Nitrogen-containing aromatic fused ring compound as well as preparation method and application thereof

Abstract

The invention discloses a nitrogenous aromatic fused ring compound as shown in a general formula I as well as a preparation method and application thereof, belongs to the technical field of medicinal chemistry, and particularly relates to application of the compound or pharmaceutically acceptable salt thereof as an HDAC6 inhibitor in the aspect of resisting idiopathic pulmonary fibrosis. The invention also relates to a pharmaceutical composition taking the compounds and pharmaceutically acceptable salts thereof as active ingredients. The invention also relates to a pharmaceutical preparation containing at least one of the compounds or salts thereof. The dosage form of the pharmaceutical preparation is selected from one or more of tablets, capsules, injections, suppositories, patches, inhalable powder preparations, suspensions, emulsions or ointments.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to nitrogen-containing aromatic fused-ring histone deacetylase family inhibitors, their preparation methods and uses, and particularly the indole histone deacetylase family inhibitors have anti-idiopathic pulmonary fibrosis activity. Background Technology

[0002] Epigenetic regulation governs many cellular processes and significantly influences key disease mechanisms. Histone deacetylases (HDACs) play a crucial role as biomarkers and therapeutic targets due to their involvement in specific pathophysiological pathways. HDACs are enzymes responsible for removing acetyl groups from histones, leading to reduced gene transcription, and are primarily involved in chromatin-related biological processes. HDACs can deacetylate histone and non-histone substrates, including transcription factors such as p53 and Rb. They also regulate key protein substrates, such as α-tubulin, actin, and cortical actin, thereby affecting many cellular processes, including apoptosis, signal transduction, DNA repair, replication, and recombination.

[0003] Due to the limitations of pirfenidone and nintedanib in the treatment of idiopathic pulmonary fibrosis (IPF) and the lack of promising clinical candidates, unprecedented efforts are needed to enrich the available treatment options for IPF and other rare fibrotic diseases. Increasing evidence suggests that HDACs are involved in the initiation and progression of fibrosis in organs such as the lungs, heart, liver, and kidneys; preliminary studies in animal models have shown that HDAC inhibitors can improve various forms of fibrosis. Among these, HDAC6 (a tubulin-associated deacetylase) plays a crucial role in the pathogenesis and progression of fibrotic diseases via epithelial-mesenchymal transition (EMT): abnormal expression of HDAC6 activates TGF-β1, promotes Smad2 / 3 phosphorylation, and forms a complex with Smad4, further promoting the EMT process in alveolar epithelial cells and ultimately leading to fibrotic lesions. One of the mechanisms of action of the marketed drug pirfenidone is to inhibit the HDAC6-mediated enhanced TGF-β1 activity, thereby achieving a therapeutic effect on IPF.

[0004] Recent reports indicate that siRNA or tubacin inhibition of HDAC6 reduces TGF-β1-induced EMT markers and interferes with the Smad3 response to TGF-β1. Since Smad3 is a core element of TGF-β1 signaling, its inactivation inhibits HDAC6-dependent α-tubulin deacetylation, highlighting the role of HDAC6 in EMT via the TGF-β1-Smad3 signaling pathway. Studies have demonstrated that the efficacy of pan-HDAC inhibitors (such as SAHA and panobinostat) against IPF and fibrotic lung is primarily based on the reduction of TGF-β1-induced fibroblast-myofibroblast differentiation and fibroblast proliferation. Recently, HDAC6 inhibitors have also been reported to protect mice from pulmonary fibrosis by inhibiting TGF-β1-induced collagen expression and reducing Akt phosphorylation. This related pharmacological mechanism has now been confirmed by our immunohistochemical studies of IPF lung tissue with HDAC6 overexpression.

[0005] Based on extensive literature review, this invention designed and synthesized a series of nitrogen-containing aromatic fused-ring derivatives and conducted anti-idiopathic pulmonary fibrosis activity tests. Unexpectedly, it was discovered that these derivatives exhibited activity in inhibiting the occurrence and progression of idiopathic pulmonary fibrosis. Summary of the Invention

[0006] The purpose of this invention is to design and synthesize a class of nitrogen-containing aromatic fused-ring derivatives and to test their anti-idiopathic pulmonary fibrosis activity. Unexpectedly, this invention revealed that the derivatives exhibit activity against the occurrence and progression of idiopathic pulmonary fibrosis.

[0007] To achieve the objectives of this invention, the following technical solution is adopted: In a first aspect, the present invention provides nitrogen-containing aromatic fused-ring derivatives having the following general formula I, or pharmaceutically acceptable salts thereof, or optically active forms thereof:

[0008] in: R is derived from: (1) hydroxyl, (2) amino, (3) methylamino.

[0009] Rings A and B are each derived from any one of the following groups: (1) benzene ring, (2) pyridine ring, (3) pyrrole ring, (4) indole ring, (5) quinoline ring, (6) isoquinoline ring, (7) 1,2,3,4-tetrahydroquinoline ring, (8) 1,2,3,4-tetrahydroisoquinoline ring, (9) tetrahydropyrrole ring, (10) morpholine ring, (11) caprolactam ring, (12) cyclohexylimine ring, (13) azaheptan-4-one ring, (14) 1,2,3,4-tetrahydrobenzo[b]azaheptan-5-one ring, (15) piperidine ring, (16) piperazine ring, (17) acridine ring, (18) 9H-pyrido[2,3- b] Indole ring, (19) 1-methyl-1,2,3,4-tetrahydroisoquinoline ring, (20) 1-phenyl-1,2,3,4-tetrahydroisoquinoline ring, (21) 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline ring, (22) 4,4-dimethyl-1,2,3,4-tetrahydroquinoline ring, (23) 1,2,3,4-tetrahydrobenzo(e)(1,4)diaza-5-one ring, (24) thiophene ring, (25) oxazole ring, (26) pyrazole ring, (27) imidazole ring, (28) thiazole ring, (30) cyclohexane ring, and each of the above groups may be arbitrarily replaced by one or more: hydrogen atom, halogen atom, C 1-6 Alkyl, C 1-6 Alkylamino, C 3-7 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfonylamino, benzyloxycarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 It is substituted by one or more of the following substituents: alkoxysulfonyl, trihalomethyl, hydroxy, cyano, nitro, amino, phenyl, and benzyl.

[0010] The C ring exists only under specific conditions and is derived from any one of the following groups: (1) benzene ring, (2) pyridine ring, (3) pyrrole ring, (4) pyran ring, (5) morpholine ring, (6) piperidine ring, and each of the above groups may be arbitrarily replaced by one or more of the following: hydrogen atom, halogen atom, C ring. 1-6 It is substituted by one or more substituents selected from alkyl, trihalomethyl, hydroxy, cyano, nitro, amino, phenyl, and benzyl.

[0011] X is derived from: (1) methylene, (2) nitrogen atom, (3) oxygen atom, (4) sulfur atom.

[0012] Y is derived from: (1) methylene, (2) nitrogen atom, (3) oxygen atom, (4) sulfur atom, (5) amide bond, (6) carbonyl group.

[0013] Linker is taken from: (1)C 4-8Alkyl, (2) substituted with various phenyl groups, substituted with various benzyl groups, substituted with various benzyloxy groups, substituted with various benzoyl groups, substituted with various pyridyl groups, wherein each of the above groups is substituted with one or more substituents selected from hydrogen atoms, halogen atoms, trihalomethyl groups, hydroxyl groups and amino groups.

[0014] Alternatively, in the above-mentioned compounds or their pharmaceutically acceptable salts or their optically active forms, the compounds are selected from:

[0015] In the second aspect, the synthetic route for preparing the nitrogen-containing aromatic fused-ring derivatives or pharmaceutically acceptable salts or optically active forms, racemates or diastereomers of the present invention represented by general formula I is as follows: Using aromatic fused-ring compounds with secondary or primary amines as starting materials, the intermediate M1 is first substituted or acylated with methyl halogenated carboxylic acids or acyl chlorides with terminal methyl esters under alkaline conditions. M1 then undergoes ammonolysis with hydroxylamine under alkaline conditions to give compounds A1~A45 of general formula I, wherein rings A, B, and C, Linker and R groups are as described above.

[0016]

[0017] Derived from the following compounds:

[0018] Derived from the following structure:

[0019] The linker group is derived from the following structure:

[0020] Synthetic routes for compounds A1–A45. Reagents and conditions: (i) methyl 4-bromomethylbenzoate (or methyl 6-bromomethylnicotinate, methyl 3-fluoro-4-(bromomethyl)benzoate), K2CO3, KI, anhydrous DMF, room temperature; or methyl 4-chloroformylbenzoate, triethylamine, anhydrous DCM, 0°C; or methyl 7-bromoheptanoate, K2CO3, KI, anhydrous DMF, room temperature to 120°C; or monomethyl octanoate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), triethylamine, anhydrous DMF, room temperature; (ii) 50 wt% aqueous hydroxylamine solution, NaOH, a mixed solvent of THF and MeOH, 0°C.

[0021] In a third aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect above, or a pharmaceutically acceptable salt thereof or an optically active form thereof, and a pharmaceutically acceptable carrier.

[0022] In a fourth aspect, the present invention provides a pharmaceutical preparation comprising the pharmaceutical composition described in the third aspect above, wherein the dosage form of the pharmaceutical preparation is selected from one or more of the following: tablets, capsules, injections, suppositories, patches, inhalable powders, suspensions, emulsions, or ointments.

[0023] In a fifth aspect, the present invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof or an optically active form thereof, or the pharmaceutical composition described in the third aspect or the pharmaceutical formulation described in the fourth aspect, in the preparation of an HDAC6 inhibitor.

[0024] In a sixth aspect, the present invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt thereof or an optically active form thereof, or the pharmaceutical composition described in the third aspect or the pharmaceutical preparation described in the fourth aspect in the preparation of an anti-idiopathic pulmonary fibrosis drug.

[0025] Alternatively, in the above applications, the anti-idiopathic pulmonary fibrosis drug has activity against the occurrence and progression of idiopathic pulmonary fibrosis.

[0026] Compared with the prior art, the present invention has the following advantages: This invention involves the design and synthesis of a class of nitrogen-containing aromatic fused-ring derivatives, and their anti-idiopathic pulmonary fibrosis activity was tested. Unexpectedly, these derivatives exhibited activity against the occurrence and progression of idiopathic pulmonary fibrosis. This invention provides new insights for exploring drugs that can effectively treat idiopathic pulmonary fibrosis and has significant clinical implications. Attached Figure Description

[0027] Figure 1 : Toxicity test of compounds A42 (A) and A44 (B) on HELF cells; Figure 2 : An assay of the inhibitory effect of compounds A42 (A) and A44 (B) on HDAC6 activity in HELF cells during TGF-β1-induced in vitro pulmonary fibrosis; Figure 3 Effects of compounds A42 (A) and A44 (B) on the expression of HDAC6-related substrate proteins in HELF cells during TGF-β1-induced in vitro pulmonary fibrosis; p <0.001 (Model group vs. control group);** p <0.01, *** p<0.001 (SAHA group vs. model group, Tubastatin A group vs. model group, A42 group vs. model group, A44 group vs. model group); Figure 4 Effects of compounds A42 (A) and A44 (B) on the expression of fibrosis-related substrates in HELF cells during TGF-β1-induced in vitro pulmonary fibrosis; p <0.01 (Model group vs. control group);** p <0.01 (SAHA group vs. model group, Tubastatin A group vs. model group, A42 group vs. model group, A44 group vs. model group). Figure 5 : Pharmacodynamic studies in a bleomycin-induced mouse pulmonary fibrosis model; (A) Changes in body weight of mice in each group during in vivo pulmonary fibrosis testing; (B) Pathological changes in mouse lung tissue during in vivo pulmonary fibrosis testing; (C) Effects of A42 and A44 on collagen deposition in mouse lung tissue observed by Masson's trichrome staining; (D) Effects of compounds A42 and A44 on HDAC6 activity in mouse lung tissue; (E) Quantitative analysis of collagen deposition. p <0.0001 (Model group vs. control group); * p <0.05,** p <0.01, **** p <0.0001 (Nidanibu group vs. model group, Tubastatin A group vs. model group, A42 group vs. model group, A44 group vs. model group); Figure 6 Analysis of biomarkers related to pulmonary fibrosis in mice; (A) Changes in α-SMA expression in mouse lung tissue; (B) Quantitative analysis of α-SMA; (C) Changes in p-Smad2 expression in mouse lung tissue; (D) Quantitative analysis of p-Smad2; (E) Changes in p-Smad3 expression in mouse lung tissue; (F) Quantitative analysis of p-Smad3. p <0.0001 (Model group vs. control group);** p <0.01, **** p <0.0001 (Nidanibu group vs. model group, Tubastatin A group vs. model group, A42 group vs. model group, A44 group vs. model group). Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0029] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0030] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available products.

[0031] Example 1: N -Hydroxy-4-(1,2,3,4-tetrahydroquinoline-1-formyl)benzamide (A1) Under ice bath conditions, 1,2,3,4-tetrahydroquinoline (1.20 g, 9.01 mmol) was dissolved in 30 mL of anhydrous DCM, and TEA (1.88 mL, 13.51 mmol) was added. Then, methyl 4-chloroformylbenzoate (2.68 g, 13.51 mmol) was added in portions, and the mixture was stirred for 0.5 h. The reaction was monitored by TLC. The reaction solution was then concentrated to remove the solvent, yielding a crude product. This crude product was purified by column chromatography (PE:EA = 5:1) to give 2.13 g of a pale yellow solid, with a yield of 95.95%.

[0032] Under ice bath conditions, NaOH (1.44 g, 36.06 mmol) was dissolved in hydroxylamine (50%, wt. aqueous, 23.82 mL, 360.60 mmol). The resulting pale yellow solid (2.13 g, 7.21 mmol) was dissolved in THF / MeOH (40 mL, 1:1, v / v) and added dropwise to the alkaline solution. The mixture was stirred for 0.5 h, and the reaction was monitored by TLC. Subsequently, the reaction solution was concentrated to remove most of the solvent, and the resulting mixture was suspended in 50 mL of water. The pH was adjusted to 6–7 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL / time × 3), the organic layers were combined, and extracted with saturated brine (50 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 50:1~30:1, 0.3% CH3COOH) to obtain 1.00 g of white solid, with a yield of 46.74%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.28 (s, 1H), 9.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 7.20 (dd,J = 7.6, 1.5 Hz, 1H), 7.00 (td, J = 7.5, 1.3 Hz, 1H), 6.90 (t, J =7.7 Hz, 1H), 6.78 (s, 1H), 3.75 (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 1.95 (p, J = 6.6 Hz, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 169.09, 163.86, 139.59,139.09, 134.25, 132.11, 129.00, 128.54 (2C), 127.20 (2C), 125.96, 125.45,125.01, 44.83, 26.67, 24.00. ESI-HRMS: Calcd for C 17 H 16 N₂NaO₃[M+Na] + , 319.1059;found 319.1061.

[0033] Example 2: N -hydroxy-6-((3,4-dihydroquinoline-1(2) H )-methyl)nicotinamide (A2) At room temperature, 1,2,3,4-tetrahydroquinoline (1.20 g, 9.01 mmol) was dissolved in 30 mL of anhydrous DMF, followed by the sequential addition of K₂CO₃ (2.49 g, 18.02 mmol), KI (3.74 g, 22.52 mmol), and methyl 6-bromomethylnicotinate (2.28 g, 10.81 mmol). The mixture was stirred for 2 h, and the reaction was monitored by TLC. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL / time × 3). The organic layers were combined and extracted with saturated brine (30 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent, yielding a crude product. Column chromatography (PE:EA = 10:1) yielded 2.44 g of a pale yellow oil, with a yield of 95.92%.

[0034] Under ice bath conditions, NaOH (1.73 g, 43.21 mmol) was dissolved in hydroxylamine (50%, wt. aqueous, 28.54 mL, 432.10 mmol). The resulting pale yellow oil (2.44 g, 8.64 mmol) was dissolved in THF / MeOH (40 mL, 1:1, v / v) and added dropwise to the alkaline solution. The mixture was stirred for 0.5 h, and the reaction was monitored by TLC. The reaction solution was then concentrated to remove most of the solvent, and the resulting mixture was suspended in 50 mL of water. The pH was adjusted to 6–7 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL / time × 3), the organic layers were combined, and extracted again with saturated brine (50 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH=50:1~30:1, 0.3% CH3COOH) to obtain 1.60 g of yellow solid, with a yield of 65.54%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.32 (s, 1H), 9.17 (s, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.02 (dd, J =8.2, 2.3 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 7.3, 1.6 Hz, 1H), 6.84(td, J = 7.7, 1.7 Hz, 1H), 6.46 (td, J = 7.2, 1.0 Hz, 1H), 6.33 (d, J = 8.4 Hz,1H), 4.57 (s, 2H), 3.47 (t, J = 5.6 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 1.97 –1.92 (m, 2H). 13 C NMR (151 MHz, DMSO- d6) δ 162.00, 161.40, 147.17, 144.08,134.74, 128.21, 126.25 (2C), 121.21, 119.76, 114.99, 109.82, 55.78, 49.36,26.89, 21.22. ESI-HRMS: Calcd for C 16 H 18 N3O2[M+H] + , 284.1399; found 284.1403.

[0035] Example 3: N -hydroxy-4-((3,4-dihydroquinoline-1(2) H )-methyl)-3-fluorobenzamide (A3) At room temperature, 1,2,3,4-tetrahydroquinoline (0.584 g, 4.38 mmol) was dissolved in 30 mL of anhydrous DMF, followed by the sequential addition of K₂CO₃ (1.21 g, 8.77 mmol), KI (1.46 g, 8.77 mmol), and methyl 3-fluoro-4-(bromomethyl)benzoate (1.30 g, 5.26 mmol). The mixture was stirred for 2 h, and the reaction was monitored by TLC. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL / time × 3). The organic layers were combined and extracted with saturated brine (30 mL / time × 2). The organic layers were dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent, yielding a crude product. Column chromatography (PE:EA = 50:1) yielded 1.02 g of a pale yellow oil, with a yield of 77.71%.

[0036] Under ice bath conditions, NaOH (0.681 g, 17.04 mmol) was dissolved in hydroxylamine (50%, wt. aqueous, 11.25 mL, 170.37 mmol). The resulting pale yellow oil (1.02 g, 3.41 mmol) was dissolved in THF / MeOH (40 mL, 1:1, v / v) and added dropwise to the alkaline solution. The mixture was stirred for 0.5 h, and the reaction was monitored by TLC. The reaction solution was then concentrated to remove most of the solvent, and the resulting mixture was suspended in 50 mL of water. The pH was adjusted to 6–7 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL / time × 3), the organic layers were combined, and extracted again with saturated brine (50 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 50:1~30:1, 0.3% CH3COOH) to obtain 0.85 g of brown solid, with a yield of 83.04%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.25 (s, 1H), 9.14 (s, 1H), 7.58 – 7.50 (m, 2H), 7.25 (t, J = 7.8Hz, 1H), 6.91 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 – 6.86 (m, 1H), 6.48 (t, J = 7.3Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 4.54 (s, 2H), 3.37 (t, J = 5.6 Hz, 2H), 2.74(t, J = 6.3 Hz, 2H), 1.96 – 1.91 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 171.45,159.43 (d, J = 244.5 Hz), 144.04, 132.77 (d, J = 6.6 Hz), 128.26, 128.22 (d, J =19.1 Hz), 127.83 (d, J = 4.8 Hz), 126.35, 122.25, 121.30, 115.12, 113.22 (d, J=23.2 Hz), 109.79, 48.85, 47.65 (d, J = 3.8 Hz), 26.93, 21.17. ESI-HRMS: Calcdfor C 17 H 18 FN2O2[M+H] + , 301.1352; found 301.1352.

[0037] Example 4: N -hydroxy-7-(3,4-dihydroquinoline-1(2) H )-yl)heptanamide (A4) At room temperature, 1,2,3,4-tetrahydroquinoline (1.00 g, 7.51 mmol) was dissolved in 30 mL of anhydrous DMF, followed by the sequential addition of K₂CO₃ (2.08 g, 15.02 mmol), KI (3.12 g, 18.77 mmol), and methyl 7-bromoheptanoate (3.35 g, 15.02 mmol). The mixture was heated to 120 °C and stirred for 2 h, with the reaction monitored by TLC. After the reaction solution was allowed to cool to room temperature, it was poured into 100 mL of water and extracted with ethyl acetate (30 mL / time × 3). The organic layers were combined and extracted with saturated brine (30 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent, yielding a crude product. Column chromatography (PE:EA = 50:1) yielded 1.96 g of a pale yellow oil, with a yield of 89.96%.

[0038] Under ice bath conditions, NaOH (1.42 g, 35.59 mmol) was dissolved in hydroxylamine (50%, wt. aqueous, 23.51 mL, 355.86 mmol). The resulting pale yellow oil (1.96 g, 7.12 mmol) was dissolved in THF / MeOH (40 mL, 1:1, v / v) and added dropwise to the alkaline solution. The mixture was stirred for 0.5 h, and the reaction was monitored by TLC. The reaction solution was then concentrated to remove most of the solvent, and the resulting mixture was suspended in 50 mL of water. The pH was adjusted to 6–7 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL / time × 3), the organic layers were combined, and extracted again with saturated brine (50 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 50:1~30:1, 0.3% CH3COOH) to obtain 0.61 g of brown oily substance, with a yield of 30.82%. 1 H NMR (600 MHz, DMSO- d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 6.95 – 6.91 (m, 1H), 6.83 (dd, J = 7.3, 1.7 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 6.42 (t, J = 7.2 Hz, 1H), 3.23 – 3.20 (m,2H), 3.20 – 3.17 (m, 2H), 2.65 (t, J = 6.3 Hz, 2H), 1.94 (t, J = 7.3 Hz, 2H),1.85 – 1.81 (m, 2H), 1.52 – 1.45 (m, 4H), 1.28 (m, J = 7.1, 4.1, 3.5 Hz, 4H). 13 CNMR (151 MHz, DMSO- d 6) δ 168.48, 144.39, 128.22, 126.29, 120.99, 114.23,109.63, 49.89, 48.08, 31.59, 27.90, 27.02, 25.69, 24.68, 24.51, 21.16. ESI-HRMS: Calcd for C 16 H 25 N₂O₂[M+H] + , 277.1916; found 277.1921. Retention time2.354 min, HPLC purity = 96.72%.

[0039] Example 5: N -hydroxy-8-(3,4-dihydroquinoline-1(2) H )-yl)-8-oxooctylamide (A5) At room temperature, monomethyl succinate (2.03 g, 10.81 mmol) was dissolved in 30 mL of anhydrous DMF, followed by the addition of EDCI (2.07 g, 10.81 mmol), HOBt (1.46 g, 10.81 mmol), and TEA (1.50 mL, 10.81 mmol), and the mixture was stirred for 0.5 h. Then, 1,2,3,4-tetrahydroquinoline (1.20 g, 9.01 mmol) was added, and the mixture was stirred for another 24 h. The reaction was monitored by TLC. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (30 mL / time × 3). The organic layers were combined and extracted with saturated brine (30 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was then subjected to column chromatography (PE: EA = 20:1) to obtain 2.01 g of a pale yellow oily substance, with a yield of 73.63%.

[0040] Under ice bath conditions, NaOH (1.32 g, 33.12 mmol) was dissolved in hydroxylamine (50%, wt. aqueous, 21.88 mL, 331.25 mmol). The resulting pale yellow oil (2.01 g, 6.62 mmol) was dissolved in THF / MeOH (40 mL, 1:1, v / v) and added dropwise to the alkaline solution. The mixture was stirred for 0.5 h, and the reaction was monitored by TLC. The reaction solution was then concentrated to remove most of the solvent, and the resulting mixture was suspended in 50 mL of water. The pH was adjusted to 6–7 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL / time × 3), the organic layers were combined, and extracted with saturated brine (50 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 50:1~30:1, 0.3% CH3COOH) to obtain 0.25 g of brown oily substance, with a yield of 12.18%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (s, 1H), 8.65 (s, 1H), 7.39 (s, 1H), 7.20 – 7.14 (m, 2H), 7.08 (t, J = 7.5 Hz, 1H), 3.66 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 6.7 Hz, 2H), 2.45(t, J= 7.4 Hz, 2H), 1.92 – 1.88 (m, 2H), 1.87 – 1.83 (m, 2H), 1.50 (p, J = 7.2Hz, 2H), 1.44 (p, J = 7.3 Hz, 2H), 1.19 (s, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ171.20, 168.47, 165.50, 138.27, 127.82, 125.10, 124.08, 123.99, 39.44, 33.11,31.59, 27.77, 27.73, 25.63, 24.39, 23.12, 18.86. ESI-HRMS: Calcd forC 17 H 24 N₂NaO₃[M+Na] + , 327.1685; found 327.1689.

[0041] Example 6: N -Hydroxy-4-(((1,2,3,4-tetrahydronaphth-1-yl)amino)methyl)benzamide (A6) At room temperature, 1,2,3,4-tetrahydro-1-naphthylamine (1.326 g, 9.01 mmol) was dissolved in 30 mL of anhydrous DMF, followed by the sequential addition of K₂CO₃ (2.49 g, 18.02 mmol), KI (3.74 g, 22.52 mmol), and methyl 4-bromomethylbenzoate (2.48 g, 10.81 mmol). The mixture was stirred for 2 h, and the reaction was monitored by TLC. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (30 mL / time × 3). The organic layers were combined and extracted with saturated brine (30 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent, yielding a crude product. Column chromatography (PE:EA = 20:1) yielded 1.95 g of a pale yellow oil, with a yield of 73.67%.

[0042] Under ice bath conditions, NaOH (1.32 g, 33.01 mmol) was dissolved in hydroxylamine (50%, wt. aqueous, 21.80 mL, 330.08 mmol). The resulting pale yellow oil (1.95 g, 6.60 mmol) was dissolved in THF / MeOH (40 mL, 1:1, v / v) and added dropwise to the alkaline solution. The mixture was stirred for 0.5 h, and the reaction was monitored by TLC. The reaction solution was then concentrated to remove most of the solvent, and the resulting mixture was suspended in 50 mL of water. The pH was adjusted to 6–7 with 1 M hydrochloric acid. The mixture was then extracted with ethyl acetate (50 mL / time × 3), the organic layers were combined, and extracted with saturated brine (50 mL / time × 2). The organic layers were then dried over anhydrous sodium sulfate. Finally, the sodium sulfate solid was filtered off, and the filtrate was concentrated to remove the solvent to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 50:1~30:1, 0.3% CH3COOH) to obtain 1.08 g of white solid, with a yield of 55.13%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.17 (s, 1H), 8.95 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.49 (d, J =8.0 Hz, 2H), 7.41 – 7.38 (m, 1H), 7.14 – 7.10 (m, 2H), 7.07 – 7.04 (m, 1H), 3.89 – 3.78 (m, 2H), 3.68 (t, J = 5.4 Hz, 1H), 2.78 – 2.62 (m, 2H), 1.99 – 1.92(m, 1H), 1.82 (q, J = 5.7 Hz, 2H), 1.63 (dp, J = 17.2, 5.9 Hz, 1H). 13 C NMR (151MHz, DMSO- d 6) δ 164.67, 144.97, 139.46, 137.61, 131.56, 129.21, 129.12,128.37 (2C), 127.22 (2C), 126.89, 125.90, 54.39, 49.90, 29.35, 28.01, 19.32.ESI-HRMS: Calcd for C 18 H 20 N₂NaO₂[M+Na] +, 319.1422; found 319.1419.

[0043] Example 7: N 1 -hydroxy- N 4 -(1,2,3,4-tetrahydronaphth-1-yl)terephthalamide (A7) The preparation method was the same as in Example 1, except that the starting material was replaced with 1,2,3,4-tetrahydro-1-naphthylamine. The product was a white solid with a yield of 67.16%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.33 (s, 1H), 9.17 (s, 1H), 8.88 (d, J = 8.6Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.20 – 7.11 (m, 4H), 5.25 (td, J = 8.4, 4.7 Hz, 1H), 2.83 – 2.73 (m, 2H), 2.02 – 1.94 (m, 2H), 1.86 – 1.73 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 165.74, 163.84, 137.97, 137.71,137.18, 135.52, 129.25, 128.31, 127.96 (2C), 127.22 (2C), 127.17, 126.36,47.76, 30.30, 29.37, 20.90. ESI-HRMS: Calcd for C 18 H 18 N₂NaO₃[M+Na] + , 333.1215;found 333.1223.

[0044] Example 8: N -Hydroxy-6-(((1,2,3,4-tetrahydronaphth-1-yl)amino)methyl)nicotinamide (A8) The preparation method is the same as in Example 2, except that the starting material is replaced with 1,2,3,4-tetrahydro-1-naphthylamine. The product is a brown solid with a yield of 43.71%. 1 H NMR (600 MHz, DMSO- d6) δ 11.37 (s, 1H), 9.18 (s, 1H), 8.85 (d, J = 2.1Hz, 1H), 8.09 (dd, J = 8.1, 2.3 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.42 (dd, J =5.5, 3.6 Hz, 1H), 7.16 – 7.13 (m, 2H), 7.09 – 7.06 (m, 1H), 4.01 – 3.93 (m,2H), 3.78 (t, J = 5.1 Hz, 1H), 2.79 – 2.63 (m, 2H), 2.00 – 1.92 (m, 1H), 1.83(qd, J = 9.1, 8.4, 4.1 Hz, 2H), 1.64 (ddt, J = 12.6, 10.3, 6.0 Hz, 1H). 13 C NMR (151 MHz, DMSO-) d 6) δ 171.45, 146.53, 136.65, 134.48, 128.31, 128.16 (2C), 127.61, 126.04, 124.90, 124.72, 121.12, 53.69, 50.56, 28.20, 26.89, 18.08.ESI-HRMS: Calcd for C 17 H 20 N3O2[M+H] + , 298.1556; found 298.1558.

[0045] Example 9: N -Hydroxy-4-(((1,2,3,4-tetrahydronaphth-1-yl)amino)methyl)-3-fluorobenzamide (A9) The preparation method was the same as in Example 3, except that the starting material was replaced with 1,2,3,4-tetrahydro-1-naphthylamine. The product was a white solid with a yield of 68.05%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.28 (s, 1H), 9.11 (s, 1H), 7.66 (t, J = 7.7Hz, 1H), 7.60 (dd, J= 8.0, 1.6 Hz, 1H), 7.50 (dd, J = 10.9, 1.6 Hz, 1H), 7.35(dd, J = 5.4, 3.7 Hz, 1H), 7.14 – 7.10 (m, 2H), 7.08 – 7.04 (m, 1H), 3.89 –3.81 (m, 2H), 3.70 (t, J = 5.3 Hz, 1H), 2.78 – 2.63 (m, 2H), 1.95 (dtd, J = 12.4,6.4, 5.9, 2.0 Hz, 1H), 1.82 (dt, J = 7.8, 5.0 Hz, 2H), 1.67 – 1.60 (m, 1H). 13 CNMR (151 MHz, DMSO- d 6) δ 162.19, 159.38 (d, J = 244.5 Hz), 138.38, 136.55,132.44 (d, J = 6.9 Hz), 130.71 (d, J = 15.0 Hz), 129.69 (d, J = 5.0 Hz), 128.06, 127.96 (d, J = 104.2 Hz), 125.83, 124.85, 122.13, 112.75 (d, J = 23.5 Hz), 53.62,42.13, 28.27, 27.07, 18.25. ESI-HRMS: Calcd for C 18 H 20 FN2O2[M+H] + , 315.1509;found 315.1514.

[0046] Example 10: N -Hydroxy-7-((1,2,3,4-tetrahydronaphth-1-yl)amino)-heptanamide (A10) The preparation method is the same as in Example 4, except that the starting material is replaced with 1,2,3,4-tetrahydro-1-naphthylamine. A brown oily substance was obtained, with a yield of 21.20%. 1 H NMR (600 MHz, DMSO- d6) δ 10.33 (s, 1H), 8.66 (s, 1H), 7.47 (d, J = 9.0Hz, 1H), 7.20 – 7.16 (m, 1H), 7.16 – 7.10 (m, 2H), 7.08 – 7.04 (m, 1H), 4.72 – 4.59 (m, 1H), 4.08 – 3.87 (m, 2H), 2.69 (tq, J = 16.8, 8.0, 5.9 Hz, 2H), 1.94(t, J = 7.4 Hz, 2H), 1.89 (dq, J = 10.0, 4.9, 4.0 Hz, 2H), 1.74 – 1.63 (m, 2H), 1.55 (p, J = 6.8 Hz, 2H), 1.49 (p, J = 7.4 Hz, 2H), 1.34 – 1.25 (m, 4H). 13 C NMR (151 MHz, DMSO-) d 6) δ 168.46, 137.36, 136.28, 128.06, 127.17, 126.01, 125.15,54.31, 47.93, 31.59, 29.48, 28.15, 28.04, 27.67, 24.51, 24.47, 19.51. ESI-HRMS: Calcd for C 17 H 27 N₂O₂[M+H] + , 291.2073; found 291.2078.

[0047] Example 11: N 1 -hydroxy- N 8 -(1,2,3,4-tetrahydronaphth-1-yl)octadiamide (A11) The preparation method was the same as in Example 5, except that the starting material was replaced with 1,2,3,4-tetrahydro-1-naphthylamine. The product was a white solid with a yield of 42.91%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.33 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 8.7Hz, 1H), 7.13 (q,J = 3.1 Hz, 3H), 7.08 (q, J = 4.4, 3.8 Hz, 1H), 4.96 (q, J = 7.5Hz, 1H), 2.78 – 2.66 (m, 2H), 2.10 (td, J = 7.3, 3.3 Hz, 2H), 1.93 (t, J = 7.4Hz, 2H), 1.85 (pd, J = 8.5, 6.9, 3.0 Hz, 2H), 1.74 – 1.61 (m, 2H), 1.50 (dp, J =29.1, 7.3 Hz, 4H), 1.25 (dh, J = 8.0, 5.0, 4.0 Hz, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 170.92, 168.49, 137.15, 136.42, 128.10, 127.53, 126.01, 125.20, 45.47,34.75, 31.65, 29.37, 28.20, 27.78 (2C), 24.74, 24.49, 19.36. ESI-HRMS: Calcdfor C 18 H 26 N₂NaO₃[M+Na] + , 341.1841; found 341.1845.

[0048] Example 12: N -hydroxy-4-((1-phenyl-3,4-dihydroisoquinoline-2(1) H )-yl)methyl)benzamide (A12) The preparation method was the same as in Example 6, except that the starting material was replaced with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The product was a white solid with a yield of 88.88%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.15 (s, 1H), 9.00 (s, 1H), 7.69 (d, J =8.0 Hz, 2H), 7.36 (ddd, J = 15.1, 7.8, 5.4 Hz, 6H), 7.28 – 7.25 (m, 1H), 7.13(d,J = 7.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.01 (td, J = 7.5, 1.4 Hz, 1H), 6.66(d, J = 7.8 Hz, 1H), 4.66 (s, 1H), 3.51 (dd, J = 180.0, 14.1 Hz, 2H), 3.01 – 2.92(m, 2H), 2.79 – 2.73 (m, 1H), 2.49 – 2.44 (m, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ163.56, 143.45, 141.85, 137.45, 133.70, 130.85, 128.66 (2C), 127.84, 127.81,127.69 (2C), 127.52 (2C), 126.62, 126.27 (2C), 125.24, 124.96, 67.09, 56.98,46.07, 27.99. ESI-HRMS: Calcd for C 23 H 23 N₂O₂[M+H] + , 359.1760; found 359.1763.

[0049] Example 13: N 4-Hydroxy-(1-Pheny-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)benzamide (A13) The preparation method was the same as in Example 1, except that the starting material was replaced with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. A white solid was obtained, with a yield of 88.07%. ¹H NMR (600 MHz, DMSO-) d 6) δ 11.30 (s, 1H), 9.12 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.31 – 7.20(m, 6H), 7.17 (d, J = 7.7 Hz, 1H), 6.84 (s, 1H), 3.36 – 3.30 (m, 2H), 2.99(ddd,J = 17.3, 11.4, 6.1 Hz, 1H), 2.78 (dt, J = 16.4, 3.5 Hz, 1H). 13 C NMR (151MHz, DMSO- d 6) δ 168.12, 162.83, 141.78, 138.05, 133.87, 133.84, 132.99,128.34, 127.98, 127.82 (2C), 127.59 (2C), 126.82, 126.58 (2C), 126.51, 125.82(2C), 125.60, 54.25, 40.39, 27.74. ESI-HRMS: Calcd for C 23 H 20 N₂NaO₃[M+Na] + ,395.1372; found 395.1376. Retention time 3.122 min, HPLC purity = 96.93%.

[0050] Example 14: N -hydroxy-6-((1-phenyl-3,4-dihydroisoquinoline-2(1) H )-methyl)nicotinamide (A14) The preparation method is the same as in Example 2, except that the starting material is replaced with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The product is a white solid with a yield of 75.29%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.32 (s, 1H), 9.18 (s, 1H), 8.79 (d, J =2.3 Hz, 1H), 8.07 (dd, J = 8.1, 2.3 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.38 –7.32 (m, 4H), 7.27 – 7.24 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.10 (td, J = 7.5, 1.3 Hz, 1H), 7.01 (td, J = 7.6, 1.5 Hz, 1H), 6.66 (d, J= 7.7 Hz, 1H), 4.76 (s,1H), 3.65 (dd, J = 94.1, 15.0 Hz, 2H), 3.08 – 2.95 (m, 2H), 2.79 (dt, J = 16.1,4.0 Hz, 1H), 2.58 (ddd, J = 11.7, 9.7, 3.9 Hz, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ161.99, 161.49, 146.57, 143.23, 137.42, 134.67, 133.65, 128.74 (2C), 127.84(2C), 127.68 (2C), 126.67, 126.27, 125.29, 125.00, 121.04, 66.78, 59.03,46.69, 28.08. ESI-HRMS: Calcd for C 22 H 22 N3O2[M+H] + , 360.1712; found 360.1717.

[0051] Example 15: N -hydroxy-4-((1-phenyl-3,4-dihydroisoquinoline-2(1) H )-methyl)-3-fluorobenzamide (A15) The preparation method was the same as in Example 3, except that the starting material was replaced with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The product was a white solid with a yield of 24.83%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.27 (s, 1H), 9.12 (s, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 10.8, 1.7 Hz, 1H),7.38 – 7.32 (m, 4H), 7.28 – 7.24 (m, 1H), 7.14 (dd, J = 7.7, 1.4 Hz, 1H), 7.09(td, J = 7.4, 1.3 Hz, 1H), 7.01 (td,J = 7.5, 1.5 Hz, 1H), 6.66 (d, J = 7.8 Hz,1H), 4.71 (s, 1H), 3.61 – 3.50 (m, 2H), 3.04 – 2.94 (m, 2H), 2.81 – 2.51 (m,2H). 13 C NMR (151 MHz, DMSO- d 6) δ 162.16, 159.67 (d, J = 244.9 Hz), 143.22,137.36, 133.59, 132.85 (d, J = 6.8 Hz), 130.04 (d, J = 5.0 Hz), 128.69 (2C), 128.24 (d, J = 14.4 Hz), 127.83, 127.82, 127.66 (2C), 126.68, 125.29, 125.00,122.24, 112.99 (d, J = 23.7 Hz), 67.13, 50.05, 46.22, 27.92. ESI-HRMS: Calcdfor C 23 H 22 FN2O2[M+H] + , 377.1665; found 377.1669.

[0052] Example 16: N -hydroxy-7-(1-phenyl-3,4-dihydroisoquinoline-2(1) H )-yl)heptanamide (A16) The preparation method was the same as in Example 4, except that the starting material was replaced with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The product was a white solid with a yield of 54.61%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.29 (s, 1H), 8.64 (s, 1H), 7.32 –7.28 (m, 2H), 7.26 – 7.22 (m, 3H), 7.13 – 7.10 (m, 1H), 7.06 (td, J = 7.4, 1.3Hz, 1H), 6.97 (td, J = 7.6, 1.4 Hz, 1H), 6.61 (d, J= 7.7 Hz, 1H), 4.52 (s, 1H), 3.13 (dt, J = 11.4, 4.6 Hz, 1H), 3.00 (ddd, J = 15.4, 9.7, 5.1 Hz, 1H), 2.79 (dt, J = 16.1, 4.0 Hz, 1H), 2.49 – 2.44 (m, 1H), 2.38 (dt, J = 12.6, 7.9 Hz, 1H),2.21 (ddd, J = 12.8, 7.7, 5.3 Hz, 1H), 1.86 (t, J = 7.5 Hz, 2H), 1.43 – 1.35 (m,4H), 1.18 – 1.04 (m, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 168.47, 143.87, 137.90,133.90, 128.67 (2C), 127.83, 127.71, 127.44 (2C), 126.35, 125.06, 124.83,67.23, 53.00, 46.07, 31.58, 28.17, 27.74, 25.79, 25.25, 24.48. ESI-HRMS:Calcd for C 22 H 29 N₂O₂[M+H] + , 353.2229; found 353.2234.

[0053] Example 17: N -hydroxy-8-oxo-8-(1-phenyl-3,4-dihydroisoquinoline-2(1 H )-Octadecylamide (A17) The preparation method was the same as in Example 5, except that the starting material was replaced with 1-phenyl-1,2,3,4-tetrahydroisoquinoline. The product was a white solid with a yield of 54.11%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.32 (s, 1H), 8.65 (s, 1H), 7.28 (t, J =7.6 Hz, 2H), 7.24 (dd, J= 4.8, 1.3 Hz, 2H), 7.22 – 7.19 (m, 2H), 7.17 (d, J =7.5 Hz, 1H), 7.12 (d, J = 7.2 Hz, 2H), 6.71 (s, 1H), 3.78 (dt, J = 13.4, 5.3 Hz,1H), 3.42 (ddd, J = 13.9, 9.7, 4.8 Hz, 1H), 2.93 (ddd, J = 15.8, 9.6, 5.7 Hz,1H), 2.78 (dt, J = 16.2, 4.7 Hz, 1H), 2.41 (ddt, J = 53.9, 15.3, 7.4 Hz, 2H),1.92 (t, J = 7.4 Hz, 2H), 1.55 – 1.45 (m, 4H), 1.26 (ddd, J = 16.6, 12.6, 6.0 Hz, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 170.53, 168.49, 142.03, 134.90, 134.34,128.01, 127.87, 127.74, 127.58 (2C), 127.08 (2C), 126.39, 125.51, 53.94,39.43, 31.90, 31.63, 27.85 (2C), 27.59, 24.43, 23.96. ESI-HRMS: Calcd forC 23 H 29 N₂O₃[M+H] + , 381.2178; found 381.2183.

[0054] Example 18: N -hydroxy-4-((2,2,4-trimethyl-3,4-dihydroquinoline-1(2) H )-yl)methyl)benzamide (A18) The preparation method was the same as in Example 6, except that the starting material was replaced with 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The product was a white solid with a yield of 61.66%. 1 H NMR (400 MHz, DMSO- d6) δ 11.12 (s, 1H), 8.96 (s, 1H), 7.72– 7.64 (m, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.10 (dt, J = 7.6, 1.4 Hz, 1H), 6.81(td, J = 7.8, 1.6 Hz, 1H), 6.52 (td, J = 7.4, 1.1 Hz, 1H), 6.12 (dd, J = 8.4, 1.1Hz, 1H), 4.48 (dd, J = 215.8, 18.3 Hz, 2H), 2.95 (dp, J = 12.3, 6.3 Hz, 1H), 1.91– 1.57 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H), 1.23 (s, 3H), 1.22 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 164.74, 145.15, 144.76, 131.48, 127.75, 127.46 (2C), 127.04, 126.37 (2C), 126.05, 116.03, 112.45, 54.61, 48.95, 46.72, 29.38,27.25, 24.59, 20.44. ESI-HRMS: Calcd for C 20 H 25 N₂O₂[M+H] + , 325.1916; found325.1919.

[0055] Example 19: N-hydroxy-4-(2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline-1-formyl)benzamide (A19) The preparation method was the same as in Example 1, except that the starting material was replaced with 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The product was a white solid with a yield of 94.10%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.20 (s, 1H), 9.04 (s, 1H), 7.55(d, J = 8.3 Hz, 2H), 7.27 (d, J= 7.8 Hz, 2H), 7.19 (d, J = 7.5 Hz, 1H), 6.98 (td, J = 7.5, 1.2 Hz, 1H), 6.77 (td, J = 7.7, 1.5 Hz, 1H), 6.45 (dd, J = 7.9, 1.1 Hz, 1H), 3.01 (ddt, J = 15.3, 8.5, 4.1 Hz, 1H), 2.03 (dd, J = 12.8, 2.8 Hz, 1H), 1.70(s, 3H), 1.54 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.21 (t, J = 12.6 Hz, 1H). 13 C NMR (151 MHz, DMSO-) d 6) δ 169.52, 162.71, 140.47, 138.87, 138.73, 133.07, 127.99(2C), 126.09, 125.87 (2C), 124.95, 123.69, 122.32, 57.76, 50.64, 27.72,27.29, 24.21, 16.12. ESI-HRMS: Calcd for C 20 H 23 N₂O₃[M+H] + , 339.1709; found339.1709.

[0056] Example 20: N -hydroxy-6-((2,2,4-trimethyl-3,4-dihydroquinoline-1(2) H )-methyl)nicotinamide (A20) The preparation method was the same as in Example 2, except that the starting material was replaced with 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The product was a white solid with a yield of 39.24%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.32 (s, 1H), 9.16 (s, 1H), 8.87(d, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.2, 2.2 Hz, 1H), 7.31 (d,J = 8.2 Hz, 1H), 7.12(dt, J = 7.7, 1.4 Hz, 1H), 6.82 (td, J = 7.9, 1.7 Hz, 1H), 6.55 (td, J = 7.4, 1.1Hz, 1H), 6.07 (d, J = 8.2 Hz, 1H), 4.78 (d, J = 18.5 Hz, 1H), 4.27 (d, J = 18.5 Hz, 1H), 2.96 (dp, J = 12.4, 6.4 Hz, 1H), 1.89 (dd, J = 13.0, 4.8 Hz, 1H), 1.64 (t, J =12.8 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H), 1.26 (s, 3H), 1.23 (s, 3H). 13 C NMR (151MHz, DMSO- d 6) δ 163.10, 162.10, 146.99, 143.96, 134.83, 126.87, 126.13,126.09, 125.16, 119.42, 115.25, 111.14, 53.65, 50.48, 45.56, 28.32, 26.20,23.54, 19.39. ESI-HRMS: Calcd for C 19 H 24 N3O2[M+H] + , 326.1869; found 326.1871.

[0057] Example 21: N -hydroxy-4-((2,2,4-trimethyl-3,4-dihydroquinoline-1(2) H )-methyl)-3-fluorobenzamide (A21) The preparation method was the same as in Example 3, except that the starting material was replaced with 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The product was a white solid with a yield of 44.06%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.24 (s, 1H), 9.10 (s, 1H), 7.54(dd,J = 11.1, 1.6 Hz, 1H), 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.12 (dt, J = 7.5, 1.4 Hz, 1H), 6.88 – 6.81 (m, 1H), 6.56 (t, J = 7.3 Hz, 1H), 6.09 (d, J = 8.3 Hz, 1H), 4.49 (dd, J = 206.0, 18.6 Hz, 2H), 2.96 (dp, J =12.2, 6.2 Hz, 1H), 1.92 – 1.60 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H), 1.23 (s, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 163.34, 159.78 (d, J = 244.2 Hz), 144.87, 133.49,130.97 (d, J = 14.2 Hz), 128.64, 127.80, 127.22, 126.24, 123.33, 116.33, 114.01(d, J = 23.2 Hz), 111.96, 54.70, 46.60, 43.26, 29.18, 27.20, 24.44, 20.45. ESI-HRMS: Calcd for C 20 H 24 N₂O₂F [M+H] + , 343.1822; found 343.1826.

[0058] Example 22: N -Hydroxy-7-(2,2,4-trimethyl-3,4-dihydroquinoline-1(2) H )-yl)heptanamide (A22) The preparation method was the same as in Example 4, except that the starting material was replaced with 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The product was a white solid with a yield of 26.09%. 1 H NMR (600 MHz, DMSO- d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 7.04(d, J = 7.4 Hz, 1H), 6.99 – 6.95 (m, 1H), 6.50 (t, J = 7.3 Hz, 1H), 6.43 (d, J =8.3 Hz, 1H), 3.29 (ddd, J = 15.6, 10.7, 5.3 Hz, 1H), 2.94 (ddd, J = 15.4, 10.6,5.2 Hz, 1H), 2.79 (dp, J = 12.3, 6.4 Hz, 1H), 1.95 (t, J = 7.4 Hz, 2H), 1.74 (dd, J = 12.9, 4.8 Hz, 1H), 1.50 (p, J = 7.3 Hz, 4H), 1.38 (t, J = 12.7 Hz, 1H), 1.30(tq, J = 9.8, 6.2, 5.3 Hz, 4H), 1.26 (s, 3H), 1.24 (d, J = 6.7 Hz, 3H), 1.11 (s, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ 168.49, 143.92, 126.51, 126.16, 124.96,114.17, 110.22, 53.11, 45.89, 43.84, 31.58, 28.57, 28.10, 27.83, 26.21,25.64, 24.55, 23.95, 19.36. ESI-HRMS: Calcd for C 19 H 31 N₂O₂[M+H] + , 319.2386;found 319.2386.

[0059] Example 23: N -Hydroxy-8-oxo-8-(2,2,4-trimethyl-3,4-dihydroquinoline-1(2) H )-yl)octylamide (A23) The preparation method was the same as in Example 5, except that the starting material was replaced with 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline. The product was a white solid with a yield of 49.30%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 8.62 (s, 1H), 7.22– 7.12 (m, 3H), 7.02 – 6.96 (m, 1H), 2.69 (ddt, J = 14.8, 8.0, 3.9 Hz, 1H),2.25 (ddt, J = 68.4, 14.6, 7.3 Hz, 2H), 1.93 – 1.79 (m, 3H), 1.59 (s, 3H), 1.49– 1.35 (m, 7H), 1.28 (d, J = 6.7 Hz, 3H), 1.16 – 1.03 (m, 5H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.64, 168.42, 139.66, 138.18, 125.27, 124.30, 123.96, 122.21,57.43, 51.13, 36.12, 31.56, 27.86, 27.64, 27.42, 27.08, 25.53, 24.68, 24.36,16.09. ESI-HRMS: Calcd for C 20 H 30 N₂O₃Na [M+Na] + , 369.2154; found 369.2157.

[0060] Example 24: N -hydroxy-4-((2,3-dihydro-4-) H -benzo[ b [1,4]oxazin-4-yl)methyl)-benzamide (A24) The preparation method is the same as in Example 6, except that the starting material is replaced with 3,4-dihydro-2 H -1,4-Benzoxazine. White solid, yield 64.77%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.16 (s, 1H), 8.99 (s, 1H), 7.71 (d, J =8.2 Hz, 2H), 7.36 (d,J = 8.0 Hz, 2H), 6.68 (ddd, J = 12.5, 7.5, 1.6 Hz, 2H),6.59 (dd, J = 8.1, 1.6 Hz, 1H), 6.51 (td, J = 7.5, 1.6 Hz, 1H), 4.50 (s, 2H), 4.22 (t, J = 4.4 Hz, 2H), 3.40 (t, J = 4.4 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ163.51, 142.94, 141.27, 134.55, 130.88, 126.52 (2C), 126.38 (2C), 120.68,116.47, 115.25, 111.71, 63.48, 53.10, 46.63. ESI-HRMS: Calcd for C 16 H 17 N₂O₃[M+H] + , 285.1239; found 285.1244.

[0061] Example 25: N -hydroxy-4-(3,4-dihydro-2H-benzo[ b [1,4]Oxazin-4-formyl)benzamide (A25) The preparation method is the same as in Example 1, except that the starting material is replaced with 3,4-dihydro-2 H -1,4-Benzoxazine. White solid, yield 18.29%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.33 (s, 1H), 9.13 (s, 1H), 7.80 (d, J =8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.43 – 7.06 (m, 1H), 7.01 (ddd, J = 8.6,7.2, 1.6 Hz, 1H), 6.91 (dd, J = 8.2, 1.5 Hz, 1H), 6.73 (t, J = 7.7 Hz, 1H), 4.33(t,J = 4.5 Hz, 2H), 3.86 (t, J = 4.5 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 167.06,162.71, 145.43, 137.45, 133.65, 127.50 (2C), 126.35 (2C), 125.04, 124.79,123.42, 118.99, 116.36, 65.16, 47.99. ESI-HRMS: Calcd for C 16 H 15 N₂O₄[M+H] + ,299.1032; found 299.1036.

[0062] Example 26: N -hydroxy-6-((2,3-dihydro-4-) H -benzo[ b [1,4]oxazine-4-yl)methyl)nicotinamide (A26) The preparation method is the same as in Example 2, except that the starting material is replaced with 3,4-dihydro-2 H -1,4-Benzoxazine. White solid, yield 59.88%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.33 (s, 1H), 9.17 (s, 1H), 8.86 (d, J =2.2 Hz, 1H), 8.04 (dd, J = 8.1, 2.2 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.69 (dd, J = 8.1, 1.7 Hz, 1H), 6.64 (td, J = 7.7, 1.6 Hz, 1H), 6.50 (t, J = 6.9 Hz, 2H),4.60 (s, 2H), 4.24 (t, J = 4.4 Hz, 2H), 3.54 (t, J = 4.4 Hz, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 161.97, 160.79, 147.10, 142.93, 134.77, 134.33, 126.39, 120.68,120.42, 116.45, 115.24, 111.44, 63.55, 55.24, 47.13. ESI-HRMS: Calcd forC 15 H 16 N3O3[M+H] + , 286.1192; found 286.1196.

[0063] Example 27: N -hydroxy-4-((2,3-dihydro-4-) H -benzo[ b [1,4]oxazine-4-yl)methyl)-3-fluorobenzamide (A27) The preparation method is the same as in Example 3, except that the starting material is replaced with 3,4-dihydro-2 H -1,4-Benzoxazine. White solid, yield 70.33%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.27 (s, 1H), 9.12 (s, 1H), 7.59 –7.52 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 6.69 (t, J = 7.4 Hz, 2H), 6.60 (d, J = 7.6Hz, 1H), 6.53 (td, J = 7.5, 1.5 Hz, 1H), 4.55 (s, 2H), 4.22 (t, J = 4.3 Hz, 2H), 3.41 (t, J = 4.4 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 162.11, 159.36 (d, J = 245.0Hz), 143.00, 134.28, 133.02 (d, J = 6.7 Hz), 128.64 (d, J = 4.9 Hz), 127.70 (d, J=15.0 Hz), 122.28, 120.76, 116.69, 115.33, 113.26 (d, J = 23.3 Hz), 111.55,63.43, 47.34, 46.56. ESI-HRMS: Calcd for C 16 H 16 N₂O₃F [M+H] + , 303.1145; found303.1149.

[0064] Example 28: N -hydroxy-7-(2,3-dihydro-4-hydroxyl ... H -benzo[ b [1,4]oxazin-4-yl)heptanamide (A28) The preparation method is the same as in Example 4, except that the starting material is replaced with 3,4-dihydro-2 H -1,4-Benzoxazine. White solid, yield 29.38%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.32 (s, 1H), 8.64 (s, 1H), 6.76 –6.70 (m, 1H), 6.68 – 6.61 (m, 2H), 6.47 (t, J = 7.7 Hz, 1H), 4.14 (t, J = 4.4 Hz, 2H), 3.27 (t, J = 4.4 Hz, 2H), 3.20 (t, J = 7.5 Hz, 2H), 1.94 (t, J = 7.4 Hz, 2H), 1.49 (p, J = 6.9 Hz, 4H), 1.29 (dt, J = 7.7, 4.3 Hz, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 168.48, 142.95, 134.63, 120.73, 115.82, 115.15, 111.28, 63.39, 49.35,45.60, 31.58, 27.85, 25.64, 24.48, 24.45. ESI-HRMS: Calcd for C 15 H 23 N₂O₃[M+H] +,279.1709; found 279.1712.

[0065] Example 29: N -hydroxy-8-oxo-8-(2,3-dihydro-4- ...8-(2,3-dihydro-4-hydroxy- H Benzo[ b [1,4]Oxazin-4-yl)octamide (A29) The preparation method is the same as in Example 5, except that the starting material is replaced with 3,4-dihydro-2 H -1,4-Benzoxazine. White solid, yield 14.92%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.44 – 10.18 (m, 1H), 8.66 (s, 1H),7.69 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 7.9 Hz, 2H), 4.24 (t, J = 4.6Hz, 2H), 3.85 (t, J = 4.6 Hz, 2H), 2.55 (t, J = 7.4 Hz, 2H), 1.92 (t, J = 7.4 Hz, 2H), 1.51 (dp, J = 29.3, 7.2 Hz, 4H), 1.24 (dq, J = 11.1, 6.0 Hz, 4H). 13 C NMR (101MHz, DMSO- d 6) δ 170.54, 168.47, 145.72, 128.30, 125.73, 123.61, 119.10,116.16, 65.58, 32.90, 31.61, 27.82, 27.73, 24.40, 24.03. ESI-HRMS: Calcd forC 16 H 22 N₂O₄Na [M+Na] + , 329.1477; found 329.1480.

[0066] Example 30: N -hydroxy-4-((1-methyl-3,4-dihydroisoquinoline-2(1) H )-yl)methyl)benzamide (A30) The preparation method was the same as in Example 6, except that the starting material was replaced with 1-methyl-1,2,3,4-tetrahydroisoquinoline. The product was a white solid with a yield of 25.13%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.17 (s, 1H), 9.01 (s, 1H), 7.73 –7.70 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.09 (tdd, J = 9.6, 4.6, 2.7 Hz, 4H), 3.84 – 3.81 (m, 1H), 3.81 – 3.70 (m, 2H), 3.00 – 2.79 (m, 2H), 2.62 (ddt, J =16.2, 9.2, 4.3 Hz, 2H), 1.31 (d, J = 6.6 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ163.62, 142.23, 139.43, 133.23, 130.82, 128.04, 127.68 (2C), 126.66, 126.27(2C), 125.13, 124.99, 56.45, 55.05, 42.75, 26.39, 18.62. ESI-HRMS: Calcd forC 18 H 21 N₂O₂[M+H] + , 297.1603; found 297.1609.

[0067] Example 31: N -hydroxy-6-((1-methyl-3,4-dihydroisoquinoline-2(1) H )-methyl)nicotinamide (A31) The preparation method is the same as in Example 2, except that the starting material is replaced with 1-methyl-1,2,3,4-tetrahydroisoquinoline. A yellow solid was obtained, with a yield of 90.66%. 1 H NMR (600 MHz, DMSO- d 6) δ 8.82 (dd, J = 2.3, 0.8 Hz, 1H), 8.09 (dd, J = 8.1, 2.3 Hz, 1H), 7.61 (d, J= 8.1 Hz, 1H), 7.13 – 7.07 (m, 4H), 3.88 (s,2H), 3.85 (q, J = 6.7 Hz, 1H), 3.04 – 2.98 (m, 1H), 2.89 – 2.82 (m, 1H), 2.66(dq, J = 15.4, 4.1 Hz, 2H), 1.32 (d, J = 6.7 Hz, 3H). 13 C NMR (151 MHz, DMSO- d 6) δ162.03, 146.56, 139.38, 134.62, 133.20, 128.31, 128.03, 127.61, 126.64,125.14, 124.99, 121.32, 58.74, 55.32, 43.34, 26.58, 18.76. ESI-HRMS: Calcdfor C 17 H 20 N3O2[M+H] + , 298.1556; found 298.1559.

[0068] Example 32: N -hydroxy-4-((1-methyl-3,4-dihydroisoquinoline-2(1) H )-methyl)-3-fluorobenzamide (A32) The preparation method is the same as in Example 3, except that the starting material is replaced with 1-methyl-1,2,3,4-tetrahydroisoquinoline. A yellow solid was obtained, with a yield of 82.46%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.28 (s, 1H), 9.17 (s, 1H), 7.62 –7.57 (m, 2H), 7.52 (dd, J = 10.9, 1.5 Hz, 1H), 7.14 – 7.06 (m, 4H), 3.84 (t, J =6.6 Hz, 1H), 3.82 – 3.73 (m, 2H), 3.01 – 2.96 (m, 1H), 2.81 (ddt, J = 12.3,8.8, 5.0 Hz, 1H), 2.67 – 2.59 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H).13 C NMR (151MHz, DMSO- d 6) δ 160.54, 158.91, 139.36, 133.15, 132.77 (d, J = 7.4 Hz), 130.24(d, J = 4.2 Hz), 128.79 (d, J = 14.3 Hz), 128.00, 126.62, 125.14, 125.00, 122.21,112.98 (d, J = 24.0 Hz), 55.37, 49.53, 43.01, 26.48, 18.84. ESI-HRMS: Calcd forC 18 H 20 FN2O2[M+H] + , 315.1509; found 315.1514.

[0069] Example 33: N -hydroxy-7-(1-methyl-3,4-dihydroisoquinoline-2(1) H )-yl)heptanamide (A33) The preparation method is the same as in Example 4, except that the starting material is replaced with 1-methyl-1,2,3,4-tetrahydroisoquinoline. A brown oily substance was obtained, with a yield of 83.59%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.34 (s, 1H), 7.12 – 7.03 (m, 4H), 3.79 (q, J = 6.6 Hz, 1H), 2.94 – 2.75 (m, 2H), 2.65 – 2.59 (m, 2H), 2.49 – 2.43(m, 2H), 1.93 (t, J = 7.4 Hz, 2H), 1.51 – 1.41 (m, 4H), 1.31 – 1.23 (m, 4H), 1.21 (d, J = 6.7 Hz, 3H). 13 C NMR (151 MHz, DMSO- d6) δ 169.54, 140.97, 134.55,128.98, 127.66, 126.02, 125.91, 56.17, 53.66, 43.91, 32.71, 29.04, 27.70,27.46, 27.12, 25.62, 19.19. ESI-HRMS: Calcd for C 17 H 27 N₂O₂[M+H] + , 291.2073;found 291.2076.

[0070] Example 34: N -hydroxy-4-((2-oxo-2,3,4,5-tetrahydro-1-hydroxyl) H -benzo[ b Aza-1-yl)methyl)benzamide (A34) The preparation method was the same as in Example 6, except that the starting material was replaced with 1,3,4,5-tetrahydro-2H-1-benzozazepine-2-one. The product was a white solid with a yield of 71.26%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.13 (s, 1H), 8.99 (s, 1H), 7.65 – 7.61 (m, 2H), 7.34 (dd, J = 8.1, 1.2 Hz, 1H), 7.29 – 7.25 (m, 3H), 7.20(dd, J = 7.5, 1.7 Hz, 1H), 7.13 (td, J = 7.4, 1.3 Hz, 1H), 5.04 (s, 2H), 2.54 –2.51 (m, 2H), 2.21 (t, J = 7.1 Hz, 2H), 2.08 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6)δ 171.43, 163.37, 141.16, 140.69, 134.50, 131.02, 128.78, 126.98 (2C),126.91, 126.37 (2C), 125.49, 121.80, 48.89, 32.13, 28.76, 27.82. ESI-HRMS:Calcd for C 18 H 18 N₂NaO₃[M+Na] +, 333.1215; found 333.1219.

[0071] Example 35: N -Hydroxy-6-((2-oxo-2,3,4,5-tetrahydro-1-hydroxyl) H -benzo[ b (Aza-1-yl)methyl)nicotinamide (A35) The preparation method is the same as in Example 2, except that the starting material is replaced with 1,3,4,5-tetrahydro-2 H -1-Benzaza-2-one. White solid, yield 65.78%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.32 (s, 1H), 9.18 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.03 (dd, J = 8.1, 2.2 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.36 (dd, J = 8.1, 1.2 Hz, 1H), 7.26 (ddd, J = 17.3, 7.5, 1.6 Hz, 2H), 7.14 (td, J = 7.4, 1.2 Hz, 1H), 5.09 (s, 2H), 2.76 (d, J = 8.4 Hz, 2H), 2.21 (t, J = 7.1 Hz, 2H), 2.15 – 2.03 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 171.36, 161.92, 159.59,146.76, 141.96, 134.73, 134.55, 128.75, 126.87, 126.42, 125.39, 121.77,121.03, 51.92, 32.20, 28.79, 27.79. ESI-HRMS: Calcd for C 17 H 18 N3O3[M+H] + ,312.1348; found 312.1353.

[0072] Example 36: N-hydroxy-4-((2-oxo-2,3,4,5-tetrahydro-1-hydroxyl) H -benzo[ b (A36)-(1-yl)methyl)-3-fluorobenzamide The preparation method is the same as in Example 3, except that the starting material is replaced with 1,3,4,5-tetrahydro-2 H -1-Benzaza-2-one. White solid, yield 53.17%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.24 (s, 1H), 9.12 (s, 1H), 7.51 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 (dd, J = 10.7, 1.6 Hz, 1H), 7.40 (t, J = 7.7Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28 (td, J = 7.6, 1.6 Hz, 1H), 7.21 (dd, J =7.5, 1.6 Hz, 1H), 7.16 – 7.12 (m, 1H), 5.07 (s, 2H), 2.55 (t, J = 7.1 Hz, 2H), 2.20 (t, J = 7.1 Hz, 2H), 2.06 (s, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 171.25,161.96, 159.05 (d, J = 246.4 Hz), 141.04, 134.51, 133.24 (d, J = 7.4 Hz), 129.87(d, J = 4.6 Hz), 128.71, 127.22 (d, J = 15.4 Hz), 126.87, 125.58, 122.26, 121.79,113.04 (d, J = 23.4 Hz), 43.00 (d, J = 3.3 Hz), 32.11, 28.53, 27.66. ESI-HRMS: Calcd for C 18 H 18FN2O3[M+H] + , 329.1301; found 329.1306.

[0073] Example 37: N -Hydroxy-7-(2-oxo-2,3,4,5-tetrahydro-1-hydroxyl) H -benzo[ b (A37)-(1-yl)heptanamide The preparation method is the same as in Example 4, except that the starting material is replaced with 1,3,4,5-tetrahydro-2 H -1-Benzaza-2-one. Brown oily substance, yield 81.04%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.30 (s, 1H), 8.63 (s, 1H),7.35 – 7.30 (m, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.18 (td, J = 7.1, 1.9 Hz, 1H),3.75 (s, 2H), 2.64 (t, J = 6.9 Hz, 2H), 2.15 – 1.94 (m, 4H), 1.88 (t, J = 7.4 Hz, 2H), 1.40 (dd, J = 14.6, 7.9 Hz, 4H), 1.21 – 1.13 (m, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 171.83, 169.50, 142.48, 135.93, 129.75, 128.07, 126.45, 123.21,47.00, 33.29, 32.60, 29.84, 28.76, 28.69, 28.03, 26.69, 25.46. ESI-HRMS:Calcd for C 17 H 25 N₂O₃[M + H] + , 305.1865; found 305.1866.

[0074] Example 38: N -hydroxy-4-((9,9-dimethylacridine-10(9) H )-yl)methyl)benzamide (A38) The preparation method is the same as in Example 6, except that the starting material is replaced with 9,9-dimethyl-9,10-dihydroacridine. White solid, yield 52.36%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.15 (s, 1H), 9.00 (s, 1H), 7.71 –7.68 (m, 2H), 7.47 (dd, J = 7.7, 1.6 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.07(ddd, J = 8.5, 7.3, 1.5 Hz, 2H), 6.94 (td, J = 7.5, 1.1 Hz, 2H), 6.72 (dd, J = 8.2,1.1 Hz, 2H), 5.27 (s, 2H), 1.54 (s, 6H). 13 C NMR (151 MHz, DMSO- d 6) δ 163.52,140.05, 139.34 (2C), 130.85, 130.74 (2C), 126.64 (2C), 126.12 (2C), 125.75(2C), 123.96 (2C), 120.04 (2C), 112.34 (2C), 48.83, 35.18, 28.89 (2C). ESI-HRMS: Calcd for C 23 H 23 N₂O₂[M+H] + , 359.1760; found 359.1763.

[0075] Example 39: N -hydroxy-6-((9,9-dimethylacridine-10(9) H )-methyl)nicotinamide (A39) The preparation method was the same as in Example 2, except that the starting material was replaced with 9,9-dimethyl-9,10-dihydroacridine. The product was a white solid with a yield of 27.49%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.34 (s, 1H), 9.19 (s, 1H), 8.90 (d, J =2.2 Hz, 1H), 8.01 (dd, J= 8.2, 2.3 Hz, 1H), 7.47 (dd, J = 7.7, 1.6 Hz, 2H), 7.10– 7.06 (m, 3H), 6.94 (td, J = 7.4, 1.1 Hz, 2H), 6.72 – 6.69 (m, 2H), 5.32 (s, 2H), 1.54 (s, 6H). 13 C NMR (151 MHz, DMSO- d 6) δ 161.92, 159.55, 147.38, 139.36(2C), 134.91, 130.87 (2C), 126.49, 126.09 (2C), 123.89 (2C), 120.09 (2C),120.03, 112.25 (2C), 50.98, 35.19, 28.70 (2C). ESI-HRMS: Calcd for C 22 H 22 N3O2[M+H] + , 360.1712; found 360.1715.

[0076] Example 40: N -hydroxy-4-((9,9-dimethylacridine-10(9) H )-methyl)-3-fluorobenzamide (A40) The preparation method was the same as in Example 3, except that the starting material was replaced with 9,9-dimethyl-9,10-dihydroacridine. The product was a white solid with a yield of 26.79%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.26 (s, 1H), 9.14 (s, 1H), 7.64 (dd, J = 10.9, 1.6 Hz, 1H), 7.48 (dd, J = 7.8, 1.5 Hz, 2H), 7.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.09 (td, J = 8.2, 7.7, 1.5 Hz, 2H), 6.98 – 6.93 (m, 2H), 6.86 (t, J = 7.8Hz, 1H), 6.74 (d, J= 8.1 Hz, 2H), 5.28 (s, 2H), 1.53 (s, 6H). 13 C NMR (151 MHz, DMSO- d 6) δ 162.10, 159.25 (d, J = 244.8 Hz), 139.10 (2C), 133.08 (d, J = 6.6 Hz),130.89 (2C), 127.64 (d, J = 4.7 Hz), 126.41 (d, J = 14.6 Hz), 126.19 (2C), 123.98(2C), 122.16, 120.21 (2C), 113.60 (d, J = 22.4 Hz), 112.15 (2C), 43.64 (d, J =4.2 Hz), 35.18, 28.78 (2C). ESI-HRMS: Calcd for C 23 H 22 FN2O2[M+H] + , 377.1665;found 377.1666.

[0077] Example 41: N -hydroxy-7-(9,9-dimethylacridine-10(9) H )-yl)heptanamide (A41) The preparation method was the same as in Example 4, except that the starting material was replaced with 9,9-dimethyl-9,10-dihydroacridine. The product was a white solid with a yield of 52.96%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.34 (s, 1H), 8.66 (s, 1H), 7.40 (dd, J = 7.7, 1.5 Hz, 2H), 7.19 (ddd, J = 8.4, 7.2, 1.5 Hz, 2H), 7.02 (d, J = 8.1 Hz,2H), 6.94 – 6.90 (m, 2H), 3.94 – 3.88 (m, 2H), 1.96 (t, J = 7.4 Hz, 2H), 1.71(p, J = 7.7 Hz, 2H), 1.52 (p, J= 7.5 Hz, 2H), 1.45 (s, 6H), 1.42 (d, J = 8.0 Hz, 2H), 1.36 – 1.29 (m, 2H). 13 C NMR (151 MHz, DMSO- d 6) δ 168.48, 139.45 (2C), 130.90 (2C), 126.11 (2C), 123.72 (2C), 119.56 (2C), 111.92 (2C), 44.28,35.11, 31.59, 28.23 (2C), 27.76, 25.59, 24.75, 24.53. ESI-HRMS: Calcd forC 22 H 29 N₂O₂[M+H] + , 353.2229; found 353.2234.

[0078] Example 42: N -hydroxy-4-((9) H -pyrido[2,3- b Indole-9-yl)methyl)benzamide (A42) The preparation method is the same as in Example 6, except that the starting material is replaced with 9 H -pyrido[2,3- b Indole. White solid, yield 78.44%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.11 (d, J = 1.9 Hz, 1H), 8.99 (d, J = 2.0 Hz, 1H), 8.60 (dd, J = 7.7, 1.6 Hz, 1H), 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 8.24 (d, J =7.7 Hz, 1H), 7.63 (dd, J = 10.1, 8.3 Hz, 3H), 7.49 (td, J = 7.7, 7.1, 1.2 Hz,1H), 7.32 – 7.27 (m, 4H), 5.77 (s, 2H). 13 C NMR (151 MHz, DMSO- d6) δ 163.39,150.33, 145.60, 140.29, 138.35, 131.32, 128.25, 126.60 (2C), 126.36 (2C),126.30, 120.85, 119.50, 119.36, 115.06, 114.55, 109.45, 43.22. ESI-HRMS:Calcd for C 19 H 16 N3O2[M+H] + , 318.1243; found 318.1247.

[0079] Example 43: N -hydroxy-6-((9) H -pyrido[2,3- b Indole-9-yl)methyl)nicotinamide (A43) The preparation method is the same as in Example 2, except that the starting material is replaced with 9 H -pyrido[2,3- b Indole. White solid, yield 33.79%. 1 H NMR (600 MHz, DMSO- d 6) δ 11.30 (s, 1H), 9.18 (s, 1H), 8.78 (d, J = 2.1Hz, 1H), 8.60 (dd, J = 7.7, 1.6 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.25 (d, J = 7.7 Hz, 1H), 7.98 (dd, J = 8.1, 2.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.49(t, J = 7.7 Hz, 1H), 7.31 – 7.28 (m, 2H), 7.10 (d, J = 8.2 Hz, 1H), 5.86 (s, 2H). 13 C NMR (151 MHz, DMSO- d6) δ 161.83, 158.96, 150.34, 146.99, 145.51, 138.67,135.16, 128.19, 126.81, 126.29, 120.80, 120.11, 119.50, 119.40, 115.08,114.65, 109.45, 45.35. ESI-HRMS: Calcd for C 18 H 15 N4O2[M+H] + , 319.1195; found319.1200.

[0080] Example 44: N -hydroxy-4-((9) H -pyrido[2,3- b Indole-9-yl)methyl)-3-fluorobenzamide (A44) The preparation method is the same as in Example 3, except that the starting material is replaced with 9 H -pyrido[2,3- b Indole. White solid, yield 90.67%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.25 (d, J = 1.7 Hz, 1H), 9.13 (d, J = 1.8 Hz, 1H), 8.60 (dd, J = 7.7, 1.6 Hz, 1H), 8.49 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (d, J =7.7 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.54 – 7.49 (m, 1H), 7.42 (dd, J = 8.0, 1.7Hz, 1H), 7.33 – 7.29 (m, 2H), 6.93 (t, J = 7.8 Hz, 1H), 5.81 (s, 2H). 13 C NMR (101 MHz, DMSO-) d 6) δ 161.99, 158.98 (d, J = 245.9 Hz), 150.27, 145.60, 138.39,133.50 (d, J= 7.0 Hz), 128.27, 128.21 (d, J = 4.4 Hz), 126.95 (d, J = 14.9 Hz), 126.41, 122.52 (d, J = 3.2 Hz), 120.90, 119.64, 119.43, 115.20, 114.67, 113.36(d, J = 23.0 Hz), 109.23, 37.70 (d, J = 4.2 Hz). ESI-HRMS: Calcd for C 19 H 15 FN3O2[M+H] + , 336.1148; found 336.1153. Retention time 3.187 min, HPLC purity =98.42%.

[0081] Example 45: N -hydroxy-7-(9 H -pyrido[2,3- b Indole-9-yl)heptanamide (A45) The preparation method is the same as in Example 4, except that the starting material is replaced with 9 H -pyrido[2,3- b Indole. White solid, yield 55.79%. 1 H NMR (600 MHz, DMSO- d 6) δ 10.31 (s, 1H), 8.64 (s, 1H), 8.54 (dd, J =7.6, 1.6 Hz, 1H), 8.48 (dd, J = 4.8, 1.6 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.53 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 7.6, 4.8 Hz, 1H), 4.46 (t, J = 7.2 Hz, 2H), 1.90 (t, J= 7.4 Hz, 2H), 1.80 (p, J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 2H), 1.32 – 1.25 (m, J = 5.2, 4.4 Hz, 4H). 13 C NMR (151 MHz, DMSO- d 6) δ 168.45, 150.30, 145.36, 138.49,127.93, 126.13, 120.71, 119.12, 118.99, 114.47, 114.34, 109.14, 40.17, 31.56,27.67, 27.64, 25.53, 24.40. ESI-HRMS: Calcd for C 18 H 22 N3O2[M+H] + , 312.1712; found 312.1713. Retention time 3.042 min, HPLC purity = 95.16%.

[0082] Example 46: Pharmacological study of the compounds of the present invention Pharmacological tests have demonstrated that the compounds provided by this invention have therapeutic activity for idiopathic pulmonary fibrosis.

[0083] (1) Tests on the inhibitory activity and selectivity of compounds A1~A45 against HDAC6 The inhibitory activity of compounds A1-A45 against HDAC6 and their selectivity for other HDAC isotypes were tested using substrate-enzyme binding assays.

[0084] Recombinant human HDAC1, 2, 4, 6, 7, 10, and 11 proteins were purchased from BPS Bioscience, USA. All reactions were performed in the black half of a 96-well microplate. Recombinant HDAC proteins were diluted to 1 µg / mL with experimental buffer, using Boc-Lys(Ac)-AMC (for HDAC1, 2, 6, and 10) and Boc-Lys(Tfa)-AMC (for HDAC4, 7, and 11) as substrates. HDACs were mixed with 20 μL of samples at different concentrations in a 96-well plate, followed by the addition of 20 μL of fluorescent substrate. After incubation at 37°C for 120 min, 50 μL of developing agent was added to each well, and the plate was incubated at 37°C for 30 min to develop the fluorescence signal. The fluorescence intensity of each well was measured at an excitation wavelength of 355 nm and an emission wavelength of 460 nm. Enzyme binding inhibition could be observed by comparing fluorescence intensities.

[0085] The test results are shown in Tables 1 and 2.

[0086] Table 1. Inhibitory activity of compounds A1-A45 against HDAC6

[0087] *Positive control drug.

[0088] Table 2. Selectivity test of preferred active compounds A3, A34, A36, A42 and A44 for HDAC isotypes

[0089] *Data are expressed as mean ± standard deviation of three independent experiments.

[0090] (2) Toxicity test of compounds A42 and A44 on HELF cells HELF cells were cultured in MEM medium containing 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin at pH 7.23. The cells used in the above experiments were then cultured in a 37 ℃ incubator (conditions: 5% CO2, saturated humidity).

[0091] MTT assay for the inhibitory effect of drugs on cell proliferation: The cells were passaged to the logarithmic growth phase, digested normally with 0.25% trypsin, and then prepared into a cell suspension using FBS-free or FBS-containing medium. The suspension was then cultured at 6 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of 100 µL / mL in 96-well plates. After 12 h of culture, the original medium was aspirated, and culture medium containing serially diluted drug was immediately added. The control group was replaced with culture medium containing an equal volume of DMSO. The cells were then placed in an incubator for further culture. After 48 h, the culture medium in the 96-well plates was aspirated, and 100 µL of culture medium containing 10% MTT (5 mg / mL) was immediately added. The plates were then incubated for another 4 h. After incubation, the original medium in the wells was discarded, and 150 µL of DMSO was immediately added. The cell culture plates were shaken for 10 min, and the absorbance (OD) value was measured at 492 nm using a microplate reader. Finally, the cell proliferation inhibition rate was calculated using the following formula:

[0092] Test results are as follows Figure 1 As shown.

[0093] (3) Inhibition test of compounds A42 and A44 on HDAC6 activity in HELF cells during TGF-β1-induced in vitro pulmonary fibrosis After normal digestion of the cells in the culture flasks, they were seeded into 6-well plates and incubated for 12 h until adherence. The original liquid in the wells was removed using a pipette, and culture medium containing serially diluted drugs was added. After 48 h of cell culture, the cells were removed and placed on an ice pack, and the surface was washed with PBS buffer. 50 μL of pre-prepared cell lysis buffer was added evenly to each well, and the plates were incubated on ice for 10 min. The fully lysed cells were then collected using a scraper and centrifuged at 4°C for 15 min (14000 rpm). After centrifugation, the supernatant was quickly transferred to a 0.5 mL EP tube using a pipette, taking care not to touch the precipitate. The sample concentration was quantified using a BCA kit. The sample protein concentration was uniformly diluted with cell lysis buffer. Then, 30 μL of protein sample and 20 μL of Ac-Lys(Ac)-AMC fluorescent substrate (final concentration 400 μM per well) were added to each well of a black 96-well plate, and the plates were incubated at 37°C for 120 min. Then, 50 μL of the stop solution was added to each well using a pipette, and the reaction was stopped by incubation at 37°C for 15 min. The intensity of the fluorescence generated during the reaction was detected using an ELISA reader (Ex: 380 nm, Em: 460 nm).

[0094] Experimental results are as follows Figure 2 As shown.

[0095] (4) Effects of compounds A42 and A44 on changes in the expression of HDAC6-related substrate proteins in HELF cells during TGF-β1-induced in vitro pulmonary fibrosis. 1) Extraction of total protein and quantification of protein concentration Pre-prepared RIPA high-efficiency lysis buffer with 1% PMSF was added. Cells were placed on ice and washed with PBS. After removing the liquid from the wells with a pipette, 100 µL of the pre-prepared lysis buffer was added evenly and incubated on ice for 10 min. Cells were scraped from the culture dish using a scraper and collected into pre-chilled EP (1.5 mL) tubes, followed by centrifugation at 4°C for 15 min (12000 rpm). After centrifugation, the supernatant was transferred into pre-chilled 0.5 mL EP tubes and quantified using a BCA kit.

[0096] 2) Sample preparation Add protein loading buffer (5×) to the extracted protein supernatant in proportion, boil in a water bath for 10 min, and store at -20℃ after cooling to room temperature. Avoid repeated freeze-thaw cycles on the sample.

[0097] 3) SDS-PAGE gel electrophoresis a. Gel Preparation: According to the preparation methods for gels of different concentrations, add the corresponding solvents in sequence to clean centrifuge tubes, mix thoroughly, and immediately add to the assembled gel casting plate. Then, evenly add isopropanol and press the gel surface flat. After the gel solidifies, remove the isopropanol. Prepare the upper gel using the same method. After adding the glass casting plate, quickly insert the comb into the middle of the glass plate, ensuring no air bubbles are generated. After the upper gel solidifies, transfer the casting plate to the electrophoresis apparatus, pour in 1× electrophoresis buffer, and evenly pull the comb vertically out, ensuring the gel does not deform.

[0098] b. Electrophoresis: Based on the quantified protein concentration, ensure the total amount of protein sample loaded into each well is the same (10-30 µg) to calculate the actual sample weight for each well. After loading the protein samples, set the electrophoresis apparatus to 60 V and run for 40 min, then adjust to 90 V and continue running for approximately 60 min, until bromophenol blue is observed at the bottom of the glass gel plate, at which point electrophoresis is terminated.

[0099] c. Transfer: Using the wet transfer method, place the gel and PVDF membrane between two layers of filter paper, wrap each layer of filter paper with a layer of sponge, and remove any air bubbles between the layers. Place the fixed transfer clamp into the electroporator, place small ice packs in the gaps, and slowly pour in 1× transfer buffer. Then set the voltage of the electroporator to 100 V and perform electroporation at a low temperature of 4℃. Adjust the transfer time flexibly according to the different molecular weights of the target protein.

[0100] d. Antibody incubation: After transfer, place the PVDF membrane in the pre-prepared blocking buffer and block on a shaker for 1 hour. Wash with 1 × TBST and incubate overnight at 4°C with diluted primary antibody. The next day, wash the membrane and add diluted secondary antibody, then incubate on a shaker at room temperature for another 1 hour.

[0101] e. Development: Using a gel imaging system, ECL luminescent solution is uniformly dropped onto the PVDF membrane, and the protein bands are then developed.

[0102] Test results are as follows Figure 3 As shown.

[0103] (5) Effects of compounds A42 and A44 on the expression of fibrosis-related substrates in HELF cells during TGF-β1-induced in vitro pulmonary fibrosis. The testing method is the same as (4).

[0104] Test results are as follows Figure 4 As shown.

[0105] (6) Changes in body weight of mice in each group during the in vivo pulmonary fibrosis model test Construction of a pulmonary fibrosis model: Forty-eight C57BL / 6J mice were randomly divided into eight groups: control group, BLM model group, nintedanib group, Tubastatin A group, A42 gavage group, A42 intraperitoneal injection group, A44 gavage group, and A44 intraperitoneal injection group.

[0106] Mice were anesthetized with 1% sodium pentobarbital and suspended on a rack. The mouse's tongue was gently pulled out with forceps. When alternating light and dark openings appeared in the trachea, a 22G cannula was inserted (the up-and-down movement of the water column indicates that the cannula has been inserted into the trachea). Then, BLM (3.5 mg / kg) was slowly injected using a syringe. The mouse was rotated from side to side to ensure that the BLM was evenly distributed in the lungs (for mice weighing 15-19 g, the insertion depth was 38 mm; for mice weighing 20-25 g, the insertion depth was 39 mm).

[0107] Drug preparation: A42 and A44 were first added to 1% DMSO, followed by normal saline, and sonicated for 5 minutes. Nintedanib and Tubastatin A were dissolved directly in normal saline.

[0108] Dosage: The dosage for the Nintedanib group, Tubastatin A group, A42 gavage group, A42 intraperitoneal injection group, A44 gavage group, and A44 intraperitoneal injection group was 50 mg / kg. The remaining groups were given drug-free solvents.

[0109] Administration method: According to the experimental design, administration was divided into gavage and intraperitoneal injection, once a day for 28 consecutive days.

[0110] Test results are as follows Figure 5 As shown in (A).

[0111] (7) Effects of compounds A42 and A44 on pathological changes in lung tissue of mice with pulmonary fibrosis model Paraffin section preparation and dewaxing and rehydration: 1) Dehydration: The lung tissue obtained by perfusion was placed in a tissue embedding box and incubated overnight with running water. Then, dehydration was carried out by sequentially soaking the tissue in 70%, 80% and 90% ethanol solutions for 1 hour each, and then soaking it in 95% and 100% ethanol solutions for 2 hours and 1 hour respectively. 2) Transparent: Place in xylene I and xylene II for 15 min each; 3) Wax impregnation: Dehydrated and transparent lung tissue is immersed in molten paraffin wax for impregnation; 4) Embedding: Embedding is performed using a biological tissue embedding machine; 5) Cut the embedded tissue into 5 μm thick paraffin sections using a paraffin microtome, and dry and preserve them; Dewaxing and rehydration: Soak in xylene I and xylene II for 15 min → Soak in anhydrous ethanol I and anhydrous ethanol II for 5 min → Soak in 95% ethanol, 85% ethanol, and 75% ethanol for 5 min → Rinse with running water for 2 min.

[0112] H&E staining: 1) Bake lung slices in a 60℃ oven for 1 hour; 2) Dewax and rehydrate using the method described above; 3) Hematoxylin staining: Place the lung sections in hematoxylin for 30 seconds and then rinse with running water for 2 minutes; 4) Hydrochloric acid-alcohol differentiation: Place the sections in hematoxylin differentiation solution for extraction 2-3 times, then rinse with running water for 2 minutes; 5) Blueing: Place the lung slices in the blueing solution for extraction twice, then rinse with running water for 2 minutes; 6) Eosin staining: Place the lung sections in eosin staining solution for 40 seconds and then rinse with running water for 2 minutes; 7) After rinsing the lung slices, immerse them in anhydrous ethanol II and anhydrous ethanol I for 2 min each, and then immerse them in xylene II and xylene I for 10 min each. 8) After mounting with neutral resin, observe and photograph using an upright microscope.

[0113] Test results are as follows Figure 5 (B) Figure 5 (C) Figure 5 As shown in (E).

[0114] (8) Effects of compounds A42 and A44 on HDAC6 activity in lung tissue of mice with pulmonary fibrosis model Take an appropriate amount of lung tissue and place it into a 1.5 mL EP tube. Add 1 mL of RIPA lysis buffer per 0.1 g of tissue. Homogenize the tissue using an ultrasonic homogenizer and centrifuge at 12,000 rpm for 15 min. Then, transfer the supernatant to a 0.5 mL EP tube and quantify the protein concentration to 5 mg / mL. Add 30 μL of protein sample and 20 μL of Boc-Lys(Ac)-AMC fluorescent substrate to each well of the microplate and incubate at 37°C for 120 min. Add 50 μL of stop solution to the well and incubate at 37°C for another 15 min. Detect the fluorescence intensity using a microplate reader.

[0115] Test results are as follows Figure 5 As shown in (D).

[0116] (9) Effects of compounds A42 and A44 on changes in relevant biomarkers in lung tissue of mice with pulmonary fibrosis model 1) Dewaxing and rehydration were performed according to method (8); 2) Antigen retrieval: Prepare a sodium citrate buffer solution with pH=6 using citric acid and sodium citrate in a beaker. Place the lung slices in the beaker and heat in a microwave oven for 20 min (7 min on high and 13 min on low). After cooling to room temperature, wash three times with PBS solution for 5 min each time. 3) Blocking endogenous catalase: Draw a circle around the lung slice with a histochemical pen, add H2O2 from the kit to the lung slice, place it in a humidified chamber and incubate at room temperature for 10-15 min, wash three times with PBS for 5 min each time; 4) Blocking: Prepare a blocking solution containing 0.3% Triton X-100, add the blocking solution dropwise, place the sections in a humidified chamber and incubate in a 37°C oven for 1 h; 5) Primary antibody incubation: Discard the blocking solution, add the prepared primary antibody dropwise onto the lung slices, and incubate overnight at 4°C. 6) Secondary antibody incubation: The next day, remove the humidified chamber, warm it to room temperature, and wash with PBST solution for 5 × 5 min. Take the HRP-labeled IgG secondary antibody from the immunohistochemistry kit, add it to the lung slices, place them in a humidified chamber, and incubate at 37°C for 1 h. Wash with PBST solution 5 times, 5 min each time. 7) DAB reaction: Prepare fresh DAB solution and add it dropwise to the lung slices. After the color turns slightly yellow, rinse with running water for 5 minutes. 8) Hematoxylin counterstaining: Place the lung sections in hematoxylin for 30 seconds and rinse with running water for 5 minutes; 9) Hydrochloric acid alcohol differentiation: The lung slices were placed in hematoxylin differentiation solution for extraction and then rinsed with running water for 5 min; 10) Mounting: Place lung tissue sections in 75%, 85%, and 95% alcohol for 5 min each, then in xylene I and xylene II for 15 min each, and add a small amount of neutral resin to mount. 11) Photography: Observe and photograph using an upright microscope.

[0117] Test results are as follows Figure 6 As shown.

[0118] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. If such modifications and variations fall within the scope of this invention and its equivalents, then this invention is also intended to include such modifications and variations.

Claims

1. A nitrogen-containing aromatic fused-ring compound of general formula I or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula is: in: R is derived from: (1) hydroxyl, (2) amino, (3) methylamino; Rings A and B are each derived from any one of the following groups: (1) benzene ring, (2) pyridine ring, (3) pyrrole ring, (4) indole ring, (5) quinoline ring, (6) isoquinoline ring, (7) 1,2,3,4-tetrahydroquinoline ring, (8) 1,2,3,4-tetrahydroisoquinoline ring, (9) tetrahydropyrrole ring, (10) morpholine ring, (11) caprolactam ring, (12) cyclohexylimine ring, (13) azaheptan-4-one ring, (14) 1,2,3,4-tetrahydrobenzo[b]azaheptan-5-one ring, (15) piperidine ring, (16) piperazine ring, (17) acridine ring, (18) 9H-pyrido[2,3- b] Indole ring, (19) 1-methyl-1,2,3,4-tetrahydroisoquinoline ring, (20) 1-phenyl-1,2,3,4-tetrahydroisoquinoline ring, (21) 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline ring, (22) 4,4-dimethyl-1,2,3,4-tetrahydroquinoline ring, (23) 1,2,3,4-tetrahydrobenzo(e)(1,4)diaza-5-one ring, (24) thiophene ring, (25) oxazole ring, (26) pyrazole ring, (27) imidazole ring, (28) thiazole ring, (30) cyclohexane ring, and each of the above groups may be arbitrarily replaced by one or more: hydrogen atom, halogen atom, C 1-6 Alkyl, C 1-6 Alkylamino, C 3-7 cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylsulfonylamino, benzyloxycarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 It is substituted by one or more substituents selected from alkoxysulfonyl, trihalomethyl, hydroxy, cyano, nitro, amino, phenyl, and benzyl; The C ring exists only under specific conditions and is derived from any one of the following groups: (1) benzene ring, (2) pyridine ring, (3) pyrrole ring, (4) pyran ring, (5) morpholine ring, (6) piperidine ring, and each of the above groups may be arbitrarily replaced by one or more of the following: hydrogen atom, halogen atom, C ring. 1-6 It is substituted by one or more substituents selected from alkyl, trihalomethyl, hydroxy, cyano, nitro, amino, phenyl, and benzyl; X is derived from: (1) methylene, (2) nitrogen atom, (3) oxygen atom, (4) sulfur atom; Y is derived from: (1) methylene, (2) nitrogen atom, (3) oxygen atom, (4) sulfur atom, (5) amide bond, (6) carbonyl group; Linker is taken from: (1)C 4-8 Alkyl, (2) substituted with various phenyl groups, substituted with various benzyl groups, substituted with various benzyloxy groups, substituted with various benzoyl groups, substituted with various pyridyl groups, wherein each of the above groups is substituted with one or more substituents selected from hydrogen atoms, halogen atoms, trihalomethyl groups, hydroxyl groups and amino groups.

2. The nitrogen-containing aromatic fused-ring compound or its pharmaceutically acceptable salt according to claim 1, characterized in that, The nitrogen-containing aromatic fused-ring compounds are selected from the following compounds: 。 3. A method for preparing a nitrogen-containing aromatic fused-ring compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: Aromatic fused-ring compounds with secondary or primary amines are used as starting materials and undergo substitution or acylation reactions with methyl halogenated carboxylic acids or acyl chlorides with terminal methyl esters under alkaline conditions to obtain intermediate M1. M1 undergoes ammonolysis reaction with hydroxylamine under alkaline conditions to obtain the compound shown in general formula I. 。 4. The preparation method according to claim 3, characterized in that, The R group is the corresponding group at the corresponding position in compounds A1~A45; Derived from the following compounds: Derived from the following structure: The linker group is derived from the following structure: Reagents and conditions: In step i: methyl 4-bromomethylbenzoate or methyl 6-bromomethylnicotinate or methyl 3-fluoro-4-(bromomethyl)benzoate, K2CO3, KI, anhydrous DMF, room temperature; or methyl 4-chloroformylbenzoate, triethylamine, anhydrous DCM, 0°C; or methyl 7-bromoheptanoate, K2CO3, KI, anhydrous DMF, room temperature to 120°C; or monomethyl octanoate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, triethylamine, anhydrous DMF, room temperature; In step ii: hydroxylamine aqueous solution, NaOH, a mixed solvent of THF and MeOH, 0°C.

5. A pharmaceutical composition, characterized in that, It comprises the nitrogen-containing aromatic fused-ring compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A pharmaceutical preparation, characterized in that, The pharmaceutical composition comprising claim 5, wherein the dosage form of the pharmaceutical formulation is selected from one or more of the following: tablets, capsules, injections, suppositories, patches, inhalable powder formulations, suspensions, emulsions, and ointments.

7. The use of the nitrogen-containing aromatic fused-ring compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, or the pharmaceutical formulation of claim 6, in the preparation of an HDAC6 inhibitor.

8. The use of the nitrogen-containing aromatic fused-ring compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, or the pharmaceutical formulation of claim 6, in the preparation of an anti-idiopathic pulmonary fibrosis drug.

9. The application according to claim 7, characterized in that, The anti-idiopathic pulmonary fibrosis drug has activity against the occurrence and progression of idiopathic pulmonary fibrosis.

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