, J =8.6Hz, 1H), 7.56(q, J =8.9, 7.6 Hz, 5H), 7.46 (d, J =8.3Hz,1H),7.30–7.28(m,1H),7.21(dd, J =9.0, 2.6 Hz, 1H), 6.87 (d, J =8.2Hz,2H),2.26(s,3H).

[0094] MSm / z: 469.14258 (M+1).

[0095] Example 28 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea The product obtained in Example 13 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated to reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, yield 47.87%.

[0096] 1 HNMR (400MHz, DMSO-) d 6)δ9.51(s,1H),8.95(s,1H),8.62(s,1H),8.57(s,1H),7.94(d, J =1.9Hz,2H),7.70(d, J =8.5Hz, 1H), 7.54(dd, J =18.0,8.2Hz,4H),7.45(d, J =8.7Hz, 1H), 7.38(d, J =9.0Hz,2H),7.27(d, J =7.9Hz, 1H), 6.89(d, J =4.0Hz,2H),6.87(d, J =3.6Hz,2H),3.72(s,3H).

[0097] MSm / z: 451.17647 (M+1).

[0098] Example 29 1-(3-chlorophenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)urea The product obtained in Example 14 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a milky white solid 1-(3-chlorophenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea, yield 48.78%.

[0099] 1 HNMR (400MHz, DMSO-) d 6)δ9.66(s,1H),9.61(s,1H),8.51(s,1H),7.92(s,1H),7.76(d, J =4.0Hz,2H),7.73(s,1H),7.60(d, J =8.5Hz, 3H), 7.54(d, J =8.6Hz,3H),7.33(dt, J =15.8,8.1Hz,3H),7.02(d, J =7.6Hz, 1H), 6.87(d, J =8.1Hz, 2H).

[0100] MSm / z: 455.12693 (M+1).

[0101] Example 30 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazol-1-yl)phenyl)-3-(m-tolyl)urea The product obtained in Example 15 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a blue solid 1-(4-(5-(4-hydroxyphenyl)-1 H-benzo[ d Imidazol-1-yl)phenyl)-3-(m-tolyl)urea, yield 38.47%.

[0102] 1 HNMR (400MHz, DMSO-) d 6)δ9.53(s,1H),8.97(s,1H),8.70(s,1H),8.50(s,1H),7.92(s,1H),7.71(d, J =8.3Hz,2H),7.60(d, J =8.4Hz, 3H), 7.55(d, J =8.6Hz, 3H), 7.33(s, 1H), 7.27(d, J =8.1Hz, 1H), 7.18(t, J =7.8Hz, 1H), 6.87(d, J =8.1Hz,2H),6.82(d, J =7.4Hz, 1H), 2.29(s, 3H).

[0103] MSm / z: 435.18155 (M+1).

[0104] Example 31 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)urea The product obtained in Example 16 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a light brown solid, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(5-(4-hydroxyphenyl)-1- H -benzo[ d Imidazol-1-yl)phenyl)urea, yield 62.93%.

[0105] 1 HNMR (400MHz, DMSO-) d6)δ9.49(s,1H),9.28(s,1H),9.16(s,1H),8.52(s,1H),8.14(d, J =2.5Hz, 1H), 7.92(d, J =1.6Hz, 1H), 7.73(d, J =8.9Hz,2H),7.68(d, J =2.5Hz, 1H), 7.63(dd, J =10.3,2.9Hz,3H),7.60(s,1H),7.55(d, J =8.7Hz, 3H), 6.87(d, J =8.6Hz, 2H).

[0106] MSm / z: 523.11431 (M+1).

[0107] Example 32 1-(4-chloro-2-methylphenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazole-1-yl)phenyl)urea The product prepared in Example 17 (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated to reflux for 3 hours. After the reaction was completed as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a off-white solid 1-(4-chloro-2-methylphenyl)-3-(4-(5-(4-hydroxyphenyl)-1- H -benzo[ d Imidazol-1-yl)phenyl)urea, yield 22.78%.

[0108] 1 HNMR (400MHz, DMSO-) d 6)δ9.51(s,1H),9.36(s,1H),8.52(s,1H),8.10(s,1H),7.92(s,2H),7.71(d, J =8.7Hz,2H),7.61(d, J =8.5Hz, 3H), 7.55(d, J =8.8Hz,3H),7.31–7.28(m,1H),7.23(d, J=9.3Hz, 1H), 6.87(d, J =7.8Hz,2H),2.27(s,3H).

[0109] MSm / z: 469.14258 (M+1).

[0110] Example 33 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Preparation of imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea The 4-(5-bromo-1-dimethylamine) prepared in Example 3 was used... H -benzo[ d Imidazol-1-yl)aniline (0.3 g, 1.04 mmol, 1 equiv) was dissolved in anhydrous dichloromethane (DCM, 10 mL), and the corresponding 4-methoxyaryl isocyanate (1.56 mmol, 1.5 equiv) was slowly added. After the addition was complete, the reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed by TLC monitoring, the reaction solution was filtered, the filter cake was washed with diethyl ether, dried, and purified by rapid column chromatography (eluent: DCM / MeOH = 9.8:0.2) to give 1-(4-(5-bromo-1-yl)aniline. H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea. 1-(4-(5-bromo-1-yl)phenyl)-3-(4-methoxyphenyl)urea. H -benzo[ d Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea (0.6 mmol, 1 equiv) and pinacol 4-hydrophenylboronic acid (0.72 mmol, 1 equiv) were dissolved in dioxane / water (4:1, 30 mL total) under nitrogen purging. Then, Pd(PPh3)4 (0.06 mmol, 1 equiv) and potassium carbonate (1.8 mmol, 3 equiv) were added, and the mixture was heated under reflux for 3 hours. After the reaction was complete as monitored by TLC, the reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH) to give a pale yellow solid 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, yield 22.5%.

[0111] 1 HNMR (400MHz, DMSO-) d 6)δ9.49(s,1H),8.89(s,1H),8.58(s,1H),8.50(s,1H),7.92(s,1H),7.70(d, J=8.4Hz,2H),7.60(d, J =6.0Hz, 3H), 7.55(d, J =8.3Hz,3H),7.40(d, J =8.5Hz,2H),6.88(t, J =8.7Hz, 4H), 3.73(s, 3H).

[0112] MSm / z: 451.17647 (M+1).

[0113] Example 34 4-(1-(3-(3-(m-tolyl)ureido)phenyl)-1 H -benzo[ d Preparation of imidazole-5-yl)phenyl-m-tolyl carbamate Using 4-fluoro-3-nitrobromobenzene as a starting material, it was reacted with 3-aminoacetanilide in K2CO3 / DMF at 80–90°C for 16 hours. After reduction of the nitro group by SnCl2·2H2O, formic acid was added at 120°C to cyclize and form a benzimidazole ring. This ring, along with 4-hydroxyphenylboronic acid pinacol ester and potassium carbonate, was dissolved in anhydrous dioxane. Pd(PPh3)4 was added, and the mixture was refluxed under nitrogen protection for 3 hours, then dissolved in concentrated hydrochloric acid and refluxed for 1 hour. 4-(1-(3-aminophenyl)-1 H -benzo[ d Imidazol-5-yl)phenol (0.3 g, 1.04 mmol, 1 equiv) was slowly added to a solution of 3-methylaryl isocyanate (1.56 mmol, 1.5 equiv) in anhydrous DCM (10 mL), and the reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was filtered, washed with diethyl ether, dried, and purified by column chromatography (DCM / MeOH 9.8:0.2) to give the target product as a white solid in 47.34% yield.

[0114] 1 HNMR (400MHz, DMSO-) d 6) δ10.22(s,1H),9.04(s,1H),8.75(s,1H),8.63(s,1H),8.08(s,1H),7.98(s,1H),7.80(d, J =8.2Hz,2H),7.76(d, J =8.5Hz, 1H), 7.69(d, J =8.5Hz,1H),7.55(t, J =8.0Hz, 1H), 7.47(d, J=8.2Hz,1H),7.36(s,1H),7.35–7.31(m,4H),7.30–7.14(m,4H),6.88(d, J =7.5Hz, 1H), 6.81(d, J =7.4Hz,1H),2.29(s,3H),2.28(s,3H).

[0115] MSm / z: 568.2343 (M+1).

[0116] The present invention will now be described in detail with reference to the embodiments and accompanying drawings.

[0117] Performance testing; The target products will be referred to as compounds 1-34 in the following text.

[0118] 1. Test on the inhibitory activity of FLT3 kinase phosphorylation in acute myeloid leukemia cells; 1-Phenylon-1-methyl-1-ethylhexyl ... H -benzo[ d The effect of imidazole compounds on the phosphorylation level of FLT3 kinase (p-FLT3) in MOLM-13 cells. MOLM-13 cells in logarithmic growth phase were resuspended in complete culture medium and counted at 1×10⁻⁶. 6 Cells were seeded at a density of 1 mL in each well of a 24-well plate. The following day, cells were treated with either DMSO or 100 nM of the test compound. After incubation at 37°C in a 5% CO2 incubator for 24 hours, cell lysates were collected. The human p-FLT3 (Tyr591) ELISA kit was then administered according to the instructions: 50 μL each of the standard and cell lysate were added to a 24-well plate pre-coated with anti-p-FLT3 antibody and incubated at 37°C for 1 hour. The liquid was discarded, and 100 μL of biotin-labeled detection antibody was added to each well, incubating at 37°C for 1 hour. After thorough washing, 100 μL of TMB substrate was added, and the reaction was incubated at room temperature in the dark for 15 minutes. Finally, 50 μL of stop solution was added to terminate the reaction. The absorbance (OD value) of each well was measured at 450 nm using an iMark microplate reader, and the relative content of p-FLT3 in the sample was calculated based on the standard curve.

[0119] The inhibitory effect of compounds 1–34 on p-FLT3 levels in MOLM-13 cells is detailed in the following results. Figure 1 .

[0120] Figure 1The results showed that the compounds of the present invention could significantly inhibit the phosphorylation of FLT3. Among them, compounds 2, 3, 4, 5, 7, 18, 26 and 31 showed high inhibition rates of p-FLT3 at a concentration of 100 nM, indicating that they have potent FLT3 kinase inhibitory activity at the cellular level.

[0121] 2. Test on the inhibitory effect on the proliferation of acute myeloid leukemia cells; Detection of 1-phenyl-1-ylgen by cell proliferation inhibition assay H -benzo[ d Effects of imidazole compounds on the proliferation of acute myeloid leukemia cells MOLM-13 and MV4-11. MOLM-13 and MV4-11 cells in logarithmic growth phase were resuspended in culture medium and counted. The cell suspension was then cultured at 2.5 × 10⁻⁶. 4 Cells were seeded at a density of [missing information - likely a specific density] into 96-well plates. 200 μL of cell suspension was added to each well. The next day, cells were treated with DMSO or different concentrations of compounds. Cells were then incubated for 48 hours. After 48 hours, 20 μL of CCK-8 solution was added directly to each well. The plate was gently shaken to mix. Cells were then returned to the incubator and incubated in the dark for 1–4 hours. The absorbance (OD value) of each well was measured using an iMark microplate reader at 450 nm.

[0122] The inhibitory effect of compound 1-34 on the proliferation of MOLM-13 cells is shown in the figure below. Figure 2 A.

[0123] Figure 2 Test results showed that the compounds of the present invention could significantly inhibit the proliferation of MOLM-13 cells, with compounds 14, 15, 16, 17, 29, 30, 31, and 32 showing cell viability of less than 50% at a concentration of 0.1 μM.

[0124] The inhibitory effect of compound 1-34 on the proliferation of MV4-11 cells is shown in the figure below. Figure 2 B.

[0125] Figure 2 The B test results showed that the compounds of the present invention could significantly inhibit the proliferation of MV4-11 cells, and the cell survival rate of compounds 14, 15, 16, 17, 29, 30, 31 and 32 was less than 50% at a concentration of 0.1 μM.

[0126] Table 1 shows the test results for compounds 14, 15, 16, 17, 29, 30, 31, and 32, which have an IC50 effect on MOLM-13 cells. 50 The values ​​were 0.297, 0.205, 0.065, 0.616, 0.021, 0.172, 0.002, and 0.018 μM, respectively. Compound 31 exhibited the strongest inhibitory effect on cell proliferation, with an IC50 value of [missing value].50 The value is lower than that of other compounds, indicating that it can effectively kill cancer cells at extremely low concentrations, making it a highly potent precursor compound. Specific results are shown in Table 1.

[0127] Table 1; Table 2 shows the test results for compounds 14, 15, 16, 17, 29, 30, 31, and 32, which have an IC50 effect on MV4-11 cells. 50 The values ​​were 2.711, 0.474, 0.633, 2.845, 0.286, 3.066, 0.033, and 3.711 μM, respectively. Compound 31 exhibited the strongest inhibitory effect on cell proliferation, with an IC50 value of [missing value]. 50 The value is lower than that of other compounds, and the kinase inhibitory activity is strong, indicating that it can effectively kill cancer cells at extremely low concentrations. It is a highly potent lead compound. The specific results are shown in Table 2.

[0128] Table 2; 3. Tests on the inhibitory effect of compound 31 on FLT3 kinase The inhibitory effect of compound 31 on FLT3 kinase activity was evaluated using an in vitro kinase activity assay. A commercially available recombinant human FLT3 kinase and its accompanying kinase activity assay kit (ADP-Glo™ KinaseAssay) were used. FLT3 kinase, ATP, substrate, and different concentrations of the test compound were mixed, and the reaction plate was incubated at 37°C for 45 minutes. After the reaction, 25 µL of ADP-Glo ​​reagent was added to each well to terminate the kinase reaction. The plate was sealed with aluminum foil and incubated at room temperature for 45 minutes. During incubation, the KinaseDetection reagent was thawed. 50 µL of KinaseDetection reagent was added to each well. The plate was sealed again with aluminum foil and incubated at room temperature in the dark for 45 minutes. The luminescence signal of each well was read using a chemiluminescence detector to indirectly characterize kinase activity. The DMSO-treated group served as a 100% kinase activity control, and the enzyme-free group served as a blank background.

[0129] The inhibitory effect of compound 31 on FLT3 kinase activity is detailed in the following results. Figure 3 .

[0130] Figure 3 The results showed that the compounds of this invention could significantly inhibit the activity of FLT3 kinase, IC50. 50 It reached 1.03 nM.

[0131] 4. Compound 31 has a weak inhibitory effect on the proliferation of solid tumor cell lines; The effects of compound 31 on solid tumor cell lines HCT116 (colon cancer), PC3 (prostate cancer), MKN28 (gastric cancer), A549 (non-small cell lung cancer), and MDA-MB-231 (triple-negative breast cancer) were detected using a cell proliferation inhibition assay. Cell suspensions were incubated at 2.5 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of [missing information - likely a specific density] into 96-well plates. 200 μL of cell suspension was added to each well. The next day, cells were treated with DMSO or different concentrations of compound 31. Cells were then incubated for 48 hours. After 48 hours, 20 μL of CCK-8 solution was added directly to each well. The plate was gently shaken to mix. Cells were then returned to the incubator and incubated in the dark for 1–4 hours. The absorbance (OD value) of each well was measured using an iMark microplate reader at 450 nm.

[0132] Compound 31 inhibited the proliferation of HCT116, PC3, MKN28, A549, and MDA-MB-231 cells. Specific results are shown in [link to results]. Figure 4 .

[0133] Figure 4 Test results showed that compound 31, even at the same concentration and up to 1 μM, did not exhibit significant inhibitory effects on five solid tumor cell lines: HCT116, PC3, MKN28, A549, and MDA-MB-231, and cell viability was above 50% in all cases (see details). Figure 4 The results suggest that the compound has a weak inhibitory effect on the proliferation of solid tumor cells, but a selective inhibitory effect on acute myeloid leukemia cells, which may be related to the high frequency of FLT3 mutations in these cells.

[0134] 5. Flow cytometry analysis was used to detect the effect of compound 31 on the cell cycle of acute myeloid leukemia cells MOLM-13 and MV4-11; (1) MOLM-13 and MV4-11 cells were seeded in 6-well plates at a suitable cell density and incubated at 37°C for 24 hours. After changing the culture medium, the control group was given DMSO and different concentrations of compound 31 and incubated for 48 hours. (2) Collect cells in EP tubes and wash twice with ice-cold PBS; (3) Add 250 μL of ice-cold PBS to the lower layer of cells, mix well by pipetting, and slowly fix the cells in 750 μL of ice-cold ethanol. Place in a refrigerator at 4°C overnight. (4) After centrifugation to remove ethanol, wash twice with ice-cold PBS. Add 100 μL of PBS to the lower cell pellet to resuspend the cells. Add 200 μL of pre-prepared PI staining solution to each tube, wrap with aluminum foil, and stain at 4°C for 1 hour. Filter through a nylon mesh and analyze using a flow cytometer.

[0135] (5) Analyze the flow cytometry results using FlowJo 7.6.1 software.

[0136] Effects of compound 31 on the cell cycle of MOLM-13 After 48 hours of treatment of MOLM-13 cells with compound 31 (concentrations: 1, 10 nM), the percentage of cells in the G0 / G1 phase significantly increased from 60.3% in the 10 nM group to 86.9% in the control group, indicating that compound 31 can arrest the cell cycle of MOLM-13 cells in the G0 / G1 phase. Figure 5 A.

[0137] Effects of compound 31 on the cell cycle of MV4-11 cells; After MV4-11 cells were treated with compound 31 (concentrations: 0.1, 1 μM) for 48 hours, the percentage of cells in the G0 / G1 phase significantly increased from 67.4% in the 1 μM group to 97.2% in the control group, indicating that compound 31 can arrest the cell cycle of MV4-11 cells in the G0 / G1 phase. Figure 5 B.

[0138] 6. Flow cytometry was used to detect the regulatory effect of compound 31 on apoptosis in acute myeloid leukemia cells MOLM-13 and MV4-11; (1) MOLM-13 and MV4-11 cells were seeded in 6-well plates at a suitable cell density and incubated at 37°C for 24 hours. After changing the culture medium, the control group was given DMSO and different concentrations of compound 31 and incubated for 48 hours. (2) Aspirate the culture medium, wash with PBS, and add the corresponding culture medium back to each well and mix by pipetting to form a cell suspension; (3) Aspirate the cell suspension and place it into a 1.5 mL EP tube. Centrifuge the EP tube in a centrifuge for 5 minutes at a speed of 1000 rpm. After centrifugation, discard the supernatant and wash the cell pellet twice with ice-cold PBS. (4) Set the final cell concentration to 1×10⁻⁶. 5 To determine the cell concentration, calculate the required concentration (cells / mL) and add 100 μL of 1× Binding Buffer. Resuspend the cells to achieve the desired concentration. Add 2.5 μL of Annexin-V staining solution and 2.5 μL of LPI staining solution for double staining. After adding the staining solutions, incubate at room temperature in the dark for 15 minutes. Stop the reaction by adding 200 μL of 1× Binding Buffer to each tube. Filter the cells through a nylon mesh and analyze using a flow cytometer.

[0139] The regulatory effect of compound 31 on apoptosis in MOLM-13 cells.

[0140] Compound 31 significantly induced apoptosis in MOLM-13 cells, see [link to article]. Figure 6 A.

[0141] The regulatory effect of compound 31 on apoptosis in MV4-11 cells.

[0142] Compound 31 significantly induced apoptosis in MV4-11 cells, see [link to article]. Figure 6 B.

[0143] 7. Western blot analysis of the effects of compound 31 on FLT3 and its downstream molecules in MOLM-13 and MV4-11 acute myeloid leukemia cells; (1) MOLM-13 and MV4-11 cells were seeded at an appropriate density in 6-well plates and incubated at 37°C and 5% CO2 for 24 hours; control group (DMSO) and different concentrations of compound 31 were added respectively, and the treatment continued for 48 hours. (2) Discard the culture medium, centrifuge to collect cells, gently wash the cells twice with pre-cooled PBS, add 50 μL of pre-cooled RIPA lysis buffer (containing protease inhibitor and phosphatase inhibitor), and lyse on ice for 30 minutes. (3) Subsequently, centrifuge at 4℃ and 12000rpm for 15 minutes, and collect the supernatant as the total protein extract; determine the protein concentration using the BCA method; (4) Based on the test results, take an equal amount of protein sample (usually 30–50 μg) and mix it with 5×SDS loading buffer, and denature it in a water bath for 5 minutes; (5) The denatured protein sample was added to a 10% SDS-PAGE gel for electrophoresis separation, and then transferred to a PVDF membrane (220mA constant current transfer for 2.5 hours). (6) After the transfer is completed, block with 5% skim milk at room temperature for 1 hour, add primary antibodies (such as p-FLT3, p-AKT, p-ERK, p-STAT5 and other related pathway protein antibodies and internal reference GAPDH antibody), and incubate at 4°C overnight; (7) The next day, wash the membrane three times with TBST for 10 minutes each time, add the HRP-labeled secondary antibody of the corresponding species, and incubate at room temperature for 1 hour; wash the membrane three times with TBST again. (8) Use ECL chemiluminescence reagent for development and acquire images through a chemiluminescence imaging system.

[0144] Effects of compound 31 on FLT3 and its downstream molecules in MOLM-13 cells.

[0145] Compound 31 significantly reduced the levels of p-FLT3, p-ERK, p-STAT5, and p-AKT proteins in MOLM-13 cells, see [link to article]. Figure 7 A.

[0146] Effects of compound 31 on FLT3 and its downstream molecules in MV4-11 cells.

[0147] Compound 31 significantly reduced the levels of p-FLT3, p-ERK, p-STAT5, and p-AKT proteins in MV4-11 cells, see [link to article]. Figure 7 B.

[0148] 8. The in vivo antitumor effect of compound 31 on an acute myeloid leukemia MOLM-13 xenograft model; (1) Cell Culture: Pass MOLM-13 cells to ensure they are in the logarithmic growth phase and in good condition. (2) Nude Mouse Housing: BALB / c nude mice are housed in a sterile environment. Keepers must wear sterile masks, caps, gloves, and gowns. Bedding, food, and water used by the mice must be autoclaved before use. After stabilization for about one week, MOLM-13 cells are expanded. (3) Tumor Implantation: The required expanded MOLM-13 cells are collected, counted, and prepared into 5×10⁻⁶ cells. 7 Cells / mL were resuspended in PBS. After mixing, 0.1 mL of cell suspension was drawn using a 1 mL syringe with a No. 6 needle and subcutaneously injected into nude mice on the left abdomen. (4) Drug intervention: When the tumor grew to 5 mm × 5 mm × 5 mm, 30 mice were randomly divided into 3 groups (control group, novel compound 3150 mg / kg / day, novel compound 31100 mg / kg / day), with 10 mice in each group. The drugs were administered continuously for 12 days, and body weight and tumor volume (volume = shortest diameter) were measured every 2 days. 2 × longest diameter / 2), and adjust the administration volume according to changes in body weight. (6) Sacrifice and dissection: 12 days later, sacrifice the mice, remove the tumor, weigh it, and fix it with 4% paraformaldehyde.

[0149] In vivo antitumor assay of compound 31 against an acute myeloid leukemia MOLM-13 xenograft model.

[0150] Twelve days after oral administration of the compound, tumor volume and weight were significantly smaller in the treatment groups compared to the control group. Specifically, tumor volume and weight were significantly smaller in the compound 31 (50 and 100 mg / kg) treatment groups compared to the control group. There were no significant differences in body weight among the treatment groups, indicating that no significant toxic side effects were observed in any treatment group. These results demonstrate that compound 31 has a significant antitumor effect with low toxicity. Figure 8 .

[0151] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A 1-phenyl-1-ylamine as an FLT3 kinase inhibitor H -benzo[ d Imidazole compounds, characterized in that: 1-Phenylon-1, as shown in structural formula (I) H -benzo[ d Imidazole compounds or their pharmaceutically acceptable salts: （Ⅰ）； in, R1 is selected from one of -C(O)NH-, SO2, C(O), and -C(S)NH-; R2, R3 and R4 are independently selected from one of hydrogen atom, C1-6 alkyl group, halogen, CF3, -OCH3; R5 is selected from halogens and 4-hydroxyphenyl.

2. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 1 H -benzo[ d Imidazole compounds, characterized in that: wherein, R1 is -C(O)NH-, R2, R3 and R4 are selected from one of hydrogen atom, methyl, -OCH3, CF3 and chlorine atom, R2, R3 and R4 may be the same or different; R5 is selected from one of 4-hydroxyphenyl and bromine atom; Alternatively, R1 may be SO2, R2, R3, and R4 may be selected from hydrogen atoms, -OCH3, and chlorine atoms, and R2, R3, and R4 may be the same or different; R5 may be selected from 4-hydroxyphenyl and bromine atoms. Alternatively, R1 may be C(O), R2, R3, and R4 may be selected from hydrogen atoms, -OCH3, and chlorine atoms, and R2, R3, and R4 may be the same or different; R5 may be selected from 4-hydroxyphenyl and bromine atoms. Alternatively, R1 can be -C(S)NH-, R2, R3 and R4 can be selected from hydrogen atoms, -OCH3 and chlorine atoms, and R2, R3 and R4 can be the same or different; R5 can be a bromine atom.

3. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 1 H -benzo[ d Imidazole compounds, characterized in that: It is any one of the following compounds: Compound 1: N-(3-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide; Compound 2: N-(3-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide; Compound 3: N-(4-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide; Compound 4: N-(4-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide; Compound 5: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)thiourea; Compound 6: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea; Compound 7: 1-(4-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-3-(3-chlorophenyl)thiourea; Compound 8: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-methoxyphenyl)thiourea; Compound 9: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea; Compound 10: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea; Compound 11: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea; Compound 12: 1-[3-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea; Compound 13: 1-(3-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea; Compound 14: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea; Compound 15: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea; Compound 16: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea; Compound 17: 1-[4-(5-bromo-1-] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea; Compound 18: N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzamide; Compound 19: N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzamide; Compound 20: 3-chloro-N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)benzenesulfonamide; Compound 21: N-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide; Compound 22: 3-chloro-N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)benzenesulfonamide; Compound 23: N-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide; Compound 24: 1-(3-chlorophenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea; Compound 25: 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-3-(m-tolyl)urea; Compound 26: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea; Compound 27: 1-(4-chloro-2-methylphenyl)-3-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea; Compound 28: 1-(3-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea; Compound 29: 1-(3-chlorophenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea; Compound 30: 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)-3-(m-tolyl)urea; Compound 31: 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea; Compound 32: 1-(4-chloro-2-methylphenyl)-3-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d Imidazol-1-yl)phenyl)urea; Compound 33: 1-(4-(5-(4-hydroxyphenyl)-1 H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea.

4. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 3 H -benzo[ d A method for preparing imidazole compounds, characterized in that: Compound 1, compound 2, compound 3, and compound 4 are the first compound; The preparation method of the first compound includes the following steps: dissolving a benzenesulfonamide compound in pyridine, cooling in an ice bath, adding a benzenesulfonyl chloride derivative; raising the reaction mixture to room temperature and stirring, concentrating the reaction solution under reduced pressure, pouring it into ice water, filtering, washing the filter cake, and drying to obtain the first compound; Benzenesulfonamide compounds are selected from 3-(5-bromo-1-yl) H -benzo[ d Imidazol-1-yl)aniline, 4-(5-bromo-1-yl)aniline H -benzo[ d One of imidazole-1-yl)aniline; The benzenesulfonyl chloride derivative is selected from one of 4-methoxybenzenesulfonyl chloride or 3-chlorobenzenesulfonyl chloride; Compounds 20, 21, 22, and 23 are second compounds; The preparation method of the second compound includes the following steps: Benzenesulfonamide derivatives and pinacol 4-hydrophenylboronic acid were dissolved in dioxane aqueous solution, nitrogen gas was introduced, and then Pd(PPh3)4 and potassium carbonate were added. The mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, filtered, the filter cake was washed, and dried to obtain the second compound. Benzenesulfonamide derivatives are selected from N-(3-(5-bromo-1-) H -benzo[ d Imidazol-1-yl)phenyl)-3-chlorobenzenesulfonamide, N-(3-(5-bromo-1) H -benzo[ d Imidazol-1-yl)phenyl)-4-methoxybenzenesulfonamide, N-(4-(5-bromo-1) H -benzo[ d One of imidazole-1-yl)phenyl)-3-chlorobenzenesulfonamides.

5. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 3 H -benzo[ d A method for preparing imidazole compounds, characterized in that: Compounds 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17 are third compounds; The preparation method of the above-mentioned third compound includes the following steps: Aromatic amine compounds are dissolved in anhydrous N,N-dimethylformamide or anhydrous dichloromethane, and the corresponding aryl isothiocyanate derivatives are slowly added. After the addition is complete, the reaction mixture is stirred at room temperature. The reaction solution is concentrated under reduced pressure, poured into ice water, filtered, the filter cake is washed, and dried to obtain the third compound. Aromatic amine compounds are selected from 3-(5-bromo-1-methyl)-2-methyl ... H -benzo[ d Imidazol-1-yl)aniline, 4-(5-bromo-1-yl)aniline H -benzo[ d One of imidazole-1-yl)aniline; The aryl isothiocyanate derivatives are 3-chloroaryl isothiocyanate and 4-methoxyaryl isothiocyanate; the aryl isocyanate derivatives are selected from one of 3-chloroaryl isocyanate, 3-methylaryl isocyanate, 4-chloro-3-trifluoromethylaryl isocyanate, 4-chloro-2-methylaryl isocyanate, and 4-methoxyaryl isocyanate.

6. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 3 H -benzo[ d A method for preparing imidazole compounds, characterized in that: Compounds 18 and 19 are the fourth compounds; The preparation method of the above-mentioned fourth compound includes the following steps: Aromatic amine compounds were dissolved in pyridine, and acyl chloride derivatives were added. The reaction mixture was stirred at room temperature, filtered, and washed to obtain an intermediate. The intermediate and 4-hydrophenylboronic acid pinacol ester were dissolved in dioxane aqueous solution, nitrogen gas was introduced, Pd(PPh3)4 and potassium carbonate were added, and the mixture was heated under reflux for 2-4 hours. The reaction mixture was cooled, concentrated under reduced pressure, and purified by column chromatography to obtain the fourth compound. Aromatic amine compounds are selected from 3-(5-bromo-1-methyl)-2-methyl ... H -benzo[ d Imidazol-1-yl)aniline, 4-(5-bromo-1-yl)aniline H -benzo[ d One of imidazole-1-yl)aniline; The acyl chloride derivative is 4-methoxybenzoyl chloride.

7. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 3 H -benzo[ d A method for preparing imidazole compounds, characterized in that: Compounds 24, 25, 26, 27, 28, 29, 30, 31, 32, and 33 are the fifth compound; The preparation of the fifth compound mentioned above includes the following steps: Urea derivatives and 4-hydrophenylboronic acid pinacol ester were dissolved in dioxane aqueous solution, nitrogen gas was introduced, Pd(PPh3)4 and potassium carbonate were added, and the mixture was heated under reflux for 2-4 hours. Urea derivatives are selected from 1-(4-(5-bromo-1-) H -benzo[ d [Imidazol-1-yl)phenyl)-3-(3-chlorophenyl)urea, 1-[3-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, 1-[3-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea, 1-[3-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, 1-(3-(5-bromo ... H -benzo[ d [Imidazol-1-yl)phenyl)-3-(4-methoxyphenyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(3-chlorophenyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(m-tolyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea, 1-[4-(5-bromo-1] H -benzo[ d [Imidazol-1-yl)phenyl]-3-(4-chloro-2-methylphenyl)urea, 1-(4-(5-bromo ... H -benzo[ d One of the imidazole-1-yl)phenyl)-3-(4-methoxyphenyl)urea.

8. The 1-phenyl-1-hydroxyl group as an FLT3 kinase inhibitor according to claim 3 H -benzo[ d A method for preparing imidazole compounds, characterized in that: Compound 13 is the sixth compound. The preparation method of the sixth compound mentioned above includes the following steps: dissolving 1,1'-carbonyldiimidazole in anhydrous DCM and cooling it in an ice bath; then adding triethylamine, and under a nitrogen atmosphere, adding anhydrous DCM solution of p-methoxyaniline dropwise to the above-mentioned cooled solution, and continuing to stir the reaction in an ice bath for 1-3 hours to obtain a reaction solution; 3-(5-bromo-1- H -benzo[ d A solution of imidazole-1-yl)aniline was added dropwise to the above reaction solution. The reaction system was then raised to room temperature and stirred continuously. The reaction solution was concentrated under reduced pressure, filtered, washed, dried, and purified by rapid column chromatography to obtain the sixth compound.

9. A pharmaceutical composition comprising a compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is in the form of an oral formulation or an injection.

10. A 1-phenyl-1-ethylhexyl group as an FLT3 kinase inhibitor according to any one of claims 1 to 3 H -benzo[ d The use of imidazole compounds or the pharmaceutical composition of claim 9 as active ingredients in the preparation of antitumor drugs with inhibitory activity against human acute myeloid leukemia cell lines MOLM-13 and MV4-11.

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