An N-H aporphine nitrogen-containing heterocyclic derivative, and a preparation method and application thereof

Abstract

The application belongs to the technical field of medicines, and relates to an N-H aporphine nitrogen-containing heterocyclic derivative, a preparation method and application thereof.The N-H aporphine nitrogen-containing heterocyclic derivative comprises a compound shown in a general formula M, isomers thereof and pharmaceutically acceptable salts or hydrates thereof.The application introduces a nitrogen-containing heterocyclic ring into an aporphine derivative, and the disclosed N-H aporphine nitrogen-containing heterocyclic derivative can be applied in the preparation of medicines for preventing and / or treating obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes and drug addiction.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a nitrogen-containing heterocyclic derivative of NH apophene, its preparation method and application. Background Technology

[0002] Serotonin (5-HT) receptors are involved in regulating a wide range of physiological responses in the human body, such as cognition, memory processing, mood, circadian rhythm behavior, and appetite. The serotonin 2 receptor (5-HT2) family includes 5-HT... 2C receptors, 5-HT 2B receptors and 5-HT 2A The receptor has three subtypes, belonging to the G protein-coupled receptor family. They work by interacting with G... q / 11 Coupling plays a physiological role. Among them, 5-HT 2C 5-HT receptors are mainly concentrated in the central nervous system, and activation of these receptors is unlikely to produce peripheral side effects. This makes them an ideal target for treating central nervous system disorders, such as depression, schizophrenia, obesity, addiction, and epilepsy (including Dravet and Lennox-Gastaut syndromes). Selective activation of 5-HT... 2C Receptors can avoid activation of 5-HT 2A receptors and 5-HT 2B The hallucinations and cardiac side effects caused by receptors necessitate the development of selective 5-HT receptors. 2C Receptor agonists are of great significance in the treatment of central nervous system diseases.

[0003] Nitrogen-containing heterocycles exist as subunits in nature, and the natural products they form play important roles in life activities, such as vitamins, hormones, and antibiotics. Nitrogen heterocycles are also found in various drugs, such as diazepam, chlorpromazine, and captopril. The apophene derivatives involved in the prior art are characterized by a fused tetracyclic structure, including rings A and D, where rings A and D are benzene rings. Although there are reports of apophene derivatives with a heterocyclic D ring, tetrahydroisoquinoline is present in these compounds. N -Replaced with an alkyl group (such as methyl), it acts as a ligand for dopamine receptors and interacts with 5-HT. 2C Receptor-independent. In existing technologies, targeting 5-HT... 2C receptor N -H apophene nitrogen-containing heterocyclic derivatives have not yet been reported. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention introduces nitrogen-containing heterocycles into apophene derivatives, thereby providing an NH apophene nitrogen-containing heterocyclic derivative, its preparation method, and its application.

[0005] The present invention adopts the following technical solution: A sort ofN -H apophene nitrogen-containing heterocyclic derivative, the N The general chemical structural formula of the nitrogen-containing heterocyclic derivative of -H apophene is shown below: ; Wherein, R1 and R2 are independently selected from one or more of hydrogen, alkyl, alkynyl, alkenyl, halogen, haloalkyl, cyano, nitro, aryl, hydroxyl, carboxyl, alkoxy, alkoxyacyl, oxime, amino, amide, acyloxy, acyl, sulfonyl, sulfonamide, urea, thiourea, or carbamoyl; preferably, R1 is one or more of alkyl, alkoxy, hydroxyl, hydrogen, or halogen; and R2 is one or more of alkyl, alkoxy, hydroxyl, hydrogen, or halogen. Ar1 is a substituted or unsubstituted ring, including substituted or unsubstituted aromatic rings and substituted or unsubstituted heterocycles. Preferably, the substituted or unsubstituted heterocycle includes nitrogen. Ar2 is a substituted or unsubstituted ring, including substituted or unsubstituted aromatic rings and substituted or unsubstituted heterocycles. Preferably, the substituted or unsubstituted heterocycle includes nitrogen.

[0006] In this invention, the number of carbon atoms in the alkyl group is 1 to 20, preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 8, for example 1, 2, 3, 4, 5, 6, 7, 8 or any value within the range.

[0007] In this invention, the number of carbon atoms in the alkoxy group is 1 to 20, preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 8, for example 1, 2, 3, 4, 5, 6, 7, 8 or any value within the range.

[0008] In this invention, the number of carbon atoms in the alkynyl group is 1 to 20, preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 8, for example 1, 2, 3, 4, 5, 6, 7, 8 or any value within the range.

[0009] In this invention, the number of carbon atoms in the alkenyl group is 1 to 20, preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 8, for example 1, 2, 3, 4, 5, 6, 7, 8 or any value within the range.

[0010] In this invention, the number of carbon atoms in the haloalkyl group is 1 to 20, preferably 1 to 15, more preferably 1 to 10, and even more preferably 1 to 8, for example 1, 2, 3, 4, 5, 6, 7, 8 or any value within the range; wherein the halogen is one or more of fluorine, chlorine, bromine or iodine, and the number and type of halogen are not limited, such as trifluoromethyl, difluoromethyl, monofluoromethyl or trifluoroethyl.

[0011] In this invention, the halogen is one or more of fluorine, chlorine, bromine or iodine.

[0012] In this invention, the alkyl and alkoxy groups include saturated or unsaturated aliphatic alkyl groups and aromatic alkyl groups. The aliphatic alkyl groups are preferably C1-C8 alkyl groups, and can be straight-chain alkyl groups, branched alkyl groups, spirocyclic alkyl groups, bridged cyclic alkyl groups, alkenyl alkyl groups, alkynyl alkyl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, alkoxyalkyl groups, alkoxyacyl alkyl groups, and cycloalkylalkyl groups. More preferably, the aliphatic alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, allyl, alkynyl, cyclobutenyl, cyclohexenyl, 2,2-difluoroethyl, and 2-fluoroethyl. The aromatic alkyl groups are alkyl groups containing aromatic groups, and the aromatic groups are aryl or heteroaryl. Preferably, the aromatic alkyl groups include, without limitation, aralkyl or heteroaryl, such as substituted aryloxyalkyl; substituted or unsubstituted benzyl; substituted or unsubstituted phenethyl; substituted or unsubstituted phenylpropyl, etc.

[0013] In this invention, the substituted or unsubstituted heterocycles include substituted or unsubstituted aromatic heterocycles, preferably substituted or unsubstituted nitrogen-containing aromatic heterocycles.

[0014] In this invention, the substituted or unsubstituted ring is a monocyclic or fused ring.

[0015] Preferably, the nitrogen-containing aromatic heterocycles include, but are not limited to: pyrrole, thiazolyl, aminothiazolyl, triazole, thiadiazole, pyrazolyl, imidazole, oxazolyl, isoxazolyl, quinolinyl, benzopyrrole, benzothiazolyl, benzoxazolyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazole, etc.

[0016] In this invention, the substituents in the substituted or unsubstituted aromatic rings or substituted or unsubstituted heterocycles are selected from one or more of halogens, amino groups, hydroxyl groups, alkoxyyl groups, acyl groups, sulfonyl groups, sulfonamide groups, carbamoyl groups, and alkylamine groups. Preferably, the halogen is one or more of fluorine, chlorine, bromine, or iodine; the alkylamine group has 1 to 10 carbon atoms, preferably 1 to 8, more preferably 1 to 5, and even more preferably 1 to 3, for example 1, 2, 3, or any value within the range.

[0017] This invention discloses a pharmaceutical composition comprising the above-mentioned... N -H apophene nitrogen-containing heterocyclic derivatives or pharmacologically acceptable salts, esters, hydrates, solvates, crystalline forms, enantiomers, stereoisomers, ethers, metabolites, and prodrugs. Furthermore, the pharmaceutical composition may also include other drugs. This invention prepares pharmaceutical compositions using the above-mentioned NH apophene nitrogen-containing heterocyclic derivatives as active ingredients, or as described above... N -H apophene nitrogen-containing heterocyclic derivatives and other drugs are used to prepare a pharmaceutical composition.

[0018] The present invention discloses the above. N -H apophene, a nitrogen-containing heterocyclic derivative or a pharmacologically acceptable salt, ester, hydrate, solvate, crystalline form, enantiomer, stereoisomer, ether, metabolite, prodrug, or the use of the pharmaceutical composition thereof in the preparation of a 5-hydroxytryptamine 2C receptor agonist or a 5-hydroxytryptamine 2C / 2A receptor agonist; the use of the 5-hydroxytryptamine 2C receptor agonist or a 5-hydroxytryptamine 2C / 2A receptor agonist in the preparation of a medicament for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, or drug addiction. That is, the 5-hydroxytryptamine 2C receptor agonist or a 5-hydroxytryptamine 2C / 2A receptor agonist is used for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, or drug addiction.

[0019] In one embodiment of the present invention, the 5-hydroxytryptamine 2C receptor agonist or 5-hydroxytryptamine 2C / 2A receptor agonist is used in the preparation of a medicament for the prevention and / or treatment of depression, anxiety, obsessive-compulsive disorder or drug addiction.

[0020] Furthermore, the present invention discloses the above-mentioned N -H Apofel's nitrogen-containing heterocyclic derivative or pharmacologically acceptable salt, ester, hydrate, solvate, crystalline form, enantiomer, stereoisomer, ether, metabolite, prodrug, or the use of the pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, or drug addiction.

[0021] In one embodiment of the present invention, the drug further includes pharmaceutically or pharmacologically acceptable salts, esters, hydrates, solvates, crystalline forms, enantiomers, stereoisomers, ethers, metabolites, and prodrugs.

[0022] Furthermore, the salt is selected from one or more of inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates.

[0023] In one embodiment of the present invention, the inorganic acid salt includes, but is not limited to, at least one of hydrochloride, hydrobromide, nitrate, sulfate and phosphate; preferably, the organic acid salt includes, but is not limited to, at least one of formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartrate and citrate; preferably, the alkyl sulfonate includes, but is not limited to, at least one of methanesulfonate and ethyl sulfonate; the aryl sulfonate includes, but is not limited to, at least one of benzenesulfonate and p-toluenesulfonate.

[0024] The technical solution of the present invention has the following advantages compared with the prior art: This invention designs apophene-like compounds with a general formula structure that differs from existing apophene derivatives. Some compounds with this structure exhibit activation of 5-HT. 2C or 5-HT 2A / 2C The role of receptors, and the effect on 5-HT 2B The receptor has no agonistic effect and exhibits high safety. The apophene-like compounds of this invention are used as 5-HT... 2C When used as a 5-HT receptor agonist, it can be used for the prevention or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, and drug addiction; while as a 5-HT receptor agonist... 2A / 2C When used as a receptor agonist, it can be used for the prevention or treatment of depression, anxiety, obsessive-compulsive disorder, and addiction. Attached Figure Description

[0025] Figure 1 for N Schematic diagram of the preparation of nitrogen-containing heterocyclic derivatives S1 and S2 of -H apophene.

[0026] Figure 2 for N Schematic diagram of the preparation of -H apophene nitrogen-containing heterocyclic derivatives S3 to S15.

[0027] Figure 3 for N Schematic diagram of the preparation of -H apophene nitrogen-containing heterocyclic derivatives S16 to S19.

[0028] Figure 4 for N Schematic diagram of the preparation of -H apophene nitrogen-containing heterocyclic derivatives S20 to S28.

[0029] Figure 5 for N Schematic diagram of the preparation of -H apophene nitrogen-containing heterocyclic derivatives S29 to S42. Detailed Implementation

[0030] 5-HT in the central nervous system 2A Receptors are involved in the regulation of cognitive states, associative learning, mood, and circadian rhythms; therefore, 5-HT... 2A The efficacy of receptor agonists is being investigated for various neurological indications, including adjunctive psychotherapy for patients with terminal illness or post-traumatic stress disorder (PTSD)-related fear and anxiety, major depressive disorder, treatment-resistant depression, addiction, obsessive-compulsive disorder, etc. Furthermore, as a potent tumor necrosis factor (TNF-α)-mediated inflammation inhibitor, it may be used in novel treatments for inflammatory diseases. 5-Hydroxytryptamine 2C (5-HT) 2CBecause 5-HT receptors are primarily expressed in the central nervous system, they have a low risk of causing peripheral side effects; therefore, 5-HT receptors... 2C Receptors have become ideal targets for treating central nervous system disorders, such as Dravet syndrome (intractable childhood epilepsy), obesity, anxiety, schizophrenia, and drug addiction. 5-HT... 2B Receptors are mainly distributed in heart valves, etc., when 5-HT is stimulated. 2B When 5-HT receptors are activated, it may induce valvular heart disease. Therefore, developing low-5-HT receptors is crucial. 2B 5-HT receptor activity 2A / 2C or 5-HT 2C Receptor-selective agonists are essential for the treatment of central nervous system disorders. Currently, there are specific technologies targeting 5-HT... 2C Nitrogen-containing heterocyclic derivatives of NH apophene receptors have not yet been reported. This invention designs apophene-like compounds with the general formula M and discovers that compounds with this structure respond to 5-HT... 2C or 5-HT 2A / 2C All receptors exhibited excellent activation activity, while 5-HT... 2B The receptor has no agonistic effect. N The general chemical structural formula of the nitrogen-containing heterocyclic derivative of -H apophene is shown below (chemical formula M):

[0031] Includes the following two general formulas;

[0032] Wherein, R1 and R2 are independently selected from hydrogen, alkyl, alkynyl, alkenyl, halogen, haloalkyl, cyano, nitro, aryl, hydroxyl, carboxyl, alkoxy, alkoxyacyl, oxime, amino, amide, acyloxy, acyl, sulfonyl, sulfonamide, urea, thiourea, or carbamoyl; preferably, R1 is one or more of alkyl, alkoxy, hydroxyl, hydrogen, or halogen; R2 is one or more of alkyl, alkoxy, hydroxyl, hydrogen, or halogen; preferably, R1 is selected from C1-C8 alkoxy, hydroxyl, hydrogen, or halogen; more preferably, R1 is selected from C1-C3 alkoxy, hydroxyl, chlorine, or bromine; preferably, R2 is selected from C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, hydrogen, or halogen; more preferably, R2 is selected from C1-C3 alkyl, C1-C3 alkoxy, hydrogen, chlorine, or bromine.

[0033] Ar1 is a substituted or unsubstituted ring, including a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heterocycle, preferably, the substituted or unsubstituted heterocycle includes nitrogen; Ar2 is a substituted or unsubstituted ring, including a substituted or unsubstituted aromatic ring or a substituted or unsubstituted heterocycle, preferably, the substituted or unsubstituted heterocycle includes nitrogen.

[0034] In this invention, the substituted or unsubstituted heterocycles include substituted or unsubstituted aromatic heterocycles, preferably substituted or unsubstituted nitrogen-containing aromatic heterocycles.

[0035] In this invention, the substituted or unsubstituted ring is a monocyclic or fused ring.

[0036] Preferably, the nitrogen-containing aromatic heterocycles include, but are not limited to: pyrrole, thiazolyl, aminothiazolyl, triazole, thiadiazole, pyrazolyl, imidazole, oxazolyl, isoxazolyl, quinolinyl, benzopyrrole, benzothiazolyl, benzoxazolyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazole, etc.

[0037] In this invention, the substituents in the substituted or unsubstituted aromatic rings or substituted or unsubstituted heterocycles are selected from one or more of halogens, amino groups, hydroxyl groups, alkoxyyl groups, acyl groups, sulfonyl groups, sulfonamide groups, carbamoyl groups, and alkylamine groups. Preferably, the halogen is one or more of fluorine, chlorine, bromine, or iodine; the alkylamine group has 1 to 10 carbon atoms, preferably 1 to 8, more preferably 1 to 5, and even more preferably 1 to 3, for example 1, 2, 3, or any value within the range.

[0038] Preferably, Ar1 and Ar2 are monosubstituted, disubstituted, or unsubstituted phenyl, pyrimidinyl, indolyl, isoindolyl, indazole, azindolyl, 2,3-2H-indole, thiophene, tetrazolyl, triazolyl, indolone, thiazolyl, pyrrole, imidazolyl, pyrazolyl, quinolinyl, isoquinolinyl, naphthyl, oxazolyl, isoxazolyl, pyridinyl, carbazole, benzothiophene, benzofuranyl, benzothiazolyl, benzoimidazolyl, benzoxazolyl, or benzotriazolyl.

[0039] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments are not intended to limit the present invention. The raw materials used in the present invention are all existing products or conventionally prepared according to existing methods, and the specific preparation operations and performance tests are all conventional methods.

[0040] In the following embodiments of the present invention, the structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was performed using an Agilent 400MHz or 600MHz instrument, with deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) as the solvents, and tetramethylsilane (TMS) as the internal standard. MS was performed using GCT Premier. TM (CI) mass spectrometry measurements, unless otherwise specified, all measurements were taken using CI source (70 eV).

[0041] Thin-layer chromatography uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.2mm in size. Column chromatography generally uses Yantai Huanghai 100-200 mesh or 200-300 mesh silica gel as the carrier.

[0042] Nitrogen purging in the reaction means connecting a nitrogen balloon with a volume of approximately 1 L to the reaction flask. Hydrogen purging in the reaction means connecting a hydrogen balloon with a volume of approximately 1 L to the reaction flask. The reaction conditions are at room temperature (rt), with a temperature range of 20-30℃.

[0043] In the following embodiments of the present invention, all solvents were redistilled before use, and the anhydrous solvents used were obtained by drying according to standard methods. The synthetic route of the compound in Example 1 is as follows: Figure 1 As shown.

[0044] Synthesis of Intermediate 1: References ( J. Org. Chem Intermediate 1 was synthesized using the method described in 2000, 65, 6743-6748.

[0045] Synthesis of Intermediate 2: PCC (pyridine chlorochromate, 3.0 eq) was added to a round-bottom flask, along with approximately equal volume of silica gel powder (100-200 mesh) and 3 Å molecular sieve (approximately 1 / 3 by weight), and mixed thoroughly. Intermediate 1 was dissolved in anhydrous dichloromethane (0.2 M) and poured into the round-bottom flask. The mixture was stirred at room temperature for 6 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated. Column chromatography purification was performed using PE:EA = 10:1 as the eluent to obtain a pale yellow oily substance 2, with a yield of 53%.

[0046] Synthesis of Intermediate 3: Lithium aluminum hydride (8.0 eq) was added to a double-necked flask under nitrogen protection. Anhydrous tetrahydrofuran (1.0 M) was added at 0 °C and stirred for 5 min. Intermediate 2 (1.0 eq) was dissolved in anhydrous toluene (0.5 M) and injected into the double-necked flask. After stirring for 5 min, the mixture was heated to 90 °C and stirred for 12 h. The mixture was cooled and quenched at 0 °C with water (8.0 eq), 15% sodium hydroxide aqueous solution (16.0 eq), and another portion of water (16.0 eq). The colloid was removed by filtration, and the filtrate was collected, dried over anhydrous sodium sulfate, and concentrated by filtration. No further purification was required. The filtrate was dissolved in tetrahydrofuran, and di-tert-butyl dicarbonate (Boc2O) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by column chromatography with PE / EA = 2:1 as the eluent to obtain a colorless oily substance in 46% yield. The solution (1.0 eq) was dissolved in dichloromethane (0.2 M), and Dysmart oxidant (DMP) was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete as monitored by TLC, saturated sodium thiosulfate solution was added at 0 °C until no bubbles were observed, followed by neutralization with saturated sodium bicarbonate solution to alkalinity, and stirring for 1 h. The mixture was then extracted with dichloromethane (30 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was used for purification, with PE / EA = 8:1 as the eluent, to give a white solid 3 in 36% yield.

[0047] Synthesis of Intermediate 4: Intermediate 3 (1.0 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred at room temperature, and the reaction endpoint was monitored by TLC. The reaction solution was concentrated, then placed at 0°C, diluted with dichloromethane, and neutralized to alkalinity with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. No further purification was required. The mixture was dissolved in dichloromethane, and at 0°C, the corresponding acid-binding agent (2.5 eq) and protecting group reagent (1.5 eq) from the table were added. The mixture was stirred at room temperature, and the reaction was monitored by TLC until the end of the reaction. The mixture was diluted with water, extracted with dichloromethane, dried, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography with PE / EA = 8:1 as the eluent to obtain white solid 4, with a yield of 51%.

[0048] Synthesis of Intermediate 5: Intermediate 4 (1.0 eq) was dissolved in anhydrous toluene (0.2 M) under nitrogen protection and heated to 110 °C. Aluminum trichloride (5.0 eq) was then added, followed by stirring for 2.5 h. The reaction mixture was cooled and placed at 0 °C. The reaction was quenched with 10 mL of 1 M dilute hydrochloric acid aqueous solution, then diluted with 20 mL of ethyl acetate. Saturated sodium bicarbonate was added until all the solids in the system were dissolved. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification was performed with PE / EA = 3:1 as the eluent to give yellow solid 5 in 81% yield.

[0049] Synthesis of intermediate 6: Intermediate 5 (1.0 eq) was dissolved in dichloromethane (0.2 M), and TEA (2.5 eq), TsCl (1.5 eq), and DMAP (0.2 eq) were added at 0 °C. The mixture was reacted at room temperature for 2 h. The reaction solution was concentrated and purified by column chromatography with PE / EA = 3:1 as the eluent to obtain intermediate 6, with a yield of 94%.

[0050] Synthesis of intermediate 7a: Intermediate 4 (1.0 eq) was dissolved in ethanol, and aminourea hydrochloride (5.0 eq) and sodium acetate (5.0 eq) were added. The mixture was heated at 80 °C for 2 h. After cooling and concentration, the mixture was extracted with water and dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and without further purification, dissolved in anhydrous dichloromethane. Thionyl chloride (25.0 eq) was added, and the mixture was heated to 40 °C under nitrogen protection for 12 h. The reaction mixture was concentrated and purified by column chromatography. A partial product was obtained with PE / EA / DCM = 2:1:1. The polarity was increased to DCM / MeOH = 50:1 to obtain another partial product. The two products were combined to obtain intermediate 7a in 51% yield.

[0051] Intermediate 7b is synthesized from intermediate 6 as raw material, following the steps of intermediate 7a. Then, gray solid 7b is synthesized following the steps of intermediate 5, with a yield of 35%.

[0052] Synthesis of compound S1: Intermediate 7a (1.0 eq) was dissolved in methanol (10 mL), and 4M KOH aqueous solution (10 mL) was added. The mixture was stirred at room temperature, and the reaction was monitored by TLC. After completion, the reaction solution was concentrated to dryness. The residue was ultrasonically washed with DCM:MeOH:EA = 5:1:5, then filtered, and the filtrate was concentrated. Column chromatography was used for purification, with DCM / MeOH / ammonia = 10:1:0.1 as the eluent, to give white solid S1 in 38% yield.

[0053] Synthesis of compound S2: Intermediate 7b (1.0 eq) was dissolved in methanol (10 mL), and 4M KOH aqueous solution (10 mL) was added. The mixture was refluxed at 80 °C, and the reaction was monitored by TLC. After completion, the reaction solution was concentrated to dryness. The residue was ultrasonically washed with DCM:MeOH:EA = 5:1:5, then filtered, and the filtrate was concentrated. Column chromatography purification was performed with DCM / MeOH / ammonia = 10:1:0.1 as the eluent to give white solid S2 in 31% yield.

[0054] Compound S1 (2-methoxy-5,6,6a,7-tetrahydro-4H-benzo[1,2,3]thiadiazo[4,5-g]quinoline): 1 HNMR (400 MHz, DMSO-d 6 ) δ 7.45 (s, 1H), 6.77 (s, 1H), 4.00 (dd, J = 14.3, 6.2Hz, 1H), 3.81 (s, 3H), 3.71 – 3.57 (s, 1H), 3.22 (d, J = 7.9 Hz, 1H), 2.94 –2.84 (m, 2H), 2.73 – 2.60 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 158.73,157.57, 148.49, 137.71, 127.66, 126.03, 115.07, 107.34, 55.67, 53.12, 43.53,29.28, 28.55.MS (CI) calcd for C 13 H 13 N3OS [M+H] + : 260.0858. Compound S2 (5,6,6a,7-tetrahydro-4H-benzo[1,2,3]thiadiazo[4,5-g]quinoline-2-ol): 1 H NMR (400 MHz, DMSO-) d 6 ) δ 9.62 (s, 1H), 7.34 (s, 1H), 6.57 (d, J = 2.5 Hz, 1H), 3.96 (dd, J = 14.3, 6.0 Hz, 1H), 3.65 – 3.55 (m, 1H), 3.22 – 3.15 (m, 1H), 2.84 (d, J = 3.2 Hz, 1H), 2.82 – 2.68 (m, 2H), 2.66 – 2.56 (m, 1H). 13 C NMR (101 MHz, DMSO-) d 6 ) δ 157.82, 156.78, 148.17, 137.48, 127.49, 124.50, 116.37,108.87, 53.15, 43.65, 29.22, 28.68. MS (CI) calcd for C 12 H 11N3OS [M+H] + :246.0701.

[0055] The synthetic route of the compound in Example 2 is as follows: Figure 2 As shown.

[0056] Synthesis of intermediate 8: Intermediate 6 (1.0 eq) was dissolved in dichloromethane, and NBS (1.5 eq) and TsOH (0.3 eq) were added. The mixture was stirred at 40 °C for 4 h. After concentration, column chromatography purification was performed with PE / EA = 7:1 as the eluent to give white solid 8 in 71% yield.

[0057] Synthesis of intermediate 9a: Intermediate 8 (1.0 eq) was dissolved in ethanol, and then... N -Propylthiourea (2.0 eq) was heated to 80 °C and stirred for 4 h. After the reaction was complete, the mixture was concentrated. The product was purified by column chromatography to obtain a white solid with a yield of 58%.

[0058] Synthesis of intermediate 9b: Using intermediate 8 and thiourea as raw materials, the reaction was carried out in accordance with the steps of intermediate 9a, and the product obtained was a white solid with a yield of 56%.

[0059] Intermediate 9c with intermediate 8 and N Using methylthiourea as a raw material, the reaction was carried out according to the steps of intermediate 9a to obtain a white solid with a yield of 62%.

[0060] Intermediate 9d with intermediate 8 and N Using ethylthiourea as a raw material, the reaction was carried out according to the steps of intermediate 9a to obtain a white solid with a yield of 58%.

[0061] Intermediate 9e with intermediate 8 and N,N Using dimethylthiourea as a raw material, the reaction was carried out according to the steps of intermediate 9a to obtain a white solid with a yield of 45%.

[0062] Intermediate 9f was prepared by reacting intermediate 8 and 1-(2-methylallyl)thiourea as raw materials according to the steps of intermediate 9a to obtain a white solid with a yield of 50%.

[0063] Synthesis of intermediate 10a: Intermediate 4 (1.0 eq) was dissolved in acetic acid (0.5 M), and ZnCl2 (2.0 eq) and phenylhydrazine (1.5 eq) were added. Under nitrogen protection, the mixture was heated to 100 °C and stirred for 4 h. After the reaction was complete, the acetic acid was evaporated under reduced pressure, the crude product was washed with methanol, and filtered to obtain a white solid 10a in 59% yield.

[0064] Synthesis of intermediate 10b: Using intermediate 10a as raw material, white solid 10b was synthesized according to the steps of synthesizing intermediate 5, with a yield of 67%.

[0065] Synthesis of intermediate 10c: Intermediate 10a (1.0 eq) was dissolved in acetonitrile (0.2 M), and cesium carbonate (2.5 eq) and iodomethane, bromopropane, or bromopropylene (1.5 eq) were added. The mixture was heated to 90 °C and stirred for 6 h. After the reaction was complete, the filtrate was filtered and concentrated. The intermediate was purified by column chromatography. Then, following the steps for synthesizing intermediate 5, white solid 10c was synthesized in 41% yield.

[0066] Synthesis of intermediate 10d: Using intermediate 10a and bromopropane as raw materials, the intermediate was synthesized following the steps for synthesizing intermediate 10c. Then, following the steps for synthesizing intermediate 5, a white solid was obtained with a yield of 46%.

[0067] Synthesis of intermediate 10e: Using intermediate 10a and bromopropylene as raw materials, the intermediate was synthesized following the steps for synthesizing intermediate 10c. Then, following the steps for synthesizing intermediate 5, a white solid was obtained with a yield of 35%.

[0068] Synthesis of intermediate 11a: Intermediate 8 (1.0 eq) was dissolved in toluene, and formamide (2.0 eq) and acetic acid (2.0 eq) were added. The mixture was heated to 120 °C and stirred for 4 h. After the reaction was complete, the solution was concentrated. The product was purified by column chromatography, and the yields were white solids, respectively, with yields of 58%.

[0069] Synthesis of intermediate 11b: Using intermediate 8 and acetamide as raw materials, a white solid was synthesized according to the steps for synthesizing intermediate 11a, with a yield of 73%.

[0070] Synthesis of intermediate 12a-b: Intermediate 11a-b was dissolved in anhydrous toluene (0.2 M) under nitrogen protection and heated to 110 °C. Aluminum trichloride (5.0 eq) was added, followed by stirring for 2.5 h. The reaction mixture was cooled and placed at 0 °C. The reaction was quenched with 10 mL of 1 M dilute hydrochloric acid aqueous solution, then diluted with 20 mL of ethyl acetate. Saturated sodium bicarbonate was added until all the solids in the system were dissolved. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification was performed using PE / EA = 3:1 as the eluent to give yellow solid 12a-b, with yields of 75% and 81%, respectively.

[0071] Synthesis of compounds S3-S15: The synthesis methods are the same as those for compounds S1-S2.

[0072] Compound S3 (9-(propylamino)-5,6,6a,7-tetrahydro-4H-benzo[de]thiazo[4,5-g]quinoline-2-ol) was synthesized from 9a using the same procedure as S1, with a yield of 37%. 1H NMR (400 MHz, DMSO- d 6 ) δ 7.22(s, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.64 (t, J = 4.1 Hz, 1H), 6.55 (dt, J =2.0, 0.9 Hz, 1H), 4.14 (dt, J = 5.6, 4.8 Hz, 1H), 3.71–3.60 (m, 1H), 3.49(td, J = 5.1, 4.1 Hz, 2H), 3.19–2.98 (m, 5H), 2.95–2.82 (m, 1H), 1.70–1.60 (m, 1H), 1.65–1.56 (m, 1H), 0.96 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 163.96, 156.05, 143.92, 135.71, 131.00, 128.58, 119.79, 116.56, 108.46,53.62, 47.65, 43.17, 30.22, 29.07, 22.71, 11.42. MS (ESI) calcd for C 16 H 19 N3OS[M+H] + : 302.1327.

[0073] Compound S4 (9-amino-5,6,6a,7-tetrahydro-4H-benzo[de]thiazo[4,5-g]quinoline-2-ol) was synthesized from 9b using the same procedure as S2, with a yield of 33%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.16 (s,1H), 6.94 (s, 2H), 6.82 (d, J = 2.5 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 3.98 (dd, J = 14.3, 6.6 Hz, 1H), 3.25 (q, J= 7.3 Hz, 1H), 3.18 (d, J = 9.4 Hz, 2H), 2.92 – 2.70 (m, 4H). 13C NMR (101 MHz, DMSO- d 6) δ 166.89, 156.32,144.75, 135.76, 131.56, 123.40, 116.34, 113.57, 108.30, 53.95, 43.51, 29.01,7.87. MS (ESI) calcd for C 13 H 13 N3OS [M+H] + : 260.0858.

[0074] Compound S5 (9-(methylamino)-5,6,6a,7-tetrahydro-4H-benzo[de]thiazo[4,5-g]quinoline-2-ol) was synthesized from 9c using the same procedure as S2, with a yield of 41%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 6.97(s, 2H), 6.90 (s, 1H), 6.50 (s, 1H), 3.96 (dd, J = 14.3, 6.7 Hz, 1H), 3.71(s, 3H), 3.20 – 3.14 (m, 1H), 2.87 – 2.77 (m, 3H), 2.68 – 2.52 (m, 2H), 2.46– 2.39 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 167.00, 158.28, 144.51, 136.37,131.61, 125.71, 117.01, 112.32, 106.28, 55.33, 54.11, 43.65, 29.50, 29.11. MS(ESI) calcd for C 14 H 15 N3OS [M+H] + : 274.1014.

[0075] Compound S6 (9-(ethylamino)-5,6,6a,7-tetrahydro-4H-benzo[de]thiazo[4,5-g]quinoline-2-ol) was synthesized from 9d using the same procedure as S2, with a yield of 40%.1 H NMR (400 MHz, DMSO- d 6 ) δ 7.22 (s, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.98 (t, J = 3.3 Hz, 1H), 6.55 (dt, J = 2.0, 0.9 Hz, 1H), 4.14 (dt, J = 5.6, 4.8 Hz, 1H), 3.71 – 3.60 (m, 1H), 3.57 (qd, J = 6.0, 3.4 Hz, 2H), 3.18 – 3.06 (m, 1H), 3.11 – 2.98 (m, 4H), 2.96 – 2.82 (m,1H), 1.30 (t, J = 6.0 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 164.30, 156.05,143.92, 135.71, 131.00, 128.58, 119.79, 116.56, 108.46, 53.62, 43.17, 40.57,30.22, 29.07, 14.52. MS (ESI) calcd for C 15 H 17 N3OS [M+H] + : 288.1171.

[0076] Compound S7 (9-(dimethylamino)-5,6,6a,7-tetrahydro-4H-benzo[de]thiazo[4,5-g]quinoline-2-ol) was synthesized from 9e using the same procedure as S2, with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.22(s, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.55 (dt, J = 2.0, 0.9 Hz, 1H), 4.14 (dt, J= 5.6, 4.8 Hz, 1H), 3.71–3.60 (m, 1H), 3.12 (s, 6H), 3.14–3.04 (m, 2H), 3.10– 2.99 (m, 1H), 3.00 (dd, J = 4.8, 1.0 Hz, 2H), 2.98–2.82 (m, 1H). 13 C NMR (101 MHz, DMSO-) d 6 ) δ 164.02, 156.05, 145.66, 135.71, 130.72, 128.64, 124.47,116.56, 108.50, 53.19, 43.17, 39.15, 30.20, 29.07. MS (ESI) calcd forC 15 H 17 N3OS [M+H] + : 288.1171.

[0077] Compound S8 (9-((2-methylallyl)amino)-5,6,6a,7-tetrahydro-4H-benzo[de]thiazole[4,5-g]quinoline-2-ol) was synthesized from 9f using the same procedure as S2, with a yield of 32%. 1 H NMR (400 MHz, DMSO- d 6 )δ 7.40 (t, J = 4.4 Hz, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.55 (dt, J = 2.0, 0.9Hz, 1H), 4.85 (dp, J = 2.5, 1.2 Hz, 1H), 4.80 (dq, J = 2.5, 1.2 Hz, 1H), 4.14(dt, J = 5.6, 4.8 Hz, 1H), 4.02 (ddt, J = 4.2, 3.1, 1.1 Hz, 2H), 3.71–3.60(m, 1H), 3.19–2.98 (m, 5H), 2.95 – 2.82 (m, 1H), 1.76 (d, J = 2.7 Hz, 2H). 13 CNMR (101 MHz, DMSO- d 6) δ 162.48, 156.05, 143.92, 142.06, 135.71, 130.82,128.58, 119.84, 116.56, 111.44, 108.49, 53.62, 50.46, 43.17, 30.22, 29.07,20.67. MS (ESI) calcd for C 17 H 19 N3OS [M+H] + : 314.1327.

[0078] Compound S9 (2-methoxy-4,5,6,6a,7,12-hexahydroisoquinoline[8,1-ab]carbazole) was synthesized from 10a using the same procedure as that used to synthesize S1, with a yield of 52%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.40 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.15–7.06 (m, 2H), 7.04–6.97(m, 1H), 6.55 (d, J = 2.5 Hz, 1H), 3.99 (dd, J = 14.0, 6.6 Hz, 1H), 3.78 (s,3H), 3.25–3.20 (m, 1H), 3.09 (dd, J = 14.8, 6.6 Hz, 1H), 2.91–2.81 (m, 2H), 2.64–2.52 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 158.39, 137.34, 136.93,133.23, 128.92, 127.06, 126.97, 122.16, 119.43, 118.82, 112.37, 111.80,110.26, 105.65, 55.54, 54.66, 43.74, 29.70, 27.71. MS (ESI) calcd for C 19 H 18 N₂O[M+H] + : 291.1497.

[0079] Compound S10 (4,5,6,6a,7,12-hexahydroisoquinoline[8,1-ab]carbazole-2-ol) was synthesized from 10b using the same procedure as S2, with a yield of 43%. 1 H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.50 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.10 (ddd, J =8.2, 7.0, 1.2 Hz, 1H), 7.05 –6.99 (m, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 4.21 (dd, J = 14.0, 6.5 Hz, 1H), 3.38 (dd, J = 7.0, 1.9 Hz, 2H), 3.18 (dd, J = 14.7, 6.5 Hz, 1H), 3.08–2.91 (m, 2H), 2.72 –2.60 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.87, 137.42, 135.51, 133.13, 129.14, 126.86,122.27, 119.56, 118.76, 113.96, 111.94, 108.97, 107.51, 65.39, 53.90, 42.76,27.86, 26.48. MS (ESI) calcd for C 18 H 16 N2O [M+H] + : 277.1341.

[0080] Compound S11 (12-methyl-4,5,6,6a,7,12-hexahydroisoquinolino[8,1-ab]carbazole-2-ol) was synthesized from 10c using the same procedure as S1, with a yield of 55%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.36 (s, 1H), 7.52 (d, J= 7.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.17 (ddd, J = 8.2, 7.0,1.2 Hz, 1H), 7.09–7.02 (m, 2H), 6.46 (d, J = 2.3 Hz, 1H), 3.96 (s, 1H), 3.87(dd, J = 14.0, 6.0 Hz, 1H), 3.22–3.17 (m, 1H), 3.06 (dd, J = 14.7, 6.0 Hz,1H), 2.91–2.80 (m, 2H), 2.56 (d, J = 13.1 Hz, 1H), 2.43 (d, J = 14.3 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 156.09, 139.12, 136.80, 134.32, 128.75, 126.36,125.84, 122.31, 119.73, 118.85, 113.88, 111.41, 110.38, 108.77, 54.62, 43.23,32.72, 29.59, 27.89. MS (ESI) calcd for C 19 H 18 N2O [M+H] + : 291.1497.

[0081] Compound S12 (12-propyl-4,5,6,6a,7,12-hexahydroisoquinoline[8,1-ab]carbazole-2-ol) was synthesized from 10d using the same procedure as S1, with a yield of 47%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.36 (s, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.15 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.04 (t, J =7.4 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.45 (d,J = 2.1 Hz, 1H), 4.43–4.23(m, 2H), 3.82 (dd, J = 14.0, 5.9 Hz, 1H), 3.18 (d, J = 5.0 Hz, 1H), 3.04 (dd, J = 14.7, 6.0 Hz, 1H), 2.89–2.79 (m, 2H), 2.55 (d, J = 13.3 Hz, 1H), 2.42 (t, J = 14.3 Hz, 1H), 1.92–1.71 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (1010MHz, DMSO- d 6 ) δ 156.11, 138.80, 136.90, 133.55, 128.88, 126.75, 125.99,122.34, 119.76, 118.91, 113.95, 112.10, 110.62, 108.06, 54.59, 46.23, 43.22,29.79, 27.98, 23.79, 11.50. MS (ESI) calcd for C 21 H 22 N2O [M+H] + : 319.1810.

[0082] Compound S13 (12-allyl-4,5,6,6a,7,12-hexahydroisoquinolino[8,1-ab]carbazole-2-ol) was synthesized from 10e using the same procedure as S1, with a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.77–7.68(m, 1H), 7.42–7.28 (m, 2H), 7.18 (ddd, J = 7.0, 6.4, 2.4 Hz, 1H), 6.99 (s,1H), 6.91 (d, J = 2.2 Hz, 1H), 6.44 (dt, J = 2.0, 1.0 Hz, 1H), 5.86 (tt, J=10.6, 5.2 Hz, 1H), 5.11 (dddt, J = 20.8, 10.8, 1.8, 1.0 Hz, 2H), 4.79 (ddt, J = 5.2, 1.8, 1.0 Hz, 2H), 3.93 (dt, J = 6.1, 4.3 Hz, 1H), 3.47–3.32 (m, 1H), 3.13–2.99 (m, 2H), 2.98 (dd, J = 4.3, 2.0 Hz, 2H), 2.99–2.90 (m, 1H), 2.95–2.82 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 155.33, 138.50, 135.43, 133.88,132.85, 128.84, 126.44, 125.54, 125.11, 121.50, 120.95, 117.32, 115.91,111.63, 111.03, 106.91, 54.39, 45.83, 43.17, 29.22, 26.82. MS (ESI) calcd forC 21 H 20 N2O [M+H] + : 317.1654.

[0083] Compound S14 (5,6,6a,7-tetrahydro-4H-benzo[de]oxazolo[4,5-g]quinoline-2-ol) was synthesized from 12a using the same procedure as S1, with a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.01 (s, 1H),7.18–7.07 (m, 2H), 6.52 (dt, J = 2.0, 0.9 Hz, 1H), 4.14 (dt, J = 6.1, 5.1 Hz,1H), 3.36–3.25 (m, 1H), 3.19–2.98 (m, 5H), 2.97–2.82 (m, 1H). 13 C NMR (101MHz, DMSO- d 6) δ 156.25, 153.02, 146.56, 136.40, 135.80, 129.77, 129.00,116.54, 109.19, 53.89, 43.17, 29.20, 29.06. MS (ESI) calcd for C 21 H 20 N2O [M+H] + :229.0977.

[0084] Compound S15 (9-methyl-5,6,6a,7-tetrahydro-4H-benzo[de]oxazolo[4,5-g]quinoline-2-ol) was synthesized from 12b using the same procedure as S1, with a yield of 39%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.15–7.04(m, 2H), 6.53 (dt, J = 2.0, 0.9 Hz, 1H), 4.12 (dt, J = 6.0, 5.0 Hz, 1H), 3.36–3.25 (m, 1H), 3.19 – 2.95 (m, 5H), 2.95–2.82 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 162.31, 156.38, 145.17, 135.98, 135.41, 129.15, 129.00, 116.54,109.15, 53.95, 43.17, 29.81, 29.06, 14.40. MS (ESI) calcd for C 14 H 14 N₂O₂ [M+H] + :243.1134.

[0085] The synthetic route of the compound in Example 3 is as follows: Figure 3 As shown.

[0086] Synthesis of intermediate 13a: Intermediate 3 (1.0 eq) was dissolved in dichloromethane, and trifluoroacetic acid was added. The mixture was stirred at room temperature for 6 h. The solution was concentrated, neutralized with sodium bicarbonate, extracted with dichloromethane, and concentrated again. The crude product was dissolved in dichloromethane, and triethylamine (2.5 eq) and benzyl bromide (1.5 eq) were added at 0 °C. The mixture was stirred at room temperature for 1 h, concentrated, and purified by column chromatography with PE / EA = 8:1 as the eluent, yielding a colorless oily product in 48% yield.

[0087] Intermediate 13b was synthesized from intermediate 3 and allyl chloroformate following the steps of synthesizing intermediate 13a to obtain a pale yellow oily substance with a yield of 55%.

[0088] Intermediate 13c was synthesized from intermediate 3 and benzyl chloroformate as raw materials, following the steps for synthesizing intermediate 13a, to obtain a pale yellow oily substance with a yield of 45%.

[0089] Synthesis of intermediate 14: Intermediate 13a (1.0 eq) was dissolved in ethanol, and hydroxylamine hydrochloride (2.5 eq) and sodium acetate (2.5 eq) were added. The mixture was heated to 90 °C and stirred for 6 h. After concentration, the mixture was purified by column chromatography with PE / EA = 4:1 as the eluent to obtain a colorless oily product in 78% yield.

[0090] Synthesis of intermediate 15a: Intermediate 14 (1.0 eq) was dissolved in dimethyl sulfoxide, sodium hydroxide (5.0 eq) was added, and the mixture was heated to 100 °C. A dimethyl sulfoxide solution of dichloromethane (2.5 eq) was added dropwise over 2 h. The mixture was extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, filtered, and purified by concentrated column chromatography with PE / EA = 10:1 as the eluent, yielding a colorless oily product in 29% yield.

[0091] Synthesis of Intermediate 15: Intermediate 15a was dissolved in dichloromethane, 10% Pd / C (0.2 eq) was added, hydrogen gas was introduced, and the mixture was stirred at room temperature for 12 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. Then, it was dissolved in dichloromethane, and triethylamine and trifluoroacetic anhydride were added at 0 °C. The mixture was then moved to room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated, and the solution was purified by column chromatography with PE / EA = 5:1 as the eluent to give a yellow solid in 45% yield.

[0092] Synthesis of intermediate 16a: Intermediate 13a (1.0 eq) was dissolved in anhydrous toluene (0.2 M) under nitrogen protection and stirred at -78°C for 5 min. Then, potassium tert-butoxide solution (1.0 M in THF, 1.3 eq) was injected, and the mixture was stirred for 5 min before being brought to room temperature and stirred for 30 min. Ethyl formate (2.0 eq) was then injected, and the mixture was stirred at room temperature for 2 h. After the reaction was complete as monitored by TLC, methanol was added to quench the reaction, and the concentrate was used to obtain crude 16a in 81% yield.

[0093] Intermediate 16b was synthesized from intermediate 13b using the same steps as intermediate 16a, with a yield of 68%.

[0094] Intermediate 16c was synthesized from intermediate 13c using the same steps as intermediate 16a, with a yield of 55%.

[0095] Synthesis of Intermediate 17: 16c (1.0 eq) was dissolved in pyridine (0.2 M), and hydroxylamine hydrochloride (2.0 eq) was added. The mixture was heated to 110 °C overnight. The reaction solution was concentrated under reduced pressure, diluted with 1 M dilute hydrochloric acid aqueous solution, and then extracted with dichloromethane (30 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was used as the eluent, with PE / EA = 5:1, to obtain Intermediate 17 as a yellow oil in 31% yield.

[0096] Synthesis of Intermediate 18: 16b (1.0 eq) was dissolved in acetic acid (0.2 M), and hydroxylamine hydrochloride (2.0 eq) was added. The mixture was heated to 80 °C overnight. The reaction solution was concentrated under reduced pressure, diluted with 1 M dilute hydrochloric acid aqueous solution, and then extracted with dichloromethane (30 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification was performed with PE / EA as eluent (5:1) to obtain Intermediate 18 as a yellow oil in 43% yield.

[0097] Synthesis of intermediate 19: 16a (1.0 eq) was dissolved in ethanol, and hydrazine hydrate (1.5 eq) was added. The mixture was heated to 80 °C, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography with PE / EA / TEA = 20:1:0.1 as the eluent. Intermediate 19 was obtained as a gray solid with a yield of 45%.

[0098] Synthesis of Intermediate 20: Intermediate 19 was dissolved in dichloromethane, 10% Pd / C (0.2 eq) was added, hydrogen gas was introduced, and the mixture was stirred at room temperature for 12 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. It was then dissolved in dichloromethane, and at 0 °C, triethylamine (2.5 eq) and trifluoroacetic anhydride (1.5 eq) were added. The mixture was stirred for 1 h, concentrated, and purified by column chromatography with PE / EA as the eluent (5:1). The yield was 79%.

[0099] Synthesis of intermediate 21: Using intermediate 20 as raw material, it was synthesized in the same steps as 12a, with a yield of 54%.

[0100] Synthesis of compound S16 (4,5,6,6a,7,10-hexahydrobenzo[de]pyrrolo[2,3-g]quinoline-2-ol). Intermediate 15 was dissolved in anhydrous toluene (0.2 M) under nitrogen protection and heated to 110 °C. Aluminum trichloride (5.0 eq) was added, followed by stirring for 2.5 h. The reaction mixture was cooled and placed at 0 °C. The reaction was quenched with 20 mL of 1 M dilute hydrochloric acid aqueous solution, then diluted with 50 mL of ethyl acetate. Saturated sodium bicarbonate was added until all the solids in the system were dissolved. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. Subsequently, compound S16 was synthesized using the same method as compound S1, yielding a yellow solid in 51% yield. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.69 (d, J = 6.9 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 6.75 (dd, J = 6.9, 3.3 Hz, 1H), 6.52 (dt, J =2.1, 1.0 Hz, 1H), 6.46 (d, J = 3.3 Hz, 1H), 3.93 (dt, J = 6.2, 4.9 Hz, 1H), 3.47 – 3.32 (m, 1H), 3.13 – 2.95 (m, 4H), 2.95 – 2.82 (m, 1H), 2.87 – 2.72(m, 1H). 13 C NMR (101MHz, DMSO- d 6 ) δ 155.22, 135.49, 126.10, 125.46, 123.72,122.66, 120.26, 115.77, 107.22, 106.64, 55.93, 43.17, 29.83, 29.03. MS (ESI)calcd for C 14 H 14 N2O [M+H] + :227.1184. Synthesis of compound S17 (5,6,6a,7-tetrahydro-4H-benzo[de]isoxazole[3,4-g]quinoline-2-ol). Intermediate 17 was dissolved in 48% hydrobromic acid and heated to 120°C with stirring for 6 h. The solution was concentrated, neutralized with concentrated ammonia, and the solvent was further concentrated. The residue was washed with dichloromethane:methanol = 5:1, filtered, and the filtrate was concentrated. The solution was purified by column chromatography using DCM / MeOH / NH3·H2O = 15:1:0.1 to give a yellow solid, S17, in 13% yield. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.58 (s, 1H), 9.34 (s, 1H), 7.52 (s, 1H), 6.96 (s, 1H), 6.44 (s, 1H), 3.95 (dd, J = 13.5, 5.9Hz, 1H), 3.27 (s, 1H), 3.16 (s, 1H), 2.93 (d, J = 8.6 Hz, 2H), 2.89 – 2.79(m, 1H), 2.60 (d, J = 13.3 Hz, 1H), 2.40 (d, J = 13.9 Hz, 1H). 13 C NMR (101MHz, DMSO- d 6 ) δ 161.83, 155.88, 150.46, 135.45, 128.88, 127.92, 119.45,116.68, 110.01, 54.75, 43.17, 29.06, 26.38. MS (ESI) calcd for C 13 H 12 N₂O₂ [M+H] + 229.0977. The synthesis of compound S18 (5,6,6a,7-tetrahydro-4H-benzo[de]isoxazole[5,4-g]quinoline-2-ol) was carried out using intermediate 18 as a starting material, following the same steps as 12a, with a yield of 48%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.53 (s,1H), 7.16 – 7.05 (m, 2H), 6.53 (dt, J = 2.1, 1.0 Hz, 1H), 3.88 (td, J= 7.3,6.1 Hz, 1H), 3.47 – 3.33 (m, 1H), 3.13 – 2.95 (m, 5H), 2.95 – 2.82 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 157.67, 154.96, 150.27, 136.18, 128.13, 125.19,116.19, 115.78, 108.78, 55.16, 43.17, 29.16, 27.60. MS (ESI) calcd forC 13 H 12 N₂O₂ [M+H] + : 229.0977. The synthesis of compound S19 (4,5,6,6a,7,10-hexahydrobenzo[de]pyrazolo[3,4-g]quinoline-2-ol) was carried out using intermediate 21 as a starting material, following the same method as the synthesis of S1, with a yield of 11%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.58 (s, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 3.83 (dd, J = 13.1, 5.7 Hz, 1H), 3.23 – 3.17 (m, 1H), 3.09 – 3.00 (m,1H), 2.92 – 2.80 (m, 2H), 2.66 – 2.58 (m, 1H), 2.33 (ddd, J = 14.8, 13.0, 1.9Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 157.94, 156.50, 154.48, 137.67, 127.40,124.45, 118.06, 113.76, 108.61, 53.43, 43.35, 29.13, 24.93. MS (ESI) calcdfor C 13 H 13 N3O [M+H] +: 228.1137.

[0101] The synthetic route of the compound in Example 4 is as follows: Figure 4 As shown.

[0102] Synthesis of intermediate 22a: Intermediate 15 (1.0 eq) was dissolved in acetonitrile, and cesium carbonate (2.5 eq) and iodomethane (2.5 eq) were added. The mixture was refluxed at 90 °C for 4 h. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and purified by column chromatography with PE / EA = 5:1 as the eluent to obtain a yellow oily substance 22a-c.

[0103] Synthesis of intermediate 22b: Using intermediate 15 and bromopropane as raw materials, the synthesis method is the same as that of 22a.

[0104] Synthesis of intermediate 22c: Using intermediate 15 and 1-allylane as raw materials, the synthesis method is the same as that of 22a.

[0105] Synthesis of intermediate 23a-c: Using intermediate 22a-c as raw material, the synthesis method is the same as that of 12a.

[0106] Synthesis of intermediates 24a-f: Using intermediate 20 as raw material, the synthesis method is the same as that of intermediate 22a-c to obtain intermediates 24a-c and 24d-f.

[0107] Synthesis of intermediate 25a-c: Using intermediate 24a-c as raw material, the synthesis method is the same as that of intermediate 12a.

[0108] Synthesis of intermediate 25d-f: Using intermediate 24d-f as raw material, the synthesis method is the same as that of intermediate 12a.

[0109] The synthesis of compound S20 (10-methyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrrolo[2,3-g]quinoline-2-ol) was carried out using intermediate 23a as a starting material, and the synthesis method was the same as that of S1, with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.03 (s, 1H), 7.00 – 6.90 (m, 2H), 6.39 (dt, J = 2.0, 1.0 Hz, 1H), 6.17 (d, J = 4.8 Hz, 1H), 3.94 (dt, J = 6.1, 4.3 Hz, 1H), 3.83 (d, J= 0.7 Hz, 3H), 3.47– 3.32 (m, 1H), 3.13 – 3.02 (m, 1H), 3.07 – 3.00 (m, 1H), 3.05 – 2.90 (m,2H), 2.95 – 2.82 (m, 1H), 2.87 – 2.72 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ155.17, 135.16, 130.18, 128.89, 126.09, 125.48, 116.83, 115.89, 107.92,105.20, 55.72, 43.17, 33.84, 29.38, 29.22. MS (ESI) calcd for C 15 H 16 N2O [M+H] + :241.1341. The synthesis of compound S21 (10-propyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrrolo[2,3-g]quinoline-2-ol) was carried out using intermediate 23b as a starting material, and the synthesis method was the same as that of S1, with a yield of 41%. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.07 – 6.98 (m, 2H), 6.95 (d, J = 2.2 Hz, 1H), 6.42 (dt, J = 2.0, 0.9 Hz, 1H), 6.25 (d, J = 4.8 Hz, 1H), 4.03 (td, J = 4.2, 1.3 Hz, 2H), 3.94 (dt, J =6.1, 4.3 Hz, 1H), 3.47 – 3.32 (m, 1H), 3.13 – 2.99 (m, 3H), 2.99 – 2.83 (m,2H), 2.88 – 2.72 (m, 1H), 1.78 (qt, J = 7.1, 4.2 Hz, 2H), 0.90 (t, J = 7.2Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 155.27, 135.32, 130.31, 126.53, 126.23,125.00, 117.67, 115.89, 107.10, 104.45, 55.58, 48.35, 43.17, 29.32, 29.22,22.86, 11.07. MS (ESI) calcd for C 17 H 20 N2O [M+H] + : 269.1654. The synthesis of compound S22 (10-allyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrrolo[2,3-g]quinoline-2-ol) was carried out using intermediate 23c as a starting material, and the synthesis method was the same as that of S1, with a yield of 40%. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.07 – 6.97 (m, 2H), 6.95 (d, J = 2.2 Hz, 1H), 6.42 (dt, J = 2.0, 0.9 Hz, 1H), 6.20 (d, J = 4.9 Hz, 1H), 5.88 (tt, J = 10.7, 5.2 Hz, 1H), 5.12 (dddt, J = 12.0, 10.8, 1.9, 1.0 Hz, 2H), 4.72 – 4.58 (m, 2H), 3.94 (dt, J = 6.1, 4.3Hz, 1H), 3.47 – 3.32 (m, 1H), 3.13 – 2.98 (m, 3H), 2.98 – 2.83 (m, 2H), 2.88– 2.72 (m, 1H). 13 C NMR (400 MHz, DMSO- d 6 ) δ 155.27, 135.32, 132.32, 129.92,126.67, 126.19, 125.50, 117.81, 117.61, 115.89, 106.88, 104.41, 55.58, 49.22,43.17, 29.31, 29.22. MS (ESI) calcd for C 17 H 18N2O [M+H] + : 267.1497. The synthesis of compound S23 (10-methyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrazole[3,4-g]quinoline-2-ol) was carried out using intermediate 25a as a starting material, and the synthesis method was the same as that of S1, with a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.53(s, 1H), 7.14 (s, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.43 (dt, J = 2.1, 1.0 Hz,1H), 3.90 (s, 3H), 3.88 (dt, J = 6.2, 5.2 Hz, 1H), 3.47 – 3.32 (m, 1H), 3.13 – 2.83 (m, 5H), 2.88 – 2.73 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 155.69,137.39, 135.42, 134.40, 130.47, 125.36, 116.87, 115.86, 108.62, 55.57, 43.17,38.12, 29.24, 27.39. MS (ESI) calcd for C 14 H 15 N3O [M+H] + : 242.1293. The synthesis of compound S24 (10-propyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrazole[3,4-g]quinoline-2-ol) was carried out using intermediate 25b as a starting material, and the synthesis method was the same as that of S1, with a yield of 45%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.52(s, 1H), 7.15 (s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.46 (dt, J = 2.1, 1.0 Hz, 1H), 4.19 (td, J = 4.2, 1.0 Hz, 2H), 3.88 (dt, J= 6.2, 5.2 Hz, 1H), 3.47 –3.32 (m, 1H), 3.13 – 3.04 (m, 1H), 3.09 – 2.99 (m, 2H), 3.04 – 2.94 (m, 1H),2.98 – 2.83 (m, 1H), 2.88 – 2.73 (m, 1H), 2.00 – 1.78 (m, 2H), 0.93 (t, J =7.6 Hz, 3H). 13 C NMR (1010 MHz, DMSO- d 6 ) δ 155.85, 140.28, 135.90, 135.45,129.82, 125.24, 116.91, 115.87, 107.61, 55.43, 52.27, 43.17, 29.24, 27.30,21.75, 11.04. MS (ESI) calcd for C 16 H 19 N3O [M+H] + : 270.1606. The synthesis of compound S25 (10-allyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrazole[3,4-g]quinoline-2-ol) was carried out using intermediate 25c as a starting material, and the synthesis method was the same as that of S1, with a yield of 36%. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.51 (s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.46 (dt, J = 2.0, 1.0 Hz, 1H), 5.91(tt, J = 11.2, 5.0 Hz, 1H), 5.20 (dddt, J = 19.9, 11.2, 1.9, 1.0 Hz, 2H),4.61 (dt, J = 5.0, 1.0 Hz, 2H), 3.88 (dt, J = 6.3, 5.2 Hz, 1H), 3.47 – 3.32(m, 1H), 3.13 – 2.83 (m, 5H), 2.88 – 2.73 (m, 1H). 13 C NMR (101 MHz, DMSO-d 6 )δ 155.85, 139.08, 135.43, 135.04, 131.22, 129.23, 125.18, 117.76, 117.69,115.87, 107.72, 55.43, 49.93, 43.17, 29.24, 27.33. MS (ESI) calcd for C 16 H 17 N3O[M+H] + : 268.1450.

[0110] The synthesis of compound S26 (10-methyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrazole[3,4-g]quinoline-2-ol) was carried out using intermediate 25d as a starting material, and the synthesis method was the same as that of S1, with a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.48(s, 1H), 7.15 – 7.07 (m, 2H), 6.53 (dt, J = 2.0, 0.9 Hz, 1H), 3.89 (s, 3H), 3.47 – 3.32 (m, 1H), 3.13 – 2.98 (m, 3H), 3.01 – 2.82 (m, 2H), 2.88 – 2.72(m, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 155.76, 146.60, 135.17, 131.16, 127.73,124.47, 116.54, 116.33, 109.56, 55.17, 43.17, 39.46, 29.06, 28.57. MS (ESI)calcd for C 14 H 15 N3O [M+H] + : 242.1293. The synthesis of compound S27 (9-propyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrazole[3,4-g]quinoline-2-ol) was carried out using intermediate 25e as a starting material, and the synthesis method was the same as that of S1, with a yield of 41%. 1 H NMR (400 MHz, DMSO- d) δ 7.54(s, 1H), 7.17 – 7.07 (m, 2H), 6.53 (dt, J = 2.0, 0.9 Hz, 1H), 4.12 (td, J =4.1, 1.4 Hz, 2H), 3.90 (dt, J = 6.2, 5.2 Hz, 1H), 3.47 – 3.32 (m, 1H), 3.13 –3.04 (m, 1H), 3.09 – 2.98 (m, 2H), 3.02 – 2.82 (m, 2H), 2.82 – 2.72 (m, 1H),1.96 – 1.80 (m, 2H), 1.01 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ155.76, 147.74, 135.17, 132.22, 127.75, 125.88, 118.39, 116.54, 109.50,55.04, 54.46, 43.17, 29.06, 28.48, 22.73, 11.03. MS (ESI) calcd for C 16 H 19 N3O[M+H] + : 270.1606. The synthesis of compound S28 (9-allyl-4,5,6,6a,7,10-hexahydrobenzo[de]pyrazole[3,4-g]quinoline-2-ol) was carried out using intermediate 25f as a starting material, and the synthesis method was the same as that of S1, with a yield of 44%. 1 H NMR (400 MHz, DMSO- d ) δ7.60 (s, 1H), 7.17 – 7.07 (m, 2H), 6.53 (dt, J = 2.0, 0.9 Hz, 1H), 5.88 (tt, J = 11.3, 5.0 Hz, 1H), 5.18 (dddt, J = 22.5, 11.2, 1.8, 1.0 Hz, 2H), 4.70 –4.53 (m, 2H), 3.90 (dt, J= 6.2, 5.2 Hz, 1H), 3.47 – 3.32 (m, 1H), 3.13 –2.83 (m, 5H), 2.78 (dt, J = 6.2, 3.7 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ155.76, 146.98, 135.17, 132.22, 131.37, 127.75, 126.15, 117.91, 117.04,116.54, 109.50, 55.04, 53.98, 43.17, 29.06, 28.49. MS (ESI) calcd for C 14 H 15 N3O[M+H] + : 242.1293.

[0111] The synthetic route of the compound in Example 5 is as follows: Figure 5 As shown.

[0112] Synthesis of intermediate 26a-f: according to the literature ( ACS Chem. Neurosci. The intermediate 26a-f was synthesized by the method described in 2020, 11, 549−559.

[0113] Synthesis of intermediate 27a: starting material 26a (1.0 eq) was dissolved in anhydrous dichloromethane, and triethylamine (2.5 eq) and trifluoromethanesulfonic anhydride (1.5 eq) were added at 0°C. The mixture was reacted at room temperature for 2 h, concentrated, and purified by column chromatography with PE / EA = 25:1 as the eluent to obtain intermediate 27a in 71% yield.

[0114] Intermediate 27b was synthesized from 26b using the same steps as 27a to obtain a white solid with a yield of 70%.

[0115] Intermediate 27c was synthesized from 26c using the same steps as 27a to obtain a white solid with a yield of 71%.

[0116] Intermediate 27d was synthesized from 26d using the same steps as 27a to obtain a white solid with a yield of 75%.

[0117] Intermediate 27e was synthesized from 26e using the same steps as 27a to obtain a white solid with a yield of 73%.

[0118] Intermediate 27f was synthesized from 26f using the same steps as 27a to obtain a white solid with a yield of 68%.

[0119] Synthesis of intermediate 28a: Starting material 27a (1.0 eq), cesium carbonate (2.5 eq), Xantphos (0.3 eq), and Pd₂(dba)₂ (0.1 eq) were placed in a double-necked flask under nitrogen protection. Anhydrous dioxane was injected into the reactor, and the mixture was heated to 90°C. After 24 h, the mixture was filtered. After the reaction was complete, the mixture was extracted three times with ethyl acetate and water. The ethyl acetate layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was dissolved in tetrahydrofuran, and 6 M was slowly added dropwise. After 30 min, the solution was neutralized with saturated sodium bicarbonate solution at 0 °C, then extracted with dichloromethane and water, dried and concentrated, and purified by column chromatography to obtain intermediate 28a with a yield of 47%.

[0120] Intermediate 28b was synthesized from 27b using the same steps as 28a to obtain a white solid with a yield of 52%.

[0121] Intermediate 28c was synthesized from 27c using the same steps as 28a to obtain a white solid with a yield of 63%.

[0122] Intermediate 28d was synthesized from 27d using the same steps as 28a to obtain a white solid with a yield of 56%.

[0123] Intermediate 28e was synthesized from 27e using the same steps as 28a to obtain a white solid with a yield of 52%.

[0124] Intermediate 28f was synthesized from 27f using the same steps as 28a to obtain a white solid with a yield of 61%.

[0125] Synthesis of intermediates 29a and 29d: Intermediate 28a (1.0 eq) was dissolved in 1,4-dioxane, and formaldehyde (1.1 eq) and hydrochloric acid (0.2 eq) were added. The mixture was refluxed at 120 °C. After the reaction was completed, the mixture was cooled and filtered to obtain intermediates 29a and 29d in yields of 17% and 23%, respectively.

[0126] Intermediates 29b and 29e were synthesized from intermediate 28b using the same steps as intermediate 29a, with yields of 20% and 25%, respectively.

[0127] Intermediates 29c and 29f were synthesized from intermediate 28c using the same steps as intermediate 29a, with yields of 21% and 22%, respectively.

[0128] Synthesis of intermediate 30a: Intermediate 28d (1.0 eq), potassium acetate (0.5 eq), acetic anhydride (0.5 eq), acetic acid (0.2 eq), and amyl nitrite (1.2 eq) were dissolved in toluene and refluxed at 120 °C in the dark. After 8 h of reaction, the reaction was monitored by TLC. The mixture was extracted with ethyl acetate and water, and the ethyl acetate layer was washed with saturated sodium chloride solution. The solution was dried, concentrated, and purified by column chromatography to obtain intermediate 30a in 66% yield.

[0129] Intermediate 30b was synthesized from intermediate 28e using the same method as intermediate 30a to obtain a white solid with a yield of 59%.

[0130] Intermediate 30c was synthesized from intermediate 28f using the same method as intermediate 30a to obtain a white solid with a yield of 64%.

[0131] Intermediate 31 was synthesized from 30c using the same method as synthesis 12a, with a yield of 56%.

[0132] Synthesis of intermediate 32a: Intermediate 31 was dissolved in acetonitrile, and K2CO3, KI, and bromopropane were added. The mixture was heated to 60°C overnight. After the reaction was complete, the solid was removed by filtration, the filtrate was concentrated, and purified by column chromatography with PE / EA = 15:1 as the eluent to obtain a pale yellow solid 32a in 71% yield.

[0133] Intermediate 32b was synthesized from intermediate 31 and 1-bromopropene using the same method as intermediate 32a to obtain a white solid with a yield of 69%.

[0134] Intermediate 32c was synthesized from intermediate 31 and 3-bromo-1,1-difluoropropane using the same method as intermediate 32a to obtain a white solid with a yield of 68%.

[0135] Intermediate 32d was synthesized from intermediate 31 and (2-bromomethyl)cyclopropane using the same method as intermediate 32a to obtain a white solid with a yield of 62%.

[0136] Intermediate 32e was synthesized from intermediate 31 and 4-bromo-2-methylbut-1-ene using the same method as intermediate 32a to obtain a white solid with a yield of 67%.

[0137] The synthesis of compound S29 (1,2-(2-1')pyrrolo-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride) was carried out using intermediate 29a as a starting material, similar to the synthesis of compound S1, with a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.99 (d,J = 6.6 Hz, 1H), 7.99 – 7.91 (m, 1H), 7.70 – 7.64 (m, 1H), 7.41 – 7.32 (m, 2H), 7.25 (dd, J = 6.6, 3.7 Hz, 1H), 6.81 (d, J = 3.8 Hz, 1H), 3.86 (dt, J = 6.2, 5.1 Hz, 1H), 3.16 – 3.07 (m, 1H), 3.11 – 3.05 (m,1H), 3.07 – 3.03 (m, 2H), 3.04 (t, J = 1.1 Hz, 1H), 3.00 – 2.86 (m, 2H). MS(ESI) calcd for C 18 H 17 ClN2 [M+H] + : 291.1392.

[0138] The synthesis of compound S30 (12-chloro-3,5,6,7,7a,8-hexahydrobenzo[g]indole[6,5,4-de]quinoline) was performed using intermediate 29b as a starting material, similar to the synthesis of compound S1, with a yield of 51%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.97 (d, J = 6.6 Hz, 1H), 7.52 – 7.43 (m, 1H), 7.43 – 7.31 (m, 2H), 7.26 (dd, J = 6.6, 3.7 Hz, 1H), 6.81 (dd, J = 3.7, 0.5 Hz, 1H), 3.90 (dt, J = 6.2, 5.0 Hz, 1H),3.19 – 2.81 (m, 7H). 13 C NMR (101 MHz, DMSO- d 6) δ 135.49, 134.92, 132.75,132.20, 130.97, 129.77, 127.64, 126.13, 125.34, 125.05, 124.38, 123.34,110.00, 102.99, 54.44, 43.17, 37.07, 28.81. MS (ESI) calcd for C 18 H 15 ClN2 [M+H] + :295.1002.

[0139] The synthesis of compound S31 (12-methoxy-3,5,6,7,7a,8-hexahydrobenzo[g]indole[6,5,4-de]quinoline) was carried out using intermediate 29c as a starting material, similar to the synthesis of compound S1, with a yield of 53%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.97(d, J = 6.6 Hz, 1H), 7.44 (d, J = 0.5 Hz, 1H), 7.30 – 7.17 (m, 3H), 6.98 –6.86 (m, 1H), 6.81 (dd, J = 3.7, 0.4 Hz, 1H), 3.90 (s, 3H), 3.90 (dt, J =6.2, 5.0 Hz, 1H), 3.19 – 2.99 (m, 3H), 3.02 – 2.83 (m, 4H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 156.45, 137.07, 135.12, 132.25, 128.94, 126.47, 125.35, 124.01,123.49, 122.05, 121.05, 109.89, 108.92, 102.65, 56.11, 54.69, 43.17, 37.43,28.81. MS (ESI) calcd for C 19 H 18 N2O [M+H] + : 291.1497. The synthesis of compound S32 (2,3-(2-1')pyrrolo-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride) was carried out using intermediate 29d as a starting material, similar to the synthesis of compound S1, with a yield of 42%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.99 (d, J = 6.6 Hz, 1H), 7.97 (dd, J = 7.3, 1.4 Hz, 1H), 7.67 (ddt, J = 7.8, 2.3, 1.0 Hz, 1H), 7.63 (s, 1H), 7.41 – 7.29 (m, 2H), 7.21 (dd, J =6.6, 3.8 Hz, 1H), 6.61 (d, J = 3.9 Hz, 1H), 3.86 (dt, J = 6.2, 5.1 Hz, 1H),3.14 – 3.02 (m, 5H), 2.91 (t, J = 4.3 Hz, 2H). MS (ESI) calcd for C 18 H 17 ClN2 [M+H] + : 291.1392.

[0140] The synthesis of compound S33 (11-chloro-1,4,5,6,6a,7-hexahydrobenzo[g]indole[4,5,6-de]quinoline) was performed using intermediate 29e as a starting material, similar to the synthesis of compound S1, with a yield of 48%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.97 (d, J = 6.6 Hz, 1H), 7.59 (d, J = 0.5 Hz, 1H), 7.49 (dd, J = 6.4, 3.0 Hz, 1H),7.48 – 7.31 (m, 2H), 7.21 (dd, J = 6.6, 3.8 Hz, 1H), 6.66 – 6.58 (m, 1H), 3.90 (dt, J= 6.2, 5.0 Hz, 1H), 3.18 – 2.97 (m, 4H), 2.96 – 2.87 (m, 2H), 2.87 (dt, J = 6.2, 3.7 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 135.88, 134.96,131.92, 131.07, 129.82, 128.66, 128.42, 127.77, 126.54, 125.82, 125.60,125.41, 106.61, 100.90, 54.95, 42.35, 37.07, 24.73. MS (ESI) calcd forC 18 H 15 ClN2 [M+H] + : 295.1002.

[0141] The synthesis of compound S34 (11-methoxy-1,4,5,6,6a,7-hexahydrobenzo[g]indole[4,5,6-de]quinoline) was performed using intermediate 29f as a starting material, similar to the synthesis of compound S1, with a yield of 47%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.97(d, J = 6.6 Hz, 1H), 7.47 (d, J = 0.4 Hz, 1H), 7.28 – 7.16 (m, 3H), 6.99 –6.87 (m, 1H), 6.66 – 6.58 (m, 1H), 3.90 (s, 3H), 3.90 (dt, J = 6.2, 5.0 Hz,1H), 3.16 – 3.05 (m, 2H), 3.09 – 3.00 (m, 1H), 3.05 – 2.88 (m, 2H), 2.91 (d, J = 1.3 Hz, 1H), 2.93 – 2.84 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 154.36,135.85, 135.64, 130.58, 129.78, 128.28, 126.16, 125.82, 124.69, 123.23,121.30, 109.40, 106.84, 100.90, 56.09, 55.24, 42.35, 37.43, 24.73. MS (ESI)calcd for C 19 H 18 N2O [M+H] + : 291.1497. The synthesis of compound S35 (1,2-(2-1',2')pyrazolyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol) was carried out using intermediate 30a as a starting material, similar to the synthesis of compound S2, with a yield of 35%. 1 H NMR (400 MHz, DMSO- d 6 ) δ8.48 (d, J = 0.5 Hz, 1H), 8.03 – 7.89 (m, 1H), 7.78 – 7.67 (m, 1H), 7.44 –7.29 (m, 2H), 3.90 (dt, J = 6.2, 4.9 Hz, 1H), 3.19 – 3.06 (m, 1H), 3.12 –2.99 (m, 3H), 3.02 – 2.81 (m, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 141.97,135.86, 135.79, 133.45, 131.76, 128.89, 128.28, 128.07, 127.37, 127.01,126.14, 118.63, 110.06, 55.00, 43.17, 36.70, 28.75. MS (ESI) calcd for C 17 H 15 N3[M+H] + : 262.1344. The synthesis of compound S36 (12-chloro-3,5,6,7,7a,8-hexahydrobenzo[g]indazole[6,5,4-de]quinoline) was performed using intermediate 30b as a starting material, similar to the synthesis of compound S2, with a yield of 31%. 1 H NMR (400 MHz, DMSO- d6 ) δ 8.38 (s, 1H), 7.48 (dd, J = 6.7, 2.6 Hz, 1H), 7.46 – 7.32 (m, 3H), 3.90 (dt, J = 6.1,5.0 Hz, 1H), 3.19 – 2.81 (m, 7H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 140.02, 135.71,135.41, 132.77, 132.47, 130.69, 129.77, 127.63, 127.03, 125.12, 124.27,119.75, 109.69, 54.70, 43.17, 37.08, 28.84. MS (ESI) calcd for C 17 H 14 ClN3 [M+H] + 296.0955. The synthesis of compound S37 (12-methoxy-3,5,6,7,7a,8-hexahydrobenzo[g]indazole[6,5,4-de]quinoline) was carried out using intermediate 30c as a starting material, similar to the synthesis of compound S2, with a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.38(d, J = 0.4 Hz, 1H), 7.37 (d, J = 0.4 Hz, 1H), 7.32 – 7.17 (m, 2H), 6.93 (dd, J = 7.1, 2.2 Hz, 1H), 3.90 (s, 3H), 3.96 – 3.84 (m, 1H), 3.19 – 2.99 (m, 3H), 3.02 – 2.83 (m, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 156.79, 140.09, 137.06,135.21, 132.11, 128.94, 127.21, 125.05, 121.43, 121.03, 118.07, 109.74,108.92, 56.11, 54.95, 43.17, 37.43, 28.84. MS (ESI) calcd for C 18 H 17 N3O [M+H] + :292.1450. The synthesis of compound S38 (12-propoxy-3,5,6,7,7a,8-hexahydrobenzo[g]indazole[6,5,4-de]quinoline) was carried out using intermediate 32a as a starting material, similar to the synthesis of compound S2, with a yield of 37%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.41–8.34 (m, 1H), 7.40–7.34 (m, 1H), 7.31–7.21 (m, 2H), 6.93–6.81 (m, 1H), 4.02(t, J = 5.4 Hz, 2H), 3.90 (dt, J = 6.1, 5.0 Hz, 1H), 3.19–2.83 (m, 7H), 1.82(qt, J = 7.8, 5.4 Hz, 2H), 1.08 (t, J = 7.8 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 156.32, 140.09, 136.64, 135.21, 132.11, 130.00, 127.21, 125.08, 121.82,121.03, 118.07, 111.23, 109.74, 71.37, 54.95, 43.17, 37.43, 28.84, 22.70,10.64. MS (ESI) calcd for C 20 H 21 N3O [M+H] + : 320.1763. The synthesis of compound S39 (12-allyloxy-3,5,6,7,7a,8-hexahydrobenzo[g]indazole[6,5,4-de]quinoline) was carried out using intermediate 32b as a starting material, similar to the synthesis of compound S2, with a yield of 31%. 1 H NMR (400 MHz, DMSO- d 6 ) δ8.38 (s, 1H), 7.37 (s, 1H), 7.27–7.14 (m, 2H), 6.90 (dd, J = 6.4, 2.9 Hz, 1H), 5.94 (tt, J = 16.7, 5.5 Hz, 1H), 5.33 (dddt, J = 25.0, 16.7, 2.3, 1.0Hz, 2H), 4.65 (dt, J = 5.5, 1.0 Hz, 2H), 3.90 (dt, J = 6.1, 5.0 Hz, 1H), 3.19– 2.83 (m, 7H). 13 C NMR (400 MHz, DMSO- d 6 ) δ 156.28, 140.09, 136.74, 135.21,132.96, 132.11, 130.00, 127.21, 125.09, 121.34, 121.05, 118.07, 117.91,110.59, 109.74, 70.05, 54.95, 43.17, 37.43, 28.84. MS (ESI) calcd for C 20 H 19 N3O[M+H] + : 318.1606. The synthesis of compound S40 (12-(3,3-difluoropropoxy)-3,5,6,7,7a,8-hexahydrobenzo[g]indazole[6,5,4-de]quinoline) was carried out using intermediate 32c as a starting material, similar to the synthesis of compound S2, with a yield of 25%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.41–8.34 (m, 1H), 7.40–7.34 (m, 1H), 7.31–7.21 (m, 2H), 6.93–6.81(m, 1H), 6.07 (t, J= 5.4 Hz, 0H), 4.24 (t, J = 7.4 Hz, 2H), 3.90 (dt, J =6.1, 5.0 Hz, 1H), 3.19–2.99 (m, 3H), 3.02–2.83 (m, 4H), 2.32–2.02 (m, 2H). 13 CNMR (101 MHz, DMSO- d 6 ) δ 156.70, 140.09, 136.62, 135.21, 132.11, 130.00,127.21, 125.08, 122.01, 121.03, 120.15, 118.07, 116.58, 113.01, 111.28,109.74, 62.65, 62.52, 62.38, 54.95, 43.17, 37.43, 33.22, 32.86, 32.50, 28.84.MS (ESI) calcd for C 20 H 19 F2N3O [M+H] + : 356.1574. The synthesis of compound S41 (12-(2-cyclopropylethoxy)-3,5,6,7,7a,8-hexahydrobenzo[g]indazole[6,5,4-de]quinoline) was performed using intermediate 32d as a starting material, similar to the synthesis of compound S2, with a yield of 38%. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.38 (d, J = 0.4 Hz, 1H), 7.37 (d, J = 0.4 Hz, 1H), 7.31–7.21 (m,2H), 6.93–6.81 (m, 1H), 4.17–3.98 (m, 2H), 3.90 (dt, J = 6.1, 5.0 Hz, 1H),3.19–2.99 (m, 3H), 3.02–2.83 (m, 4H), 1.85–1.58 (m, 2H), 1.34 (dq, J = 11.6, 5.8 Hz, 1H), 0.42 (d, J = 5.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 156.60,140.09, 136.64, 135.21, 132.11, 130.00, 127.21, 125.08, 121.82, 121.03,118.07, 111.23, 109.74, 67.70, 54.95, 43.17, 37.43, 34.39, 28.84, 9.96, 6.30.MS (ESI) calcd for C 22 H 23 N3O [M+H] + : 349.1919. The synthesis of compound S42 (12-((3-methylbut-3-en-1-yl)oxy)-3,5,6,7,7a,8-hexahydrobenzo[g]indazolo[6,5,4-de]quinoline) was performed using intermediate 32e as a starting material, similar to the synthesis of compound S2, with a yield of 36%. 1 H NMR (400 MHz, DMSO-) d 6 ) δ 8.38 (s, 1H), 7.37 (s, 1H), 7.31–7.19 (m, 2H), 6.93–6.82(m, 1H), 4.87 (dp, J = 8.2, 1.2 Hz, 2H), 4.26–4.12 (m, 2H), 3.90 (dt, J =6.1, 5.0 Hz, 1H), 3.19–3.00 (m, 3H), 3.05–2.83 (m, 4H), 2.42 (tq, J = 6.4,0.9 Hz, 2H), 1.75 (d, J = 2.8 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 155.97,141.51, 140.09, 136.64, 135.21, 132.11, 130.00, 127.21, 125.08, 121.82,121.03, 118.07, 112.63, 111.19, 109.74, 68.52, 54.95, 43.17, 37.43, 36.87,28.84, 22.80. MS (ESI) calcd for C 22 H 23 N3O [M+H]+ : 349.1919.

[0142] Example 6: Determination of calcium ion current

[0143] Some compounds from the above examples were selected as experimental subjects to test their activity against 5HT receptor calcium ion flux, using conventional techniques. Eight hours prior to the calcium flux assay, stably transfected 5-HT... 2A / 2B / 2C HEK293T cells of the receptor were seeded at a density of 15,000 cells / well in 384-well plates containing DMEM with 1% dialyzed FBS. After removing the medium, the cells (20 μL / well) were incubated at 37°C for 1 h with Fluo-4 direct dye (Invitrogen) reconstituted in FLIPR buffer (19 HBSS, 2.5 mmol / L probenecid and 20 mmol / L HEPES, pH 7.4). After dye loading, the cells were placed in FLIPRTETRA fluorescence imaging plate readers (Molecular Devices); a drug dilution prepared at a 3-fold concentration in FLIPR buffer and aliquoted into the 384-well plates were also added to the FLIPRTETRA. The fluid module and plate reader of the FLIPRTETRA were programmed to read baseline fluorescence for 10 seconds (1 read / second), then add 10 μL of drug / well and read for 6 minutes (1 read / second). The fluorescence in each well was normalized to the average of the first 10 degrees (i.e., baseline fluorescence). Then, the maximum fold increase occurring within 60 s after drug addition, exceeding the baseline fluorescence induced by the carrier or drug, was determined.

[0144] Table 1. Effects of compounds on 5HT at 1 μM concentration. 2C Receptor activation rate

[0145] Table 2. Results of calcium ion flux assay for representative compounds on the 5HT2 receptor

[0146] (In the table: "NA" indicates no activity, "-" indicates that no activity assay was performed.) Table 1 shows the effects of compounds on 5HT. 2C The results of receptor calcium flux activity assay, compared with existing 5-HT... 2C Compared to receptor agonists, N- H The nitrogen-containing heterocyclic derivatives of apophene are the first structures reported in this invention. Derivatives with thiazole, pyrrole, and pyrazole structures have the ability to activate 5-HT. 2CThe role of the receptor. Table 2 shows the results of calcium flux assays for representative compounds on the 5HT2 receptor, among which representative compounds S29-S31 and S35-S42 show the effects of 5-HT2 receptor calcium flux activity. 2C The receptor selectivity of this invention is significantly superior to that of existing apophene compounds. Furthermore, the compounds of this invention exhibit better receptor selectivity for 5-HT. 2B The receptor has almost no agonistic activity, therefore this invention has a high degree of safety.

[0147] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A nitrogen-containing heterocyclic derivative of NH apophene, characterized in that, The general chemical structural formula of the nitrogen-containing heterocyclic derivative of NH apophene is shown below: ； R1 and R2 are independently selected from one or more of hydrogen, alkyl, alkynyl, alkenyl, halogen, haloalkyl, cyano, nitro, aryl, hydroxyl, carboxyl, alkoxy, alkoxyacyl, oxime, amino, amide, acyloxy, acyl, sulfonyl, sulfonamide, urea, thiourea or carbamoyl. Ar1 is a substituted or unsubstituted ring; Ar2 represents a substituted or unsubstituted ring.

2. The nitrogen-containing heterocyclic derivative of NH apophene according to claim 1, characterized in that, The alkyl group has 1 to 20 carbon atoms; the alkoxy group has 1 to 20 carbon atoms; the alkynyl group has 1 to 20 carbon atoms; the alkenyl group has 1 to 20 carbon atoms; the haloalkyl group has 1 to 20 carbon atoms; the halogen is one or more of fluorine, chlorine, bromine or iodine; the substituted or unsubstituted ring is a monocyclic or fused ring.

3. The nitrogen-containing heterocyclic derivative of NH apophene according to claim 1, characterized in that, R1 is one or more of alkyl, alkoxy, hydroxy, hydrogen, or halogen; R2 is one or more of alkyl, alkoxy, hydroxy, hydrogen, or halogen; among alkyl and alkoxy, alkyl includes saturated or unsaturated aliphatic alkyl and aromatic alkyl; Ar1 ​​includes substituted or unsubstituted aromatic rings and substituted or unsubstituted heterocycles; Ar2 includes substituted or unsubstituted aromatic rings and substituted or unsubstituted heterocycles.

4. The nitrogen-containing heterocyclic derivative of NH apophene according to claim 3, characterized in that, Substituted or unsubstituted heterocycles include substituted or unsubstituted aromatic heterocycles.

5. The nitrogen-containing heterocyclic derivative of NH apophene according to claim 3, characterized in that, Substituted or unsubstituted heterocycles include nitrogen.

6. The nitrogen-containing heterocyclic derivative of NH apophene according to claim 1, characterized in that, In the substituted ring, the substituent is selected from one or more of halogen, amino, hydroxy, alkoxy, acyloxy, acyl, sulfonyl, sulfonamide, carbamoyl, and alkylamine.

7. A pharmaceutical composition comprising the nitrogen-containing heterocyclic derivative of NH apophene as claimed in claim 1, or a pharmacologically acceptable salt, ester, hydrate, solvate, crystalline form, enantiomer, stereoisomer, ether, metabolite, or prodrug.

8. The use of the nitrogen-containing heterocyclic derivative of NH apophene according to claim 1 or a pharmacologically acceptable salt, ester, hydrate, solvate, crystalline form, enantiomer, stereoisomer, ether, metabolite, prodrug, or the pharmaceutical composition according to claim 7 in the preparation of 5-hydroxytryptamine 2C receptor agonists or 5-hydroxytryptamine 2C / 2A receptor agonists.

9. The application according to claim 8, characterized in that, The 5-hydroxytryptamine 2C receptor agonist or 5-hydroxytryptamine 2C / 2A receptor agonist is used for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, or drug addiction.

10. The use of the nitrogen-containing heterocyclic derivative of NH apophene according to claim 1 or a pharmacologically acceptable salt, ester, hydrate, solvate, crystalline form, enantiomer, stereoisomer, ether, metabolite, prodrug, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, or drug addiction.

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