N-benzyl-3-phenylamide derivatives, pharmaceutical compositions containing the same and applications thereof

Abstract

The present invention provides an N-benzyl-3-phenylamide derivative, a pharmaceutical composition containing the same and an application thereof. The N-benzyl-3-phenylamide derivative is a compound with a structure represented by formula (I) or a pharmaceutically acceptable salt thereof. The N-benzyl-3-phenylamide derivative of the present invention shows obvious inhibitory activity on PLAGL2 and has broad application prospects and practical value for diseases mediated by PLAGL2.

Description

Technical Field

[0001] The present invention belongs to the field of compounds, and in particular relates to an N-benzyl-3-phenylamide derivative, a pharmaceutical composition containing the same and application thereof. Background Art

[0002] PLAGL2 (Pleomorphic adenoma gene like-2) belongs to the PLAG gene family, as a zinc finger transcription factor, which regulates the expression of many important genes in the body and participates in many important physiological functions, including cell transformation, migration and apoptosis. It is also related to the actin cytoskeleton and angiogenesis, and plays an important role in the occurrence and development of many diseases. PLAGL2 dysregulation is a common phenomenon in different malignant tumors, such as liver cancer, neuroblastoma, non-small cell lung cancer, prostate cancer, colorectal cancer and leukemia.

[0003] Most of the anti-tumor drugs currently used work through epidermal growth factor receptor (HER). This family includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3) and HER4 (erbB4). The HER family plays an important regulatory role in cell physiological processes. EGFR (epidermal growth factor receptor, referred to as EGFR, ErbB-1 or HER1) is a member of the epidermal growth factor receptor (HER) family. EGFR is widely distributed on the cell surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes, etc. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. Small molecule EGFR inhibitors enter the cell, and after the small molecule binds to the intracellular end of the EGFR receptor in the cell, it can block the phosphorylation of the receptor end, thereby further inhibiting downstream signal transduction and preventing EGFR-dependent cell proliferation. Although EGFR drugs have a satisfactory effect in inhibiting malignant tumors, continuous use will make cancer cells insensitive to such drugs. Inhibition of the PLAGL2 gene will restore the effectiveness of erlotinib and overcome acquired drug resistance. Combination therapy can synergistically increase apoptosis in NSCLC cell lines and inhibit tumor growth in vivo. PLAGL2 is a potential new target for the treatment of various cancers. PLAGL2 inhibitors are potential therapeutic drugs for various tumor diseases and deserve further study. Summary of the invention

[0004] The purpose of the present invention is to provide an N-benzyl-3-phenylamide derivative and its application, and also to provide a pharmaceutical composition containing the N-benzyl-3-phenylamide derivative. The N-benzyl-3-phenylamide derivative can inhibit the activity of PLAGL2 and has application prospects in the treatment of various malignant tumors.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] The pharmaceutically acceptable salts include salts formed with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid or succinic acid.

[0007] As a further improvement of the technical solution, the N-benzyl-3-phenylamide derivative is N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazine-1-yl)benzamide;

[0008] N-(4-fluorobenzyl)-3-((4-ethylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0009] N-(4-fluorobenzyl)-3-((4-cyanophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0010] N-(4-fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0011] N-(4-fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0012] N-(4-fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0013] N-(4-fluorobenzyl)-3-((4-methoxyphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0014] N-(4-fluorobenzyl)-3-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonamido)-4-(4-methylpiperazine-1)benzamide;

[0015] N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(3-oxopiperazin-1-yl)benzamide;

[0016] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)-benzamide;

[0017] N-(4-fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzamide;

[0018] N-(4-Fluorobenzyl)3-((4-cyanophenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)-benzamide;

[0019] N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0020] N-(4-fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0021] N-(4-fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0022] N-(4-fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0023] N-(4-fluorobenzyl)-3-((3,4-difluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0024] N-(4-fluorobenzyl)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0025] N-(4-fluorobenzyl)-3-(naphthalene-2-sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0026] N-(4-fluorobenzyl)-3-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonamido)-4-(4-isopropylpiperazine-1)benzamide;

[0027] N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-(tert-butyl)piperazin-1-yl)benzamide;

[0028] N-(4-fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-(tert-butyl)piperazin-1-yl)benzamide;

[0029] N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide;

[0030] N-(4-fluorobenzyl)-3-((4-ethylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide;

[0031] N-(4-fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide;

[0032] N-(4-fluorobenzyl)-3-((2-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide;

[0033] N-(4-fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide;

[0034] N-(4-fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide;

[0035] N-(4-fluorobenzyl)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide;

[0036] N-(4-fluorobenzyl)-3-((4-cyanophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide;

[0037] N-(2-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide;

[0038] N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperidin-1-yl)benzamide;

[0039] N-(4-fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-cyclopropylpiperazin-1-yl)benzamide;

[0040] N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzamide;

[0041] N-(3-fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0042] N-(3,5-difluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0043] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-benzylpiperidin-1-yl)-benzamide;

[0044] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-benzylpiperidin-1-yl)-benzamide;

[0045] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-cyclohexylpiperazin-1-yl)-benzamide;

[0046] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-cyclohexylpiperazin-1-yl)-benzamide;

[0047] N-(4-trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0048] N-(4-trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzamide;

[0049] N-(4-trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0050] N-(4-(trifluoromethyl)benzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide;

[0051] N-(4-trifluoromethyl)benzyl)-3-((4-methylphenyl)sulfonamido)-4-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzamide;

[0052] N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0053] N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide;

[0054] N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0055] N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide;

[0056] N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide;

[0057] N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide;

[0058] N-(4-fluorobenzyl)-3-(2-fluorobenzamide)-4-(4-methylpiperazin-1-yl)benzamide;

[0059] N-(4-fluorobenzyl)-3-benzamide-4-(4-methylpiperazin-1-yl)benzamide;

[0060] N-(5-(4-benzylpiperidin-1-carbonyl)-2-(4-isopropylpiperazin-1-yl)phenyl)-4-methylbenzenesulfonamide;

[0061] N-(5-(4-benzylpiperidin-1-carbonyl)-2-(4-isopropylpiperazin-1-yl)phenyl)-4-fluorobenzenesulfonamide;

[0062] or N-(5-(4-benzylpiperidin-1-carbonyl)-2-(4-methyl-1,4-diazepin-1-yl)phenyl)-4-fluorobenzenesulfonamide.

[0063] The present invention discloses a pharmaceutical composition, which comprises the N-benzyl-3-phenylamide derivative and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable excipients refer to excipients and additives used in the production of drugs and the preparation of prescriptions, including solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, aromatics, anti-adhesives, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, etc. Pharmaceutically acceptable carriers refer to systems that can change the way drugs enter the human body and their distribution in the body, control the release rate of drugs, and deliver drugs to target organs, including microcapsules and microspheres, nanoparticles, liposomes, etc. When the pharmaceutical composition is used for solid tumor diseases, the preferred composition form is active ingredient + carrier.

[0064] The N-benzyl-3-phenylamide derivatives have PLAGL2 inhibitory activity. The present invention also discloses an application of the N-benzyl-3-phenylamide derivatives. The N-benzyl-3-phenylamide derivatives are used to prepare drugs for preventing and / or treating PLAGL2-mediated diseases.

[0065] As a further improvement of the technical method, the PLAGL2-mediated diseases include pain, inflammation, immune dysfunction, neurological and psychiatric disorders, respiratory diseases, urinary, reproductive disorders, abnormal embryonic development, cell metabolism, abnormal differentiation and malignant tumors.

[0066] As a further improvement of the technical method, the malignant tumor is liver cancer, breast cancer, rectal cancer, gastric cancer or prostate cancer.

[0067] The N-benzyl-3-phenylamide derivatives have PLAGL2 inhibitory activity. The present invention also discloses an application of the N-benzyl-3-phenylamide derivatives. The N-benzyl-3-phenylamide derivatives are used to prepare PLAGL2 inhibitors.

[0068] The present invention also discloses a method for preparing the N-benzyl-3-phenylamide derivatives, comprising:

[0069]

[0070] in

[0071] Step 1: Compound Ⅰ reacts with substituted amine to obtain compound Ⅱ;

[0072] Step 2: Compound II is refluxed with a nitrogen-containing heterocycle under the action of alkaline potassium carbonate to obtain compound III;

[0073] Step 3: Compound III is converted into IV under the conditions of palladium carbon and hydrogen;

[0074] Step 4: Compound IV is reacted with substituted benzenesulfonyl chloride or substituted benzoyl chloride under alkaline pyridine conditions to obtain the compound of the present invention.

[0075] The present invention has outstanding substantive features and significant progress compared to the prior art. Specifically, the compound of the present invention inhibits the transcription function of PLAGL2 by binding to it, making it unable to complete signal transduction, thereby achieving the purpose of blocking the PLAGL2-EGFR-HIF-1 / 2α signaling pathway. Furthermore, the compound of the present invention exhibits a high PLAGL2 inhibitory effect at a concentration of 10 μM and has high application value. Furthermore, the preparation method of the compound of the present invention has simple steps and strong feasibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 This is the vector plasmid map of PLAGL2-ZsGreen.

[0077] Figure 2 This is the vector plasmid map of MPL. DETAILED DESCRIPTION

[0078] The technical solution of the present invention is further described in detail below through specific implementation methods.

[0079] In the following examples, "room temperature" means about 10° C. to about 35° C. The ratios expressed for mixed solvents are volume mixing ratios, and % means wt % unless otherwise specified.

[0080] In silica gel column chromatography, basic silica gel refers to silica gel bonded with aminopropylsilane. In high performance liquid chromatography (HPLC), C18 refers to silica gel bonded with octadecyl. The ratio of elution solvents is a volume mixing ratio unless otherwise specified.

[0081] In the following Examples and Experimental Examples, the following abbreviations are used.

[0082] DCM: dichloromethane,

[0083] MeOH: Methanol

[0084] DMSO: dimethyl sulfoxide,

[0085] DIEA: N,N-diisopropylethylamine,

[0086] HATU:2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0087] M: molar concentration.

[0088] Using Fourier transform NMR, the 1 H-NMR (proton nuclear magnetic resonance spectroscopy). For analysis, ACD / SpecManager or the like is used. Peaks of active hydrogen (eg, hydroxyl group, amino group, etc.) are not described.

[0089] MS (mass spectrum) is measured by LC / MS (liquid chromatography mass spectrometer). As the ionization method, ESI (electrospray ionization) method etc. are used. The data represent those measured values. Usually, the molecular ion peak is observed. In the case of salt, the molecular ion peak or fragment ion peak of the free form is usually observed.

[0090] Example 1

[0091] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonylamino)-4-(4-methylpiperazin-1-yl)benzamide

[0092] a) 4-Chloro-N-(4-fluorobenzyl)-3-nitrobenzamide

[0093] At room temperature, add HATU (1.5 g), DIEA (3 ml) and p-fluorobenzylamine (0.92 g) dissolved in DCM to 4-chloro-3-nitrobenzoic acid (1 g) and 8 mL DCM, and react at room temperature for 3 hours. After the reaction is completed, add water for extraction. Purify by silica gel column chromatography to obtain 0.61 g of the title compound with a yield of 61.9%.

[0094] 1 H NMR (300MHz, CDCl3) δ8.90(t,J=5.7Hz,2H),8.44(d,J=2.3Hz,2H),8.13(dd,J=8.0,2.2Hz, 2H),7.81(d,J=7.9Hz,2H),7.42–7.27(m,3H),7.09(t,J=7.9Hz,4H),4.55(d,J=3.7Hz,1H).

[0095] b) N-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)-3-nitrobenzamide

[0096] At room temperature, 4-chloro-N-(4-fluorobenzyl)-3-nitrobenzamide (0.6 g), 1-methylpiperazine (0.11 ml) and potassium carbonate (0.6 g) were dissolved in DMF (0.9 ml) and refluxed at 80°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water. The mixture was extracted three times with 20 mL of DCM. The organic phases were combined, dried over anhydrous Na2SO4, and dried under reduced pressure to obtain 0.6 g of the title compound with a yield of 92.1%.

[0097] 1 H NMR (300MHz, CDCl3) δ8.29(d,J=2.4Hz,1H),8.12(s,1H),8.01(d,J=8.7,2.4Hz,2H),7.61-7.56(m,2H),7.13-7.01(m,3H),3.20 -3.17(m,4H),2.59-2.56(m,4H),2.36(s,3H).

[0098] c) 3-amino-N-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)benzamide

[0099] At room temperature, add 0.2 g Pd / C to N-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)-3-nitrobenzamide (0.6 g) and 4 mL MeOH, and react at room temperature for 4 hours under hydrogen protection. After the reaction is completed, filter and dry the filtrate under reduced pressure to obtain 0.5 g of the title compound with a yield of 89.7%.

[0100] d) N-(4-fluorobenzyl)-3-((4-methylphenyl)sulfonylamino)-4-(4-methylpiperazin-1-yl)benzamide

[0101] At 0°C, 3-amino-N-(4-fluorobenzyl)-4-(4-methylpiperazin-1-yl)benzamide (0.5 g) was dissolved in 10 mL of pyridine, and p-toluenesulfonyl chloride (0.4 g) was added and reacted at room temperature for 3 hours. After the reaction was completed, the mixture was dried under reduced pressure, extracted, and purified by silica gel column chromatography to obtain 0.23 g of the title compound as a white solid, with a yield of 56.2%.

[0102] 1 H NMR (300MHz, DMSO-d6) δ8.96(t,J=6.1Hz,2H),7.79(d,J=2.0Hz,2H),7.67(d,J=8.2Hz,3H),7.63(dd,J=8.4,2.1Hz,2H),7.38–7.27( m,7H),7.16(d,J=6.2Hz,2H),7.15–7.09(m,3H),4.42(d,J=5.9Hz,4H),2.64(t,J=4.7Hz,7H),2.38(s,7H),2.33(s,5H),2.21(s,5H).

[0103] Example 2

[0104] N-(4-Fluorobenzyl)-3-((4-ethylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0105] 4-Ethylbenzenesulfonyl chloride (0.739 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to prepare compound (2) to obtain 0.22 g of a white solid. The yield was 52.2%.

[0106] The experimental data are as follows:

[0107] 1H NMR (300MHz, Methanol-d4) δ7.97(d,J=4.5Hz,1H),7.72(d,J=8.0Hz,4H),7.58(dd,J=8.3,2.1Hz,1H),7.39–7.26(m,8H),7.2 7–7.13(m,1H),7.04(d,J=6.2Hz,1H),4.51(s,2H),3.03(s,1H),2.74(s,3H),2.69(s,2H),2.64(t,2H),1.18(t,J=7.1Hz,3H).

[0108] Example 3

[0109] N-(4-Fluorobenzyl)-3-((4-cyanophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0110] 4-Cyanobenzenesulfonyl chloride (0.741 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to prepare compound (3) to obtain 0.23 g of a white solid. The yield was 50.9%.

[0111] The experimental data are as follows:

[0112] 1 H NMR (300MHz, Methanol-d4) δ8.02(d,J=8.1Hz,1H),7.90(d,J=8.2Hz,1H),7.73(s,1H),7.65(d,J=8.1Hz,1H) ,7.33(t,J=7.0Hz,1H),7.24(d,J=8.3Hz,1H),7.05(t,J=8.6Hz,1H),4.49(s,1H),3.39(s,2H),3.08(s,2H).

[0113] Example 4

[0114] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0115] 4-Fluorobenzenesulfonyl chloride (0.736 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to prepare compound (4) to obtain 0.24 g of a white solid. Yield: 53.0%.

[0116] The experimental data are as follows:

[0117] 1H NMR (300MHz, Methanol-d4) δ7.93–7.85(m,1H),7.58(dd,J=8.3,2.1Hz,1H),7.34(dd,J=8.5,5.5Hz,1H),7.26– 7.16(m,1H),7.12(t,J=8.8Hz,0H),7.03(t,J=8.8Hz,1H),4.51(s,1H),2.72(s,1H),2.68(s,3H),2.42(s,2H).

[0118] Example 5

[0119] N-(4-Fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0120] 4-Chlorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to prepare compound (5) to obtain 0.23 g of a white solid. The yield was 52.6%.

[0121] The experimental data are as follows:

[0122] 1 H NMR (300MHz, Methanol-d4) δ7.92(s,1H),7.81(d,J=8.9Hz,2H),7.58(d,J=8.3Hz,1H),7.50(d,J=8.9Hz,2H),7.3 9–7.29(m,2H),7.18(d,J=8.4Hz,1H),7.04(t,J=8.8Hz,2H),4.51(s,3H),2.71(s,3H),2.58(s,3H),2.36(s,3H).

[0123] Example 6

[0124] N-(4-Fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0125] 4-Bromobenzenesulfonyl chloride (0.738 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to prepare compound (6) to obtain 0.22 g of a white solid. The yield was 51.8%.

[0126] The experimental data are as follows:

[0127] 1H NMR (300MHz, Methanol-d4) δ7.85 (s, 1H), 7.66 (d, J = 8.3Hz, 1H), 7.59–7.46 (m, 1H), 7.30–7.20 (m, 1H) ),7.09(d,J=8.4Hz,0H),6.95(t,J=8.7Hz,1H),4.43(s,1H),2.64(s,1H),2.52(s,2H),2.29(s,1H).

[0128] Example 7

[0129] N-(4-Fluorobenzyl)-3-((4-methoxyphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0130] 4-Methoxybenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to prepare compound (7) to obtain 0.22 g of a white solid. Yield: 51.8%.

[0131] The experimental data are as follows:

[0132] 1 H NMR (300MHz, Methanol-d4) δ8.03(d,J=2.1Hz,1H),7.79(d,J=8.9Hz,2H),7.58(dd,J=8.3,2.1Hz,1H),7.39(dd,J=8.4,5.6Hz,2H),7 .22(d,J=8.3Hz,1H),7.08(t,J=8.8Hz,2H),7.00(d,J=8.9Hz,2H),4.55(s,2H),3.83(s,3H),2.68(s,2H),2.61(s,4H),2.38(s,3H).

[0133] Example 8

[0134] N-(4-Fluorobenzyl)-3-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonamido)-4-(4-methylpiperazine-1)benzamide

[0135] 2,3-dihydro-1,4-benzodioxy-6-sulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (8) to obtain 0.21 g of a white solid with a yield of 50.7%. The experimental data are as follows:

[0136] 1H NMR (300MHz, Methanol-d4) δ7.99(d,J=2.3Hz,1H),7.58(dd,J=8.2,2.2Hz,1H),7.42–7.30(m,2H),7.29(dd,J=8.4,2.3Hz,1H),7. 21(d,J=8.3Hz,1H),7.06(t,J=8.7Hz,2H),6.89(d,J=8.5Hz,1H),4.53(s,2H),4.25(s,2H),2.69(s,3H),2.61(s,6H),2.38(s,3H).

[0137] Example 9

[0138] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(3-oxopiperazin-1-yl)benzamide

[0139] 2-Piperazinone (0.738 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (9) to obtain 0.21 g of a white solid with a yield of 51.1%. The experimental data are as follows:

[0140] 1 H NMR (300MHz, DMSO-d6) δ9.17(t,J=6.0Hz,1H),8.42(d,J=2.2Hz,1H),8.07(dd,J=8.9,2.2Hz,1H),7.40–7.29(m,3 H),7.14(t,J=8.9Hz,1H),4.45(d,J=5.7Hz,1H),4.02(s,1H),3.92–3.79(m,1H),3.52–3.42(m,1H),2.45(s,2H).

[0141] Example 10

[0142] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)-benzamide

[0143] 4-Ethylpiperazine (0.737 mmol) was used to replace 4-methylphenylpiperazine in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (10) to obtain 0.22 g of a white solid with a yield of 51.8%. The experimental data are as follows:

[0144] 1H NMR (300MHz, Methanol-d4) δ7.87(d,J=2.1Hz,1H),7.63(d,J=8.3Hz,2H),7.49(dd,J=8.3,2.1Hz,1H),7.31–7.25(m,1H),7.22(d,J=8.1H z,2H),7.12(t,J=8.9Hz,2H),6.98(t,J=8.8Hz,2H),4.44(s,2H),2.78(s,5H),2.69(t,J=5.9Hz,5H),2.28(s,3H),1.14(t,J=7.3Hz,3H).

[0145] Embodiment 11

[0146] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzamide

[0147] 4-Fluorobenzenesulfonyl chloride (0.736 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 10, and the other steps were carried out according to the preparation method in Example 1 to obtain compound (11) to obtain 0.21 g of a white solid with a yield of 51.8%. The experimental data are as follows:

[0148] 1 H NMR (300MHz, Methanol-d4) δ7.99–7.89(m,1H),7.61(d,J=8.2Hz,0H),7.41–7.34(m,1H),7.25(q,J=8.2Hz,1H ),7.08(t,J=8.5Hz,1H),4.55(s,1H),2.77(s,1H),2.68(s,3H),2.59(q,J=7.3Hz,1H),1.18(t,J=7.2Hz,1H).

[0149] Example 12

[0150] N-(4-Fluorobenzyl)3-((4-cyanophenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)-benzamide

[0151] 4-Cyanobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 10. The other steps were carried out according to the preparation method in Example 1 to obtain compound (12) as a white solid (0.21 g). The yield was 51.9%. The experimental data are as follows:

[0152] 1H NMR (300MHz, Methanol-d4) δ8.01(d,J=8.2Hz,1H),7.94(d,J=8.3Hz,0H),7.88(d,J=8.2Hz,1H),7.77(d,J=9.6Hz,1H),7.62(d,J=8.3Hz, 1H),7.36–7.30(m,1H),7.20(d,J=8.4Hz,0H),7.04(t,J=8.8Hz,1H),4.49(s,1H),3.16(s,1H),3.09–2.95(m,3H),1.30(t,J=7.3Hz,1H).

[0153] Embodiment 13

[0154] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0155] 4-Isopropylpiperazine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (14) as a white solid (0.22 g). The yield was 52.3%. The experimental data are as follows:

[0156] 1 H NMR (300MHz, Methanol-d4) δ7.91(d,J=2.1Hz,1H),7.69(t,J=8.7Hz,3H),7.55(dd,J=8.3,2.1Hz,1H),7.38–7.25(m,4H),7.17(dd,J= 10.8,8.2Hz,2H),7.03(t,J=8.8Hz,2H),4.50(s,2H),3.26–3.12(m,1H),3.06(s,2H),2.84(s,3H),2.34(s,3H),1.26(d,J=6.6Hz,7H).

[0157] Embodiment 14

[0158] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0159] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to obtain compound (15) to obtain 0.24 g of a white solid with a yield of 54.0%. The experimental data are as follows:

[0160] 1H NMR (300MHz, Methanol-d4) δ7.92(dd,J=8.9,5.0Hz,1H),7.88–7.80(m,1H),7.60(dd,J=8.3,2.1Hz,1H),7.33(dd,J=8.5,5.6Hz,1H),7.26(t,J=8.7Hz,1 H),7.20(d,J=8.4Hz,0H),7.12(t,J=8.8Hz,0H),7.04(t,J=8.8Hz,1H),4.50 (s,1H),3.49–3.34(m,0H),3.28(s,1H),3.01(s,1H),1.35(d,J=6.6Hz,3H).

[0161] Embodiment 15

[0162] N-(4-Fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0163] 4-Chlorobenzenesulfonyl chloride (0.738 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to obtain compound (16) to obtain 0.21 g of a white solid with a yield of 50.8%. The experimental data are as follows:

[0164] 1 H NMR(300MHz, Methanol-d4)δ7.84(s,1H),7.65(dd,J=16.4,7.3Hz,3H),7.52(s,1H),7.41–7.29(m,1H),7.19(d, J=8.9Hz,1H),7.04(t,J=8.5Hz,1H),4.50(s,1H),3.31(s,1H),3.21(s,1H),2.97(s,1H),1.33(d,J=6.6Hz,3H).

[0165] Example 16

[0166] N-(4-Fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0167] 4-Bromobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to obtain compound (17) as a white solid (0.22 g). The yield was 51.9%. The experimental data are as follows:

[0168] 1H NMR(300MHz, Methanol-d4)δ7.92(s,1H),7.78(d,J=8.5Hz,4H),7.69(d,J=8.4Hz,4H),7.60(t,J=9.1Hz,2H),7.41–7.33(m, 3H),7.20(d,J=8.3Hz,2H),7.07(t,J=8.6Hz,4H),4.54(s,4H),2.95(p,J=6.5Hz,1H),2.84(s,14H),1.21(d,J=6.5Hz,12H).

[0169] Embodiment 17

[0170] N-(4-Fluorobenzyl)-3-((3,4-difluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0171] 3,4-difluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to prepare compound (18) to obtain 0.21 g of a white solid. Yield: 51.4%.

[0172] The experimental data are as follows:

[0173] 1H NMR (300MHz, Methanol-d4) δ7.84(ddd,J=9.7,7.3,2.2Hz,1H),7.78(d,J=2.1Hz,1H),7.71(d,J=8.7Hz,1H),7.60(dd,J=8.3,2.1Hz,1H),7.49–7.38(m,1H) ,7.33(dd,J=8.5,5.4Hz,1H),7.19(d,J=8.4Hz,1H),7.04(t,J=8.8Hz,1H),4. 50(s,1H),3.22–3.13(m,1H),3.06(s,1H),2.98(s,1H),1.27(d,J=6.5Hz,4H).

[0174] Embodiment 18

[0175] N-(4-Fluorobenzyl)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0176] 4-Trifluoromethylbenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to obtain compound (19) as a white solid (0.22 g). The yield was 51.8%. The experimental data are as follows:

[0177] 1H NMR (300MHz, Methanol-d4) δ8.02(d,J=8.2Hz,2H),7.88(d,J=2.1Hz,1H),7.82(d,J=8.3Hz,1H),7.59(dd,J=8.3,2.1Hz,1H),7.3 8–7.29(m,1H),7.15(d,J=8.4Hz,1H),7.04(t,J=8.8Hz,1H),4.51(s,2H),2.89–2.70(m,4H),2.67(s,1H),1.13(d,J=6.5Hz,4H).

[0178] Embodiment 19

[0179] N-(4-Fluorobenzyl)-3-(naphthalene-2-sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0180] 4-Naphthylbenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to obtain compound (20) as a white solid (0.22 g). The yield was 50.7%. The experimental data are as follows:

[0181] 1H NMR (300MHz, Methanol-d4) δ8.41(s,1H),7.99(s,1H),7.94–7.81(m,1H),7.74(d,J=8.5Hz,0H),7.63–7.52(m,1H),7.50(d,J=8.4Hz,1H),7.3 4–7.23(m,2H),7.07(d,J=8.3Hz,1H),6.98(t,J=8.7Hz,1H),4.46(s,2 H),2.67–2.59(m,1H),2.54(s,2H),2.50(s,3H),1.01(d,J=6.4Hz,4H).

[0182] Embodiment 20

[0183] N-(4-Fluorobenzyl)-3-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonamido)-4-(4-isopropylpiperazine-1)benzamide

[0184] 2,3-dihydro-1,4-benzodioxy-6-sulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 14. The other steps were carried out according to the preparation method in Example 1 to obtain compound (21) to obtain 0.21 g of a white solid with a yield of 51.7%. The experimental data are as follows:

[0185] 1H NMR(300MHz,Chloroform-d)δ7.88(s,1H),7.55(d,J=8.2Hz,1H),7.36–7.28(m,4H),7.17(d,J=8.3Hz,2H),7.02 (t,J=8.5Hz,3H),6.84(d,J=8.5Hz,2H),4.58(s,3H),4.24(d,J=6.1Hz,4H),2.71(s,13H),1.14(d,J=6.5Hz,9H).

[0186] Embodiment 21

[0187] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-(tert-butyl)piperazin-1-yl)benzamide

[0188] 4-tert-butylpiperazine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (22) as a white solid (0.22 g). The yield was 51.8%. The experimental data are as follows:

[0189] 1 H NMR (300MHz, Methanol-d4) δ7.94(d,J=2.1Hz,1H),7.71(d,J=8.3Hz,2H),7.55(dd,J=8.3,2.1Hz,1H),7.38–7.31(m,1H),7.28( d,J=8.1Hz,2H),7.15(d,J=8.3Hz,1H),7.04(t,J=8.8Hz,2H),4.51(s,2H),2.89(s,3H),2.78(s,1H),2.35(s,3H),1.21(s,8H).

[0190] Embodiment 22

[0191] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-(tert-butyl)piperazin-1-yl)benzamide

[0192] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 22. The other steps were carried out according to the preparation method in Example 1 to obtain compound (23) to obtain 0.23 g of a white solid with a yield of 52.8%. The experimental data are as follows:

[0193] 1H NMR(300MHz, Methanol-d4)δ7.89–7.82(m,1H),7.53(dd,J=8.3,2.1Hz,0H),7.31(t,J=6.0Hz,1H),7.2 0(t,J=8.7Hz,1H),7.13(d,J=8.4Hz,1H),7.01(t,J=8.8Hz,1H),4.47(s,1H),2.76(s,3H),1.14(s,3H).

[0194] Embodiment 23

[0195] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide

[0196] 4-Methyl homopiperazine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (24) as a white solid (0.22 g). The yield was 51.8%. The experimental data are as follows:

[0197] 1 H NMR (300MHz, Methanol-d4) δ7.68(d,J=8.2Hz,1H),7.62(dd,J=8.5,2.1Hz,1H),7.48(d,J=2.1Hz,1H),7.32(dd,J=8.5,4.8Hz,2H),7.20(dd,J=8.3,4.9H z,1H),7.05(t,J=8.8Hz,1H),4.48(s,1H),3.63–3.52(m,1H),3.45(t,J=5.1 Hz,1H),3.11(t,J=6.0Hz,1H),3.00(s,2H),2.37(s,2H),2.25–2.15(m,1H).

[0198] Embodiment 24

[0199] N-(4-Fluorobenzyl)-3-((4-ethylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide

[0200] 4-Ethylbenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 24. The other steps were carried out according to the preparation method in Example 1 to prepare compound (25) to obtain 0.21 g of a light yellow solid. Yield: 50.9%.

[0201] The experimental data are as follows:

[0202] 1H NMR (400MHz, Methanol-d4) δ7.75 (s, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.66 (d, J = 2.1Hz, 1H), 7.56(dd,J=8.4,2.2Hz,1H),7.35(s,1H),7.33(t,J=4.2Hz,2H),7.30(s,1H),7.25(d,J=8. 2Hz,1H),7.15(d,J=8.4Hz,1H),7.04(t,J=8.8Hz,2H),4.48(s,2H),3.29(s,5H),3.02(t,J =6.0Hz,2H),2.82(s,3H),2.66(qd,J=7.6,2.2Hz,4H),2.04(p,J=5.8Hz,2H),1.20(t,3H).

[0203] Embodiment 25

[0204] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide

[0205] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 24. The other steps were carried out according to the preparation method in Example 1 to prepare compound (26) to obtain 0.22 g of a light yellow solid. Yield: 51.5%.

[0206] The experimental data are as follows:

[0207] 1H NMR(300MHz, Methanol-d4)δ7.77(dd,J=7.8,4.3Hz,1H),7.52(d,J=8.5Hz,1H),7.36(s,1H),7.26–7.13(m,2H),7.12–7.04(m,1H) ,6.97(t,J=8.2Hz,1H),4.39(s,1H),3.43(d,J=4.8Hz,1H),3.38(s,2H),3.09(t,J=6.2Hz,1H),2.86(s,2H),2.08(t,J=5.8Hz,1H).

[0208] Embodiment 26

[0209] N-(4-Fluorobenzyl)-3-((2-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide

[0210] Substituting 2-fluorobenzenesulfonyl chloride (0.737 mmol) for 4-methylbenzenesulfonyl chloride in step (d) of Example 24, the other steps were carried out according to the preparation method in Example 1 to prepare compound (27) to obtain 0.22 g of a light yellow solid. Yield: 52.7%.

[0211] The experimental data are as follows:

[0212] 1H NMR(300MHz, Methanol-d4)δ7.99–7.90(m,1H),7.53(d,J=2.2Hz,1H),7.51–7.42(m,1H),7.34–7.25(m,1H),7.24–7.19(m,1H) ,7.18–7.10(m,1H),7.08–6.96(m,1H),4.44(s,1H),3.36–3.24(m,2H),3.14(t,J=5.8Hz,1H),2.85(s,1H),2.04–1.88(m,1H).

[0213] Embodiment 27

[0214] N-(4-Fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide

[0215] 4-Chlorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 24. The other steps were carried out according to the preparation method in Example 1 to prepare compound (28) to obtain 0.23 g of a light yellow solid. Yield: 53.0%.

[0216] The experimental data are as follows:

[0217] 1H NMR (300MHz, Methanol-d4) δ7.96(d,J=8.6Hz,1H),7.80(d,J=2.2Hz,1H),7.62(d,J= 8.6Hz,1H),7.56(dd,J=8.3,2.1Hz,1H),7.47(dd,J=8.5,5.5Hz,1H),7.23(d,J=2.2H z,1H),7.19(d,J=8.8Hz,1H),4.64(s,2H),3.37(t,J=6.0Hz,1H),3.29(t,J=5.8Hz,1 H), 3.22 (d, J = 5.9Hz, 1H), 3.15 (t, J = 5.7Hz, 1H), 2.84 (s, 2H), 2.07 (h, J = 5.3Hz, 2H).

[0218] Embodiment 28

[0219] N-(4-Fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide

[0220] 4-Bromobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 24. The other steps were carried out according to the preparation method in Example 1 to prepare compound (29) to obtain 0.23 g of a light yellow solid. Yield: 53.6%.

[0221] The experimental data are as follows:

[0222] 1H NMR (300MHz, Methanol-d4) δ7.74(d,J=8.6Hz,1H),7.66(d,J=8.7Hz,1H),7.63–7.54(m,1H),7.52(dd,J=8.4,2.1Hz,0H),7.34(dd,J=8.5,5.5Hz,1H),7.09 (q,J=8.6Hz,1H),4.50(s,1H),3.34(tt,J=4.1,2.3Hz,2H),3.25(t,J=5.4Hz, 1H),3.18(t,J=5.9Hz,1H),2.84(s,1H),2.12–1.99(m,1H),1.52–1.25(m,1H).

[0223] Embodiment 29

[0224] N-(4-Fluorobenzyl)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide

[0225] 4-Trifluoromethylbenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 24. The other steps were carried out according to the preparation method in Example 1 to obtain compound (30) to obtain 0.22 g of a light yellow solid with a yield of 52.4%. The experimental data are as follows:

[0226] 1H NMR(300MHz, Methanol-d4)δ8.02(t,J=6.5Hz,2H),7.83(d,J=8.3Hz,2H),7.75 (d,J=8.2Hz,1H),7.56–7.49(m,1H),7.37–7.26(m,1H),7.13(d,J=8.9Hz,1H), 7.05(t,J=8.8Hz,1H),4.48(s,2H),3.42(d,J=4.5Hz,1H),3.34(dt,J=3.3,1.7 Hz,1H),3.22(t,J=6.0Hz,2H),2.93(s,2H),2.10(t,J=5.6Hz,1H),1.31(s,1H).

[0227] Embodiment 30

[0228] N-(4-Fluorobenzyl)-3-((4-cyanophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide

[0229] 4-Cyanobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 24. The other steps were carried out according to the preparation method in Example 1 to prepare compound (31) to obtain 0.22 g of a light yellow solid. Yield: 52.2%.

[0230] The experimental data are as follows:

[0231] 1H NMR (300MHz, Methanol-d4) δ7.95(d,J=8.5Hz,1H),7.80(d,J=8.5Hz,1H),7.44(d,J=2.1Hz,1H),7.40(dd,J=8.3,2.1Hz,1H),7.32–7.24(m ,1H),7.06(d,J=3.7Hz,1H),7.05–7.00(m,1H),4.45(s,1H),3.40–3.34(m,1H),3.31(t,J=1.6Hz,1H),3.24(t,J=6.0Hz,1H),2.89(s,2H).

[0232] Embodiment 31

[0233] N-(2-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide

[0234] 2-methylbenzylamine (0.737 mmol) was used to replace 4-methylbenzylamine in step (a) of Example 24. The other steps were carried out according to the preparation method in Example 1 to obtain compound (32) to obtain 0.21 g of a light yellow solid with a yield of 51.3%. The experimental data are as follows:

[0235] 1H NMR (300MHz, Methanol-d4) δ7.73(d,J=2.1Hz,1H),7.69(d,J=8.1Hz,3H),7.47(dd,J= 8.4,2.1Hz,1H),7.31(d,J=8.1Hz,1H),7.26(d,J=8.2Hz,2H),7.17–7.10(m,1H),7.08( d,J=8.2Hz,2H),4.56(s,3H),3.15(t,J=5.7Hz,2H),3.02(d,J=5.8Hz,2H),2.98(d,J=6 .6Hz,2H),2.94(d,J=6.5Hz,2H),2.61(s,4H),2.33(s,4H),1.89(p,J=6.8,5.9Hz,3H).

[0236] Embodiment 32

[0237] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperidin-1-yl)benzamide

[0238] 4-Methylpiperazine in step (b) of Example 1 was replaced with 4-methylpiperidine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (33) to obtain 0.21 g of a white solid with a yield of 51.3%. The experimental data are as follows:

[0239] 1 H NMR(300MHz,Chloroform-d)δ7.90(d,J=2.0Hz,1H),7.68(d,J=8.1Hz,2H),7.54( dd,J=8.3,2.0Hz,1H),7.32(dd,J=8.4,5.5Hz,2H),7.18(d,J=8.0Hz,2H),7.10(d ,J=8.3Hz,1H),7.03(t,J=8.6Hz,2H),4.59(d,J=5.8Hz,2H),2.50(d,J=7.8Hz,4H ),2.35(s,3H),1.67(d,J=12.0Hz,2H),1.42–1.20(m,3H),0.99(d,J=6.3Hz,3H).

[0240] Embodiment 33

[0241] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-cyclopropylpiperazin-1-yl)benzamide

[0242] 4-Cyclopropylpiperazine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (34) as a white solid (0.21 g). The yield was 51.5%. The experimental data are as follows:

[0243] 1 H NMR (300MHz, DMSO-d6) δ8.87(s,1H),7.69(d,J=25.9Hz,4H),7.25(d,J=27.7Hz,5H),7. 02(s,3H),4.30(s,2H),3.29(s,5H),2.50(s,6H),1.53(s,1H),0.24(d,J=39.3Hz,4H).

[0244] Embodiment 34

[0245] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzamide

[0246] 2,8-diazaspiro[4,5]decane-1-one (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (34) to obtain 0.21 g of a white solid with a yield of 51.5%. The experimental data are as follows:

[0247] 1H NMR(300MHz,Methanol-d4)δ7.98(d,J=2.1Hz,1H),7.66(d,J=8.3Hz,2H),7.48( dd,J=8.3,2.1Hz,1H),7.30(dd,J=8.5,5.5Hz,2H),7.21(d,J=8.1Hz,2H),7.14(d ,J=8.3Hz,1H),6.99(t,J=8.8Hz,1H),4.47(d,J=4.0Hz,2H),2.52(d,J=8.3Hz,2H ),2.27(s,3H),2.03(t,J=6.9Hz,2H),1.97–1.83(m,1H),1.40(d,J=10.4Hz,2H).

[0248] Embodiment 35

[0249] N-(3-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0250] 2-Fluorobenzylamine (0.737 mmol) was used to replace 4-fluorobenzylamine in step (a) of Example 1. The other steps were followed by the preparation method in Example 1 to obtain compound (37) as a white solid with a yield of 0.23 g: 54.8%. The experimental data are as follows:

[0251] 1H NMR (300MHz, Methanol-d4) δ7.98(d,J=2.1Hz,1H),7.70(d,J=8.0Hz,2H),7.56(dd,J=8.3,2.1Hz,1H),7.39–7.33(m,1H),7.29(d,J=8.2 Hz,2H),7.17(dd,J=11.6,8.1Hz,2H),7.06(d,J=9.7Hz,1H),6.99(t,J=8.6Hz,1H),4.54(s,2H),2.64(s,2H),2.55(s,5H),2.35(s,7H).

[0252] Embodiment 36

[0253] N-(3,5-difluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0254] 3,5-difluorobenzylamine (0.737 mmol) was used to replace 4-fluorobenzylamine in step (a) of Example 1. The other steps were followed by the preparation method in Example 1 to obtain compound (38) to obtain 0.22 g of a white solid with a yield of 51.5%. The experimental data are as follows:

[0255] 1H NMR (300MHz, Methanol-d4) δ8.01(d,J=2.1Hz,1H),7.75(d,J=8.1Hz,2H),7.62(dd,J=8.3,2.1Hz,1H),7.33(d,J=8.0Hz,2H ),7.24(d,J=8.4Hz,1H),6.96(d,J=6.2Hz,1H),6.87(t,J=9.1Hz,1H),4.57(s,2H),2.75(s,8H),2.50(s,3H),2.38(s,3H).

[0256] Embodiment 37

[0257] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-benzylpiperidin-1-yl)-benzamide

[0258] 4-Benzylpiperidine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (39) as a white solid (0.20 g). The yield was 50.0%. The experimental data are as follows:

[0259] 1H NMR(300MHz,Chloroform-d)δ7.90(d,J=2.0Hz,1H),7.69(d,J=8.3Hz,2H),7.52(dd ,J=8.2,2.1Hz,1H),7.32(d,J=6.3Hz,2H),7.21–7.11(m,3H),7.07(d,J=8.3Hz,1H) ,7.01(t,J=8.6Hz,2H),6.56(t,J=5.8Hz,1H),4.57(d,J=5.7Hz,2H),2.59(d,J=6.6 Hz,2H),2.55–2.38(m,3H),2.33(s,3H),1.68(d,J=11.9Hz,2H),1.51–1.24(m,1H).

[0260] Embodiment 38

[0261] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-benzylpiperidin-1-yl)-benzamide

[0262] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 39. The other steps were carried out according to the preparation method in Example 1 to obtain compound (40) as a white solid (0.22 g). The yield was 51.4%. The experimental data are as follows:

[0263] 1H NMR (300MHz, Chloroform-d) δ7.92(d,J=1.9Hz,1H),7.83(dd,J=8.8,5.1Hz,2H),7.52(d,J=6.2Hz,1H),7.30(d,J=7.7Hz,3H),7.16(d,J=8.4Hz,1H),7.10( s,1H),7.03(dd,J=17.1,8.6Hz,3H),6.56(d,J=5.9Hz,1H),4.58(d,J=5.6Hz, 2H),2.60(d,J=6.6Hz,2H),2.52(s,5H),1.77–1.62(m,5H),1.50–1.22(m,2H).

[0264] Embodiment 39

[0265] N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-cyclohexylpiperazin-1-yl)-benzamide

[0266] 4-Methylpiperazine in step (b) of Example 1 was replaced with 4-cyclohexylpiperazine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (41) to obtain 0.22 g of a white solid with a yield of 52.3%. The experimental data are as follows:

[0267] 1H NMR(300MHz,Chloroform-d)δ7.91(s,1H),7.69(d,J=8.0Hz,2H),7.53(d,J=6.1Hz ,1H),7.35–7.28(m,1H),7.20(d,J=7.9Hz,2H),7.14(d,J=8.3Hz,1H),7.02(t,J=8. 6Hz,2H),6.58(t,J=5.9Hz,1H),4.58(d,J=5.7Hz,2H),2.69(s,5H),2.61(s,3H),2. 38(s,1H),1.87(dd,J=18.6,9.5Hz,6H),1.66(d,J=11.4Hz,1H),1.38–1.03(m,2H).

[0268] Embodiment 40

[0269] N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-cyclohexylpiperazin-1-yl)-benzamide

[0270] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 41. The other steps were carried out according to the preparation method in Example 1 to obtain compound (42) to obtain 0.22 g of a white solid with a yield of 51.9%. The experimental data are as follows:

[0271] 1H NMR (300MHz, Chloroform-d) δ7.92 (s, 1H), 7.82 (dd, J = 8.7, 4.9Hz, 3H), 7.52 (d, J = 8. 2Hz,1H),7.34–7.29(m,3H),7.14(d,J=8.3Hz,1H),7.08(t,J=8.4Hz,2H),7.01(t,J= 8.5Hz,2H),6.67(t,J=5.9Hz,1H),4.57(d,J=5.6Hz,3H),2.64(s,4H),2.61(s,6H),2 .30(t,J=9.4Hz,2H),1.94–1.75(m,10H),1.65(d,J=11.2Hz,2H),1.44–1.24(m,2H).

[0272] Embodiment 41

[0273] N-(4-Trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0274] 4-Trifluoromethylbenzylamine (0.737 mmol) was used to replace 4-methylbenzylamine in step (a) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (43) as a white solid (0.22 g). The yield was 51.3%. The experimental data are as follows:

[0275] 1H NMR (300MHz, Methanol-d4) δ8.04(d,J=2.1Hz,1H),7.77(d,J=8.3Hz,2H),7.71–7.64(m,3H),7.57(d,J=8.1Hz,2H ),7.35(d,J=8.0Hz,2H),7.27(d,J=8.3Hz,1H),4.68(s,2H),3.00(s,1H),2.82(s,2H),2.68(s,3H),2.41(s,3H).

[0276] Embodiment 42

[0277] N-(4-Trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzamide

[0278] 4-Methylpiperazine in step (b) of Example 43 was replaced with 4-ethylpiperazine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (44) as a white solid with a yield of 0.23 g: 53.1%. The experimental data are as follows:

[0279] 1H NMR(300MHz, Methanol-d4)δ7.99(s,1H),7.71(d,J=7.9Hz,3H),7.67–7.56(m,4H),7.51(d,J=8.0Hz,3H),7.2 8(d,J=7.9Hz,3H),7.20(d,J=9.4Hz,2H),4.62(s,3H),2.85–2.64(m,20H),2.34(s,6H),1.19(t,J=7.2Hz,4H).

[0280] Embodiment 43

[0281] N-(4-Trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0282] 4-Isopropylpiperazine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 44. The other steps were carried out according to the preparation method in Example 1 to obtain compound (45) as a white solid (0.21 g). The yield was 50.8%. The experimental data are as follows:

[0283] 1H NMR (300MHz, Methanol-d4) δ7.98(d,J=2.1Hz,1H),7.70(d,J=8.0Hz,2H),7.56(dd,J=8.3,2.1Hz,1H),7.39–7.33(m,1H),7.29(d,J=8.2 Hz,2H),7.17(dd,J=11.6,8.1Hz,2H),7.06(d,J=9.7Hz,1H),6.99(t,J=8.6Hz,1H),4.54(s,2H),2.64(s,2H),2.55(s,5H),2.35(s,7H).

[0284] Embodiment 44

[0285] N-(4-(Trifluoromethyl)benzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide

[0286] 4-Isopropylpiperazine in step (b) of Example 45 was replaced with 4-methylhomopiperazine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (46) to obtain 0.20 g of a light yellow solid with a yield of 49.2%. The experimental data are as follows:

[0287] 1H NMR (300MHz, Methanol-d4) δ7.70–7.63(m,1H),7.62(d,J=6.6Hz,1H),7.50(d,J=2.1Hz,0H),7.47(d,J=8.1Hz,1H),7.30(d,J=8.0Hz,1H),7.19 (d,J=8.4Hz,0H),4.57(s,1H),3.62–3.50(m,1H),3.45(d,J=5.1Hz,1H) ,3.10(t,J=6.1Hz,1H),2.98(s,1H),2.34(s,1H),2.19(q,J=5.8Hz,1H).

[0288] Embodiment 45

[0289] N-(4-trifluoromethyl)benzyl)-3-((4-methylphenyl)sulfonamido)-4-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzamide

[0290] 2,8-diazaspiro[4,5]decane-1-one (0.737 mmol) was used to replace 4-isopropylpiperazine in step (b) of Example 45, and the other steps were followed by the preparation method in Example 1 to obtain compound (46) to obtain 0.22 g of a white solid with a yield of 51.8%. The experimental data are as follows:

[0291] 1H NMR(300MHz, Methanol-d4)δ8.06(d,J=2.0Hz,1H),7.72(d,J=6.4Hz,1H),7.63( d,J=8.1Hz,2H),7.56(dd,J=8.3,2.1Hz,1H),7.52(d,J=8.1Hz,2H),7.26(d,J=8. 1Hz,2H),7.20(d,J=8.3Hz,1H),4.62(s,2H),3.39–3.26(m,2H),2.62–2.53(m,3H ),2.33(s,3H),2.09(t,J=6.9Hz,2H),2.02–1.90(m,1H),1.46(d,J=12.7Hz,2H).

[0292] Embodiment 46

[0293] N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0294] 4-Fluorobenzylamine in step (a) of Example 1 was replaced with 4-fluoro-α-methylbenzylamine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (48) to obtain 0.21 g of a white solid with a yield of 50.5%. The experimental data are as follows:

[0295] 1H NMR (300MHz, Methanol-d4) δ7.95(d,J=2.1Hz,1H),7.69(d,J=8.3Hz,1H),7.56(dd,J=8.3,2.1Hz,1H),7.40(dd,J=8.6,5.5Hz,1H),7.28(d,J= 8.0Hz,1H),7.17(d,J=8.3Hz,1H),7.05(t,J=8.8Hz,1H),5.20(q,J=7.0Hz,1H),2.63(s,2H),2.55(s,2H),2.35(s,4H),1.54(d,J=7.1Hz,2H).

[0296] Embodiment 47

[0297] N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide

[0298] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 49. The other steps were carried out according to the preparation method in Example 1 to obtain compound (50) as a white solid (0.22 g). The yield was 51.8%. The experimental data are as follows:

[0299] 1H NMR (300MHz, Methanol-d4) δ7.95(d,J=2.0Hz,1H),7.92(d,J=5.2Hz,1H),7.64(dd,J=8.4,2.1Hz,1H),7.45(dd,J=8.5,5.5Hz,1H) ,7.26(q,J=8.4Hz,2H),7.10(t,J=8.8Hz,1H),5.25(q,J=7.0Hz,1H),2.75(s,1H),2.62(s,1H),2.40(s,2H),1.59(d,J=7.0Hz,2H).

[0300] Embodiment 48

[0301] N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0302] 4-Isopropylpiperazine (0.737 mmol) was used to replace 4-methylpiperazine in step (b) of Example 50. The other steps were carried out according to the preparation method in Example 1 to obtain compound (51) to obtain 0.22 g of a white solid with a yield of 51.7%. The experimental data are as follows:

[0303] 1H NMR (300MHz, Methanol-d4) δ7.85(d,J=2.1Hz,1H),7.62(d,J=8.3Hz,1H),7.47(dd,J=8.3,2.1Hz,1H),7.32(dd,J=8.5,5.5Hz,1H),7.20(d,J=8.1H z,2H),7.09(d,J=8.3Hz,1H),6.97(t,J=8.8Hz,1H),5.12(q,J=7.0Hz,1H ),2.58(s,6H),2.27(s,2H),1.46(d,J=7.1Hz,2H),1.04(d,J=6.5Hz,3H).

[0304] Embodiment 49

[0305] N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide

[0306] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 51. The other steps were carried out according to the preparation method in Example 1 to obtain compound (51) as a white solid (0.22 g). The yield was 51.1%. The experimental data are as follows:

[0307] 1H NMR(300MHz, Methanol-d4)δ7.90(d,J=5.1Hz,1H),7.88–7.83(m,1H),7.57(dd,J=8.3,2.1Hz,1H),7.39(dd,J=8.5,5.5Hz,1H),7.23(t,J=8.7Hz,1H),7. 17(d,J=8.4Hz,1H),7.05(t,J=8.8Hz,1H),5.19(q,J=7.0Hz,1H),2.74(dd,J =6.3,3.1Hz,3H),2.69(s,1H),1.54(d,J=7.0Hz,2H),1.13(d,J=6.4Hz,3H).

[0308] Embodiment 50

[0309] N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide

[0310] 4-Isopropylpiperazine in step (b) of Example 51 was replaced with 4-methylhomopiperazine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (53) to obtain 0.23 g of a light yellow solid with a yield of 52.2%. The experimental data are as follows:

[0311] 1H NMR (300MHz, Methanol-d4) δ7.72–7.61(m,2H),7.53(d,J=8.0Hz,1H),7.36(dd,J=8.6 ,5.5Hz,1H),7.27(d,J=8.1Hz,2H),7.20(d,J=7.9Hz,1H),7.11(d,J=8.2Hz,1H),7.04( t,J=8.8Hz,1H),5.14(q,J=7.0Hz,1H),3.28–3.15(m,3H),3.05(t,J=6.0Hz,2H),2.77 (s,2H),2.34(s,4H),2.05–1.94(m,1H),1.50(d,J=7.0Hz,2H),1.32(d,J=21.9Hz,1H).

[0312] Embodiment 51

[0313] N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide

[0314] Substituting 4-fluorobenzenesulfonyl chloride (0.737 mmol) for 4-methylbenzenesulfonyl chloride in step (d) of Example 53, the other steps were carried out by referring to the preparation method in Example 1 to prepare compound (54) to obtain 0.21 g of a light yellow solid. Yield: 50.8%.

[0315] The experimental data are as follows:

[0316] 1H NMR (300MHz, Methanol-d4) δ7.85 (dd, J=8.9, 5.1Hz, 1H), 7.58 (d, J=2.1Hz, 1H), 7.42 (dd, J=8 .3,2.1Hz,1H),7.35(dd,J=8.5,5.5Hz,1H),7.18(t,J=8.7Hz,1H),7.07(d,J=1.9Hz,1H),7.0 5–6.99(m,1H),5.15(q,J=7.0Hz,1H),3.20(t,J=5.9Hz,1H),3.11(t,J=5.9Hz,1H),3.01(t,J =5.9Hz,1H),2.95(t,J=5.6Hz,1H),2.64(s,2H),1.90(p,J=6.6Hz,2H),1.50(d,J=7.1Hz,2H).

[0317] Embodiment 52

[0318] N-(4-Fluorobenzyl)-3-(2-fluorobenzamide)-4-(4-methylpiperazin-1-yl)benzamide

[0319] 2-Fluorobenzoyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 1. The other steps were carried out according to the preparation method in Example 1 to obtain compound (55) as a white solid (0.21 g). The yield was 50.8%. The experimental data are as follows:

[0320] 1 H NMR (300MHz, Methanol-d4) δ9.77(s,1H),8.96(d,J=5.7Hz,1H),8.22(d,J=1.9Hz,1H),7.79(d,J=7.5Hz,1H),7.65(d,J=9.9Hz,1H),7.60– 7.46(m,1H),7.40–7.26(m,2H),7.26–7.15(m,1H),7.09(s,1H),4.62–4.51(m,2H),3.31–3.13(m,4H),3.09(d,J=5.8Hz,1H),2.51(s,3H).

[0321] Embodiment 53

[0322] N-(4-Fluorobenzyl)-3-benzamide-4-(4-methylpiperazin-1-yl)benzamide

[0323] The 2-fluorobenzoyl chloride in step (d) of Example 55 was replaced with benzoyl chloride (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (56) as a white solid with a yield of 0.20 g: 49.9%. The experimental data are as follows:

[0324] 1H NMR(300MHz, DMSO-d6)δ9.08(s,1H),8.03(d,J=10.6Hz,1H),7.92(d,J=8.1Hz,4H),7.83(s,1H),7.51–7.29(m,7H ),7.19(t,J=8.8Hz,4H),4.50(s,1H),3.98(s,3H),3.66(s,2H),2.50(d,J=8.2Hz,8H),2.41(s,5H),1.91(s,5H).

[0325] Embodiment 54

[0326] N-(5-(4-Benzylpiperidin-1-carbonyl)-2-(4-isopropylpiperazin-1-yl)phenyl)-4-methylbenzenesulfonamide

[0327] 4-Benzylpiperidine (0.737 mmol) was used to replace 4-fluorobenzylamine in step (a) of Example 14, and the other steps were followed by the preparation method in Example 1 to obtain compound (57) as a white solid (0.22 g) with a yield of 51.8%. The experimental data are as follows:

[0328] 1 H NMR(300MHz, Methanol-d4)δ7.82(dd,J=8.8,5.2Hz,3H),7.39(d,J=1.9Hz,2H),7.21( d,J=4.0Hz,3H),7.19(d,J=2.3Hz,3H),7.16(d,J=3.7Hz,1H),7.12(d,J=7.1Hz,4H),7 .07(d,J=8.1Hz,1H),4.50(s,2H),3.55(s,0H),2.80–2.69(m,1H),2.65(s,16H),2.53 (d,J=7.0Hz,5H),1.89–1.47(m,2H),1.39(s,1H),1.23(s,1H),1.08(d,J=6.5Hz,13H).

[0329] Embodiment 55

[0330] N-(5-(4-Benzylpiperidin-1-carbonyl)-2-(4-isopropylpiperazin-1-yl)phenyl)-4-fluorobenzenesulfonamide

[0331] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 57. The other steps were carried out according to the preparation method in Example 1 to obtain compound (58) as a white solid (0.23 g). The yield was 52.9%. The experimental data are as follows:

[0332] 1 H NMR(300MHz, Methanol-d4)δ7.82(dd,J=8.8,5.2Hz,3H),7.39(d,J=1.9Hz,2H),7.21( d,J=4.0Hz,3H),7.19(d,J=2.3Hz,3H),7.16(d,J=3.7Hz,1H),7.12(d,J=7.1Hz,4H),7 .07(d,J=8.1Hz,1H),4.50(s,2H),3.55(s,0H),2.80–2.69(m,1H),2.65(s,16H),2.53 (d,J=7.0Hz,5H),1.89–1.47(m,2H),1.39(s,1H),1.23(s,1H),1.08(d,J=6.5Hz,13H).

[0333] Embodiment 56

[0334] N-(5-(4-Benzylpiperidin-1-carbonyl)-2-(4-methyl-1,4-diazepin-1-yl)phenyl)-4-fluorobenzenesulfonamide

[0335] 4-Isopropylpiperazine in step (b) of Example 57 was replaced by 4-methylhomopiperazine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (59) to obtain 0.21 g of a light yellow solid with a yield of 51.1%. The experimental data are as follows:

[0336] 1H NMR(300MHz,Methanol-d4)δ7.83(s,1H),7.22(s,1H),7.13(s,3H),7.01(s,0H),3.41(s,2H),3.03(s,1H),2.88(s ,1H),2.53(s,1H),2.07(s,1H),1.66(d,J=77.6Hz,1H),1.33(d,J=47.5Hz,1H),1.10(s,1H),0.83(d,J=6.9Hz,1H).

[0337] Embodiment 57

[0338]

[0339] a)(4-Benzylpiperidin-1-yl)(4-chloro-3-nitrophenyl)methanone

[0340] At room temperature, HATU (1.5 g), DIEA (3 ml) and 4-(0.9 benzylpiperidine 2 g) dissolved in DCM were added to 4-chloro-3-nitrobenzoic acid (1 g) and 8 mL DCM, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, water was added for extraction. Purification by silica gel column chromatography gave 0.61 g of the title compound with a yield of 62.3%.

[0341] 1H NMR(300MHz,Chloroform-d)δ7.92(d,J=1.9Hz,1H),7.60(d,J=8.2Hz,1H),7.55(dd,J=8.3,1.9Hz,1H),7.35–7.25(m,3H),7.25–7.17(m,1H),7.1 7–7.09(m,2H),4.64(s,1H),3.64(s,1H),3.02(s,1H),2.75(s,1H),2.58 (d,J=6.9Hz,2H),1.93–1.56(m,3H),1.29(td,J=28.2,25.6,15.6Hz,2H).

[0342] b) (4-Benzylpiperidin-1-yl)(4-(4-isopropylpiperazin-1-yl)-3-nitrophenyl)methanone

[0343] At room temperature, (4-benzylpiperidin-1-yl)(4-chloro-3-nitrophenyl)methanone (0.6 g), 1-isopropylpiperazine (0.12 ml) and potassium carbonate (0.6 g) were dissolved in DMF (0.9 ml) and refluxed at 80°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water. The mixture was extracted three times with 20 mL of DCM. The organic phases were combined, dried over anhydrous Na2SO4, and dried under reduced pressure to obtain 0.6 g of the title compound with a yield of 89.7%.

[0344] 1H NMR(300MHz, Methanol-d4)δ7.87(d,J=2.1Hz,1H),7.60(dd,J=8.5,2.1Hz,1H),7.37–7.24(m,3H),7.24–7.15(m,3H),4.58(s,1H),3.78(s,1H), 3.34(p,J=1.6Hz,1H),3.17(dd,J=6.4,3.3Hz,4H),2.79–2.66(m,5H),2 .66(s,0H),1.98–1.55(m,3H),1.41–1.18(m,3H),1.14(d,J=6.5Hz,6H).

[0345] c)(3-amino-4-(4-isopropylpiperazin-1-yl)phenyl)(4-benzylpiperidin-1-yl)methanone

[0346] At room temperature, add 0.2 g of Pd / C to (4-benzylpiperidin-1-yl)(4-(4-isopropylpiperazin-1-yl)-3-nitrophenyl)methanone (0.6 g) and 4 mL of MeOH, and react at room temperature for 4 hours under hydrogen protection. After the reaction is completed, filter and dry the filtrate under reduced pressure to obtain 0.5 g of the title compound with a yield of 92.5%.

[0347] d) N-(5-(4-benzylpiperidin-1-carbonyl)-2-(4-isopropylpiperazin-1-yl)phenyl)-4-methylbenzenesulfonamide

[0348] At 0°C, (3-amino-4-(4-isopropylpiperazin-1-yl)phenyl)(4-benzylpiperidin-1-yl)methanone (0.5 g) was dissolved in 10 mL of pyridine, p-toluenesulfonyl chloride (0.4 g) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the mixture was dried under reduced pressure, extracted, and purified by silica gel column chromatography to obtain 0.22 g of the title compound and 0.22 g of a white solid, with a yield of 52.2%.

[0349] 1 H NMR(300MHz, Methanol-d4)δ7.82(dd,J=8.8,5.2Hz,3H),7.39(d,J=1.9Hz,2H),7.21( d,J=4.0Hz,3H),7.19(d,J=2.3Hz,3H),7.16(d,J=3.7Hz,1H),7.12(d,J=7.1Hz,4H),7 .07(d,J=8.1Hz,1H),4.50(s,2H),3.55(s,0H),2.80–2.69(m,1H),2.65(s,16H),2.53 (d,J=7.0Hz,5H),1.89–1.47(m,2H),1.39(s,1H),1.23(s,1H),1.08(d,J=6.5Hz,13H).

[0350] Embodiment 58

[0351]

[0352] 4-Fluorobenzenesulfonyl chloride (0.737 mmol) was used to replace 4-methylbenzenesulfonyl chloride in step (d) of Example 57. The other steps were carried out according to the preparation method in Example 1 to obtain compound (58) as a white solid (0.23 g). The yield was 52.8%. The experimental data are as follows:

[0353] 1H NMR(300MHz, Methanol-d4)δ7.82(dd,J=8.8,5.2Hz,3H),7.39(d,J=1.9Hz,2H),7.21( d,J=4.0Hz,3H),7.19(d,J=2.3Hz,3H),7.16(d,J=3.7Hz,1H),7.12(d,J=7.1Hz,4H),7 .07(d,J=8.1Hz,1H),4.50(s,2H),3.55(s,0H),2.80–2.69(m,1H),2.65(s,16H),2.53 (d,J=7.0Hz,5H),1.89–1.47(m,2H),1.39(s,1H),1.23(s,1H),1.08(d,J=6.5Hz,13H).

[0354] Embodiment 59

[0355]

[0356] 4-Isopropylpiperazine in step (b) of Example 57 was replaced by 4-methylhomopiperazine (0.737 mmol), and the other steps were followed by the preparation method in Example 1 to obtain compound (59) to obtain 0.22 g of a light yellow solid with a yield of 51.1%. The experimental data are as follows:

[0357] 1H NMR(300MHz,Methanol-d4)δ7.83(s,1H),7.22(s,1H),7.13(s,3H),7.01(s,0H),3.41(s,2H),3.03(s,1H),2.88(s ,1H),2.53(s,1H),2.07(s,1H),1.66(d,J=77.6Hz,1H),1.33(d,J=47.5Hz,1H),1.10(s,1H),0.83(d,J=6.9Hz,1H).

[0358] Embodiment 60

[0359] Dual luciferase drug screening assay - Evaluate the inhibitory effect of compounds on the nuclear transcription of PLAGL2.

[0360] Experimental principle:

[0361] A reporter system that uses luciferin as a substrate to detect firefly luciferase activity. Based on the binding of transcription factors to specific sequences in their target promoters, the expression of genes is inhibited or enhanced. In the fluorescent reporter gene experiment, the promoter sequence recognized by PLAGL2 is inserted into the reporter gene plasmid in front of the luciferase expression sequence. If there is a PLAGL2 inhibitor in the system, PLAGL2 cannot activate the target promoter, the luciferase activity is inhibited, and the luciferin oxidation reaction cannot occur.

[0362] In the experiment: green fluorescent protein plasmid ZsGreen, firefly luciferase reporter plasmid MPL containing platelet growth factor promoter sequence, sea cucumber luciferase plasmid RLN, membrane protein expression plasmid PVSV-G, packaging plasmid packaging plasmids and recombinant reporter gene plasmid PLAGL2-ZsGreen were purchased from Novagen. PLAGL2-ZsGreen is a promoter sequence recognized by PLAGL2 inserted in front of the luciferase expression sequence. The vector name is: PLVX-IRES-ZsGreen1, and the vector plasmid map is shown in Figure 1 MPL is a firefly luciferase reporter plasmid containing the platelet growth factor promoter sequence. The vector name is: MPL pGL3-Basic. The vector plasmid map can be found at Figure 2 .

[0363] Experimental steps: Digest and count the 293T cells in the logarithmic growth phase and plate them on two 10 cm dishes (1×10 6 / dish), culture for 12 hours until adhered. Dilute 10ug plasmid in dish one (the mass ratio of ZsGreen, MPL and RLN is 1:3:1) and 10ug plasmid in dish two (the mass ratio of PLAGL2-ZsGreen, MPL and RLN is 1:3:1) into 200uL JetPrime buffer, mix well, add 4uL JetPrime, and vortex for 10 seconds. Then incubate for 10min at 37℃, 5% CO2, and 100% saturated humidity. Add 200pl of transfection solution to each dish, shake well and put it in the incubator. Measure transfection efficiency according to Vazyme Dual Luciferase Reporter AssayKit (Cat.DL101-01). Plate 96-well plates (5000 cells / 100uL complete medium per well) and incubate for 24h under the same conditions. Prepare 10uM drug solution with blank culture medium and administer for 24h. The inhibition rate was determined and calculated according to Vazyme Dual Luciferase Reporter Assay Kit (Cat. DL101-01).

[0364] Table 1 Experimental results

[0365]

[0366] The results showed that the above 14 compounds exhibited a good inhibitory effect on PLAGL2 transcription factor at a concentration of 10 μM.

[0367] Embodiment 61

[0368] MST affinity assay - testing the affinity of compounds for PLAGL2

[0369] Experimental steps: 293T stable transfectants were constructed by PLAGL2-ZsGreen plasmid and plasmid containing only ZsGreen. The membrane protein expression plasmid (PVSV-G), packaging plasmid (packaging plasmids), and plasmid containing PLAGL2-ZsGreen (purchased from Norvegant) were mixed and added to 293T cells, incubated at 37°C, 5% CO2, and 100% saturated humidity for 6 hours, and 12 ml of fresh DMEM culture medium containing 10wt% FBS was added, and cultured for 24 hours to obtain transfected 293T cells. In addition, the membrane protein expression plasmid (PVSV-G), packaging plasmid (packaging plasmids), and plasmid containing only ZsGreen (purchased from Norvegant) were transfected into 293T cells in the same manner as a control. After 24 hours of transfection, the culture medium was replaced with DMEM complete culture medium containing 10wt% FBS and cultured for 48 hours. All supernatants of cultured cells were collected and centrifuged at 4°C, 500rpm for 10 minutes to remove floating cells and their debris. After centrifugation, the supernatant was filtered with a 0.45μm PVDF filter to obtain a lentiviral stock solution. 293T cells were plated in a 24-well plate. After 24 hours, fresh culture medium was replaced, virus solution was added, and cultured at 37°C for 12 hours. The culture medium containing virus solution was replaced with fresh culture medium. The culture was continued for two weeks, and the fluorescence expression was observed under a fluorescence microscope to obtain PLAGL2-ZsGreen plasmid and 293T stable transfected strains containing only ZsGreen plasmid. Phosphate buffered saline (PBST) (0.05% Tween20) with 2% DMSO was used to buffer the gradient dilution of compounds to maintain the DMSO constant in the system. The supernatant of the protein lysate diluted with PBST was added. After thorough mixing, the samples were collected by capillary tube sampling and detected by micro-thermophoresis (MST) NT.115. The results are shown in Table 2.

[0370] Table 2 Experimental results

[0371] Example 1 Example 10 Example 4 Embodiment 14 Embodiment 25 Kd(nm) 171.89 228.12 601.28 426.91 156.32 S / N 9.3 12.2 33.9 8.4 44.1

[0372] The results showed that the above compounds showed good affinity to PLAGL2 transcription factor.

[0373] Embodiment 62

[0374] Experimental procedures: The flanks of 6-week-old BALB / c nude mice were inoculated with LM3 cells (2×10 6 When the tumor volume reaches 100mm 3 At 4 pm, the mice were randomly divided into 4 groups, 6 in each group, and treatment was started. DMSO, the compound of Example 1 (5 mg / kg, 30 mg / kg) and sorafenib (30 mg / kg) in a 0.9% saline solution were intraperitoneally injected once a day. Body weight was recorded once a day, and tumor volume (tumor volume V (mm)) was recorded every two days. 3 )=length (mm)×width (mm)) / 2). When the tumor volume reaches 2000mm 3 At 4 pm, the mice were killed, dissected, and the tumor weights were calculated. The results are shown in Table 3.

[0375] Table 3 Experimental results

[0376] Tumor inhibition rate DMSO (30 mg / kg) - Example 1 (5 mg / kg) 45.83％ Example 1 (30 mg / kg) 47.34％ Sorafenib (30 mg / kg) 43.09％

[0377] “-” in the table indicates no tumor inhibition rate.

[0378] The above pharmacological data show that the compound of Example 1 of the present invention exhibits a higher tumor inhibition effect than the positive drug Sorafenib.

[0379] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. An N-benzyl-3-phenylamide compound, characterized in that: Selected from: N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonylamino)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-ethylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-cyanophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-methoxyphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonamido)-4-(4-methylpiperazine-1)benzamide N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)-benzamide N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)3-((4-cyanophenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)-benzamide N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((2,3-dihydrobenzo[b][1,4]dioxin)-6-sulfonamido)-4-(4-isopropylpiperazine-1)benzamide N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-ethylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((2-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-chlorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-bromophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-(trifluoromethyl)phenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-cyanophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperidin-1-yl)benzamide N-(4-Fluorobenzyl)-3-((4-methylphenyl)sulfonamido)-4-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzamide N-(4-Trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(4-Trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-ethylpiperazin-1-yl)benzamide N-(4-Trifluoromethylbenzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(4-(Trifluoromethyl)benzyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide N-(4-trifluoromethyl)benzyl)-3-((4-methylphenyl)sulfonamido)-4-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzamide N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methylpiperazin-1-yl)benzamide N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-isopropylpiperazin-1-yl)benzamide N-(1-(4-fluorophenyl)ethyl)-3-((4-methylphenyl)sulfonamido)-4-(4-methyl-1,4-diazepan-1-yl)benzamide N-(1-(4-fluorophenyl)ethyl)-3-((4-fluorophenyl)sulfonamido)-4-(4-methyl-1,4-diazepin-1-yl)benzamide N-(4-fluorobenzyl)-3-benzamide-4-(4-methylpiperazin-1-yl)benzamide.

2. A pharmaceutical composition, characterized in that It comprises the N-benzyl-3-phenylamide compound as claimed in claim 1 and pharmaceutically acceptable excipients.

3. Use of the N-benzyl-3-phenylamide compound according to claim 1 in the preparation of a drug for treating PLAGL2-mediated diseases, characterized in that: The PLAGL2-mediated disease is a malignant tumor; the malignant tumor is liver cancer, breast cancer, colorectal cancer, gastric cancer or prostate cancer.

4. Use of the N-benzyl-3-phenylamide compound according to claim 1 in the preparation of a PLAGL2 inhibitor.

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