Pyrrolo[3,2-b]pyridine top / HDAC double-target inhibitor, preparation method therefor, pharmaceutical composition thereof, and use thereof

Abstract

The present invention relates to a pyrrolo[3,2-b]pyridine Top / HDAC double-target inhibitor, a preparation method therefor, a pharmaceutical composition thereof, and use thereof, pertaining to the technical field of pharmaceuticals. Disclosed is a pyrrolo[3,2-b]pyridine Top / HDAC double-target inhibitor. The inhibitor is a substituted pyrrolo[3,2-b]pyridine compound represented by general formula V, or a stereoisomer, a hydrate or a pharmaceutically acceptable salt thereof. The inhibitor has effective and excellent Top / HDAC double-target inhibitory activity, and features low cost, good curative effect, and low toxicity. The intermediate products in the synthesis process have high yield, reducing resource waste and thereby facilitating cost reduction. When applied in antitumor drugs, the inhibitor requires a small dose and exhibits significant activity.

Description

A pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, its preparation method, pharmaceutical composition, and applications. Technical Field

[0001] This invention relates to a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, its preparation method, pharmaceutical composition, and applications, belonging to the field of pharmaceutical technology. Background Technology

[0002] Since histone deacetylases (HDACs) were discovered as important drug targets for anti-tumor therapy, after more than 30 years of research, several inhibitors have been approved for marketing, such as vorinostat (SAHA), panobinostat, belinostat, and chidamide. However, these HDAC inhibitors are currently only used clinically to treat hematologic malignancies such as T-cell lymphoma, and there are no HDAC inhibitors available for the treatment of solid tumors. Furthermore, these marketed drugs have experienced serious gastrointestinal reactions, hematological adverse reactions, and even fatal toxicity and drug resistance during clinical treatment. Therefore, developing a new class of highly effective and low-toxicity HDAC inhibitors for the treatment of solid tumors holds great promise.

[0003] With in-depth research on HDAC inhibitors, many HDAC inhibitors for the treatment of solid tumors have entered clinical trials. Furthermore, the combination of HDAC inhibitors with other drugs has shown positive effects in the treatment of solid tumors. Currently, many projects are in clinical trials, such as vorinostat (SAHA) in combination with the alkylating agent temozolomide for the treatment of glioma (NCT01236560), in combination with paclitaxel or carboplatin for the treatment of advanced solid tumors (NCT01281176), and in combination with olaparib for the treatment of relapsed, refractory, and metastatic breast cancer (NCT04308330); belistat in combination with talazoparib for the treatment of metastatic breast cancer, prostate cancer, and ovarian cancer (NCT04703920), and in combination with cisplatin and etoposide for the treatment of small cell lung cancer (NCT00926640), etc. However, the combined use of multiple drugs is prone to drug interactions in vivo, ultimately leading to adverse pharmacokinetics and increased toxic side effects. Therefore, utilizing single molecules with multi-target effects instead of multiple drug combinations has become a new paradigm in drug development. Based on these research findings, the development of multifunctional HDAC inhibitors has become an important direction in anti-tumor drug research and development, such as the development of LSD1 / HDAC6 and PI3K / HDAC dual-target inhibitors, both of which have entered clinical trials. Among the many drugs used in combination with HDAC inhibitors, the combination of topoisomerase inhibitors and HDAC inhibitors has also shown positive effects in the treatment of solid tumors in preclinical studies. For example, in the HCT116 xenograft tumor model, the combination of the HDAC inhibitor CG2 and the Top1 inhibitor irinotecan showed stronger anti-tumor activity than either drug alone; in in vitro anti-tumor activity studies, the HDAC inhibitor SAHA can increase the activity of the Top1 inhibitor topotecan and the Top2 inhibitor... or Cytotoxicity against small cell lung cancer cell lines. While there have been some reports on the development of Top / HDAC dual-target inhibitors, none have yet entered clinical trials. Summary of the Invention

[0004] The purpose of this invention is to address the deficiencies of existing technologies by proposing a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, its preparation method, pharmaceutical composition, and applications. The inhibitor exhibits highly efficient and excellent Top / HDAC dual-target inhibitory activity, and is low in cost, effective, and low in toxicity. The intermediate product yield during the synthesis process is high, reducing resource waste and thus lowering costs. When applied to antitumor drugs, it requires a small dosage and exhibits significant activity.

[0005] The development of multifunctional HDAC inhibitors has become an important direction in the research and development of new anti-tumor drugs. While there have been some reports on the development of Top / HDAC dual-target inhibitors, none have yet entered clinical trials. Based on existing research, this invention utilizes a pharmacophore fusion strategy to introduce the pyrrolo[3,2-b]pyridine fused polycyclic skeleton with topoisomerase (Top) inhibitory activity as the active fragment into the Cap of the HDAC inhibitor SAHA, designing and synthesizing a series of pyrrolo[3,2-b]pyridine isohydroxamic acid derivatives. Furthermore, by substituting ZBG groups into the obtained isohydroxamic acid derivatives, a series of pyrrolo[3,2-b]pyridine hydrazide derivatives were synthesized.

[0006] This invention solves the technical problem through the following technical solution: First, it provides a pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor, which is a substituted pyrrolo[3,2-b]pyridine compound represented by general formula V, or its stereoisomer, hydrate, or pharmaceutically acceptable salt: Among them, rings A and B are substituted benzene rings, pyridine, pyrimidine, and other aromatic heterocycles; R 1 Selected from hydrogen, chlorine, or oxygen atoms; L is selected from the following groups: R 2 Selected from the following groups:

[0007] Preferably, in the inhibitor of general formula V, the hydrogen bonded to carbon is replaced with the hydrogen isotope deuterium.

[0008] 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.

[0009] Preferably, a pharmaceutically acceptable salt refers to the conversion of a basic group in a parent compound into a salt form; wherein, the pharmaceutically acceptable salt is a basic group, more preferably an inorganic or organic acid salt of an amino group or amino group; the reaction is carried out by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system.

[0010] Preferably, the basic group of the compound in this invention can form a salt with an acid. Specifically, the salt can be formed with inorganic acids, especially hydrohalic acids (such as hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, phosphoric acid, carbonic acid, etc.; lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid; aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; organic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, citric acid, maleic acid, malic acid or succinic acid; or amino acids, such as aspartic acid or glutamic acid.

[0011] Preferably, the compounds and pharmaceutically acceptable salts of the present invention also include solvates or hydrates.

[0012] Preferably, the structural formula of the compound in the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor of the present invention includes isomers, such as enantiomers, diastereomers, geometric isomers or conformational isomers, specifically R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers.

[0013] Preferably, the inhibitor is one of the following: (1) N-hydroxy-5-(5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide; (2) 5-(9-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide; (3) N-hydroxy-5-(9-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide; (4) 5-(8-fluoro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide; (5) 5-(8-chloro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide; (6) 5-(8-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide; (7) N-hydroxy-5-(8-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide; (8) 5-(8-(difluoromethoxy)-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide; (9) 5-(8-ethoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide; (10) N-hydroxy-5-(8-isopropoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide; (11) N-hydroxy-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxanepentan[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)pentanamide; (12) N-hydroxy-6-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)hexanamide; (13) N-hydroxy-7-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)heptamide; (14) N-hydroxy-8-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)octamide; (15) N-hydroxy-9-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)nonanoamide;(16) N-hydroxy-10-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)decanoamide; (17) N-hydroxy-3-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)benzamide; (18) N-hydroxy-4-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)benzamide; (19) 5-(5-chloro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxypentaamide; (20) 6-(5-chloro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxyhexanamide; (21) 7-(5-chloro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxyheptanamide; (22) 7-(12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxyheptamide; (23) 8-(12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxyoctamide; (24) 9-(12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxynonamide; (25) N′-ethyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)valeryl hydrazide; (26) 5-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N′-propylvaleryl hydrazide; (27) N′-butyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)valeryl hydrazide; (28)6-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N′-propylhexanehydrazine;(29) 8-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N′-propyloctanohydrazide; (30) N′-ethyl-4-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)benzoylhydrazide; (31) 4-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)-N′-propylbenzoylhydrazide.

[0014] This invention further provides a method for preparing the above-mentioned inhibitor: using o-nitrobenzaldehyde A1-A11 with different substituents as a raw material, it reacts with methoxyamine to generate compound B1-B11, which then undergoes an addition reaction with homophthalic anhydride to generate the key intermediate C1-C11. Intermediate C1-C11 subsequently undergoes a reduction reaction with sodium sulfide to generate the parent nucleus 1a-k. The parent nucleus 1a-k then reacts with phosphorus oxychloride to generate the parent nucleus 4k. The specific synthetic route is as follows: Using pyrrolo[3,2-b]pyridine derivatives 1a-k and 4k with different substituents as raw materials, compounds 2a-2k, 3a-3g, and 5a-5e were generated by reacting them with ethyl 5-bromopentanoate, ethyl 6-bromohexanoate, ethyl 7-bromoheptanoate, ethyl 8-bromooctanoate, ethyl 9-bromononanoate, ethyl 10-bromodecanoate, ethyl 3-bromomethylbenzoate, and ethyl 4-bromomethylbenzoate. These compounds were then reacted with hydroxylamine to generate the final products (1)-(21). (22)-(24) are the products obtained by reducing the corresponding substrates with zinc powder. Using 2k, 3a, 3c, and 3g as raw materials, compounds 6a-6d were generated by reacting them with hydrazine hydrate. These compounds were then reacted with acetaldehyde, propionaldehyde, and butyraldehyde to generate 7a-7g. 7a-7g was subsequently reduced with sodium borohydride to generate the final products (25)-(31). The specific synthetic route is as follows:

[0015] 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.

[0016] The above-mentioned pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitors or pharmaceutical compositions are used in the preparation of medicaments for the prevention, treatment or adjunctive treatment of proliferative diseases, metabolic diseases, nervous system diseases or tuberous sclerosis caused by excessive activation of topoisomerase or histone deacetylase.

[0017] Preferably, the proliferative diseases include colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain cancer, cervical cancer, cancers of the CNS, malignant glioma, myeloproliferative disease, hematologic malignancy, or lymphoma.

[0018] The above-mentioned pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitors or pharmaceutical compositions are used in the preparation of drugs for inhibiting the growth of cancer cells.

[0019] 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 activity, and has excellent in vitro anti-proliferative activity against a variety of tumor cells; (2) It has low cost, good efficacy, low toxicity, and high yield of intermediate products in the synthesis process, which reduces resource waste and thus helps to reduce costs; (3) It has significant oral 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. Attached Figure Description

[0020] Figure 1 shows the activity screening results of Top1 and Top2 in some embodiments of the present invention.

[0021] Figure 2 shows the in vivo antitumor efficacy results of Example 10. Detailed Implementation

[0022] The technical solution of the present invention will be further described below with reference to the embodiments and accompanying drawings.

[0023] Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., and Beijing Coupling Technology Co., Ltd., and were used without further purification unless otherwise stated. Common reagents were purchased from Xilong Chemical Co., Ltd., Nanjing Chemical Reagent Co., Ltd., Sinopharm Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Co., Ltd. Unless otherwise stated, all temperatures in the examples are in degrees Celsius.

[0024] In the examples described below, silica gel columns were used. The silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Co., Ltd. Nuclear magnetic resonance spectroscopy was performed using CDCl3 or DMSO-d6 as solvents (in ppm), with TMS (0 ppm) as the reference standard. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0025] For ease of description, some raw materials will be described using their abbreviations in the examples described below. Their full names and corresponding descriptions 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; CDCl3 is deuterated chloroform; DMSO-d6 is hexadeuterated dimethyl sulfoxide; Et3N is triethylamine; NaH is sodium hydride; and TABI is tetrabutylammonium iodide.

[0026] Example 1 The synthesis of N-hydroxy-5-(5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide was carried out as follows: The parent nucleus 1a (1.0 mmol, 234.1 mg) was dissolved in 20 mL of DMF, followed by the addition of K₂CO₃ (6.0 mmol, 827.4 mg) and ethyl 5-bromopentanoate (1.0 mmol, 209.1 mg). The mixture was stirred overnight in an oil bath at 80 °C. After the reaction was complete, the reaction solution was poured into cold water and stirred. The aqueous solution was extracted three times with ethyl acetate, and the organic phase was collected. 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 the crude product. The crude product 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. The mixture was stirred in an oil bath at 50 °C for 2 h. After the reaction was completed, the product was purified by silica gel column chromatography (DCM:MeOH = 10:1-5:1 / v:v) to give a white solid (1), yield: 82%. 1H NMR (300MHz, DMSO-d6) δ12.03 (s, 1H), 10.45 (s, 1H), 8.75 (s, 1H), 8.42 (d, J = 8.0Hz, 1H), 8.34 (d, J = 8.1Hz, 1H), 8.07 (d, J = 7.8Hz, 1H), 7.90 (t, J = 7.4Hz, 1H), 7.73-7.54 (m, 2H), 7.39 (t, J=7.4Hz, 1H), 7.21 (t, J=7.4Hz, 1H), 4.60 (t, J=6.0Hz, 2H), 2.11 (t, J=7.0Hz, 2H), 1.95-1.78 (m, 4H).13C NMR (75MHz, 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

[0027] Synthesis of 5-(9-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 1b, and other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 60%. 1H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.41 (d, J= 8.0Hz, 1H), 8.34 (d, J=8.1Hz, 1H), 7.99 (d, J=8.4Hz, 1H), 7.92 (t, J=7.4Hz, 1 H), 7.77 (s, 1H), 7.68 (t, J=7.6Hz, 1H), 7.33 (d, J=8.3Hz, 1H), 4.58 (t, J=6.1 Hz, 2H), 2.11 (t, J=7.2Hz, 2H), 1.88 (dt, J=11.2, 5.7Hz, 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 C20H18B.N3O3 m / z [M+H]+428.0604, found [M+H]+428.0602. Example 3

[0028] Synthesis of N-hydroxy-5-(9-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide: The parent nucleus 1a in Example 1 was replaced with 1c, and other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 62%. 1H NMR (300MHz, DMSO-d6) δ 11.88 (s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.35 (d, J = 7.8Hz, 1H), 8.31 (d, J = 8.0Hz, 1H), 7.92 (d, J = 8.5Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.59 (t, J=7.5Hz, 1H), 7.06 (s, 1H), 6.85 (d, J=8.6Hz, 1H), 4.58 (t , J=5.9Hz, 2H), 3.87 (s, 3H), 2.10 (t, J=7.0Hz, 2H), 1.98-1.71 (m, 4H).13C NMR (101MHz, 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

[0029] Synthesis of 5-(8-fluoro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 1d, and other steps and operations were the same as in Example 1; a red solid was obtained, with a yield of 65%. ¹H NMR (300MHz, DMSO-d6) δ 12.12 (s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.41 (d, J = 8.1Hz, 1H), 8.34 (d, J = 8.1Hz, 1H), 7.91 (t, J = 7.4Hz, 1H), 7.74 (dd, J = 9.2, 2.5Hz, 1H), 7.68 ( t, J=7.6Hz, 1H), 7.61 (dd, J=8.7, 4.2Hz, 1H), 7.24 (td, J=9.0, 2.5Hz, 1H), 4.59 (t, J= 6.0Hz, 2H), 2.11 (t, J=7.0Hz, 2H), 1.89 (q, J=6.6, 5.8Hz, 2H), 1.84-1.72 (m, 2H).13C NMR (101MHz, DMSO) δ169.04, 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 C20H18FN3O3m / z[M+H]+368.1405, found[M+H]+368.1406. Example 5

[0030] Synthesis of 5-(8-chloro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 1e, and other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 64%. 1H NMR (300MHz, DMSO-d6) δ12.24 (s, 1H), 10.40 (s, 1H), 8.74 (s, 1H), 8.41 (d, J = 7.9Hz, 1H), 8.34 (d, J = 8.2Hz, 1H), 8.01 (d, J = 1.9Hz, 1H), 7. 13C NMR (101MHz, DMSO) δ169.04, 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

[0031] Synthesis of 5-(8-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 1f, and 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=8.2Hz, 1H), 7.58 (d, J=8.6Hz, 1H), 7.49 (dd, J=8.6, 2.0Hz, 1H), 4.59 (t, J=6.2Hz, 2H), 2.11 (t, J=7.3Hz, 2H), 1.96-1.84 (m, 2H), 1.84-1.73 (m, 2H).13C NMR (101MHz, 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 C20H18BrN3O3 m / z [M+H]+428.0604, found [M+H]+428.0603. Example 7

[0032] Synthesis of N-hydroxy-5-(8-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide: The parent nucleus 1a in Example 1 was replaced with 1g, and other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 68%. 1H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H), 10.45 (s, 1H), 8.76 (s, 1H), 8.39 (d, J=8.1Hz, 1H), 8.33 (d, J=8.1Hz, 1H), 7.88 (t, J=7.4Hz, 1H), 7.64 (t, J=7.6H z, 1H), 7.57-7.44 (m, 2H), 7.03 (dd, J=8.7, 2.5Hz, 1H), 4.60 (t, J=6.1Hz, 2 H), 3.88 (s, 3H), 2.12 (t, J=7.1Hz, 2H), 1.90 (m, 2H), 1.86-1.74 (m, 2H).13C NMR (101MHz, 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

[0033] Synthesis of 5-(8-(difluoromethoxy)-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 1L, and other steps and operations were the same as in Example 1; a gray solid was obtained, with a yield of 62%. ¹H NMR (300MHz, DMSO-d6) δ 12.17 (s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.42 (d, J = 8.1Hz, 1H), 8.35 (d, J = 8.1Hz, 1H), 7.92 (t, J = 7.5Hz, 1H), 7.80 (d, J = 2.3Hz, 1H), 7.67 ( dd, J=16.1, 8.3Hz, 2H), 7.23 (dd, J=8.7, 2.4Hz, 1H), 7.27 (t, J=74.9Hz, 1H), 4.60 (t, J=6.0Hz, 2H), 2.11 (t, J=7.1Hz, 2H), 1.97-1.85 (m, 2H), 1.85-1.73 (m, 2H).13C NMR (101MHz, 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

[0034] Synthesis of 5-(8-ethoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 1i, and other steps and operations were the same as in Example 1; a yellow powdery solid was obtained, with a yield of 70%. ¹H NMR (300MHz, DMSO-d6) δ 11.84 (s, 1H), 10.44 (s, 1H), 8.74 (s, 1H), 8.38 (d, J = 8.0Hz, 1H), 8.33 (d, J = 8.2Hz, 1H), 7.88 (t, J = 7.4Hz, 1H), 7.64 (t, J = 7.6Hz, 1H), 7 .54-7.42 (m, 2H), 7.02 (dd, J=8.6, 2.5Hz, 1H), 4.59 (t, J=6.0Hz, 2H), 4.13 (q, J= 6.8Hz, 2H), 2.11 (t, J=7.0Hz, 2H), 1.92-1.77 (m, 4H), 1.39 (t, J=6.9Hz, 3H).13C NMR (101MHz, DMSO) δ 169.05, 154.58, 152.64, 133.15, 130.55, 128.74, 126.41, 125.79, 125.06, 124.66, 122.46, 121.14, 117.76, 115.45, 112.69, 101.01, 65.16, 63.48, 32.09, 28.25, 22.16, 14.98. ESI-HRMS calcd for C22H23N3O4 m / z [M+H]+394.1761, found [M+H]+394.1760. Example 10 Synthesis of N-hydroxy-5-(8-isopropoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinoline-11-yl)pentanamide: The parent nucleus 1a in Example 1 was replaced with 1j, and 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) δ 11.84 (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, 2.4Hz, 1H), 4.66 (q, J=6.0Hz, 1H), 4.62-4 .55(m, 2H), 2.11(t, J=7.0Hz, 2H), 2.00-1.71(m, 4H), 1.31(d, J=6.0Hz, 6H).13C NMR (101MHz, 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-HRMS calcd for C23H25N3O4 m / z [M+H]+408.1918, found [M+H]+408.1911. Example 11 Synthesis of N-hydroxy-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxanepenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)pentanamide: The parent nucleus 1a in Example 1 was replaced with 1k, and other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 64%. 1H NMR (400MHz, DMSO-d6) δ11.88 (s, 1H), 10.45 (s, 1H), 8.74 (s, 1H), 8.32 (d, J = 8.2Hz, 1H), 8.29 (d, J = 8.2Hz, 1H), 7.90-7.74 (m, 1H), 7.57 (t, J =7.7Hz, 1H), 7.43 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.57 (t, J = 6.1Hz, 2H), 2.10 (t, J = 7.2Hz, 2H), 1.91-1.84 (m, 2H), 1.83-1.75 (m, 2H).13C NMR (101MHz, 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. Example 12 Synthesis of N-hydroxy-6-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)hexanoamide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 6-bromohexanoate. Other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 70%. 1H NMR (400MHz, DMSO-d6) δ11.87 (s, 1H), 10.39 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 8.28 (d, J = 8.2Hz, 1H), 7.84 (t, J = 7.2Hz, 1H), 7.56 (t, J = 7.5Hz, 1H) , 7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J=6.4Hz, 2H), 2.03 (t, J =7.2Hz, 2H), 1.92-1.85(m, 2H), 1.68-1.61(m, 2H), 1.56-1.48(m, 2H).13C NMR (101MHz, 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 for C22H21N3O5 m / z [M+H]+408.1554, found [M+H]+408.1558. Example 13 Synthesis of N-hydroxy-7-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)heptanamide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 7-bromoheptanoate. Other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 68%. 1H NMR (300MHz, DMSO-d6) δ11.87 (s, 1H), 10.44-10.30 (m, 1H), 8.70 (d, J = 1.6Hz, 1H), 8.35-8.26 (m, 2H), 7.84 (t, J = 7.5Hz, 1H), 7.57 (t, J = 7.6Hz, 1H) , 7.42 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J=6.4Hz, 2H), 1.98 (t, J =7.2Hz, 2H), 1.92-1.82(m, 2H), 1.61-1.48(m, 4H), 1.42-1.32(m, 2H).13C NMR (101MHz, 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-HRMS calcd for C23H23N3O5 m / z [M+H]+422.1710, found [M+H]+422.1708. Example 14 Synthesis of N-hydroxy-8-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)octanoamide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 8-bromooctanoate. Other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 74%. 1H NMR (300MHz, DMSO-d6) δ11.88 (s, 1H), 10.59-10.04 (m, 1H), 8.69 (s, 1H), 8.28 (d, J=8.1Hz, 2H), 7.83 (s, 1H), 7.56 (t, J=7.5Hz, 1H), 7.42 (s , 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J=6.3Hz, 2H), 1.96 (t, J=7.4Hz, 2H), 1.89-1.82 (m, 2H), 1.56-1.47 (m, 4H), 1.41-1.28 (m, 4H).13C NMR (101MHz, 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. Example 15 Synthesis of N-hydroxy-9-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)nonanoamide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 9-bromononanoate. Other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 72%. 1H NMR (400MHz, DMSO-d6) δ11.89 (s, 1H), 10.35 (s, 1H), 8.68 (s, 1H), 8.46-8.15 (m, 2H), 7.83 (t, J=6.9Hz, 1H), 7.56 (t, J=7.4Hz, 1H), 7.41 (s , 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J=6.4Hz, 2H), 1.94 (t, J=7.3Hz, 2H), 1.90-1.83 (m, 2H), 1.55-1.45 (m, 4H), 1.43-1.14 (m, 6H).13C NMR (101MHz, 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 for C25H27N3O5 m / z [M+H]+450.2023, found [M+H]+450.2021. Example 16 Synthesis of N-hydroxy-10-(5-oxo-5,6-dihydro-12H-[1,3]dioxapentane[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)decanoic acid amide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 10-bromodecanoate. Other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 70%. ¹H NMR (400MHz, DMSO-d6) δ 11.86 (s, 1H), 10.34 (s, 1H), 8.68 (s, 1H), 8.31 (d, J = 8.2Hz, 1H), 8.29-8.21 (m, 1H), 7.83 (t, J = 7.5Hz, 1H), 7.56 (t, J = 7.6Hz, 1H), 7.42 ( s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.54 (t, J=6.4Hz, 2H), 1.93 (t, J=7.4Hz, 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 (101MHz, DMSO) δ 169.22, 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. Example 17 Synthesis of N-hydroxy-3-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)benzamide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 3-bromomethylbenzoate. Other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 54%. 1H NMR (300MHz, DMSO-d6) δ11.93 (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, J=7.6Hz, 1H), 7.72 (d, J=7.7Hz, 1H), 7.63-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.14 (s, 1H), 6.08 (s, 2H), 5.74 (s, 2H).13C NMR (101MHz, DMSO) δ 164.17, 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. Example 18 Synthesis of N-hydroxy-4-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclohexano[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)benzamide: The parent nucleus 1a in Example 1 was replaced with 1k, and ethyl 5-bromopentanoate was replaced with ethyl 4-bromomethylbenzoate. Other steps and operations were the same as in Example 1; a red solid was obtained with a yield of 52%. 1H NMR (300MHz, DMSO-d6) δ11.93 (s, 1H), 11.24 (d, J=1.8Hz, 1H), 9.06 (s, 1H), 8.35 (dd, J=8.2, 3.6Hz, 2H), 7.86 (t, J=7.6Hz, 1H), 7.83-7.66 (m, 4H), 7.59 (t, J=7.7Hz, 1H), 7.46 (s, 1H), 7.14 (s, 1H), 6.07 (s, 2H), 5.73 (s, 2H).13C NMR (101MHz, 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. Example 19 Synthesis of 5-(5-chloro-12H-[1,3]dioxanepenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxypentanamide: The parent nucleus 1a in Example 1 was replaced with 4k, and other steps and operations were the same as in Example 1; a yellow solid was obtained with a yield of 67%. 1H NMR (400MHz, DMSO-d6) δ 10.33 (s, 1H), 8.68 (s, 1H), 8.47 (d, J = 8.6Hz, 1H), 8.38 (d, J = 8.5Hz, 1H), 7.94 (t, J = 7.7Hz, 1H), 7.72 (t, J = 7. 8Hz, 1H), 7.49 (d, J=3.7Hz, 2H), 6.12 (s, 2H), 4.72 (t, J=7.2Hz, 2H), 1.97 (t, J=7.3Hz, 2H), 1.83-1.75 (m, 2H), 1.64-1.56 (m, 2H).13C NMR (101MHz, 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-HRMS calcd for C21H18ClN3O4 m / z [M+H]+412.1059, found [M+H]+412.1052. Example 20 Synthesis of 6-(5-chloro-12H-[1,3]dioxanepentano[4′,5′:5,6]indolano[3,2-c]isoquinoline-12-yl)-N-hydroxyhexanoamide: The parent nucleus 1a in Example 1 was replaced with 4k, and ethyl 5-bromopentanoate was replaced with ethyl 6-bromohexanoate. Other steps and operations were the same as in Example 1. A yellow solid was obtained with a yield of 64%. 1H NMR (300MHz, DMSO-d6) δ10.32 (s, 1H), 8.68 (s, 1H), 8.43 (dd, J=16.6, 7.2Hz, 2H), 7.95 (s, 1H), 7.74 (s, 1 H), 7.49 (d, J=9.7Hz, 2H), 6.12 (s, 2H), 4.70 (t, J=7.0Hz, 2H), 2.00-1.70 (m, 4H), 1.61-1.31 (m, 4H).13C NMR (101MHz, 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. Example 21 Synthesis of 7-(5-chloro-12H-[1,3]dioxanepentano[4′,5′:5,6]indolano[3,2-c]isoquinoline-12-yl)-N-hydroxyheptanoamide: The parent nucleus 1a in Example 1 was replaced with 4k, and ethyl 5-bromopentanoate was replaced with ethyl 7-bromoheptanoate. Other steps and operations were the same as in Example 1. A yellow solid was obtained with a yield of 65%. 1H NMR (300MHz, DMSO-d6) δ10.34 (s, 1H), 8.67 (s, 1H), 8.46 (dd, J=19.5, 7.8Hz, 2H), 7.98 (t, J=7.4Hz, 1H), 7.75 (t, J=7.3Hz, 1H), 7.52 (d, J =7.9Hz, 2H), 6.13 (s, 2H), 4.72 (t, J = 7.0Hz, 2H), 1.91 (t, J = 7.1Hz, 2H), 1.78 (t, J = 10.6Hz, 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. Example 22 Synthesis of 7-(12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxyheptamide: 1.0 mmol (21) was dissolved in 20 mL of acetic acid, and 5 mL of 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 was completed, the acetic acid in the reaction solution was evaporated to dryness 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 (300MHz, DMSO-d6) δ10.39 (s, 1H), 9.06 (s, 1H), 8.67 (s, 1H), 8.47 (d, J= 8.5Hz, 1H), 8.27 (d, J=8.0Hz, 1H), 7.90 (t, J=7.6Hz, 1H), 7.66 (t, J=7.4Hz, 1H), 7.63(s, 1H), 7.53(s, 1H), 6.12(s, 2H), 4.77(t, J=7.0Hz, 2H), 1.91(t, J=7.2Hz, 2H), 1.87-1.71 (m, 2H), 1.52-1.33 (m, 4H), 1.32-1.24 (m, 2H).13C NMR (101MHz, 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-HRMS calcd for C23H23N3O4 m / z [M+H]+406.1761, found [M+H]+406.1758. Example 23 Synthesis of 8-(12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxyoctamide: Following the synthesis method of Example 22, a yellow solid was obtained in 78% yield. 1H NMR (300MHz, DMSO-d6) δ10.31 (s, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.46 (d, J= 8.5Hz, 1H), 8.26 (d, J=8.0Hz, 1H), 7.88 (t, J=7.6Hz, 1H), 7.65 (t, J=6.6Hz, 1 H), 7.63 (s, 1H), 7.51 (s, 1H), 6.12 (s, 2H), 4.76 (t, J=7.3Hz, 2H), 1.89 (t, J= 7.3Hz, 2H), 1.80 (t, J=7.7Hz, 2H), 1.48-1.38 (m, 4H), 1.31-1.08 (m, 4H).13C NMR (101MHz, 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. Example 24 Synthesis of 9-(12H-[1,3]dioxanepenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N-hydroxynonanoamide: Following the synthesis method of Example 22, a yellow solid was obtained in 75% yield. 1H NMR (400MHz, DMSO-d6) δ10.32 (s, 1H), 9.05 (s, 1H), 8.67 (s, 1H), 8.44 (d, J= 8.5Hz, 1H), 8.25 (d, J=8.0Hz, 1H), 7.98-7.79 (m, 1H), 7.63 (d, J=8.3Hz, 2H), 7.49 (s, 1H), 6.11 (s, 2H), 4.74 (t, J=7.3Hz, 2H), 1.89 (t, J=7.4Hz, 2H), 1.8 4-1.77(m, 2H), 1.43-1.32(m, 4H), 1.30-1.21(m, 2H), 1.21-1.10(m, 4H).13C NMR (101MHz, 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. Example 25 Synthesis of N′-ethyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)pentanoylhydrazine: The parent nucleus 1k (1.0 mmol, 280.1 mg) was dissolved in 20 mL of DMF, followed by the addition of K2CO3 (6.0 mmol, 827.4 mg) and ethyl 5-bromopentanoate (1.0 mmol, 209.1 mg). The mixture was stirred overnight in an oil bath at 80 °C. After the reaction was complete, the reaction solution was poured into cold water and stirred. The aqueous solution was extracted three times with ethyl acetate, and the organic phase was collected. 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 the crude product. The crude product was purified by silica gel column chromatography (PE:EA = 5:1-2:1 / v:v) to obtain a white solid 2k. 2kJ (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 overnight in an oil bath at 80 °C. After the reaction was complete, the product was purified by silica gel column chromatography (DCM:MeOH = 10:1-5:1 / v:v) to give a 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 overnight at room temperature. MgSO4 was removed by filtration, and the methanol was evaporated to dryness to give 7a. Dissolve 7a (1.0 mmol, 418.2 mg) in 20 mL of methanol, then add sodium borohydride (10.0 mmol, 378.3 mg) and stir overnight. After the reaction is complete, the solid is 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. Example 26. Synthesis of 5-(5-oxo-5,6-dihydro-12H-[1,3]dioxanepentano[4′,5′:5,6]indolano[3,2-c]isoquinoline-12-yl)-N′-propylpentanoylhydrazine: Acetaldehyde in Example 25 was replaced with propionaldehyde, and other steps and operations were the same as in Example 25; a white solid was obtained, with a yield of 76%. ¹H NMR (300MHz, DMSO-d6) δ 11.87 (s, 1H), 9.31 (s, 1H), 8.30 (t, J = 7.8Hz, 2H), 7.91-7.77 (m, 1H), 7.57 (t, J = 7.6Hz, 1H), 7.42 (s, 1H), 7.12 (d, J = 0.6Hz, 1H), 6.06 (s, 2H), 4.81 (s, 1H), 4.56 (t, J=6.1Hz, 2H), 2.61 (t, J=7.0Hz, 2H), 2.16 (t, J=7.0Hz , 2H), 1.84 (dt, J=21.1, 7.1Hz, 4H), 1.43-1.31 (m, 2H), 0.83 (t, J=7.4Hz, 3H).13C NMR (101MHz, 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. Example 27 Synthesis of N′-butyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxanepentano[4′,5′:5,6]indolano[3,2-c]isoquinoline-12-yl)pentanoylhydrazine: Acetaldehyde in Example 25 was replaced with butyraldehyde, and other steps and operations were the same as in Example 25; a white solid was obtained, with a yield of 73%. ¹H NMR (300MHz, DMSO-d6) δ 11.87 (s, 1H), 9.30 (d, J = 4.7Hz, 1H), 8.30 (t, J = 8.6Hz, 2H), 7.84 (t, J = 7.6Hz, 1H), 7.56 (t, J = 7.7Hz, 1H), 7.42 (s, 1H), 7.12 (d, J = 1.9Hz, 1H). 6.06 (s, 2H), 4.78 (d, J=5.9Hz, 1H), 4.56 (t, J=6.0Hz, 2H), 2.67-2.61 (m, 2H), 2.16 (t, J=7.1Hz, 2H), 1.90-1.75 (m, 4H), 1.36-1.20 (m, 4H), 0.83 (t, J=7.2Hz, 3H).13C NMR (101MHz, DMSO) δ 171.06, 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. Example 28 Synthesis of 6-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N′-propylhexanehydrazine: Ethyl 5-bromopentanoate in Example 25 was replaced with ethyl 6-bromohexanoate, and acetaldehyde was replaced with propionaldehyde; other steps and operations were the same as in Example 25; a white solid was obtained in 74% yield. 1H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H), 9.26 (d, J = 6.0Hz, 1H), 8.31 (d, J = 8.3Hz, 1H), 8.28 (d, J = 7 .9Hz, 1H), 7.84 (t, J=7.6Hz, 1H), 7.66-7.49 (m, 1H), 7.41 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.8 0-4.76 (m, 1H), 4.55 (t, J=6.4Hz, 2H), 2.60 (td, J=7.1, 4.9Hz, 2H), 2.08 (t, J=7.2Hz, 2H), 1.92- 1.85(m, 2H), 1.68-1.61(m, 2H), 1.55-1.48(m, 2H), 1.41-1.32(m, 2H), 0.83(t, J=7.4Hz, 3H).13C NMR (101MHz, 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. Example 29 Synthesis of 8-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)-N′-propyloctanohydrazide: Ethyl 5-bromopentanoate in Example 25 was replaced with ethyl 8-bromooctanoate, and acetaldehyde was replaced with propionaldehyde; other steps and operations were the same as in Example 25; a white solid was obtained in 69% yield. 1H NMR (400MHz, DMSO-d6) δ11.86 (s, 1H), 9.22 (d, J = 6.0Hz, 1H), 8.31 (d, J = 8.3Hz, 1H), 8.27 (d , J=8.1Hz, 1H), 7.92-7.73(m, 1H), 7.56(t, J=7.6Hz, 1H), 7.42(s, 1H), 7.12(s, 1H), 6.06(s , 2H), 4.80-4.75 (m, 1H), 4.55 (t, J=6.5Hz, 2H), 2.60 (td, J=7.1, 4.9Hz, 2H), 2.02 (t, J=7.3 Hz, 2H), 1.90-1.83 (m, 2H), 1.56-1.48 (m, 4H), 1.44-1.19 (m, 6H), 0.84 (t, J=7.4Hz, 3H).13C NMR (101MHz, 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. Example 30 Synthesis of N′-ethyl-4-(5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)benzoylhydrazine: Ethyl 5-bromopentanoate in Example 25 was replaced with ethyl 4-bromomethylbenzoate, and other steps and operations were the same as in Example 25; a white solid was obtained in 45% yield. 1H NMR (400MHz, DMSO-d6) δ12.35 (s, 1H), 10.09 (d, J = 5.8Hz, 1H), 8.45 (d, J = 8.3Hz, 1H), 8.34 (d, J = 8.3Hz, 1H), 7.87 (t, J = 8.0Hz, 3H), 7.70 (d, J = 8.0Hz, 2H ), 7.58 (t, J=7.7Hz, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 6.07 (s, 2H), 5.72 (s, 2H) ), 5.07 (d, J = 6.3Hz, 1H), 2.84-2.77 (m, 2H), 1.02 (t, J = 7.1Hz, 3H).ESI-HRMS calcd for C26H22N4O4 m / z[M+H]+455.1714, found[M+H]+455.1719. Example 31 Synthesis of 4-((5-oxo-5,6-dihydro-12H-[1,3]dioxacyclopenta[4′,5′:5,6]indolo[3,2-c]isoquinoline-12-yl)methyl)-N′-propylbenzoylhydrazine: Ethyl 5-bromopentanoate in Example 25 was replaced with ethyl 4-bromomethylbenzoate, and acetaldehyde was replaced with propionaldehyde. Other steps and operations were the same as in Example 25; a white solid was obtained with a yield of 55%. 1H NMR (300MHz, DMSO-d6) δ12.34 (s, 1H), 10.19-10.01 (m, 1H), 8.45 (d, J=8.2 Hz, 1H), 8.34 (d, J=8.3Hz, 1H), 7.97-7.79 (m, 3H), 7.79-7.63 (m, 2H), 7.58 (t, J=7.6Hz, 1H), 7.44 (s, 1H), 7.13 (s, 1H), 6.06 (s, 2H), 5.72 (s, 2H), 5.0 9(s, 1H), 2.74(s, 2H), 1.52-1.39(m, 2H), 0.89(t, J=7.4Hz, 3H).ESI-HRMS calcd for C27H24N4O4 m / z[M+H]+469.1870, found[M+H]+469.1874. In vitro antitumor activity screening was conducted for the embodiments of this invention: The MTT assay was used to evaluate the inhibitory activity of compounds on tumor cell proliferation, and the IC50 values ​​of each compound against 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 formazan crystals, which are then deposited in the cells. In dead cells, mitochondria are inactivated and therefore lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells. The absorbance value was measured at 490 nm using an ELISA reader. Within a certain cell number range, the amount of formazan crystals formed is directly proportional to the number of living cells. The number of living cells was determined based on the absorbance (OD) value measured by the ELISA reader; the higher the OD value, the stronger the cell activity and the greater the number of living cells, thus calculating the cell viability.

[0035] The experimental method is as follows: (1) Cell inoculation: Tumor cells were prepared into a single cell suspension using a culture medium containing 10% fetal bovine serum. 100 μL of the tumor cell suspension with a density of 2×104 cells / mL was inoculated into each well of a 96-well plate and cultured at 37°C in a 5% CO2 incubator for 24 h.

[0036] (2) Adding the sample solution: After the cells have adhered to the 96-well plate, add 100 μL of sample solution to each well. Measure 6 concentrations for each sample, with 3 replicates for each concentration. Add an equal volume of the same culture medium containing 0.1% DMSO to the negative control group. After adding the drug, continue incubating the 96-well plate in an incubator for 72 h.

[0037] (3) Detection: Add 10 μL of 5 mg / mL MTT solution to each well and continue culturing at 37℃ for 4 h. Discard the supernatant, add 100 μL of DMSO to each well, mix well on a plate shaker, and then detect the OD value with an ELISA reader at a wavelength of 490 nm.

[0038] (4) The raw data were standardized using ExCel software. IC50 was calculated using GraphPad Prism 8. The formula for calculating the tumor cell growth inhibition rate is: Growth inhibition rate (%) = 1 - (OD value of the treatment group - OD value of the blank group) / (OD value of the negative control group - OD value of the blank group) × 100%.

[0039] Table 1. Antitumor activity (IC50, μM) and HDAC1 inhibitory activity (IC50, nM) of Examples 1-31 As shown in Table 1, most of the embodiments in this invention exhibited micromolar levels of in vitro antiproliferative activity against different tumor cell lines, with Examples 14 and 22 demonstrating the best antitumor activity. Specifically, Example 14 showed superior antitumor activity compared to the positive control drugs SAHA, irinotecan, etoposide, and their combination. Screening of ten different tumor cell lines revealed that the H1975 cell line was the most sensitive to Example 14. Example 14 showed an IC50 value against the H1975 cell line. 50 The concentration was 0.13 μM, significantly better than the positive control group. Therefore, the embodiments of the present invention can potentially be used for the clinical treatment of the aforementioned tumors.

[0040] Table 2. In vitro antitumor activity (IC50) of Examples 14 and 22 50 (μM) HDAC1 activity inhibition experiments were conducted on the embodiments of this invention: We screened the inhibitory activity of all embodiments against HDAC1, and the results showed that the inhibitory activity of several embodiments against HDAC1 was superior to that of the positive control drug HDAC inhibitor SAHA, such as embodiments 12-14 and embodiments 21-24, whose IC50 values ​​against HDAC1 were significantly higher. 50 The activity values ​​ranged from 2 to 9.4 nM, significantly superior to that of SAHA (IC50). 50 =17nM).

[0041] Topoisomerase activity inhibition experiments were conducted on the embodiments of the present invention: Embodiments 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 embodiments, most, such as Embodiments 11-15 and Embodiments 21-24, exhibited excellent inhibitory activity against Top1 and Top2.

[0042] HDAC subtype selective screening experiments were conducted on Examples 14 and 22 of this invention: Examples 14 and 22, which exhibited good in vitro antitumor activity, were selected for HDAC subtype selective screening experiments, and their structures are shown in Table 3. Examples 14 and 22 showed good inhibitory activity against HDAC1, 2, 3, 6, and 10, with IC50 values ​​of [missing value]. 50 With a value of 2.7-15 nM, its activity is superior to vorinostat and it belongs to the HDAC pan-inhibitor class.

[0043] Table 3. Inhibition activity (IC) of each HDAC subtype in Examples 14 and 22 50 (nM) The antitumor efficacy of Example 14 of this invention was studied in nude mice: The drug used was Example 14. The cell line used was the human non-small cell lung cancer cell line H1975. The test animals were SPF-grade Balb / c nude mice; male; 6 mice per group. The drug dosage and positive control group settings are shown in Table 4.

[0044] Drug preparation method: Example 14 (50mg / kg and 100mg / kg): Weigh 50mg or 100mg of the test compound powder and dissolve it in 0.5mL of DMSO. Then add 1.5mL 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 shake to mix well and make up to 5mL to prepare test solutions of 10mg / mL and 20mg / mL. Use this solution as the oral administration preparation.

[0045] SAHA (100mg / kg): The preparation method is the same as that in Example 14.

[0046] Irinotecan (20 mg / kg): Weigh 20 mg of the test compound powder and dissolve it in 0.5 mL of DMSO. Then add 1 mL of PEG400 and mix well. Finally, add 3.5 mL of physiological saline and sonicate and vibrate to mix well to prepare a 4 mg / mL test solution. This solution is used as the intraperitoneal injection preparation.

[0047] Table 4. Drug Dosage Preparation and Positive Control Group

[0048] Experimental Methods: Establishment of a human non-small cell lung cancer xenograft model. Logarithmically growing H1975 cells were subcutaneously inoculated into the right forelimb of nude mice at a dose of 5 × 10⁶ cells / mouse. When the subcutaneous tumor grew to approximately 80 mm³, the tumor-bearing mice and human colon cancer-bearing mice were randomly divided into 5 groups (n=6 per group): a blank control group, a low-dose group (Example 14), a high-dose group (Example 14), a positive control group (SAHA), and a group treated with SAHA + irinotecan. All experimental groups were administered drugs according to the methods shown in Table 4. The body weight and tumor size of each group were monitored daily. After the drug administration cycle was completed, the mice were sacrificed, and tumor tissue and major organs were harvested, weighed, and fixed.

[0049] Experimental results showed that the test drug Example 14 exhibited good antitumor activity in a human small cell lung cancer xenograft model. It showed significant antitumor activity at a dose of 50 mg / kg, with a TGI value of 59.9% and a T / C value of 42.5%. When the dose was increased to 100 mg / kg, Example 14 showed even higher antitumor activity, with a TGI value of 77.5% and a T / C value of 12.2%, which was superior to 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%).

[0050] In summary, Example 14 is a Top / HDAC dual-target inhibitor with significant in vivo anti-tumor activity.

[0051] The pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor of this 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. It can be used as a small molecule with anti-tumor activity for the development of new anti-tumor drugs.

[0052] In addition to the above-described embodiments, the present invention may have other implementations. All technical solutions formed by equivalent substitution or equivalent transformation fall within the protection scope claimed by the present invention.

Claims

1. A pyrrolo[3,2-b]pyridine-based Top / HDAC dual-target inhibitor, characterized in that, The inhibitor is a substituted pyrrolo[3,2-b]pyridine compound represented by general formula V, or a stereoisomer, hydrate or pharmaceutically acceptable salt thereof: wherein A, B ring is a substituted benzene ring, pyridine, pyrimidine; R 1 is a hydrogen, chlorine or oxygen atom; L is selected from the group consisting of R 2 selected from the group consisting of 2. The pyrrolo[3,2-b]pyridine-based Top / HDAC dual-target inhibitors according to claim 1, characterized in that: In the inhibitors of Formula V, the hydrogen attached to the carbon is replaced with deuterium, an isotope of hydrogen.

3. The pyrrolo[3,2-b]pyridine-based Top / HDAC dual-target inhibitor according to claim 1 or 2, characterized in that: The inhibitors are one of the following, (1) N-hydroxy-5-(5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11- yl)pentanamide; (2) 5-(9-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N- hydroxypentanamide; (3) N-hydroxy-5-(9-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin- 11-yl)pentanamide; (4) 5-(8-fluoro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N- hydroxypentanamide; (5) 5-(8-chloro-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N- hydroxypentanamide; (6) 5-(8-bromo-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N- hydroxypentanamide; (7) N-hydroxy-5-(8-methoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin- 11-yl)pentanamide; (8) 5-(8-(difluoromethoxy)-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11- yl)-N-hydroxypentanamide; (9) 5-(8-ethoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin-11-yl)-N- hydroxypentanamide; (10) N-hydroxy-5-(8-isopropoxy-5-oxo-5,6-dihydro-11H-indolo[3,2-c]isoquinolin- 11-yl)pentanamide; (11) N-hydroxy-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2- c]isoquinolin-12-yl)pentanamide; (12) N-hydroxy-6-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2- c]isoquinolin-12-yl)hexanamide; (13) N-hydroxy-7-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2- c]isoquinolin-12-yl)heptanamide; (14) N-hydroxy-8-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2- c]isoquinolin-12-yl)octanamide; (15) N-hydroxy-9-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2- c]isoquinolin-12-yl)nonanamide; (16) N-hydroxy-10-(5-oxo-5,6-dihydro-12H- [1,3] dioxolo [4',5':5,6] indolo [3,2-c] isoquinolin-12- yl)decanamide; (17) N-hydroxy-3-((5-oxo-5,6-dihydro-12H- [1,3] dioxolo [4',5':5,6] indolo [3,2-c] isoquinolin-12- yl)methyl)benzamide; (18) N-hydroxy-4-((5-oxo-5,6-dihydro-12H- [1,3] dioxolo [4',5':5,6] indolo [3,2-c] isoquinolin-12- yl)methyl)benzamide; (19) 5-(5-chloro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N- hydroxyvaleramide; (20) 6-(5-chloro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N- hydroxyhexanamide; (21) 7-(5-chloro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N- hydroxyheptanamide; (22) 7-(12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N- hydroxyheptanamide; (23) 8-(12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N- hydroxyoctanamide; (24) 9-(12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)-N- hydroxynonanamide; (25) N'-ethyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin- 12-yl)valerohydrazide; (26) 5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)- N'-propylvalerohydrazide; (27) N'-butyl-5-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin- 12-yl)valerohydrazide; (28) 6-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)- N'-propylhexanohydrazide; (29) 8-(5-oxo-5,6-dihydro-12H-[1,3]dioxolo[4',5':5,6]indolo[3,2-c]isoquinolin-12-yl)- N'-propyloctanohydrazide; (30) N'-ethyl-4-(5-oxo-5,6-dihydro-12H- [1,3] dioxolo [4',5':5,6] indolo [3,2-c] isoquinolin-12-yl)methyl) benzohydrazide; (31) 4-((5-oxo-5,6-dihydro-12H- [1,3] dioxolo [4',5':5,6] indolo [3,2-c] isoquinolin-12-yl)methyl)-N'-propyl benzohydrazide.

4. A method for preparing a pyrrolo[3,2-b]pyridine-based Top / HDAC dual-target inhibitor, characterized in that: The o-nitrobenzaldehyde A1-A11 with different substituents as raw material, after reaction with methoxyamine, compound B1-B11 is generated, then addition reaction with pentafluorophthalic anhydride generates key intermediates C1-C11, intermediates C1-C11 then with sodium sulfide reduction reaction, generate the nucleus 1a-k, the nucleus 1a-k then with phosphorus oxychloride reaction, generate the nucleus 4k, the synthesis route as follows: Again with pyrrolo[3,2-b]pyridine derivatives 1a-k and 4k with different substituents as raw material, after reaction with 5-bromo pentanoic acid ethyl ester, 6-bromo hexanoic acid ethyl ester, 7-bromo heptanoic acid ethyl ester, 8-bromo octanoic acid ethyl ester, 9-bromo nonanoic acid ethyl ester, 10-bromo decanoic acid ethyl ester, 3-bromomethyl benzoic acid ethyl ester and 4-bromomethyl benzoic acid ethyl ester, compound 2a-2k, 3a-3g and 5a-5e are generated, then with hydroxylamine reaction generates final product (1)-(21), (22)-(24) is the product after zinc powder reduction of the corresponding substrate; Compounds 6a-6d were generated from 2k, 3a, 3c, 3g by reaction with hydrazine hydrate, followed by reaction with acetaldehyde, propionaldehyde and butyraldehyde to generate 7a-7g. Reduction of 7a-7g with sodium borohydride generated the final products (25)-(31). The specific synthesis routes are as follows, 5. A pharmaceutical composition, characterized by: The composition comprises at least one pharmaceutically acceptable adjuvant, auxiliary agent or carrier, and the pyrrolo[3,2-b]pyridine Top / HDAC dual-target inhibitor as claimed in any one of claims 1-3.

6. 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 5 in the preparation of a medicament for preventing, treating or adjuvant treatment of a proliferative disease, metabolic disease, nervous system disease or tuberous sclerosis caused by over-activation of topoisomerase Top or histone acetyltransferase HDAC.

7. 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 5 in the preparation of a medicament for inhibiting growth of cancer cells.

Images