Phenylpiperazine and quinazoline hybrid compound as well as preparation method and application thereof

Abstract

The invention discloses a phenylpiperazine and quinazoline hybrid compound as well as a preparation method and application thereof, belongs to the technical field of medicines, and particularly relates to an N-[2-(4-phenylpiperazine-1-yl) ethyl]-2-[(quinazoline-4-yl) amino] benzamide derivative with a structural formula as shown in a formula I and pharmaceutically acceptable salt thereof. The N-[2-(4-phenylpiperazine-1-yl) ethyl]-2-[(quinazoline-4-yl) amino] benzamide derivative or the pharmaceutically acceptable salt of the compound can be combined with an existing medicine or independently used as an influenza virus inhibitor, and has a better inhibition effect on various influenza A viruses.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a... N Preparation of 2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives and their application as antiviral drugs for influenza. Background Technology

[0002] Influenza viruses primarily infect the respiratory system of humans and animals, belonging to an important class of respiratory pathogens. Human infection with the virus can manifest as a variety of clinical symptoms, including cough, headache, and fever. The pathological progression of influenza is significantly accelerated in high-risk groups, particularly children, the elderly, immunocompromised individuals, cancer patients, and those with chronic underlying diseases such as diabetes and heart disease (SCHAUWVLIEGHE A, RIJNDERS B, PHILIPS N, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study). Lancet respiratory medicine , 2018, 6(10): 782-792.). Currently, the main effective means of controlling influenza focus on vaccination and small molecule-based antiviral drug therapy.

[0003] Currently, clinically available anti-influenza drugs mainly fall into three categories: inhibitors targeting the M2 protein, inhibitors targeting neuraminidase (NA), and drugs that inhibit RNA polymerase. However, the prevalence of drug-resistant viral strains is continuously increasing. Therefore, the development of next-generation anti-influenza drugs is of paramount importance.

[0004] RNA-dependent RNA polymerase (RdRP) is considered a highly attractive drug target due to its central role in influenza virus gene transcription and replication (SHANKARAN S, BEARMAN GML. Influenza virus resistance to neuraminidase inhibitors: Implications for treatment). Current infectious disease reports, 2012, 14(2): 155-160.). The structural features of RdRP are highly conserved across all influenza virus strains and exhibit high specificity for both the host and cells. Compared to M2 ion channel proteins and neuraminidase (NA), intervention strategies targeting this site are expected to be less likely to induce drug resistance. Therefore, this invention selected influenza virus RNA polymerase as the target site and, using computer simulation screening technology, obtained a class of N The -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivative showed promising virtual evaluation results. Based on this, a reasonable chemical synthesis route was designed, and this series of compounds was successfully prepared. Specific in vitro antiviral activity experiments were then conducted. Summary of the Invention

[0005] The technical problem solved by this invention is to provide a N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives, their preparation methods, and applications, specifically as shown in Formula I. N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives, their prodrugs and pharmaceutically active metabolites, as well as stereoisomers of the compound and their pharmaceutically acceptable salts, and provide their use in the preparation of medicaments for the treatment of influenza-related diseases.

[0006] The structural formula is shown in Formula I. N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives, their prodrugs and pharmaceutically active metabolites, and stereoisomers of the compound and their pharmaceutically acceptable salts:

[0007] Wherein, R represents one or more substituents at any position, and each R is independently selected from hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, and allyloxy.

[0008] Furthermore, R is independently selected from hydrogen, fluorine, chlorine, methoxy, methyl, trifluoromethoxy, trifluoromethyl, allyloxy, ethoxy, and tert-butyl.

[0009] Furthermore, the aforementioned N The -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivative is any one of the following compounds:

[0010] The present invention also provides a pharmaceutical composition comprising the following as shown in Formula I. N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives and pharmaceutically acceptable carriers or diluents.

[0011] This pharmaceutical composition is used to prepare a drug for treating influenza virus diseases. For example, using an aqueous saline solution as a carrier with a pH of 7.4, the pharmaceutical composition can be introduced into the patient's bloodstream in solution form via local injection.

[0012] The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable excipients such as carriers or diluents, in the form of a pharmaceutical composition, in accordance with conventional pharmaceutical practices. Routes of administration include oral administration or non-gastrointestinal routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes.

[0013] For oral administration, in addition to tablets or capsules, aqueous solutions or suspensions can also be used. When administered orally, the active pharmaceutical ingredient is combined with an orally viable, non-toxic, and pharmaceutically acceptable inert carrier to form a pharmaceutical composition. For oral administration in tablet or capsule form, carriers include lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and sorbitol; for oral administration in liquid form, carriers include ethanol, glycerin, water, and combinations thereof. Furthermore, pharmaceutically acceptable binders, lubricants, disintegrants, and colorants may be added to the pharmaceutical composition. Binders include starch, gelatin, natural sugars (such as glucose or lactose), corn sweeteners, natural and synthetic gums (such as gum arabic), tragacanth gum or sodium alginate, carboxymethyl cellulose, polyethylene glycol, and waxes. Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. When an aqueous suspension is administered orally, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners or flavoring agents may also be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is typically prepared, and the pH of the solution should be appropriately adjusted and buffered. For intravenous administration, the total solute concentration should be controlled to maintain the isotonicity of the formulation.

[0014] The present invention N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives can also be used in combination with known agents used to treat or prevent influenza. Preferred combinations include compounds of the present invention with M2 ion channel protein inhibitors, compounds of the present invention with neuraminidase inhibitors, compounds of the present invention with interferon inducers, compounds of the present invention with antisense oligonucleotides, and compounds of the present invention with inosine monophosphate dehydrogenase inhibitors.

[0015] The term "giving" and its variations (e.g., "giving" compound) in relation to this invention means: to give N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives or prodrugs of this compound are introduced into the animal system requiring treatment. When N When a 2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivative or its prodrug is provided in combination with one or more other active agents, "giving" and its variations can be understood to include both simultaneous and successive introduction. N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives or their prodrugs, as well as other pharmaceutical agents. Typically, the prodrug is... NA functional derivative of -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide, which is readily converted into the desired compound in vivo. In this invention, the term "given" will include those specifically disclosed. N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives or compounds that may not be specifically disclosed, but which can be converted into specific compounds in vivo after administration to a patient.

[0016] When the compounds of the present invention are administered to human subjects, the daily dose will generally be determined by the prescribing physician, and the dose will generally vary according to the individual patient's age, weight, response, and the severity of the patient's symptoms. In one exemplary application, an appropriate amount of the compound is administered to the treated mammal. When used for the indicated effects, the oral dose of the present invention will be from about 0.01 mg / kg body weight per day (mg / kg / day) to about 100 mg / kg / day, preferably from 0.01 mg / kg / day to 10 mg / kg / day, and most preferably from 0.1 mg / kg / day to 5.0 mg / kg / day. For oral administration, the composition is preferably provided in tablet form, wherein the tablets comprise 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 mg of the active ingredient, preferably from 1 mg to 100 mg of the active ingredient. For intravenous injection, the most preferred dose during constant-rate infusion is 0.1 mg / kg / min to 10 mg / kg / min. The compounds of the present invention or pharmaceutical compositions comprising such compounds can be administered as a once-daily dose, or the total daily dose can be divided into two, three, or four daily doses. For administration via a transdermal drug delivery system, the dosage is continuous rather than intermittent throughout the dosing regimen.

[0017] The dosage regimen for using the compounds of this invention must be selected based on a variety of factors, including the patient's (or subject's) type, species, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt used. General technicians, veterinarians, or clinicians can readily determine and prescribe effective dosages for prevention, control, or prevention of condition progression.

[0018] In the method of the present invention, the compounds described in detail herein can form an active ingredient and, depending on the different forms of administration such as oral tablets, capsules, elixirs, syrups, etc., can be mixed with a rationally selected appropriate pharmaceutical diluent, excipient or carrier (collectively referred to herein as "carrier" substances), and the mixing method conforms to conventional pharmaceutical practices.

[0019] Pharmaceutically acceptable salts of the compounds of this invention refer to conventional acid addition salts or base addition salts formed by the combination of a suitable nontoxic organic acid or inorganic acid or organic base or inorganic base, which retain the biopotency and properties of the compound of formula I. Acid addition salts include hydrochlorides, hydrobroms, hydroiodates, nitrates, phosphates, sulfates, perchlorates, thiocyanates, hydrogen sulfates, persulfates, borates, formates, acetates, propionates, valerates, neovalerates, hexanoates, heptanoates, octanoates, isooctanoates, undecanoates, laurates, palmitates, stearates, oleates, cyclopropionates, oxalates, malonates, succinates, maleates, fumarates, adipates, azelaates, acrylates, succinates, crotonates, tigrinates, itacrates, sorbates, cinnamates, glycolates, lactates, malates, tartrates, citrates, tartrites, mandelates, diphenylglycolates, tropidines, ascorbic acid salts, gluconates, glucono-p-ethyl, gluconate, mannitolates, lactobionates, benzoates, terephthalates, paraphthalates, furoate, nicotinic acid salts, and isophthalates. Nicotinate, salicylate, acetylsalicylic acid, butyrate, gallate, caffeate, ferulic acid, picrate, camphorate, camphor sulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, p-aminobenzenesulfonate, aminosulfonate, taurine, 2-hydroxyethanesulfonate, glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartate, asparagine, glutamate, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, ethylenediaminetetraacetic acid, pyruvate, α-ketoglutarate, alginate, cyclopentanepropionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthylcarboxylate, 2-naphthylsulfonate, dihydroxynaphthylate, lauryl sulfate, glycerol phosphate, pectin fatty acid salts, etc. Base addition salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts of organic bases such as dicyclohexylamine salts and N-methyl-D-glucosamine salts. Furthermore, basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides, such as chloro, bromine, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfate esters, such as dimethyl, diethyl, dibutyl, and dipentyl sulfate; long-chain halides, such as chloro, bromine, and iodides of decyl, lauryl, myristyl, and stearoyl groups; and aralkyl halides, such as bromides of benzyl and phenethyl groups.

[0020] The present invention also provides the general formula I shown N A method for preparing -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide derivatives includes the following steps:

[0021] Wherein, R is as described in general formula I.

[0022] Preparation of compound M1: Diethanolamine reacts with sulfoxide to give dichloroethylamine (1); dichloroethylamine (1) reacts with R-substituted aniline to give R-substituted phenylpiperazine hydrochloride (2); R-substituted phenylpiperazine hydrochloride (2) reacts with chloroacetonitrile to give intermediate compound (3); intermediate compound (3) is reduced by lithium aluminum hydride to give intermediate compound (4); intermediate compound (4) reacts with o-aminobenzoic acid to give compound M1; Preparation of compound M2: methyl 2-aminobenzoate (5) reacted with formamide to give 4-hydroxyquinazoline (6); 4-hydroxyquinazoline (6) reacted with sulfoxide to give compound M2; Preparation of the final product: Compound M1 reacts with compound M2 to obtain the final product, compound of general formula I.

[0023] The beneficial effects of this invention are: The compounds provided by this invention are novel influenza virus inhibitors that act on RNA polymerase, used to inhibit influenza viruses. Compared with currently marketed antiviral drugs that target other targets, influenza virus inhibitors acting on RNA polymerase are more stable. These influenza virus inhibitor compounds have broad therapeutic effects against influenza. Furthermore, the preparation method of these compounds is simple, yields are stable, and the prepared compounds can effectively treat influenza-related diseases. Detailed Implementation

[0024] The technical solution of the present invention will be described in detail below with reference to the specific embodiments. However, it should be understood that the present invention is not limited to the specific examples described below.

[0025] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0026] Example 1: N Preparation of 2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-01) Step A: Preparation of 4-hydroxyquinazoline 30.1 g (0.2 mol) of methyl 2-aminobenzoate, 100 mL of formamide, and 3 mL of formic acid were added to a 250 mL pear-shaped flask. The mixture was stirred in an oil bath at 150 °C for 8 h. Upon cooling, a white solid precipitated. The solid was filtered to obtain 18.8 g of white solid, yielding 67%. Mp: 217.5 °C.

[0027] Step B: Preparation of 4-chloroquinazoline 14.6 g (0.1 mol) of 4-hydroxyquinazoline, 60 mL of thionyl chloride, and 0.1 mL of triethylamine were added to a 100 mL round-bottom flask. The mixture was refluxed at 80 °C for 12 h. The thionyl chloride was distilled off under reduced pressure, and the mixture was stirred with 30 mL of dichloromethane. The mixture was then filtered to obtain 10.7 g of a yellow solid, with a yield of 65.2%. Mp: 96.4~97.6 °C.

[0028] Step C: Preparation of dichloroethylamine hydrochloride 20.01 mL (0.2 mol) of diethanolamine was mixed with 60 mL of chloroform and added to a 250 mL three-necked flask. 40 mL (0.56 mol) of thionyl chloride was dissolved in 40 mL of chloroform and added to a 100 mL constant-pressure dropping funnel, which was then attached to the three-necked flask. A spherical condenser and a glass stopper were installed in the three-necked flask. The mixture was then slowly added dropwise to the diethanolamine and chloroform mixture at 35 °C (approximately 4 h). The mixture was then heated under reflux for 5 h, slightly cooled, and the thionyl chloride and chloroform were evaporated to dryness using a rotary evaporator. The mixture was recrystallized from 95% ethanol, filtered, and dried to give 11.59 g of a white solid, with a yield of 33.1%. ESI-MS m / z: 142.2 [M+H] + .

[0029] Step D: Preparation of 1-(2,3-dichlorophenyl)piperazine hydrochloride 0.056 mol of 2,3-dichloroaniline, 10 g (0.056 mol) of dichloroethylamine hydrochloride, and 7.7 g (0.056 mol) of potassium carbonate were dissolved in 30 mL of n-butanol. The solution was added to a 100 mL round-bottom flask, a spherical condenser was installed, and the mixture was heated to 120 °C under reflux for 24 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was filtered while hot to remove potassium chloride. The filtrate was then cooled, and a white solid precipitated. The filtrate was filtered, washed with 5 mL of n-butanol, and dried. 5.57 g of a white solid was obtained, with a yield of 37.2%.

[0030] Step E: Preparation of 2-[4-(2,3-dichlorophenyl)piperazin-1-yl]acetonitrile 0.01 mol of 1-(2,3-dichlorophenyl)piperazine hydrochloride, 0.02 mol of chloroacetonitrile, and 0.02 mol of potassium carbonate were added to a 100 mL flask. 60 mL of acetonitrile was added as solvent. A spherical condenser was installed, and the mixture was heated to reflux. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature and filtered to remove excess potassium carbonate and the generated potassium chloride. The filtrate was evaporated to dryness using a rotary evaporator and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1, V / V) to give 2.60 g of a white solid, with a yield of 96.4%.

[0031] Step F: Preparation of 2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethylamine 0.01 mol of 2-[4-(2,3-dichlorophenyl)piperazin-1-yl]acetonitrile was added to a 100 mL flask, along with 20 mL of tetrahydrofuran as a solvent. A drying tube was attached, and the mixture was stirred in an ice bath for 5 min. Then, 0.76 g (0.02 mol) of lithium aluminum hydride was added in portions, and the reaction was monitored by TLC. After the reaction was complete, 0.5 mL of water was slowly added dropwise, at which point a large amount of gas was released. Then, 0.5 mL of 15% sodium hydroxide solution was added, followed by 2 mL of water. The mixture was stirred, and the solution changed from gray to milky white. The solution was then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was dried over anhydrous magnesium sulfate, filtered to remove the drying agent, and the filtrate was evaporated to dryness using a rotary evaporator to obtain a yellow oily compound. ESI-MS m / z: 275.3 [M+H] + .

[0032] Step G: 2-Amino -N- Preparation of {2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}benzamide 0.01 mol of 2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethylamine, 1.51 g (0.011 mol) of anthranilic acid, 3.8 g (0.02 mol) of EDCI, and HOBt were added. 2.7 g (0.02 mol) and 3.0 g (0.03 mol) of triethylamine were added to a 250 mL round-bottom flask, along with 70 mL of dichloromethane as a solvent. A drying tube was attached, and the mixture was stirred at room temperature. The reaction was monitored by TLC. Once the reaction was complete, 70 mL of water was added to the system. While stirring, the pH was adjusted to approximately 4 with 1 mol / L dilute HCl. The mixture was allowed to stand, and the layers were separated. The aqueous layer was retained, and its pH was adjusted to approximately 10 with 1 mol / L dilute NaOH solution. Ethyl acetate was added for extraction, and the mixture was allowed to stand. The layers were separated, and the ethyl acetate layer was retained. Anhydrous magnesium sulfate was added to the ethyl acetate layer for drying. The drying agent was removed by filtration, and the ethyl acetate was evaporated to dryness using a rotary evaporator to obtain 1.46 g of a white solid, with a yield of 37.1%.

[0033] Step H: N Preparation of 2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-01) 2-amino -N-5 mmol of {2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}benzamide, 1.80 g (11 mmol) of 4-chloroquinazoline, and 3.04 g (0.03 mol) of triethylamine were added to a 100 mL flask, followed by 20 mL of anhydrous ethanol. A spherical condenser was installed, and the mixture was heated to reflux. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was cooled and evaporated to dryness using a rotary evaporator. The solution was then separated by silica gel column chromatography (methanol:dichloromethane = 1:80, V / V) to give 0.82 g of a white solid, with a yield of 31.6%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.46 (s, 1H), 8.97 – 8.90 (m, 1H), 8.83 (t, J = 5.6 Hz, 1H), 8.72 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95 – 7.88 (m,1H), 7.85 (dt, J = 8.0, 1.7 Hz, 2H), 7.76 (ddd, J = 8.3, 6.7, 1.5 Hz, 1H), 7.62 (dd, J = 15.8, 1.5 Hz, 1H), 7.32 – 7.17 (m, 3H), 6.91 (dd, J = 7.6, 2.1Hz, 1H), 3.51 (q, J = 6.4 Hz, 2H), 2.89 (s, 4H), 2.58 (d, J = 10.1 Hz, 6H); ESI-MS m / z:521.2 [M+H] + .

[0034] Example 2: 2-[(quinazolin-4-yl)amino] -N- Preparation of {2-[4-(p-Tolyl)piperazin-1-yl]ethyl}benzamide (Z-02) The preparation method of Example 1 was followed to obtain 0.68 g of white solid, with a yield of 27.2%. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.95 (dd, J = 8.4, 1.1 Hz, 1H), 8.84 (s, 1H), 8.71(s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.97 – 7.73 (m, 5H), 7.61 (dd, J = 15.7,1.5 Hz, 1H), 7.26 – 7.17 (m, 1H), 6.97 (d, J = 8.2 Hz, 2H), 6.71 (d, J = 8.5Hz, 2H), 3.51 (d, J = 6.2 Hz, 2H), 2.98 (s, 4H), 2.56 (s, 5H), 2.18 (s, 3H);ESI-MS m / z: 467.3 [M+H] + .

[0035] Example 3: N Preparation of 2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-03) The sample was prepared according to the method in Example 1, yielding 0.67 g of a white solid with a yield of 28.5%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.46 (s, 1H), 8.94 (dd, J = 8.4, 1.2 Hz, 1H), 8.84 (t, J = 5.6Hz, 1H), 8.71 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.92 (ddd, J = 8.2, 6.9, 1.3Hz, 1H), 7.89 – 7.80 (m, 2H), 7.77 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.66 –7.57 (m, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 7.00 (t, J = 8.9 Hz, 2H), 6.86– 6.78 (m, 2H), 3.51 (q, J = 6.3 Hz, 2H), 2.98 (t, J = 5.0 Hz, 4H), 2.55 (d,J = 8.3 Hz, 6H); ESI-MS m / z: 471.3 [M+H] + .

[0036] Example 4:N Preparation of 2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide (Z-04) The sample was prepared according to the method in Example 1, yielding 0.72 g of a white solid with a yield of 31.7%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.48 (s, 1H), 8.95 (dd, J = 8.5, 1.1 Hz, 1H), 8.85 (t, J = 5.7Hz, 1H), 8.71 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.92 (ddd, J = 8.1, 6.8, 1.2Hz, 1H), 7.89 – 7.73 (m, 3H), 7.61 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.19 (dtd, J = 18.3, 7.4, 1.5 Hz, 3H), 6.82 (d, J = 8.2 Hz, 2H), 6.75 (t, J = 7.3Hz, 1H), 3.51 (q, J = 6.4 Hz, 2H), 3.04 (t, J = 4.9 Hz, 4H), 2.61 – 2.52 (m,6H); ESI-MS m / z: 453.3 [M+H] + .

[0037] Example 5: N Preparation of 2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-05) The sample was prepared according to the method in Example 1, yielding 0.79 g of a white solid with a yield of 32.8%. 1 H NMR (400 MHz, DMSO- d6) δ 12.46 (s, 1H), 8.94 (dd, J = 8.4, 1.2 Hz, 1H), 8.84 (t, J = 5.6Hz, 1H), 8.71 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.98 – 7.70 (m, 5H), 7.26 –7.17 (m, 1H), 6.77 (s, 4H), 3.67 (s, 3H), 3.50 (q, J = 6.4 Hz, 2H), 2.92 (s,4H), 2.55 (d, J = 8.9 Hz, 6H).;ESI-MS m / z: 483.3 [M+H] + .

[0038] Example 6: 2-[(quinazolin-4-yl)amino] -N- Preparation of {2-[4-(m-tolyl)piperazin-1-yl]ethyl}benzamide (Z-06) The preparation method of Example 1 was followed to obtain 0.69 g of white solid, with a yield of 29.5%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.49 (s, 1H), 9.00 – 8.92 (m, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.92 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.85 (ddd, J = 7.7, 6.4, 1.4 Hz, 2H), 7.78 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.65 – 7.56(m, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.67 –6.53 (m, 3H), 3.51 (q, J = 6.3 Hz, 2H), 3.03 (t, J = 4.9 Hz, 4H), 2.56 (q, J= 7.7, 6.3 Hz, 6H), 2.22 (s, 3H); ESI-MS m / z: 467.3 [M+H] + .

[0039] Example 7: NPreparation of 2-[4-(2-chlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-07) The preparation method of Example 1 was followed to obtain 0.65 g of white solid, with a yield of 26.6%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.49 (s, 1H), 8.95 (dd, J = 8.4, 1.1 Hz, 1H), 8.84 (t, J = 5.7Hz, 1H), 8.73 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.96 – 7.81 (m, 3H), 7.76(ddd, J = 8.3, 6.7, 1.6 Hz, 1H), 7.62 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.37(dd, J = 7.9, 1.5 Hz, 1H), 7.23 (tdd, J = 7.6, 4.1, 1.4 Hz, 2H), 7.01 (td, J= 7.7, 1.5 Hz, 1H), 6.92 (dd, J = 8.1, 1.5 Hz, 1H), 3.51 (q, J = 6.3 Hz, 2H), 2.89 (t, J = 4.4 Hz, 4H), 2.58 (dd, J = 13.5, 6.8 Hz, 6H);ESI-MS m / z: 487.3[M+H] + .

[0040] Example 8: 2-[(quinazolin-4-yl)amino] -N- Preparation of {2-[4-(o-tolyl)piperazin-1-yl]ethyl}benzamide (Z-08) The preparation method of Example 1 was followed to obtain 0.69 g of white solid, with a yield of 29.7%. 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.96 (d, J = 8.4 Hz, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.73 (s, 1H), 8.18 (dd, J = 16.3, 8.4 Hz, 1H), 7.95 – 7.83 (m, 3H), 7.76 (td,J = 7.1, 6.2, 2.7 Hz, 2H), 7.67 – 7.57 (m, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.16 – 7.04 (m, 2H), 6.92 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 3.52(q, J = 6.4 Hz, 2H), 3.37 (s, 3H), 2.75 (t, J = 4.7 Hz, 3H), 2.61 – 2.55 (m,4H), 2.20 (s, 3H); ESI-MS m / z: 467.2 [M+H] + .

[0041] Example 9: 2-[(quinazolin-4-yl)amino] -N- Preparation of {2-{4-[2-(trifluoromethoxy)phenyl]piperazin-1-yl}ethyl}benzamide (Z-09) The sample was prepared according to the method in Example 1, yielding 0.72 g of a white solid with a yield of 26.9%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.50 (s, 1H), 8.95 (s, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.17 (s,1H), 7.86 (s, 2H), 7.74 (s, 2H), 7.60 (s, 1H), 7.22 (s, 3H), 7.03 (s, 1H), 6.89 (s, 1H), 3.44 (d, J = 53.9 Hz, 8H), 2.90 (s, 4H); ESI-MS m / z: 537.3 [M+H] + .

[0042] Example 10: 2-[(quinazolin-4-yl)amino] -N- Preparation of {2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl}benzamide (Z-10) The sample was prepared according to the method in Example 1, yielding 0.79 g of a white solid with a yield of 30.7%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.47 (s, 1H), 8.95 (dd, J = 8.4, 1.1 Hz, 1H), 8.85 (t, J = 5.4Hz, 1H), 8.71 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95 – 7.73 (m, 4H), 7.61(dd, J = 15.7, 1.5 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 15.2, 1.2Hz, 1H), 7.15 – 7.01 (m, 3H), 3.51 (q, J = 6.4 Hz, 2H), 3.15 (t, J = 5.0 Hz, 4H), 2.57 (q, J = 7.9, 6.7 Hz, 6H); ESI-MS m / z: 521.3 [M+H] + .

[0043] Example 11: N Preparation of 2-{4-[4-(allyloxy)phenyl]piperazin-1-yl}ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-11) The preparation method of Example 1 was followed to obtain 0.72 g of white solid, with a yield of 28.4%. 1 H NMR (400 MHz, DMSO- d6) δ 12.47 (s, 1H), 8.95 (d, J = 8.4 Hz, 1H), 8.84 (s, 1H), 8.71 (s,1H), 8.19 (d, J = 8.2 Hz, 1H), 7.95 – 7.73 (m, 4H), 7.66 – 7.56 (m, 1H), 7.21(t, J = 7.5 Hz, 1H), 6.77 (q, J = 9.3 Hz, 4H), 6.01 (ddt, J = 17.2, 10.4, 5.2Hz, 1H), 5.36 (dq, J = 17.3, 1.8 Hz, 1H), 5.23 (dt, J = 10.5, 1.6 Hz, 1H), 4.46 (dt, J = 5.1, 1.6 Hz, 2H), 3.51 (q, J = 6.3 Hz, 2H), 2.92 (d, J = 5.0Hz, 4H), 2.55 (d, J = 8.4 Hz, 6H); ESI-MS m / z: 509.3 [M+H] + .

[0044] Example 12: N- Preparation of {2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-12) The preparation method of Example 1 was followed to obtain 0.67 g of white solid, with a yield of 27.6%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.46 (s, 1H), 8.97 – 8.90 (m, 1H), 8.84 (t, J = 5.5 Hz, 1H), 8.71(s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.97 – 7.73 (m, 4H), 7.67 – 7.55 (m, 1H), 7.26 – 7.14 (m, 3H), 6.86 – 6.79 (m, 2H), 3.50 (q, J = 6.3 Hz, 2H), 3.04 (t,J = 4.9 Hz, 4H), 2.56 (t, J = 5.1 Hz, 6H);ESI-MS m / z: 487.2 [M+H] + .

[0045] Example 13: NPreparation of 2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-13) The sample was prepared according to the method in Example 1, yielding 0.63 g of a white solid with a yield of 26.7%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.46 (s, 1H), 8.94 (dd, J = 8.4, 1.1 Hz, 1H), 8.83 (t, J = 5.5Hz, 1H), 8.72 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.92 (ddd, J = 8.2, 6.7, 1.1Hz, 1H), 7.87 – 7.81 (m, 2H), 7.77 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.66 –7.57 (m, 1H), 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.14 – 7.00 (m, 2H), 6.99 –6.89 (m, 1H), 6.80 (s, 1H), 3.50 (q, J = 6.4 Hz, 2H), 2.92 (t, J = 4.8 Hz, 4H), 2.62 – 2.53 (m, 6H); ESI-MS m / z: 471.3 [M+H] + .

[0046] Example 14: N Preparation of 2-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-14) The preparation method of Example 1 was followed to obtain 0.73 g of white solid, with a yield of 29.1%. 1 H NMR (400 MHz, DMSO- d6) δ 12.46 (s, 1H), 8.94 (dd, J = 8.4, 1.1 Hz, 1H), 8.85 (s, 1H), 8.71(s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.94 – 7.75 (m, 4H), 7.61 (ddd, J = 8.6,7.3, 1.5 Hz, 1H), 7.26 – 7.15 (m, 2H), 7.05 – 6.94 (m, 1H), 6.81 (dt, J =9.3, 3.5 Hz, 1H), 3.54 – 3.46 (m, 2H), 3.03 (s, 4H), 2.56 (s, 6H);ESI-MS m / z: 505.2 [M+H] + .

[0047] Example 15: N Preparation of 2-[4-(4-ethoxyphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-15) The sample was prepared according to the method in Example 1, yielding 0.71 g of a white solid with a yield of 28.9%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.46 (s, 1H), 8.94 (dd, J = 8.5, 1.2 Hz, 1H), 8.83 (s, 1H), 8.71(s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.95 – 7.73 (m, 4H), 7.61 (ddd, J = 8.5,7.3, 1.5 Hz, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 6.75 (s, 4H), 3.92 (q, J =6.9 Hz, 2H), 3.50 (d, J = 6.7 Hz, 2H), 2.92 (s, 4H), 2.56 (s, 6H), 1.28 (t, J= 7.0 Hz, 3H);ESI-MS m / z: 497.3 [M+H] + .

[0048] Example 16: N Preparation of 2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-16) The preparation method of Example 1 was followed to obtain 0.65 g of white solid, with a yield of 26.1%. 1 H NMR (400 MHz, DMSO- d 6) δ 12.47 (s, 1H), 8.95 (dd, J = 8.4, 1.1 Hz, 1H), 8.85 (t, J = 5.6Hz, 1H), 8.72 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.96 – 7.73 (m, 4H), 7.61(ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 7.11 (d, J =8.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 8.5, 2.6 Hz, 1H), 3.50(q, J = 6.4 Hz, 2H), 3.03 (t, J = 4.8 Hz, 4H), 2.59 – 2.53 (m, 6H), 2.20 (s,3H);ESI-MS m / z: 501.3 [M+H] + .

[0049] Example 17: N Preparation of 2-{4-[4-(tert-butyl)phenyl]piperazin-1-yl}ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-17) The sample was prepared according to the method in Example 1, yielding 0.75 g of a white solid with a yield of 29.6%. 1 H NMR (400 MHz, DMSO- d6) δ 12.55 (s, 1H), 8.99 (dd, J = 8.4, 1.1 Hz, 1H), 8.87 (t, J = 5.7Hz, 1H), 8.73 (s, 1H), 8.18 (dd, J = 17.8, 8.3 Hz, 1H), 7.96 – 7.82 (m, 3H),7.79 – 7.73 (m, 1H), 7.62 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.26 – 7.13 (m,3H), 6.78 – 6.71 (m, 2H), 3.52 (q, J = 6.4 Hz, 2H), 3.01 (t, J = 4.9 Hz, 4H), 2.56 (q, J = 7.1, 5.4 Hz, 6H), 1.22 (s, 9H); ESI-MS m / z: 509.3 [M+H] + .

[0050] Example 18: N Preparation of 2-[4-(2,4-dimethylphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-18) The preparation method of Example 1 was followed to obtain 0.64 g of white solid, with a yield of 26.7%. 1 H NMR (400 MHz, DMSO- d6) δ 12.50 (s, 1H), 8.97 (dd, J = 8.4, 1.1 Hz, 1H), 8.84 (t, J = 5.7Hz, 1H), 8.73 (s, 1H), 8.18 (dd, J = 12.9, 8.6 Hz, 1H), 7.98 – 7.81 (m, 3H),7.76 (ddd, J = 8.3, 5.7, 1.6 Hz, 1H), 7.67 – 7.57 (m, 1H), 7.22 (td, J = 7.6,1.2 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.65 (d, J =1.7 Hz, 1H), 3.51 (q, J = 6.4 Hz, 2H), 2.74 (t, J = 4.7 Hz, 4H), 2.63 – 2.53(m, 6H), 2.17 (d, J = 18.7 Hz, 6H); ESI-MS m / z: 481.3 [M+H] + .

[0051] Example 19: N Preparation of 2-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide (Z-19) The preparation method of Example 1 was followed to obtain 0.63 g of white solid, with a yield of 24.7%. 1 H NMR (400 MHz, DMSO- d6) δ 12.50 (s, 1H), 8.96 (dd, J = 8.5, 1.2 Hz, 1H), 8.85 (t, J = 5.6Hz, 1H), 8.72 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.95 – 7.73 (m, 4H), 7.61(ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 6.01 (d, J =2.1 Hz, 2H), 5.94 (t, J = 2.1 Hz, 1H), 3.68 (s, 6H), 3.50 (q, J = 6.3 Hz,2H), 3.07 (t, J = 4.7 Hz, 4H), 2.55 (d, J = 6.4 Hz, 6H); ESI-MS m / z: 513.3 [M+H] + .

[0052] Example 20: Cytotoxicity test of the target compound The MTT assay based on Madin-Daby canine kidney cells (MDCK) was used to test the cytotoxicity of target compounds Z-01 to Z-19, examining their cytotoxicity at the cellular level. Different concentrations of the target compounds were added to the MDCK cell culture medium, and the absorbance (OD) values ​​were read using an enzyme-linked immunosorbent assay (ELISA) analyzer. The survival rate of MDCK cells was calculated (MDCK cell survival rate = absorbance value of experimental group / absorbance value of blank control group). The results are shown in Table 1. A lower MDCK cell survival rate indicates a stronger inhibitory effect of the target compound on MDCK cell growth, and thus greater cytotoxicity. The final results are expressed as CC... 50 exhibit.

[0053] Table 1. Inhibitory effect of the target compound on MDCK cells

[0054] All tested compounds showed CC against MDCK. 50 All are greater than 100 μM.

[0055] Example 21: The protective effect of the compound on diseased cells The MTT assay was used to investigate the protective effect of the target compound against influenza virus-infected cells. Different concentrations of the target compound were added to the culture medium of the infected cells, and the absorbance (OD) values ​​were read using an enzyme-linked immunosorbent assay (ELISA) analyzer. The cell viability was calculated (cell viability = absorbance value of the experimental group / absorbance value of the virus-free control group). The final results were expressed as EC50. 50 The results are shown in Table 2.

[0056] Table 2. Protective effect of the target compound on diseased cells.

[0057] In the diseased cell protection experiment, compounds Z-01, Z-04, Z-05, Z-06, Z-08, Z-09, Z-11, Z-12, Z-15, Z-17, and Z-19 all showed good protective effects, among which compounds Z-04, Z-08, Z-11, Z-12, and Z-17 had more prominent protective effects.

[0058] In the formulations described below, "active ingredient" refers to the compound of Formula I or its salt or solvation.

[0059] Example 22: Gelatin Capsules

[0060] Example 23: Tablets

[0061] Example 24: Tablets

[0062] The active ingredient, starch, and cellulose are thoroughly mixed through a 45-mesh US sieve. The resulting powder is then mixed with polyvinylpyrrolidone and passed through a 14-mesh US sieve. The resulting granules are dried at 50-60°C and passed through an 18-mesh US sieve. Sodium carboxymethyl cellulose, magnesium stearate, and talc are first passed through a 60-mesh US sieve and then added to the granules. After mixing, the mixture is compressed into tablets using a tableting machine.

[0063] Example 25: Suspension agent

[0064] The drug is passed through a 45-mesh US sieve and mixed with sodium carboxymethyl cellulose and syrup to form a uniform paste. Benzoic acid solution, flavoring agent and coloring agent are diluted with some water and added while stirring. Then, enough water is added to reach the desired volume.

[0065] Example 26: Aerosol

[0066] The active ingredient is mixed with ethanol, and the resulting mixture is added to propellant 22, cooled to 30°C, and transferred to a container. The required amount is then added to a stainless steel container and diluted with the remaining propellant before installing the valve device.

[0067] Example 27: Suppositories

[0068] The active ingredient was passed through a 60-mesh US sieve and suspended in a pre-melted saturated fatty acid glyceride compound. The mixture was then poured into a standard 2g suppository mold and cooled.

[0069] Example 28: Injectable Formulation

[0070] The above solution is administered intravenously to the patient at a rate of approximately 1 mL / min.

[0071] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments. However, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A phenylpiperazine-quinazoline hybrid compound of the structural formula shown in Formula I, or a pharmaceutically acceptable salt thereof: ； in, R represents one or more substituents at any position, each R being independently selected from hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, halogen-substituted C1-C4 alkoxy, and allyloxy.

2. The phenylpiperazine-quinazoline hybrid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R is independently selected from hydrogen, fluorine, chlorine, methoxy, methyl, trifluoromethoxy, trifluoromethyl, allyloxy, ethoxy, and tert-butyl.

3. The phenylpiperazine-quinazoline hybrid compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, Selected from any of the following compounds: N -{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; 2-[(quinazolin-4-yl)amino] -N- {2-[4-(p-tolyl)piperazin-1-yl]ethyl}benzamide; N -{2-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -[2-(4-phenylpiperazin-1-yl)ethyl]-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; 2-[(quinazolin-4-yl)amino] -N- {2-[4-(m-tolyl)piperazin-1-yl]ethyl}benzamide; N -{2-[4-(2-chlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; 2-[(quinazolin-4-yl)amino] -N- {2-[4-(o-tolyl)piperazin-1-yl]ethyl}benzamide; 2-[(quinazolin-4-yl)amino] -N- {2-{4-[2-(trifluoromethoxy)phenyl]piperazin-1-yl}ethyl}benzamide; 2-[(quinazolin-4-yl)amino] -N- {2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl}benzamide; N -{2-{4-[4-(allyloxy)phenyl]piperazin-1-yl}ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N- {2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(2-fluorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(3-chloro-4-fluorophenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(4-ethoxyphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(3-chloro-4-methylphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-{4-[4-(tert-butyl)phenyl]piperazin-1-yl}ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(2,4-dimethylphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide; N -{2-[4-(3,5-dimethoxyphenyl)piperazin-1-yl]ethyl}-2-[(quinazolin-4-yl)amino]benzamide.

4. A method for preparing the phenylpiperazine-quinazoline hybrid compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Includes the following steps: ； Wherein, R is as described in claim 1.

5. A pharmaceutical composition, characterized in that, This includes the phenylpiperazine-quinazoline hybrid compound as described in any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent as the active ingredient.

6. The use of the phenylpiperazine-quinazoline hybrid compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3 in the preparation of an influenza virus therapeutic.

7. The use of the pharmaceutical composition of claim 5 in the preparation of an influenza virus treatment drug.

8. The application according to claim 6 or 7, characterized in that, By acting on the RNA polymerase of influenza virus with an effective amount of a phenylpiperazine-quinazoline hybrid compound or a pharmaceutically acceptable salt thereof, the replication of influenza virus is inhibited.

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