Indole compounds for targeted inhibition of hdac6 and methods of making and using the same

Abstract

This invention is a divisional application of patent application number 202311457833.6. This invention belongs to the field of compound synthesis technology, specifically relating to an indole compound that targets and inhibits HDAC6, its preparation method, and its applications. The indole compound that targets and inhibits HDAC6 of this invention is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. Experimental results show that the indole compound that targets and inhibits HDAC6 provided by this invention not only has superior selective inhibitory activity against HDAC6 protein but also inhibits the proliferation of gastric cancer cells in a concentration-dependent manner. Therefore, the compound of this invention has good application prospects in the preparation of inhibitory drugs based on the HDAC6 target and drugs that inhibit the proliferation activity of gastric cancer cells, and is of great significance in the development of anti-tumor drugs and the treatment of related diseases.

Description

[0001] This invention is a divisional application of a patent application entitled "Novel Indole Derivatives, Preparation Methods and Applications", the original application was filed on November 4, 2023, and the application number is 202311457833.6. Technical Field

[0002] This invention belongs to the field of compound synthesis technology, specifically relating to an indole compound that targets and inhibits HDAC6, its preparation method, and its application. Background Technology

[0003] Globally, cancer is the second leading cause of death after cardiovascular disease. Treatment methods for cancer mainly include surgery, radiotherapy, and chemotherapy. Currently, molecularly targeted therapy targets specific oncogenic sites at the cellular and molecular level, effectively intervening in signaling pathways closely related to cancer development and progression to achieve highly effective tumor treatment. Compared to traditional anti-tumor chemotherapy drugs, the rational use of targeted drugs can significantly reduce the side effects of chemotherapy, resulting in better cancer treatment outcomes.

[0004] Numerous studies have shown that the epigenetic modifications of histones, including acetylation and deacetylation, play crucial roles in many biological processes. Under the regulation of histone acetylation enzymes (HATs) and histone deacetylases (HDACs), the level of histone acetylation in the human body maintains a dynamic balance. However, studies have found high expression of HDACs in many tumor cells. Therefore, HDACs have remained a popular target for tumor-targeted therapy.

[0005] HDAC6, as a member of the class IIb histone deacetylase family, differs from other Zn... 2+ HDAC6, a type of HDAC-dependent inhibitor, possesses more distinct characteristics. Located in the cytoplasm, HDAC6 contains two catalytic domains (CD1 and CD2) and a ubiquitin-binding zinc finger domain, playing a crucial role in cancer, neurological disorders, inflammation, and other diseases. Existing research confirms that aberrant expression of HDAC6 is closely related to the development and progression of gastric cancer; its overexpression can induce the transformation of normal cells into gastric cancer cells, leading to cancer. Therefore, inhibiting HDAC6 activity can help prevent the development and progression of gastric cancer. However, there are currently few reported studies on the use of HDAC6 inhibitors for the treatment of gastric cancer.

[0006] Therefore, developing more potent and selective small-molecule HDAC6 inhibitors is of significant research value and application importance for the treatment and prognosis of gastric cancer. Summary of the Invention

[0007] To address the aforementioned problems, the primary objective of this invention is to provide an indole compound that targets and inhibits HDAC6, which not only exhibits superior selective inhibition of HDAC6 but also inhibits the proliferation of gastric cancer cells in a concentration-dependent manner.

[0008] A second objective of this invention is to provide a method for preparing the above-mentioned indole compounds that target and inhibit HDAC6.

[0009] A third objective of this invention is to provide the application of the aforementioned indole compounds that target and inhibit HDAC6.

[0010] To achieve the objective of this invention, the technical solution adopted is as follows: An indole compound that targets and inhibits HDAC6, which is a compound of Formula I or a pharmaceutically acceptable salt thereof: ; In Formula I, R1 is selected from one of H, 5-CH3, 6-CH3, 7-CH3, 5-OCH3, 5-Br, 6-Br, and 6-OCH3; R2 is selected from H, One of them; R3 is H or CH3; R4 is ; The specific structure of the indole compound that targets and inhibits HDAC6 is shown below: .

[0011] The preparation method of the above-mentioned indole compounds that target and inhibit HDAC6 is as follows: ;

[0012] When R2 is H, the preparation method of an indole compound that targets and inhibits HDAC6 includes the following steps: (1) Raw material A, raw material B, condensing agent a, and basic substance a are condensed in solvent a to obtain intermediate C; (2) Intermediate C and hydroxylamine aqueous solution were reacted in solvent b, and then alkaline substance b was added to react. After the reaction was completed, acidic substance and water were added, and the mixture was filtered to obtain the indole compound M that targets and inhibits HDAC6. When R2 is not H, the preparation method of the indole compound that targets and inhibits HDAC6 includes the following steps: ①The raw material A, raw material B, condensing agent a, and basic substance a are condensed in solvent a to obtain intermediate C; ② Intermediate C, basic substance c, and raw material a are reacted in solvent d to obtain intermediate E; the raw material a is a brominated compound; ③ Intermediate E is reacted with an aqueous solution of hydroxylamine in solvent b, and then alkaline substance b is added to continue the reaction. After the reaction is complete, acidic substance and water are added, and the mixture is filtered to obtain the indole compound F that targets and inhibits HDAC6.

[0013] To improve the solubility of raw materials and the yield of products, as a preferred embodiment, solvent a is dichloromethane, solvent b is a mixed solution of dichloromethane and methanol, and solvent d is N,N-dimethylformamide.

[0014] As a preferred embodiment, the alkaline substance a is triethylamine, the alkaline substance b is sodium hydroxide, and the alkaline substance c is potassium hydroxide; the acidic substance is hydrochloric acid.

[0015] As a preferred embodiment, the condensing agent a is EDCI or HOBT.

[0016] As a preferred embodiment, the brominated compound is one of benzyl bromide, bromomethylcyclopropane, and 4-fluorobenzyl bromide.

[0017] The application of the aforementioned indole compounds that target and inhibit HDAC6 is specifically in the preparation of inhibitory drugs based on the HDAC6 target, or in the preparation of drugs for targeted cancer therapy based on the HDAC6 target; the cancer being gastric cancer.

[0018] Furthermore, the aforementioned drug comprises at least one indole compound that targets and inhibits HDAC6, and a pharmaceutically acceptable excipient. The mass content of the indole compound that targets and inhibits HDAC6 is preferably 90% to 98%. This invention does not impose any special limitations on the excipients; any pharmaceutically acceptable excipient well known to those skilled in the art can be used.

[0019] As a preferred embodiment, the targeted cancer treatment drug is a drug that inhibits the proliferation activity of gastric cancer cells; the gastric cancer cells are MGC-803 cells.

[0020] The beneficial effects of this invention are: The indole compounds targeting and inhibiting HDAC6 provided by this invention have novel structures and exhibit good inhibitory effects on HDAC6, making them suitable for use as HDAC6 inhibitors. Furthermore, these compounds inhibit the proliferative activity of gastric cancer cells by forming stable complexes through chelation with metal ions within the cells. The method for preparing the indole compounds targeting and inhibiting HDAC6 provided by this invention utilizes mild synthetic conditions, is easy to implement, and yields compounds with high yield and high purity.

[0021] Experimental results show that, compared with the positive control vorinostat (SAHA), the indole compound targeting HDAC6 provided by this invention not only exhibits superior selective inhibition of HDAC6 protein but also inhibits the proliferation of gastric cancer cells (MGC-803) in a concentration-dependent manner. Therefore, the compound of this invention has promising applications in the preparation of HDAC6-targeted inhibitory drugs and drugs that inhibit the proliferation of gastric cancer cells, and is of great significance for the development of HDAC6-targeted inhibitory drugs and anti-tumor drugs, as well as the research and treatment of related diseases. Detailed Implementation

[0022] The present invention will be further described below with reference to specific embodiments, but this does not constitute a limitation on the present invention.

[0023] Example 1

[0024] Z-1, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0025] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the dichloromethane was evaporated. The sample was then stir-fried with silica gel (100-200 mesh) and packed into a 200-300 mesh silica gel column. The intermediate was purified using a solution of petroleum ether / ethyl acetate as the mobile phase, with a yield of 93% and a purity of 97%.

[0026] (2) Dissolve 1 mmol of the intermediate obtained in step (1) in a DCM:MeOH=2:1 solution, add 30 mmol of hydroxylamine aqueous solution (50% water) under stirring at 650 rpm at room temperature, stir at room temperature for 0.5 h, then add 10 mmol of sodium hydroxide and react for 10-30 min. After the reaction of the raw materials is complete, evaporate the organic solvent, add water to dissolve the system, then place it in an ice bath, add dilute hydrochloric acid to adjust the pH to 3-4, let it stand and filter, and then beat the obtained solid with ethyl acetate. Finally, dry to obtain the target compound Z-1 with a yield of 85%, a purity of 97%, a white solid, and a melting point of 199.9-201.2℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.58(s, 1H), 11.17 (s, 1H), 9.00 (s, 1H), 8.49 (d, J = 6.1 Hz, 1H), 8.22 – 8.12(m, 1H), 8.08 (d, J = 2.8 Hz, 1H), 7.77 – 7.67 (m, 2H), 7.42 (dd, J = 12.1,8.1 Hz, 3H), 7.19–7.04 (m, 2H), 4.52 (d, J = 6.0 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 165.12, 164.64, 144.28, 136.62, 131.60, 128.35, 127.49,127.35, 126.62, 122.37, 121.47, 120.85, 112.30, 110.84, 42.14. HR-MS(ESI):calcd. C 17 H 15 N3O3, [M+H]+ m / z: 310.1191, found: 310.1194.

[0027] Example 2

[0028] Z-2, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0029] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the dichloromethane was evaporated. The sample was then stir-fried with silica gel (100-200 mesh) and packed into a column (200-300 mesh). The intermediate was purified by separation using a mobile phase of petroleum ether / ethyl acetate in a certain proportion; the yield was 93% and the purity was 97%.

[0030] (2) Dissolve 1 mmol of the substance obtained in step (1) in DMF, add 3 mmol of potassium hydroxide and 2 mmol of methyl bromide under stirring at 650 rpm at room temperature, and react for 3-4 h. After the reaction is complete as monitored by TLC, extract three times with ethyl acetate and water. Wash the upper organic phase with saturated NaCl solution, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, add silica gel to stir-fry the sample, pack into a column, and separate and purify the intermediate using petroleum ether / ethyl acetate as the mobile phase; the yield is 93% and the purity is 97%.

[0031] (3) Dissolve 1 mmol of the substance obtained in step (2) in a DCM:MeOH=2:1 solution, add 30 mmol of hydroxylamine aqueous solution (50% water) under stirring at 650 rpm at room temperature, stir at room temperature for 0.5 h, add 10 mmol of sodium hydroxide and react for 10-30 min. After the reaction of the raw materials is complete, evaporate the organic solvent, add water to dissolve the system, and then place it in an ice bath. Add dilute hydrochloric acid to adjust the pH to 3-4, let it stand and filter, and then beat the obtained solid with ethyl acetate. Finally, dry to obtain the target compound with a yield of 75%, a purity of 97%, a white solid, and a melting point of 193.0-193.2℃. 1 H NMR (400 MHz, DMSO-d6, ppm) δ11.17 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H), 7.71 (d, J = 8.0Hz, 2H), 7.49 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.6Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.50 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H). 13 CNMR (101 MHz, DMSO-d6, ppm)δ164.75, 164.66, 144.23, 137.22, 132.36, 131.62,127.49, 127.35, 126.93, 122.46, 121.60, 121.12, 110.70, 109.89, 42.17, 33.45.HR-MS(ESI): calcd. C 18 H 17 N3O3, [M+H]+ m / z: 324.1348, found: 324.1349.

[0032] Example 3

[0033] Z-3, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 2 in that bromomethane in step (2) is replaced with bromoethane, while the rest is the same as in Example 2. The compound with the structure shown in Formula Z-3 has a yield of 80%, is a white solid, and has a melting point of 207.0-207.3℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 11.38 – 11.02 (m, 1H), 9.00 (s, 1H), 8.49 (dt, J = 6.2, 3.7 Hz, 1H), 8.20–8.08 (m, 2H), 7.71 (dd, J = 8.3, 2.1 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 8.3, 2.1 Hz, 2H), 7.17 (dt, J = 26.7, 7.0 Hz, 2H), 4.52 (dd, J= 14.2, 5.8 Hz, 2H), 4.24 (qd, J = 7.3, 2.1 Hz, 2H), 1.41 (td, J = 7.3, 2.1Hz, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ164.79, 164.65, 144.22, 136.29,131.63, 130.64, 127.70, 127.56, 127.36, 127.10, 122.41, 121.73, 121.11,110.71, 110.03, 42.18, 41.21, 15.59. HR-MS(ESI): calcd. C 19 H 19 N3O3, [M+H]+ m / z:338.1504, found: 338.1507.

[0034] Example 4

[0035] Z-4, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 2 in that bromomethane in step (2) is replaced with bromopropane, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-4 is 78%, a white solid with a melting point of 203.0-203.4℃. 1H NMR (400MHz, DMSO-d6, ppm) δ11.16 (s, 1H), 8.97 (s, 1H), 8.46 (d, J = 6.1 Hz, 1H), 8.16 (d, J = 7.8 Hz,1H), 8.10 (s, 1H), 7.75–7.67 (m, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.41 (d, J =8.0 Hz, 2H), 7.17 (dt, J = 25.7, 7.3 Hz, 2H), 4.51 (d, J = 6.0 Hz, 2H), 4.17(t, J = 6.9 Hz, 2H), 1.81 (h, J = 7.2 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). 13 CNMR (101 MHz, DMSO-d6, ppm) δ 164.79, 164.64, 144.20, 136.63, 131.64, 131.37,127.58, 127.35, 127.01, 122.40, 121.71, 121.05, 110.82, 109.93, 47.94, 42.20,23.37, 11.6. HR-MS(ESI): calcd. C 20 H 21 N3O3, [M+H]+ m / z: 352.1661, found:352.1662.

[0036] Example 5

[0037] Z-5, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that bromomethane in step (2) is replaced with isobromopropane, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-5 is 76%, a white solid with a melting point of 189.9-191.2℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ8.49 (d, J = 6.1 Hz, 1H), 8.33–8.10 (m, 2H), 7.73 (d, J = 7.9 Hz, 2H), 7.56(d, J = 8.2 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.17 (dt, J = 25.7, 7.4 Hz,2H), 4.78 (h, J = 6.8 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 1.48 (d, J = 6.6 Hz,6H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.90, 164.60, 144.13, 136.09, 131.64,127.65, 127.35, 127.13, 122.38, 121.75, 121.19, 110.82, 110.07, 47.41, 42.19,22.89. HR-MS(ESI): calcd. C 20 H 21 N3O3, [M+H]+ m / z: 352.1661, found: 352.1666.

[0038] Example 6

[0039] Z-6, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that bromomethane in step (2) is replaced with isobromobutane, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-6 is 69%, a white solid with a melting point of 177.8-178.5℃. 1H NMR (400 MHz, DMSO-d6,ppm)δ8.49 (d, J = 6.2 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 8.10 (s, 1H), 7.72(d, J = 7.9 Hz, 2H), 7.53 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.17 (dt, J = 26.6, 7.3 Hz, 2H), 4.51 (d, J = 5.8 Hz, 2H), 4.20 (t, J = 7.0 Hz, 2H), 1.77 (p, J = 7.2 Hz, 2H), 1.33–1.22 (m, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13 C NMR(101 MHz, DMSO-d6, ppm)δ164.82, 164.45, 144.04, 136.58, 131.72, 131.31,127.57, 127.28, 127.00, 122.43, 121.71, 121.07, 110.78, 109.92, 46.06, 42.19,32.08, 19.92, 13.98. HR-MS(ESI): calcd. C 21 H 23 N3O3, [M+H]+ m / z: 366.1817, found: 366.1818.

[0040] Example 7

[0041] Z-7, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that bromomethane in step (2) is replaced with bromomethylcyclopropane, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-7 is 67%, a white solid with a melting point of 177.7-178.7℃. 1H NMR (400 MHz, DMSO-d6,ppm) δ 8.51 (t, J = 6.0 Hz, 1H), 8.23–8.13 (m, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.17 (dt, J = 26.0, 7.3Hz, 2H), 4.51 (d, J = 5.8 Hz, 2H), 4.08 (d, J = 7.0 Hz, 2H), 1.27 (dd, J =15.9, 6.8 Hz,1H), 0.57 (q, J = 5.4, 4.9 Hz, 2H), 0.42 (t, J = 5.0 Hz, 2H). 13 CNMR (101 MHz, DMSO-d6, ppm)δ164.82, 164.54, 144.20, 136.67, 131.65, 131.07,127.56, 127.33, 126.99, 122.40, 121.66, 121.08, 110.86, 110.01, 50.52, 42.18,31.62, 30.31, 11.68, 4.33. HR-MS(ESI): calcd. C 21 H 21 N3O3, [M+H]+ m / z: 364.1661, found: 364.1666.

[0042] Example 8

[0043] Z-8, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that bromomethane in step (2) is replaced with benzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-8 is 87%, a white solid with a melting point of 137.1-137.9℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ11.20(s, 1H), 9.01 (s, 1H), 8.58 (t, J = 6.0 Hz, 1H), 8.23–8.15 (m, 2H), 7.72 (d,J = 7.9 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.34 (t,J = 7.2 Hz, 2H), 7.27 (t, J = 8.3 Hz, 3H), 7.21–7.10 (m, 2H), 5.47 (s, 2H),4.50 (d, J = 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.71, 164.65,144.15, 137.90, 136.65, 131.71, 131.65, 129.16, 128.11, 127.73, 127.60,127.37, 127.12, 122.65, 121.77, 121.26, 111.12, 110.59, 49.95, 42.23. HR-MS(ESI): calcd. C 24 H 21 N3O3, [M+H]+ m / z: 400.1661, found: 400.1666.

[0044] Example 9

[0045] Z-9, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 4-methoxybenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-9 is 72%, a white solid with a melting point of 146.7-147.6 °C. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.20 (s, 1H), 9.06 (d, J = 13.2 Hz, 1H), 8.55 (t, J = 6.0 Hz,1H), 8.16 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.0 Hz,1H), 7.41 (d, J = 8.0 Hz, 2H), 7.30 – 7.10 (m, 4H), 6.90 (d, J = 8.2 Hz, 2H), 5.37 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 164.79, 159.25, 144.15, 136.54, 131.59, 131.50, 129.65, 129.32,127.60, 127.35, 127.13, 122.59, 121.71, 121.24, 114.53, 111.16, 110.39,55.55, 49.47, 42.21. HR-MS(ESI): calcd. C 25 H 23 N3O4, [M+H]+ m / z: 430.1767, found: 430.1768.

[0046] Example 10

[0047] Z-10, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that bromomethane in step (2) is replaced with 4-methylbenzyl bromide. Compound Z-10 has a yield of 66%, is a white solid, and has a melting point of 131.6-132.0℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ11.19 (s, 1H), 9.01(s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 8.27–8.04 (m, 2H), 7.71 (d, J = 8.0 Hz,2H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.14 (p, J = 7.3,6.6 Hz, 7H), 5.41 (s, 2H), 4.52 (dd, J = 13.8, 5.9 Hz, 2H), 2.25 (s, 3H). 13 CNMR (101 MHz, DMSO-d6, ppm)δ164.72, 144.15, 137.36, 136.61, 134.80, 131.64,129.68, 127.81, 127.59, 127.35, 127.15, 122.57, 121.75, 121.21, 111.13,110.48, 49.77, 42.21, 21.13. HR-MS(ESI): calcd.C 25 H 23 N3O3, [M+H]+ m / z:414.1817, found: 414.1818.

[0048] Example 11

[0049] Z-11, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 2-methylbenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-11 is 55%, it is a white solid with a melting point of 189.5-190.7℃. 1H NMR (400 MHz, DMSO-d6,ppm) δ 8.57 (d, J = 6.3 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.97 (s, 1H), 7.68(d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.18(dq, J = 13.4, 7.8, 7.0 Hz, 4H), 7.09 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.7Hz, 1H), 5.43 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 2.27 (s, 3H). 13 C NMR (101MHz, DMSO-d6, ppm) δ 164.68, 164.49, 144.08, 136.97, 136.37, 135.68, 131.70,131.44, 130.83, 128.15, 127.71, 127.56, 127.30, 127.03, 126.63, 122.67,121.86, 121.30, 111.05, 110.60, 48.07, 42.18, 19.24. HR-MS(ESI): calcd.C 25 H 23 N3O3, [M+H]+ m / z: 414.1817, found: 414.1822.

[0050] Example 12

[0051] Z-12, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 3-methylbenzyl bromide. The yield of the structure shown in Formula Z-12 is 67%, a white solid with a melting point of 110.0-111.3℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ11.18 (s,1H), 8.99 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.17 (d, J = 7.9 Hz, 2H), 7.77–7.68 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.26–7.01(m, 6H), 5.42 (s, 2H), 4.50 (d, J = 5.8 Hz, 2H), 2.26 (s, 3H). 13 C NMR (101MHz, DMSO-d6, ppm) δ164.71, 144.14, 138.34, 137.81, 136.67, 131.69, 129.08,128.80, 128.32, 127.59, 127.35, 127.10, 124.90, 122.63, 121.75, 121.24,111.11, 110.53, 49.96, 42.22, 21.47. HR-MS(ESI): calcd. C 25 H 23 N3O 3, [M+H]+ m / z:414.1817, found: 414.1823.

[0052] Example 13

[0053] Z-13, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 4-fluorobenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-13 is 69%, a white solid with a melting point of 141.1-142.2 °C. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.43 – 10.89 (m, 1H), 9.05 (s, 1H), 8.57 (t, J = 5.9 Hz, 1H), 8.17 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.32 (dd, J = 8.4, 5.5 Hz, 2H), 7.17 (td, J = 8.3,7.5, 3.3 Hz, 4H), 5.46 (s, 2H), 4.50 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 164.68, 163.28, 160.85, 144.14, 136.55, 134.09, 134.06,131.65, 131.59, 129.95, 129.87, 127.60, 127.37, 127.14, 122.68, 121.78,121.30, 116.07, 115.86, 111.08, 110.69, 49.17,42.22. HR-MS(ESI): calcd.C 24 H 20 FN3O3, [M+H]+ m / z: 418.1567, found: 418.1573.

[0054] Example 14

[0055] Z-14, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 4-cyanobenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Z-14 is 59%, a white solid with a melting point of 198.9-201.3℃. 1H NMR (400 MHz, DMSO-d6,ppm) δ 11.58 (s, 1H), 9.00 (s, 1H), 8.52 (dt, J = 19.4, 5.9 Hz, 1H), 8.18 (d,J = 8.7 Hz,1H), 7.83 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.63 (d,J = 7.9 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.31 (t,J = 8.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.21–7.07 (m, 2H), 5.50 (d, J =18.5 Hz, 2H), 4.52 (t, J = 5.0 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ168.00, 165.12, 164.69, 144.28, 141.00, 136.62, 133.27, 133.14, 131.73,128.44, 128.35, 127.61, 127.49, 127.35, 127.13, 126.62, 126.19, 122.71,122.36, 121.78, 121.47, 121.33, 120.84, 112.30, 111.12, 110.83, 42.24, 42.14.HR-MS(ESI): calcd. C 25 H 20 N4O3, [M+H]+ m / z: 425.1613, found: 425.1614.

[0056] Example 15

[0057] Z-15, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 3-cyanobenzyl bromide. The yield of the structure shown in Z-15 is 56%, a white solid with a melting point of 155.7-156.6 °C. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.17 (s,1H), 8.98 (s, 1H), 8.57 (t, J = 6.2 Hz, 1H), 8.26–8.14 (m, 2H), 7.79 (d, J=7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62–7.49 (m, 2H), 7.39 (dd, J = 13.4,7.4 Hz, 4H), 7.16 (p, J = 7.2 Hz, 2H), 5.50 (d, J = 8.1 Hz, 2H), 4.50 (d, J =5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ168.05, 164.69, 144.13, 138.05,136.63, 135.18, 131.81, 131.73, 131.65, 130.56, 129.84, 129.19, 129.09,127.63, 127.60, 127.37, 127.21, 127.14, 127.06, 122.70, 121.79, 121.31,111.10, 110.70, 110.66, 49.85, 42.23. HR-MS(ESI): calcd. C 25 H 20 N4O3, [M+H]+ m / z: 425.1613, found: 425.1614.

[0058] Example 16

[0059] Z-16, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 2-cyanobenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-16 is 45%, it is a white solid with a melting point of 149.1-151.7℃. 1H NMR (400 MHz, DMSO-d6,ppm) δ 11.18 (s, 1H), 8.99 (s, 1H), 8.58 (dd, J = 15.4, 9.5 Hz, 1H), 8.17(dd, J = 27.1, 6.2 Hz, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 31.0, 7.7Hz, 3H), 7.52 (t, J = 7.3 Hz, 1H), 7.44–7.36 (m, 2H), 7.36–7.31 (m, 1H),7.24–7.11 (m, 2H), 7.06 (d, J = 7.9 Hz, 1H), 5.68 (d, J = 16.3 Hz, 2H), 4.50 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ170.84, 164.73, 164.65,144.15, 136.79, 135.88, 135.81, 133.88, 132.20, 131.64, 130.57, 129.84,128.56, 128.26, 128.01, 127.92, 127.74, 127.60, 127.49, 127.36, 127.10,122.69, 121.75, 121.28, 111.01, 110.58, 47.61, 42.24. HR-MS (ESI): calcd.C 25 H 20 N4O3, [M+H]+ m / z: 425.1613, found: 425.1616.

[0060] Example 17

[0061] Z-17, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 2-nitrobenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Z-17 is 43%, a pale yellow solid with a melting point of 157.8-158.1℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.19 (s, 1H), 9.01 (s, 1H), 8.60 (t, J = 5.8 Hz, 1H), 8.25–8.14(m, 2H), 8.11 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.60 (dt, J = 22.1, 7.5 Hz,2H), 7.44 (dd, J = 23.7, 6.5 Hz, 3H), 7.23–7.13 (m, 2H), 6.62 (d, J = 7.6 Hz,1H), 5.88 (s, 2H), 4.51 (d, J = 5.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.65, 147.77, 144.08, 136.89, 134.85, 133.44, 132.00, 131.61, 129.43,128.74, 127.62, 127.35, 126.99, 125.65, 123.01, 121.85, 121.60, 111.20,111.14, 47.52, 42.23. HR-MS(ESI): calcd. C 24 H 20 N4O5, [M+H]+ m / z: 445.1512, found: 445.1515.

[0062] Example 18

[0063] Z-18, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 3-nitrobenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-18 is 57%, a pale yellow solid with a melting point of 165.9-167.3℃. 1 H NMR (400 MHz, DMSO- d 6,ppm) δ 11.18 (s, 1H), 8.99 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.28 – 8.11 (m,4H), 7.73 (d, J = 8.0 Hz, 2H), 7.68 – 7.61 (m, 2H), 7.57 (d, J= 8.1 Hz, 1H), 7.44 (dd, J = 20.5, 7.9 Hz, 2H), 7.18 (p, J = 7.0 Hz, 2H), 5.66 (s, 2H), 4.52 (d, J = 6.1 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6, ppm) δ 164.63, 148.43, 144.08,140.24, 136.56, 134.34, 131.69, 130.83, 129.84, 127.74, 127.60, 127.37,127.12, 123.15, 122.90, 122.42, 121.85, 121.48, 111.05, 49.03, 42.24. HR-MS(ESI): calcd. C 24 H 20 N4O5, [M+H] + m / z : 445.1512, found: 445.1513.

[0064] Example 19

[0065] Z-19, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the bromomethane in step (2) is replaced with 4-nitrobenzyl bromide, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-19 is 62%, a pale yellow solid with a melting point of 172.9-174.1℃. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.58 (dq, J = 12.3, 6.2 Hz, 1H), 8.31–8.15 (m, 3H), 7.92 (d,J = 7.9 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.61–7.37 (m, 4H), 7.37–7.24 (m,2H), 7.15 (ddt, J = 22.3, 14.7, 6.4 Hz, 2H), 5.81 – 5.39 (m, 2H), 4.57–4.48(m, 2H). 13C NMR (101 MHz, DMSO-d6, ppm) δ167.70, 164.61, 147.45, 146.01,145.67, 137.90, 136.60, 131.81, 131.64, 129.84, 129.63, 129.54, 129.15,128.71, 128.11, 127.76, 127.73, 127.62, 127.36, 127.14, 124.37, 122.89,122.64, 121.87, 121.77, 121.48, 119.89, 111.03, 49.95, 49.26, 42.26. HR-MS(ESI): calcd. C 24 H 20 N4O5, [M+H]+ m / z: 445.1512, found: 445.1513.

[0066] Example 20

[0067] Z-20, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0068] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution and then dried with anhydrous sodium sulfate. The dichloromethane was evaporated, and the mixture was packed into a column with silica gel (100-200 mesh) and sample-graded using a (200-300 mesh) column. The intermediate was purified using a (petroleum ether / ethyl acetate) solution as the mobile phase. The yield was 93%, and the purity was 97%.

[0069] (2) Dissolve 1 mmol of the substance obtained in step (1) and 0.6 mmol of anhydrous potassium phosphate in toluene, add the solution while stirring at 650 rpm at room temperature, then add 1.2 mmol of bromobenzene, 0.3 mmol of catalyst CuI and 2.1 mmol of trans-(1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine, and react in an oil bath at 110 °C for 4-5 h under nitrogen protection. After the reaction is completed, the system is extracted three times with ethyl acetate and water, the upper organic phase is washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness. Silica gel is added to stir the sample, and the sample is packed into a column. Petroleum ether / ethyl acetate is used as the mobile phase for separation and purification to obtain an intermediate with a yield of 93% and a purity of 97%.

[0070] (3) Dissolve 1 mmol of the substance obtained in step (2) in a DCM:MeOH=2:1 solution, add 30 mmol of hydroxylamine aqueous solution (50% water) under stirring at 650 rpm at room temperature, stir at room temperature for 0.5 h, then add 10 mmol of sodium hydroxide and react for 10-30 min. After the reaction of the raw materials is complete, evaporate the organic solvent, add water to dissolve the system, then place it in an ice bath, add dilute hydrochloric acid to adjust the pH to 3-4, let it stand and filter, and then beat the obtained solid with ethyl acetate. Finally, dry to obtain the target compound Z-20 with a yield of 73%, a white solid with a melting point of 129.8-131.2℃. 1 H NMR (400 MHz, DMSO-d6, ppm)δ11.21 (s,1H), 9.02 (s, 1H), 8.72 (t, J = 6.0 Hz, 1H), 8.42 (s, 1H), 8.36–8.14 (m, 1H),7.73 (d, J = 8.0 Hz, 2H), 7.68–7.60 (m, 4H), 7.57–7.52 (m, 1H), 7.49 (dp, J =5.3, 2.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.26 (tt, J = 7.7, 5.8 Hz, 2H),4.55 (d, J = 5.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6, ppm) δ 167.69, 164.51,145.87, 143.93, 138.80, 136.05, 131.69, 131.15, 130.48, 129.86, 129.70,127.88, 127.80, 127.76, 127.61, 127.39, 124.70, 123.64, 122.19, 122.13,112.33, 111.17, 42.24. HR-MS(ESI): calcd. C 23 H 19 N3O3, [M+H]+ m / z: 386.1504, found: 386.1515.

[0071] Example 21

[0072] Z-21, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 4-methoxybromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-21 is 75%, a white solid with a melting point of 177.8-179.3℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 8.65 (t, J = 6.1 Hz, 1H), 8.36–8.22 (m, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.60–7.50 (m, 2H), 7.47–7.38 (m, 3H), 7.29–7.11 (m, 4H), 4.54 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ164.57, 158.90, 143.80,136.52, 131.64, 131.34,127.57, 127.49, 127.32, 126.34, 123.44, 122.08,121.90, 115.53, 111.77, 111.06, 55.99, 42.23. HR-MS(ESI): calcd. C 24 H 21 N3O4, [M+H]+ m / z: 416.1610, found: 416.1619.

[0073] Example 22 Z-22, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 4-methylbromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-22 is 68%, a white solid with a melting point of 121.4-122.8℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 11.19 (s, 1H), 8.98 (s, 1H), 8.69 (t, J = 6.1 Hz, 1H), 8.38 (s, 1H),8.31–8.22 (m, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 7.2 Hz, 3H), 7.43 (d, J = 7.9 Hz, 4H), 7.24 (tt, J = 7.7, 5.8 Hz, 2H), 4.54 (d, J = 5.8 Hz, 2H), 2.41 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 164.63, 164.54, 143.95,137.40, 136.31, 136.18, 131.71, 131.10, 130.86, 129.87, 127.69, 127.60,127.40, 124.59, 123.54, 122.14, 122.02, 112.08, 111.16, 42.25, 21.09. HR-MS(ESI): calcd. C 24 H 21 N3O3, [M+H]+ m / z: 400.1661, found: 400.1668.

[0074] Example 23 Z-23, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 3-methylbromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-23 is 46%, a white solid with a melting point of 159.6-161.7℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ 8.69 (t, J = 6.0 Hz, 1H), 8.39 (s, 1H), 8.33–8.24 (m, 1H), 7.74 (d, J = 7.9Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.9Hz, 4H), 7.26 (dq, J = 13.2, 7.0 Hz, 3H), 4.55 (d, J = 5.9 Hz, 2H), 2.43 (s,3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ164.54, 143.79, 140.22, 138.73, 136.03,131.05, 130.23, 128.52, 127.75, 127.60, 127.33, 125.10, 123.62, 122.15,122.10, 121.68, 112.19, 111.27, 42.25, 21.39. HR-MS(ESI): calcd. C 24 H 21 N3O3, [M+H]+ m / z: 400.1661, found: 400.1668.

[0075] Example 24 Z-24, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 3-cyanobromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-24 is 67%, a white solid with a melting point of 190.5-191.3℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ 11.22 (s, 1H), 8.75 (q, J = 6.2 Hz, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.29 (d,J = 7.5 Hz, 1H), 8.19–8.09 (m, 2H), 7.94 (t, J = 9.3 Hz, 1H), 7.84 – 7.69 (m,3H), 7.64 (d, J = 7.7 Hz, 1H), 7.54 – 7.47 (m, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.29 (p, J = 7.0 Hz, 2H), 4.57 (dd, J = 13.8, 5.7 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 167.56, 164.44, 143.84, 141.11, 135.80, 133.18, 131.67,130.89, 129.88, 129.81, 127.95, 127.77, 127.63, 127.39, 124.34, 123.99,122.43, 122.24, 112.87, 111.35, 42.26. HR-MS(ESI): calcd. C 24 H 18 N4O3, [M+H]+ m / z: 411.1457, found: 411.1458.

[0076] Example 25 Z-25, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 4-cyanobromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-25 is 61%, a white solid with a melting point of 197.7-198.3℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ 8.74 (q, J = 6.6 Hz, 1H), 8.44 (d, J = 5.5Hz, 1H), 8.29 (d, J = 7.5 Hz,1H), 7.96 (d, J = 24.8 Hz, 1H), 7.88 – 7.76 (m, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.68–7.57 (m, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.27 (q, J = 7.2 Hz, 2H), 6.00 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.54, 150.64, 143.84, 138.69, 135.97, 135.62, 131.69, 131.05, 130.37,127.77, 127.62, 127.37, 124.95, 124.73, 123.85, 123.76, 122.20, 121.40,112.46, 111.23, 42.27. HR-MS(ESI): calcd. C 24 H 18 N4O3, [M+H]+ m / z: 411.1457, found: 411.1458.

[0077] Example 26 Z-26, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 2-cyanobromobenzene, while the rest is the same as in Example 2. The obtained product has a yield of 57% and is a white solid with a melting point of 178.9-180.3 °C, having the structure shown in Formula Z-26. 1 H NMR (400 MHz, DMSO-d6, ppm) δ8.83–8.49 (m, 1H), 8.44–8.27 (m, 1H), 8.15 (d, J = 7.2 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.82 –7.63 (m, 4H), 7.43–7.10 (m, 6H), 4.53 (d, J =10.7 Hz, 2H). 13C NMR (101 MHz, DMSO-d6, ppm) δ 164.21, 140.53, 136.95, 135.54,135.09, 131.57, 129.80, 128.89, 127.44, 127.25, 126.99, 123.94, 122.50,122.25, 116.56, 113.26, 111.14, 110.09, 42.33. HR-MS(ESI): calcd. C 24 H 18 N4O3,[M+H]+ m / z: 411.1457, found: 411.1458.

[0078] Example 27 Z-27, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 2-nitrobromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-27 is 35%, a yellowish-brown solid with a melting point of 159.7-161.2℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 11.19 (s, 1H), 9.03 (s, 1H), 8.67 (dt, J = 20.9, 6.3 Hz, 1H), 8.40 (s,1H), 8.28 (t, J = 6.8 Hz, 1H), 8.21 –8.12 (m, 1H), 7.89 (dd, J = 28.7, 8.0Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 4.4 Hz, 2H), 7.55 (d, J = 7.4Hz, 1H), 7.52–7.39 (m, 2H), 7.24 (dp, J = 15.7, 6.2, 5.4 Hz, 2H), 4.55 (p, J= 9.5, 7.6 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 164.54, 143.91, 138.76,136.05, 131.66, 131.08, 130.49,127.91,127.74,127.61, 127.38, 124.70, 123.69,122.16, 112.30,111.18,42.25. HR-MS(ESI): calcd. C23 H 18 N4O5, [M+H]+ m / z:431.1355, found: 431.1358.

[0079] Example 28 Z-28, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 3-nitrobromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-28 is 58%, a pale yellow solid with a melting point of 176.8-178.3℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 11.21 (s, 1H), 9.06 (s, 1H), 8.73 (d, J = 24.9 Hz, 1H), 8.51 (s, 1H), 8.42 (d, J = 9.9 Hz, 1H), 8.30 (d, J = 8.1 Hz, 2H), 8.17 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.29 (dt, J = 17.2, 8.8 Hz, 2H), 4.68–4.40 (m, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.58, 164.46, 164.34, 143.77, 141.69,139.67, 135.80, 131.99, 131.71, 130.94, 130.78, 127.96, C 23 H 18 N4O5, [M+H]+ m / z: 431.1355, found: 431.1358.

[0080] Example 29 Z-29, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 4-nitrobromobenzene, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-29 is 60%, a yellow solid with a melting point of 179.5-180.0℃. 1 H NMR (400 MHz, DMSO-d6, ppm)δ 11.19 (s, 1H), 8.99 (s, 1H), 8.77 (q, J = 5.6 Hz, 1H), 8.51 (s, 1H), 8.35 –8.27 (m, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.92-7.81 (d, J = 7.9 Hz, 2H), 7.76–7.71 (m, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.55 – 7.47 (m, 1H), 7.44 (dd, J =8.0, 3.4 Hz, 1H), 7.30 (tp, J = 14.2, 7.1 Hz, 2H), 4.57 (dd, J = 11.8, 7.8Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.51, 164.17, 145.82, 144.23, 143.70,135.56, 131.77, 130.74, 130.48, 129.84, 128.33, 127.64, 127.41, 126.33,126.08, 124.67, 124.34, 122.93, 122.44, 121.07, 113.98, 111.50, 42.31. HR-MS(ESI): calcd. C 23 H 18 N4O5, [M+H]+ m / z: 431.1355, found: 431.1358.

[0081] Example 30 Z-30, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that bromobenzene in step (2) is replaced with 3-bromophenol, while the rest is the same as in Example 2. The yield of the structure shown in Formula Z-30 is 20%, a pale purple solid with a melting point of 160.5-161.2℃. 1H NMR (400 MHz, DMSO-d6,ppm) δ 11.21 (s, 1H), 9.91 (s, 1H), 9.04 (s, 1H), 8.65 (t, J = 6.0 Hz, 1H), 8.27 (d, J = 11.2 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 7.3 Hz, 5H), 7.28–7.16 (m, 2H), 6.99 (d, J = 8.2 Hz, 2H), 4.54 (d, J = 5.8 Hz, 2H). 13 CNMR (101 MHz, DMSO-d6, ppm)δ164.65, 157.30, 144.00, 136.61, 131.64, 131.39,130.14, 127.59, 127.37, 126.44, 123.34, 122.00, 121.81, 116.74, 111.47,111.11, 42.21. HR-MS(ESI): calcd. C 23 H 19 N3O4, [M+H]+ m / z: 402.1454, found: 402.1460.

[0082] Example 31 Z-31, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that bromobenzene in step (2) is replaced with 3-bromobenzyl alcohol, while the rest is the same as in Example 2. The yield of Z-31 is 66%, a white solid with a melting point of 164.9-165.6℃. 1 H NMR (400 MHz, DMSO-d6, ppm)δ11.25(s, 1H), 9.09 (s, 1H), 8.73 (t, J = 6.2 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J =7.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.54 (dd, J = 18.8, 5.3 Hz, 5H), 7.43(d, J = 7.9 Hz, 2H), 7.25 (p, J = 7.0 Hz, 2H), 5.50 (d, J = 5.8 Hz, 1H), 4.57(dd, J = 24.7, 5.0 Hz, 4H). 13C NMR (101 MHz, DMSO-d6, ppm)δ164.65,157.30,144.00, 136.61,131.64, 131.39, 130.14, 127.59, 127.37, 126.44, 123.34,122.00, 121.81, 116.74, 111.47, 111.11, 45.77,42.21. HR-MS(ESI): calcd.C 24 H 21 N3O4, [M+H]+ m / z: 416.1610, found: 416.1615.

[0083] Example 32 Z-32, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 3-bromofuran, while the rest is the same as in Example 2. The yield of the structure shown in Formula 32 is 77%, a white solid with a melting point of 185.9-187.4℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 8.65 (d, J = 6.1 Hz, 1H), 8.36 (s, 2H), 8.26 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.28 (dt, J = 21.2, 7.3 Hz, 2H), 7.03 (d, J = 1.9 Hz,1H), 4.55 (d, J = 5.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ164.46, 164.35,144.75, 143.78, 136.04, 135.26, 131.80, 130.79, 127.60, 127.49, 127.35,126.76, 123.77, 122.18, 122.05, 112.24, 111.59, 107.69, 42.26. HR-MS(ESI):calcd. C 21 H 17 N3O4, [M+H]+ m / z: 376.1297, found: 376.1298.

[0084] Example 33 Z-33, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 20 in that the bromobenzene in step (2) is replaced with 3-bromothiophene, while the rest is the same as in Example 2. The compound of formula Z-33 has a yield of 70%, is a white solid, and has a melting point of 188.4-189.3℃. 1 H NMR (400 MHz, DMSO-d6, ppm) δ11.22 (s, 1H), 8.74 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 8.26 (d, J = 7.7 Hz,1H), 7.83 (d, J = 4.9 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.1 Hz,1H), 7.49 (d, J = 4.9 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 7.27 (dt, J = 19.9,7.2 Hz, 2H), 4.54 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ164.50, 143.92, 137.18, 136.13, 131.63, 131.12, 128.15, 127.62, 127.44,127.38, 123.94, 123.76, 122.18, 122.04, 116.88, 111.95, 111.48, 42.24. HR-MS(ESI): calcd. C 21 H 17 N3O3S, [M+H]+ m / z: 392.1069, found: 392.1075.

[0085] Example 34 Z-34, an indole compound that targets and inhibits HDAC6, has the following structural formula: The difference between the preparation process and that of Example 1 is that the indole-3-carboxylic acid in step (1) is changed to 5-methylindole-3-carboxylic acid, while the rest is the same as in Example 1. Z-34 yield is 68%, white solid, melting point 186.8-187.7℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.49 (d, J = 2.9 Hz, 1H), 11.19 (s,1H), 9.03 (s,1H), 8.48 (t, J =6.0 Hz, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.96 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.01–6.95 (m, 1H), 4.51 (d, J = 5.9 Hz, 2H), 2.39 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ165.24, 144.35, 134.97,131.54, 129.44, 128.36, 127.50, 127.33, 126.83,123.91, 121.11, 111.94, 110.32, 42.13, 21.80. HR-MS(ESI): calcd. C 18 H 17 N3O3, [M+H]+ m / z: 324.1348, found: 324.1349.

[0086] Example 35 Z-35, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 1 in that the indole-3-carboxylic acid in step (1) is replaced with 6-methylindole-3-carboxylic acid, while the rest is the same as in Example 1. The yield of Z-35 is 66%, a white solid with a melting point of 171.5-172.0 °C. 1 H NMR (400 MHz, DMSO-d6, ppm)δ11.57–11.32 (m,1H), 11.19(s, 1H), 9.16–8.87 (m, 1H), 8.48 (t, J =6.2 Hz, 1H), 8.06–7.93 (m, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.9Hz, 2H), 7.22 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 4.50 (d, J = 5.9 Hz, 2H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6, ppm) δ 165.17, 164.56, 144.24, 137.06,131.69, 131.45, 127.76, 127.48, 127.31, 124.49, 122.61, 121.15, 112.04,110.74, 42.13, 21.77. HR-MS(ESI): calcd. C 18 H 17 N3O3, [M+H]+ m / z: 324.1348, found: 324.1350.

[0087] Example 36 Z-36, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that indole-3-carboxylic acid in step (1) is replaced with 6-methylindole-3-carboxylic acid, and bromobenzene in step (2) is replaced with benzyl bromide. The rest is the same as in Example 2. The yield of Z-36 is 72%, a white solid with a melting point of 184.1-184.3℃. 1 H NMR (600 MHz, DMSO-d6, ppm) δ11.16 (s, 1H), 8.98 (s, 1H), 8.48 (t,J = 6.1 Hz, 1H), 8.08 (d, J = 1.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.72–7.68 (m, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.36–7.32 (m, 3H), 7.29–7.25 (m, 1H), 7.25–7.21 (m, 2H), 6.97 (dd, J = 8.2, 1.4 Hz, 1H), 5.42 (s, 2H), 4.49 (d, J =6.0 Hz, 2H), 2.38 (s, 3H). 13 C NMR (101MHz, DMSO-d6, ppm)δ164.76, 164.65,144.18, 138.01, 137.09, 131.92, 131.64, 131.13, 129.16, 128.06, 127.61,127.36, 124.98, 123.02, 121.49, 110.76, 110.56, 49.76, 42.22, 21.91. HR-MS(ESI): calcd. C 25 H23 N3O3, [M+H]+ m / z: 414.1817, found: 414.1828.

[0088] Example 37 Z-37, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 1 in that the indole-3-carboxylic acid in step (1) is replaced with 7-methylindole-3-carboxylic acid, while the rest is the same as in Example 1. Z-37 yield is 60%, white solid, melting point 157.8-158.6℃. 1 H NMR (400 MHz, DMSO-d6, ppm)δ11.59(d, J = 3.0Hz, 1H), 11.17 (s, 1H), 8.98 (s, 1H), 8.50 (t, J= 6.0 Hz,1H), 8.10(d, J = 2.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 8.0 Hz,2H), 7.40 (d, J = 8.0 Hz, 2H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 7.0 Hz,1H), 4.51 (d, J = 5.9 Hz, 2H), 2.47 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ165.18, 144.29, 136.16, 131.61, 129.80, 128.07, 127.51, 127.35, 126.36,122.84,121.39, 121.05, 119.09, 111.19, 42.14, 17.12. HR-MS(ESI):calcd.C 18 H 17 N3O3, [M+H]+ m / z: 324.1348, found: 324.1355.

[0089] Example 38 Z-38, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 1 in that indole-3-carboxylic acid in step (1) is replaced with 5-methoxyindole-3-carboxylic acid, while the rest is the same as in Example 1. The obtained compound Z-38 has a yield of 68%, is a white solid, and has a melting point of 196.6-197.7℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.45 (s, 1H), 11.17 (s, 1H), 8.99 (s, 1H), 8.46 (d, J = 5.7 Hz, 1H), 8.04 (d, J = 3.2 Hz, 1H), 7.72 (dd, J = 8.1, 2.3Hz, 2H), 7.68 (d, J = 2.8 Hz, 1H), 7.43–7.37 (m, 2H), 7.32 (dd, J = 8.9, 2.8Hz, 1H), 6.79 (dd, J = 8.8, 2.8 Hz, 1H), 4.51 (d, J = 5.8 Hz, 2H), 3.76 (d, J= 2.6 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 165.26, 164.67, 154.84,144.36, 131.60, 128.60, 127.47, 127.36, 112.97, 112.64, 110.45, 103.00,55.67, 42.12. HR-MS(ESI): calcd. C 18 H 17 N3O4, [M+H]+ m / z: 340.1297, found:340.1298.

[0090] Example 39 Z-39, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 1 in that the indole-3-carboxylic acid in step (1) is replaced with 5-bromoindole-3-carboxylic acid, while the rest is the same as in Example 1. The resulting product, with the structure shown in Formula Z-39, has a yield of 70%, is a white solid, and has a melting point of 191.6-192.5 °C. 1H NMR (400 MHz, DMSO-d6, ppm) δ11.80 (s, 1H), 11.19 (s, 1H), 9.01 (s, 1H), 8.60 (t, J = 5.5 Hz, 1H), 8.33 (t, J = 2.9 Hz, 1H), 8.15 (d, J = 3.2 Hz, 1H), 7.74 (dd, J = 8.1, 3.8 Hz, 2H), 7.42 (td, J = 9.2, 3.7 Hz, 3H), 7.32–7.26 (m,1H), 4.53 (t, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 164.66,144.07, 135.32, 131.65, 129.68, 128.47, 127.52, 127.37, 124.94, 123.67,114.41, 113.74, 110.41, 42.15. HR-MS(ESI): calcd. C 17 H 14 BrN3O3, [M+H]+ m / z:388.0297, found: 388.0299.

[0091] Example 40 Z-40, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 1 in that the indole-3-carboxylic acid in step (1) is replaced with 6-bromoindole-3-carboxylic acid, while the rest is the same as in Example 1. The obtained product has a yield of 70% and is a white solid with a melting point of 195.4-196.3 °C, having the structure shown in Formula Z-40. 1 HNMR (400 MHz, DMSO-d6, ppm) δ 11.70 (s, 1H), 11.17 (s, 1H), 9.00 (s, 1H), 8.59 (t, J = 6.1 Hz, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.76–7.68 (m, 2H), 7.65(d, J = 1.7 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.25 (dd, J = 8.5, 1.8 Hz,1H), 4.52 (d, J = 5.9 Hz, 2H). 13C NMR (101 MHz, DMSO-d6, ppm) δ 164.69,144.08, 137.48, 131.64, 129.20, 127.61, 127.52, 127.37, 125.75, 123.81,123.22, 115.11, 114.96, 111.00, 42.15. HR-MS(ESI): calcd. C 17 H 14 BrN3O3, [M+H]+m / z: 388.0297, found: 388.0299.

[0092] Example 41 Z-41, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 1 in that indole-3-carboxylic acid in step (1) is replaced with 6-methoxyindole-3-carboxylic acid, while the rest is the same as in Example 1. The obtained compound Z-41 has a yield of 72%, is a white solid, and has a melting point of 170.8-171.2℃. 1 H NMR(400 MHz, DMSO-d6, ppm) δ 11.39 (d, J = 2.9 Hz, 1H), 11.20 (s, 1H), 9.04 (s,1H), 8.49 (t, J = 6.1 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 4.50 (d, J = 5.9 Hz, 2H), 3.77 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ165.20, 164.72, 156.32, 144.30, 137.39,131.55, 127.50, 127.34, 127.08, 122.04, 120.73, 111.05, 110.84, 95.18, 55.63,42.12. HR-MS(ESI): calcd. C 18 H 17 N3O4, [M+H]+ m / z: 340.1297, found: 340.1298.

[0093] Example 42 Z-42, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that the indole-3-carboxylic acid in step (1) is replaced with 2-methylindole-3-carboxylic acid, while the rest is the same as in Example 2. The yield of compound Z-42 is 38%, a white solid with a melting point of 185.4-186.5℃. 1 H NMR (600 MHz, DMSO-d6, ppm) δ 11.16 (s, 1H), 8.98 (s, 1H), 8.25 (t, J = 6.0 Hz, 1H), 7.86–7.80(m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.49–7.46 (m, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.15–7.10 (m, 2H), 7.02 (d, J = 7.5 Hz, 2H), 5.49 (s, 2H), 4.54 (d, J = 5.9 Hz (2H), 2.58 s (3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ165.73, 140.52, 138.10, 136.30, 129.79,129.16, 127.73, 127.58, 127.35, 126.69, 125.80, 121.93, 120.88, 120.10,110.55, 109.09, 46.17, 42.77, 12.02. HR-MS(ESI): calcd. C 13 H 13 N3O3, [M+H]+ m / z:414.1817, found: 414.1825.

[0094] Example 43 Z-43, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 1 in that indole-3-carboxylic acid in step (1) is replaced with 2-methylindole-3-carboxylic acid, while the rest is the same as in Example 2. The obtained compound Z-43 has a yield of 50%, is a white solid, and has a melting point of 134.4-135.2℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ11.49 (s, 1H), 11.17 (s, 1H), 9.00 (d, J = 11.1 Hz, 1H), 7.99 (t, J = 6.1 Hz, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.36 – 7.30 (m, 1H), 7.13–7.02 (m, 2H), 4.53 (d, J = 6.0 Hz, 2H), 2.60 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ165.91,164.65, 144.37, 140.10, 135.15, 131.53, 127.51, 127.32, 126.49, 121.49,120.38, 119.90, 111.40, 107.95, 42.57, 13.82. HR-MS(ESI): calcd. C 18 H 17 N3O3, [M+H]+ m / z: 324.1348, found: 324.1350.

[0095] Example 44 Z-44, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that indole-3-carboxylic acid in step (1) is replaced with 2-methylindole-3-carboxylic acid, and bromobenzene in step (2) is replaced with bromomethylcyclopropane. The rest is the same as in Example 2. The obtained compound Z-44 has a yield of 72%, is a white solid, and has a melting point of 125.4-126.7℃. 1H NMR (400 MHz, DMSO-d6, ppm)δ11.17 (s, 1H),8.98 (s, 1H), 8.18 (d, J = 6.2 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.74 (d, J= 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.12 (dt,J = 18.6, 7.1 Hz, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.11 (d, J = 6.7 Hz, 2H), 2.65 (s, 3H), 1.16 (td, J = 8.0, 4.0 Hz, 1H), 0.52 – 0.31 (m, 4H). 13 C NMR (101MHz, DMSO-d6, ppm) δ 165.86, 164.63, 144.25, 140.19, 136.12, 131.56, 127.54,127.36, 125.70, 121.63, 120.59, 119.91, 110.55, 108.65, 46.61, 42.67, 12.06,11.78. HR-MS(ESI): calcd. C 22 H 23 N3O3, [M+H]+ m / z: 378.1817, found: 378.1832.

[0096] Example 45 Z-45, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 2 in that indole-3-carboxylic acid in step (1) is replaced with 2-methylindole-3-carboxylic acid, and bromobenzene in step (2) is replaced with 4-fluorobenzyl bromide. The obtained compound Z-45 has a yield of 56%, is a white solid, and has a melting point of 168.9-170.3℃. 1H NMR (400 MHz, DMSO-d6, ppm) δ11.09 (s, 1H), 9.25–8.81 (m, 1H), 8.25 (t,J = 6.1 Hz, 1H), 7.86–7.79 (m, 1H), 7.76–7.70 (m, 2H), 7.50–7.42 (m, 3H), 7.14 (ddd, J = 8.9, 6.9, 2.1 Hz, 4H), 7.07 (dd, J = 8.4, 5.6 Hz, 2H), 5.47(s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 2.59 (s, 3H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 165.68, 163.01, 160.60, 144.15, 140.40, 136.18, 134.30, 134.27,131.61, 129.80, 128.80, 128.72, C 25 H 22 FN3O3, [M+H]+ m / z: 432.1723, found: 432.1726.

[0097] Example 46 Z-46, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0098] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution and then dried with anhydrous sodium sulfate. The dichloromethane was evaporated, and the mixture was packed into a column with silica gel (100-200 mesh) and sample-graded using a (200-300 mesh) column. The intermediate was purified using a (petroleum ether / ethyl acetate) solution as the mobile phase. The yield was 93%, and the purity was 97%.

[0099] (2) Dissolve 1 mmol of the substance obtained in step (1) in DMF, add 3 mmol of potassium hydroxide and 2 mmol of benzyl bromide under stirring at 650 rpm at room temperature, and react for 3-4 h. After the reaction is complete as monitored by TLC, extract three times with ethyl acetate and water. Wash the upper organic phase with saturated NaCl solution, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, add silica gel to stir-fry the sample, pack into a column, and separate and purify the intermediate using petroleum ether / ethyl acetate as the mobile phase; the yield is 93% and the purity is 97%.

[0100] (3) Dissolve 1 mmol of the substance obtained in step (2) in methanol solution, add 2-3 mL of water, and add 10 mmol of sodium hydroxide solution while stirring at 650 rpm at room temperature. After dissolving at room temperature, place the mixture in an oil bath at 60°C under reflux for 4-5 h. After the reaction is complete as monitored by TLC, evaporate the methanol to remove it, add water to dissolve the mixture, and then place it in an ice bath. Adjust the pH to 3-4 with concentrated hydrochloric acid. Finally, allow it to stand, filter, and dry to obtain the intermediate. The yield is 95%, and the purity is 97%.

[0101] (4) Dissolve 1 mmol of the product from step (3) in DMF, add 1.2 mmol of EDCI and 0.5 mmol of DMAP as condensing agents, stir at room temperature for 0.5 h, then add 1.1 mmol of N-Boc-1,2-phenylenediamine, and react at room temperature for 2-3 h. After the reaction is complete, extract the system three times with ethyl acetate and water, wash the upper layer with saturated NaCl solution, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, add silica gel to stir the sample, pack into a column, and separate and purify the intermediate by column chromatography. The yield was 62%, and the purity was 97%.

[0102] (5) Dissolve 1 mmol of the product from step (4) in 1,4-dioxane, add 100 mmol of hydrochloric acid and react for 2.5 h. A precipitate will form during the reaction. After the reaction is complete, evaporate the 1,4-dioxane solution to dryness under reduced pressure, add water to dissolve the system, add saturated sodium bicarbonate solution under ice bath conditions to adjust the solution to a weakly alkaline state, let stand for 15 min, filter, and dry to obtain compound Z-46 with a yield of 67% and a purity of 98%. Compound Z-46 has a yield of 67%, is a white solid, and has a melting point of 210.3-211.1 °C. 1H NMR (400MHz, DMSO-d6, ppm) δ9.96 (s, 1H), 8.60 (d, J = 5.9 Hz, 1H), 8.24–8.14 (m, 2H), 8.00 (d, J = 8.0 Hz, 2H), 7.51 (dd, J = 21.8, 7.9 Hz, 3H), 7.37–7.23 (m, 6H), 7.15 (dq, J = 20.0, 7.2 Hz, 3H), 7.04 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.5Hz, 1H), 5.47 (s, 2H), 4.56 (d, J = 5.9 Hz, 2H), 3.56 (d, J = 2.2 Hz, 2H). 13 CNMR (101 MHz, DMSO-d6, ppm)δ165.86, 164.74, 144.77, 137.91, 136.66, 133.07,131.75, 129.16, 128.39, 128.12, 127.73, 127.53, 127.31, 127.14, 126.98,122.65, 121.77, 121.26, 119.53, 111.13, 110.63, 49.97, 42.26. HR-MS(ESI):calcd. C 30 H 26 N4O2, [M+H]+ m / z: 475.2134, found: 475.2137.

[0103] Example 47 Z-47, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0104] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dichloromethane was evaporated. The sample was then stir-fried with silica gel (100-200 mesh), packed into a column (200-300 mesh), and purified using petroleum ether / ethyl acetate solution as the mobile phase to obtain the intermediate. The yield was 93%, and the purity was 97%.

[0105] (2) Dissolve 1 mmol of the substance obtained in step (1) in DMF, add 3 mmol of potassium hydroxide and 2 mmol of benzyl bromide under stirring at 650 rpm at room temperature, and react for 3-4 h. After the reaction is complete as monitored by TLC, extract three times with ethyl acetate and water. Wash the upper organic phase with saturated NaCl solution, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, add silica gel to stir-fry the sample, pack into a column, and separate and purify the intermediate using petroleum ether / ethyl acetate as the mobile phase; the yield is 93% and the purity is 97%.

[0106] (3) Dissolve 1 mmol of the substance obtained in step (2) in methanol solution, add 2-3 mL of water, add 10 mmol of sodium hydroxide solution while stirring at 650 rpm at room temperature, stir until dissolved, and then place in an oil bath at 60℃ under reflux for 4-5 h. After the reaction is complete as monitored by TLC, evaporate to dryness to remove methanol, add water to dissolve the system, and then place it in an ice bath. Adjust the pH to 3-4 with concentrated hydrochloric acid, and finally let it stand, filter, and dry to obtain compound Z-47. The yield of compound Z-47 is 83%, a white solid, with a melting point of 284.6-285.4℃. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.61 (t, J = 6.0 Hz, 1H), 8.23 ​​– 8.14 (m,2H), 7.91 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.37 – 7.30 (m, 2H), 7.30–7.23 (m, 3H), 7.21–7.10 (m, 2H), 5.47 (s, 2H), 4.54 (d, J = 5.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6, ppm) δ 167.85, 164.79,145.87, 137.85, 136.63, 131.74, 129.98, 129.84, 129.16, 128.13, 127.72,127.70, 127.10, 122.68, 121.76, 121.30, 111.13, 110.50, 49.96, 42.28. HR-MS(ESI): calcd. C 24 H2N2O3, [M+H]+ m / z: 385.1552, found: 385.1559.

[0107] Example 48 Z-48, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0108] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution and then dried with anhydrous sodium sulfate. The dichloromethane was evaporated, and the mixture was packed into a column with silica gel (100-200 mesh) and sample-graded using a (200-300 mesh) column. The intermediate was purified using a (petroleum ether / ethyl acetate) solution as the mobile phase. The yield was 93%, and the purity was 97%.

[0109] (2) Dissolve 1 mmol of the substance obtained in step (1) and 0.6 mmol of anhydrous potassium phosphate in toluene, add the solution while stirring at 650 rpm at room temperature, then add 1.2 mmol of bromobenzene, 0.3 mmol of catalyst CuI and 2.1 mmol of trans-(1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine, and react in an oil bath at 110 °C for 4-5 h under nitrogen protection. After the reaction is completed, the system is extracted three times with ethyl acetate and water, the upper organic phase is washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness. Silica gel is added to stir the sample, and the sample is packed into a column. Petroleum ether / ethyl acetate is used as the mobile phase for separation and purification to obtain an intermediate with a yield of 93% and a purity of 97%.

[0110] (3) Dissolve 1 mmol of the substance obtained in step (2) in methanol solution, add 2-3 mL of water, and add 10 mmol of sodium hydroxide solution while stirring at 650 rpm at room temperature. After dissolving at room temperature, place the mixture in an oil bath at 60°C and reflux for 4-5 h. After the reaction is complete as monitored by TLC, evaporate the methanol to remove it, add water to dissolve the mixture, and then place it in an ice bath. Adjust the pH to 3-4 with concentrated hydrochloric acid. Finally, allow it to stand, filter, and dry to obtain the intermediate. The yield is 95%, and the purity is 97%.

[0111] (4) Dissolve 1 mmol of the product from step (3) in DMF, add 1.2 mmol EDCI and 0.5 mmol DMAP as condensing agents, stir at room temperature for 0.5 h, then add 1.1 mmol N-Boc-1,2-phenylenediamine, and react at room temperature for 2-3 h. After the reaction is complete, extract the system three times with ethyl acetate and water, wash the upper layer with saturated NaCl solution, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, add silica gel to stir the sample, pack into a column, and separate and purify the intermediate by column chromatography. The yield was 62%, and the purity was 97%.

[0112] (5) Dissolve 1 mmol of the product from step (4) in 1,4-dioxane, add 100 mmol of hydrochloric acid, and react for 2.5 h. A precipitate will form during the reaction. After the reaction is complete, evaporate the 1,4-dioxane solution to dryness under reduced pressure, dissolve the system in water, add saturated sodium bicarbonate solution under ice bath conditions to adjust the solution to a weakly alkaline state, let stand for 15 min, filter, and dry to obtain compound Z-48. Compound Z-48 has a yield of 56%, is a white solid, and has a melting point of 207.3-208.0 °C. 1H NMR (400 MHz, DMSO-d6,ppm)δ10.08 (s, 1H), 8.78 (d, J = 6.4 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.35–8.26 (m, 1H), 8.04 (d, J = 7.9 Hz, 2H), 7.69–7.60 (m, 4H), 7.58–7.46 (m, 4H), 7.38 (d, J = 7.9 Hz, 1H), 7.26 (tt, J = 7.1, 5.4 Hz, 2H), 7.15 (dd, J = 8.0,1.9 Hz, 2H), 7.03–6.95 (m, 1H), 4.60 (d, J = 5.9 Hz, 2H), 3.57 (s, 2H).13CNMR (101 MHz, DMSO-d6, ppm)δ165.90, 164.56, 144.64, 138.81, 136.07, 133.01,131.19, 130.49, 128.46, 127.89, 127.81, 127.54, 127.40, 126.99, 124.71,123.65, 122.19, 122.14, 112.37, 111.19, 42.29. HR-MS(ESI): calcd. C 29 H 24 N4O2,[M+H]+ m / z: 461.1977, found: 461.1983.

[0113] Example 49 Z-49, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0114] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution and then dried with anhydrous sodium sulfate. The dichloromethane was evaporated, and the mixture was packed into a column with silica gel (100-200 mesh) and sample-graded using a (200-300 mesh) column. The intermediate was purified using a (petroleum ether / ethyl acetate) solution as the mobile phase. The yield was 93%, and the purity was 97%.

[0115] (2) Dissolve 1 mmol of the substance obtained in step (1) and 0.6 mmol of anhydrous potassium phosphate in toluene, add the solution while stirring at 650 rpm at room temperature, then add 1.2 mmol of bromobenzene, 0.3 mmol of catalyst CuI and 2.1 mmol of trans-(1R,2R)-N,N-dimethyl-1,2-cyclohexanediamine, and react in an oil bath at 110 °C for 4-5 h under nitrogen protection. After the reaction is completed, the system is extracted three times with ethyl acetate and water, the upper organic phase is washed with saturated NaCl solution, dried with anhydrous sodium sulfate, and the organic phase is evaporated to dryness. Silica gel is added to stir the sample, and the sample is packed into a column. Petroleum ether / ethyl acetate is used as the mobile phase for separation and purification to obtain an intermediate with a yield of 93% and a purity of 97%.

[0116] (3) Dissolve 1 mmol of the substance obtained in step (2) in methanol solution, add 2-3 mL of water, add 10 mmol of sodium hydroxide solution while stirring at 650 rpm at room temperature, stir until dissolved, and then place in an oil bath at 60℃ under reflux for 4-5 h. After the reaction is complete as monitored by TLC, evaporate to dryness to remove methanol, add water to dissolve the system, and then place it in an ice bath. Adjust the pH to 3-4 with concentrated hydrochloric acid, and finally let it stand, filter, and dry to obtain compound Z-49. The yield of compound Z-49 is 72%, white solid, melting point 257.3-258.2℃. 1 HNMR (400 MHz, DMSO-d6, ppm)δ8.72 (d, J = 6.2 Hz, 1H), 8.41 (s, 1H), 8.29 (d,J = 7.3 Hz, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 4.5 Hz, 4H), 7.55 (d,J = 7.7 Hz, 1H), 7.47 (t, J = 7.4 Hz, 3H), 7.26 (p, J = 7.2 Hz, 2H), 4.58 (d,J = 5.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm) δ 167.74, 164.54, 145.80,138.80, 136.07, 131.13, 130.48, 129.88, 129.81, 127.90, 127.79, 127.75,124.71, 123.66, 122.19, 122.14, 112.32, 111.18, 42.31. HR-MS(ESI): calcd.C 23 H 18N2O3, [M+H]+ m / z: 371.1395, found: 371.1398.

[0117] Example 50 Z-50, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0118] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dichloromethane was evaporated. The mixture was then packed into a column with silica gel (100-200 mesh) and sample-grade silica gel (200-300 mesh). The intermediate was purified by separation using petroleum ether / ethyl acetate as the mobile phase; the yield was 93%, and the purity was 97%.

[0119] (2) Dissolve 1 mmol of the substance obtained in step (1) in methanol solution, add 2-3 mL of water, and add 10 mmol of sodium hydroxide solution while stirring at 650 rpm at room temperature. After dissolving at room temperature, place the mixture in an oil bath at 60°C under reflux for 4-5 h. After the reaction is complete as monitored by TLC, evaporate the methanol to remove it, add water to dissolve the mixture, and then place it in an ice bath. Adjust the pH to 3-4 with concentrated hydrochloric acid. Finally, allow it to stand, filter, and dry to obtain the intermediate. The yield is 95%, and the purity is 97%.

[0120] (3) Dissolve 1 mmol of the product from step (2) in DMF, add 1.2 mmol EDCI and 0.5 mmol DMAP as condensing agents, stir at room temperature for 0.5 h, then add 1.1 mmol N-Boc-1,2-phenylenediamine, and react at room temperature for 2-3 h. After the reaction is complete, extract the system three times with ethyl acetate and water, wash the upper layer with saturated NaCl solution, dry with anhydrous sodium sulfate, evaporate the organic phase to dryness, add silica gel to stir the sample, pack into a column, and separate and purify the intermediate by column chromatography. The yield was 62%, and the purity was 97%.

[0121] (4) Dissolve 1 mmol of the product from step (3) in 1,4-dioxane, add 100 mmol of hydrochloric acid, and react for 2.5 h. A precipitate will form during the reaction. After the reaction is complete, evaporate the 1,4-dioxane solution to dryness under reduced pressure, add water to dissolve the system, add saturated sodium bicarbonate solution under ice bath conditions to adjust the solution to a weakly alkaline state, let stand for 15 min, filter, and dry to obtain compound Z-50. Compound Z-50 has a yield of 72%, is a white solid, and has a melting point of 201.3-202.2℃. 1 H NMR (400 MHz, DMSO-d6,ppm) δ 11.58 (d, J = 3.0 Hz, 1H), 9.63 (s, 1H), 8.53 (t, J = 6.1 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.45 (dd, J = 11.1, 8.0 Hz, 3H), 7.20–7.05 (m, 3H), 6.97 (td, J = 7.6, 1.5Hz, 1H), 6.81–6.75 (m, 1H), 6.61 (t, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.56 (d,J = 6.0 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ165.69, 165.14, 144.62,143.30, 136.63, 133.44, 128.35, 128.27, 127.40, 127.15, 126.93, 126.63,124.01, 122.37, 121.48, 120.86, 116.97, 116.76, 112.31, 110.87, 42.18. HR-MS(ESI): calcd.C 23 H 20 N4O2, [M+H]+ m / z: 385.1664, found: 385.1672.

[0122] Example 51 Z-51, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process is as follows:

[0123] (1) 1 mmol of indole-3-carboxylic acid and 1.1 mmol of methyl 4-aminomethylbenzoate were placed in a 250 mL round-bottom flask and dissolved in dichloromethane. 2 mmol of EDCI and 0.2 mmol of HOBT were added sequentially while stirring at room temperature, followed by 1.1 mmol of triethylamine. The mixture was kept at room temperature for 4 h, and monitored by thin-layer chromatography. The mixture was extracted three times with dichloromethane and water. The lower organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the dichloromethane was evaporated. The mixture was then packed into a column with silica gel (100-200 mesh) and sample-grade silica gel (200-300 mesh). The intermediate was purified by separation using petroleum ether / ethyl acetate as the mobile phase; the yield was 93%, and the purity was 97%.

[0124] (2) Dissolve 1 mmol of the substance obtained in step (1) in methanol solution, add 2-3 mL of water, add 10 mmol of sodium hydroxide solution while stirring at 650 rpm at room temperature, stir until dissolved, and then place in an oil bath at 60℃ under reflux for 4-5 h. After the reaction is complete as monitored by TLC, evaporate to dryness to remove methanol, add water to dissolve the system, and then place it in an ice bath. Adjust the pH to 3-4 with concentrated hydrochloric acid, and finally let it stand, filter, and dry to obtain Z-51. The yield of compound Z-51 is 85%, white solid, melting point 237.8-238.5℃. 1 H NMR(400 MHz, DMSO-d6, ppm)δ12.85 (s, 1H), 11.59 (s, 1H), 8.53 (d, J = 6.1 Hz,1H), 8.23 ​​– 8.06 (m, 2H), 7.95 – 7.89 (m, 2H), 7.45 (t, J = 7.7 Hz, 3H), 7.19–7.07 (m, 2H), 4.56 (d, J = 5.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6, ppm)δ167.74, 165.14, 146.20, 136.62, 129.85, 129.66, 128.38, 127.63, 126.62,122.38, 121.48, 120.86, 112.30, 110.79, 42.19. HR-MS(ESI): calcd. C 17 H 14 N2O3,[M+H]+ m / z: 295.1082, found: 295.1087.

[0125] Example 52 Z-52, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 50 in that the indole-3-carboxylic acid in step (1) is replaced with 6-methylindole-3-carboxylic acid. Compound Z-52 has a yield of 73%, is a white solid, and has a melting point of 223.7-224.6℃. 1 H NMR (400 MHz, DMSO-d6, ppm) δ11.45(s, 1H), 9.69 (d, J = 3.9 Hz, 1H), 8.50 (d, J = 5.7 Hz, 1H), 8.02 (q, J= 4.0, 3.3 Hz, 2H), 7.96 (dd, J= 8.3, 3.1 Hz, 2H), 7.46 (dd, J = 8.4, 3.1 Hz, 2H), 7.25–7.15 (m, 2H), 7.03–6.89 (m, 2H), 6.83 (dd, J= 8.1, 3.5 Hz, 1H), 6.69–6.60 (m, 1H),5.34 (s, 2H), 4.55 (d, J = 6.1 Hz, 2H), 2.39 (d, J = 2.9 Hz, 3H). 13 C NMR(101MHz,DMSO-d6,ppm)δ165.72,165.19,144.71,142.47,137.07,133.36,131.44,128.27,127.78, 127.42, 127.16, 126.91,124.51,124.45, 122.61, 121.15,117.56, 117.17, 112.04, 110.78, 42.17, 21.77. HR-MS(ESI): calcd. C 24 H 22 N4O2, [M+H]+ m / z: 399.1821, found: 399.1826.

[0126] Example 53 Z-53, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 51 in that the indole-3-carboxylic acid in step (1) is replaced with 6-methylindole-3-carboxylic acid, while the rest is the same as in Example 51. The obtained compound Z-53 has a yield of 78%, is a white solid, and has a melting point of 227.8-228.7℃. 1H NMR(400 MHz, DMSO-d6, ppm)δ11.43 (s, 1H), 8.45 (d, J = 6.1 Hz, 1H), 8.05 – 7.95(m, 2H), 7.94 – 7.87 (m, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H), 6.93 (dd, J = 8.2, 1.5 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H), 2.39 (s, 3H). 13 C NMR (101MHz, DMSO-d6, ppm) δ 167.93, 165.16, 145.88, 137.05, 131.44, 129.79, 127.76,127.54, 124.50, 122.60, 121.15, 112.02, 110.72, 42.18, 21.76. HR-MS(ESI):calcd. C 18 H 16 N2O3, [M+H]+ m / z: 309.1239, found: 309.1244.

[0127] Example 54 Z-54, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that of Example 50 in that the indole-3-carboxylic acid in step (1) is replaced with 6-bromoindole-3-carboxylic acid, while the rest is the same as in Example 50. Compound Z-54 has a yield of 77%, is a white solid, and has a melting point of 231.2-232.1℃. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 11.43 (s, 1H), 9.67 (d, J = 3.9 Hz, 1H), 8.50 (d, J = 5.7 Hz, 1H), 8.01 (q, J = 4.0, 3.3 Hz, 2H), 7.94 (dd, J = 8.3, 3.1 Hz, 2H), 7.43 (dd,J = 8.4, 3.1 Hz, 2H), 7.25–7.14 (m, 2H), 7.03–6.89(m, 2H), 6.82 (dd,J = 8.1,3.5Hz, 1H), 6.69–6.60(m, 1H), 5.35 (s, 2H), 4.57 (d, J = 6.1 Hz, 2H). 13C NMR (101MHz, DMSO-d6, ppm)δ165.72, 165.19, 144.71, 142.47, 137.07, 133.36, 131.44,128.27, 127.78, 127.42, 127.16, 126.91, 124.51, 124.45, 122.61, 121.15,117.56, 117.17, 112.04, 110.78, 42.17.HR-MS(ESI): calcd. C 23 H 19 BrN4O2,[M+H]+ m / z:463.0769, found: 463.0772.

[0128] Example 55 Z-55, an indole compound that targets and inhibits HDAC6, has the following structural formula: The preparation process differs from that in Example 51 in that the indole-3-carboxylic acid in step (1) is replaced with 6-bromoindole-3-carboxylic acid. Compound Z-55 has a yield of 70%, is a white solid, and has a melting point of 230.2-231.1℃. 1 H NMR (400 MHz, DMSO-d6, ppm)δ11.43(s, 1H), 8.45 (d, J = 6.1 Hz, 1H), 8.05–7.95 (m, 2H), 7.94–7.87 (m, 2H), 7.43(d, J = 8.0 Hz, 2H), 7.21 (s,1H), 6.93 (dd, J = 8.2, 1.5 Hz, 1H), 4.53 (d, J =5.9 Hz, 2H). 13 C NMR (101MHz, DMSO-d6, ppm)δ167.93,165.16,145.88,137.05,131.44,129.79,127.76,127.54,124.50,122.60,121.15,112.02,110.72,42.18. HR-MS(ESI):calcd. C 17 H 13 BrN2O3, [M+H]+ m / z:373.0188, found: 373.0189.

[0129] Experimental Example 1 Compounds with structures shown in formulas Z-1 to Z-55 were subjected to in vitro enzyme activity assays as follows: Utilizing the deacetylation property of HDAC6, recombinant HDAC6 protein was first incubated with a polypeptide containing acetylated lysine and an AMC fluorescent group at 37°C for 20 min to expose the AMC fluorescent group. Trypsin was then added to hydrolyze the polypeptide, releasing the fluorescent group. Using a microplate reader, the change in fluorescence intensity was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm to evaluate the inhibition rate of the target compound. Vorinostat (SAHA) was used as a positive control. Based on a set concentration gradient, the fluorescence intensity after treatment with the compound at different concentrations was measured, and the inhibition rate was calculated. The HDAC1 assay was performed similarly. The IC50 of the compounds was calculated using GraphPad Prism 8.0 software. 50 Inhibition rate = (positive control fluorescence intensity - compound fluorescence intensity) / (positive control fluorescence intensity - blank group fluorescence intensity) × 100%. The results of the inhibition activity test are shown in Table 1.

[0130] Table 1. Selective inhibitory activity of the compounds of the present invention for HDAC6

[0131] Using SAHA as a positive control, compounds with an HDAC6 inhibition rate of over 60% were selected, and their IC50 for HDAC6 was determined. 50 The values ​​and experimental results are shown in Table 2.

[0132] Table 2. IC performance of some compounds of the present invention on HDAC6 50 value

[0133] As shown in Tables 1 and 2, the indole compounds provided by this invention exhibit good selective inhibition of HDAC6 compared to the positive control SAHA.

[0134] Experimental Example 2 Compound Z-7, which exhibits highly efficient and selective inhibition of HDAC6, was selected, and its inhibitory effect on the proliferation of human gastric cancer cells MGC-803 was tested using the MTT assay. Specifically, the cells were cultured in a high-glucose medium containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. MGC-803 cells were seeded at a density of 2500 cells / well in 96-well plates and cultured for 12 hours. After cell attachment, a 100 μM stock solution of the test compound was prepared into gradient concentrations, and 200 μL was added to each well. After incubation for 48 or 72 hours, 20 μL of 5 mg / mL MTT solution was added to each well, and the plates were cultured for another 5 hours. The supernatant was then discarded, and 150 μL of DMSO solution was added to each well. The plates were shaken at low speed for 15 minutes to fully dissolve the formazan crystals. Blank and negative control wells were also included, and the absorbance of each well was measured at 490 nm using an enzyme-linked immunosorbent assay (ELISA) reader. The inhibition rate was calculated and fitted using GraphPad Prism 8.0 software to obtain the IC. 50 Value. Inhibition rate (%) = 1 - (OD-treated group - OD blank group) / (OD negative control group - OD blank group) × 100%. The experimental results are shown in Table 3.

[0135] Table 3. Comparison of proliferation inhibition between compound Z-7 of the present invention and SAHA.

[0136] The results in Table 3 show that the indole compound Z-7 of the present invention has a good inhibitory effect on the proliferation of MGC-803 cells, and its inhibitory effect on the proliferation of MGC-803 cells is significantly better than that of the positive control SAHA.

[0137] In summary, the indole compounds provided by this invention can effectively inhibit the proliferative activity of gastric cancer cells by chelating with metal ions within the cells to form stable complexes. Experimental results show that, compared with the positive control SAHA, the indole compounds provided by this invention not only exhibit superior selective inhibition of HDAC6 but also inhibit gastric cancer cell proliferation in a concentration-dependent manner, demonstrating promising application prospects in the preparation of HDAC6-targeted inhibitory drugs or drugs that inhibit the proliferative activity of gastric cancer cells.

Claims

1. An indole compound that targets and inhibits HDAC6, characterized in that, The compound represented by Formula I or a pharmaceutically acceptable salt thereof: ； In Formula I, R1 is selected from one of H, 5-CH3, 6-CH3, 7-CH3, 5-OCH3, 5-Br, 6-Br, and 6-OCH3; R2 is selected from H, One of them; R3 is H or CH3; R4 is ; The specific structure of the indole compound that targets and inhibits HDAC6 is shown below: 。 2. A method for preparing an indole compound that targets and inhibits HDAC6 as described in claim 1, characterized in that, The technical route of the preparation method is shown below: ； When R2 is H, the preparation method of an indole compound that targets and inhibits HDAC6 includes the following steps: (1) Raw material A, raw material B, condensing agent a, and basic substance a are condensed in solvent a to obtain intermediate C; (2) Intermediate C and hydroxylamine aqueous solution were reacted in solvent b, and then alkaline substance b was added to react. After the reaction was completed, acidic substance and water were added, and the mixture was filtered to obtain the indole compound M that targets and inhibits HDAC6. When R2 is not H, the preparation method of the indole compound that targets and inhibits HDAC6 includes the following steps: ①The raw material A, raw material B, condensing agent a, and basic substance a are condensed in solvent a to obtain intermediate C; ② Intermediate C, basic substance c, and raw material a are reacted in solvent d to obtain intermediate E; the raw material a is a brominated compound; ③ Intermediate E is reacted with an aqueous solution of hydroxylamine in solvent b, and then alkaline substance b is added to continue the reaction. After the reaction is complete, acidic substance and water are added, and the mixture is filtered to obtain the indole compound F that targets and inhibits HDAC6.

3. The method for preparing an indole compound that targets and inhibits HDAC6 according to claim 2, characterized in that, Solvent a is dichloromethane, solvent b is a mixed solution of dichloromethane and methanol, and solvent d is N,N-dimethylformamide.

4. The method for preparing an indole compound that targets and inhibits HDAC6 according to claim 2, characterized in that, The alkaline substance a is triethylamine, the alkaline substance b is sodium hydroxide, and the alkaline substance c is potassium hydroxide; the acidic substance is hydrochloric acid.

5. The method for preparing an indole compound that targets and inhibits HDAC6 according to claim 2, characterized in that, The condensing agent a is EDCI or HOBt.

6. The application of an indole compound that targets and inhibits HDAC6 as described in claim 1, characterized in that, Application in the preparation of inhibitory drugs based on the HDAC6 target, or application in the preparation of drugs for targeted cancer therapy based on the HDAC6 target; wherein the cancer is gastric cancer.

7. The application of the indole compound targeting and inhibiting HDAC6 according to claim 6, characterized in that, The targeted cancer treatment drug is a drug that inhibits the proliferation activity of gastric cancer cells; the gastric cancer cells are MGC-803 cells.

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