Apophylline derivatives, processes for their preparation and use

Abstract

This invention provides an apophene derivative, its preparation method, and its application. The general formula of the apophene derivative structure described in this invention is shown below: Among them, R 1 C 1 -C 8 alkoxy or hydrogen, R 2 For hydroxyl or hydrogen; R 3 Selected from C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, C 2 -C 10 alkynyl group, C 2 -C 10 alkenyl, halogen, C 1 -C 8 Halogenated, cyano, nitro, or aryl. The use of the 5-hydroxytryptamine 2A receptor agonist and 5-hydroxytryptamine 2C receptor agonist described in this invention in the preparation of medicaments for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, and drug addiction.

Description

Apoffei derivatives, their preparation methods and applications Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to an apofel derivative, its preparation method, and its application. Background Technology

[0002] 5-HT receptors are widely distributed in the central and peripheral nervous systems and participate in regulating a wide range of physiological responses, such as cognition, memory processing, mood, circadian rhythm behavior, and appetite. Among them, the 5-HT2 receptor includes three highly homologous subtypes, namely 5-HT2 receptors. 2A 5-HT 2B and 5-HT 2C Receptors, via G q / 11 Proteins activate corresponding downstream intracellular effector molecules, such as phospholipase C (PLC), whose activity depends on phosphatidylinositol and / or intracellular calcium ion concentration, as well as protein kinase C (PKC). PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 promotes the release of calcium ions from intracellular calcium stores, increasing the intracellular calcium ion concentration. Calcium ions bind to PKC in the cytoplasm and accumulate on the plasma membrane. DAG, phosphatidylserine, and calcium ions jointly activate PKC, subsequently causing various corresponding biological effects.

[0003] 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-α (TNF-α)-mediated inflammation inhibitor, it may be used in novel treatments for inflammatory diseases. 5-Hydroxytryptamine 2C (5-HT) 2C Because 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 2CReceptor-selective agonists are essential for the treatment of central nervous system diseases.

[0004] Currently, there is no highly agonistic 5-HT. 2A / 2C Reports of receptor agonists, including publicly marketed or preclinically investigated 5-HT receptor agonists. 2C Highly selective receptor agonists are also rare; for example, only lorcaserin and pencalcerin have been marketed or entered clinical trials. Therefore, there is still a need to develop compounds with novel structures, high selectivity, high activity, and good drug-like properties.

[0005] Apophene derivatives can be isolated from natural products or obtained through organic synthesis and modification. Due to their diverse structures, they exhibit a wide range of biological activities, such as anticancer, anti-inflammatory, antioxidant, antiplatelet aggregation, anti-Parkinson's disease, antiviral, adrenergic receptor activity, antirheumatic, antimalarial, and antibacterial activities. Although the application of apophene derivatives in the treatment of central nervous system diseases has been studied for many years, it is mainly as a dopamine D2 receptor and 5-HT receptor agonist. 1A receptor, 5-HT 2A and 5-HT 2B The ligands of the receptor, and even some compounds with unknown targets (such as CN112999225A and CN113004201A), but which act on 5-HT 2C Receptors have only been explored in recent years.

[0006] In existing technologies, targeting 5-HT 2C Apofex receptor agonists still exist for 5-HT 2C Receptor agonist activity is weak, such as 1857 (ACS CentSci, 2020, 6, 213-25) and 18b (ACS Chem Neurosci, 2020, 11, 549-59; ZL201910594756.6); and 5-HT 2C Defects such as poor receptor selectivity, such as 11b and 11f (Bioorganic Chemistry 123(2022)105795; ZL201910594756.6), ultimately limit their further clinical development. However, those with 5-HT... 2A and 5-HT 2C No dual agonists of the receptor have been reported. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides an apofel derivative, its preparation method, and its applications.

[0008] The first objective of this invention is to provide an apofel derivative, the general structural formula of which is shown below:

[0009] Wherein, R1 is a C1-C8 alkoxy group or hydrogen.

[0010] R2 is a hydroxyl group or hydrogen;

[0011] R3 is selected from C1-C8 alkyl, C1-C8 alkoxy, C2-C 10 alkynyl group, C2-C 10 Alkenyl, halogen, C1-C8 haloalkyl, cyano, nitro or aryl.

[0012] In one embodiment of the present invention, when R2 is a hydroxyl group, R1 is selected from C1-C8 alkoxy and hydrogen, and R3 is selected from halogen, C1-C8 alkoxy, and C1-C8 alkyl.

[0013] In one embodiment of the present invention, when R2 is a hydroxyl group, R1 is selected from hydrogen, and R3 is independently selected from halogen, C1-C8 alkoxy, and C1-C8 alkyl.

[0014] In one embodiment of the present invention, when R2 is a hydroxyl group, R1 is selected from C1-C8 alkoxy groups, and R3 is independently selected from halogens and C1-C8 alkoxy groups.

[0015] In one embodiment of the invention, the halogen is fluorine, chlorine, bromine or iodine.

[0016] Furthermore, C1-C8 haloalkyl groups are alkyl groups containing 1-8 carbons of halogen, and the number and type of halogen are not limited, such as trifluoromethyl, difluoromethyl, monofluoromethyl or trifluoroethyl;

[0017] C2-C 10 The alkenyl group is an alkenyl group with 2-10 carbon atoms, such as ethylene, propylene, butene, styrene, or styrene;

[0018] C2-C 10 Alkyne groups have 2-10 carbon atoms, such as acetylene, propyne, butyne, phenylacetylene, or phenylpropyne.

[0019] C1-C8 alkyl (R) and C1-C8 alkoxy (RO-), wherein the alkyl (R) specifically includes aliphatic alkyl and aromatic alkyl; wherein the aliphatic alkyl is preferably C1-C8 alkyl, and can be straight-chain alkyl, branched alkyl, spirocyclic alkyl, bridged cyclic alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxyalkyl, alkoxyacylalkyl, cycloalkylalkyl, more preferably, the aliphatic alkyl includes, without limitation: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, allyl, alkynyl, cyclobutenyl, cyclohexenyl, 2,2-difluoroethyl, 2-fluoroethyl; the aromatic alkyl includes, without limitation: aralkyl or heteroaralkyl, such as substituted aryloxy-substituted or unsubstituted benzyl; substituted or unsubstituted phenethyl; substituted or unsubstituted phenylpropyl, etc.

[0020] Aryl refers to substituted or unsubstituted aryl or heteroaryl groups. Aryl groups are not limited to substituted or unsubstituted phenyl groups, naphthyl rings, phenyl rings, etc. The substituents are selected from one or more of halogens, amino groups, hydroxyl groups, oxime groups, alkoxyyl groups, acyl groups, sulfonyl groups, sulfonamide groups, urea groups, thiourea groups, and carbamoyl groups.

[0021] The heteroaryl group includes, without limitation, substituted or unsubstituted aromatic heterocyclic groups and benzo[a]heterocyclic substituents; and without limitation, quinoline, isoquinoline, indole, benzofuran ring, furan ring, benzothiophene ring, thiophene ring, pyridine ring, pyrrole ring, etc.

[0022] Furthermore, the isomers include R-type isomers and S-type isomers.

[0023] In one embodiment of the present invention, R3 is selected from halogens, C1-C8 alkoxy groups, or C1-C8 alkyl groups.

[0024] A second objective of this invention is to provide a method for preparing the aforementioned apofel derivative, comprising the following steps:

[0025]

[0026] (1) Compound and Dehydration condensation yields amide compounds

[0027] The Under the action of dehydrating agent and reducing agent, PG protecting group is introduced to obtain;

[0028] (2) The result obtained in step (1) The catalyst and ligand undergo coupling cyclization to obtain;

[0029] (3) The result obtained in step (2) The deprotection reaction was carried out to obtain the [deprotection reaction].

[0030]

[0031] In one embodiment of the present invention, in step (1), the and The molar ratio is 1:1-1.5.

[0032] In one embodiment of the present invention, in step (1), the dehydrating agent is one or more of phosphorus pentoxide, phosphorus oxychloride and phosphorus pentachloride.

[0033] In one embodiment of the present invention, in step (1), the reducing agent is selected from one or more of NaBH4 (sodium borohydride), LiAlH4 (lithium aluminum hydride), BH3·THF (tetrahydrofuran borane), KBH4 (potassium borohydride) and SnCl2 (tin dichloride).

[0034] In one embodiment of the present invention, in step (1), the protecting group is selected from one or more of Tfa (trifluoroacetyl), Ts (p-toluenesulfonyl), and Boc (tert-butyloxycarbonyl).

[0035] In one embodiment of the present invention, in step (2), the catalyst is selected from one or more of Pd(PPh3)4 (tetraphenylphosphine palladium), Pd(dppf)Cl2 (1,1'-bis(diphenylphosphine)ferrocene palladium dichloride), Pd(OAc)2 (palladium acetate) and Pd2(dba)3 (tris(dibenzylacetone) palladium).

[0036] In one embodiment of the present invention, in step (2), the ligand is selected from one or more of PhDavephos (2-diphenylphosphine-2'-(N,N-dimethylamino)biphenyl), PCy3BHF4 (tricyclohexylphosphine tetrafluoroborate), (t-Bu)2PMeHBF4 (di-tert-butylmethylphosphine tetrafluoroborate or di-tert-butylmethylphosphine tetrafluoroborate), and PPh3 (triphenylphosphine).

[0037] In a specific embodiment of the present invention, one or two of R1, R2, and R3 are hydrogen, and the other groups are non-hydrogen substituents. The preparation method of the compound represented by formula M is as follows:

[0038]

[0039] Step 1: Dissolve phenethylamine M1 containing a substituent and o-bromophenylacetic acid M2, substituted or unsubstituted, in anhydrous dichloromethane. Add HOBt and EDC while stirring, and stir the resulting reaction mixture at room temperature. After the reaction is complete, an amide compound of formula M3 is obtained.

[0040] Step 2: The amide compound of formula M3 and the dehydrating agent are placed in a solvent to undergo a ring-closing reaction, and then a reduction reaction is carried out under the action of a reducing agent. After the reaction is complete, a trifluoroacetyl protecting group is introduced to obtain the compound of formula M4.

[0041] Step 3: The compound of formula M4 is reacted at 130°C in the presence of a base, ligand and catalyst. After the reaction is complete, the compound of formula M5 is obtained.

[0042] Step 4: The compound of formula M5 is deprotected and formed into a salt by a reducing agent to obtain the compound of formula M.

[0043] A third object of the present invention is to provide a pharmaceutical composition comprising the aforementioned apoffei derivative.

[0044] A fourth object of the present invention is to provide the use of the aforementioned apophyte derivative and the aforementioned pharmaceutical composition in the preparation of serotonin 2A receptor agonists and serotonin 2C receptor agonists, and the use of the aforementioned serotonin 2A receptor agonists and serotonin 2C receptor agonists in the preparation of medicaments for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, or drug addiction.

[0045] In one embodiment of the present invention, the 5-hydroxytryptamine 2A receptor agonist and 5-hydroxytryptamine 2C receptor agonist are used in the preparation of medicaments for the prevention and / or treatment of depression, anxiety, obsessive-compulsive disorder or drug addiction.

[0046] In one embodiment of the invention, the drug further includes a pharmaceutically or pharmacologically acceptable carrier.

[0047] In one embodiment of the present invention, the carrier is selected from one or more of the following: disintegrant, diluent, lubricant, adhesive, humectant, flavoring agent, suspending agent, surfactant, and preservative.

[0048] In one embodiment of the present invention, the dosage form of the pharmaceutical composition is tablets, capsules, soft capsules, granules, pills, oral liquids, emulsions, dry suspensions, dry extracts, or injections.

[0049] 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.

[0050] In one embodiment of the present invention, the salt is selected from one or more of inorganic acid salts, organic acid salts, alkyl sulfonates and aryl sulfonates.

[0051] 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.

[0052] The technical solution of the present invention has the following advantages compared with the prior art:

[0053] This invention is designed with a general formula Apophenoid compounds with this structure were found to have effects on 5-HT. 2C or 5-HT 2A / 2C All receptors exhibited excellent activation activity, while 5-HT... 2B The receptor has no agonistic effect. This invention reveals and elucidates the relationship between the structure and activity of apophene compounds on a larger scale, in a more in-depth and comprehensive manner, and has significant application value. The apophene 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

[0054] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein...

[0055] Figure 1 shows the in vivo anti-schizophrenia activity assay results in Example 68 of the present invention. Detailed Implementation

[0056] 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, but the embodiments are not intended to limit the present invention.

[0057] 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).

[0058] 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.

[0059] 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℃.

[0060] 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.

[0061] The synthetic routes for compounds S1-S9 are shown below:

[0062]

[0063] Synthesis of intermediate 3a-i: Phenylacetic acid derivative 2a-i (1.0 eq) was dissolved in anhydrous dichloromethane solution (0.2 M) under ice-water bath conditions. 1-hydroxybenzotriazole (1.2 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq), and p-methoxyphenethylamine 1-1 (1.2 eq) were added sequentially with stirring. The mixture was gradually brought to room temperature and stirred overnight. The reaction was monitored by TLC until completion. The mixture was extracted with dichloromethane and water. The organic phase was washed sequentially with 1N dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solution was dissolved in a small amount of dichloromethane, cooled in an ice bath, and stirred to crystallize, yielding a white solid 3a-i in 78-92% yield.

[0064] Synthesis of intermediate 4a-i: Amide 3a-i (1.0 eq) and phosphorus pentoxide (5.0 eq) were refluxed in toluene for 3 h. After cooling, the toluene was concentrated. The mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and then dissolved in methanol (0.2 M). Sodium borohydride (3.0 eq) was added to the mixture in portions under an ice-water bath, and the resulting mixture was stirred at room temperature for 3 h. The methanol was concentrated, diluted with 50 mL of water, and extracted with dichloromethane. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was performed, yielding a yellow oily substance in two steps at 55-65% yield.

[0065] At room temperature, triethylamine (2.5 eq) was added to a solution of a yellow oily substance (1.0 eq) in dichloromethane (0.2 M). The mixture was cooled to 0 °C, and trifluoroacetic anhydride (1.2 eq) was added dropwise to the mixture, which was then gradually brought to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane (50 mL) and then washed with 1 N HCl, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was performed to give a white solid 4a-i in 80-85% yield.

[0066] Synthesis of intermediate 5a-i: Potassium carbonate (2.5 eq), 2-diphenylphosphine-2'-(N,N-dimethylamino)biphenyl (0.2 eq), palladium acetate (0.1 eq), and 4a-i (1.0 eq) were placed in a round-bottom flask under nitrogen protection. Then, N,N-dimethylacetamide (0.2 M) was added as solvent, and the resulting mixture was heated at 130 °C for 4 h. The N,N-dimethylacetamide was concentrated, diluted with water, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was performed to give 5a-i as a white solid in 40-45% yield.

[0067] Synthesis of compounds S1-S9: Intermediate 5a-i (1.0 eq) and ethanol (0.2 M) were added to a round-bottom flask. Sodium borohydride (20 eq) was then added sequentially in an ice bath. The flask was purged with nitrogen, and the reaction mixture was stirred at room temperature for 60 minutes. The solvent was then evaporated under reduced pressure, and the residue was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and column chromatography was performed. The solution was salted with ethyl acetate of hydrogen chloride, and the solvent was evaporated to dryness. This process was repeated three times, yielding white solids S1-S9 in 40-56% yields.

[0068] Example 1: Synthesis of compound S1 (8-chloro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0069] The mixture was synthesized using 2-bromo-6-chlorophenylacetic acid 2a as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.36 (s, 1H), 9.81 (s, 1H), δ8.28 (d, J = 7.7Hz, 1H), 7.4 1–7.27(m,3H),7.19(d,J=8.6Hz,1H),4.39(dd,J=14.1,3.4Hz,1H),3.91(s,3H ),3.77(dd,J=12.0,5.7Hz,1H),3.70(dd,J=14.2,4.4Hz,1H),3.45–3.37(m,1H ), 3.25 (d, J = 6.1Hz, 1H), 3.08 (dd, J = 16.9, 4.1Hz, 1H), 2.75 (t, J = 14.3Hz, 1H). 13 C NMR(151MHz,DMSO-d6)δ155.94,133.56,132.17,130.00,129.81,129.56,127.99,127.63 (d,J=15.7Hz),121.83,120.69,112.81,54.96,52.82,41.22,29.21,24.14.MS(CI)calcd for C 17 H 17 Cl2NO[M+H] + 322.23.

[0070] Example 2: Synthesis of compound S2 (9-chloro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0071] The mixture was synthesized using 2-bromo-5-chlorophenylacetic acid 2b as a starting material, following the steps described above. 1 H NMR(400MHz, DMSO-d6)δ9.91(s,2H),8.22(d,J=8.5Hz,1H),7.51(s,1H),7.42–7.14( m,3H),4.33(d,J=13.3Hz,1H),3.86(s,3H),3.59(d,J=6.4Hz,1H),3.22–2.89(m,5H). 13C NMR(101MHz,DMSO-d6)δ155.5,136.0,131.9,130.9,130.6,130.1,128.1,127.4,123.4,120.1,113.2,56.4,52.2,32.7,24.7.MS(CI)calcd for C 17 H 17 Cl2NO[M+H] + 322.23.

[0072] Example 3: Synthesis of compound S3 (10-chloro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0073] The mixture was synthesized using 2-bromo-4-chlorophenylacetic acid 2c as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),9.81(s,1H),8.22(s,1H),7.41(d,J=7.8Hz,1H),7.33(d,J=7.6Hz,1H),7.26(d,J=8.4Hz,1 H),7.18(d,J=8.5Hz,1H),4.31(d,J=12.4Hz,1H),3.88(s,3H),3.57(d,J=5.6Hz,1H),3.25–3.10(m,3H),2.94(t,J=14.3Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ155.62,133.51,132.52,131.90,131.21,130.55,130.17, 128.38,127.56,123.51,119.82,113.12,56.50,52.23,32.29,24.63.MS(CI)calcd for C 17 H 17 Cl2NO[M+H] + 322.23.

[0074] Example 4: Synthesis of compound S4 (11-chloro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0075] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d as a starting material, following the steps described above. 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.65(s,1H),7.41(dd,J=20.2,7.0Hz,2H),7.30(s,2H),7.16(d, J=8.2Hz,1H),4.18(d,J=12.0Hz,1H),3.84(s,3H),3.57(s,1H),3.26–3.09(m,3H),2.98–2.78(m,2H). 13 C NMR(151MHz,DMSO-d6)δ154.99,137.37,133.18,132.75,130.68,130.44,129.77, 128.82,126.66,122.52,119.05,112.51,55.50,52.43,40.54,24.14.MS(CI)calcd forC 17 H 17 Cl2NO[M+H] + 322.23.

[0076] Example 5: Synthesis of compound S5 (8-fluoro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0077] The mixture was synthesized using 2-bromo-6-fluorophenylacetic acid 2e as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.09 (s, 2H), 8.09 (d, J = 8.0Hz, 1H), 7.37 (dd, J = 14. 8,7.7Hz,1H),7.27(d,J=8.6Hz,1H),7.18(dt,J=8.5,4.4Hz,2H),4.34(dd,J= 14.2,4.4Hz,1H),3.87(s,3H),3.59(t,J=9.5Hz,1H),3.43(dd,J=14.3,4.6H z, 1H), 3.21 (d, J = 7.1Hz, 2H), 2.94 (t, J = 11.8Hz, 1H), 2.72 (t, J = 14.3Hz, 1H). 13 C NMR(151MHz,DMSO-d6)δ159.1(d,J=241.6Hz),155.7,133.8,130.9,130.4,128.4(d,J=7.6Hz),125.1,12 3.4,120.3(d,J=18.1Hz),120.2,114.5(d,J=22.7Hz),113.2,56.4,51.9,40.6,24.6,24.4.MS(CI)calcd for C17 H 17 ClFNO[M+H] + 305.78.

[0078] Example 6: Synthesis of compound S6 (9-fluoro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0079] The mixture was synthesized using 2-bromo-5-fluorophenylacetic acid 2f as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ9.88(s,2H),8.25(dd,J=8.3,6.3Hz,1H),7.29(d,J=8.1Hz,1H),7.19(dd,J=25.2,8.4Hz, 3H), 4.33 (d, J=11.1Hz, 1H), 3.86 (s, 3H), 3.58 (d, J=6.9Hz, 1H), 3.23–3.10 (m, 3H), 2.95 (dd, J=26.0, 13.2Hz, 2H). 13 C NMR(151MHz,DMSO-d6)δ161.96,160.33,155.24,136.49(d,J=8.5Hz),131.04(d,J=8.1Hz),130.70,1 29.62,128.12,123.33,120.37,115.24,115.09,114.15,114.02,113.10,40.67,24.67.MS(CI)calcd for C 17 H 17 ClFNO[M+H] + 305.78.

[0080] Example 7: Synthesis of compound S7 (10-fluoro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0081] The above steps were followed to synthesize the product using 2g of 2-bromo-4-fluorophenylacetic acid as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.75(s,1H),7.99(d,J=10.1Hz,1H),7.41(t,J=7.1Hz,1H),7.26(d,J=8.5Hz,1H),7.17(d ,J=8.6Hz,1H),7.12(t,J=7.3Hz,1H),4.31(s,1H),3.88(s,3H),3.57(s,1H),3.27–3.07(m,3H),2.92(dd,J=17.3,10.2Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ162.21,160.62,155.65,133.42(d,J=9.1Hz),131.08,130.44,129.93(d,J=8.3Hz),129 .57,123.39,120.08,115.55,115.39,114.51,114.37,113.08,56.42,52.45,40.56,32.12,24.62.MS(CI)calcd for C 17 H 17 ClFNO[M+H] + 305.78.

[0082] Example 8: Synthesis of compound S8 (11-fluoro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0083] The mixture was synthesized using 2-bromo-3-fluorophenylacetic acid 2h as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.67(s,1H),7.39–7.27(m,2H),7.25(d,J=6.5Hz,1H) ,7.17(d,J=7.3Hz,2H),4.22(d,J=11.8Hz,1H),3.83(s,3H),3.58(s,1H),3.26–2.84(m,5H). 13 C NMR(151MHz,DMSO-d6)δ159.4(d,J=253.7Hz),155.3,136.7,132.1,130.3,129.5(d,J=9.1Hz),123.9,12 2.9,119.4(d,J=15.1Hz),117.4,115.7(d,J=24.2Hz),112.9,56.3,52.4,40.6,33.3,24.3.MS(CI)calcd for C 17 H17 ClFNO[M+H] + 305.78.

[0084] Example 9: Synthesis of compound S9 (1,9-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0085] The mixture was synthesized using 2-bromo-5-methoxyphenylacetic acid 2i as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.67(s,1H),8.16(d,J=8.8Hz,1H),7.13(q,J=8.5Hz,2H),6.95(s,1H),6.90(d,J=8.8Hz,1H),4. 27(d,J=11.2Hz,1H),3.84(s,3H),3.79(s,3H),3.55(s,1H),3.19(d,J=10.1Hz,2H),3.11–3.03(m,1H),2.94(dd,J=30.5,13.9Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ158.72,155.07,135.40,130.44,130.28,128.66,124.29,123 .31,121.34,113.73,113.04,112.91,56.34,55.64,52.50,33.36,24.71.MS(CI)calcd forC 18 H 20 ClNO2[M+H] + 317.81.

[0086] The synthetic routes for compounds S10-S23 are shown below:

[0087]

[0088] The synthesis of intermediate 6a-n is the same as that of intermediate 3a-i.

[0089] Synthesis of intermediate 7a-n: Phosphorus oxychloride (3.0 eq) was added to an acetonitrile (0.2 M) solution of amide 6a-c (1.0 eq), and the mixture was refluxed for 2 h. After cooling, the acetonitrile was concentrated and neutralized with a saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane, concentrated, and then dissolved in methanol (0.2 M). Subsequent steps were the same as for the synthesis of intermediate 4a-i. Column chromatography yielded a white solid, 7a-c.

[0090] The synthesis of intermediate 8a-n is the same as that of intermediate 5a-c.

[0091] Synthesis of intermediate 9a-n: Intermediate 8a-c (1.0 eq) was dissolved in appropriate amounts of methanol and dichloromethane, 10% Pd / C (0.2 eq) was added, hydrogen gas was introduced, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until the reaction was complete. After filtration, DCM extraction, salt washing, drying, and separation of the crude product by silica gel column chromatography, a white solid 9a-c was obtained.

[0092] The synthesis of compounds S10-S23 is the same as that of compounds S1-S9.

[0093] Example 10: Synthesis of compound S10 (1-methoxy-9-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0094] The mixture was synthesized using 2-bromo-5-chlorophenylacetic acid 2b and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.05(s,1H),9.70(s,1H),9.44(s,1H),8.25(d,J=8.6Hz,1H),7.52(s,1H),7.43 (d,J=8.5Hz,1H),6.76(s,1H),4.24(s,1H),3.58(d,J=15.3Hz,4H),3.23–3.06(m,3H),2.97–2.81(m,2H). 13 C NMR(101MHz,DMSO-d6)δ151.24,144.78,136.38,132.41,130.72,129.91,128.48, 127.91,127.17,125.29,120.75,116.53,60.09,51.82,33.06,24.98.MS(CI)calcd for C 17 H 17 Cl2NO2[M+H] + 338.23.

[0095] Example 11: Synthesis of compound S11 (1-methoxy-11-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0096] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1H NMR(300MHz,DMSO-d6)δ10.15(s,1H),9.63(s,1H),9.28(s,1H),7.53-7.25(m,3H),6.81(s,1H),4.08 (s,1H),3.56(s,1H),3.42(s,3H),3.25(s,1H),3.09(d,J=10.5Hz,2H),2.82(dd,J=24.4,11.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ150.71,145.18,137.71,132.94,130.77,129.90,129.27, 126.85,125.97,124.03,122.71,116.51,60.89,52.22,34.90,24.58.MS(CI)calcd for C 17 H 17 Cl2NO2[M+H] + 338.23.

[0097] Example 12: Synthesis of compound S12 (1,9-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0098] The mixture was synthesized using 2-bromo-5-methoxyphenylacetic acid 2i and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),9.55(s,1H),8.21(d,J=8.7Hz,1H),7.51(d,J=7.3Hz,2H),7.43(t,J=7.3Hz,2H),7.35(t,J=7.0Hz,1H),6.96( dd,J=14.7,7.2Hz,3H),5.17(s,2H),4.23(s,1H),3.80(s,3H),3.63(s,3H ),3.56(d,J=6.6Hz,1H),3.24–3.04(m,3H),2.92(dd,J=29.4,14.5Hz,2H). 13C NMR (151MHz, DMSO-d6) δ159.13,152.26,145.23,137.35,135.82,129.84,128.95,128.36,128.06,127.02,126. 39,123.97,121.99,113.99,113.46,112.95,70.34,60.16,55.62,51.99,40.58,33.60,25.32.MS(CI)calcdfor C 18 H 20 ClNO3[M+H] + 333.81.

[0099] Example 13: Synthesis of compound S13 (1-methyl-11-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0100] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d and 3-benzyloxy-4-methylphenethylamine 1b as raw materials, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ7.45(dd,J=7.9,1.3Hz,1H),7.37(t,J=8.1Hz,1H),7.32(dq,J=8.2,1.1Hz,1H),6.75(s,1H),6.49(t,J=1.0H z,1H),3.89(dt,J=6.2,4.9Hz,1H),3.45–3.35(m,1H),3.11–3.05(m,1H),3.05(dddd,J=7.2,5.3,2.9,1.2Hz,4H),2.95–2.85(m,1H). 13 C NMR(101MHz,DMSO-d6)δ155.14,135.27,133.31,131.21,131.16,130.71,129.73,127.8 3,127.13,124.81,120.83,114.46,54.58,43.21,36.85,28.81,12.48.MS(CI)calcdfor C 17 H 17 Cl2NO[M+H] + 333.23.

[0101] Example 14: Compound S14 (1-ethyl-11-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline).

[0102] Synthesis of 2-ol hydrochloride

[0103] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d and 3-benzyloxy-4-ethylphenethylamine 1c as raw materials, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ7.46(dd,J=7.9,1.3Hz,1H),7.38(t,J=8.0Hz,1H),7.33(dq,J=8.1,1.1Hz,1H),6.91(s,1H),6.48(t,J=1.0Hz,1H),3 .90(dt,J=6.0,5.0Hz,1H),3.45–3.35(m,1H),3.11–3.01(m,5H),2.93 –2.84(m,1H),2.87–2.72(m,2H),1.30(s,1H),1.30(d,J=14.5Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ152.49,135.13,134.45,131.74,130.75,130.41,129.75,127.65 ,127.03,124.68,123.64,115.60,54.40,43.21,37.00,28.81,20.85,14.56.MS(CI)calcd for C 18 H 19 Cl2NO[M+H] + 336.26.

[0104] Example 15: Synthesis of compound S15 (1,11-dichloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0105] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d and 3-benzyloxy-4-chlorophenylethylamine 1a as raw materials, following the steps described above. 1 HNMR(400MHz,DMSO-d6)δ10.50(s,1H),10.33(s,1H),9.63(s,1H),7.44–7.22(m,3H),6.88(d,J= 2.6Hz,1H),3.98(d,J=12.8Hz,1H),3.47(s,1H),3.19–2.96(m,3H),2.78(q,J=13.6,13.1Hz,2H). 13C NMR(101MHz,DMSO-d6)δ152.60,135.13,134.81,132.02,131.19,130.54,129.78, 129.01,127.95,125.43,117.76,115.40,54.36,43.21,37.00,28.84.MS(CI)calcd for C 16 H 14 Cl3NO2[M+H] + 341.64.

[0106] Example 16: Synthesis of compound S16 (1-methoxy-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0107] The mixture was synthesized using 2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1 H NMR(400MHz,DMSO-d6)δ7.25–7.14(m,1H),6.86(dd,J=7.9,1.5Hz,1H),6.5 0(t,J=1.0Hz,1H),4.02(t,J=5.4Hz,2H),3.86(dt,J=6.2,4.9Hz,1H),3.84( s,2H),3.45–3.36(m,1H),3.13–3.02(m,4H),2.98(ddd,J=12.5,5.0,0.9Hz ,1H),2.93–2.84(m,1H),1.82(qt,J=7.8,5.3Hz,2H),1.08(t,J=7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ154.88,147.79,144.76,135.49,130.06,129.94,127.37,124.10,121.2 1,120.55,115.74,111.24,71.37,60.28,54.39,43.21,37.36,28.85,22.69,10.64.MS(CI)calcd for C 20 H 24 Cl2NO3[M+H] + 361.14.

[0108] Example 17: Synthesis of compound S17 (1-chloro-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0109] The mixture was synthesized using 2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-chlorophenylethylamine 1d as raw materials, following the steps described above. 1 H NMR(400MHz,DMSO-d6)δ7.24(t,J=8.1Hz,1H),7.19(dq,J=8.0,1.0Hz,1H),6.86(dd ,J=8.0,1.4Hz,1H),6.73(s,1H),6.50(t,J=1.0Hz,1H),4.02(t,J=5.4Hz,2H),3.90 (dt,J=6.2,5.1Hz,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.98(ddd,J=12.5,5. 0,0.9Hz,1H),2.93–2.85(m,1H),1.82(qt,J=7.8,5.3Hz,2H),1.08(t,J=7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ154.76,152.16,135.89,134.21,132.39,129.84,128.88,121.59,12 1.43,116.79,115.73,111.41,71.37,54.63,43.21,37.37,28.84,22.70,10.64.MS(CI)calcd for C 19 H 21 Cl2NO2[M+H] + 366.28.

[0110] Example 18: Synthesis of compound S18 (1-methyl-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0111] The mixture was synthesized using 2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-methylphenethylamine 1b as raw materials, following the steps described above. 1H NMR(400MHz,DMSO-d6)δ7.22(t,J=8.0Hz,1H),7.17(dq,J=8.1,1.1Hz,1H),6.86(dd ,J=8.0,1.4Hz,1H),6.74(s,1H),6.46(t,J=1.0Hz,1H),4.02(t,J=5.4Hz,2H),3.89 (dt,J=6.2,5.0Hz,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.97(ddd,J=12.3,4. 9,1.0Hz,1H),2.94–2.85(m,1H),1.82(qt,J=7.8,5.3Hz,2H),1.08(t,J=7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ154.87,154.28,136.72,133.48,132.63,130.08,127.53,122.07,120.8 0,119.74,114.48,110.41,71.37,54.83,43.21,37.21,28.81,22.70,12.51,10.64.MS(CI)calcd for C 20 H 24 ClNO2[M+H] + 345.87.

[0112] Example 19: Synthesis of compound S19 (1-ethyl-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0113] The mixture was synthesized using 2-bromo-3-propoxyphenylacetic acid 2j and 3-benzyloxy-4-ethylphenethylamine 1c as raw materials, following the steps described above. 1H NMR (400MHz, DMSO-d6) δ7.25(t,J=8.1Hz,1H),7.18(dq,J=8.1,1.1Hz,1H),6.91(s,1H),6.87( dd,J=8.1,1.3Hz,1H),6.45(t,J=0.9Hz,1H),4.02(t,J=5.4Hz,2H),3.90(dt,J=6.2,5.1Hz,1H ),3.45–3.35(m,1H),3.11–3.02(m,4H),2.97(ddd,J=12.3,4.9,1.0Hz,1H),2.93–2.84(m,1H) ,2.86–2.71(m,2H),1.82(qt,J=7.8,5.3Hz,2H),1.30(t,J=7.2Hz,3H),1.08(t,J=7.8Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ155.03,152.25,136.22,133.71,132.86,130.04,127.81,123.47,121.36,1 20.72,115.90,110.34,71.37,54.66,43.21,37.36,28.81,22.70,20.81,14.56,10.64.MS(CI)calcd for C 21 H 26 ClNO2[M+H] + 359.89.

[0114] Example 20: Synthesis of compound S20 (1-methoxy-11-cyclopropylmethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0115] The mixture was synthesized using 2-bromo-3-cyclopropylmethoxyphenylacetic acid 2k and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1H NMR(400MHz,DMSO-d6)δ7.25–7.14(m,1H),6.82(dd,J=7.9,1.5Hz,1H),6.50( t,J=1.0Hz,1H),4.03(d,J=4.6Hz,2H),3.86(dt,J=6.2,4.9Hz,1H),3.84(s,2H ),3.45–3.36(m,1H),3.13–3.02(m,4H),2.98(ddd,J=12.5,5.0,0.9Hz,1H),2 .93–2.84(m,1H),1.36(dddd,J=12.4,6.1,4.5,1.7Hz,1H),0.63–0.46(m,4H). 13 C NMR(125MHz,Common NMR Solvents)δ155.33,147.79,144.76,135.68,130.07,129.94,127.37,124.10,121.22,1 20.38,115.74,111.44,74.01,60.28,54.39,43.21,37.36,28.85,11.84,4.02.MS(CI)calcd for C 21 H 24 ClNO3[M+H] + 373.14.

[0116] Example 21: Synthesis of compound S21 (1-methoxy-11-cyclobutyroxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0117] The mixture was synthesized using 2-bromo-3-cyclobutoxyphenylacetic acid 2l and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1 H NMR(400MHz,DMSO-d6)δ7.25–7.14(m,1H),6.82(dd,J=7.9,1.5Hz,1H),6.50 (t,J=1.0Hz,1H),4.04(d,J=4.5Hz,2H),3.86(dt,J=6.2,4.9Hz,1H),3.84(s, 2H),3.45–3.36(m,1H),3.13–3.02(m,4H),2.98(ddd,J=12.5,5.0,0.9Hz,1H) ,2.93–2.84(m,1H),2.09–1.99(m,1H),1.84–1.78(m,1H),1.81–1.63(m,4H). 13C NMR(101MHz,DMSO-d6)δ155.47,147.79,144.76,135.68,130.07,129.94,127.37,124.10,121.22,1 20.38,115.74,111.44,71.88,60.28,54.39,43.21,37.36,35.12,28.85,27.51,19.88.MS(CI)calcd forC 22 H 26 ClNO3[M+H] + 387.90.

[0118] Example 22: Synthesis of compound S22 (1,11-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0119] The mixture was synthesized using 2-bromo-3-methoxyphenylacetic acid 2m and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.48(s,1H),9.30(s,1H),7.28(t,J=7.8Hz,1H),7.04(d,J=8.3Hz,1H),6.96(d,J=7.3Hz,1H),6.71(s,1H), 4.00(s,1H),3.80(s,3H),3.59(s,3H),3.51(s,1H),3.20(s,1H),3.11(d ,J=12.7Hz,1H),3.00(d,J=13.8Hz,1H),2.83(s,1H),2.78–2.65(m,1H). 13 C NMR(101MHz,DMSO-d6)δ155.28,147.79,144.76,136.45,129.94,128.90,127.37,124.26 ,121.39,121.04,115.74,109.10,60.28,56.11,54.39,43.21,37.36,28.85.MS(CI)calcd for C 18 H 20 ClNO3[M+H] + 333.81.

[0120] Example 23: Synthesis of compound S23 (1-chloro-11-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0121] The mixture was synthesized using 2-bromo-3-methoxyphenylacetic acid 2m and 3-benzyloxy-4-chlorophenylethylamine 1d as raw materials, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ7.23(t,J=8.0Hz,1H),7.19(ddt,J=8.1,1.7,0.9Hz,1H),6.89(dd,J=7.9,1.5Hz,1H),6.73(s,1H),6.50(t,J=0 .9Hz,1H),3.90(s,3H),3.93–3.87(m,1H),3.45–3.35(m,1H),3.11–3.02(m,4H),2.98(ddd,J=12.5,5.0,0.9Hz,1H),2.94–2.85(m,1H). 13 C NMR(101MHz,DMSO-d6s)δ155.06,152.16,135.98,134.21,132.40,128.91,128.88,121 .39,121.03,116.79,115.73,109.20,56.11,54.63,43.21,37.37,28.84.MS(CI)calcd for C 17 H 17 Cl2NO2[M+H] + 338.23.

[0122] The synthesis of compounds S24-S34 is shown below:

[0123]

[0124] The synthesis of intermediate 10a-g is the same as that of intermediate 3a-i.

[0125] The synthesis of intermediate 11a-g is the same as that of intermediate 7a-c.

[0126] The synthesis of intermediate 12a-g is the same as that of intermediate 5a-i.

[0127] Synthesis of intermediate 13a-g: Intermediate 12a-f (1 eq) was dissolved in DCM and placed at -78°C under nitrogen protection. A solution of boron tribromide in dichloromethane (3 eq) was added dropwise. The reaction was carried out at -78°C for 0.5 h, followed by reaction at room temperature for 1 h. After quenching with water, the mixture was extracted with ethyl acetate, washed with salt, dried, filtered, and crystallized to obtain intermediate 13a-f.

[0128] Synthesis of intermediate 14a-g: At 0 °C, trifluoromethanesulfonic anhydride (1.2 eq) and triethylamine (2.5 eq) were added to a solution of 13a-d (1.0 eq) in dichloromethane (0.2 M). The reaction mixture was stirred for 30 min and then quenched with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The product was obtained by column chromatography. In a round-bottom flask, triethylamine (8.0 eq) and anhydrous N,N-dimethylformamide (0.2 M) were added, followed by dropwise addition of 98% formic acid (8.0 eq). Then, the above product (1.0 eq) was added, followed by the sequential addition of palladium acetate (0.04 eq) and 1,1'-bis(diphenylphosphine)ferrocene (0.08 eq). The mixture was heated to 60 °C. After 15 min, the mixture was cooled to room temperature, diluted with water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography yielded a white product 14a-d.

[0129] Example 24: Synthesis of compound S24 (8-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0130] The mixture was synthesized using 2-bromo-6-chlorophenylacetic acid 2a as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.68(d,J=7.0Hz,1H),9.25(s,1H),7.77(s,1H),7.46(d,J=21.6Hz,2H),7. 16(s,1H),6.69(s,1H),4.48(s,1H),3.65(s,2H),3.29(s,1H),3.13(s,1H),2.97(s,1H),2.77(d,J=9.6Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ158.01,135.72,133.65,133.07,130.81,129.40(d,J=42.8Hz ),129.17,123.53,119.07,115.61,110.70,51.38,40.95,29.18,25.27.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 308.20.

[0131] Example 25: Synthesis of compound S25 (9-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0132] The mixture was synthesized using 2-bromo-5-chlorophenylacetic acid 2b as a starting material, following the steps described above.1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 9.44 (d, J = 30.2Hz, 1H), 7.75 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.13 (s, 1H) ,6.65(s,1H),4.41(d,J=13.2Hz,1H),3.59(s,1H),3.28(s,1H),3.15(d,J=14.2Hz,2H),2.93(t,J=15.0Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ157.99,135.42,133.44,133.21,132.89,132.36,128.81, 128.32,126.21,119.23,115.31,110.22,51.53,40.93,32.33,25.33.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 308.20.

[0133] Example 26: Synthesis of compound S26 (10-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0134] The mixture was synthesized using 2-bromo-4-chlorophenylacetic acid 2c as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),9.77(d,J=20.2Hz,1H),9.44(s,1H),7.77(s,1H),7.39(dd,J=23.3,7.9Hz,2H),7.18(s,1H ),6.68(s,1H),4.39(d,J=12.1Hz,1H),3.68–3.48(m,1H),3.25(d,J=12.0Hz,1H),3.16(d,J=13.5Hz,2H),2.92(t,J=13.9Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ158.02,135.43,133.22,133.01,132.02,130.94,128. 29,124.08,119.43,115.66,110.53,51.58,40.85,32.04,25.31.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 308.20.

[0135] Example 27: Synthesis of compound S27 (11-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0136] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.78(s,1H),9.50(d,J=7.0Hz,1H),7.63(s,1H),7.50(d,J=7.8Hz,1H),7.40(d, J=7.1Hz,1H),7.30(t,J=7.6Hz,1H),6.69(s,1H),4.25(s,1H),3.56(s,1H),3.25–3.10(m,3H),2.89(t,J=13.8Hz,2H). 13 CNMR(151MHz,DMSO-d6)δ156.72,137.27,132.34,131.82,131.33,131.11,130.65,129.4 0,128.10,121.38-121.28(m),115.19,114.82,51.45,40.45,34.21,25.27.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 308.20.

[0137] Example 28: Synthesis of compound S28 (11-fluoro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0138] The mixture was synthesized using 2-bromo-3-fluorophenylacetic acid 2j as a starting material, following the steps described above. 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),9.76(s,1H),9.52(s,1H),7.34(s,2H),7.29–7.18(m,2H),6.67(s, 1H), 4.35 (d, J = 12.1Hz, 1H), 3.58 (d, J = 7.2Hz, 1H), 3.22 (t, J = 18.6Hz, 3H), 2.94 (dd, J = 26.2, 13.8Hz, 2H). 13C NMR (151MHz, DMSO-d6) δ160.66,159.01,157.38,136.39,132.79,130.16,129.88(d,J=9.4Hz),125.17,121.24( d,J=10.0Hz),120.12,116.22,116.06,115.23,114.06(d,J=15.2Hz),51.56,40.66,33.10,25.43.MS(CI)calcd for C 16 H 15 ClFNO[M+H] + 291.75.

[0139] Example 29: Synthesis of compound S29 (11-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0140] The mixture was synthesized using 2-bromo-3-methylphenylacetic acid 2k as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),9.67(s,1H),9.27(d,J=9.6Hz,1H),7.25(d,J= 6.8Hz,1H),7.21(q,J=7.0Hz,2H),7.11(d,J=1.9Hz,1H),6.63(d,J=1.6Hz,1H),4.1 9(s,1H),3.57(d,J=9.7Hz,1H),3.27–3.20(m,1H),3.14(dd,J=12.5,5.4Hz,1H),3. 05(dd,J=13.8,4.1Hz,1H),2.86(dd,J=30.0,15.9Hz,2H),2.54(s,3H).MS(CI)calcd for C 17 H 18 ClNO[M+H] + 287.79.

[0141] Example 30: Synthesis of compound S30 (11-ethyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0142] The mixture was synthesized using 2l of 2-bromo-3-ethylphenylacetic acid as a raw material, following the steps described above. 1H NMR(400MHz, DMSO-d6)δ7.33(dq,J=8.1,1.0Hz,1H),7.23(d,J=15.9Hz,0H),7.16(d q,J=7.8,1.0Hz,1H),7.08(s,1H),7.02(d,J=2.2Hz,1H),6.51(dt,J=2.1,1.0Hz,1H ),3.91(dt,J=6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–2.97(m,4H),2.93–2.85(m, 1H), 2.81 (dt, J=6.2, 3.8Hz, 1H), 2.76 (qd, J=7.3, 1.0Hz, 2H), 1.22 (t, J=7.3Hz, 3H). 13 C NMR(151MHz,DMSO-d6)δ155.86,140.14,134.97,134.90,134.70,132.28,128.26,128.25 ,127.81,125.10,115.69,110.96,55.07,43.17,37.37,29.09,27.66,15.45.MS(CI)calcd for C18H 20 ClNO[M+H] + :301.1233.

[0143] Example 31: Synthesis of compound S31 (8-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0144] The mixture was synthesized using 2-bromo-6-chlorophenylacetic acid 2a as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ9.91(s,2H),7.90(d,J=7.2Hz,1H),7.80(d,J=7.3Hz,1H),7.49(d,J=7.6Hz,1H),7.44(d,J=6.7H z,2H),7.29(d,J=7.2Hz,1H),4.57(d,J=11.6Hz,1H),3.63(d,J=16.4Hz,2H),3.27(d,J=12.7Hz,2H),3.08–2.82(m,2H). 13C NMR(151MHz,DMSO-d6)δ135.66,133.04,132.39,131.82,130.59,129.57,129.34,129 .02,128.39,123.75,123.65(d,J=29.4Hz),51.49,40.80,28.78,25.13.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 292.20.

[0145] Example 32: Synthesis of compound S32 (9-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0146] The mixture was synthesized using 2-bromo-5-chlorophenylacetic acid 2b as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.74(s,1H),7.89(s,1H),7.77(s,1H),7.54(s,1H),7. 43(s,2H),7.26(s,1H),4.53(s,1H),3.62(s,2H),3.25–3.12(m,2H),3.03(d,J=14.1Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ135.20,133.06,132.23,131.98,128.93(d,J=28.8Hz),128.33,126.47,123.03,51.61,40.78,31.89,25.20.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 292.20.

[0147] Example 33: Synthesis of compound S33 (10-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0148] The mixture was synthesized using 2-bromo-4-chlorophenylacetic acid 2c as a starting material, following the steps described above. 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),9.69(s,1H),7.94(s,1H),7.84(d,J=7.6Hz,1H),7.48–7.34(m,3H),7.28 (d,J=7.5Hz,1H),4.52(s,1H),3.63(s,1H),3.28(s,1H),3.22(d,J=14.8Hz,2H),3.00(dd,J=18.7,9.1Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ135.35,133.14,131.94,131.72,130.91,129.45,128.9 9,128.75,128.40,124.34,123.42,51.70,40.70,31.59,25.17.MS(CI)calcdfor C 16 H 15 Cl2NO[M+H] + 292.20.

[0149] Example 34: Synthesis of compound S34 (11-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride)

[0150] The mixture was synthesized using 2-bromo-3-chlorophenylacetic acid 2d as a starting material, following the steps described above. 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),9.58(s,1H),8.13(d,J=7.7Hz,1H),7.52(d,J=7.8Hz,1H),7.43(d,J=6.3Hz,2H),7.32(d d,J=12.6,7.5Hz,2H),4.40(d,J=10.8Hz,1H),3.62(s,1H),3.28(s,2H),3.19(d,J=16.7Hz,1H),2.96(dd,J=31.0,16.3Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ137.02,131.29,131.13,130.91,130.72,129.57,129.19,128.06,127.68,127.00,51.67,40.37,33.73,25.12.MS(CI)calcd for C 16 H 15 Cl2NO[M+H] + 292.20.

[0151] The synthetic routes for compounds S35-S49 are shown below:

[0152]

[0153] The synthesis of intermediate 14 is the same as the synthesis of intermediate 3a-i.

[0154] The synthesis of intermediate 15 is the same as that of intermediate 7a-c.

[0155] The synthesis of intermediate 16 is the same as that of intermediate 5a-i.

[0156] The synthesis of intermediate 17 is the same as that of intermediate 9a-c.

[0157] Synthesis of Intermediate 18: At room temperature, triethylamine (1.5 eq) was added to a DCM (0.2 M) solution of debenzylidene intermediate 17 (1 eq). The mixture was cooled to 0 °C, and 4-dimethylaminopyridine (0.2 eq) and 4-toluenesulfonyl chloride (1.2 eq) were added dropwise to the mixture. The mixture was gradually brought to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane, and then washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated by evaporation. Column chromatography yielded a white solid, 18.

[0158] The synthesis of intermediate 19 is the same as that of intermediate 13a-f.

[0159] Synthesis of intermediate 20a-n: Intermediate 19 (1.0 eq) and the corresponding haloalkane were placed in acetone, and potassium carbonate (2.0 eq) and potassium iodide (2.0 eq) were added. The mixture was refluxed, and the reaction was monitored by TLC. The solvent was concentrated, and column chromatography was used to give a white solid 20a-n.

[0160] Example 35: Synthesis of compound S35 (11-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0161] Synthesis of compounds S1-S9, 1H NMR (300MHz, DMSO-d6) δ9.96(s,1H),9.51(s,1H),9.26(s,1H),7.67(s,1H),7.27(t,J=7.8Hz,1H),7.08(d,J=8.4Hz,1H),6.97(d,J= 7.5Hz,1H),6.57(s,1H),4.25(s,1H),3.87(s,3H),3.56(s,1H),3.18(s,1H),3.15-2.99(m,2H),2.85(t,J=14.3Hz,2H).MS(CI)calcd for C 17 H 18 ClNO2[M+H] + 303.79.

[0162] Example 36: Synthesis of compound S36 (11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0163] 10 mL of potassium hydroxide (0.5 M MeOH / H₂O) solution was added to intermediate 20a (1 eq), and the mixture was refluxed at 80 °C for 5 h, then cooled to room temperature. The solvent was concentrated, and a saturated sodium chloride solution was added to the mixture, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The product eluted by column chromatography was unstable at room temperature and was converted to salt three times with ethyl acetate solution of hydrogen chloride to give a white solid S36. 1 HNMR(300MHz,DMSO-d6)δ10.24(s,1H),9.50(s,2H),7.73(s,1H),7.24(t,J=7.8Hz,1H),7 .05(d,J=8.2Hz,1H),6.94(d,J=7.2Hz,1H),6.59(s,1H),4.20(d,J=16.2Hz,1H),4.16-4.0 7(m,1H),3.88(dd,J=15.1,6.7Hz,1H),3.53(s,1H),3.19(d,J=9.9Hz,2H),3.08(dd,J=14. 1,3.7Hz,1H),2.88(t,J=13.3Hz,2H),1.82(dd,J=11.8,5.7Hz,2H),1.01(t,J=7.2Hz,3H). 13C NMR(101MHz,DMSO-d6)δ156.91,156.47,135.57,132.66,131.61,129.29,122.09,121.21 ,120.29,115.31,113.95,112.79,70.33,51.86,33.99,25.50,22.59,11.23.MS(CI)calcd for C 19 H 22 ClNO2[M+H] + 331.84.

[0164] Example 37: Synthesis of compound S37 (11-cyclopropylmethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0165] Synthesis of compound S36 using intermediate 20b as a starting material. 1 H NMR (300MHz, DMSO-d6) δ10.57(s,1H),9.90-9.49(m,2H),7.78(s,1H),7.21(t,J=7.7Hz, 1H),7.01(d,J=8.2Hz,1H),6.92(d,J=7.2Hz,1H),6.60(s,1H),4.17(s,1H),4.06-3.95(m ,1H),3.84–3.75(m,1H),3.48-3.37(m,1H),3.12(dd,J=18.2,14.2Hz,3H),2.88(dd,J=2 8.3,13.9Hz,2H),1.31(s,1H),0.56(d,J=7.6Hz,2H),0.35(d,J=4.0Hz,2H).MS(CI)calcd for C 20 H 22 ClNO2[M+H] + 343.85.

[0166] Example 38: Synthesis of compound S38 (11-allyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0167] Synthesis of compound S36 using intermediate 20c as a starting material. 1H NMR (300MHz, DMSO-d6) δ10.25(s,1H),9.58(d,J=23.2Hz,2H),7.71(s,1H),7.24(t,J=7.8H z,1H),7.06(d,J=8.3Hz,1H),6.96(d,J=7.2Hz,1H),6.59(s,1H),6.19–6.03(m,1H),5.43(d ,J=17.4Hz,1H),5.27(d,J=10.6Hz,1H),4.75(d,J=9.6Hz,1H),4.65–4.51(m,1H),4.22(d,J =11.1Hz, 1H), 3.54 (d, J = 5.2Hz, 1H), 3.14 (dd, J = 30.2, 11.0Hz, 3H), 2.87 (t, J = 13.1Hz, 2H). 13 C NMR(101MHz,DMSO-d6)δ156.90,155.93,135.69,134.05,132.53,131.70,129.24,122.31, 121.51,120.37,117.61,115.34,114.04,113.26,69.50,51.83,33.98,25.49.MS(CI)calcd forC 19 H 20 ClNO2[M+H] + 329.82.

[0168] Example 39: Synthesis of compound S39 (11-propargyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline hydrochloride-2-ol)

[0169] The synthesis of compound S36 was carried out using intermediate 20d as a starting material. 1 H NMR (300MHz, DMSO-d6) δ10.03(s,1H),9.54(s,1H),9.34(s,1H),7.65(s,1H),7.28(t,J=7.9Hz,1H),7.15(d,J=8.1Hz,1H),7.01(d,J=7.1Hz,1H ),6.59(s,1H),4.91(s,2H),4.25(d,J=11.5Hz,1H),3.58(d,J=18.2Hz,2H),3.12(dd,J=26.1,12.8Hz,3H),2.86(t,J=13.3Hz,2H).MS(CI)calcd forC 19 H 18 ClNO2[M+H] + 327.81.

[0170] Example 40: Synthesis of compound S40 (11-(2-fluoroethoxy)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0171] Synthesis of compound S36 using intermediate 20e as a starting material. 1 H NMR (400MHz, DMSO-d6) δ10.32(d,J=8.4Hz,1H),9.55(s,2H),7.73(t,J=8.6Hz,1H),7.29-7.2 2(m,1H),7.07(d,J=8.3Hz,1H),6.99(d,J=7.4Hz,1H),6.60(t,J=4.5Hz,1H),4.99-4.68(m,2 H),4.47-4.33(m,1H),4.27(dd,J=16.8,8.4,Hz,1H),4.21(dd,J=8.0,4.2Hz,1H),3.54(d,J= 6.2Hz,1H),3.25-3.15(m,2H),3.14-3.05(m,1H),2.89(dd,J=16.2,12.5Hz,2H).MS(CI)calcd for C 18 H 19 ClNO2[M+H] + 335.80.

[0172] Example 41: Synthesis of compound S41 (11-(2,2-difluoroethoxy)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0173] Synthesis of compound S36 using intermediate 20f as a starting material. 1 H NMR (300MHz, DMSO-d6) δ10.32(s,1H),9.56(s,2H),7.66(s,1H),7.27(t,J=7.7H z,1H),7.11(d,J=8.2Hz,1H),7.03(d,J=7.2Hz,1H),6.71(s,1H),6.60(s,1H),6 .52(s,1H),6.34(s,1H),4.48(dd,J=26.4,12.7Hz,1H),4.29(dd,J=26.8,12.7H z,2H),3.47–3.35(m,1H),3.14(dd,J=22.4,10.0Hz,3H),2.89(t,J=13.9Hz,2H). 13C NMR(101MHz,DMSO-d6)δ157.05,155.21,132.13,131.77,129.31,122.41,120.35,115.31,114.23,113.16,67.52,51.75,33.87,25.47.MS(CI)calcdfor C 18 H 18 ClNO2[M+H] + 353.79.

[0174] Example 42: Synthesis of compound S42 (11-((2-methylallyl)oxy)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0175] Using 20g of intermediate as a starting material, the same method as for the synthesis of compound S36 was employed. 1 H NMR(300MHz,DMSO-d6)δ9.79(s,1H),9.50(s,1H),9.17(s,1H),7.69(s,1H),7.29–7 .21(m,1H),7.06(d,J=8.2Hz,1H),6.98(d,J=7.3Hz,1H),6.59(s,1H),5.04(d,J=34 .9Hz,2H),4.66(d,J=13.2Hz,1H),4.47(d,J=13.0Hz,1H),4.25(s,1H),3.57(s,1H) ,3.19(s,1H),3.17–2.99(m,2H),2.88(d,J=21.1Hz,2H),1.80(s,3H).MS(CI)calcd for C 20 H 22 ClNO2[M+H] + 343.85.

[0176] Example 43: Synthesis of compound S43 (11-cyclobutyroxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0177] Using intermediate 20h as a starting material, the same method as the synthesis of compound S36 was employed. 1H NMR(300MHz,DMSO-d6)δ7.24(t,J=8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H ),6.86(dd,J=8.0,1.4Hz,1H),6.46(dt,J=2.1,1.0Hz,1H),4.04(d,J=4.6Hz,2H), 3.90(dt,J=6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.84(m,2 H),2.81(dt,J=6.4,3.8Hz,1H),2.09–1.99(m,1H),1.85–1.64(m,6H).MS(CI)calcd for C 21 H 24 ClNO2[M+H] + 357.14.

[0178] Example 44: Synthesis of compound S44 (11-(2-chloroethyl)oxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0179] Synthesis of compound S36 using intermediate 20i as a starting material. 1 H NMR(300MHz,DMSO-d6)δ7.24(t,J=8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m ,2H),6.89(dd,J=8.0,1.4Hz,1H),6.46(dt,J=2.1,1.0Hz,1H),4.32(q,J=2.2H z,2H),3.90(dt,J=6.2,5.0Hz,1H),3.82(t,J=2.3Hz,2H),3.44–3.35(m,1H),3 .10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J=6.4,3.8Hz,1H).MS(CI)calcd for C 18 H 19 Cl2NO2[M+H] + 351.07.

[0180] Example 45: Synthesis of compound S45 (11-trifluoroethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0181] Synthesis of compound S36 using intermediate 20j as a starting material. 1H NMR(300MHz,DMSO-d6)δ7.24(t,J=8.1Hz,1H),7.21–7.16(m,1H),7.02–6.9 6(m,2H),6.94(dd,J=8.0,1.4Hz,1H),6.46(dt,J=2.1,1.0Hz,1H),4.68(qd ,J=9.0,3.1Hz,2H),3.90(dt,J=6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3 .01(m,3H),2.97–2.84(m,2H),2.81(dt,J=6.4,3.8Hz,1H).MS(CI)calcdfor C 18 H 17 ClF3NO2[M+H] + 371.09.

[0182] Example 46: Synthesis of compound S46 (11-benzyloxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0183] Synthesis of compound S36 using intermediate 20k as a starting material. 1 H NMR(300MHz,DMSO-d6)δ7.42(dq,J=7.1,1.1Hz,2H),7.39–7.32(m,2H),7.35–7.26(m,1H) ,7.24(t,J=8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.92(dd,J=8.0,1.4Hz,1H) ,6.46(dt,J=2.1,1.0Hz,1H),5.19(t,J=1.2Hz,2H),3.90(dt,J=6.2,5.0Hz,1H),3.44–3. 35(m,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J=6.4,3.8Hz,1H).MS(CI)calcd for C 23 H 22 ClNO2[M+H] + 379.13.

[0184] Example 47: Synthesis of compound S47 (11-p-methylbenzyloxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0185] The synthesis of compound S36 was carried out using intermediate 20l as a raw material. 1H NMR(300MHz, DMSO-d6)δ7.30(dt,J=7.9,1.1Hz,2H),7.24(t,J=8.0Hz,1H),7.21–7.1 6(m,1H),7.19–7.13(m,2H),7.02–6.96(m,2H),6.92(dd,J=8.0,1.4Hz,1H),6.46(dt ,J=2.1,1.0Hz,1H),5.15(q,J=1.1Hz,2H),3.90(dt,J=6.2,5.0Hz,1H),3.44–3.35(m ,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J=6.4,3.8Hz,1H).MS(CI)calcd for C 24 H 24 ClNO2[M+H] + 393.1.

[0186] Example 48: Synthesis of compound S48 (11-cyclohexylmethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0187] Synthesis of compound S36 using intermediate 20m as a raw material. 1 H NMR(300MHz, DMSO-d6)δ7.24(t,J=8.0Hz,1H),7.21–7.16(m,1H),7.02–6.96(m,2H),6.86(dd, J=8.0,1.4Hz,1H),6.46(dt,J=2.1,1.0Hz,1H),4.06(dd,J=11.4,4.9Hz,1H),4.00(dd,J=11.4 ,5.1Hz,1H),3.90(dt,J=6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.84(m, 2H),2.81(dt,J=6.4,3.8Hz,1H),1.92(tt,J=6.4,5.1Hz,1H),1.69–1.36(m,11H).MS(CI)calcd forC 23 H 28 ClNO2[M+H] + 385.18.

[0188] Example 49: Synthesis of compound S49 (11-(4'-chlorobenzylmethyl)oxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0189] Synthesis of compound S36 using intermediate 20n as a starting material. 1 H NMR (300MHz, DMSO-d6) δ7.48–7.38(m,4H),7.25–7.16(m,2H),7.02–6.96(m,2H),6.92(dd,J=8.0,1.4Hz,1H),6.46(dt,J=2.1,1.0Hz,1H),5.15( q,J=0.9Hz,2H),3.90(dt,J=6.2,5.0Hz,1H),3.44–3.35(m,1H),3.10–3.01(m,3H),2.97–2.85(m,2H),2.81(dt,J=6.4,3.8Hz,1H).MS(CI)calcd forC 23 H 21 Cl2NO2[M+H] + 413.09.

[0190] Example 50: Synthesis of compound S50 (1,11-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0191] Following the synthetic method for S11, compound S50 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ9.79(s,1H),9.50(s,1H),9.17(s,1H),7.27(s,1H),6.97(s,1H),6.90(s,1H),6.82(s,1H),4.64 (s,1H),4.05(s,1H),3.89(s,3H),3.76(s,3H),3.33(s,1H),3.22(d,J=4.0Hz,2H),2.91(s,1H),2.75(d,J=19.9Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ156.27,151.22,146.82,137.07,132.08,130.97,129.51,127.67 ,120.48,119.09,115.33,112.20,60.70,56.83,54.17,43.55,35.58,29.18.MS(CI)calcd for C 18 H 19 ClNO3[M+H] + 297.35.

[0192] Example 51: Synthesis of compound S51 (1-methoxy-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0193] Following the synthetic method for S11, compound S51 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),4.58(s,1H),4.0 3(s,1H),3.99(s,2H),3.92(s,3H),3.35(s,1H),3.25(d,J=1.8Hz,2H),2.96(s,1H),2.77(d,J=20.0Hz,2H),1.74(s,2H),0.99(s,3H). 13 C NMR(101MHz,DMSO-d6)δ156.46,151.22,146.83,135.73,132.08,130.97,128.98,127.66,122.1 5,121.14,115.33,114.04,72.25,60.70,54.17,43.55,35.58,29.18,21.58,10.60.MS(CI)calcd for C 20 H 24 ClNO3[M+H] + 361.87.

[0194] Example 52: Synthesis of compound S52 (11-(cyclopropylmethoxy)-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0195] Following the synthesis method of S11, compound S52 was synthesized. 1H NMR(300MHz,DMSO-d6)δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H ),6.95(s,1H),6.87(s,1H),5.99(s,1H),4.05(s,1H),3.94–3.90(m,5H),3.35(s,1H),3 .25(s,1H),3.24(s,1H),2.96(s,1H),2.79(s,1H),2.75(s,1H),1.11(t,J=9.9Hz,1H),0 .51(dd,J=3.7,2.7Hz,1H),0.49(d,J=1.3Hz,1H),0.26–0.20(m,1H),0.20–0.15(m,1H). 13 C NMR(101MHz,DMSO-d6)δ155.99,151.22,146.82,136.57,132.08,130.97,129.09,127.67,122.4 3,121.00,115.33,114.20,74.00,60.70,54.17,43.55,35.58,29.18,10.70,7.85.MS(CI)calcd for C 21 H 24 ClNO3[M+H] + 373.88.

[0196] Example 53: Synthesis of compound S53 (11-(allyloxy)-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0197] Following the synthetic method for S11, compound S53 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.39(s,1H),9.49(s,1H),9.17(s,1H),7.19(s,1H),6 .95(s,1H),6.87(s,1H),6.84(s,1H),6.07(d,J=7.0Hz,2H),5.43(s,1H),5.31 (s,1H),4.69(t,J=1.9Hz,1H),4.67(t,J=1.9Hz,1H),4.04(s,1H),3.92(s,3H) ,3.35(s,1H),3.27(s,1H),3.25(s,1H),2.98(s,1H),2.79(s,1H),2.75(s,1H). 13C NMR(101MHz,DMSO-d6)δ155.99,151.22,146.83,136.57,132.93,132.08,130.97,129.08,127.66 ,122.42,121.00,117.23,115.33,114.20,70.87,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C 20 H 22 ClNO3[M+H] + 359.85.

[0198] Example 54: Synthesis of compound S54 (11-(2-fluoroethoxy)-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0199] Following the synthetic method for S11, compound S54 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.40(s,1H),9.22(s,1H),9.10(s,1H),7.32(s,1H),7.0 2(s,1H),6.95(s,1H),6.87(s,1H),6.03(s,1H),5.10(t,J=5.1Hz,1H),4.91(t,J =5.2Hz,1H),4.20(t,J=5.1Hz,1H),4.10(t,J=5.2Hz,1H),4.04(s,1H),3.92(s,3 H),3.35(s,1H),3.26(s,1H),3.25(s,1H),2.97(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d6)δ156.46,151.22,146.83,135.73,132.08,130.97,128.98,127.66,12 2.15,121.14,115.33,114.04,85.83,69.46,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C 19 H 21 ClNO3[M+H] + 365.83.

[0200] Example 55: Synthesis of compound S55 (11-(2,2-difluoroethoxy)-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0201] Following the synthetic method for S11, compound S55 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.47(s,1H),9.47(s,1H),9.21(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.14(s,1H), 5.96(s,1H),4.40(s,2H),4.03(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.23(s,1H),2.95(s,1H),2.79(s,1H),2.75(s,1H). 13 CNMR(101MHz,DMSO-d6)δ155.99,151.22,146.83,136.57,132.08,130.97,129.08,127.66 ,122.42,121.00,115.33,114.20,68.23,60.70,54.17,43.55,35.58,29.18.MS(CI)calcd for C 19 H 20 ClF2NO3[M+H] + 383.82.

[0202] Example 56: Synthesis of compound S56 (1-methoxy-11-((2-methylallyl)oxy)-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0203] Following the synthetic method for S11, compound S56 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.50(s,1H),9.44(s,1H),9.31(s,1H),7.19(s,1H),6.95(s,1H),6.87(s,1H),6.84(s,1H),6.00(s,1H),4.98(s,1H), 4.82(s,1H),4.45(s,2H),4.05(s,1H),3.92(s,3H),3.35(s,1H),3.27( s,1H),3.25(s,1H),2.98(s,1H),2.79(s,1H),2.75(s,1H),1.66(s,3H). 13C NMR(101MHz,DMSO-d6)δ155.54,151.22,146.83,140.25,137.40,132.08,130.97,129.14,127.66,12 2.76,120.96,115.33,114.39,113.66,72.94,60.70,54.17,43.55,35.58,29.18,19.21.MS(CI)calcd for C 21 H 24 ClNO3[M+H] + 373.88.

[0204] Example 57: Synthesis of compound S57 ((S)-11-chloro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0205] Following the synthetic method for S11, compound S57 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.48(s,1H),7.42(s,1H),7.15(s,1H),6.87(s,1H), 4.48(s,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.11(s,1H),3.03(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d6)δ150.54,142.01,139.03,130.57,129.64,129.41,128.19,127 .88,125.87,125.57,124.93,115.98,60.70,54.76,43.49,36.31,30.35.MS(CI)calcd for C 17 H 17 Cl2NO2[M+H] + 338.23.

[0206] Example 58: Synthesis of compound S58 ((R)-11-chloro-1-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0207] Following the synthetic method for S11, compound S58 was synthesized. 1H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.48(s,1H),7.42(s,1H),7.15(s,1H),6.87(s,1H), 4.48(s,1H),4.04(s,1H),3.92(s,3H),3.35(s,1H),3.25(s,1H),3.11(s,1H),3.03(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d6)δ150.54,142.01,139.03,130.57,129.64,129.41,128.19,127 .88,125.87,125.57,124.93,115.98,60.70,54.76,43.49,36.31,30.35.MS(CI)calcd for C 17 H 17 Cl2NO2[M+H] + 338.23.

[0208] Example 59: Synthesis of compound S59 ((S)-1,11-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0209] Following the synthetic method for S11, compound S59 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.00(s ,1H),4.04(s,1H),3.92(s,3H),3.79(s,3H),3.35(s,1H),3.25(s,1H),3.15(s,1H),3.07(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d6)δ156.50,151.51,146.82,137.13,131.39,130.11,129.62,127.39 ,120.55,119.38,115.30,112.27,60.70,56.83,54.76,43.49,37.44,30.35.MS(CI)calcd for C 18 H 20 ClNO3[M+H]+ 333.81.

[0210] Example 60: Synthesis of compound S60 ((R)-1,11-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0211] Following the synthetic method for S11, compound S60 was synthesized. 1 H NMR(300MHz,DMSO-d6)δ10.59(s,1H),9.48(s,1H),9.17(s,1H),7.32(s,1H),7.02(s,1H),6.95(s,1H),6.87(s,1H),6.00(s ,1H),4.04(s,1H),3.92(s,3H),3.79(s,3H),3.35(s,1H),3.25(s,1H),3.15(s,1H),3.07(s,1H),2.79(s,1H),2.75(s,1H). 13 C NMR(101MHz,DMSO-d6)δ156.50,151.51,146.82,137.13,131.39,130.11,129.62,127.39 ,120.55,119.38,115.30,112.27,60.70,56.83,54.76,43.49,37.44,30.35.MS(CI)calcd for C 18 H 20 ClNO3[M+H] + 333.81.

[0212] The synthetic routes for compounds S61-S66 are shown below:

[0213]

[0214] Example 61: Synthesis of compound S61 (1,11-dichloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0215] The mixture was synthesized using 2-bromo-5-chlorophenylacetic acid and 3-benzyloxy-4-chlorophenylethylamine 1-5 as raw materials, following the steps described above. 1HNMR(300MHz,DMSO-d6)δ7.46(dd,J=7.9,1.5Hz,1H),7.37(t,J=8.0Hz,1H),7.33(dq,J=8.2,1.1Hz,1H),6.76(s,1H), 6.56–6.52(m,1H),3.91(dt,J=6.2,5.0Hz,1H),3.45–3.36(m,1H),3.11–3.02(m,5H),2.93–2.85(m,1H).MS(CI)calcd for C 16 H 14 Cl3NO[M+H] + 342.64.

[0216] Example 62: Synthesis of compound S62 (1-methoxy-11-chloro-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0217] The sample was synthesized from 2-bromo-5-chlorophenylacetic acid and 3-benzyloxy-4-methoxyphenethylamine 1a according to the steps described above. ¹H NMR (300 MHz, DMSO-d6) δ 7.44 (d, J = 1.7 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 6.54 (t, J = 1.0 Hz, 1H), 3.83 (s, 3H), 3.10–3.04 (m, 3H). MS (CI) calcd for C 17 H 17 Cl2NO2[M+H] + :337.06.MS(CI)calcd for C 17 H 17 Cl2NO2[M+H]+: 338.23.

[0218] Example 63: Synthesis of compound S63 (1-methoxy-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0219] The mixture was synthesized using 2-bromo-5-propoxyphenylacetic acid and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1H NMR(300MHz,DMSO-d6)δ7.25–7.14(m,1H),6.86(dd,J=7.9,1.5Hz,1H),6.50 (t,J=1.0Hz,1H),4.02(t,J=5.4Hz,2H),3.86(dt,J=6.2,4.9Hz,1H),3.84(s, 2H),3.43–3.37(m,1H),3.13–3.02(m,4H),2.98(ddd,J=12.5,5.0,0.9Hz,1H ),2.93–2.86(m,1H),1.86–1.78(m,2H),1.08(t,J=7.8Hz,3H)..MS(CI)calcd for C 20 H 24 ClNO3[M+H] + 361.87.

[0220] Example 64: Synthesis of compound S64 (1,11-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0221] The mixture was synthesized using 2-bromo-5-methoxyphenylacetic acid and 3-benzyloxy-4-methoxyphenylethylamine 1a as raw materials, following the steps described above. 1 H NMR(300MHz, DMSO-d6)δ7.23–7.15(m,3H),6.88(dd,J=7.8,1.6Hz,1H),6.50(t,J=1.0H z,1H),3.92–3.82(m,6H),3.12–3.02(m,4H),2.99(dd,J=4.9,0.9Hz,1H)..MS(CI)calcd for C 18 H 20 ClNO3[M+H] + :333.81.

[0222] Example 65: Synthesis of compound S65 (1-chloro-11-methoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0223] The sample was synthesized from 2-bromo-5-methoxyphenylacetic acid and 3-benzyloxy-4-chlorophenylethylamine 1-5 according to the steps described above. ¹H NMR (300 MHz, DMSO-d6). δ 7.23 (t, J = 8.0 Hz, 1H), 7.22–7.16 (m, 1H), 6.89 (dd, J = 7.9, 1.5 Hz, 1H), 6.73 (s, 1H), 6.50 (t, J = 0.9 Hz, 1H), 3.90 (s, 3H), 3.93–3.87 (m, 1H), 3.44–3.36 (m, 1H), 3.10–3.02 (m, 4H), 2.98 (ddd, J = 12.5, 5.0, 0.9 Hz, 1H), 2.93–2.86 (m, 1H). MS (CI) calcd for C 17 H 17 Cl2NO2[M+H] + 333.06.

[0224] Example 66: Synthesis of compound S66 (1-chloro-11-propoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2-ol hydrochloride)

[0225] The mixture was synthesized using 2-bromo-5-propoxyphenylacetic acid and 3-benzyloxy-4-chlorophenylethylamine 1-5 as raw materials, following the steps described above. 1 H NMR (300MHz, DMSO-d6).δ7.24(t,J=8.1Hz,2H),7.21–7.16(m,2H),6.86(dd,J=8.0 ,1.4Hz,2H),6.73(s,2H),6.50(t,J=1.0Hz,2H),4.02(t,J=5.4Hz,4H),3.90(dt,J= 6.2,5.1Hz,2H),3.43–3.37(m,1H),3.10–3.02(m,8H),2.98(ddd,J=12.5,5.0,0.9 Hz,2H),2.93–2.87(m,1H),1.86–1.78(m,4H),1.08(t,J=7.8Hz,6H)..MS(CI)calcd forC 19 H 21 Cl2NO2[M+H] + 366.28.

[0226] Example 67: Determination of calcium ion current

[0227] Some compounds from the above examples and some compounds used as controls were selected as experimental subjects to test their activity against 5HT receptor calcium ion flux. Eight hours before the calcium flux assay, stably transfected 5-HT... 2A / 2B / 2CHEK 293T cells were seeded at a density of 15,000 cells / well in 384-well plates containing DMEM with 1% dialyzed FBS. After removing the medium, 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, 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 384-well plates were also added to the FLIPRTETRA. The FLIPRTETRA fluid module and plate reader were programmed to read baseline fluorescence for 10 seconds (1 read / second), followed by the addition of 10 μL of drug / well and reading 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 seconds after drug addition, exceeding the baseline fluorescence induced by the carrier or drug, was determined.

[0228] Table 1: Results of calcium ion flux assay for some compounds on the 5HT2 receptor

[0229]

[0230]

[0231] NA indicates no activity, and "-" indicates that no activity assay was performed.

[0232] As can be seen from Table 1:

[0233] 1. Compared with currently reported apofex-like 5-HT 2C Compared to receptor agonists, the vast majority of compounds are more active than 1857[EC]. 50 (E max )=308nM(86.1%),ACS Cent Sci,2020,6,213-25] and 18b[EC 50 (E max =103 nM (95.9%), ACS Chem Neurosci, 2020, 11, 549-59; ZL201910594756.6] at least 2-6 times stronger, such as compound S11; representative compound S11 with its 5-HT 2C The receptor selectivity is significantly better than that of 11b[5-HT]. 2C EC 50 (E max) = 51 nM (93.6%); 5-HT 2B EC 50 (E max )=794.3nM (25.4%); 5-HT 2A EC 50 (E max )=317.7nM(55.2%)] and 11f[5-HT2C:EC 50 (E max ) = 23.6 nM (101.8%); 5-HT 2B EC 50 (E max ) = 278.4 nM (63.5%); 5-HT 2A EC 50 (E max )=596.4nM(44.9%)](Bioorganic Chemistry 123(2022)105795;ZL201910594756.6), and almost no 5-HT 2B Receptor agonist activity; other similar trisubstituted compounds S50-S64 exhibit the same properties. Therefore, the compounds of this invention have better safety.

[0234] 2. This invention is the first to report a class of materials that also possess 5-HT 2A and 5-HT 2C A dual agonist of the receptor, and its effect on 5-HT 2B The receptor is almost inactive. For example, compounds S35-S42 possess 5-HT... 2C Receptor agonist activity and 5-HT 2A Receptor equivalent, EC 50 It even reached a maximum of 4.85 nM, and contained almost no 5-HT. 2B Receptor activity.

[0235] 3. Regardless of the substituents R1 and R2, R3 at the 11-position is generally more active than R3 at the 8-, 9-, or 10-positions, such as compounds S4, S11, S27-29, and S35-S42.

[0236] 4. When R2 is H, regardless of whether R1 is a small H group or a large OMe group, and regardless of the type or position of the substituent in R3, the compound almost loses its activity, such as compounds S1-S3, S5-S9, and S19-S21. However, when R2 is OH, regardless of whether R1 is a small H group or a large OMe group, and regardless of the type of substituent in R3, the compound exhibits activity towards 5-HT. 2C The receptors all exhibit good agonistic activity, such as compounds S11-S12, S24, S26-S29, and S35-S42.

[0237] Example 68: In vivo anti-schizophrenia activity test

[0238] Further selection of products with better 5-HT 2C The receptor-active compounds S36 and S62 were tested for activity in a classic phencyclidine (PCP)-induced in vivo antipsychotic model. As shown in Figure 1, both compounds S36 and S62 significantly improved PCP-induced spontaneous movement, suggesting that compounds S36 and S62 have potential effects against positive symptoms of schizophrenia.

[0239] 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. An apofphene derivative, characterized in that, The general structural formula of the apoffei derivative is shown below: Where R2 is a hydroxyl group; when R1 is OMe, R3 is Cl or OMe; when R1 is hydrogen, R3 is R3'O, and R3' is selected from...

2. A method for preparing the apofphene derivative according to claim 1, characterized in that, Includes the following steps: (1) Compound and Dehydration condensation yields amide compounds The Under the action of dehydrating agent and reducing agent, PG protecting group is introduced to obtain (2) The result obtained in step (1) The catalyst and ligand undergo coupling cyclization to obtain; (3) The result obtained in step (2) The deprotection reaction was carried out to obtain the [deprotection reaction].

3. The preparation method according to claim 2, characterized in that, In step (1), the reducing agent is selected from one or more of NaBH4, LiAlH4, BH3·THF, KBH4 and SnCl2.

4. The preparation method according to claim 2, characterized in that, In step (1), the PG protecting group is selected from one or more of trifluoroacetyl, p-toluenesulfonyl and tert-butoxycarbonyl.

5. The preparation method according to claim 2, characterized in that, In step (2), the catalyst is selected from one or more of tetratriphenylphosphine palladium, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, palladium acetate, and tridibenzylacetone palladium.

6. The preparation method according to claim 2, characterized in that, In step (2), the ligand is selected from one or more of 2-diphenylphosphine-2'-(N,N-dimethylamino)biphenyl, tricyclohexylphosphine tetrafluoroborate, di-tert-butylmethylphosphine tetrafluoroborate or di-tert-butylmethylphosphine tetrafluoroborate and triphenylphosphine.

7. A pharmaceutical composition, characterized in that, Includes the apofifine derivative as described in claim 1.

8. The use of the apofex derivative of claim 1 and the pharmaceutical composition of claim 7 in the preparation of serotonin 2A receptor agonists and serotonin 2C receptor agonists, and the use of the serotonin 2A receptor agonists and serotonin 2C receptor agonists in the preparation of medicaments for the prevention and / or treatment of obesity, urinary incontinence, depression, anxiety, obsessive-compulsive disorder, epilepsy, schizophrenia, pain, diabetes, and drug addiction.

9. The application according to claim 8, characterized in that, The use of the 5-hydroxytryptamine 2A receptor agonist and 5-hydroxytryptamine 2C receptor agonist in the preparation of drugs for the prevention and / or treatment of depression, anxiety, obsessive-compulsive disorder and drug addiction.

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