A benzamide derivative, a preparation method and use thereof

Abstract

The application discloses a benzamide derivative, a preparation method and application thereof, and belongs to the field of organic synthesis. The benzamide derivative is prepared by adding a reactant of formula-2 into a reaction bottle, then adding a solvent A, and then adding an intermediate of formula-3, and then performing a reaction in the presence of a base; after the reaction is completed, water is added for dilution, and the benzamide derivative is obtained by extracting with ethyl acetate, concentrating the ethyl acetate layer under reduced pressure, and purifying the crude product. The benzamide derivative has a significant effect in an in-vitro anti-tumor activity test, and especially shows excellent anti-proliferation capacity on human colon cancer cells HCT116. The synthesis route is simple, the atomic economy is high, the cost is low, and the method is beneficial to large-scale implementation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry and pharmacy, and particularly relates to a benzamide derivative, a preparation method and use thereof. BACKGROUND

[0002] During the process of life activities, the DNA of cells is often damaged by various endogenous factors (active oxygen free radicals, etc.) and exogenous factors (ultraviolet radiation, ionizing radiation and chemical carcinogens, etc.). DNA damage can affect the normal expression of genes and cause gene mutations, thereby affecting the normal physiological functions of cells (Eur. J. Med. Chem, 2020, 203, 112570). During the process of life evolution, cells have formed and developed various mechanisms to cope with DNA damage, among which the most important one is the DNA damage repair reaction. The enzymes involved in this process are called DNA damage repair enzymes, which are essential for maintaining the integrity and stability of the genome (Nature, 2012, 481(7381), 287-294).

[0003] Poly(ADP-ribose) polymerases (PARPs) are a class of important nuclear proteases responsible for catalyzing the cleavage of nicotinamide adenine dinucleotide (NAD + ) into nicotinamide and ADP-ribose, and transferring ADP-ribose to target proteins, causing ADP-ribosylation, which is one of the important post-translational modification methods in eukaryotic cells (Cancer Lett, 2017, 386, 47-56). Among the PARP family, PARP-1 is a typical DNA repair enzyme containing a DNA binding domain for DNA damage response, and plays an important role in DNA damage repair, especially DNA single-strand break repair. When DNA single strand breaks, as a sensor of DNA damage, PARP-1 is activated by recognizing the damaged DNA fragments, and ADP-ribosylates target proteins, and then recruits DNA repair factors such as XRCC1-Lig3 complex to the DNA single-strand break site to repair the damaged DNA (J. Med. Chem, 2020, 63, 15541-15563). It is worth noting that the survival and proliferation of tumor cells also depend on the participation of DNA repair enzymes including PARP-1. Given the importance of PARP-1 in DNA single-strand break repair, PARP-1 has become an important target for the development of new anti-tumor drugs.

[0004] The initial development of PARP-1 inhibitors is as a chemoradiotherapy sensitizer for tumors, and the subsequent discovery of the synthetic lethality mechanism enables the wide application of PARP-1 inhibitors in the clinic. Specifically, when the function of PARP-1 is inhibited, the DNA with single-strand breaks in the cell will gradually increase and eventually lead to DNA double-strand breaks. In normal cells, these double-strand broken DNAs can be effectively repaired by the homologous recombination pathway, however, it is found that cells carrying BRCA1 / 2 gene mutations have defects in homologous recombination repair, resulting in damaged DNA that cannot be repaired in time, ultimately leading to cell death (CA Cancer JClin, 2011, 61, 31-49). Therefore, for tumor patients with BRCA1 / 2 mutations, PARP-1 inhibitors can target the killing of tumor cells.

[0005] Up to now, there are 6 PARP-1 inhibitors on the market worldwide, namely olaparib, rucatinib, talazoparib, niraparib, fluzoparib and pamiparib. These drugs bring therapeutic effects to cancer patients, but also face many problems and challenges, such as serious toxic side effects and inevitable drug resistance (Mol Cancer, 2020, 19, 107). In addition, the selection of PARP-1 inhibitors in the clinic is still limited, and the types of PARP-1 inhibitors need to be expanded. Therefore, there is an urgent need to develop new PARP-1 inhibitors with high efficiency, high selectivity and low toxicity, which has a good application prospect. SUMMARY

[0006] The purpose of the present application is to overcome the deficiencies in the prior art, and to provide a benzamide derivative, or a pharmaceutically acceptable salt or prodrug, which can efficiently inhibit PARP-1 and has low toxicity to normal cells.

[0007] Another purpose of the present application is to provide a preparation method of the above-mentioned benzamide derivative.

[0008] Still another purpose of the present application is to provide the use of the above-mentioned benzamide derivative as a PARP-1 inhibitor in the preparation of an antitumor drug.

[0009] The purpose of the present application is achieved by the following technical solutions:

[0010] A benzamide derivative, or a pharmaceutically acceptable salt or prodrug, the chemical structure of the benzamide derivative is shown in formula-1:

[0011]

[0012] wherein: X is NH or O; Y is ureido (-NHCONH-), amido (-NHCO-), acetamido (-NHCOCH2-), or propionamido (-NHCOCH2CH2-); R is a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, or a bromine atom; the Y group attached to the B ring can be attached at any of the possible positions on the B ring, and the R group attached to the C ring can be attached at any of the possible positions on the C ring.

[0013] The benzamide derivative of formula-1 is preferably selected from any one of the following:

[0014] (1) 2-(2-(3-phenylureido)benzylamino)benzamide;

[0015] (2) 2-(2-(3-(3-methylphenyl)ureido)benzylamino)benzamide;

[0016] (3) 2-(2-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide;

[0017] (4) 2-(2-(3-(3-fluorophenyl)ureido)benzylamino)benzamide;

[0018] (5) 2-(2-(3-(3-chlorophenyl)ureido)benzylamino)benzamide;

[0019] (6) 2-(2-(3-(3-bromophenyl)ureido)benzylamino)benzamide;

[0020] (7) 2-(3-(3-phenylureido)benzylamino)benzamide;

[0021] (8) 2-(3-(3-(3-methylphenyl)ureido)benzylamino)benzamide;

[0022] (9) 2-(3-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide;

[0023] (10) 2-(3-(3-(3-fluorophenyl)ureido)benzylamino)benzamide;

[0024] (11) 2-(3-(3-(3-chlorophenyl)ureido)benzylamino)benzamide;

[0025] (12) 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide;

[0026] (13) 2-(4-(3-phenylureido)benzylamino)benzamide;

[0027] (14) 2-(4-(3-(3-methylphenyl)ureido)benzylamino)benzamide;

[0028] (15) 2-(4-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide;

[0029] (16) 2-(4-(3-(3-fluorophenyl)ureido)benzylamino)benzamide;

[0030] (17) 2-(4-(3-(3-chlorophenyl)ureido)benzylamino)benzamide;

[0031] (18) 2-(4-(3-(3-bromophenyl)ureido)benzylamino)benzamide;

[0032] (19) 2-(2-(3-phenylureido)benzyloxy)benzamide;

[0033] (20) 2-(2-(3-(3-methylphenyl)ureido)benzyloxy)benzamide;

[0034] (21) 2-(2-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide;

[0035] (22) 2-(2-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide;

[0036] (23) 2-(2-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide;

[0037] (24) 2-(2-(3-(3-bromophenyl)ureido)benzyloxy)benzamide;

[0038] (25) 2-(3-(3-phenylureido)benzyloxy)benzamide;

[0039] (26) 2-(3-(3-(3-methylphenyl)ureido)benzyloxy)benzamide;

[0040] (27) 2-(3-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide;

[0041] (28) 2-(3-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide;

[0042] (29) 2-(3-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide;

[0043] (30) 2-(3-(3-(3-bromophenyl)ureido)benzyloxy)benzamide;

[0044] (31) 2-(4-(3-phenylureido)benzyloxy)benzamide;

[0045] (32) 2-(4-(3-(3-methylphenyl)ureo)benzyloxy)benzamide;

[0046] (33) 2-(4-(3-(3-methoxyphenyl)ureo)benzyloxy)benzamide;

[0047] (34) 2-(4-(3-(3-fluorophenyl)ureo)benzyloxy)benzamide;

[0048] (35) 2-(4-(3-(3-chlorophenyl)ureo)benzyloxy)benzamide;

[0049] (36) 2-(4-(3-(3-bromophenyl)ureo)benzyloxy)benzamide;

[0050] (37) 2-(3-(2-chlorobenzamido)benzylamino)benzamide;

[0051] (38) 2-(3-(3-chlorobenzamido)benzylamino)benzamide;

[0052] (39) 2-(3-(4-chlorobenzamido)benzylamino)benzamide;

[0053] (40) 2-(3-(2-bromobenzoamido)benzylamino)benzamide;

[0054] (41) 2-(3-(3-bromobenzamido)benzylamino)benzamide;

[0055] (42) 2-(3-(4-bromobenzamido)benzylamino)benzamide;

[0056] (43) 2-(3-(2-chlorophenylacetamido)benzylamino)benzamide;

[0057] (44) 2-(3-(3-chlorophenylacetamido)benzylamino)benzamide;

[0058] (45) 2-(3-(4-chlorophenylacetamido)benzylamino)benzamide;

[0059] (46) 2-(3-(2-bromophenylacetamido)benzylamino)benzamide;

[0060] (47) 2-(3-(3-bromophenylacetamido)benzylamino)benzamide;

[0061] (48) 2-(3-(4-bromophenylacetamido)benzylamino)benzamide;

[0062] (49) 2-(3-(2-chlorobenzamido)benzyloxy)benzamide;

[0063] (50) 2-(3-(4-chlorobenzamido)benzyloxy)benzamide;

[0064] (51) 2-(3-(4-chlorobenzamido)benzyloxy)benzamide;

[0065] (52) 2-(3-(2-bromobenzamido)benzyloxy)benzamide;

[0066] (53) 2-(3-(3-bromobenzamido)benzyloxy)benzamide;

[0067] (54) 2-(3-(4-bromobenzamido)benzyloxy)benzamide;

[0068] (55) 2-(3-(2-chlorophenylacetamido)benzyloxy)benzamide;

[0069] (56) 2-(3-(3-chlorophenylacetamido)benzyloxy)benzamide;

[0070] (57) 2-(3-(4-chlorophenylacetamido)benzyloxy)benzamide;

[0071] (58) 2-(3-(2-bromophenylacetamido)benzyloxy)benzamide;

[0072] (59) 2-(3-(3-bromophenylacetamido)benzyloxy)benzamide;

[0073] (60) 2-(3-(4-bromophenylacetamido)benzyloxy)benzamide.

[0074] The benzamide derivative of formula-1, preferably 2-(3-(3-(3-chlorophenyl)ureido)benzylamino)benzamide (11), 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide (12), 2-(2-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (29), 2-(3-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (30), 2-(3-(4-chlorobenzamido)benzyloxy)benzamide (51), 2-(3-(4-bromobenzamido)benzyloxy)benzamide (54), 2-(3-(4-chlorophenylacetamido)benzyloxy)benzamide (57) or 2-(3-(4-bromophenylacetamido)benzyloxy)benzamide (60); further, more preferably 2-(3-(4-chlorobenzamido)benzyloxy)benzamide (51) or 2-(3-(4-bromobenzamido)benzyloxy)benzamide (54).

[0075] The synthetic route of the benzamide derivative of formula-1 is shown below:

[0076] The synthetic route of the benzamide derivative of formula-1 is shown below:

[0077] wherein, X in formula -2 is NH or O; Y group in formula -3 is urea group (-NHCONH-), formamide group (-NHCO-), acetamide group (-NHCOCH2-) or propionamide group (-NHCOCH2CH2-).

[0078] The method for preparing the benzamide derivative (formula -1) comprises the following steps: adding reactant formula -2 into a reaction bottle, then adding solvent A, and then adding intermediate formula -3, and reacting in the presence of a base; after the reaction is completed, diluting with water and extracting with ethyl acetate, concentrating the ethyl acetate layer under reduced pressure, and purifying the crude product to obtain the benzamide derivative (formula -1).

[0079] The solvent A includes but is not limited to N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile or acetone, and preferably is N,N-dimethylformamide. The base includes but is not limited to sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide, and preferably is cesium carbonate or potassium tert-butoxide. The molar ratio of formula -2, formula -3 and the base is 1:(0.75-1.5):(1-2), and preferably the molar ratio is 1:1:1.5. The reaction time is 8-18 h, and preferably the time is 12 h. The reaction temperature is 15-80℃, and preferably the temperature is 25℃. The purification method is column chromatography or recrystallization.

[0080] The preparation methods of the above intermediate formula -3 are as follows, respectively:

[0081] 1. When the Y group is urea group (-NHCONH-), the synthesis route of the intermediate (formula -3) is as follows:

[0082]

[0083] The specific steps are as follows:

[0084] (1) Preparation of substituted benzoyl azide (formula -5): adding substituted benzoyl hydrazine (formula -4) into a reaction bottle, adding solvent B to it, then adding aqueous sodium nitrite solution, and slowly adding aqueous hydrochloric acid dropwise under stirring and cooling to react; after the reaction is completed, standing, separating the organic layer, concentrating under reduced pressure, and purifying the residue to obtain substituted benzoyl azide (formula -5). In the above steps, the solvent B includes but is not limited to dichloromethane, trichloromethane, methyl tert-butyl ether, acetic acid, toluene or acetonitrile, and preferably is dichloromethane. The molar ratio of substituted benzoyl hydrazine, sodium nitrite and hydrochloric acid is 1:(1-1.5):(1-1.5), and preferably the molar ratio is 1:1.2:1.3; the reaction time is 2-5 h, and preferably the time is 2.5 h; the reaction temperature is 0-5℃, and preferably the temperature is 0℃. The purification method is column chromatography.

[0085] (2) Preparation of 1-hydroxymethylphenyl-3-substituted phenyl urea (Formula-7): Substituted benzoyl azide (Formula-5) was added to a reaction flask, dissolved with solvent C, stirred, heated, and subjected to a de-nitrogen rearrangement reaction to obtain substituted phenyl isocyanate (Formula-6); then amino-substituted benzyl alcohol was added, and stirring was continued until solid was precipitated, and the solid was filtered under suction to obtain 1-hydroxymethylphenyl-3-substituted phenyl urea (Formula-7). In the above step, the solvent C includes, but is not limited to, acetonitrile, toluene, 1,4-dioxane, or 1,2-dichloroethane, and preferably is 1,2-dichloroethane. The de-nitrogen rearrangement reaction time is 2 to 5 h, and preferably is 2.5 h; and the reaction temperature is 80 to 100 °C, and preferably is 80 °C. The molar ratio of the substituted benzoyl azide (Formula-5) to the amino-substituted benzyl alcohol is 1:(0.8 to 1), and preferably is 1:0.9.

[0086] (3) Preparation of 1-chloromethylphenyl-3-substituted phenyl urea (Formula-3, Y = -NHCONH-): 1-Hydroxymethylphenyl-3-substituted phenyl urea (Formula-7) was added to a reaction flask, and dichloromethane or N,N-dimethylformamide was used as a solvent, and thionyl chloride was slowly added dropwise with stirring; after the reaction was completed, water was added for dilution, and extraction was performed with ethyl acetate, and 1-chloromethylphenyl-3-substituted phenyl urea (Formula-3) was obtained by concentration under reduced pressure. In the above step, the molar ratio of Formula-7 to thionyl chloride is 1:(1 to 2), and preferably is 1:1.5. The reaction time is 5 to 12 h, and preferably is 8 h. The reaction temperature is 0 to 25 °C, and preferably is 0 °C. When N,N-dimethylformamide is used as a solvent, triethylamine can be added as an additive to effectively promote the reaction.

[0087] 2. When the Y group is a carboxamide group (-NHCO-), the synthesis route of the intermediate (Formula-3) is as follows:

[0088]

[0089] The specific steps are as follows:

[0090] (1) Preparation of N-(hydroxymethylphenyl)-substituted benzamide (Formula-9): To a reaction flask was added amino-substituted benzyl alcohol, solvent D to dissolve it, and triethylamine as an acid binding agent. Substituted benzoyl chloride diluted in solvent D was added dropwise slowly with stirring. After the reaction was completed, it was concentrated under reduced pressure, and purified by post-treatment to obtain N-(hydroxymethylphenyl)-substituted benzamide (Formula-9). In the above step, the solvent D includes, but is not limited to, dichloromethane, trichloromethane, toluene, 1,4-dioxane or 1,2-dichloroethane, and preferably dichloromethane. The molar ratio of amino-substituted benzyl alcohol, triethylamine and substituted benzoyl chloride was 1:(1-1.5):(1-1.5), and preferably 1:1.5:1. The reaction time was 8-18 h, and preferably 12 h. The reaction temperature was 0-40 °C, and preferably 25 °C. The post-treatment purification was column chromatography.

[0091] (2) Preparation of N-(chloromethylphenyl)-substituted benzamide (Formula-3, Y = -NHCO-): To a reaction flask was added N-(hydroxymethylphenyl)-substituted benzamide (Formula-9), and solvent E was added. Sulfurous acid chloride was added dropwise slowly with stirring. After the reaction was completed, it was diluted with water and extracted with ethyl acetate. N-(chloromethylphenyl)-substituted benzamide (Formula-3) was obtained by concentration under reduced pressure. In the above step, the molar ratio of Formula-9 and sulfurous acid chloride was 1:(1-2), and preferably 1:1.5. The reaction time was 5-12 h, and preferably 8 h. The reaction temperature was 0-25 °C, and preferably 0 °C. The solvent E was dichloromethane, trichloromethane or 1,2-dichloroethane, and preferably dichloromethane.

[0092] 3. When the Y group is an acetamide group (-NHCOCH2-), the synthesis route of the intermediate (Formula-3) is as follows:

[0093]

[0094] The specific steps are as follows:

[0095] (1) Preparation of 2-substituted phenyl-N-(hydroxymethyl phenyl)acetamide (Formula-11): In a reaction flask, add amino-substituted benzyl alcohol, dissolve it with solvent D, then add triethylamine as an acid binding agent, and slowly drop the solution of substituted phenylacetyl chloride diluted with solvent D under stirring, respectively; after the reaction is completed, concentrate under reduced pressure, and purify by post-treatment to obtain 2-substituted phenyl-N-(hydroxymethyl phenyl)acetamide (Formula-11). In the above step, the solvent D includes but is not limited to dichloromethane, trichloromethane, toluene, 1,4-dioxane or 1,2-dichloroethane, preferably dichloromethane. The molar ratio of amino-substituted benzyl alcohol, triethylamine and substituted phenylacetyl chloride is 1:(1-1.5):(1-1.5), preferably 1:1.5:1, the reaction time is 8-18 h, preferably 12 h; the reaction temperature is 0-40℃, preferably 25℃. The post-treatment purification is column chromatography.

[0096] (2) Preparation of 2-substituted phenyl-N-(chloromethyl phenyl)acetamide (Formula-3, Y=-NHCOCH2-): In a reaction flask, add 2-substituted phenyl-N-(hydroxymethyl phenyl)acetamide (Formula-11), then add solvent E, and slowly drop the solution of sulfuric chloride under stirring; after the reaction is completed, dilute with water and extract with ethyl acetate, and concentrate under reduced pressure to obtain 2-substituted phenyl-N-(chloromethyl phenyl)acetamide (Formula-3). In the above step, the molar ratio of Formula-11 and sulfuric chloride is 1:(1-2), preferably 1:1.5. The reaction time is 5-12 h, preferably 8 h. The reaction temperature is 0-25℃, preferably 0℃. The solvent E is dichloromethane, trichloromethane or 1,2-dichloroethane, preferably dichloromethane.

[0097] It is found in the present study that the benzamide derivatives of Formula-1 have certain proliferation inhibition effects on human colon cancer cells (HCT116, DLD-1 and SW480), human breast cancer cells (MDA-MB-231), human cervical cancer cells (HeLa), human lung cancer cells (A549) and human malignant melanoma cells (A375), especially on HCT116 cells. In particular, enzyme activity experiments show that preferred compounds 12, 30, 51 and 54 have significant PARP-1 inhibitory activity. Mechanism studies show that compounds 12, 30 and 54 can effectively inhibit the proliferation of HCT116 cells by inducing cell cycle arrest and apoptosis. Thus, the benzamide derivatives of the present application have significant PARP-1 inhibitory activity. In addition, cell activity experiments show that the preferred compounds 12, 30, 51 and 54 of the present application have significant antiproliferative activity on tumor cells while having low toxicity on normal cells.

[0098] The benzamide derivative and the pharmaceutically acceptable salt thereof can be used for preparing a medicine for treating a disease related to abnormal PARP-1 activity, and particularly, the disease related to abnormal PARP-1 activity is a tumor, so the benzamide derivative and the pharmaceutically acceptable salt thereof can be used for preparing an anti-tumor medicine.

[0099] The benzamide derivative (Formula-1) can be administered orally or non-orally. When administered orally, the benzamide derivative is mixed with a conventional pharmaceutically acceptable carrier to prepare a conventional solid preparation, including granules, capsules or tablets, etc. by using a conventional preparation technology. When administered non-orally, the benzamide derivative is prepared into an injection, an infusion or a suppository, etc. by using a conventional preparation technology. The administration amount is varied according to the administration route, the age and weight of a patient, the disease to be treated and the severity, etc.

[0100] An anti-tumor medicine composition contains a therapeutically effective amount of the above benzamide derivative (Formula-1) as an active ingredient, and one or more pharmaceutically acceptable carriers. The medicine composition of various dosage forms can be prepared according to the conventional production method in the pharmaceutical field, such as mixing the active ingredient with one or more carriers, and then preparing the desired dosage form. The pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, including excipients, disintegrants, binders, lubricants, antioxidants, coating agents, coloring agents, fragrances or surfactants.

[0101] Compared with the prior art, the present application has the following advantages and effects:

[0102] (1) The benzamide derivative of the present application has a significant effect in the in vitro anti-tumor activity test, and particularly, shows excellent anti-proliferation ability to human colon cancer cells HCT116.

[0103] (2) The preliminary mechanism study shows that the above benzamide derivative can inhibit tumor cell proliferation by targeting the inhibition of PARP-1 activity, inducing cell cycle arrest and apoptosis.

[0104] (3) The synthetic route of the present application is simple, has high atom economy, is low in cost, is conducive to large-scale implementation, and can be used in combination with various pharmaceutical carriers, so that the medicine is convenient to use. BRIEF DESCRIPTION OF DRAWINGS

[0105] Figure 1 Effects of compounds 12, 30 and 54 on the cell cycle of HCT116.

[0106] Figure 2 Effects of compounds 12, 30 and 54 on the apoptosis of HCT116. DETAILED DESCRIPTION

[0107] In order to facilitate the understanding of the present application, the present application will be described in detail below in conjunction with specific examples. It should be pointed out that, for those skilled in the art, the present application can also be changed and improved in many ways without departing from the concept of the present application, and these all belong to the protection scope of the present application.

[0108] Example 1: Preparation of 2-(2-(3-phenylureido)benzylamino)benzamide (1)

[0109] Step 1: Preparation of benzoyl azide

[0110] Into a 250 mL round bottom flask was added benzoyl hydrazine (3 g, 22 mmol), dichloromethane (80 mL), an aqueous solution of sodium nitrite (1.82 g, 26.4 mmol) (20 mL), cooled to 0 °C, and an aqueous solution of 37% hydrochloric acid (2.82 g, 28.6 mmol) (25 mL) was added dropwise with stirring. After the addition was completed, the reaction was continued for 2.5 h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the organic layer was separated, concentrated under reduced pressure, and purified by column chromatography to obtain benzoyl azide as a light yellow oily liquid, 2.82 g, yield: 87%.

[0111] Step 2: Preparation of 1-(2-(hydroxymethyl)phenyl)-3-phenylurea

[0112] Into a 250 mL round bottom flask was added benzoyl azide (1.5 g, 10.2 mmol), 1,2-dichloroethane (40 mL), and the reaction was stirred at 80 °C for 2.5 h. Then, 2-aminobenzyl alcohol (1.13 g, 9.2 mmol) was added, and the stirring was continued until a solid was precipitated. After cooling, the solid was filtered under suction, washed with petroleum ether, and dried to obtain 1-(2-(hydroxymethyl)phenyl)-3-phenylurea as a light yellow solid, 1.9 g, yield: 77%.

[0113] Step 3: Preparation of 1-(2-(chloromethyl)phenyl)-3-phenylurea

[0114] Into a 100 mL round bottom flask was added 1-(2-(hydroxymethyl)phenyl)-3-phenylurea (1.2 g, 4.95 mmol), dichloromethane (15 mL), and an aqueous solution of thionyl chloride (884 mg, 7.43 mmol) diluted with dichloromethane (5 mL) was added dropwise at 0 °C. The reaction was continued for 8 h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (20 mL x 3). The combined organic phase was concentrated under reduced pressure to obtain 1-(2-(chloromethyl)phenyl)-3-phenylurea, which was used directly in the next step.

[0115] Step 4: Preparation of 2-(2-(3-phenylureido)benzylamino)benzamide (1)

[0116] A 100 mL round bottom flask was charged with 2-aminobenzamide (68 mg, 0.5 mmol), 1-(2-(chloromethyl)phenyl)-3-phenylurea (130 mg, 0.5 mmol), cesium carbonate (244 mg, 0.75 mmol), N,N-dimethylformamide (12 mL), and the reaction was stirred at room temperature for 12 h, monitoring the reaction progress by thin layer chromatography. After the reaction was completed, the reaction was diluted with 100 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure. The crude product was purified by column chromatography to give 2-(2-(3-phenylureido)benzylamino)benzamide (1) as a white solid, 144 mg, yield: 80%. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.47 (t, J = 5.5 Hz, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.25 (dt, J = 20.5, 7.7 Hz, 6H), 7.03 (t, J = 7.5 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.55 (t, J = 7.5 Hz, 1H), 4.37 (d, J = 5.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.07, 153.33, 150.01, 140.33, 137.28, 132.96, 130.33, 129.53, 129.27 (2C), 128.05, 127.63, 123.77, 123.09, 122.23, 118.64 (2C), 115.02, 114.90, 112.11, 43.14. HRMS (ESI) m / z: calculated for C 21 H 21 N4O2[M+H] + : 361.1659, found: 361.1651.

[0117] Example 2: Preparation of 2-(2-(3-phenylureido)benzylamino)benzamide (1)

[0118] Step 1: Preparation of benzoyl azide

[0119] Into a 250 mL round bottom flask was placed benzoyl hydrazine (3 g, 22 mmol), dichloromethane (80 mL), sodium nitrite (1.67 g, 24.2 mmol) in water (20 mL), cooled to 2 °C, and hydrochloric acid (2.61 g, 26.4 mmol) in water (25 mL) was added dropwise with stirring. After the addition was complete, the reaction was continued for 2 h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was complete, the organic layer was separated, and concentrated under reduced pressure. The residue was purified by column chromatography to give benzoyl azide as a yellowish oil, 2.74 g, yield: 85%.

[0120] Step 2: Preparation of l-(2-(hydroxymethyl)phenyl)-3-phenylurea

[0121] Into a 250 mL round bottom flask was placed benzoyl azide (1.5 g, 10.2 mmol), 1,2-dichloroethane (50 mL), and the reaction was stirred at 83 °C for 2 h. Then 2-aminobenzyl alcohol (1.26 g, 10.2 mmol) was added, and the reaction was stirred until solid precipitated. The solid was collected by suction filtration, washed with petroleum ether, and dried to give l-(2-(hydroxymethyl)phenyl)-3-phenylurea as a yellowish solid, 1.8 g, yield: 73%.

[0122] Step 3: Preparation of l-(2-(chloromethyl)phenyl)-3-phenylurea

[0123] Into a 100 mL round bottom flask was placed l-(2-(hydroxymethyl)phenyl)-3-phenylurea (1.2 g, 4.95 mmol), dichloromethane (15 mL), and thionyl chloride (766 mg, 6.44 mmol) diluted in dichloromethane (5 mL) was added dropwise at 5 °C. The reaction was stirred for 5 h, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the residue was diluted with 50 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, and concentrated under reduced pressure to give l-(2-(chloromethyl)phenyl)-3-phenylurea, which was used directly in the next step.

[0124] Step 4: Preparation of 2-(2-(3-phenylureido)benzylamino)benzamide (1)

[0125] Into a 100 mL round bottom flask was added 2-aminobenzamide (68 mg, 0.5 mmol), 1-(2-(chloromethyl)phenyl)-3-phenylurea (156 mg, 0.6 mmol), cesium carbonate (325 mg, 1 mmol), N,N-dimethylformamide (15 mL), and the reaction was stirred at room temperature for 18 h, monitoring the reaction progress by thin layer chromatography. After the reaction was complete, the reaction was diluted with 120 mL of water and extracted with ethyl acetate (20 mL x 3). The organic layers were combined and concentrated under reduced pressure. The crude product was purified by column chromatography to yield 2-(2-(3-phenylureido)benzylamino)benzamide (1) as a white solid, 138 mg, yield: 77%.

[0126] Example 3: Preparation of 2-(2-(3-phenylureido)benzylamino)benzamide (1)

[0127] Step 1: Preparation of benzoyl azide

[0128] Into a 250 mL round bottom flask was added benzoyl hydrazine (3 g, 22 mmol), dichloromethane (80 mL), sodium nitrite (1.98 g, 28.6 mmol) in water (20 mL), and the reaction was cooled to 5 °C. A solution of 37% hydrochloric acid (3.26 g, 33 mmol) in water (25 mL) was added dropwise with stirring. After the addition was complete, the reaction was stirred for an additional 3 h, monitoring the reaction progress by thin layer chromatography. After the reaction was complete, the organic layer was separated and concentrated under reduced pressure. The crude product was purified by column chromatography to yield benzoyl azide as a yellowish oil, 2.52 g, yield: 78%.

[0129] Step 2: Preparation of 1-(2-(hydroxymethyl)phenyl)-3-phenylurea

[0130] Into a 250 mL round bottom flask was added benzoyl azide (1.5 g, 10.2 mmol), 1,2-dichloroethane (45 mL), and the reaction was stirred at 82 °C for 4 h. 2-aminobenzyl alcohol (1 g, 8.2 mmol) was added and the reaction was stirred until a solid precipitated. The reaction was cooled and filtered, and the solid was washed with petroleum ether and dried to yield 1-(2-(hydroxymethyl)phenyl)-3-phenylurea as a yellowish solid, 1.7 g, yield: 69%.

[0131] Step 3: Preparation of 1-(2-(chloromethyl)phenyl)-3-phenylurea

[0132] Into a 100 mL round bottom flask was placed 1-(2-(hydroxymethyl)phenyl)-3- phenylurea (1.2 g, 4.95 mmol), dichloromethane (15 mL), and oxalyl chloride (1.18 g, 9.91 mmol) diluted in dichloromethane (5 mL) was added dropwise under ice bath conditions. The reaction was stirred for 10 h, and the reaction progress was monitored by thin layer chromatography. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, and the residue was diluted with 50 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure to give 1-(2-(chloromethyl)phenyl)-3-phenylurea, which was used directly in the next step.

[0133] Step 4: Preparation of 2-(2-(3-phenylureido)benzylamino)benzamide (1)

[0134] Into a 100 mL round bottom flask was placed 2-aminobenzamide (68 mg, 0.5 mmol), 1-(2-(chloromethyl)phenyl)-3-phenylurea (195 mg, 0.75 mol), cesium carbonate (325 mg, 1 mmol), and N,N-dimethylformamide (10 mL). The reaction was stirred for 10 h at room temperature, and the reaction progress was monitored by thin layer chromatography. After the reaction was complete, the reaction mixture was diluted with 80 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure. The crude product was purified by column chromatography to give 2-(2-(3-phenylureido)benzylamino)benzamide (1) as a white solid, 128 mg, yield: 71%.

[0135] Example 4: Preparation of 2-(2-(3-(3-methylphenyl)ureido)benzylamino)benzamide (2)

[0136] Using 3-methylbenzhydrazide as the starting material, 3-methylbenzhydrazide azide was prepared according to the procedure described in Step 1 of Example 1. Using 3-methylbenzhydrazide azide and 2-aminobenzyl alcohol as the starting materials, 1-(2-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea was prepared according to the procedure described in Step 2 of Example 1. Using 1-(2-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea as the starting material, 1-(2-(chloromethyl)phenyl)-3-(3-methylphenyl)urea was prepared according to the procedure described in Step 3 of Example 1. Using 2-aminobenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-methylphenyl)urea as the starting materials, 2-(2-(3-(3-methylphenyl)ureido)benzylamino)benzamide (2) was prepared according to the procedure described in Step 4 of Example 1 as a white solid, 144 mg, yield: 77%. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.63 (dd, J = 7.8, 1.2 Hz, 1H), 7.31 (s, 1H), 7.28 - 7.12 (m, 6H), 7.02 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.55 (t, J = 7.3 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H), 2.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 172.07, 153.29, 150.00, 140.23, 138.42, 137.30, 132.97, 130.21, 129.53, 129.12, 128.05, 127.63, 123.71, 122.98, 119.17, 115.82, 114.99, 114.90, 112.10, 43.13, 21.71. HRMS (ESI) m / z: calcd for C 22 H 23 N4O2[M+H] + : 375.1816, found: 375.1813.

[0137] Example 5: Preparation of 2-(2-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide (3)

[0138] Step 1 in Example 1 to give 3-methoxybenzoyl azide, and 2-aminobenzyl alcohol as raw materials, according to Step 2 in Example 1 to give 1-(2-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea, according to Step 3 in Example 1 to give 1-(2-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea, and 2-aminobenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea as raw materials, according to Step 4 in Example 1 to give 2-(2-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide (3), white solid, 156 mg, yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.47 (t, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.9, 1.2 Hz, 1H), 7.29 - 7.14 (m, 6H), 7.06 - 7.00 (m, 1H), 6.95 (dd, J = 8.0, 1.1 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.55 (t, J = 7.6 Hz, 2H), 4.36 (d, J = 5.6 Hz, 2H), 3.73 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 172.06, 160.17, 153.24, 149.99, 141.54, 137.19, 132.96, 130.31, 130.04, 129.52, 128.04, 127.64, 123.81, 123.11, 114.99, 114.90, 112.10, 110.92, 107.70, 104.33, 55.38, 43.11. HRMS (ESI) m / z: calculated for C 22 H 23 N4O3[M+H] + : 391.1765, found: 391.1764.

[0139] Example 6: Preparation of 2-(2-(3-(3-fluorophenyl)ureido)benzylamino)benzamide (4)

[0140] Step 1 in Example 1 to give 3-fluorobenzoyl azide, and 2-aminobenzyl alcohol as raw materials, according to Step 2 in Example 1 to give 1-(2-(hydroxymethyl)phenyl)-3-(3-fluorophenyl)urea, according to Step 3 in Example 1 to give 1-(2-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea, and 2-aminobenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea as raw materials, according to Step 4 in Example 1 to give 2-(2-(3-(3-fluorophenyl)ureido)benzylamino)benzamide (4), white solid, 117 mg, yield: 78%. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.48 (t, J = 5.5 Hz, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 12.0 Hz, 1H), 7.35 - 7.16 (m, 5H), 7.12 (d, J = 8.2 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.78 (td, J = 8.5, 2.1 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 6.56 (t, J = 7.4 Hz, 1H), 4.38 (d, J = 5.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.07, 164.10, 161.71, 153.21, 149.99, 142.23 (d, J = 11.3 Hz), 136.95, 132.96, 130.79 (d, J = 10.0 Hz), 130.71, 129.53, 128.07, 127.66, 124.11, 123.40, 115.01, 114.92, 114.31 (d, J = 2.0 Hz), 112.11, 108.52 (d, J = 21.1 Hz), 105.28 (d, J = 26.5 Hz), 43.12. HRMS (ESI) m / z: calcd for C 21 H 20 FN4O2[M+H] + : 379.1565, found: 379.1562.

[0141] Example 7: Preparation of 2-(2-(3-(3-chlorophenyl)ureido)benzylamino)benzamide (5)

[0142] Using 3-chlorobenzoylhydrazine as the raw material, 3-chlorobenzoyl azide was prepared according to step 1 of example 1, using 3-chlorobenzoyl azide and 2-aminobenzyl alcohol as the raw material, 1-(2-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea was prepared according to step 2 of example 1, 1-(2-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea was prepared according to step 3 of example 1, using 2-aminobenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea as the raw material, 2-(2-(3-(3-chlorophenyl)ureido)benzylamino)benzamide (5) was prepared according to step 4 of example 1, white solid, 150 mg, yield: 76%. 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.48 (t, J = 5.4 Hz, 1H), 8.21 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 6.8 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.34 - 7.17 (m, 6H), 7.06 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.55 (t, J = 7.5 Hz, 1H), 4.37 (d, J = 5.4 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.06, 153.20, 149.98, 141.90, 136.91, 133.69, 132.96, 130.89, 130.78, 129.52, 128.06, 127.66, 124.16, 123.46, 121.83, 117.97, 117.02, 115.00, 114.92, 112.10, 43.11. HRMS (ESI) m / z: calcd for C 21 H 20 ClN4O2[M+H] + : 395.1269, found: 395.1269.

[0143] Example 8: Preparation of 2-(2-(3-(3-bromophenyl)ureido)benzylamino)benzamide (6)

[0144] Using 3-bromobenzhydrazide as the raw material, 3-bromobenzoyl azide was prepared according to step 1 of Example 1, using 3-bromobenzoyl azide and 2-aminobenzyl alcohol as the raw material, 1-(2-(hydroxymethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 2 of Example 1, 1-(2-(chloromethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 3 of Example 1, using 2-aminobenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-bromophenyl)urea as the raw material, 2-(2-(3-(3-bromophenyl)ureido)benzylamino)benzamide (6) was prepared according to step 4 of Example 1, white solid, 174 mg, yield: 80%. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.47 (t, J = 4.9 Hz, 1H), 8.20 (s, 1H), 7.88 (t, J = 1.8 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.62 (dd, J = 7.8, 1.1 Hz, 1H), 7.32 - 7.19 (m, 6H), 7.14 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.55 (t, J = 7.5 Hz, 1H), 4.37 (d, J = 4.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.06, 153.19, 149.99, 142.04, 136.91, 132.96, 131.20, 130.80, 129.52, 128.07, 127.66, 124.74, 124.17, 123.47, 122.23, 120.83, 117.41, 115.02, 114.93, 112.11, 43.12. HRMS (ESI) m / z: calcd for C 21 H 20 BrN4O2[M+H] + : 439.0764, found: 439.3764.

[0145] Example 9: Preparation of 2-(3-(3-phenylureido)benzylamino)benzamide (7)

[0146] Step 1 in Example 1 to give benzoyl azide, and 1-(3-(hydroxymethyl)phenyl)-3- phenylurea was prepared from benzoyl azide and 3-aminobenzyl alcohol according to Step 2 in Example 1, and 1-(3-(chloromethyl)phenyl)-3-phenylurea was prepared according to Step 3 in Example 1, and 2-(3-(3-phenylureido)benzylamino)benzamide (7) was prepared from 2-aminobenzamide and 1-(3-(chloromethyl)phenyl)-3-phenylurea according to Step 4 in Example 1 as a white solid, 130 mg, yield: 72%. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 7.86 (s, 1H), 7.62 (dd, J = 7.9, 1.3 Hz, 1H), 7.42 (t, J = 8.8 Hz, 3H), 7.35 (s, 1H), 7.30 - 7.16 (m, 5H), 6.96 (t, J = 7.4 Hz, 2H), 6.60 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.1 Hz, 1H), 4.36 (d, J = 4.0 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.10, 152.92, 150.08, 140.92, 140.40, 140.14, 132.97, 129.52, 129.42, 129.25 (2C), 122.27, 120.97, 118.62 (2C), 117.11, 116.95, 114.67, 114.60, 111.99, 46.56. HRMS (ESI) m / z: calcd for C 21 H 21 N4O2[M+H] + : 361.1659, found: 361.1656.

[0147] Example 10: Preparation of 2-(3-(3-(3-methylphenyl)ureido)benzylamino)benzamide (8)

[0148] Step 1: 3-methylbenzoyl azide was prepared from 3-methylbenzohydrazide according to step 1 of example 1. Step 2: 1-(3-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 3-methylbenzoyl azide and 3-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(3-(chloromethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 1-(3-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea according to step 3 of example 1. Step 4: 2-(3-(3-(3-methylphenyl)ureido)benzylamino)benzamide (8) was prepared from 2-aminobenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-methylphenyl)urea according to step 4 of example 1, as a white solid, 144 mg, yield: 77%. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 28.9 Hz, 2H), 7.26 - 7.09 (m, 5H), 6.94 (d, J = 6.7 Hz, 1H), 6.78 (d, J = 6.4 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 6.53 (t, J = 6.6 Hz, 1H), 4.35 (d, J = 3.2 Hz, 2H), 2.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 172.11, 152.90, 150.09, 140.91, 140.43, 140.05, 138.41, 132.97, 129.53, 129.41, 129.08, 123.02, 120.94, 119.14, 117.07, 116.92, 115.81, 114.67, 114.60, 111.99, 46.57, 21.69. HRMS (ESI) m / z: calculated for C 22 H 23 N4O2[M+H] + : 375.1816, found: 375.1811.

[0149] Example 11: Preparation of 2-(3-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide (9)

[0150] Step 1: 3-methoxybenzoyl azide was prepared from 3-methoxybenzohydrazide according to step 1 of example 1. Step 2: 1-(3-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 3-methoxybenzoyl azide and 3-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(3-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 1-(3-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea according to step 3 of example 1. Step 4: 2-(3-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide (9) was prepared from 2-aminobenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea according to step 4 of example 1, as a white solid, 150 mg, yield: 77%. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 18.2 Hz, 3H), 7.86 (s, 1H), 7.63 (s, 1H), 7.37 (d, J = 11.3 Hz, 2H), 7.18 (s, 5H), 6.93 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 21.8 Hz, 3H), 4.36 (s, 2H), 3.73 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 172.11, 160.17, 152.86, 150.08, 141.37, 140.91, 140.33, 132.97, 130.00, 129.52, 129.42, 121.02, 117.16, 117.00, 114.67, 114.61, 111.99, 110.94, 107.73, 104.35, 55.40, 46.56. HRMS (ESI) m / z: calcd for C 22 H 23 N4O3[M+H] + : 391.1765, found: 391.1760.

[0151] Example 12: Preparation of 2-(3-(3-(3-fluorophenyl)ureido)benzylamino)benzamide (10)

[0152] Using 3-fluorobenzohydrazide as the raw material, 3-fluorobenzoyl azide was prepared according to step 1 of example 1, using 3-fluorobenzoyl azide and 3-aminobenzyl alcohol as the raw material, 1-(3-(hydroxymethyl)phenyl)-3-(3-fluorophenyl)urea was prepared according to step 2 of example 1, 1-(3-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea was prepared according to step 3 of example 1, using 2-aminobenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea as the raw material, 2-(3-(3-(3-fluorophenyl)ureido)benzylamino)benzamide (10) was prepared according to step 4 of example 1, white solid, 154 mg, yield: 82%. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.62 (t, J = 5.5 Hz, 1H), 7.86 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 11.9 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.26 (ddd, J = 24.3, 15.9, 7.8 Hz, 4H), 7.10 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.4 Hz, 1H), 4.36 (d, J = 5.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.11, 164.08, 161.68, 152.78, 150.07, 142.04 (d, J = 11.5 Hz), 140.97, 140.11, 132.97, 130.77 (d, J = 9.7 Hz), 129.48 (d, J = 8.7 Hz), 121.24, 117.30, 117.14, 114.68, 114.62, 114.36 (d, J = 1.4 Hz), 111.99, 108.58 (d, J = 21.1 Hz), 105.29 (d, J = 26.5 Hz), 46.54. HRMS (ESI) m / z: calcd for C 21 H 20 FN4O2[M+H] + : 379.1565, found: 379.1561.

[0153] Example 13: Preparation of 2-(3-(3-(3-chlorophenyl)ureido)benzylamino)benzamide (11)

[0154] Using 3-chlorobenzoylhydrazine as the raw material, 3-chlorobenzoyl azide was prepared according to step 1 of example 1, using 3-chlorobenzoyl azide and 3- aminobenzyl alcohol as the raw material, 1-(3-(hydroxymethyl)phenyl)-3-(3- chlorophenyl)urea was prepared according to step 2 of example 1, 1-(3-(chloromethyl) phenyl)-3-(3-chlorophenyl)urea was prepared according to step 3 of example 1, using 2-aminobenzamide and 1-(3-(chloromethyl)phenyl)-3-(3- chlorophenyl)urea as the raw material, 2-(3-(3-(3-chlorophenyl)ureido)benzylamino) benzamide (11) was prepared according to step 4 of example 1, white solid, 146 mg, yield: 74%. 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.77 (s, 1H), 8.61 (t, J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 7.25 (ddd, J = 24.3, 16.2, 7.8 Hz, 5H), 7.01 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 4.36 (d, J = 5.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.10, 152.78, 150.06, 141.71, 140.97, 140.10, 133.66, 132.97, 130.85, 129.52, 129.44, 121.89, 121.25, 117.97, 117.31, 117.16, 117.07, 114.68, 114.60, 111.99, 46.53. HRMS (ESI) m / z: calcd for C 21 H 20 ClN4O2[M+H] + : 395.1269, found: 395.1263.

[0155] Example 14: Preparation of 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide (12)

[0156] Using 3-bromobenzohydrazide as the raw material, 3-bromobenzoyl azide was prepared according to step 1 of example 1, using 3-bromobenzoyl azide and 3-aminobenzyl alcohol as the raw material, 1-(3-(hydroxymethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 2 of example 1, 1-(3-(chloromethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 3 of example 1, using 2-aminobenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-bromophenyl)urea as the raw material, 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide (12) was prepared according to step 4 of example 1, white solid, 176 mg, yield: 80%. 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.76 (s, 1H), 8.61 (t, J = 5.3 Hz, 1H), 7.84 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.36 (s, 1H), 7.21 (ddd, J = 30.1, 20.5, 8.3 Hz, 7H), 6.96 (d, J = 7.4 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.4 Hz, 1H), 4.36 (d, J = 5.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.10, 152.76, 150.06, 141.86, 140.97, 140.09, 132.97, 131.17, 129.52, 129.43, 124.79, 122.19, 121.25, 120.82, 117.46, 117.31, 117.16, 114.68, 114.60, 111.98, 46.53. HRMS (ESI) m / z: calcd for C 21 H 20 BrN4O2[M+H] + : 439.0764, found: 439.0769.

[0157] Example 15: Preparation of 2-(4-(3-phenylureido)benzylamino)benzamide (13)

[0158] Step 1: Benzoyl azide was prepared from benzoyl hydrazide according to Step 1 of Example 1.

[0159] Step 2: 1-(4-(hydroxymethyl)phenyl)-3-phenylurea was prepared from benzoyl azide and 4-aminobenzyl alcohol according to Step 2 of Example 1.

[0160] Step 3: Into a 100 mL round bottom flask was placed 1-(4-(hydroxymethyl)phenyl)-3- phenylurea (1.2 g, 4.95 mmol), N,N-dimethylformamide (10 mL), triethylamine (1 mL), and sulfurous dichloride (884 mg, 7.43 mmol) was added dropwise slowly under ice bath condition. The reaction was stirred for 8 h, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure to give 1-(4-(chloromethyl)phenyl)-3-phenylurea, which was used directly in the next step.

[0161] Step 4: 2-(4-(3-phenylureido)benzylamino)benzamide (13) was prepared from 2- aminobenzamide and l-(4-(chloromethyl)phenyl)-3-phenylurea following Step 4 of Example 1 as a white solid, 131 mg, yield: 72%. 1 HNMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 8.51 (t, J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.61 (dd, J = 7.9, 1.4 Hz, 1H), 7.46 - 7.40 (m, 4H), 7.30 - 7.17 (m, 6H), 6.96 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.55 - 6.49 (m, 1H), 4.30 (d, J = 5.6 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.10, 153.01, 150.06, 140.19, 138.94, 133.31, 132.94, 129.50, 129.24 (2C), 128.13 (2C), 122.25, 118.86 (2C), 118.63 (2C), 114.63, 112.02, 46.16. HRMS (ESI) m / z: calculated for C 21 H 21 N4O2[M+H] + : 361.1659, found: 361.1659.

[0162] Example 16: Preparation of 2-(4-(3-(3-methylphenyl)ureido)benzylamino)benzamide (14)

[0163] 3-methylbenzoyl azide was prepared from 3-methylbenzoylhydrazine following Step 1 of Example 1, l-(4-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 3-methylbenzoyl azide and 4-aminobenzyl alcohol following Step 2 of Example 1, l-(4-(chloromethyl)phenyl)-3-(3-methylphenyl)urea was prepared following Step 3 of Example 15, and 2-(4-(3-(3-methylphenyl)ureido)benzylamino)benzamide (14) was prepared from 2- aminobenzamide and l-(4-(chloromethyl)phenyl)-3-(3-methylphenyl)urea following Step 4 of Example 1 as a white solid, 138 mg, yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 26.4 Hz, 3H), 7.84 (s, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.41 (d, J = 7.3 Hz, 2H), 7.25 (dd, J = 19.6, 11.3 Hz, 5H), 7.15 (d, J = 6.5 Hz, 2H), 6.78 (d, J = 6.0 Hz, 1H), 6.64 (d, J = 7.7 Hz, 1H), 6.53 (t, J = 6.7 Hz, 1H), 4.30 (s, 2H), 2.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 152.99, 150.05, 140.13, 138.99, 138.40, 133.23, 132.94, 129.50, 129.08, 128.13 (2C), 122.98, 119.11, 118.78 (2C), 115.79, 114.62, 112.02, 46.16, 21.70. HRMS (ESI) m / z: calculated for C 22 H 22 N4O2Na[M+Na] + : 397.1635, found: 397.1635.

[0164] Example 17: Preparation of 2-(4-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide (15)

[0165] Step 1 in Example 1 to give 3-methoxybenzoyl azide, and 1-(4-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 3-methoxybenzoyl azide and 4-aminobenzyl alcohol according to Step 2 in Example 1, and 2-(4-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide (15) was prepared from 2-aminobenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea according to Step 4 in Example 1. It was a white solid, 144 mg, yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 10.1 Hz, 2H), 8.51 (s, 1H), 7.84 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.29 - 7.13 (m, 6H), 6.92 (d, J = 7.7 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 8.1 Hz, 2H), 4.30 (d, J = 5.0 Hz, 2H), 3.73 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 160.16, 152.93, 150.06, 141.43, 138.87, 133.36, 132.94, 130.01, 129.50, 128.13 (2C), 118.89 (2C), 114.62, 112.02, 110.94, 107.66, 104.37, 55.39, 46.16. HRMS (ESI) m / z: calcd for C 22 H 23 N4O3[M+H] + : 391.176, found: 391.1761.

[0166] Example 18: Preparation of 2-(4-(3-(3-fluorophenyl)ureido)benzylamino)benzamide (16) 3-Fluorobenzoyl hydrazide was used as the raw material to prepare 3- fluorobenzoyl azide according to step 1 of example 1, 1-(4-(hydroxymethyl)phenyl)-3- (3-fluorophenyl)urea was prepared from 3-fluorobenzoyl azide and 4-aminobenzyl alcohol according to step 2 of example 1, 1-(4-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea was prepared according to step 3 of example 15, 2-(4-(3-(3-fluorophenyl)ureido)benzylamino)benzamide (16) was prepared from 2-aminobenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea according to step 4 of example 1, white solid, 148 mg, yield: 78%. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.70 (s, 1H), 8.51 (t, J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.61 (dd, J = 7.8, 1.1 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 (dd, J = 13.5, 7.8 Hz, 3H), 7.21 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.77 (td, J = 8.4, 2.1 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.4 Hz, 1H), 4.30 (d, J = 5.6 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 164.08, 161.69, 152.86, 150.05, 142.11 (d, J = 11.1 Hz), 138.65, 133.62, 132.94, 130.77 (d, J = 9.5 Hz), 129.51, 128.14 (2C), 119.05 (2C), 114.63, 114.35, 112.02, 108.53 (d, J = 21.2 Hz), 105.27 (d, J = 26.3 Hz), 46.14. HRMS (ESI) m / z: calcd for C 21 H 19 FN4O2Na [M + Na] + : 401.1384, found: 401.1389.

[0167] Example 19: Preparation of 2-(4-(3-(3-chlorophenyl)ureido)benzylamino)benzamide (17)

[0168] Using 3-chlorobenzoylhydrazine as the raw material, 3-chlorobenzoyl azide was prepared according to step 1 of example 1, using 3-chlorobenzoyl azide and 4-aminobenzyl alcohol as the raw material, 1-(4-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea was prepared according to step 2 of example 1, 1-(4-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea was prepared according to step 3 of example 15, using 2-aminobenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea as the raw material, 2-(4-(3-(3-chlorophenyl)ureido)benzylamino)benzamide (17) was prepared according to step 4 of example 1, it was a light yellow solid, 168 mg, yield: 86%. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 7.84 (s, 1H), 7.71 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.24 (tt, J = 16.0, 8.1 Hz, 6H), 7.01 (d, J = 7.0 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 4.31 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 152.85, 150.05, 141.79, 138.63, 133.66, 133.63, 132.94, 130.86, 129.50, 128.13 (2C), 121.85, 119.06 (2C), 117.96, 117.06, 114.62 (2C), 112.01, 46.13. HRMS (ESI) m / z: calcd for C 21 H 19 ClN4O2Na[M+Na] + : 417.1089, found: 417.1086.

[0169] Example 20: Preparation of 2-(4-(3-(3-bromophenyl)ureido)benzylamino)benzamide (18)

[0170] Step 1 in Example 1 to give 3-bromobenzoyl azide, and 1-(4-(chloromethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 3 in Example 15, and 2-(4-(3-(3-bromophenyl)ureido)benzylamino)benzamide (18) was prepared according to step 4 in Example 1 using 2-aminobenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-bromophenyl)urea as starting materials, as a white solid, 177 mg, yield: 81%. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.71 (s, 1H), 8.51 (t, J = 4.9 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.34 - 7.17 (m, 6H), 7.14 (d, J = 7.4 Hz, 2H), 6.63 (d, J = 8.3 Hz, 1H), 6.52 (t, J = 7.4 Hz, 1H), 4.30 (d, J = 5.1 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 152.83, 150.04, 141.93, 138.62, 133.63, 132.94, 131.17, 129.50, 128.13 (2C), 124.75, 122.19, 120.81, 119.06 (2C), 117.45, 114.62 (2C), 112.01, 46.12. HRMS (ESI) m / z: calculated for C 21 H 19 BrN4O2Na[M + Na] + : 461.0584, found: 461.0580.

[0171] Example 21: Preparation of 2-(2-(3-phenylureido)benzyloxy)benzamide (19)

[0172] Step 1: Benzoyl azide was prepared from benzoyl hydrazine according to Step 1 of Example 1.

[0173] Step 2: 1-(2-(hydroxymethyl)phenyl)-3-phenylurea was prepared from benzoyl azide and 2-aminobenzyl alcohol according to Step 2 of Example 1.

[0174] Step 3: 1-(2-(chloromethyl)phenyl)-3-phenylurea was prepared according to Step 3 of Example 1.

[0175] Step 4: Into a 100 mL round bottom flask, was placed 2-hydroxybenzamide (68 mg, 0.5 mmol), 1-(chloromethyl)phenyl-3-phenylurea (129 mg, 0.5 mmol), potassium tert-butoxide (83 mg, 0.75 mmol), then N,N-dimethylformamide (12 mL), and the reaction mixture was stirred at room temperature for 18 h, TLC was used to monitor the reaction progress. After completion, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (25 mL x 3). The combined organic phase was concentrated under reduced pressure, and the crude product was purified by column chromatography to give 2-(2-(3-phenylureido)benzyloxy)benzamide (19) as a white solid, 135 mg, yield: 75%.1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.53 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.68 (dd, J = 7.6, 1.5 Hz, 1H), 7.52 - 7.44 (m, 4H), 7.37 - 7.24 (m, 4H), 7.07 (dd, J = 13.0, 6.8 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H), 5.24 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.82, 156.17, 153.12, 140.15, 138.58, 132.50, 130.41, 130.33, 129.41, 129.27 (2C), 126.47, 124.97, 123.24, 122.47, 122.36, 121.39, 118.69 (2C), 114.38, 68.73. HRMS (ESI) m / z: calculated for C 21 H 19 N3O3Na [M + Na] + : 384.1319, found: 384.1313.

[0176] Example 22: Preparation of 2-(2-(3-(3-methylphenyl)ureido)benzyloxy)benzamide (20)

[0177] Step 1: 3-methylbenzoyl azide was prepared from 3-methylbenzohydrazide according to step 1 of example 1. Step 2: 1-(2-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 3-methylbenzoyl azide and 2-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(2-(chloromethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 1-(2-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea according to step 3 of example 1. Step 4: 2-(2-(3-(3-methylphenyl)ureido)benzyloxy)benzamide (20) was prepared from 2-hydroxybenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-methylphenyl)urea according to step 4 of example 21 as a white solid, 126 mg, yield: 68%. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.51 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.68 (dd, J = 7.5, 1.3 Hz, 1H), 7.49 (t, J = 7.1 Hz, 2H), 7.37 - 7.24 (m, 4H), 7.15 (t, J = 7.8 Hz, 1H), 7.07 (td, J = 7.4, 2.4 Hz, 2H), 6.79 (d, J = 7.3 Hz, 1H), 5.24 (s, 2H), 2.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.88, 156.15, 153.09, 140.07, 138.65, 138.43, 132.49, 130.38, 130.36, 129.41, 129.10, 126.39, 125.01, 123.18, 123.11, 122.42, 121.39, 119.21, 115.90, 114.38, 68.77, 21.69. HRMS (ESI) m / z: calculated for C 22 H 21 N3O3Na[M+Na] + :398.1475, found:398.1471.

[0178] Example 23: Preparation of 2-(2-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide (21)

[0179] Step 1 in Example 1 to give 3-methoxybenzoyl azide, and 2-aminobenzyl alcohol as the raw material, according to step 2 in Example 1 to give 1-(2-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea, according to step 3 in Example 1 to give 1-(2-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea, and 2-hydroxybenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea as the raw material, according to step 4 in Example 21 to give 2-((2-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide (21), white solid, 146 mg, yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.51 (s, 1H), 7.92 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 7.69 (dd, J = 7.5, 1.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.37 - 7.28 (m, 2H), 7.18 (dd, J = 14.6, 6.2 Hz, 2H), 7.07 (dd, J = 14.6, 7.2 Hz, 2H), 6.94 (d, J = 7.9 Hz, 1H), 6.55 (dd, J = 8.1, 1.9 Hz, 1H), 5.24 (s, 2H), 3.73 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 168.79, 160.18, 156.16, 153.06, 141.37, 138.49, 132.51, 130.43, 130.35, 130.02, 129.41, 126.52, 124.93, 123.31, 122.54, 121.39, 114.34, 111.03, 107.76, 104.48, 68.67, 55.40. HRMS (ESI) m / z: calcd for C 22 H 21 N3O4Na [M + Na] + : 414.1424, found: 414.1423.

[0180] Example 24: Preparation of 2-(2-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide (22) 3-Fluorobenzohydrazide was used as the raw material to prepare 3- fluorobenzazide according to step 1 of Example 1, 1-(2-(hydroxymethyl)phenyl)-3-(3- fluorophenyl)urea was prepared from 3-fluorobenzazide and 2-aminobenzyl alcohol according to step 2 of Example 1, 1-(2-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea was prepared according to step 3 of Example 1, 2-(2-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide (22) was prepared from 2-hydroxybenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea according to step 4 of Example 21, white solid, 117 mg, yield: 62%. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.61 (s, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.38 - 7.27 (m, 3H), 7.15 - 7.04 (m, 3H), 6.78 (td, J = 8.4, 2.2 Hz, 1H), 5.25 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.84, 164.10, 161.71, 156.15, 153.00, 142.05 (d, J = 11.3 Hz), 138.25, 132.52, 130.80 (d, J = 9.8 Hz), 130.43, 130.33, 129.42, 126.73, 124.94, 123.53, 122.64, 121.41, 114.41, 108.67 (d, J = 21.2 Hz), 105.34 (d, J = 26.5 Hz), 68.68. HRMS (ESI) m / z: calcd for C 21 H 18 FN3O3Na [M + Na] + : 402.1224, found: 402.1221.

[0181] Example 25: Preparation of 2-(2-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (23)

[0182] Step 1 in Example 1 to give 3-chlorobenzoyl azide, and 2-aminobenzyl alcohol as the raw material, according to step 2 in Example 1 to give 1-(2-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea, according to step 3 in Example 1 to give 1-(2-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea, and 2-hydroxybenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea as the raw material, according to step 4 in Example 21 to give 2-(2-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (23), white solid, 165 mg, yield: 84%. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.61 (s, 1H), 7.96 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.68 (dd, J = 7.6, 1.5 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.35 (dd, J = 12.1, 4.6 Hz, 1H), 7.33 - 7.26 (m, 3H), 7.12 - 7.04 (m, 2H), 7.02 (dt, J = 6.9, 2.0 Hz, 1H), 5.25 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.90, 156.12, 152.98, 141.71, 138.25, 133.71, 132.51, 130.89, 130.40, 130.35, 129.43, 126.73, 124.97, 123.55, 122.64, 121.99, 121.42, 118.01, 117.10, 114.42, 68.71. HRMS (ESI) m / z: calcd for C 21 H 18 ClN3O3Na[M+Na] + : 418.0929, found: 418.0922.

[0183] Example 26: Preparation of 2-(2-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (24)

[0184] Step 1: 3-Bromobenzoyl azide was prepared from 3-bromobenzohydrazide according to step 1 of example 1. Step 2: 1-(2-(hydroxymethyl)phenyl)-3-(3-bromophenyl)urea was prepared from 3-bromobenzoyl azide and 2-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(2-(chloromethyl)phenyl)-3-(3-bromophenyl)urea was prepared from 1-(2-(hydroxymethyl)phenyl)-3-(3-bromophenyl)urea according to step 3 of example 1. Step 4: 2-(2-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (24) was prepared from 2-hydroxybenzamide and 1-(2-(chloromethyl)phenyl)-3-(3-bromophenyl)urea according to step 4 of example 21 as a white solid, 183 mg, yield: 83%. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.61 (s, 1H), 7.96 (s, 1H), 7.90 - 7.85 (m, 2H), 7.81 (s, 1H), 7.68 (dd, J = 7.6, 1.4 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.38 - 7.29 (m, 3H), 7.24 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.12 - 7.04 (m, 2H), 5.25 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.90, 156.12, 152.96, 141.85, 138.24, 132.51, 131.20, 130.40, 130.35, 129.43, 126.73, 124.98, 124.90, 123.55, 122.64, 122.24, 121.43, 120.85, 117.49, 114.42, 68.71. HRMS (ESI) m / z: calcd for C 21 H 18 Br N3O3Na [M + Na] + : 462.0424, found: 462.0427.

[0185] Example 27: Preparation of 2-(3-(3-phenylureido)benzyloxy)benzamide (25)

[0186] Step 1: 2-(3-(hydroxymethyl)phenyl)-3-phenylurea was prepared from 2- hydroxybenzamide according to the procedure described in Example 1, Step 2. Step 2: 1-(3-(chloromethyl)phenyl)-3-phenylurea was prepared from 2- (3-(hydroxymethyl)phenyl)-3-phenylurea according to the procedure described in Example 1, Step 3. Step 3: 2-(3-(3-phenylureido)benzyloxy)benzamide (25) was prepared from 2- hydroxybenzamide and 1-(3-(chloromethyl)phenyl)-3-phenylurea according to the procedure described in Example 21, Step 4. It was obtained as a white solid, 135 mg, yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.67 (s, 1H), 7.82 (dd, J = 7.7, 1.6 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J = 9.9 Hz, 2H), 7.46 (dd, J = 10.2, 4.9 Hz, 4H), 7.30 (dt, J = 15.6, 7.9 Hz, 3H), 7.20 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 5.24 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 156.69, 152.95, 140.45, 140.09, 137.70, 132.81, 131.25, 129.57, 129.27 (2C), 123.62, 122.35, 121.58, 121.18, 118.68 (2C), 118.32, 117.68, 113.87, 70.54. HRMS (ESI) m / z: calculated for C 21 H 19 N3O3Na [M + Na] + : 384.1319, found: 384.1313.

[0187] Example 28: Preparation of 2-(3-(3-(3-methylphenyl)ureido)benzyloxy)benzamide (26)

[0188] Step 1: 3-methylbenzoyl azide was prepared from 3-methylbenzohydrazide according to step 1 of example 1. Step 2: 1-(3-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 3-methylbenzoyl azide and 3-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(3-(chloromethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 1-(3-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea according to step 3 of example 1. Step 4: 2-(3-(3-(3-methylphenyl)ureido)benzyloxy)benzamide (26) was prepared from 2-hydroxybenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-methylphenyl)urea according to step 4 of example 21, as a white solid, 126 mg, yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.59 (s, 1H), 7.83 (dd, J = 7.7, 1.5 Hz, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.48 - 7.42 (m, 2H), 7.34 - 7.28 (m, 2H), 7.21 (t, J = 8.5 Hz, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 5.24 (s, 2H), 2.27 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 156.70, 152.93, 140.48, 140.01, 138.43, 137.69, 132.81, 131.25, 129.56, 129.10, 123.62, 123.09, 121.54, 121.17, 119.19, 118.28, 117.67, 115.86, 113.87, 70.56, 21.70. HRMS (ESI) m / z: calculated for C 22 H 21 N3O3Na[M+Na] + : 398.1475, found: 398.1474.

[0189] Example 29: Preparation of 2-(3-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide (27)

[0190] Step 1: 3-methoxybenzoyl azide was prepared from 3-methoxybenzohydrazide according to step 1 of example 1. Step 2: 1-(3-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 3-methoxybenzoyl azide and 3-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(3-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 1-(3-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea according to step 3 of example 1. Step 4: 2-(3-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide (27) was prepared from 2-hydroxybenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea according to step 4 of example 21 as a light yellow solid, 143 mg, yield: 76%. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.70 (s, 1H), 7.82 (dd, J = 7.7, 1.6 Hz, 1H), 7.62 (s, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.48 - 7.42 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 7.18 (dd, J = 16.3, 8.1 Hz, 3H), 7.11 (d, J = 7.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.55 (dd, J = 8.1, 2.1 Hz, 1H), 5.24 (s, 2H), 3.73 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 160.17, 156.69, 152.89, 141.34, 140.40, 137.69, 132.79, 131.24, 130.01, 129.56, 123.64, 121.62, 121.17, 118.36, 117.73, 113.87, 110.98, 107.78, 104.41, 70.54, 55.40. HRMS (ESI) m / z: calculated for C 22 H 21 N3O4Na [M + Na] + : 414.1424, found: 414.1428.

[0191] Example 30: Preparation of 2-(3-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide (28)

[0192] Step 1: 3-Fluorobenzoyl azide was prepared from 3-fluorobenzohydrazide following step 1 of Example 1. Step 2: l-(3-(hydroxymethyl)phenyl)-3-(3-fluorophenyl)urea was prepared from 3-fluorobenzoyl azide and 3-aminobenzyl alcohol following step 2 of Example 1. Step 3: l-(3-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea was prepared from l-(3- (hydroxymethyl)phenyl)-3-(3-fluorophenyl)urea following step 3 of Example 1. Step 4: 2-(3-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide (28) was prepared from 2-hydroxybenzamide and l-(3-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea following step 4 of Example 21 as a white solid, 149 mg, yield: 76%. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.81 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.55 - 7.41 (m, 4H), 7.36 - 7.26 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.12 (t, J = 7.1 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 5.25 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.81, 164.08, 161.69, 156.68, 152.82, 142.00 (d, J = 11.4 Hz), 140.17, 137.74, 132.79, 131.25, 130.78 (d, J = 9.8 Hz), 129.59, 123.66, 121.84, 121.18, 118.19 (d, J = 63.2 Hz), 114.41 (d, J = 2.2 Hz), 113.87, 108.65 (d, J = 21.0 Hz), 105.35 (d, J = 26.6 Hz), 70.52. HRMS (ESI) m / z: calculated for C 21 H 18 FN3O3Na [M + Na] + : 402.1224, found: 402.1223.

[0193] Example 31: Preparation of 2-(3-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (29)

[0194] Step 1: 3-chlorobenzoyl azide was prepared from 3-chlorobenzoylhydrazine according to step 1 of example 1. Step 2: 1-(3-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea was prepared from 3-chlorobenzoyl azide and 3-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(3-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea was prepared from 1-(3-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea according to step 3 of example 1. Step 4: 2-(3-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (29) was prepared from 2-hydroxybenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea according to step 4 of example 21 as a white solid, 154 mg, yield: 78%. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.81 (s, 1H), 7.82 (dd, J = 7.5, 1.2 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.46 (dd, J = 11.0, 4.4 Hz, 2H), 7.29 (dt, J = 12.9, 8.0 Hz, 3H), 7.20 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.03 (dd, J = 13.6, 6.5 Hz, 2H), 5.24 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.81, 156.67, 152.81, 141.67, 140.14, 137.74, 133.67, 132.80, 131.23, 130.88, 129.59, 123.65, 121.96, 121.87, 121.18, 118.52, 118.03, 117.91, 117.13, 113.86, 70.50. HRMS (ESI) m / z: calcd for C 21 H 18 ClN3O3Na[M+Na] + : 418.0929, found: 418.0923.

[0195] Example 32: Preparation of 2-(3-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (30)

[0196] Using 3-bromobenzohydrazide as the starting material, 3-bromobenzoyl azide was prepared according to step 1 of example 1, and using 3-bromobenzoyl azide and 3-aminobenzyl alcohol as the starting material, 1-(3-(hydroxymethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 2 of example 1, and 1-(3-(chloromethyl)phenyl)-3-(3-bromophenyl)urea was prepared according to step 3 of example 1, and using 2-hydroxybenzamide and 1-(3-(chloromethyl)phenyl)-3-(3-bromophenyl)urea as the starting material, 2-(3-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (30) was prepared according to step 4 of example 21, as a white solid, 184 mg, yield: 82%. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.82 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 7.62 (s, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 7.48 - 7.42 (m, 2H), 7.32 (dd, J = 14.2, 6.9 Hz, 2H), 7.22 (dd, J = 18.3, 8.3 Hz, 2H), 7.14 (t, J = 7.2 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 5.24 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 156.67, 152.79, 141.82, 140.14, 137.73, 132.79, 131.24, 131.19, 129.59, 124.86, 123.65, 122.21, 121.87, 121.18, 120.88, 118.52, 117.92, 117.52, 113.86, 70.50. HRMS (ESI) m / z: calcd for C 21 H 18 BrN3O3Na[M+Na] + : 462.0424, found: 462.0428.

[0197] Example 33: Preparation of 2-(4-(3-phenylureido)benzyloxy)benzamide (31)

[0198] Step 1 in Example 1 to give benzoyl azide, and 1-(4-(hydroxymethyl)phenyl)-3- phenylurea was prepared from benzoyl azide and 4-aminobenzyl alcohol according to Step 2 in Example 1, and 1-(4-(chloromethyl)phenyl)-3-phenylurea was prepared according to Step 5 in Example 15, and 2-(4-(3-phenylureido)benzyloxy)benzamide (31) was prepared from 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-phenylurea according to Step 4 in Example 21 as a white solid, 151 mg, yield: 84%. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.67 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.46 (dt, J = 17.9, 8.7 Hz, 8H), 7.32 - 7.26 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.07 - 7.00 (m, 1H), 7.00 - 6.93 (m, 1H), 5.18 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.81, 156.79, 152.97, 140.18, 140.11, 132.79, 131.21, 130.06, 129.32 (2C), 129.27 (2C), 123.63, 122.35, 121.12, 118.69 (2C), 118.64 (2C), 113.96, 70.47. HRMS (ESI) m / z: calcd for C 21 H 19 N3O3Na[M+Na] + : 384.1319, found: 384.1312.

[0199] Example 34: Preparation of 2-(4-(3-(3-methylphenyl)ureido)benzyloxy)benzamide (32)

[0200] Step 1: 3-methylbenzoyl azide was prepared from 3-methylbenzohydrazide according to step 1 of example 1. Step 2: 1-(4-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 3-methylbenzoyl azide and 4-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(4-(chloromethyl)phenyl)-3-(3-methylphenyl)urea was prepared from 1-(4-(hydroxymethyl)phenyl)-3-(3-methylphenyl)urea according to step 3 of example 15. Step 4: 2-(4-(3-(3-methylphenyl)ureido)benzyloxy)benzamide (32) was prepared from 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-methylphenyl)urea according to step 4 of example 21 as a white solid, 130 mg, yield: 70%. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.59 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.58 (s, 1H), 7.43 (dt, J = 31.9, 16.0 Hz, 6H), 7.29 (s, 1H), 7.23 (d, J = 8.3 Hz, 2H), 7.18 - 7.13 (m, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 6.3 Hz, 1H), 5.18 (s, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 166.82, 156.78, 152.94, 140.20, 140.02, 138.43, 132.81, 131.21, 130.02, 129.32 (2C), 129.11, 123.61, 123.10, 121.12, 119.20, 118.59 (2C), 115.88, 113.95, 70.45, 21.70. HRMS (ESI) m / z: calcd for C 22 H 21 N3O3Na[M+Na] + :398.1475, found:398.1474.

[0201] Example 35: Preparation of 2-(4-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide (33)

[0202] Step 1: 3-methoxybenzoyl azide was prepared from 3-methoxybenzohydrazide according to step 1 of example 1. Step 2: 1-(4-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 3-methoxybenzoyl azide and 4-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(4-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea was prepared from 1-(4-(hydroxymethyl)phenyl)-3-(3-methoxyphenyl)urea according to step 3 of example 15. Step 4: 2-(4-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide (33) was prepared from 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-methoxyphenyl)urea according to step 4 of example 21, as a white solid, 150 mg, yield: 75%. 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.81 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.58 (s, 1H), 7.51 - 7.44 (m, 6H), 7.30 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.03 (t, J = 7.3 Hz, 1H), 6.80 - 6.76 (m, 1H), 5.18 (s, 2H), 3.73 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 166.83, 156.76, 152.83, 141.70, 139.87, 133.68, 132.79, 131.20, 130.89, 130.38, 129.31 (2C), 123.66, 121.96, 121.13, 118.86 (2C), 118.04, 117.14, 113.95, 70.41, 55.38. HRMS (ESI) m / z: calcd for C 22 H 21 N3O4Na[M+Na] + : 414.1424, found: 414.1427.

[0203] Example 36: Preparation of 2-(4-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide (34)

[0204] Step 1: 3-Fluorobenzoyl azide was prepared from 3-fluorobenzohydrazide according to step 1 of example 1. Step 2: 1-(4-(hydroxymethyl)phenyl)-3-(3-fluorophenyl)urea was prepared from 3-fluorobenzoyl azide and 4-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(4-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea was prepared from 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea according to step 4 of example 21. 2-(4-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide (34) was prepared from 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-fluorophenyl)urea according to step 4 of example 21 as a white solid, 133 mg, yield: 71%. 1 H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.36 (s, 1H), 7.81 (d, J = 6.5 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.4 Hz, 3H), 7.45 - 7.38 (m, 3H), 7.27 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.76 (t, J = 7.1 Hz, 1H), 5.18 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.79, 156.79, 153.03, 142.30 (d, J = 11.8 Hz), 140.17, 132.80, 131.21, 130.77, 130.67, 130.12, 129.29 (2C), 123.61, 121.11, 118.74 (2C), 114.34 (d, J = 2.4 Hz), 113.95, 108.42 (d, J = 20.9 Hz), 105.23 (d, J = 26.4 Hz), 70.49. HRMS (ESI) m / z: calcd for C 21 H 18 FN3O3Na[M+Na] + :402.1224, found:402.1224.

[0205] Example 37: Preparation of 2-(4-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (35)

[0206] Step 1: 3-chlorobenzoyl azide was prepared from 3-chlorobenzohydrazide according to step 1 of example 1. Step 2: 1-(4-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea was prepared from 3-chlorobenzoyl azide and 4-aminobenzyl alcohol according to step 2 of example 1. Step 3: 1-(4-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea was prepared from 1-(4-(hydroxymethyl)phenyl)-3-(3-chlorophenyl)urea according to step 3 of example 15. Step 4: 2-(4-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide (35) was prepared from 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-chlorophenyl)urea according to step 4 of example 21. It was a light yellow solid, 134 mg, yield: 68%. 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.82 (s, 1H), 7.84 - 7.78 (m, 1H), 7.71 (s, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.5 Hz, 3H), 7.44 (t, J = 7.0 Hz, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 3.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.6 Hz, 2H), 5.18 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.82, 156.76, 152.83, 141.70, 139.86, 133.67, 132.79, 131.20, 130.88, 130.38, 129.31 (2C), 123.65, 121.96, 121.12, 118.85 (2C), 118.04, 117.13, 113.94, 70.41. HRMS (ESI) m / z: calcd for C 21 H 18 ClN3O3Na[M+Na] + : 418.0929, found: 418.0924.

[0207] Example 38: Preparation of 2-(4-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (36)

[0208] Step 1 in Example 1 to give 3-bromobenzoyl azide, and 4-aminobenzyl alcohol as the raw material, according to step 2 in Example 1 to give 1-(4-(hydroxymethyl)phenyl)-3-(3-bromophenyl)urea, according to step 3 in Example 15 to give 1-(4-(chloromethyl)phenyl)-3-(3-bromophenyl)urea, and 2-hydroxybenzamide and 1-(4-(chloromethyl)phenyl)-3-(3-bromophenyl)urea as the raw material, according to step 4 in Example 21 to give 2-(4-(3-(3-bromophenyl)ureido)benzyloxy)benzamide (36), white solid, 157 mg, yield: 72%. 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.82 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 7.6, 1.7 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.6 Hz, 3H), 7.44 (t, J = 7.2 Hz, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 5.18 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 166.82, 156.76, 152.81, 141.84, 139.86, 132.79, 131.19 (2C), 130.38, 129.30 (2C), 124.86, 123.66, 122.20, 121.12, 120.89, 118.86 (2C), 117.53, 113.94, 70.41. HRMS (ESI) m / z: calculated for C 21 H 18 BrN3O3Na[M+Na] + : 462.0424, found: 462.0419.

[0209] Example 39: Preparation of 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37)

[0210] Step 1: Preparation of N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide

[0211] Into a 100 mL round bottom flask was added 3-aminobenzyl alcohol (800 mg, 6.5 mmol), dichloromethane (20 mL), then triethylamine (986 mg, 9.75 mmol), and a solution of 2-chlorobenzoyl chloride (1.14 g, 6.5 mmol) in dichloromethane (15 mL) was added dropwise slowly under ice bath condition. After the addition was completed, the reaction was allowed to proceed at room temperature for 12 h, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide as a light yellow solid, 1.41 g, yield: 83%.

[0212] Step 2: Preparation of N-(3-(chloromethyl)phenyl)-2-chlorobenzamide

[0213] Into a 100 mL round bottom flask was added N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide (1.05 g, 4 mmol), dichloromethane (20 mL), and a solution of thionyl chloride (716 mg, 6 mmol) in dichloromethane (10 mL) was added dropwise slowly at 0 °C. The reaction was allowed to proceed at 25 °C for 8 h, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give N-(3-(chloromethyl)phenyl)-2-chlorobenzamide as a white solid, 960 mg, yield: 86%.

[0214] Step 3: Preparation of 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37)

[0215] In a 100 mL round bottom flask was added 2-aminobenzamide (68 mg, 0.5 mmol), N-(3-(chloromethyl)phenyl)-2-chlorobenzamide (140 mg, 0.5 mmol), cesium carbonate (244 mg, 0.75 mmol), N,N-dimethylformamide (12 mL), and the reaction was stirred at 25 °C for 12 h, monitoring the reaction progress by thin layer chromatography. After the reaction was complete, the reaction was diluted with 100 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure. The crude product was purified by column chromatography to give 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37) as a white solid, 147 mg, yield: 78%. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.63 (s, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.64 (d, J = 6.3 Hz, 1H), 7.56 (s, 1H), 7.51 - 7.47 (m, 1H), 7.46 - 7.41 (m, 1H), 7.30 (d, J = 6.6 Hz, 2H), 7.18 (d, J = 5.8 Hz, 3H), 7.09 (d, J = 7.0 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 6.53 (s, 1H), 4.38 (d, J = 4.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.08, 165.40, 150.09, 141.01, 139.68, 137.48, 132.98, 131.49, 130.07, 129.63, 129.53, 129.37, 127.99, 127.68, 122.92, 118.61, 118.52, 114.71, 114.59, 111.99, 46.64. HRMS (ESI) m / z: calcd for C 21 H 19 ClN3O2[M+H] + : 380.1160, found: 380.1162.

[0216] Example 40: Preparation of 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37)

[0217] Step 1: Preparation of N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide

[0218] Into a 100 mL round bottom flask was placed 3-aminobenzyl alcohol (800 mg, 6.5 mmol), dichloromethane (20 mL), followed by triethylamine (657 mg, 6.5 mmol), and a solution of 2-chlorobenzoyl chloride (1.14 g, 6.5 mmol) in dichloromethane (15 mL) was added dropwise at ice bath temperature. After the addition was complete, the reaction mixture was stirred at 40 °C for 10 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography to afford N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide as a light yellow solid, 1.19 g, yield: 70%.

[0219] Step 2: Preparation of N-(3-(chloromethyl)phenyl)-2-chlorobenzamide

[0220] Into a 100 mL round bottom flask was placed N-(3-(hydroxymethyl)phenyl)-2- chlorobenzamide (1.05 g, 4 mmol), dichloromethane (20 mL), and sulfurous dichloride (573 mg, 4.81 mmol) in dichloromethane (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography to afford N-(3-(chloromethyl)phenyl)-2-chlorobenzamide as a white solid, 915 mg, yield: 82%.

[0221] Step 3: Preparation of 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37)

[0222] Into a 100 mL round bottom flask was placed 2-aminobenzamide (68 mg, 0.5 mmol), N-(3-(chloromethyl)phenyl)-2-chlorobenzamide (209 mg, 0.75 mmol), cesium carbonate (325 mg, 1 mmol), N,N-dimethylformamide (12 mL), and the reaction mixture was stirred at 50 °C for 10 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined, concentrated under reduced pressure, and the crude product was purified by column chromatography to afford 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37) as a white solid, 132 mg, yield: 70%.

[0223] Example 41: Preparation of 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37)

[0224] Step 1: Preparation of N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide

[0225] Into a 100 mL round bottom flask was placed 3-aminobenzyl alcohol (800 mg, 6.5 mmol), 1,2-dichloroethane (20 mL), then triethylamine (788 mg, 7.8 mmol), and a solution of 2-chlorobenzoyl chloride (1.25 g, 7.15 mmol) in 1,2-dichloroethane (15 mL) was added dropwise at ice bath condition. After the addition was completed, the reaction mixture was stirred at room temperature for 10 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide as a light yellow solid, 1.27 g, yield: 75%.

[0226] Step 2: Preparation of N-(3-(chloromethyl)phenyl)-2-chlorobenzamide

[0227] Into a 100 mL round bottom flask was placed N-(3-(hydroxymethyl)phenyl)-2- chlorobenzamide (1.05 g, 4 mmol), dichloromethane (20 mL), and a solution of thionyl chloride (716 mg, 6 mmol) in dichloromethane (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 8 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to give N-(3-(chloromethyl)phenyl)-2-chlorobenzamide as a white solid, 893 mg, yield: 80%.

[0228] Step 3: Preparation of 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37)

[0229] Into a 100 mL round bottom flask was placed 2-aminobenzamide (68 mg, 0.5 mmol), N-(3-(chloromethyl)phenyl)-2-chlorobenzamide (168 mg, 0.6 mmol), cesium carbonate (195 mg, 0.6 mmol), N,N-dimethylformamide (12 mL), and the reaction mixture was stirred at room temperature for 18 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phase was combined and concentrated under reduced pressure. The crude product was purified by column chromatography to give 2-(3-(2-chlorobenzamido)benzylamino)benzamide (37) as a white solid, 136 mg, yield: 72%.

[0230] Example 42: Preparation of 2-(3-(3-chlorobenzamido)benzylamino)benzamide (38)

[0231] N-(3-(hydroxymethyl)phenyl)-3-chlorobenzamide was prepared according to step 1 of example 39 using 3-chlorobenzoyl chloride, N-(3-(chloromethyl)phenyl)-3- chlorobenzamide was prepared according to step 2 of example 39, and 2-(3-(3- chlorobenzamido)benzylamino)benzamide (38) was prepared according to step 3 of example 39 using 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-3- chlorobenzamide as starting materials, as a white solid, 140 mg, yield: 74%. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.64 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.10 (d, J = 7.3 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.3 Hz, 1H), 4.39 (d, J = 5.0 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 164.50, 150.11, 140.88, 139.61, 137.36, 133.64, 132.97, 131.83, 130.84, 129.53, 129.23, 127.89, 126.98, 123.09, 119.50, 119.40, 114.72, 114.64, 111.99, 46.70. HRMS (ESI) m / z: calcd for C 21 H 18 ClN3O2Na[M+Na] + :402.0980, found:402.0982.

[0232] Example 43: Preparation of 2-(3-(4-chlorobenzamido)benzylamino)benzamide (39)

[0233] N-(3-(hydroxymethyl)phenyl)-4-chlorobenzamide was prepared according to step 1 of example 39 using 4-chlorobenzoyl chloride, N-(3-(chloromethyl)phenyl)-4- chlorobenzamide was prepared according to step 2 of example 39, and 2-(3-(4- chlorobenzamido)benzylamino)benzamide (39) was prepared according to step 3 of example 39 using 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-4- chlorobenzamide as starting materials, as a white solid, 148 mg, yield: 78%.1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.64 (t, J = 5.7 Hz, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.86 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.64 - 7.61 (m, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.20 (t, J = 7.3 Hz, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.4 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 164.88, 150.11, 140.85, 139.69, 136.83, 134.09, 132.97, 130.11 (2C), 129.52, 129.22, 128.89 (2C), 123.00, 119.49, 119.39, 114.71, 114.62, 111.99, 46.70. HRMS (ESI) m / z: calcd for C 21 H 18 ClN3O2Na[M+Na] + :402.0980, found:402.0981.

[0234] Example 44: Preparation of 2-(3-(2-bromobenzamido)benzylamino)benzamide (40)

[0235] N-(3-(hydroxymethyl)phenyl)-2-bromobenzamide was prepared from 2-bromobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-2-bromobenzamide was prepared according to step 2 of example 39, 2-(3-(2-bromobenzamido)benzylamino)benzamide (40) was prepared from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-bromobenzamide according to step 3 of example 39 as a light yellow solid, 159 mg, yield: 75%. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.63 (t, J = 5.7 Hz, 1H), 7.86 (s, 1H), 7.72 - 7.68 (m, 2H), 7.63 (dd, J = 10.5, 4.0 Hz, 2H), 7.53 (dd, J = 7.5, 1.6 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.41 (td, J = 7.7, 1.7 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 6.8 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.2 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.08, 166.29, 150.09, 140.99, 139.70, 139.63, 133.13, 132.98, 131.59, 129.53, 129.35, 129.31, 128.15, 122.90, 119.44, 118.62, 118.54, 114.71, 114.58, 111.99, 46.64. HRMS (ESI) m / z: calcd for C 21 H 19 BrN3O2[M+H] + : 424.0655, found: 424.0651.

[0236] Example 45: Preparation of 2-(3-(3-bromobenzamido)benzylamino)benzamide (41)

[0237] N-(3-(hydroxymethyl)phenyl)-3-bromobenzamide was prepared from 3-bromobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-3-bromobenzamide was prepared according to step 2 of example 39, 2-(3-(3-bromobenzamido)benzylamino)benzamide (41) was prepared from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-3-bromobenzamide according to step 3 of example 39 as a white solid, 147 mg, yield: 69%. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.64 (t, J = 5.7 Hz, 1H), 8.14 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.79 (dd, J = 8.0, 0.8 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.65 - 7.61 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.21 (t, J = 7.4 Hz, 2H), 7.11 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 6.54 (t, J = 7.4 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.10, 164.42, 150.10, 140.88, 139.60, 137.54, 134.73, 132.98, 131.09, 130.72, 129.53, 129.23, 127.35, 123.10, 122.12, 119.51, 119.41, 114.73, 114.64, 111.99, 46.70. HRMS (ESI) m / z: calculated for C 21 H 18 BrN3O2Na[M+Na] + : 446.0475, found: 446.0471.

[0238] Example 46: Preparation of 2-(3-(4-bromobenzamido)benzylamino)benzamide (42)

[0239] N-(3-(hydroxymethyl)phenyl)-4-bromobenzamide was prepared from 4-bromobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-4-bromobenzamide was prepared according to step 2 of example 39, 2-(3-(4-bromobenzamido)benzylamino)benzamide (42) was prepared from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-4-bromobenzamide according to step 3 of example 39 as a white solid, 156 mg, yield: 74%. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.64 (s, 1H), 7.90 (d, J = 7.5 Hz, 3H), 7.79 - 7.66 (m, 4H), 7.62 (d, J = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.20 (d, J = 7.0 Hz, 2H), 7.10 (d, J = 6.2 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.53 (t, J = 6.7 Hz, 1H), 4.38 (d, J = 3.3 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 165.00, 150.11, 140.86, 139.68, 134.46, 132.97, 131.83 (2C), 130.29 (2C), 129.53, 129.22, 125.77, 123.01, 119.49, 119.39, 114.71, 114.63, 111.99, 46.70. HRMS (ESI) m / z: calcd for C 21 H 18 BrN3O2Na[M+Na] + : 446.0475, found: 446.0475.

[0240] Example 47: Preparation of 2-(3-(2-chlorophenylacetamido)benzylamino)benzamide (43)

[0241] Using 2-chlorophenylacetyl chloride as the starting material, N-(3- (hydroxymethyl)phenyl)-2-(2-chlorophenyl)acetamide was prepared according to step 1 of Example 39, and N-(3-(chloromethyl)phenyl)-2-(2-chlorophenyl)acetamide was prepared according to step 2 of Example 39, and using 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-(2-chlorophenyl)acetamide as the starting material, 2-(3-(2-chlorophenylacetamido)benzylamino)benzamide (43) was prepared according to step 3 of Example 39 as a white solid, 134 mg, yield: 68%. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.62 (t, J = 5.8 Hz, 1H), 7.86 (s, 1H), 7.62 (dd, J = 7.9, 1.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.45 - 7.39 (m, 2H), 7.30 (ddd, J = 8.0, 3.0, 2.0 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.20 (dd, J = 11.3, 4.1 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 4.35 (d, J = 5.7 Hz, 2H), 3.82 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 168.37, 150.08, 140.95, 139.93, 134.43, 134.15, 132.97, 132.66, 129.53, 129.45, 129.34, 129.02, 127.51, 122.31, 118.07, 117.89, 114.69, 114.59, 111.96, 46.60, 41.23. HRMS (ESI) m / z: calcd for C 22 H 20 ClN3O2Na[M+Na] + : 416.1136, found: 416.1135.

[0242] Example 48: Preparation of 2-(3-(3-chlorophenylacetamido)benzylamino)benzamide (44)

[0243] Step 1: N-(3-(hydroxymethyl)phenyl)-2-(3-chlorophenyl)acetamide was prepared from 3-chlorophenylacetyl chloride according to step 1 of example 39, step 2: N-(3-(chloromethyl)phenyl)-2-(3-chlorophenyl)acetamide was prepared from N-(3-(hydroxymethyl)phenyl)-2-(3-chlorophenyl)acetamide according to step 2 of example 39, step 3: 2-(3-(3-chlorophenylacetamido)benzylamino)benzamide (44) was prepared from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-(3-chlorophenyl)acetamide according to step 3 of example 39, as a white solid, 129 mg, yield: 66%. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.61 (t, J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.34 (dd, J = 13.9, 6.5 Hz, 2H), 7.29 - 7.24 (m, 2H), 7.22 - 7.14 (m, 2H), 7.02 (d, J = 7.5 Hz, 1H), 6.54 (dd, J = 17.9, 8.0 Hz, 2H), 4.35 (d, J = 5.7 Hz, 2H), 3.65 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 168.98, 150.07, 140.98, 139.80, 138.85, 133.26, 132.97, 130.58, 129.54, 129.35, 128.41, 127.00, 122.43, 118.13, 117.94, 114.69, 114.59, 111.96, 46.57, 43.10. HRMS (ESI) m / z: calcd for C 22 H 20 ClN3O2Na[M+Na] + : 416.1136, found: 416.1138.

[0244] Example 49: Preparation of 2-(3-(4-chlorobenzeneacetamido)benzylamino)benzamide (45)

[0245] Step 1: N-(3-(hydroxymethyl)phenyl)-2-(4-chlorophenyl)acetamide was prepared from 4-chlorophenylacetyl chloride according to step 1 of example 39, step 2 of example 39 was applied to prepare N-(3-(chloromethyl)phenyl)-2-(4-chlorophenyl)acetamide, step 3 of example 39 was applied to prepare 2-(3-(4-chlorobenzeneacetamido)benzylamino)benzamide (45) from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-(4-chlorophenyl)acetamide as a white solid, 149 mg, yield: 76%. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.61 (t, J = 5.7 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.36 (d, J = 7.8 Hz, 4H), 7.22 (dt, J = 24.7, 7.8 Hz, 3H), 7.02 (d, J = 7.5 Hz, 1H), 6.53 (dd, J = 16.6, 8.2 Hz, 2H), 4.34 (d, J = 5.7 Hz, 2H), 3.63 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.08, 169.18, 150.08, 140.95, 139.84, 135.45, 132.96, 131.72, 131.50 (2C), 129.52, 129.33, 128.67 (2C), 122.40, 118.14, 117.94, 114.69, 114.60, 111.96, 46.59, 42.88. HRMS (ESI) m / z: calcd for C 22 H 20 ClN3O2Na[M+Na] + : 416.1136, found: 416.1137.

[0246] Example 50: Preparation of 2-(3-(2-bromophenylacetamido)benzylamino)benzamide (46)

[0247] Using 2-bromophenylacetyl chloride as the starting material, N-(3- (hydroxymethyl)phenyl)-2-(2-bromophenyl)acetamide was prepared according to step 1 of Example 39, and N-(3-(chloromethyl)phenyl)-2-(2-bromophenyl)acetamide was prepared according to step 2 of Example 39. Using 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-(2-bromophenyl)acetamide as the starting materials, 2-(3-(2-bromophenylacetamido)benzylamino)benzamide (46) was prepared according to step 3 of Example 39 as a white solid, 152 mg, yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.62 (s, 1H), 7.86 (s, 1H), 7.61 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.42 - 7.38 (m, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.23 - 7.17 (m, 3H), 7.02 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 4.35 (s, 2H), 3.83 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.08, 168.31, 150.07, 140.93, 139.95, 136.20, 132.97, 132.71 (2C), 129.53, 129.34, 129.23, 128.05, 125.06, 122.30, 118.06, 117.87, 114.70, 114.59, 111.97, 46.61, 43.68. HRMS (ESI) m / z: calculated for C 22 H 20 BrN3O2Na[M+Na] + : 460.0631, found: 460.0631.

[0248] Example 51: Preparation of 2-(3-(3-bromophenylacetamido)benzylamino)benzamide (47)

[0249] Step 1: N-(3-(hydroxymethyl)phenyl)-2-(3-bromophenyl)acetamide was prepared from 3-bromophenylacetyl chloride according to step 1 of Example 39, step 2: N-(3-(chloromethyl)phenyl)-2-(3-bromophenyl)acetamide was prepared from N-(3-(hydroxymethyl)phenyl)-2-(3-bromophenyl)acetamide according to step 2 of Example 39, step 3: 2-(3-(3-bromophenylacetamido)benzylamino)benzamide (47) was prepared from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-(3-bromophenyl)acetamide according to step 3 of Example 39, as a light yellow solid, 146 mg, yield: 67%. 1HNMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.61 (t, J = 5.1 Hz, 1H), 7.83 (d, J = 6.9 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 3H), 7.45 (d, J = 7.4 Hz, 1H), 7.35 - 7.25 (m, 3H), 7.22 (d, J = 9.9 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.54 (dd, J = 18.5, 8.1 Hz, 2H), 4.35 (d, J = 5.2 Hz, 2H), 3.64 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.09, 168.99, 150.08, 140.98, 139.80, 139.14, 132.96, 132.40, 130.88, 129.88, 129.52, 129.34, 128.78, 122.44, 121.92, 118.15, 117.96, 114.70, 114.61, 111.97, 46.59, 43.06. HRMS (ESI) m / z: calcd for C 22 H 20 BrN3O2Na[M+Na] + : 460.0631, found: 460.0634.

[0250] Example 52: Preparation of 2-(3-(4-bromophenylacetamido)benzylamino)benzamide (48)

[0251] Step 1: N-(3-(hydroxymethyl)phenyl)-2-(4-bromophenyl)acetamide was prepared from 4-bromophenylacetyl chloride according to step 1 of example 39, step 2 of example 39 was applied to prepare N-(3-(chloromethyl)phenyl)-2-(4-bromophenyl)acetamide, step 3 of example 39 was applied to prepare 2-(3-(4-bromophenylacetamido)benzylamino)benzamide (48) from 2-aminobenzamide and N-(3-(chloromethyl)phenyl)-2-(4-bromophenyl)acetamide as a white solid, 140 mg, yield: 64%. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.61 (t, J = 5.7 Hz, 1H), 7.86 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.56 - 7.49 (m, 4H), 7.31 - 7.24 (m, 3H), 7.20 (dd, J = 16.1, 8.2 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 6.53 (dd, J = 15.6, 8.0 Hz, 2H), 4.34 (d, J = 5.6 Hz, 2H), 3.61 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 172.08, 169.10, 150.07, 140.96, 139.84, 135.88, 132.97, 131.90 (2C), 131.60 (2C), 129.52, 129.33, 122.40, 120.20, 118.13, 117.92, 114.69, 114.59, 111.96, 46.58, 42.94. HRMS (ESI) m / z: calcd for C 22 H 20 BrN3O2Na[M+Na] + : 460.0631, found: 460.0634.

[0252] Example 53: Preparation of 2-(3-(2-chlorobenzamido)benzyloxy)benzamide (49)

[0253] Step 1: N-(3-(hydroxymethyl)phenyl)-2-chlorobenzamide was prepared according to Step 1 of Example 39 using 2-chlorobenzoyl chloride as starting material.

[0254] Step 2: N-(3-(chloromethyl)phenyl)-2-chlorobenzamide was prepared according to Step 2 of Example 39.

[0255] Step 3: Into a 100 mL round bottom flask, was placed 2-hydroxybenzamide (69 mg, 0.5 mmol), N-(3-(chloromethyl)phenyl)-2-chlorobenzamide (141 mg, 0.5 mmol), potassium tert-butoxide (68 mg, 0.6 mmol), and N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature for 18 h, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (25 mL x 3). The organic phase was combined and concentrated under reduced pressure. The crude product was purified by column chromatography to give 2-(3-(2-chlorobenzamido)benzyloxy)benzamide (49) as a white solid, 111 mg, yield: 58%. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 7.86 (s, 1H), 7.82 (dd, J = 7.7, 1.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.58 (ddd, J = 12.3, 6.2, 4.8 Hz, 4H), 7.51 (dd, J = 7.6, 5.8 Hz, 1H), 7.45 (td, J = 7.6, 1.4 Hz, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.07 - 7.02 (m, 1H), 5.27 (s, 2H). 13 C NMR (100 MHz, DMSO) δ 166.80, 165.48, 156.66, 139.66, 137.77, 137.38, 132.80, 131.59, 131.24, 130.39, 130.12, 129.57, 129.40, 127.73, 123.69, 123.53, 121.21, 119.73, 119.09, 113.88, 70.49. HRMS (ESI) m / z: calcd for C 21 H 17 ClN2O3Na[M + Na] + : 403.0820, found: 403.0823.

[0256] Example 54: Preparation of 2-(3-(3-chlorobenzamido)benzyloxy)benzamide (50)

[0257] N-(3-(hydroxymethyl)phenyl)-3-chlorobenzamide was prepared from 3-chlorobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-3-chlorobenzamide was prepared according to step 2 of example 39, 2-(3-(3-chlorobenzamido)benzyloxy)benzamide (50) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-3-chlorobenzamide according to step 3 of example 51 as a white solid, 124 mg, yield: 65%. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.02 (t, J = 1.7 Hz, 1H), 7.92 (dd, J = 4.1, 1.9 Hz, 2H), 7.83 (dd, J = 7.7, 1.7 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.48 - 7.44 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 164.60, 156.70, 139.62, 137.61, 137.29, 133.69, 132.81, 131.92, 131.27, 130.89, 129.44, 127.91, 126.99, 123.70, 123.68, 121.23, 120.62, 120.03, 113.90, 70.59. HRMS (ESI) m / z: calcd for C 21 H 17 ClN2O3Na[M + Na] + : 403.0820, found: 403.0821.

[0258] Example 55: Preparation of 2-(3-(4-chlorobenzamido)benzyloxy)benzamide (51)

[0259] N-(3-(hydroxymethyl)phenyl)-4-chlorobenzamide was prepared from 4-chlorobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-4-chlorobenzamide was prepared according to step 2 of example 39, 2-(3-(4-chlorobenzamido)benzyloxy)benzamide (51) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-4-chlorobenzamide according to step 3 of example 51 as a white solid, 122 mg, yield: 64%. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.91 (s, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.8 Hz, 3H), 7.54 (s, 1H), 7.49 - 7.43 (m, 1H), 7.43 - 7.37 (m, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 5.27 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.79, 164.97, 156.70, 139.71, 137.59, 136.93, 134.02, 132.81, 131.26, 130.13 (2C), 129.43, 128.95 (2C), 123.68, 123.62, 121.22, 120.60, 120.02, 113.90, 70.60. HRMS (ESI) m / z: calcd for C 21 H 17 ClN2O3Na[M+Na] + : 403.0820, found: 403.0823.

[0260] Example 56: Preparation of 2-(3-(2-bromobenzamido)benzyloxy)benzamide (52)

[0261] N-(3-(hydroxymethyl)phenyl)-2-bromobenzamide was prepared from 2-bromobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-2-bromobenzamide was prepared according to step 2 of example 39, 2-(3-(2-bromobenzamido)benzyloxy)benzamide (52) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-bromobenzamide according to step 3 of example 51 as a white solid, 133 mg, yield: 62%. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.86 (s, 1H), 7.82 (dd, J = 7.7, 1.7 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.61 (s, 1H), 7.56 (dd, J = 7.5, 1.5 Hz, 2H), 7.50 (d, J = 6.9 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 5.4, 3.7 Hz, 1H), 7.39 (t, J = 5.8 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 5.27 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.80, 166.37, 156.67, 139.68, 139.53, 137.76, 133.19, 132.81, 131.68, 131.25, 129.57, 129.32, 128.19, 123.68, 123.52, 121.22, 119.74, 119.47, 119.10, 113.88, 70.50. HRMS (ESI) m / z: calculated for C 21 H 17 BrN2O3Na[M+Na] + : 447.0315, found: 447.0315.

[0262] Example 57: Preparation of 2-(3-(3-bromobenzamido)benzyloxy)benzamide (53)

[0263] N-(3-(hydroxymethyl)phenyl)-3-bromobenzamide was prepared from 3-bromobenzoyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-3-bromobenzamide was prepared according to step 2 of example 39, 2-(3-(3-bromobenzamido)benzyloxy)benzamide (53) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-3-bromobenzamide according to step 3 of example 51 as a white solid, 128 mg, yield: 60%. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 7.81 (td, J = 8.2, 1.2 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 5.28 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 166.79, 164.51, 156.69, 139.62, 137.61, 137.47, 134.82, 132.81, 131.26, 131.14, 130.73, 129.44, 127.37, 123.69, 122.16, 121.23, 120.61, 120.03, 113.91, 70.59. HRMS (ESI) m / z: calcd for C 21 H 17 BrN2O3Na[M+Na] + : 447.0311, found: 447.0315.

[0264] Example 58: Preparation of 2-(3-(4-bromobenzamido)benzyloxy)benzamide (54)

[0265] N-(3-(hydroxymethyl)phenyl)-4-bromobenzamide was prepared from 4-bromobenzoyl chloride according to step 1 of Example 39, N-(3-(chloromethyl)phenyl)-4-bromobenzamide was prepared according to step 2 of Example 39, and 2-(3-(4-bromobenzamido)benzyloxy)benzamide (54) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-4-bromobenzamide according to step 3 of Example 51 as a white solid, 139 mg, yield: 65%. 1 H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.91 (s, 1H), 7.81 (td, J = 8.2, 1.2 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 5.28 (s, 2H). 13CNMR (100 MHz, DMSO-d6) δ 166.79, 165.10, 156.70, 139.70, 137.59, 134.38, 132.81, 131.89 (2C), 131.26, 130.30 (2C), 129.43, 125.88, 123.67, 123.63, 121.23, 120.60, 120.02, 113.91, 70.59. HRMS (ESI) m / z: calculated for C 21 H 17 BrN2O3Na[M+Na] + : 447.0315, found: 447.0313.

[0266] Example 59: Preparation of 2-(3-(2-chlorophenylacetamido)benzyloxy)benzamide (55)

[0267] N-(3-(hydroxymethyl)phenyl)-2-(2-chlorophenyl)acetamide was prepared from 2-chlorophenylacetyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-2-(2-chlorophenyl)acetamide was prepared according to step 2 of example 39, and 2-(3-(2-chlorophenylacetamido)benzyloxy)benzamide (55) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-(2-chlorophenyl)acetamide according to step 3 of example 51 as a white solid, 143 mg, yield: 72%. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.70 (s, 1H), 7.59 (d, J = 5.3 Hz, 2H), 7.52 (s, 1H), 7.44 (d, J = 2.3 Hz, 3H), 7.37 - 7.28 (m, 3H), 7.19 (t, J = 6.9 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H), 5.23 (s, 2H), 3.84 (s, 2H). 13 CNMR (100 MHz, DMSO-d6) δ 168.48, 166.77, 156.68, 139.92, 137.69, 134.36, 134.16, 132.80, 132.66, 131.25, 129.54, 129.47, 129.06, 127.53, 123.64, 122.94, 121.20, 119.23, 118.63, 113.88, 70.53, 41.25. HRMS (ESI) m / z: calculated for C 22 H 19CIN2O3Na [M+Na] + : 417.0976, found: 417.0975.

[0268] Example 60: Preparation of 2-(3-(3-chlorophenylacetamido)benzyloxy)benzamide (56)

[0269] N-(3-(hydroxymethyl)phenyl)-2-(3-chlorophenyl)acetamide was prepared from 3-chlorophenylacetyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-2-(3-chlorophenyl)acetamide was prepared according to step 2 of example 39, 2-(3-(3-chlorophenylacetamido)benzyloxy)benzamide (56) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-(3-chlorophenyl)acetamide according to step 3 of example 51 as a white solid, 154 mg, yield: 78%. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.85 - 7.79 (m, 1H), 7.70 (s, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.51 (s, 1H), 7.44 (dd, J = 13.6, 6.5 Hz, 2H), 7.32 (dt, J = 17.1, 7.6 Hz, 4H), 7.18 (t, J = 8.5 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 3.68 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 169.10, 166.79, 156.66, 139.79, 138.77, 137.71, 133.28, 132.80, 131.25, 130.59, 129.56, 128.42, 127.03, 123.63, 123.06, 121.19, 119.29, 118.69, 113.86, 70.47, 43.10. HRMS (ESI) m / z: calculated for C 22 H 19 CIN2O3Na [M+Na] + : 417.0976, found: 417.0970.

[0270] Example 61: Preparation of 2-(3-(4-chlorophenylacetamido)benzyloxy)benzamide (57)

[0271] N-(3-(hydroxymethyl)phenyl)-2-(4-chlorophenyl)acetamide was prepared according to step 1 of example 39 using 4-chlorophenylacetyl chloride, N-(3-(chloromethyl)phenyl)-2-(4- chlorophenyl)acetamide was prepared according to step 2 of example 39, 2-(3-(4- chlorophenylacetamido)benoxy)benzamide (57) was prepared according to step 3 of example 51 using 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-(4- chlorophenyl)acetamide as starting materials, as a white solid, 151 mg, yield: 76%. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 7.3 Hz, 2H), 7.51 (s, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.40 - 7.31 (m, 5H), 7.18 (t, J = 7.6 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 3.65 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 169.29, 166.78, 156.66, 139.84, 137.69, 135.38, 132.79, 131.76, 131.51 (2C), 131.25, 129.53, 128.70 (2C), 123.64, 123.02, 121.20, 119.29, 118.67, 113.87, 70.50, 42.88. HRMS (ESI) m / z: calcd for C 22 H 19 ClN2O3Na[M + Na] + : 417.0976, found: 417.0972.

[0272] Example 62: Preparation of 2-(3-(2-bromophenylacetamido)benoxy)benzamide (58)

[0273] N-(3-(hydroxymethyl)phenyl)-2-(2-bromophenyl)acetamide was prepared according to step 1 of example 39 using 2-bromophenylacetyl chloride, N-(3-(chloromethyl)phenyl)-2-(2- bromophenyl)acetamide was prepared according to step 2 of example 39, 2-(3-(2- bromophenylacetamido)benoxy)benzamide (58) was prepared according to step 3 of example 51 using 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-(2- bromophenyl)acetamide as starting materials, as a white solid, 154 mg, yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.82 (dd, J = 7.7, 1.6 Hz, 1H), 7.70 (s, 1H), 7.60 (t, J = 5.8 Hz, 3H), 7.52 (s, 1H), 7.47 - 7.40 (m, 2H), 7.38 - 7.32 (m, 2H), 7.24 - 7.17 (m, 3H), 7.03 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 3.85 (s, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 168.42, 166.77, 156.68, 139.94, 137.68, 136.13, 132.80, 132.72, 131.26, 129.54, 129.27, 128.07, 125.06, 123.64, 122.92, 121.20, 119.22, 118.62, 113.88, 70.53, 43.70. HRMS (ESI) m / z: calculated for C 22 H 19 BrN2O3Na[M+Na] + : 461.0471, found: 461.0473.

[0274] Example 63: Preparation of 2-(3-(3-bromophenylacetamido)benzyloxy)benzamide (59)

[0275] Step 1: N-(3-(hydroxymethyl)phenyl)-2-(3-bromophenyl)acetamide was prepared from 3-bromophenylacetyl chloride according to step 1 of Example 39, and N-(3-(chloromethyl)phenyl)-2-(3-bromophenyl)acetamide was prepared according to step 2 of Example 39. Step 3: 2-(3-(3-bromophenylacetamido)benzyloxy)benzamide (59) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-(3-bromophenyl)acetamide according to step 3 of Example 51 as a white solid, 159 mg, yield: 72%. 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.60 - 7.53 (m, 3H), 7.50 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 9.8, 5.4 Hz, 2H), 7.30 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 8.3 Hz, 2H), 7.03 (t, J = 7.5 Hz, 1H), 5.23 (s, 2H), 3.67 (s, 2H). 13C NMR (100 MHz, DMSO-d6) δ 169.10, 166.78, 156.66, 139.79, 139.06, 137.71, 132.79, 132.42, 131.25, 130.90, 129.92, 129.55, 128.80, 123.65, 123.06, 121.93, 121.20, 119.29, 118.70, 113.88, 70.49, 43.06. HRMS (ESI) m / z: calcd for C 22 H 19 BrN2O3Na[M+Na] + : 461.0471, found: 461.0474.

[0276] Example 64: Preparation of 2-(3-(4-bromophenylacetamido)benzyloxy)benzamide (60)

[0277] N-(3-(hydroxymethyl)phenyl)-2-(4-bromophenyl)acetamide was prepared from 4-bromophenylacetyl chloride according to step 1 of example 39, N-(3-(chloromethyl)phenyl)-2-(4-bromophenyl)acetamide was prepared according to step 2 of example 39, and 2-(3-(4-bromophenylacetamido)benzyloxy)benzamide (60) was prepared from 2-hydroxybenzamide and N-(3-(chloromethyl)phenyl)-2-(4-bromophenyl)acetamide according to step 3 of example 51 as a white solid, 150 mg, yield: 68%. 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.81 (dd, J = 7.6, 1.4 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.2 Hz, 3H), 7.46 - 7.41 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 7.8 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 3.63 (s, 2H). 13CNMR (100 MHz, DMSO-d6) δ 169.21, 166.78, 156.66, 139.83, 137.69, 135.80, 132.79, 131.90 (2C), 131.62 (2C), 131.25, 129.53, 123.64, 123.03, 121.20, 120.23, 119.28, 118.67, 113.87, 70.49, 42.95. HRMS (ESI) m / z: calculated for C 22 H 19 BrN2O3Na[M+Na] + : 461.0471, found: 461.0457.

[0278] Example 65: Preparation of 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide (12) hydrochloride salt

[0279] A solution of hydrogen chloride in methanol was prepared by slowly adding 10 mL of acetyl chloride to 17 mL of anhydrous methanol at 0°C. To the above solution was added 300 mg of 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide, stirred well and filtered to give 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide hydrochloride salt as a white solid, 260 mg, yield: 80%.

[0280] Example 66: Preparation of tablets

[0281] A solid powder of 60 mg of 2-(3-(4-bromobenzamide)benzyloxy)benzamide (54) was mixed with 1 g of dextrose, 10 g of corn starch and 1.5 g of corn starch paste having a mass fraction of 5%, and the mixture was granulated by the wet granulation method. Then, 1 g of magnesium stearate was added, and tablets for oral administration were obtained by the compression method.

[0282] Example 67: Preparation of capsules

[0283] A solid powder of 50 mg of 2-(3-(4-bromobenzamide)benzyloxy)benzamide (54) was mixed with 35 mg of lactose, and the mixture was filled into a capsule in an amount of 95 mg / capsule to obtain a capsule for oral administration.

[0284] Example 68: Preparation of injection solution

[0285] A solid powder of 30 mg of 2-(3-(4-bromobenzamide)benzyloxy)benzamide (54) was dissolved in 10 mL of physiological saline to obtain an injection solution.

[0286] Test Example 1: Test of in vitro anti-tumor activity of benzamide derivatives

[0287] Experimental method: MTT method

[0288] Cell culture: Human colon cancer cells (HCT116 and DLD-1), human non-small cell lung cancer cells (A549) and human normal colon epithelial cells (NCM460) were cultured using RPMI1640 medium containing 10% FBS, human breast cancer cells (MDA-MB-231), human cervical cancer cells (Hela), human malignant melanoma cells (A375) and human colon cancer cells (SW480) were cultured using DMEM medium containing 10% FBS.

[0289] Cells in the logarithmic phase were inoculated in 96-well plates at a density of 3000-5000 cells per well and incubated in a CO2 incubator overnight. After 48h treatment with a specific concentration of compound (1-60), 20μL of MTT solution was added to each well, and the incubation was continued in a CO2 incubator for 4h. The supernatant was then discarded, and 150μL of DMSO was added to each well to dissolve the blue-purple formazan crystals. The OD value was determined at a wavelength of 570nm using a microplate reader, and the inhibition rate and half maximal inhibitory concentration (IC 50 ) were calculated. The results are shown in Tables 1, 2 and 3.

[0290] Table 1. Inhibition rate of the proliferation of human cancer cells HCT116, MDA-MB-231, HeLa, A549 and A375 by compounds (1-36) of the present application at a concentration of 20μM

[0291]

[0292]

[0293] As shown in Table 1, a plurality of compounds (1-36) of the present application showed good proliferation inhibition activity (inhibition rate > 50%) on the tested cancer cells at a concentration of 20μM, among which the proliferation inhibition rates of compound 12 and compound 30 on HCT116 cells reached 91.0% and 90.7% respectively at a concentration of 20μM.

[0294] Further, the IC 50 values of compound 8, 11, 12, 15, 17, 18, 29, 30, 35, 36 and positive control olaparib are shown in Table 2.

[0295] Table 2. Proliferation inhibition activity of compounds 8, 11, 12, 15, 17, 18, 29, 30, 35, 36 and olaparib on human cancer cells HCT116, MDA-MB-231, HeLa, A549, A375 and human normal liver cells L02

[0296]

[0297] As shown in Table 2, the representative compounds of the present application (1-36) showed significant proliferation inhibitory activity against the above-mentioned five cancer cells. In particular, compound 12 showed IC50values of 7.87 μM, 13.72 μM, 14.34 μM, 12.36 μM and 15.14 μM against HCT116, MDA-MB-231, HeLa, A549 and A375 cell lines, respectively. Compound 30 showed IC50values of 8.93 μM, 14.24 μM, 13.28 μM, 26.39 μM and 19.46 μM against HCT116, MDA-MB-231, HeLa, A549 and A375 cell lines, respectively. In addition, compared with olaparib, compound 12 and 30 showed cytotoxicity of 100.3 μM and 71.13 μM against human normal liver cells, respectively, while olaparib showed cytotoxicity of 60.67 μM against human normal liver cells LO2, indicating that compound 12 and 30 have lower toxicity against human normal liver cells. 50 50

[0298] Table 3. Proliferation inhibitory activity of the compounds (37-60) of the present application and olaparib against human cancer cells HCT116, DLD-1, SW480 and human normal colon epithelial cells NCM460

[0299]

[0300] As shown in Table 3, a plurality of compounds among the compounds (37-60) of the present application showed effective anti-proliferative activity (IC 50 <20 μM) against the tested human colon cancer cells. Among them, compound 51 and compound 54 showed excellent proliferation inhibitory activity against HCT116 cells, with IC 50 values of 0.33 μM and 0.30 μM, respectively. At the same time, compound 54 also showed the most effective proliferation inhibitory activity against DLD-1 cells, with an IC 50 value of 2.83 μM. For SW480 cells, compound 41 showed the most significant proliferation inhibitory activity, with an IC 50 value of 5.08 μM. In addition, it was found that compound 51 and compound 54 had lower cytotoxicity against human normal colon epithelial cells NCM460, with selectivity indexes (SI) of 1020.03 and 1639.29, respectively.

[0301] Test Example 2: Evaluation of PARP-1 enzyme inhibitory activity of compounds 12, 30, 51, 54 and olaparib ​​

[0302] The human poly(ADP-ribose) polymerase (PARP-1) assay kit was used, and the procedure was performed according to the manufacturer's instructions. The results are shown in Table 4. Compounds 12, 30, 51, and 54 exhibited potent PARP-1 inhibitory activity, with IC50 values ​​of [missing information]. 50 The values ​​were 5.17 nM, 6.06 nM, 1.28 nM and 0.25 nM, respectively, all of which were better than the positive control olaparib (8.06 nM).

[0303] Table 4. Inhibitory activities of compounds 12, 30, 51, 54 and olaparib against PARP-1 enzyme.

[0304]

[0305] Test Example 3: Effects of compounds 12, 30, and 54 on the HCT116 cell cycle

[0306] Experimental method: Flow cytometry

[0307] Cells in the logarithmic growth phase were seeded at a density of 200,000 per well in 6-well plates and incubated overnight in a CO2 incubator. After treatment with compounds 12 (7.5 μM, 15 μM, and 30 μM), 30 (10 μM, 20 μM, and 40 μM), and 54 (0.3 μM, 1.5 μM, and 7.5 μM) for 48 h, the cells were washed with 1 mL of pre-chilled PBS, digested with an appropriate amount of trypsin, and centrifuged. The supernatant was discarded, and the cell pellet was fixed overnight at 4°C with 1 mL of pre-chilled 70% ethanol. The cell pellet was resuspended in 1 mL of pre-chilled PBS. PI staining solution was added, and the cells were incubated at 37°C in the dark for 30 min before flow cytometry analysis.

[0308] Experimental results are as follows Figure 1 As shown, compounds 12, 30, and 54 effectively arrested HCT116 cells in the G2 / M phase. Compared with the control group, with increasing compound concentrations, the percentage of cells in the G2 / M phase treated with compounds 12, 30, and 54 increased from 27.8% to 34.6%, from 27.4% to 34.1%, and from 28.6% to 41.0%, respectively. Simultaneously, the percentage of cells in the G0 / G1 phase decreased from 66.4% to 55.9%, from 63.7% to 55.3%, and from 60.7% to 49.7%, respectively. These results indicate that compounds 12, 30, and 54 can arrest the cell cycle in the G2 / M phase, thereby inhibiting the proliferation of HCT116 cells.

[0309] Test Example 4: Effects of compounds 12, 30, and 54 on apoptosis in HCT116 cells

[0310] Experimental method: Flow cytometry

[0311] HCT116 cells in logarithmic phase were seeded in 6-well plates at a density of 200,000 cells per well and incubated in a CO2incubator overnight. After treatment with compound 12 (37.5 μM, 5 μM and 10 μM), 30 (5 μM, 10 μM and 20 μM) and 54 (0.3 μM, 1.5 μM and 7.5 μM) for 48 h, the cells were washed twice with 1 mL pre-cooled PBS, digested with an appropriate amount of trypsin, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, 500 μL of 1 x Binding Buffer solution was added to each tube and transferred to a 1.5 mL EP tube, 5 μL of FITC and 10 μL of PI were added for staining, and the mixture was incubated at room temperature for 5 min in the dark. The cells were detected on a flow cytometer. The results are shown in Figure 6. The apoptosis rates of HCT116 cells treated with different concentrations of compound 12 were 10.10% (3.75 μM), 13.63% (7.5 μM) and 45.05% (15 μM), respectively. The apoptosis rates of HCT116 cells treated with different concentrations of compound 30 were 4.86% (5 μM), 14.00% (10 μM) and 41.40% (20 μM), respectively. The apoptosis rates of HCT116 cells treated with different concentrations of compound 54 were 9.37% (0.3 μM), 25.66% (1.5 μM) and 42.09% (7.5 μM), respectively. The above results show that compounds 12, 30 and 54 can significantly induce apoptosis of HCT116 cells in a dose-dependent manner. Figure 2 HCT116 cells in logarithmic phase were seeded in 6-well plates at a density of 200,000 cells per well and incubated in a CO2incubator overnight. After treatment with compound 12 (37.5 μM, 5 μM and 10 μM), 30 (5 μM, 10 μM and 20 μM) and 54 (0.3 μM, 1.5 μM and 7.5 μM) for 48 h, the cells were washed twice with 1 mL pre-cooled PBS, digested with an appropriate amount of trypsin, centrifuged at 1000 rpm for 5 min, the supernatant was discarded, 500 μL of 1 x Binding Buffer solution was added to each tube and transferred to a 1.5 mL EP tube, 5 μL of FITC and 10 μL of PI were added for staining, and the mixture was incubated at room temperature for 5 min in the dark. The cells were detected on a flow cytometer. The results are shown in Figure 6. The apoptosis rates of HCT116 cells treated with different concentrations of compound 12 were 10.10% (3.75 μM), 13.63% (7.5 μM) and 45.05% (15 μM), respectively. The apoptosis rates of HCT116 cells treated with different concentrations of compound 30 were 4.86% (5 μM), 14.00% (10 μM) and 41.40% (20 μM), respectively. The apoptosis rates of HCT116 cells treated with different concentrations of compound 54 were 9.37% (0.3 μM), 25.66

Claims

1. A benzamide derivative or a pharmaceutically acceptable salt, characterized by: The structure of the benzamide derivative is shown in formula-1: Formula -1 Wherein: X is NH or O; Y is urea group (-NHCONH-), amide group (-NHCO-), acetamide group (-NHCOCH2-) or propionamide group (-NHCOCH2CH2-), the -NH- in Y group is connected with B ring; R is hydrogen atom, methyl, ethyl, methoxy, ethoxy, fluorine atom, chlorine atom or bromine atom; the Y group connected with B ring can be connected at any possible position of B ring, and the R group connected with C ring can be connected at any possible position of C ring.

2. The benzamide derivative or pharmaceutically acceptable salt according to claim 1, characterized by: The benzamide derivative is any one of the following: (1) 2-(2-(3-phenylureido)benzylamino)benzamide; (2) 2-(2-(3-(3-methylphenyl)ureido)benzylamino)benzamide; (3) 2-(2-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide; (4) 2-(2-(3-(3-fluorophenyl)ureido)benzylamino)benzamide; (5) 2-(2-(3-(3-chlorophenyl)ureido)benzylamino)benzamide; (6) 2-(2-(3-(3-bromophenyl)ureido)benzylamino)benzamide; (7) 2-(3-(3-phenylureido)benzylamino)benzamide; (8) 2-(3-(3-(3-methylphenyl)ureido)benzylamino)benzamide; (9) 2-(3-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide; (10) 2-(3-(3-(3-fluorophenyl)ureido)benzylamino)benzamide; (11) 2-(3-(3-(3-chlorophenyl)ureido)benzylamino)benzamide; (12) 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide; (13) 2-(4-(3-phenylureido)benzylamino)benzamide; (14) 2-(4-(3-(3-methylphenyl)ureido)benzylamino)benzamide; (15) 2-(4-(3-(3-methoxyphenyl)ureido)benzylamino)benzamide; (16) 2-(4-(3-(3-fluorophenyl)ureido)benzylamino)benzamide; (17) 2-(4-(3-(3-chlorophenyl)ureido)benzylamino)benzamide; (18) 2-(4-(3-(3-bromophenyl)ureido)benzylamino)benzamide; (19) 2-(2-(3-phenylureido)benzyloxy)benzamide; (20) 2-(2-(3-(3-methylphenyl)ureido)benzyloxy)benzamide; (21) 2-(2-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide; (22) 2-(2-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide; (23) 2-(2-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide; (24) 2-(2-(3-(3-bromophenyl)ureido)benzyloxy)benzamide; (25) 2-(3-(3-phenylureido)benzyloxy)benzamide; (26) 2-(3-(3-(3-methylphenyl)ureido)benzyloxy)benzamide; (27) 2-(3-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide; (28) 2-(3-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide; (29) 2-(3-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide; (30) 2-(3-(3-(3-bromophenyl)ureido)benzyloxy)benzamide; (31) 2-(4-(3-phenylureido)benzyloxy)benzamide; (32) 2-(4-(3-(3-methylphenyl)ureido)benzyloxy)benzamide; (33) 2-(4-(3-(3-methoxyphenyl)ureido)benzyloxy)benzamide; (34) 2-(4-(3-(3-fluorophenyl)ureido)benzyloxy)benzamide; (35) 2-(4-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide; (36) 2-(4-(3-(3-bromophenyl)ureido)benzyloxy)benzamide; (37) 2-(3-(2-chlorobenzamido)benzylamino)benzamide; (38) 2-(3-(3-chlorobenzamido)benzylamino)benzamide; (39) 2-(3-(4-chlorobenzamido)benzylamino)benzamide; (40) 2-(3-(2-bromobenzamido)benzylamino)benzamide; (41) 2-(3-(3-bromobenzamido)benzylamino)benzamide; (42) 2-(3-(4-bromobenzamido)benzylamino)benzamide; (43) 2-(3-(2-chlorobenzamide)benzylamino)benzamide; (44) 2-(3-(3-chlorobenzamide)benzylamino)benzamide; (45) 2-(3-(4-chlorobenzamide)benzylamino)benzamide; (46) 2-(3-(2-bromobenzamide)benzylamino)benzamide; (47) 2-(3-(3-bromobenzamide)benzylamino)benzamide; (48) 2-(3-(4-bromobenzamide)benzylamino)benzamide; (49) 2-(3-(2-chlorobenzamide)benzyloxy)benzamide; (50) 2-(3-(3-chlorobenzamide)benzyloxy)benzamide; (51) 2-(3-(4-chlorobenzamide)benzyloxy)benzamide; (52) 2-(3-(2-bromobenzamide)benzyloxy)benzamide; (53) 2-(3-(3-bromobenzamide)benzyloxy)benzamide; (54) 2-(3-(4-bromobenzamide)benzyloxy)benzamide; (55) 2-(3-(2-chlorobenzamide)benzyloxy)benzamide; (56) 2-(3-(3-chlorobenzamide)benzyloxy)benzamide; (57) 2-(3-(4-chlorobenzamide)benzyloxy)benzamide; (58) 2-(3-(2-bromobenzamide)benzyloxy)benzamide; (59) 2-(3-(3-bromobenzamide)benzyloxy)benzamide; (60) 2-(3-(4-bromobenzamide)benzyloxy)benzamide.

3. The benzamide derivative or pharmaceutically acceptable salt according to claim 2, characterized by: The benzamide derivative is 2-(3-(3-(3-chlorophenyl)ureido)benzylamino)benzamide, 2-(3-(3-(3-bromophenyl)ureido)benzylamino)benzamide, 2-(2-(3-(3-chlorophenyl)ureido)benzyloxy)benzamide, 2-(3-(3-(3-bromophenyl)ureido)benzyloxy)benzamide, 2-(3-(4-chlorobenzamido)benzyloxy)benzamide, 2-(3-(4-bromobenzamido)benzyloxy)benzamide, 2-(3-(4-chlorobenzeneacetamido)benzyloxy)benzamide or 2-(3-(4-bromobenzeneacetamido)benzyloxy)benzamide.

4. A method of preparing the benzamide derivative according to claim 1, characterized by The method comprises the following steps: adding a reactant of formula-2 into a reaction bottle, then adding a solvent A, and then adding an intermediate of formula-3, and reacting in the presence of a base; after the reaction is completed, diluting with water, extracting, concentrating under reduced pressure, and purifying to obtain the benzamide derivative; and the reaction formula is as follows: In the formula-2 and formula-3, X, Y and R are as defined in claim 1.

5. The method for preparing benzamide derivatives according to claim 4, characterized in that: The solvent A is selected from N , N dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile or acetone; and the base is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide.

6. The method for preparing benzamide derivatives according to claim 4, characterized in that: The molar ratio of the reactant of formula-2, the intermediate of formula-3 and the base is 1:(0.75-1.5):(1-2).

7. The method according to claim 4, characterized in that: (1) when the Y group is -NHCONH-, the preparation steps of the intermediate of formula-3 are as follows: (1-1) preparation of substituted benzoyl azide: adding substituted benzoyl hydrazine into a reaction bottle, adding a solvent B into the reaction bottle, then adding an aqueous sodium nitrite solution, and slowly adding an aqueous hydrochloric acid solution dropwise under stirring and cooling to react; after the reaction is completed, standing, separating the organic layer, concentrating under reduced pressure, and purifying the residue to obtain the substituted benzoyl azide; (1-2) preparation of 1-hydroxymethylphenyl-3-substituted phenyl urea: adding the substituted benzoyl azide into a reaction bottle, dissolving the substituted benzoyl azide with a solvent C, stirring, heating, and obtaining substituted phenyl isocyanate through denitrogenation rearrangement reaction; then adding amino-substituted benzyl alcohol, continuing to stir until solid is precipitated, cooling, and suction filtering to obtain the 1-hydroxymethylphenyl-3-substituted phenyl urea; (1-3) Preparation of 1-chloromethylphenyl-3-substituted phenyl urea: 1-hydroxymethylphenyl-3-substituted phenyl urea was added to a reaction flask, and stirred with dichloromethane or dimethylformamide as a solvent, and slowly added dropwise with stirring with sulfoxyl chloride; after the reaction was completed, diluted with water and extracted with ethyl acetate, and concentrated under reduced pressure to obtain 1-chloromethylphenyl-3-substituted phenyl urea. N , N - dimethylformamide as a solvent, and slowly added dropwise with stirring with sulfoxyl chloride; after the reaction was completed, diluted with water and extracted with ethyl acetate, and concentrated under reduced pressure to obtain 1-chloromethylphenyl-3-substituted phenyl urea. (2) when the Y group is -NHCO-, the preparation steps of the intermediate of formula-3 are as follows: (2-1) N Preparation of (hydroxymethylphenyl)-substituted benzamide: in a reaction flask, the amino-substituted benzyl alcohol was dissolved in solvent D, and triethylamine was added as an acid binding agent. A solution of the substituted benzoyl chloride diluted in solvent D was added dropwise slowly with stirring. After the reaction was completed, it was concentrated under reduced pressure, and purified by post-treatment to obtain N a (hydroxymethylphenyl)-substituted benzamide. (2-2) N -(hydroxymethylphenyl)-substituted benzamide, and then adding a solvent E, slowly dropping chlorosulfoxide under stirring; after the reaction is completed, diluting with water and extracting with ethyl acetate, and concentrating under reduced pressure to obtain N -(hydroxymethylphenyl)-substituted benzamide; and then adding a solvent E, slowly dropping chlorosulfoxide under stirring; after the reaction is completed, diluting with water and extracting with ethyl acetate, and concentrating under reduced pressure to obtain N -(chloromethylphenyl)-substituted benzamide. (3) when the Y group is -NHCOCH2-, the preparation steps of the intermediate of formula-3 are as follows: (3-1) 2-substituted phenyl group N Preparation of (hydroxymethylphenyl)acetamide: aminosubstituted benzyl alcohol was added to a reaction flask, dissolved with solvent D, and triethylamine was added as an acid binding agent. A solution of substituted phenylacetyl chloride diluted with solvent D was added dropwise slowly with stirring. After the reaction was completed, it was concentrated under reduced pressure, and purified by post-treatment to obtain 2-substituted phenyl- N (hydroxymethylphenyl)acetamide. (3-2) 2-substituted phenyl group N Preparation of (hydroxymethylphenyl)acetamide: 2-substituted phenyl group N (hydroxymethylphenyl)acetamide was added to a reaction flask, solvent E was added, and chlorosulfoxide was slowly added dropwise with stirring; after the reaction was complete, water was added for dilution and extraction was performed with ethyl acetate, and 2-substituted phenyl group N (chloromethylphenyl)acetamide was obtained by concentration under reduced pressure.

8. Use of the benzamide derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: The benzamide derivative is used for preparing a medicine for treating a disease related to abnormal activity of PARP-1.

9. The use of the benzamide derivatives and pharmaceutically acceptable salts according to claim 8, characterized by: The benzamide derivative is used for preparing an antitumor medicine.

10. An antitumor pharmaceutical composition, characterized by: The benzamide derivative is used for preparing an antitumor medicine.

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