Quinoline SIRT3 inhibitor as well as preparation method and application thereof

Abstract

The invention provides a quinoline SIRT3 inhibitor as well as a preparation method and application thereof. According to the invention, a 2-phenyl-quinoline structure is used as a skeleton mother nucleus, an active fragment 4-(4-methylpiperazine-1-yl) aniline is introduced into a 4-carboxyl group, different carboxyl substituent groups are introduced into a para-amino group of a 2-phenyl group to form an amide, and a compound shown as a formula I is synthesized. Experiments prove that the inhibition activity of part of quinoline compounds on SIRT3 is superior to that of a positive control drug (an inhibitor niacinamide), and the quinoline compounds can be used as lead compounds for developing a novel efficient SIRT3 inhibitor. In addition, the compound shows good activity in an in-vitro anti-tumor cell proliferation test, and has a relatively great development prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry and relates to quinoline SIRT3 inhibitors and preparation methods and applications thereof. Background Art

[0002] Histone deacetylases (HDACs) are a class of hydrolytic enzymes with complex functions. In the cell nucleus, nucleosomes, composed of histone octamers wrapped around DNA, are the structural units of chromosomes. Histone deacetylases (HDACs) hydrolyze acetyl groups from the terminal amino groups of lysine residues in histones (see Reaction Equation 1), increasing the positive charge density of histones and, in turn, enhancing their affinity for negatively charged DNA, leading to the repression of gene transcription. Furthermore, deacetylation of nucleosomal histones is closely linked to chromatin assembly, DNA repair, and recombination. Recently, an increasing number of non-histone proteins, such as transcription factors, cytoskeletal proteins, and molecular chaperones, have been identified as substrates for HDACs. Precisely because of the complex functions of HDACs, dysregulated expression and activity of HDACs are closely associated with numerous diseases, including cancer, neurodegenerative diseases, viral infections, inflammation, leukemia, malaria, and diabetes. Cancer is undoubtedly the most serious threat to human health. Studies have shown that HDACs are closely related to the occurrence and development of tumor cells, such as inhibiting tumor cell differentiation and apoptosis, promoting tumor cell proliferation, migration and angiogenesis, and enhancing tumor cell resistance to chemotherapy drugs.

[0003]

[0004] Reaction Formula I Currently, 18 members of the HDACs family have been found in the human body, which can be divided into four categories according to their structure, function and distribution. Among them, class I (HDAC1, 2, 3 and 8), class II (IIa: HDAC4, 5, 7 and 9; IIb: HDAC6, 10), and class IV (HDAC11) are zinc ion-dependent hydrolases, while class III HDACs (SIRT 1-7) are NAD + Research has shown that zinc-dependent HDACs are closely associated with tumors. HDAC inhibitors (HDACi) can effectively inhibit cancer cell proliferation and promote apoptosis. Furthermore, HDACi have the advantages of a broad anti-tumor spectrum and low toxicity and side effects, showing strong inhibitory activity against solid tumors, leukemias, and lymphomas. Therefore, the design of inhibitors targeting HDACs has become a hot topic in anti-tumor drug research.

[0005] As class III HDACs, Sirtuins are a class of NAD +Seven enzymes in this family of Sirtuins (SIRT1-7) are known to play important roles in cellular regulation. They are involved in a variety of cellular and tissue functions, such as regulating oxidative stress, repairing DNA, increasing genomic stability, and influencing apoptosis, development, metabolism, and aging. SIRT3, a member of the Sirtuins primarily located in mitochondria, has recently attracted significant attention due to its potent mitochondrial deacetylase activity and its ability to target multiple metabolic pathways within mitochondria, playing a crucial role in regulating normal cellular metabolism and function. Mitochondria are the primary site of energy metabolism in cells and participate in numerous biological functions, such as energy conversion, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. It is currently believed that approximately 35% of mitochondrial proteins are deacetylated, with SIRT3 playing a key role.

[0006] Inhibiting SIRT3 and regulating tumor cell metabolism has become a hot topic in the development of new anti-tumor drugs. Current SIRT3 inhibitors have shown significant potential in the treatment of tumor types such as leukemia. However, the development of SIRT3 inhibitors is still in its infancy, with a lack of active molecules entering clinical research. Moreover, existing SIRT3 inhibitors lack structural diversity, and subtype-selective skeletons are rarely reported. Therefore, there is an urgent need to develop active SIRT3 inhibitor molecules with novel structures to provide new therapies for the treatment of tumors, especially leukemia. Summary of the Invention

[0007] To address the shortcomings of the existing technology, the present invention provides quinoline SIRT3 inhibitors, their preparation methods, and applications. This invention utilizes a 2-phenyl-quinoline structure as a core skeleton. The active fragment 4-(4-methylpiperazin-1-yl)aniline is introduced at the 4-carboxyl group. Various carboxyl substituents are then introduced at the para-amine group of the 2-phenyl group to form amides to synthesize the target derivatives. Experimental studies have demonstrated that some of the quinoline compounds described in this invention exhibit superior SIRT3 inhibitory activity compared to the positive control drug (nicotinamide), suggesting their potential as lead compounds for the development of novel, highly effective SIRT3 inhibitors. Furthermore, these compounds have demonstrated promising activity against tumor cell proliferation in vitro, demonstrating their promising development prospects.

[0008] The technical solution of the present invention is as follows: a quinoline SIRT3 inhibitor as shown in structural formula I, and a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof.

[0009]

[0010] Where R can be: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Any of .

[0011] Specifically, the quinoline SIRT3 inhibitor is one of the following compounds: 2-(4-(3-bromobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G1); 2-(4-(2-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G2); 2-(4-(4-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G3); N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(4-(trifluoromethoxy)benzamido)phenyl)quinoline-4-carboxamide (G4); 2-(4-(4-ethylbenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G5); 2-(4-(2-chlorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G6); 2-(4-(3-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G7); 2-(4-Benzamidophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G8); 2-(4-cinnamamidophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G9); N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(3-nitrobenzamido)phenyl)quinoline-4-carboxamide (G10); N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(2-(trifluoromethyl)benzamido)phenyl)quinoline-4-carboxamide (G11); 2-(4-(3,5-difluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G12); 2-(4-(4-ethynylbenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G13); 2-(4-(3-chlorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G14); 2-(4-(2,4-difluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G15); 2-(4-(4-bromo-2-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G16); 2-(4-(4-(4-fluoro-2-(trifluoromethyl)benzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G17); 2-(4-(3-chloro-4-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G18); 2-(4-(3,5-dichlorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G19); 2-(4-(2-Chloro-4-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G20).

[0012] The terms and definitions used above have the following meanings: "Pharmaceutically acceptable salts" refer to salt forms of compounds that are therapeutically effective and non-toxic. They can form anionic salts with any acidic group (such as a carboxyl group) or cationic salts with any basic group (such as an amino group). Many such salts are known in the art, including cationic salts formed on any acidic group (such as a carboxyl group) or anionic salts formed on any basic group (such as an amino group). Many of these salts are known in the art, such as cationic salts including salts of alkali metals (such as sodium and potassium) and alkaline earth metals (such as magnesium and calcium) and organic salts (such as ammonium salts). Anionic salts can also be obtained by treating the compound of Formula I with a corresponding acid, including inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-propanetriol, methanesulfonic acid, ethanesulfonic acid, benzenemethylsulfonic acid, 4-methylbenzenesulfonic acid, cyclohexylsulfinic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like. These salts are well known to those skilled in the art, and those skilled in the art can prepare any salt provided by knowledge in the art. Furthermore, those skilled in the art may prefer one salt over another based on factors such as solubility, stability, and ease of formulation. The determination and optimization of these salts are within the skill of the art.

[0013] "Prodrug" refers to a compound that is obtained by chemically modifying a drug and is inactive or has low activity in vitro, but releases active drugs through enzymatic or non-enzymatic conversion in the body to exert its pharmacological effect.

[0014] The compound represented by structural formula I may also exist in other protected forms or derivative forms, which are obvious to those skilled in the art and should all be included in the scope of the present invention.

[0015] Some derivatives of the present invention can exist in free form or in salt form. Those skilled in the art are aware of pharmaceutically acceptable salts of many compound types and methods for their preparation. Pharmaceutically acceptable salts include conventional non-toxic salts, including quaternary ammonium salts formed from such compound bases and inorganic or organic acids.

[0016] The compounds of the present invention may form hydrates or solvates. Methods for forming hydrates by lyophilizing a compound with water or forming solvates when concentrated in solution with a suitable organic solvent are known to those skilled in the art.

[0017] The present invention further provides a method for preparing quinoline SIRT3 inhibitors, characterized by a Pfitzinger reaction between compound A (diketone indoline) and 1-(4-aminophenyl)ethan-1-one to produce intermediate AH-1. Intermediate AH-1 then reacts with acyl chlorides of different substituents to produce key intermediates MC1-MC20. Finally, MC1-MC20 undergo a condensation reaction with 4-(4-methylpiperazin-1-yl)aniline to produce target compounds G1-G20. The synthetic route is shown below.

[0018]

[0019] Reaction formula II Reagents in the above synthetic route reaction formula: (a) KOH, EtOH, 80-90°C; (b) THF (tetrahydrofuran), rt (room temperature); (c) TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), Et3N, DCM (dichloromethane).

[0020] The specific steps are as follows: (1) Preparation of 2-(4-aminophenyl)-quinoline-4-carboxylic acid (Intermediate AH-1) Dissolve the diketoindoline in a KOH solution, add an ethanol solution of p-aminoacetophenone dropwise, and heat under reflux at 80-90°C for 5-10 hours; remove the solvent using a rotary evaporator, then dilute the concentrate with water and adjust the pH to 5-6 with an acid. A large amount of solid precipitates, which is filtered to obtain 2-(4-aminophenyl)-quinoline-4-carboxylic acid; (2) Preparation of key intermediates MC1-MC20 Dissolve 2-(4-aminophenyl)-quinoline-4-carboxylic acid in tetrahydrofuran and add NaHCO3 in an ice bath. After 10-30 minutes, remove the ice bath and add acyl chlorides with different substituents. Allow to react at room temperature for 3-5 hours. After the reaction, remove the solvent using a rotary evaporator, add water, and filter to obtain the key intermediates MC1-MC20. (3) Preparation of target compounds G1-G20 The key intermediates MC1-MC20 were dissolved in dichloromethane, and Et3N and TBTU were added in an ice bath. After 10-30 minutes, the ice bath was removed, 4-(4-methylpiperazin-1-yl)aniline was added, and the reaction was carried out at room temperature for 5-10 hours. After completion of the reaction, the target compounds G1-G20 were obtained by post-treatment.

[0021] The above post-treatment is as follows: remove the solvent with a rotary evaporator, dissolve the product in ethyl acetate, wash with saturated sodium bicarbonate and saturated brine in sequence, dry with anhydrous magnesium sulfate, filter, evaporate the solvent to obtain a crude product, and recrystallize the crude product from ethyl acetate to obtain the target compound G1-G20.

[0022] The in vitro enzyme inhibition test of the compound represented by general formula I proved that the compound is an effective SIRT3 inhibitor. Then the MTT method further verified that multiple quinoline SIRT3 inhibitors showed good anti-tumor activity in the in vitro anti-tumor cell proliferation test.

[0023] The present invention also provides the use of a compound of Formula I in the preparation of a medicament for preventing or treating mammalian diseases associated with abnormal SIRT3 activity expression. The mammalian diseases associated with abnormal SIRT3 activity expression include cancer, neurodegenerative diseases, viral infections, inflammation, and diabetes.

[0024] Therefore, the present invention also relates to a pharmaceutical composition containing the compound represented by general formula I.

[0025] The pharmaceutical composition of the present invention comprises a therapeutic amount of a compound represented by formula I and one or more pharmaceutically acceptable carriers and / or excipients.

[0026] The pharmaceutical carrier used in the present invention can be solid or liquid.

[0027] Typical solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, and the like. A solid carrier may include one or more substances that may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, or tablet-disintegrant; it may also be an encapsulating material. In powders, the carrier is a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins.

[0028] Typical liquid carriers include syrups, peanut oil, olive oil, water, and the like. Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, tinctures, and sealed compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers, or osmotic pressure-regulating agents. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives such as those described above, such as cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric and polyhydric alcohols, such as ethylene glycol) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). Carriers for parenteral administration can also be oils and fats such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used for sterile liquid compositions for parenteral administration. The liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. Sterile solutions or suspensions of liquid pharmaceutical compositions can be administered, for example, intravenously, intramuscularly, intraperitoneally, or subcutaneously. Injections can be administered as a single bolus or gradually over a 30-minute intravenous infusion. The compounds can also be administered orally as liquid or solid compositions.

[0029] The carrier or excipient may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate, and may also include waxes, ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate, and the like.

[0030] A wide variety of pharmaceutical forms can be used when administering the compounds of this invention. If a solid carrier is used, the formulation can be in the form of a tablet, a powder placed in a hard capsule, a pellet, a lozenge, or a troche. The amount of solid carrier varies widely, but preferably ranges from about 25 mg to about 1.0 g. If a liquid carrier is used, the formulation can be in the form of a syrup, an emulsion, a soft capsule, a sterile injectable solution or suspension in an ampoule, a vial, or a non-aqueous liquid suspension.

[0031] To obtain a stable, water-soluble dosage form, the compound or its pharmaceutically acceptable salt can be dissolved in an aqueous solution of an organic or inorganic acid, 0.3 M succinic acid or citric acid solution. Alternatively, acidic derivatives can be dissolved in a suitable alkaline solution. If a soluble form is not available, the compound can be dissolved in a suitable cosolvent or a combination thereof. Examples of such suitable cosolvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, polyoxyethylene fatty acid esters, fatty alcohols, or glycerol hydroxy fatty acid esters, etc., in concentrations ranging from 0-60% of the total volume.

[0032] The invention relates to a kind of compound of the present invention and its invention relates to a kind of compound of the present invention.The compound of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.The pharmaceutical composition of the present invention comprises the pharmaceutical composition of the present invention and its preparation.

[0033] Experimental studies have demonstrated that some of the quinoline compounds described in this invention exhibit superior SIRT3 inhibitory activity compared to the positive control drug (nicotinamide), making them promising candidates for the development of novel, highly effective SIRT3 inhibitors. Furthermore, these compounds have demonstrated promising activity against tumor cell proliferation in vitro, demonstrating their potential for development. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the principle diagram of enzyme activity test. In the figure, NAD + AMC is nicotinamide adenine dinucleotide, trypsin is trypsin, and AMC is 4-amino-7-methylcoumarin. DETAILED DESCRIPTION

[0035] The present invention will be further described below with reference to the embodiments, but is not limited thereto.

[0036] Example 1: Synthesis of quinoline SIRT3 inhibitor (G1) (1) Preparation of 2-(4-aminophenyl)-quinoline-4-carboxylic acid Dissolve 0.45 g (3.4 mmol) of the diketoindoline in 10 mL of 33% KOH solution. Slowly add 20 mL of a solution of 0.51 g (3.74 mmol) of p-aminoacetophenone in ethanol dropwise. Heat under reflux at 85°C for 8 h. Remove the solvent using a rotary evaporator, dilute the concentrate with 100 mL of water, and adjust the pH to 5-6 with 3 mol / L HCl. A large amount of solid precipitates, which is filtered to yield 0.35 g of a red solid. Yield: 39%. ESI-MS m / z: 265.09 [M+H] + .

[0037] (2) Preparation of 2-(4-(3-bromobenzamido)phenyl)quinoline-4-carboxylic acid 0.35 g (1.32 mmol) of 2-(4-aminophenyl)-quinoline-4-carboxylic acid was dissolved in 20 mL of THF. 0.33 g (3.97 mmol) of NaHCO₃ was added in an ice bath. After 20 minutes, the ice bath was removed and 0.32 g (1.46 mmol) of 3-bromobenzoyl chloride was added. The reaction was continued at room temperature for 4 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the product was filtered with water to obtain 0.44 g of a yellow solid. Yield: 74%. ESI-MS m / z: 447.03 [M+H]. + .

[0038] (3) Preparation of 2-(4-(3-bromobenzylamino)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide 0.32 g (0.72 mmol) of 2-(4-(3-bromobenzamido)phenyl)quinoline-4-carboxylic acid was dissolved in 20 mL of anhydrous dichloromethane. Under ice-cooling conditions, 0.08 g (0.79 mmol) of Et3N and 0.25 g (0.79 mmol) of TBTU were added. After 20 minutes, the ice-cooling bath was removed, and 0.165 g (0.79 mmol) of 4-(4-methylpiperazin-1-yl)aniline was added. The reaction was continued at room temperature for 8 hours. After the reaction, the solvent was removed using a rotary evaporator, and the product was dissolved in 100 mL of ethyl acetate. The product was washed sequentially with saturated sodium bicarbonate (3 × 50 mL) and saturated brine (1 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to obtain the crude product. The crude product was recrystallized from ethyl acetate to obtain 0.23 g of a white solid (Compound G1). Yield: 52%. ESI-MS m / z: 620.16 [M+H + ].

[0039] The preparation method of G2~G20 refers to Example 1, except that 3-bromobenzoyl chloride is replaced by acyl chlorides with different substituents.

[0040] Those skilled in the art may modify the above steps to improve yield. They may determine the synthetic route based on basic knowledge in the art, such as selecting reactants, solvents, and temperatures, and may use various conventional protecting groups to prevent side reactions and thereby improve yield. These conventional protection methods can be found, for example, in T. Greene, Protecting Groups in Organic Synthesis.

[0041] HRMS of each compound, 1 H NMR and 13 C NMR data are shown below.

[0042] Compound G1: HRMS C 34H 30 BrN5O2[M+H + calculated 620.16164, found 620.16144. 1 1H NMR (400 MHz, DMSO) δ 10.61 (d, J J = 13.4 Hz, 2H), 9.84 – 9.76 (m, 1H), 8.42 (d, J J = 8.1 Hz, 2H), 8.32 (s, 1H), 8.21 (s, 1H), 8.19 – 8.11 (m, 2H), 8.02 (d, J J = 8.5 Hz, 3H), 7.85 (t, J J = 7.6 Hz, 2H), 7.68 (d, J J = 8.6 Hz, 2H), 7.64 (d, J J = 7.6 Hz, 1H), 7.54 (t, J J = 7.7 Hz, 1H), 7.00 (d, J J = 8.4 Hz, 2H), 3.16 (s, 4H), 2.55 (s, 4H), 2.29 (s, 3H). 13 13C NMR (101 MHz, DMSO) δ 165.22, 164.64, 155.74, 148.67 – 148.53, 148.31, 143.72, 137.40, 133.91, 131.21, 130.79, 128.29, 127.45, 125.66, 122.21, 121.55, 120.82, 116.11, 54.91, 48.73, 45.98。

[0043] Compound G2: HRMS C 34 H 30 FN5O2[M+H + calculated 560.24171, found 560.24420. 1 1H NMR (400 MHz, DMSO) δ 10.65 (d, J J = 25.5 Hz, 2H), 8.41 (d, J J = 8.3 Hz, 2H), 8.31 (s, 1H), 8.16 (d, J J = 8.3 Hz, 2H), 7.96 (d,J = 8.3 Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H),7.73 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.61(s, 1H), 7.47 – 7.30 (m, 2H), 6.99 (d, J = 8.4 Hz, 2H), 3.14 (s, 4H), 2.48 (s,4H), 2.24 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 165.21, 163.47, 157.87, 155.73,154.63, 148.33, 141.04, 137.13, 133.89, 131.18, 130.82–130.82, 130.56,129.95, 128.41, 127.53, 125.67, 125.12, 123.65, 121.54, 120.22, 116.80,116.05, 55.10, 48.92, 46.28。

[0044] Compound G3: HRMS C 34 H 30 FN5O2[M+H + calc. 560.24171 found 560.24420. 1 H NMR(400 MHz, DMSO) δ 10.63 (s, 1H), 10.52 (s, 1H), 8.41 (d, J = 8.4 Hz, 2H), 8.32(s, 1H), 8.20 – 8.14 (m, 2H), 8.10 (dd, J = 7.4, 5.9 Hz, 2H), 8.02 (d, J = 8.4Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H), 7.73 – 7.60 (m, 3H), 7.41 (t, J = 8.6 Hz, 2H),7.00 (d, J= 8.6 Hz, 2H), 3.17 (s, 4H), 2.59 (s, 4H), 2.32 (s, 3H). 13 C NMR (101MHz, DMSO) δ 165.18, 155.79, 148.44, 148.13, 143.70, 141.34, 133.74, 131.68,131.33, 130.99, 130.70, 129.95, 128.27, 127.50, 125.66, 123.64, 121.57, 120.77, 116.84, 116.07, 115.78, 54.81, 48.62, 45.81.

[0045] Compound G4: HRMS C 35 H 30 F3N5O3[M+H + ]calc. 626.23343 ound 626.23511. 1 H NMR (400 MHz, DMSO) δ 10.61 (d, J = 11.8 Hz, 2H), 8.41 (d, J = 8.1 Hz, 2H), 8.31 (s,1H), 8.14 (t, J = 7.6 Hz, 4H), 8.01 (d, J = 8.1 Hz, 2H), 7.72 – 7.61 (m, 4H), 7.57 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 3.19 (s, 4H), 2.68 (s, 4H), 2.39 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 165.25, 165.02, 148.46, 147.94, 143.70,134.41, 133.86, 131.46, 130.65, 129.96, 128.30, 127.53, 127.03, 125.65,124.61, 123.64, 121.58, 121.24, 120.77, 116.83, 116.25, 110.35, 54.55, 48.35,45.39.

[0046] Compound G5: HRMS C36 H 35 N5O2[M+H + calculated 570.28243, found 570.27417. 1 1H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 10.42 (s, 1H), 8.40 (d, J J = 8.2 Hz, 2H), 8.32(s, 1H), 8.21 – 8.13 (m, 2H), 8.04 (d, J J = 8.2 Hz, 2H), 7.95 (d, J J = 7.7 Hz, 2H),7.84 (t, J J = 7.7 Hz, 1H), 7.69 (d, J J = 8.4 Hz, 2H), 7.67 – 7.62 (m, 1H), 7.40 (d, J J = 7.7 Hz, 2H), 7.00 (d, J J = 8.5 Hz, 2H), 3.15 (s, 5H), 2.71 (q, J J = 7.5 Hz, 2H),2.27 (s, 3H), 1.23 (t, J J = 7.5 Hz, 5H). 13 13C NMR (101 MHz, DMSO) δ 166.11, 165.24,155.82, 148.44, 148.24, 143.69, 141.54, 133.55, 132.70, 131.26, 130.68,129.95, 128.55–128.13, 127.47, 125.66, 123.63, 121.57, 120.68, 116.83,116.09, 54.96, 48.79, 46.06, 28.58,​​​​​​​​​​​​= 8.1 Hz, 2H), 8.31(s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.84 (t, J = 7.6 Hz,1H), 7.68 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 7.0 Hz, 2H), 7.61 (d, J = 7.9 Hz, 1H),7.55 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.99 (d, J = 8.2 Hz, 2H), 3.14(s, 5H), 2.49 – 2.44 (m, 3H), 2.25 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 148.36,131.72, 130.72, 130.18, 129.75–129.37, 128.43, 127.53, 125.66, 121.54,120.09, 116.79, 116.06, 55.06, 48.89, 46.22, 40.68, 40.51, 40.20, 39.99,39.78, 39.57, 39.36.

[0048] Compound G7: HRMS C 34 H 30 FN5O2[M+H + calc. 560.24171 found 560.23370. 1 H NMR(400 MHz, DMSO) δ 10.62 (s, 1H), 10.56 (s, 1H), 8.42 (d, J = 8.2 Hz, 2H), 8.32(s, 1H), 8.16 (dd, J = 8.1, 3.6 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 7.86 (dd, J =14.9, 8.1 Hz, 3H), 7.69 (d, J= 8.6 Hz, 2H), 7.63 (dd, J = 13.1, 7.2 Hz, 2H),7.49 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 3.16 (s, 4H), 2.54 (s, 4H),2.29 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 165.23, 155.74, 148.43, 148.20, 143.72,141.13, 133.91, 131.10, 130.72, 129.95, 128.29, 124.45, 123.65, 121.56,120.83, 116.84, 116.11, 54.91, 48.73。

[0049] Compound G8: HRMS C 34 H 31 N5O2[M+H + calc. 542.25113 found 542.25323. 1 H NMR(400 MHz, DMSO) δ 10.62 (s, 1H), 10.50 (s, 1H), 8.75 – 8.69 (m, 1H), 8.41 (d, J = 8.1 Hz, 2H), 8.32 (s, 1H), 8.16 (dd, J = 8.2, 3.9 Hz, 2H), 8.03 (t, J = 8.2Hz, 4H), 7.84 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.66 – 7.60 (m, 2H),7.57 (t, J = 7.2 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 3.14 (s, 5H), 2.55 (s, 1H),2.49 – 2.42 (m, 2H), 2.25 (s, 3H). 1313C NMR (101 MHz, DMSO) δ 166.25, 165.24, 155.80, 148.29, 143.70, 141.43, 135.27, 133.67, 132.23, 131.20, 130.71, 129.95, 128.93, 128.22, 127.51, 125.65, 123.63, 121.57, 120.74, 116.82, 116.07, 55.03, 48.86, 46.18. Compound G9: HRMS C 36 H 33 N5O2 [M+H + calc. 568.26678 found 568.26697. 1 1H NMR (400 MHz, DMSO) δ 10.56 (d, J J = 45.1 Hz, 2H), 8.39 (d, J J = 8.2 Hz, 2H), 8.30 (s,1H), 8.15 (t, J J = 7.8 Hz, 2H), 7.94 (d, J J = 8.3 Hz, 2H), 7.84 (t, J J = 7.6 Hz, 1H),7.70 (s, 1H), 7.67 (d, J J = 6.6 Hz, 4H), 7.63 (s, 1H), 7.53 – 7.39 (m, 3H), 7.00(d, J J = 8.5 Hz, 2H), 6.91 (d, J J = 15.8 Hz, 1H), 3.16 (s, 4H), 2.54 (s, 4H), 2.29(s, 3H). 13C NMR (101 MHz, DMSO) δ 165.23, 164.24, 155.79, 148.44, 148.20,143.67, 141.46, 141.05, 135.14, 133.44, 131.28, 130.69, 130.39, 129.74,129.49–129.36, 128.49, 128.28, 127.46, 125.67, 123.61, 122.58, 121.55,119.75, 116.80, 116.11, 54.92, 48.74, 45.99.

[0050] Compound G10: HRMS C 34 H 30 N6O4[M+H + ] calc. 587.23621 found 587.22717. 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 10.63 (s, 1H), 8.86 (s, 1H), 8.46 (dd, J =15.7, 7.7 Hz, 4H), 8.33 (s, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.1 Hz,2H), 7.93 – 7.81 (m, 2H), 7.67 (dd, J = 15.8, 8.0 Hz, 3H), 7.00 (d, J = 8.4 Hz, 2H), 3.16 (s, 5H), 2.57 (s, 4H), 2.30 (s, 3H). 13 C NMR (101 MHz, DMSO) δ165.23, 164.03, 155.71, 148.35, 143.73, 140.92, 136.61, 134.76, 134.14,131.29, 130.75, 128.34, 123.66, 122.99, 121.57, 120.98, 116.86, 116.13, 54.86, 48.68, 45.90.

[0051] Compound G11: HRMS C 35 H 30 F3N5O2[M+H +Calculated 610.23851, found 610.22888. 1 H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 10.63 (s, 1H), 8.86 (s, 1H), 8.46 (dd, J J = 15.7, 7.7 Hz, 4H), 8.33 (s, 1H), 8.16 (d, J J = 8.3 Hz, 2H), 8.04 (d, J J = 8.1 Hz, 2H), 7.93 – 7.81 (m, 2H), 7.67 (dd, J J = 15.8, 8.0 Hz, 3H), 7.00 (d, J J = 8.4 Hz, 2H), 3.16 (s, 5H), 2.57 (s, 4H), 2.30 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 166.27, 165.25, 155.74, 148.41, 148.06, 143.78, 141.05, 133.98, 133.17, 131.36, 130.71, 129.97, 129.06, 128.44, 127.55, 125.64, 123.64, 121.56, 120.15,  116.81, 116.19, 54.71, 48.52, 45.66.

[0052] Compound G12: HRMS C 34 H 29 F2N5O2 [M + H + calculated 578.234492, found 578.23492. 1 1H NMR (400 MHz, DMSO) δ 10.61 (d, J J = 10.0 Hz, 2H), 8.43 (d, J J = 8.3 Hz, 2H), 8.32 (s, 1H), 8.16 (dd, J J = 8.1, 4.4 Hz, 2H), 8.01 (d, J J = 8.3 Hz, 2H), 7.85 (t, J J = 7.7 Hz, 1H), 7.75 (d, J= 6.9 Hz, 2H), 7.67 (dd, J = 16.0, 8.1 Hz, 3H), 7.57 (t, J =9.0 Hz, 1H), 7.00 (d, J = 8.6 Hz, 2H), 3.17 (s, 4H), 2.59 (s, 4H), 2.32 (s,3H). 13 C NMR (101 MHz, DMSO) δ 165.22, 155.69, 148.43, 148.13, 143.73, 140.83,134.13, 131.51 – 131.38, 131.02, 128.32, 125.66, 123.66, 121.57, 120.91,116.85, 116.15, 111.85, 111.59, 54.81, 48.63, 45.82。

[0053] Compound G13: HRMS C 36 H 31 NºO₂[M+H + calc. 567.25448 found 567.24945. 1 H NMR(400 MHz, DMSO) δ 10.95 (s, 1H), 10.73 (s, 1H), 8.41 (d, J = 8.1 Hz, 2H), 8.32(s, 1H), 8.23 (d, J = 7.8 Hz, 2H), 8.16 (t, J = 8.9 Hz, 2H), 8.06 (t, J = 9.1 Hz,4H), 7.84 (t, J [[ID=2⑨]]= 7.5 Hz, 1H), 7.73 – 7.60 (m, 3H), 6.98 (d, J = 8.4 Hz, 2H),3.13 (s, 4H), 2.47 (s, 2H), 2.23 (s, 3H), 1.18 (t, J [[ID=3③]]= 7.1 Hz, 3H). 13 It should be noted that in the original text, "N5O2" might be a typo and should perhaps be "N₅O₂". The translation has been done as accurately as possible based on the given text.C NMR (101MHz, DMSO) δ 165.22, 164.83, 155.76, 148.37 139.20, 132.93, 131.23, 130.67,129.24, 128.28, 127.50, 121.60, 120.96, 118.82, 117.01, 116.01, 60.23, 56.46,55.10, 48.92, 46.27, 21.25, 19.03, 14.56.

[0054] Compound G14: HRMS C 34 H 30 ClN5O2[M+H + ] calc. 576.21216 found 576.21515. 1 H NMR (400 MHz, DMSO) δ 10.60 (d, J = 11.5 Hz, 2H), 8.42 (d, J = 8.3 Hz, 2H), 8.32 (s,1H), 8.21 – 8.12 (m, 2H), 8.07 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.97 (d, J =7.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.73 – 7.64 (m, 4H), 7.60 (t, J = 8.1 Hz,1H), 6.99 (d, J = 8.5 Hz, 2H), 3.13 (s, 4H), 2.48 (s, 4H), 2.24 (s, 3H). 13 C NMR(101 MHz, DMSO) δ 165.22, 164.73, 155.75, 148.38, 143.73, 141.13, 137.22,133.84, 132.05, 131.20, 130.95, 130.71, 129.95, 128.30, 127.97, 127.52,127.07, 125.68, 123.66, 121.57, 120.83, 116.85, 116.06, 55.06, 48.88, 46.21.

[0055] Compound G15: HRMS C34 H 29 F2N5O2[M+H + Calculated 578.23229, found 578.22369. 1 1H NMR (400 MHz, DMSO) δ 10.66 (d, J J = 18.5 Hz, 2H), 8.41 (d, J J = 8.2 Hz, 2H), 8.32 (s,1H), 8.16 (dd, J J = 8.1, 3.7 Hz, 2H), 7.95 (d, J J = 8.2 Hz, 2H), 7.83 (dt, J J = 14.6,7.3 Hz, 2H), 7.67 (dd, J J = 20.1, 8.0 Hz, 3H), 7.47 (t, J J = 9.9 Hz, 1H), 7.27 (t, J J = 8.4 Hz, 1H), 7.00 (d, J J = 8.5 Hz, 2H), 3.18 (s, 4H), 2.61 (s, 4H), 2.33 (s,3H). 13 13C NMR (101 MHz, DMSO) δ 165.24, 162.61, 155.70, 148.42, 148.08, 143.73,140.​​​​​​​​​​​​​​= 8.5 Hz, 2H), 8.30(s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.84 (t, J = 7.6 Hz,1H), 7.78 (d, J = 9.7 Hz, 1H), 7.72 – 7.64 (m, 4H), 7.61 (t, J = 8.5 Hz, 1H),7.00 (d, J = 8.7 Hz, 2H), 3.17 (s, 4H), 2.62 (s, 4H), 2.34 (s, 3H). 13 C NMR (101MHz, DMSO) δ 165.23, 162.59, 155.67, 148.41, 148.06, 143.74, 140.83, 134.05,131.96, 131.36, 130.73, 128.41, 127.58, 125.65, 123.65, 121.57, 120.28,119.99, 116.51, 116.18 – 116.08, 54.71, 48.52, 45.66。

[0057] Compound G17: HRMS C 35 H 29 F4N5O2[M+H + calc. 628.22909 found 628.23169. 1 H NMR(400 MHz, DMSO) δ 10.85 (s, 1H), 10.64 (s, 1H), 8.41 (d, J = 8.5 Hz, 2H), 8.31(s, 1H), 8.16 (d, J = 8.5 Hz, 2H), 7.90 (t, J = 8.0 Hz, 3H), 7.88 – 7.80 (m, 3H),7.73 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.9 Hz, 3H), 7.65 (d, J = 7.5 Hz, 1H), 6.99(d, J= 8.8 Hz, 2H), 3.14 (s, 5H), 2.49 – 2.42 (m, 2H), 2.26 (s, 4H). 13 C NMR(101 MHz, DMSO) δ 165.28, 161.26, 155.72, 148.35, 143.81, 140.95, 134.08,131.95, 131.22, 130.72, 129.97, 128.46, 127.55, 125.66, 123.67, 121.55,120.18, 119.97, 116.82, 116.08, 55.02, 48.85, 46.15。

[0058] Compound G18: HRMS C 34 H 29 ClFN5O2[M + H[[ID=]10] + calc. 594.20274 found 594.20581. 1 HNMR (40)0 MHz, DMSO) δ 10.65 (s, 1H), 10.59 (s, 1H), 8.42 (d, J = 8.2 Hz, 2H),8.32 (s, 1H), 8.27 (d, J = 7.0 Hz, 1H), 8.20 – 8.13 (m, 2H), 8.01 (d, J = 8.2 Hz,3H), 7.84 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.64 (dd, J = 17.2, 8.5Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 3.88 – 3.38 (m, 3H), 2.87 (s, 4H), 2.52 (s,3H), 1.22 (s, 1H). 13C NMR (101 MHz, DMSO) δ 165.29, 163.83, 158.44, 155.74,148.44, 147.59, 143.67, 141.08, 133.96, 132.84, 131.70, 130.74, 129.66,128.31, 127.54, 123.64, 121.61, 120.84, 120.31, 119.43, 117.68, 117.47,116.86, 116.42, 54.04, 47.83, 44.59.

[0059] Compound G19: HRMS C 34 H 29 Cl2N5O2[M+H + ] calc. 610.17319 found 610.17603. 1 HNMR (400 MHz, DMSO) δ 10.64 (d, J = 15.1 Hz, 2H), 8.40 (d, J = 8.4 Hz, 2H), 8.29(s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 8.07 – 7.94 (m, 4H), 7.85 (dd, J = 15.8, 8.5Hz, 2H), 7.66 (d, J = 8.3 Hz, 3H), 6.98 (d, J = 8.6 Hz, 2H), 3.13 (s, 4H), 2.47(s, 4H), 2.23 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 165.27, 163.44, 155.72,148.41, 143.71, 140.76, 138.37, 134.86, 134.19, 131.57, 131.07, 130.78,129.94, 128.32, 127.62, 127.04, 123.64, 121.65, 120.95, 116.84, 116.06,55.02, 48.85, 46.19.

[0060] Compound G20: HRMS C 34 H 29 ClFN5O2[M+H +]calc. 594.20274 found 594.20557. 1 H NMR (400 MHz, DMSO) δ 10.72 (d, J = 59.8 Hz, 2H), 8.39 (d, J = 8.3 Hz, 2H), 8.29 (s,1H), 8.16 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.84 (t, J = 7.6 Hz, 1H),7.77 – 7.70 (m, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 3.14 (s, 4H), 2.53 (s, 4H), 2.27 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 165.29, 164.91, 161.54,155.72, 148.32, 143.74, 140.91, 133.95, 131.92, 131.65–131.06, 130.77,129.94, 128.45, 127.59, 125.62, 123.63, 121.65, 120.18, 117.72, 117.47,116.80, 116.12, 115.04, 60.29, 54.87, 48.70, 45.95.

[0061] Example 2: In vitro testing of target compounds for inhibiting SIRT3 activity Principle of enzyme activity test: Due to the high homology of the catalytic centers of each subtype of SIRTs, we chose SIRT1, SIRT2 and SIRT3 for enzyme activity testing. The SIRTs activity fluorescence analysis method (two-step method) can quickly and conveniently detect SIRTs activity, with simple operation and high sensitivity. In the first step, a lysine HDACs fluorescent substrate (Boc-AcBKA) containing an acetylated side chain is incubated with SIRT1, SIRT2, and SIRT3 to remove the acetyl group and activate the substrate. In the second step, BKA is hydrolyzed with trypsin to produce the fluorescent group AMC (i.e., chromophore), and the fluorescence intensity is measured at the emission wavelength / excitation wavelength (390nm / 460nm), so that the inhibition rate is calculated based on the fluorescence intensity of the inhibitor group and the control group. See the principle of enzyme activity test. Figure 1 .

[0062] The experiment was performed in a 96-well plate with a total reaction volume of 60 μL in a buffer of 50 mM Tris, 137 mM NaCl, and 2.7 mM KCl, pH 8.0. The reaction groups were added with: 0.2 μM protein SIRT3, 10 μM fluorescent substrate AcBKA, 200 μM NAD + , 20μM compounds G1~G20. The control group was added with 0.2 μM protein SIRT3, 10 μM fluorescent substrate AcBKA, 200 μM NAD + , DMSO. Incubate at 37°C, 140 rpm for 2 hours. Then, add a solution containing 3-4 U / μL trypsin and 8 mM nicotinamide to a total volume of 60 μL. After incubation at 37°C, 140 rpm for 20 minutes, fluorescence was read using a plate reader (λex = 390 nm, λem = 460 nm). Data were processed using GraphPad Prism 7.0. Nicotinamide, a reported inhibitor, was used as a positive control. The results are shown in Table 1.

[0063]

[0064] Table 1. In vitro enzyme inhibition test results

[0065] Remark: a The inhibition percentage at a dose of 20 μM is shown. Each value is the mean of three experiments, and the value after “±” indicates the standard deviation.

[0066] The above test results show that the quinoline compounds of the present invention exhibit strong inhibitory activity against SIRT3, and in the test, the inhibitory activity of G2, G3, G6, G8, G9, and G10 against SIRT3 is above 90%, which is better than the positive control drug nicotinamide (84.07%). They have good development potential and can be used as lead compounds for the development of new and highly effective SIRT3 inhibitors.

[0067] Example 3: Activity test of target compound in inhibiting cell proliferation (in vitro) The cellular activity of the compound was tested using the MTT assay. Cell suspensions of human tumor cell lines were inoculated in 96-well plates, and culture medium containing different concentrations of the compound was added to each well. After incubation, the plates were stained with MTT. After further incubation, the absorbance (OD value) of each well was measured at 570 nm on a microplate reader, and the cell growth inhibition rate was calculated to determine the activity of the compound.

[0068] The in vitro activity test of quinoline SIRT3 inhibitors in inhibiting cancer cell proliferation is as follows.

[0069] 1. Materials: MOLM-13 (human acute myeloid leukemia) cell line, MTT, 10% fetal bovine serum, 96-well plate.

[0070] 2. Methods: Cell culture MOLM-13 tumor cell lines were cultured using conventional methods. Cells in the logarithmic growth phase were used in all experiments.

[0071] Cell growth assay (MTT method): MOLM-13 cell suspension was adjusted to 1×10 5 / mL, were seeded in 96-well plates (50 μl / well), 5000 cells / well. 4 hours after plating, 50 μL of different concentrations of compound were added to each well, and three replicates were set for each concentration. The wells without cells were read as blanks, the wells with cells but no compound were used as compound negative controls, and Ara-C (cytarabine) was used as compound positive controls. Incubate at 37°C, 5% carbon dioxide for 48 hours, add 10 μL of 0.5% MTT staining solution to each well, continue incubation for 4 hours, centrifuge at 2500 rpm for 30 minutes, then discard the culture medium in the wells, and add dimethyl sulfoxide (200 μL / well). The absorbance OD value of each well was measured at 570 nm on a microplate reader, and the cell growth inhibition rate was calculated according to the following formula. The IC was calculated based on the growth inhibition rate. 50 value.

[0072]

[0073] Table 2 Cell proliferation assay results

[0074] Note: The values ​​are the average of three experiments, and the values ​​after “±” represent the standard deviation.

[0075] The results of the cell proliferation experiment are shown in Table 2. The experiment showed that multiple quinoline SIRT3 inhibitors showed good anti-tumor activity in the in vitro anti-tumor cell proliferation experiment. Among them, the anti-tumor activity of G10, G12, and G15 was better than that of the positive control Ara-C, and they have good development prospects.

Claims

1. A quinoline SIRT3 inhibitor of structural formula I, or a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof; 2. The quinoline SIRT3 inhibitor according to claim 1, wherein: The quinoline SIRT3 inhibitor is any one of the following compounds: 2-(4-(3-bromobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G1); 2-(4-(2-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G2); 2-(4-(4-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G3); N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(4-(trifluoromethoxy)benzamido)phenyl)quinoline-4-carboxamide (G4); 2-(4-(4-ethylbenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G5); 2-(4-(2-chlorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G6); 2-(4-(3-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G7); 2-(4-Benzamidophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G8); 2-(4-cinnamamidophenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G9); N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(3-nitrobenzamido)phenyl)quinoline-4-carboxamide (G10); N-(4-(4-methylpiperazin-1-yl)phenyl)-2-(4-(2-(trifluoromethyl)benzamido)phenyl)quinoline-4-carboxamide (G11); 2-(4-(3,5-difluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G12); 2-(4-(4-ethynylbenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G13); 2-(4-(3-chlorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G14); 2-(4-(2,4-difluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G15); 2-(4-(4-bromo-2-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G16); 2-(4-(4-(4-fluoro-2-(trifluoromethyl)benzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G17); 2-(4-(3-chloro-4-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G18); 2-(4-(3,5-dichlorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G19); 2-(4-(2-Chloro-4-fluorobenzamido)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)quinoline-4-carboxamide (G20).

3. The method for preparing the quinoline SIRT3 inhibitor according to claim 2, wherein: The diketone indoline reacts with 1-(4-aminophenyl)ethan-1-one in a Pfitzinger reaction to obtain intermediate AH-1, which is then reacted with acyl chlorides of different substituents to obtain key intermediates MC1-MC20. Finally, MC1-MC20 undergoes a condensation reaction with 4-(4-methylpiperazin-1-yl)aniline to obtain the target compounds G1-G20.

4. The method for preparing the quinoline SIRT3 inhibitor according to claim 3, wherein: The reagents in the reaction formula of the synthetic route are: (a) KOH, EtOH, 80-90°C; (b) THF, room temperature; (c) TBTU, Et3N, DCM.

5. Use of the quinoline SIRT3 inhibitor according to claim 2 in the preparation of a medicament for preventing or treating mammalian diseases associated with abnormal expression of SIRT3 activity.

6. The use according to claim 5, characterized in that: The mammalian disease associated with abnormal expression of SIRT3 activity is any one of cancer, neurodegenerative disease, viral infection, inflammation and diabetes.

7. A pharmaceutical composition containing the quinoline SIRT3 inhibitor according to claim 2, characterized in that: It comprises a therapeutic amount of a compound represented by general formula I and one or more pharmaceutically acceptable carriers and / or excipients.

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