CN117362200A - Benzenemethylamine compound and synthesis method and application thereof - Google Patents

Abstract

The invention discloses a benzylamine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, as well as a synthesis method and application thereof. The biscarbamyl ester derivative containing a benzylamine structure provided by the invention has a significant effect of inhibiting butyrylcholinesterase, and can be used as a butyrylcholinesterase inhibitor, and can be used to prepare treatments or Drugs to prevent diseases related to butyrylcholinesterase, such as hyperlipidemia, Alzheimer's disease, Parkinson's disease, etc.

Description

Benzylamine compounds and their synthesis methods and applications

Technical field

The invention belongs to the field of medicine, and in particular relates to a biscarbamyl ester derivative containing a benzylamine structure and its synthesis method and application.

Background technique

Butyrylcholinesterase (BChE) is a serine hydrolase that is widely present in various organs, tissues and plasma in the human body. Research shows that butyrylcholinesterase plays a certain function in the human body (Protein Pept Lett, 2009, 16(10):1215-24.). Butyrylcholinesterase has the function of hydrolyzing acetylcholine and can be used as a target for the treatment of neurodegenerative diseases. Studies have shown that butyrylcholinesterase inhibitors have neuroprotective and improved memory deficits and can be used to treat Alzheimer's disease. Disease and other neurodegenerative diseases (Pharmacology & Therapeutics 148 (2015): 34-46; Eur J Med Chem. 2022 Sep 5; 239: 114510; J MedChem. 2021 Jul 8; 64 (13): 9302-9320). In addition, studies have found that BChE levels in serum have a certain correlation with cholesterol and triglycerides. The level of BChE activity also shows a positive correlation with risk factors for cardiovascular and cerebrovascular diseases. Patients with hyperlipidemia, obesity and hypertension The BChE activity in the body is higher than that in normal humans (Clin Biochem, 2005, 38(9):799-805; Clin Chem, 2006, 52(5):845-852; Res Exp Med( Berl),1982,181(3):181-187.). In summary, butyrylcholinesterase inhibitors have the potential to treat neurodegenerative diseases and hyperlipidemia and other related diseases.

Contents of the invention

Based on this, the present invention provides a new biscarbamyl ester derivative containing a benzylamine structure, which compound can effectively inhibit the activity of butyrylcholinesterase.

The present invention includes the following technical solutions.

On the one hand, the present invention provides a benzylamine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

Wherein, R ₁ and R ₂ are independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₁₂ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, R ₅ substituted or Unsubstituted C ₆ -C ₁₄ aryl;

R ₃ and R ₄ are each independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₁₂ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, R ₅ substituted or unsubstituted C ₆ -C ₁₄ aryl group, or R ₃ , R ₄ and the nitrogen atom connected thereto together form an R ₅ substituted or unsubstituted 3-12 membered heterocyclic group;

Each R ₅ is independently selected from: hydrogen, halogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkynyl, C ₂ -C ₁₂ alkenyl, C ₆ -C ₁₀ aryl.

Wherein, the pharmaceutically acceptable salts include but are not limited to: sulfate, hydrogen sulfate, hydrochloride, hydrobromide, dihydrogen phosphate, methanesulfonate, bromide salt, acetate, Oxalate, maleate, fumarate, succinate, 2-naphthyl sulfate, gluconate, citrate, tartrate, lactate, pyruvate, isethyl sulfonate Acid, benzenesulfonate, p-toluenesulfonate.

On the other hand, the present invention also provides a preparation method of the benzylamine compound, which includes the following steps:

Step 1: React compound (I-1) with compound (I-2) to obtain compound (I-3);

Step 2: React compound (I-3) with a halogenating reagent to obtain compound (I-4);

Step 3: React compound (I-4) with compound (I-5) to obtain the benzylamine compound;

The reaction formula is as follows:

Among them, R ₁ , R ₂ , R ₃ and R ₄ are as described in the present invention.

In a third aspect, the present invention also provides applications of the benzylamine compounds or their pharmaceutically acceptable salts or their stereoisomers, including the following:

Use of the benzylamine compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of butyrylcholinesterase inhibitors.

The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer is used in the preparation of drugs for treating or preventing diseases related to butyrylcholinesterase.

Wherein, the diseases related to butyrylcholinesterase include hyperlipidemia (for example, hyperlipidemia includes hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, etc.), neurodegenerative diseases (for example, , including Alzheimer's disease, Parkinson's disease, etc.).

In a fourth aspect, the present invention also provides a pharmaceutical preparation for treating or preventing diseases related to butyrylcholinesterase, which is prepared from active ingredients and pharmaceutically acceptable excipients. The active ingredient Including the benzylamine compounds or their pharmaceutically acceptable salts or their stereoisomers.

The dosage forms of the preparation include but are not limited to: capsules, granules, tablets, pills, powders, drops, ointments, patches, liniments, sprays, powders, suppositories, sustained-release agents, and injections.

In a fifth aspect, the present invention also provides a method for treating or preventing diseases related to butyrylcholinesterase, which method includes: administering a safe and effective amount of the benzylamine compound or its pharmaceutically acceptable Accept the salt or its stereoisomer; or administer a safe and effective amount of the pharmaceutical preparation.

The biscarbamyl ester derivative containing a benzylamine structure provided by the invention has a significant effect of inhibiting butyrylcholinesterase, and can be used as a butyrylcholinesterase inhibitor, and can be used to prepare treatments or Drugs to prevent diseases related to butyrylcholinesterase, such as hyperlipidemia, Alzheimer's disease, Parkinson's disease, etc.

Detailed ways

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings commonly understood by those skilled in the technical field belonging to the present invention. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not used to limit the present invention.

The terms "including" and "having" and any variations thereof herein are intended to cover a non-exclusive inclusion. For example, a process, method, device, product or equipment that includes a series of steps is not limited to the listed steps or modules, but optionally also includes unlisted steps, or optionally also includes steps for these processes, Other steps inherent to the method, product, or device.

The "plurality" mentioned in the present invention means two or more. "And/or" describes the relationship between related objects, indicating that there can be three relationships. For example, A and/or B can mean: A exists alone, A and B exist simultaneously, and B exists alone. The character "/" generally indicates that the related objects are in an "or" relationship.

In the compounds described in the present invention, when any variable (such as R ⁵ , etc.) appears more than once in any component, the definition of each occurrence is independent of the definitions of each other occurrence. Likewise, combinations of substituents and variables are allowed as long as the combination renders the compound stable. A line drawn from a substituent into a ring system indicates that the bond indicated can be attached to any substitutable ring atom. If a ring system is polycyclic, it means that such bonds are only to any appropriate carbon atoms adjacent to the ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by techniques in the art and the methods set forth below. If a substituent is itself substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, the definition of "C ₁ -C ₆ " in "C ₁ -C ₆ alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C ₁ -C ₆ alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

The term "cycloalkyl" as used herein refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "heterocyclyl" used in the present invention is a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent (including monocyclic, spirocyclic, paracyclic, bridged, etc.), in which one or more ring atoms are selected from Heteroatoms of N, O or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon, for example, including but not limited to: aziridinyl, azetidinyl, tetracyclinyl Hydropyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.

The term "halogen" or "halogen" as used herein means chlorine, fluorine, bromine and iodine.

In one embodiment of the present invention, the present invention provides a benzylamine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

Wherein, R ₁ and R ₂ are independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₁₂ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, R ₅ substituted or Unsubstituted C ₆ -C ₁₄ aryl;

R ₃ and R ₄ are each independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₁₂ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, R ₅ substituted or unsubstituted C ₆ -C ₁₄ aryl group, or R ₃ , R ₄ and the nitrogen atom connected thereto together form an R ₅ substituted or unsubstituted 3-12 membered heterocyclic group;

Each R ₅ is independently selected from: hydrogen, halogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkynyl, C ₂ -C ₁₂ alkenyl, C ₆ -C ₁₀ aryl.

In some embodiments, R ₁ and R ₂ are independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₆ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₆ cycloalkyl , R ₅ substituted or unsubstituted phenyl.

In some embodiments, R ₁ and R ₂ are not hydrogen at the same time.

In some embodiments, R ₁ and R ₂ are independently selected from: methyl, ethyl, n-propyl, and isopropyl.

In some embodiments, R ₃ and R ₄ are independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₆ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₈ cycloalkyl , R ₅ substituted or unsubstituted phenyl, or R ₃ , R ₄ and the nitrogen atom connected thereto together form an R ₅ substituted or unsubstituted 3-8-membered heterocyclyl group.

In some embodiments, R ₃ and R ₄ are independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₃ -C ₆ alkyl, R ₅ substituted or unsubstituted cyclopentyl, R ₅ substituted or Unsubstituted cyclohexyl, R ₅ substituted or unsubstituted cycloheptyl, R ₅ substituted or unsubstituted phenyl, or R ₃ , R ₄ and the nitrogen atom connected to them together form R ₅ substituted or unsubstituted 3- 6-membered heterocyclyl; the 3-6-membered heterocyclyl is: aziridinyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, or Piperazinyl.

In some embodiments, R ₃ and R ₄ are not hydrogen at the same time.

In some embodiments, one of R ₃ and R ₄ is hydrogen, and the other is not hydrogen.

In some embodiments, each R ₅ is independently selected from: hydrogen, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyl, and phenyl.

In some embodiments, each R ₅ is independently selected from: hydrogen, fluorine, chlorine, iodine, methyl, ethyl, propyl, ethynyl, vinyl, phenyl.

In some embodiments, R ₃ and R ₄ are independently selected from: hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl-substituted propyl, n-butyl, isobutyl, tert. Butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 4-iodophenyl, 4-fluorophenyl, 4-chlorophenyl , 3-ethynylphenyl, or R ₃ , R ₄ and the nitrogen atom to which they are connected together form tetrahydropyrrolyl, piperidinyl, or morpholinyl.

In some embodiments, the benzylamine compound is selected from the following compounds:

The present invention includes the free form of the compound of formula (I), as well as its pharmaceutically acceptable salts and stereoisomers. The stereoisomers described in the present invention are (depending on their structure) as enantiomers, diastereomers, syn-/anti-isomers, cis/trans (cis -/trans-isomer) isomer, epimer and (E)-/(Z)-isomer. The compounds of formula (I) can be used in the context of the present invention in the form of pure stereoisomers or in the form of any mixture of stereoisomers, in the latter case the racemates are preferred.

The term "free form" refers to amine compounds that exist in non-salt form. The "pharmaceutically acceptable salts" include but are not limited to: sulfate, hydrogen sulfate, hydrochloride, hydrobromide, dihydrogen phosphate Salt, methanesulfonate, bromide, acetate, oxalate, maleate, fumarate, succinate, 2-naphthyl sulfate, gluconate, citrate , tartrate, lactate, pyruvate, isethionate, benzenesulfonate, p-toluenesulfonate.

In another embodiment of the present invention, the present invention provides a method for preparing the benzylamine compounds, which includes the following steps:

Step 1: React compound (I-1) with compound (I-2) to obtain compound (I-3);

Step 2: React compound (I-3) with a halogenating reagent to obtain compound (I-4);

Step 3: React compound (I-4) with compound (I-5) to obtain the benzylamine compound;

The reaction formula is as follows:

Among them, R ₁ , R ₂ , R ₃ and R ₄ are as described above.

Wherein, the reaction in step 1 is carried out under alkaline conditions, and the base is preferably an inorganic base, such as potassium carbonate, sodium carbonate, etc.; the reaction in step 1 is carried out in an organic solvent, for example, the solvent can be acetonitrile, etc.; step 2 The halogenating reagent can be a commonly used reagent for halogenation reactions in this field, preferably dichlorosulfoxide; the reaction in step 2 is carried out in an organic solvent, for example, the solvent can be dichloromethane, etc.; the reaction in step 3 is carried out in an alkali It is carried out in the presence of a halogenated quaternary ammonium salt. The base is preferably an inorganic base, such as potassium carbonate, sodium carbonate, etc. The halogenated quaternary ammonium salt is preferably tetrabutylammonium bromide, etc., and its reaction solvent is preferably is acetonitrile.

In another embodiment of the present invention, there is provided the use of the benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer in the preparation of a butyrylcholinesterase inhibitor.

In another embodiment of the present invention, the benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer is provided for the preparation of a method for treating or preventing diseases related to butyrylcholinesterase. Applications in medicine.

Among them, diseases related to butyrylcholinesterase include but are not limited to: hyperlipidemia, neurodegenerative diseases, etc.; the hyperlipidemia includes hypercholesterolemia, hypertriglyceridemia and hyperlipoproteinemia. etc.; the neurodegenerative diseases include but are not limited to Alzheimer's disease, Parkinson's disease, etc.

In another embodiment of the present invention, a pharmaceutical preparation (or pharmaceutical composition) for treating or preventing diseases related to butyrylcholinesterase is provided, which is composed of active ingredients and pharmaceutically acceptable excipients. Prepared, the active ingredient includes the benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer.

Among them, the dosage of the active ingredients contained is within the safe and effective dose range. The "safe and effective dose" means that the amount of active ingredients is sufficient to significantly improve the condition without causing serious side effects.

"Pharmaceutically acceptable excipients" or "carriers" refer to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity .

"Compatibility" here refers to the ability of each component in the composition or preparation to be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.

Some examples of pharmaceutically acceptable excipients (or carriers) include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The method of administration of the active ingredients or pharmaceutical compositions or pharmaceutical preparations of the present invention is not particularly limited. Representative methods of administration include but are not limited to: oral, transdermal, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc. That is, the dosage forms of its pharmaceutical preparations include but are not limited to: capsules, granules, tablets, pills, powders, drops, ointments, patches, liniments, sprays, powders, suppositories, sustained-release agents, injections, etc.

Solid dosage forms for oral administration include capsules, granules, tablets, pills, powders, etc. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or excipient or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:

(a) Fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid;

(b) Binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic;

(c) humectants, such as glycerin;

(d) Disintegrating agents, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

(e) Retarder, such as paraffin;

(f) Absorption accelerator, for example, quaternary ammonium compound;

(g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

(h) Adsorbent, for example, kaolin;

(i) Lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

The solid dosage form can also be prepared using coating and shell materials, such as enteric casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.

Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

In another embodiment of the present invention, there is also provided a method for treating or preventing diseases related to butyrylcholinesterase, the method comprising: administering a safe and effective amount of the benzylamine compound or its Pharmaceutically acceptable salts or stereoisomers thereof; or administering a safe and effective amount of the pharmaceutical preparation (or pharmaceutical composition). When administering the compounds of the present invention or pharmaceutical compositions or pharmaceutical preparations, a safe and effective amount of the compounds of the present invention is administered to mammals (such as humans) in need of treatment, wherein the dosage when administered is considered pharmaceutically effective and does not produce serious side effects. dosage. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as hypolipidemic drugs, histamine _H1 receptor antagonists (carbastine), etc.). During combined administration, the original administration mode and dosage of the drug remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently. When the compound of formula (I) is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula (I). Drug combinations also include administration of a compound of formula (I) with one or more other known drugs for overlapping periods of time. When a compound of formula (I) is used in combination with one or more other drugs, the dosage of the compound of formula (I) or the known drug may be lower than when they are used alone.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples are usually carried out according to conventional conditions in the field, such as those described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. Suggested conditions.

The benzylamine compounds in the following examples were synthesized through the following synthesis route 1-2.

Synthesis route 1:

Reagents and reaction conditions: (a) potassium carbonate, acetonitrile, room temperature; (b) SOCl ₂ , dichloromethane, room temperature; (c) potassium carbonate, tetrabutylammonium bromide, acetonitrile, room temperature.

Synthesis route 2:

Reagents and reaction conditions: (a) potassium carbonate, crystal water potassium carbonate, pyridine, ethyl acetate, 70°C; (b) SOCl ₂ , dichloromethane, room temperature; (c) potassium carbonate, tetrabutylammonium bromide, Acetonitrile, room temperature.

Example 1: Synthesis of Intermediate 4 (Synthetic Route 1)

Step 1: Synthesis of intermediate 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl alcohol (compound shown in structural formula 3)

Place 6g of 3,5-dihydroxybenzyl alcohol, 11.82g of potassium carbonate, 120ml of acetonitrile and 13.8g of N,N-dimethylcarbamoyl chloride in a 250mL reaction bottle and stir at room temperature for 24 hours. Filter, evaporate the filtrate to dryness, then add ethyl acetate to reconstitute, wash twice with water, dry over anhydrous magnesium sulfate, filter, and evaporate the filtrate to obtain a crude product, which can be directly used in the next step without purification.

Step 2: Synthesis of intermediate 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride (compound shown in structural formula 4)

Take 12g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl alcohol and 5.6g of dichlorosulfoxide in 120ml of methylene chloride, and react at room temperature for 20 hours. The reaction mixture was evaporated to dryness to obtain crude product, which was directly used in the next step without purification.

Example 2 Synthesis of Intermediate 8 (Synthetic Route 2)

Step 1: Synthesis of intermediate 3,5-bis(N-methyl-N-ethylcarbamoyloxy)benzyl alcohol (compound shown in structural formula 7)

Place 6g 3,5-dihydroxybenzyl alcohol, 11.11g crystal water potassium carbonate and 2.55g potassium carbonate into a 250mL reaction bottle, then add 100mL ethyl acetate, 0.5ml pyridine and 15.6g N-methyl-N-ethyl Carbamoyl chloride, stir and react at 70°C for 27 hours, then add 60 mL of water, stir and react at 70°C for 1.5 hours, stop heating, separate the liquids, wash the organic phase twice, dry over anhydrous magnesium sulfate, filter, and rotary evaporate the filtrate to obtain crude Product, proceed directly to the next step without purification.

Step 2: Synthesis of intermediate 3,5-bis(N-methyl-N-ethylcarbamoyloxy)benzyl chloride (compound shown in structural formula 8)

Take 13.3g of 3,5-bis(N-methyl-N-ethylcarbamoyloxy)benzyl alcohol and 5.6g of dichlorosulfoxide in 120ml of dichloromethane, and react at room temperature for 19 hours. The reaction mixture was evaporated to dryness to obtain crude product, which was directly used in the next step without purification.

Example 3: Synthesis of Compound 5-1

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.27g of tert-butylamine, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile and react at room temperature for 18 hours . The reaction mixture was filtered, the filtrate was evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, the filtrate was rotary evaporated, a small amount of ethyl acetate was added to redissolve, and crystallized to obtain 17 mg of the product, collected The rate is 2%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 7.32 (s, 2H), 6.96 (d, J = 1.8Hz, 1H), 3.97 (s, 2H), 3.04 (s, 6H), 2.96 (s, 6H) ,1.41(s,9H).

Example 4: Synthesis of compound 5-2

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.32g of tert-pentylamine, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile at room temperature. 40 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was dichloromethane and methanol) to obtain 78 mg of product, yield 7%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 7.01 (d, J = 2.1Hz, 2H), 6.83 (t, J = 2.1Hz, 1H), 3.69 (s, 2H), 3.06 (s, 6H), 2.99 (s,6H),1.49(q,J＝7.5Hz,2H),1.10(s,6H),0.88(t,J＝7.5Hz,3H).

Example 5: Synthesis of Compound 5-3

Dissolve 1g 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.36g cyclohexylamine, 1.38g potassium carbonate and 50mg tetrabutylammonium bromide in 40ml acetonitrile and react at room temperature 69 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was dichloromethane and methanol) to obtain 131 mg of product, with a yield of 11%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 7.02 (d, J = 2.1Hz, 2H), 6.87 (t, J = 2.1Hz, 1H), 3.84 (s, 2H), 3.06 (s, 6H), 2.99 (s,6H),2.59-2.53(m,2H),1.95(d,J＝9.1Hz,2H),1.74(d,J＝9.0Hz,2H),1.61(d,J＝10.3Hz,1H) ,1.26-1.17(m,5H).

Example 6: Synthesis of Compound 5-4

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.32g of cyclopentylamine, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile at room temperature. 21 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness, and crystallized using ethyl acetate to obtain 224 mg of the product, with a yield of 19%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 6.96 (d, J = 2.0Hz, 2H), 6.84 (t, J = 2.0Hz, 1H), 3.59 (s, 2H), 3.20 (dq, J = 16.0, 8.0Hz,1H),3.07(s,6H),2.99(s,6H),1.82-1.42(m,8H).

Example 7: Synthesis of Compound 5-5

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.32g of piperidine, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile at room temperature for 18 seconds Hour. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The resulting residue was separated and purified by column chromatography (the eluent was petroleum ether, Ethyl acetate and methanol) to obtain 39 mg of product, yield 3%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 6.95 (d, J = 1.7Hz, 2H), 6.87 (s, 1H), 3.47 (s, 2H), 3.07 (s, 6H), 3.00 (s, 6H) ,2.40(s,4H),1.61-1.56(m,4H),1.42(s,2H).

Example 8: Synthesis of Compound 5-6

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.26g of pyrrolidine, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile and react at room temperature for 21 hours. . The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was dichloromethane and methanol) to obtain 131 mg of product, with a yield of 12%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 6.96 (d, J = 2.1Hz, 2H), 6.87 (t, J = 2.1Hz, 1H), 3.60 (s, 2H), 3.06 (s, 6H), 2.99 (s,6H),2.52(s,4H),1.80-1.76(m,4H).

Example 9: Synthesis of Compounds 5-7

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.32g of morpholine, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile and react at room temperature for 28 hours. . The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was petroleum ether and acetic acid) Ethyl ester), 518 mg of product was obtained, with a yield of 47%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 6.96 (d, J = 2.2Hz, 2H), 6.86 (t, J = 2.2Hz, 1H), 3.72-3.69 (m, 4H), 3.46 (s, 2H) ,3.07(s,6H),3.00(s,6H),2.45(s,4H).

Example 10: Synthesis of Compounds 5-8

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.34g of aniline, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile and react at room temperature for 28 hours. , the reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness, and the residue was separated and purified by column chromatography (the eluent was petroleum ether and Ethyl acetate), 123 mg of product was obtained, with a yield of 10%.

¹ H NMR (500MHz, DMSO) δ = 7.04 (dd, J = 8.5, 7.3Hz, 2H), 6.96 (d, J = 2.1Hz, 2H), 6.78 (t, J = 2.1Hz, 1H), 6.56- 6.50(m,3H),6.30(s,1H),4.26(d,J＝4.6Hz,2H),3.01(s,6H),2.89(s,6H).

Example 11: Synthesis of Compounds 5-9

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.82g of 4-iodoaniline, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile at room temperature for 19 seconds Hour. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was petroleum ether and acetic acid) Ethyl ester), 195 mg of product was obtained, with a yield of 12%.

¹ H NMR (500MHz, DMSO) δ = 7.31 (d, J = 8.7Hz, 2H), 6.93 (d, J = 2.0Hz, 2H), 6.79 (t, J = 2.1Hz, 1H), 6.54 (t, J＝6.1Hz,1H),6.41(d,J＝8.8Hz,2H),4.25(d,J＝6.0Hz,2H),3.01(s,6H),2.89(s,6H).

Example 12: Synthesis of Compounds 5-10

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.41g of 4-fluoroaniline, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile at room temperature. Reaction time is 19 hours. The reaction mixture was filtered and evaporated to dryness, then reconstituted with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness, and crystallized with ethyl acetate to obtain 331 mg of the product, with a yield of 27%.

¹ H NMR (500MHz, DMSO) δ = 6.96 (d, J = 2.1Hz, 2H), 6.91-6.86 (m, 2H), 6.79 (t, J = 2.2Hz, 1H), 6.53 (ddd, J = 6.8 ,5.3,3.0Hz,2H),6.24(t,J＝6.2Hz,1H),4.23(d,J＝6.2Hz,2H),3.01(s,6H),2.89(s,6H).

Example 13: Synthesis of Compound 5-11

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.43g of 3-aminophenylacetylene, 1.38g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile. React at room temperature for 46 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness, and crystallized from ethyl acetate to obtain 77 mg of the product, with a yield of 6%. ¹ H NMR (500MHz, DMSO) δ = 7.05 (t, J = 8.0Hz, 1H), 6.95 (d, J = 2.1Hz, 2H), 6.80 (t, J = 2.1Hz, 1H), 6.65-6.58 ( m,3H),6.50(t,J＝6.1Hz,1H),4.27(d,J＝6.0Hz,2H),4.00(s,1H),3.01(s,6H),2.89(s,6H).

Example 14: Synthesis of Compounds 5-12

Dissolve 1g of 3,5-bis(N,N-dimethylcarbamoyloxy)benzyl chloride, 0.5g α,α-dimethylbenzylamine, 1.38g potassium carbonate and 50mg tetrabutylammonium bromide in 40ml In acetonitrile, react at room temperature for 70 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness, and the residue was separated and purified by column chromatography (the eluent was petroleum ether and acetic acid) Ethyl ester), 556 mg of product was obtained, with a yield of 42%.

¹ H NMR (500MHz, DMSO) δ = 7.54-7.50 (m, 2H), 7.32 (t, J = 7.7Hz, 2H), 7.19 (t, J = 7.3Hz, 1H), 6.93 (d, J = 2.1 Hz,2H),6.75(t,J＝2.1Hz,1H),3.33(s,2H),3.02(s,6H),2.90(s,6H),1.42(s,6H).

Example 15: Synthesis of Compound 9-1

Dissolve 1g of 3,5-bis(N-methyl-N-ethylcarbamoyloxy)benzyl chloride, 0.25g of tert-butylamine, 1.27g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile at room temperature. Reaction time is 21.5 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was dichloromethane and Methanol), 90 mg of product was obtained, with a yield of 8%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 7.01 (d, J = 4.1Hz, 2H), 6.85 (s, 1H), 3.75 (s, 2H), 3.41 (dq, J = 21.6, 7.0Hz, 4H) ,3.00(d,J＝29.8Hz,6H),1.23-1.16(m,15H).

Example 16: Synthesis of Compound 9-2

Dissolve 1g of 3,5-bis(N-methyl-N-ethylcarbamoyloxy)benzyl chloride, 0.3g of tert-pentylamine, 1.27g of potassium carbonate and 50mg of tetrabutylammonium bromide in 40ml of acetonitrile. , reacted at room temperature for 21.5 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was dichloromethane and methanol) to obtain 229 mg of product, with a yield of 20%.

¹ H NMR (500MHz, CDCl ₃ ) δ = 7.02 (d, J = 4.3Hz, 2H), 6.84 (s, 1H), 3.70 (s, 2H), 3.41 (dq, J = 21.5, 7.0Hz, 4H) ,3.00(d,J＝30.3Hz,6H),1.50(q,J＝7.4Hz,2H),1.20(dt,J＝21.2,7.1Hz,6H),1.12(s,6H),0.88(t, J＝7.5Hz,3H).

Example 17: Synthesis of Compound 9-3

Dissolve 0.5g 3,5-bis(N-methyl-N-ethylcarbamoyloxy)benzyl chloride, 0.14g piperidine, 0.63g potassium carbonate and 25mg tetrabutylammonium bromide in 40ml acetonitrile , reacted at room temperature for 19.5 hours. The reaction mixture was filtered and evaporated to dryness, then redissolved with ethyl acetate, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The residue was separated and purified by column chromatography (the eluent was dichloromethane and Methanol), 360 mg of product was obtained, with a yield of 63%.

¹ H NMR (500MHz, DMSO) δ = 6.90 (s, 2H), 6.81 (s, 1H), 3.44-3.38 (m, 4H), 3.31 (dd, J = 14.2, 7.2Hz, 2H), 3.01 (s ,3H),2.89(s,3H),2.32(s,4H),1.53-1.46(m,4H),1.39(d,J＝4.4Hz,2H),1.18(t,J＝7.0Hz,3H) ,1.10(t,J＝7.0Hz,3H).

Example 18: Test for inhibiting butyrylcholinesterase activity

18.1 Solution ① configuration

Dissolve 3.549g anhydrous disodium hydrogen phosphate in 150mL ultrapure water, use ultrasonic to dissolve, then transfer to a 250mL volumetric flask, dilute to volume and set aside.

18.2 Solution ② configuration

Dissolve 1.1998g of anhydrous sodium dihydrogen phosphate in 30mL of ultrapure water, use ultrasonic to help dissolve, then transfer to a 100mL volumetric flask, dilute to volume and set aside.

18.3 Configuration of solution PB1

Add solution ① to an appropriate amount of solution ②, adjust the pH to 7, and store at low temperature for later use.

18.4 Configuration of solution PB2

Add solution ① to an appropriate amount of solution ②, adjust the pH to 8, and store at low temperature for later use.

18.5 Configuration of solution ③

Dissolve 75 mg of sodium bicarbonate in 30 ml of PB1, transfer to a 50 mL volumetric flask, and set to volume.

18.6 Preparation of chromogen and substrate

Use solution ③ to prepare 5,5'-dithiobisnitrobenzoic acid (DTNB) into an 8.5mM solution, and use ultrapure water to prepare thiobutyrylcholine iodide (BTCH) into a 50mM solution. Follow the instructions for DTNB : BTCH: PB2 = 8:1:11 ratio to prepare the required working fluid for later use.

18.7 Configure compound test solutions

Use acetonitrile: ultrapure water = 10:90 to prepare the test compound into a compound test solution with a concentration of 1×10 ^-3 ~ 1×10 ^-9 M, and set aside.

18.8 Preparation of enzyme reaction test solution

Use PB2 solution to dilute the horse BChE stock solution to 0.04U/mL and 0.1U/mL, and prepare it for immediate use.

18.9 Determination methods

Preheat the compound test solution, working solution and 200 μL of enzyme solution in a 37°C environment for 5 minutes. Take 25 μL of the compound test solution and place it in the enzyme solution, mix well, and react at 37°C for 60 minutes. Then add 25 μL of the working solution to the reaction system, mix well, and measure the absorbance at 37°C, 15 times, with an interval of 20 s, and the detection wavelength is 412 nm. Use an equal volume of acetonitrile: ultrapure water = 10:90 solution to replace the compound test solution as a control group. Use 200 μL of PB ₂ solution instead of the enzyme solution as a blank group. Each concentration was measured three times, and linear regression was performed using the negative logarithm of the molar concentration of the compound and the enzyme inhibition rate to obtain the IC ₅₀ value of the compound for inhibiting butyrylcholinesterase (BChE) activity.

18.10 The test results are shown in Table 1.

Table 1 IC ₅₀ values of compounds against butyrylcholinesterase (BChE)

Compound number or name IC ₅₀ (μM)BChE 5-1 0.419±0.025 5-2 0.153±0.016 5-3 0.002±0.000 5-4 0.239±0.017 5-5 0.019±0.001 5-6 0.17±0.012 5-7 >10 5-8 0.667±0.05 5-9 0.454±0.008 5-10 0.182±0.02 5-11 2.345±0.257 5-12 0.090±0.006 9-1 0.283±0.011 9-2 0.482±0.089 9-3 0.013±0.002 bambutro 0.119±0.004

The following conclusions can be drawn from the activity data in Table 1: the benzylamine compounds of the present invention have better activity in inhibiting butyrylcholinesterase, and some compounds have better inhibitory activity against butyrylcholinesterase than the positive control. The drug bambuterol is more active.

The technical features of the above-described embodiments can be combined in any way. To simplify the description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, All should be considered to be within the scope of this manual.

The above-mentioned embodiments only express several implementation modes of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the scope of protection of the patent of the present invention should be determined by the appended claims.

Claims (14)

1. A benzylamine compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, Wherein, R ₁ and R ₂ are independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₁₂ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, R ₅ substituted or Unsubstituted C ₆ -C ₁₄ aryl; R ₃ and R ₄ are each independently selected from: hydrogen, R ₅ substituted or unsubstituted C ₁ -C ₁₂ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₁₂ cycloalkyl, R ₅ substituted or unsubstituted C ₆ -C ₁₄ aryl group, or R ₃ , R ₄ and the nitrogen atom connected thereto together form an R ₅ substituted or unsubstituted 3-12 membered heterocyclic group; Each R ₅ is independently selected from: hydrogen, halogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkynyl, C ₂ -C ₁₂ alkenyl, C ₆ -C ₁₀ aryl. 2. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that R ₁ and R ₂ are independently selected from: hydrogen, R ₅ substitution or Unsubstituted C ₁ -C ₆ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₆ cycloalkyl, R ₅ substituted or unsubstituted phenyl. 3. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 2, characterized in that R ₁ and R ₂ are independently selected from: methyl, ethyl, n-propyl, isopropyl. 4. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that R ₃ and R ₄ are independently selected from: hydrogen, R ₅ substitution or Unsubstituted C ₁ -C ₆ alkyl, R ₅ substituted or unsubstituted C ₃ -C ₈ cycloalkyl, R ₅ substituted or unsubstituted phenyl, or R ₃ and R ₄ together with the nitrogen atom connected to them R ₅ substituted or unsubstituted 3-8 membered heterocyclyl is formed. 5. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 4, characterized in that R ₃ and R ₄ are independently selected from: hydrogen, R ₅ substitution or Unsubstituted C ₃ -C ₆ alkyl, R ₅ substituted or unsubstituted cyclopentyl, R ₅ substituted or unsubstituted cyclohexyl, R ₅ substituted or unsubstituted cycloheptyl, R ₅ substituted or unsubstituted Phenyl, or R ₃ , R ₄ and the nitrogen atom connected to them together form R ₅ substituted or unsubstituted 3-6-membered heterocyclic group; the 3-6-membered heterocyclic group is: aziridinyl, nitrogen Heterocyclobutanyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl. 6. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to any one of claims 1 to 5, characterized in that each R ₅ is independently selected from: hydrogen, halogen , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkenyl, phenyl. 7. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 6, characterized in that each _R is independently selected from: hydrogen, fluorine, chlorine, iodine, Methyl, ethyl, propyl, ethynyl, vinyl, phenyl. 8. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that R ₃ and R ₄ are independently selected from: hydrogen, methyl, ethanol. base, n-propyl, isopropyl, phenyl-substituted propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, cyclopentyl, cyclo Hexyl, cycloheptyl, phenyl, 4-iodophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-ethynylphenyl, or R ₃ , R ₄ and the nitrogen atom connected to them together form tetrahydrogen pyrrolyl, piperidinyl, or morpholinyl. 9. The benzylamine compound or its pharmaceutically acceptable salt or its stereoisomer according to claim 1, characterized in that the benzylamine compound is selected from the following compounds: 10. A method for preparing benzylamine compounds according to any one of claims 1 to 9, characterized in that it includes the following steps: Step 1: React compound (I-1) with compound (I-2) to obtain compound (I-3); Step 2: React compound (I-3) with a halogenating reagent to obtain compound (I-4); Step 3: React compound (I-4) with compound (I-5) to obtain the benzylamine compound; The reaction formula is as follows: Wherein, R ₁ , R ₂ , R ₃ and R ₄ are as described in claims 1-9. 11. The preparation method of benzylamine compounds according to claim 10, characterized in that the reaction in step 1 is carried out under alkaline conditions; and/or, The halogenating reagent described in step 2 is sulfoxide chloride; and/or, The reaction described in step 3 is carried out in the presence of a base and a halogenated quaternary ammonium salt. 12. Use of the benzylamine compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a butyrylcholinesterase inhibitor. 13. The benzylamine compound according to any one of claims 1 to 9 or its pharmaceutically acceptable salt or its stereoisomer in the preparation of medicines for treating or preventing diseases related to butyrylcholinesterase Applications; Preferably, the diseases related to butyrylcholinesterase include hyperlipidemia and neurodegenerative diseases; Preferably, the hyperlipidemia includes hypercholesterolemia, hypertriglyceridemia and hyperlipoproteinemia; the neurodegenerative diseases include Alzheimer's disease and Parkinson's disease. 14. A pharmaceutical preparation for treating or preventing diseases related to butyrylcholinesterase, characterized in that it is prepared from active ingredients and acceptable auxiliary materials in medicines, and the active ingredients include claim 1 - The benzylamine compound described in any one of -9 or its pharmaceutically acceptable salt or its stereoisomer.