Compound for FBXO44 inhibitor, composition and application thereof

Abstract

The invention discloses a polysubstituted amine compound, a pharmaceutical composition containing the polysubstituted amine compound and an application of the polysubstituted amine compound in tumor resistance. The structure of the polysubstituted amine compound is shown as a formula I in the specification. Through multiple experiments, the inventor of the invention proves that the compound disclosed by the invention has a remarkable inhibiting effect on FBXO44, and can be combined with the FBXO44 in cells to inhibit down-regulation of the FBXO44 on MTSS1, so that the formation of tumor cell microfilament skeletons is disturbed, and the compound has a strong anti-proliferation effect on gastric cancer cell strains such as NUGC4 and the like. Therefore, the compound disclosed by the invention can be used as an FBXO44 inhibitor to be applied to medicines for treating solid tumors or leukemia related to human or animal cell proliferation.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a compound for use as an inhibitor of E3 ubiquitin ligase FBXO44 and its application. Background Technology

[0002] Adenocarcinoma of the esophagogastric junction (AEG) refers to adenocarcinoma within a 5cm range above and below the esophagogastric junction (EGJ). Along with esophageal and gastric cancer, it is classified as an upper gastrointestinal malignancy and is one of the most important health problems worldwide. In recent years, the incidence and mortality rates of AEG have ranked among the highest of all malignant tumors and are showing an upward trend. Asia is a high-incidence region for AEG, with East Asia and Southeast Asia accounting for as much as 59% of new cases globally. The incidence of AEG in my country is also on the rise, with a median overall survival (OS) of <13 months. The standard treatment for early-stage AEG is surgical resection. However, due to the lack of effective early screening methods, the proportion of early-stage AEG in my country remains <20%, and most AEG patients are diagnosed at an advanced stage, resulting in a poor prognosis. For locally advanced or unresectable tumors, preoperative and postoperative chemotherapy is usually used. In clinical treatment, in addition to surgery and radiotherapy / chemotherapy, targeted drugs (HER2-targeting antibody-drug conjugate Enhertu) and immunotherapy drugs (pembrolizumab) have shown certain clinical efficacy. However, due to its high spatiotemporal heterogeneity, targeted and immunotherapeutic drugs for AEG remain scarce and urgently require further development. Due to the lack of precision diagnostic methods, the 5-year survival rate for AEG patients is only 20-25%, lower than that for esophageal and gastric cancer patients. Therefore, constructing an effective molecular subtyping system for AEG, identifying and validating potential drug targets and prognostic biomarkers, and subsequently developing targeted therapies is one of the most pressing clinical needs.

[0003] Genomic changes translate into changes at the protein level, thereby affecting phenotype, and protein function can be further regulated through post-translational modifications. Therefore, the application of proteomics and various modified proteomics in tumor molecular subtyping is receiving increasing attention. In tumor mechanism research, comparing proteomic differences between normal and tumor tissues to identify specific protein molecules, constructing prognostic molecular subtyping, and discovering molecular targets for new drug design and molecular biomarkers for early diagnosis is a widely used research approach. The applicant previously conducted a multidimensional integrated analysis combining genomics, transcriptomics, proteomics, and phosphorylated proteomics based on clinical samples of AEG. Combined with pathological phenotypes, prognostic information, and confirmatory experiments, a novel molecular subtyping of AEG was preliminarily established, identifying several genes closely related to patient survival. Among them, high expression of FBXO44 was most strongly correlated with poor patient prognosis. Mechanistic studies showed that FBXO44 promotes abnormalities in the RAC1 signaling pathway in AEG tumors by degrading MTSS1, leading to microfilament cytoskeleton abnormalities and thus mediating tumor development and progression. However, no active molecules that directly intervene in FBXO44 have been reported in the literature. Therefore, research on FBXO44 inhibitors is expected to yield novel and highly specific anti-AEG lead molecules, which has important research significance and application value. Summary of the Invention

[0004] This invention relates to pharmaceutically active compounds and their pharmaceutically acceptable salts, which can be used to treat malignant tumors.

[0005] This invention provides a compound as shown in general formula I:

[0006]

[0007] and its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein:

[0008] R0 is selected from H, amino, substituted or unsubstituted aliphatic rings, aliphatic heterocycles, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, and C1-C4 alkoxy groups.

[0009] R2 and R3 are independently selected from H, -(CH2)-Y, -(C=O)-Y, -(S=O)-Y, -(SO2)-Y, or R2 and R3 are linked together to form a substituted aromatic heterocycle;

[0010] Where Y is selected from H, substituted or unsubstituted aromatic rings, aromatic heterocyclic rings, fused rings, and fused heterocyclic rings;

[0011] Ring A is selected from substituted or unsubstituted aromatic rings, aromatic heterocyclic rings, fused rings, and fused heterocyclic rings;

[0012] X is selected from

[0013] Furthermore, the preferred compounds of the present invention have the structure shown in general formula II:

[0014]

[0015] And its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein the substituents are defined as in general formula 1;

[0016] R1 is selected from H, substituted or unsubstituted aromatic rings, aromatic heterocycles, fused rings, fused heterocycles, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, and C1-C4 alkoxy groups.

[0017] Furthermore, according to the present invention, the preferred compounds have the structure shown in general formula III or III':

[0018]

[0019] and its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein the substituents are defined as in general formula I:

[0020] R4 is selected from H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy.

[0021] B and Z are independently selected from CH and N, respectively. When B or Z has a substitution, B or Z is C.

[0022] The C ring is selected from five-membered aromatic rings or aromatic heterocyclic rings, six-membered aromatic rings or aromatic heterocyclic rings.

[0023] Furthermore, according to the present invention, the preferred compounds have the structure shown in general formula IV or IV':

[0024]

[0025] and its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein the substituents are defined as in general formula I:

[0026] M is selected from N, NH, S, and O. Furthermore, in general formula IV, C is selected from N. In general formula IV', C is selected from NH, S, and O.

[0027] As a further preferred option, R0 is selected from H, substituted or unsubstituted aliphatic rings, aliphatic heterocycles, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, and C1-C4 alkoxy groups.

[0028] R1 is selected from H, substituted or unsubstituted aromatic rings, aromatic heterocycles, fused rings, fused heterocycles, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, and C1-C4 alkoxy groups.

[0029] R 2，R3 is independently selected from H, -(CH2)-Y, -(C=O)-Y, -(S=O)-Y, and -(SO2)-Y;

[0030] Where Y is selected from H, substituted or unsubstituted aromatic rings, aromatic heterocyclic rings, fused rings, and fused heterocyclic rings;

[0031] X is selected from

[0032] R4 is selected from H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy.

[0033] B and Z are independently selected from CH and N, respectively.

[0034] C is selected from NH, S, and O.

[0035] Furthermore, the R0 is selected from amino, 3-6 alkyl, 3-8 heteroalkyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, and the above substituents may be further replaced by Boc, C1-C5 alkyl acyl, C1-C5 acyl with C=C or C≡C, Boc-NH-, C1-C5 alkyl acyl amino with C=C or C≡C, and 4-8 N or O hybridized heteroalkyl.

[0036] R2 and R3 are independently selected from H, 4-8 membered aromatic rings, benzoyl group or -(CH2)n-CH Y1Y2, where n is 0, 1 or 2, and Y1 and Y2 are independently selected from H, 4-8 membered aromatic rings, 4-8 membered aromatic rings or 4-10 membered aromatic heterocycles, wherein the aromatic ring or aromatic heterocycle may be further substituented by C1-C3 alkyl group, C1-C3 alkoxy group or benzene ring; or R2 and R3 are linked together to form a substituted 3-6 membered aromatic heterocycle, wherein there are one or more substituents selected from benzene ring;

[0037] Ring A is selected from 5-7 membered aromatic rings and 5-7 membered aromatic heterocycles, wherein the heteroatom in the aromatic heterocycle is one or more N atoms;

[0038] R1 is selected from H, C1-C4 alkoxycarbonyl, C1-C5 hydrocarbon acyl with carbon-carbon double or triple bonds, and 4-8 heteroalkyl.

[0039] As a preferred embodiment, R1 is selected from tert-butoxycarbonyl, H, allyl, ynylbutyryl, and pyridyl.

[0040] As a specific preferred embodiment, R2 and R3 are independently selected from benzyl, benzothiophene-substituted methyl, indole-substituted methyl, methoxy-substituted benzothiophene-substituted methyl, thiophene-substituted methyl, methyl-substituted indole-substituted methyl, naphthiophene-substituted methyl, phenyl-substituted furanyl-substituted methyl, methyl, phenyl, pyridine-substituted methyl, H, diphenyl-substituted methyl, dibenzyl-substituted methyl, indole-substituted ethyl, and benzoyl.

[0041] As a specific preferred embodiment, ring A is a benzene ring, a pyridine ring, or a pyrimidine ring. Preferably, R0 and X occur at the para or meta position of ring A.

[0042] More specifically, the preferred compound of the present invention is:

[0043] 4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1)

[0044] 1-(dibenzylamino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol(2)

[0045] 1-(4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazin-1-yl)prop-2-en-1-one(3)

[0046] 1-(4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazin-1-yl)pent-4-yn-1-one(4)

[0047] 1-(4-aminophenoxy)-3-(dibenzylamino)prop-2-ol (5)

[0048] N-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)acrylamide (6)

[0049] 4-(3-(dibenzylamino)-2-hydroxypropoxy)benzyl)tert-butyl carbamate (7)

[0050] N-(4-(3-(dibenzylamino)-2-hydroxypropoxy)benzyl)acrylamide (8)

[0051] 1-(dibenzylamino)-3-(3-(piperazin-1-yl)phenoxy)prop-2-ol (9)

[0052] N,N-Dibenzyl-2-methoxy-3-(4-(piperazin-1-yl)phenoxy)propyl-1-amine (10)

[0053] 1-(dibenzylamino)-3-(4-(4-(piperidin-4-yl)piperazin-1-yl)phenoxy)prop-2-ol(11)

[0054] 1-(dibenzylamino)-3-((6-(piperazin-1-yl)pyridin-3-yl)oxy)prop-2-ol(12)

[0055] 1-(dibenzylamino)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)prop-2-ol(13)

[0056] 1-(2,5-Diphenyl-1H-pyrrolo-1-yl)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (14)

[0057] 1-((benzo[b]thiophene-6-ylmethyl)(benzyl)amino)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (15)

[0058] 1-(((1H-indol-6-yl)methyl)(benzyl)amino)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (16)

[0059] 1-(benzyl((5-methoxybenzo[b]thiophen-2-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (17)

[0060] 1-(benzyl(thieno[3,2-b]thieno-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (18)

[0061] 1-(benzyl((1-methyl-1H-indol-6-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (19)

[0062] 1-(benzyl(naphthyl-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (20)

[0063] 1-(benzyl((5-phenylfuran-2-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (21)

[0064] 1-(benzyl(methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (22)

[0065] 1-(benzyl(phenyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (23)

[0066] 1-(bis(pyridin-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (24)

[0067] 1-(phenylhydrazineamino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (25)

[0068] 1-((1,3-diphenylprop-2-yl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (26)

[0069] 1-((2-(1H-indol-3-yl)ethyl)(benzyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (27)

[0070] N-Benzyl-N-(2-hydroxy-3-(4-(piperazin-1-yl)phenoxy)propyl)benzamide (28)

[0071] 2-(Dibenzylamino)-N-(4-(piperazin-1-yl)phenyl)acetamide (29)

[0072] 2-(Dibenzylamino)-N-(4-(piperazin-1-yl)benzyl)acetamide (30)

[0073] and its optical isomers or pharmaceutically acceptable salts or solvates thereof

[0074] More specifically, the preferred compound of the present invention is:

[0075]

[0076]

[0077] This invention utilizes methods well-known to those skilled in the art to prepare salts of the substituted piperidine-nitrogen heterocyclic compounds described herein. The salts can be organic acid salts, inorganic acid salts, etc., including citric acid salts, fumarates, oxalates, malates, lactates, camphor sulfonates, p-toluene sulfonates, methanesulfonates, etc.; and inorganic acid salts including hydrohalates, sulfates, phosphates, nitrates, etc. For example, they can form methanesulfonates and trifluoromethanesulfonates with lower alkyl sulfonic acids, such as methanesulfonic acid and trifluoromethanesulfonic acid; they can form p-toluene sulfonates and benzene sulfonates with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; they can form corresponding salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, or citric acid; and they can form glutamate or aspartate salts with amino acids, such as glutamic acid or aspartic acid. It can also form corresponding salts with inorganic acids, such as hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid, or phosphoric acid.

[0078] A second object of the present invention is to provide a pharmaceutical composition comprising at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients. The active ingredient may be any one or more of the following: the compound of the present invention, an optical isomer of the compound, a pharmaceutically acceptable salt of the compound or its optical isomer, or a solvate of the compound or its optical isomer. Further, the amount of the active ingredient added is a therapeutically effective amount.

[0079] The carrier includes conventional pharmaceutical diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbents, lubricants, etc. Flavoring agents, sweeteners, etc., may also be added if necessary. The drug of this invention can be formulated into various forms such as tablets, powders, granules, capsules, oral liquids, and injections. All of the above dosage forms can be prepared according to conventional pharmaceutical methods.

[0080] This invention also provides the use of compounds of formulas (I) to (IV), their optical isomers, or pharmaceutically acceptable salts or solvates thereof in the preparation of antitumor drugs. The tumors mentioned include neuroblastoma, breast cancer, sarcoma, lung cancer, prostate cancer, colon cancer, rectal cancer, kidney cancer, thyroid cancer, leukemia, glioma, head cancer, neck cancer, thyroid cancer, pancreatic cancer, liver cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, gastrointestinal stromal carcinoma, skin cancer, and multiple myeloma.

[0081] This invention also provides the use of the compounds described herein, their optical isomers, or pharmaceutically acceptable salts or solvates thereof, in the preparation of FBXO44 inhibitors, particularly in the preparation of medicaments for treating proliferative diseases, including cancer. In other words, this invention provides the use of the compounds or their pharmaceutically acceptable salts, alone or in combination with other drugs, in the treatment of proliferative diseases (such as cancer). Antitumor drugs that can be used in combination with the compounds provided by this invention or their pharmaceutically acceptable salts include, but are not limited to, at least one of the following: mitotic inhibitors (such as vinblastine, vindesine, and vinorelbine); microtubule degradation inhibitors (such as paclitaxel); alkylating agents (such as cisplatin, carboplatin, and cyclophosphamide); antimetabolites (5-fluorouracil, terbufos, methotrexate, cytarabine, and hydroxyurea); intercalable antibiotics (such as areopyram, mitomycin, and bleomycin); enzymes (such as aspartase); topoisomerase inhibitors (such as etoposide and camptothecin); biological response modifiers (such as interferon); and proteasome inhibitors (such as bortezomib).

[0082] Through multiple experiments, the inventors of this invention have confirmed that the compound of this invention has a significant inhibitory effect on FBXO44. It can bind to the FBXO44 protein at the protein or cellular level, inhibiting the degradation of MTSS1 by FBXO44, and exhibits potent anti-proliferative effects against gastric cancer cells NUGC4, MKN1, MKN74, and AZ521. Therefore, the compound of this invention can be used as an FBXO44 inhibitor in the treatment of human or animal cell proliferation-related solid tumors or hematological malignancies. Attached Figure Description

[0083] Figure 1 MST technology was used to test the binding affinity between compound DQ2405 and FBXO44;

[0084] Figure 2 (A) HEK293T cells were co-transfected with FBXO44 and MTSS1, and the interaction between FBXO44 and MTSS1 was detected by Western blotting under given concentrations of DQ2405. (B) The interaction between FBXO44 and MTSS1 proteins was detected using purified FBXO44 and MTSS1 proteins in DQ2405 culture or without culture. (C) The effect of 5 μM DQ2405 treatment on actin filaments was analyzed using immunofluorescence.

[0085] Figure 3 Western blot was used to detect the protein levels of MTSS1, Rac1, NCKAP1, HSPC300, CYFIP2, ABI2, WAVE2 and β-actin in NUGC4 and AZ521 cells treated with a specified concentration of DQ2405.

[0086] Figure 4 Compound DQ2405 inhibits the growth of gastric cancer NUGC4 cell line xenograft tumors. (A) Display of tumor samples from CDX model mice; bar chart showing tumor weight (B) and volume (C) of collected CDX model samples; (D) Western blot analysis of FBXO44, MTSS1, Rac1, NCKAP1, HSPC300, CYFIP2, ABI2, WAVE2, and β-actin protein levels in tumor tissues of the CDX model control group and DQ2405 treatment group; (E) Immunohistochemistry analysis of E-Cadherin, Ki67, DAPI, and MTSS1 expression in tumor tissues of the CDX model control group and DQ2405 treatment group.

[0087] Figure 5Compound DQ2405 inhibits tumor growth in a gastric cancer PDX model. (A) A bar chart shows the tumor volume of samples collected from the PDX model; (B) A graph shows the weight changes of PDX model mice; (C) A display of tumor samples from PDX model mice; (D) A bar chart shows the tumor weight of samples collected from the PDX model. Detailed Implementation

[0088] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0089]

[0090]

[0091]

[0092] Route 1. Synthetic route of compound 3

[0093] Preparation Example 1. 4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (Compound 1) (L10)

[0094] Step 1. 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (1-2)

[0095] 4-(piperazin-1-yl)phenol (2.0 g, 11.2 mmol) was dissolved in dichloromethane (40 mL), and triethylamine (2.3 g, 22.4 mmol) was added under ice bath conditions. Then, di-tert-butyl dicarbonate (2.9 g, 13.4 mmol) was added dropwise. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was evaporated, and the mixture was poured into water and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. The solid was purified by column chromatography to give a white solid (1-2); ESI-MS: m / z = 279 [M+H] + .

[0096] Step 2.4-(4-(ethylene oxide-2-ylmethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1-3)

[0097] Intermediate 1-2 (2.0 g, 7.2 mmol) was dissolved in acetone, and potassium carbonate (3.0 g, 21.6 mmol) and epichlorohydrin (2.7 g, 28.8 mmol) were added sequentially. The mixture was stirred at 60 °C for 12 h. Potassium carbonate (3.0 g, 21.6 mmol) and epichlorohydrin (2.7 g, 28.8 mmol) were added again, and the mixture was stirred at 60 °C for another 12 h. After the reaction was complete, the mixture was poured into water and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. The solution was purified by column chromatography to give a white solid (1-3); ESI-MS: m / z = 335 [M+H]. + .

[0098] Step 3. 4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (compound 1) (L10)

[0099] Intermediate 1-3 (1 g, 3.0 mmol) was dissolved in anhydrous ethanol, and dibenzylamine (651.0 mg, 3.3 mmol) was added. The mixture was stirred at 70 °C for 12 h. After the reaction was completed, the solvent was evaporated and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. The mixture was purified by column chromatography to give a white solid (1-4), which is compound 1. 1 H NMR (400MHz, CDCl3) δ7.36–7.26(m,10H),6.89–6.84(m,2H),6.81–6.76(m,2H),4.09(dq,J=7.4,5.5Hz,1H),3.8 8–3.77(m,4H),3.62–3.50(m,6H),3.00(t,J=5.0Hz,4H),2.69–2.64(m,2H),1.49(s,9H).ESI-MS:m / z=532[M+H] + .

[0100] Preparation Example 2.1-(dibenzylamino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 2) (L5)

[0101] Steps 1-3 are the same as in Example 1;

[0102] Step 4. Dissolve compound 1 (100.0 mg, 0.2 mmol) in 0.5 mL of dichloromethane, add it dropwise to 2.0 mmol / L ethyl hydrochloride solution, stir at room temperature for 30 min, after the reaction is complete, evaporate the solvent, add saturated sodium bicarbonate solution, extract with ethyl acetate (3 × 50 mL), wash the organic phase with saturated brine (3 × 30 mL), dry with anhydrous sodium sulfate, remove the solvent to obtain white solid compound 2;1 H NMR(500MHz,DMSO-d6)δ7.37–7.28(m,8H),7.26–7.19(m,2H),6.86–6.79(m,2H ),6.74–6.67(m,2H),3.95(m,J=6.2,3.8Hz,1H),3.85(dd,J=9.9,3.9Hz,1H),3 .69–3.61(m,3H),3.53(d,J=13.7Hz,2H),2.91(dd,J=6.3,3.5Hz,4H),2.83(dd ,J=6.4,3.6Hz,4H),2.57(dd,J=13.1,6.5Hz,1H),2.46(dd,J=13.1,5.8Hz,1H). 13 C NMR (126MHz, DMSO-d6) δ152.16,146.03,139.28,128.61,128.12,126.78,117. 18,114.85,71.24,67.20,58.39,56.34,50.69,45.64.HRMS(ESI)(m / z):calcd for C 27 H 33 N3O2[M+H] + 432.2651, found 432.2656.

[0103] Preparation Example 3.1 -(4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazin-1-yl)prop-2-en-1-one (Compound 3) (L19)

[0104] Steps 1-4 are described in Example 2;

[0105] Step 5. Compound 2 (50.0 mg, 0.1 mmol) was dissolved in anhydrous dichloromethane, and triethylamine (30.3 mg, 0.3 mmol) was added. Acryloyl chloride (18.1 mg, 0.2 mmol) was added dropwise under ice bath conditions. The mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was evaporated and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Column chromatography yielded an oily liquid, compound 3. 1H NMR(500MHz, CDCl3)δ7.36–7.26(m,10H),6.89–6.84(m,2H),6.82–6.77(m,2H),6.6 0(dd,J=16.8,10.6Hz,1H),6.32(dd,J=16.8,1.9Hz,1H),5.72(dd,J=10.6,1.9Hz,1H ),4.09(q,J=6.8,6.4Hz,1H),3.86–3.78(m,6H),3.70(t,J=4.9Hz,2H),3.54(d,J=13 .3Hz,2H),3.06(dd,J=6.1,4.2Hz,4H),2.67(d,J=6.9Hz,2H).ESI-MS:m / z=486[M+H] + .

[0106] Preparation Example 4.1 -(4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazin-1-yl)pent-4-yn-1-one (Compound 4) (L17)

[0107]

[0108] Compound 2 (100.0 mg, 0.2 mmol) was dissolved in anhydrous DMF, and HATU (114.0 mg, 0.3 mmol), DIPEA (38.7 mg, 0.3 mmol), and 4-pentyneic acid (39.2 mg, 0.4 mmol) were added. The mixture was stirred at room temperature for 30 min. After the reaction was complete, the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Column chromatography yielded an oily liquid, compound 4; 1H NMR (500MHz, CDCl3) δ7.38–7.26(m,10H),6.88–6.83(m,2H),6.81–6.75(m,2H),4.11(dd,J=14.6,7.5Hz,1H),3.85–3.74(m,6H),3 .62(t,J=5.1Hz,2H),3.54(d,J=13.5Hz,2H),3.20(s,1H),3.04(dt,J=13.9,5.2Hz,4H),2.70–2.55(m,6H).ESI-MS:m / z=512[M+H] + .

[0109] Preparation Example 5. 1-(4-aminophenoxy)-3-(dibenzylamino)prop-2-ol (Compound 5) (L14)

[0110]

[0111] The synthesis steps are the same as in Example 2, with p-aminophenol used instead of compound 1-1 to prepare compound 5; 1 H NMR (400MHz, CDCl3) δ7.37–7.26(m,10H),7.17(d,J=8.5Hz,2H),6.81–6.77(m,2H),4.80(s,1H),4.23(d,J=5.9Hz,2H),4. 10(p,J=6.2Hz,1H),3.87–3.76(m,4H),3.55(d,J=13.4Hz,2H),2.68(d,J=6.7Hz,2H),1.46(s,9H).ESI-MS:m / z=363[M+H] + .

[0112] Preparation Example 6. N-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)acrylamide (compound 6) (L3)

[0113]

[0114] The synthesis steps are the same as in step 5 of Example 3, except that compound 5 is used instead of compound 2 to prepare compound 6; 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),7.49–7.43(m,2H),7.37–7.26(m,10H),6.81–6.75(m,2H),6.40(dd,J=16.9,1.4Hz,1H),6.24(dd,J=16.8,10.2H z,1H),5.72(dd,J=10.2,1.5Hz,1H),4.10(q,J=6.8Hz,1H),3.89–3.77(m, 4H),3.56(d,J=13.5Hz,2H),2.68(d,J=6.7Hz,2H).ESI-MS:m / z=417[M+H] + .

[0115] Preparation Example 7.4: 4-(3-(dibenzylamino)-2-hydroxypropoxy)benzyl)carbamate tert-butyl ester (Compound 7) (L11)

[0116]

[0117] The synthesis steps are the same as in Example 1, except that 4-hydroxybenzylamine was used instead of compound 1-1 to prepare compound 7; 1H NMR (400MHz, CDCl3) δ7.37–7.26(m,10H),7.17(d,J=8.5Hz,2H),6.81–6.77(m,2H),4.80(s,1H),4.23(d,J=5.9Hz,2H),4. 10(p,J=6.2Hz,1H),3.87–3.76(m,4H),3.55(d,J=13.4Hz,2H),2.68(d,J=6.7Hz,2H),1.46(s,9H).ESI-MS:m / z=477[M+H] + .

[0118] Preparation Example 8. N-(4-(3-(dibenzylamino)-2-hydroxypropoxy)benzyl)acrylamide (Compound 8) (L4)

[0119]

[0120] The synthesis steps are the same as in Example 3, except that 4-hydroxybenzylamine was used instead of compound 1-1 to prepare compound 8; 1 H NMR (400MHz, CDCl3) δ7.37–7.27(m,10H),7.22–7.15(m,2H),6.82–6.76(m,2H) ,6.31(dd,J=16.9,1.5Hz,1H),6.09(dd,J=17.0,10.3Hz,1H),5.87(s,1H),5.65 (dd,J=10.3,1.4Hz,1H),4.43(d,J=5.7Hz,2H),4.10(h,J=5.7Hz,1H),3.88–3. 78(m,4H),3.54(d,J=13.4Hz,2H),2.67(d,J=6.7Hz,2H).ESI-MS:m / z=431[M+H] + .

[0121] Preparation Example 9. 1-(dibenzylamino)-3-(3-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 9) (L33)

[0122]

[0123] The synthesis steps are the same as in Example 2, with compound 9 prepared by replacing compound 1-1 with m-hydroxyphenylpiperazine; 1H NMR(500MHz,DMSO-d6)δ7.37–7.33(m,4H),7.30(dd,J=8.4,6.7Hz,4H),7.25–7.20(m,2H),7.07(t ,J=8.1Hz,1H),6.49(dd,J=8.2,2.2Hz,1H),6.30–6.22(m,2H),4.84(s,1H),3.96(s,1H),3.88(dd ,J=9.8,3.8Hz,1H),3.69–3.63(m,3H),3.53(d,J=13.7Hz,2H),3.01–2.98(m,4H),2.84–2.79(m,4 H),2.57(dd,J=13.1,6.7Hz,1H),2.46(dd,J=13.1,5.8Hz,1H),1.23(s,1H).ESI-MS:m / z=432[M+H] + .

[0124] Preparation Example 10. N,N-Dibenzyl-2-methoxy-3-(4-(piperazin-1-yl)phenoxy)propyl-1-amine (Compound 10) (L44)

[0125]

[0126] Compound 1 (200.0 mg, 0.4 mmol) was dissolved in anhydrous tetrahydrofuran. Sodium hydride (28.8 mg, 1.2 mmol) was added in portions under ice bath conditions. After stirring for half an hour, potassium iodide (56.8 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, ice water was added dropwise to quench the reaction. The solvent was evaporated and the mixture was poured into water. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Column chromatography yielded a white solid. Then, following step 4 of Example 2, the Boc protecting group was removed to obtain compound 10. 1 H NMR(500MHz,DMSO-d6)δ7.36–7.29(m,8H),7.26–7.21(m,2H),6.86–6.81(m ,2H),6.72–6.68(m,2H),3.90(dd,J=10.4,3.5Hz,1H),3.74(dd,J=10.4,5.7 Hz,1H),3.65–3.53(m,5H),3.31(s,3H),2.91(dd,J=6.4,3.5Hz,4H),2.82(d d,J=6.3,3.5Hz,4H),2.61–2.52(m,2H),1.23(s,1H).ESI-MS:m / z=446[M+H] + .

[0127] Preparation Example 11. 1-(dibenzylamino)-3-(4-(4-(piperidin-4-yl)piperazin-1-yl)phenoxy)prop-2-ol (Compound 11) (L41)

[0128]

[0129] Preparation of intermediate 11-1: N-tert-butoxycarbonyl-4-piperidinone (1.0 g, 5 mmol) and compound 1-1 (890.0 mg, 5 mmol) were dissolved in anhydrous methanol and stirred at 50 °C for 6 h. Sodium borohydride (756.6 mg, 20 mmol) was added in portions, and the mixture was stirred at 50 °C for 12 h. After the reaction was complete, the solvent was evaporated and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Column chromatography yielded a white solid, intermediate 11-1, ESI-MS: m / z = 362 [M+H]. + .

[0130]

[0131] Preparation of compound 11: Referring to Example 2, compound 11 was prepared by replacing compound 1-2 with compound 11-1; 1 H NMR(500MHz,DMSO-d6)δ7.36–7.28(m,8H),7.25–7.20(m,2H),6.86–6.82(m,2H),6.72–6.67(m,2H),4 .83(d,J=4.8Hz,1H),3.94(s,1H),3.84(dd,J=9.9,3.8Hz,1H),3.68–3.60(m,3H),3.53(d,J=13.7Hz, 2H),3.00–2.92(m,6H),2.60(t,J=5.0Hz,4H),2.56(dd,J=13.1,6.6Hz,1H),2.47–2.36(m,3H),2.29– 2.20(m,1H),1.99(dt,J=17.0,7.1Hz,1H),1.70(d,J=12.0Hz,2H),1.23(s,1H).ESI-MS:m / z=515[M+H] + .

[0132] Preparation Example 12. 1-(dibenzylamino)-3-((6-(piperazin-1-yl)pyridin-3-yl)oxy)prop-2-ol (Compound 12) (L50)

[0133]

[0134] Preparation of intermediate 12-3: Compound 12-1 (10.0 g, 29.2 mmol), pinacol borate (22.3 g, 87.6 mmol), palladium acetate (217.0 mg, 0.9 mmol), and potassium acetate (8.6 g, 87.6 mmol) were dissolved in DMF, purged with nitrogen, and stirred at 85 °C for 12 h. After the reaction was complete, the solvent was evaporated and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and then... The solvent was removed and column chromatography yielded a white solid, intermediate 12-2. Intermediate 12-2 (1.0 g, 3.2 mmol) was dissolved in a 1:1 mixture of tetrahydrofuran and water. Sodium perborate tetrahydrate (4.0 g, 26.0 mmol) was added, and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was evaporated, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Column chromatography yielded a white solid, intermediate 12-3.

[0135] ESI-MS: m / z = 280 [M+H] + .

[0136]

[0137] Preparation of compound 12: Referring to Example 2, compound 12 was prepared by replacing compound 1-2 with compound 12-3; 1 H NMR(500MHz,DMSO-d6)δ7.77(d,J=3.0Hz,1H),7.35–7.32(m,4H),7.29(dd,J=8.3,6.7Hz,4H),7.25–7.2 0(m,2H),7.12(dd,J=9.1,3.1Hz,1H),6.74(d,J=9.1Hz,1H),3.95(qd,J=6.1,3.7Hz,1H),3.89(dd,J=9.9 ,3.7Hz,1H),3.70(dd,J=9.8,6.0Hz,1H),3.65(d,J=13.7Hz,2H),3.52(d,J=13.7Hz,2H),3.29–3.23(m,4 H),2.81–2.76(m,4H),2.57(dd,J=13.0,6.6Hz,1H),2.45(dd,J=13.0,5.8Hz,1H).ESI-MS:m / z=433[M+H] + .

[0138] Preparation Example 13. 1-(dibenzylamino)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)prop-2-ol (Compound 13) (L51)

[0139]

[0140] Referring to Example 12, compound 13 was prepared by replacing compound 12-1 with 5-bromo-2-(4-BOC-piperazin-1-yl)pyrimidine; 1 H NMR(500MHz,DMSO-d6)δ8.05(s,2H),7.36–7.32(m,4H),7.29(dd,J=8.3,6.7Hz,4 H),7.23–7.18(m,2H),3.93(qd,J=6.1,5.3,2.4Hz,2H),3.79–3.73(m,1H),3.65( d,J=13.7Hz,2H),3.57–3.53(m,4H),3.51(d,J=13.7Hz,2H),2.76–2.72(m,4H),2 .57(dd,J=13.0,6.5Hz,1H),2.44(dd,J=13.0,5.4Hz,1H).ESI-MS:m / z=434[M+H] + .

[0141] Preparation Example 14: 1-(2,5-diphenyl-1H-pyrrolo-1-yl)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (Compound 14) (L6)

[0142]

[0143] Step 1.2,5-Diphenyl-1H-pyrrole (14-2)

[0144] Compound 14-1 (850.0 mg, 3.6 mmol) and ammonium acetate (1.6 g, 20.3 mmol) were dissolved in acetic acid and stirred at 100 °C for 4 h. After the reaction was complete, the mixture was filtered and washed to obtain a light pink solid (14-2); ESI-MS: m / z = 220 [M+H] + .

[0145] Step 2.2 - [(4-(trifluoromethyl)phenoxy)methyl]ethylene oxide (14-4)

[0146] Referring to step 2 of Example 1, trifluoromethylphenol was used to replace intermediates 1-2 to prepare a colorless liquid (14-4); ESI-MS: m / z = 219 [M+H] + .

[0147] Step 3.1-(2,5-Diphenyl-1H-pyrrolo-1-yl)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (Compound 14)

[0148] Referring to step 3 of Example 1, intermediate 1-3 was replaced with intermediate 14-4, and dibenzylamine was replaced with intermediate 14-2 to prepare a white solid, compound 14; 1 H NMR (400MHz, CDCl3) δ7.47–7.37(m,10H),7.35–7.29(m,2H),6.57(d,J=8.6Hz,2H),6.32(s,2H),4.41(dd,J=7.0,1.3 Hz, 2H), 3.69 (dh, J=10.4, 3.5Hz, 1H), 3.50 (dd, J=9.7, 3.5Hz, 1H), 3.26 (dd, J=9.7, 5.3Hz, 1H). ESI-MS: m / z=438[M+H] + .

[0149] Preparation Example 15.1-((benzo[b]thiophene-6-ylmethyl)(benzyl)amino)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (Compound 15) (L8)

[0150]

[0151] Preparation of intermediate 15-2: 15-1 (1.0 g, 6.0 mmol) and benzylamine (642.0 mg, 6.0 mmol) were dissolved in anhydrous methanol and stirred at 50 °C for 6 h. Sodium borohydride (684.0 mg, 18 mmol) was added in portions, and the mixture was stirred at 50 °C for 12 h. After the reaction was complete, the solvent was evaporated and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Column chromatography yielded a colorless oil (15-2). ESI-MS: m / z = 254 [M+H] + .

[0152]

[0153] Referring to step 3 of Example 1, intermediate 1-3 was replaced with intermediate 14-4, and dibenzylamine was replaced with intermediate 15-2 to prepare a yellow oily compound 15. 1 H NMR(400MHz,Chloroform-d)δ7.82–7.76(m,2H),7.51–7.47(m,2H),7.43(d,J=5.4Hz,1H),7.37–7.27(m,7H),6.88–6.81(m ,2H),4.11(q,J=5.9Hz,1H),3.95–3.80(m,4H),3.63(dd,J=26.5,13.3Hz,2H),2.72(d,J=6.8Hz,2H).ESI-MS:m / z=472[M+H] + .

[0154] Preparation Example 16. 1-(((1H-indol-6-yl)methyl)(benzyl)amino)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (Compound 16) (L9)

[0155]

[0156] Referring to Example 15, indole-6-carboxaldehyde was used to replace intermediate 15-1 to prepare a yellow oily compound 16; 1 HNMR(400MHz,Chloroform-d)δ8.17(s,1H),7.61(d,J=8.1Hz,1H),7.52–7.45(m,2H),7.3 6–7.27(m,6H),7.19(dd,J=3.2,2.4Hz,1H),7.09(dd,J=8.1,1.5Hz,1H),6.86–6.80(m,2H) ,6.54(ddd,J=3.1,2.0,0.9Hz,1H),4.15–4.06(m,1H),3.93(d,J=13.2Hz,1H),3.90–3.83 (m,3H),3.61(dd,J=22.6,13.3Hz,2H),2.71(dd,J=6.8,2.6Hz,2H).ESI-MS:m / z=455[M+H] + .

[0157] Preparation Example 17.1-(benzyl((5-methoxybenzo[b]thiophene-2-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 17) (L23)

[0158]

[0159] Referring to Example 15, 2-aldehyde-5-methoxybenzothiophene was used to replace intermediate 15-1 to obtain an amine fragment intermediate. Then, referring to Example 2, the obtained amine fragment intermediate was used to replace dibenzylamine to prepare a white solid, compound 17. 1H NMR(500MHz,DMSO-d6)δ7.76(d,J=8.8Hz,1H),7.42–7.36(m,2H),7.32(dd,J=8.3,6.8Hz,2H),7.30–7.21(m,3H),6.93(d d,J=8.8,2.5Hz,1H),6.85–6.78(m,2H),6.73–6.66(m,2H),4.01–3.94(m,1H),3.95–3.90(m,1H),3.92–3.85(m,2H),3.79 (s,3H),3.75(d,J=13.8Hz,1H),3.69(dd,J=9.9,6.3Hz,1H),3.62(d,J=13.8Hz,1H),2.90(dd,J=6.4,3.5Hz,4H),2.81(dd ,J=6.3,3.4Hz,4H),2.66(dd,J=13.2,6.5Hz,1H),2.54(dd,J=13.2,5.7Hz,1H),1.35–1.21(m,1H).ESI-MS:m / z=518[M+H] + .

[0160] Preparation Example 18. 1-(benzyl(thieno[3,2-b]thieno-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 18) (L24)

[0161]

[0162] Referring to Example 15, amine fragments were obtained by replacing intermediate 15-1 with thieno[3,2-B]thieno-2-carboxaldehyde, and then a white solid, compound 18, was prepared according to Example 2. 1 H NMR(500MHz,DMSO-d6)δ7.58(d,J=5.2Hz,1H),7.40–7.36(m,3H),7.34–7.29(m,3H),7.27–7.22(m, 1H),6.86–6.81(m,2H),6.74–6.69(m,2H),4.01–3.83(m,5H),3.74(d,J=13.7Hz,1H),3.69(dd,J=9 .8,6.3Hz,1H),3.62(d,J=13.7Hz,1H),2.96(dd,J=6.5,3.4Hz,4H),2.89(dd,J=6.5,3.5Hz,4H),2. 66(dd,J=13.2,6.4Hz,1H),2.54(dd,J=13.2,5.8Hz,1H),1.36–1.21(m,1H).ESI-MS:m / z=494[M+H]+ .

[0163] Preparation Example 19. 1-(benzyl((1-methyl-1H-indol-6-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 19) (L42)

[0164]

[0165] Referring to Example 15, amine fragments were obtained by replacing intermediate 15-1 with 1-methyl-1H-indole-6-carboxaldehyde, and then a white solid, compound 19, was prepared according to Example 2. 1 H NMR (500MHz, DMSO-d6) δ7.47(d,J=8.1Hz,1H),7.40–7.33(m,3H),7.32(t,J=7.5Hz,2H),7.28–7.20(m,2H),7.04( dd,J=8.0,1.3Hz,1H),6.85–6.79(m,2H),6.71–6.64(m,2H),6.37(d,J=3.0Hz,1H),3.94(dq,J=9.8,5.8,4.3Hz,1H ),3.87(dd,J=9.9,3.6Hz,1H),3.76(d,J=13.3Hz,1H),3.73(s,3H),3.69(d,J=13.7Hz,1H),3.66–3.53(m,4H),2. 96–2.90(m,4H),2.85(t,J=4.9Hz,4H),2.59(dd,J=13.1,6.8Hz,1H),2.47(d,J=5.8Hz,1H).ESI-MS:m / z=485[M+H] + .

[0166] Preparation Example 20: 1-(benzyl(naphthyl-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 20) (L43)

[0167]

[0168] Referring to Example 15, amine fragments were obtained by replacing intermediate 15-1 with 2-naphthaldehyde, and then a white solid, compound 20, was prepared according to Example 2. 1H NMR(500MHz, DMSO-d6)δ7.89–7.81(m,4H),7.52(dd,J=8.5,1.7Hz,1H),7.51–7.44(m,2H),7.40–7.36( m,2H),7.32(dd,J=8.3,6.8Hz,2H),7.26–7.21(m,1H),6.82–6.77(m,2H),6.68–6.63(m,2H),3.97(qd,J =6.2,3.8Hz,1H),3.88–3.78(m,2H),3.74–3.67(m,2H),3.65–3.57(m,2H),2.89(dd,J=6.3,3.5Hz,4H), 2.82(dd,J=6.4,3.4Hz,4H),2.62(dd,J=13.1,6.5Hz,1H),2.53(d,J=5.9Hz,1H).ESI-MS:m / z=482[M+H] + .

[0169] Preparation Example 21.1-(benzyl((5-phenylfuran-2-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 21) (L45)

[0170]

[0171] Referring to Example 15, amine fragments were obtained by replacing intermediate 15-1 with 5-phenyl-2-furfural, and then a white solid, compound 21, was prepared according to Example 2. 1 H NMR(500MHz,DMSO-d6)δ7.70–7.66(m,2H),7.43–7.36(m,4H),7.33(t,J=7.6Hz,2H),7.30–7 .22(m,2H),6.88(d,J=3.2Hz,1H),6.78–6.69(m,4H),6.41(d,J=3.3Hz,1H),3.98–3.90(m,2 H),3.77–3.63(m,5H),2.87(dd,J=6.3,3.3Hz,4H),2.81(dd,J=6.4,3.3Hz,4H),2.65(dd,J= 13.1,6.7Hz,1H),2.57(dd,J=13.1,5.6Hz,1H),1.22(d,J=1.9Hz,1H).ESI-MS:m / z=498[M+H] + .

[0172] Preparation Example 22: 1-(benzyl(methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 22) (L20)

[0173]

[0174] Referring to Example 2, a white solid, compound 22, was prepared by replacing dibenzylamine with N-methylbenzylamine. 1 H NMR (500MHz, CDCl) 3) δ7.35–7.26(m,5H),6.90–6.82(m,4H),4.10(dq,J=9.4,4.8Hz,1H),3.93(d,J=5.0Hz,2H),3.68(d,J=13.1Hz,1H),3.53(d,J=13.1 Hz,1H),3.06(s,8H),2.65(dd,J=12.4,9.6Hz,1H),2.54(dd,J=12.4,4.0Hz,1H),2.28(s,3H),1.25(s,1H).ESI-MS:m / z=356[M+H] + .

[0175] Preparation Example 23: 1-(benzyl(phenyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 23) (L25)

[0176]

[0177] Referring to Example 2, a white solid, compound 23, was prepared by replacing dibenzylaniline with N-benzylaniline. 1 H NMR (400MHz, DMSO-d6) δ7.32–7.25(m,2H),7.24–7.16(m,3H),7.11–7.04(m,2H),6.88–6. 80(m,4H),6.71–6.66(m,2H),6.58–6.52(m,1H),4.75–4.55(m,2H),4.15–4.08(m,1H),3. 88(d,J=5.0Hz,2H),3.67(dd,J=15.0,5.1Hz,1H),3.45(dd,J=15.0,7.0Hz,1H),2.92(dd, J=6.4,3.4Hz,4H),2.84(dd,J=6.4,3.4Hz,4H),1.27–1.22(m,1H).ESI-MS:m / z=418[M+H] + .

[0178] Preparation Example 24: 1-(bis(pyridin-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 24) (L36)

[0179]

[0180] Referring to Example 2, a white solid, compound 24, was prepared by replacing dibenzylamine with dimethylpyridinium amine; 1 H NMR(500MHz,DMSO-d6)δ8.48(dt,J=4.8,1.4Hz,2H),7.72(td,J=7.6,1.8Hz,2H),7.50(d,J=7.8Hz,2H) ,7.24(ddd,J=7.5,4.8,1.2Hz,2H),6.86–6.79(m,2H),6.74–6.68(m,2H),5.04(d,J=4.7Hz,1H),3.95(s ,1H),3.88–3.76(m,5H),3.70(dd,J=9.9,5.9Hz,1H),2.90(dd,J=6.4,3.5Hz,4H),2.82(dd,J=6.4,3.5 Hz,4H),2.71(dd,J=13.2,5.8Hz,1H),2.59(dd,J=13.2,6.4Hz,1H),1.23(s,1H).ESI-MS:m / z=434[M+H] + .

[0181] Preparation Example 25: 1-(phenylhydrazineamino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 25) (L48)

[0182]

[0183] Referring to Example 2, a white solid, compound 25, was prepared by replacing dibenzylamine with diphenylmethylamine; 1 H NMR (500MHz, DMSO-d6) δ7.41 (dd, J=7.7, 2.2Hz, 4H), 7.27 (td, J=7.6, 2.1Hz, 4H), 7.2 0–7.15(m,2H),6.86–6.82(m,2H),6.81–6.76(m,2H),4.81(s,1H),3.91(dq,J=10.5,5 .0Hz,2H),3.84–3.79(m,1H),2.90(dd,J=6.2,3.5Hz,4H),2.82(dd,J=6.3,3.5Hz,4H) ,2.60(dd,J=11.6,4.5Hz,1H),2.55–2.51(m,1H),1.23(s,1H).ESI-MS:m / z=418[M+H] + .

[0184] Preparation Example 26. 1-((1,3-diphenylprop-2-yl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 26) (L49)

[0185]

[0186] Referring to Example 2, a white solid, compound 26, was prepared by replacing dibenzylamine with 1,3-diphenyl-2-aminopropane; 1 H NMR(500MHz,DMSO-d6)δ7.25(td,J=7.5,4.4Hz,4H),7.17(td,J=6.9,6.2,2.0H z,6H),6.86–6.81(m,2H),6.76–6.71(m,2H),3.71(ddt,J=21.5,7.7,4.3Hz,3H) ,2.99(p,J=6.4Hz,1H),2.90(dd,J=6.2,3.5Hz,4H),2.82(t,J=4.9Hz,4H),2.71 (dd,J=11.7,4.0Hz,1H),2.67–2.55(m,5H),1.23(s,1H).ESI-MS:m / z=446[M+H] + .

[0187] Preparation Example 27. 1-((2-(1H-indol-3-yl)ethyl)(benzyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (Compound 27) (L40)

[0188]

[0189] Referring to Example 15, tryptamine (3-(2-aminoethyl)indole) was used instead of benzylamine, and benzaldehyde was used instead of intermediate 15-1 to obtain an amine fragment. Then, referring to Example 2, a white solid, compound 27, was obtained. 1H NMR(500MHz,DMSO-d6)δ10.72(s,1H),7.36–7.27(m,6H),7.25–7.20(m,1H),7.06–7.00(m,2H),6.89(ddd, J=8.0,6.9,1.0Hz,1H),6.85–6.80(m,2H),6.78–6.72(m,2H),4.78(s,1H),3.97–3.87(m,2H),3.79(d,J=13 .8Hz,1H),3.76–3.71(m,1H),3.68(d,J=13.7Hz,1H),2.90(dd,J=6.4,3.4Hz,4H),2.87–2.83(m,1H),2.81( dd,J=6.2,3.7Hz,4H),2.79–2.67(m,3H),2.59(dd,J=13.1,5.6Hz,1H),1.23(s,1H).ESI-MS:m / z=485[M+H] + .

[0190] Preparation Example 28. N-Benzyl-N-(2-hydroxy-3-(4-(piperazin-1-yl)phenoxy)propyl)benzamide (Compound 28) (L29)

[0191]

[0192] Referring to step 3 of Example 2, benzylamine was replaced with dibenzylamine to obtain intermediate 28-1. Then, referring to step 5 of Example 3, benzoyl chloride was replaced with acryloyl chloride to obtain intermediate 28-2. Finally, referring to step 4 of Example 2, the Boc protecting group was removed to obtain compound 28. 1 H NMR (400MHz, DMSO-d6) δ7.39(dd,J=25.2,6.7Hz,8H),7.28(d,J=6.8Hz,1H),7.14(d,J=7.4Hz,1H),6.84(dt,J=14.1,8.3Hz,3H),6.62(d,J=8.5Hz,1H), 5.35(d,J=17.2Hz,1H),4.80(dd,J=83.1,15.3Hz,1H),4.64–4.50(m,1H),4. 10(d,J=86.6Hz,1H),3.88(s,1H),3.64–3.54(m,2H),2.96(s,4H),2.89(d,J

[0193] =6.0Hz,4H),1.24(q,J=4.0Hz,1H).ESI-MS:m / z=446[M+H] + .

[0194] Preparation Example 29. 2-(Dibenzylamino)-N-(4-(piperazin-1-yl)phenyl)acetamide (Compound 29) (L46)

[0195]

[0196] Step 1. Methyl bromoacetate (1.5 g, 10.1 mmol), dibenzylamine (2.0 g, 10.1 mmol), and potassium carbonate (2.8 g, 20.2 mmol) were dissolved in acetonitrile. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the solvent was evaporated and purified by column chromatography to obtain a colorless oil, 29-2. ESI-MS: m / z = 270 [M+H]. + .

[0197] Step 2. Dissolve intermediate 29-2 (814.0 mg, 3.0 mmol) in a 1:1 mixture of tetrahydrofuran and water, add sodium hydroxide (483.5 mg, 12.0 mmol), stir at 60 °C for 12 h, and after the reaction is complete, evaporate the solvent to dryness, extract with ethyl acetate (3 × 50 mL), wash the organic phase with saturated brine (3 × 30 mL), dry with anhydrous sodium sulfate, remove the solvent, and column chromatography yields white solid 29-3, ESI-MS: m / z = 256 [M + H]. + .

[0198] Step 3. Referring to Example 4, intermediate 29-3 was used to replace 4-pentynic acid, and 1-Boc-4-(4-aminophenyl)piperazine was used to replace compound 2, to obtain intermediate 29-4. ESI-MS: m / z = 515 [M+H] + .

[0199] Step 4. Referring to step 4 of Example 2, replace compound 1 with intermediate 29-4 to obtain compound 29. 1 HNMR(500MHz,DMSO-d6)δ9.46(s,1H),7.44–7.39(m,6H),7.34(dd,J=8.4,6.8Hz,4H),7.28–7.22(m,2H),6.87–6.82( m,2H),3.74(s,4H),3.18(s,2H),2.99–2.94(m,4H),2.82(dd,J=6.1,3.8Hz,4H),1.22(s,1H).ESI-MS:m / z=415[M+H] + .

[0200] Preparation Example 30: 2-(dibenzylamino)-N-(4-(piperazin-1-yl)benzyl)acetamide (Compound 30) (L52)

[0201]

[0202] Referring to steps 3 and 4 of Example 29, tert-butyl 4-[4-(aminomethyl)phenyl]tetrahydropyrazine carboxylate was used instead of compound 1-Boc-4-(4-aminophenyl)piperazine, and intermediate 29-3 was used instead of 2-(dibenzyl)acetic acid to obtain compound 30. 1 HNMR(500MH z,DMSO-d6)δ8.10(t,J=6.1Hz,1H),7.40–7.34(m,4H),7.32(t,J=7.5Hz,4H),7.29–7.22(m,2H),7.10–7.04(m,2H),6.86–6.79(m,2 H),4.19(d,J=6.0Hz,2H),3.61(s,4H),3.00(s,2H),2.98(dd,J=6.3,3.8Hz,4H),2.81(dd,J=6.1,3.9Hz,4H).ESI-MS:m / z=429[M+H] + .

[0203] Biological Experiment

[0204] Example 31: Inhibitory Activity of FBXO44

[0205] Logarithmically growing gastric cancer cells were seeded into 6-well culture plates. After cell attachment, candidate compounds of varying concentrations were added. The plates were cultured at 37°C with 5% CO2 for 48 hours. Total protein was extracted, and after SDS-PAGE and transfer to a membrane, the plates were blocked with 5% skim milk for 1 hour. Then, the plates were incubated overnight with MTSS1 and FBXO44 primary antibodies. The next day, after washing the membrane, the plates were incubated with secondary antibody for 1 hour. After washing again, the membranes were developed with ECL developing solution.

[0206] Detection results: As shown in Table 1, most compounds showed in vitro inhibitory activity (IC50) against FBXO44. 50 All are less than 10 μM.

[0207] Table 1. In vitro inhibitory activity of the compounds of the present invention against FBXO44, A represents IC50. 50 <10μM; B indicates IC 50 10-100μM; C indicates IC 50 100-200μM.

[0208]

[0209] As shown in Table 1, the compounds of this invention exhibit excellent in vitro inhibitory activity against FBXO44.

[0210] Example 32: NUGC4 cell proliferation inhibition experiment

[0211] Detection steps: NUGC4 cells were cultured at a concentration of 3 × 10⁻⁶.4 Cells were seeded at a density of 10 cells / well into 96-well plates and incubated in a 5% CO2 cell culture incubator for 24 hours (37°C). After cell attachment, serially diluted test compounds were added, and the plates were incubated for another 72 hours. 10 μL of CCK8 solution was added to each well, and the plates were incubated for 2 hours. The absorbance at 450 nm was measured using a microplate reader and converted to the viability percentage. The viability percentage was calculated as: Viability (%) = (Experimental group - Blank group) / (Control group - Blank group) × 100%. Data were analyzed using GraphPad Prism 8.0 software, and IC50 was fitted. 50 value.

[0212] Detection results: As shown in Table 2, the compound has good anti-tumor proliferation activity against NUGC4 cells.

[0213] Example 33: AZ521 Cell Proliferation Inhibition Experiment

[0214] Detection steps: AZ521 cells were cultured at a concentration of 3 × 10⁻⁶. 4 Cells were seeded at a density of 10 cells / well into 96-well plates and incubated in a 5% CO2 cell culture incubator for 24 hours (37°C). After cell attachment, serially diluted test compounds were added, and the plates were incubated for another 72 hours. 10 μL of CCK8 solution was added to each well, and the plates were incubated for 2 hours. The absorbance at 450 nm was measured using a microplate reader and converted to the viability percentage. The viability percentage was calculated as: Viability (%) = (Experimental group - Blank group) / (Control group - Blank group) × 100%. Data were analyzed using GraphPad Prism 8.0 software, and IC50 was fitted. 50 value.

[0215] Detection results: As shown in Table 2, the compound has good anti-tumor proliferation activity against AZ521 cells.

[0216] Example 34 MKN1 cell proliferation inhibition experiment

[0217] Detection steps: MKN1 cells were cultured at a concentration of 3 × 10⁻⁶. 4 Cells were seeded at a density of 10 cells / well into 96-well plates and incubated in a 5% CO2 cell culture incubator for 24 hours (37°C). After cell attachment, serially diluted test compounds were added, and the plates were incubated for another 72 hours. 10 μL of CCK8 solution was added to each well, and the plates were incubated for 2 hours. The absorbance at 450 nm was measured using a microplate reader and converted to the viability percentage. The viability percentage was calculated as: Viability (%) = (Experimental group - Blank group) / (Control group - Blank group) × 100%. Data were analyzed using GraphPad Prism 8.0 software, and IC50 was fitted. 50 value.

[0218] Detection results: As shown in Table 2, the compound has good anti-tumor proliferation activity against MKN1 cells.

[0219] Example 35 MKN74 Cell Proliferation Inhibition Experiment

[0220] Detection steps: MKN74 cells were cultured at 3 × 10⁻⁶. 4 Cells were seeded at a density of 10 cells / well into 96-well plates and incubated in a 5% CO2 cell culture incubator for 24 hours (37°C). After cell attachment, serially diluted test compounds were added, and the plates were incubated for another 72 hours. 10 μL of CCK8 solution was added to each well, and the plates were incubated for 2 hours. The absorbance at 450 nm was measured using a microplate reader and converted to the viability percentage. The viability percentage was calculated as: Viability (%) = (Experimental group - Blank group) / (Control group - Blank group) × 100%. Data were analyzed using GraphPad Prism 8.0 software, and IC50 was fitted. 50 value.

[0221] Detection results: As shown in Table 2, the compound has good anti-tumor proliferation activity against MKN74 cells.

[0222] Table 2. In vitro inhibitory activity of the compounds of the present invention against NUGC4 cells, AZ521 cells, MKN74 cells and MKN1 cells, where A represents IC50. 50 <10μM; B indicates IC 50 10-100μM; C indicates IC 50 >100μM.

[0223]

[0224]

[0225] As shown in the table above, the compounds of the present invention have a strong inhibitory effect on the proliferation of gastric cancer cell lines, indicating that the compounds of the present invention have potent anti-gastric cancer activity.

[0226] Example 36: Compound Binding Experiment with FBXO44

[0227] Detection steps: After the purified FBXO44 protein was labeled with the RED-NHS second-generation protein labeling kit, it was incubated with different concentrations of compound DQ2405 for 30 minutes. The binding ability of the protein to FBXO44 was detected by micro-thermophoresis, and the dissociation constant Kd value was calculated.

[0228] Test results: such as Figure 1 As shown, compound DQ2405 is directly bound to FBXO44, with a Kd value of 7.8 μM.

[0229] Example 37: Compound Inhibition of FBXO44-MTSS1 Binding Experiment

[0230] Detection procedure: Flag-FBXO44 and Myc-MTSS1 were co-transfected into the HEK-293 cell line. After the cells stably expressed these two proteins, a concentration gradient of compounds was added for co-incubation. The interaction between the two was then detected using Co-IP.

[0231] Test results: such as Figure 2 As shown in Figure A, compound DQ2405 can inhibit the binding of FBXO44 to MTSS1 in a dose-dependent manner.

[0232] Detection steps: After co-incubating the purified GST-MTSS1, GST-Flag-FBXO44 and compound DQ2405 for a certain period of time, the interaction between FBXO44 and MTSS1 before and after drug administration was investigated by performing IP on Flag.

[0233] Test results: such as Figure 2 As shown in B, compound DQ2405 can significantly inhibit the binding of FBXO44 and MTSS1.

[0234] Detection steps: Logarithmically growing gastric cancer cells were seeded into 6-well culture plates. After the cells adhered, a certain concentration of compound DQ2405 was added, and the cells were cultured at 37°C in an incubator containing 5% CO2 for 36 hours. Then, the cells were permeabilized, and MTSS1 mouse primary antibody and F-actin rabbit primary antibody were added and incubated for a certain period of time. Then, secondary antibodies of different fluorescence species were added. Finally, the cells were stained with DAPI, mounted, and photographed under a microscope.

[0235] Test results: such as Figure 2 As shown in Figure C, DQ2405 can promote MTSS1 expression and inhibit the formation of lamellar foot.

[0236] Example 38: Experiment on the antitumor mechanism of the compound

[0237] Logarithmically growing gastric cancer cells were seeded into 6-well culture plates. After cell attachment, candidate compounds of varying concentrations were added. The plates were cultured at 37°C with 5% CO2 for 48 hours. Total protein was extracted, and after SDS-PAGE and transfer to a membrane, the plates were blocked with 5% skim milk for 1 hour. Then, the plates were incubated overnight with a primary antibody against the RAC1 signaling pathway protein. The next day, the plates were washed and incubated with a secondary antibody for 1 hour. After washing again, the plates were developed with ECL developing solution.

[0238] Test results: such as Figure 3 As shown, compound DQ2405 inhibits FBXO44, upregulates MTSS1, and thus affects the RAC1 signaling pathway, ultimately leading to the formation of lamellar filopodia.

[0239] Example 39: Detection of oral plasma exposure in mice

[0240] Blood samples were collected at different time points after the test compound was administered orally at a single dose of 10 mg / kg to ICR mice.

[0241] Preparation and processing of standard curves and quality control samples: Take the mixed stock solution of the test compounds and dilute it with 50% methanol and water to prepare standard working solutions with concentrations of 20, 40, 100, 200, 400, 1000, 2000, 4000, 10000, and 20000 ng / mL for each compound, and quality control working solutions with concentrations of 60, 600, and 16000 ng / mL. Take 47.5 μL of blank matrix and add 2.50 μL of standard curve working solution and quality control working solution respectively to prepare standard curves with concentrations of 1.00, 2.00, 5.00, 10.00, 20.00, 50.00, 100.00, 200.00, 500.00, and 1000.00 ng / mL for each compound, and quality control samples with concentrations of 3.00, 30.00, and 800.00 ng / mL. Add 400 μL of acetonitrile (containing 2 ng / mL of internal standard verapamil) to each sample. Vortex at 700 rcf for 10 min, then centrifuge at 3300 rcf and 4℃ for 10 min. Take the supernatant for LC-MS / MS analysis.

[0242] Unknown sample preparation and processing: Take 50 μL of the sample to be tested, add 400 μL of acetonitrile (containing 2 ng / mL of internal standard verapamil), vortex at 700 rcf for 10 min, then centrifuge at 3300 rcf and 4℃ for 10 min, and take the supernatant for LC-MS / MS analysis.

[0243]

[0244] As shown in the table above, the compounds of this invention have good in vivo exposure levels and have the potential for oral administration.

[0245] Example 40: In vivo antitumor efficacy of the compound in the CDX model of NUGC4

[0246] This invention uses a mouse model inoculated with NUGC4 gastric cancer cells under the armpit to evaluate the in vivo antitumor activity of compound DQ2405.

[0247] Experimental method: 3×10 5 NuGC4 cells were injected into the axilla of nude mice, and the tumors were allowed to grow to 50-100 mm. 3Subsequently, nude mice were randomly divided into three groups: a blank control group (saline, n=6); a DQ2405 group (n=6, intraperitoneal administration, 50 mg / kg / day); and a cisplatin group (n=6, intraperitoneal administration, 3 mg / kg / 3 days). Administration continued for 9 days. Tumor volume was measured at different time points; after 9 days, the tumor was completely dissected and weighed.

[0248] Experimental results are as follows Figure 4 As shown, compound DQ2405 exhibits an inhibition rate comparable to cisplatin against NUGC4 xenograft tumors, demonstrating significant in vivo anti-gastric cancer activity.

[0249] Example 41: In vivo antitumor efficacy of the compound in a PDX model derived from a gastric cancer patient.

[0250] This invention uses a mouse model inoculated with tumors derived from gastric cancer patients via axillary inoculation to evaluate the in vivo antitumor activity of compound DQ2405.

[0251] Experimental method: Gastric cancer tissue was cut into 2*2mm pieces. 3 In the armpit of nude mice, when the tumor grows to 50-100 mm 3 Subsequently, nude mice were randomly divided into four groups: a blank control group (n=6, saline); a low-dose DQ2405 group (n=6, intraperitoneal administration, 50 mg / kg / day); a high-dose DQ2405 group (n=6, intraperitoneal administration, 80 mg / kg / day); and a cisplatin group (n=6, intraperitoneal administration, 3 mg / kg / 3 days). Administration continued for 16 days. Tumor volume was measured at different time points; after 16 days, the tumor was completely dissected and weighed.

[0252] Experimental results are as follows Figure 5 As shown, compound DQ2405 exhibited antitumor activity comparable to cisplatin in the PDX model, demonstrating significant in vivo anti-gastric cancer activity, and DQ2405 showed superior safety compared to the cisplatin group.

Claims

1. Compounds represented by general formula I: and its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein: R0 is selected from H, amino, substituted or unsubstituted aliphatic ring, aliphatic heterocycle, C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy. R2 and R3 are independently selected from H, -(CH2)-Y, -(C=O)-Y, -(S=O)-Y, -(SO2)-Y, or R2 and R3 are linked together to form a substituted aromatic heterocycle; Where Y is selected from H, substituted or unsubstituted aromatic rings, aromatic heterocyclic rings, fused rings, and fused heterocyclic rings; Ring A is selected from substituted or unsubstituted aromatic rings, aromatic heterocyclic rings, fused rings, and fused heterocyclic rings; X is selected from 2. The compound according to claim 1, characterized in that, It has the structure shown in Formula II: And its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein the substituents are defined as in claim 1; R1 is selected from H, substituted or unsubstituted aromatic rings, aromatic heterocycles, 3-8 membered heteroalkyl groups, fused rings, fused heterocycles, C1-C5 alkyl groups, halogenated C1-C5 alkyl groups, C1-C5 alkoxy groups, C1-C5 alkoxy carbonyl groups, and C1-C5 unsaturated alkyl acyl groups.

3. The compound according to claim 2, characterized in that, The R0 is selected from amino, 3-6 alkyl, 3-8 heteroalkyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, and the above substituents may be further replaced by Boc, C1-C5 alkyl acyl, C1-C5 acyl with C=C or C≡C, Boc-NH-, C1-C5 alkyl acyl amino with C=C or C≡C, and 4-8 N or O hybridized heteroalkyl. R2 and R3 are independently selected from H, 4-8 membered aromatic rings, benzoyl group or -(CH2)n-CH Y1Y2, where n is 0, 1 or 2, and Y1 and Y2 are independently selected from H, 4-8 membered aromatic rings, 4-8 membered aromatic rings or 4-10 membered aromatic heterocycles, wherein the aromatic ring or aromatic heterocycle may be further substituented by C1-C3 alkyl group, C1-C3 alkoxy group or benzene ring; or R2 and R3 are linked together to form a substituted 3-6 membered aromatic heterocycle, wherein there are one or more substituents selected from benzene ring; Ring A is selected from 5-7 membered aromatic rings and 5-7 membered aromatic heterocycles, wherein the heteroatom in the aromatic heterocycle is one or more N atoms; R1 is selected from H, C1-C4 alkoxycarbonyl, C1-C5 hydrocarbon acyl with carbon-carbon double or triple bonds, and 4-8 heteroalkyl.

4. The compound according to claim 3, characterized in that, The compound has the structure shown in general formula III or III': and its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein: R4 is selected from H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, and C1-C4 alkoxy. B and Z are independently selected from C, CH, and N, respectively; The C ring is selected from five-membered aromatic rings or aromatic heterocyclic rings, six-membered aromatic rings or aromatic heterocyclic rings.

5. The compound according to claim 4, characterized in that, The compound has the structure shown in general formula III or III': and its optical isomers or pharmaceutically acceptable salts or solvates thereof, wherein: M is selected from N, NH, S, and O.

6. The compound according to claim 1, characterized in that, The compounds mentioned are selected from: 4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1) 1-(dibenzylamino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol(2) 1-(4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazin-1-yl)prop-2-en-1-one (3) 1-(4-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)piperazin-1-yl)pent-4-yn-1-one (4) 1-(4-aminophenoxy)-3-(dibenzylamino)prop-2-ol (5) N-(4-(3-(dibenzylamino)-2-hydroxypropoxy)phenyl)acrylamide (6) 4-(3-(dibenzylamino)-2-hydroxypropoxy)benzyl)tert-butyl carbamate (7) N-(4-(3-(dibenzylamino)-2-hydroxypropoxy)benzyl)acrylamide (8) 1-(dibenzylamino)-3-(3-(piperazin-1-yl)phenoxy)prop-2-ol (9) N,N-Dibenzyl-2-methoxy-3-(4-(piperazin-1-yl)phenoxy)propyl-1-amine (10) 1-(dibenzylamino)-3-(4-(4-(piperidin-4-yl)piperazin-1-yl)phenoxy)prop-2-ol(11) 1-(dibenzylamino)-3-((6-(piperazin-1-yl)pyridin-3-yl)oxy)prop-2-ol(12) 1-(dibenzylamino)-3-((2-(piperazin-1-yl)pyrimidin-5-yl)oxy)prop-2-ol(13) 1-(2,5-Diphenyl-1H-pyrrolo-1-yl)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (14) 1-((benzo[b]thiophene-6-ylmethyl)(benzyl)amino)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (15) 1-(((1H-indol-6-yl)methyl)(benzyl)amino)-3-(4-(trifluoromethyl)phenoxy)prop-2-ol (16) 1-(benzyl((5-methoxybenzo[b]thiophen-2-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (17) 1-(benzyl(thieno[3,2-b]thieno-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (18) 1-(benzyl((1-methyl-1H-indol-6-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (19) 1-(benzyl(naphthyl-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (20) 1-(benzyl((5-phenylfuran-2-yl)methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (21) 1-(benzyl(methyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (22) 1-(benzyl(phenyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (23) 1-(bis(pyridin-2-ylmethyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (24) 1-(phenylhydrazineamino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (25) 1-((1,3-diphenylprop-2-yl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (26) 1-((2-(1H-indol-3-yl)ethyl)(benzyl)amino)-3-(4-(piperazin-1-yl)phenoxy)prop-2-ol (27) N-Benzyl-N-(2-hydroxy-3-(4-(piperazin-1-yl)phenoxy)propyl)benzamide (28) 2-(Dibenzylamino)-N-(4-(piperazin-1-yl)phenyl)acetamide (29) 2-(Dibenzylamino)-N-(4-(piperazin-1-yl)benzyl)acetamide (30) And its optical isomers or pharmaceutically acceptable salts or solvates thereof.

7. A pharmaceutical composition comprising at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient is selected from any one or more of the compounds of any one of claims 1 to 6, optical isomers of the compounds, pharmaceutically acceptable salts of the compounds or their optical isomers, and solvates of the compounds or their optical isomers.

8. A formulation made from the pharmaceutical composition of claim 7, wherein the formulation is a tablet, powder, granule, capsule, oral liquid, or injection.

9. Use of the compound according to any one of claims 1-6 or the pharmaceutical composition or formulation according to claim 7 or 8 in the preparation of an antitumor drug.

10. The use according to claim 9, characterized in that, The tumors mentioned are selected from neuroblastoma, breast cancer, sarcoma, lung cancer, prostate cancer, colon cancer, rectal cancer, kidney cancer, pancreatic cancer, leukemia, glioma, head cancer, neck cancer, thyroid cancer, pancreatic cancer, liver cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, stomach cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal cancer, skin cancer, and multiple myeloma.

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