WO2020239050A1 - 2-(2-chloro-4-methylphenyl)quinazoline-4(3h)-ketone compound and medical use thereof - Google Patents

Abstract

Disclosed are a 2-(2-chloro-4-methylphenyl)quinazoline-4(3H)-ketone compound represented by formula (I), a preparation method therefor, and use thereof in, for example, sedative hypnotic, anticonvulsant, antidepressant, anti-anxiety drugs.

Description

2-(2-chloro-4-methylphenyl)quinazoline-4(3H)-one compound and its medical use Technical field

The invention belongs to the field of pharmaceutical research, and specifically relates to 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compounds, a preparation method thereof, and its use for sedation, hypnosis, anticonvulsant, Use of antidepressant, anti-anxiety and other drugs.

Background technique

The global incidence of sleep disorders is as high as 27%, and it has become one of the major health problems of human concern. Commonly used sedative and hypnotic drugs in clinical practice have adverse effects such as impairment of cognitive and memory functions, fragmentary disturbance of consciousness, and memory loss. Therefore, the development of sedative and hypnotic drugs with high efficiency, low toxicity and no residues in the next day has important clinical significance.

GABA _A receptors are important targets of sedative and hypnotics. GABA _A receptor agonists are the most widely used sedative and hypnotic drugs in clinical practice, including barbiturates such as Phenobarbital and Secobarbital ( Secobarbital) etc.; Benzodiazepine

Drugs such as Diazepam, Clonazepam, Nitrazepam, Estazolam, Lorazepam, Midazolam, etc. ; Non-benzodiazepine

Class drugs, such as Zolpidem (Zolpidem), Zopiclone (Zopiclone), Eszopiclone (Eszopiclone) and so on. These drugs are also used clinically for anti-depression, anti-anxiety, rapid anesthesia, etc. However, the existing drugs have daytime sleepiness, dizziness, cognitive and memory impairment, and long-term application is prone to tolerance and dependence (J Clin Psychiatry, 2004, 65(8): 20-25.), and may cause abuse tendency. Some drugs have fragmented disturbances of consciousness, memory loss and other adverse reactions (Journal of Medical Toxicology, 2013, 9(2): 163～171.). Therefore, the study of sedative hypnotics that quickly induce sleep, does not affect sleep structure, eliminates quickly in the body, does not remain in the next day, does not damage cognitive function, and has no dependence or withdrawal symptoms. It has important practical significance.

GABA _A receptor belongs to the pentameric ligand-gated anion channel of the Cys ring receptor family. 19 genes encoding different subunits have been found in the human genome, including α _1-6 , β _1-3 , and γ _{1- 3.} δ, ε, ρ, π, and ρ _1-3 (previously called GABAc receptors) (Cold Spring Harbor Perspectives in Biology, 2012, 4(3): 829-841). Due to the different permutations and combinations of subunits, there are many different subtypes of GABA _A receptors (Cell and Tissue Research, 2006, 326(2): 505-516.). The functions of different subtypes are different, and there are multiple drug action sites. According to the characteristics of GABA _A receptors and the research progress of subunits, the design of GABA _A receptor agonists can find new high-efficiency and low-toxicity sedative and hypnotic drugs.

In the previous study of selective PI3Kδ inhibitors (Chinese Patent Application No. 201710508033.0), the inventor of the present invention unexpectedly discovered that the compound WJ3008 (the structural formula is shown below) has a good sedative and hypnotic effect, and subsequent studies proved that the compound is GABA _A Receptor agonists.

Summary of the invention

According to one aspect of the present invention, there is provided a 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) or a pharmaceutically acceptable salt thereof .

Wherein, R ₁ and R ₂ are each independently hydrogen, halogen atom, C1 to C15 linear or branched alkyl, halogen substituted C1 to C15 linear or branched alkyl, C1 to C15 alkoxy Group, C1 to C15 alkylamino, C2 to C20 alkenyl or C5 to C20 aryl;

W is C1 to C15 linear or branched alkyl, C2 to C20 alkenyl, saturated or unsaturated three to seven membered heterocyclic ring, saturated or unsaturated three to seven membered heterocyclic ring substituted C1 to C3 Alkyl, substituted or unsubstituted C3 to C20 cycloalkyl or substituted or unsubstituted C3 to C20 aryl.

Wherein, the halogen atom is fluorine, chlorine or bromine.

The saturated or unsaturated three to seven heterocyclic ring contains 1 to 3 heteroatoms selected from O, S and N.

In the substituted or unsubstituted C3 to C20 cycloalkyl group, "substituted" means that there are 1 to 3 C1 to C6 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C20 cycloalkyl group.

In the substituted or unsubstituted C3 to C20 aryl group, "substituted" means that there are 1 to 3 C1 to C6 alkyl groups on the C3 to C20 aryl group.

Preferably, R ₁ and R ₂ are each independently hydrogen, a halogen atom, a C1 to C10 linear or branched alkyl group, a halogen-substituted C1 to C10 linear or branched alkyl group, and a C1 to C10 alkane. Oxy, C1 to C10 alkylamino, C2 to C10 alkenyl or C5 to C10 aryl;

W is C1 to C10 linear or branched alkyl, C2 to C10 alkenyl, saturated or unsaturated five-membered or six-membered heterocycle, saturated or unsaturated five-membered or six-membered heterocycle substituted C1 or C2 alkyl group, substituted or unsubstituted C3 to C10 cycloalkyl group or substituted or unsubstituted C3 to C10 aryl group.

The saturated or unsaturated five-membered or six-membered heterocyclic ring contains 1 or 2 heteroatoms selected from O and S.

In the substituted or unsubstituted C3 to C10 cycloalkyl group, "substituted" means that there are 1 to 3 C1 to C3 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C10 cycloalkyl group.

In the substituted or unsubstituted C3 to C10 aryl group, "substituted" means that there are 1 to 3 C1 to C3 alkyl groups on the C3 to C10 aryl group.

Preferably, R ₁ and R ₂ are each independently hydrogen, a halogen atom, a C1 to C6 linear or branched alkyl group, a halogen-substituted C1 to C6 linear or branched alkyl group, and a C1 to C6 alkyl group. Oxy, C1 to C6 alkylamino, C2 to C6 alkenyl or C5 to C10 aryl;

W is C1 to C6 linear or branched alkyl, C2 to C6 alkenyl, saturated or unsaturated five-membered or six-membered heterocycle, saturated or unsaturated five-membered or six-membered heterocycle substituted C1 or C2 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl or substituted or unsubstituted C3 to C8 aryl.

The saturated or unsaturated five-membered or six-membered heterocyclic ring contains 1 or 2 heteroatoms selected from O and S.

In the substituted or unsubstituted C3 to C10 cycloalkyl group, "substituted" refers to the presence of 1 or 2 C1 to C3 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C8 cycloalkyl group.

In the substituted or unsubstituted C3 to C10 aryl group, "substituted" means that there are 1 or 2 C1 to C3 alkyl groups on the C3 to C10 aryl group.

Preferably, R ₁ and R ₂ are each independently hydrogen, a halogen atom, and the number of carbon atoms is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 straight chain or branched chain alkyl, the number of carbon atoms substituted by halogen atoms is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 straight chain Or branched chain alkyl, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 alkoxy group with carbon number C1 , C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 Alkylamino, with carbon number of C2, C3, C4, C5, C6, C7, C8 , C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkenyl, carbon number is C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups;

W is selected from alkyl groups having carbon atoms of C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, and carbon atoms of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkenyl, saturated or unsaturated three to seven membered heterocyclic ring, saturated or unsaturated three to seven membered heterocyclic ring substituted C1, C2 or C3 alkyl, substituted or unsubstituted C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 ring Alkyl, or substituted or unsubstituted C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl.

Further preferably, R ₁ and R ₂ are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl or trifluoro Ethyl;

W is chlorophenyl, methylphenyl, ethylphenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, methylcyclooctyl, Ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, ethylcycloheptyl, ethylcyclooctyl, furanyl, pyridyl, thienyl, pyrrolyl, tetrahydrofuranyl, Tetrahydropyrrolyl, tetrahydrothienyl, furyl methyl, pyridyl methyl, thienyl methyl, pyrrolyl methyl, tetrahydrofuryl methyl, tetrahydropyrrolyl methyl, tetrahydrothienyl methyl, furan Ethyl ethyl, pyridyl ethyl, thienyl ethyl, pyrrolyl ethyl, tetrahydrofuryl ethyl, tetrahydropyrrolyl ethyl, or tetrahydrothienyl ethyl.

Preferably, the compound represented by formula (I) according to the present invention is selected from the following compounds and pharmaceutically acceptable salts thereof:

Another aspect of the present invention relates to 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) or a pharmaceutically acceptable salt thereof for preparation Uses of drugs for treating sedation, hypnosis, anticonvulsants, tumors, antibacterial infections, anti-HIV infections, anti-TB infections, anti-Parkinson's syndrome, anti-inflammatory, antipyretic, regulating cardiovascular and regulating cell and enzyme activity functions .

Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of 2-(2-chloro-4-methylphenyl)quinazoline-4(3H) represented by formula (I) -Ketone compounds or pharmaceutically acceptable salts thereof as active ingredients and pharmaceutically acceptable excipients.

According to another aspect of the present invention, there is provided a 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) or a pharmaceutically acceptable compound thereof New method of preparation of accepted salt. The reaction process is shown in Figure 1.

The specific method is as follows:

1) The substituted or unsubstituted 2-nitrobenzoic acid of formula II is subjected to amide condensation reaction with W-NH ₂ to obtain the compound of formula III;

Wherein, R ₁ and R ₂ in formula II have the same definition as formula I, and W in W-NH ₂ has the same definition as formula I.

The definitions of R ₁ and R ₂ in Ⅲ are the same as those in formula II, and the definition of W is the same as that of W in W-NH ₂ ;

2) Reducing the nitro group in the compound of formula III to obtain the compound of formula IV;

Among them, R ₁ , R ₂ , and W in formula IV have the same definition as formula III,

3) The compound represented by formula IV and the compound represented by formula V are subjected to Schiff base condensation reaction and heated to cyclize to obtain the compound represented by formula I.

The reduction reaction in step 2) of the above method is specifically carried out in the presence of the NH ₄ COOH-Pd/C system.

Using substituted or unsubstituted 2-nitrobenzoic acid as raw material, through amide condensation, reduction, Schiff base condensation and heating cyclization, the target product 2-(2-chloro-4-methylphenyl)quinazoline is obtained -4(3H)-ketone compounds. The specific reaction conditions of each step of amide condensation, reduction, Schiff base condensation can be carried out according to conventional designs in the art, for example, the amide condensation can refer to the literature (J.Org.Chem.27(11):3851-3855. ), the reduction can refer to the literature (Bioorganic&Medicinal Chemistry Letters, 20(3), 1128-1133), the Schiff base condensation and heating ring combination, can refer to the literature (Advanced Synthesis&catalysis, 360(24): 4764 -4773) Preparation.

Description of the drawings

Figure 1 is a reaction scheme for preparing the compound of formula I in the present invention.

Figure 2 is a graph showing the drug metabolism conversion spectrum of the representative compound 9050 in rat liver microsomes.

The best way to implement the invention

Hereinafter, the present invention will be described in detail. Before proceeding with the description, it should be understood that the terms used in this specification and the appended claims should not be construed as being limited to general and dictionary meanings, but should be allowed to allow the inventor to define the terms appropriately for the best interpretation. Based on the principle of the present invention, the explanation is based on the meaning and concept corresponding to the technical aspects of the present invention. Therefore, the description presented here is only a preferred example for illustrative purposes, and is not intended to limit the scope of the present invention. It should be understood that, without departing from the spirit and scope of the present invention, others can be derived from it. Price method or improvement method.

The present invention uses WJ3008 as the lead compound to optimize the structure, and finds that the compound with the structure shown in formula (I) is a potent GABA _A receptor agonist and has a good sedative and hypnotic effect. Among them, the substitution of chlorine at position 10 in the molecule is very important to improve the efficacy, and the substitution of methyl at position 12 can avoid the side effects of muscle relaxation caused by the compound, and the methyl at position 12 can be rapidly metabolized into hydroxymethyl in liver microsomes. Base, accelerate the metabolic rate of the compound, and achieve the purpose of quick-acting and short-acting.

The "pharmaceutically acceptable salt" is a conventional non-toxic salt formed by the reaction of a compound of general formula (I) with an inorganic acid or an organic acid. For example, the conventional non-toxic salt can be prepared by reacting a compound of general formula (I) with an inorganic acid or an organic acid. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc., And the organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid , Malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p- Amino benzene sulfonic acid, 2-acetoxy benzoic acid and isethionic acid, etc.; or compounds of general formula (I) and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, Malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid form esters and then form sodium, potassium, calcium, aluminum or ammonium salts with inorganic bases; or compounds of general formula (I) and organic bases Formed methylamine salt, ethylamine salt or ethanolamine salt; or the compound of general formula (I) forms ester with lysine, arginine or ornithine and then with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid Or the corresponding inorganic acid salts formed by phosphoric acid or the corresponding organic acid salts formed with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.

The compound of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of its hydrate, solvate or prodrug. Therefore, hydrates, solvates or prodrugs of the compounds of the present invention or pharmaceutically acceptable salts thereof are also included in the scope of the present invention.

The term "pharmaceutically acceptable" as used here refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient. Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the content of this document is incorporated herein by reference.

For drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. When the substituent is a keto group (ie =O), it means that two hydrogen atoms are replaced. Ketone substitution does not occur on aromatic groups.

When any variable (such as R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.

Another aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of a compound represented by formula (I), and its stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, and hydrates And one or more of the crystal forms, and at least one excipient, diluent or carrier.

A typical formulation is prepared by mixing the compound represented by formula (I) of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art, including such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents , Water and other substances.

The specific carrier, diluent or excipient used will depend on the mode and purpose of the compound of the present invention. The solvent is generally selected on the basis of the solvent considered by those skilled in the art to be safe and effective for administration to mammals. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300) and the like. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids, Coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives enable the drug to be manufactured or used in an acceptable form.

When the compound of formula (I) described in the present invention is used in combination with at least one other drug, the two drugs or more drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition. The compound or pharmaceutical composition of formula (I) of the present invention can be administered separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other local or systemic administration form. Medicine to the subject.

These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids Agents, coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives, so that the pharmaceutical composition can be manufactured or used in an acceptable form.

The drug of the present invention is preferably administered by oral route. Solid dosage forms for oral administration may include capsules, tablets, powder or granular formulations. In a solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerin, etc.; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; Solution blockers such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Wait. In the case of capsules and tablets, the dosage form may also include buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, which use lactose and high molecular weight polyethylene glycol as excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the present invention or its composition, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.) ); Glycerin; Tetrahydrofurfuryl alcohol; Fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these substances.

In addition to these inert diluents, the composition may also include excipients, such as one or more of wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents and perfumes.

As for the suspension, in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

The compound or pharmaceutical composition of the present invention can be administered in other topical dosage forms, including ointments, powders, sprays and inhalants. The drug can be mixed with pharmaceutically acceptable excipients, diluents or carriers and any required preservatives, buffers or propellants under sterile conditions. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

Another aspect of the present invention provides compounds represented by formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolic precursors, pharmaceutically acceptable salts, esters, Use of the prodrug or its hydrate or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases or symptoms related to the abnormal activity of GABA _A.

The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can exist in suitable solid or liquid carriers or diluents. In addition, it is suitable for sterilization equipment for injection or drip.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the formulation formulation contains 0.05-200 mg of the compound of formula (I), preferably, the unit dose of the formulation formulation contains 0.1 mg-100 mg of the compound of formula (I).

The compounds and pharmaceutical compositions of the present invention can be used clinically on mammals, including humans and animals, and can be administered via oral, nose, skin, lung, or gastrointestinal tract. Most preferably it is oral. The most preferred daily dose is 0.01-200 mg/kg body weight, taken at one time, or 0.01-100 mg/kg body weight in divided doses. Regardless of the method of administration, the individual's optimal dose should be determined based on the specific treatment. Usually start with a small dose and gradually increase the dose until the most suitable dose is found.

The present invention also proves that the compound involved in formula (I) can be rapidly metabolized in the body (the following reaction formula 2). Animal experiments prove that the compound can take effect within 1 minute after intraperitoneal injection, and wake up after 2 hours, with spontaneous activity It has no effect and can be developed into a strong short-acting sedative and hypnotic drug to avoid residual effects the next day.

The experimental methods in the following examples are conventional methods unless otherwise specified.

The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified. The melting point is measured by YRT-3 melting point instrument. ¹ H-NMR and ¹³ C-NMR were measured by LSI-IST-005/JNM-ECA400 nuclear magnetic resonance instrument. ESI-MS is measured by LSI-IST-003/G6230A mass spectrometer. The thin layer chromatography plate adopts Merck GF254 fluorescent plate. The ultraviolet high-pressure mercury lamp is provided by Shanghai Jiguang Special Lighting Appliance Factory. The chemical reagents used are all chemically pure or analytically pure.

Example 1 2-(2-Chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one (Compound No. 9050)

The first step is the preparation of 2-nitro-N-phenylbenzamide

Weigh 2.0g (0.012mol) o-nitrobenzoic acid into a 100mL reaction flask, add 7.1g (0.06mol) thionyl chloride, place the reaction flask in an oil bath, heat to reflux at 80°C, after 2 hours The reaction was terminated, the solvent was removed by concentration under reduced pressure, 20 mL of dichloromethane was added, and the solvent was removed again by concentration under reduced pressure to obtain a pale yellow oil. 20 mL of dichloromethane was added to form an acid chloride solution for use. Add 1.11g (0.012mol) of aniline to a 100mL reaction flask, add 1.42g (0.018mol) of triethylamine, dissolve it with 20mL of dichloromethane, add a dropping funnel on the reaction flask, evacuate nitrogen protection, and place the reaction flask in In an ice bath, place the acid chloride solution in a dropping funnel and slowly add dropwise to the aniline solution. After about 2 hours, the dropwise addition is complete. After stirring for 6 hours, sample TLC for detection to terminate the reaction. The reaction solution was concentrated under reduced pressure to obtain a yellow oil. After adding 20 mL of distilled water and sonicating for 5 minutes, the solid was washed out. The filter cake was washed twice with distilled water and dried to obtain 2.68 g of beige solid. The yield was 90.2%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.09 (d, J = 2.6 Hz, 1H, NH), 7.73-7.76 (m, 1H, ArH), 7.63-7.56 (m, 5H, ArH), 7.37 (t, J = 8.1 Hz, 2H, ArH), 7.18 (t, J = 7.5 Hz, 1H, ArH); ¹³ CNMR (100MHz, CDCl ₃ ) δ (ppm): 164.4, 146.3, 137.3, 134.0, 132.9 ,130.8,129.2,128.6,125.3,124.8,123.0,120.5.

The second step is the preparation of 2-amino-N-phenylbenzamide

Weigh 2.2g (0.009mol) 2-nitro-N-phenylbenzamide into a 100mL reaction flask, add 50mL ethanol and stir to dissolve, add 1.72g (0.027mol) ammonium formate, 0.44g palladium on carbon, and heat for 80 Reflux in the condenser at °C. After 3 hours, the reaction was detected by TLC. The raw material point disappeared completely and the reaction was terminated. The reaction solution was filtered to remove the palladium carbon, the filter cake was washed twice with ethanol, the reaction solution was concentrated under reduced pressure to obtain a pale yellow solid, and 3 mL of 70% ethanol aqueous solution was added to recrystallize. After heating and dissolving, it was naturally cooled, and a white solid precipitated out. The solid is 1.62g, and the yield is 94.5%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 7.76 (s, 1H, NH), 7.56 (d, J = 8.4 Hz, 2H, NH), 7.46 (d, J = 8.1 Hz, 1H, ArH) ,7.36(t,J=7.8Hz,2H,ArH),7.27-7.23(m,1H,ArH),7.16-7.12(m,1H,ArH),6.72-6.69(m,2H,ArH),5.49( s, 2H, NH); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm): 167.7, 149.0, 137.9, 132.8, 129.1, 127.3, 124.6, 120.6, 117.6, 116.9, 116.3.

The third step is the preparation of 2-(2-chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one

Add 212mg (1mmol) of 2-amino-N-phenylbenzamide into a 50mL reaction flask, add 5mL of N,N-dimethylacetamide (DMA) to dissolve, and then add 170.0mg (1.1mmol) of 2-chloro-4 -Methylbenzaldehyde, 7.2mg (0.05mmol) of cuprous bromide, the reaction flask is placed in an oil bath, and heated at 120°C in an open, 8 hours later, sampling TLC for detection, the reaction of the raw materials is complete, and the reaction is terminated. The reaction solution was transferred to a separatory funnel, 40 mL ethyl acetate was added, and the mixture was extracted twice with 20 mL saturated sodium chloride aqueous solution, and the aqueous phase was extracted once with 20 mL ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove nothing. Water sodium sulfate was added with appropriate amount of silica gel powder and concentrated under reduced pressure, purified by column chromatography (petroleum ether: ethyl acetate = 6:1, v/v), recrystallized, and dried to obtain 227 mg of white solid, yield: 60.3%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.23-8.21 (dd, J ₁ = 8.1 Hz, J ₂ = 1.1 Hz, 1H, ArH), 7.94-7.90 (m, 1H, ArH), 7.77(d,J=7.8Hz,1H,ArH),7.64(t,J=7.1Hz,1H,ArH),7.47(d,J=7.8Hz,1H,ArH),7.39-7.28(m,5H, ArH), 7.16 (s, 1H, ArH), 7.05 (d, J = 7.5 Hz, 1H, ArH), 2.21 (s, 3H, CH ₃ ); ¹³ C NMR (100MHz, CDCl ₃ )δ (ppm): 162.2, 153.2, 147.3, 141.1, 136.8, 134.8, 131.8, 130.1, 130.0, 129.0, 128.9, 128.1, 127.8, 127.6, 127.2, 121.4, 21.1; HRMS (ESI, m/z) calculated value C ₂₁ H ₁₆ ClN ₂ O[(M+H) ⁺ ], 347.0946; measured value, 347.0946.

Example 2 2-(2-Chloro-4-methylphenyl)-7-fluoro-3-phenylquinazolin-4(3H)-one (Compound No. 1646)

Using 2-amino-4-fluoro-N-phenylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 285 mg of white solid was obtained according to the preparation method of Example 1. Yield: 77.7%; ¹ H NMR (400MHz,DMSO-d ₆ )δ(ppm): 8.30-8.26(dd,J ₁ =8.6Hz,J ₂ =6.6Hz,1H,ArH),7.62-7.59(dd,J ₁ =10.0Hz,J ₂ =2.5Hz,1H,ArH),7.54-7.45(m,2H,ArH),7.41-7.39(m,1H,ArH),7.31-7.26(m,4H,ArH),7.17(s,1H,ArH) , 7.06 (d, J = 7.8 Hz, 1H, ArH), 2.20 (s, 3H, CH ₃ ); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm): 168.0, 161.5, 154.4, 149.4, 141.3, 136.6 ,131.6,130.1,130.0,129.8,129.1,129.0,128.0,127.3,118.1,116.5,116.3,113.4,113.1,21.1; HRMS (ESI, m/z) calculated value C ₂₀ H ₁₅ ClFN ₂ O[(M+ H) ⁺ ], 365.0851; measured value, 365.0851.

Example 3 2-(2-Chloro-4-methylphenyl)-3-methylquinazolin-4(3H)-one (Compound No.: 1605)

Using 2-amino-N-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method in Example 1, 465 mg of white solid was obtained, and the yield was 66.1%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.21-8.19 (dd, J ₁ ＝7.8Hz, J ₂ ＝1.1Hz, 1H, ArH), 7.88-7.84 (m, 1H, ArH), 7.69–7.67(m,1H,ArH),7.61-7.54(m,2H,ArH),7.50(s,1H,ArH),7.36-7.34(dd,J ₁ =7.8Hz,J ₂ =0.84Hz,1H ,ArH),3.3(s,3H,NCH ₃ ),2.21(s,3H,CH ₃ ); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm): 162.3,153.9,147.3,141.9,134.4,132.0, 131.8, 130.4, 129.3, 128.4, 127.6, 127.3, 126.8, 120.9, 32.5, 21.2; HRMS (ESI, m/z) calculated value C ₁₆ H ₁₄ ClN ₂ O[(M+H) ⁺ ], 285.0789; measured value , 285.0790.

Example 4 2-(2-Chloro-4-methylphenyl)-3-ethylquinazolin-4(3H)-one (Compound No.: 1614)

Using 2-amino-N-ethylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method of Example 1, 517 mg of white solid was obtained, and the yield was 86.0%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.22-8.19 (dd, J ₁ =7.8Hz, J ₂ =1.1Hz, 1H, ArH), 7.88-7.84 (m, 1H, ArH), 7.68(d,J=7.8Hz,1H,ArH),7.62-7.57(m,2H,ArH),7.51(s,1H,ArH),7.36(d,J=7.8Hz,1H,ArH), 4.10- 4.01(m,1H,NCH ₂ ),3.57-3.48(m,1H,NCH ₂ ),2.41(s,3H,ArCH ₃ ),1.06(t,J=7.1Hz,3H,CH ₂ CH ₃ ), ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm): 161.8, 153.6, 147.3, 141.8, 134.3, 132.1, 131.7, 130.4, 129.4, 128.1, 127.6, 127.2, 126.8, 121.3, 40.8, 21.2, 13.9; HRMS (ESI , m/z) calculated value C ₁₇ H ₁₆ ClN ₂ O[(M+H) ⁺ ], 299.0946; measured value, 299.0946.

Example 5 2-(2-Chloro-4-methylphenyl)-3-(furan-2-ylmethyl)quinazolin-4(3H)-one (Compound No.: 1140)

Using 2-amino-N-(furan-2-ylmethyl)benzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 230 mg of a white solid was obtained according to the preparation method of Example 1. The yield: 65.2%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.23-8.21 (dd, J ₁ ＝7.8Hz, J ₂ ＝1.1Hz, 1H, ArH), 7.91-7.86 (m, 1H, ArH), 7.71-7.69(dd,J ₁ =8.1Hz,J ₂ =0.5Hz,1H,ArH),7.64-7.60(m,1H,ArH),7.47-7.44(m,3H,ArH),7.31-7.29(m ,1H,CH),6.31-6.30(m,1H,CH),6.01-6.00(m,1H,CH), 5.26(d,J=15.8Hz,1H,CH ₂ ), 4.79(d,J=15.8 Hz, 1H, CH ₂ ), 2.4 (s, 3H, CH ₃ ); ¹³ C NMR (100MHz, DMSO-d ₆ ) δ(ppm): 161.2, 153.4, 149.2, 147.2, 143.1, 142.3, 135.4, 131.7, 131.2,130.6,130.1,128.4,128.2,127.9,126.9,121.0,111.1,108.8,41.7,21.3; HRMS (ESI, m/z) calculated value C ₂₀ H ₁₆ ClN ₂ O ₂ [(M+H) ⁺ ] ,351.0895; measured value,351.0895.

Example 6 2-(2-Chloro-4-methylphenyl)-3-(thiophen-2-ylmethyl)quinazolin-4(3H)-one (Compound No.: 1144)

Using 2-amino-N-(thiophen-2-ylmethyl)benzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method of Example 1, 270 mg of white solid was obtained. Yield: 75.6%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.26-8.24 (dd, J ₁ =7.8Hz, J ₂ = 1.1Hz, 1H, ArH), 7.90-7.86 (m, 1H, ArH), 7.71-7.69(dd,J ₁ =8.1Hz,J ₂ =0.5Hz,1H,ArH), 7.65-7.60(m,1H,ArH),7.49(s,1H,ArH),7.43(d,J=7.8 Hz,1H,ArH),7.38-7.36(dd,J ₁ =5.0Hz,J ₂ =1.4Hz,1H,ArH),7.33-7.31(m,1H,CH),6.86-6.84(dd,J ₁ = 5.0Hz, J ₂ = 3.3Hz, 1H, CH), 6.49-6.48 (dd, J ₁ = 3.3Hz, J ₂ = 1.1Hz, 1H, CH), 5.39 (d, J = 15.4Hz, 1H, CH ₂ ), 4.95 (d, J = 15.4 Hz, 1H, CH ₂ ), 2.42 (s, 3H, CH ₃ ); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm): 161.9, 153.2, 147.2, 142.1, 137.8 ,134.6,132.2,131.1,130.5,130.2,128.0,127.7,127.6,127.5,127.1,126.3,126.1,121.2,43.5,21.3; HRMS (ESI, m/z) calculated value C ₂₀ H ₁₆ ClN ₂ OS[( M+H) ⁺ ], 367.0666; measured value, 367.0666.

Example 7 2-(2-Chloro-4-methylphenyl)-3-(o-tolyl)quinazolin-4(3H)-one (Compound No.: 1642)

Using 2-amino-N-(o-tolyl)benzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 280 mg of white solid was obtained according to the preparation method of Example 1, and the yield was 77.2%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.25-8.23 (dd, J ₁ = 8.1 Hz, J ₂ = 1.1 Hz, 1H, ArH), 7.96-7.92 (m, 1H, ArH), 7.79(d,J=8.1Hz,1H,ArH),7.65(t,J=7.2Hz,1H,ArH),7.56-7.41(m,1H,ArH),7.24-7.02(m,6H,ArH), 2.21 (s, 3H, CH ₃ ), 2.12 (s, 3H, CH ₃ ); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm): 161.6, 153.2, 147.5, 141.1, 134.8, 132.1, 130.7, 130.2, 129.3,127.9,127.6,127.3,126.9,121.3,21.1,18.1; HRMS (ESI, m/z) calculated value C ₂₂ H ₁₈ ClN ₂ O[(M+H) ⁺ ], 361.1102; measured value, 361.1103.

Example 8 2-(2-Chloro-4-methylphenyl)-3-cyclopentyl-7-fluoroquinazolin-4(3H)one (Compound No.: 2013)

Using 2-amino-N-cyclopentyl-4-fluorobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 258 mg of white solid was obtained according to the preparation method of Example 1, and the yield was 72.5%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.34-8.30 (dd, J ₁ =8.6Hz, J ₂ =5.8Hz, 1H, ArH), 7.55-7.53(m, 1H, ArH), 7.51 7.34 (m, 4H, ArH), 7.25-7.20 (m, 1H, ArH), 4.21-4.13 (m, 1H, NCH), 2.49-2.40 (m, 2H, CH ₂ ), 2.09-1.89 (m, 3H ,CH ₂ ),1.68-1.60(m,1H,CH ₂ ),1.58-1.38(m,2H,CH ₂ ); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm): 167.6,161.0,155.8,149.0 ,141.7,142.4,131.8,130.4,129.3,128.7,128.3,119.1,115.9,112.4,61.9,29.2,29.1,26.2,26.1,21.2; HRMS (ESI, m/z) calculated value C ₂₀ H ₁₉ ClFN ₂ O [(M+H) ⁺ ], 357.1164; measured value, 357.1164.

Example 9 2-(2-Chloro-4-methylphenyl)-3-cyclohexyl-7-fluoroquinazolin-4(3H)-one (Compound No.: 2008)

Using 2-amino-N-cyclohexyl-4-fluorobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 280 mg of white solid was obtained according to the preparation method of Example 1, and the yield was 75.7%. ¹ H NMR (400MHz, CDCl ₃ )δ (ppm): 8.32-8.28 (dd, J ₁ =8.6Hz, J ₂ =5.8Hz, 1H, ArH), 7.36-7.32 (m, 2H, ArH), 7.26 7.18 (m, 3H, ArH), 3.64-3.58 (m, 1H, NCH ₂ ), 2.82-2.52 (m, 2H, CH ₂ ), 2.40 (s, 3H, CH ₃ ), 1.96-1.80 (m, 2H ,CH ₂ ),1.76-1.52(m,3H,CH ₂ ),1.27-0.88(m,3H,CH ₂ ); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm): 167.7,161.7,155.6,148.9 ,141.6,132.3,130.4,129.4,129.3,128.4,128.2,119.3,116.0,112.6,63.1,29.0,28.9,26.4,26.2,25.0,21.3; HRMS (ESI, m/z) calculated value C ₂₁ H ₂₁ ClFN ₂ O[(M+H) ⁺ ], 371.1321; measured value, 371.1322.

Example 10 2-(2-Chloro-4-methylphenyl)-3-cyclopropylquinazolin-4(3H)-one (Compound No.: 1619)

Using 2-amino-N-cyclopropylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 504 mg of white solid was obtained according to the preparation method of Example 1, and the yield was 80.6%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.18-8.15 (dd, J ₁ = 8.1 Hz, J ₂ = 1.1 Hz, 1H, ArH), 7.85-7.81 (m, 1H, ArH), 7.68-7.54(m,3H,ArH),7.46(s,1H,ArH), 7.32(d,J=7.8Hz,1H,ArH), 2.98-2.92(m,1H,NCH), 2.40(s,3H) , NCH), 0.81-0.76 (m, 1H, CH ₂ ), 0.65-0.56 (m, 3H, CH ₂ ); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm): 163.3, 155.2, 147.0, 141.4, 134.3, 132.8, 132.0, 130.3, 129.8, 127.9, 127.5, 127.3, 126.7, 121.5, 28.3, 21.2, 10.8, 9.2; HRMS (ESI, m/z) calculated value C ₁₈ H ₁₆ ClN ₂ O[(M+H ) ⁺ ], 311.0946; actual measured value, 311.0946.

Example 11 2-(2-Chloro-4-methylphenyl)-3-cyclopropylquinazolin-4(3H)-one (Compound No.: 1631)

Using 2-amino-N-cyclobutylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 440 mg of white solid was obtained according to the preparation method of Example 1. The yield: 67.4%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.19-8.19 (dd, J ₁ = 8.1 Hz, J ₂ = 1.1 Hz, 1H, ArH), 7.86-7.82 (m, 1H, ArH), 7.65(d,J=7.8Hz,1H,ArH),7.59-7.53(m,2H,ArH),7.47(s,1H,ArH),7.33(d,J=7.8Hz,1H,ArH),4.42- 4.36 (m, 1H, NCH), 2.80-2.62 (m, 2H, CH ₂ ), 2.40 (s, 3H, CH ₃ ), 2.06-2.04 (m, 1H, CH ₂ ), 1.84-1.82 (m, 1H ,CH ₂ ),1.73-1.68(m,1H,CH ₂ ),1.57-1.50(m,1H,CH ₂ ); ¹³ CNMR(100MHz,DMSO-d ₆ )δ(ppm): 162.2,153.5,146.9, 142.1, 135.0, 132.6, 131.4, 130.5, 130.1, 128.7, 127.8, 127.5, 126.5, 121.9, 54.2, 28.7, 28.4, 21.1, 15.0; HRMS (ESI, m/z) calculated value C ₁₉ H ₁₈ ClN ₂ O[ (M+H) ⁺ ], 325.1102; measured value, 325.1102.

Example 12 2-(2-Chloro-4-methylphenyl)-3-cyclopentylquinazolin-4(3H)-one (Compound No.: 1625)

Using 2-amino-N-cyclopentylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 340 mg of white solid was obtained according to the preparation method of Example 1. The yield was 55.4%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.19-8.17 (dd, J ₁ = 8.1 Hz, J ₂ = 1.4 Hz, 1H, ArH), 7.86-7.82 (m, 1H, ArH), 7.65(d,J=7.6Hz,1H,ArH),7.59-7.57(m,1H,ArH),7.52(s,1H,ArH),7.50(s,1H,ArH),7.35-7.33(m,1H) ,ArH),4.17-4.09(m,1H,NCH),2.40(s,3H,CH ₃ ),2.33-2.24(m,1H,CH ₂ ),2.21-2.12(m,1H,CH ₂ ),1.96 -1.75(m,3H,CH ₂ ),1.65-1.57(m,1H,CH ₂ ),1.50-1.32(m,2H,CH ₂ ); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm): 161.8 ,154.5,146.9,141.5,134.2,132.7,131.9,130.4,128.8,128.3,127.4,127.2,126.4,122.4,61.9,29.2,29.1,26.2,26.1,21.2; HRMS (ESI, m/z) calculated value C ₂₀ H ₂₀ ClN ₂ O[(M+H) ⁺ ], 339.1259; found value, 339.1259.

Example 13 2-(2-Chloro-4-methylphenyl)-3-cyclohexylquinazolin-4(3H)-one (Compound No.: 1624)

Using 2-amino-N-cyclohexylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 281 mg of white solid was obtained according to the preparation method of Example 1, and the yield was 78.9%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.18-8.16 (dd, J ₁ = 8.1Hz, J ₂ = 1.1Hz, 1H, ArH), 7.85-7.81 (m, 1H, ArH), 7.64(d,J=1.1Hz,1H,ArH),7.59-7.55(m,2H,ArH),7.51(s,1H,ArH),7.35-7.33(m,1H,ArH),3.54-3.48(m ,1H,NCH),2.71-2.62(m,1H,ArH),2.41(s,3H,CH ₃ ),2.39-2.35(m,1H,CH ₂ ),1.75(d,J=10.3Hz,1H, CH ₂ ), 1.67 (d, J = 1.06 Hz, 1H, CH ₂ ), 1.50 (d, J = 12.6 Hz, 1H, CH ₂ ), 1.09-1.03 (m, 1H, CH ₂ ), 0.9-0.75 ( m,2H,CH ₂ ),1.50-1.32(m,2H,CH ₂ ); ¹³ CNMR(100MHz,CDCl ₃ )δ(ppm): 162.4,154.2,146.9,141.4,134.2,132.6,131.9,130.3,128.5 ,128.2,127.3,127.1,126.6,122.6,63.0,29.0,28.9,26.5,26.3,25.0,21.3; HRMS (ESI, m/z) calculated value C ₂₁ H ₂₂ ClN ₂ O[(M+H) ⁺ ] , 353.1415; measured value, 353.1415.

Example 14 2-(2-Chloro-4-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (Compound No.: 1633)

Using 2-amino-N-(tetrahydro-2H-pyran-4-yl)benzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method of Example 1, 530mg of white solid was obtained, yield : 74.3%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.20-8.18 (dd, J ₁ ＝7.8Hz, J ₂ ＝0.84Hz, 1H, ArH), 7.87-7.83 (m, 1H, ArH), 7.66(d,J ₁ ＝7.8Hz,1H,ArH), 7.60-7.56(m,2H,ArH), 7.52(s,1H,ArH), 7.34(d,J ₁ ＝7.8Hz,1H,ArH), 3.90(d,J ₁ ＝7.5Hz,1H,NCH),3.86-3.73(m,2H,OCH ₂ ),3.03-2.92(m,2H,OCH ₂ ),2.91-2.85(m,1H,CH ₂ ) ,2.74-2.64(m,1H,CH ₂ ),2.42(s,3H,CH ₃ ),1.65-1.57(m,2H,CH ₂ ); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm): 162.3 ,153.8,146.7,141.8,134.4,132.2,131.9,130.5,128.6,128.4,127.4,126.7,122.4,68.0,67.7,59.8,29.3,29.0,21.3; HRMS (ESI, m/z) calculated value C ₂₀ H ₂₀ ClN ₂ O ₂ [(M+H) ⁺ ], 355.1208; measured value, 355.1209.

Example 15 2-(2-Chloro-4-methylphenyl)-3-cyclobutyl-7-methylquinazolin-4(3H)-one (Compound No.: CSS0206)

Using N-cyclobutyl-2-amino-4-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 530 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 70%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.18 (d, J = 8.1 Hz, 1H, ArH), 7.48 (s, 1H, ArH), 7.32-7.30 (m, 3H, ArH), 7.21 7.18(m,1H,ArH),4.50-4.41(m,1H,NCH),3.05-2.92(m,1H,CH ₂ ),2.83-2.75(m,1H,CH ₂ ),2.47(s,3H, CH ₃ ),2.41(s,3H,CH ₃ ),2.27-2.19(m,1H,CH ₂ ),1.92-1.81(m,2H,CH ₂ ),1.63-1.51(m,1H,CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₀ H ₂₀ ClN ₂ O[(M+H) ⁺ ], 339.1259; measured value, 339.1258.

Example 16 2-(2-Chloro-4-methylphenyl)-3-cyclopentyl-7-methylquinazolin-4(3H)-one (Compound No.: CSS0207)

Using N-cyclopentyl-2-amino-4-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 500 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 78%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.17 (d, J = 8.1 Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7.32-7.25 (m, 3H, ArH), 7.21 7.19(m,1H,ArH),4.22-4.11(m,1H,NCH),2.47(s,3H,CH ₃ ),2.45-2.44(m,1H,CH ₂ ),2.41(s,3H,CH ₃ ),2.23-2.22(m,1H,CH ₂ ),2.12-1.98(m,2H,CH ₂ ),1.95-1.85(m,1H,CH ₂ ),1.66-1.56(m,1H,CH ₂ ), 1.54-1.45(m,1H,CH ₂ ),1.43-1.34(m,1H,CH ₂ ); HRMS(ESI,m/z) calculated value C ₂₁ H ₂₂ ClN ₂ O[(M+H) ⁺ ], 353.1415; measured value, 353.1415.

Example 17 2-(2-Chloro-4-methylphenyl)-3-cyclohexyl-7-methyl-4(3H)-one (Compound No.: CSS0208)

Using N-cyclohexyl-2-amino-4-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 500 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 80%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.17 (d, J = 8.4 Hz, 1H, ArH), 7.48 (s, 1H, ArH), 7.33-7.23 (m, 3H, ArH), 7.20- 7.18(m,1H, ArH),3.61-3.55(m,1H,NCH),2.83-2.73(m,1H,CH ₂ ),2.62-2.55(m,1H,CH ₂ ),2.47(s,3H, CH ₃ ),2.42(s,3H,CH ₃ ),1.90-1.71(m,3H,CH ₂ ),1.62-1.50(m,2H,CH ₂ ),1.26-1.16(m,1H,CH ₂ ), 1.08-0.97(m,1H,CH ₂ ),0.95-0.83(m,1H,CH ₂ ); HRMS(ESI,m/z) calculated value C ₂₂ H ₂₄ ClN ₂ O[(M+H) ⁺ ], 367.1572; measured value, 367.1572.

Example 18 2-(2-Chloro-4-methylphenyl)-3-ethyl-7-methylquinazolin-4(3H)-one (Compound No.: CSS0214)

Using N-ethyl-2-amino-4-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 400 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 88%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.22 (d, J = 8.1 Hz, 1H, ArH), 7.50 (s, 1H, ArH), 7.36-7.32 (m, 3H, ArH), 7.23 7.21(m,1H,ArH),4.31-4.22(m,1H,NCH),3.63-3.55(m,1H,CH ₂ ), 2.49(s,3H,CH ₃ ),2.41(s,3H,CH ₃ ), 1.16-1.11 (m, 3H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₁₈ H ₁₈ ClN ₂ O[(M+H) ⁺ ], 313.1102; measured value, 313.1103.

Example 19 2-(2-Chloro-4-methylphenyl)-3-cyclopropyl-7-methylquinazolin-4(3H)-one (Compound No.: CSS0215)

Using N-cyclopropyl-2-amino-4-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 520 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 88%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.19 (d, J = 8.1 Hz, 1H, ArH), 7.50 (s, 1H, ArH), 7.37-7.30 (m, 3H, ArH), 7.21 7.16 (m, 1H, ArH), 3.09-3.03 (m, 1H, NCH), 2.48 (s, 3H, CH ₃ ), 2.40 (s, 3H, CH ₃ ), 0.99-0.91 (m, 1H, CH ₂ ), 0.79-0.68 (m, 2H, CH ₂ ), 0.51-0.43 (m, 1H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₁₉ H ₁₈ ClN ₂ O[(M+H) ⁺ ],325.1102; measured value,325.1102.

Example 20 2-(2-Chloro-4-methylphenyl)-3-((1S,4S)-4-methylcyclohexyl)quinazolin-4(3H)-one (Compound No.: XT0241)

Using N-[(1S,4S)-4-methylcyclohexyl]-2-aminobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 500 mg of white solid was obtained according to the preparation method of Example 1. The rate is 80%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.30-8.26 (m, 1H, ArH), 7.75-7.68 (m, 2H, ArH), 7.54-7.44 (m, 1H, ArH), 7.34 (s ,1H,ArH),7.28-7.19(m,2H,ArH),3.63-3.55(m,1H,CH ₂ ),2.90-2.58(m,2H,CH ₂ ),2.43(s,3H,CH ₃ ) ,1.89-1.39(m,5H,CH ₂ ),0.80(s,3H,CH ₃ ),0.77-0.55(m,2H,CH ₂ ); HRMS(ESI,m/z) calculated value C ₂₂ H ₂₄ ClN ₂ O[(M+H) ⁺ ], 367.1572; measured value, 367.1572.

Example 21 2-(2-Chloro-4-methylphenyl)-3-(1,2,3,4-tetrahydronaphthalene-1-yl)quinazolin-4(3H)-one (Compound No. : XT0242)

Using N-(1,2,3,4-tetrahydronaphthalene-1-yl)-2-aminobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, a white solid was obtained according to the preparation method of Example 1 550mg, the yield is 85%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.20 (d, J = 7.8Hz, 1H, ArH), 7.79-7.70 (m, 2H, ArH), 7.55-7.18 (m, 4H, ArH), 7.13-6.89 (m, 4H, ArH), 5.13-4.96 (m, 1H, CH ₂ ), 3.07-2.99 (m, 1H, CH ₂ ), 2.84-2.69 (m, 2H, CH ₂ ), 2.40 (s ,3H,CH ₃ ),2.31-2.23(m,1H,CH ₂ ),2.07-1.99(m,1H,CH ₂ ),1.62-1.53(m,1H,CH ₂ ); HRMS(ESI,m/z ) Calculated value C ₂₅ H ₂₂ ClN ₂ O[(M+H) ⁺ ], 401.1415; measured value, 401.1413.

Example 22 2-(2-Chloro-4-methylphenyl)-3-cyclopentyl-7-methoxyquinazolin-4(3H)-one (compound number: XT0243)

Using N-cyclopentyl-2-amino-4-methoxybenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 550 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 85%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.18 (d, J = 8.6Hz, 1H, ArH), 7.33-7.20 (m, 3H, ArH), 7.10-7.05 (m, 2H, ArH), 4.22-4.13 (m, 1H, NCH), 3.87 (s, 3H, CH ₃ ), 2.41 (s, 3H, CH ₃ ), 2.32-2.23 (m, 1H, CH ₂ ), 2.09-1.87 (m, 3H ,CH ₂ ),1.66-1.36(m,4H,CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₁ H ₂₂ ClN ₂ O ₂ [(M+H) ⁺ ], 369.1364; measured value, 369.1364 .

Example 23 2-(2-Chloro-4-methylphenyl)-3-cyclopentyl-6-methylquinazolin-4(3H)-one (Compound No.: XT0248)

Using N-cyclopentyl-2-amino-5-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 510 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 80%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.09 (s, 1H, ArH), 7.61-7.49 (m, 2H, ArH), 7.32-7.19 (m, 3H, ArH), 4.23-4.14 (m ,1H,NCH),2.48(s,3H,CH ₃ ),2.45-2.43(m,1H,CH ₂ ),2.41(s,3H,CH ₃ ),2.32-2.22(m,1H,CH ₂ ), 2.11-1.85(m,3H,CH ₂ ),1.66-1.35(m,3H,CH ₂ ); HRMS(ESI,m/z) calculated value C ₂₁ H ₂₂ ClN ₂ O[(M+H) ⁺ ], 353.1415; measured value, 353.1414.

Example 24 2-(2-Chloro-4-methylphenyl)-3-(pent-3-yl)quinazolin-4(3H)-one (compound number: XT0250)

Using N-(pent-3-yl)-2-aminobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 500 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 80%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.31-8.28 (m, 1H, ArH), 7.76-7.68 (m, 2H, ArH), 7.51-7.46 (m, 1H, ArH), 7.33-7.19 (m,3H,ArH),3.52(s,1H,CH ₂ ),2.41(s,3H,CH ₃ ),2.28-2.09(m,3H,CH ₂ ),1.95-1.85(m,1H,CH ₂ ), 0.84 (t, 3H, CH ₃ ), 0.75 (t, 3H, CH ₃ ); HRMS (ESI, m/z) calculated value C ₂₀ H ₂₂ ClN ₂ O[(M+H) ⁺ ],341.1415; Measured value, 341.1416.

Example 25 2-(2-Chloro-4-methylphenyl)-3-(3-methylcyclohexyl)-4(3H)-one (compound number: XT0304)

Using N-(3-methylcyclohexyl)-2-aminobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method of Example 1, 450 mg of white solid was obtained, with a yield of 75%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.29 (d, J = 7.8Hz, 1H, ArH), 7.74-7.73 (m, 2H, ArH), 7.52-7.48 (m, 1H, ArH), 7.33(s,1H,ArH),7.28-7.26(m,1H,ArH),7.22-7.19(m,1H,ArH),3.68-3.65(m,1H,NCH), 2.51-2.48(m,1H, CH ₂ ), 2.42 (s, 3H, CH ₃ ), 1.89-1.73 (m, 2H, CH ₂ ), 1.62-1.50 (m, 3H, CH ₂ ), 1.30-1.24 (m, 2H, CH ₂ ), 0.95-0.85 (m, 4H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₂ H ₂₄ ClN ₂ O[(M+H) ⁺ ], 367.1572; measured value, 367.1572.

Example 26 2-(2-Chloro-4-methylphenyl)-3-cyclohexyl-6-fluoro-4(3H)-one (compound number: XT0308)

Using N-cyclohexyl-2-amino-5-fluorobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 550 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 83%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 7.92-7.89 (dd, J ₁ =8.6Hz, J ₂ =2.8Hz, 1H, ArH), 7.71-7.67 (m, 1H, ArH), 7.45 7.41(m,1H,ArH),7.34(s,1H,ArH),7.26-7.24(m,1H,ArH),7.21-7.17(m,1H,ArH),3.63-3.56(m,1H,NCH) ,2.81-2.68(m,1H,CH ₂ ),2.60-2.49(m,1H,CH ₂ ),2.42(s,3H,CH ₃ ),1.89-1.71(m,3H,CH ₂ ),1.57-1.51 (m, 2H, CH ₂ ), 1.26-0.83 (m, 3H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₁ H ₂₁ ClFN ₂ O[(M+H) ⁺ ], 371.1321; measured Value, 371.1322.

Example 27 2-(2-Chloro-4-methylphenyl)-3-cyclohexyl-6-chloro-4(3H)-one (Compound No.: XT0310)

Using N-cyclohexyl-2-amino-5-chlorobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 520 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 80%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.25-8.24 (m 1H, ArH), 7.76-7.61 (m, 2H, ArH), 7.34 (s, 1H, ArH), 7.25-7.19 (m, 2H, ArH), 3.63-3.56 (m, 1H, NCH), 2.80-2.70 (m, 1H, CH ₂ ), 2.59-2.49 (m, 1H, CH ₂ ), 2.42 (s, 3H, CH ₃ ), 1.89-1.71 (m, 3H, CH ₂ ), 1.61-1.51 (m, 2H, CH ₂ ), 1.24-0.84 (m, 3H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₁ H ₂₁ Cl ₂ N ₂ O[(M+H) ⁺ ],387.1025; measured value,387.1025

Example 28 2-(2-Chlorophenyl)-3-(pent-3-yl)-7-methoxyquinazolin-4(3H)-one (compound number: XT0312)

Using N-(but-2-yl)-2-amino-4-methoxybenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method of Example 1, 520 mg of white solid was obtained, yield 84%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.20-8.17 (m, 1H, ArH), 7.34-7.25 (m, 2H, ArH), 7.21-7.18 (m, 1H, ArH), 7.10-7.04 (m, 2H, ArH), 3.87 (s, 3H, CH ₃ ), 3.88-3.70 (m, 1H, CH ₂ ), 2.40 (s, 3H, CH ₃ ), 2.32-2.17 (m, 1H, CH ₂ ),2.12-1.75(m,1H,CH ₂ ),1.71-1.45(m,3H,CH ₃ ),0.83-0.71(m,3H,CH ₃ ); HRMS(ESI,m/z) calculated value C ₂₀ H ₂₂ ClN ₂ O ₂ [(M+H) ⁺ ], 357.1364; found value, 357.1363.

Example 29 2-(2-Chloro-4-methylphenyl)-3-(thiophen-2-yl)quinazolin-4(3H)-one (Compound No.: ZXW1602)

Using N-(thiophen-2-yl)-2-aminobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 350 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 55%. Pale yellow solid; yield 55%; ¹ H NMR (400MHz, DMSO) δ (ppm): 8.69–8.67 (m, 1H, ArH), 8.40–8.36 (m, 1H, ArH), 8.23–8.21 (m, 1H,ArH),8.13-8.08(m,1H,ArH),7.99-7.88(m,3H,ArH),7.67(s,1H,ArH),7.58-7.56(m,1H,ArH),7.52-7.50 (m, 1H, ArH), 2.71 (s, 3H, CH ₃ ); HRMS (ESI, m/z) calculated value C ₁₉ H ₁₄ ClN ₂ O ₅ [(M+H) ⁺ ], 335.0510; measured value, 335.0510.

Example 30 6,8-Dichloro-(2-chloro-4-methylphenyl)-3-phenyl-quinazolin 4(3H)-one (compound number: XT0326

Using N-(phenyl)-2-amino-3,5-dichlorobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 500 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 80% . ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.24 (d, J = 2.2Hz, 1H, ArH), 7.85 (d, J = 2.2Hz, 1H, ArH), 7.28-7.23 (m, 5H, ArH), 7.17-7.15 (m, 1H, ArH), 7.04 (s, 1H, ArH), 6.96-6.94 (m, 1H, ArH), 2.23 (s, 3H, ArCH ₃ ); HRMS (ESI, m /z) Calculated value C ₂₁ H ₁₄ Cl ₃ N ₂ O [(M+H) ⁺ ], 415.0166; measured value, 415.0166.

Example 31 8-Methyl-(2-chloro-4-methylphenyl)-3-cyclopentylquinazolin-4(3H)-one (compound number: XT0330)

Using N-(phenyl)-2-amino-3-methylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 510 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 81%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.16-8.14 (m, 1H, ArH), 7.59-7.57 (m, 1H, ArH), 7.39-7.27 (m, 3H, ArH), 7.22-7.20 (m,1H,ArH),4.22-4.14(m,1H,CH),2.54(s,3H,ArCH ₃ ),2.51-2.44(m,1H,CH ₂ ),2.43(s,3H,ArCH ₃ ) , 2.32-2.19 (m, 1H, CH ₂ ), 2.13-1.85 (m, 3H, CH ₂ ), 1.65-1.35 (m, 3H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₁ H ₂₂ ClN ₂ O[(M+H) ⁺ ], 353.1415; found value, 353.1415.

Example 32 7-Trifluoromethyl-(2-chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one (Compound No.: XT0338)

Using N-(phenyl)-2-amino-3-trifluoromethylbenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 541mg of white solid was obtained according to the preparation method of Example 1, with a yield of 84% . ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.49-8.47 (m, 1H, ArH), 8.12-8.11 (m, 1H, ArH), 7.77-7.75 (m, 1H, ArH), 7.38-7.29 (m,4H,ArH),7.17-7.07(m,3H,ArH),6.97-6.92(m,1H,ArH),.2.25(s,3H,ArCH ₃ ); HRMS(ESI,m/z) calculation Value C ₂₂ H ₁₅ ClF ₃ N ₂ O[(M+H) ⁺ ], 415.0820; measured value, 415.0819.

Example 33 5-Methoxy-(2-chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one (Compound No. XT0340)

Using N-(phenyl)-2-amino-6-methoxybenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, according to the preparation method of Example 1, 544 mg of white solid was obtained, and the yield was 82%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 7.72-7.68 (m, 1H, ArH), 7.39-7.37 (m, 2H, ArH), 7.25-7.19 (m, 3H, ArH), 7.15-7.12 (m, 1H, ArH), 7.06-7.03 (m, 2H, ArH), 6.97-6.91 (m, 2H, ArH), 3.99 (s, 3H, ArOCH ₃ ), 2.22 (s, 3H, ArCH ₃ ); HRMS (ESI, m/z) calculated value C ₂₂ H ₁₈ ClN ₂ O ₂ [(M+H) ⁺ ], 377.1051; measured value, 377.1051.

Example 34 6,7-Difluoro-(2-chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one (Compound No.: XT0342)

Using N-(phenyl)-2-amino-4,5-difluorobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 383 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 80% . ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.14-8.19 (m, 1H, ArH), 7.62-7.57 (m, 1H, ArH), 7.36-7.35 (m, 1H, ArH), 7.29-7.28 (m,3H,ArH),7.13-7.06(m,3H,ArH),6.96-6.94(m,1H,ArH),.2.24(s,3H,ArCH ₃ ); HRMS(ESI,m/z) calculation Value C ₂₁ H ₁₄ ClF ₂ N ₂ O[(M+H) ⁺ ], 383.0757; measured value, 383.0757.

Example 35 7-bromo-(2-chloro-4-methylphenyl)-3-phenylquinazolin-4(3H)-one (compound number: XT0346)

Using N-(phenyl)-2-amino-4-bromobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 425 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 81%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.22-8.20 (m, 1H, ArH), 7.99-7.98 (m, 1H, ArH), 7.67-7.68 (m, 1H, ArH), 7.36 (s ,1H,ArH),7.28-7.24(m,3H,ArH),7.13-7.05(m,3H,ArH),6.96-6.93(m,1H,ArH),2.24(s,3H,ArCH ₃ ); HRMS (ESI, m/z) calculated value C ₂₁ H ₁₅ BrClN ₂ O[(M+H) ⁺ ], 425.0051; measured value, 425.0051.

Example 36 2-(2-Chloro-4-methylphenyl)-3-cycloheptylquinazolin-4(3H)-one (Compound No.: XT0302)

Using N-(phenyl)-2-aminobenzamide and 2-chloro-4-methylbenzaldehyde as raw materials, 350 mg of white solid was obtained according to the preparation method of Example 1, with a yield of 82%. ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm): 8.31-8.28 (m, 1H, ArH), 7.75-7.69 (m, 2H, ArH), 7.51-7.47 (m, 1H, ArH), 7.35 (s ,1H,ArH),7.30-7.20(m,2H,ArH),3.77(s,1H,CH ₂ ),2.70-2.46(m,2H,CH ₂ ),2.43(s,3H,CH ₃ ),1.99 -1.92(m,1H,CH ₂ ),1.83-1.77(m,1H,CH ₂ ),1.70-1.58(m,2H,CH ₂ ),1.51-1.39(m,3H,CH ₂ ),1.30-1.17 (m, 3H, CH ₂ ); HRMS (ESI, m/z) calculated value C ₂₂ H ₂₄ ClN ₂ O [(M+H) ⁺ ], 367.1572; measured value, 367.1572.

Example 37 Cytotoxicity test

With methaqualone (QUA) as a positive control drug, CCK8 was used to detect the toxicity of 36 compounds on Hep G2 cells, and each compound was tested at three concentrations of 30 μM, 10 μM, and 3 μM. Preliminary evaluation of the safety of the compound.

OD _S : absorbance value of sample well (compound to be tested)

OD _NC : Absorbance value of negative wells (cell + medium + DMSO)

OD _STSP : Absorbance value of positive control well (cell + culture medium + Staurosporine)

Example 38 Pharmacodynamic study of inducing hypnotic behavior

Diazepam (DZP) and methaqualone (QUA) were used as positive control drugs, and the compounds in Table 2 were used as control drugs for pharmacodynamic study. After intraperitoneal injection of the compound, the induced behavioral effect was observed, and the rate of disappearance of the righting reflex in mice was recorded. The results are shown in Table 3 below.

Table 2

Table 3 Pharmacodynamic studies on inducing hypnotic behavior

Administration method: gavage; sedation: the animal does not lose the flip reflex, but sedation, spontaneous activity is significantly reduced; -: not tested. The hypnotic duration of all test compounds was within 25 minutes, and the duration was shorter than diazepam, achieving the short-acting purpose. (Convulsions, paralysis) means that after the administration, the mice have a convulsive effect within 1-2 minutes, and then lose their righting reflex, and the body is paralyzed.

As a result, it was found that the key structural feature of the present invention is that the substitution of chlorine at position 10 in formula (I) is very critical to the improvement of drug efficacy, and the substitution of methyl at position 12 can avoid the side effects of muscle relaxation caused by the compound before convulsions.

Example 39 Study on drug metabolism of rat liver microsomes

1. Testing equipment and analysis conditions

Testing equipment Thermo Scientific Q Exactive combined quadrupole Orbitrap mass spectrometer. Chromatographic conditions: Phenomenex C 18 (150mm×2.1mm, 5μm) column; mobile phase: water (containing 0.1% formic acid, A)-acetonitrile (containing 0.1% formic acid, B); gradient elution (0～30min, 98%～2%A; 30.01min, 98%A; 30.01～35min, 98%A); column temperature 25℃; flow rate 0.3mL/min; injection volume 5μL.

Electrospray ion source (ESI) adopts positive scan mode, electrospray voltage is 2.8kV; sheath gas flow rate is 35arb; auxiliary gas flow rate is 10arb; capillary temperature is 320℃; full scan (Full scan): resolution: 70000; Scan range: 50-500m/z; secondary data dependent scan (Full MS/dd-MS2): resolution: 17500.

2. Sample pretreatment

The liver microsomes were pre-processed with the direct protein precipitation method. In the incubation system, take 50μL each at 0min and 60min, add 200μL acetonitrile, vortex for 1min, centrifuge at 4℃ (13800×g) for 10min, and take 100μL of the supernatant. Sample analysis.

3. In vitro metabolic transformation experiment of representative compound 9050

The total reaction volume of rat liver microsomes is 250μL, and the final concentration of each component in the incubation system is (9050 is 50μM, liver microsomal protein concentration is 1.185mg/mL, NADPH concentration is 1mM, incubated at 37°C), respectively, taken at 0 and 60 minutes 50 μL to 200 μL of ice-cold acetonitrile and mix to stop the reaction. Shake for 2 min, centrifuge at 4°C, 13 800 × g for 10 min, and quantitatively take 100 μL of the supernatant for analysis.

4. Experimental results

The representative compound 9050 is incubated in rat liver microparticles and can be quickly converted into hydroxylated metabolites (1h), which is consistent with the speculation of drug molecular design, as shown in Figure 2.

Industrial application

The next day residual effect is one of the main limitations of current sedative and hypnotic drugs. Compared with the existing first-line sedative and hypnotic drugs, diazepam and midazolam, the compound of the present invention has stronger pharmacological effects, faster metabolism, and reduces the residual effect of the next day. It is expected to be developed as a new type of high-efficiency and low-toxicity sedative and hypnotic drugs . In addition, the preparation process of the compound is simple, the key step of the compound reaction is catalyzed by cheap metal copper, the yield is higher, the energy consumption is lower, and it is more environmentally friendly.

Claims (12)

1. A 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) or a pharmaceutically acceptable salt, ester, isomer, Racemates, prodrugs, solvates, hydrates:

   

   Wherein, R ₁ and R ₂ are each independently hydrogen, halogen atom, C1 to C15 linear or branched alkyl, halogen substituted C1 to C15 linear or branched alkyl, C1 to C15 alkoxy Group, C1 to C15 alkylamino, C2 to C20 alkenyl or C5 to C20 aryl;

   W is C1 to C15 linear or branched alkyl, C2 to C20 alkenyl, saturated or unsaturated three to seven membered heterocyclic ring, saturated or unsaturated three to seven membered heterocyclic ring substituted C1 to C3 Alkyl, substituted or unsubstituted C3 to C20 cycloalkyl or substituted or unsubstituted C3 to C20 aryl;

   Wherein the halogen atom is fluorine, chlorine or bromine;

   The saturated or unsaturated three to seven heterocyclic ring contains 1 to 3 heteroatoms selected from O, S and N;

   In the substituted or unsubstituted C3 to C20 cycloalkyl group, "substituted" means that there are 1 to 3 C1 to C6 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C20 cycloalkyl group;

   In the substituted or unsubstituted C3 to C20 aryl group, "substituted" means that there are 1 to 3 C1 to C6 alkyl groups on the C3 to C20 aryl group.
2. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt or ester thereof , Isomers, racemates, prodrugs, solvates, hydrates, characterized in that: said R ₁ and R ₂ are each independently hydrogen, halogen atom, C1 to C10 linear or branched alkyl , Halogen substituted C1 to C10 linear or branched alkyl, C1 to C10 alkoxy, C1 to C10 alkylamino, C2 to C10 alkenyl or C5 to C10 aryl;

   W is C1 to C10 linear or branched alkyl, C2 to C10 alkenyl, saturated or unsaturated five-membered or six-membered heterocycle, saturated or unsaturated five-membered or six-membered heterocycle substituted C1 or C2 alkyl, substituted or unsubstituted C3 to C10 cycloalkyl or substituted or unsubstituted C3 to C10 aryl;

   The saturated or unsaturated five-membered or six-membered heterocyclic ring contains 1 or 2 heteroatoms selected from O and S;

   In the substituted or unsubstituted C3 to C10 cycloalkyl group, "substituted" means that there are 1 to 3 C1 to C3 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C10 cycloalkyl group;

   In the substituted or unsubstituted C3 to C10 aryl group, "substituted" means that there are 1 to 3 C1 to C3 alkyl groups on the C3 to C10 aryl group.
3. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt or ester thereof , Isomers, racemates, prodrugs, solvates, hydrates, characterized in that: said R ₁ and R ₂ are each independently hydrogen, halogen atom, C1 to C6 linear or branched alkyl , Halogen substituted C1 to C6 linear or branched alkyl, C1 to C6 alkoxy, C1 to C6 alkylamino, C2 to C6 alkenyl or C5 to C10 aryl;

   W is C1 to C6 linear or branched alkyl, C2 to C6 alkenyl, saturated or unsaturated five-membered or six-membered heterocycle, saturated or unsaturated five-membered or six-membered heterocycle substituted C1 or C2 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl or substituted or unsubstituted C3 to C8 aryl;

   The saturated or unsaturated five-membered or six-membered heterocyclic ring contains 1 or 2 heteroatoms selected from O and S;

   In the substituted or unsubstituted C3 to C10 cycloalkyl group, "substituted" refers to the presence of 1 or 2 C1 to C3 alkyl groups or cyclic C5 to C6 aryl groups on the C3 to C8 cycloalkyl group;

   In the substituted or unsubstituted C3 to C10 aryl group, "substituted" means that there are 1 or 2 C1 to C3 alkyl groups on the C3 to C10 aryl group.
4. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt or ester thereof , Isomers, racemates, prodrugs, solvates, hydrates, characterized in that: the R ₁ and R ₂ are each independently a hydrogen, a halogen atom, and the number of carbon atoms is C1, C2, C3, C4 , C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 straight or branched chain alkyl, the number of carbon atoms substituted by halogen atoms is C1, C2, C3, C4, C5, C6 , C7, C8, C9, C10, C11, C12, C13, C14 or C15 straight chain or branched chain alkyl, carbon number is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, or C15 alkoxy, containing C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 Alkylamino, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkenyl, carbon The number of atoms is C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups;

   W is selected from alkyl groups having carbon atoms of C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, and carbon atoms of C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkenyl groups with carbon number C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13 , C14, C15, C16, C17, C18, C19 or C20 aryl, saturated or unsaturated three to seven membered heterocyclic ring, saturated or unsaturated three to seven membered heterocyclic ring substituted C1, C2 or C3 alkane Group, substituted or unsubstituted C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 cycloalkyl, or substituted or unsubstituted Substituted C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups.
5. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt or ester thereof , Isomer, racemate, prodrug, solvate, hydrate, wherein said R ₁ and R ₂ are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl , Methoxy, ethoxy, propoxy, trifluoromethyl and trifluoroethyl;

   W is chlorophenyl, methylphenyl, ethylphenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, methylcycloheptyl, methylcyclooctyl, Ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, ethylcycloheptyl, ethylcyclooctyl, furanyl, pyridyl, thienyl, pyrrolyl, tetrahydrofuranyl, Tetrahydropyrrolyl, tetrahydrothienyl, furyl methyl, pyridyl methyl, thienyl methyl, pyrrolyl methyl, tetrahydrofuryl methyl, tetrahydropyrrolyl methyl, tetrahydrothienyl methyl, furan Ethyl ethyl, pyridyl ethyl, thienyl ethyl, pyrrolyl ethyl, tetrahydrofuryl ethyl, tetrahydropyrrolyl ethyl, or tetrahydrothienyl ethyl.
6. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to claim 1, or a pharmaceutically acceptable salt or ester thereof , Isomer, racemate, prodrug, solvate, hydrate, characterized in that: the compound represented by formula (I) is selected from any of the following compounds:

   

   

   

   
7. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to any one of claims 1-6 or a pharmaceutically Acceptable salts, esters, isomers, racemates, prodrugs, solvates, and hydrates are characterized in that: the isomers include stereoisomers, tautomers, enantiomers, and diastereomers. Enantiomer.
8. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to any one of claims 1-7 or its pharmaceutically acceptable Application of accepted salts, esters, isomers, racemates, prodrugs, solvates, and hydrates in the preparation of drugs with at least one of the following functions: treatment of sedation and hypnosis, anticonvulsants, treatment of tumors, and antibacterial infections , Anti-HIV infection, anti-TB infection, anti-Parkinson's disease, anti-inflammatory, antipyretic, regulating cardiovascular and regulating cell and enzyme activity function, preventing and/or treating diseases or symptoms related to abnormal CDK activity .
9. The 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to any one of claims 1-7 or its pharmaceutically acceptable Use of accepted salts, esters, isomers, racemates, prodrugs, solvates, and hydrates in the treatment of at least one of the following diseases: treatment of sedation and hypnosis, anticonvulsants, treatment of tumors, antibacterial infections, anti-HIV Infection, anti-TB infection, anti-Parkinson's syndrome, anti-inflammatory, antipyretic, regulating cardiovascular and regulating cell and enzyme activity functions, preventing and/or treating diseases or symptoms related to abnormal CDK activity.
10. A pharmaceutical composition comprising an effective amount of 2-(2-chloro-4-methylphenyl)quinazole represented by the formula (I) in any one of claims 1-7 Pholin-4(3H)-ketone compounds or pharmaceutically acceptable salts, esters, isomers, racemates, prodrugs, solvates and hydrates thereof are used as active ingredients and pharmaceutically acceptable excipients.
11. The pharmaceutical composition according to claim 10, characterized in that: the pharmaceutical composition has at least one of the following effects: treatment of sedation and hypnosis, anticonvulsant, treatment of tumor, antibacterial infection, anti-HIV infection, anti-TB infection , Anti-Parkinson's syndrome, anti-inflammatory, antipyretic, regulating cardiovascular and regulating cell and enzyme activity functions, preventing and/or treating diseases or symptoms related to abnormal GABA _A activity.
12. The method for preparing 2-(2-chloro-4-methylphenyl)quinazolin-4(3H)-one compound represented by formula (I) according to any one of claims 1-7, comprising: The steps described:

    1) The substituted or unsubstituted 2-nitrobenzoic acid of formula II is subjected to amide condensation reaction with W-NH ₂ to obtain the compound of formula III;

    

    Wherein, R ₁ and R ₂ in formula II have the same definition as formula I, and W in W-NH ₂ has the same definition as formula I.

    The definitions of R ₁ and R ₂ in Ⅲ are the same as those in formula II, and the definition of W is the same as that of W in W-NH ₂ ;

    2) Reducing the nitro group in the compound of formula III to obtain the compound of formula IV;

    

    Among them, R ₁ , R ₂ , and W in formula IV have the same definition as formula III,

    3) The compound represented by formula IV and the compound represented by formula V are subjected to Schiff base condensation reaction and heated to cyclize to obtain the compound represented by formula I.

    

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