Thiochromone derivative, preparation method and application

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a thiochromone derivative, a preparation method and application, the structural formula of the thiochromone derivative is as follows: # imgabs0 #, R is H, Ar is # imgabs1 # imgabs2 #, R1 is halogen or C1-3 alkyl, R2 is C1-3 alkoxy, R3 is halogen or C1-3 alkyl, R4 is halogen or C1-3 alkyl, R3 is halogen or C1-3 alkyl, R4 is halogen or C1-3 alkyl, and R4 is halogen or C1-3 alkyl. R is NO2, Ar is # imgabs3 #, R3 is chlorine, C1-3 alkyl or C1-3 halogenated alkyl, R4 is halogen, C1-3 alkyl, C1-3 alkoxy or C1-3 halogenated alkyl, and R5 is halogen or C1-3 halogenated alkyl, and the compound has a good MAO-B inhibition effect and selectivity relative to inhibition of MAO-A.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical drugs, and particularly relates to a thiochromone derivative, a preparation method and uses thereof. Background Art

[0002] Monoamine oxidases (MAOs) are outer mitochondrial membrane enzymes that are widely present in the brain and peripheral tissues (such as the heart, lungs, liver, intestine, and placenta), and can catalyze the oxidation of monoamine compounds represented by neurotransmitters (norepinephrine, dopamine, tyramine, serotonin) to generate corresponding aldehyde compounds, as well as ammonia (substituted ammonia) and hydrogen peroxide by-products. Overexpressed MAOs will increase the concentration of H 2 O 2 and cause oxidative stress. Monoamine oxidases include monoamine oxidase A and B, namely MAO-A and MAO-B.

[0003] It has been demonstrated that inhibiting MAO-B is an effective strategy for regulating dyslipidemia, mainly including elevated total cholesterol and low-density lipoprotein cholesterol (LDL-C), elevated triglycerides and / or reduced high-density lipoprotein (HDL) cholesterol. In 2023, Wang and colleagues found that inhibiting MAO-B could effectively reduce the production of serum triglycerides (TG) and cholesterol, and enhance the clearance of low-density lipoprotein (LDL) and cholesterol. Tian and his colleagues also found that after selegiline inhibited MAO-B in mice fed a high-fat diet (HFD), their blood lipid levels were lower and the plaque area was smaller than that of mice not taking selegiline. These evidences suggest that MAO-B may be an effective potential therapeutic target. However, traditional non-selective MAOs inhibitors inevitably inhibit the function of MAO-A while inhibiting the function of MAO-B, which will enhance the sympathomimetic effect of amines and tyramine in the diet, thus leading to a rapid and fatal increase in blood pressure, namely the "cheese effect". In clinical studies, it was found that improving the selectivity of MAOs inhibitors for MAO-B can avoid this safety problem. Therefore, improving selectivity is the core of further developing MAO-B inhibitors.

[0004] Currently, MAO B inhibitors are mainly divided into irreversible and reversible inhibitors, which bind through the formation of stable covalent bonds or hydrogen bonds and hydrophobic interactions with specific sites, respectively. Structurally, MAO B inhibitors can mainly be divided into phenethylamine or benzylamine-based, nitrogen-containing five-membered heterocyclic, flavonoid, and coumarin-based MAO-B inhibitors. Selegiline, rasagiline, and safinamide currently used clinically are all phenethylamine or benzylamine-based MAO B inhibitors. However, the types of MAO B-selective inhibitors in current clinical use are very limited and difficult to meet the diversity of treatment needs. At the same time, the selectivity of phenethylamine or benzylamine-based MAO B inhibitors is dose-dependent, and long-term use will increase the incidence of heart disease and hypertension. Therefore, the development of highly efficient and highly selective MAO B inhibitors is of great clinical significance for the treatment of various diseases such as cardiovascular and cerebrovascular diseases, Alzheimer's disease, Parkinson's disease, depression, schizophrenia, and cancer. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a thiochromone derivative, a preparation method and uses thereof, which have a high effect of inhibiting MAO-B and selectivity relative to inhibiting MAO-A.

[0006] An embodiment of the present invention provides a thiochromone derivative, and the structural formula of the thiochromone derivative is as follows:

[0007]

[0008] wherein R is H, and Ar is wherein R 1 is a halogen or a C1-3 alkyl group, and R 2 is a C1-3 alkoxy group;

[0009] wherein R is NO 2 , and Ar is wherein R 3 is chlorine, a C1-3 alkyl group or a C1-3 haloalkyl group, and R 4 is a halogen, a C1-3 alkyl group, a C1-3 alkoxy group or a C1-3 haloalkyl group, and R 5 is a halogen or a C1-3 haloalkyl group.

[0010] The thiochromone derivatives of the present invention may also be pharmaceutically acceptable salts of thiochromone derivatives, including their acid addition salts or base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, esylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoylbenzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrophosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and hydroxynaphthoate, etc.

[0011] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0012] The pharmaceutically acceptable salts of the compounds in the present invention can be prepared by one or more of the following three methods:

[0013] 1. Reacting the compound with the desired acid or base; 2. Using the desired acid or base to remove an acid- or base-labile protecting group from a suitable precursor of the compound, or to open a suitable cyclic precursor such as a lactone or lactam; 3. Reacting with a suitable acid or base or using a suitable ion exchange column to convert one salt of the compound into another salt. All three of these reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from fully ionized to almost non-ionized.

[0014] The present invention also provides compositions for treating or ameliorating various MAO-related diseases, which can be prepared by mixing one or more of the compounds described herein or their pharmaceutically acceptable salts or tautomers with pharmaceutically acceptable carriers, excipients, binders, diluents, etc. The pharmaceutical compositions of the invention can be prepared by methods well known in the art including but not limited to conventional granulation, mixing, dissolution, encapsulation, lyophilization, emulsification or trituration, etc. The compositions include but are not limited to the form of granules, powders, tablets, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the present invention can be formulated for various routes of administration, such as oral administration, transmucosal administration, rectal administration, topical administration or subcutaneous administration, as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. The compounds of the present invention can also be administered topically rather than systemically.

[0015] For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills and capsules are acceptable solid dosage forms. These can be prepared, for example, by mixing one or more of the compounds of the invention or their pharmaceutically acceptable salts or tautomers with at least one additive or excipient such as starch or other additives. Suitable additives or excipients include but are not limited to sucrose, lactose, cellulosesugars, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymeric compounds or glycerides, methylcellulose and hydroxypropylmethylcellulose, etc. Optionally, oral dosage forms can contain other components that facilitate administration, such as inert diluents, or lubricants such as magnesium stearate, or preservatives such as p-hydroxybenzoic acid or sorbic acid, or antioxidants such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents or fragrances. Additionally, dyes or pigments can be added for identification. Tablets and pills can be further treated with suitable coating materials known in the art.

[0016] Liquid dosage forms for oral administration include but are not limited to the form of emulsions, syrups, elixirs, suspensions, pastes and solutions, which can contain inert diluents such as water. Sterile liquids such as but not limited to oils, water, alcohols and their combinations can be used to prepare the pharmaceutical preparations as liquid suspensions or solutions. For oral or parenteral administration, pharmaceutically suitable surfactants, suspending agents or emulsifying agents can be added.

[0017] The compounds can also be administered locally, (intradermally) subcutaneously or transdermally to the skin or mucosa. Preparations for this purpose include, but are not limited to, gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, cachets, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, petrolatum, glycerin, polyethylene glycol and propylene glycol.

[0018] The compounds can also be administered nasally, and the pharmaceutical preparation can be a spray or an aerosol, which contains a suitable solvent and optionally other compounds, such as but not limited to stabilizers, antimicrobial agents, antioxidants, pH regulators, surfactants, bioavailability regulators and combinations thereof. Propellants for aerosols can include compressed air, nitrogen, carbon dioxide or hydrocarbon low-boiling solvents.

[0019] Injectable dosage forms generally include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents. The injectable form can be in the solution phase or in the form of a suspension, which is prepared with a solvent or a diluent. Acceptable solvents or excipients include sterile water, Ringer's solution or isotonic saline solutions. Optionally, sterile oils can be used as solvents or suspending agents. Generally, the oils or fatty acids are non-volatile and include natural or synthetic oils, fatty acids, glycerol monoesters, glycerol diesters or glycerol triesters.

[0020] For rectal administration, the pharmaceutical preparation can be in the form of suppositories, ointments, enemas, tablets or creams, which release the compounds in the intestine, sigmoid flexure or rectum. Rectal suppositories are prepared by mixing one or more of the inventive compounds, or pharmaceutically acceptable salts or tautomers of the compounds, and acceptable excipients such as cocoa butter or polyethylene glycol, which is in the solid phase at normal storage temperatures and in the liquid phase at a temperature suitable for releasing the drug in the body, such as in the rectum. Oils can also be used in the preparation of soft gelatin-type preparations and suppositories. Water, normal saline, aqueous dextrose and related sugar solutions, and glycerin can be used in the preparation of suspension preparations, which can also contain suspending agents such as pectin, carbomer, methylcellulose, hydroxypropylcellulose or carboxymethylcellulose, as well as buffers and preservatives.

[0021] The inventive compositions can also include, for example, micelles or liposomes or other encapsulated forms, or can be administered in an extended-release form to provide a delayed storage or delivery effect. Thus, the pharmaceutical preparation can be compressed into granules or cylinders and can be implanted intramuscularly or subcutaneously, as a depot injection or as an implant such as a stent. Such implants can be made of known substances such as silicone and biodegradable polymers.

[0022] The composition may comprise, for example, from about 0.1% to more than about 90% by weight of the active substance, depending on the method of administration. When the composition comprises dosage units, each unit may contain, for example, from about 0.1 to more than 500 mg of the active ingredient. The dosage for treatment of adults, for example, may be from about 0.1 to 1000 mg / day, depending on the route of administration and the frequency of administration.

[0023] The specific dosage may be adjusted according to the condition of the MAO-related disease, the age, weight, general health, sex and diet of the subject, the dosing interval, the route of administration, the excretion rate, and the drug combination. Any of the above dosage forms containing an effective amount are within the scope of routine experimentation and, thus, within the scope of the present invention. Generally, the total daily dose may typically be from about 1 mg / kg / day to about 500 mg / kg / day, administered as a single dose or divided doses. Typically, the dosage for humans may be from about 5 mg to about 100 mg / day, administered as a single dose or multiple doses. The therapeutically effective dose or amount may vary according to the route of administration and the dosage form.

[0024] The pharmaceutical preparation of the present invention may be the compound of the present invention or in combination with one or more additional agents, which may include, but are not limited to, cyclosporin A, rapamycin, tacrolimus, sirolimus, everolimus, azathioprine, buquineran, deoxyspergualin, leflunomide, aspirin, paracetamol, ibuprofen, naproxen, piroxicam, methotrexate, anti-inflammatory steroids (such as prednisolone or dexamethasone), etc. These combinations may be administered as the same or separate dosage forms, via the same or different routes of administration, and according to the same or different dosing schedules in accordance with standard pharmaceutical practice.

[0025] Preferably, the R 1 is F, Cl or methyl.

[0026] Preferably, the R 2 is methoxy.

[0027] Preferably, the R 3 is chlorine, methyl or trifluoromethyl.

[0028] Preferably, the R 4 is F, Cl, methyl, methoxy or trifluoromethyl.

[0029] Preferably, the R 5 is F, Cl or trifluoromethyl.

[0030] Preferably, the structural formula of the thiochromone derivative is as follows:

[0031]

[0032] More preferably, the structural formula of the thiochromone derivative is as follows:

[0033]

[0034] An embodiment of the present invention provides a preparation method of the thiochromone derivative, including the following steps:

[0035] The compound 1 solution is mixed with liquid bromine and reacted to obtain compound 2. The solvent of the compound 1 solution is acetic acid;

[0036] Toluene, absolute ethanol and water are sequentially added to the mixture of compound 2, and the temperature is raised for reaction to obtain compound 3; the mixture of compound 2 is a mixture of compound 2, tetrakis(triphenylphosphine)palladium, 2-thiopheneboronic acid and potassium carbonate, or the mixture of compound 2 is a mixture of compound 2, tetrakis(triphenylphosphine)palladium, 2-substituted thiopheneboronic acid and potassium carbonate;

[0037] The N-bromosuccinimide solution is added to the compound 3 solution and reacted to obtain compound 4; the solvents of the N-bromosuccinimide solution and the compound 3 solution are tetrahydrofuran;

[0038] Toluene, absolute ethanol and water are sequentially added to the mixture of compound 4, and the temperature is raised for reaction to obtain compound 5a; the mixture of compound 4 is a mixture of compound 4, tetrakis(triphenylphosphine)palladium, phenylboronic acid and potassium carbonate, or the mixture of compound 4 is a mixture of compound 4, tetrakis(triphenylphosphine)palladium, substituted phenylboronic acid and potassium carbonate; The reaction route is as follows:

[0039]

[0040] An embodiment of the present invention provides a use of the thiochromone derivative, and the thiochromone derivative is used to prepare a drug for inhibiting MAO-B. The thiochromone derivative of the present invention can inhibit MAO-B and can also inhibit MAO-A, and the effect of inhibiting MAO-B is significantly better than the effect of inhibiting MAO-A, that is, the thiochromone derivative of the present application has inhibitory selectivity.

[0041] Preferably, the drug is a drug for treating Alzheimer's disease, Parkinson's disease, depression, schizophrenia or cancer.

[0042] The beneficial effects of the present invention are as follows. By analyzing the crystal structure of the complex of hMAO-B (PDB: 6FW0) and serotonin, it is found that the residues Tyr326, Tyr435, and Cys172 are the key points for the interaction between small molecule inhibitors and the active region of hMAO-B. In the present invention, an isoxazole module is introduced into the thiochromone core to strengthen the interaction between the small molecule and Tyr326. However, the isoxazole module fails to interact with the key residue Cys172. Therefore, in the present invention, by introducing a nitro group into the thiophene module, a new type of hMAO-B inhibitor with higher potency and selectivity is designed through the strong interaction between the nitro group and Cys172. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 1H-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 1;

[0044] Figure 2 13C-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 1;

[0045] Figure 3 1H-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 3;

[0046] Figure 4 13C-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 3;

[0047] Figure 5 1H-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 4;

[0048] Figure 6 13C-NMR nuclear magnetic resonance spectrum of the thiochromone compound prepared in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0049] The following are the definitions of the various terms or symbols used herein:

[0050] Symbol represents a connection point.

[0051] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0052] The term "substituted aromatic ring" refers to an aromatic ring substituent containing 3 to about 20 carbon atoms, preferably 5 to 10 carbon atoms. The aromatic ring substituent can be a monocyclic or poly-fused ring, with 0 - 3 substituents thereon, and the substituent types include but are not limited to, for example, methyl, trifluoromethyl, methoxy, halogen, etc.

[0053] If a substituent is described as "independently selected from" a group, each substituent is selected independently of the others. Thus, each substituent can be the same as or different from the other substituents.

[0054] The term "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient and thus exert biological activity.

[0055] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the appropriate biological activity.

[0056] The phrase "treating" refers to alleviating symptoms associated with a disease, disorder or condition, or halting further development or worsening of those symptoms. Depending on the disease and condition of the patient, the term "treating" as used herein includes one or more curative, alleviating and prophylactic treatments. The compounds of the present invention can also be administered together with other drugs and therapeutic agents.

[0057] The phrase "therapeutically effective" refers to the ability of an agent to prevent or improve the severity of a disease while avoiding the adverse side effects typically associated with alternative treatments. The phrase "therapeutically effective" should be understood as equivalent to the phrase "effective for treatment, prevention or improvement", both of which are intended to qualify the amount of each agent used in combination therapy that is capable of achieving the goal of improving the severity of cancer, cardiovascular disease or pain and inflammation, as well as the morbidity of each agent itself during treatment, while avoiding the adverse side effects typically associated with alternative treatments.

[0058] Unless otherwise specified in the following examples, the reagents, starting materials and solvents used in the following examples were purchased from commercial suppliers (such as Aldrich, Adamas-beta, Sigma, etc.) and were used without further purification.

[0059] Example 1

[0060] The reaction route is as follows:

[0061]

[0062] The specific steps are as follows:

[0063] Step a: Place compound 1 (4.8663 g, 30.0 mmol, 1.0 equivalent) and the solvent acetic acid (50.0 mL) in a dry three-necked flask (150 mL), heat to 90 °C and stir to dissolve. Quickly add liquid bromine (14.3829 g, 90.0 mmol, 3.0 equivalents), and stir at 90 °C for 5 h. After the reaction is completed, use an aqueous solution of saturated sodium thiosulfate to remove the excess Br 2 . Extract the organic phase with dichloromethane and saturated brine, combine the organic layers, dry over anhydrous sodium sulfate, and purify by column chromatography (petroleum ether / ethyl acetate, 5 / 1) to obtain 5.7864 g of a magenta solid product 2 with a yield of 80%. The spectral analysis data is as follows:

[0064] 1 H NMR (500 MHz, Chloroform-d): δ 8.58 (d, J = 6.9 Hz, 1H), 8.27 (s, 1H), 7.66 - 7.57 (m, 3H). 13 C NMR (126 MHz, Chloroform-d): δ 136.79, 136.69, 131.68, 130.98, 129.68, 128.36, 126.45, 118.92.

[0065] Step b: Compound 2 (4.8220 g, 20.0 mmol, 1.0 equivalent), Pd(PPh 3 ) 4 (2.3111 g, 10 mol%, 0.1 equivalent), 2-thiopheneboronic acid (5.1184 g, 40.0 mmol, 2.0 equivalents) and potassium carbonate (13.8210 g, 100.0 mmol, 5.0 equivalents) are placed in a dry Schlenk reaction flask (250 mL). Under nitrogen, inject toluene (40.0 mL), absolute ethanol (40.0 mL) and water (20.0 mL) in sequence, stir and dissolve at room temperature, then heat to 100 °C and stir for 24 h. After the reaction is completed, rotary evaporate to remove the organic phase, filter the reaction solution with DCM as the solvent, and concentrate the filtrate. Extract once with distilled water and saturated brine respectively. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated. Purify by column chromatography (petroleum ether / ethyl acetate, 5 / 1) to obtain 4.2513 g of a yellow-green solid product 3 with a yield of 87%. The spectral analysis data is as follows:

[0066] 11H NMR (500 MHz, Chloroform-d): δ 8.67 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 7.64 - 7.59 (m, 2H), 7.57 (ddd, J = 8.2, 6.0, 2.4 Hz, 1H), 7.51 (dd, J = 3.7, 1.0 Hz, 1H), 7.43 (dd, J = 5.1, 0.9 Hz, 1H), 7.10 (dd, J = 5.1, 3.8 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d): δ 137.24, 136.23, 132.43, 132.08, 131.27, 129.57, 129.19, 127.89, 127.52, 126.45, 126.26, 124.77。

[0067] Step c: Compound 3 (3.6650 g, 15.0 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (20 mL) in a three-necked flask (150 mL). N-Bromosuccinimide (4.0046 g, 22.5 mmol, 1.5 equiv) was dissolved in tetrahydrofuran (30 mL). The THF solution of NBS (N-Bromosuccinimide) was slowly added dropwise through a constant pressure dropping funnel under ice bath conditions in the dark. After stirring for 2 h under ice bath conditions, the mixture was warmed to room temperature and stirred for 5 h. After completion of the reaction, THF was removed by rotary evaporation. The organic phase was extracted with dichloromethane and saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / dichloromethane / ethyl acetate, 5 / 1 / 1) gave 3.3939 g of yellow solid product 4 (70%). The spectral analysis data are as follows:

[0068] 1 1H NMR (500 MHz, Chloroform-d): δ 8.68 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 7.69 - 7.63 (m, 2H), 7.61 (ddd, J = 8.3, 6.0, 2.4 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 4.0 Hz, 1H). 13 13C NMR (126 MHz, Chloroform-d): δ 176.91, 138.08, 136.18, 131.92, 131.73, 131.49, 129.60, 128.68, 128.59, 128.09, 126.50, 123.74, 115.73。

[0069] Step d: Compound 4 (0.6464 g, 2.0 mmol, 1.0 equiv), Pd(PPh 3 ) 4(0.2311 g, 20 mol%, 0.2 eq), phenylboronic acid (0.4877 g, 4.0 mmol, 4.0 eq), and potassium carbonate (1.3821 g, 10.0 mmol, 10.0 eq) were placed in a dry Schlenk reaction flask (25 mL). Under nitrogen, toluene (4.0 mL), absolute ethanol (4.0 mL), and water (2.0 mL) were successively injected. After stirring and dissolving at room temperature, the temperature was raised to 95 °C and stirred for 24 h. After the reaction was completed, the organic phase was removed by rotary evaporation. The reaction solution was filtered using DCM as the solvent, and the filtrate was concentrated. It was extracted once with distilled water and once with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / dichloromethane / ethyl acetate, 10 / 1 / 1) gave 0.5639 g of the yellow solid product 5a with a yield of 88%. The spectral analysis data is as follows:

[0070] 1 H NMR (500 MHz, Chloroform-d): δ 8.70 (d, J = 7.7 Hz, 1H), 8.25 (s, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.67 - 7.62 (m, 2H), 7.60 (ddd, J = 11.9, 5.7, 2.8 Hz, 1H), 7.50 (d, J = 3.9 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.32 - 7.27 (m, 2H). 13 C NMR (126 MHz, Chloroform-d): δ 177.07, 145.86, 136.38, 136.19, 134.44, 131.97, 131.87, 131.27, 129.56, 129.07, 128.87, 127.91, 127.50, 126.44, 125.75, 125.55, 122.42。

[0071] Example 2

[0072] The reaction route is as follows:

[0073]

[0074] The specific steps are as follows: Step e: Compound 5a (0.3204 g, 1.0 mmol, 1.0 eq) and Fe(NO 3 ) 3 ·9H 2O (0.5252 g, 1.3 mmol, 1.3 equiv) was placed in a dry Schlenk reaction flask (25 mL). Under nitrogen, acetic acid (3.0 mL) was injected and stirred at room temperature until dissolved, then the temperature was raised to 50 °C and stirred for 12 h. After the reaction was completed, the organic phase was extracted with dichloromethane and saturated brine. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether / dichloromethane / ethyl acetate, 10 / 1 / 1) gave 0.2923 g of the yellow solid product 6a in 80% yield. The spectral analysis data are as follows:

[0075] 1 H NMR (500 MHz, Chloroform-d): δ 8.61 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.68 (dd, J = 6.2, 1.1 Hz, 2H), 7.63 - 7.59 (m, 3H), 7.47 - 7.42 (m, 2H), 7.41 - 7.37 (m, 1H). 13 C NMR (126 MHz, Chloroform-d): δ 176.29, 145.05, 142.89, 138.70, 137.11, 136.21, 132.13, 131.91, 131.80, 129.66, 129.26, 129.08, 128.43, 127.46, 126.62, 125.77, 119.46。

[0076] Example 3

[0077]

[0078] The thiochromone compound was prepared according to the method of Example 1, except that the phenylboronic acid compound was replaced with 2-methylphenylboronic acid compound.

[0079] The spectral analysis data are as follows:

[0080] 1 H NMR (500 MHz, Chloroform-d): δ 8.70 (d, J = 7.8 Hz, 1H), 8.25 (s, 1H), 7.67 - 7.62 (m, 2H), 7.62 - 7.57 (m, 1H), 7.52 (d, J = 3.8 Hz, 1H), 7.51 - 7.47 (m, 1H), 7.28 (t, J = 5.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.08 (d, J = 3.8 Hz, 1H), 2.50 (s, 3H). 1313C NMR (126 MHz, Chloroform-d): δ 177.15, 145.12, 136.86, 136.26, 136.02, 134.18, 132.06, 131.96, 131.29, 130.83, 130.34, 129.61, 129.29, 127.92, 127.80, 126.48, 125.97, 125.91, 124.91, 21.38。

[0081] Example 4

[0082]

[0083] The thiochromone oxide was prepared according to the method of Example 2, except that compound 5a was replaced with compound 5b.

[0084] The spectral analysis data are as follows:

[0085] 1 1H NMR (500 MHz, Chloroform-d): δ 8.62 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.71 - 7.66 (m, 2H), 7.64 (s, 1H), 7.62 (ddd, J = 8.3, 6.2, 2.1 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.33 (dd, J = 6.2, 1.4 Hz, 2H), 7.28 (dd, J = 7.5, 2.6 Hz, 1H), 2.51 (s, 3H). 13 13C NMR (126 MHz, Chloroform-d): δ 176.33, 144.44, 142.06, 137.75, 136.26, 136.19, 131.93, 131.87, 131.74, 131.17, 130.18, 129.72, 129.18, 128.46, 127.53, 126.64, 126.40, 122.87, 21.10。

[0086] The structural formula of the product prepared in the embodiment of the present invention is as follows:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093] Activity test

[0094] The determination of monoamine oxidase B inhibitory activity was selected from the Abcam Monoamine Oxidase B Inhibitor Screening Kit.

[0095] The kit mainly consists of MAO-B Assay Buffer, OxiRed Probe (in DMSO), MAO-B Enzyme, MAO-B Substrate and Developer. Before use, dilute MAO-B Enzyme and Developer into the pre-working storage concentration with a specified amount of MAO-B Assay Buffer respectively, and dilute MAO-B Substrate into the pre-working storage concentration with ultrapure water.

[0096]

[0097] The calculation method of the selectivity index is MAO-A IC 50 / MAO-B IC 50 , and the larger the number, the higher the inhibitory efficiency against MAO B.

[0098] As can be seen from the above table, the compounds of the present application have a high effect of inhibiting MAO-B and have a high selectivity for the MAO B subtype.

[0099] Those of ordinary skill in the art should understand that: the discussion of any of the above embodiments is only exemplary and is not intended to imply that the protection scope of the present application is limited to these examples; under the concept of the present application, the technical features between the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations in different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of brevity.

[0100] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omission, modification, equivalent substitution, improvement, etc. made within the spirit and principle of one or more embodiments of the present application shall be included in the protection scope of the present application.

Claims

1. A thiochromone derivative, characterized in that: The structural formula of the thiochromone derivative is as follows: ； The R is H, the Ar is , or , R1 is halogen or C1-3 alkyl, and R2 is C1-3 alkoxy; R is NO2, Ar is , or , R3 is chlorine, C1-3 alkyl or C1-3 haloalkyl, R4 is halogen, C1-3 alkyl, C1-3 alkoxy or C1-3 haloalkyl, and R5 is halogen or C1-3 haloalkyl.

2. The thiochromone derivative according to claim 1, characterized in that: The R1 is F, Cl or methyl.

3. The thiochromone derivative according to claim 1, characterized in that: The R2 is a methoxy group.

4. The thiochromone derivative according to claim 1, characterized in that: The R3 is chlorine, methyl or trifluoromethyl.

5. The thiochromone derivative according to claim 1, characterized in that: The R4 is F, Cl, methyl, methoxy or trifluoromethyl.

6. The thiochromone derivative according to claim 1, characterized in that: The R5 is F, Cl or trifluoromethyl.

7. The thiochromone derivative according to claim 1, characterized in that: The structural formula of the thiochromone derivative is as follows: , , , , , , , , , or .

8. The thiochromone derivative according to claim 1, characterized in that: The structural formula of the thiochromone derivative is as follows: , , or .

9. A method for preparing a thiochromone derivative as claimed in any one of claims 1 to 8, characterized in that: The following steps are included: The solution of compound 1 is mixed with liquid bromine, and reacted to obtain compound 2, wherein the solvent of the solution of compound 1 is acetic acid; Toluene, anhydrous ethanol and water are sequentially added to a mixed solution of compound 2, and the temperature is raised to react to obtain compound 3; the mixed solution of compound 2 is a mixed solution of compound 2, tetrakis(triphenylphosphine)palladium, 2-thiopheneboric acid and potassium carbonate, or the mixed solution of compound 2 is a mixed solution of compound 2, tetrakis(triphenylphosphine)palladium, 2-substituted thiopheneboric acid and potassium carbonate; Adding N-bromosuccinimide solution to the solution of compound 3 to react, thereby obtaining compound 4; the solvent of the N-bromosuccinimide solution and the solution of compound 3 is tetrahydrofuran; Toluene, anhydrous ethanol and water are sequentially added to a mixture of compound 4, and the temperature is raised to react to obtain compound 5a; the mixture of compound 4 is a mixture of compound 4, tetrakis(triphenylphosphine)palladium, phenylboric acid and potassium carbonate, or the mixture of compound 4 is a mixture of compound 4, tetrakis(triphenylphosphine)palladium, substituted phenylboric acid and potassium carbonate; the reaction route is as follows: 。 10. Use of a thiochromone derivative as claimed in any one of claims 1 to 8, characterized in that: The thiochromone derivative is used for preparing a drug for inhibiting MAO-B.

11. The use according to claim 10, characterized in that: The drug is a drug for treating Alzheimer's disease, Parkinson's disease, depression, schizophrenia or cancer.

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