A type of 3-arylindole KDM1A / HDACs dual-target inhibitor and its preparation method and application

Abstract

The present invention discloses a 3-aryl indole KDM1A / HDACs dual-target inhibitor, a preparation method thereof and an application thereof in the preparation of an anti-tumor drug, and belongs to the technical field of pharmaceutical chemistry. It has the following general formula: #imgabs0# wherein R is preferably CH3 and H; n is preferably 2, 3, 4 and 5. This class of compounds has strong KDM1A / HDACs dual inhibitory activity and in vitro anti-tumor activity, and the inhibitory activity against KDM1A and HDAC1 is at the nanomolar level. Among them, the IC values ​​of compounds I-3 and I-4 on KDM1A are 50 The IC values ​​of HDAC1 and HDAC2 were 39.0±3.5 nM and 89.7±11.6 nM, which were 20 and 9 times of the positive control drug GSK2879552, respectively. 50 The concentrations of compounds I-3 and I-4 were 1.4 nM and 0.56 nM, respectively, which were 10 and 25 times that of the positive control drug SAHA. Compounds I-3 and I-4 showed strong inhibitory activity in four tumor cell lines: human gastric cancer MGC-803, human colon cancer HCT-116, human esophageal cancer ECA-109 and EC-1. They can be used as candidate or lead compounds for further development to develop anti-tumor drugs, and the synthesis method is simple, which is conducive to promotion and application.

Description

Technical Field

[0001] The present invention specifically relates to a class of 3-arylindole KDM1A / HDAC dual-target inhibitors, a preparation method thereof and application in the preparation of anti-tumor drugs, and belongs to the technical field of pharmaceutical chemistry. Background Art

[0002] Malignant tumors pose a serious threat to human health. Although traditional chemotherapy drugs, targeted drugs, immunotherapy drugs and other anti-tumor drugs have achieved certain clinical results, due to the complex mechanisms of tumor occurrence and development, clinical practice has confirmed that anti-tumor drugs that work through a single mechanism of action are more likely to develop drug resistance and are difficult to cure tumors. Abnormal expression or mutation of epigenetic regulatory proteins is an important mechanism driving the occurrence and development of malignant tumors, immune escape and resistance to immunotherapy. Epigenetic drugs have become a hot area in the current research and development of anti-tumor drugs. Recent studies have found that epigenetic drugs can also enhance the immunogenicity of tumors and improve the effect of tumor immunotherapy.

[0003] Histone lysine-specific demethylase 1 (KDM1A) is the first reported histone demethylase. Its main function is to remove the mono- and di-methylation modifications (H3K4me1 / 2) of histone 3 lysine 4 (H3K4) in a flavin adenine dinucleotide-dependent manner. It silences the expression of downstream genes by changing the chromatin structure and is one of the important epigenetic regulatory proteins that regulate gene transcription. KDM1A is abnormally highly expressed in a variety of malignant tumors such as colon cancer, lung cancer, breast cancer, prostate cancer, and leukemia. Abnormally expressed KDM1A promotes the occurrence and development of tumors by changing the chromatin structure and silencing the expression of downstream genes. KDM1A can also demethylate non-histone proteins such as p53 and DNA methyltransferase 1, inhibit p53-mediated transcriptional activation and pro-apoptotic effects, affect the dynamic balance of DNA methylation / demethylation, and thus affect the tumor cell cycle and promote tumor proliferation. KDM1A downregulates the expression of E-cadherin protein by binding to the SNAG domain at the N-terminus of SNAIL1 protein, promoting epithelial-mesenchymal transition and enhancing the ability of tumor metastasis and invasion.

[0004] KDM1A can not only directly regulate the relevant signaling pathways in tumor cells to promote tumor proliferation, metastasis and invasion, but tumor cells also hijack the enhanced KDM1A to establish an immunosuppressive microenvironment through various mechanisms, promoting tumor immune escape and immunotherapy resistance. Knockout of KDM1A can reduce the stability of RNA-induced silencing complexes in tumor cells, enhance the expression of endogenous retroviral elements, and then activate the interferon signaling pathway to promote anti-tumor immune response. In the B16 melanoma mouse model that does not respond to PD-1 immunotherapy, knockout of KDM1A can effectively improve the immunogenicity of the tumor, enhance CD8+T cell infiltration in the tumor and increase the sensitivity to CD8+T cell immune activity, greatly improving the therapeutic effect of anti-PD-1. In triple-negative breast cancer with poor tumor immunogenicity, KDM1A inhibitors can significantly increase the expression of CD8+T cell chemokines CXCL9 and CXCL10 and enhance the tumor infiltration of CD8+T cells. KDM1A inhibitors combined with PD-1 antibodies can significantly inhibit the growth and lung metastasis of breast cancer. In addition, KDM1A-mediated epigenetic regulation is also closely related to the maintenance of pluripotency of tumor stem cells and resistance to tumor chemotherapy drugs. Inhibiting the activity of KDM1A or knocking out KDM1A can effectively inhibit tumor growth, invasion and metastasis. KDM1A has become one of the hot targets for tumor epigenetic therapy. Currently, seven KDM1A small molecule inhibitors, including IMG-7289, GSK2879552, TAK-418, ORY-2001, INCB059872, CC-90011 and SP-2577, have entered Phase I / II clinical trials for the treatment of acute myeloid leukemia and non-small cell lung cancer.

[0005] Histone deacetylases (HDACs) are an important class of histone deacetylases that are mainly responsible for removing acetylation modifications from lysine residues at the tail of histones and silencing gene transcription. HDACs regulate a variety of cellular processes in eukaryotes, including apoptosis, cell cycle, growth and differentiation. In a variety of malignant tumors such as leukemia, lymphoma, cervical cancer, colorectal cancer, and breast cancer, the expression level of HDACs is abnormally elevated, and is positively correlated with the poor prognosis of a variety of malignant tumors such as leukemia, lymphoma, cervical cancer, and colorectal cancer. In the past three decades, HDACs have been one of the hot targets for the development of anti-tumor drugs. Currently, five HDACs small molecule inhibitors, including Vorinostat (SAHA), Romidepsin, Belinostat, Panobinostat and Chidamide, have been approved by the FDA and CFDA for the treatment of malignant lymphoma, myeloma and other tumors. In addition, there are multiple HDACs inhibitors in clinical trials.

[0006] KDM1A and HDACs not only play an important role in the occurrence and development of tumors, but also have a close regulatory relationship between them, and they play the demethylase and deacetylase activities interdependently. KDM1A and HDAC1 / 2 co-exist in multiple protein complexes such as CoREST, Sin3A, and NuRD, and participate in regulating the transcription of multiple genes. HDAC1 can remove the acetylation modification on lysine 374 in the substrate binding region of KDM1A, promote the effective binding of KDM1A and histone H3, enhance the demethylase activity of KDM1A, and then inhibit the expression of downstream target genes. Inhibiting the activity of HDAC1 with the HDACs inhibitor SAHA can interfere with the binding of KDM1A to H3 and reduce the activity of KDM1A. In breast cancer, both KDM1A and HDAC5 are significantly overexpressed. HDAC5 stabilizes KDM1A's deubiquitinase USP28, enhances KDM1A deubiquitination, reduces KDM1A degradation via the ubiquitination-proteasome pathway, and upregulates intracellular KDM1A protein levels, thereby promoting the occurrence and development of breast cancer and conferring stem cell-like characteristics to breast cancer cells. On the contrary, inhibiting HDAC5 activity or knocking out HDAC5 promotes KDM1A ubiquitination degradation, inhibiting the proliferation and invasion of breast cancer cells. The combination of KDM1A inhibitors and HDACs inhibitors shows good synergistic anti-tumor effects in a variety of malignant tumors such as acute myeloid leukemia, breast cancer, glioblastoma, rhabdomyosarcoma, and Ewing's sarcoma. Therefore, the discovery of new, highly active KDM1A / HDACs dual-target inhibitors that exert synergistic anti-tumor effects by simultaneously inhibiting KDM1A and HDACs is expected to discover new and efficient anti-tumor lead compounds, which is of great significance for studying the physiological functions of KDM1A and HDACs and developing new and efficient anti-tumor drugs. In order to discover new KDM1A / HDACs dual-target inhibitors, the starting point of this application is to explore the synthesis of a class of 3-arylindole compounds and verify their KDM1A and HDACs dual-target inhibitory activity and in vitro anti-tumor activity. At present, there are no reports on the synthesis, KDM1A / HDACs inhibitory activity and anti-tumor activity of this class of compounds. Summary of the invention

[0007] From the above, it can be seen that one purpose of the present invention is to provide a class of 3-aryl indole compounds to provide a possibility for new drug screening.

[0008] Another object of the present invention is to provide a method for preparing such 3-aryl indole compounds.

[0009] Another object of the present invention is to provide the use of the 3-aryl indole compounds in the preparation of anti-tumor drugs with KDM1A / HDACs as targets.

[0010] To achieve the above object, the general structural formula of the 3-aryl indole compounds involved in the present invention is:

[0011]

[0012] In the general formula I, R is CH 3 , any one of H, and n is any one of 2, 3, 4, and 5.

[0013] Preferably: In the general formula I, the substituent represented by R and the number of carbon atoms represented by n are shown in the following table:

[0014]

[0015]

[0016] To achieve the above second purpose, the synthesis reaction flow of the compound of the present invention is as follows:

[0017]

[0018] Preparation method of compound 2: Compound 1 and ethyl bromoalkanoate are reacted in N,N-dimethylformamide (DMF) in the presence of NaH under stirring in an ice bath. After the reaction is completed, the organic phases are extracted, combined, washed, dried, filtered, and the filtrate is concentrated in vacuo. The concentrate is separated by column chromatography to obtain compound 2.

[0019] Preparation method of compound 3: Compound 2 and N-bromosuccinimide (NBS) are reacted in DMF with stirring at room temperature. After the reaction is completed, the organic phases are extracted, combined, washed, dried, filtered, and the filtrate is vacuum concentrated. The concentrate is separated by column chromatography to obtain compound 3.

[0020] Preparation method of compound 4: Compound 3 and 2-methyl-3-aminophenylboronic acid pinacol ester are heated and stirred in toluene in the presence of a basic compound and a palladium catalyst for reaction. After the reaction is completed, the organic phases are extracted, combined, washed, dried, filtered, the filtrate is concentrated under reduced pressure, and the concentrate is separated by column chromatography to obtain compound 4. The basic compound is selected from one of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, and potassium phosphate, and the palladium catalyst is selected from one of tetrakis(triphenylphosphine)palladium, palladium acetate, bis(dibenzylideneacetone)palladium, and palladium dichloride.

[0021] Preparation method of compound I: In dichloromethane solution, compound 4 and NH 2 OK / NH 2 After the reaction is completed, the reaction system is concentrated in vacuo, the concentrate is dissolved in water, the pH is adjusted to 6-7, filtered, washed, the solid is collected, and purified by column chromatography to obtain compound I.

[0022] Advantages of the present invention: The 3-aryl indole compounds synthesized by the present invention have strong KDM1A / HDACs dual inhibitory activity and in vitro anti-tumor activity, and the inhibitory activity against KDM1A and HDAC1 is at the nanomolar level. Among them, the IC values ​​of compounds I-3 and I-4 against HDAC1 are 50 They are 1.4nM and 0.56nM respectively, which are 10 times and 25 times that of the positive control drug SAHA. Compounds I-3 and I-4 have strong inhibitory activity in four tumor cell lines: human gastric cancer MGC-803, human colon cancer HCT-116, human esophageal cancer ECA-109 and EC-1. Among them, the inhibitory activity of compounds I-3 and I-4 on MGC-803 is 24 times and 10 times that of the positive control drugs GSK2879552 and SAHA, respectively, and is equivalent to the inhibitory activity of the KDM1A / HDACs dual-target inhibitor 4SC-202, which is undergoing phase I clinical trials; the inhibitory activity on HCT-116 cells is 5 times and 10 times that of SAHA and 4SC-202, respectively. The compounds of the present invention represent a class of KDM1A / HDACs dual-target inhibitors with a new structure and high activity, which provide a basis for the research and development of KDM1A / HDACs dual-target inhibitor drugs and an effective tool for the study of the biological functions of KDM1A and HDACs. They can be used as candidate or lead compounds for further development in the development of anti-tumor drugs, and the synthesis method is simple, which is conducive to popularization and application. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 After treating MGC-803 cells with different concentrations of the compounds I-3 and I-4 of the present invention and 5 μM of the positive control drugs SAHA and GSK2879552 for 48 hours, Western Blot was used to detect the changes in the expression levels of KDM1A substrate H3K4me1 / me2 and HDACs substrate Ac-H3. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is described in detail below with reference to the reaction scheme and examples.

[0025] Example 1 Synthesis of ethyl 5-(5-cyano-1H-indol-1-yl)pentanoate (2a)

[0026]

[0027] Sodium hydride (1440.0 mg, 36.0 mmol) was added to a 100 mL two-necked flask, and anhydrous DMF (30 mL) was added under nitrogen protection. The anhydrous DMF (5 mL) solution of compound 1a (853.0 mg, 6.0 mmol) was slowly added dropwise to the reaction bottle under ice bath. After stirring for 5 min, 5-bromovalerate (1379.9 mg, 6.6 mmol) was slowly added dropwise. After the addition, the reaction was stirred in an ice bath for 1.5 hours. Water and ethyl acetate were added to the reaction system for extraction. The ethyl acetate layer was combined, washed with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (petroleum ether: acetone = 4:1) to obtain compound 2a (778.6 mg), a colorless oil, with a yield of 48.0%. 1 H NMR (400 MHz, CDCl 3 )δ7.96(d,1H,J=0.8Hz),7.44 -7.36(m,1H),7.22(d,1H,J=3.2Hz),6.57(d,1H,J=3.2Hz),4.17(t,2H,J=7.2Hz),4.11(q,2H, J=7.2Hz),2.32(t,2H,J=7.2Hz),1.92-1.84(m,2H),1.67-1.60(m,2H),1.23(t,3H,J=7.2Hz). 13 C NMR (101 MHz, CDCl 3 )δ173.04,137.44,130.08,128.26,126.62,124.40,120.91,110.18,102.37,102.31,60.50,46.35,33.61,29.61,22.23,14.23.HRMS(ESI)calcd for C 16 H 18 N 2 NaO 2 [M+Na] + :293.1260,Found:293.1258.

[0028] Example 2 Synthesis of 6-(5-cyano-1H-indol-1-yl)hexanoic acid ethyl ester (2b)

[0029]

[0030] According to the method of Example 1, ethyl 6-bromohexanoate (1472.5 mg, 6.6 mmol) was used to replace ethyl 5-bromovalerate to obtain the target compound 2b (546.0 mg), a colorless oily liquid, with a yield of 32.0%. 1H NMR (400 MHz, CDCl 3 )δ7.97(d,1H,J=0.8Hz),7.44-7.37(m,2H),7.21(d,1H,J=3.2Hz),6.57(dd,1H,J 1 =0.8Hz,J 2 =3.2Hz),4.17-4.08(m,4H),2.28(t,2H,J=7.6Hz),1.90-1.82(m,2H),1.69-1.62(m,2H),1.37-1.28(m,2H),1.23(t,3H,J=7.2Hz). 13 CNMR (101MHz, CDCl 3 )δ173.41,137.44,130.10,128.24,126.61,124.37,120.91,110.18,102.26,60.37,46.41,34.00,29.92,26.35,24.42,14.24.HRMS(ESI)calcd for C 17 H 20 N 2 NaO 2 [M+Na] + :307.1417,Found:307.1417.

[0031] Example 3 Synthesis of ethyl 7-(5-cyano-1H-indol-1-yl)heptanoate (2c)

[0032]

[0033] According to the method of Example 1, 5-bromovalerate ethyl ester was replaced with 7-bromoheptanoic acid ethyl ester (1565.1 mg, 6.6 mmol) to obtain the target compound 2c (698.2 mg) as a colorless oil with a yield of 39.0%. 1 H NMR (400 MHz, CDCl 3 )δ7.97(d,1H,J=0.8Hz),7.44-7.37(m,2H),7.21(d,1H,J=3.2Hz),6.57(d,1H,J=2.8Hz),4.16-4.09(m,4 H),2.27(t,2H,J=7.2Hz),1.88-1.81(m,2H),1.64-1.56(m,2H),1.37-1.28(m,4H),1.24(t,3H,J=7.2Hz). 13 C NMR (101 MHz, CDCl 3)δ173.59,137.46,130.04,128.22,126.60,124.35,120.88,110.17,102.28,10 2.21,60.27,46.54,34.09,30.00,28.61,26.56,24.67,14.24.HRMS(ESI)calcd for C 18 H 22 N 2 NaO 2 [M+Na] + :321.1573,Found:321.1571.

[0034] Example 4 Synthesis of 8-(5-cyano-1H-indol-1-yl)octanoic acid ethyl ester (2d)

[0035]

[0036] According to the method of Example 1, 5-bromovalerate ethyl ester was replaced with 8-bromooctanoate ethyl ester (1657.7 mg, 6.6 mmol) to obtain the target compound 2d (759.2 mg) as a light yellow oil with a yield of 40.5%. 1 H NMR (400 MHz, CDCl 3 )δ7.97(d,1H,J=0.8Hz),7.44-7.36(m,2H),7.21(d,1H,J=3.2Hz),6.57(dd,1H,J 1 =0.4Hz,J 2 =3.2Hz),4.15-4.09(m,4H),2.27(t,2H,J=7.2Hz),1.86-1.79(m,2H),1.63-1.55(m,2H),1.34-1.27(m,6H),1.25(t,3H,J=7.2Hz). 13 CNMR (101MHz, CDCl 3 )δ173.76,137.47,130.10,128.22,126.60,124.32,120.94,110.21,102.22,102.1 8,60.26,46.63,34.22,30.15,28.91,28.84,26.72,24.78,14.27.HRMS(ESI)calcd for C 19 H 24 N 2 NaO 2 [M+Na] + :335.1730,Found:335.1736.

[0037] Example 5 Synthesis of 6-(5-cyano-6-methyl-1H-indol-1-yl)hexanoic acid ethyl ester (2e)

[0038]

[0039] According to the method of Example 1, compound 1b (937.1 mg, 6.0 mmol) was used to replace compound 1a, and ethyl 6-bromohexanoate (1472.5 mg, 6.6 mmol) was used to replace ethyl 5-bromovalerate to obtain the target compound 2e (823.5 mg) as a colorless oil with a yield of 46.0%. 1 H NMR (400 MHz, CDCl 3 )δ7.90(s,1H),7.19(s,1H),7.12(d,1H,J=3.2Hz),6.50(dd,1H,J 1 =0.8Hz,J 2 =3.2Hz),4.14-4.08(m,4H),2.64(s,3H),2.28(t,2H,J=7.2Hz),1.88-1 .80(m,2H),1.70-1.62(m,2H),1.38-1.30(m,2H),1.23(t,3H,J=7.2Hz). 13 CNMR (101MHz, CDCl 3 )δ173.44,137.99,133.65,129.56,126.80,126.39,120.11,110.46,103.59,101 .88,60.36,46.28,34.02,29.87,26.36,24.44,20.97,14.24.HRMS(ESI)calcdfor C 18 H 22 N 2 NaO 2 [M+Na] + :321.1573,Found:321.1572.

[0040] Example 6 Synthesis of ethyl 7-(5-cyano-6-methyl-1H-indol-1-yl)heptanoate (2f)

[0041]

[0042] According to the method of Example 1, compound 1b (937.1 mg, 6.0 mmol) was used to replace compound 1a, and ethyl 7-bromoheptanoate (1565.1 mg, 6.6 mmol) was used to replace ethyl 5-bromovalerate to obtain the target compound 2f (937.2 mg) as a colorless oil with a yield of 50.0%. 1 H NMR (400 MHz, CDCl 3 )δ7.90(s,1H),7.20(s,1H),7.12(d,1H,J=3.2Hz),6.49(d,1H,J=8.4Hz),4.14-4.07(m,4H),2.62(s,3H),2.37 (t,2H,J=7.6Hz),3.76(s,3H),1.86-1.79(m,2H),1.64-1.57(m,2H),1.39-1.28(m,4H),1.24(t,3H,J=7.2Hz). 13 CNMR (101MHz, CDCl 3 ) 13 C NMR (101 MHz, CDCl 3 )δ173.62,138.02,133.62,129.55,126.78,126.38,120.12,110.48,103.56,101.8 4,60.28,46.41,34.12,29.96,28.65,26.58,24.70,20.96,14.26.HRMS(ESI)calcd for C 19 H 24 N 2 NaO 2 [M+Na] + :3 3 5.1 7 3 0,Found:3 35.1 7 2 8.

[0043] Example 7 Synthesis of ethyl 5-(3-bromo-5-cyano-1H-indol-1-yl)pentanoate (3a)

[0044]

[0045] Compound 2a (540.7 mg, 2.0 mmol) was added to a 50 mL two-necked flask and dissolved in anhydrous DMF (10 mL). N-bromosuccinimide (NBS) (391.6 mg, 2.2 mmol) in anhydrous DMF (10 mL) was slowly added dropwise under nitrogen protection. The mixture was stirred at room temperature for 2 hours. After the reaction, water and ethyl acetate were added to the system for extraction. The ethyl acetate layers were combined, washed with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 3a (593.7 mg), a colorless oily liquid, with a yield of 85.0%. 1 HNMR (400MHz, CDCl 3 )δ7.91(d,1H,J=1.2Hz),7.47(dd,1H,J 1 =1.2Hz,J 2 =8.4Hz),7.38(d,1H,J=8.4Hz),7.25(s,1H),4.17-4.08(m,4H),2.33(t,2 H,J=7.2Hz),1.92-1.84(m,2H),1.68-1.60(m,2H),1.24(t,3H,J=7.2Hz). 13 C NMR (101 MHz, CDCl 3 )δ172.91,137.10,128.92,127.31,125.45,125.28,120.19,110.57,103.45,90.84,60.55,46.69,33.53,29.61,22.13,14.22.HRMS(ESI)calcd for C 16 H 17 Bn 2 NaO 2 [M+Na] + :371.0366,Found:371.0367.

[0046] Example 8 Synthesis of 6-(3-bromo-5-cyano-1H-indol-1-yl)hexanoic acid ethyl ester (3b)

[0047]

[0048] According to the method of Example 7, compound 2b (568.7 mg, 2.0 mmol) was used to replace compound 2a to obtain compound 3b (639.3 mg), a colorless oily liquid, with a yield of 88.0%. 1 H NMR (400 MHz, CDCl 3)δ7.89(d,1H,J=1.6Hz),7.46(dd,1H,J 1 =1.6Hz,J 2 =8.4Hz),7.37(d,1H,J=8.4Hz),7.25(s,1H),4.17-4.08(m,4H),2.29(t,2H,J=7.2H z),1.89-1.81(m,2H),1.69-1.61(m,2H),1.38-1.29(m,2H),1.23(t,3H,J=7.2Hz). 13 C NMR (101 MHz, CDCl 3 )δ173.39,137.08,129.03,127.22,125.34,125.18,120.25,110.63,103.2 7,90.63,60.41,46.74,33.93,29.92,26.25,24.35,14.24.HRMS(ESI)calcd for C 17 H 19 Bn 2 NaO 2 [M+Na] + :385.0522,Found:385.0531.

[0049] Example 9 Synthesis of ethyl 7-(3-bromo-5-cyano-1H-indol-1-yl)heptanoate (3c)

[0050]

[0051] According to the method of Example 7, compound 2c (596.8 mg, 2.0 mmol) was used to replace compound 2a to obtain compound 3c (709.3 mg), a colorless oily liquid, with a yield of 94.0%. 1 H NMR (400 MHz, CDCl 3 )δ7.91(d,1H,J=1.2Hz),7.47(dd,1H,J 1 =1.6Hz,J 2 =8.8Hz),7.38(d,1H,J=8.8Hz),7.24(s,1H),4.14-4.08(m,4H),2.27(t,2H,J=7.2H z),1.87-1.80(m,2H),1.64-1.57(m,2H),1.37-1.31(m,4H),1.25(t,3H,J=7.2Hz). 13 C NMR (101 MHz, CDCl 3)δ173.58,137.11,128.98,127.23,125.35,125.23,120.26,110.62,103.31,9 0.63,60.32,46.89,34.07,30.02,28.58,26.50,24.63,14.27.HRMS(ESI)calcd for C 18 H 21 Bn 2 NaO 2 [M+Na] + :399.0679,Found:399.0679.

[0052] Example 10 Synthesis of 8-(3-bromo-5-cyano-1H-indol-1-yl)octanoic acid ethyl ester (3d)

[0053]

[0054] According to the method of Example 7, compound 2d (624.8 mg, 2.0 mmol) was used to replace compound 2a to obtain compound 3d (713.7 mg), a white solid, with a yield of 91.2%, Mp: 66-67 ° C. 1 H NMR (400 MHz, CDCl 3 )δ7.92(d,1H,J=1.6Hz),7.47(dd,1H,J 1 =1.6Hz,J 2 =8.8Hz),7.38(d,1H,J=8.8Hz),7.24(s,1H),4.14-4.09(m,4H),2.27(t,2H,J=7.2H z),1.86-1.76(m,2H),1.63-1.56(m,2H),1.38-1.32(m,6H),1.25(t,3H,J=7.2Hz). 13 C NMR (101 MHz, CDCl 3 )δ173.72,137.12,128.98,127.23,125.35,125.24,120.26,110.62,103.31,90.6 1,60.27,46.98,34.20,30.17,28.87,28.81,26.64,24.77,14.28.HRMS(ESI)calcd for C 19 H 24 Bn 2 O 2 [M+H] + :391.1016,Found:391.1019.

[0055] Example 11 Synthesis of 6-(3-bromo-5-cyano-6-methyl-1H-indol-1-yl)hexanoic acid ethyl ester (3e)

[0056]

[0057] According to the method of Example 7, compound 2e (596.8 mg, 2.0 mmol) was used to replace compound 2a to obtain compound 3e (686.6 mg), a yellow oily liquid, with a yield of 91.0%. 1 H NMR (400 MHz, CDCl 3 )δ7.84(s,1H),7.19(s,1H),7.15(s,1H),7.12(d,1H,J=3.2Hz),4.14-4.07(m,4H),2.65(s,3H),2. 29(t,2H,J=7.2Hz),1.87-1.80(m,2H),1.70-1.63(m,2H),1.38-1.30(m,2H),1.24(t,3H,J=7.2Hz). 13 CNMR (101MHz, CDCl 3 )δ173.36,137.56,134.87,128.37,125.51,125.44,119.42,110.77,1 04.71,90.36,60.39,46.58,33.95,29.87,26.27,24.37,20.96,14.24.

[0058] Example 12 Synthesis of ethyl 7-(3-bromo-5-cyano-6-methyl-1H-indol-1-yl)heptanoate (3f)

[0059]

[0060] According to the method of Example 7, compound 2f (624.8 mg, 2.0 mmol) was used to replace compound 2a to obtain compound 3f (641.7 mg), a white solid, with a yield of 82.0%, Mp: 65-66 ° C. 1 H NMR (400 MHz, CDCl 3 )δ7.84(s,1H),7.20(s,1H),7.15(s,1H),4.14-4.05(m,4H),2.65(s,3H),2.28(t,2H,J= 7.2Hz),1.86-1.78(m,2H),1.64-1.57(m,2H),1.40-1.28(m,4H),1.25(t,3H,J=7.2Hz). 13C NMR (101 MHz, CDCl 3 )δ173.59,137.57,134.84,128.37,125.48,125.44,119.46,110.79,104.66,90.3 0,60.32,46.74,34.09,29.97,28.60,26.51,24.64,20.98,14.27.HRMS(ESI)calcd forC 19 H 23 Bn 2 NaO 2 [M+Na] + :413.0835,Found:413.0838.

[0061] Example 13 Synthesis of ethyl 5-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)pentanoate (4a)

[0062]

[0063] Compound 3a (698.4 mg, 2.0 mmol), tetrakis(triphenylphosphine)palladium (462.2 mg, 0.4 mmol), toluene (5 mL) and 2M potassium carbonate aqueous solution (1.85 mL, 3.7 mmol) were added to a 50 mL two-necked flask. Under nitrogen protection, an anhydrous ethanol solution (5 mL) of 2-methyl-3-aminophenylboronic acid pinacol ester (512.9 mg, 2.2 mmol) was added dropwise. The mixture was heated and stirred at 92 °C for 7 hours. Water and ethyl acetate were added to the system for extraction. The ethyl acetate layers were combined, washed with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound 4a (554.9 mg) as a colorless oil with a yield of 73.9%. HRMS (ESI) calcd for C 19 H 23 Bn 2 NaO 2 [M+Na] + :413.0835,Found:413.0838.

[0064] Example 14 Synthesis of ethyl 6-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)hexanoate (4b)

[0065]

[0066] According to the method of Example 13, compound 3b (726.5 mg, 2.0 mmol) was used to replace 3a to obtain compound 4b (555.4 mg) as a colorless oil with a yield of 71.3%. HRMS (ESI) calculation for C 24 H 28 N 3 O 2 [M+H] + :390.2176,Found:390.2174.

[0067] Example 15 Synthesis of ethyl 7-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)heptanoate (4c)

[0068]

[0069] According to the method of Example 13, compound 3c (754.6 mg, 2.0 mmol) was used to replace 3a to obtain compound 4c (518.1 mg) as a colorless oil with a yield of 64.2%. HRMS (ESI) calculation for C 25 H 29 N 3 NaO 2 [M+Na] + :426.2152,Found:426.2154.

[0070] Example 16 Synthesis of 8-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)octanoic acid ethyl ester (4d)

[0071]

[0072] According to the method of Example 13, compound 3d (782.6 mg, 2.0 mmol) was used to replace 3a to obtain compound 4d (587.9 mg) as a colorless oil with a yield of 70.4%. HRMS (ESI) calculation for C 26 H 32 N 3 O 2 [M+H] + :418.2489,Found:418.2490.

[0073] Example 17 Synthesis of 6-(3-(3-amino-2-methylphenyl)-5-cyano-6-methyl-1H-indol-1-yl)hexanoic acid ethyl ester (4e)

[0074]

[0075] According to the method of Example 13, compound 3e (754.6 mg, 2.0 mmol) was used to replace 3a to obtain compound 4e (481.8 mg) as a colorless oil with a yield of 59.7%. HRMS (ESI) calculation for C 25 H 30 N 3 O 2 [M+H] + :404.2333,Found:404.2337.

[0076] Example 18 Synthesis of ethyl 7-(3-(3-amino-2-methylphenyl)-5-cyano-6-methyl-1H-indol-1-yl)heptanoate (4f)

[0077]

[0078] According to the method of Example 13, compound 3f (782.6 mg, 2.0 mmol) was used to replace 3a to obtain compound 4f (461.0 mg) as a colorless oil with a yield of 55.2%. HRMS (ESI) calculation for C 26 H 32 N 3 O 2 [M+H] + :418.2489,Found:418.2484.

[0079] Example 19 Synthesis of 5-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)-N-hydroxypentanamide (I-1)

[0080]

[0081] Under ice bath stirring, potassium hydroxide anhydrous methanol solution (7.0 g, 45 mL methanol) was slowly added dropwise to hydroxylamine hydrochloride anhydrous methanol solution (5.84 g, 20 mL methanol), stirred for 10 minutes after addition, and filtered to obtain NH 2 OK-NH 2 Compound 4a (375.5 mg, 1.0 mmol) was added to a 25 mL two-necked flask and dissolved in anhydrous dichloromethane (5 mL). Stirred for 5 min under nitrogen protection and ice bath, and then NH 2 OK-NH 2OH methanol solution (16.4 mL), continue to react for 0.5 hours under ice bath, concentrate the reaction system under reduced pressure, dissolve the concentrate with distilled water (20 mL), adjust pH to 6-7 with dilute HCl, solid precipitates, filter, collect the solid, separate and purify by column chromatography (dichloromethane: methanol = 10: 1) to obtain compound I-1 (199.3 mg), white solid, yield: 55.0%, Mp: 90-91 ° C. 1 H NMR (400 MHz, DMSO-d 6 )δ10.39(s,1H),8.73(s,1H),7.77-7.73(m,2H),7.61(s,1H),7.53(d,1H,J=8.8Hz),6.97(t,1H,J=7.6Hz),6.67(d,1H,J=7 .6Hz), 6.57 (d, 1H, J = 7.2Hz), 4.93 (s, 2H), 4.30 (t, 2H, J = 6.8Hz), 2.01-1.94 (m, 5H), 1.80-1.72 (m, 2H), 1.53-1.45 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ169.18,147.76,137.72,133.51,130.30,127.38,126.33,125.42,124.29,121.05,119.93, 119.22,117.24,113.56,112.00,101.65,45.84,32.25,29.89,22.93,15.21.HRMS(ESI)calcd for C 21 H 23 N 4 O 2 [M+H] + :363.1816,Found:363.1813.

[0082] Example 20 Synthesis of 6-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)-N-hydroxyhexanamide (I-2)

[0083]

[0084] According to the method of Example 19, compound 4b (389.5 mg, 1.0 mmol) was used to replace 4a to obtain compound I-2 (60.2 mg), a light yellow solid, with a yield of 16.0%, Mp: 77-78 ° C. 1 H NMR (400 MHz, DMSO-d 6)δ10.32(s,1H),8.70(s,1H),7.76-7.71(m,2H),7.60(s,1H),7.52(dd,1H,J 1 =1.6Hz,J 2 =8.4Hz),6.96(t,1H,J=7.6Hz),6.66(d,1H,J=7.6Hz),6.56(d,1H,J=7.2Hz),4.92(s,2H),4.27(t,2H, J=7.2Hz),1.98(s,3H),1.92(t,2H,J=7.2Hz),1.84-1.76(m,2H),1.56-1.48(m,2H),1.29-1.20(m,2H). 13 C NMR (101 MHz, DMSO-d 6 )δ169.30,147.76,137.71,133.53,130.27,127.36,126.33,125.41,124.28,121.07,119.93,119 .23,117.21,113.55,111.99,101.61,46.03,32.57,30.00,26.28,25.18,15.21.HRMS(ESI)calcd for C 22 H 25 N 4 O 2 [M+H] + :377.1972,Found:377.1970.

[0085] Example 21 Synthesis of 7-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)-N-hydroxyheptylamide (I-3)

[0086]

[0087] According to the method of Example 19, compound 4c (403.5 mg, 1.0 mmol) was used to replace 4a to obtain compound I-3 (140.6 mg), a yellow solid, with a yield of 36.0%, Mp: 100-101°C. 1 H NMR (400 MHz, DMSO-d 6)δ10.33(s,1H),8.73(s,1H),7.76-7.73(m,2H),7.61(s,1H),7.52(d,1H,J=8.0Hz),6.97(t,1H,J=7.6Hz),6.67(d,1H,J=7.6Hz),6.57(d,1H ,J=7.6Hz),4.93(s,2H),4.28(t,2H,J=6.0Hz),1.99(s,3H),1.92(t,2H,J=7.2Hz),1.86-1.72(m,2H),1.53-1.38(m,2H),1.27-1.25(m,4H). 13 C NMR (101 MHz, DMSO-d 6 )δ169.43,147.76,137.71,133.54,130.30,127.37,126.33,125.40,124.27,121.06,119.93,119.21 ,117.18,113.55,111.97,101.61,46.10,32.61,30.11,28.61,26.41,25.51,15.18.HRMS(ESI)calcd for C 23 H 25 N 4 O 2 [MH] - :389.1983,Found:389.1985.

[0088] Example 22 Synthesis of 8-(3-(3-amino-2-methylphenyl)-5-cyano-1H-indol-1-yl)-N-hydroxyoctanamide (I-4)

[0089]

[0090] According to the method of Example 19, compound 4d (417.5 mg, 1.0 mmol) was used to replace 4a to obtain compound I-4 (220.5 mg), a yellow solid, with a yield of 54.5%, Mp: 72-73 ° C. 1 H NMR (400 MHz, DMSO-d 6 )δ10.16(brs,1H),9.09(brs,1H),7.72(s,2H),7.59(s,1H),7.52(s,1H),6.96(s,1H),6.66(s,1H ),6.55(s,1H),4.92(s,2H),4.27(s,2H),1.97-1.77(m,7H),1.50-1.37(m,2H),1.34-1.07(m,6H).13 C NMR (101 MHz, DMSO-d 6 )δ169.44,147.75,137.71,133.53,130.32,127.36,126.32,125.38,124.26,121.06,119.92,119.20,11 7.15,113.53,111.97,101.59,46.10,32.64,30.20,28.97,28.73,26.56,25.49,15.17.HRMS(ESI)calcd for C 24 H 27 N 4 O 2 [MH] - :403.2139,Found:403.2145.

[0091] Example 23 Synthesis of 6-(3-(3-amino-2-methylphenyl)-5-cyano-6-methyl-1H-indol-1-yl)-N-hydroxyhexanamide (I-5)

[0092]

[0093] According to the method of Example 19, compound 4e (403.5 mg, 1.0 mmol) was used to replace 4a to obtain compound I-5 (136.7 mg), a white solid, with a yield of 35.0%, Mp: 127-128 ° C. 1 H NMR (400 MHz, DMSO-d 6 )δ10.27(s,1H),8.85(s,1H),7.66(s,1H),7.62(s,1H),7.50(s,1H),6.96(t,1H,J=7.6Hz),6.66(d,1H,J=7.6Hz),5.56(d,1H,J=7.2Hz),4. 92(s,2H),4.22(t,2H,J=7.2Hz),2.58(s,3H),1.98(s,3H),1.92(t,2H,J=7.2Hz),1.83-1.75(m,2H),1.58-1.50(m,2H),1.30-1.22(m,2H). 13 C NMR (101 MHz, DMSO-d 6)δ169.31,147.73,138.19,133.70,133.15,129.66,126.30,125.71,125.61,120.18,119.89,119.19 ,116.92,113.49,111.97,102.94,45.95,32.60,29.92,26.30,25.18,20.76,15.19.HRMS(ESI)calcd for C 23 H 27 N 4 O 2 [M+H] + :391.2129,Found:391.2129.

[0094] Example 24 Synthesis of 7-(3-(3-amino-2-methylphenyl)-5-cyano-6-methyl-1H-indol-1-yl)-N-hydroxyheptylamide (I-6)

[0095]

[0096] According to the method of Example 19, compound 4f (417.5 mg, 1.0 mmol) was used to replace 4a to obtain compound I-6 (80.9 mg), a light yellow solid, with a yield of 20.0%, Mp: 59-60 ° C. 1 H NMR (400 MHz, DMSO-d 6 )δ10.35(s,1H),8.68(s,1H),7.65(s,1H),7.62(s,1H),7.50(s,1H),6.96(t,1H,J=7.6Hz),6.66(d,1H,J=7.6Hz),6.55(d,1H,J=7.6Hz),4. 92(s,2H),4.22(t,2H,J=7.2Hz),2.58(s,3H),1.98(s,3H),1.92(t,2H,J=7.2Hz),1.82-1.74(m,2H),1.50-1.42(m,2H),1.28-1.25(m,4H). 13 CNMR (101MHz, DMSO-d 6)δ169.49,147.74,138.18,133.70,133.14,129.71,126.30,125.71,125.60,120.18,119.87,119.15,11 6.87,113.47,111.96,102.93,46.00,32.64,30.03,28.61,26.42,25.52,20.76,15.18.HRMS(ESI)calcd for C 24 H 29 N 4 O 2 [M+H] + :405.2285,Found:405.2286.

[0097] (II) Evaluation of biological activity

[0098] 1. Experimental methods for evaluating KDM1A inhibitory activity

[0099] The sample is obtained by purifying the above compound synthesized in the example; sample stock solution: weigh 3-5 mg of the sample and place it in a 1.5 mL EP tube, then use DMSO to prepare a solution with a concentration of 20 mM, store it at -20°C in the dark, and dilute it with DMSO according to the required concentration during the experiment. After the sample to be tested is incubated with KDM1A protein at room temperature, the KDM1A reaction substrate H3K4me2 is added and incubated for reaction, and finally the fluorescent dye Amplex and horseradish peroxidase HRP are added and incubated at room temperature, and the fluorescence value is detected on the microplate reader at an excitation light of 530 nm and an emission light of 590 nm.

[0100]

[0101] The test results were calculated using SPSS software. 50 value.

[0102] 2. Experimental methods for evaluating HDAC1 inhibitory activity

[0103] Weigh 3-5 mg of sample into a 1.5 mL EP tube, then prepare a 10 mM solution with DMSO, store at -20 °C in the dark, and dilute with DMSO according to the required concentration during the experiment. Prepare 1× buffer (modified Tris buffer). HDAC enzyme is diluted with 1× buffer to 1.67× final concentration. Trypsin and acetyl peptide substrate are mixed to prepare substrate solution, which is diluted with 1× buffer to 2.5× final concentration. Transfer 250 nL of the test compound to a 384-well plate using Echo550. Then, add 15 μL of enzyme solution to the 384-well plate and pre-incubate with the test compound at room temperature for 15 min. Use 15 μL of 1× buffer as a negative control. Then add 10 μL of substrate solution to the 384 wells to start the reaction. Use EnVision to detect fluorescence intensity at an excitation wavelength of 355 nm and an emission wavelength of 460 nm.

[0104] 3. In vitro antitumor activity assay

[0105] The sample is the compound synthesized in the example; sample stock solution: 3-5 mg of the sample is weighed and placed in a 1.5 mL EP tube, and then prepared with DMSO to a concentration of 10 mmol / L solution, stored at -20°C away from light, and diluted with culture medium according to the required concentration during the experiment.

[0106] Take cells in the logarithmic growth phase, digest and count them, adjust the cell density with culture medium, inoculate 4000-5000 cells / well into 96-well plates, 100μL per well, and culture for 24h. Add different concentrations of drugs diluted with culture medium (10μM, 2.5μM, 0.625μM, 0.1563μM, 0.0391μM, 0.0098μM, 0.0024μM, 0.006μM), set 3 replicates for each concentration, and set up blank control group and positive control group. After 72h of drug action, add 40μL CellTiter-Glo Reagent to each well, shake and mix for 2min, continue to incubate at room temperature for 10min, detect fluorescence intensity with microplate reader, and calculate inhibition rate. The calculation formula is as follows:

[0107] Inhibition rate (%) = (maximum fluorescence intensity - fluorescence intensity of the drug-treated group) / (maximum fluorescence intensity - minimum fluorescence intensity) × 100%.

[0108] 4. Evaluation of KDM1A and HDACs inhibitory activity at the cellular level

[0109] Human gastric cancer MGC-803 cells (10 6The cells were inoculated with 100 cells / well on a six-well plate and incubated with compounds I-3, I-4, SAHA, GSK2879552, 4SC-202 and DMSO for 48 hours. The cells were then washed twice with phosphate-buffered saline, treated with RIPA lysis buffer and protease inhibitors (100:1), centrifuged, and the supernatant was collected. The protein concentration was determined by the BCA method. Equal amounts of cell extracts were then electrophoresed by SDS-PAGE and transferred to a nitrocellulose membrane, and detected by an enhanced chemiluminescence instrument using H3K4me1 / me2 antibody, Ac-H3 antibody, and H3 antibody, respectively.

[0110] 5. Experimental results

[0111] Table 1 Evaluation results of KDM1A and HDAC1 inhibitory activity

[0112]

[0113] a IC 50 Values ​​are the averages of three independent repeated experiments and are expressed as mean ± SD;

[0114] b GSK2879552, a selective inhibitor of KDM1A, has entered Phase II clinical trials;

[0115] c SAHA, also known as Vorinostat, is an HDAC1 inhibitor and a marketed drug;

[0116] b ND: Not detected.

[0117] It can be seen from the experimental results in Table 1 that the compounds of the present invention have good inhibitory activity against KDM1A and HDAC1, IC 50 The values ​​were all at the nanomolar level. The inhibitory activity of all compounds on KDM1A was less than 100 nM, among which the IC 50 The activity of most compounds on HDAC1 was significantly better than that of the positive control GSK2879552. 50 Less than 10 nM, better than the positive control SAHA. In particular, the IC of compounds I-3 and I-4 against HDAC1 50 The inhibitory activities against HDAC1 were 10 times and 25 times that of the positive control SAHA.

[0118] Since the inhibitory activities of compounds I-3 and I-4 on KDM1A and HDAC1 were significantly better than those of the positive controls GSK2879552 and SAHA, we evaluated the in vitro antitumor activities of compounds I-3 and I-4 on four solid tumor cell lines (human gastric cancer MGC-803, human colon cancer HCT-116, human esophageal cancer ECA-109 and EC-1).

[0119] Table 2 Evaluation results of in vitro antitumor activity of compounds I-3 and I-4

[0120]

[0121] a Compounds were incubated with cells for 72 h;

[0122] b KDM1A inhibitor, entering Phase II clinical trials;

[0123] c HDACs inhibitors, which are already on the market;

[0124] d KDM1A / HDAC dual-target inhibitor, Phase I clinical trial;

[0125] e Not detected.

[0126] The experimental results in Table 2 show that compounds I-3 and I-4 have good inhibitory activity against the four cell lines tested. From the data in the table, it can be seen that the IC values ​​of target compounds I-3 and I-4 for MGC-803 cells are 50 The inhibitory activities of I-3 on MGC-803 cells were 0.41±0.04μM and 0.88±0.06μM, respectively. ... 50 =9.98±1.18μM) and the marketed HDAC inhibitor SAHA (IC 50 =3.92±0.59μM), and 4SC-202 (IC 50 =3.92±0.59μM) had comparable inhibitory activity; while compound I-3 (IC 50 =0.22±0.03 μM) and I-4 (IC 50 =0.17±0.04μM) against HCT-116 cells, respectively. 50 =2.71±0.43 μM) and 4SC-202 (IC 50=1.22±0.19 μM) by 5 and 10 times; Compounds I-3 and I-4 had an effect on EC-1 (IC 50 The values ​​were 2.48±0.04 and 1.14±0.06 μM) and ECA-109 cells (IC 50 The inhibitory activity of SAHA (IC 50 The values ​​were 1.51±0.18, 3.11±0.45μM) and 4SC-202 (IC 50 The values ​​were 1.51±0.18 and 3.11±0.45 μM, respectively.

[0127] We used Western blot to evaluate whether compounds I-3 and I-4 could inhibit the activity of KDM1A and HDACs at the cellular level. After incubating compounds I-3 (1.25, 2.5, 5 μM) and I-4 (1.25, 2.5, 5 μM) with human gastric cancer MGC-803 cells for 48 hours, Western Blot was used to detect changes in the expression levels of KDM1A substrate H3K4me1 / me2 and HDACs substrate Ac-H3. SAHA, GSK2879552 and 4SC-202 were used as positive controls. Figure 1 As shown, compounds I-3 and I-4 can upregulate the expression of H3K4me1 / me2 and Ac-H3 in cells in a concentration-dependent manner, indicating that compounds I-3 and I-4 can effectively inhibit the activity of KDM1A and HDACs in cells. The compounds of the present invention represent a class of KDM1A / HDACs dual-target inhibitors with a new structure, have good in vitro anti-tumor activity, can be used as further developed candidate or lead compounds, and are used in the preparation of anticancer drugs, providing a basis for the research and development of KDM1A / HDACs dual-target inhibitor drugs, and providing an effective tool for the study of the biological functions of KDM1A and HDACs.

Claims

1. A 3-aryl indole compound, characterized in that: It has the structure shown in general formula I: In the general formula I, R is any one of CH3 and H; n is any one of 2, 3, 4 and 5.

2. A 3-aryl indole compound according to claim 1, characterized in that: Select one of the following compounds:

3. A method for preparing a 3-aryl indole compound as claimed in claim 1 or 2, characterized in that: This is accomplished by the following steps: (a) Compound 1 and ethyl bromoalkanoate are reacted in N,N-dimethylformamide (DMF) in the presence of NaH under stirring in an ice bath. After the reaction is completed, the organic phases are extracted, combined, washed, dried, filtered, and the filtrate is concentrated in vacuo. The concentrate is separated by column chromatography to obtain Compound 2; (b) Compound 2 and N-bromosuccinimide (NBS) were reacted in DMF under stirring at room temperature. After the reaction was completed, the organic phases were extracted, combined, washed, dried, filtered, and the filtrate was concentrated in vacuo. The concentrate was separated by column chromatography to obtain Compound 3; (c) Compound 3 and 2-methyl-3-aminophenylboronic acid pinacol ester are heated and stirred in toluene in the presence of a basic compound and a palladium catalyst. After the reaction is completed, the organic phases are extracted, combined, washed, dried, filtered, and the filtrate is concentrated under reduced pressure. The concentrate is separated by column chromatography to obtain Compound 4; the basic compound is selected from one of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and potassium phosphate, and the palladium catalyst is selected from one of tetrakis(triphenylphosphine)palladium, palladium acetate, bis(dibenzylideneacetone)palladium and palladium dichloride; (d) Compound 4 was reacted with a methanol solution of NH2OK / NH2OH in a dichloromethane solution. After the reaction was completed, the reaction system was concentrated in vacuo, the concentrate was dissolved in water, the pH was adjusted to 6-7, filtered, washed, the solid was collected, and purified by column chromatography to obtain Compound I.

4. Use of a 3-arylindole compound as claimed in any one of claims 1 or 2 in the preparation of a drug, characterized in that: It is used as an active ingredient in the preparation of KDM1A / HDACs dual-target inhibitor drugs.

5. Use of a 3-arylindole compound as claimed in any one of claims 1 or 2 in the preparation of a drug, characterized in that: It is used as an active ingredient in preparing medicines for treating gastric cancer, colon cancer or esophageal cancer.

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