Tricyclic fused compound, and pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a tricyclic fused compound, and a pharmaceutical composition thereof and the use thereof. Moreover, specifically disclosed is a tricyclic fused compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention can reduce drug hallucinogenic effects while maintaining a good antidepressant effect.

Description

Tricyclic compounds, their pharmaceutical compositions and applications

[0001] This application claims priority to Chinese Patent Application No. 2024107016343, filed on May 31, 2024, and Chinese Patent Application No. 2025106834734, filed on May 26, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to tricyclic compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0003] Serotonin is a monoamine neurotransmitter that performs various biological functions, including mood, cognition, reward, learning, and memory, through different receptor subtypes (Young SN. J Psychiatry Neurosci. 2007 Nov; 32(6):394-9). The 5-HT2A receptor belongs to a family of serotonin receptors, currently composed of more than 15 different receptors encoded by different genes, divided into 7 major categories: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 (Roth BL, Lopez E, The Neuroscientist. 2000; 6(4):252-262).

[0004] The 5-HT2A receptor is one of the receptors for serotonin. Downstream signaling primarily occurs through two pathways: one is Gq / 11-coupled, which activates phospholipase C, leading to increased formation of inositol triphosphate and diacylglycerol, triggering their downstream signaling events. The other pathway involves β-blocker proteins, which act as a signal transduction scaffold, activating downstream signaling pathways such as ERK (McCorvy JD, Roth BL. Pharmacol Ther. 2015 Jun; 150:129-42). Non-classical pathways also include atypical signaling pathways associated with the 5-HT2A receptor, such as the Src / Akt pathway coupled with phospholipase A2 and β-blocker proteins (Maroteaux L, Ayme-Dietrich E, Aubertin-Kirch G, et al. Pharmacol Ther. 2017 Feb; 170:14-36).

[0005] Stimulation of 5-HT2A receptors leads to neuronal excitation in various brain regions. Among all 14 serotonin receptor subtypes, 5-HT2A receptors are widely distributed in the central nervous system and have the highest concentration among monoaminergic receptors in the cerebral cortex. They are distributed in structural regions involved in emotion regulation, such as the median / dorsolateral raphe nucleus, locus coeruleus, and ventral tegmental area. A, P, Matosiuk D, et al. Int J Mol Sci. 2021 Dec 21; 23(1):10). Consistent with their location in the brain, they are not only associated with various central physiological functions, including memory, sleep, nociception, eating, and reward behavior, but also with many neuropsychiatric disorders, such as schizophrenia, depression, and anxiety (Guiard BP, Di Giovanni G. Front Pharmacol. 2015 Mar 17; 6:46). Many new antipsychotic drugs (such as aripiprazole, biriperazole, and pimovancrine) have a high affinity for HT2A receptors, which may be the reason why they have better efficacy and lower side effects (McCreary AC, Newman-Tancredi A. Curr Pharm Des. 2015; 21(26):3725-31). Experiments using mice with 5-HT2A receptor knockout confirmed that cortical 5HT2A plays a role in anxiety regulation, and that cortical serotonin signaling can significantly affect behavior in conflict anxiety tests (Weisstaub NV, Zhou M, Lira A, et al. Science. 2006 Jul 28; 313(5786):536-40).

[0006] Depression is one of the chronic mental disorders affecting humans today. Esketamine, approved by the FDA in 2019, is the first fast-acting antidepressant on the market. It can be used in combination with oral antidepressants to treat treatment-resistant depression. However, as an analogue of ketamine, esketamine carries a certain risk of addiction and should be used under the supervision of healthcare professionals. Meanwhile, hallucinogens such as ergotamine and psilocybin, which target 5-HT2A, have been widely used by psychotherapists since the 1960s as adjunctive therapy for depression, anxiety-related disorders, and addiction. These hallucinogens, as agonists or partial agonists of the 5-HT2A receptor (Lopez-Gimenez, JFand J. Gonzalez-Maeso. Curr Top Behav Neurosci. 2018, 36:45-73), can provide rapid antidepressant effects, but their hallucinogenic effects limit their use. Currently available medications for treating depression with 5-HT2A still suffer from problems such as slow onset of action, limited efficacy, significant individual variability, and substantial side effects. Summary of the Invention

[0007] The technical problem this invention aims to solve is to overcome the shortcomings of existing antidepressants, such as slow onset of action or hallucinogenic side effects. To this end, this invention provides a tricyclic compound, its pharmaceutical composition, and its applications. The compound of this invention maintains good antidepressant effects while reducing the hallucinogenic effects of drugs.

[0008] The present invention overcomes the above-mentioned technical problems through the following technical solution.

[0009] This invention provides a tricyclic compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0010] A carbon atom marked with an asterisk (*) indicates that when it is a chiral carbon atom, it has an S configuration, an R configuration, or a mixture thereof.

[0011] A carbon atom marked with a "#" indicates that, when it is a chiral carbon atom, it has an S configuration, an R configuration, or a mixture thereof;

[0012] X 1 For N or CR 1 ;

[0013] X 2 For N or CR 2 ;

[0014] X 3 For N or CR 3 ;

[0015] X 4 For N or CR 4 ;

[0016] X 5 For NR 5 C=O or CR 5-2 R 5-3 ;

[0017] R 1 R 2 R 3 and R 4 Independently, H, halogen, CN, OH, NR a R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -C(O)R 1-1 or -NR a C(O)R 1-2 ;

[0018] R 1-1 OR a or NR a R b ;

[0019] R 1-2 It is a C1-C6 alkyl or C3-C6 cycloalkyl;

[0020] R 5 H, C1-C6 alkyl, C3-C6 cycloalkyl, or -C(O)R 5-1 ;

[0021] R 5-1 It is a C1-C6 alkyl or C3-C6 cycloalkyl;

[0022] R 5-2 and R 5-3 It is independently H or C1-C6 alkyl;

[0023] It can be a single bond or a double bond;

[0024] when When it is a double bond, X 6 For C, R 10 It does not exist;

[0025] when When it is a single bond, X 6 For N or CR 6 And R 6 and R 10 Independently H or C1-C6 alkyl; or, R 6 and R 10 Together with the carbon atoms they are connected to, they form bridging portions;

[0026] n1 is either 0 or 1;

[0027] n2 is 1 or 2;

[0028] R 7 R 8 and R 9 Independently, it is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl;

[0029] Or, R 8 and R 9 Together with the carbon atoms they are connected to, they form bridging portions;

[0030] L is -(CR) L1 R L2 )m1-, wherein -(CR L1 R L2 )m1- or 2-(CR L1 R L2 -Some optional parts are replaced by -Y-;

[0031] m1 can be 1, 2, 3, 4 or 5;

[0032] R L1 and R L2 Independently, it is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0033] Each Y is independently -O-, -S-, -NR a -, -C(O)-, -C≡C-, -C(O)-NR a -、-CR L3 =CR L4 -、

[0034] R L3 and R L4 Independently H or halogen;

[0035] Ring A is

[0036] Ring A 1 Independently phenyl or "a 5-6 membered monocyclic heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms";

[0037] Ring A 2 Independently defined as "a 5-6 membered monocyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms";

[0038] n3 can be 0, 1, 2, 3 or 4;

[0039] R 11 Independent of halogen, CN, OH, NR a R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl;

[0040] R a and R b It can be independently H, C1-C6 alkyl or C3-C6 cycloalkyl.

[0041] In certain preferred embodiments of the present invention, certain groups in the tricyclic compound of Formula I or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in one embodiment of the present invention"), X 1 For CR 1 .

[0042] In one aspect of the present invention, X 2 For CR 2 .

[0043] In one aspect of the present invention, X 3 For CR 3 .

[0044] In one aspect of the present invention, X 4 For CR 4 .

[0045] In one aspect of the present invention, X 5 and X 6 Meet any of the following conditions:

[0046] (i)X 5 For NR 5 , For a single key, X 6 For CR 6 ;

[0047] (ii)X 5 For NR 5 , It is a double bond, X 6 The answer is C;

[0048] (iii)X 5 For C=O or CR 5-2 R 5-3 X 6 Let N be the number of elements in the array.

[0049] In one aspect of the present invention, R 5-2 and R 5-3 H is independent.

[0050] In one aspect of the present invention, R 1 R 2 R 3 and R 4 Independently H, halogen, CN, NR a R b C1-C6 alkyl, C1-C6 alkoxy, -C(O)R 1-1 or -NR a C(O)R 1-2 .

[0051] In one aspect of the present invention, R 1 R 2 R 3 and R 4 Independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or -C(O)-NR a R b.

[0052] In one aspect of the present invention, It is a single key.

[0053] In one embodiment of the present invention, n1 and n2 satisfy the following conditions: (i) n1 is 0 or 1, and n2 is 1; or (ii) n1 is 0 and n2 is 2; preferably, n1 is 1 and n2 is 1.

[0054] In one aspect of the present invention, R 7 R 8 and R 9 Independently H, halogen, or C1-C6 alkoxy; for example, R 7 R 8 and R 9 H stands for H independently.

[0055] In one embodiment of the present invention, m1 is 2, 3 or 4.

[0056] In one aspect of the present invention, R L1 and R L2 Independently H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; for example, R L1 and R L2 H stands for H independently.

[0057] In one embodiment of the present invention, each Y is independently -O-, -C(O)-, or

[0058] In one aspect of the present invention, ring A 1 It can be phenyl or pyridyl independently.

[0059] In one aspect of the present invention, ring A 2 Independently defined as "a 5-6 membered monocyclic heterocyclic alkyl group selected from one or two of N and O, with one or two heteroatoms", such as tetrahydrofuranyl or pyrrolidinyl.

[0060] In one embodiment of the present invention, ring A is... For example, ring A is a benzotetrahydrofuran ring.

[0061] In one embodiment of the present invention, n3 is 0.

[0062] In one embodiment of the present invention, each halogen is independently F, Cl, Br or I.

[0063] In one embodiment of the invention, each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example methyl, ethyl, or isopropyl, for example methyl.

[0064] In one embodiment of the present invention, each C1-C6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy.

[0065] In one embodiment of the present invention, each C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclopropyl.

[0066] In one aspect of the present invention, for

[0067] In one aspect of the present invention, R 5 H, methyl, ethyl, isopropyl, cyclopropyl, For example, R 5 It is H or methyl; for example, R 5 For H.

[0068] In one aspect of the present invention, when When it is a single bond, X 6 For N or CR 6 And R 6 and R 10 H stands for H independently.

[0069] In one aspect of the present invention, R 1 For H.

[0070] In one aspect of the present invention, R 2 For H, methoxy, F, Cl, CN, NH2, Or ethyl.

[0071] In one aspect of the present invention, R 3 It can be H, F, or Cl.

[0072] In one aspect of the present invention, R 4 For H, F, Cl, Br, I, methyl, methoxy or -COOH.

[0073] In one aspect of the present invention, for

[0074] In one embodiment of the present invention, L is... For example, L is

[0075] In one aspect of the present invention, for For example,

[0076] In one aspect of the present invention, the tricyclic compound as shown in Formula I is a compound as shown in Formula I-1, I-2, I-3 or I-4:

[0077] in,

[0078] X 7 For N or CR 12 ;

[0079] X 8 For N or CR 13 ;

[0080] X 9 For N or CR 14 ;

[0081] R 12 R 13 and R 14 Independently H, halogen, CN, NR a R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl;

[0082] n4 is 0, 1, or 2;

[0083] *、#、X 1 X 2 X 3 X 4 R 5 R 6 R 7 R 8 R 9 R 10 L, ring A 2 and R 11 The definition is as described in any one of the present invention.

[0084] In one aspect of the present invention, X 8 For CR 13 .

[0085] In one aspect of the present invention, X 9 For CR 14 .

[0086] In one aspect of the present invention, R 12 R 13 and R14 H stands for H independently.

[0087] In one embodiment of the present invention, n4 is 0.

[0088] The present invention also provides any of the following tricyclic compounds or pharmaceutically acceptable salts thereof:

[0089] The present invention also provides any of the following tricyclic compounds or pharmaceutically acceptable salts thereof:

[0090] The compound that elutes first under the following conditions: column: Daicel ChiralPak IH (40mm ID×250mm, 10μm); mobile phase: n-Hexane / Ethanol [0.1% NH3H2O] = 65 / 35; flow rate: 80mL / min. Preferably, under the conditions described, the retention time of the compound that elutes first is 3.138min.

[0091] Compounds that elute later under the following conditions: Column: Daicel ChiralPak IH (40mm ID×250mm, 10μm); Mobile phase: n-Hexane / Ethanol [0.1% NH3H2O] = 65 / 35; Flow rate: 80mL / min. Preferably, under the conditions described, the retention time of the compound that elutes later is 5.182min.

[0092] The compound that elutes first under the following conditions: chromatographic column: Daicel ChiralCel OD (40mm ID×250mm, 10μm); mobile phase: CO2 / MeOH [0.1% NH3H2O ​​(V / V)] = 75 / 25; flow rate: 120mL / min. Preferably, under the conditions described, the retention time of the compound that elutes first is 3.473min.

[0093] Compounds that elute later under the following conditions: Column: Daicel ChiralCel OD (40mm ID×250mm, 10μm); Mobile phase: CO2 / MeOH[0.1% NH3H2O ​​(V / V)]=75 / 25; Flow rate: 120mL / min. Preferably, under the conditions described, the retention time of the compounds that elute earlier is 4.175min.

[0094] The above retention time test conditions are not a limitation on the compound. As long as the above test conditions are used to determine the retention time, and the obtained retention time is the same as or within the error range described above, and the compound is a stereoisomer of the compound limited by the retention time described above, then it falls within the protection scope of this invention.

[0095] The present invention also provides a pharmaceutical composition comprising:

[0096] (1) Tricyclic compounds as described in any one of the present invention, or pharmaceutically acceptable salts thereof, and

[0097] (2) Pharmaceutically acceptable excipients.

[0098] This invention also provides the use of tricyclic compounds as described in any one of these inventions, pharmaceutically acceptable salts thereof, or pharmaceutical compositions as described above, wherein the use is selected from:

[0099] (1) Preparation of 5-HT 2A Receptor agonists;

[0100] (2) Preparation of treatment and / or prevention with 5-HT 2A Drugs for receptor-related diseases;

[0101] (3) Prepare drugs for the treatment and / or prevention of depression.

[0102] The present invention also provides a treatment and / or prevention of 5-HT 2A A method for treating receptor-related diseases, comprising: administering a therapeutically effective amount of a tricyclic compound of Formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above to a patient in need.

[0103] The present invention also provides a method for treating and / or preventing depression, comprising: administering to a patient in need a therapeutically effective amount of a tricyclic compound as described in any one of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

[0104] In one aspect of the present invention, the 5-HT 2A Depression is a receptor-related disorder.

[0105] Terminology Explanation

[0106] Unless otherwise specified, the terms used in this invention have the following meanings:

[0107] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0108] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0109] The "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site; the "-" at the end of a structural segment This refers to the structural segment being connected to the rest of the molecule through this site, for example, It refers to cyclohexyl.

[0110] When the linking groups listed in this invention do not specify their linking direction, the linking direction is the same as the reading order from left to right. Examples are given below. The linking group L is At this time Connect them in the same direction as the reading order from left to right. and does not constitute

[0111] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0112] The term "alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0113] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, where the definition of halogen is the same as that of the term "halogen," and the definition of alkyl is the same as that of the term "alkyl." Halogenated alkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, etc.

[0114] The term "one or more" refers to one, two, or three.

[0115] The term "alkoxy group" refers to the group -OR X R XThe definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0116] The term "haloalkoxy" refers to the group -OR X ', R X The definition of ' is the same as the term "haloalkyl". Haloalkoxy groups include, but are not limited to: -O-CF3, -O-CHF2, -O-CH2CF3, etc.

[0117] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6), which is a monocyclic group. Cycloalkyl groups include, but are not limited to: wait.

[0118] The term "halogenated cycloalkyl" refers to a cycloalkyl group substituted with one or more halogens, wherein the definition of halogen is the same as that of the term "halogen," and the definition of alkyl group is the same as that of the term "cycloalkyl." Halogenated cycloalkyl groups include, but are not limited to: wait.

[0119] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 Aryl groups are unsaturated cyclic hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two). When polycyclic, adjacent monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl and naphthyl groups.

[0120] The term "therapeutic effective dose" refers to the amount given to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the type of compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0121] The term "pharmaceuticalally acceptable excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0122] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0123] The term "prevention" refers to reducing the risk of developing a disease.

[0124] The term "patient" refers to any animal, typically a mammal such as a human, that requires treatment or prevention of disease. Mammals include, but are not limited to: cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0125] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0126] The reagents and raw materials used in this invention are all commercially available.

[0127] The positive and progressive effects of this invention are as follows:

[0128] The positive and progressive effects of this invention are as follows: the compound of this invention has a good affinity for the 5-HT2A receptor, and while maintaining a good antidepressant effect, it can reduce depression and hallucinogenic effects. Its concentration in plasma changes very little, showing good plasma stability. It also has a good plasma protein binding rate, low drug interaction in vivo, moderate permeability, and low risk of efflux of transporter substrates. Attached Figure Description

[0129] Figure 1: Effects of the test substances on head twitching responses in C57BL / 6J mice (Mean ± SEM, n = 10). ***P < 0.001 compared to the negative control group; DOI (positive compound). Detailed Implementation

[0130] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0131] Preparation Examples

[0132] Intermediate A: 3-(2,3-dihydrobenzofuran-7-yl)propionaldehyde

[0133] Step 1: At room temperature, 2,3-dihydrobenzofuran-7-carboxaldehyde (1.0 g, 6.7 mmol) and methyl (triphenylphosphino)acetate (3.36 g, 10.05 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was concentrated under vacuum to obtain a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-10%) to obtain A-1 (1.18 g, yield: 76.1%) as a white solid. MS m / z (ESI): 205.1 [M+H] +

[0134] Step 2: At room temperature, A-1 (1.18 g, 5.8 mmol) was dissolved in methanol (10 mL), and then 10% wet palladium on carbon (310 mg, 0.29 mmol) was added. The reaction solution was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, washed with methanol, and the filtrates were combined and concentrated under vacuum to obtain A-2 (1.15 g, yield: 96.6%) as a colorless, viscous oil. The crude product was not purified and was used directly in the next step of the reaction. MS m / z (ESI): 207.1 [M+H] +

[0135] Step 3: At room temperature, A-2 (500 mg, 2.4 mmol) was dissolved in tetrahydrofuran (8 mL), cooled to 0°C under a nitrogen atmosphere, and then 8 mL of a 1 M lithium aluminum hydride tetrahydrofuran solution was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was stirred at 0°C, and ethyl acetate (20 mL) was slowly added for dilution. Sodium sulfate decahydrate was added, filtered through diatomaceous earth, washed with methanol, and concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-15%) to obtain A-3 (340 mg, yield: 78.7%) as a colorless oily liquid. MS m / z (ESI): 179.1 [M+H] +

[0136] Step 4: At room temperature, A-3 (3g, 16.9mmol) was dissolved in dichloromethane (100mL) under a nitrogen atmosphere, and then DMP (21.4g, 50.6mmol) was added. The mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was washed with saturated sodium bicarbonate aqueous solution. The organic phase was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-20%) to obtain A (2.5g, yield: 84.2%) as a colorless oily liquid.

[0137] Intermediate B: 3-(3-chloropyridin-2-yl)propionaldehyde

[0138] Step 1: (2-Formylpyridin-3-yl) tert-butyl carbamate (750 mg, 3.37 mmol) was dissolved in tetrahydrofuran (20 mL), and ethoxyformylmethylenetriphenylphosphine (1.4 g, 4.04 mmol) was added. The mixture was stirred at 70 °C for 2 h. The reaction solution was concentrated and purified by normal-phase column chromatography (petroleum ether: ethyl acetate = 3:1) to give compound B-1 (pale yellow oil, 940 mg, yield 96%). MS m / z (ESI): 293.6 [M+H] +

[0139] Step 2: Compound B-1 (940 mg, 3.22 mmol) was dissolved in ethyl acetate (15 mL), and then 10% wetted palladium on carbon (35 mg, 0.32 mmol) was added. The mixture was stirred at 28 °C for 15 min under hydrogen atmosphere. The reaction solution was filtered and concentrated to obtain compound B-2 (pale yellow oil, 830 mg, yield 88%). MS m / z (ESI): 295.7 [M+H] +

[0140] Step 3: Compound B-2 (830 mg, 2.82 mmol) was dissolved in tetrahydrofuran (15 mL). Under nitrogen protection and at 0°C, LiAlH4 (4.23 mL, 1 M in THF, 4.23 mmol) was added. After reacting at room temperature for 30 min, sodium sulfate decahydrate was added to the reaction solution until no more bubbles were produced with stirring. The mixture was then filtered, and the filtrate was concentrated and purified by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain compound B-3 (colorless oil, 460 mg, yield 65%). MS m / z (ESI): 253.6 [M+H] +

[0141] Step 4: Compound B-3 (460 mg, 1.82 mmol) was dissolved in hydrochloric acid / dioxane (10 mL). After reacting at room temperature for 30 min, the reaction solution was reversed to prepare the solution (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). Acetonitrile was removed under reduced pressure, and the solution was lyophilized to obtain compound B-4 (white solid, 240 mg, yield 88%). MS m / z (ESI): 153.2 [M+H] +

[0142] Step 5: Compound B-4 (240 mg, 1.58 mmol), copper chloride (45 mg, 0.32 mmol), cuprous chloride (311 mg, 3.15 mmol), and tert-butyl nitrite (325 mg, 3.15 mmol) were dissolved in acetonitrile (15 mL). The mixture was reacted at 25 °C for 0.5 h under nitrogen protection, followed by a further reaction at 50 °C for 2 h. The reaction solution was filtered and purified by normal-phase column chromatography (dichloromethane:methanol = 10:1) to obtain compound B-5 (yellow oil, 50 mg, yield 19%). MS m / z (ESI): 172.1 [M+H] +

[0143] Step 6: Compound B-5 (50 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), and PCC (440 mg, 2.04 mmol) was added. The mixture was reacted at room temperature for 0.5 h. The reaction solution was then filtered, and the filtrate was washed with saturated sodium bicarbonate aqueous solution (10 mL * 2). The organic phase was concentrated to give the title compound B (brown solid, 45 mg crude product, yield 92%). MS m / z (ESI): 170.1 [M + H] +

[0144] Intermediate C: 2-(2,3-dihydrobenzofuran-7-yl)acetaldehyde

[0145] Step 1: Add 7-bromo-2,3-dihydrobenzofuran (5.0 g, 25.1 mmol), potassium vinyl fluoroborate (6.7 g, 50.2 mmol), Pd(dppf)Cl2.CH2Cl2 (0.8 g, 1.25 mmol), and potassium carbonate (7.0 g, 50.2 mmol) to a 100 mL single-necked flask, followed by the addition of dioxane / water (45 mL, V1 / V2 = 8:1). After the addition is complete, slowly heat to 110 °C under a nitrogen atmosphere and stir overnight. After the reaction was confirmed to be complete by TLC, the reaction solution was cooled to room temperature, filtered under reduced pressure, water (30 mL) was added to the filtrate, and the solution was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-2%) to obtain a pale yellow oily substance C-1 (3.20 g, yield: 87%).

[0146] Step 2: Compound C-1 (1.0 g, 6.8 mmol) and anhydrous THF (10 mL) were added together to a 100 mL three-necked flask. Borane dimethyl sulfide solution (2 M, 6 mL) was slowly added dropwise under N2 and an ice-water bath. After the addition was complete, the mixture was stirred at room temperature for 3 h. Subsequently, 10% NaOH aqueous solution (7 mL) and 30% H2O2 solution (1 mL) were slowly added dropwise under an ice-water bath. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-30%) to obtain a pale yellow oily substance C-2 (0.6 g, yield: 54%). 1H NMR (500MHz, CDCl3) δ7.09 (dd, J=7.3, 0.9Hz, 1H), 6.97 (d, J=7.5Hz, 1H), 6.80 (t, J=7.4Hz, 1H ), 4.56 (t, J = 8.7Hz, 2H), 3.86 (t, J = 6.3Hz, 2H), 3.22 (t, J = 8.7Hz, 2H), 2.86 (t, J = 6.3Hz, 2H).

[0147] Step 3: At room temperature, C-2 (600 mg, 3.7 mmol) and anhydrous DCM (10 mL) were added together to a 50 mL single-necked flask, followed by the addition of Dysmartin reagent (2.3 g, 5.5 mmol) in portions. After the addition was complete, the mixture was stirred at room temperature for 1 hour. After the reaction was confirmed to be complete by TLC, the reaction solution was filtered. The filtrate was slowly adjusted to alkaline pH by adding saturated NaHCO3 solution dropwise. The mixture was extracted with DCM (20 mL x 2), and the organic phases were combined and washed with saturated brine (30 mL x 1). The mixture was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-10%) to obtain a colorless oily substance C (0.4 g, yield: 67%).

[0148] Intermediate D: tert-butyl-7-(3-carbonylpropyl)dihydroindole-1-carboxylic acid ester

[0149] Step 1: Refer to Step 1 of intermediate A. MS m / z (ESI): 216.3 [M+H] +

[0150] Step 2: Refer to step 2 in section A. MS m / z(ESI): 218.3 [M+H] +

[0151] Step 3: Add D-2 (3.8 g, 17.5 mmol), TEA (3.5 g, 35 mmol), and DMAP (214 mg, 1.75 mmol) to 50 ml of DCM, then add Boc2O (4.6 g, 21.0 mmol). React at room temperature for 16 hours. The reaction was stopped by LC-MS. The solution was concentrated and passed through a column (PE / EA = 10 / 1) to obtain D-3 (5 g, colorless oil, yield: 91%). MS m / z (ESI): 318.2 [M+H] +

[0152] Step 4: Refer to step 2 in intermediate F. MS m / z (ESI): 320.2 [M+H] + .

[0153] Step 5: Refer to step 3 in section A. MS m / z (ESI): 278.3 [M+H]+ .

[0154] Step 6: Refer to step 4 in section A. MS m / z (ESI): 276.3 [M+H] + .

[0155] Intermediate E: 6-chloro-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0156] Step 1: Dissolve 10 g (50.7 mmol) of (2-chloro-4-fluorophenyl)hydrazine hydrochloride in 150.0 mL of isopropanol, add 8.9 g (66 mmol) of 4-oxopiperidone hydrochloride and 10.0 mL of concentrated hydrochloric acid, and stir at 100 °C for 12 h under nitrogen protection. The reaction was confirmed by LC-MS. After filtration and concentration, compound E-1 (yellow solid, 11 g, yield 96.7%) was obtained. MS m / z (ESI): 224.9, 226.9 [M+H] + .

[0157] Step 2: Compound E-1 (5 g, 22.3 mmol) was dissolved in trifluoroacetic acid (100.0 mL), and NaBH3CN (14 g, 223 mmol) was added. The mixture was stirred at 20 °C for 3 h under nitrogen protection. The reaction was monitored by LC-MS until complete, and methanol (20.0 mL) was added. The mixture was concentrated under reduced pressure, and the crude product was dissolved in an aqueous sodium hydroxide solution, extracted with ethyl acetate, dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give E (yellow solid, 3.5 g, yield 69.3%). MS m / z (ESI): 227.1, 229.1 [M+H] +

[0158] Intermediate F: 3-(2,3-dihydrofurano[2,3-c]pyridin-7-yl)propionaldehyde

[0159] Step 1: 7-chlorofurano[2,3-c]pyridine (300 mg, 1.96 mmol), ethyl(E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)acrylate (660 mg, 2.92 mmol), Pd(dppf)Cl2.CH2Cl2 complex (30 mg, 0.04 mmol), and potassium carbonate (540 mg, 3.92 mmol) were added together into a 25 mL single-necked reaction flask. Then, dioxane (4 mL) and water (1 mL) were added separately. After the addition was complete, the mixture was purged with nitrogen three times, and the temperature was slowly raised to 100 °C and stirred for 16 h. After the reaction was completed as detected by LCMS, the reaction solution was filtered, and then water (30 mL) was added. The solution was extracted with ethyl acetate (3 x 20 mL), the organic phases were combined, washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by normal-phase column chromatography (eluting gradient: 10% EA / PE) to give compound F-1 (white solid, 180 mg, yield 42%). MS m / z (ESI): 218.4 [M+H] + .

[0160] Step 2: Compound F-1 (50 mg, 0.23 mmol) was added to a 25 mL single-necked reaction flask, followed by the addition of methanol (10 mL) and 10% Pd / C (wet basis, 10 mg). After the additions were complete, the mixture was purged with hydrogen three times, and the reaction was stirred at room temperature for 16 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound F-2 (crude product, 50 mg, yield 99%). The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 222.5 [M+H] +

[0161] Step 3: Compound F-2 (50 mg, 0.23 mmol) was added to a 25 mL three-necked flask, followed by anhydrous tetrahydrofuran (3 mL). Lithium aluminum hydride (25 mg, 0.69 mmol) was added in portions under nitrogen and an ice-water bath. The mixture was stirred for 0.5 h under an ice-water bath. After the reaction was complete as detected by LCMS, Na₂SO₄·10H₂O was slowly added to quench the reaction mixture. The mixture was filtered, and the filter cake was washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by normal-phase column chromatography (eluent gradient: 30% EA / PE) to obtain the title compound F-3 (pale yellow oil, 25 mg, yield 62%). MS m / z (ESI): 180.5 [M+H] +

[0162] Step 4: Compound F-3 (25 mg, 0.14 mmol) and anhydrous dichloromethane (3 mL) were added together to a 10 mL single-necked reaction flask, followed by the addition of PCC (60 mg, 0.28 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 h. After the reaction was completed as determined by LCMS, dichloromethane (10 mL) was added to the reaction solution, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 x 10 mL), and the organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude compound F (reddish-brown oil, 30 mg). The crude product was not further purified and was used directly in the next reaction step.

[0163] Example 1: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide

[0164] Step 1: The preparation method of 1-1 is the same as the synthesis method in the first step of Example 9.

[0165] Step 2: Compound 1-1 (1.5 g, 6.86 mmol) and 4-oxopiperidone hydrochloride (0.93 g, 6.86 mmol) were added together to a 100 mL single-necked flask, followed by the addition of dioxane (15 mL) and concentrated hydrochloric acid (1 mL). After the addition was complete, the mixture was slowly heated to reflux under nitrogen protection and stirred overnight. The reaction was confirmed by LC-MS. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dioxane. The crude compound 1-2 (brown solid, 1.2 g, yield 71%) was evaporated to dryness under reduced pressure. The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 247.5 [M+H] + .

[0166] Step 3: The preparation method for steps 1-3 is the same as the synthesis method in step 3 of Example 9. MS m / z (ESI): 407.7 [M+H] + .

[0167] Step 4: Compounds 1-3 (20 mg, 0.05 mmol), methylamine hydrochloride (4 mg, 0.06 mmol), and anhydrous DMF (2 mL) were added together to a 10 mL single-necked flask. Then, HATU (40 mg, 0.1 mmol) and DIEA (30 mg, 0.25 mmol) were added separately. After the addition was complete, the mixture was stirred at room temperature for 2 h. The reaction was detected by LCMS. The reaction solution was filtered, and the filtrate was directly purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E1 (white solid, 12 mg, yield 60%). 1 H NMR (500MHz, CDCl3) δ9.69(s,1H),7.04(dd,J=12.8,4.7Hz,2H),6.97(d,J=7.5Hz,1H),6.87(d,J=2.1Hz,1H),6.78(t,J=7.4Hz,1H),6.27(d,J=4.3Hz,1 H),4.55(t,J=8.7Hz,2H),3.86(s,3H),3.71(s,2H),3.21(t,J=8.7Hz,2H), 3.04(d,J=4.9Hz,3H),2.90(s,4H),2.73-2.62(m,4H),2.01-1.94(m,2H).MS m / z(ESI):420.5[M+H] + .

[0168] Example 2: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide

[0169] Step 1: The preparation method for step 2-1 is the same as the second step of the synthesis of intermediate E. MS m / z (ESI): 249.6 [M+H] + .

[0170] Step 2: The preparation method for step 2-2 is the same as the synthesis method in step 3 of Example 9. MS m / z (ESI): 409.7 [M+H] + .

[0171] Step 3: The preparation method of E2 is the same as the fourth synthesis method in Example 1. 1H NMR (500MHz, CDCl3) δ7.04(d,J=7.3Hz,1H),6.92(d,J=7.4Hz,1H),6.89(d, J=2.1Hz,1H),6.76(t,J=7.4Hz,1H),6.68(d,J=2.4Hz,1H),5.94-5.42(m,3H ),4.54(t,J=8.7Hz,2H),3.92-3.86(m,1H),3.76(s,3H),3.20(t,J=8.7Hz,3 H),2.80-2.39(m,7H),2.32-2.25(m,1H),2.11-1.97(m,1H),1.87(s,3H).MS m / z (ESI): 408.5 [M+H] + .

[0172] Example 4: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide

[0173] Example 4-1: (4aS,9bR)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide or (4aR,9bS)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6- Formamide or (4aR,9bS)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide or (4aS,9bR)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide

[0174] Example 4-2: (4aR,9bS)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide or (4aS,9bR)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6- Formamide or (4aS,9bR)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide or (4aR,9bS)-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-N,N-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxamide

[0175] Step 1: The preparation method of E4 is the same as the fourth synthesis method in Example 1. 1 H NMR (500MHz, CDCl3) δ7.04(d,J=6.5Hz,1H),6.92(d,J=7.5Hz,1H),6.76(dd,J=10.2 ,4.7Hz,2H),6.59(d,J=2.4Hz,1H),4.54(t,J=8.7Hz,3H),3.86(s,1H),3.73(s,3H), 3.19(dd,J=19.4,10.7Hz,3H),3.08(s,6H),2.84-2.66(m,1H),2.58(t,J=7.6Hz,3H) ,2.51-2.30(m,3H),2.25(t,J=10.0Hz,1H),2.10-1.94(m,1H),1.92-1.77(m,3H).MS m / z(ESI):436.7[M+H] + .

[0176] Step 2: (400 mg, 0.919 mmol) was separated by SFC (column: Daicel ChiralPak IH, 40 mm ID × 250 mm, 10 μm; mobile phase: n-Hexane / Ethanol [0.1% NH3H2O] = 65 / 35; flow rate: 80 mL / min) to obtain white solid E4-1 (PK1: 165.60 mg, purity 93%, yield 41%, ee 100%, RT = 3.138 min, OROT = +63.4) and white solid E4-2 (PK2: 146.88 mg, purity 92%, yield 36%, ee 100%, RT = 5.182 min, OROT = -60.6).

[0177] E4-1: 1 H NMR (400MHz, DMSO-d6) δ7.06(d,J=6.8Hz,1H),6.93(d,J=7.2Hz,1H),6.84(s,1H),6.74(t,J=7.2Hz,1H),6.53(s,1H),5.22(s,1H),4.50(t ,J=8.8Hz,2H),3.79-3.68(m,1H),3.65(s,3H),3.21-3.04(m,3H),3.10(s,6H),2.55-2.52(m,1H),2.48-2.07(m,7H),2.02-1.54(m,4H).MS m / z(ESI):436.4[M+H] + .

[0178] E4-2: 1 H NMR (400MHz, DMSO-d6) δ7.04 (dd, J=6.8Hz, 1.0Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 6.81 (d, J= 2.4Hz,1H),6.73(d,J=7.6Hz,1H),6.48(d,J=2.4Hz,1H),5.12(d,J=1.6Hz,1H),4.49(t,J =8.8Hz,2H),3.69-3.65(m,1H),3.64(s,3H),3.15(t,J=8.8Hz,2H),3.07-2.98(m,1H),2. 93(s,6H),2.63-2.53(m,1H),2.50-2.40(m,2H),2.39-2.08(m,5H),1.83-1.60(m,4H).MS m / z(ESI):436.4[M+H] + .

[0179] Example 9: 6-Chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0180] Step 1: Dissolve 2-chloro-4-methoxyaniline hydrochloride (2.0 g, 12.7 mmol) in concentrated hydrochloric acid (20.0 mL) and water (20.0 mL), cool to 0 °C, add NaNO2 (1.6 g, 24 mmol), stir for 2 h, then add SnCl2 (10.6 g, 56 mmol) at 0 °C, and continue stirring for 14 h. After the reaction is complete as detected by LCMS, add water (30.0 mL), filter to obtain filter cake compound 9-1 (white solid, 2.00 g, yield 94.3%). MS m / z (ESI): 173.5 [M+H] + .

[0181] Step 2: The preparation method for 9-2 is the same as the synthesis method in step one of intermediate E. MS m / z (ESI): 237.1 [M+H] + .

[0182] Step 3: Compound 9-2 (50 mg, 0.211 mmol) was dissolved in DCM / MeOH (1:1, 10 mL), intermediate A (37 mg, 0.211 mmol) and Na(OAc)3BH (210 mg, 1 mmol) were added, and the mixture was reacted at 20 °C for 20 min. The reaction was monitored by TLC until complete. The mixture was quenched with water, extracted with DCM, dried over sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain 9-3 (yellow gel, 40 mg, yield 47.5%). MS m / z (ESI): 397.5 [M+H] + .

[0183] Step 4: Compound 9-3 (40 mg, 0.1 mmol) was dissolved in trifluoroacetic acid (3 mL), and NaBH3CN (32 mg, 0.5 mmol) was added. The mixture was stirred at 20 °C for 1 h under nitrogen protection. The reaction was checked by LCMS until complete. The solution was dried, extracted with DCM, dried, concentrated, and purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E9 (white solid, 18 mg, yield 45%). MS m / z (ESI): 399.5 [M+H] + .

[0184] Example 18: 6-Chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0185] Example 19: (4aR,9bS)-6-chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole or (4aS,9bR)-6-chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0186] Example 20: (4aS,9bR)-6-chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole or (4aR,9bS)-6-chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0187] Step 1: Compound E (300 mg, 1.23 mmol) was dissolved in DCM / MeOH (1:1, 100 mL), and compound A (217 mg, 1.23 mmol) and Na(OAc)3BH (2.6 g, 12.3 mmol) were added. The mixture was reacted at 20 °C for 20 min. The reaction was detected by TLC and quenched with water. The mixture was extracted with DCM, dried with sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (DCM:MeOH = 97:3) to obtain E18 (yellow gel, 300 mg, yield 58.5%).

[0188] E18: 1H NMR (400MHz, CDCl3) δ7.05 (dd, J=7.3, 1.0Hz, 1H), 6.92 (d, J=7.5Hz, 1H), 6.81 (dd, J=9.0,2.4Hz,1H),6.79-6.74(m,2H),4.55(t,J=8.7Hz,2H),3.90(dd,J=11.0,4.7 Hz,1H),3.81(s,1H),3.32(s,1H),3.20(t,J=8.7Hz,2H),2.71(s,1H),2.61-2.52( m,4H),2.45(s,2H),2.37(dd,J=11.8,8.8Hz,1H),1.85(dd,J=15.0,7.5Hz,3H).MS m / z(ESI): 387.2 [M+H] + .

[0189] Step 2: E18 (300 mg, 0.777 mmol) was separated by SFC (column: Daicel ChiralCel OD, 40 mm ID × 250 mm, 10 μm; mobile phase: CO2 / MeOH [0.1% NH3H2O ​​(V / V)] = 75 / 25; flow rate: 120 mL / min) to obtain white solid E19 (PK1: 126.1 mg, purity 95%, yield 42%, ee 98.40%, RT = 3.473 mins, optical rotation = -101.49°) and white solid E20 (PK2: 133.1 mg, purity 96%, yield 44%, ee 98.94%, RT = 4.175 mins, optical rotation = +94.03°).

[0190] E19: 1 H NMR (400MHz, DMSO-d6) δ7.12-6.97(m,3H),6.92(d,J=7.2Hz,1H),6.79-6.68(m,1H),5.64(s,1H),4.50( t,J=8.8Hz,2H),3.77(s,1H),3.32(s,3H),3.16(t,J=8.8Hz,2H),2.92-2.56(m,2H),2.38-1.42(m,8H). 19 F NMR(377MHz,DMSO-d6)δ-125.53(s,1F).MS m / z(ESI):387.2[M+H] + .

[0191] E20: 1H NMR (400MHz, DMSO-d6) δ7.20-6.99(m,3H),6.94(d,J=7.0Hz,1H),6.75(t,J=7.2Hz,1H),6.08-5.36(m, 1H), 4.50 (t, J = 8.8Hz, 2H), 4.00-3.67 (m, 1H), 3.64-3.36 (m, 2H), 3.25-2.81 (m, 5H), 2.46-1.47 (m, 8H). 19 F NMR(377MHz,DMSO-d6)δ-124.49(s,1F).MS m / z(ESI):387.2[M+H] + .

[0192] Example 27: 6-Chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)-2-fluoropropyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0193] Step 1: 7-Bromo-2,3-dihydrobenzofuran (2g, 10mmol), allyltributyltinane (3.5g, 11mmol), Pd(PPh3)4 (580mg, 0.5mmol) and CsF (3.04g, 20mmol) were added to a three-necked flask containing 20mL of 1,4-dioxane. The mixture was purged three times with N2, heated to 110℃, and reacted for 16h. The reaction was detected by TLC to indicate completion. The mixture was filtered, concentrated, and water and EA were added. The mixture was separated, dried with sodium sulfate, concentrated, and the crude product was purified by column chromatography (EtOAc / PE = 0.2%) to obtain 27-1 (1.3g, yield: 90%) as a colorless oily liquid. 1 H NMR (500MHz, CDCl3) δ7.07 (d, J = 7.5Hz 1H), 6.95 (d, J = 7.5Hz 1H), 6.80 (t, J = 7.5Hz, 1H), 6.04-5.96 (m, 1H), 5.10-5.05 (m, 2H), 4.56 (t, J = 8.5Hz, 2H), 3.35 (d, J = 7.0Hz, 2H), 3.22 (t, J = 8.5Hz, 2H).

[0194] Step 2: 27-1 (1.1 g, 6.88 mmol) was added to a single-necked flask containing 20 mL of DCM. m-CPBA (2.79 g, 13.75 mmol) was added in portions. The mixture was reacted at room temperature for 16 h. The reaction was detected by TLC and the mixture was filtered. Sat. NaHCO3 (aq) was added. The mixture was separated, dried with sodium sulfate, and concentrated. The crude product was purified by column chromatography (EtOAc / PE = 0-2%) to obtain 27-2 (600 mg, yield: 50%) as a colorless oily liquid.

[0195] Step 3: Intermediate E (230 mg, 0.88 mmol), 27-2 (300 mg, 1.70 mmol), K2CO3 (480 mg, 3.48 mmol), and DMF (5 mL) were added to the reaction flask. The mixture was purged with N2 three times, heated to 120 °C, and reacted for 16 h. The reaction was confirmed by LC-MS. Water and EA were added, and the mixture was separated. The aqueous phase was extracted twice with EA. The combined organic phases were washed three times with Sat. NaCl, dried, filtered, and concentrated. The crude product was purified by column chromatography (MeOH / DCM = 0.2%) to obtain 27-3 (165 mg, yield: 46.6%) as a colorless oily liquid. MS m / z (ESI): 403.3, 405.3 [M+H] + .

[0196] Step 4: Add BAST (54 mg, 0.24 mmol) to a three-necked flask containing 5 mL of DCM, replace with N2 three times, cool to -78 °C, add 27-3 (50 mg, 0.12 mmol), allow to rise naturally to room temperature, and react for 16 h. LC MS showed that 50% of the product was formed. Quench the reaction with sat.NaHCO3 (aq), extract with DCM, dry, concentrate, and purify the crude product using Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E27 (white solid, 7 mg, yield 14%). 1 H NMR (500MHz, CDCl3) δ7.10-7.04(m,1H),7.01-6.91(m,1H),6.82-6.74(m,3H),5.04-4.93(m,1H),4.57-4.5 3(m,2H),3.88-3.73(m,2H),3.28-3.19(m,3H),3.00-2.84(m,3H),2.74-2.38(m,5H),1.99-1.68(m,2H).MS m / z(ESI):405.3,407.5[M+H] + .

[0197] Example 28: 6-Chloro-2-(4-(2,3-dihydrobenzofuran-7-yl)butyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0198] Step 1: 7-Bromobenzofuran (600 mg, 3 mmol) and 3-butyn-1-ol (420 mg, 6 mmol) were dissolved in DMF (5 mL). Et3N (5 mL), CuI (114 mg, 0.6 mmol), and Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) were added sequentially with stirring. The reaction mixture was stirred at 90 °C for 16 hours under nitrogen protection until the reaction was complete. The reaction solution was poured into ice water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate (30 mL x 2), filtered, and concentrated. Column chromatography (ethyl acetate / petroleum ether: 0%–50%) yielded compound 28-1 (white solid, 520 mg, 92% yield). MS m / z (ESI): 189.2 [M+H] + .

[0199] Step 2: Compound 28-1 (360 mg, 2 mmol) was dissolved in MeOH (10 mL), and wet Pd(OH)₂ / C (50 mg, 20%) was added under nitrogen protection with stirring. The mixture was purged three times with hydrogen. The reaction was carried out under hydrogen protection at 25 °C with stirring for 16 hours until the reaction was complete. The reaction system was filtered and concentrated to obtain product 28-2 (colorless oil, 190 mg, yield: 50%). MS m / z (ESI): 193.3 [M+H] + .

[0200] Step 3: The preparation method of 28-3 is the same as the synthesis method in step 6 of intermediate B.

[0201] Step 4: The preparation method of E28 is the same as the synthesis method in the first step of Example 29. 1H NMR(500MHz,CD3OD)δ7.01(d,J=10.0Hz,1H),6.90-6.84(m,3H),6.72(t,J=7 .5Hz,1H),4.48(t,J=10.0Hz,2H),3.89-3.85(m,1H),3.29-3.27(m,1H),3.15 (t,J=10.0Hz,2H),2.95-2.91(m,1H),2.82-2.78(m,1H),2.69-2.65(m,1H),2 .59-2.56(m,4H),2.33-2.29(m,1H),2.05-1.93(m,2H),1.63-1.58(m,4H).MS m / z (ESI): 401.5 [M+H] +

[0202] Example 29: 6-Chloro-2-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0203] Step 1: Compound E (20 mg, 0.088 mmol) was dissolved in DCM / MeOH (1:1, 3 mL), and compound C (14 mg, 0.088 mmol) and Na(OAc)3BH (93 mg, 0.44 mmol) were added. The mixture was reacted at 20 °C for 20 min. The reaction was detected by TLC and quenched with water. The mixture was extracted with DCM, dried with sodium sulfate, concentrated, and purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E29 (white solid, 8 mg, yield 41.5%). 1 H NMR (500MHz, CDCl3) δ7.04 (dt, J=21.6, 10.8Hz, 1H), 6.93 (t, J=9.3Hz, 1H), 6.8 1(dd,J=9.0,2.3Hz,1H),6.77(t,J=7.4Hz,2H),4.65-4.35(m,2H),3.91(d,J=4. 1Hz,1H),3.80(s,1H),3.37-3.19(m,2H),3.20(t,J=8.7Hz,2H),2.79(s,3H),2. 63(s,3H),2.40(dd,J=11.6,9.0Hz,1H),2.00(s,1H),1.84(d,J=10.3Hz,1H).MS m / z (ESI): 373.5 [M+H] +

[0204] Example 31: 6-Chloro-2-((2-(2,3-dihydrobenzofuran-7-yl)cyclopropyl)methyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0205] Step 1: Compound C-1 (1.6 g, 12.5 mmol), ethyl diazonate (2.2 g, 18.75 mmol), and N-methylimidazole (3 g, 18.75 mmol) were dissolved in toluene (20 mL). Then, compound meso-tetraphenylporphyrin cobalt (84 mg, 0.125 mmol) was added, and the reaction was carried out at 80 °C under nitrogen protection for 48 h. The reaction was detected by TLC upon completion. The mixture was quenched with water, extracted with DCM, dried over sodium sulfate, concentrated, and the crude product was purified by column chromatography (EtOAc / PE = 0-15%) to obtain 31-1 (1 g, yield: 39.3%) as a colorless oily liquid. MS m / z (ESI): 233.1 [M+H] +

[0206] Step 2: The preparation method for 31-2 is the same as the synthesis method in step 3 of intermediate A. MS m / z (ESI): 173.0 [M+H-18] + .

[0207] Step 3: The preparation method for 31-3 is the same as the synthesis method in step four of intermediate A. MS m / z (ESI): 189.0 [M+H] + .

[0208] Step 4: The preparation method of E31 is the same as the synthesis method in step one of E29. 1 H NMR(500MHz, CDCl3)δ7.01(d,J=7.2Hz,1H),6.84-6.74(m,2H),6.73-6.63(m,2H),4.58-4.44(m,2H),3.90(s,1H),3.80(s,1H),3.37-3.09(m,3H) ,2.52(dd,J=138.4,73.7Hz,5H),1.94(d,J=69.2Hz,1H),1.90-1.67(m,2H),1.28(dd,J=32.9,17.4Hz,2H),1.02(s,1H),0.77(d,J=4.5Hz,1H).MS m / z(ESI):399.5[M+H] +

[0209] Example 33: 6-Chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-9b-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0210] Step 1: (2-Chloro-4-fluorophenyl)hydrazine hydrochloride (300 mg, 1.5 mmol) and 3-methylpiperidin-4-one hydrochloride (225 mg, 1.5 mmol) were added together to a 25 mL single-necked flask, followed by glacial acetic acid (5 mL). After the addition was complete, the mixture was slowly heated to 50 °C and stirred for 16 h. The reaction was confirmed by LC-MS. The reaction solution was cooled to room temperature, and water (30 mL) was added. Extraction was performed using EA (20 mL x 3). The organic phases were combined, and the pH was adjusted to alkaline with saturated NaHCO3 solution. The mixture was dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by column chromatography (MeOH / DCM = 0.3%) to obtain a brown solid 33-1 (70 mg, yield: 20%). MS m / z (ESI): 239.1 [M+H] + .

[0211] Step 2: Compound 33-1 (40 mg, 0.17 mmol), intermediate A (32 mg, 0.18 mmol), and DCM / MeOH (5 mL, V1 / V2 = 4:1) were added to a 25 mL single-necked flask, followed by the addition of NaCNBH3 (180 mg, 0.85 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 h. The reaction was confirmed by LCMS. The pH of the system was adjusted to alkaline with saturated NaHCO3 solution. The mixture was extracted with DCM (20 mL x 2), and the organic phases were combined. The mixture was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography (MeOH / DCM = 0.3%) to obtain a brown solid E33 (28 mg, yield: 42%). 1 H NMR (500MHz, CD3OD) δ7.07-6.99(m,2H),6.86(dd,J=9.2,2.2Hz,2H),6.72(t,J=7.4Hz,1H),4.48(t,J=8.7Hz,2H),3.16( t,J=8.7Hz,2H),2.95-2.90(m,2H),2.80-2.73(m,2H),2.60-2.53(m,4H),2.40(s,3H),2.17(s,3H),1.89-1.80(m,2H).MS m / z(ESI):401.3[M+H] + .

[0212] Example 39: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-6-carboxylic acid

[0213] Step 1: Compound 2-hydrazinobenzoate (3.0 g, 15.9 mmol) and 4-oxopiperidone hydrochloride (2.4 g, 15.9 mmol) were added together to a 100 mL single-necked flask, followed by the addition of glacial acetic acid (15 mL) and concentrated hydrochloric acid (3 mL). After the addition was complete, the mixture was slowly heated to 120 °C under nitrogen protection and stirred for 0.5 h, then cooled to 80 °C and stirred overnight. The reaction was confirmed by LC-MS. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with glacial acetic acid and acetonitrile, respectively. The filter cake was then evaporated under reduced pressure to obtain crude compound 39-1 (brown solid, 3.0 g, yield 87%). The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 217.1 [M+H] + .

[0214] Step 2: The preparation method for 39-2 is the same as the synthesis method in step two of intermediate E. MS m / z (ESI): 219.4 [M+H] + .

[0215] Step 3: The preparation method of E39 is the same as the first step of the synthesis method in Example 29. 1 H NMR(500MHz,CD3OD)δ7.62(dd,J=7.9,1.1Hz,1H),7.17(d,J=7.0Hz,1H),7.05(dd,J=7.3, 1.0Hz,1H),6.91(d,J=7.5Hz,1H),6.74(t,J=7.4Hz,1H),6.68-6.62(m,1H),4.51(t,J=8.7 Hz,2H),3.95-3.87(m,1H),3.30-3.25(m,1H),3.22-3.15(m,3H),3.14-3.04(m,1H),3.03- 2.93(m,1H),2.8-2.77(m,2H),2.61-2.51(m,3H),2.15-2.05(m,2H),2.01-1.91(m,2H).MS m / z(ESI):379.7[M+H] + .

[0216] Example 40: 6-Bromo-2-(3-(2,3-dihydrobenzofuran-7-yl)-2-fluoropropyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0217] Step 1: 40-1 Reference intermediate E, Step 1 synthesis method. MS m / z (ESI): 251.3, 253.3 [M+H] + .

[0218] Step 2: 40-2 Reference intermediate E, Step 2 synthesis method. MS m / z (ESI): 253.5, 255.6 [M+H] + .

[0219] Step 3: 40-3 Refer to Step 3 of E27 for synthesis method. MS m / z (ESI): 429.3, 431.3 [M+H] + .

[0220] Step 4: E40 follows the same synthesis method as Step 4 of E27. 1 H NMR (500MHz, CDCl3) δ7.18(d,J=7.5Hz,1H),7.08(d,J=7.0Hz,1H),7.01(t,J=7 .0Hz,1H),6.96(d,J=7.5Hz,1H),6.77(t,J=7.5Hz,1H),6.61-6.58(m,1H),5.0 2-4.91(m,1H),4.54(t,J=8.5Hz,2H),3.91-3.86(m,2H),3.32-3.30(m,1H),3. 20(t,J=8.5Hz,2H),3.02-2.32(m,8H),2.00-1.97(m,1H),1.86-1.79(m,1H).MS m / z (ESI): 431.5, 433.5 [M+H] + .

[0221] Example 44: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0222] Step 1: Compound E51 (50 mg, 0.12 mmol) and methanol (10 mL) were added together to a 50 mL single-necked flask, followed by Pd / C (wet, 10%, 50 mg). After the addition was complete, the mixture was stirred at room temperature for 2 h under H2 atmosphere. The reaction was detected by LCMS to indicate completion. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was then directly purified and separated by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E44 (white solid, 35 mg, yield 70%). 1H NMR(500MHz, CDCl3)δ7.80(s,1H),7.17(dd,J=8.7,4.3Hz,1H),7.08-7.00(m,2H),6.97(d,J=7.5Hz,1H),6.85(td,J=9.1,2.4Hz,1H),6.7 8(t,J=7.4Hz,1H),4.56(t,J=8.7Hz,2H),3.70(s,2H),3.21(t,J=8.7Hz,2H),2.97-2.82(m,4H),2.73-2.60(m,4H),2.03-1.93(m,2H).MS m / z(ESI):351.7[M+H] + .

[0223] Example 46: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxynitrile

[0224] Step 1: 4-Hydroxybenzonitrile hydrochloric acid (2 g, 11.8 mmol) was dissolved in ethanol (60.0 mL). The reaction mixture was allowed to react at room temperature for 1 h. LC-MS showed the formation of phenylhydrazone. The reaction mixture was dried, and acetic acid (80.0 mL) was added, followed by boron trifluoride diethyl ether solution (3.0 mL). The mixture was stirred at 100 °C for 17 h under nitrogen protection. The reaction mixture was dried, extracted with DCM, dried over sodium sulfate, and concentrated to obtain the crude product (yellow solid, 2 g, yield: 85.7%). MS m / z (ESI): 198.2 [M+H] + .

[0225] Step 2: The preparation method of E46 is the same as the synthesis method in step one of E29. 1 H NMR (500MHz, CDCl3) δ7.95 (s, 1H), 7.52-7.42 (m, 3H), 7.39 (dd, J = 7.4, 2.6Hz, 2H), 4.44 (s, 1H), 4.02-3.85 (m, 3H), 3. 70-3.56(m,1H),3.56-3.46(m,2H),3.37(dd,J=17.4,9.6Hz,3H),3.23(s,2H),2.89(t,J=8.0Hz,2H),2.36(s,2H).MS m / z(ESI):358.2[M+H] + .

[0226] Example 50: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-amine

[0227] Example 57: N-(2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)acetamide

[0228] Step 1: Compound (4-nitrophenyl)hydrazine hydrochloride (3.0 g, 15.9 mmol) and 4-oxopiperidone hydrochloride (2.4 g, 15.9 mmol) were added together with glacial acetic acid (40 mL) into a 100 mL single-necked flask, followed by the addition of NaOAc (1.3 g, 15.9 mmol). After the addition was complete, the mixture was slowly heated to 80 °C under nitrogen protection and stirred for 1.5 h. After the reaction was complete as determined by TLC, the reaction solution was cooled to room temperature, and then concentrated H₂SO₄ (4 mL) was slowly added dropwise. After the addition was complete, the mixture was heated to 90 °C and stirred overnight. The reaction was then confirmed to be complete by LCMS. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate and acetonitrile, respectively. The filter cake was then evaporated under reduced pressure to obtain crude compound 57-1 (brown solid, 3.0 g, yield 87%). The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 218.2 [M+H] + .

[0229] Step 2: The preparation method of 57-2 is the same as the third step of the synthesis method in Example 9. MS m / z (ESI): 378.5 [M+H] + .

[0230] Step 3: The preparation method of E50 is the same as the synthesis method in Example 44. 1 H NMR (500MHz, CD3OD) δ7.19(d,J=8.6Hz,1H),7.09(d,J=6.7Hz,1H),6.98(d,J=7.5Hz,1H),6.91(d,J=1.8Hz,1H),6.82-6.74(m,2H),4.62-4.5 0(m,3H),4.42(s,2H),3.66(s,2H),3.35-3.31(m,1H),3.19(t,J=8.7Hz,2H),3.29-3.12(m,2H),2.72(t,J=7.3Hz,2H),2.21-2.14(m,2H).MS m / z(ESI):348.6[M+H] + .

[0231] Step 4: The preparation method of E57 is the same as the fourth synthesis method in Example 1. 1H NMR (500MHz, CDCl3) δ7.57(s,1H),7.20(d,J=8.6Hz,1H),7.11-7.04(m,2H),6.97(d,J=7.5Hz,1H),6.79(t,J=7.4Hz,1H),4.56(t,J=8.7Hz,2H),3 .76-3.70(m,2H),3.40(s,1H),3.22(t,J=8.7Hz,2H),2.94-2.84(m,4H), 2.75-2.65(m,2H),2.64-2.61(m,2H),2.16(s,3H),2.02-1.96(m,2H).MS m / z(ESI):390.5[M+H] + .

[0232] Example 56: 6-Bromo-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c:4,5-c']dipyridine

[0233] Step 1: 2-Bromo-3-hydrazinopyridine (1.00 g, 5.31 mmol) was dissolved in ethanol (20.0 mL), and ethyl 4-carbonylhexahydropyridine-1-carboxylic acid ester (0.91 g, 5.31 mmol) and concentrated sulfuric acid (1.0 mL, 18.7 mmol) were added. The reaction was carried out at 110 °C for 18 h, and after filtration and concentration, compound 56-1 was given (yellow solid, 512 mg, yield 26%). MS m / z (ESI): 324.2, 326.2 [M+H] + .

[0234] Step 2: Compound 56-1 (300 mg, 0.92 mmol) was dissolved in ethanol (4.0 mL), potassium hydroxide (155 mg, 2.77 mmol) and water (2.0 mL) were added, and the mixture was stirred at 100 °C for 36 h. The reaction was stopped by TLC. After filtration and concentration, compound 56-2 was purified by normal phase to obtain a yellow solid (150 mg, yield 64%). MS m / z (ESI): 251.8, 253.8 [M+H] + .

[0235] Step 3: At room temperature, compound 56-2 (50.0 mg, 0.19 mmol), 3-(2,3-dihydrobenzofuran-7-yl)propionaldehyde (38.0 mg, 0.21 mmol), and acetic acid (0.05 mL, 0.93 mmol) were dissolved in THF (3.0 mL), and sodium cyanoborohydride (24.7 mg, 0.39 mmol) was added. The reaction was carried out at 0 °C for 2 h under nitrogen protection. After TLC detection to confirm the completion of the reaction, the mixture was filtered and purified (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to give compound E56 (white solid, 11.1 mg, yield 13%). 1 H NMR (400MHz, CDCl3) δ7.97 (d, J = 5.6Hz, 1H), 7.23-7.09 (m, 1H), 7.06-6.97 (m, 2H), 6.82-6.78 (m, 1H), 4.58 (t, J=8.4Hz,2H),3.78-3.73(m,2H),3.22(t,J=4.0Hz,2H),3.03(s,4H),2.77-2.67(m,4H),2.05-1.98(m,2H).MS m / z(ESI):412.2,414.2[M+H] + .

[0236] Example 62: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-5-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0237] Step 1: The preparation method of 62-1 is the same as the first step of the synthesis method for E64. MS m / z (ESI): 317.3 [M+H] + .

[0238] Step 2: The preparation method for 62-2 is the same as the synthesis method in step two of E78. MS m / z (ESI): 219.4 [M+H] + .

[0239] Step 3: The preparation method of E62 is the same as the synthesis method of the first step of E29. 1H NMR (500MHz, CDCl3) δ7.03(d,J=8.5Hz,1H),6.93(d,J=7.5Hz,1H),6.76(t,J=7.5H z,1H),6.71(d,J=2.5Hz,1H),6.67(dd,J=2.5,8.5Hz,1H),6.50(d,J=8.5Hz,1H),4. 53(t,J=8.5Hz,2H),3.74(s,3H),3.21-3.12(m,4H),2.82(s,1H),2.69-2.64(m,4H) ,2.57(t,J=8.0Hz,2H),2.42-2.32(m,2H),2.26-2.20(m,1H),2.01-1.80(m,5H).MS m / z(ESI):379.5[M+H] +

[0240] Example 63: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5-ethyl-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0241] Example 65: 5-Cyclopropyl-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0242] 66-1 (30 mg, 0.082 mmol) was dissolved in DCM (3.0 mL) and DMF (1.0 mL), AcOH (5 mg, 0.083 mmol) was added, followed by 1-ethoxy-1-trimethylsiloxycyclopropane (40 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 h. After the reaction was completed as detected by LCMS, sodium bicarbonate aqueous solution (15.0 mL) was added, followed by extraction with ethyl acetate (30.0 mL). The organic phase was concentrated and filtered to prepare purified compounds (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to give compound E63 (white solid, 10.1 mg, yield 31%) and compound E65 (white solid, 5.5 mg, yield 15%).

[0243] E63: 1H NMR(500MHz,CD3OD)δ7.02(d,J=5.0Hz,1H),6.90(d,J=5.0Hz,1H),6.75-6.71( m,2H),6.66(dd,J=10.0,5.0Hz,1H),6.49(d,J=10.0Hz,1H),4.50(t,J=10.0Hz ,2H),3.70(s,3H),3.49-3.40(m,1H),3.29-3.21(m,1H),3.19-3.01(m,4H),2. 92-2.76(m,2H),2.58-2.42(m,5H),2.20-1.85(m,5H),1.06(t,J=7.5Hz,3H).MS m / z(ESI): 393.6 [M+H] + .

[0244] E65: 1 H NMR(500MHz,CD3OD)δ7.02(d,J=5.0Hz,1H),6.89(d,J=10.0Hz,1H),6.84(d,J=10.0Hz,1H ),6.75-6.71(m,2H),6.65(dd,J=10.0Hz,5.0Hz,1H),4.50(t,J=10.0Hz,2H),3.70(s,3H) ,3.44-3.41(m,1H),3.17(t,J=10.0Hz,2H),3.15-3.08(m,1H),2.79-2.76(m,1H),2.65-2 .50(m,3H),2.45-2.37(m,3H),2.27-2.20(m,2H),1.96-1.81(m,4H),0.76-0.53(m,4H).MS m / z(ESI):405.6[M+H] +

[0245] Example 64: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5-isopropyl-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0246] Step 1: 200 mg (0.66 mmol) of tert-butyl-8-methoxy-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid ester was dissolved in DMSO (5.0 mL), cooled to 0 °C, and KOH (185 mg, 3.3 mmol) was added. The mixture was stirred for 15 min, and 170 mg (1.0 mmol) of iodoisopropane was added at 0 °C. The mixture was stirred for another 1 h at room temperature. After the reaction was complete as detected by LCMS, water (15.0 mL) and ethyl acetate (30.0 mL) were added for extraction. The crude product was concentrated and purified by normal-phase chromatography to give compound 64-1 (white solid, 77 mg, yield 34%). MS m / z (ESI): 345.2 [M+H] + .

[0247] Step 2: The preparation method for 64-2 is the same as the synthesis method in step 2 of intermediate E. MS m / z (ESI): 247.1 [M+H] + .

[0248] Step 3: The preparation method of E64 is the same as the synthesis method in step 3 of Example 9. 1 H NMR(500MHz,CD3OD)δ7.02(d,J=7.5Hz,1H),6.89(d,J=7.5Hz,1H),6.74(t,J =7.5,2H),6.63-6.56(m,2H),4.50(t,J=10.0Hz,2H),3.74(s,3H),3.71-3.5 2(m,2H),3.19-3.11(m,3H),2.74-2.70(m,1H),2.61-2.40(m,6H),2.26-2.2 2(m,1H),2.03-1.81(m,4H),1.28(d,J=5.0Hz,3H),1.17(d,J=5.0Hz,3H).MS m / z (ESI): 407.5 [M+H] +

[0249] Example 66: 1-(2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indol-5-yl)ethane-1-one

[0250] Step 1: The preparation method of 66-1 is the same as the synthesis method in step 3 of E9. MS m / z (ESI): 365.3 [M+H] +

[0251] Step 2: Compound 66-1 (30 mg, 0.082 mmol) and triethylamine were dissolved in DCM (5.0 mL), cooled to 0 °C, and acetyl chloride (10 mg, 0.12 mmol) was added. The mixture was stirred at room temperature for 2 h. After the reaction was completed as detected by LCMS, the crude product was concentrated and purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E66 (off-white solid, 25 mg, yield 75%). 1 H NMR(500MHz,CD3OD)δ7.91(d,J=5.0Hz,1H),7.03(d,J=10.0Hz,1H),6.97(s, 1H),6.89(d,J=5.0Hz,1H),6.76-6.71(m,2H),4.52(t,J=10.0Hz,2H),4.51(s ,1H),3.77(s,3H),3.68-3.56(m,2H),3.18(t,J=10.0Hz,2H),2.79-2.49(m, 6H),2.25(s,3H),2.20-2.02(m,2H),1.87-1.84(m,2H),1.57-1.54(m,1H).MS m / z (ESI): 407.6 [M+H] +

[0252] Example 67: Cyclopropyl(2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-methoxy-1,2,3,4,4a,9b-hexahydro-5H-pyrido[4,3-b]indol-5-yl) methyl ketone

[0253] The synthesis of E67 is the second step of the synthesis method of E66. 1 H NMR(500MHz,CD3OD)δ7.89(s,1H),7.02(d,J=5.0Hz,1H),6.97(s,1H),6.89(d,J=5.0Hz,1H), 6.73(t,J=7.5Hz,2H),4.73(s,1H),4.52(t,J=10.0Hz,2H),3.77(s,3H),3.64(d,J=10.0Hz,1 H),3.53(s,1H),3.18(t,J=10.0Hz,2H),2.73(d,J=10.0Hz,1H),2.66-2.48(m,2H),2.47-2.3 3(m,3H),2.16-2.01(m,3H),1.86-1.80(m,2H),1.65-1.59(m,1H),1.00(s,2H)0.90(s,2H).MS m / z(ESI):433.6[M+H]+

[0254] Example 72: 2-(3-(dihydroindole-7-yl)propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0255] Example 73: 2-(3-(dihydroindole-7-yl)propyl)-8-methoxy-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0256] Step 1: 72-1 Reference intermediate E, Step 1 synthesis method. MS m / z(ESI): 203.3 [M+H] + .

[0257] Step 2: 72-2 Refer to Step 3 of E9 for the synthesis method. MS m / z (ESI): 462.4 [M+H] + .

[0258] Step 3: Add E72-2 (50 mg, 0.11 mmol) to 5 mL of DCM, then add 2 mL of TFA, and react at room temperature for 16 h. LC-MS was used to confirm the completeness of the reaction. The reaction solution was concentrated, redissolved in methanol, and purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E72 (yellow solid, 16 mg, yield 40%). E72: 1 H NMR (500MHz, CDCl3) δ7.90(s,1H),7.18(d,J=8.5Hz,1H),6.99(d,J=8.0Hz,1H),6.88(d,J=7.5Hz,1H),6.82(d,J=2.0Hz,1H),6.78(dd,J=2.5,8.5Hz,1 H),6.68(t,J=7.5Hz,1H),3.84(s,3H),3.72(s,2H),3.40(t,J=8.5Hz,2H), 2.98(t,J=8.5Hz,2H),2.92(s,4H),2.68-2.61(m,4H),2.03-1.97(m,2H).MS m / z(ESI):362.4[M+H] + .

[0259] Step 4: E73 follows the same synthesis method as step 2 in intermediate E. E73: 1H NMR (500MHz, CDCl3) δ6.99(d,J=7.5Hz,1H),6.83(d,J=7.5Hz,1H),6.73(m,1H),6.66(t,J=7.5Hz,1H),6.63(d,J=1.5Hz ,2H),3.91-3.88(m,1H),3.74(s,3H),3.53(t,J=8.5Hz,2H),3.27(s,1H),3.04(t,J=8.5Hz,2H),2.81-1.86(m,12H).MS m / z(ESI):364.2[M+H] + .

[0260] Example 74: 6-Bromo-8-fluoro-2-(3-(dihydroindole-7-yl)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0261] Step 1: The preparation method of 74-1 is the same as the first step of the synthesis method in Example 9.

[0262] Step 2: The preparation method of 74-2 is the same as the second step of the synthesis method in Example 9. MS m / z (ESI): 269.2, 271.2 [M+H] + .

[0263] Step 3: The preparation method of 74-3 is the same as the second step of the synthesis method in Example 78. MS m / z (ESI): 271.1, 273.1 [M+H] + .

[0264] Step 4: The preparation method of 74-4 is the same as the synthesis method in step 3 of Example 9. MS m / z (ESI): 530.2, 532.2 [M+H] + .

[0265] Step 5: The preparation method of E74 is the same as the third synthesis method in Example 73. 1H NMR (500MHz, CDCl3) δ6.97 (dd, J=19.0, 7.9Hz, 2H), 6.85 (d, J=7.5Hz, 1H), 6.79 (d, J=7 .7Hz,1H),6.67(t,J=7.4Hz,1H),3.94(s,1H),3.79(s,1H),3.53(t,J=8.3Hz,2H),3.36 -3.26(m,1H),3.05(t,J=8.4Hz,2H),2.70-2.64(m,1H),2.58-2.50(m,4H),2.44-2.38 (m,1H),2.34-2.26(m,2H),2.23-2.17(m,1H),2.03-1.93(m,2H),1.88–1.80(m,2H).MS m / z(ESI):430.2,432.2[M+H] + .

[0266] Example 75: 2-(3-(dihydroindole-7-yl)propyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxynitrile

[0267] Step 1: The preparation method of 75-1 follows the synthesis method in step 3 of E9. MS m / z (ESI): 457.3 [M+H] + .

[0268] Step 2: At room temperature, compound 75-1 (12 mg, 0.026 mmol) was dissolved in MeOH (2.0 mL), and HCl / Dioxane (0.3 mL, 1.2 mmol) was added. The reaction was carried out at 20 °C for 1 h. After LCMS detection, the reaction was purified by filtration (eluent (v / v): acetonitrile / (water + 0.05% HCl) = 30%-70%) to give compound E75 (brown solid, 11.1 mg, hydrochloride yield, 82.5%). 1H NMR (500MHz, CD3OD) δ7.95 (s, 1H), 7.49 (t, J = 9.0Hz, 2H), 7.46-7.42 (m, 1H), 7.42 -7.37(m,2H),4.84(d,J=14.8Hz,1H),4.43(d,J=14.1Hz,1H),3.93(dd,J=18.5,1 0.6Hz,3H),3.69-3.55(m,2H),3.48(dt,J=19.5,9.8Hz,2H),3.39(t,J=7.7Hz,2H ),3.22(d,J=14.6Hz,1H),2.89(t,J=7.9Hz,2H),2.35(dd,J=18.2,8.8Hz,2H).MS m / z (ESI): 357.5 [M+H] + .

[0269] Example 76: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-7-methoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole

[0270] Step 1: Dissolve 7-bromobenzofuran (200 mg, 1 mmol) in THF (30.0 mL), cool to -78 °C, add n-butyllithium (0.48 mL, 1.2 mmol), stir at -78 °C for 15 min, add 3-chloro-N-methoxy-N-methylpropionamide (0.48 mL, 1.2 mmol), heat to room temperature and stir for 3 hours. After the reaction is complete as detected by LCMS, quench with saturated ammonium chloride aqueous solution (30 mL, 1.2 mmol), extract with ethyl acetate (30 mL), concentrate, and purify the crude product by normal phase column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 76-1 (yellow oil, 40 mg, yield 19%).

[0271] Step 2: Compound 76-1 (40 mg, 0.19 mmol), compound 78-2 (50 mg, 0.21 mmol), and sodium iodide (15 mg, 0.1 mmol) were dissolved in DMSO (3.0 mL) and stirred overnight at room temperature. After the reaction was detected by LCMS, the crude product was filtered and purified by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E76 (off-white solid, 12 mg, yield 15%). 1H NMR (500MHz, CD3OD) δ7.70(d,J=10.0Hz,1H),7.47(d,J=5.0Hz,2H),7.36-7.21(m,1H),7.07(d,J=10.0Hz,1H),6.94(t,J=7.5Hz,1 H),4.76(t,J=10.0Hz,2H),4.47-4.34(m,1H),4.15-3.64(m,11H),3.27(t,J=10.0Hz,2H),2.70-2.47(m,2H),2.04-1.98(m,1H).MS m / z(ESI):379.5[M+H] +

[0272] Example 78: (4aS,9bR)-8-methoxy-2-(3-(2-methoxyphenyl)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0273] Step 1: The preparation method of 78-1 is the same as the synthesis method of intermediate E in step one. MS m / z (ESI): 203.3 [M-Boc+H] +

[0274] Step 2: Compound 78-1 (100 mg, 0.33 mmol), triethylsilane (190 mg, 1.65 mmol), and TFA (5 mL) were added together to a 25 mL single-necked reaction flask, and the mixture was stirred at room temperature for 16 h. After the reaction was completed by LCMS, the reaction solvent was removed under reduced pressure, and the crude product was directly separated by reverse-phase chromatography (C18 column, eluent gradient: acetonitrile / (water + 0.05% HCl)) to give compound 78-2 (pale yellow solid, 30 mg, yield 45%). MS m / z (ESI): 205.4 [M+H] + .

[0275] Step 3: Compound 78-2 (30 mg, 0.15 mmol) and 1-(3-bromopropyl)-2-methoxybenzene (37 mg, 0.16 mmol) were added to a 10 mL reaction flask, followed by the addition of anhydrous DMSO (2 mL) and DIPEA (57 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 16 h after the addition was complete. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly subjected to reverse-phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound E78 (pale yellow solid, 15 mg, yield 29%). 1H NMR (500MHz, CD3OD) δ7.15 (td, J=8.1, 1.7Hz, 1H), 7.10 (dd, J=7.4, 1.6Hz, 1H), 6.89 (d, J=8.1H z,1H),6.83(td,J=7.4,1.0Hz,1H),6.76(d,J=2.4Hz,1H),6.66-6.58(m,2H),3.80(s,3H),3.75 -3.68(m,4H),3.18-3.10(m,1H),2.71(dd,J=11.9,5.9Hz,1H),2.64-2.52(m,3H),2.44(td,J=1 1.0,3.3Hz,1H),2.41-2.34(m,2H),2.31-2.23(m,1H),1.96-1.88(m,1H),1.85-1.76(m,3H).MS m / z(ESI):353.6[M+H] +

[0276] Example 81: (4aS,9bR)-8-methoxy-2-(3-(2-methoxyphenyl)propyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0277] E81 was synthesized using the same method as E62. 1 H NMR (500MHz, CDCl3) δ7.04(d,J=8.5Hz,1H),6.93(d,J=7.5Hz,1H),6.76(t,J=7.5Hz,1H),6.70(d ,J=2.5Hz,1H),6.65(dd,J=2.5,8.5Hz,1H),6.45(d,J=8.5Hz,1H),4.54(t,J=8.5Hz,2H),3.75(s ,3H),3.22-3.15(m,3H),2.99-2.93(m,2H),2.69(s,3H),2.67-2.63(m,1H),2.60-2.55(m,2H),2 .47-2.39(m,2H),2.32-2.29(m,1H),2.14-2.09(m,1H),1.89-1.83(m,3H),1.70-1.63(m,1H).MS m / z(ESI):379.5[M+H] +

[0278] Example 82: 6-Chloro-2-(2-((2,3-dihydrobenzofuran-7-yl)oxo)ethyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0279] Step 1: 7-Methoxybenzofuran (1 g, 6.74 mmol) was added to DCM (10 mL), substituted with N2 three times, cooled to -78 °C, and then 1 M BBr3 was added to DCM (10.2 mL). The mixture was allowed to rise naturally to room temperature and reacted for 16 h. TLC showed the starting material had disappeared. The reaction solution was cooled to 0 °C, and the reaction was quenched with sat.NH4Cl (aq). The mixture was separated, dried, concentrated, and column-secreted (PE / EA = 10 / 1) to obtain 82-1 (colorless oil, 280 mg, yield: 31%). MS m / z (ESI): 133.0 [MH] - .

[0280] Step 2: Compound 82-1 (280 mg, 2.09 mmol), Pd / C (50 mg), Pd(OH)2 / C (50 mg), and MeOH (10 mL) were added to a 50 mL single-necked reaction flask. The mixture was purged with H2 three times, and then stirred at 60 °C for 16 h. After the reaction was complete as determined by LCMS, the mixture was filtered and concentrated to obtain compound 82-2 (brown liquid, 260 mg, yield 93%). MS m / z (ESI): 135.0 [MH] - .

[0281] Step 3: Compound 82-2 (200 mg, 1.47 mmol) and 1,2-dibromoethane (1.37 g, 7.35 mmol) were added to a 50 mL reaction flask, followed by water (10 mL), NaOH (176 mg, 4.41 mmol), and TBAB (142 mg, 0.44 mmol). After the addition was complete, the mixture was heated to 90 °C and stirred for 16 h. After the reaction was complete, the mixture was extracted three times with EA, the organic phases were combined, dried, concentrated, and column chromatography (PE / EA = 10 / 1) to obtain compound 82-3 (pale yellow liquid, 130 mg, yield 36%).

[0282] Step 4: Compound 82-3 (15 mg, 0.059 mmol) and E (18 mg, 0.07 mmol) were added to a 10 mL reaction flask, followed by the addition of DMF (2 mL), K2CO3 (17 mg, 0.118 mmol), and NaI (1 mg, 0.0059 mmol). The reaction was then carried out at 80 °C for 16 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly subjected to reverse-phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound E82 (white solid, 11 mg, yield 47%). 1 H NMR (500MHz, CDCl3)δ 1H NMR (500MHz, CDCl3) δ6.92-6.69(m,5H),4.61(t,J=9.0Hz,2H),4.19(t,J=6.0Hz,2H),3.90(dd,J=9.5 4.5Hz,1H),3.80(s,1H),3.31(dd,J=9.5 6.5Hz,1H),3.23(t,J=9.0Hz,2H),2.85(t,J=6.0Hz,3H),2.65-2.61(m,2H),2.49-2.45(m,1H),2.04-1.97(m,1H),1.86-1.81(m,1H).MS m / z(ESI):389.4,391.2[M+H] +

[0283] Example 83: 6-Chloro-2-(4-(2,3-dihydrobenzofuran-7-yl)butan-2-yl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0284] Step 1: Refer to Step 1 of intermediate B. MS m / z (ESI): 219.2 [M+H] +

[0285] Step 2: Refer to step 2 in section B. MS m / z(ESI): 221.2 [M+H] + .

[0286] Step 3: Dissolve 83-2 (320 mg, 1.45 mmol) in MeOH (2 mL) and saturated NaOH aqueous solution (2 mL), and react at room temperature for 12 h. LC MS showed that the starting material disappeared. After extraction with EA and water, the aqueous phase was adjusted to pH 3-4 with 1N HCl. After extraction with EA again, the organic phase was dried and then evaporated to dryness to obtain 83-3 (260 mg, white solid, yield 93%). MS m / z (ESI): 191.2 [MH] - .

[0287] Step 4: Dissolve 83-3 (260 mg, 1.35 mmol), N,O-dimethylhydroxylamine hydrochloride (158 mg, 1.62 mmol), and DIEA (525 mg, 4.05 mmol) in DMF (5 mL), then add HATU (770 mg, 2.02 mmol) and react at room temperature for 2 h. LC MS showed that the starting material disappeared. Extract the reaction solution with EA and water, wash the organic phase with saturated brine, dry the organic phase, and then evaporate it to dryness before column chromatography (PE / EA = 3 / 1) to obtain 83-4 (300 mg, yellow oil, yield 94%). MS m / z (ESI): 236.5 [M+H]+ .

[0288] Step 5: Dissolve 83-4 (250 mg, 1.06 mmol) in THF (3 mL). Under N2 protection, lower the reaction solution to -78 °C, then add 3 M CH3MgCl in THF (0.7 mL, 2.13 mmol) and allow the reaction system to heat naturally. React at room temperature for 2 h. LC-MS showed that the starting material disappeared. Quench the reaction solution with saturated ammonium chloride. After extraction with EA, dry the organic phase and evaporate it to dryness before column chromatography (PE / EA = 5 / 1) to obtain 83-5 (180 mg, yellow oil, yield 89%).

[0289] Step 6: Compound 83-5 (10 mg, 0.053 mmol) and E (13 mg, 0.053 mmol) were added to a 10 mL reaction flask, followed by the addition of DCM (3 mL). After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. Then, NaBH(OAc)3 (34 mg, 0.16 mmol) was added and the reaction was allowed to proceed at 50 °C for 12 h. After the reaction was completed, the reaction mixture was filtered, concentrated, and redissolved with MeOH. The filtrate was directly subjected to reverse-phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound E83 (white solid, 3 mg, yield 14%). 1 H NMR (500MHz, CDCl3)δ 1 H NMR (500MHz, CDCl3) δ7.04 (d, J = 7.0Hz, 1H), 6.94-6.89 (m, 1H), 6.84-6.70 (m, 3H), 4.57-4.50 (m, 2H), 3.89 (s, 1H),3.78(s,1H),3.28-3.18(m,3H),2.78-2.32(m,7H),1.85-1.77(m,2H),1.33-1.25(m,3H),1.00(s,3H).MS m / z(ESI):402.4[M+H] +

[0290] Example 84: 6-Chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)-2-methylpropyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0291] Step 1: The preparation method of 84-1 follows the same procedure as the first step of intermediate A. MS m / z (ESI): 233.2 [M+H] + .

[0292] Step 2: The preparation method of 84-2 is the same as the second step of the synthesis method for intermediate A. MS m / z (ESI): 235.2 [M+H] + .

[0293] Step 3: The preparation method of 84-3 is the same as the third step of the synthesis of intermediate A. MS m / z (ESI): 193.2 [M+H] + .

[0294] Step 4: The preparation method of 84-4 is the same as the fourth step of the synthesis method of intermediate A.

[0295] Step 5: The preparation method of E84 is the same as the synthesis method in the first step of Example 29.

[0296] 1 H NMR(500MHz,DMSO-d6)δ7.10(dt,J=7.1,3.1Hz,3H),6.95(t,J=8.3Hz,1H),6.79–6.73(m,1H), 5.98–5.95(m,1H),4.49(dt,J=12.6,8.8Hz,2H),3.85(d,J=22.6Hz,1H),3.66(ddd,J=25.3,12 .2,6.5Hz,1H),3.53–3.47(m,1H),3.22–3.10(m,3H),2.99(ddd,J=25.7,17.4,11.6Hz,2H),2. 92–2.86(m,1H),2.76–2.53(m,2H),2.43–2.27(m,3H),2.02–1.78(m,1H),0.95–0.88(m,3H).MS m / z(ESI):401.2[M+H] + .

[0297] Example 85: 6-Bromo-2-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0298] Step 1: Compound E87 (40 mg, 0.09 mmol) and anhydrous methanol (3 mL) were added to a 25 mL single-necked flask. NaBH4 (8 mg, 0.18 mmol) was added under an ice-water bath and nitrogen atmosphere. After the addition was complete, the mixture was allowed to react at room temperature for 1 h with stirring. After the reaction was detected by LCMS, water (20 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 15 min. The mixture was extracted with ethyl acetate (3 x 20 mL), and the organic phases were combined. The mixture was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was directly purified and separated by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E85-1 (white solid, 25 mg, yield 62%). 1 H NMR(500MHz,CD3OD)δ7.21–7.12(m,2H),7.12–7.04(m,2H),6.82(q,J=7.4Hz,1H ),6.59(ddd,J=8.0,7.3,5.9Hz,1H),4.96–4.88(m,1H),4.58–4.47(m,2H),3.86 –3.76(m,1H),3.24(ddd,J=16.4,12.2,7.2Hz,1H),3.21–3.12(m,2H),2.80–2.7 0(m,1H),2.63–2.40(m,4H),2.26(dd,J=11.6,9.2Hz,1H),2.01–1.82(m,4H).MS m / z (ESI): 429.5, 431.5 [M+H] + .

[0299] Step 2: Compound E85-1 (15 mg, 0.03 mmol) and anhydrous DCM (3 mL) were added to a 25 mL three-necked reaction flask. The mixture was cooled to -70 °C under N2 protection and a dry ice ethanol bath. BAST (15 mg, 0.06 mmol) was then slowly added dropwise. After the addition was complete, the mixture was allowed to rise to room temperature and stirred for 1 h. After the reaction was detected by LCMS, water (2 mL) was slowly added to the reaction solution under an ice-water bath to quench the reaction. The reaction solution was then concentrated under reduced pressure. The crude product was directly purified and separated by Prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E85 (white solid, 7 mg, yield 48%). 1H NMR (500MHz, CD3OD) δ7.20–7.09(m,3H),7.04(t,J=7.8Hz,1H),6.84(t,J=7 .5Hz,1H),6.57(t,J=7.6Hz,1H),5.71–5.55(m,1H),4.62–4.47(m,2H),3.82 (td,J=6.9,4.1Hz,1H),3.29–3.15(m,3H),2.77–2.67(m,1H),2.59(td,J=1 0.5,4.7Hz,1H),2.55–2.42(m,3H),2.28–2.05(m,3H),1.99–1.83(m,2H).MS m / z (ESI): 431.5, 433.5 [M+H] + .

[0300] Example 86: 6-Bromo-2-(2-((2,3-dihydrobenzofuran-7-yl)oxo)ethyl)-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0301] The synthesis of E86 is performed in step 4 of E82. 1 H NMR (500MHz, CDCl3) δ7.18(d,J=8.0Hz,1H),7.01(d,J=7.5Hz,1H),6.83(d,J=7.5Hz ,1H),6.81-6.71(m,2H),6.60(t,J=8.0Hz,1H),4.60(t,J=9.0Hz,2H),4.18(t,J=6. 0Hz,2H),3.93-3.90(m,2H),3.37-3.33(m,1H),3.22(t,J=9.0Hz,2H),2.86-2.80(m ,3H),2.75-2.57(m,2H),2.39-2.35(m,1H),2.05-1.99(m,1H),1.89-1.84(m,1H).MS m / z(ESI):415.2,417.2[M+H] + .

[0302] Example 87: 3-(6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)-1-(2,3-dihydrobenzofuran-7-yl)propane-1-one

[0303] Step 1: Compound 2,3-dihydrobenzofuran-7-carboxaldehyde (1.0 g, 6.75 mmol) and anhydrous THF (20 mL) were added together to a 100 mL three-necked reaction flask. The mixture was cooled to -78 °C under N2 protection and a dry ice ethanol bath. Then, vinyl magnesium chloride (10 mL, 1 M / THF) was slowly added dropwise. After the addition was complete, the mixture was allowed to rise to room temperature and stirred for 2 h. After the reaction was detected by TLC, the reaction solution was quenched by slowly adding saturated NH4Cl (50 mL) solution under an ice-water bath. The mixture was extracted with ethyl acetate (3 x 30 mL), and the organic phases were combined. The mixture was washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluting gradient: 50% EA / PE) to give compound 87-1 (colorless oil, 1.1 g, yield 84%).

[0304] Step 2: Compound 87-1 (1.1 g, 6.24 mmol) and anhydrous dichloromethane (20 mL) were added to a 100 mL single-necked reaction flask, followed by the addition of Dysmartin reagent (5.3 g, 12.48 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 h. After the reaction was complete as detected by LCMS, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by normal-phase column chromatography (elution gradient: 20% EA / PE) to obtain compound 87-2 (colorless oil, 0.72 g, yield 65%). MS m / z (ESI): 175.0 [M+H] + .

[0305] Step 3: Compound 87-2 (100 mg, 0.57 mmol), 40-2 (145 mg, 0.57 mmol), and anhydrous DCM (10 mL) were added to a 25 mL single-necked reaction flask, followed by Et3N (170 mg, 1.71 mmol). After the addition was complete, the mixture was stirred at room temperature for 3 h. After the reaction was completed as detected by LCMS, the filtrate was concentrated under reduced pressure, and the crude product was purified by normal-phase column chromatography (elution gradient: 100% EA / PE) to obtain the title compound E87 (off-white solid, 88 mg, yield 36%). 1H NMR(500MHz,CD3OD)δ7.60(t,J=8.1Hz,1H),7.43–7.39(m,1H),7.18–7.10(m,1H),7. 04(t,J=6.3Hz,1H),6.92–6.80(m,1H),6.58(td,J=8.3,5.0Hz,1H),4.69(td,J=8.8, 3.6Hz,2H),3.89–3.79(m,1H),3.30–3.18(m,5H),2.84–2.70(m,3H),2.68–2.59(m,1 H),2.52(td,J=11.1,3.6Hz,1H),2.19(dd,J=11.6,9.9Hz,1H),2.00–1.87(m,2H).MS m / z(ESI):427.2[M+H] +

[0306] Example 89: 6-Chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-4-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0307] Step 1: 7-Chloro-5-fluoro-1H-indole (2 g, 11.8 mmol) and N-benzyl-2,2-dimethoxyethane-1-amine (2.5 g, 13 mmol) were added together to a 100 mL single-necked flask, followed by the addition of acetic acid (2 mL) and finally formaldehyde (1.5 mL, 37%, 18.5 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 h under nitrogen protection. The reaction was confirmed by LC-MS. The solution was quenched with NaOH (2 M, 50 mL), extracted with ethyl acetate, dried, filtered, and the crude compound 89-1 (brown liquid, 2 g, 45% yield) was obtained by rotary evaporation of the organic phase. The crude compound was used directly in the next step without further purification. MS m / z (ESI): 377.1, 379.1 [M+H] + .

[0308] Step 2: Compound 89-1 (1.3 g, 3.4 mmol) was dissolved in dioxane (15 mL) and concentrated hydrochloric acid (15 mL). The mixture was slowly heated to 100 °C for 1 h under nitrogen protection. The reaction was complete as determined by LC-MS. The solution was dried, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution. Extraction with ethyl acetate was performed, and the solution was dried, filtered, and purified by normal-phase column chromatography to obtain compound 89-2 (yellow solid, 700 mg, yield 61.4%). The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 311.0, 333.0 [M+H] + .

[0309] Step 3: Compound 89-2 (500 mg, 1.5 mmol) was dissolved in methanol (2 mL) and THF (16 mL), then Pd / C (160 mg, 10%, 0.15 mmol) was added. After addition, the reaction was carried out at room temperature for 1 h under a hydrogen atmosphere. The reaction was confirmed by LCMS. The solution was dried, and the pH was adjusted to 9-10 with saturated sodium bicarbonate solution. Extraction with ethyl acetate was performed, and the solution was dried, filtered, and purified by normal-phase column chromatography to obtain compound 89-3 (yellow solid, 700 mg, yield 61.4%). The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 267.1, 269.1 [M+H- t Bu-H2O] + .

[0310] Step 4: Compound 89-3 (100 mg, 0.29 mmol) was dissolved in dioxane (3 mL), and then dioxane hydrochloride solution (1.5 mL, 4 M, 6 mmol) was added. This reaction was carried out at 20 °C for 1 h. LC MS showed that the reaction was complete, and the product was dried to obtain compound 89-4 (white solid, 50 mg, yield 68.5%). The crude product was not further purified and was used directly in the next step. MS m / z (ESI): 255.1, 257.1 [M+H] + .

[0311] Step 5: The preparation method of E89 is the same as the synthesis method in step 3 of Example 9.

[0312] 1 H NMR(500MHz, CDCl3)δ8.26(s,1H),7.06(d,J=7.3Hz,1H),7.04–6.94(m,3H),6.79(t,J=7.4Hz,1H),4.63(s,1H),4.56(t,J=8.7Hz,2H) ,3.64(d,J=20.9Hz,2H),3.52(s,3H),3.22(t,J=8.7Hz,2H),3.03(s,1H),2.88(s,1H),2.67(dd,J=22.8,15.2Hz,4H),1.97(s,2H).MS m / z(ESI):415.3[M+H] +

[0313] Example 94: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,3,4,10b-tetrahydropyranadiazono[2,1-a]isoindole-6(2H)-one

[0314] The synthesis of E94 follows the synthesis method of the first step in Example 29. 1H NMR(500MHz,CD3OD)δ7.78(d,J=10.0Hz,1H),7.63-7.57(m,2H),7.53-7.50(m,1H),7.03(d,J=10.0 Hz,1H),6.92(d,J=10.0Hz,1H),6.74(t,J=7.5Hz,1H),4.58(dd,J=10.0Hz,5.0Hz,1H),4.52(t,J=1 0.0Hz,2H),4.29-4.25(m,1H),3.59-3.55(m,1H),3.30-3.25(m,1H),3.18(t,J=10.0Hz,2H),3.04- 3.00(m,1H),2.63(t,J=7.5Hz,2H),2.50-2.47(m,2H),1.98-1.85(m,3H),1.59(t,J=10.0Hz,1H).MS m / z(ESI):348.7[M+H] +

[0315] Example 95: 2-(3-(2,3-dihydrobenzofuran-7-yl)-2-fluoropropyl)-1,3,4,10b-tetrahydropyranadiazono[2,1-a]isoindole-6(2H)-one

[0316] Step 1: The preparation method of 95-1 follows the synthesis method in step 3 of E27. MS m / z (ESI): 365.5 [M+H] +

[0317] Step 2: The preparation method of E95 is the same as the synthesis method in step 4 of E27. 1 H NMR (500MHz, CDCl3) δ7.86(d,J=7.5Hz,1H),7.52(t,J=7.5Hz,1H),7.47(t,J=7.5Hz,1H),7.39(t ,J=6.5Hz,1H),7.10(d,J=7.0Hz,1H),7.01(d,J=7.5Hz,1H),6.81(t,J=7.5,1.0Hz,1H),5.09-4. 99(m,1H),4.58-4.51(m,3H),4.36-4.32(m,1H),3.50-3.43(m,1H),3.31-3.26(m,1H),3.23(t,J =8.5Hz,2H),3.01-2.93(m,3H),2.76-2.66(m,2H),2.20-2.10(m,1H),1.81(q,J=10.5Hz,1H).MS m / z(ESI):367.6[M+H] +

[0318] Example 96: 7-Bromo-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,3,4,10b-tetrahydropyranadiazono[2,1-a]isoindol-6(2H)-one

[0319] Step 1: Methyl 2-bromo-6-methylbenzoate (690 mg, 3.0 mmol) was dissolved in CCl4 (10 mL), followed by the addition of NBS (536 mg, 3.0 mmol) and BPO (72 mg, 0.3 mmol). The mixture was heated under reflux for 16 h. The solvent was removed under reduced pressure, and then acetonitrile (10 mL), DIPEA (774 mg, 6 mmol), and tert-butyl(2-aminoethyl)carbamate (576 mg, 3.6 mmol) were added sequentially. The mixture was heated under reflux for 16 h, filtered, concentrated, and purified by normal phase to give compound 96-1 (off-white solid, 610 mg, 80% yield). MS m / z (ESI): 255.2, 257.0 [M+H-Boc] + .

[0320] Step 2: Compound 96-1 (600 mg, 1.7 mmol) was dissolved in THF (15 mL). The reaction solution was cooled to -78 °C, and LDA (5.6 mL, 5.6 mmol) was added. The mixture was stirred at -78 °C for 1 h. Then, (1H-benzo[d][1,2,3]triazol-1-yl) (300 mg, 2.2 mmol) was added, and the mixture was heated to room temperature and stirred for 1 h. The reaction was quenched with water (25 mL) and methanol (2.5 mL). The mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, concentrated, and purified by normal phase to give compound 96-2 (white solid, 240 mg, yield 40%). MS m / z (ESI): 285.2, 287.0 [M+H-Boc] + .

[0321] Step 3: Compound 96-2 (80 mg, 0.21 mmol) was dissolved in DCM (2 mL), Et3N (60 mg, 0.6 mmol) was added, followed by Ms2O (52 mg, 0.3 mmol). The mixture was stirred at 25 °C for 1 h. Water (10 mL) and DCM (10 mL) were added to separate the layers. The organic layer was washed with water (10 mL), dried with anhydrous sodium sulfate, filtered, concentrated, and DCM (2 mL) was added. HCl / dioxane (2.0 mL, 8 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was then concentrated to obtain an intermediate as a white solid, which was dissolved in DMF (10 mL). K2CO3 (33 mg, 0.24 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS until it ended. Water (15 mL) and DCM (15 mL) were added to separate the layers. The organic layer was washed with water (15 mL), concentrated, and purified by normal phase to obtain compound 96-3 (anhydrous oil, 24 mg, yield 42%). MS m / z(ESI): 267.8 [M+H] + .

[0322] Step 4: The synthesis of E96 follows the synthesis method in step 3 of Example 9. 1 H NMR (500MHz, CD3OD) δ7.65-7.57(m,2H),7.50-7.46(m,1H),7.01-6.86(m,2H),6.73-6.69(m,1H),4.60(dd,J=10.0Hz,5.0Hz,1H),4.49(t,J=10.0H z,2H),4.13-4.09(m,1H),3.94-3.90(m,1H),3.80-3.71(m,2H),3.16(t,J =10.0Hz,2H),3.11-2.95(m,2H),2.73-2.56(m,4H),1.89-1.78(m,2H).MS m / z(ESI):427.3[M+H] +

[0323] Example 97: 2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,3,4,6,10b-hexahydropyranadiazono[2,1-a]isoindole

[0324] Compound E94 (20 mg, 0.057 mmol) was dissolved in THF (1 mL), followed by the addition of boranetetrahydrofuran solution (1 mL, 1.0 mmol). The mixture was heated and stirred for 3 h, cooled to room temperature, and methanol (5 mL) was added. After stirring at room temperature for 1 h, the reaction mixture was filtered. The filtrate was directly separated by reverse-phase chromatography (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to give compound E97 (pale yellow solid, 6.5 mg, yield 34%). 1 H NMR (500MHz, CD3OD) δ7.33-7.29(m,4H),7.01(d,J=5.0Hz,1H),6.86(d,J=5.0Hz,1H),6.71(t,J=7.5Hz,1H),4.52(t,J=10.0Hz,2H),4.43-4.38(m ,2H),4.12(d,J=15.0Hz,1H),3.22-3.14(m,3H),3.02-2.96(m,2H),2.92 -2.76(m,2H),2.61-2.50(m,1H),2.49-2.39(m,4H),1.81-1.75(m,2H).MS m / z(ESI):334.7[M+H] +

[0325] Example 98: trans-6-chloro-2-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-8-fluoro-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole

[0326] E52 (250 mg, 0.65 mmol) was dissolved in borane dimethyl sulfide (3.2 mL, 6.49 mmol) and reacted overnight at 80 °C under nitrogen protection. The reaction was monitored by LC-MS until complete, quenched with methanol, and then extracted with DCM and water. The mixture was filtered, concentrated, and purified by silica gel column chromatography (DCM:

[0327] The crude compound was obtained by MeOH = 10:1. The crude compound was further separated by phase preparation (C18 column, eluent gradient: acetonitrile / (water + 0.05% TFA)) to obtain compound E98 (white solid, 4 mg, TFA salt, yield 1.2%). 1 H NMR(400MHz,CD3OD)δ7.10-7.05(m,J

[0328] =7.4,1.0Hz,1H),6.99-6.91(m,3H),6.79(t,J=7.6Hz,1H),4.56(t,J=8.8Hz,2H),4.26(d,J=9.8Hz,

[0329] 1H),3.74(d,J=12.8Hz,1H),3.41-3.98(m,1H),3.28-3.18(m,5H),3.15-3.06(m,1H),2.96(s,1H),2.71

[0330] (t,J=7.2Hz,2H),2.38(d,J=11.2Hz,1H),2.11-2.09(m,3H).MS m / z(ESI):387.4[M+H] +

[0331] The compounds in the other examples were prepared according to the corresponding synthetic methods, as shown in Table 1 below.

[0332] Table 1

[0333] Example 1: Affinity test of the compound to the 5-HT2A receptor

[0334] Affinity was determined using a radioligand competition assay. A plasmid vector containing the 5-HT2A receptor sequence was transfected into HEK293 cells (ATCC, CRL-1573). After selection, HEK293 cells stably expressing the 5-HT2A receptor were obtained, seeded in 10cm culture dishes, and cultured overnight. The culture medium was then removed, and 3mL of lysis buffer was added. The cells were incubated at 4°C for 10 minutes. After cell detachment, the cells were centrifuged at 1500rpm for 5 minutes at 4°C, and the supernatant was discarded. The cell pellet was transferred to a tissue homogenizer, and 3mL of lysis buffer was added. The cells were thoroughly homogenized until lysed, and then centrifuged at 12000rpm for 5 minutes at 4°C, and the supernatant was discarded. The pellet contained the cell membrane fraction of the 5-HT2A receptor and was resuspended in 10mL of binding buffer. Prepare a 96-well plate, add the serially diluted test compound to the plate, along with 100 μl of membrane stock solution and 100 μl of [3H]-ketanserin radioactive ligand, and incubate at 300 rpm for 1 hour. Simultaneously prepare a UniFilter. TM Plate (GF / B), soaked in 50 μl of 0.3% PEI to extract UniFilter. TM Plate for 0.5 hours, then incubate the aforementioned membrane and ligand mixture through a UniFilter. TMThe filter plate was filtered and washed four times with cleaning buffer. The filter plate was then dried at 50°C for 1 hour. After drying, the bottom of the filter plate was sealed with sealing film, and 50 μl of liquid scintillation buffer was added. The amount of [3H]-ketanserin bound to the filter plate was read on the instrument and compared with the control well to calculate the inhibition rate. Data were analyzed using Prism software, and the IC50 was obtained by fitting the data using a "log(inhibitor) vs. response-variable slope" model. 50 The affinity Ki values ​​of different compounds for the 5-HT2A receptor were obtained after further processing, as shown in Table 2.

[0335] Table 2

[0336] Example 2: Functional activity assay of downstream beta-arrestin of 5-HT2A receptor

[0337] 2.1 Method 1: The Promega NanoBit assay kit was primarily used. Specifically, a 5HT2A receptor plasmid with LgBiT at the C-terminus and a beta-arrestin plasmid with SmBiT at the N-terminus were constructed. Before transfection, 4 x 10^6 HEK293 cells (ATCC, CRL-1573) were seeded in 10 cm culture dishes and cultured overnight. Then, 10 μg of 5HT2AR-LgBiT and 10 μg of pBiT2.1-N-SmBiT-beta arrestin plasmid, along with transfection reagent, were mixed and added to the culture dish for transfection. After 24 hours of culture, the cells were transferred to 384-well plates (20,000 cells per well), and the target compound or 5-HT was added as a positive control. The plates were incubated overnight at 37°C with 5% CO2. The next day, 5 μL of diluted NanoBit assay solution was added, and the luminescence value was read using a microplate reader. Using the highest 5-HT concentration as 100% for downstream pathway activation, data were analyzed using Prism software. A "log(agonist) vs. response - Variable slope (four parameters)" model was used to fit the data, yielding EC50 values. 50 and E max .

[0338] 2.2 Method Two: The Promega NanoBret kit was primarily used. Specifically, the following plasmids were constructed: a 5HT2A receptor plasmid with Nanoluc at its C-terminus, a beta-arrestin plasmid with a Halo-tag at its C-terminus, and a pcDNA3.1 plasmid expressing GRK2. Before transfection, HEK293 cells (ATCC, CRL-1573) were seeded in 6-well plates and cultured overnight. The Nanoluc-5HT2A, GRK2, and beta-arrestin-halotag plasmids were mixed at a ratio of 1:1:10 and added to the 6-well plates along with the transfection reagent, with a transfection volume of 2 μg per well. Four hours later, the cells were digested and transferred to 384-well plates at 20,000 cells per well, with the target compound or 5-HT added as a positive control. The plates were incubated overnight at 37°C and 5% CO2. The next day, diluted NanoBRET was added. TM Nano-Glo substrates were read at 618 nm / 460 nm using a microplate reader. The highest 5-HT concentration was taken as 100% for downstream pathway activation. Data were analyzed using Prism software, and a "log(agonist) vs. response - Variable slope (four parameters)" model was used to fit the data to derive EC50. 50 and E max .

[0339] Table 3 'a' represents the data obtained using Method 1, while the rest are obtained using Method 2.

[0340] Example 3: Detection of downstream calcium flow activity of the 5-HT2A receptor

[0341] 3.1 Method 1: Downstream calcium flux activity assay of the compound and 5-HT2A receptor was performed using HEK293 cells (ATCC, CRL-1573) stably expressing the 5-HT2A receptor. The HEK293 cells stably expressing the 5-HT2A receptor were constructed as described in Example 1. The 5-HT2A receptor was stably expressed in HEK293 cells using lentiviral infection to form HEK293-5HT2AR cells. These cells were seeded at 25,000 cells / well in 384-well plates and incubated overnight at 37°C with 5% CO2. The next day, the cell culture medium was aspirated, and buffer containing FLIPR Calcium 6 dye was added, followed by incubation at room temperature for 30 minutes. Simultaneously, 384-well plates containing the compound were prepared and placed in an MD FLIPR instrument to read the calcium flux signal values. When analyzing the data, the highest 5-HT concentration was taken as 100% of the downstream pathway activation level. Prism software was used to analyze the data, and a "log(agonist) vs. response - Variable slope (four parameters)" model was used to fit the data to obtain EC 50 and E max .

[0342] 3.2 Method 2: Assay for Downstream Calcium Flow Activity of the Compound and the 5-HT2A Receptor. HEK293 cells (ATCC, CRL-1573) were transiently transfected with the 5-HT2A receptor. Specifically, the full-length 5-HT2A gene was inserted into the pcDNA3.1 vector, and HEK293 cells were transfected with Lipofectamine 3000 reagent. After 4-6 hours, the cells were seeded at 20,000 cells / well in 384-well plates and incubated overnight at 37°C and 5% CO2. The next day, the cell culture medium was aspirated, and buffer containing FLIPR Calcium 6 dye was added, and the cells were incubated at room temperature for 30 minutes. Simultaneously, prepare 384-well plates containing the compound, place them in the MD FLIPR instrument, and read the calcium flux signal values. When analyzing the data, the highest 5-HT concentration reading is used as 100% for downstream pathway activation. Prism software is used to analyze the data, and a "log(agonist) vs. response - Variable slope (four parameters)" model is used to fit the data to obtain EC50 values. 50 and E max .

[0343] Table 4 b Data was obtained from Method 1, and the rest were obtained from Method 2. Example 4: Animal Depressive-like Behavior Test (FST)

[0344] Forced swimming is a common test used to assess depressive-like symptoms in mice. In this experiment, 7-8 week old male C57BL / 6J mice were used, with 12 mice per group. Twenty-four hours before the test, mice were placed in a 5L glass beaker with a water level of 15cm and swam for 15 minutes. On the day of the test, mice were injected intraperitoneally with a blank solvent (5% DMSO, 10% polyethylene glycol-15-hydroxystearate, 85% saline), ketamine (20 mpk), or the test substance (15 mpk) 30 minutes later, and then placed in the same beaker for 6 minutes. The immobility time of the mice in the last four minutes was analyzed using software (Shanghai Jiliang, JLBehv-FSG-4). The percentage of immobility time in each treatment group compared to the immobility time in the control group using the same batch of solvent was calculated for statistical analysis. If the data followed a normal distribution, the independent samples t-test was used as the statistical method. If the data did not follow a normal distribution, a non-parametric test was used. See Table 5 for details.

[0345] Table 5 c: The data is the average of multiple experiments.

[0346] Experimental results show that compounds E4, E18, E19, E30, and E35 of this invention can significantly reduce immobility time and the ratio of immobility time to solvent control, and the effect is significantly better than that of the positive control ketamine, suggesting that these compounds can improve depressive-like mood in mice.

[0347] Example 5: Head Twitch Response Test (HTR) in Mice

[0348] The mouse head twitching test is commonly used to assess the hallucinogenic effects of compounds. Classic serotonin-based hallucinogens induce rapid, rhythmic, paroxysmal left-right head rotations in mice. Observers evaluate the potential hallucinogenic effects of the compound by recording the number of head movements. The experiment used 6-8 week old C57BL / 6J mice, with 10 mice in each group. On Day 1, the animals were placed in a test chamber for acclimatization for 20 minutes. Subsequently, each group of animals was intraperitoneally injected with a blank solvent (5% DMSO, 10% polyethylene glycol-15-hydroxystearate, 85% physiological saline), the positive compound hallucinogen DOI (2,5-dimethoxy-4-iodophenylpropane-2-amine) (1 mg / kg), or the test substance (50 mg / kg). The number of head twitches in the mice was recorded within 70 minutes (from 0 to 70 minutes after administration). On Day 2, 24 hours ± 5 minutes after administration, the number of head twitches in the mice was recorded within 30 minutes. Data Analysis: The number of head twitches was described using mean ± standard error. Quantitative Indicators: When the data followed a normal distribution and had homogeneous variances, one-way ANOVA was used for statistical testing; when the variances were unequal, the Kruskal-Wallis H rank-sum test (KW test) was used for statistical analysis. All statistical analyses were performed using GraphPad Prism 9.0 software, and the results are shown in Table 6 and Figure 1. Figure 1 shows that within 70 minutes of administration, the positive control compound DOI produced a significant hallucinogenic effect, while the compound of this invention, consistent with the blank control, did not produce a significant hallucinogenic effect. Even 24 hours after administration, no hallucinogenic effect was observed in the compound of this invention.

[0349] Table 6

[0350] Example 6: Plasma Stability

[0351] The purpose of this study was to evaluate the metabolic stability of the drug in the plasma of humans, cynomolgus monkeys, beagle dogs, SD rats, and CD1 mice. Experimental steps: (1) Take an appropriate amount of blank plasma into an EP tube, add the working solution of the analyte to a final concentration of 1 μM, and vortex to mix; (2) Place the sample in a 37℃ water bath, in duplicate; incubation time points are 0 min, 10 min, 30 min, 60 min, and 120 min; (3) Take 20 μL of sample from the incubation system, add 300 μL of protein precipitant containing internal standard; (4) Centrifuge all samples for 10 min (5500 g); (5) Take 150 μL of the supernatant into a 96-well plate, add 150 μL of ultrapure water, vortex to mix, and analyze by LC-MS / MS. Calculation of elimination half-life (T1 / 2):

[0352] 1) Residual percentage of original drug % = At / A0 × 100%

[0353] At: Peak area ratio of analyte to internal standard at non-zero incubation time points

[0354] A0: Peak area ratio of sample analyte to internal standard at time zero

[0355] 2) Elimination half-life of the test substance (T1 / 2) = 0.693 / K

[0356] Wherein, the elimination rate constant (K) = -2.303 × Slope, where Slope is the slope of the straight line obtained by plotting the logarithmic percentage of the remaining parent organism against incubation time. The results are shown in Table 7.

[0357] Table 7

[0358] The data in the table correspond to humans, cynomolgus monkeys, beagle dogs, SD rats, and CD1 mice, respectively. The test results show that the half-lives of compounds (E19 and E4) in the plasma of all five species are greater than 289 mins, indicating minimal changes in drug concentration in plasma before and after incubation, demonstrating good plasma stability.

[0359] Example 7: Plasma protein binding (CYP enzyme inhibition)

[0360] The purpose of this study was to investigate the in vitro inhibitory effects of the test substance on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes and to evaluate its potential metabolic drug-drug interactions. Experimental steps: (1) 100× specific inhibitor: Dilute the corresponding stock solution with 50% acetonitrile-water to prepare the corresponding concentration of inhibitor working solution. (2) 200× compound: Add 20 μL of stock solution to 80% acetonitrile-water, vortex to mix and obtain the working solution. Dilute the solution with 80% acetonitrile-water at a ratio of 3 from the highest concentration point to 6 concentrations, with the 8th concentration being 0 μM. (3) 200× substrate: Dilute the corresponding stock solution with 50% acetonitrile-water to prepare the corresponding concentration of substrate working solution. (4) Use PB solution as solvent to prepare 4 mM NADPH solution. (5) Human liver microsomes (source: Corning, Cat No. 452117, 0.1 mg / mL) mixture: Add 1013 μL of PB solution to a centrifuge tube, add 2200 μL of MgCl2 (6 mM) solution, 20.7 μL of human liver microsome solution, and 22 μL of 200× substrate working solution, vortex to mix, and dispense into 148 μL / tube. (6) Human liver microsomes (0.2 mg / mL) mixture: Add 993 μL of PB solution to a centrifuge tube, add 2200 μL of MgCl2 (6 mM) solution, 41.3 μL of human liver microsome solution, and 22 μL of 200× substrate working solution, vortex to mix, and dispense into 148 μL / tube. (7) Add 2 μL of a series of 100× specific inhibitors or 1 μL of 200× compound / 80% acetonitrile-water to the aliquoted human liver microsomal substrate mixture, and pre-incubate in a 37°C water bath for 5 min. Simultaneously, preheat NADPH in a 37°C water bath for 5 min. (8) Add 50 μL / well of 4 mM NADPH solution and incubate for 5 min (2C8, 3A Mid), 10 min (2B6, 2C9, 2D6, 3A Tes), 20 min (1A2), and 30 min (2C19). (9) Take 100 μL of sample and add 300 μL / well of internal standard working solution to terminate the reaction, vortex, and centrifuge. (10) Take 100 μL of the supernatant and add it to 300 μL of water (1A2, 2C8). Take 150 μL of the supernatant and add it to 150 μL of water (other subtypes). Vortex to mix and analyze by LC-MS / MS. Data analysis: At different concentrations of the analyte or positive inhibitor, the percentage of remaining activity is determined by the ratio of the amount of characteristic metabolites of the probe substrate generated to the amount generated when the analyte or positive inhibitor is absent.If a significant decrease in metabolite production is observed at the highest concentration setpoint, the half-maximal inhibitory concentration (IC50) will be calculated using the log(inhibitor) vs. response--variable slope formula in GraphPad Prism software.

[0361] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*Hillslope))

[0362] X: Log(concentration of the test compound or positive inhibitor);

[0363] Y: Percentage of remaining activity;

[0364] Top and Bottom: These refer to the theoretical highest and lowest percentages of remaining activity, respectively.

[0365] Hillslope: slope coefficient or gradient.

[0366] The results are shown in Table 8.

[0367] Table 8

[0368] Generally, an IC50 < 1 indicates a strong inhibitory effect on CYP enzymes, while an IC50 > 10 indicates a low risk of inhibition. The data in the table show that the compounds of this invention maintain a low risk of inhibition against CYP enzymes, thus avoiding unnecessary drug interactions in vivo.

Claims

1. A tricyclic compound as shown in Formula I, or a pharmaceutically acceptable salt thereof: A carbon atom marked with an asterisk (*) indicates that when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof. A carbon atom marked with "#" indicates that when it is a chiral carbon atom, it is in the S configuration, R configuration, or a mixture thereof; X 1 For N or CR 1 ; X 2 For N or CR 2 ; X 3 For N or CR 3 ; X 4 For N or CR 4 ; X 5 For NR 5 C=O or CR 5-2 R 5-3 ; R 1 R 2 R 3 and R 4 Independently, H, halogen, CN, OH, NR a R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, -C(O)R 1-1 or -NR a C(O)R 1-2 ; R 1-1 OR a or NR a R b ; R 1-2 It is a C1-C6 alkyl or C3-C6 cycloalkyl; R 5 H, C1-C6 alkyl, C3-C6 cycloalkyl, or -C(O)R 5-1 ; R 5-1 It is a C1-C6 alkyl or C3-C6 cycloalkyl; R 5-2 and R 5-3 It is independently H or C1-C6 alkyl; It can be a single bond or a double bond; when When it is a double bond, X 6 For C, R 10 It does not exist; when When it is a single bond, X 6 For N or CR 6 And R 6 and R 10 Independently H or C1-C6 alkyl; or, R 6 and R 10 Together with the carbon atoms they are connected to, they form bridging portions; n1 is either 0 or 1; n2 is 1 or 2; R 7 R 8 and R 9 Independently, it is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; Or, R 8 and R 9 Together with the carbon atoms they are connected to, they form bridging portions; L is -(CR) L1 R L2 )m1-, wherein -(CR L1 R L2 )m1- or 2-(CR L1 R L2 -Some optional parts are replaced by -Y-; m1 can be 1, 2, 3, 4 or 5; R L1 and R L2 Independently, it is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; Each Y is independently -O-, -S-, -NR a -, -C(O)-, -C≡C-, -C(O)-NR a -、-CR L3 =CR L4 -、 R L3 and R L4 Independently H or halogen; Ring A is Ring A 1 Independently phenyl or "5-6 membered monocyclic heteroaryl group selected from 1, 2 or 3 of N, O and S, with 1, 2 or 3 heteroatoms"; Ring A 2 Independently defined as "a 5-6 membered monocyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; n3 can be 0, 1, 2, 3 or 4; R 11 Independent of halogen, CN, OH, NR a R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; R a and R b It can be independently H, C1-C6 alkyl or C3-C6 cycloalkyl.

2. The tricyclic compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1)X 1 For CR 1 ; (2)X 2 For CR 2 ; (3)X 3 For CR 3 ; (4)X 4 For CR 4 ; (5)X 5 and X 6 Meet any of the following conditions: (i)X 5 For NR 5 , For a single key, X 6 For CR 6 ; (ii)X 5 For NR 5 , It is a double bond, X 6 The answer is C; and (iii)X 5 For C=O or CR 5-2 R 5-3 X 6 Let N be the number of people in the group. (6)R 5-2 and R 5-3 For H to be independent; (7)R 1 R 2 R 3 and R 4 Independently H, halogen, CN, NR a R b C1-C6 alkyl, C1-C6 alkoxy, -C(O)R 1- 1 or -NR a C(O)R 1-2 ; (8) It is a single bond; (9) n1 and n2 satisfy the following conditions: (i) n1 is 0 or 1, n2 is 1; or (ii) n1 is 0, n2 is 2; (10)R 7 R 8 and R 9 Independently, it can be H, halogen, or C1-C6 alkoxy. (11) m1 is 2, 3 or 4; (12)R L1 and R L2 Independently, it is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; (13) Each Y is independently -O-, -C(O)-, or (14) Ring A 1 It can be phenyl or pyridinyl independently; (15) Ring A 2 Independently defined as "a 5-6 membered monocyclic heterocyclic alkyl group selected from one or two of N and O, with one or two heteroatoms", such as tetrahydrofuranyl or pyrrolidinyl; and (16) n3 is 0.

3. The tricyclic compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1)R 1 R 2 R 3 and R 4 Independently H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or -C(O)-NR a R b ; (2) n1 is 1, n2 is 1; (3)R 7 R 8 and R 9 H is independent; (4) For example, R L1 and R L2 H independently; and (5) Ring A is For example, ring A is a benzotetrahydrofuran ring.

4. The tricyclic compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) Each halogen is independently F, Cl, Br or I; (2) Each C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl or isopropyl, for example methyl; (3) Each C1-C6 alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy; and (4) Each C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

5. The tricyclic compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) for For example, and (2) for 6. The tricyclic compound of formula I as described in claim 1, characterized in that, It meets one or more of the following conditions: (1)R 5 H, methyl, ethyl, isopropyl, cyclopropyl, For example, R 5 It is H or methyl; for example, R 5 For H; (2) When When it is a single bond, X 6 For N or CR 6 And R 6 and R 10 H is independent; (3)R 1 For H; (4)R 2 For H, methoxy, F, Cl, CN, NH2, Or ethyl; (5)R 3 It can be H, F, or Cl; (6)R 4 For H, F, Cl, Br, I, methyl, methoxy or -COOH; (7) L is For example, L is and (8) for 7. The tricyclic compound of formula I as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, characterized in that, The tricyclic compounds shown in Formula I are compounds shown in Formula I-1, I-2, I-3 or I-4: in, X 7 For N or CR 12 ; X 8 For N or CR 13 ; X 9 For N or CR 14 ; R 12 R 13 and R 14 Independently H, halogen, CN, NR a R b C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl or C3-C6 halocycloalkyl; n4 is 0, 1, or 2; *、#、X 1 X 2 X 3 X 4 R 5 R 6 R 7 R 8 R 9 R 10 L, ring A 2 and R 11 The definition is as described in any one of claims 1-6.

8. The tricyclic compound of formula I as described in claim 7, characterized in that, It meets one or more of the following conditions: (1)X 8 For CR 13 ; (2)X 9 For CR 14 ; (3)R 12 R 13 and R 14 H independently; and (4) n4 is 0.

9. Any of the following tricyclic compounds or their pharmaceutically acceptable salts, 10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) The tricyclic compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-9, and (2) Pharmaceutically acceptable excipients.

11. Use of the tricyclic compound of any one of claims 1-9, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 10, wherein the use is selected from: (1) Preparation of 5-HT 2A Receptor agonists; (2) Preparation of treatment and / or prevention with 5-HT 2A Drugs for receptor-related diseases; for example, those related to 5-HT. 2A Depression is a receptor-related disorder. (3) Prepare drugs for the treatment and / or prevention of depression.

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