A pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, preparation method, pharmaceutical composition and application thereof

Abstract

The present invention relates to a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, a preparation method and a pharmaceutical composition and application thereof, and belongs to the field of medical technology. The present invention discloses a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, wherein the inhibitor is a substituted pyrrolo[3,2-b]pyridine compound shown in general formula V, or a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof; the inhibitor has high efficiency and excellent Top / HDAC dual-target inhibitory activity, and has low cost, good efficacy, low toxicity, high yield of intermediate products in the synthesis process, reduces resource waste, and is conducive to reducing costs; the inhibitor is applied to anti-tumor drugs with a small dosage and significant activity.

Description

Technical Field

[0001] The present invention relates to a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, a preparation method and a pharmaceutical composition and application thereof, belonging to the technical field of medicine. Background Art

[0002] Since histone deacetylases (HDACs) were discovered as important drug targets for anti-tumor treatment, after more than 30 years of exploration, a number of inhibitors have been approved for marketing, such as vorinostat (SAHA), panobinostat, belinostat and chidamide. However, these HDAC inhibitors are only used in the clinical treatment of hematological tumors such as T-cell lymphoma, and no HDAC inhibitors are currently on the market for the treatment of solid tumors. In addition, these marketed drugs have severe gastrointestinal reactions, adverse blood reactions, and even fatal toxicity and drug resistance during clinical treatment. Therefore, the development of a new class of highly effective and low-toxic HDAC inhibitors for the treatment of solid tumors has a very broad prospect.

[0003] As researchers conduct in-depth studies on HDAC inhibitors, many HDAC inhibitors for the treatment of solid tumors have entered the clinic, and HDAC inhibitors combined with other drugs have also shown a positive effect on the treatment of solid tumors. Currently, many projects have entered clinical research, such as vorinostat (SAHA) combined with the alkylating agent temozolomide for the treatment of gliomas (NCT01236560), combined with paclitaxel or carboplatin for the treatment of advanced solid tumors (NCT01281176), combined with olaparib for the treatment of recurrent, refractory and metastatic breast cancer (NCT04308330); Belinostat (Belinostat) combined with Talazoparib for the treatment of metastatic breast cancer, prostate cancer and ovarian cancer (NCT04703920), combined with cisplatin and etoposide for the treatment of small cell lung cancer (NCT00926640), etc. However, the combination of multiple drugs is prone to drug interactions in the body, which ultimately causes adverse pharmacokinetics and increases toxic side effects. The use of a single molecule with multi-target effects instead of a combination of multiple drugs has become a new model for the development of new drugs. Based on these research results, the development of multifunctional HDAC inhibitors has become an important direction for the development of new anti-tumor drugs, such as the development of LSD1 / HDAC6 and PI3K / HDAC dual-target inhibitors, both of which have entered clinical research. Among the many drugs used in combination with HDAC inhibitors, the combination of topoisomerase inhibitors and HDAC inhibitors has also shown a positive effect on the treatment of solid tumors in preclinical studies. For example, in the HCT116 xenograft tumor model, the combination of HDAC inhibitor CG2 and Top1 inhibitor irinotecan showed stronger antitumor activity than the two drugs alone; in in vitro antitumor activity studies, the HDAC inhibitor SAHA can increase the cytotoxicity of Top1 inhibitor topotecan and Top2 inhibitor Epirubicin or Amrubicin to small cell lung cancer cell lines. Although there have been some reports on the development of Top / HDAC dual-target inhibitors, none of them have entered clinical research. Summary of the invention

[0004] The purpose of the present invention is to address the defects of the prior art and to propose a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, a preparation method, a pharmaceutical composition and an application thereof. The inhibitor has high-efficiency and excellent Top / HDAC dual-target inhibitory activity, and has low cost, good efficacy, low toxicity, a high yield of intermediate products in the synthesis process, reduces resource waste, and is conducive to reducing costs; the inhibitor is used in a small dosage in anti-tumor drugs and has significant activity.

[0005] The development of multifunctional HDAC inhibitors has become an important direction for the research and development of new anti-tumor drugs. Although there have been some reports on the development of Top / HDAC dual-target inhibitors, none of them have entered clinical research. Based on the existing research foundation, the present invention uses a pharmacophore fusion strategy to introduce a pyrrolo[3,2-b]pyridine fused polycyclic skeleton with topoisomerase (Top) inhibitory activity as an active fragment into the Cap of the HDAC inhibitor SAHA, and designs and synthesizes a series of pyrrolo[3,2-b]pyridine hydroxamic acid derivatives. In addition, a series of pyrrolo[3,2-b]pyridine hydrazide derivatives were synthesized by replacing the ZBG group of the obtained hydroxamic acid derivatives.

[0006] The present invention solves the technical problem through the following technical solution: First, a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor is provided, which is a substituted pyrrolo[3,2-b]pyridine compound shown in general formula V, or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof: Among them, rings A and B are substituted aromatic heterocycles such as benzene rings, pyridine, and pyrimidine;

[0007] R 1 selected from hydrogen, chlorine or oxygen atoms;

[0008] L is selected from the following groups: ;

[0009] R 2 Selected from the following groups: .

[0010] Preferably, in the inhibitor of the general formula V, the hydrogen attached to the carbon is replaced by deuterium, an isotope of hydrogen.

[0011] More preferably, the alkyl group is replaced by a deuterated alkyl group, the alkoxy group is replaced by a deuterated epoxy group, the benzene ring is replaced by a deuterated benzene ring, and the aromatic ring is replaced by a deuterated aromatic ring.

[0012] Preferably, the pharmaceutically acceptable salt refers to a salt form in which the basic group in the parent compound is converted; wherein the pharmaceutically acceptable salt is an inorganic or organic acid salt of a basic group, more preferably an amine or amino group; the basic group in the parent compound reacts with 1-4 equivalents of an acid in a solvent system.

[0013] Preferably, the basic group of the compound of the present invention can form a salt with an acid, and the acid salt is specifically a salt formed with an inorganic acid, especially a hydrohalic acid (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; a salt formed with a lower alkyl sulfonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid; a salt formed with an aryl sulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid; a salt formed with an organic acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; a salt formed with an amino acid, such as aspartic acid or glutamic acid.

[0014] Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include solvate or hydrate forms.

[0015] Preferably, the structural formula of the compound in the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor of the present invention includes isomeric forms, such as enantiomers, diastereomers, geometric isomers or conformational isomers, specifically R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers.

[0016] Preferably, the inhibitor is one of the following:

[0017] (1) N-hydroxy-5-(5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide;

[0018] (2) 5-(9-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide;

[0019] (3) N-hydroxy-5-(9-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide;

[0020] (4) 5-(8-fluoro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide;

[0021] (5) 5-(8-chloro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide;

[0022] (6) 5-(8-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide;

[0023] (7) N-hydroxy-5-(8-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide;

[0024] (8) 5-(8-(difluoromethoxy)-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide;

[0025] (9) 5-(8-ethoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide;

[0026] (10) N-hydroxy-5-(8-isopropoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide;

[0027] (11) N-hydroxy-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)pentanamide;

[0028] (12) N-hydroxy-6-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)hexanamide;

[0029] (13) N-hydroxy-7-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)heptylamide;

[0030] (14) N-hydroxy-8-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)octanamide;

[0031] (15) N-hydroxy-9-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)nonanamide;

[0032] (16) N-hydroxy-10-(5-oxo-5,6-dihydro-12H-[1,3]dioxopentan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)decanamide;

[0033] (17) N-hydroxy-3-((5-oxo-5,6-dihydro-12H-[1,3]dioxol-[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)benzamide;

[0034] (18) N-hydroxy-4-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclohexano[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)benzamide;

[0035] (19) 5-(5-chloro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxypentanamide;

[0036] (20) 6-(5-chloro-12H-[1,3]dioxolato[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyhexanamide;

[0037] (21) 7-(5-chloro-12H-[1,3]dioxolato[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyheptylamide;

[0038] (22) 7-(12H-[1,3]dioxol-[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyheptylamide;

[0039] (23) 8-(12H-[1,3]dioxol-[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyoctanamide;

[0040] (24) 9-(12H-[1,3]dioxolato[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxynonanamide;

[0041] (25) N'-ethyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxol-[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)valeryl hydrazide;

[0042] (26) 5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N'-propylvalerylhydrazide;

[0043] (27) N'-butyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)valeryl hydrazide;

[0044] (28) 6-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N'-propylhexane hydrazide;

[0045] (29) 8-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N'-propyloctanoylhydrazide;

[0046] (30) N'-ethyl-4-(5-oxo-5,6-dihydro-12H-[1,3]dioxol-[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)benzohydrazide;

[0047] (31) 4-((5-Oxo-5,6-dihydro-12H-[1,3]dioxol-[4′,5′:5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)-N′-propylbenzohydrazide.

[0048] The present invention further provides a method for preparing the above inhibitor: using o-nitrobenzaldehyde A1-A11 with different substituents as raw materials, reacting with methoxyamine to generate compounds B1-B11, and then reacting with perphthalic anhydride to generate key intermediates C1-C11. Intermediates C1-C11 then undergo a reduction reaction with sodium sulfide to generate parent nuclei 1a-k. Parent nuclei 1a-k then react with phosphorus oxychloride to generate parent nuclei 4k. The specific synthesis route is as follows: Then, pyrrolo[3,2-b]pyridine derivatives 1a-k and 4k with different substituents were used as raw materials to react with ethyl 5-bromovalerate, ethyl 6-bromohexanoate, ethyl 7-bromoheptanoate, ethyl 8-bromooctanoate, ethyl 9-bromononanoate, ethyl 10-bromodecaneate, ethyl 3-bromomethylbenzoate and ethyl 4-bromomethylbenzoate to generate compounds 2a-2k, 3a-3g and 5a-5e, which were then reacted with hydroxylamine to generate the final products (1)-(21). (22)-(24) are the products of the corresponding substrates reduced by zinc powder. 2k, 3a, 3c, 3g were used as raw materials to react with hydrazine hydrate to generate compounds 6a-6d, which were then reacted with acetaldehyde, propionaldehyde and butyraldehyde to generate 7a-7g. 7a-7g were then reduced with sodium borohydride to generate the final products (25)-(31). The specific synthetic route is as follows: .

[0049] The present invention further provides a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the above-mentioned pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor.

[0050] The use of the above-mentioned pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor or pharmaceutical composition in the preparation of a drug for preventing, treating or assisting in the treatment of proliferative diseases, metabolic diseases, nervous system diseases or tuberous sclerosis caused by overactivation of topoisomerase or histone deacetylase.

[0051] Preferably, the proliferative disease comprises colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain cancer, cervical cancer, cancer of the CNS, malignant glioma, myeloproliferative disease, blood cancer or lymphoma.

[0052] Use of the above-mentioned pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor or pharmaceutical composition in the preparation of a drug for inhibiting the growth of cancer cells.

[0053] Compared with the prior art, the present invention has the following significant advantages: (1) It has the characteristics of highly efficient inhibition of topoisomerase and histone deacetylase activities, and has excellent in vitro anti-proliferative activity against a variety of tumor cells; (2) It has low cost, good efficacy, low toxicity, and a high yield of intermediate products in the synthesis process, which reduces resource waste and is conducive to reducing costs; (3) It has significant oral and effective in vivo anti-tumor activity and low toxicity, which is superior to the currently marketed HDAC inhibitors and the combination of HDAC inhibitors and Top inhibitors. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG1 shows the activity screening results of Top1 and Top2 in some embodiments of the present invention.

[0055] FIG2 shows the results of the in vivo anti-tumor efficacy of Example 10. DETAILED DESCRIPTION

[0056] The technical solution of the present invention is further described below in conjunction with embodiments and drawings.

[0057] Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., Beijing Coupling Technology Co., Ltd., etc., and were used without further purification unless otherwise indicated. General reagents were purchased from Xilong Chemical Co., Ltd., Nanjing Chemical Reagent Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Co., Ltd., etc. In the examples, all temperatures are set in degrees Celsius unless otherwise indicated.

[0058] In the examples described below, the chromatographic column used was a silica gel column, and the silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Co., Ltd. The NMR spectra were chromatographically measured with CDCl3 or DMSO-d6 as solvent (in ppm), and TMS (0 ppm) as reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets). The coupling constant is expressed in Hertz (Hz).

[0059] For the convenience of description, some raw materials are described by their abbreviations in the following examples. Their full names and references are as follows: DMF is N,N-dimethylformamide; DCM is dichloromethane; MeOH is methanol; PE is petroleum ether; EA is ethyl acetate; THF is tetrahydrofuran; CDC13 is deuterated chloroform; DMSO-d6 is hexadeuterated dimethyl sulfoxide; Et3N is triethylamine; NaH is sodium hydride, and TABI is tetrabutylammonium iodide.

[0060] Example 1

[0061] The synthesis of N-hydroxy-5-(5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide was carried out as follows: the mother nucleus 1a (1.0 mmol, 234.1 mg) was dissolved in 20 mL DMF, and K2CO3 (6.0 mmol, 827.4 mg) and ethyl 5-bromopentanoate (1.0 mmol, 209.1 mg) were added, and stirred overnight in an oil bath at 80 °C. After the reaction was completed, the reaction solution was poured into cold water and stirred, and the aqueous solution was extracted with ethyl acetate three times, the organic phase was collected, and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=5:1-2:1 / v:v) to obtain a white solid 2a. 2a (1.0 mmol, 362.2 mg) was suspended in 20 mL of methanol, and KOH (10.0 mmol, 560 mg) and hydroxylamine aqueous solution (30.0 mmol, 1.0 g) were added, and stirred in a 50 °C oil bath for 2 h. After the reaction, it was purified by silica gel column chromatography (DCM:MeOH=10:1-5:1 / v:v) to obtain a white solid (1) with a yield of 82%.1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 10.45 (s, 1H), 8.75 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.90 (t, J = 7.4 Hz, 1H), 7.73–7.54 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 4.60 (t, J = 6.0 Hz, 2H), 2.11 (t, J = 7.0 Hz, 2H), 1.95–1.78 (m, 4H). 13C NMR (75 MHz, DMSO) δ 169.11, 154.99, 138.18, 130.64, 128.90, 126.32, 125.90, 125.10, 124.71, 123.99, 122.31, 121.24, 119.18, 119.00, 117.80, 111.86, 65.23, 32.11, 28.26, 22.19. ESI-HRMS calcd for C20H19N3O3 m / z [M + H]+ 350.1499, found [M + H]+ 350.1497.。 Example 2

[0062] Synthesis of 5-(9-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 1b, and the other steps and operations were the same as Example 1; a yellow solid was obtained with a yield of 60%. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.44(s, 1H), 8.74 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 2.11 (t, J= 7.2 Hz, 2H), 1.88 (dt, J = 11.2, 5.7 Hz, 2H), 1.80 (m, 2H). 13C NMR (101MHz, DMSO) δ 169.05, 155.40, 138.81, 130.87, 128.49, 126.31, 126.21, 125.14,124.48, 122.14, 121.35, 121.28, 120.62, 118.03, 117.27, 114.34, 65.33, 32.06,28.19, 22.13. ESI-HRMS calcd for C20H18BrN3O3 m / z [M + H]+ 428.0604, found [M+ H]+ 428.0602. Example 3

[0063] Synthesis of N-hydroxy-5-(9-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide: The mother core 1a in Example 1 was replaced by 1c, and the other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 62%. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s,1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.35 (d, J = 7.8 Hz, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5Hz, 1H), 7.06 (s, 1H), 6.85 (d, J = 8.6 Hz, 1H), 4.58 (t, J = 5.9 Hz, 2H), 3.87 (s, 3H), 2.10 (t, J = 7.0 Hz, 2H), 1.98–1.71 (m, 4H). 13C NMR (101 MHz, DMSO) δ 169.04, 158.04, 154.99, 139.45, 130.46, 129.33, 126.15, 125.14,124.99, 123.16, 120.82, 119.76, 116.85, 116.45, 109.11, 94.81, 65.13, 55.30,32.06, 28.23, 22.13. ESI-HRMS calcd for C21H21N3O4 m / z [M + H]+ 380.1605,found [M + H]+ 380.1601. Example 4

[0064] Synthesis of 5-(8-fluoro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 1d, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 65%. 1H NMR (300 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.91 (t, J = 7.4 Hz, 1H), 7.74 (dd, J = 9.2, 2.5 Hz, 1H), 7.68 (t, J = 7.6Hz, 1H), 7.61 (dd, J = 8.7, 4.2 Hz, 1H), 7.24 (td, J = 9.0, 2.5 Hz, 1H), 4.59(t, J = 6.0 Hz, 2H), 2.11 (t, J = 7.0 Hz, 2H), 1.89 (q, J = 6.6, 5.8 Hz, 2H), 1.84–1.72 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.04, 157.98, 155.66, 154.93,134.64, 130.75, 128.60, 128.55, 126.33, 126.30, 125.61, 125.11, 122.48,122.39, 121.27, 118.16, 112.99, 112.89, 112.80, 112.54, 103.76, 103.53,65.24, 32.05, 28.18, 22.11. ESI-HRMS calcd for C20H18FN3O3 m / z [M + H]+368.1405, found [M + H]+ 368.1406. Example 5

[0065] Synthesis of 5-(8-chloro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 1e, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 64%. 1H NMR (300 MHz, DMSO-d6) δ 12.24 (s, 1H),10.40 (s, 1H), 8.74 (s, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 8.2 Hz,1H), 8.01 (d, J = 1.9 Hz, 1H), 7.92 (t, J = 7.3 Hz, 1H), 7.77–7.50 (m, 2H), 7.38 (dd, J = 8.4, 2.2 Hz, 1H), 4.59 (t, J = 6.0 Hz, 2H), 2.10 (t, J = 7.1Hz, 2H), 2.02–1.64 (m, 4H). 13C NMR (101 MHz, DMSO) δ 169.04, 155.23, 136.42,130.83, 127.96, 126.40, 126.24, 125.17, 125.11, 124.44, 123.67, 123.32,121.31, 118.23, 117.97, 113.44, 65.30, 40.15, 39.94, 39.73, 39.52, 39.31,39.10, 38.89, 32.06, 28.18, 22.12. ESI-HRMS calcd for C20H18ClN3O3 m / z [M +H]+ 348.1109, found [M + H]+ 384.1111. Example 6

[0066] Synthesis of 5-(8-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 1f, and the other steps and operations were the same as in Example 1; a gray solid was obtained with a yield of 54%. 1H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.42 (s, 1H), 8.71 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 8.2 Hz, 1H), 8.34 (d, J= 8.3 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.92 (t, J = 8.3 Hz, 1H), 7.68 (t, J= 8.2 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 8.6, 2.0 Hz, 1H), 4.59(t, J = 6.2 Hz, 2H), 2.11 (t, J = 7.3 Hz, 2H), 1.96–1.84 (m, 2H), 1.84–1.73(m, 2H). 13C NMR (101 MHz, DMSO) δ 169.04, 155.27, 136.65, 130.87, 127.79,126.97, 126.44, 126.21, 125.12, 124.96, 123.97, 121.32, 120.99, 118.24,113.91, 111.43, 65.31, 32.05, 28.17, 22.11. ESI-HRMS calcd for C20H18BrN3O3m / z [M + H]+ 428.0604, found [M + H]+ 428.0603. Example 7

[0067] Synthesis of N-hydroxy-5-(8-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide: The mother core 1a in Example 1 was replaced by 1g, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 68%. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H),10.45 (s, 1H), 8.76 (s, 1H), 8.39 (d, J = 8.1 Hz, 1H), 8.33 (d, J = 8.1 Hz,1H), 7.88 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.57–7.44 (m, 2H), 7.03 (dd, J = 8.7, 2.5 Hz, 1H), 4.60 (t, J = 6.1 Hz, 2H), 3.88 (s, 3H), 2.12(t, J = 7.1 Hz, 2H), 1.90 (m, 2H), 1.86–1.74 (m, 2H). 13C NMR (101 MHz, DMSO)δ 169.10, 154.62, 153.45, 133.19, 130.58, 128.77, 126.43, 125.82, 125.09,124.70, 122.46, 121.16, 117.79, 115.05, 112.75, 100.16, 65.20, 55.49, 32.11,28.27, 22.19. ESI-HRMS calcd for C21H21N3O4 m / z [M + H]+ 380.1605, found [M +H]+ 380.1602. Example 8

[0068] Synthesis of 5-(8-(difluoromethoxy)-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 1h, and the other steps and operations were the same as Example 1; a gray solid was obtained with a yield of 62%. 1H NMR (300 MHz, DMSO-d6) δ 12.17(s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.35 (d, J =8.1 Hz, 1H), 7.92 (t, J = 4.60 (t, J = 6.0 Hz, 2H), 2.11 (t, J = 7.1 Hz, 2H), 1.97–1.85 (m, 2H),1.85–1.73 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.03, 155.06, 144.26, 144.23,144.20, 135.51, 130.79, 128.56, 126.31, 125.39, 125.12, 122.38, 121.27,119.74, 118.14, 117.52, 117.19, 114.63, 112.93, 108.72, 65.30, 32.06, 28.19,22.12. ESI-HRMS calcd for C21H19F2N3O4 m / z [M + H]+ 416.1416, found [M + H]+416.1411. Example 9

[0069] Synthesis of 5-(8-ethoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 1i, and the other steps and operations were the same as in Example 1; a yellow powdery solid was obtained with a yield of 70%. 1H NMR (300 MHz, DMSO-d6) δ 11.84(s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.33 (d, J =8.2 Hz, 1H), 7.88 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.54–7.42(m, 2H), 7.02 (dd, J = 8.6, 2.5 Hz, 1H), 4.59 (t, J = 6.0 Hz, 2H), 4.13 (q, J= 6.8 Hz, 2H), 2.11 (t, J = 7.0 Hz, 2H), 1.92-1.77 (m, 4H), 1.39 (t, J = 6.9Hz, 3H). 13C NMR (101 MHz, DMSO) δ 169.05, 154.58, 152.64, 133.15, 130.55,128.74, 126.41, ESI-HRMS calcd forC22H23N3O4 m / z [M + H]+ 394.1761, found [M + H]+ 394.1760.

[0070] Example 10

[0071] Synthesis of N-hydroxy-5-(8-isopropoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)pentanamide: The mother core 1a in Example 1 was replaced by 1j, and the other steps and operations were the same as in Example 1; a yellow powdery solid was obtained with a yield of 72%. 1H NMR (300 MHz, DMSO-d6) δ11.84 (s, 1H), 10.44 (s, 1H), 8.80–8.66 (m, 1H), 8.39 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.88 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H),7.57–7.40 (m, 2H), 7.01 (dd, J = 8.7, 2.4 Hz, 1H), 4.66 (q, J = 6.0 Hz, 1H), 4.62–4.55 (m, 2H), 2.11 (t, J = 7.0 Hz, 2H), 2.00–1.71 (m, 4H), 1.31 (d, J =6.0 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 169.05, 154.59, 151.25, 133.37,130.53, 128.68, 126.39, 125.78, 125.06, 124.74, 122.62, 121.15, 117.77,116.79, 112.63, 103.87, 70.32, 65.15, 32.09, 28.25, 22.17, 22.11. ESI-HRMScalcd for C23H25N3O4 m / z [M + H]+ 408.1918, found [M + H]+ 408.1911.

[0072] Embodiment 11

[0073] Synthesis of N-hydroxy-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolano[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)pentanamide: The mother core 1a in Example 1 was replaced with 1k, and the other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 64%. 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.45 (s, 1H), 8.74 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.90 – 7.74 (m, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.57 (t, J = 6.1 Hz, 2H), 2.10 (t,J = 7.2 Hz, 2H), 1.91–1.84 (m, 2H), 1.83–1.75 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.06, 154.77, 146.61, 142.33, 133.74, 130.51, 129.38, 126.33,125.07, 125.04, 123.22, 120.72, 116.85, 115.75, 100.80, 97.31, 92.69, 65.10,32.08, 28.25, 22.16. ESI-HRMS calcd for C21H19N3O5 m / z [M + H]+ 394.1397, found [M + H]+ 394.1394.

[0074] Example 12

[0075] Synthesis of N-hydroxy-6-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)hexanamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 6-bromohexanoate, and the other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 70%. 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.39 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J = 6.4 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H), 1.92–1.85 (m, 2H), 1.68–1.61 (m, 2H), 1.56-1.48 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.13, 154.80, 146.59, 142.31,133.72, 130.47, 129.39, 126.31, 125.04, 123.19, 120.69, 116.83, 115.75,100.78, 97.28, 92.67, 65.42, 32.32, 28.39, 25.54, 25.07. ESI-HRMS calcd forC22H21N3O5 m / z [M + H]+ 408.1554, found [M + H]+ 408.1558.

[0076] Embodiment 13

[0077] Synthesis of N-hydroxy-7-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)heptylamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 7-bromovalerate, and the other steps and operations were the same as those in Example 1; a yellow solid was obtained with a yield of 68%. 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.44–10.30 (m, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.35–8.26 (m, 2H), 7.84 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J = 6.4 Hz, 2H), 1.98 (t, J = 7.2 Hz, 2H), 1.92–1.82 (m, 2H), 1.61–1.48 (m, 4H), 1.42–1.32 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.11, 154.08, 144.83, 134.78,133.91, 130.27, 129.35, 127.18, 126.46, 125.81, 123.85, 122.20, 121.19,115.79, 111.17, 100.73, 59.81, 32.20, 29.52, 28.36, 25.92, 25.00. ESI-HRMScalcd for C23H23N3O5 m / z [M + H]+ 422.1710, found [M + H]+ 422.1708.

[0078] Embodiment 14

[0079] Synthesis of N-hydroxy-8-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)octanamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 8-bromooctanoate, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 74%. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.59–10.04 (m, 1H), 8.69(s, 1H), 8.28 (d, J = 8.1 Hz, 2H), 7.83 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H),7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J = 6.3 Hz, 2H), 1.96 (t,J = 7.4 Hz, 2H), 1.89–1.82 (m, 2H), 1.56–1.47 (m, 4H), 1.41–1.28 (m, 4H). 13CNMR (101 MHz, DMSO) δ 169.24, 154.85, 146.61, 142.34, 133.75, 130.50, 129.42,126.33, 125.08, 125.04, 123.21, 120.72, 116.88, 115.78, 100.81, 97.30, 92.70,65.53, 32.32, 28.67, 28.65, 25.82, 25.18. ESI-HRMS calcd for C24H25N3O5 m / z[M + H]+ 436.1867, found [M + H]+ 436.1867.

[0080] Embodiment 15

[0081] Synthesis of N-hydroxy-9-(5-oxo-5,6-dihydro-12H-[1,3]dioxolano[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)nonanamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 9-bromononanoate, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 72%. 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.35 (s, 1H), 8.68 (s,1H), 8.46–8.15 (m, 2H), 7.83 (t, J = 6.9 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H),7.41 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J = 6.4 Hz, 2H), 1.94 (t,J = 7.3 Hz, 2H), 1.90–1.83 (m, 2H), 1.55–1.45 (m, 4H), 1.43–1.14 (m, 6H). 13CNMR (101 MHz, DMSO) δ 169.15, 154.80, 146.57, 142.29, 133.71, 130.45, 129.38,126.31, 125.03, 125.00, 123.17, 120.70, 116.85, 115.74, 100.77, 97.25, 92.67,65.50, 32.28, 28.85, 28.78, 28.63, 25.87, 25.16. ESI-HRMS calcd forC25H27N3O5 m / z [M + H]+ 450.2023, found [M + H]+ 450.2021.

[0082] Example 16

[0083] Synthesis of N-hydroxy-10-(5-oxo-5,6-dihydro-12H-[1,3]dioxopentan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)decylamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 10-bromodecanate, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 70%. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.34 (s, 1H), 8.68(s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.29 – 8.21 (m, 1H), 7.83 (t, J = 7.5 Hz,1H), 7.56 (t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.54(t, J = 6.4 Hz, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.88–1.81 (m, 2H), 1.53 – 1.43(m, 4H), 1.35 (t, J = 7.1, 3H), 1.29–1.21 (m, 6H). 13C NMR (101 MHz, DMSO) δ169.22, 154.84, 146.60, 142.32, 133.74, 130.46, 129.43, 126.33, 125.03,123.20, 120.70, 116.88, 115.78, 100.79, 97.28, 92.68, 65.51, 32.32, 29.00,28.91, 28.80, 28.66, 28.64, 25.87, 25.20. ESI-HRMS calcd for C26H29N3O5 m / z[M + H]+ 464.2180, found [M + H]+ 464.2185.

[0084] Embodiment 17

[0085] Synthesis of N-hydroxy-3-((5-oxo-5,6-dihydro-12H-[1,3]dioxolano[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)benzamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 3-bromomethylbenzoate, and the other steps and operations were the same as those in Example 1; a red solid was obtained with a yield of 54%. 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 11.31 (s, 1H), 9.08 (s, 1H), 8.41–8.29 (m, 2H), 8.04 (s, 1H), 7.91–7.82 (m, 1H), 7.79 (d, 13C NMR (101 MHz, DMSO) δ164.17, 154.19, 146.68, 142.38, 138.13, 133.78, 133.01, 130.76, 130.59,129.18, 128.50, 126.58, 126.35, 126.15, 125.17, 125.02, 123.44, 120.75,116.69, 115.68, 100.81, 97.31, 92.68, 66.68. ESI-HRMS calcd for C24H17N3O5 m / z [M + H]+ 428.1241, found [M + H]+ 428.1241.

[0086] Embodiment 18

[0087] Synthesis of N-hydroxy-4-((5-oxo-5,6-dihydro-12H-[1,3]dioxano[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)benzamide: the mother nucleus 1a in Example 1 was changed to 1k, 5-bromovalerate was changed to 4-bromomethylbenzoate, and the other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 52%. 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 11.24 (d, J =1.8 Hz, 1H), 9.06 (s, 1H), 8.35 (dd, J = 8.2, 3.6 Hz, 2H), 7.86 (t, J = 7.6Hz, 1H), 7.83–7.66 (m, 4H), 7.59 (t, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.14 (s,1H), 6.07 (s, 2H), 5.73 (s, 2H). 13C NMR (101 MHz, DMSO) δ 164.11, 154.15,146.70, 142.40, 141.02, 133.78, 132.14, 130.65, 129.17, 127.80, 127.04,126.36, 125.24, 125.00, 123.46, 120.78, 116.69, 115.67, 100.84, 97.31, 92.72,66.51. ESI-HRMS calcd for C24H17N3O5 m / z [M + H]+ 428.1241, found [M + H]+428.1238.

[0088] Embodiment 19

[0089] Synthesis of 5-(5-chloro-12H-[1,3]dioxol[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxypentanamide: The mother core 1a in Example 1 was replaced by 4k, and the other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 67%. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s,1H), 8.68 (s, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.94(t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 3.7 Hz, 2H), 6.12(s, 2H), 4.72 (t, J = 7.2 Hz, 2H), 1.97 (t, J = 7.3 Hz, 2H), 1.83–1.75 (m,2H), 1.64-1.56 (m, 2H). 13C NMR (101 MHz, DMSO) δ 168.78, 148.05, 143.24,141.95, 136.04, 132.55, 131.16, 127.30, 126.31, 125.64, 124.84, 122.82,121.56, 114.27, 101.33, 97.26, 91.65, 44.82, 32.02, 29.06, 22.48. ESI-HRMScalcd for C21H18ClN3O4 m / z [M + H]+ 412.1059, found [M + H]+ 412.1052.

[0090] Embodiment 20

[0091] Synthesis of 6-(5-chloro-12H-[1,3]dioxolan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyhexanamide: the mother nucleus 1a in Example 1 was replaced by 4k, 5-bromovalerate was replaced by 6-bromohexanoate, and the other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 64%. 1H NMR(300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.68 (s, 1H), 8.43 (dd, J = 16.6, 7.2 Hz,2H), 7.95 (s, 1H), 7.74 (s, 1H), 7.49 (d, J = 9.7 Hz, 2H), 6.12 (s, 2H), 4.70(t, J = 7.0 Hz, 2H), 2.00–1.70 (m, 4H), 1.61–1.31 (m, 4H). 13C NMR (101 MHz, DMSO) δ 168.92, 148.04, 143.21, 141.90, 135.97, 132.53, 131.11, 127.29,126.30, 125.64, 124.86, 122.81, 121.45, 114.27, 101.29, 97.25, 91.55, 45.01,32.09, 29.09, 25.66, 24.90. ESI-HRMS calcd for C22H20ClN3O4 m / z [M + H]+426.1215, found [M + H]+ 426.1217.

[0092] Embodiment 21

[0093] Synthesis of 7-(5-chloro-12H-[1,3]dioxolan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyheptylamide: the mother core 1a in Example 1 was replaced by 4k, 5-bromovalerate was replaced by 7-bromovalerate, and the other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 65%. 1HNMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.67 (s, 1H), 8.46 (dd, J = 19.5, 7.8Hz, 2H), 7.98 (t, J = 7.4 Hz, 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.52 (d, J = 7.9Hz, 2H), 6.13 (s, 2H), 4.72 (t, J = 7.0 Hz, 2H), 1.91 (t, J = 7.1 Hz, 2H), 1.78 (t, J = 10.6 Hz, 2H), 1.50–1.39 (m, 4H), 1.30–1.19 (m, 3H). 13C NMR (101MHz, DMSO) δ 169.03, 148.07, 143.23, 141.91, 136.01, 132.56, 131.14, 127.31,126.32, 125.66, 124.88, 122.83, 121.48, 114.28, 101.29, 97.27, 91.56, 45.03,32.16, 29.17, 28.30, 25.73, 24.93. ESI-HRMS calcd for C23H22ClN3O4 m / z [M +H]+ 440.1372, found [M + H]+ 440.1383.

[0094] Embodiment 22

[0095] Synthesis of 7-(12H-[1,3]dioxolane[4',5':5,6]indol[3,2-c]isoquinolin-12-yl)-N-hydroxyheptylamide: 1.0 mmol (21) was dissolved in 20 mL acetic acid, and 5 mL water and zinc powder (3.0 mmol, 196.2 mg) were added. The mixture was stirred in an oil bath at 70 °C for 4 h. After the reaction, the acetic acid in the reaction solution was dried by spin drying and purified by silica gel column chromatography (DCM:MeOH=10:1-5:1 / v:v) to obtain a yellow solid with a yield of 72%. 1H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.47 (d, J =8.5 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 7.66 (t, J =7.4 Hz, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 6.12 (s, 2H), 4.77 (t, J = 7.0 Hz,2H), 1.91 (t, J = 7.2 Hz, 2H), 1.87–1.71 (m, 2H), 1.52–1.33 (m, 4H), 1.32–1.24 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.06, 147.65, 144.98, 142.88,135.68, 134.49, 130.22, 129.30, 126.34, 125.09, 123.69, 120.68, 115.30,101.12, 97.53, 91.54, 45.01, 32.16, 29.37, 28.34, 25.81, 24.95. ESI-HRMScalcd for C23H23N3O4 m / z [M +H]+ 406.1761, found [M + H]+ 406.1758.

[0096] Embodiment 23

[0097] Synthesis of 8-(12H-[1,3]dioxol[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxyoctanamide: Referring to the synthesis method of Example 22, a yellow solid was obtained with a yield of 78%. 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.06 (s, 1H), 8.66 (s,1H), 8.46 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 7.6 1.80 (t, J = 7.7 Hz, 2H),1.48–1.38 (m, 4H), 1.31–1.08 (m, 4H). 13C NMR (101 MHz, DMSO) δ 169.09,147.63, 144.97, 142.87, 135.70, 134.50, 130.16, 129.29, 126.33, 125.10,125.06, 123.69, 120.67, 115.30, 101.12, 97.53, 91.53, 45.01, 32.19, 29.51,28.54, 28.51, 26.03, 25.03. ESI-HRMS calcd for C24H25N3O4 m / z [M + H]+420.1918, found [M + H]+ 420.1921.

[0098] Embodiment 24

[0099] Synthesis of 9-(12H-[1,3]dioxolan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N-hydroxynonanamide: Referring to the synthesis method of Example 22, a yellow solid was obtained with a yield of 75%. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.05 (s, 1H), 8.67 (s, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.98 – 7.79 (m, 1H), 7.63(d, J = 8.3 Hz, 2H), 7.49 (s, 1H), 6.11 (s, 2H), 4.74 (t, J = 7.3 Hz, 2H), 1.89 (t, J = 7.4 Hz, 2H), 1.84–1.77 (m, 2H), 1.43–1.32 (m, 4H), 1.30–1.21 (m,2H), 1.21–1.10 (m, 4H). 13C NMR (101 MHz, DMSO) δ 169.13, 147.65, 144.99,142.89, 135.73, 134.51, 130.18, 129.32, 126.36, 125.13, 125.09, 123.72,120.68, 115.31, 101.15, 97.56, 91.55, 45.02, 32.25, 29.50, 28.75, 28.68,28.54, 26.09, 25.10. ESI-HRMS calcd for C25H27N3O4 m / z [M + H]+ 434.2074, found [M + H]+ 434.2082.

[0100] Embodiment 25

[0101] Synthesis of N'-ethyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indol[3,2-c]isoquinolin-12-yl)pentanoylhydrazide: The core 1k (1.0 mmol, 280.1 mg) was dissolved in 20 mL DMF, and K2CO3 (6.0 mmol, 827.4 mg) and ethyl 5-bromopentanoate (1.0 mmol, 209.1 mg) were added, and stirred overnight in an oil bath at 80 °C. After the reaction was completed, the reaction solution was poured into cold water and stirred, and the aqueous solution was extracted with ethyl acetate three times, the organic phase was collected, and the organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE:EA=5:1-2:1 / v:v) to obtain a white solid 2k. 2k (1.0 mmol, 406.2 mg) was suspended in 20 mL of methanol, and 10.0 mmol of hydrazine hydrate was added. The mixture was stirred in an oil bath at 80 °C for overnight reaction. After the reaction, the mixture was purified by silica gel column chromatography (DCM:MeOH=10:1-5:1 / v:v) to obtain white solid 6a. 6a (1.0 mmol, 392.15 mg) was dissolved in 20 mL of methanol, and MgSO4 (6.0 mmol, 720 mg) and acetaldehyde (1.0 mmol, 44.0 mg) were added. The mixture was reacted at room temperature overnight, MgSO4 was removed by suction, and the methanol was dried to obtain 7a. 7a (1.0 mmol, 418.2 mg) was dissolved in 20 mL of methanol, and sodium borohydride (10.0 mmol, 378.3 mg) was added and stirred overnight. After the reaction, it was purified by silica gel column chromatography (DCM:MeOH=10:1-5:1 / v:v) to obtain a white solid with a yield of 65%.1H NMR (300 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.33 (d, J = 6.5 Hz, 1H), 8.31 (dd, J = 14.3, 8.2 Hz, 2H), 7.89 – 7.77 (m, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.82 – 4.76 (m, 1H), 4.56 (t, J = 6.0 Hz, 2H), 2.78–2.59 (m, 2H), 2.17 (t, J = 7.0 Hz, 2H), 1.97 – 1.69 (m, 4H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 170.96, 154.77, 146.60, 142.32, 133.75, 130.51, 129.38, 126.34, 125.06, 123.23, 120.77, 116.86, 115.74, 100.80, 97.30, 92.69, 65.14, 45.47, 33.30, 28.24, 22.23, 13.09. ESI-HRMS calcd for C23H24N4O4 m / z [M + H]+ 421.1870, found [M + H]+ 421.1870.。

[0102] Example 26

[0103] Synthesis of 5-(5-oxo-5,6-dihydro-12H-[1,3]dioxol[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N'-propylpentanoylhydrazide: The acetaldehyde in Example 25 was replaced with propionaldehyde, and the other steps and operations were the same as those in Example 25; a white solid was obtained with a yield of 76%. 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.31 (s, 1H), 8.30 (t, J = 7.8 Hz, 2H), 7.91–7.77 (m,1H), 7.57 (t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.12 (d, J = 0.6 Hz, 1H), 6.06(s, 2H), 4.81 (s, 1H), 4.56 (t, J = 6.1 Hz, 2H), 2.61 (t, J = 7.0 Hz, 2H), 2.16 (t, J = 7.0 Hz, 2H), 1.84 (dt, J = 21.1, 7.1 Hz, 4H), 1.43–1.31 (m, 2H),0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 170.88, 154.77, 146.60,142.33, 133.73, 130.52, 129.38, 126.32, 125.06, 123.20, 120.69, 116.85,115.75, 100.80, 97.30, 92.68, 65.12, 53.06, 33.28, 28.21, 22.21, 20.79,11.62. ESI-HRMS calcd for C24H26N4O4 m / z [M + H]+ 435.2027, found [M + H]+435.2032.

[0104] Embodiment 27

[0105] Synthesis of N'-butyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxol[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)valeryl hydrazide: replace acetaldehyde in Example 25 with butyraldehyde, and other steps and operations are the same as Example 25; a white solid is obtained, solid, and the yield is 73%. 1H NMR (300MHz, DMSO-d6) δ 11.87 (s, 1H), 9.30 (d, J = 4.7 Hz, 1H), 8.30 (t, J = 8.6 Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.12(d, J = 1.9 Hz, 1H), 6.06 (s, 2H), 4.78 (d, J = 5.9 Hz, 1H), 4.56 (t, J = 6.0Hz, 2H), 2.67–2.61 (m, 2H), 2.16 (t, J = 7.1 Hz, 2H), 1.90 – 1.75 (m, 4H),1.36–1.20 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, DMSO) δ171.06, 154.87, 146.68, 142.40, 133.82, 130.63, 129.45, 126.40, 125.16,123.29, 120.75, 119.13, 116.94, 115.82, 100.88, 97.40, 92.76, 65.22, 50.93,33.36, 29.79, 28.26, 22.28, 19.85, 14.00. ESI-HRMS calcd for C25H28N4O4 m / z[M + H]+ 449.2183, found [M + H]+ 449.2189.

[0106] Embodiment 28

[0107] Synthesis of 6-(5-oxo-5,6-dihydro-12H-[1,3]dioxolan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N'-propylhexane hydrazide: In Example 25, 5-bromovalerate was replaced by 6-bromohexanoate, acetaldehyde was replaced by propionaldehyde, and other steps and operations were the same as in Example 25; a white solid was obtained with a yield of 74%. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.26 (d, J = 6.0 Hz,1H), 8.31 (d, J = 8.3 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.6 Hz,1H), 7.66–7.49 (m, 1H), 7.41 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.80–4.76(m, 1H), 4.55 (t, J = 6.4 Hz, 2H), 2.60 (td, J = 7.1, 4.9 Hz, 2H), 2.08 (t, J= 13C NMR (101) MHz, DMSO) δ 170.91,154.79, 146.57, 142.29, 133.71, 130.43, 129.39, 126.30, 124.97, 123.17,120.66, 116.84, 115.75, 100.75, 97.26, 92.64, 65.36, 53.04, 33.51, 28.36,25.44, 25.12, 20.76, 11.58. ESI-HRMS calcd for C25H28N4O4 m / z [M + H]+449.2183, found [M + H]+ 449.2192.

[0108] Embodiment 29

[0109] Synthesis of 8-(5-oxo-5,6-dihydro-12H-[1,3]dioxolan[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N'-propyloctanoylhydrazide: In Example 25, 5-bromovalerate was replaced by 8-bromooctanoate, acetaldehyde was replaced by propionaldehyde, and other steps and operations were the same as in Example 25; a white solid was obtained with a yield of 69%. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.22 (d, J = 6.0 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.92–7.73 (m, 1H), 7.56(t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.12 (s, 1H), 6.06 (s, 2H), 4.80–4.75 (m,1H), 4.55 (t, J = 6.5 Hz, 2H), 2.60 (td, J = 7.1, 4.9 Hz, 2H), 2.02 (t, J 13C NMR (101 MHz, DMSO) δ 170.95, 154.80, 146.57,142.29, 133.71, 130.43, 129.40, 126.30, 124.99, 123.17, 120.68, 116.85,115.75, 100.77, 97.25, 92.65, 65.47, 53.04, 33.48, 28.59, 28.54, 25.78,25.21, 20.77, 11.60. ESI-HRMS calcd for C27H32N4O4 m / z [M + H]+ 477.2496, found [M + H]+ 477.2504.

[0110] Embodiment 30

[0111] Synthesis of N'-ethyl-4-(5-oxo-5,6-dihydro-12H-[1,3]dioxolane[4',5':5,6]indol[3,2-c]isoquinolin-12-yl)methyl)benzohydrazide: Replace 5-bromovalerate with 4-bromomethylbenzoate in Example 25, and the other steps and operations are the same as those in Example 25; a white solid is obtained with a yield of 45%. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 10.09 (d, J = 5.8 Hz, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 8.0 Hz, 3H), 7.70 (d, J = 8.0 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.44 (s, 1H), 7.13 (s,1H), 6.07 (s, 2H), 5.72 (s, 2H), 5.07 (d, J = 6.3 Hz, 1H), 2.84 – 2.77 (m,2H), 1.02 (t, J = 7.1 Hz, 3H). ESI-HRMS calcd for C26H22N4O4 m / z [M + H]+455.1714, found [M + H]+ 455.1719.

[0112] Embodiment 31

[0113] Synthesis of 4-((5-oxo-5,6-dihydro-12H-[1,3]dioxol[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)methyl)-N'-propylbenzohydrazide: In Example 25, 5-bromovalerate was replaced by 4-bromomethylbenzoate, acetaldehyde was replaced by propionaldehyde, and other steps and operations were the same as in Example 25; a white solid was obtained with a yield of 55%. 1H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 10.19–10.01(m, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 7.97–7.79 (m,3H), 7.79–7.63 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 5.72 (s, 2H), 5.09 (s, 1H), 2.74 (s, 2H), 1.52–1.39 (m, 2H),0.89 (t, J = 7.4 Hz, 3H). ESI-HRMS calcd for C27H24N4O4 m / z [M + H]+469.1870, found [M + H]+ 469.1874.

[0114] In vitro anti-tumor activity screening was performed for the embodiments of the present invention:

[0115] The MTT method was used to evaluate the inhibitory activity of compounds on tumor cell proliferation, and the IC50 values ​​of each compound on various tumor cell lines were calculated. The detection principle is as follows: Succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline formazan and deposit it in the cells, while the mitochondria in dead cells are inactivated and do not have this function. Dimethyl sulfoxide (DMSO) can dissolve the formazan in cells, and its light absorption value is measured at a wavelength of 490 nm using an enzyme reader. Within a certain range of cell numbers, the amount of formazan crystals formed is proportional to the number of living cells. The number of living cells is determined based on the absorbance (OD) value measured by the enzyme reader. The larger the OD value, the stronger the cell activity and the more living cells there are, and the cell survival rate is then calculated.

[0116] The experimental method is as follows:

[0117] (1) Cell inoculation: Tumor cells were prepared into a single cell suspension using culture medium containing 10% fetal bovine serum. 100 μL of the tumor cell suspension at a density of 2 × 104 cells / mL was inoculated into each well of a 96-well plate and cultured in an incubator at 37 °C with 5% CO2 for 24 h.

[0118] (2) Add the sample solution to be tested: After the cells in the 96-well plate adhere to the wall, add 100 μL of sample solution to each well. Each sample is tested at 6 concentrations, and 3 replicates are set for each concentration. An equal volume of the same culture medium containing 0.1% DMSO is added to the negative control group. After the addition of the drug, the 96-well plate is placed in the incubator for another 72 h.

[0119] (3) Detection: Add 10 μL of 5 mg / mL MTT solution to each well and continue to culture at 37°C for 4 h. Discard the supernatant and add 100 μL of DMSO to each well. Mix on a plate shaker and detect the OD value using a microplate reader at a wavelength of 490 nm.

[0120] (4) The original data were normalized using Excel software. IC50 was calculated using GraphPad Prism 8. The formula for calculating tumor cell growth inhibition rate was: Growth inhibition rate (%) = 1 - (OD value of the drug group - OD value of the blank group) / (OD value of the negative control group - OD value of the blank group) × 100%.

[0121] Example MCF-7 MDA-MB-231 PC3 HCT116 H2228 Huh-7 HDAC1 Example 1 6.37±0.80 4.24±0.17 3.62±0.63 3.21±0.45 2.43±0.11 ＞8 92 Example 2 ＞8 ＞8 4.98±0.36 ＞8 2.35±0.10 ＞8 ＞500 Example 3 2.93±0.05 2.50±0.44 2.70±0.79 2.27±0.46 1.57±0.12 6.71±0.62 146 Example 4 7.35±0.30 5.50±0.71 3.74±0.61 4.17±0.58 2.70±0.35 ＞8 203 Example 5 5.72±0.08 5.28±0.29 2.94±0.58 3.28±0.32 2.52±0.24 5.01±0.41 361 Example 6 4.05±0.32 3.06±0.18 2.94±0.32 2.97±0.27 2.39±0.43 3.56±0.12 361 Example 7 4.11±0.65 3.25±0.06 3.17±0.28 3.14±0.26 3.82±0.65 ＞8 180 Example 8 3.44±0.36 2.40±0.64 1.91±0.66 2.51±0.53 2.62±0.27 5.41±0.25 186 Example 9 3.47±0.18 2.97±0.44 2.74±1.44 2.36±0.34 3.23±0.34 3.29±0.32 227 Example 10 2.31±0.14 2.20±0.04 2.48±0.22 1.59±0.16 2.53±0.31 3.46±0.18 199 Embodiment 11 2.05±0.48 1.32±0.30 2.07±0.65 1.33±0.12 1.34±0.23 3.13±0.25 96 Example 12 1.03±0.14 0.73±0.03 0.78±0.13 0.58±0.14 1.07±0.13 2.51±0.43 9.4 Embodiment 13 ＞8 ＞8 ＞8 2.78±0.64 2.41±0.11 ＞8 4.4 Embodiment 14 0.58±0.09 0.46±0.13 0.53±0.13 0.37±0.05 0.58±0.07 0.63±0.08 4.0 Embodiment 15 3.11±0.61 2.92±0.86 2.05±0.53 1.73±0.12 1.25±0.11 ＞8 57 Example 16 6.89±0.79 3.16±1.05 5.50±0.24 2.00±0.20 1.31±0.06 6.43±0.43 ＞500 Embodiment 17 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 ＞500 Embodiment 18 ＞8 ＞8 7.45±0.72 4.72±0.99 ＞8 ＞8 ＞500 Embodiment 19 5.20±1.30 2.82±0.35 2.83±0.37 2.47±0.36 2.32±0.29 4.49±0.25 4444 Embodiment 20 5.23±0.22 3.43±0.08 3.32±0.30 3.12±0.28 1.72±0.27 4.27±0.68 227 Embodiment 21 1.92±0.30 1.73±0.21 1.32±0.21 0.77±0.12 2.01±0.22 3.39±0.68 4.1 Embodiment 22 0.98±0.17 0.84±0.06 0.82±0.10 0.62±0.14 1.29±0.09 1.43±0.82 2.7 Embodiment 23 ＞8 2.22±0.10 2.50±0.16 2.68±0.65 4.60±0.24 6.59±0.65 ＜2 Embodiment 24 3.07±0.66 2.12±0.63 1.82±0.26 1.57±0.33 2.10±0.42 6.77±0.25 3.1 Embodiment 25 4.08±0.64 ＞8 3.56±0.33 3.19±0.18 2.39±0.44 7.41±0.18 1577 Embodiment 26 1.27±0.19 2.62±0.69 0.93±0.10 1.31±0.05 1.17±0.11 2.74±0.09 635 Embodiment 27 4.11±0.40 4.33±0.52 3.24±0.09 3.52±0.09 2.17±0.31 6.49±0.20 3288 Embodiment 28 ＞8 5.91±0.37 4.60±0.82 2.88±0.13 2.84±0.44 ＞8 486 Embodiment 29 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 1629 Embodiment 30 ＞8 ＞8 ＞8 ＞8 ＞8 ＞8 824 Embodiment 31 1.27±0.36 1.45±0.09 1.53±0.20 1.50±0.71 2.17±0.39 6.28±0.30 1000 SAHA 1.35±0.11 1.52±0.37 1.23±0.08 1.05±0.16 2.72±0.14 1.70±0.54 17 Irinotecan 4.59±0.70 ＞8 3.67±0.21 3.16±0.22 3.43±0.31 ＞8 Etoposide 1.18±0.41 2.87±0.19 1.59±0.36 2.00±1.12 2.51±0.04 3.80±0.55 I+S (1:1) 0.97±0.10 1.34±0.15 1.24±0.10 0.73±0.17 1.45±0.29 1.79±0.20 E+S (1:1) 0.64±0.05 1.01±0.19 0.65±0.04 0.95±0.08 0.84±0.06 0.81±0.06

[0122] As can be seen from Table 1, most of the examples in the present invention have micromolar in vitro anti-proliferative activity against different tumor cell lines, and Examples 14 and 22 show the best anti-tumor activity. Among them, the anti-tumor activity of Example 14 is better than that of the positive control drug SAHA, irinotecan, etoposide and their combination groups. By screening ten different tumor cell lines, the H1975 cell line is the most sensitive to Example 14. The IC of Example 14 on the H1975 cell line 50 The concentration of 1 μg / mL in the positive control group was 0.13 μM, which was significantly better than that in the positive control group. Therefore, it can be seen that the embodiments of the present invention can be potentially used in the clinical treatment of the above tumors.

[0123] Example H1975 H1650 HepG2 PC9 14 0.13±0.02 0.41±0.04 0.38±0.04 0.15±0.04 22 0.53±0.03 0.75±0.09 0.75±0.07 0.18±0.06 SAHA 0.55±0.03 3.13±0.24 1.58±0.17 1.13±0.14 Irinotecan 3.41±0.39 6.80±1.93 1.62±0.08 3.84±0.62 Etoposide 0.34±0.04 2.65±0.92 0.72±0.08 2.22±0.10 I+S (1:1) 0.73±0.10 1.17±0.28 0.77±0.09 0.50±0.07 E+S (1:1) 0.21±0.01 1.69±0.75 0.42±0.05 0.78±0.04

[0124] The HDAC1 activity inhibition experiment was carried out according to the embodiments of the present invention:

[0125] We screened the inhibitory activity of all the examples on HDAC1, and the results showed that the inhibitory activity of many examples on HDAC1 was better than that of the positive control drug HDAC inhibitor SAHA, such as Examples 12-14 and Examples 21-24, whose IC 50 The value was 2~9.4 nM, which was significantly better than the activity of SAHA (IC 50 =17 nM).

[0126] The topoisomerase activity inhibition experiment was carried out for the embodiments of the present invention:

[0127] Examples with good in vitro antitumor activity were selected for Top1 and Top2 inhibitory activity screening, and the results are shown in Figure 1. Among the selected examples, most of the examples, such as Examples 11-15 and Examples 21-24, showed excellent inhibitory activity against Top1 and Top2.

[0128] The HDAC subtype selectivity screening experiment was conducted for Examples 14 and 22 of the present invention:

[0129] Examples 14 and 22 with good in vitro anti-tumor activity were selected for HDAC subtype selectivity screening experiments, and their structures are shown in Table 3. Examples 14 and 22 have good inhibitory activity against HDAC1, 2, 3, 6, and 10, with IC 50 The value is 2.7-15 nM, which is more active than vorinostat and is a pan-HDAC inhibitor.

[0130] Example HDAC1 HDAC2 HDAC3 HDAC4 HDAC5 HDAC6 HDAC7 HDAC8 HDAC9 HDAC10 HDAC11 14 4.0 4.4 7.0 ＞5000 2729 15 ＞5000 ＞1000 ＞5000 4.1 ＞5000 22 2.7 ＜4.8 ＜4 ＞5000 ＞5000 ＜4 ＞5000 ＞1000 ＞5000 5.9 ＞5000 SAHA 17 24 42 ＞5000 ＞5000 8.2 ＞5000 535 ＞5000 100 ＞5000

[0131] In vivo anti-tumor efficacy study in nude mice was conducted for Example 14 of the present invention:

[0132] The drug is Example 14. The cell line is the human non-small cell lung cancer cell line H1975. The test animals are SPF grade Balb / c nude mice; male; 6 mice per group. The drug dosage and the positive control group setting are shown in Table 4.

[0133] Drug preparation method:

[0134] Example 14 (50 mg / kg and 100 mg / kg): Weigh 50 mg or 100 mg of the powder of the test compound and dissolve it in 0.5 mL of DMSO, then add 1.5 mL of PEG400 and mix well, finally add dd H2O, and adjust the pH of the solution to 3.5 with dilute hydrochloric acid, finally sonicate and oscillate to mix well and dilute to 5 mL to prepare 10 mg / mL and 20 mg / mL test sample solutions, which are used as oral administration preparations.

[0135] SAHA (100 mg / kg): The preparation method is the same as that of Example 14.

[0136] Irinotecan (20 mg / kg): Weigh 20 mg of the test compound powder and dissolve it in 0.5 mL DMSO, then add 1 mL PEG400 and mix well. Finally, add 3.5 mL of normal saline and mix by sonication and oscillation to prepare a 4 mg / mL test solution, which is used as the preparation for intraperitoneal injection.

[0137] Table 4 Drug dosage configuration and positive control group

[0138] Experimental methods: Establishment of human non-small cell lung cancer xenograft tumor model. H1975 cells in the logarithmic growth phase were inoculated subcutaneously in the right forelimb of nude mice, with a cell inoculation amount of 5×106 cells / mouse. When the subcutaneous tumor grew to about 80 mm3, the tumor-bearing mice and human colon cancer tumor-bearing mice were randomly divided into 5 groups, with 6 mice in each group, namely the blank control group, the low-dose group of Example 14, the high-dose group of Example 14, and the positive control SAHA group and the SAHA+irinotecan combination group. All experimental groups were dosed as shown in Table 4. The weight changes and tumor volume of each group of mice were monitored every day. After the dosing cycle was completed, the mice were killed, and the tumor tissues and major organs were removed, weighed and fixed.

[0139] The experimental results showed that the test drug Example 14 showed good anti-tumor activity in the human small cell lung cancer xenograft tumor model. It showed obvious anti-tumor activity at a dosage of 50 mg / kg, with a TGI value of 59.9% and a T / C value of 42.5%. When the dosage was increased to 100 mg / kg, Example 14 showed higher anti-tumor activity, with a TGI value of 77.5% and a T / C value of 12.2%, which was better than the positive control group SAHA (TGI = 36.2%, T / C = 59.2%) and the SAHA+irinotecan combination group (TGI = 65.8%, T / C = 39.1%).

[0140] In summary, Example 14 is a Top / HDAC dual-target inhibitor with significant in vivo anti-tumor effects.

[0141] The pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor of the present invention can inhibit the proliferation of various tumor cells through its efficient inhibition of topoisomerase and histone deacetylase, and exhibits good anti-tumor activity in mice, and can be used as an anti-tumor active small molecule for the development of new anti-tumor drugs.

[0142] In addition to the above implementations, the present invention may also have other implementations. Any technical solution formed by equivalent replacement or equivalent transformation falls within the protection scope required by the present invention.

Claims

1. A pyrrolo[3,2-b]pyridine-based Top / HDAC dual-target inhibitor, characterized in that: The inhibitor is one of the following, (1) N -hydroxy-5-(5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)pentanamide; (3) N -hydroxy-5-(9-methoxy-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)pentanamide; (4) 5-(8-fluoro-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)- N -Hydroxyvaleramide; (5) 5-(8-chloro-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)- N -Hydroxyvaleramide; (6) 5-(8-bromo-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)- N -Hydroxyvaleramide; (7) N -hydroxy-5-(8-methoxy-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)pentanamide; (8) 5-(8-(difluoromethoxy)-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)- N -Hydroxyvaleramide; (9) 5-(8-ethoxy-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)- N -Hydroxyvaleramide; (10) N -hydroxy-5-(8-isopropoxy-5-oxo-5,6-dihydro-11 H -Indolo[3,2- c ]isoquinolin-11-yl)pentanamide; (11) N -Hydroxy-5-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)pentanamide (12) N -Hydroxy-6-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)hexanamide; (13) N -Hydroxy-7-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)heptylamide; (14) N -Hydroxy-8-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)octanamide; (15) N -Hydroxy-9-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)nonanamide; (16) N -Hydroxy-10-(5-oxo-5,6-dihydro-12 H -[1,3]dioxopentano[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)decylamide; (18) N -hydroxy-4-((5-oxo-5,6-dihydro-12 H -[1,3]dioxacyclohexano[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)methyl)benzamide; (19) 5-(5-chloro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N -Hydroxyvaleramide; (20) 6-(5-chloro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N -Hydroxycaproamide; (21) 7-(5-chloro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N -Hydroxyheptylamide; (22) 7-(12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N -Hydroxyheptylamide; (23) 8-(12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N -Hydroxyoctanamide; (24) 9-(12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N -Hydroxynonanamide; (25) N' -ethyl-5-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)valeryl hydrazide; (26) 5-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N' -Provaleroyl hydrazide; (27) N' -butyl-5-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)valeryl hydrazide; (28) 6-(5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)- N' -propylhexane hydrazide; (31) 4-((5-oxo-5,6-dihydro-12 H -[1,3]dioxolato[4',5':5,6]indolo[3,2- c ]isoquinolin-12-yl)methyl)- N' -Propylbenzohydrazide.

2. The method for preparing the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor according to claim 1, characterized in that: Taking o-nitrobenzaldehyde A1-A11 with different substituents as raw materials, it reacts with methoxyamine to generate compounds B1-B11, which then react with perphthalic anhydride to generate key intermediates C1-C11. Intermediates C1-C11 then undergo reduction reaction with sodium sulfide to generate parent nuclei 1a-k. Parent nuclei 1a-k then react with phosphorus oxychloride to generate parent nuclei 4k. The synthetic route is as follows: Then, pyrrolo[3,2-b]pyridine derivatives 1a-k and 4k with different substituents are used as raw materials to react with ethyl 5-bromovalerate, ethyl 6-bromohexanoate, ethyl 7-bromoheptanoate, ethyl 8-bromooctanoate, ethyl 9-bromononanoate, ethyl 10-bromodecaneate, ethyl 3-bromomethylbenzoate, and ethyl 4-bromomethylbenzoate to generate compounds 2a-2k, 3a-3g, and 5a-5e, which are then reacted with hydroxylamine to generate final products (1)-(21), (22)-(24), which are the products of the corresponding substrates reduced by zinc powder; 3a, 3c, 3g are used as raw materials and reacted with hydrazine hydrate to generate compounds 6a, 6c, 6g, which are then reacted with acetaldehyde, propionaldehyde and butyraldehyde to generate 7a, 7c, 7g, which are then reduced with sodium borohydride to generate the final products (25)-(31). The specific synthetic route is as follows: ， The L is selected from the following groups , R2 is ethyl, propyl or butyl.

3. A pharmaceutical composition, characterized in that: The composition comprises at least one pharmaceutically acceptable excipient, adjuvant or carrier, and the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor according to any one of claims 1-2.

4. Use of the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor as claimed in claim 1 or the pharmaceutical composition as claimed in claim 3 in the preparation of a drug for preventing, treating or assisting in the treatment of proliferative diseases, metabolic diseases, nervous system diseases and tuberous sclerosis caused by overactivation of topoisomerase Top or histone acetyltransferase HDAC.

5. Use of the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor according to claim 1 or the pharmaceutical composition according to claim 3 in the preparation of a drug for inhibiting the growth of cancer cells.

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