A nitrogen-containing heterocyclic compound, a preparation method thereof and application thereof in preparing anti-dengue drugs

Abstract

This invention provides a nitrogen-containing heterocyclic compound, its preparation method, and its application in the preparation of anti-dengue drugs. The nitrogen-containing heterocyclic compound exhibits good anti-dengue virus activity and low cytotoxicity. Some nitrogen-containing heterocyclic compounds can achieve an inhibition rate of 99% in the initial screening at 10 µM, which is of further research value. The compounds of this invention have higher safety and therapeutic window, and have the potential to be used in the preparation of anti-dengue virus drugs, thus possessing significant value for promotion and application.

Description

Technical Field

[0001] This invention belongs to the field of compound drugs, specifically relating to a nitrogen-containing heterocyclic compound, its preparation method, and its application in the preparation of anti-dengue fever drugs. Background Technology

[0002] Dengue fever is a vector-borne infectious disease caused by the dengue virus. The dengue virus is a single-stranded positive-sense RNA virus belonging to the Flaviviridae family, with four serotypes. Clinical manifestations of dengue fever range from mild fever to life-threatening dengue hemorrhagic fever, with a high mortality rate. Currently, there are no effective antiviral drugs for dengue virus, and existing vaccines carry the risk of antibody-dependent effects, limiting their preventative effects.

[0003] Existing small molecule drugs have poor inhibitory and preventative effects against dengue virus, and suffer from problems such as high cytotoxicity and low antiviral activity. Therefore, the search for small molecule compounds with better efficacy against dengue virus is of great value. Summary of the Invention

[0004] To overcome the problems existing in the prior art, one objective of the present invention is to provide a nitrogen-containing heterocyclic compound. A second objective of the present invention is to provide a method for preparing the aforementioned nitrogen-containing heterocyclic compound. A third objective of the present invention is to provide a pharmaceutical composition. A fourth objective of the present invention is to provide applications of the aforementioned nitrogen-containing heterocyclic compound and pharmaceutical composition.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: The first aspect of this invention provides a nitrogen-containing heterocyclic compound with the structural formula shown in Formula AC: Formula A Formula B Formula C; Wherein, L1 is a single bond, alkylene group, or carbonyl group; L2 is a single bond or amide group; L3 is a single bond, alkylene group, or carbonyl group; Ar1 is: or Ar2 is or ; X is CH2 or carbonyl; Y is O, S, NH, or NCH3; R1 or R2 is independently selected from deuterium, H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkylthio, substituted or unsubstituted C1-C10 alkoxy, halogen, cyano, isocyano, nitro, phosphin, aminesulfonyl or sulfone. The substitution of R1 or R2 is independently the substitution by at least one of deuterium, halogen, cyano, isocyano, hydroxyl, carboxyl, C1-C6 alkyl, wherein the number of substitutions is from monosubstituted to the maximum number of substitutions; R7 or R8 is independently selected from deuterium, H, halogen, cyano, isocyano, nitro, phosphino, C1-C10 alkyl, C1-C10 alkoxy, halogen-substituted C1-C10 alkyl or halogen-substituted C1-C10 alkoxy. R3 is , or ; R4 is a halogen; R5 is a C1-C6 alkyl group; R6 is or ; The wavy line represents the replacement position.

[0006] Preferably, the nitrogen-containing heterocyclic compound with the structural formula of formula A has a structure selected from formulas A1-A5: Formula A1 Formula A2 Formula A3 Formula A4 Formula A5; L4 is either an alkylene group or a carbonyl group.

[0007] Preferably, the halogen refers to bromine, fluorine, chlorine, or iodine.

[0008] Preferably, R1 or R2 is independently selected from deuterium, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C1-C6 alkoxy, halogen, cyano, isocyano, nitro, phosphin, aminesulfonyl or sulfone. The substitution of R1 or R2 is independently achieved by being substituted by at least one of deuterium, halogen, cyano, isocyano, hydroxyl, carboxyl, or C1-C6 alkyl, wherein the number of substitutions is monosubstituted.

[0009] More preferably, R1 or R2 is independently selected from deuterium, H, C1-C6 alkyl, C1-C6 alkyl with carboxyl end, C1-C6 alkyl with hydroxyl end, C1-C6 alkoxy, C1-C6 alkoxy with carboxyl end, C1-C6 alkoxy with hydroxyl end, C1-C6 alkylthio, C1-C6 alkylthio with carboxyl end, C1-C6 alkylthio with hydroxyl end, halogen, cyano, isocyano, nitro, phosphin, aminesulfonyl, or sulfone.

[0010] More preferably, R1 or R2 is independently selected from deuterium, H, C1-C6 alkyl, C1-C6 alkyl with carboxyl end, C1-C6 alkyl with hydroxyl end, C1-C6 alkoxy, C1-C6 alkoxy with carboxyl end, C1-C6 alkoxy with hydroxyl end, C1-C6 alkylthio, C1-C6 alkylthio with carboxyl end, C1-C6 alkylthio with hydroxyl end, halogen, aminesulfonyl or sulfone.

[0011] More preferably, C1-C6 can have 1, 2, 3, 4, 5, or 6 carbon atoms.

[0012] Terminal carboxyl / terminal hydroxyl group: refers to a carboxyl group (–COOH) or hydroxyl group (-OH) located at the end of the molecular chain (i.e., "terminal group").

[0013] Preferably, when R1 and R2 are not deuterium and H, both R1 and R2 are meta-substituted; when either R1 or R2 is deuterium or H, the other is para-substituted.

[0014] For example, meta-substitution is , .

[0015] Preferably, R7 or R8 is independently selected from deuterium, H, halogen, cyano, isocyano, nitro, phosphino, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy.

[0016] More preferably, the nitrogen-containing heterocyclic compound is selected from the following:

[0017]

[0018]

[0019]

[0020]

[0021] .

[0022] The second aspect of this invention provides a method for preparing the nitrogen-containing heterocyclic compound described in the first aspect, wherein: The preparation method of the nitrogen-containing heterocyclic compound as shown in Formula A includes the following steps: Compound a1 and compound a2 were reacted 1 to prepare a nitrogen-containing heterocyclic compound as shown in formula A; Formula a1 Formula a2; Alternatively, the preparation method of the nitrogen-containing heterocyclic compound as shown in Formula A includes the following steps: Compound a3 and compound a4 were reacted 2 times to prepare a nitrogen-containing heterocyclic compound as shown in formula A; Formula a3 Formula a4; The preparation method of the nitrogen-containing heterocyclic compound as shown in Formula B includes the following steps: Compound b1 and compound b2 were reacted 3 times to prepare a nitrogen-containing heterocyclic compound as shown in formula B; Formula b1 Formula b2; The preparation method of the nitrogen-containing heterocyclic compound as shown in Formula C includes the following steps: Compound c1 and compound c2 were reacted 4 times to prepare a nitrogen-containing heterocyclic compound as shown in formula C; Formula c1 Formula c2; The definitions of L1, L2, L3, Ar1, Ar2, X, Y, R1, R2, R3, R4, R5, R6, R7, and R8 are as described in the first aspect.

[0023] A third aspect of the present invention provides a pharmaceutical composition comprising the nitrogen-containing heterocyclic compound or its stereoisomer, a pharmaceutically acceptable salt, solvate or polymorph described in the first aspect, together with one or more pharmaceutically acceptable excipients, diluents or carriers.

[0024] Preferably, the pharmaceutically acceptable salt includes at least one of the following: metal salt, ammonium salt, salt formed with an inorganic acid, salt formed with an organic base, salt formed with an organic acid, salt formed with a basic amino acid, and salt formed with an acidic amino acid.

[0025] More preferably, the metal salt includes alkali metal salts and alkaline earth metal salts. More preferably, the alkali metal salt includes at least one selected from sodium and potassium salts. More preferably, the alkaline earth metal salt includes at least one selected from calcium, magnesium, barium, and aluminum salts.

[0026] More preferably, the salt formed with an organic base includes at least one of the following organic bases: trimethylamine, triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine. More preferably, the salt formed with an inorganic acid includes at least one of the following inorganic acids: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. More preferably, the salt formed with an organic acid includes at least one of the following organic acids: formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. More preferably, the salt formed with a basic amino acid includes at least one of the following basic amino acids: arginine, lysine, and ornithine.

[0027] Preferably, the term "isomer" refers to the fact that the compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention envisions all such compounds, including cis and trans isomers, ( ) and (+) Enantiomers, (R) and (S) Enantiomers, diastereomers, (D) Isomer, (L) Isomers, racemic mixtures thereof, and other mixtures, such as enantiomers or diastereomer-enriched mixtures, are all within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0028] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other. Unless otherwise stated, the terms "cis-trans isomer" or "geometric isomer" arise from the inability of double bonds or single bonds on cyclic carbon atoms to rotate freely. Unless otherwise stated, the term "diastereomer" refers to stereoisomers of molecules having two or more chiral centers and being non-mirror images of each other. Unless otherwise stated, "(D)" or "(+)" indicates dextrorotatory, and "(L)" or "(...]" indicates... "(DL)" indicates left-handed rotation, and "(±)" or "(±)" indicates racemic rotation. Unless otherwise specified, the absolute configuration of a solid center is indicated by wedge-shaped solid and wedge-shaped dashed keys.

[0029] Preferably, it also includes one or more pharmaceutically acceptable excipients.

[0030] More preferably, the pharmaceutically acceptable excipient refers to a drug carrier conventional in the pharmaceutical field, including at least one of fillers, binders, disintegrants, solubilizers, suspending agents, wetting agents, pigments, fragrances, solvents, surfactants, or flavoring agents.

[0031] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives. Biological agents such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; preservatives and antioxidants.

[0032] Preferably, the dosage form of the composition includes any one of oral formulations, injectable formulations, respiratory formulations, and transdermal formulations.

[0033] More preferably, the dosage forms of oral preparations include granules, tablets, powders, capsules, oral solutions, oral suspensions, dry suspensions, oral emulsions, gels, oral liquids, emulsions, emulsions, colloidal solutions, mixtures, tinctures, drops, suspension drops, syrups, sustained-release tablets, sustained-release coated tablets, controlled-release tablets, sustained-release capsules, and controlled-release capsules.

[0034] More preferably, the dosage form of the injectable preparation includes injections, injection solutions, solutions for injection, injection solutions for intravenous infusion, suspensions for injection, sterile powders for injection, intravenous injections, emulsions for injection, emulsion injections, powder injections, injections, sterile powder injections, lyophilized powder injections, and concentrated solutions for injection.

[0035] The fourth aspect of the invention provides the use of the nitrogen-containing heterocyclic compound or its stereoisomer, pharmaceutically acceptable salt, solvate or polymorph of the first aspect, or the pharmaceutical composition of the third aspect, in the preparation of a medicament for the prevention and / or treatment of dengue fever.

[0036] Preferably, the dengue fever is caused by infection with a virus strain of DENV-1, DENV-2, DENV-3, or DENV-4.

[0037] The beneficial effects of this invention are: This invention provides a nitrogen-containing heterocyclic compound, its preparation method, and its application in the preparation of anti-dengue drugs. The nitrogen-containing heterocyclic compound exhibits good anti-dengue virus activity and low cytotoxicity. Some nitrogen-containing heterocyclic compounds can achieve an inhibition rate of 99% in the initial screening at 10 µM, which is of further research value. The compounds of this invention have higher safety and therapeutic window, and have the potential to be used in the preparation of anti-dengue virus drugs, thus possessing significant value for promotion and application. Detailed Implementation

[0038] The present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments can be obtained from conventional commercial channels or prepared and isolated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.

[0039] Example 1 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 1-(4-chlorophenyl)-N-cyclopentyl-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthesis of QXH1154), and its preparation method is as follows:

[0040] Methyl 1-Boc-piperazine-3-carboxylate (1.834 g, 7.5 mmol, 1.0 eq), 4-chlorophenylboronic acid (1.759 g, 11.25 mmol, 1.5 eq), anhydrous copper acetate (1.497 g, 7.5 mmol, 1.0 eq), and pyridine (1.2 mL, 15 mmol, 2.0 eq) were dissolved in 25 mL of DCM. The reaction mixture was stirred at room temperature under aerobic conditions for 96 hours. After the reaction was complete, the mixture was washed with water (2 × 20 mL), the organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by rapid column chromatography (PE / EA = 7:1) to give QXH1144 (595 mg, 22.4%). This was to be used in the next step.

[0041] The 1-(tert-butyl)-3-methyl-4-(4-chlorophenyl)piperazine-1,3-dicarboxylic acid ester (QXH1144) (595 mg, 0.168 mmol) obtained in the previous step was dissolved in DCM (10 ml), and then trifluoroacetic acid (TFA, 1 ml) was slowly added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and the resulting residue was diluted with ethyl acetate (EA) and neutralized with sodium carbonate solution to adjust the pH to 8–9. The aqueous layer was extracted with ethyl acetate (EA, 3 × 20 ml). All organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate (Na₂SO₄), and then concentrated under vacuum to give QXH1146 (420 mg, 98.2%). This was then prepared for the next step. 1 H NMR (500 MHz, CDCl3) δ 7.21 – 7.15(m, 2H), 6.80 – 6.71 (m, 2H), 4.34 (s, 1H), 3.66 (s, 3H), 3.54 – 3.48 (m,1H), 3.42 – 3.35 (m, 1H), 3.34 – 3.27 (m, 1H), 3.17 (s, 2H), 2.94 (s, 1H). Methyl 1-(4-chlorophenyl)piperazine-2-carboxylate (QXH1146, 248 mg, 0.97 mmol), 4-iodotrifluorotoluene (317 mg, 1.16 mmol), and cesium carbonate (Cs₂CO₃, 1.264 g, 3.88 mmol) were dissolved in dioxane (15 ml) and the mixture was purged with nitrogen three times in a sealed tube. Pd₂(dba)₃ (44 mg, 0.0485 mmol) and Davephos (19 mg, 0.0485 mmol) were added to the mixture. The mixture was stirred at 110°C for 11 hours under nitrogen. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated. The crude product was purified by rapid column chromatography (petroleum ether / ethyl acetate = 30:1, v / v) to give QXH1150 (164 mg, 42%). This was to be used in the next step. 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.81 (d, J =9.0 Hz, 2H), 4.53 (d, J= 3.5 Hz, 1H), 4.32 – 4.26 (m, 1H), 3.78 – 3.70 (m,1H), 3.65 (s, 3H), 3.62 – 3.55 (m, 1H), 3.55 – 3.49 (m, 1H), 3.33 – 3.28 (m,1H), 3.12 – 3.04 (m,1H). Methyl 1-(4-chlorophenyl)-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxylate (QXH1150 (163, 0.4 mmol)) was dissolved in a mixed solvent of methanol / tetrahydrofuran (10 mL), and an aqueous sodium hydroxide solution was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature until the reaction was complete. The solvent (methanol / tetrahydrofuran) was then evaporated, and the pH was adjusted to 3-4 at 0°C with 2 N hydrochloric acid. The precipitate was separated by filtration, washed with water, and dried under vacuum to give QXH1151 (126.6 mg, 82.3%). This was to be added to the next step. 1 H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 4.53 (d, J = 3.5 Hz, 1H), 4.30 – 4.21 (m, 1H), 3.73 – 3.64 (m, 1H), 3.55 – 3.47 (m,2H), 3.30 – 3.25 (m, 1H), 3.10 – 3.00 (m, 1H). 1-(4-chlorophenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic acid (QXH1151, 30 mg, 0.078 mmol) and cyclopentanamine (10 mg, 0.117 mmol) were dissolved in DCM (5 ml). EDCI (30 mg, 0.156 mmol) and DMAP (19 mg, 0.156 mmol) were added sequentially to this solution. The reaction mixture was stirred at room temperature and monitored by TLC (PE / EA 5:1). After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 3:1) to give QXH1154 (27.5 mg, 75.3%). 1 H NMR (500 MHz, CDCl3) ) δ 7.48 (d,J =8.5 Hz, 2H), 7.28 (s, 1H), 7.26 – 7.25 (m, 1H), 6.88 – 6.78 (m, 4H), 6.45 (d, J = 8.0 Hz, 1H), 4.18 – 4.11 (m, 1H), 4.09 – 4.04 (m, 2H), 3.72 – 3.66 (m,1H), 3.62 – 3.56 (m, 1H), 3.54 – 3.51 (m, 2H), 1.88 – 1.76 (m, 2H), 1.54 –1.45 (m, 4H), 1.33 (s, 1H), 1.23 – 1.11 (m, 2H). HRMS (ESI) calcd forC 23 H 26 ClF3N3O, 452.1711 [M + H] + ; found, 452.1719. Example 2 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 1-(4-chlorophenyl)-N-[5-methoxy-3-(methyldioxane-λ6-thio)phenyl]-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthesis of QXH1156), and its preparation method is as follows:

[0042] 1-(4-chlorophenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic acid (QXH1151, 30 mg, 0.078 mmol) and 3-methoxy-5-(methanesulfonyl)aniline (24 mg, 0.117 mmol) were dissolved in DCM (5 ml). EDCI (30 mg, 0.156 mmol) and DMAP (19 mg, 0.156 mmol) were added sequentially to this solution. The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 1:1) to give QXH1156 (7.7 mg, 16.9%). 1 H NMR (500 MHz, CDCl3) δ8.76 (s, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.35 (d, J=1.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 1.5 Hz, 1H), 6.94 – 6.86(m, 4H), 4.31 – 4.26 (m, 1H), 4.22 – 4.17 (m, 1H), 3.85 (s, 3H), 3.75 – 3.65(m, 3H), 3.62 – 3.53 (m, 2H), 3.02 (s, 3H). HRMS (ESI) calcd forC 26 H 26 ClF3N3O4S, 568.1280 [M + H] + ; found, 568.1292. Example 3 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 1-(4-chlorophenyl)-N-{3-[(2-hydroxyethyl)oxy]-5-methoxyphenyl}-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthesis of QXH1164), and its preparation method is as follows:

[0043] 1-(4-chlorophenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic acid (QXH1151) (30 mg, 0.078 mmol) and 3-methoxy-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)aniline (XJM1082) (31 mg, 0.117 mmol) were dissolved in DCM (5 ml). EDCI (30 mg, 0.156 mmol) and DMAP (19 mg, 0.156 mmol) were added sequentially to this solution. The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 3:1) to give QXH1158 (24.5 mg, 49.5%). Further reaction was to be carried out. 1 H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.48 (d, J = 8.5Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 6.92 – 6.85 (m, 4H), 6.66 (d, J = 2.5 Hz, 2H), 6.26 (d, J= 2.5 Hz, 1H), 4.67 (t, J = 3.5 Hz, 1H), 4.24 (t, J = 4.0 Hz,1H), 4.21 – 4.15 (m, 1H), 4.12 – 4.05 (m, 2H), 4.02 – 3.97 (m, 1H), 3.90 –3.83 (m, 1H), 3.79 – 3.75 (m, 1H), 3.73 (s, 4H), 3.71 – 3.62 (m, 3H), 3.62 –3.56 (m, 1H), 3.56 – 3.48 (m, 2H), 1.86 – 1.77 (m, 1H), 1.75 – 1.68 (m, 2H),1.54 – 1.48 (m, 2H). 24.5 mg of QXH1158 (0.039 mmol) was dissolved in 2 mL of methanol, and then 3.4 mg of p-toluenesulfonic acid (0.0195 mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. The mixture was then concentrated and purified by pre-prepared thin-layer chromatography (DCM / MeOH = 100 / 1) to give QXH1164 (15.7 mg, 73.2%). 1 H NMR (500MHz, CD3OD + CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.80(t, J = 8.6 Hz, 4H), 6.60 (d, J = 10.9 Hz, 2H), 6.17 (s, 1H), 4.23 (s, 1H), 4.08 – 4.02 (m, 1H), 3.91 – 3.83 (m, 2H), 3.75 – 3.66 (m, 3H), 3.65 – 3.58(m, 5H), 3.55 – 3.48 (m, 1H), 3.42 – 3.34 (m, 1H), 3.23 (s, 1H). HRMS (ESI)calcd for C 27 H 28 ClF3N3O4, 550.1715 [M + H] + ; found, 550.1750. Example 4 This embodiment provides a nitrogen-containing heterocyclic compound, specifically N-cyclopentyl-1-(3-methoxyphenyl)-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthetic steps of QXH2034), and its preparation method is as follows:

[0044] Methyl 1-tert-butyl-piperazine-3-carboxylate (2.2 g, 9 mmol), 3-methoxyphenylboronic acid (2.05 g, 13.5 mmol), anhydrous copper acetate (1.8 g, 9 mmol), and pyridine (1.4 g, 18 mmol) were dissolved in 20 mL of DCM. The reaction mixture was stirred at room temperature under aerobic conditions for 36 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (EA), washed with water (2 × 20 mL), the organic phase was separated and dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 20:1) to give QXH2009 (539 mg, 17.1%). Further reaction was planned. 1 HNMR (500 MHz, CDCl3) δ 7.16 (t, J = 8.0 Hz, 1H), 6.48 – 6.37 (m, 3H), 4.55 –4.46 (m, 1H), 4.37 (s, 1H), 4.22 – 3.99 (m, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 3.52 (s, 1H), 3.43 – 3.28 (m, 2H), 3.09 (s, 1H), 1.46 (s, 9H). The 1-(tert-butyl)-3-methyl-4-(3-methoxyphenyl)piperazine-1,3-dicarboxylic acid ester (QXH2009) obtained in the previous step (360 mg, 1.03 mmol) was dissolved in DCM (5 ml), and then trifluoroacetic acid (TFA, 1 ml) was slowly added dropwise at 0°C. The reaction mixture was stirred overnight at room temperature. Volatile substances were removed under reduced pressure. The resulting residue was diluted with ethyl acetate (EA) and neutralized with sodium carbonate solution to adjust the pH to 8–9. The aqueous layer was extracted with ethyl acetate (EA, 3 × 20 ml). All organic extracts were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate (Na₂SO₄), and concentrated under vacuum. The crude product was then purified by column chromatography (DCM:methanol = 40:1) to give QXH2016 (147.7 mg, 57.3%). Further reaction to be carried out. 1H NMR (500 MHz, CD3OD) δ 7.21 – 7.01 (m, 1H), 6.55 –6.30 (m, 3H), 4.49 (s, 1H), 3.81 – 3.60 (m, 6H), 3.49 – 3.41 (m, 1H), 3.40 –3.31 (m, 2H), 3.15 – 3.01 (m, 2H), 2.93 – 2.80 (m, 1H). The methyl 1-(3-methoxyphenyl)piperazine-2-carboxylate (QXH2016, 147 mg, 0.587 mmol), 4-iodotrifluorotoluene (191 mg, 0.704 mmol), and cesium carbonate (Cs₂CO₃, 765 mg, 3.88 mmol) obtained in the previous step were dissolved in 1,4-dioxane (15 ml) and subjected to three nitrogen purgings. Pd₂(dba)₃ (27 mg, 0.029 mmol) and Davephos (12 mg, 0.029 mmol) were added to the mixture. The reaction was stirred at 110°C under a nitrogen atmosphere for 19 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give QXH2018 (116 mg, 53.9%). Further reaction was to be carried out. 1 H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.5 Hz, 2H), 7.23 – 7.16 (m, 1H), 6.95 (d, J = 8.5 Hz,2H), 6.54 – 6.47 (m, 1H), 6.45 – 6.41 (m, 2H), 4.61 – 4.56 (m, 1H), 4.31 –4.25 (m, 1H), 3.80 (s, 3H), 3.77 – 3.71 (m, 1H), 3.66 (s, 3H), 3.62 – 3.57 (m, 2H), 3.36 – 3.28 (m, 1H), 3.14 – 3.04 (m, 1H). The methyl 1-(3-methoxyphenyl)-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxylate (QXH2004) (446 mg, 1.14 mmol) obtained in the previous step was dissolved in 10 mL of a mixture of methanol and tetrahydrofuran. Sodium hydroxide aqueous solution (70 mg, 1.746 mmol, dissolved in 5 mL of water) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature until the reaction was complete, monitored by thin-layer chromatography. The solvent (methanol and tetrahydrofuran) was then evaporated, and the pH was adjusted to 3-4 at 0°C with 2N hydrochloric acid solution. The mixture was extracted with ethyl acetate (2 × 40 mL), washed with water (30 mL) and brine (30 mL), dried on sodium sulfate, and then concentrated under vacuum. The crude product was purified by column chromatography (DCM:methanol = 100:1) to give product QXH2022. This was then prepared for the next reaction. 1 H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.5 Hz, 2H), 7.18 (t, J = 9.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.51 – 6.46 (m, 1H), 6.45 – 6.40 (m, 2H), 4.59 (s, 1H), 4.29 – 4.23 (m, 1H), 3.79 (s, 3H), 3.72 –3.66 (m, 1H), 3.63 – 3.52 (m, 2H), 3.31 – 3.24 (m, 1H), 3.09 – 3.01 (m, 1H). The 1-(3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic acid (QXH2022) (30 mg, 0.08 mmol) obtained in the previous step was then reacted with cyclopentanamine (10 mg, 0.12 mmol), EDCI (31 g, 0.16 mmol), and DMAP (20 mg, 0.16 mmol). The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA = 3 / 1) to obtain QXH2034 (19.8 mg, 55.3%). 1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 8.5 Hz, 2H), 7.22 (t, J = 8.5 Hz, 1H), 6.84 (d, J= 8.5Hz, 2H), 6.56 – 6.45 (m, 3H), 6.44 – 6.41 (m, 1H), 4.20 – 4.12 (m, 3H), 3.80 (s, 3H), 3.67 – 3.47 (m, 5H), 1.90 – 1.77 (m, 2H), 1.55 – 1.44 (m, 4H), 1.24– 1.15 (m, 2H). HRMS (ESI) calcd for C 24 H 29 F3N3O2, 448.2207 [M + H] + ; found, 448.2213. Example 5 This embodiment provides a nitrogen-containing heterocyclic compound, specifically N-(3,5-dimethoxyphenyl)-1-(3-methoxyphenyl)-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthetic steps of QXH2042), and its preparation method is as follows:

[0045] 1-(3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic acid (QXH2022) (21 mg, 0.055 mmol) was dissolved in DCM, followed by the addition of cyclopentanamine (9 mg, 0.055 mmol), EDCI (21 g, 0.11 mmol), and DMAP (13 mg, 0.11 mmol). The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA / DCM = 5 / 1 / 1) to obtain QXH2042 (11.7 mg, 41.1%). 1 H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.66 (s, 2H), 6.60 – 6.50 (m, 4H), 6.22 (s, 1H), 4.33 – 4.25 (m, 2H), 3.73 (s, 9H), 3.69 – 3.65 (m, 3H), 3.64 – 3.59 (m, 2H), 3.54 – 3.48 (m, 1H).HRMS (ESI) calcd for C 27 H 29F3N3O4, 516.2105 [M + H] + ; found, 516.2116. Example 6 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-[5-methoxy-3-({[1-(3-methoxyphenyl)-4-[4-(trifluoromethyl)phenyl]piperazin-2-yl]carbonyl}amino)phenyl]butyric acid (synthetic route QXH2044), and its preparation method is as follows:

[0046] 1-(3-Methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxylic acid (QXH2022) (30 mg, 0.079 mmol) was dissolved in DCM, followed by the addition of tert-butyl 4-(3-amino-5-methoxyphenyl)butyrate (22 mg, 0.079 mmol), EDCI (30 mg, 0.158 mmol), and DMAP (19 mg, 0.158 mmol). The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA / DCM = 5 / 1 / 1) to obtain QXH2043 (24.7 mg, 49.9%). Further reaction was to be carried out. 1 H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H),7.48 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.69 – 6.63 (m, 2H), 6.59 –6.50 (m, 3H), 6.21 (s, 1H), 5.97 (s, 1H), 4.34 – 4.24 (m, 2H), 3.95 – 3.88(m, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 3.70 – 3.58 (m, 4H), 3.54 – 3.47 (m,1H), 2.38 (t, J = 7.4 Hz, 2H), 2.07 – 1.95 (m, 2H), 1.44 (s, 9H). The tert-butyl 4-(3-methoxy-5-(1-(3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)piperazine-2-carboxamido)phenyl)butyrate (QXH2043) (24.7 mg, 0.039 mmol) obtained in the previous step was dissolved in DCM, and then trifluoroacetic acid (0.5 ml) was slowly added dropwise under ice bath conditions. The reaction mixture was left to stand overnight at room temperature. Volatiles were removed under reduced pressure. The crude product was purified by column chromatography (DCM / methanol = 50:1) to give QXH2044. 1 H NMR (500 MHz, CDCl3) δ8.57 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.68 – 6.61(m, 2H), 6.60 – 6.52 (m, 3H), 6.21 (s, 1H), 6.06 (s, 2H), 4.33 (d, J = 9.7 Hz, 1H), 4.25 (d, J = 12.3 Hz, 1H), 3.98 – 3.91 (m, 2H), 3.80 (s, 3H), 3.72 (s,3H), 3.68 (d, J = 4.3 Hz, 3H), 3.63 – 3.57 (m, 1H), 3.55 – 3.48 (m, 1H), 2.57 – 2.49 (m, 2H), 2.09 – 2.02 (m, 2H). HRMS (ESI) calcd for C 30 H 33 F3N3O6, 588.2316 [M + H] + ; found, 588.2325. Example 7 This embodiment provides a nitrogen-containing heterocyclic compound, specifically N-cyclopentyl-1-[3-(methylthio)phenyl]-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthetic route QXH2070), and its preparation method is as follows:

[0047] Methyl 1-tert-butyl-piperazine-3-carboxylate (2.32 g, 9.5 mmol), 3-(methylthio)phenylboronic acid (2.4 g, 14.25 mmol), anhydrous copper acetate (1.9 g, 9.5 mmol), and pyridine (1.5 g, 19 mmol) were dissolved in 20 mL of DCM. The reaction mixture was stirred at room temperature under aerobic conditions for 72 hours. After the reaction was complete (monitored by thin-layer chromatography), the mixture was extracted with ethyl acetate, washed with water (2 × 20 mL), the organic phase was separated and dried over anhydrous sodium sulfate, and then the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 10:1) to give QXH2056 (100 mg, 2.9%), which was then used for the next reaction. 1 H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 8.0 Hz, 1H), 6.77 –6.73 (m, 2H), 6.62 (dd, J = 8.5, 2.5 Hz, 1H), 4.56 – 4.46 (m, 1H), 4.37 (s,1H), 4.22 – 3.98 (m, 1H), 3.66 (s, 3H), 3.59 – 3.47 (m, 1H), 3.35 (s, 2H),3.08 (s, 1H), 2.46 (s, 3H), 1.46 (s, 9H). The 1-(tert-butyl)-3-methyl-4-(3-(methylthio)phenyl)piperazine-1,3-dicarboxylic acid ester (QXH2056) (118 mg, 0.322 mmol) obtained in the previous step was dissolved in 5 ml of DCM, and 0.5 ml of trifluoroacetic acid (TFA) was slowly added dropwise under ice bath. Volatile substances were removed under reduced pressure. The residue was then dissolved in ethyl acetate (EA) and the pH was adjusted to 8–9 with sodium bicarbonate (NaHCO3). All organic layers were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate (Na2SO4), and concentrated under vacuum. The crude product was purified by column chromatography (DCM / methanol = 50 / 1, v / v) to give QXH2062 (66.7 mg, 77.8%). 1 H NMR (500 MHz, CDCl3) δ 7.16 (t, J= 7.5 Hz,1H), 6.77 – 6.71 (m, 2H), 6.66 – 6.61 (m, 1H), 4.38 (s, 1H), 3.67 (s, 3H),3.53 – 3.46 (m, 1H), 3.44 – 3.32 (m, 2H), 3.20 – 3.11 (m, 2H), 2.98 – 2.88 (m, 1H), 2.46 (s, 3H). The methyl 1-[3-(methylthio)phenyl]piperazine-2-carboxylate (QXH2062, 66.7 mg, 0.25 mmol), 4-iodotrifluorotoluene (82 mg, 0.3 mmol), and cesium carbonate (Cs2CO3, 325 mg, 1.0 mmol) obtained in the previous step were dissolved in 1,4-dioxane (5 ml) and subjected to three nitrogen purgings. Pd2(dba)3 (23 mg, 0.025 mmol) and Davephos (10 mg, 0.025 mmol) were added to the mixture. The mixture was stirred at 110°C for 19 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated under vacuum. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 15:1, v / v) to give QXH2063 (72.7 mg, 70.8%). This was then used for the next reaction. 1 H NMR (500MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.95 (d, J =8.5 Hz, 2H), 6.81 – 6.74 (m, 2H), 6.68 – 6.64 (m, 1H), 4.57 (d, J = 3.0 Hz, 1H), 4.28 (d, J = 12.0 Hz, 1H), 3.76 – 3.69 (m, 1H), 3.65 (s, 3H), 3.62 – 3.55(m, 2H), 3.33 – 3.28 (m, 1H), 3.12 – 3.03 (m, 1H), 2.48 (s, 3H). The methyl 1-[3-(methylthio)phenyl]-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxylate (QXH2063) (72.7 mg, 0.177 mmol) obtained in the previous step was dissolved in methanol and tetrahydrofuran, and sodium hydroxide aqueous solution (14 mg, 0.354 mmol, dissolved in 5 ml of water) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature until the reaction was complete, and the reaction was monitored by thin-layer chromatography. The organic solvents (methanol and tetrahydrofuran) were then evaporated, and ethyl acetate was added. The pH was adjusted to 3-4 at 0°C with 2N hydrochloric acid solution. The mixture was extracted with ethyl acetate (2 × 10 ml), washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and the organic phase was concentrated. The crude product was purified by column chromatography (PE:EA = 3:1) to obtain QXH2065 (60 mg, 85.5%). This was then prepared for the next reaction. 1 H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.5 Hz, 2H), 7.19 (t, J = 8.0 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 6.81 –6.74 (m, 2H), 6.68 – 6.64 (m, 1H), 4.59 (s, 1H), 4.31 – 4.24 (m, 1H), 3.73 –3.66 (m, 1H), 3.62 – 3.54 (m, 2H), 3.32 – 3.25 (m, 1H), 3.11 – 3.03 (m, 1H), 2.47 (s, 3H). The 1-[3-(methylthio)phenyl]-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxylic acid (QXH2065) (18.4 mg, 0.046 mmol) obtained in the previous step was dissolved in DCM, followed by the addition of cyclopentanamine (6 mg, 0.07 mmol), EDCI (18 mg, 0.09 mmol), and DMAP (12 mg, 0.09 mmol). The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (PE / EA / DCM = 5 / 1 / 1) to obtain QXH2070 (14.3 mg, 67%). 1 H NMR (500 MHz, CDCl3) 1 H NMR (500 MHz, CDCl3) δ 7.48 (d, J= 8.5Hz, 2H), 7.24 (t, J = 8.0 Hz, 1H), 6.88 – 6.82 (m, 3H), 6.78 (s, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 4.22 – 4.09 (m, 3H), 3.69 – 3.64(m, 1H), 3.62 – 3.50 (m, 4H), 2.49 (s, 3H), 1.90 – 1.77 (m, 2H), 1.57 – 1.42(m, 4H), 1.24 – 1.13 (m, 2H). HRMS (ESI) calcd for C 24 H 29 F3N3OS, 464.1978 [M +H] + ; found, 464.1985. Example 8 This embodiment provides a nitrogen-containing heterocyclic compound, specifically N-(3,5-dimethoxyphenyl)-1-[3-(methylthio)phenyl]-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxamide (synthetic steps of QXH2071), and its preparation method is as follows:

[0048] The 1-[3-(methylthio)phenyl]-4-[4-(trifluoromethyl)phenyl]piperazine-2-carboxylic acid (QXH2065) (18.9 mg, 0.048 mmol) obtained in the previous step was dissolved in DCM, followed by the addition of 3,5-dimethoxyaniline (11 mg, 0.07 mmol), EDCI (18 mg, 0.09 mmol), and DMAP (12 mg, 0.09 mmol). The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by pre-thin-layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give QXH2071 (16.3 mg, 63.9%). 1 H NMR (500 MHz, CDCl3) δ 8.49 (s, 1H), 7.47(d, J = 8.5 Hz, 2H), 7.28 – 7.22 (m, 1H), 6.86 (d, J= 8.5 Hz, 4H), 6.76 – 6.71(m, 1H), 6.68 – 6.63 (m, 2H), 6.24 – 6.20 (m, 1H), 4.32 – 4.23 (m, 2H), 3.73(s, 6H), 3.70 – 3.57 (m, 4H), 3.53 – 3.47 (m, 1H), 2.48 (s, 3H). HRMS (ESI)calcd for C 27 H 29 F3N3O3S, 532.1877 [M + H] + ; found, 532.1887. Example 9 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-[(5-chloro-1H-indol-2-yl)carbonyl]-1-(4-chlorophenyl)-N-{4-[(trifluoromethyl)oxy]phenyl}piperazine-2-carboxamide (synthesis of QXH1125), and its preparation method is as follows:

[0049] Methyl 1-Boc-piperazine-3-carboxylate (346 mg, 1.42 mmol, 1.0 eq), 4-chlorophenylboronic acid (333 mg, 2.13 mmol, 1.5 eq), anhydrous copper acetate (284 mg, 1.42 mmol), and pyridine (230 μL, 2.84 mmol, 2.0 eq) were dissolved in 20 mL of DCM. The reaction mixture was stirred at room temperature under aerobic conditions for 48 hours. After the reaction was complete, the mixture was washed with water (2 × 20 mL), the organic phase was extracted with ethyl acetate and dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by rapid column chromatography (PE / EA = 7:1) to give QXH1112 (77 mg, 15.3%). This was then used for the next step. 1 H NMR (500 MHz, CDCl3) δ 7.20 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 4.57 – 4.47 (m, 1H), 4.33 (s, 1H), 4.17 (s, 1H), 3.65 (s, 3H), 3.51 (s, 1H), 3.32 (s, 2H), 3.08 (s, 1H), 1.46 (s, 9H). The 1-(tert-butyl)-3-methyl-4-(4-chlorophenyl)piperazine-1,3-dicarboxylic acid ester (QXH1112) (70 mg, 0.197 mmol) obtained in the previous step was dissolved in methanol (5 ml), and sodium hydroxide solution (32 mg, 0.8 mmol, dissolved in 1 ml water) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature until the reaction was complete, and the reaction was monitored by thin-layer chromatography. The solvent (methanol) was then evaporated, and the pH was adjusted to 3-4 with 2 N hydrochloric acid at 0°C. The precipitate was separated by filtration, washed with water, and dried under vacuum to obtain QXH1115 (63.6 mg, 94.7%), which was then used for the next reaction. 1 H NMR (500MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 8.5 Hz, 2H), 4.58 – 4.47(m, 1H), 4.33 (s, 1H), 4.10 (s, 1H), 3.53 – 3.40 (m, 1H), 3.39 – 3.21 (m,2H), 3.07 (s, 1H), 1.39 (s, 9H). First, 4-(tert-Butoxycarbonyl)-1-(4-chlorophenyl)piperazine-2-carboxylic acid (QXH1115) (20 mg, 0.059 mmol) was dissolved in DCM, and then HATU (33 mg, 0.089 mmol) and DIPEA (23 mg, 0.177 mmol) were added sequentially at 0°C. The reaction progress was monitored by thin-layer chromatography, confirming that the starting material was completely consumed after approximately 10 minutes. Subsequently, 4-(trifluoromethoxy)aniline (12.5 mg, 0.071 mmol) was introduced, and the resulting mixture was stirred continuously at room temperature. After completion, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1) to obtain QXH1116 (16 mg, 54.2%). 1 H NMR (500 MHz, CDCl3) δ 8.37 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H),7.29-7.26 (m, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.87 (d, J =7.5 Hz, 2H),4.22-4.13(m, 1H), 4.13-4.02 (m, 1H), 3.82 – 3.76 (m, 1H), 3.72 (s, 1H), 3.66-3.49 (m,2H), 3.43-3.33 (m, 1H), 1.45 (s, 9H). The 4-(4-chlorophenyl)-3-[({4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester (QXH1116) (34 mg, 0.068 mmol) obtained in the previous step was dissolved in DCM (5 ml), and then trifluoroacetic acid (TFA, 0.5 ml) was slowly added dropwise under ice bath. The reaction mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and the residue was quenched with sodium carbonate and the pH was adjusted to 8-9. The aqueous layer was extracted with ethyl acetate (EA, 2 × 10 ml). The organic extracts were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH = 30:1) to give QXH1124 (25.4 mg, 93.4%). 1 H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H),7.45 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 4.15 (s, 1H), 3.43 – 3.33 (m, 2H), 3.31 – 3.22 (m, 2H), 3.15 – 3.01 (m, 2H). First, 5-chloroindole-2-carboxylic acid (15 mg, 0.075 mmol) was dissolved in DCM solution. Then, HATU (38 mg, 0.1 mmol) and diisopropylethylamine (DIPEA) (32 mg, 0.25 mmol) were added sequentially with stirring at room temperature. The reaction progress was monitored by thin-layer chromatography (TLC), and the complete consumption of the starting material was confirmed after approximately 30 minutes. Subsequently, 1-(4-chlorophenyl)- N2-{4-[(trifluoromethyl)oxy]phenyl}piperazine-2-carboxamide (QXH1124) (25 mg, 0.0625 mmol) was prepared by stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by pre-thin-layer chromatography (PE / EA = 3 / 1) to give QXH1125 (17 mg, 47.4%). 1 H NMR (500 MHz, CDCl3) δ 9.84 (s,1H), 8.63 (s, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.25 (d, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 5.09 – 4.88 (m, 1H), 4.35 (s, 1H), 4.11 (s, 1H), 4.00 – 3.55(m, 4H). 13 C NMR (151 MHz, CDCl3) δ 169.1, 163.2, 147.5, 146.1, 135.4, 134.3,130.2 (2C), 130.0, 128.5, 126.7, 126.3, 125.3, 121.9 (2C), 121.4 (2C), 121.4,119.7, 117.0, 113.1, 106.2, 63.1 (2C), 45.1. HRMS (ESI) calcd forC 27 H 22 Cl2F3N4O3, 577.1016 [M + H] + ; found, 577.1031. Example 10 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-[(6-chloro-1H-indol-2-yl)carbonyl]-1-(4-chlorophenyl)-N-{4-[(trifluoromethyl)oxy]phenyl}piperazine-2-carboxamide (QXH1136 synthesis step), the preparation method of which is as follows:

[0050] First, 6-chloroindole-2-carboxylic acid (100 mg, 0.293 mmol) was dissolved in DCM solution. Then, HATU (116 mg, 0.304 mmol) and diisopropylethylamine (98 mg, 0.76 mmol) were added sequentially under stirring at 0 °C. The reaction progress was monitored by thin-layer chromatography (TLC), and the complete consumption of the starting material was confirmed after approximately 20 minutes. Subsequently, 1-(4-chlorophenyl)-N-(4-(trifluorophenyl)piperazine-2-carboxamide (QXH1134) (76 mg, 0.19 mmol) was added, and the resulting mixture was stirred continuously at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain QXH1136 (100 mg, 91.4%). 1 H NMR (500 MHz, CDCl3) δ 10.17 (s, 1H), 8.69 (s, 1H),7.59 – 7.47 (m, 3H), 7.42 (s, 1H), 7.34 – 7.27 (m, 2H), 7.17 – 7.10 (m, 2H),7.10 – 7.04 (m, 1H), 7.01 – 6.81 (m, 3H), 4.93 (s, 1H), 4.37 – 4.27 (m, 1H), 4.08 (s, 1H), 3.98 – 3.73 (m, 2H), 3.61 (s, 2H). 13 C NMR (151 MHz, CDCl3+CD3OD) δ 173.9, 167.6, 151.8, 149.7, 140.5, 139.9, 134.2, 133.4 (2C), 129.8,129.6, 126.7, 125.7 (2C), 125.5 (2C), 125.3, 123.6, 120.6 (2C), 115.7, 110.1,65.7, 48.8, 33.6.HRMS (ESI) calcd for C 27 H 22 Cl2F3N4O3, 577.1016 [M + H] + ; found, 577.1027. Example 11 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-[(5-chloro-1H-indol-2-yl)carbonyl]-1-(4-chlorophenyl)-N-(3,5-dimethoxyphenyl)piperazine-2-carboxamide (synthesis of QXH1166), and its preparation method is as follows:

[0051] The synthesis steps for QXH1130 are the same as those for QXH1115. 4-(tert-Butoxycarbonyl)-1-(4-chlorophenyl)piperazine-2-carboxylic acid (QXH1130) (200 mg, 0.587 mmol) and 3,5-dimethoxyaniline (135 mg, 0.88 mmol) were dissolved in DCM (5 ml). EDCI (225 mg, 1.17 mmol) and DMAP (143 mg, 1.17 mmol) were added sequentially to this solution. The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA / DCM = 2:1:1) to give QXH1162 (260 mg, 93%).

[0052] tert-Butyl 4-(4-chlorophenyl)-3-((3,5-dimethoxyphenyl)formamido)piperazine-1-carboxylic acid ester (QXH1162) (260 mg, 0.546 mmol) was dissolved in DCM (10 ml) and then mixed with trifluoroacetic acid (TFA, 1 ml) at 0°C. The reaction mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure, and the resulting residue was diluted with ethyl acetate (EA) and neutralized with sodium carbonate solution (Na2CO3) to adjust the pH to 8–9. The aqueous layer was extracted with ethyl acetate (EA, 2 × 10 ml). The crude product was purified by column chromatography (DCM / MeOH = 50:1, v / v) to give QXH1163 (163 mg, 79.6%).

[0053] 1-(4-chlorophenyl)-N-(3,5-dimethoxyphenyl)piperazine-2-carboxamide (QXH1163) (50 mg, 0.133 mmol) and 5-chloro-1H-indole-2-carboxylic acid (39 mg, 0.2 mmol) were dissolved in DCM (5 ml). EDCI (51 mg, 0.266 mmol) and DMAP (32.5 mg, 0.266 mmol) were added sequentially to this solution. The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH = 100:1) to give QXH1166 (63.3 mg, 86%). 1 H NMR (500 MHz, DMSO- d6) δ 11.79 (s, 1H), 10.11 (s, 1H), 7.53 – 7.31 (m, 2H), 7.28 (d, J = 8.5Hz, 2H), 7.17 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.75 (s, 3H), 6.21(d, J = 2.0 Hz, 1H), 4.79 – 4.67 (m, 1H), 4.51 (s, 1H), 4.36 (s, 1H), 3.97 –3.71 (m, 3H), 3.67 (s, 7H). Example 12 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (5-chloro-1H-indol-2-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3079), and its preparation method is as follows:

[0054] A 10 mL ethanol solution of 1-chloro-4-(epoxyethyl)benzene (1 g, 4.25 mmol, 1.0 eq) was mixed with 2-methylaminoethanol (1.018 g, 6.59 mmol, 1.5 eq). The resulting mixture was stirred at 75°C until the reaction was complete, and the reaction was monitored by thin-layer chromatography. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (DCM / methanol = 30:1) to obtain impure QXH3054 as a colorless oil, which was to be used in the next step.

[0055] The impure QXH3054 obtained above was dissolved in 20 ml of chloroform, and then 4.3 ml of SOCl2 solution was diluted in 10 ml of chloroform. This solution was then slowly added dropwise under an ice bath. When the addition was complete, the reaction mixture was heated to reflux and stirred for 3.5 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The resulting oily substance was dissolved in DCM, and the organic phase was washed with saturated sodium bicarbonate solution. The combined DCM layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to obtain impure QXH3059 as a yellow oily substance, to be added to the next step.

[0056] The QXH3059 obtained above was dissolved in 15 ml of acetonitrile, and 3,5-dimethoxyaniline was added and mixed at room temperature. The reaction mixture was heated to reflux and stirred overnight. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The residue was purified by column chromatography (DCM / methanol = 30:1) to give impure QXH3058 (212 mg, 28.8%) as a brown oil. 1 H NMR (500 MHz, CDCl3) δ 7.27 – 7.22 (m, 2H), 7.17 (d, J = 8.6 Hz, 2H),6.07 (s, 2H), 5.99 (s, 1H), 4.41 – 4.34 (m, 1H), 3.67 (s, 6H), 3.47 – 3.40(m, 1H), 3.23 – 3.14 (m, 1H), 2.81 – 2.74 (m, 1H), 2.71 – 2.64 (m, 1H), 2.59 – 2.53 (m, 1H), 2.47 – 2.39 (m, 1H), 2.31 (s, 3H). 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)-4-methylpiperazine (QXH3058) (1.68 g, 4.85 mmol) was dissolved in DCE (10 ml), and 1-chloroethylchloroformic acid (2.6 ml, 24.25 mmol, 5.0 eq) and DIPEA (4.8 ml, 29 mmol, 6.0 eq) were added at room temperature. After reacting for 4 hours, the solvent (DCE) was evaporated. Then methanol (5 ml) was added, and the mixture was heated under reflux overnight. After cooling, the mixture was evaporated and extracted with EA. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH = 30:1) to give impure QXH3064 (1 g) as a brown oil. This was to be added to the next step. 1 H NMR (500 MHz, CDCl3)δ 7.24 – 7.17 (m, 4H), 6.06 (d, J = 2.2 Hz, 2H), 5.99 (s, 1H), 4.35 – 4.26 (m,1H), 3.67 (s, 6H), 3.49 – 3.37 (m, 1H), 3.22 – 3.04 (m, 4H), 3.02 – 2.95 (m,1H), 2.26 (s, 2H). First, the 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (38 mg, 0.11 mmol, 1.0 eq) obtained in the previous step was dissolved in DCM. Then, 5-chloroindole-2-carboxylic acid (22 mg, 0.11 mmol, 1.0 eq), HATU (65 mg, 0.17 mmol, 1.5 eq), and DIPEA (40 μL, 0.23 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 3:1) to obtain a yellow solid QXH3079 (32 mg, 55%). 1 H NMR (500 MHz, CDCl3) δ 9.92 (s, 1H), 7.34 –7.21 (m, 5H), 7.21 – 7.15 (m, 1H), 7.13 (d, J = 7.1 Hz, 1H), 6.82 (s, 1H), 6.02 – 5.98 (m, 1H), 5.96 (d, J = 2.1 Hz, 2H), 4.68 (s, 1H), 4.49 – 3.96 (m,4H), 3.79 – 3.68 (m, 7H), 3.63 – 3.52 (m, 1H). HRMS (ESI) calcd forC 27 H 26 Cl2N3O3, 510.1346 [M + H] + ; found, 510.1354. Example 13 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (6-chloro-1H-indol-2-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3081), and its preparation method is as follows:

[0057] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (35 mg, 0.11 mmol, 1.0 eq) was dissolved in DCM. Then, 5-chloro-1H-indole-2-carboxylic acid (21 mg, 0.11 mmol, 1.0 eq), HATU (60 mg, 0.16 mmol, 1.5 eq), and DIPEA (37 μL, 0.21 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to give a white solid QXH3081 (13 mg, 24%). 1 H NMR (500 MHz, CDCl3) δ 10.20 (s, 1H), 7.55 (d, J =8.6 Hz, 1H), 7.43 (s, 1H), 7.35 – 7.19 (m, 4H), 7.10 (d, J HRMS (ESI) calcd for C 27 H 26 Cl2N3O3, 510.1346[M + H] + ; found, 510.1355. Example 14 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (7-chloro-1H-indol-2-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3085), and its preparation method is as follows:

[0058] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (28 mg, 0.08 mmol, 1.0 eq) was dissolved in DCM. Then, 7-chloro-1H-indole-2-carboxylic acid (18 mg, 0.08 mmol, 1.0 eq), HATU (48 mg, 0.13 mmol, 1.5 eq), and DIPEA (29 μL, 0.17 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA:DCM = 2:1:1) to give a white solid QXH3085 (27 mg, 63%). 1 H NMR (500 MHz, CDCl3)δ 9.41 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 7.25 – 7.20 (m, 3H), 7.06 (t, J =7.8 Hz, 1H), 6.75 (s, 1H), 6.00 (s, 1H), 5.96 (s, 2H), 4.63 (s, 1H), 4.46 –4.21 (m, 2H), 4.17 – 4.01 (m, 1H), 3.87 – 3.60 (m, 8H), 3.56 – 3.45 (m, 1H).HRMS (ESI) calcd for C 27 H 26 Cl2N3O3, 510.1346 [M + H] + ; found, 510.1356. Example 15 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (4-chloro-1H-indol-2-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3087), and its preparation method is as follows:

[0059] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (30 mg, 0.09 mmol, 1.0 eq) was dissolved in DCM. Then, 4-chloro-1H-indole-2-carboxylic acid (19 mg, 0.09 mmol, 1.0 eq), HATU (51 mg, 0.13 mmol, 1.5 eq), and DIPEA (31 μL, 0.18 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to obtain a white solid, QXH3087. 1 H NMR (500 MHz, CDCl3) δ 9.92 (s, 1H), 7.34 – 7.21 (m, 5H), 7.21– 7.15 (m, 1H), 7.13 (d, J = 7.1 Hz, 1H), 6.82 (s, 1H), 6.02 – 5.98 (m, 1H), 5.96 (d, J = 2.1 Hz, 2H), 4.68 (s, 1H), 4.49 – 3.96 (m, 4H), 3.79 – 3.68 (m,7H), 3.63 – 3.52 (m, 1H). HRMS (ESI) calcd for C 27 H 26 Cl2N3O3, 510.1346 [M + H] + ;found, 510.1354. Example 16 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (5-chloro-1H-indol-3-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (QXH3084), and its preparation method is as follows:

[0060] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (20 mg, 0.06 mmol, 1.0 eq) was dissolved in DCM. Then, 5-chloro-1H-indole-3-carboxylic acid (13 mg, 0.06 mmol, 1.0 eq), HATU (23 mg, 0.09 mmol, 1.5 eq), and DIPEA (22 μL, 0.12 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA:DCM = 2:1:1) to give a white solid QXH3084 (15 mg, 48.9%). 1 H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H), 7.36 –7.11 (m, 8H), 6.05 – 5.97 (m, 3H), 4.53 (s, 1H), 4.22 – 4.15 (m, 1H), 4.02(s, 1H), 3.85 – 3.74 (m, 2H), 3.69 (d, J = 3.9 Hz, 6H), 3.63 – 3.53 (m, 1H),3.43 – 3.35 (m, 1H). HRMS (ESI) calcd for C 27 H 26 Cl2N3O3, 510.1346 [M + H] + ;found, 510.1349. Example 17 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (6-chloro-1H-indol-3-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (QXH3091), and its preparation method is as follows:

[0061] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (52 mg, 0.16 mmol, 1.0 eq) was dissolved in DCM. Then, 6-chloro-1H-indole-3-carboxylic acid (33 mg, 0.16 mmol, 1.0 eq), HATU (89 mg, 0.23 mmol, 1.5 eq), and DIPEA (54 μL, 0.31 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:methanol = 100:1) to give a white solid, QXH3091. 1 H NMR (500 MHz, CDCl3) δ 9.88 – 9.63 (m, 1H), 7.49 (d, J =8.5 Hz, 1H), 7.24 – 7.16 (m, 4H), 7.12 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.03– 5.95 (m, 3H), 4.51 (s, 1H), 4.21 – 4.11 (m, 1H), 4.04 – 3.94 (m, 1H), 3.86– 3.80 (m, 1H), 3.80 – 3.73 (m, 1H), 3.69 (s, 6H), 3.62 – 3.52 (m, 1H), 3.37(s, 1H), 2.81 (s, 1H). HRMS (ESI) calcd for C 27 H 26 Cl2N3O3, 510.1346 [M + H] + ;found, 510.1355. Example 18 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (5-chloro-1-methylindole-3-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3066), and its preparation method is as follows:

[0062] A solution of 5-chloro-1H-indole-3-carboxylic acid (500 mg, 2.56 mmol, 1.0 mmoleq) was placed in dry DMF (5 ml), and potassium carbonate (883 mg, 6.39 mmol, 2.5 mmoleq) was added at room temperature. CH3I (400 μL, 6.39 mmol, 2.5 mmoleq) was then added, and the resulting mixture was stirred overnight at 50 °C. The reaction mixture was poured into water (10 ml) and extracted with EA (2 × 20 ml). The organic phase was washed with water (2 × 10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give QXH3062 (513 mg, 89.6%). 1 H NMR (500MHz, CDCl3) δ 8.12 (s, 1H), 7.75 (s, 1H), 7.23 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H). Methyl 5-chloro-1-methyl-1H-indole-3-carboxylic acid (QXH3062) (513 mg, 2.29 mmol, 1.0 eq) was dissolved in a mixture of methanol and tetrahydrofuran, and LiOH solution (110 mg, 4.59 mmol, 2.0 eq, dissolved in 5 mL of water) was added dropwise under ice bath conditions. The resulting mixture was stirred at 70 °C until the reaction was complete, and the reaction was monitored by thin-layer chromatography. The organic solvent was then evaporated, and the pH was adjusted to 3–4 at 0 °C with 2 M hydrochloric acid (aqueous solution). The precipitate was separated by filtration, washed with water, and dried under vacuum to obtain a yellow solid, QXH3063 (478 mg, 100%). 1 H NMR (500 MHz, DMSO- d 6) δ 12.08(s, 1H), 8.11 (s, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.27(dd, J = 8.7, 2.1 Hz, 1H), 3.86 (s, 3H). First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (80 mg, 0.24 mmol, 1.0 eq) was dissolved in DCM. Then, 5-chloro-1-methyl-1H-indole-3-carboxylic acid (QXH3063) (50 mg, 0.24 mmol, 1.0 eq), HATU (136 mg, 0.36 mmol, 1.5 eq), and DIPEA (84 μL, 0.48 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:methanol = 100:1) to obtain a colorless oil, QXH3066 (78 mg, 62%). 1 H NMR (500 MHz, CDCl3) δ 7.56(s, 1H), 7.18 – 7.10 (m, 7H), 5.93 (s, 3H), 4.46 (s, 1H), 4.15 – 4.05 (m,1H), 3.97 – 3.89 (m, 1H), 3.76 – 3.70 (m, 2H), 3.69 – 3.66 (m, 3H), 3.61 (s,6H), 3.55 – 3.46 (m, 1H), 3.34 – 3.24 (m, 1H). HRMS (ESI) calcd forC 28 H 28 Cl2N3O3, 524.15O3 [M + H] + ; found, 524.1511. Example 19 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (6-chloro-1-methylindole-3-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3074), and its preparation method is as follows:

[0063] A solution of 6-chloro-1H-indole-3-carboxylic acid (500 mg, 2.56 mmol, 1.0 mmoleq) was placed in dry DMF (5 ml), and potassium carbonate (883 mg, 6.39 mmol, 2.5 mmoleq) was added at room temperature. CH3I (400 μL, 6.39 mmol, 2.5 mmoleq) was then added, and the resulting mixture was stirred overnight at 50 °C. The reaction mixture was poured into water (10 ml) and extracted with EA (2 × 20 ml). The organic phase was washed with water (2 × 10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to give QXH3067 (547 mg, 95.5%). 1 H NMR (500MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 1H), 7.74 (s, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.23 (dd, J = 8.6, 1.9 Hz, 1H), 3.90 (s, 3H), 3.78 (s, 3H). The obtained methyl 6-chloro-1-methylindole-3-carboxylate (QXH3067) (534 mg, 2.39 mmol, 1.0 eq) was dissolved in tetrahydrofuran solution (10 ml), and lithium hydroxide solution (114 mg, 4.78 mmol, 4.0 eq, dissolved in 5 ml water) was added under ice bath conditions. The resulting mixture was stirred at 80 °C until the reaction was complete, and the reaction was monitored by thin-layer chromatography (TLC). The organic solvent was then evaporated, and the pH was adjusted to 3–4 at 0 °C with 2N hydrochloric acid solution. The precipitate was separated by filtration, washed with water, and dried under vacuum to obtain QXH3069 (500 mg, 100%) as a yellow solid. 1 H NMR (500 MHz, DMSO- d 6) δ 12.24 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 3.84 (s, 3H). First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (98 mg, 0.29 mmol, 1.0 eq) was dissolved in DCM. Then, 6-chloro-1-methyl-1H-indole-3-carboxylic acid (QXH3069) (61 mg, 0.29 mmol, 1.0 eq), HATU (167 mg, 0.44 mmol, 1.5 eq), and DIPEA (102 μL, 0.59 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:methanol = 150:1) to give a yellow solid QXH3074 (120 mg, 77.8%). 1 H NMR (500 MHz, CDCl3) δ7.55 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.25 – 7.14 (m, 6H), 6.00 (s, 3H), 4.54 (s, 1H), 4.21 – 4.14 (m, 1H), 4.03 – 3.97 (m, 1H), 3.87 – 3.77 (m, 2H),3.75 (s, 3H), 3.70 (s, 6H), 3.62 – 3.55 (m, 1H), 3.43 – 3.34 (m, 1H). HRMS(ESI) calcd for C 28 H 28 Cl2N3O3, 524.15O3 [M + H] + ; found, 524.1514. Example 20 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (5-chloro-1H-indol-3-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3083), and its preparation method is as follows:

[0064] A solution of 6-chloro-1H-indole-2-carboxylic acid (500 mg, 2.56 mmol, 1.0 eq) was dissolved in dry DMF (5 mL), and potassium carbonate (883 mg, 6.39 mmol, 2.5 eq) was added at room temperature. CH3I (400 μL, 6.39 mmol, 2.5 eq) was then added, and the resulting mixture was stirred overnight at 50 °C. The reaction mixture was poured into water (10 mL) and extracted with EA (2 × 20 mL). The organic phase was washed with water (2 × 10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum to give a yellow solid QXH3078 (564 mg, 98.5%). 1 H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 8.8 Hz, 1H), 7.37 (s, 1H), 7.24 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H), 4.03 (s, 3H), 3.91 (s, 3H). 6-Chloro-1-methylindole-2-carboxylic acid ester (QXH3078) (555 mg, 2.48 mmol, 1.0 eq) was dissolved in THF solution (10 mL), and LiOH solution (233 mg, 9.73 mmol, 4.0 eq, dissolved in 5 mL water) was slowly added dropwise under ice bath conditions. The resulting mixture was stirred at room temperature until the reaction was complete, and the reaction was monitored by thin-layer chromatography. The organic solvent was then evaporated, and the pH was adjusted to 3–4 at 0°C with 2N hydrochloric acid solution. The precipitate was separated by filtration, washed with water, and dried under vacuum to give a white solid QXH3080 (513 mg, 99%). 1 H NMR (500 MHz, DMSO- d 6) δ 13.06 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.23 (s, 1H), 7.13 (dd, J = 8.5,1.9 Hz, 1H), 4.01 (s, 3H). First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (44 mg, 0.13 mmol, 1.0 eq) was dissolved in DCM. Then, 6-chloro-1-methylindole-2-carboxylic acid (28 mg, 0.13 mmol, 1.0 eq), HATU (75 mg, 0.20 mmol, 1.5 eq), and DIPEA (46 μL, 0.26 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA:DCM = 2:1:1) to give a white solid QXH3083 (47 mg, 67.9%). 1 H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.5Hz, 1H), 7.34 (s, 2H), 7.26 – 7.07 (m, 4H), 6.49 (s, 1H), 6.07 – 5.88 (m,3H), 4.57 (s, 1H), 4.25 – 4.16 (m, 1H), 4.09 – 3.97 (m, 2H), 3.94 – 3.80 (m,2H), 3.71 (s, 7H), 3.65 – 3.44 (m, 3H). HRMS (ESI) calcd for C 28 H 28 Cl2N3O3, 524.15O3 [M + H] + ; found, 524.1505 Example 21 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (5-chloro-1-methylindole-2-yl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3075), and its preparation method is as follows:

[0065] A solution of 5-chloro-1H-indole-2-carboxylic acid (500 mg, 2.56 mmol, 1.0 eq) was dissolved in dry DMF (5 mL), and potassium carbonate (883 mg, 6.39 mmol, 2.5 eq) was added at room temperature. CH3I (400 μL, 6.39 mmol, 2.5 eq) was then added, and the resulting mixture was stirred overnight at 50 °C. The reaction mixture was poured into water (10 mL) and extracted with EA (2 × 20 mL). The organic phase was washed with water (2 × 10 mL) and brine (10 mL), dried over Na2SO4, and then concentrated under vacuum to give a yellow solid QXH3071 (551 mg, 96%). 1 H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.30 (s, 2H), 7.20 (s, 1H), 4.06 (s, 3H), 3.91 (s, 3H). Methyl 5-chloro-1-methyl-1H-indole-2-carboxylic acid (QXH3071) (544 mg, 2.43 mmol, 1.0 eq) was dissolved in tetrahydrofuran (THF) (10 mL), and lithium hydroxide solution (9.73 mmol, 4.0 eq, dissolved in 5 mL of water) was added dropwise under ice bath conditions. The resulting mixture was stirred at 85 °C until the reaction was complete, and the reaction was monitored by thin-layer chromatography (TLC). The solvent (THF) was then evaporated, and the pH was adjusted to 3–4 at 0 °C with 2 M hydrochloric acid (aqueous solution). The precipitate was separated by filtration, washed with water, and dried under vacuum to give a white solid QXH3072 (500 mg, 98.4%). 1 H NMR (500 MHz, DMSO- d 6) δ 7.74 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.19 (s, 1H), 4.02 (s, 3H). First, a dichloromethane solution of 2-(4-chlorophenyl)-1-(3,5-dimethoxypiperazine (QXH3064)) (86 mg, 0.26 mmol, 1.0 eq) was prepared. Then, 6-chloro-1-methyl-1H-indole-3-carboxylic acid (QXH3072) (54 mg, 0.26 mmol, 1.0 eq), HATU (147 mg, 0.39 mmol, 1.5 eq), and diisopropylethylamine (90 μL, 0.52 mmol, 2.0 eq) were added sequentially with stirring at room temperature, and the mixture was stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to obtain a yellow solid QXH3075 (62 mg, 45.8%). 1 H NMR (500 MHz, CDCl3)δ 7.48 (s, 1H), 7.27 – 6.93 (m, 6H), 6.35 (s, 1H), 6.00 – 5.81 (m, 3H), 4.47(s, 1H), 4.14 – 4.05 (m, 1H), 4.02 – 3.87 (m, 2H), 3.84 – 3.73 (m, 1H), 3.61 (s, 8H), 3.52 – 3.29 (m, 3H). HRMS (ESI) calcd for C 28 H 28 Cl2N3O3, 524.15O3 [M +H] + ; found, 524.1507. Example 22 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl](5-fluoro-1H-indol-2-yl)methyl ketone (synthesis of QXH3093), and its preparation method is as follows:

[0066] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (32 mg, 0.096 mmol, 1.0 eq) was dissolved in DCM. Then, 5-fluoro-1H-indole-2-carboxylic acid (15 mg, 0.087 mmol, 0.9 eq), HATU (55 mg, 0.14 mmol, 1.5 eq), and DIPEA (33 μL, 0.19 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to give a white solid QXH3093 (23 mg, 48.5%). 1 H NMR (500 MHz, CDCl3)δ 9.65 (s, 1H), 7.37 – 7.18 (m, 6H), 7.09 – 7.00 (m, 1H), 6.70 (s, 1H), 6.07 – 5.90 (m, 3H), 4.64 (s,1H), 4.42 – HRMS (ESI) calcd for C 27 H 26 ClFN3O3, 496.1612[M + H] + ; found, 496.1619. Example 23 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl](5,7-difluoro-1H-indol-2-yl)methyl ketone (synthesis of QXH3096), and its preparation method is as follows:

[0067] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (25.6 mg, 0.077 mmol, 1.0 eq) was dissolved in DCM. Then, 5,7-difluoro-1H-indole-2-carboxylic acid (15 mg, 0.077 mmol, 1.0 eq), HATU (44 mg, 0.12 mmol, 1.5 eq), and DIPEA (27 μL, 0.15 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to give a white solid QXH3096 (15.6 mg, 39.6%). 1 H NMR (500 MHz, CDCl3) δ 9.90 (s, 1H), 7.20 (s,2H), 7.18 – 7.12 (m, 2H), 7.05 – 6.94 (m, 1H), 6.76 – 6.67 (m, 1H), 6.64 (s,1H), 5.96 – HRMS (ESI) calcdfor C 27 H 25 ClF₂N₃O₃, 512.1548 [M + H] + ; found, 512.1552. Example 24 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl](5,7-difluoro-1H-indol-2-yl)methyl ketone (synthesis of QXH3097), and its preparation method is as follows:

[0068] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxypiperazine (QXH3064)) (41 mg, 0.12 mmol, 1.0 eq) was dissolved in DCM. Then, 5,6-difluoro-1H-indole-2-carboxylic acid (24 mg, 0.12 mmol, 1.0 eq), HATU (70 mg, 0.18 mmol, 1.5 eq), and DIPEA (43 μL, 0.25 mmol, 2.0 eq) were added sequentially with stirring at room temperature, and the mixture was stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give a white solid QXH3097 (23 mg, 48.5%). 1 H NMR (500 MHz, CDCl3) δ 9.93 (s, 1H), 7.40 – 7.11 (m, 6H), 6.69 (s, 1H), 6.07 – 5.83 (m, 3H), 4.66 (s, 1H), 4.37 (s, 1H), 4.32– 4.23 (m, 1H), 4.19 – 3.79 (m, 2H), 3.79 – 3.65 (m, 7H), 3.62 – 3.50 (m,1H). HRMS (ESI) calcd for C 27 H 25 ClF₂N₃O₃, 512.1548 [M + H] + ; found, 512.1559. Example 25 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl]{5-[(trifluoromethyl)oxy]-1H-indol-2-yl} methyl ketone (synthesis of QXH3101), and its preparation method is as follows:

[0069] First, a DCM solution of 2-(4-chlorophenyl)-1-(3,5-dimethoxypiperazine (QXH3064)) (22.5 mg, 0.068 mmol, 1.0 eq) was prepared and stirred overnight at room temperature. Then, 5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (16 mg, 0.068 mmol, 1.0 eq), HATU (39 mg, 0.102 mmol, 1.5 eq), and DIPEA (24 μL, 0.136 mmol, 2.0 eq) were added sequentially. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate:dichloromethane = 2:1:1) to give a yellow solid QXH3101 (19 mg, 49.9%). 1 H NMR (500 MHz, CDCl3) δ9.76 (s, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.31 – 7.20 (m, 4H), 7.15 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 6.01 (s, 1H), 5.97 (s, 2H), 4.65 (s,1H), 4.47 – 4.22 (m, 2H), 4.19 – 3.91 (m, 2H), 3.76 – 3.65 (m, 7H), 3.59 –3.47 (m, 1H). HRMS (ESI) calcd for C 28 H 26 ClF3N3O4, 560.1559 [M + H] + ; found, 560.1566. Example 26 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl](5-methoxy-1H-indole-2-yl)methyl ketone (QXH3103), and its preparation method is as follows:

[0070] 2-(4-chlorophenyl)-1-(3,5-dimethoxypiperazine (QXH3064)) (30 mg, 0.09 mmol, 1.0 eq) was dissolved in DCM solution, and then 5-methoxy-1H-indole-2-carboxylic acid (17 mg, 0.09 mmol, 1.0 eq), HATU (51 mg, 0.135 mmol, 1.5 eq), and diisopropylethylamine (31 μL, 0.18 mmol, 2.0 eq) were added sequentially with stirring at room temperature, and the mixture was stirred overnight. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give a yellow solid QXH3103 (6.8 mg, 14.9%). 1 H NMR (500 MHz, CDCl3) δ 9.34 (s, 1H), 7.34– 7.27 (m, 3H), 7.25 – 7.20 (m, 2H), 7.05 – 7.01 (m, 1H), 6.98 – 6.94 (m,1H), 6.67 (s, 1H), 6.02 – 5.93 (m, 3H), 4.64 (s, 1H), 4.43 – 4.21 (m, 2H), 4.11 (s, 1H), 3.84 (s, 4H), 3.74 – 3.63 (m, 7H), 3.58 – 3.48 (m, 1H). HRMS(ESI) calcd for C 28 H 29 ClN3O4, 506.1842 [M + H] + ; found, 506.1849. Example 27 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl](5,6-dimethoxy-1H-indol-2-yl)methyl ketone (synthesis of QXH3104), and its preparation method is as follows:

[0071] First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3064) (25 mg, 0.075 mmol, 1.0 eq) was dissolved in DCM. Then, 5,6-dimethoxy-1H-indole-2-carboxylic acid (17 mg, 0.075 mmol, 1.0 eq), HATU (43 mg, 0.11 mmol, 1.5 eq), and DIPEA (26 μL, 0.15 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA:DCM = 2:1:1) to give a yellow solid QXH3104 (11 mg, 27.3%). 1 H NMR (500 MHz, CDCl3) δ 9.37 (s,1H), 7.32 – 7.19 (m, 4H), 7.01 (s, 1H), 6.85 (s, 1H), 6.66 (s, 1H), 6.01 –5.89 (m, 3H), 4.64 (s, 1H), 4.44 – 4.26 (m, 2H), 4.10 (s, 1H), 3.96 – 3.84(m, 7H), 3.76 – 3.65 (m, 7H), 3.59 – 3.51 (m, 1H). HRMS (ESI) calcd forC 29 H 31 ClN3O5, 536.1947 [M + H] + ; found, 536.1952. Example 28 This embodiment provides a nitrogen-containing heterocyclic compound, specifically {4-[(6-chloro-1H-indol-2-yl)carbonyl]-2-(4-chlorophenyl)piperazin-1-yl}(3,5-dimethoxyphenyl)methyl ketone (synthesis of QXH1113), and its preparation method is as follows:

[0072] tert-butyl 3-(4-chlorophenyl)piperazine-1-carboxylic acid ester (200 mg, 0.67 mmol) and 3,5-dimethoxybenzoic acid (QXH1088) (183 mg, 1.0 mmol) were dissolved in a 30% (v / v) pyridine-DCM mixture. EDCI (257 mg, 1.34 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by thin-layer chromatography, and the reactants were concentrated under vacuum. The residue was purified by column chromatography (PE / EA = 3 / 1) to give QXH1104 (301 mg, 97.4%). 1 H NMR (500 MHz, CDCl3) δ 7.34 (s, 4H), 6.51 (d, J = 15.0 Hz,3H), 6.17 – 5.70 (m, 1H), 4.62 (s, 1H), 3.78 (s, 8H), 3.30 (s, 1H), 3.02 (s,2H), 1.45 (s, 9H). tert-Butyl 3-(4-chlorophenyl)-4-(3,5-dimethoxybenzoyl)piperazine-1-carboxylic acid ester (QXH1104) (41 mg, 0.067 mmol) was dissolved in DCM, and 1 mL of trifluoroacetic acid was slowly added dropwise under ice bath conditions. The reaction mixture was stirred at room temperature. Volatile substances were removed under reduced pressure, and the pH of the resulting residue was adjusted to 8–9 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic extracts were washed with deionized water, dried over anhydrous sodium sulfate (Na₂SO₄), and concentrated under vacuum. The residue was purified by column chromatography (DCM / methanol = 50 / 1) to give QXH1107 (152.5 mg, 65%). 1 H NMR (500 MHz, CDCl3) δ 7.34 (s, 4H), 6.53 (s,2H), 6.50 (s, 1H), 6.17 – 5.70 (m, 1H), 4.62 (s, 1H), 4.15 – 3.47 (m, 8H), 3.30 (s, 1H), 3.02 (s, 2H), 1.45 (s, 9H). (2-(4-chlorophenyl)piperazin-1-yl)(3,5-dimethoxyphenyl) methyl ketone (QXH1107) (35 mg, 0.097 mmol) and 6-chloro-1H-indole-2-carboxylic acid (38 mg, 0.194 mmol) were dissolved in a 30% pyridine-DCM mixture. EDCI (38 mg, 0.194 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by thin-layer chromatography, and the reactants were concentrated under vacuum. The residue was purified by column chromatography (PE / EA = 1 / 1) to give QXH1113. 1 H NMR (500 MHz, CDCl3) δ 9.69 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.39(s, 1H), 7.28 (s, 3H), 7.09 (d, J HRMS (ESI) calcd for C 28 H 26 Cl2N3O4, 538.1295 [M + H] + ; found, 538.1313. Example 29 This embodiment provides a nitrogen-containing heterocyclic compound, specifically {4-[(5-chloro-1H-indol-2-yl)carbonyl]-2-(4-chlorophenyl)piperazin-1-yl}(3,5-dimethoxyphenyl)methyl ketone (synthesis of QXH1131), and its preparation method is as follows:

[0073] First, 5-chloroindole-2-carboxylic acid (52 mg, 0.262 mmol) was dissolved in DCM, followed by the sequential addition of HATU (133 mg, 0.349 mmol) and DIPEA (113 mg, 0.872 mmol) at 0°C. The reaction was monitored by thin-layer chromatography, confirming complete consumption of the starting material after approximately 20 minutes. Subsequently, (2-(4-chlorophenyl)piperazin-1-yl)(3,5-dimethoxyphenyl)methyl ketone (QXH1107) (78 mg, 0.218 mmol) was introduced, and the resulting mixture was stirred continuously at room temperature. After completion, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 1 / 1) to obtain QXH1131 (88.5 mg, 75.4%). 1 H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 7.57 (s, 1H), 7.33 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 6.72 – 6.43 (m,4H), 6.05 (s, 1H), 5.04 (s, 1H), 4.46 (s, 1H), 3.99 – 3.16 (m, 11H). HRMS(ESI) calcd for C 28 H 26 Cl2N3O4, 538.1295 [M + H] + ; found, 538.1299. Example 30 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (4-chlorophenyl)[3-(4-chlorophenyl)-4-(3,5-dimethoxyphenyl)piperazin-1-yl] methyl ketone (synthesis of QXH3055), and its preparation method is as follows:

[0074] The synthesis steps for QXH3049 are the same as those for QXH3064. First, 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazine (QXH3049) (16 mg, 0.072 mmol, 1.0 eq) was dissolved in DCM. Then, 4-chlorobenzoic acid (11 mg, 0.072 mmol, 1.5 eq), HATU (27 mg, 0.072 mmol, 1.5 eq), and DIPEA (17 μL, 0.096 mmol, 2.0 eq) were added sequentially at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to obtain QXH3055 (10 mg, 44.2%). 1 H NMR (500 MHz, CDCl3) δ 7.41 – 7.01 (m, 8H), 6.11 – 5.84 (m,3H), 4.65 – 4.34 (m, 1H), 4.30 – 4.00 (m, 1H), 3.94 – 3.51 (m, 10H), 3.50 –3.31 (m, 1H). Example 31 This embodiment provides a nitrogen-containing heterocyclic compound, specifically (5-chloro-1H-indol-2-yl)[3-(4-chlorophenyl)-4-[(3,5-dimethoxyphenyl)methyl]piperazin-1-yl]methyl ketone (synthesis of QXH1126), and its preparation method is as follows:

[0075] 3-(4-chlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.337 mmol) and 3,5-dimethoxybenzaldehyde were dissolved in methanol / acetic acid (99:1 mixture, 5 ml). After stirring magnetically for 1 hour at room temperature, NaCNBH3 (28 mg, 0.438 mmol) was added to the mixture. The mixture was stirred for another 24 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 ml) and saturated sodium bicarbonate solution (20 ml). The organic phase was separated, dried over anhydrous sodium sulfate, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 7:1) to give QXH1121 (96 mg, 63.7%). 1 H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 6.41 (s, 2H), 6.33 (s, 1H), 3.97 (s, 2H), 3.77 (s,6H), 3.72 – 3.64 (m, 1H), 3.26 – 3.17 (m, 1H), 2.96 (s, 1H), 2.92 – 2.86 (m,1H), 2.85 – 2.74 (m, 2H), 2.13 – 2.02 (m, 1H), 1.45 (s, 9H). 3-(4-chlorophenyl)-4-[(3,5-dimethoxyphenyl)methyl]piperazine-1-carboxylic acid-2-methylpropyl-2-yl ester (QXH1121) (92 mg, 0.2 mmol) was dissolved in DCM (5 ml), and then trifluoroacetic acid (TFA, 0.5 ml) was slowly added dropwise under ice bath. The reaction mixture was stirred at room temperature for 24 hours. Volatile substances were removed under reduced pressure, and the pH of the resulting residue was adjusted to 8–9 with a saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2 × 10 ml). The combined organic extracts were washed with deionized water, dried over anhydrous sodium sulfate (Na₂SO₄), and concentrated under vacuum. The crude product was purified by column chromatography (DCM / MeOH = 20:1) to give QXH1123 (57 mg, 82.1%).

[0076] First, 5-chloro-1H-indole-2-carboxylic acid (39 mg, 0.197 mmol) was dissolved in DCM, followed by the sequential addition of HATU (100 mg, 0.262 mmol) and DIPEA (85 mg, 0.656 mmol) with stirring at room temperature. The reaction was monitored by thin-layer chromatography, confirming complete consumption of the starting material after approximately 30 minutes. Subsequently, 2-(4-chlorophenyl)-1-(3,5-dimethoxybenzyl)piperazine (QXH1123) (57 mg, 0.164 mmol) was introduced, and the resulting mixture was stirred continuously at room temperature. After completion, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 5 / 1) to obtain QXH1126 (85.2 mg, 98.8%). 1 H NMR (500 MHz, CDCl3) δ 10.06 – 9.82 (m, 1H),7.57 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 (d, J= 6.7 Hz, 2H), 7.34 – 7.30(m, 1H), 7.22 – 7.12 (m, 1H), 6.65 (s, 1H), 6.43 (s, 2H), 6.36 (s, 1H), 4.62(s, 2H), 3.78 (s, 6H), 3.76 – 3.68 (m, 1H), 3.51 – 2.94 (m, 4H), 2.91 – 2.79(m, 1H), 2.28 – 2.16 (m, 1H). HRMS (ESI) calcd for C 28 H 28 Cl2N3O3, 524.15O3 [M +H] + ; found, 524.1511. Example 32 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-[(5-chloro-1-methylindole-2-yl)carbonyl]-6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazin-2-one (synthesis of QXH3168), and its preparation method is as follows:

[0077] 4-Chlorobenzene oxide (980 μL, 5.44 mmol, 1.0 eq) was dissolved in a dry ethanol solution (3 mL) and mixed with N-benzylglycine ethyl ester (1 mL, 5.44 mmol, 1.0 eq). The mixture was then stirred at 110°C until the reaction was complete (monitored by thin-layer chromatography). After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 10:1) to give impure QXH3154 (625 mg, 33%) as a colorless oil.

[0078] QXH3154 (625 mg, 1.8 mmol, 1.0 eq) was placed in a dry, double-necked round-bottom flask. Nitrogen purging was performed three times. Ultra-dry tetrahydrofuran (5 mL) was injected. The reaction mixture was cooled to 0°C, and TEA (1 mL, 7.2 mmol, 4.0 eq) was added dropwise. After complete addition, stirring was maintained at 0°C for 30 minutes. Then, ethanesulfonyl chloride (510 μL, 5.39 mmol, 3.0 eq) was added dropwise while maintaining a constant temperature bath at 0°C. The reaction vessel was gradually heated to room temperature and stirred at this temperature for 4 hours. 3,5-Dimethoxyaniline (825 mg, 5.39 mmol, 3.0 eq) was added, and the mixture was stirred overnight at room temperature. The reaction progress was monitored by thin-layer chromatography. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (15 mL) and transferred to a separating funnel. The organic layer was washed with saturated sodium bicarbonate aqueous solution (2 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give an impure brown solution QXH3157 (818 mg, 26%).

[0079] Ethyl benzyl[2-(4-chlorophenyl)-2-[(3,5-dimethoxyphenyl)amino]ethyl]amino}acetate (QXH3157) (503 mg, 1.04 mmol, 1.0 eq) was dissolved in 5 mL of DCM. Trifluoroacetic acid was slowly added dropwise under ice bath conditions, and the reaction was heated in an oil bath at 50°C until complete. After the reaction, the mixture was neutralized with 10 mL of water and extracted twice with DCM. The aqueous layer was adjusted to alkalinity with saturated sodium bicarbonate solution and then extracted with DCM. All organic phases were combined and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified by column chromatography (PE:EA = 1:1) to give a yellow oil, QXH3160 (194 mg, 42.7%). 1 H NMR (500 MHz, CDCl3) δ 7.29 – 7.20 (m, 8H),7.18 – 7.10 (m, 2H), 6.28 – 6.25 (m, 1H), 6.21 (d, J = 2.2 Hz, 2H), 4.80 (t, J= 4.3 Hz, 1H), 3.65 (s, 6H), 3.62 – 3.53 (m, 3H), 3.36 – 3.23 (m, 1H), 3.08 –2.96 (m, 1H), 2.84 – 2.75 (m, 1H). HRMS (ESI) calcd for C 25 H 26 ClN₂O₃, 437.1627[M + H] + ; found, 437.1635. QXH3160 (194 mg, 0.44 mmol, 1.0 eq) and DIPEA (460 μL, 2.64 mmol, 6.0 eq) were dissolved in DCE (5 mL) at room temperature. Then, 1-chloroethylchloroformic acid (240 μL, 2.22 mmol, 5.0 eq) was added, and the resulting solution was stirred at room temperature for 1 hour. The reaction was then heated to 50°C in an oil bath for 5 days. After evaporation, the residue was dissolved in MeOH and heated under reflux (90°C) for 2 days. After evaporation, the residue was separated into layers between EA and saturated NaHCO3 (aqueous solution). The aqueous layer was extracted with EA. The combined EA layers were washed with brine and dried (Na2SO4). Filtration and concentration yielded a brown oil. The crude reaction mixture was purified by rapid chromatography to give the brown oil QXH3162 (2.46 g, 60.9%). 1 H NMR (500 MHz, CDCl3) δ7.32 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.28 (s, 3H), 4.87 (s, 1H), 3.84 – 3.74 (m, 2H), 3.67 (s, 6H), 3.56 – 3.44 (m, 1H), 3.15 – 3.03 (m, 1H). First, 6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazin-2-one (QXH3162) (28 mg, 0.08 mmol, 1.0 eq) was dissolved in DCM. Then, 5-chloro-1-methyl-1H-indole-2-carboxylic acid (QXH3072) (17 mg, 0.08 mmol, 1.0 eq), HATU (46 mg, 0.12 mmol, 1.5 eq), and DIPEA (28 μL, 0.16 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:methanol = 60:1) to give QXH3168 (40 mg, 92.8%) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 7.44 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.18 – 7.01 (m, 4H), 6.31 –6.10 (m, 3H), 5.87 (s, 1H), 5.16 – 4.79 (m, 2H), 4.60 – 4.16 (m, 2H), 4.01 –3.94 (m, 1H), 3.62 (s, 6H), 3.44 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 165.1,162.5, 161.2 (2C), 142.2, 136.6, 134.6, 130.9, 129.3 (2C), 128.2 (2C), 126.9,126.3, 124.5, 121.0, 111.2, 105.2 (2C), 104.0, 99.6, 63.2, 55.5 (2C), 51.4,47.0, 31.2. HRMS (ESI) calcd for C 28 H 26 Cl2N3O4, 538.1295 [M + H] + ; found, 538.1306. Example 33 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)-4-({5-[(trifluoromethyl)oxy]-1H-indol-2-yl}carbonyl)piperazin-2-one (synthesis of QXH3167), and its preparation method is as follows:

[0080] First, 6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazin-2-one (QXH3162) (24 mg, 0.069 mmol, 1.0 eq) was dissolved in DCM. Then, 5-(trifluoromethoxy)indole-2-carboxylic acid (17 mg, 0.069 mmol, 1.0 eq), HATU (39 mg, 0.104 mmol, 1.5 eq), and DIPEA (24 μL, 0.138 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:methanol = 40:1) to give a yellow solid QXH3167 (20 mg, 54%). 1 H NMR (500 MHz, CDCl3) δ 9.64(s, 1H), 7.45 (s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.26 – 7.20 (m, 2H), 7.20 –7.11 (m, 3H), 6.32 (s, 2H), 6.30 (s, 2H),5.18 – 5.07 (m, 1H), 5.03 (s, 1H),4.72 – 4.59 (m, 1H), 4.16 (s, 1H), 3.68 (s, 6H). HRMS (ESI) calcd forC 28 H 24 ClF3N3O5, 574.1352 [M + H] + ; found, 574.1362. Example 34 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-[(5-chloro-1H-indol-2-yl)carbonyl]-6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazin-2-one (synthesis of QXH3125), and its preparation method is as follows:

[0081] First, 6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazin-2-one (QXH3123) (15 mg, 0.034 mmol, 1.0 eq) was dissolved in DCM. Then, 5-chloroindole-2-carboxylic acid (10 mg, 0.05 mmol, 1.5 eq), HATU (19 mg, 0.05 mmol, 1.5 eq), and DIPEA (12 μL, 0.068 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:methanol = 50:1) to give QXH3125 as a yellow solid. 1 H NMR (500 MHz, CDCl3)δ 9.61 (s, 1H), 7.55 (s,1H), 7.34 – 7.09 (m, 6H), 6.94 – 5.83 (m, 4H), 5.18 – 4.95 (m, 2H), 4.79 –4.40 (m, 2H), 4.15 (s, 1H), 3.68 (s, 6H). HRMS (ESI) calcd for C 27 H 24 Cl2N3O4, 524.1139 [M + H] + ; found, 524.1149. Example 35 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 4-benzyl-6-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)piperazin-2-one (synthesis of QXH3136), and its preparation method is as follows:

[0082] The synthesis of QXH3135 is the same as that of QXH3160. QXH3135 (116 mg, 0.239 mmol, 1.0 eq) was dissolved in 3 mL of DCM. 25 μL of TFA was slowly added dropwise under ice bath conditions, and the reaction was heated in an oil bath at 50°C until complete. After the reaction was complete, the reaction was terminated with 10 mL of water, and the mixture was extracted twice with DCM. The aqueous layer was adjusted to alkalinity with saturated sodium bicarbonate solution and then extracted with DCM. All organic phases were mixed and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a yellow oil, QXH3136 (42 mg, 40%). 1 H NMR (500 MHz, CDCl3)δ 7.24(d, J= 6.3 Hz, 8H), 7.18 – 7.10 (m, 2H), 6.28 – 6.25 (m, 1H), 6.21 (d, J = 2.2Hz, 2H), 4.80 (t, J = 4.3 Hz, 1H), 3.65 (s, 6H), 3.62 – 3.53 (m, 3H), 3.36 –3.23 (m, 1H), 3.08 – 2.96 (m, 1H), 2.84 – 2.75 (m, 1H), Example 36 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)pyrrolidine-3-yl]{6-[(trifluoromethyl)oxy]-2,3-dihydro-1H-indol-1-yl} methyl ketone (synthesis of QXH2148), and its preparation method is as follows:

[0083] 4-Chlorobenzaldehyde (974 mg, 6.93 mmol) and 3,5-dimethoxyaniline (1.06 g, 6.93 mmol) were dissolved in acetonitrile (5 ml) and stirred for 1 hour. Then, diethyl 1,1-cyclopropyl dicarboxylate (1.29 g; 6.93 mmol), CeCl7H2O (516 mg, 1.386 mmol), and Lil (926 mg, 6.93 mmol) were added. The mixture was stirred at 100°C for 24 hours. When the reaction was complete (as shown by thin-layer chromatography), the reaction mixture was diluted with H2O (30 ml) and extracted with ethyl acetate (2 × 20 ml). The organic phase was separated and dried over anhydrous Na2SO4, and the organic solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 15:1) to give a white solid QXH2120 (719 mg, 22.5%). 1 H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 9.0 Hz,2H), 5.85 (s, 1H), 5.65 (d, J= 2.0 Hz, 2H), 5.41 (s, 1H), 4.31 – 4.16 (m,2H), 3.96 – 3.87 (m, 1H), 3.84 – 3.75 (m, 2H), 3.76 – 3.70 (m, 1H), 3.66 (s,6H), 3.34 – 3.26 (m, 1H), 2.95 – 2.85 (m, 1H), 2.53 – 2.44 (m, 1H), 1.25 (t, J = 7.0 Hz, 4H), 1.06 (t, J = 7.0 Hz, 3H). QXH2120 (288 mg, 0.623 mmol) was dissolved in 10 mL of a 1:1 mixture of ethanol and water, followed by the addition of KOH (175 mg, 3.115 mmol). The mixture was refluxed at 75°C. After the reaction was complete, the pH was adjusted to 3-4 with 2N hydrochloric acid solution. The organic phase was washed with water (2 × 15 mL) and brine (15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (DCM / MeOH = 90 / 1) to give QXH2146 (152 mg, 67.4%). 1 H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H),5.87 (s, 1H), 5.66 (s, 2H), 5.02 (s, 1H), 3.74 – 3.68 (m, 1H), 3.66 (s, 6H),3.60 – 3.52 (m, 1H), 3.04 – 2.93 (m, 1H), 2.40 – 2.15 (m, 2H). 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid (QXH2136) (30 mg, 0.083 mmol), 6-(trifluoromethoxy)indole (17 mg, 0.083 mmol), and TCFH (26 mg, 0.091 mmol) were dissolved in formamide (5 mL). NMI (14 μL, 0.174 mmol) was added to this solution. The reaction mixture was stirred at room temperature and monitored by TLC (PE / EA 5:1). After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 8:1) to give QXH2148 (38 mg, 83.7%). 1 H NMR (500 MHz, CDCl3) δ8.20 (s, 1H), 7.30 – 7.22 (m, 4H), 7.14 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.8Hz, 1H), 5.86 (s, 1H), 5.69 (s, 2H), 5.06 (d, J = 4.9 Hz, 1H), 4.06 – 3.99 (m,1H), 3.87 – 3.76 (m, 2H), 3.73 – 3.67 (m, 1H), 3.65 (s, 6H), 3.20 – 3.04 (m,3H), 2.44 – 2.23 (m, 2H). Example 37 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)-N-{2-methyl-5-[(trifluoromethyl)oxy]phenyl}pyrrolidine-3-carboxamide (synthesis of QXH2150), and its preparation method is as follows:

[0084] The synthesis of QXH2136 is the same as that of QXH2146.

[0085] 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid (QXH2136) (30 mg, 0.083 mmol), 2-methyl-5-(trifluoromethoxy)aniline (16 mg, 0.083 mmol), and TCFH (26 mg, 0.091 mmol) were dissolved in acetonitrile (5 mL). NMI (14 μL, 0.174 mmol) was added to this solution. The reaction mixture was stirred at room temperature and monitored by TLC (PE / EA 1:1). After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 5:1) to give a brown solid QXH2150 (11 mg, 24.8%). 1 H NMR (500MHz, CDCl3) δ 8.03 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 – 7.15 (m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 5.90 (s, 1H), 5.71 (s, 2H), 5.03 (d, J = 3.9 Hz, 1H), 3.86 – 3.79 (m, 1H), 3.77 – 3.71 (m, 1H), 3.67 (s,7H), 3.02 – 2.92 (m, 1H), 2.44 – 2.31 (m, 2H), 1.99 (s, 3H). Example 38 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)-N-[4-(trifluoromethyl)phenyl]pyrrolidine-3-carboxamide (synthesis of QXH2170), and its preparation method is as follows:

[0086] 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid (QXH2146) (30 mg, 0.08 mmol, 1.0 eq), 4-(trifluoromethoxy)aniline (14 mg, 0.08 mmol, 1.0 eq), and TCFH (22 mg, 0.08 mmol, 1.0 eq) were dissolved in acetonitrile solution (5 mL). NMI (13 μL, 0.16 mmol, 2.0 eq) was added to this solution. The reaction mixture was stirred at room temperature and monitored by TLC (PE / EA 5:1). After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 3:1) to give a yellow oil, QXH2170 (31 mg, 77.8%). 1 H NMR (500 MHz, CDCl3) δ 7.56 (s, 4H), 7.33 – 7.25 (m, 4H), 7.20 (d, J = 8.2 Hz, 2H), 5.88 (s, 1H), 5.68 (d, J = 2.1 Hz, 2H), 4.98 (d, J = 4.9 Hz,1H), 3.84 – 3.77 (m, 1H), 3.77 – 3.68 (m, 1H), 3.66 (s, 6H), 2.94 – 2.83 (m,1H), 2.40 – 2.30 (m, 2H). Example 39 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 2-(4-chlorophenyl)-1-(3,5-dimethoxy)-N-{4-[(trifluoromethyl)oxy]phenyl}pyrrolidine-3-carboxamide (synthesis of QXH2165), and its preparation method is as follows:

[0087] 2-(4-chlorophenyl)-1-(3,5-dimethoxyphenyl)pyrrolidine-3-carboxylic acid (QXH2146) (30 mg, 0.08 mmol, 1.0 eq), 4-(trifluoromethoxy)aniline (14 mg, 0.08 mmol, 1.0 eq), and TCFH (22 mg, 0.08 mmol, 1.0 eq) were dissolved in acetonitrile (5 mL). NMI (13 μL, 0.16 mmol, 2.0 eq) was added to this solution. The reaction mixture was stirred at room temperature and monitored by TLC (PE / EA 5:1). After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE / EA = 3:1) to give a yellow solid, QXH2165 (31 mg, 77.8%). 1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 9.1 Hz, 2H), 7.28 (d, J = 8.4 Hz,2H), 7.23 (s, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 5.87 (s,1H), 5.67 (d, J = 2.2 Hz, 2H), 4.97 (d, J = 5.0 Hz, 1H), 3.83 – 3.76 (m, 1H), 3.73 – 3.67 (m, 1H), 3.65 (s, 6H), 2.92 – 2.81 (m, 1H), 2.39 – 2.29 (m, 2H). Example 40 This embodiment provides a nitrogen-containing heterocyclic compound, specifically 2,N-bis(4-chlorophenyl)-1-[5-methoxy-3-(methyldioxane-λ6-thio)phenyl]pyrrolidine-2-carboxamide (synthesis of QXH3170), and its preparation method is as follows:

[0088] In a 250 ml double-necked flask, 30 ml of toluene was added, and the mixture was purged twice with nitrogen. Then, ethyl methyl ethyl 4-chlorobenzoylformate (2 g, 9.4 mmol, 1.0 eq), 3-methoxy-5-(methylsulfonyl)aniline (2.08 g, 10.34 mmol, 1.1 eq), and PISA (162 mg, 0.94 mmol, 0.1 eq) were added to the flask, and the mixture was stirred until dissolved. The reaction mixture was heated to 130 °C and stirred under nitrogen for approximately 12 hours. After the reaction was complete, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE:EA = 2:1) to give an impure yellow oil, QXH3156 (2 g). 1 H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.46(d, J = 8.7 Hz, 2H), 7.24 (s, 1H), 7.10 (s, 1H), 6.75 (s, 1H), 4.22 – 4.13 (m,2H), 3.86 (s, 3H), 3.05 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H). In a 250 ml double-necked flask, QXH3156 (5.22 mmol, 1.0 eq, 2.065 g), (S,S)-2,6-bis(4-isopropyl-2-oxazoline-2-yl)pyridine (0.522 mmol, 0.1 eq, 157 mg), and indium iodide (0.522 mmol, 0.1 eq, 127 mg) were added and purged with nitrogen (twice). The mixture was then dissolved in tetrahydrofuran (15 ml). Allyl borate pinacol ester (4.9 ml, 26 mmol, 5.0 eq) and methanol (29.95 mmol, 5 eq, 1.2 ml) were added dropwise to this solution. The reaction mixture was allowed to stand overnight. After confirming complete consumption of the starting materials by thin-layer chromatography, the reaction mixture was filtered through a diatomaceous earth mat to remove residual indium iodide, and the mat was rinsed with DCM (3 × 10 ml). All solvents were evaporated under reduced pressure. The crude reaction mixture was purified by column chromatography to give impure QXH3158 (2.46 g, 62.2%) as a yellow oil. 1 H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.8 Hz, 2H), 7.34 (d, J=8.7 Hz, 2H), 6.70 (s, 1H), 6.62 (s, 1H), 5.98 (s, 1H), 5.66 (s, 1H), 5.64 –5.56 (m, 1H), 5.18 – 4.99 (m, 2H), 4.27 – 4.18 (m, 1H), 4.14 – 4.03 (m, 1H), 3.67 (s, 3H), 3.28 – 3.16 (m, 2H), 2.92 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). In a 250 ml double-necked flask, impure QXH3158 (1.0 mmoleq, 3.9 g) was added, followed by two nitrogen purgings. Then, 10 ml of tetrahydrofuran was added and the mixture was cooled to -70°C. BH3·DMS (10 mmoleq, 5.3 ml) was added dropwise to the reaction mixture. The reaction mixture was stirred at this temperature for 2 hours, then slowly heated to room temperature and stirred overnight. After the overnight reaction, the reaction mixture was cooled to 0°C, and a mixture of sodium acetate (3.67 g, dissolved in approximately 5 ml of water) and 1.4 ml of H2O2 solution was added. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred overnight. The reaction was terminated with a saturated sodium thiosulfate solution. The aqueous layer was extracted with EA (3 × 30 ml) and dried over anhydrous Na2SO4. After filtration, all solvents were evaporated under reduced pressure. The crude reaction mixture was purified by column chromatography to give a colorless oil, QXH3163 (667 mg). 1 H NMR (500 MHz, CDCl3)δ 7.48 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 18.2 Hz, 2H), 5.98 (s, 1H), 5.82(s, 1H), 4.25 – 4.16 (m, 1H), 4.15 – 4.05 (m, 1H), 3.66 (s, 3H), 3.64 – 3.52(m, 2H), 2.92 (d, J = 2.4 Hz, 3H), 2.71 – 2.60 (m, 1H), 2.56 – 2.43 (m, 1H), 1.62 – 1.51 (m, 1H), 1.45 – 1.30 (m, 1H), 1.21 – 1.07 (m, 3H). In a 250 mL two-necked flask, QXH3163 (0.2 mmol, 1.0 eq, 93 mg) was added and purged twice with nitrogen. It was then dissolved in 5 mL of DCM, followed by the addition of triamine (0.4 mmol, 2.0 eq, 55 μL). Ethylsulfonyl chloride (0.3 mmol, 1.5 eq, 29 μL) was added dropwise at 0°C. The reaction mixture was then heated to room temperature and stirred overnight. After confirming complete consumption of the starting material, the reaction was stopped with a saturated aqueous solution of sodium bicarbonate (5 mL). The aqueous layer was extracted with EA (2 × 10 mL) and dried over anhydrous sodium sulfate. After filtration, all solvents were evaporated under reduced pressure. The crude reaction mixture was purified by column chromatography (PE:EA = 2:1) to give QXH3165 (45 mg, 51.2%) as a colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.40 – 7.20 (m, 4H), 6.73 (d, J = 38.6 Hz, 2H), 6.05(s, 1H), 4.23 – 4.05 (m, 2H), 3.81 – 3.73 (m, 1H), 3.71 – 3.59 (m, 4H), 2.96(d, J = 2.6 Hz, 3H), 2.85 – 2.75 (m, 1H), 2.30 – 2.19 (m, 1H), 2.11 – 2.00 (m,1H), 1.97 – 1.84 (m, 1H), 1.11 – 1.01 (m, 3H). 45 mg (0.103 mmol, 1.0 eq) of QXH3165 was dissolved in methanol, and 30 mg (0.75 mmol, 4.0 eq) of sodium hydroxide (dissolved in 2 ml of water) was added. The resulting mixture was stirred at 80°C. The solvent (methanol) was then evaporated, and the pH was adjusted to 3-4 at 0°C with 2N hydrochloric acid solution. The precipitate was separated by filtration, washed with water, and dried under vacuum to give QXH3166 (42 mg, 100%) as a white solid. 1H NMR (500 MHz, CDCl3)δ7.34 – 7.24 (m, 4H), 6.77 (s, 1H), 6.67 (s, 1H), 6.09 (s, 1H), 3.82 – 3.76(m, 1H), 3.73 – 3.68 (m, 1H), 3.63 (s, 3H), 2.94 (s, 3H), 2.90 – 2.77 (m,1H), 2.38 – 2.22 (m, 1H), 2.15 – 2.04 (m, 1H), 1.99 – 1.85 (m, 1H). First, 2-(4-chlorophenyl)-1-(3-methoxy-5-(methanesulfonyl)phenyl)pyrrolidine-2-carboxylic acid (QXH3166) (45 mg, 0.109 mmol, 1.0 eq) was dissolved in DCM solution. Then, 4-chloroaniline (14 mg, 0.109 mmol, 1.0 eq), HATU (62 mg, 0.16 mmol, 1.5 eq), and diisopropylethylamine (38 μL, 0.218 mmol, 2.0 eq) were added sequentially at room temperature. After stirring overnight, the reaction was completed. The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a yellow solid QXH3170 (11 mg, 19.4%). 1 H NMR (500 MHz, CDCl3) δ7.99 (s, 1H), 7.30 – 7.27 (m, 2H), 7.22 – 7.16 (m, 5H), 6.72 (s, 1H), 6.62(s, 1H), 6.08 (s, 1H), 3.87 – 3.77 (m, 1H), 3.75 – 3.66 (m, 1H), 3.54 (s,3H), 2.97 – 2.86 (m, 1H), 2.79 (s, 3H), 2.40 – 2.30 (m, 1H), 2.09 – 1.91 (m,2H). Example 41 This embodiment provides a nitrogen-containing heterocyclic compound, specifically [2-(4-chlorophenyl)-1-[5-methoxy-3-(methyldioxane-λ6-thio)phenyl]pyrrolidine-2-yl]{6-[(trifluoromethyl)oxy]-2,3-dihydro-1H-indol-1-yl} methyl ketone (synthesis of QXH3173), and its preparation method is as follows:

[0089] First, 2-(4-chlorophenyl)-1-(3-methoxy-5-(methanesulfonyl)phenyl)pyrrolidine-2-carboxylic acid (QXH3172) (41 mg, 0.1 mmol, 1.0 eq) was dissolved in DCM. Then, 1H-indole, 2,3-dihydro-6-(trifluoromethoxy) (20 mg, 0.1 mmol, 1.0 eq), HATU (57 mg, 0.15 mmol, 1.5 eq), and DIPEA (35 μL, 0.2 mmol, 2.0 eq) were added sequentially with stirring at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 2:1) to give a white solid, QXH3173. 1 H NMR (500 MHz, CDCl3) δ 8.71 –8.63 (m, 1H), 8.44 – 8.36 (m, 1H), 7.51 – 7.43 (m, 3H), 7.41 – 7.34 (m, 2H), 6.91 (s, 1H), 6.80 (s, 1H), 6.31 (s, 1H), 4.04 – 3.86 (m, 2H), 3.72 (s, 3H), 3.42 – 3.29 (m, 1H), 3.12 – 2.97 (m, 4H), 2.67 – 2.56 (m, 1H), 2.44 – 2.34(m, 1H), 2.21 – 2.11 (m, 1H). Anti-dengue virus activity test experiment A549 cells were fed at a rate of 1.5 × 10⁻⁶. 4 A549 cells were seeded in 96-well plates and cultured at 37°C for 16-18 h in a 5% CO2 incubator. Two hours before viral infection, the above-mentioned inhibitors were added to the cultured cells, while the control group received the same volume of DMSO (three replicates for each experimental condition). Twenty-four h after viral infection, the proportion of infected virus-antigen-positive cells was detected by flow cytometry. The inhibitory activity of the compounds against DENV-2 was tested at a concentration of 10 µM.

[0090] The antiviral activity of compounds is expressed as the inhibition rate of viral replication. The antiviral activity of some compounds is shown in Table 1 below. The calculation formula is as follows: Inhibition rate (%) = 1 - Proportion of virus-infected positive cells in the compound group.

[0091] Table 1

[0092] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A nitrogen-containing heterocyclic compound, characterized in that, Its structural formula is shown in equation AC: Formula A Formula B Formula C; Wherein, L1 is a single bond, alkylene group, or carbonyl group; L2 is a single bond or amide group; L3 is a single bond, alkylene group, or carbonyl group; Ar1 is: or Ar2 is or ; X is CH2 or carbonyl; Y is O, S, NH, or NCH3; R1 or R2 is independently selected from deuterium, H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkylthio, substituted or unsubstituted C1-C10 alkoxy, halogen, cyano, isocyano, nitro, phosphin, aminesulfonyl or sulfone. The substitution of R1 or R2 is independently the substitution by at least one of deuterium, halogen, cyano, isocyano, hydroxyl, carboxyl, C1-C6 alkyl, wherein the number of substitutions is from monosubstituted to the maximum number of substitutions; R7 or R8 is independently selected from deuterium, H, halogen, cyano, isocyano, nitro, phosphino, C1-C10 alkyl, C1-C10 alkoxy, halogen-substituted C1-C10 alkyl or halogen-substituted C1-C10 alkoxy. R3 is , or ; R4 is a halogen; R5 is a C1-C6 alkyl group; R6 is or ; The wavy line represents the replacement position.

2. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that, The nitrogen-containing heterocyclic compound with the structural formula as shown in Formula A has a structure selected from Formulas A1-A5: Formula A1 Formula A2 Formula A3 Formula A4 Formula A5; L4 is either an alkylene group or a carbonyl group.

3. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that, R1 or R2 is independently selected from deuterium, H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C1-C6 alkoxy, halogen, cyano, isocyano, nitro, phosphin, aminesulfonyl or sulfone. The substitution of R1 or R2 is independently achieved by being substituted by at least one of deuterium, halogen, cyano, isocyano, hydroxyl, carboxyl, or C1-C6 alkyl, wherein the number of substitutions is monosubstituted.

4. The nitrogen-containing heterocyclic compound according to claim 3, characterized in that, R1 or R2 is independently selected from deuterium, H, C1-C6 alkyl, C1-C6 alkyl with carboxyl terminus, C1-C6 alkyl with hydroxyl terminus, C1-C6 alkoxy, C1-C6 alkoxy with carboxyl terminus, C1-C6 alkoxy with hydroxyl terminus, C1-C6 alkylthio, C1-C6 alkylthio with carboxyl terminus, C1-C6 alkylthio with hydroxyl terminus, halogen, cyano, isocyano, nitro, phosphin, aminesulfonyl, or sulfone.

5. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that, When R1 and R2 are not deuterium and H, both R1 and R2 are meta-substitutions; when either R1 or R2 is deuterium or H, the other is a para-substitution.

6. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that, R7 or R8 is independently selected from deuterium, H, halogen, cyano, isocyano, nitro, phosphino, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy.

7. The nitrogen-containing heterocyclic compound according to claim 1, characterized in that, The nitrogen-containing heterocyclic compound is selected from the following: 。 8. A method for preparing the nitrogen-containing heterocyclic compound according to any one of claims 1-7, characterized in that: The preparation method of the nitrogen-containing heterocyclic compound as shown in Formula A includes the following steps: Compound a1 and compound a2 were reacted 1 to prepare a nitrogen-containing heterocyclic compound as shown in formula A; Formula a1 Formula a2; Alternatively, the preparation method of the nitrogen-containing heterocyclic compound as shown in Formula A includes the following steps: Compound a3 and compound a4 were reacted 2 times to prepare a nitrogen-containing heterocyclic compound as shown in formula A; Formula a3 Formula a4; The preparation method of the nitrogen-containing heterocyclic compound as shown in Formula B includes the following steps: Compound b1 and compound b2 were reacted 3 times to prepare a nitrogen-containing heterocyclic compound as shown in formula B; Formula b1 Formula b2; The preparation method of the nitrogen-containing heterocyclic compound as shown in Formula C includes the following steps: Compound c1 and compound c2 were reacted 4 times to prepare a nitrogen-containing heterocyclic compound as shown in formula C; Formula c1 Formula c2; The definitions of L1, L2, L3, Ar1, Ar2, X, Y, R1, R2, R3, R4, R5, R6, R7, and R8 are as described in any one of claims 1-7.

9. A pharmaceutical composition, characterized in that, Includes the nitrogen-containing heterocyclic compound or its stereoisomer, pharmaceutically acceptable salt, solvate or polymorph as described in any one of claims 1-7, together with one or more pharmaceutically acceptable excipients, diluents or carriers.

10. The use of the nitrogen-containing heterocyclic compound or its stereoisomer, pharmaceutically acceptable salt, solvate or polymorph as described in any one of claims 1-7, or the pharmaceutical composition as described in claim 9, in the preparation of a medicament for the prevention and / or treatment of dengue fever.

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