A diarylacetylene compound, a preparation method thereof and an application thereof

Abstract

The present invention provides a diarylacetylene compound, a preparation method and an application thereof. The bioactive isoindoline-piperazinylurea mother nucleus group contained therein is further chemically modified to produce many compounds with higher biological activities or pharmaceutically acceptable salts, hydrates, solvates, metabolites, prodrugs or pharmaceutical compositions thereof, expanding the wide application of such compounds in biomedicine and the prospect of drug formulation development. Such compounds can target the STAT3 protein, significantly inhibit the proliferation of various tumor cells such as lung cancer, breast cancer, liver cancer, pancreatic cancer and gastric cancer at low doses (nanomolar), and can effectively inhibit the growth of transplanted tumors in mice, indicating that such compounds have the prospect of being developed into drugs for preventing and / or treating tumors and other diseases related to abnormal STAT3 signaling.

Description

Technical Field

[0001] The present invention belongs to the field of tumor targeted therapy, and particularly relates to a diarylacetylene compound, a preparation method thereof and an application thereof. Background Art

[0002] According to the data released by the International Agency for Research on Cancer (IARC) of the World Health Organization, there were 19.3 million new cancer cases and 9.96 million cancer deaths globally in 2020. It is estimated that by 2030, the number of new cancer cases per year globally will increase by 69% to 21 million; in 2030, the number of cancer death cases is expected to rise by 72%, and the number of deaths will increase from 7.6 million in 2008 to 13 million. Worldwide, the prevention and treatment of cancer still has a long way to go. Conventional anti-tumor drugs such as paclitaxel, doxorubicin and vincristine have the advantages of broad anti-cancer spectrum and definite curative effect, but have the problem of large toxic and side effects. Although there are now a variety of means for targeted cancer therapy clinically, there are generally phenomena such as low treatment response rate or drug resistance, resulting in very limited treatment options for patients. Therefore, actively exploring and developing new anti-cancer drugs has important clinical significance.

[0003] Signal Transducer and Activator of Transcription 3 (STAT3 for short) is one of the core regulatory factors of cell signal transduction. In normal cells, STAT3 is usually transiently activated, while in about 70% of human malignant tumor cells, STAT3 can be constitutively activated in response to various cytokine, growth factor and oncogene signals. Activated STAT3 forms a dimer through the SH2 domain, then enters the nucleus, binds to specific DNA sequences, regulates the transcriptional expression of almost the entire genomic target genes, and participates in various pro-cancer events. For example, by up-regulating the expression of cyclin D1 or proto-oncogene c-MYC, it promotes the proliferation of tumor cells; by up-regulating the expression of anti-apoptotic genes such as BCL-2, BCL-XL and Survivin, it promotes the survival of tumor cells; by up-regulating the expression of vascular endothelial growth factor (VEGF), it promotes tumor angiogenesis; by up-regulating the expression of IL-6, IL-10, matrix metalloproteinases (MMPs) and transforming growth factor β (TGF-β), it regulates the epithelial-mesenchymal transition (EMT) and tumor stem cell (CSC)-like transformation of tumor cells. A large number of studies have shown that STAT3 is significantly associated with poor prognosis of tumors such as lung cancer, breast cancer, gastric cancer, liver cancer, pancreatic cancer, prostate cancer and leukemia. Significantly inhibiting tumor proliferation, survival, angiogenesis, drug resistance, immune escape, metastasis and recurrence can be achieved by gene knockdown or inhibiting the expression of STAT3. Therefore, the treatment method targeting STAT3 has the advantages of broad anti-cancer spectrum bandwidth and good curative effect.

[0004] A class of diarylacetylene compounds with a brand-new structural formula was synthesized in this application. Through some biological technology analyses, it was found that this class of compounds could effectively inhibit the activation of STAT3 signal, and could significantly inhibit the proliferation of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myelodysplastic syndrome and melanoma cells at extremely low doses. In a breast cancer xenograft model in animals, its drug efficacy was close to that of albumin-bound paclitaxel at the same dose, and there were no obvious toxic and side effects. Therefore, this class of compounds has the prospect of being developed into drugs for preventing and / or treating tumors and other diseases related to abnormal STAT3 signal. Summary of the Invention

[0005] The purpose of the present invention is to provide a diarylacetylene compound, its preparation method and application.

[0006] Based on the above purpose, the present invention adopts the following technical solutions:

[0007] A diarylacetylene compound, characterized in that its structural formula is as shown in General Formula I:

[0008]

[0009] Among them, R1 is selected from H, F, Cl, Br, I, -CN, -CH3, -CF3, -OCH3, -OCF3, -SO2NH2;

[0010] R2 is selected from

[0011] W, X, Y, G, Q, V are each independently selected from C, N.

[0012] The above diarylacetylene compound is specifically a compound with the following structure:

[0013]

[0014]

[0015] A biologically acceptable salt formed by the above diarylacetylene compound and at least one of acetic acid, dihydrofolic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid and ethylenediaminetetraacetic acid.

[0016] The preparation method of the diarylacetylene compound is characterized in that the synthetic route is as follows:

[0017]

[0018] The specific synthesis steps are as follows:

[0019] (1) Dissolve Compound 1, Compound 2, HBTU and DIEA in DMF, stir and react completely at 20 - 30 °C. After the reaction solution is diluted with ethyl acetate and washed with saturated brine, the organic phase is dried by rotation to obtain a crude product, and the crude product is slurried with ethyl acetate to obtain Compound 3;

[0020] (2) Dissolve Compound 3, Compound 4 and potassium carbonate in DMF, stir and react completely at 75 - 85 °C. After the reaction solution is diluted with ethyl acetate and washed with saturated brine, the organic phase is dried by rotation to obtain a crude product, and the crude product is slurried with ethyl acetate to obtain Compound 5;

[0021] (3) Dissolve Compound 5, Compound 6, Pd(PPh3)2Cl2, CuI and TEA in DMF, stir and react completely at 75 - 85 °C. After the reaction solution is diluted with ethyl acetate and washed with saturated brine, the organic phase is dried by rotation to obtain a crude product, and the crude product is purified by column chromatography to obtain the target compound.

[0022] Preferably, in step (1), the molar ratio of Compound 1, Compound 2, HBTU and DIEA is 1:1:1.2:3; in step (2), the molar ratio of Compound 3, Compound 4 and potassium carbonate is 1:1:1.2; in step (3), the molar ratio of Compound 5, Compound 6, Pd(PPh3)2Cl2, CuI and TEA is 1:5:0.1:0.2:5.

[0023] The application of the above-mentioned diarylacetylene compound and its biologically acceptable salt in the preparation of anti-tumor drugs. The anti-tumor drug is a drug for treating diseases related to STAT3 signal transduction.

[0024] Preferably, the anti-tumor drug refers to a drug for treating lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myeloproliferative neoplasm and melanoma.

[0025] Specifically, the present invention synthesizes a class of diarylacetylene compounds with a completely new structure, such as ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1, and ID230315A-1. The inhibitory effect of such compounds on the proliferation of various cancer cells was detected by the CCK-8 method; the effect of the compounds on the in vivo growth of breast cancer was detected by a nude mouse xenograft tumor model.

[0026] The results show that the compounds ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1, and ID230315A-1 of the present invention can effectively inhibit the proliferation of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myeloproliferative neoplasm, and melanoma cells, and significantly inhibit the growth of breast cancer in mice.

[0027] In summary, the present invention provides the use and potential molecular mechanism of a new diarylacetylene compound and its derivatives in tumor treatment. Brief Description of the Drawings

[0028] Figure 1 Taking albumin-bound paclitaxel as the positive control and the solvent of ID230301A-1 (10% DMSO + 90% corn oil) as the blank control, the anti-tumor effect of ID230301A-1 in mice was evaluated.

[0029] Figure 2 It is the detection of the inhibitory effect of ID230301A-1 on STAT3 phosphorylation by Western blot. Detailed Embodiments

[0030] To make the technical objectives, technical solutions, and beneficial effects of the present invention clearer, the following further explains the technical solutions of the present invention in conjunction with the accompanying drawings and specific embodiments.

[0031] In the method for synthesizing the compound of formula I in the present invention, various raw materials used in the reaction can be prepared by those skilled in the art based on existing knowledge, or can be prepared by methods known in the literature, or can be commercially purchased. The intermediates, raw materials, reagents, reaction conditions, etc. used in the above reaction scheme can all be appropriately changed according to the existing knowledge of those skilled in the art.

[0032] In the present invention, unless otherwise specified, (i) the temperature is expressed in degrees Celsius (°C), and the operation is carried out at room temperature; more specifically, the room temperature refers to 20 - 30 °C; (ii) organic solvents are dried by common drying methods, and the evaporation of the solvent is carried out under reduced pressure using a rotary evaporator, with the bath temperature not exceeding 50 °C; the developing agent and eluent are both volume ratios; (iii) the reaction process is monitored by thin-layer chromatography (TLC); (iv) the final product has satisfactory proton nuclear magnetic resonance ( 1 1H-NMR).

[0033] Example 1: The synthesis of all compounds refers to the following route

[0034] For the specific synthesis method, taking compound ID230301A-1 as an example, the structural formula is as follows:

[0035]

[0036] The name of compound ID230301A-1 is (1-methyl-6-((5-((4-(trifluoromethyl)phenyl)ethynyl)pyrazin-2-yl)oxy)-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone,

[0037] and its synthesis route is as follows:

[0038]

[0039] Step 1. (6-hydroxy-1-methyl-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone (Compound 3)

[0040] Compound 1 (5.0 g, 26.15 mmol, 1.0 eq), compound 2 (7.17 g, 26.15 mmol, 1.0 eq), HBTU (14.90 g, 31.38 mmol, 1.2 eq) and DIEA (10.14 g, 78.46 mmol, 3.0 eq) were dissolved in 50 mL of DMF and reacted at 25 °C for 3 hours. The reaction was monitored by TLC until completion. The reaction solution was diluted with 500 mL of ethyl acetate and washed three times with saturated brine (400 mL * 3). The organic phase was dried and concentrated by rotary evaporation, triturated with 25 mL of ethyl acetate, filtered and the filter cake was collected. The filter cake was concentrated by rotary evaporation to obtain 8.5 g of yellow solid compound 3 with a yield of 72.6%.

[0041] 1 1H NMR (DMSO-d6, 300 MHz) δ: 11.16 (s, 1H), 9.19 (s, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 1.4 Hz, 1H), 6.59 (dd, J = 8.6, 2.1 Hz, 1H), 4.77 (q, J = 8.9 Hz, 2H), 3.76 (s, 4H), 3.72 (s, 3H), 3.50 (s, 2H), 2.46 - 2.41 (m, 4H).

[0042] Step 2. (4-(2-(piperidin-1-yl)ethoxy)phenyl)methanol (Compound 4)

[0043] Compound 3 (5.0 g, 11.17 mmol, 1.0 eq), compound 4 (2.69 g, 11.17 mmol, 1.0 eq) and potassium carbonate (1.85 g, 13.41 mmol, 1.2 eq) were dissolved in 50 mL of DMF and reacted at 80 °C for 2 hours. The reaction was monitored by TLC until completion. The reaction solution was diluted with 300 mL of ethyl acetate and washed three times with saturated brine (200 mL * 3). The organic phase was dried and concentrated by rotary evaporation, triturated with 18 mL of ethyl acetate, filtered and the filter cake was collected. The filter cake was concentrated by rotary evaporation to obtain 5.20 g of yellow solid compound 5 with a yield of 71.4%.

[0044] 11H NMR (DMSO-d6, 300 MHz) δ: 8.79 (d, J = 1.2 Hz, 1H), 8.67 (d, J = 1.2 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.05 (s, 1H), 7.04 (s, 1H), 7.02 (dd, J = 8.5, 2.1 Hz, 1H), 7.01 (s, 1H), 4.76 (d, J = 8.9 Hz, 2H), 3.74 (s, 3H), 3.67 (s, 4H), 3.51 (s, 2H), 2.44 (s, 4H).

[0045] (1-methyl-6-((5-((4-(trifluoromethyl)phenyl)ethynyl)pyrazin-2-yl)oxy)-1H-indol-2-yl)(4-(4-(2,2,2-trifluoroethoxy)benzyl)piperazin-1-yl)methanone (ID230301A-1)

[0046] Dissolve compound 5 (1.0 g, 1.54 mmol, 1.0 eq), compound 6 (1.31 g, 7.68 mmol, 5.0 eq), Pd(PPh3)2Cl2 (107 mg, 0.15 mmol, 0.10 eq), CuI (58.4 mg, 0.30 mmol, 0.2 eq) and TEA (776 mg, 7.68 mmol, 5.0 eq) in 20 mL of DMF, react at 80 °C for 48 h, and monitor the reaction by TLC until completion. Dilute the reaction solution with 300 mL of ethyl acetate, wash it three times with saturated brine (200 mL * 3), dry the organic phase and concentrate it under reduced pressure. Purify the crude product by column chromatography (DCM / MeOH = 70 / 1 to 20 / 1) to obtain 480 mg of yellow solid compound ID230301A-1 with a yield of 45.2%.

[0047] 11H NMR(CDCl3, 400 MHz) δ: 9.01 (s, 1H), 8.60 (s, 1H), 8.16 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.99 (dd, J = 8.5, 1.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 4.37 (q, J = 8.1 Hz, 2H), 3.87 - 3.77 (m, 7H), 3.56 - 3.54 (m, 2H), 2.53 - 2.50 (m, 4H).

[0048] Example 2: Inhibitory effects of ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1 on the proliferation of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, renal cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myeloproliferative neoplasm and melanoma cells

[0049] Logarithmic growth phase H460, MDA-MB-468, HepG2, BxPC-3, MKN-45, TPC-1, U251, CNE-1, TE-11, HuH28, SW480, NTERA-2cl.D1, Thy0517, GRC-1, PC-3, EJ-1, Hela, SKOV3, WERI-Rb-1, MPP-89, U2OS, Jurkat, MM1.S, U937, SKM-1 and MEL202 cells were collected respectively. After counting, the cell suspension concentration was adjusted to 5×10 4cells / mL, add them to a 96-well cell culture plate, with a volume of 100 μL per well. Using DMSO as a solvent control, dilute the compounds ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1 of the present invention with DMSO and add them to the culture wells, so that the final concentrations of the compounds in the system are 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 and 100 (μmol / L) respectively. After continuous culture for 48 h, add 10 μL of CCK-8 solvent to each well, incubate at 37 °C for 1 h, read the value with an enzyme-linked immunosorbent assay (ELISA) reader, measure the OD value at an absorption wavelength of 450 nm, record the results, and plot the cell growth curve with the dose of the compound as the abscissa and the absorbance value as the ordinate. The statistical results of the half maximal inhibitory concentration (IC50 value) of the compounds against tumor cells are shown in Tables 1 to 4 below:

[0050] Table 1. Inhibitory effect of CCK-8 assay on the proliferation of ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1 on lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer and thyroid cancer cells

[0051]

[0052]

[0053] Table 2. Inhibitory effect of CCK-8 assay on the proliferation of ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1 on glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer and thymoma cells

[0054]

[0055]

[0056] Table 3. Proliferation inhibitory effects of CCK-8 assays on renal cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma and mesothelioma cells of ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1

[0057]

[0058]

[0059] Table 4. Proliferation inhibitory effects of CCK-8 assays on osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myelodysplastic syndrome and melanoma cells of ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1

[0060]

[0061]

[0062] The data in Tables 1, 2, 3, and 4 show that ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1, and ID230315A-1 all have good inhibitory effects on the proliferation of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myelodysplastic syndrome, and melanoma cell lines. In this application, ID230301A-1 was taken as an example to further study the in vivo anti-tumor effect of such compounds.

[0063] Example 3: Anti-tumor Pharmacodynamic Effect of ID230301A-1 in Mice

[0064] Twenty SPF-grade, 6-week-old, female BALB / c-nude mice weighing 18 - 22 g were purchased from Beijing Spearf Bio-Technology Co., Ltd. for inoculating tumor masses. Take the transplanted tumor tissue of MDA-MB-468 cells that was successfully inoculated subcutaneously before, wash away the blood and stains with PBS, cut it into small pieces with a diameter of 1.5 mm, suck a small tumor mass with a puncture needle, wipe the animal's abdomen with an alcohol cotton ball, and then directly pierce it subcutaneously and inject the tumor mass. Put the inoculated animals back into the original cage for breeding, keep the environment clean, and avoid infection. One week after inoculating the tumor cells, observe whether milky white nodules form at the inoculation site. Measure the long diameter and short diameter of the tumor with a vernier caliper, and calculate the tumor volume according to the formula (tumor volume = long diameter × short diameter 2 × 0.5). Wait until the tumor volume reaches 100 - 150 mm 3 and then conduct grouping and drug administration. Eighteen mice that met the experimental volume requirements were randomly divided into 3 groups, with 6 mice in each group. Administer the drug by intraperitoneal injection. The dose of ID230301A-1 is 5 mg / kg per mouse, the solvent (10% DMSO + 90% corn oil, denoted as SUS Control) is the blank control, and the albumin-bound paclitaxel injection at 5 mg / kg is the positive control. Inject 100 μL each time, administer the drug once a day, and continuously administer the drug for 24 days. Detect the tumor volume and body weight of the mice every other day. The results are shown in Figure 1 .

[0065] Figure 1The results showed that during the drug administration period, the tumor volumes of the ID230301A-1 5 mg / kg group and the Paclitaxel 5 mg / kg group were significantly smaller than those of the blank control group, and the efficacy of the ID230301A-1 5 mg / kg group was better than that of the Paclitaxel 5 mg / kg group. At the end of the drug administration, compared with the blank control group, the average body weight of the mice in the Paclitaxel 5 mg / kg group was significantly reduced (p<0.05). However, the average body weight of the mice in the ID230301A-1 5 mg / kg group was not significantly reduced, nor were there any other obvious adverse reactions. These data indicate that oral administration of ID230301A-1 has good anti-tumor efficacy and safety.

[0066] Example 4: Detection of the inhibitory effect of ID230301A-1 on STAT3 signaling by Western blot

[0067] Logarithmically growing MGC803 cells were seeded into 6-well cell culture plates at 6×10 5 cells per well. After the cells adhered, ID230301A-1 was added to make its final concentrations 0, 30, 100, 300, and 1000 nM, respectively. After about 24 h, the cells were lysed with RIPA lysis buffer to collect proteins for Western blot analysis. The expression levels of the corresponding proteins were detected by anti-STAT3, p-STAT3 (Tyr705), p-STAT3 (Ser727), and GAPDH antibodies, respectively.

[0068] The results were as Figure 2 shown that compared with the solvent control wells, after treatment with 100 nM ID230301A-1 for 24 h, the expression levels of p-STAT3 (Tyr705) and p-STAT3 (Ser727) in MGC803 cells could be significantly inhibited. When the concentration of ID230301A-1 increased to 1000 nM, the expressions of p-STAT3 (Tyr705) and p-STAT3 (Ser727) were completely inhibited. It was shown that compound ID230301A-1 could inhibit the dual-site phosphorylation of STAT3 protein in a dose-dependent manner without affecting the expression of total STAT3 protein.

[0069] In summary, the above results indicate that ID230301A-1, ID230302A-1, ID230303A-1, ID230304A-1, ID230305A-1, ID230306A-1, ID230307A-1, ID230308A-1, ID230309A-1, ID230310A-1, ID230311A-1, ID230312A-1, ID230313A-1, ID230314A-1 and ID230315A-1 can significantly inhibit the proliferation of lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myelodysplastic syndrome and melanoma cells. Moreover, compared with the chemotherapeutic drug albumin-bound paclitaxel, ID230308A-1 has better efficacy and safety in mice at the same dose as ID230301A-1. The antitumor mechanism of such compounds is related to the targeted inhibition of the activation of STAT3 signaling. Therefore, such drugs have good anti-cancer effects and development potential.

[0070] According to the general approach of drug development (first conducting conventional in vitro anti-tumor screening and then carrying out targeted research), the compounds of the present invention can be applied to cancer treatment drugs related to abnormal cell proliferation and can be prepared into anti-tumor drugs by forming salts acceptable to the human body or mixing with pharmaceutical carriers.

[0071] Finally, it should be noted that the above embodiments are only used to illustrate rather than limit the technical solutions of the present invention. Any equivalent replacement of the present invention and any modification or partial replacement without departing from the spirit and scope of the present invention shall be covered by the scope of protection of the claims of the present invention.

Claims

1. A diarylacetylene compound, characterized in that, The structural formula is as shown in General Formula I: wherein, R1 is selected from H or R2 is selected from W, X, Y, G, and Q are each independently selected from C and N, and V is selected from C.

2. The diarylacetylene compound according to claim 1, wherein Specifically, it is a compound with the following structure:

3. A biologically acceptable salt, characterized in that, It is formed by using the diarylacetylene compound described in Claim 1 or 2 and at least one of acetic acid, dihydrofolic acid, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediaminetetraacetic acid.

4. The preparation method of the diarylacetylene compound according to claim 1, characterized in that, The synthesis route is as shown below: The specific synthesis steps are as follows: (1) Dissolve Compound 1, Compound 2, HBTU, and DIEA in DMF. After stirring and reacting completely at 20 - 30 °C, dilute the reaction solution with ethyl acetate and wash it with saturated brine. Rotate the organic phase to dryness to obtain a crude product, and slurry the crude product with ethyl acetate to obtain Compound 3; (2) Dissolve Compound 3, Compound 4, and potassium carbonate in DMF. After stirring and reacting completely at 75 - 85 °C, dilute the reaction solution with ethyl acetate and wash it with saturated brine. Rotate the organic phase to dryness to obtain a crude product, and slurry the crude product with ethyl acetate to obtain Compound 5; (3) Dissolve Compound 5, Compound 6, Pd(PPh3)2Cl2, CuI, and TEA in DMF. After stirring and reacting completely at 75 - 85 °C, dilute the reaction solution with ethyl acetate and wash it with saturated brine. Rotate the organic phase to dryness to obtain a crude product, and subject the crude product to column chromatography to obtain the target compound.

5. The preparation method of the diarylacetylene compound according to claim 4, wherein, In step (1), the molar ratio of Compound 1, Compound 2, HBTU, and DIEA is 1:1:1.2:3; in step (2), the molar ratio of Compound 3, Compound 4, and potassium carbonate is 1:1:1.2; in step (3), the molar ratio of Compound 5, Compound 6, Pd(PPh3)2Cl2, CuI, and TEA is 1:5:0.1:0.2:

5.

6. Use of the diarylacetylene compound according to any one of Claims 1 to 3 and its biologically acceptable salts in the preparation of an anti-tumor drug.

7. The application according to claim 6, characterized in that, The anti-tumor drug is a drug for treating diseases related to STAT3 signal transduction.

8. The application according to claim 6, wherein: The tumors include lung cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, glioma, head and neck cancer, esophageal cancer, cholangiocarcinoma, colorectal cancer, testicular cancer, thymoma, kidney cancer, prostate cancer, bladder cancer, uterine cancer, ovarian cancer, retinoblastoma, mesothelioma, osteosarcoma, lymphoma, multiple myeloma, leukemia, chronic myelodysplastic syndrome, and melanoma.

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