Fused-ring piperidine compounds and their preparation and use

Abstract

The present invention discloses a fused ring piperidine compound and its preparation method and use.The fused ring piperidine compound of the present invention is represented by formula I'.The fused ring piperidine compound of the present invention has better depression inhibitory effect and good application prospects. [Formula 1] JPEG2025502334000086.jpg35169

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese patent application No. 2022100417955, filed on January 14, 2022. This application cites the above Chinese patent application in full. [Technical field] The present invention relates to fused ring piperidine compounds and their preparation and use. [Background technology] Depression is a mental illness that has serious consequences for human health, affecting approximately 300 million people worldwide and resulting in tens of thousands of suicides each year. Depression is characterized by a pronounced and persistent low mood accompanied by symptoms such as loss of interest, sleep disturbance, and low self-esteem, and in severe cases may lead to suicidal thoughts and self-harm.

[0002] Currently known antidepressants mainly include the major categories of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. SSRI drugs are widely used in clinical practice and mainly include sertraline, escitalopram, fluoxetine, paroxetine, etc. SSRI drugs act by inhibiting the reuptake of the central neurotransmitter 5-hydroxytryptamine (5-HT) and increasing the concentration of 5-HT in the synaptic cleft. Although the efficacy of SSRI drugs has the advantage of being better tolerated and safer than traditional tricyclic antidepressants, this class of drugs still has some obvious disadvantages: (1) the onset of action is slow, taking several weeks to several months for the drug to have an effect; (2) the response rate is low, with more than one-third of patients not responding; and (3) side effects such as nausea, weight gain, and sexual dysfunction are still relatively common. Therefore, there is an urgent need to develop new antidepressants.

[0003] Early this century, clinical trials unexpectedly discovered the rapid antidepressant effect of the medical anesthetic ketamine. A single dose of ketamine under anesthesia could rapidly relieve symptoms of depression within a few hours. In March 2019, the US FDA approved S-configured ketamine (esketamine) as a nasal spray for the treatment of patients with treatment-resistant depression (Swainson et al., Expert Rev Neurother, 2019, 19(10): 899-911). In terms of mechanism of action, esketamine is a noncompetitive, subtype-nonselective, activity-dependent N-methyl-D-aspartate (NMDA) receptor antagonist that exerts its function by antagonizing NMDA (Zhang et al., Nature,2021, 596(7871): 301-305). In mouse models of depression, ketamine can reconstitute many synapses that were previously present but lost under chronic stress. However, as an antidepressant, ketamine can cause side effects such as dissociative hallucinations, and there is a risk of addiction, limiting its clinical application.

[0004] Recent studies have also shown that psychedelic drugs have great potential in the treatment of diseases such as depression, anxiety, drug addiction, and post-traumatic stress disorder (PTSD) (Nutt et al., Cell, 2020, 181(1): 24-28). Classical psychedelics mainly include psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ibogaine, etc. Among them, psilocybin showed a rapid onset of action and a sustained depression-relieving effect in phase II clinical trials, and several clinical trials using psilocybin for the rapid treatment of depression are currently underway. From the perspective of the mechanism of action, psychedelic drugs inhibit 5-HT 2A Although they act by activating receptors, it remains unclear how to selectively discover non-hallucinogenic antidepressants by modulating agonist strength and signaling pathways.

[0005] Lumateperone is a compound that has a tetracyclopiperidine core structure.

[0006] [ka]

[0007] It was approved by the US Food and Drug Administration (FDA) in December 2019 for the treatment of schizophrenia in adults (Blair, Drugs, 80(4): 417-423). In December 2021, the US FDA approved a new indication for lumateperone: to treat adult patients with depressive episodes associated with bipolar I or II disorder (bipolar depression), both as monotherapy and as adjunctive therapy to lithium salts or valproate (Calabrese; Am J Psychiatry, 2021, 178(12): 1098-1106).

[0008] From a mechanism of action perspective, lumateperone is a potent 5-HT 2A Receptor antagonists (K i =0.54 nM), postsynaptic D2 receptor antagonist (K i = 32 nM), and a 5-HT transporter (SERT) inhibitor (K i =61nM) (Li et al., J Med Chem 2014, 57, 2670-2682). Lumateperone as an antidepressant is only used for depressive episodes associated with bipolar I or II disorder, with a response rate of only 51.1% (Calabrese et al., Am J Psychiatry 2021,178: 12), and its efficacy in general and treatment-resistant depression has not yet been reported. Its antidepressant effect and mechanism of action are similar to those of antischizophrenic drugs such as lurasidone, quetiapine, and cariprazine (Calabrese et al., Am J Psychiatry 2021,178: 12). Summary of the Invention The technical problem that the present invention aims to solve is to overcome the shortcomings of the limited variety of antidepressants or hallucinogenic side effects in the prior art, and for this purpose, provide a fused ring piperidine compound and its preparation method and use.The fused ring piperidine compound of the present invention has a better depression inhibition effect and avoids hallucinogenic side effects.

[0009] The present invention overcomes the above technical problems through the following technical solutions.

[0010] The present invention provides a fused ring piperidine compound represented by formula I' or a pharma- ceutically acceptable salt thereof.

[0011] [ka]

[0012] However, X is

[0013] [ka]

[0014] and R a , R b and R c are independently hydrogen or C1-C4 alkyl, R 1 and R 2 are independently hydrogen, halogen or C1-C4 alkyl; R 3 are independently hydrogen, halogen, hydroxyl, or C1-C4 alkoxy; m is 1, 2 or 3; n is 1, 2 or 3; z is 1 or 2.

[0015] In one embodiment, the fused ring piperidine compound of formula I' is

[0016] [ka]

[0017] isn't it.

[0018] In one embodiment, the fused ring piperidine compound of formula I' is a fused ring piperidine compound of formula Ia, Ib, I or Ic,

[0019] [ka]

[0020] However, X, R 1 , R 2 , R 3 , m and n are as defined above.

[0021] In one embodiment, the fused ring piperidine compound of formula I' is a fused ring piperidine compound of formula I,

[0022] [ka]

[0023] However, X is

[0024] [ka]

[0025] and R a , R b and R c are independently hydrogen or C1-C4 alkyl, R 1 and R 2 are independently hydrogen, halogen or C1-C4 alkyl; R 3 are independently hydrogen, halogen, hydroxyl, or C1-C4 alkoxy; m is 1, 2 or 3; n is 1, 2 or 3.

[0026] In one embodiment, R a , R b and R c In the above, the C1 to C4 alkyl groups are preferably independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

[0027] In one embodiment, R 1 and R 2 In the above, the halogens are preferably F, Cl, Br or I, independently.

[0028] In one embodiment, R 1 and R 2 In the above, the C1 to C4 alkyl groups are independently preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0029] In one embodiment, R 3 In the above, the halogen is preferably F, Cl, Br or I.

[0030] In one embodiment, R 3 In the above, the C1 to C4 alkoxy is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy.

[0031] In one embodiment, R on the benzene ring 3 The substitution positions of are the ortho positions, the "ortho and para positions" or the "ortho and meta positions", where the ortho, para and meta positions are all the same as in formula I'.

[0032] [ka]

[0033] R on the benzene ring 3 Refers to the substitution position of.

[0034] In one embodiment, R on the benzene ring 3 The substitution positions of are the ortho positions, the "ortho and para positions" or the "ortho and meta positions", where the ortho, para and meta positions are all the same as in formula I.

[0035] [ka]

[0036] R on the benzene ring 3 Refers to the substitution position of.

[0037] In one embodiment, X is

[0038] [ka]

[0039] It is.

[0040] In one embodiment, X is

[0041] [ka]

[0042] and R a is C1-C4 alkyl.

[0043] In one embodiment, X is

[0044] [ka]

[0045] It is. In one embodiment, X is

[0046] [ka]

[0047] and R b and R c are independently hydrogen.

[0048] In one embodiment, X is

[0049] [ka]

[0050] It is.

[0051] In one embodiment, R 1 and R 2 is hydrogen.

[0052] In one embodiment, R 3 are independently hydrogen, hydroxyl, or C1-C4 alkoxy.

[0053] In one embodiment, n is 1 or 2.

[0054] In one embodiment, X is

[0055] [ka]

[0056] It is.

[0057] In one embodiment,

[0058] [ka]

[0059] teeth,

[0060] [ka]

[0061] It is.

[0062] In one embodiment,

[0063] [ka]

[0064] teeth,

[0065] [ka]

[0066] It is.

[0067] In one embodiment,

[0068] [ka]

[0069] teeth,

[0070] [ka]

[0071] It is.

[0072] In one embodiment,

[0073] [ka]

[0074] teeth,

[0075] [ka]

[0076] It is.

[0077] In one embodiment,

[0078] [ka]

[0079] teeth,

[0080] [ka]

[0081] It is.

[0082] In one embodiment, X is

[0083] [ka]

[0084] and R a is C1-C4 alkyl, R b and R c are independently hydrogen; R 1 and R 2 is hydrogen, R 3 are independently hydrogen, hydroxyl, or C1-C4 alkoxy; n is 1 or 2; z is 1 or 2; R on the benzene ring 3 The substitution positions are the ortho positions, the "ortho and para positions" or the "ortho and meta positions".

[0085] In one embodiment, X is

[0086] [ka]

[0087] and R a is C1-C4 alkyl, R 1 and R 2 is hydrogen, R 3 are independently hydrogen, hydroxyl, or C1-C4 alkoxy; n is 1 or 2; R on the benzene ring 3 The substitution positions are the ortho positions, the "ortho and para positions" or the "ortho and meta positions".

[0088] In one embodiment, the fused ring piperidine compound of formula I' is any one of the following compounds:

[0089] [ka] JPEG2025502334000030.jpg90169

[0090] The present invention further provides a method for preparing the fused ring piperidine compound represented by the above formula I′ or a pharma- ceutically acceptable salt thereof, comprising: Method 1, Method 2 or Method 3.

[0091] R 3 are independently hydrogen, halogen or C1-C4 alkoxy, the preparation method of the fused ring piperidine compound or a salt thereof represented by the formula I′ is method 1 or method 2.

[0092] Method 1 includes the steps of subjecting a compound represented by formula II' and a compound represented by formula III to the following substitution reaction in a solvent in the presence of a base to obtain the fused ring piperidine compound represented by formula I':

[0093] [ka]

[0094] Method 2 includes the step of subjecting a compound represented by formula II' and a compound represented by formula IV to the following reductive amination reaction in a solvent in the presence of a reducing agent to obtain the fused ring piperidine compound represented by formula I'.

[0095] [ka]

[0096] R 3 When each is independently hydroxyl, the method for preparing the fused ring piperidine compound of formula I′ or a salt thereof is method 3.

[0097] Method 3 is a method of reacting a fused ring piperidine compound represented by formula I' described in Method 1 or 2 in the presence of BBr3 in a solvent to obtain a fused ring piperidine compound represented by formula I' (i.e., R 3 is hydroxyl.

[0098] X, R in Methods 1, 2 and 3 a , R b , R c , R 1 , R 2 , m and n are all as defined above; m-1 means one less carbon than m.

[0099] In Method 1, the conditions and operations of said substitution reaction may be the usual conditions and operations for such reactions in the art, but the following conditions and operations are particularly preferred in the present invention.

[0100] The base is preferably an organic base, for example, diisopropylethylamine (DIPEA). The molar ratio of the base to the compound represented by formula II' is preferably (1-3):1, for example, 1:1.

[0101] The molar ratio of the compound represented by the formula III to the compound represented by the formula II' is preferably (1-3):1, for example, 1.5:1.

[0102] The solvent is preferably a polar aprotic organic solvent, for example dimethylsulfoxide (DMSO).

[0103] The temperature of the substitution reaction is preferably from room temperature to 80°C, more preferably from 50 to 80°C, for example, 60°C.

[0104] In Method 2, the reaction conditions and operations may be those common to such reactions in the art, but the following conditions and operations are particularly preferred in the present invention.

[0105] The solvent is preferably an alcoholic solvent, for example methanol.

[0106] The reducing agent is preferably a borane-based reducing agent, for example, sodium cyanoborohydride.

[0107] The temperature of the reductive amination reaction is preferably 0 to 60° C., for example, room temperature.

[0108] In Method 3, the reaction conditions and operations may be those common to such reactions in the art, but the following conditions and operations are particularly preferred in the present invention.

[0109] The solvent is preferably a halogenated hydrocarbon organic solvent, for example, dichloromethane.

[0110] The reaction temperature is preferably −40° C. to 40° C., more preferably 10 to 40° C., for example, room temperature.

[0111] The present invention further provides a method for preparing the fused ring piperidine compound represented by the above formula I or a pharma- ceutically acceptable salt thereof, comprising: Method 1 or Method 2.

[0112] R 3 are independently hydrogen, halogen or C1-C4 alkoxy, the method for preparing the fused ring piperidine compound represented by formula I or a salt thereof is method 1.

[0113] Method 1 includes the steps of subjecting a compound represented by formula II and a compound represented by formula III to the following substitution reaction in a solvent in the presence of a base to obtain the fused ring piperidine compound represented by formula I:

[0114] [ka]

[0115] R 3 When each is independently hydroxyl, the method for preparing the fused ring piperidine compound of formula I or a salt thereof is method 2.

[0116] Method 2 is a method of reacting the fused ring piperidine compound of formula I described in Method 1 in a solvent in the presence of BBr3 to obtain a fused ring piperidine compound of formula I (i.e., R 3 is hydroxyl.

[0117] X and R in Methods 1 and 2 a , R b , R c , R 1 , R 2 , m and n are all as defined above.

[0118] In Method 1, the conditions and operations of said substitution reaction may be the usual conditions and operations for such reactions in the art, but the following conditions and operations are particularly preferred in the present invention.

[0119] The base is preferably an organic base, such as diisopropylethylamine (DIPEA). The molar ratio of the base to the compound represented by formula II is preferably (1-3):1, such as 1:1.

[0120] The molar ratio of the compound represented by the formula III to the compound represented by the formula II is preferably (1-3):1, for example, 1.5:1.

[0121] The solvent is preferably a halogenated hydrocarbon organic solvent, for example, dichloromethane.

[0122] The temperature of the substitution reaction is preferably 50 to 80°C, for example, 60°C.

[0123] In Method 2, the reaction conditions and operations may be those common to such reactions in the art, but the following conditions and operations are particularly preferred in the present invention.

[0124] The solvent is preferably a halogenated hydrocarbon organic solvent, for example, dichloromethane.

[0125] The temperature of the substitution reaction is preferably 10 to 40° C., for example, room temperature.

[0126] The present invention further provides a pharmaceutical composition comprising the fused ring piperidine compound represented by formula I' or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0127] The present invention further provides a pharmaceutical composition comprising the fused ring piperidine compound of formula I or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0128] The present invention relates to 5-HT 2AFurther provided is the use of Substance A, which is a fused ring piperidine compound of formula I', a pharma- ceutically acceptable salt thereof or a pharmaceutical composition as described above, in the preparation of a receptor agonist.

[0129] 5-HT 2A The receptor agonist is preferably a 5-HT 2A Agonists of the downstream β-arrestin 2 recruitment signaling pathway and / or 5-HT 2A Agonists of the downstream Gq protein-activated signaling pathway, e.g., 5-HT 2A It is an agonist of the receptor downstream β-arrestin 2 recruitment signaling pathway.

[0130] The present invention relates to 5-HT 2A Further provided is the use of Substance A, which is a fused ring piperidine compound of formula I, a pharma- ceutically acceptable salt thereof or a pharmaceutical composition as described above, in the preparation of a receptor agonist.

[0131] 5-HT 2A The receptor agonist is preferably a 5-HT 2A Agonists of the downstream β-arrestin 2 recruitment signaling pathway and / or 5-HT 2A Agonists of the downstream Gq protein-activated signaling pathway, e.g., 5-HT 2A It is an agonist of the receptor downstream β-arrestin 2 recruitment signaling pathway.

[0132] The present invention further provides the use of substance A in the preparation of a medicament.

[0133] The substance A includes a fused ring piperidine compound represented by the formula I', a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition described above; The drug is 5-HT 2A It is used to treat or prevent diseases associated with the receptor.

[0134] 5-HT 2A The disease associated with the receptor is preferably 5-HT 2AReceptor downstream β-arrestin 2 recruitment signaling pathway and / or 5-HT 2A The disease is related to the downstream Gq protein-activated signaling pathway of the receptor, preferably 5-HT 2A Diseases associated with the receptor downstream β-arrestin 2 recruitment signaling pathway, such as depression.

[0135] The present invention further provides the use of substance A in the preparation of a medicament.

[0136] The substance A includes a fused ring piperidine compound represented by the formula I, a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition described above; The drug is 5-HT 2A It is used to treat or prevent diseases associated with the receptor.

[0137] 5-HT 2A The disease associated with the receptor is preferably 5-HT 2A Receptor downstream β-arrestin 2 recruitment signaling pathway and / or 5-HT 2A The disease is related to the downstream Gq protein-activated signaling pathway of the receptor, preferably 5-HT 2A Diseases associated with the receptor downstream β-arrestin 2 recruitment signaling pathway, such as depression.

[0138] The present invention further provides the use of a substance A comprising the fused ring piperidine compound represented by formula I', its pharma- ceutically acceptable salt or the above pharmaceutical composition in the preparation of a medicament for treating or preventing depression.

[0139] The present invention further provides the use of a substance A comprising the fused ring piperidine compound represented by formula I, a pharma- ceutically acceptable salt thereof, or the above pharmaceutical composition, in the preparation of a medicament for treating or preventing depression.

[0140] The present invention further provides a method for treating or preventing depression, comprising administering to a subject (e.g., a human or a mouse) in need thereof a therapeutically effective amount of substance A, which is a fused ring piperidine compound represented by formula I', a pharma- ceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0141] In the present invention, room temperature refers to 10 to 30° C. Overnight refers to 8 to 15 hours.

[0142] In the present invention, halogen is preferably fluorine, chlorine, bromine or iodine.

[0143] In the present invention, alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0144] In the present invention, alkoxy represents cyclic or non-cyclic alkyl having the stated number of carbon atoms connected by an oxygen bridge. Thus, alkoxy includes the above definitions of alkyl and cycloalkyl. In the present invention, alkoxy is preferably C1-C4 alkoxy, more preferably methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy.

[0145] In the present invention, "ns" indicates no significant difference, "*" indicates P<0.05, "**" indicates P<0.01, "***" indicates P<0.001, and "****" indicates P<0.0001.

[0146] Based on the common knowledge in the art, each of the above preferred conditions can be arbitrarily combined to obtain each of the preferred embodiments of the present invention.

[0147] All of the reagents and materials used in the present invention are commercially available.

[0148] The positive and progressive effect of the present invention is that the fused ring piperidine compound of the present invention has a better inhibitory effect on depression, and can effectively treat depression.Furthermore, the fused ring piperidine compound of the present invention can avoid hallucinogenic side effects while treating depression. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the antidepressant effect of compound I-3 in the tail suspension test in mice in Biological Test Example 5, where "*" indicates P<0.05 and "****" indicates P<0.0001. FIG. 2 shows the antidepressant effect of compound I-3 in the forced swimming test in mice in biological test Example 5, where "ns" indicates no significant difference and "****" indicates P<0.0001. FIG. 3 shows the antidepressant effect of compound I-10 in the tail suspension test in mice in Biological Test Example 5, where "ns" indicates no significant difference and "****" indicates P<0.0001. FIG. 4 shows the antidepressant effect of compound I-10 in the forced swimming test in mice in biological test Example 5, where "ns" indicates no significant difference and "****" indicates P<0.0001. FIG. 5 shows the response of compound I-3 to head convulsions in mice in Biological Test Example 6. FIG. 6 shows the response of compound I-10 to head convulsions in mice in Biological Test Example 6. FIG. 7 shows the response of compound I-23 to head spasms in mice in Biological Test Example 7. [Figure 8] Biological test Example 7 shows the antidepressant effect of compound I-23 1 day, 7 days and 14 days after a single injection in the mouse tail suspension test, where "ns" means no significant difference, "*" means P<0.05, "**" means P<0.01, "***" means P<0.001 and "****" means P<0.0001. [Mode for carrying out the invention] Example 1: Preparation of (6bR,10aS)-8-(2-methoxyphenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (Compound I-1)

[0149] [ka]

[0150] Step 1: 2-Methoxyphenylmethanol (0.54 g, 3.91 mmol), CBr4 (1.94 g, 5.87 mmol) were added to a round-bottom flask, dissolved with solvent dichloromethane (20 mL), placed in an ice-water bath, and PPh3 (1.54 g, 5.87 mmol) was added. The reaction system was stirred at room temperature for 5 h. After the reaction was completed, the solvent was removed under reduced pressure and purified by flash silica gel column (eluent: 10-30% ethyl acetate / petroleum ether) to obtain colorless oil whc46 (0.75 g, yield: 96%). 1 H NMR (800 MHz, CDCl3) δ 7.33 (d, J = 7.5 Hz, 1H), 7.31 - 7.27 (m, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.57 (s, 2H), 3.90 (s, 3H).

[0151] Step 2: Raw material (A) ((6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline, catalog number: 313368-85-3, purchased from Bide Pharmatech Ltd.) (100 mg, 0.44 mmol), whc46 (130 mg, 0.66 mmol), solvent DMSO (5 mL), and diisopropylethylamine (DIPEA) (1 mL) were added to a round bottom flask. The reaction was stirred at 60 °C overnight. After the reaction was completed, water was added, extracted with ethyl acetate, the organic phases were combined, washed once with saturated saline, concentrated, and then separated and purified by a flash silica gel column (eluent: 0-10% methanol / dichloromethane) to obtain a yellow solid I-1 (100 mg, yield: 65%). 1 H NMR (800 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 1H), 7.31 - 7.26 (m, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.48 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 3.80 - 3.78 (m, 5H),3.60 - 3.56 (m, 1H), 3.47 - 3.43 (m, 1H), 3.30 - 3.22 (m, 3H), 3.10 (dd, J = 12.0, 6.6 Hz, 1H), 2.95 - 2.91 (m, 1H), 2.85 (s, 3H), 2.79 (t, J = 9.9 Hz, 1H), 2.61 - 2.56 (m, 1H), 2.27 - 2.23 (m, 2H), 1.98 (d, J = 14.4 Hz, 1H). 13C NMR (201 MHz, CDCl3) δ 157.99, 137.70, 135.08, 131.85, 129.43, 129.02, 128.88, 120.71, 120.65, 112.74, 110.69, 109.08, 63.97, 55.51, 55.48, 55.11, 50.49, 48.16, 44.39, 40.58, 37.46, 23.81. HR-MS (ESI) m / z C 22 H 28 N3O + [M+H] + Calculated value: 350.2227; Measured value: 350.2233.

[0152] Example 2: Preparation of 2-(((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)methyl)phenol (compound I-2)

[0153] [ka]

[0154] I-1 (47 mg, 0.13 mmol) and anhydrous dichloromethane (15 mL) were added to a round-bottom flask, cooled to -78 °C under argon gas protection, and BBr3 (17% ether solution, 0.6 mL) was added. The reaction system was then stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched by adding saturated aqueous NaHCO3 at low temperature (-30 °C), and the solvent was removed. The product was then purified by flash silica gel column and further purified by preparative liquid chromatography (20-80% MeOH / H2O, t R =18.5 min) to obtain a yellow solid I-2 (40 mg, 32%). 1H NMR (800 MHz, CD3OD) δ 7.34 - 7.29 (m, 2H), 6.97 - 6.89 (m, 2H), 6.68 - 6.64 (m, 1H), 6.53 - 6.47 (m, 2H), 4.28 (s, 2H), 3.56 (t, J = 10.9 Hz, 1H), 3.52 - 3.50 (m, 1H), 3.46 - 3.40 (m, 2H), 3.37 - 3.32 (m, 2H), 3.28 - 3.22 (m, 2H), 2.87 (s, 3H), 2.79 (t, J = 10.2 Hz, 1H), 2.74 (t, J = HR-MS (ESI) m / z calcd for C 21 H 26 N3O + [M+H] + Calculated value: 336.2070; Measured value: 336.2071.

[0155] Example 3: Preparation of (6bR,10aS)-8-(2-methoxyphenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (compound I-3)

[0156] [ka]

[0157] According to the method of Step 2 of Example 1, 1-(2-bromoethyl)-2-methoxybenzene (catalog number: 36449-75-9) was reacted with raw material (A) to give compound I-3 (220 mg, 90%) as a yellow oil. 1H NMR (800 MHz, CDCl3) δ 7.17 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.83 ‐ 6.80 (m, 1H), 6.66 (t, J = 7.7 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 3.78 (s, 3H), 3.62 ‐ 3.58 (m, 1H), 3.36 ‐ 3.32 (m, 1H), 3.31‐ 3.28 (m, 1H), 3.27 -3.23 (m, 2H), 3.10 (dd, J = 11.7, 6.5 Hz, 1H), 2.93 ‐ 2.89 (m, 3H), 2.86 (s, 3H), 2.82 (t, J = 10.0 Hz, 1H), 2.72 ‐ 2.63 (m, 2H), 2.53 ‐ 2.47 (m, 1H), 2.20 - 2.10 (m, 2H), 2.04 - 1.97 (m, 1H). 13 C NMR (201 MHz, CDCl3) δ 157.51, 137.87, 135.12, 130.39, 129.53, 127.85, 127.63, 120.59, 112.76, 110.38, 109.11, 64.31, 58.45, 55.61, 55.28, 50.64, 48.74, 44.44, 41.15, 37.55, 27.40, 24.37. HR-MS (ESI) m / z C 23 H 30 N3O + [M+H] + Calculated value: 364.2383; Measured value: 364.2386. Optical rotation value: [α] D 25 = ‐54 o (c=0.1,CHCl3).

[0158] Example 4: Preparation of (6bR,10aS)-8-(3-methoxyphenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (compound I-4)

[0159] [ka]

[0160] According to the method of Step 2 of Example 1, 1-(2-bromoethyl)-3-methoxybenzene (catalog number: 2146-61-4) was reacted with raw material (A) to give compound I-4 (80 mg, 84%) as a yellow oil. 1 H NMR (800 MHz, CDCl3) δ 7.21 - 7.17 (m, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.76 - 6.72 (m, 2H), 6.66 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 3.63 - 3.59 (m, 1H), 3.32 (dt, J = 10.1, 2.9 Hz, 1H), 3.29 - 3.22 (m, 2H), 3.22 - 3.18 (m, 1H), 2.99 - 2.95 (m, 1H), 2.87 (s, 3H), 2.84 (dd, J = 10.0, 3.0 Hz, 1H), 2.82 - 2.78 (m, 2H), 2.78 - 2.74 (m, 1H), 2.64 - 2.55 (m, 2H), 2.37 - 2.33 (m, 1H), 2.05 (t, J = 11.2 Hz, 1H), 2.00 - 1.93 (m, 2H). 13C NMR (201 MHz, CDCl3) δ 159.70, 142.13, 138.03, 135.06, 130.04, 129.38, 121.16, 120.38, 114.54, 112.75, 111.37, 109.01, 64.58, 60.63, 56.30, 55.16, 50.71, 49.07, 44.41, 41.79, 37.61, 33.67, 25.06. HR-MS (ESI) m / z C 23 H 30 N3O + [M+H] + Calculated value: 364.2383; Measured value: 364.2385.

[0161] Example 5: Preparation of (6bR,10aS)-8-(4-methoxyphenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (compound I-5)

[0162] [ka]

[0163] According to the method of Step 2 of Example 1, 1-(2-bromoethyl)-4-methoxybenzene (catalog number: 14425-64-0) was reacted with raw material (A) to give compound I-5 (40 mg, 42%) as a yellow oil. 1H NMR (800 MHz, CDCl3) δ 7.13 ‐ 7.08 (m, 2H), 6.84 ‐ 6.81 (m, 2H), 6.66 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 3.78 (s, 3H), 3.61 (td, J = 11.0, 10.5, 3.1 Hz, 1H), 3.32 (dt, J = 10.1, 3.0 Hz, 1H), 3.29 ‐ 3.23 (m, 2H), 3.22 ‐ 3.18 (m, 1H), 2.99 ‐ 2.95 (m, 1H), 2.87 (s, 3H), 2.83 (td, J = 10.0, 2.9 Hz, 1H), 2.79 ‐ 2.72 (m, 3H), 2.60 ‐ 2.50 (m, 2H), 2.36 ‐ 2.30 (m, 1H), 2.04 (t, J = 11.2 Hz, 1H), 1.99 - 1.94 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.97, 138.03, 135.05, 132.52, 130.06, 129.64, 120.37, 113.89, 112.76, 109.00, 64.59, 61.02, 56.34, 55.28, 50.71, 49.09, 44.41, 41.78, 37.60, 32.71, 25.05. HR-MS (ESI) m / z C 23 H 30 N3O + [M+H] + Calculated value: 364.2383; Measured value: 364.2388.

[0164] Example 6: (6bR,10aS)-8-(2,3-ジジメトキシフェニル)-3-メチル-2,3,6b,7,8,9,10,1 Modulation of 0a-オクタヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン (Compound I-6)

[0165]

change

[0166] According to the method of Step 2 of Example 1, 1-(2-bromoethyl)-2,3-dimethoxybenzene (catalog number: 709027-29-2) was reacted with raw material (A) to give compound I-6 (130 mg, 75%) as a yellow oil. 1 H NMR (800 MHz, CDCl3) δ 6.96 (t, J = 7.9 Hz, 1H), 6.78 - 6.75 (m, 2H), 6.65 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.60 (td, J = 10.5, 3.0 Hz, 1H), 3.33 - 3.31 (m, 1H), 3.28 - 3.25 (m, 1H), 3.24 - 3.22 (m, 1H), 3.21 - 3.19 (m, 1H), 2.99 (dd, J = 11.6, 6.2 Hz, 1H), 2.86 (s, 3H), 2.84 (t, J = 8.2 Hz, 2H), 2.82 - 2.78 (m, 1H), 2.60 - 2.54 (m, 2H), 2.40 - 2.32 (m, 2H), 2.10 - 2.03 (m, 1H), 1.99 - 1.97 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 152.80, 147.35, 138.07, 135.05, 134.21, 130.12, 123.88, 122.31, 120.34, 112.81, 110.53, 108.98, 64.63, 60.81, 59.76, 56.26, 55.73, 50.71, 48.98, 44.44, 41.78, 37.61, 27.62, 25.03. HR-MS (ESI) m / z C 24 H 32 N3O2 + [M+H] + Calculated value: 394.2489; Measured value: 394.2489.

[0167] Example 7: Preparation of (6bR,10aS)-8-(2,4-methoxyphenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (Compound I-7)

[0168] [ka]

[0169] According to the method of Step 2 of Example 1, 1-(2-bromoethyl)-2,4-dimethoxybenzene (catalog number: 37567-79-6) was reacted with raw material (A) to give compound I-7 (72 mg, 84%) as a yellow oil. 1 H NMR (800 MHz, CDCl3) δ 7.12 (d, J = 8.0 Hz, 1H), 6.71 (t, J = 7.7 Hz, 1H), 6.53 (d, J = 7.4 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 6.42 - 6.41 (m, 2H), 3.86 - 3.83 (m, 1H), 3.77 (s, 3H), 3.76 (s, 3H), 3.62 (t, J = 10.1 Hz, 1H), 3.50 (dd, J = 12.1, 6.5 Hz, 1H), 3.44 - 3.39 (m, 1H), 3.36 - 3.32 (m, 1H), 3.31 (d, J = 10.3 Hz, 2H), 3.17 - 3.11 (m, 2H), 3.11 - 3.05 (m, 3H), 2.88 (s, 3H), 2.86 - 2.83 (m, 1H), 2.81 - 2.74 (m, 1H), 2.61 - 2.59 (m, 1H), 2.19 - 2.14 (m, 1H). 13C NMR (201 MHz, CDCl3) δ 160.33, 158.12, 137.07, 135.43, 131.05, 127.07, 121.49, 116.60, 112.53, 109.59, 104.43, 98.62, 62.94, 56.98, 55.37, 55.30, 53.37, 50.31, 47.85, 44.38, 38.77, 37.33, 24.75, 21.94. HR-MS (ESI) m / z C 24 H 32 N3O2 + [M+H] + Calculated value: 394.2489; Measured value: 394.2498.

[0170] Example 8: Preparation of (6bR,10aS)-8-(2,5-dimethoxy)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (Compound I-8)

[0171] [ka]

[0172] According to the method of Step 2 of Example 1, 1-(2-bromoethyl)-2,5-dimethoxybenzene (catalog number: 99187-42-5) was reacted with raw material (A) to give compound I-8 (50 mg, 13%) as a yellow oil. 1H NMR (800 MHz, CDCl3) δ 6.75 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H), 6.69 (dd, J = 8.8, 3.1 Hz, 1H), 6.66 (t, J = 7.7 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 3.60 (td, J = 10.7, 3.0 Hz, 1H), 3.31 (dt, J = 10.2, 3.0 Hz, 1H), 3.29 - 3.22 (m, 3H), 3.08 - 3.03 (m, 1H), 2.86 (s, 3H), 2.85 - 2.81 (m, 4H), 2.66 - 2.64 (m, 2H), 2.44 (t, J = 12.0 Hz, 1H), 2.12 (t, J = 11.3 Hz, 1H), 2.09 - 2.02 (m, 1H), 2.00 - 1.97 (m, 1H). 13 C NMR (201 MHz, CDCl3) δ 153.49, 151.78, 137.92, 135.05, 129.76, 129.46, 120.43, 116.63, 112.74, 111.48, 111.32, 109.01, 64.40, 58.56, 55.92, 55.77, 55.68, 50.63, 48.75, 44.39, 41.35, 37.54, 27.70, 24.58. HR-MS (ESI) m / z C 24 H 32 N3O2 + [M+H] + Calculated value: 394.2489; Measured value: 394.2489.

[0173] Example 9: Preparation of 2-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)phenol (Compound I-9)

[0174] [ka]

[0175] Following the method of Example 2, I-3 was subjected to demethylation reaction to give compound I-9 (100 mg, 70%) as a yellow solid. 1 H NMR (800 MHz, CD3OD) δ 6.98 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 6.54 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 7.3 Hz, 1H), 6.36 (d, J = 7.9 Hz, 1H), 3.48 - 3.43 (m, 1H), 3.24 - 3.21 (m, 2H), 3.14 - 3.10 (m, 2H), 2.98 - 2.96 (m, 1H), 2.86 - 2.81 (m, 1H), 2.78 (s, 3H), 2.77 - 2.76 (m, 2H), 2.72 - 2.67 (m, 1H), 2.60 - 2.57 (m, 1H), 2.55 - 2.51 (m, 1H), 2.40 (t, J = 12.2 Hz, 1H), 2.05 - 1.98 (m, 2H), 1.96 - 1.92 (m, 1H). 13 C NMR (201 MHz, CD3OD) δ 157.45, 139.31, 136.51, 131.74, 130.77, 128.82, 128.79, 121.76, 120.44, 117.55, 114.08, 110.78, 65.79, 60.28, 57.16, 51.86, 49.93, 45.67, 42.65, 38.06, 31.08, 25.37. HR-MS (ESI) m / z C 22 H 28 N3O + [M+H] + Calculated value: 350.2227; Measured value: 350.2227.

[0176] Example 10: Preparation of (6bR,10aS)-8-(3-(2-methoxy)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (Compound I-10)

[0177] [ka]

[0178] Step 1: 3-(2-methoxyphenyl)propionic acid (2.0 g, 11.1 mmol), solvent DMF (10 mL), and Cs2CO3 (10.8 g, 33.3 mmol) were added to a round-bottom flask, followed by BnBr (2.85 g, 16.7 mmol). The reaction system was stirred at room temperature overnight. After the reaction was completed, the solvent was removed and the product was separated and purified by flash silica gel column (eluent: 20-30% ethyl acetate / petroleum ether) to obtain a colorless oily product whc31 (2.8 g, yield: 97%). 1 H NMR (800 MHz, CDCl3) δ 7.36 - 7.34 (m, 2H), 7.33 - 7.29 (m, 3H), 7.21 - 7.18 (m, 1H), 7.12 (dd, J = 7.4, 1.7 Hz, 1H), 6.86 (dd, J = 7.4, 1.1 Hz, 1H), 6.85 - 6.82 (m, 2H), 5.11 (s, 2H), 3.80 (s, 3H), 2.98 - 2.95 (m, 2H), 2.69 - 2.65 (m, 2H).

[0179] Step 2: whc31 (benzyl 3-(2-methoxyphenyl)propionate, 1.0 g, 3.7 mmol) was added to a dry round-bottom flask, dissolved by adding THF (15 mL), protected with argon gas, and placed in a low-temperature reactor at -10 °C for stirring. After 10 min, DABAL-H (23 mL, 1 M in hexane) was added. Then, the reaction system was stirred at 0 °C for 5 h. After the reaction was completed, the reaction was quenched with saturated potassium sodium tartrate solution (5 mL) at low temperature (-10 °C). After removing the solvent, it was separated and purified by flash silica gel column (eluent: 20-50% ethyl acetate / petroleum ether) to obtain a colorless oil whc47 (0.50 g, yield: 81%). 1 H NMR (800 MHz, CDCl3) δ 7.19 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.83 (s, 3H), 3.60 (t, J = 6.2 Hz, 2H), 2.72 (t, J = 7.4 Hz, 2H), 1.88 - 1.82 (m, 2H).

[0180] Step 3: According to the method of Step 1 of Example 1, whc47 was subjected to bromination reaction to obtain compound whc52 (0.62 g, yield: 90%) as a colorless oil. 1 H NMR (800 MHz, CDCl3) δ 7.22 - 7.17 (m, 1H), 7.15 (dd, J = 7.4, 1.7 Hz, 1H), 6.91 - 6.87 (td, J = 7.4, 1.1 Hz, 1H), 6.85 (dd, J = 8.1, 1.1 Hz, 1H), 3.82 (s, 3H), 3.40 (t, J = 6.8 Hz, 2H), 2.78 - 2.74 (m, 2H), 2.18 - 2.12 (m, 2H).

[0181] Step 4: According to the method of Step 2 of Example 1, whc52 (1-(3-bromopropyl)-2-methoxybenzene) was reacted with raw material (A) to give compound I-10 (80 mg, 96%) as a yellow oil. 1 H NMR (800 MHz, CD3OD) δ 7.24 - 7.18 (m, 1H), 7.13 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 9.7 Hz, 1H), 6.59 (d, J = 7.3 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 3.57 - 3.53 (m, 2H), 3.47 - 3.44 (m, 1H), 3.43 - 3.40 (m, 1H), 3.39 - 3.32 (m, 2H), 3.29 - 3.25 (m, 1H), 3.19 - 3.15 (m, 1H), 3.13 - 3.04 (m, 2H), 2.88 (s, 3H), 2.84 - 2.80 (m, 1H), 2.69 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 12.3 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.16 - 2.09 (m, 1H), 2.07 - 1.99 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.02, 137.25, 134.89, 129.50, 128.97, 128.28, 127.07, 120.46, 120.11, 112.22, 110.02, 108.89, 63.48, 57.39, 54.94, 54.52, 50.15, 48.05, 43.99, 39.96, 37.13, 27.50, 25.02, 23.11. HR-MS (ESI) m / z C 24 H 32 N3O + [M+H] + Calculated value: 378.2540; Measured value: 378.2547. Optical rotation value: [α] D 25 = ‐41 o(c=0.1, CHCl3).

[0182] Example 11: Preparation of 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (Compound I-11)

[0183] [ka]

[0184] Following the method of Example 2, I-10 was subjected to a demethylation reaction to give compound I-11 (20 mg, 34%) as a grey solid. 1 H NMR (800 MHz, CD3OD) δ 7.51 (s, 1H), 7.10 (dd, J = 7.4, 1.7 Hz, 1H), 7.05 (td, J = 7.7, 1.7 Hz, 1H), 6.79 - 6.75 (m, 2H), 6.69 (d, J = 7.8 Hz, 1H), 6.62 - 6.58 (m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 3.60 - 3.56 (m, 2H), 3.53 - 3.45 (m, 1H), 3.45 - 3.41 (m, 1H), 3.40 - 3.35 (m, 1H), 3.30 - 3.26 (m, 1H), 3.18 (t, J = 13.0 Hz, 1H), 3.14 - 3.10 (m, 2H), 2.89 (s, 3H), 2.85 - 2.81 (m, 1H), 2.70 (t, J = 7.5 Hz, 2H), 2.66 (t, J = 12.3 Hz, 1H), 2.35 (d, J = 16.3 Hz, 1H), 2.19 - 2.13 (m, 1H), 2.10 - 2.06 (m, 3H). 13C NMR (201 MHz, CD3OD) δ 153.62, 136.36, 133.00, 128.48, 126.02, 124.86, 119.73, 118.03, 113.29, 111.74, 109.11, 61.41, 55.44, 52.00, 49.00, 42.49, 37.94, 35.47, 27.55, 25.44, 22.75, 20.56, 18.11, 11.71. HR-MS (ESI) m / z calcd for C 23 H 30 N3O + [M+H] + Calculated value: 364.2383; Measured value: 364.2386.

[0185] Examples 12 and 13: Preparation of (8aS,12aR)-11-(2-methoxyphenylethyl)-4-methyl-4,5,6,7,8a,9,10,11,12,12a-decahydro-[1,4]diazepine[3,2,1-hi]pyrido[4,3-b]indole (compound I-12) and (8aR,12aS)-11-(2-methoxyphenylethyl)-4-methyl-4,5,6,7,8a,9,10,11,12,12a-decahydro-[1,4]diazepine[3,2,1-hi]pyrido[4,3-b]indole (compound I-13)

[0186] [ka]

[0187] Step 1: 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one (1.6 g, 10 mmol) was added to a round-bottom flask, and a mixture of acetic acid:water (2:1) (15 mL) was added, stirred to dissolve, and cooled to 0°C. Sodium nitrite (770 mg, 11 mmol) in water (5 mL) was slowly added dropwise to the reaction solution. After the addition was completed, the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, it was filtered to obtain a pale yellow solid DW05006 (1.7 g, yield: 89%). 1H NMR (800 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.54 (dd, J = 7.9, 1.3 Hz, 1H), 7.50 (td, J = 7.8, 1.4 Hz, 1H), 7.31 (td, J = 7.7, 1.4 Hz, 1H), 7.21 (dd, J = 8.0, 1.2 Hz, 1H), 4.14 - 4.08 (m, 2H), 2.65 (dd, J = 7.5, 5.4 Hz, 2H). HRMS (ESI) m / z C9H 10 N3O2 + [M+H] + Calculated value: 192.0768, actual value: 192.0771.

[0188] Step 2: DW05006 (0.96 g, 5 mmol) was added to a round bottom flask, acetic acid (10 mL) was added, and the mixture was stirred at room temperature to dissolve, then placed in an ice bath environment, and zinc powder (1.6 g, 25 mmol) was added slowly to the reaction in batches. After the addition was complete, the reaction was stirred at room temperature for 1 hour to complete the reaction.

[0189] Step 3: The insoluble matter in the reaction solution from the previous step was removed by filtration, and N-ethoxycarbonyl-4-piperidone (0.75 mL, 5 mmol) and 0.3 mL of 1N aqueous hydrochloric acid were added to the filtrate, and the reaction system was heated to reflux and continued to react with stirring. After 2 hours, the reaction was completed. The reaction system was cooled to room temperature and most of the acetic acid was removed by distillation under reduced pressure, and cold ethanol was slowly added to precipitate a solid. Filtration gave pale yellow solid DW05007-2 (685 mg, yield: 44%). 1H NMR (800 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.77 (d, J = 7.3 Hz, 1H), 4.57 (s, 2H), 4.25 - 4.17 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.77 (t, J = 5.7 Hz, 2H), 2.91 - 2.84 (m, 2H), 2.79 (t, J = 5.6 Hz, 2H), 1.25 - 1.17 (m, 3H). HRMS (ESI) m / z C 17 H 20 N3O3 + [M+H] + Calculated value: 314.1499, measured value: 314.1521.

[0190] Step 4: DW05007-2 (626 mg, 2 mmol) was added to a round-bottom flask, trifluoroacetic acid (10 mL) was added, and the mixture was stirred at 0 °C to dissolve. Sodium cyanoborohydride (151 mg, 2.4 mmol) was added to the reaction solution in batches slowly. After the addition was completed, the reaction system was stirred at room temperature for 1 h. After the reaction was completed, 10 mL of water was added to the reaction system to quench the reaction. After removing most of the trifluoroacetic acid by vacuum distillation, the pH was adjusted to 9.0 with 2N aqueous sodium hydroxide solution. Extracted three times with ethyl acetate, the organic phase was combined, washed with saturated saline, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated, and then separated and purified by flash silica gel column (eluent: 0-50% petroleum ether / ethyl acetate) to obtain a white solid DW05008 (441 mg, yield: 70%). 1H NMR (800 MHz, CDCl3) δ 7.84 (s, 1H), 6.88 (d, J = 5.6 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H), 4.18 - 4.09 (m, 2H), 3.93 & 3.80 (1H), 3.64 - 3.59 (m, 2H), 3.51 - 3.45 (m, 1H), 3.34 - 3.30 (m, 2H), 3.24 - 3.21 (m, 1H), 3.20 - 3.07 (m, 1H), 2.91 - 2.83 (m, 2H), 1.91 (s, 2H), 1.26 (t, J = 6.8 Hz, 3H). HRMS (ESI) m / z C 17 H 22 N3O3 + [M+H] + Calculated value: 316.1656, actual value: 316.1670.

[0191] Step 5: DW05008 (315 mg, 1 mmol), iodomethane (0.1 mL, 1.2 mmol) were added to a round-bottom flask, anhydrous N,N-dimethylformamide (10 mL) was added, and the mixture was stirred at room temperature to dissolve. 60% sodium hydride (45 mg, 1.1 mmol) was added slowly in batches, and the reaction was continued with stirring at room temperature for 2 hours. After the reaction was completed, 10 mL of water was added to the reaction system to quench the reaction. Extracted three times with ethyl acetate, the organic phase was combined, washed with saturated saline, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated, and then separated and purified by flash silica gel column (eluent: 0-50% petroleum ether / ethyl acetate) to obtain colorless oil DW05009 (300 mg, yield: 91%). 1H NMR (800 MHz, CDCl3) δ 6.94 - 6.92 (m, 2H), 6.76 (t, J = 7.0 Hz, 1H), 4.17 - 4.07 (m, 2H), 3.82 (t, J = 11.6 Hz, 1H), 3.65 - 3.58 (m, 2H), 3.52 - 3.45 (m, 1H), 3.42 - 3.36 (m, 1H), 3.35 (s, 3H), 3.33 - 3.26 (m, 1H), 3.04 - 3.01 (m, 1H), 2.70 (t, J = 12.4 Hz, 1H), 2.55 (dd, J = 13.4, 4.7 Hz, 1H), 1.98 - 1.86 (m, 2H), 1.76 (s, 1H), 1.24 (t, J = 7.0 Hz, 3H). HRMS (ESI) m / z C 18 H 24 N3O3 + [M+H] + Calculated value: 330.1812, actual value: 330.1833.

[0192] Step 6: DW05009 (329 mg, 1 mmol) was added to a round bottom flask and dissolved in anhydrous tetrahydrofuran (10 mL). The reaction was placed under ice bath conditions and a solution of borane in tetrahydrofuran (1 M, 2 mL) was added dropwise. After the addition was complete, the reaction was heated to reflux for 1 hour. After the reaction was complete, the reaction was cooled to room temperature, 2N aqueous hydrochloric acid (1 mL) was added, and the mixture was heated and stirred at reflux. After 30 minutes, the reaction was returned to room temperature and 4N aqueous sodium hydroxide was added to adjust the pH to 9.0. Extracted three times with ethyl acetate, the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The organic phase was concentrated and then purified by flash silica gel column chromatography (eluent: 0-40% petroleum ether / ethyl acetate) to give a colorless oil DW05010 (300 mg, yield: 69%). HRMS (ESI) m / z C 18 H 26 N3O2 + [M+H] + Calculated value: 316.2020, actual value: 316.2031.

[0193] Step 7: DW05010 (315 mg, 1 mmol) was dissolved in n-butanol (10 mL) and potassium hydroxide (672 mg, 12 mmol) was added. The system was heated to 120 °C and stirred at reflux for 5 h. The reaction was completed and cooled to room temperature. 10 mL of water was added to the reaction system, extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and then purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give a pale yellow solid DW05011 (137 mg, yield: 56%). 1 H NMR (800 MHz, CDCl3) δ 6.75 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.1 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.50 - 3.45 (m, 1H), 3.29 - 3.22 (m, 2H), 3.14 (dt, J = 10.3, 6.6 Hz, 1H), 3.05 - 3.02 (m, 1H), 2.94 (td, J = 12.1, 3.0 Hz, 1H), 2.90 (s, 3H), 2.89 - 2.88 (m, 1H), 2.87 - 2.84 (m, 1H), 2.65 (td, J = 11.7, 3.5 Hz, 1H), 2.52 (dd, J = 12.6, 10.4 Hz, 1H), 2.02 - 1.97 (m, 1H), 1.97 - 1.94 (m, 1H), 1.92 - 1.89 (m, 1H), 1.84 - 1.80 (m, 1H). HRMS (ESI) m / z C 15 H 22 N3 + [M+H] + Calculated value: 244.1808, actual value: 244.1813.

[0194] Step 8: DW05011 (243 mg, 1 mmol), 4-methoxyphenylacetaldehyde (225 mg, 1.5 mmol) were added to a round bottom flask and methanol (10 mL) was added to dissolve. Sodium cyanoborohydride (94 mg, 1.5 mmol) was added slowly in batches. After the addition was complete, stirring was continued at room temperature overnight. After the reaction was complete, 10 mL of water was added to quench the reaction. Extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and then purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to give pale yellow oil DW05015 (302 mg, yield: 80%). 1 H NMR (800 MHz, CDCl3) δ 7.23 (td, J = 8.2, 1.5 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 6.81 (t, J = 7.7 Hz, 1H), 6.71 (d, J = 7.1 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 3.81 (s, 3H), 3.59 - 3.56 (m, 1H), 3.52 - 3.47 (m, 1H), 3.29 - 3.27 (m, 1H), 3.27 - 3.23 (m, 1H), 3.23 - 3.17 (m, 2H), 3.00 (t, J = 8.1 Hz, 2H), 2.96 - 2.84 (m, 4H), 2.92 (s, 3H), 2.82 - 2.78 (m, 1H), 2.63 (td, J = 12.0, 3.0 Hz, 1H), 2.36 - 2.34 (m, 1H), 2.29 - 2.26 (t, J = 10.5 Hz, 1H), 2.19 - 2.17 (m, 1H), 2.06 - 2.02 (m, 1H), 1.91 - 1.87 (m, 1H). 13C NMR (201 MHz, CDCl3) δ 157.44, 142.97, 140.15, 130.71, 128.66, 121.61, 121.00, 115.85, 115.56, 110.57, 62.71, 60.54, 57.60, 55.44, 55.12, 49.97, 48.66, 42.43, 39.25, 29.64, 26.55, 23.34. HRMS (ESI) m / z C 24 H 32 N3O + [M+H] + Calculated value: 378.2540, measured value: 378.2559.

[0195] Chiral analysis conditions: Apparatus: UPCC (Waters), Chiral column: CHIRALPAK OD (Daicel), Column volume: 4.6 × 100 mm (5 μm particle size packing), Temperature: 40 °C, Mobile phase: CO2 / MeOH [0.2% ammonia in methanol (7 M) = 70 / 30], Flow rate: 3.0 mL / min, Detection wavelength: 214 nm.

[0196] Chiral preparation conditions: Apparatus: SFC-150 (Waters), Chiral column: OD (Daicel), Column volume: 20 × 250 mm (10 μm particle size packing), Temperature: 35 °C, Mobile phase: CO2 / MeOH [0.2% ammonia in methanol (7 M) = 60 / 40], Flow rate: 100.0 mL / min, Detection wavelength: 214 nm. I-12 (HRMS (ESI) m / z C 24 H 32 N3O + [M+H] + Calculated value: 378.2540, Measured value: 378.2538; ee 99.64%; Optical rotation value: [α] D 25 =‐65 o (c=0.1, CHCl3), which matches the optical rotation direction of compound I-3, both are left-handed and have the same chiral configuration) and I-13 (HRMS (ESI) m / z C 24 H 32 N3O + [M+H] +Calculated value: 378.2540, Measured value: 378.2557; ee 99.44%; Optical rotation value: [α] D 25 = +103 o (c=0.1, CHCl3), which has the opposite optical rotation to that of compound I-3, is right-handed, and has the opposite chiral configuration) was prepared.

[0197] Examples 14 and 15: Preparation of (8aS,12aR)-11-(3-(2-methoxyphenyl)propyl)-4-methyl-4,5,6,7,8a,9,10,11,12,12a-decahydro-[1,4]diazepine[3,2,1-hi]pyrido[4,3-b]indole (compound I-14) and (8aR,12aS)-11-(3-(2-methoxyphenyl)propyl)-4-methyl-4,5,6,7,8a,9,10,11,12,12a-decahydro-[1,4]diazepine[3,2,1-hi]pyrido[4,3-b]indole (I-15)

[0198] [ka]

[0199] Step 1: Following the method of Step 8 of Examples 12 and 13, substituting 4-methoxyphenylpropionaldehyde for 4-methoxyphenylacetaldehyde, a pale yellow oil DW05014 (278 mg, yield: 81%) was obtained. 11H NMR (800 MHz, CDCl3) δ 7.19 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.80 (t, J = 7.6 Hz, 1H), 6.66 ‐ 6.64 (m, 2H), 3.81 (s, 3H), 3.66 ‐ 3.63 (m, 1H), 3.48 (t, J = 9.3 Hz, 1H), 3.26 ‐ 3.24 (m, 2H), 3.19 ‐ 3.15 (m, 1H), 2.96 ‐ 2.94 (m, 1H), 2.90 (s, 3H), 2.84 ‐ 2.76 (m, 3H), 2.68 ‐ 2.65 (m, 2H), 2.64 ‐ 2.62 (m, 1H), 2.47 ‐ 2.43 (m, 1H), 2.27 (t, J = 11.3 Hz, 1H), 2.17 (d, J = 15.8 Hz, 1H), 2.07 ‐ 2.05 (m, 2H), 2.04 ‐ 2.02 (m, 2H), 1.88 ‐ 1.84 (m, 1H). 13 13C NMR (201 MHz, CDCl3) δ 157.32, 1 42.65, 140.14, 129.99, 127.92, 121.62, 120.62, 115.83, 115.36, 110.46, 62.24, 57.31, 55.34, 54.90, 54.56, 49.74, 48.30, 42.21, 38.64, 29.40, 27.59, 24.13, 22.76. HRMS (ESI) m / z C 25 H 34 N3O + [M+H] + Calculated value: 392.2696, measured value: 392.2712.

[0200] Step 2: DW05014 was chirally resolved.

[0201] Chiral analysis method: Apparatus: UPCC (Waters), Chiral column: CHIRALPAK IG (Daicel), Column volume: 4.6 x 100 mm (5 μm particle size packing), Temperature: 40°C, Mobile phase: CO2 / MeOH [0.2% ammonia in methanol (7 M) = 70 / 30], Flow rate: 3.0 mL / min, Detection wavelength: 214 nm.

[0202] Chiral preparation method: Apparatus: SFC-150 (Waters), Chiral column: IG (Daicel), Column volume: 20 × 250 mm (10 μm particle size packing), Temperature: 35 °C, Mobile phase: CO2 / MeOH [0.2% ammonia in methanol (7 M) = 50 / 50], Flow rate: 100.0 mL / min, Detection wavelength: 214 nm. I-14 (HRMS (ESI) m / z C 25 H 34 N3O + [M+H] + Calculated value: 392.2697, Measured value: 392.2712; ee 99.68%; Optical rotation value: [α] D 25 =‐55 o (c=0.1, CHCl3), which matches the optical rotation direction of compound I-10, both are left-handed and have the same chiral configuration) and I-15 (HRMS (ESI) m / z C 25 H 34 N3O + [M+H] + Calculated value: 392.2696, Measured value: 392.2709; ee 100%; Optical rotation value: [α] D 25 = +95 o (c=0.1, CHCl3), which has the opposite optical rotation to that of compound I-10, is right-handed, and has the opposite chiral configuration) was prepared.

[0203] Example 16: Preparation of (7aS,11aR)-10-(2-methoxyphenylethyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (Compound I-16)

[0204] [ka]

[0205] Step 1: Tetrahydroquinoline (4 g, 30 mmol) was dissolved in a mixed solvent of glacial acetic acid (40 mL) and water (10 mL), then an aqueous solution (5 mL) of NaNO2 (2.28 g, 33 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the concentrate was dissolved in ethyl acetate and washed once with saturated aqueous NaHCO3. The organic phase was concentrated and purified by flash silica gel column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to give orange-yellow oil WHE-119 (4.5 g, yield: 92%). 1 H NMR (800 MHz, CDCl3) δ 8.06 (d, J = 8.2 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.24 - 7.19 (m, 2H), 3.92 - 3.88 (m, 2H), 2.82 - 2.79 (m, 2H), 2.01 (p, J = 6.1 Hz, 2H). HR-MS (ESI) m / z C9H 11 N2O + [M+H] + Calculated value: 163.0866, actual value: 163.0873.

[0206] Step 2: Under argon gas protection, LiAlH4 (485 mg, 12.8 mmol) was suspended in anhydrous THF (25 mL). It was cooled in an ice-water bath, and a solution of the raw material WHE-119 (1.3 g, 7.98 mmol) in THF (5 mL) was added. The reaction system was kept stirring under ice-water bath conditions for 30 min, then slowly warmed to room temperature and stirred overnight. After the reaction was completed, the reaction was quenched with sodium potassium tartrate solution, water was added and filtered. The filtrate was extracted three times with ethyl acetate, and the organic phases were combined. After concentration, it was purified by flash silica gel column chromatography (eluent: 10-30% ethyl acetate / petroleum ether) to obtain a yellow solid WHE-115 (0.95 g, yield: 81%). 1H NMR (600 MHz, CDCl3) δ 7.15 (d, J = 8.2, 1.4 Hz, 1H), 7.14 - 7.09 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 3.34 - 3.30 (m, 2H), 2.76 (t, J = 6.6 Hz, 2H), 2.09 - 2.02 (m, 2H). HR-MS (ESI) m / z C9H 13 N2 + [M+H] + Calculated value: 149.1073, actual value: 149.1075.

[0207] Step 3: WHE-115 (620 mg, 4.19 mmol) and 4,4-dihydroxypiperidine hydrochloride (650 mg, 4.2 mmol) were dissolved in ethanol (15 mL), then concentrated hydrochloric acid (0.35 mL) was added and heated to reflux for 3 h. The reaction was cooled and filtered to give a white solid WHE-109 (0.75 g, yield: 84%). 1 H NMR (600 MHz, CDCl3) δ 10.15 (s, 2H), 7.24 - 7.19 (m, 1H), 7.01 (dd, J = 8.0, 7.1 Hz, 1H), 6.95 - 6.90 (m, 1H), 4.47 (d, J = 4.6 Hz, HR-MS (ESI) m / z C 14 H 17 N2 + [M+H] + Calculated value: 213.1386, Actual value: 213.1386.

[0208] Step 4: WHE-109 (1.35 g, 6.42 mmol), TFA (13 mL) were added to a round bottom flask and cooled in an ice-water bath. Then NaBH3CN (1.2 g, 19.3 mmol) was added slowly in batches, and the reaction was slowly warmed from the ice-water bath to room temperature and stirred for 2 h. After the reaction was completed, ice was added to quench the reaction, and the pH was adjusted to alkaline (pH=14) with NaOH solution. Water was added, extracted with dichloromethane three times, and the organic phases were combined. After concentration, the crude product WHE-117 (1.3 g) was obtained and used directly in the next step. 1 H NMR (800 MHz, CDCl3) δ 6.92 (t, J = 6.7 Hz, 2H), 6.68 (t, J = 7.4 Hz, 1H), 3.44 - 3.35 (m, 2H), 3.34 - 3.26 (m, 3H), 3.16 (td, J = 13.0, HR-MS (ESI) m / z C 14 H 19 N2 + [M+H] + Calculated value: 215.1543, actual value: 215.1546.

[0209] Step 5: The crude product WHE-117 (1.3 g, 6.42 mmol) was dissolved in 1,4-dioxane (15 mL) and NaOH (500 mg, 12.8 mmol) in water (10 mL) was added, followed by Boc2O (1.54 g, 7.06 mmol). The reaction was stirred at room temperature for 2 h. After the reaction was complete, water (15 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated. Purification by flash silica gel column chromatography gave WHE-125 (1.8 g, 2-step yield: 89%). 1H NMR (800 MHz, CDCl3) δ 6.96 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 4.13 - 4.01 & 3.91 - 3.79 (m, 1H), 3.73 (d, J = 13.2 Hz, 1H), 3.49 - 3.45 (m, 1H), 3.31 - 3.27 (m, 1H), 3.26 - 3.09 (m, 2H), 3.09 - 2.97 & 2.85 - 2.80 (m, 1H), 2.73 (t, J = 6.5 Hz, 2H), 2.69 - 2.55 (m, 1H), 2.16 - 2.09 (m, 2H), 1.93 - 1.86 (m, 2H), 1.50 (s, 9H). HR-MS (ESI) m / z C 19 H 27 N2O2 + [M+H] + Calculated value: 315.2067, Actual value: 315.2067.

[0210] Step 6: Compound WHE-125 was subjected to chiral resolution to obtain WHE-125-p1 and WHE-125-p2.

[0211] Chiral analysis conditions: Chiral column: OD-H (Daicel), column capacity: 4.6 × 100 mm (5 μm particle size packing), mobile phase: CO2 / isopropanol [0.5% ammonia in methanol (7 M)] = 90 / 10, flow rate: 3.0 mL / min, wavelength: 214 nM, temperature: 40 °C, HPLC device: UPCC (Waters), peak 1 (front peak) t R =1.672min, Peak 2 (back peak) t R =1.941min.

[0212] Chiral preparation conditions: Chiral column: OD (Daicel), column volume: 20 × 250 mm (10 μm particle size packing), mobile phase: CO2 / isopropanol [0.5% ammonia in methanol (7 M)] = 85 / 15, flow rate: 80 mL / min, wavelength: 214 nM, temperature: 35 °C, HPLC device: SFC-150 (Waters).

[0213] WHE-125-P1: 1 H NMR (800 MHz, CDCl3) δ 6.94 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 4.10 - 4.05 & 3.89 - 3.81 (m, 1H), 3.74 - 3.68 (m, 1H), 3.46 - 3.35 (m, 1H), 3.29 - 3.23 (m, 1H), 3.23 - 3.11 (m, 2H), 3.06 - 2.96 & 2.81 - 2.74 (m, 1H), 2.72 - 2.68 (m, 2H), 2.65 - 2.55 (m, 1H), 2.16 - 2.09 (m, 2H), 1.94-1.91 (m, 1H), 1.89 - 1.83 (m, 1H), 1.50 (s, 9H). HR-MS (ESI) m / z C 19 H 27 N2O2 + [M+H] + Calculated value: 315.2067; Measured value: 315.2082. Optical rotation value: [α] D 25 = +128 o (c = 0.1, CHCl3).

[0214] WHE-125-p2: 1H NMR (800 MHz, CDCl3) δ 6.93 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 4.10 - 3.99 & 3.87 - 3.79 (m, 1H), 3.72 (dt, J = 13.2, 4.4 Hz, 1H), 3.44 - 3.36 (m, 1H), 3.28 - 3.25 (m, 1H), 3.21 - 3.10 (m, 2H), 3.05 - 2.96 & 2.82 - 2.75 (m, 1H), 2.71 (dd, J = 8.2, HR-MS (ESI) m / z C 19 H 27 N2O2 + [M+H] + Calculated value: 315.2067, Measured value: 315.2063. Optical rotation value: [α] D 25 = ‐115 o (c = 0.1, CHCl3).

[0215] The configurations of compounds WHE-125-P1 and WHE-125-p2 were obtained by comparing their optical rotation values ​​with those of starting materials A and WHF-108, which have known configurations.

[0216] [ka]

[0217] A (50 mg, 0.13 mmol) was added to a round bottom flask and dissolved in DCM (3 mL), Et3N (1 mL) was added, followed by Boc2O (57 mg, 0.26 mmol), and the reaction was stirred at room temperature for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, and the product was separated and purified by flash silica gel column chromatography (eluent: 0-30% ethyl acetate / petroleum ether) to give a colorless oil WHF108 (32 mg, yield: 74%). 1 H NMR (800 MHz, CDCl3) δ 6.72-6.61 (m, 1H), 6.58 - 6.48 (m, 1H), 6.46 - 6.34 (m, 1H), 4.16 - 4.07 & 3.97 - 3.86 (m, 1H), 3.85 - 3.76 (m, 1H), 3.65 - 3.53 (m, 1H), 3.42 - 3.23 (m, 3H), 3.20 - 3.05 (m, 2H), 2.80 - 2.60 (m, 5H), 1.80 - 1.71 (m, 2H), 1.49 (s, 9H). HR-MS (ESI) m / z C 19 H 27 N3O2 + [M+H] + Calculated value: 329.2098; Measured value: 329.2098. Optical rotation value: [α] D 25 = ‐53 o (c = 0.1, CHCl3); Optical rotation value of raw material A: [α] D 25 = ‐165 o (c = 0.1, CHCl3).

[0218] Step 7: WHE-125-p2 (120 mg, 0.382 mmol) was added to a round-bottom flask, followed by the addition of solvent dichloromethane (2 mL), TFA (1 mL), and stirred at room temperature for 1 h. The solvent was removed by concentrating under reduced pressure, the residue was dissolved in DMSO (3 mL), 1-(2-bromoethyl)-2-methoxybenzene (100 mg, 0.465 mmol) was added, followed by diisopropylethylamine (3 mL), and the reaction system was stirred overnight (18 h) under heating at 60 °C. After the reaction was completed, water (50 mL) was added, extracted three times with ethyl acetate, the organic phases were combined and concentrated, and the residue was separated and purified by flash silica gel column chromatography (eluent: 0-10% ethyl acetate / petroleum ether) to obtain a yellow-brown oil I-16 (70 mg, yield: 53%). 1 H NMR (800 MHz, CDCl3) δ 7.22 - 7.20 (m, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.91 - 6.89 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1H), 3.82 (s, 3H), 3.33 - 3.29 (m, 2H), 3.27-3.24 (m, 1H), 3.03 - 3.01 (m, 1H), 2.91 - 2.86 (m, 2H), 2.84 - 2.80 (m, 1H), 2.78 - 2.71 (m, 2H), 2.65 - 2.53 (m, 3H), 2.42 (td, J = 11.2, 4.3 Hz, 1H), 2.19 - 2.07 (m, 3H), 2.07 - 1.99 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.62, 149.80, 131.09, 130.41, 128.68, 127.47, 126.84, 121.07, 120.58, 120.56, 118.68, 110.38, 64.13, 58.90, 55.91, 55.34, 48.88, 44.67, 40.88, 27.91, 24.91, 24.26, 23.16. HR-MS (ESI) m / z C 23 H29 N2O + [M+H] + Calculated value: 349.2274, Measured value: 349.2276. Optical rotation value: [α] D 25 = ‐96 o (c = 0.1, CHCl3).

[0219] Example 17: Preparation of (7aR,11aS)-10-(2-methoxyphenylethyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (Compound I-17)

[0220] [ka]

[0221] Following the method of step 7 of Example 16, compound WHE-125-p1 was subjected to Boc deprotection and alkylation reaction with 1-(2-bromoethyl)-2-methoxybenzene to give tan oil I-17 (90 mg, yield: 82%). 1 H NMR (800 MHz, CDCl3) δ 7.22 - 7.17 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 6.88 (t, J = 7.5 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 3.81 (s, 3H), 3.32 - 3.26 (m, 2H), 3.23 - 3.20 (m, 1H), 3.00 - 2.96 (m, 1H), 2.88 - 2.82 (m, 2H), 2.81 - 2.76 (m, 1H), 2.73 - 2.71 (m, 2H), 2.61 - 2.51 (m, 3H), 2.37 (td, J = 11.7, 3.3 Hz, 1H), 2.18 - 1.95 (m, 5H). 13C NMR (201 MHz, CDCl3) δ 157.62, 149.80, 131.17, 130.38, 128.79, 127.43, 126.80, 121.04, 120.54, 120.53, 118.63, 110.38, 64.16, 58.96, 56.00, 55.33, 48.91, 44.65, 40.94, 27.99, 24.98, 24.26, 23.15. HR-MS (ESI) m / z C 23 H 29 N2O + [M+H] + Calculated value: 349.2274, Measured value: 349.2282. Optical rotation value: [α] D 25 = +104 o (c = 0.1, CHCl3).

[0222] Example 18: Preparation of 10-(3-(2-methoxyphenyl)propyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline (Compound I-18)

[0223] [ka]

[0224] Following the method of step 7 of example 16, compound WHE-125-p2 was subjected to Boc deprotection and alkylation reaction with 1-(3-bromopropyl)-2-methoxybenzene to give tan oil I-18 (50 mg, yield: 50%). 1H NMR (800 MHz, CDCl3) δ 7.20 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.92 ‐ 6.88 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 3.84 (s, 3H), 3.31 ‐ 3.28 (m, 2H), 3.21 ‐ 3.18 (m, 1H), 2.90 ‐ 2.88 (m, 1H), 2.75‐2.69 (m, 3H), 2.67 ‐ 2.62 (m, 2H), 2.56 (td, J = 10.4, 3.1 Hz, 1H), 2.46 ‐ 2.37 (m, 2H), 2.29 (td, J = 11.7, 3.2 Hz, 1H), 2.18 ‐ 2.08 (m, 2H), 2.03 ‐ 1.92 (m, 3H), 1.87 ‐ 1.83 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.51, 149.75, 131.19, 130.68, 129.86, 127.07, 126.75, 120.95, 120.48, 120.41, 118.58, 110.25, 64.17, 58.69, 56.14, 55.30, 49.04, 44.59, 40.99, 28.35, 27.10, 25.03, 24.26, 23.15. HR-MS (ESI) m / z C 24 H 31 N2O + [M+H] + Calculated value: 363.2431, measured value: 363.2439. Optical rotation value:[α] D 25 = ‐108 o (c = 0.1, CHCl3).

[0225] Example 19: (7aR, 11aS)-10-(3-(2-メトキシフェニル)プロピル)-5,6,7a,8,9,10,11 , Modulation of 11a-オクタヒドロ-4H-ピリド[3',4':4,5]ピロロ[3,2,1-ij]キノリン (compound I-19)

[0226] [ka]

[0227] Following the method of step 7 of Example 16, compound WHE-125-p1 was subjected to Boc deprotection and alkylation reaction with 1-(3-bromopropyl)-2-methoxybenzene to give tan oil I-19 (48 mg, yield: 46%). 1 H NMR (800 MHz, CDCl3) δ 7.09 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.80 - 6.77 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.55 (t, J = 7.4 Hz, 1H), 3.73 (s, 3H), 3.20 - 3.16 (m, 2H), 3.12 - 3.09 (m, 1H), 2.82 - 2.78 (m, 1H), 2.67 - 2.58 (m, 3H), 2.55 - 2.53 (m, 2H), 2.45 (td, J = 10.3, 3.3 Hz, 1H), 2.36 - 2.29 (m, 2H), 2.22 - 2.18 (m, 1H), 2.06 - 1.98 (m, 2H), 1.95 - 1.84 (m, 3H), 1.77 - 1.73 (m, 2H). HR-MS (ESI) m / z C 24 H 31 N2O + [M+H] + Calculated value: 363.2431, Measured value: 363.2438, Optical rotation value: [α] D 25 = +101 o (c = 0.1, CHCl3).

[0228] Example 20: Preparation of (6bR,10aS)-8-(2-methoxyphenylethyl)-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (Compound I-20)

[0229] [ka]

[0230] Step 1: Benzomorpholine (2.6 g, 20 mmol) was added to a round-bottom flask, and tetrahydrofuran (40 mL) was added to dissolve it, and the reaction system was stirred at 0 °C. 3 M hydrochloric acid (13 mL) was slowly added dropwise to the reaction system, and the reaction was continued with stirring at 0 °C. After 1 h, sodium nitrite (3.45 g, 50 mmol) aqueous solution (10 mL) was added dropwise to the reaction flask. After the dropwise addition was completed, stirring was continued at room temperature overnight. The reaction was detected to be complete by TLC, and most of the solvent was removed by vacuum distillation, extracted three times with ethyl acetate, the organic phase was combined, washed with saturated saline, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the crude product, which was purified by flash silica gel column (eluent: 0-25% ethyl acetate / petroleum ether) to obtain a yellow solid DW04027 (3.0 g, yield: 91%). 1 H NMR (800 MHz, CDCl3) δ 8.10 (dd, J = 8.2, 1.4 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.09 - 7.05 (m, 1H), 7.03 (dd, J = 8.2, 1.2 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.08 - 4.04 (m, 2H). HRMS (ESI) m / z C8H9N2O2 + [M+H] + Calculated value: 165.0659, actual value: 165.0672.

[0231] Step 2: DW04027 (1.6 g, 10 mmol) was added to a round bottom flask and dissolved in a mixture of acetic acid:water (1:1) (20 mL), and the reaction was stirred at 0-5 °C. Zinc powder (2.6 g, 40 mmol) was added slowly in batches, and the reaction was continued with stirring at room temperature for 1 h after the addition was complete. The zinc powder was filtered off, and the filtrate was adjusted to pH 9.0 with 2N NaOH, then extracted with ethyl acetate three times, the organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the crude product, which was purified by flash silica gel column (eluent: 0-35% ethyl acetate / petroleum ether) to obtain a pale yellow solid DW04028 (1.2 g, yield: 80%). 1 H NMR (800 MHz, CDCl3) δ 7.11 (dd, J = 8.0, 1.0 Hz, 1H), 6.89 - 6.87 (m, 1H), 6.78 - 6.73 (m, 2H), 4.40 - 4.32 (m, 2H), 4.12 (brs, 2H), 3.43 - 3.38 (m, 2H). HRMS (ESI) m / z C8H 11 N2O + [M+H] + Calculated value: 151.0866, actual value: 151.0871.

[0232] Step 3: DW04028 (1.5 g, 10 mmol), 4,4-piperidinediol hydrochloride (1.2 g, 10 mmol) were added to a round bottom flask and dissolved in ethanol (20 mL). Concentrated hydrochloric acid (1 mL) was slowly added dropwise to the reaction system, and after the addition was complete, the reaction system was heated to 90 °C and stirred at reflux for 3 hours. The reaction solution was cooled to room temperature and filtered to give DW04029 (1.6 g, yield: 73%) as an off-white solid. HRMS (ESI) m / z C 13 H 15 N2O + [M+H] + Calculated value: 215.1179; Measured value: 215.1185.

[0233] Step 4: DW04029 (2.1 g, 10 mmol) was added to a round bottom flask, trifluoroacetic acid (20 mL) was added to dissolve, and the reaction was stirred at 0 °C. Sodium cyanoborohydride (1.89 g, 30 mmol) was added in batches, and then stirring was continued at room temperature for 2 h. After the reaction was completed, most of the trifluoroacetic acid was removed by vacuum distillation, the pH was adjusted to 9.0 with 2N aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the crude product, which was purified by flash silica gel column (eluent: 0-10% methanol / dichloromethane) to obtain yellow oil DW04030 (1.2 g, yield: 61%). 1 H NMR (800 MHz, CDCl3) δ 6.78 - 6.73 (m, 2H), 6.73 - 6.71 (m, 1H), 4.51 (d, J = 11.1 Hz, 1H), 4.48 - 4.43 (m, 1H), 3.56 - 3.54 (m, 1H), 3.48 - 3.44 (m, 2H), 3.42 - 3.40 (m, 1H), 3.35 - 3.33 (m, 2H), 2.93 (q, J = 11.8 Hz, 1H), 2.82 (td, J = 10.5, 2.7 Hz, 1H), 2.30 - 2.21 (m, 2H). HRMS (ESI) m / z C 13 H 17 N2O + [M+H] + Calculated value: 217.1335, actual value: 217.1351.

[0234] Step 5: DW04030 (2.1 g, 10 mmol), dicarbonyl di-tert-butyl (2.2 g, 10 mmol) were added to a round-bottom flask, dioxane (25 mL) was added, and the mixture was stirred at room temperature to dissolve. Then, 1N aqueous sodium hydroxide solution (10 mL) was added, and the reaction system was stirred at room temperature overnight. After the reaction was completed, it was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The organic phase was concentrated to give the crude oil DW04032 (3.0 g, yield: 94%). HRMS (ESI) m / z C 18 H 25 N2O3 + [M+H] + Calculated value: 317.1860, measured value: 317.1871.

[0235] Step 6: DW04032 was resolved by chiral column.

[0236] Chiral analysis method: Equipment: Shimadzu, Chiral column: OJ-H (Daicel), Column volume: 4.6×250 mm (5 μm particle size packing), Temperature: 40° C., Mobile phase: n-hexane (0.1% diethylamine):ethanol (0.1% diethylamine)=70:30, Flow rate: 1.0 mL / min, Detection wavelength: 214 nm and 254 nm.

[0237] Chiral preparation method: Apparatus: Gilson-281, Chiral column: OJ (Daicel), Column volume: 20×250 mm (10 μm particle size packing), Temperature: 35° C., Mobile phase: n-hexane (0.1% diethylamine): ethanol (0.1% diethylamine) = 75:25, Flow rate: 40.0 mL / min, Detection wavelength: 214 nm. DW04032P1 (ee 100%) and DW04032P2 (ee 100%) were prepared.

[0238] Step 7: DW04032P1 (310 mg, 1 mmol) was added to a round bottom flask, dichloromethane (5 mL) was added, and the mixture was stirred at room temperature to dissolve, then trifluoroacetic acid (1 mL) was added. The reaction was continued at room temperature for 2 hours with stirring. After the reaction was completed, the reaction was adjusted to pH 9.0 by adding 2N aqueous sodium hydroxide solution, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated saline. The organic phase was concentrated to obtain the crude product, pale yellow solid DW04072P1 (208 mg, yield: 96%). HRMS (ESI) m / z C 13 H 17 N2O + [M+H] + Calculated value: 217.1335, actual value: 217.1343.

[0239] Step 8: Following the method of Step 7 of Example 16, DW04072P1 was subjected to alkylation reaction with 1-(2-bromoethyl)-2-methoxybenzene to give pale yellow oil I-20 (80 mg, yield: 49%). 1 H NMR (800 MHz, CDCl3) δ 7.10 (td, J = 8.0, 1.6 Hz, 1H), 7.06 (dd, J = 7.4, 1.4 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 7.0 Hz, 1H), 6.58 - 6.54 (m, 2H), 4.39 - 4.34 (m, 2H), 3.72 (s, 3H), 3.21 (dt, J = 10.7, 2.0 Hz, 1H), 3.20 - 3.18 (m, 1H), 3.17 - 3.13 (m, 1H), 2.96 - 2.93 (m, 1H), 2.79 - 2.75 (m, 2H), 2.75 - 2.71 (m, 1H), 2.69 - 2.64 (m, 1H), 2.54 - 2.46 (m, 2H), 2.31 (td, J = 11.5, 3.7 Hz, 1H), 2.05 (t, J = 11.3 Hz, 1H), 1.95 - 1.86 (m, 2H). 13C NMR (201 MHz, CDCl3) δ 157.60, 143.52, 138.01, 132.83, 130.35, 128.73, 127.42, 120.52, 120.36, 115.86, 113.21, 110.36, 66.85, 65.65, 60.48, 58.95, 55.91, 55.31, 48.93, 44.73, 41.58, 28.02. HRMS (ESI) m / z C 22 H 27 N2O2 + [M+H] + Calculated value: 351.2067 Measured value: 351.2079. Optical rotation value: [α] D 25 = -11 o (c=0.1, CHCl3), which coincides with the optical rotation direction of compound I-3, and both are left-handed and have the same chiral configuration.

[0240] Example 21: Preparation of (6bS,10aR)-8-(2-methoxyphenylethyl)-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (Compound I-21)

[0241] [ka]

[0242] Following the method of step 7 of Example 20, DW04072P2 was prepared using DW04032P2 as the raw material (light yellow solid 180 mg, yield: 93%). HRMS (ESI) m / z C 13 H 17 N2O + [M+H] + Calculated value: 217.1335, actual value: 217.1348.

[0243] Following the method of Step 8 of Example 20, DW04072P2 was subjected to an alkylation reaction with 1-(2-bromoethyl)-2-methoxybenzene to give a pale yellow oil I-21 (83 mg, yield: 51%). 1H NMR (800 MHz, CDCl3) δ 7.10 (td, J = 8.0, 1.6 Hz, 1H), 7.06 (td, J = 7.1, 2.0 Hz, 1H), 6.82 ‐ 6.78 (m, 1H), 6.76 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 7.0 Hz, 1H), 6.59 ‐ 6.54 (m, 2H), 4.41 ‐ 4.34 (m, 2H), 3.72 (s, 3H), 3.22 (dt, J = 10.7, 2.1 Hz, 1H), 3.20 ‐ 3.18 (m, 1H), 3.18 ‐ 3.14 (m, 1H), 2.98 ‐ 2.94 (m, 1H), 2.78 (dt, J = 11.2, 6.0 Hz, 2H), 2.76 ‐ 2.73 (m, 1H), 2.69 ‐ 2.65 (m, 1H), 2.55 ‐ 2.47 (m, 2H), 2.32 (td, J = 11.6, 3.3 Hz, 1H), 2.06 (t, J = 11.2 Hz, 1H), 1.95 - 1.87 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.61, 143.53, 138.01, 132.80, 130.36, 128.69, 127.45, 120.53, 120.39, 115.88, 113.23, 110.37, 66.86, 65.64, 60.49, 58.92, 55.87, 55.32, 48.92, 44.75, 41.55, 28.01. HRMS (ESI) m / z C 22 H 27 N2O2 + [M+H] + Calculated value: 351.2067, measured value: 351.2082. Optical rotation value:[α] D 25 = +41 o (c=0.1, CHCl3), the optical rotation direction of compound I-3 is reverse rotation, dextrorotation, and reverse rotation configuration.

[0244] Example 22: Preparation of (6bR,10aS)-8-(3-(2-methoxyphenyl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (Compound I-22)

[0245] [ka]

[0246] Following the method of Step 7 of Example 16, DW04072P1 was subjected to an alkylation reaction with 1-(3-bromopropyl)-2-methoxybenzene to give a pale yellow oil I-22 (105 mg, yield: 58%). 1 H NMR (800 MHz, CDCl3) δ 7.17 (td, J = 8.0, 1.6 Hz, 1H), 7.14 - 7.12 (m, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.69 (t, J = 6.7 Hz, 1H), 6.66 - 6.60 (m, 2H), 4.47 - 4.40 (m, 2H), 3.81 (s, 3H), 3.28 (dt, J = 10.7, 2.1 Hz, 1H), 3.27 - 3.24 (m, 1H), 3.24 - 3.20 (m, 1H), 2.96 - 2.94 (m, 1H), 2.76 - 2.73 (m, 2H), 2.64 - 2.60 (m, 2H), 2.48 - 2.39 (m, 2H), 2.31 (td, J = 11.6, 2.4 Hz, 1H), 2.07 - 2.02 (m, 2H), 2.01 - 1.96 (m, 1H), 1.95 - 1.94 (m, 1H), 1.86 - 1.81 (m, 2H). 13C NMR (201 MHz, CDCl3) δ 157.52, 143.55, 137.96, 132.73, 130.54, 129.88, 127.15, 120.44, 120.42, 115.85, 113.26, 110.28, 66.86, 65.59, 60.34, 58.52, 55.82, 55.32, 48.90, 44.72, 41.43, 28.31, 26.89. 23 H 29 N2O2 + [M+H] + Calculated value: 365.2224, Measured value: 365.2239. Optical rotation value: [α] D 25 = -10 o (c=0.1, CHCl3), which coincides with the optical rotation direction of compound I-10, and both are left-handed and have the same chiral configuration.

[0247] Example 23: Preparation of (6bS,10aR)-8-(3-(2-methoxyphenyl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-HI]pyrido[4,3-b]indole (Compound I-23)

[0248] [ka]

[0249] Following the method of Step 7 of Example 16, DW04072P2 was subjected to an alkylation reaction with 1-(3-bromopropyl)-2-methoxybenzene to give a pale yellow oil I-23 (83 mg, yield: 51%). 1H NMR (800 MHz, CDCl3) δ 7.17 (td, J = 8.1, 1.5 Hz, 1H), 7.13 ‐ 7.11 (m, 1H), 6.87 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.70 (d, J 3.26 - 3.22 (m, 2H), 2.99 ‐ 2.96 (m, 1H), 2.80 ‐ 2.72 (m, 2H), 2.64 ‐ 2.60 (m, 2H), 2.50 ‐ 2.40 (m, 2H), 2.34 (t, J = 10.3 Hz, 1H), 2.07 (t, J = 11.2 Hz, 1H), 2.04 ‐ 2.00 (m, 1H), 1.97 ‐ 1.91 (m, 1H), 1.88 ‐ 1.81 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.53, 143.58, 137.94, 130.42, 129.90, 127.20, 124.11, 120.49, 120.47, 115.89, 113.33, 110.31, 66.87, 65.53, 58.44, 55.34, 48.83, 44.74, 41.28, 31.57, 30.32, 29.85, 28.29. HRMS (ESI) m / z C 23 H 29 N2O2 + [M+H] + Calculated value: 365.2224, measured value: 365.2225. Optical rotation value:[α] D 25 = +49 o (c=0.1, CHCl3), the optical rotation direction of compound I-10 is reverse rotation, dextrorotation, and reverse rotation configuration.

[0250] Example 24: Preparation of (8aS,12aR)-11-(2-methoxyphenylethyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (Compound I-24)

[0251] [ka]

[0252] Step 1: 2-Mercaptoaniline (2.5 g, 20 mml), 1,3-dibromopropane (6.03 g, 30 mmol) and K2CO3 (8.28 g, 60 mmol) were added to a round-bottom flask, and the solvent DMF (20 mL) was added under nitrogen gas protection. The reaction system was heated and stirred at 65 °C overnight. After the reaction was completed, the solvent DMF was removed by vacuum concentration, and the product was separated and purified by flash silica gel column chromatography (eluent: 0-20% ethyl acetate / petroleum ether) to obtain reddish brown oil WHE148 (1.41 g, yield: 50%). 1 H NMR (800 MHz, CDCl3) δ 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 6.82 - 6.80 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H), 3.30 - 3.27 (m, 2H), 2.86 - 2.83 (m, 2H), 2.12 - 2.07 (m, 2H). HR-MS (ESI) m / z C9H 12 N.S. + [M+H] + Calculated value: 166.0685, actual value: 166.0688.

[0253] Step 2: In a round-bottom flask, the raw material WHE-148 (1.59 g, 9.63 mmol) was dissolved in HOAc / H2O (15 mL / 5 mL), then NaNO2 (797 mg, 11.6 mmol) was added while cooling in an ice-water bath, and the reaction was allowed to warm slowly to room temperature and stirred overnight. After the reaction was completed, the solvent was removed under reduced pressure, dissolved in ethyl acetate, washed once with saturated aqueous NaHCO3, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and concentrated, and then separated and purified by flash silica gel column chromatography to obtain a yellow-brown oily product WHF-12 (1.53 g, 82%). 1 H NMR (800 MHz, CDCl3) δ 7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.47 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 - 7.27 (m, 2H), 4.20 (t, J = 6.0 Hz, 2H), 2.91 - 2.86 (m, 2H), 2.16 (p, J = 6.0 Hz, 2H). HR-MS (ESI) m / z C9H 11 N2OS + [M+H] + Calculated value: 195.0587, Actual value: 195.0587.

[0254] Step 3: LiAlH4 (600 mg, 15.8 mmol) was suspended in anhydrous THF (20 mL) under nitrogen gas protection. After cooling in an ice-water bath, a solution of WHE-148 (1.53 g, 7.89 mmol) in anhydrous THF (5 mL) was slowly added. The reaction system was stirred for 30 minutes under ice-water bath conditions, and then stirred overnight under heating at 50 °C. After the reaction was completed, the reaction solution was cooled in an ice-water bath, quenched with an aqueous solution of potassium sodium tartrate, filtered, water was added to the filtrate, the organic phase was separated, the aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was concentrated, and then separated and purified by flash silica gel column chromatography to obtain orange-yellow oil WHE-136 (1.1 g, yield: 77%). HR-MS (ESI) m / z C9H 13 N2S + [M+H] + Calculated value: 181.0794, Actual value: 181.0794.

[0255] Step 4: WHE-136 was dissolved in ethanol (10 mL), 4,4-dihydroxypiperidine hydrochloride (1.85 g, 12.1 mmol) and hydrochloric acid (0.6 mL) were added, and the reaction system was heated to reflux overnight. After the reaction was completed, the ethanol was removed under reduced pressure, and the residue was added with water and extracted with ethyl acetate. The organic phases were combined, washed once with saturated NaHCO3 aqueous solution, concentrated under reduced pressure, and then separated and purified by flash silica gel column chromatography to obtain a pale yellow solid WHF-19 (1.4 g, yield: 94%). 1 H NMR (800 MHz, MeOD) δ 7.24 (dd, J = 7.8, 1.0 Hz, 1H), 7.02 (dd, J = 7.4, 1.0 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 4.61 - 4.57 (m, 2H), 4.38 (d, J = 1.5 Hz, 2H), 3.63 (t, J = 6.2 Hz, 2H), 3.35 - 3.31 (m, 2H), 3.10 (td, J = 6.5, 3.3 Hz, 2H), 2.38 - 2.32 (m, 2H). HR-MS (ESI) m / z C 14 H 17 N2S + [M+H] + Calculated value: 245.1107, actual value: 245.1108.

[0256] Step 5: Compound WHF-17 (1.09 g, 6.05 mmol) was dissolved in trifluoroacetic acid and cooled in an ice-water bath, then NaBH3CN (1.1 g, 17.2 mmol) was added in batches within 30 min, and the reaction was then stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was quenched by adding ice and adjusted to alkaline with aqueous NaOH. Extracted three times with ethyl acetate, the organic phases were combined and concentrated to give crude tan solid WHF-19 (1.5 g), which was used directly in the next step.

[0257] Step 6: The crude product of the previous step, compound WHF-19 (1.5 g, 6.1 mmol), was dissolved in dichloromethane (10 mL), Et3N (2 mL) was added, and then Boc2O (2.6 g, 12.2 mmol) was added. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the product was separated and purified by flash silica gel column chromatography to obtain compound WHF-21 (1.4 g, two-step yield: 67%). 1 H NMR (800 MHz, CDCl3) δ 6.94 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 4.14 - 3.97 & 3.87 - 3.79 (m, 1H), 3.71 (d, J = 13.1 Hz, 1H), 3.45 - 3.35 (m, 1H), 3.28 - 3.25 (m, 1H), 3.23 - 3.06 (m, 2H), 3.06 - 2.95 & 2.83 - 2.75 (m, 1H), 2.71 (t, J = 6.5 Hz, 2H), 2.64 - 2.57 (m, 1H), 2.15 - 2.07 (m, 2H), 1.92 - 1.88 (m, 1H), 1.86 - 1.79 (m, 1H), 1.47 (s, 9H). HR-MS (ESI) m / z C 19 H 27 N2O2S + [M+H] + Calculated value: 347.1788, Actual value: 347.1788.

[0258] Step 7: Chiral resolution of compound WHF-21 Chiral analysis conditions: Chiral column: IG (Daicel), column capacity: 4.6 × 100 mm (5 μm particle size packing), mobile phase: CO2 / MeOH [0.2% ammonia in methanol (7 M)] = 85 / 15, flow rate: 3.0 mL / min, wavelength: 214 nM, temperature: 40 °C, HPLC device: UPCC (Waters), peak 1 (front peak) t R =1.926min, Peak 2 (back peak) t R =2.344min.

[0259] Korra preparation conditions: Korra: IG (Daicel), Korra capacity: 20×250mm (10μm particle size filling), mobile phase: CO2 / MeOH [0.2% のアンモ[Nanoconazole solution (7M)]=75 / 25, flow rate: 100mL / min, wavelength: 214nM, temperature: 35°C, HPLC device: SFC-150 (Waters).

[0260] WHF-21-p1: 1 H NMR (800 MHz, CDCl3) δ 6.93 (d, J = 7.8 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 3.93 ‐ 3.86 (s, 0.5H), 3.79 ‐ 3.75 (m, 1H), 3.73 - 3.63 (m, 0.5H), 3.62 - 3.53 (m, 1H), 3.53 - 3.38 (m, 2H), 3.38 - 3.24 (m, 1H), 3.22 - 3.17 (m, 1H), 3.13 - 3.05 (m, 1.5H), 2.94 - 2.88 (m, 1H), 2.87 ‐ 2.78 (m, 0.5H), 2.11 ‐ 2.06 (m, 1H), 2.03 ‐ 1.99 (m, 1H), 1.85 ‐ 1.83 (m, 2H), 1.42 (s, 9H). Optical rotation: [α] D 25 = ‐143 o (c = 0.1, CHCl3).

[0261] WHF-21-p2: 1H NMR (800 MHz, CDCl3) δ 6.96 - 6.93 (m, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 3.94 - 3.88 (m, 0.5H), 3.81 - 3.77 (m, 1H), 3.70 - 3.64 (m, 0.5H), 3.62 - 3.55 (m, 1H), 3.53 - 3.39 (m, 2H), 3.39 - 3.16 (m, 2H), 3.14 - 3.07 (m, 1H), 3.03 - 3.00 (m, 0.5H), 2.94 - 2.90 (m, 1H), 2.86 - 2.80 (m, 0.5H), 2.12 - 2.07 (m, 1H), 2.06 - 1.99 (m, 1H), 1.86 - 1.80 (m, 2H), 1.43 (s, 9H). Optical rotation value: [α] D 25 = +135 o (c = 0.1, CHCl3).

[0262] The configurations of compounds WHF-21-p1 and WHF-21-p2 were obtained by comparing their optical rotation values ​​with those of starting materials A and WHF-108, respectively, which have known configurations.

[0263] Step 8: According to the method of Step 7 of Example 16, compound WHF-21-p1 was subjected to Boc deprotection and alkylation reaction with 1-(2-bromoethyl)-2-methoxybenzene to obtain orange-yellow oil I-24 (51 mg, yield: 59%). 1H NMR (800 MHz, CDCl3) δ 7.19 (t, J = 7.7 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.91 ‐ 6.86 (m, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 3.87 ‐ 3.82 (m, 1H), 3.81 (s, 3H), 3.59 ‐ 3.55 (m, 1H), 3.29 ‐ 3.28 (m, 1H), 3.23 ‐ 3.19 (m, 1H), 3.07 ‐ 3.05 (m, 1H), 2.95-2.92 (m, 1H), 2.91 ‐ 2.88 (m, 1H), 2.84 (t, J = 8.2 Hz, 2H), 2.80 ‐ 2.77 (m, 1H), 2.59 ‐ 2.51 (m, 2H), 2.39 ‐ 2.33 (m, 1H), 2.15-2.11 (m, 1H), 2.06 - 1.98 (m, 1H), 1.98 - 1.93 (m, 3H). 13 C NMR (201 MHz, CDCl3) δ 157.59, 152.31, 133.86, 130.37, 128.84, 128.66, 127.45, 121.31, 120.53, 119.79, 119.72, 110.37, 63.98, 58.96, 56.52, 55.33, 49.10, 47.22, 40.94, 32.03, 30.61, 28.04, 25.73. HR-MS (ESI) m / z C 23 H 29 N2OS + [M+H] + Calculated value: 381.1995, measured value: 381.2013. Optical rotation value: [α] D 25 = ‐134 o (c = 0.1, CHCl3).

[0264] Example 25: Preparation of (8aR,12aS)-11-(2-methoxyphenylethyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (Compound I-25)

[0265] [ka]

[0266] According to the method of step 7 of Example 16, compound WHF-21-p2 was subjected to Boc deprotection and alkylation reaction with 1-(2-bromoethyl)-2-methoxybenzene to give orange-yellow oil I-25 (62 mg, yield: 67%). 1 H NMR (800 MHz, CDCl3) δ 7.20 - 7.18 (m, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.91 - 6.86 (m, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.64 (t, J = 7.5 Hz, 1H), 3.86 - 3.82 (m, 1H), 3.81 (s, 3H), 3.60 - 3.56 (m, 1H), 3.30 - 3.28 (m, 1H), 3.23 - 3.20 (m, 1H), 3.08 - 3.05 (m, 1H), 2.97 - 2.88 (m, 2H), 2.84 (t, J = 8.2 Hz, 2H), 2.81 - 2.76 (m, 1H), 2.60 - 2.51 (m, 2H), 2.38 - 2.34 (m, 1H), 2.17 - 2.12 (m, 1H), 2.06 - 1.99 (m, 1H), 1.98 - 1.94 (m, 3H). 13C NMR (201 MHz, CDCl3) δ 157.60, 152.30, 133.85, 130.37, 128.85, 128.63, 127.46, 121.31, 120.54, 119.80, 119.73, 110.37, 63.98, 58.95, 56.50, 55.34, 49.10, 47.23, 40.93, 32.03, 30.61, 28.03, 25.72. HR-MS (ESI) m / z C 23 H 29 N2OS + [M+H] + Calculated value: 381.1995, Measured value: 381.1997. Optical rotation value: [α] D 25 = +142 o (c = 0.1, CHCl3).

[0267] Example 26: Preparation of (8aS,12aR)-11-(3-(2-methoxyphenyl)propyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (Compound I-26)

[0268] [ka]

[0269] According to the method of step 7 of Example 16, compound WHF-21-p1 was subjected to Boc deprotection and alkylation reaction with 1-(3-bromopropyl)-2-methoxybenzene to obtain orange-yellow oil I-26 (45 mg, yield: 50%). 1H NMR (800 MHz, CDCl3) δ 7.18 ‐ 7.16 (m, 1H), 7.12 (dd, J = 7.3, 1.7 Hz, 1H), 6.94 (dd, J = 7.8, 1.2 Hz, 1H), 6.90 ‐ 6.81 (m, 3H), 6.64 ‐ 6.59 (m, 1H), 3.85 - 3.79 (m, 4H), 3.56 - 3.52 (m, 1H), 3.28 - 3.26 (m, 1H), 3.21 - 3.17 (m, 1H), 3.07 - 3.04 (m, 1H), 2.95 ‐ 2.92 (m, 1H), 2.83 ‐ 2.77 (m, 1H), 2.71 ‐ 2.68 (m, 1H), 2.61 (t, J = 7.7 Hz, 2H), 2.44 ‐ 2.35 (m, 2H), 2.31 ‐ 2.27 (d, J = 13.2 Hz, 1H), 2.13 ‐ 2.09 (m, 1H), 2.05 - 1.98 (m, 1H), 1.97 - 1.88 (m, 3H), 1.84 - 1.80 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 157.51, 152.24, 133.72, 130.47, 129.92, 128.91, 127.18, 121.29, 120.45, 119.86, 119.77, 110.29, 63.95, 58.60, 56.42, 55.33, 49.11, 47.19, 40.79, 32.05, 30.61, 28.31, 26.92, 25.54. HR-MS (ESI) m / z C 24 H 31 N2OS + [M+H] + Calculated value: 395.2152, measured value: 395.2152. Optical rotation value: [α] D 25 = -121 o (c = 0.1, CHCl3).

[0270] Example 27: Preparation of (8aR,12aS)-11-(3-(2-methoxyphenyl)propyl)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (Compound I-27)

[0271] [ka]

[0272] According to the method of step 7 of Example 16, compound WHF-21-p2 was subjected to Boc deprotection and alkylation reaction with 1-(3-bromopropyl)-2-methoxybenzene to give orange-yellow oil I-27 (87 mg, yield: 94%). 1 H NMR (800 MHz, CDCl3) δ 7.17 (t, J = 7.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.90 - 6.82 (m, 3H), 6.62 (t, J = 7.5 Hz, 1H), 3.84 - 3.81 (m, 1H), 3.81 (s, 3H), 3.57 - 3.53 (m, 1H), 3.28 - 3.26 (m, 1H), 3.19 - 3.16 (m, 1H), 3.07 - 3.04 (m, 1H), 2.96 - 2.93 (m, 1H), 2.81 - 2.77 (m, 1H), 2.71 - 2.66 (m, 1H), 2.62 (t, J = 7.8 Hz, 2H), 2.42 - 2.34 (m, 2H), 2.28 - 2.24 (m, 1H), 2.13 - 2.09 (m, 1H), 2.04 - 1.99 (m, 1H), 1.95 - 1.87 (m, 3H), 1.83 - 1.79 (m, 2H). 13C NMR (201 MHz, CDCl3) δ 157.51, 152.24, 133.83, 130.56, 129.90, 128.84, 127.13, 121.25, 120.42, 119.78, 119.70, 110.27, 64.01, 58.65, 56.54, 55.32, 49.17, 47.15, 40.90, 32.04, 30.60, 28.33, 27.05, 25.67. HR-MS (ESI) m / z C 24 H 31 N2OS + [M+H] + Calculated value: 395.2152, Measured value: 395.2156. Optical rotation value: [α] D 25 = +130 o (c = 0.1, CHCl3).

[0273] Example 28: Preparation of (6bS,10aR)-8-(2-methoxyphenyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (Compound I-28)

[0274] [ka]

[0275] According to the method of Example 3, compound I-28 could be prepared using ent-A (prepared with reference to the method described in J Med Chem 2014, 57, 2670-2682; Bioorganic & Medicinal Chemistry Letters 13 (2003) 767-770) and 1-(2-bromoethyl)-2-methoxybenzene (catalog number: 36449-75-9) as raw materials. 1H NMR (800 MHz, CDCl3) δ 7.18 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.84 - 6.80 (m, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.41 (d, J = 7.9 Hz, 1H), 3.78 (s, 3H), 3.62 - 3.58 (m, 1H), 3.36 - 3.32 (m, 1H), 3.31- 3.28 (m, 1H), 3.27 -3.24 (m, 2H), 3.10 (dd, J = 11.4, 6.4 Hz, 1H), 2.92 - 2.89 (m, 3H), 2.86 (s, 3H), 2.82 (t, J = 9.8 Hz, 1H), 2.72 - 2.63 (m, 2H), 2.53 - 2.48 (m, 1H), 2.20 - 2.10 (m, 2H), 2.04 - 1.97 (m, 1H). HR-MS (ESI) m / z C 23 H 30 N3O + [M+H] + Calculated value: 364.2383; Measured value: 364.2390. Optical rotation value: [α] D 25 = +53 o (c = 0.1, CHCl3).

[0276] Example 29: (6bS, 10aR)-8-(3-(2-メトキシ)プロピル)-3-メチル-2,3,6b,7,8,9,10, Modulation of 10a-オクタヒドロ-1H-ピリド[3',4':4,5]ピロロ[1,2,3-de]キノキサリン (Compound I-29)

[0277]

change

[0278] According to the method of Example 10, compound I-29, a yellow oil, was prepared using ent-A (prepared with reference to the method described in J Med Chem 2014, 57, 2670-2682; Bioorganic & Medicinal Chemistry Letters 13 (2003) 767-770) and whc52 as raw materials. 1 H NMR (800 MHz, CD3OD) δ 7.23 - 7.18 (m, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 9.4 Hz, 1H), 6.58 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 3.82 (s, 3H), 3.57 - 3.52 (m, 2H), 3.47 - 3.43 (m, 1H), 3.43 - 3.40 (m, 1H), 3.39 - 3.32 (m, 2H), 3.29 - 3.25 (m, 1H), 3.19 - 3.15 (m, 1H), 3.12 - 3.04 (m, 2H), 2.88 (s, 3H), 2.84 - 2.80 (m, 1H), 2.69 (t, J = 7.4 Hz, 2H), 2.65 (t, J = 12.4 Hz, 1H), 2.36 - 2.31 (m, 1H), 2.16 - 2.09 (m, 1H), 2.07 - 2.00 (m, 2H). HR-MS (ESI) m / z C 24 H 32 N3O + [M+H] + Calculated value: 378.2540; Measured value: 378.2545. Optical rotation value: [α] D 25 = +40 o (c = 0.1, CHCl3).

[0279] Biological Test Example 1: 5-HT 2A Affinity Test of the Compounds of the Present Invention for Receptors Method: 5-HT 2AThe affinity of the compounds of the invention for the receptor was determined using radioligand competition experiments.

[0280] Step 1, Specific 5-HT 2A The cell membrane components containing the receptor were prepared. HEK-293T cells (ATCC, CRL-11268) were spread on a 10 cm culture dish and 5-HT 2A The receptor plasmid (10 ng) and PEI (40 μL) were transfected, and after 48 hours, the 10 cm culture dish was removed from the cell chamber, and the cells cultured therein were already expressing 5-HT. 2A The culture medium was removed by suction using a vacuum pump, 3 mL of lysis solution was added to each well, and the cells were placed in a refrigerated room at 4°C and left to stand for 10 minutes. After the cells peeled off, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm for 5 minutes at 4°C, and the supernatant was discarded. The cell precipitate was transferred to a tissue homogenizer, 3 mL of lysis solution was added to it, and the cells were thoroughly crushed until they were broken. Next, the cell suspension was dispensed into multiple EP tubes, centrifuged at 12000 rpm for 5 minutes at 4°C, and the supernatant was discarded. The precipitate was 5-HT 2A It was a cell membrane component that contained the receptor.

[0281] Step 2, 5-HT 2A Ligand-receptor binding experiments were performed on 293T membrane components transiently expressing the receptor. 2A A standard binding buffer was added to the cell membrane components containing the receptor, and the cell membranes were disrupted and resuspended using an electric tissue homogenizer. 30 μL of the membrane protein suspension was added to each well of a 96-well plate. Then, 30 μL of different drugs were added sequentially from left to right to the 96-well plate, so that the final drug concentration was 10 to 10 from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 Immediately after, 30 μL of [ 3 H]-LSD was added. The mixture was incubated at room temperature, away from light, for 2 hours. The detection was performed. The machine readout was membrane-bound [ 3H]-LSD, and after further data processing, 5-HT 2A K of affinity of different compounds to the receptor i Got the value.

[0282] Result: 5-HT 2A K of the affinity of the compounds of the present invention for the receptor i The values ​​are as shown in Table 1.

[0283] [Table 1]

[0284] As can be seen from Table 1, the compounds of the present invention inhibit 5-HT 2A Among them, compounds I-3, I-4, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26 and I-27 have moderate to high affinity for the 5-HT 2A K for receptors i The value was less than 0.1 μM.

[0285] Biological Test Example 2: 5-HT 2A Functional Activity Testing of Compounds of the Invention Against Receptors Method: 5-HT 2A To detect the downstream G protein signaling pathway mediated by the receptor, on the first day, 1 μg of 5-HT was added to a 6 cm culture dish containing HEK-293T cells (ATCC, CRL-11268). 2A The receptor plasmid, 1 μg of Gαq containing C-terminal Renilla luciferase (Gαq-Rluc), 1 μg of Gβ3, 1 μg of Gγ9 containing C-terminal green fluorescent protein (Gγ9-GFP) and 16 μL of PEI were transfected. 2ATo detect the downstream β-arrestin 2 signaling pathway mediated by the receptor, on the first day, 500 μg of 5-HT1C1 containing C-terminal Renilla luciferase was added to a 6 cm culture dish containing HEK-293T cells (ATCC, CRL-11268). 2A Receptor plasmid (5-HT 2A The cells were transfected with β-arrestin 2 (GFP2-Rluc), 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of β-arrestin 2 containing N-terminal green fluorescent protein (GFP2-ARRB2) and 14 μL of PEI. The next day, the fully grown cells were digested and spread on a 96-well plate with 100 μL of culture medium per well with the cell volume of a 6 cm culture dish filled with cells. Administration and detection were performed on the third day. The 96-well plate was removed from the cell chamber to remove the culture medium, and 40 μL of the substrate coelenterazine 400a (final concentration 5 μM) was added to each well, and immediately thereafter, 20 μL of drugs with different concentrations were added sequentially from left to right, so that the final concentration of the drug decreased in a gradient from bottom to top, each treatment was repeated twice, and finally detected by the instrument. The instrument readings reflected the recruitment status of β-arrestin 2 to the membrane in the cells and the dissociation status of the G protein trimer, the former of which increased the 5-HT 2A We characterized the extent of activation of the β-arrestin 2 signaling pathway downstream of the receptor, the latter of which regulates 5-HT 2A Characterize the degree of activation of G protein signaling pathways downstream of the 5-HT receptor. 2A The agonist effects of various compounds on the receptor can be characterized.

[0286] Result: 5-HT 2A The agonist activity of the compounds of the present invention against the receptors is as shown in Table 2 ("NA": no agonist activity, "\": not tested).

[0287] [Table 2]

[0288] As can be seen from Table 2, the compounds of the present invention inhibit 5-HT 2ACompounds I-9, I-10, I-13, I-15, I-17, I-19, I-21, I-23, I-25 and I-27 have moderate to strong agonist activity against the 5-HT receptor, without activating the G protein signaling pathway. 2A It had a selective activating effect on receptor-mediated β-arrestin2 recruitment.

[0289] Biological Test Example 3: Selectivity Test of Compounds I-3 and I-10 for Dopamine D2 Receptors Methods: The affinity of the compounds of the present invention for the dopamine D2 receptor was measured using a radioligand competition experiment. Step 1, cell membrane components containing specific dopamine D2 receptors were prepared. 10 ng of dopamine D2 receptor plasmid and 40 μL of PEI were transfected into a 10 cm culture dish on which HEK-293T cells (ATCC, CRL-11268) were spread, and after 48 hours, the 10 cm culture dish was removed from the cell chamber, and the cells cultured therein had already expressed dopamine D2 receptors. The culture medium was aspirated and removed using a vacuum pump, 3 mL of lysis solution was added to each well, and the cells were placed in a 4 ° C refrigerator and allowed to stand for 10 minutes. After the cells were peeled off, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm for 5 minutes in a 4 ° C centrifuge, and the supernatant was discarded. The cell precipitate was transferred to a tissue homogenizer, 3 mL of lysis solution was added to it, and the cells were thoroughly crushed until they were broken. The cell suspension was then dispensed into multiple EP tubes and centrifuged at 12,000 rpm for 5 minutes in a 4°C centrifuge, and the supernatant was discarded. The precipitate was the cell membrane component containing the dopamine D2 receptor. Step 2, a ligand-receptor binding experiment was performed on the 293T membrane component transiently expressing the dopamine D2 receptor. First, a standard binding buffer was added to the cell membrane component containing the dopamine D2 receptor, and the cell membrane was disrupted and resuspended using an electric tissue homogenizer. 30 μL of the membrane protein suspension was added to each well of the 96-well plate. Next, 30 μL of different drugs were added sequentially from left to right to the 96-well plate, so that the final drug concentration was 10% from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9Immediately after, 30 μL of [ 3 H]-methylspiperone was added. The mixture was incubated at room temperature, away from light, for 2 hours. The instrument readout was membrane-bound [ 3 H]-methylspiperone, and after further data processing, the K i Got the value.

[0290] Results: The affinity of compound I-3 for the dopamine D2 receptor was K i = 1.55 μM, and the affinity of compound I-10 for the dopamine D2 receptor is K i = 1.86 μM. Thus, compounds I-3 and I-10 had very weak affinity for dopamine receptors. Compared with lumateperone, compounds I-3 and I-10 had a significantly lower affinity for 5-HT 2A It had better selectivity against

[0291] Biological Test Example 4: Metabolic Properties of Compounds I-10 and I-23 in Mice After a single intraperitoneal administration of compound I-10 to male mice, blood samples were collected at various time points, and the concentrations of the compound in mouse plasma were measured by LC-MS / MS, and relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetic properties of the compound in mice.

[0292] Experimental design: 60 male C57 mice (purchased from Suzhou JOINN Laboratory Animal Co., Ltd.) were randomly divided into groups according to body weight, with 3 mice in each group. They were fasted with water for 12-14 hours one day before administration, and fed for 4 hours after administration. The drug was administered by intraperitoneal injection, with a dosing concentration of 1 mg / mL, and the solvent was 10% DMSO + 90% saline.

[0293] Sample collection: Before and after administration, 0.1 mL of blood was collected from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube on ice bath. Plasma was collected by centrifugation at 5000 rpm and 4°C for 10 minutes. The time points for IP blood collection and brain tissue collection were 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24 hours, with 3 mice per time point. All plasma samples were stored at -80°C before analysis and detection.

[0294] Data processing: Plasma and brain tissue drug concentrations were measured using LC-MS (API4000QTRAP triple quadrupole tandem mass spectrometer, electrospray ionization source (ESI)). The software for the data collection and control system was Analyst 1.5.1 software (Applied Biosystem). The sample peak integration method of the pattern was automatic integration, and the ratio of the peak area of ​​the sample to the peak area of ​​the internal standard was used as an index to perform regression using the concentration of the sample. Regression method: Linear regression, with a weighting coefficient of 1 / X 2 Pharmacokinetic parameters were analyzed using noncompartmental model analysis using WinNonlin Professional v6.3 (Pharsight, USA). max is the maximum measured blood drug concentration, and the area under the blood drug concentration-time curve, AUC (0→t) is calculated by the trapezoidal method, and T max was the time to reach the peak blood drug concentration after administration. Experimental data were expressed as "mean ± standard deviation" (mean ± SD, n ≥ 3) or "average" (mean, n = 2).

[0295] Experimental Results: The pharmacokinetic parameters of compounds I-10 and I-23 are shown in Table 3 below (intraperitoneal injection).

[0296] [Table 3]

[0297] Biological Test Example 5: Antidepressant Activity Test of Compounds I-3 and I-10 Methods: Acute restraint stress (ARS) is often used to induce a depressive state in mice. The forced swim test (FST) and tail suspension test (TST) are currently the most commonly used models to infer "depression-like" behaviors. C57 / bl6j wild-type mice (8 weeks old or older, purchased from Shanghai Lingchang Biotech Co., Ltd.) were immobilized in a single rodent restrainer for 5 hours. The mice were restricted in all body movements but suffered only minimal pain. During the ARS experiment, the mice were deprived of food and water. After 5 hours of restraint, independent mice from the group were released and immediately injected intraperitoneally with the test compound. After 30 minutes of recovery, the behavioral changes of the mice were evaluated by the forced swim test or tail suspension test. The control group received saline injections at the same time but did not perform the ARS step. Forced swim test: The mice in the control group and the mice after ARS stress were placed in glass beakers containing 15 cm deep water at a temperature of 25 ± 1 °C, respectively. All mice were allowed to swim for 6 min and recorded by a video camera. The immobility time was recorded during the last 4 min of the test. Immobility time was defined as the time during which the animal floated in the water without struggling and made only the movements necessary to bring its head above the water surface. Tail suspension test: Control mice and mice after restraint stress were suspended by their tails with tape for 6 min and recorded by a video camera. The immobility time during the last 4 min was manually timed and assessed by a blinded observer.

[0298] Results: The antidepressant effect of compound I-3 in the tail suspension test in mice is shown in Figure 1. As can be seen from Figure 1, compound I-3 has a significant antidepressant effect. The antidepressant effect of I-3 in the forced swimming test is shown in Figure 2. As can be seen from Figure 2, compound I-3 has a significant antidepressant effect.

[0299] The antidepressant effect of compound I-10 in the tail suspension test of mice is shown in Figure 3. As can be seen from Figure 3, compound I-10 has a significant antidepressant effect. The antidepressant effect of I-10 in the forced swimming test is shown in Figure 4. As can be seen from Figure 4, compound I-10 has a significant antidepressant effect.

[0300] Biological Test Example 6: Testing the Hallucinogenic Effects of Compounds I-3 and I-10 Methods: Head twitch responses in mice were detected based on magnetic signals to characterize the hallucinogenic effects. Mice (C57 / BL6J strain, purchased from Shanghai Lingchang Biotech Co., Ltd.) were anesthetized with 2% isoflurane. A small portion of scalp was excised from the center of the dorsal part of the skull. A custom-made small neodymium magnet (4 mm × 4 mm × 2 mm) was attached to the center of the dorsal part of the skull with dental resin. The NS pole of the magnet was kept parallel to the dorsoventral side of the implant. Mice were allowed to recover for 1 week before testing. To record precise head movements, mice were placed in a 12 cm diameter glass beaker wrapped with 150 turns of 30 gauge enameled copper wire. The coil output signal was recorded by a PowerLab / 4SP instrument using LabChart V8.1.16 software. The coil voltage was amplified and filtered with a 10 kHz low-pass filter to remove radio frequency interference, and sampled at 40 kHz. To detect mouse head twitch responses, LabChart data was processed with a digital bandpass filter of 40–200 Hz, and mouse head twitch responses were determined by searching for sinusoidal wavelets that met the following criteria: 1) containing two or more bipolar peaks, 2) with amplitudes above background noise levels, and 3) durations less than 120 ms. One hour before testing, mice were transferred to the testing room for acclimation. Mice were then transferred to a beaker for 30 min, and baseline mouse head twitch response values ​​were recorded. Immediately after baseline recording, mice were injected (intraperitoneally) with test compounds and recorded for an additional 1–2 h depending on the compound used. Statistics were taken from the first 30 min.

[0301] Results: The response of compound I-3 to head twitches in mice is shown in Figure 5. As can be seen from Figure 5, compound I-3 did not induce hallucinogenic effects in mice at the two doses shown.

[0302] The response of compound I-10 to head twitches in mice is shown in Figure 6. As can be seen from Figure 6, compound I-10 also did not induce hallucinogenic effects in mice at the two doses shown.

[0303] Biological Test Example 7: Testing the Antidepressant and Hallucinogenic Effects of Compound I-23 Antidepressant drug effect test method: For male C57BL / 6 mice (8 weeks old, purchased from Shanghai Lingchang Biotech Co., Ltd.), corticosterone was dissolved in the drinking water of the mice at a concentration of 25 μg / mL. The corticosterone solution was administered to the mice for 21 days using a drinking water bottle. The mice were maintained under a 12-hour light cycle. Fresh drinking water containing corticosterone was changed every other day for the first two weeks, and the water was gradually changed to normal drinking water without corticosterone every other day for the last week. Compound I-23 was injected once into the mice 21 days after corticosterone exposure, and the antidepressant activity of compound I-23 was tested by tail suspension test at three periods: 1 day, 7 days, and 14 days later. Tail suspension test: The mice in the control group and the treatment group were suspended by tape by their tails for 6 minutes, respectively, and recorded by a video camera. The immobility time during the last 4 min was manually timed and assessed by a blinded observer.

[0304] Hallucinogenicity Test Method: Referring to the method of Biological Test Example 6, the effect of compound I-23 in inducing head spasms in mice was tested.

[0305] result: The response of compound I-23 to head twitches in mice is shown in Figure 7. As can be seen from Figure 7, compound I-23 did not induce hallucinogenic effects in mice at the two doses shown.

[0306] The antidepressant effect of compound I-23 in the tail suspension test in mice is shown in Figure 8. As can be seen from Figure 8, compound I-23 has a significant antidepressant effect 1 day after single administration, and the mice in the 10mg / kg single injection group still have a significant antidepressant effect after 7 and 14 days.

[0307] Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely examples, and that various changes and modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims. [Brief description of the drawings]

[0308] [Figure 1] Biological Test Example 5 shows the antidepressant effect of compound I-3 in the tail suspension test in mice, where "*" represents P<0.05 and "****" represents P<0.0001. [Diagram 2] Biological Test Example 5 shows the antidepressant effect of compound I-3 in the forced swimming test in mice, where "ns" means no significant difference and "****" means P<0.0001. [Diagram 3] Biological Test Example 5 shows the antidepressant effect of compound I-10 in the tail suspension test in mice, where "ns" means no significant difference and "****" means P<0.0001. [Figure 4] Biological Test Example 5 shows the antidepressant effect of compound I-10 in the forced swimming test in mice, where "ns" means no significant difference and "****" means P<0.0001. [Diagram 5] 1 shows the response of compound I-3 to head spasms in mice in Biological Test Example 6. [Figure 6] 1 shows the response of compound I-10 to head spasms in mice in Biological Test Example 6. [Figure 7] FIG. 1 shows the response of compound I-23 to head spasms in mice in Biological Test Example 7. [Figure 8]In biological test Example 7, the antidepressant effect of compound I-23 in the tail suspension test in mice 1 day, 7 days and 14 days after a single injection is shown, where "ns" represents no significant difference, "*" represents P<0.05, "**" represents P<0.01, "***" represents P<0.001 and "****" represents P<0.0001.

Claims

1. A fused ring piperidine compound represented by formula I' or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (However, X is 【Chemistry 2】 and R ａ , R ｂ and R ｃ are independently hydrogen or C １ ~C ４ is alkyl, R １ and R ２ are independently hydrogen, halogen or C １ ~C ４ is alkyl, R ３ are independently hydrogen, halogen, hydroxyl or C １ ~C ４ is an alkoxy; m is 1, 2 or 3; n is 1, 2 or 3; z is 1 or 2.

2. The fused ring piperidine compound represented by formula I' is a fused ring piperidine compound represented by formula Ia, Ib, I or Ic, 【Chemistry 3】 However, X and R １ , R ２ , R ３ , m and n are defined as set forth in claim 1; For example, the fused ring piperidine compound represented by formula I' is a fused ring piperidine compound represented by formula I, 【Chemistry 4】 However, X is 【Chemistry 5】 and R ａ , R ｂ and R ｃ are independently hydrogen or C １ ~C ４ is alkyl, R １ and R ２ are independently hydrogen, halogen or C １ ~C ４ is alkyl, R ３ are independently hydrogen, halogen, hydroxyl or C １ ~C ４ is an alkoxy; m is 1, 2 or 3; 2. The fused ring piperidine compound of formula I' according to claim 1, wherein n is 1, 2 or 3, or a pharma- ceutically acceptable salt thereof.

3. R ａ , R ｂ and R ｃ In the above, １ ~C ４ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; And / or R １ and R ２ wherein the halogen is independently F, Cl, Br or I; And / or R １ and R ２ In the above, １ ~C ４ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or R ３ wherein the halogen is independently F, Cl, Br or I; And / or R ３ In the above, １ ~C ４ Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy; and / or R on the benzene ring ３ The fused ring piperidine compound represented by formula I' according to claim 1 or a pharma- ceutically acceptable salt thereof, characterized in that the substitution positions of are the ortho positions, the ortho and para positions, or the ortho and meta positions.

4. X is 【Chemistry 6】 For example, X is 【Chemistry 7】 and And / or R ａ is C １ ~C ４ is alkyl, And / or R ｂ and R ｃ are independently hydrogen; And / or R １ and R ２ is hydrogen, And / or R ３ are independently hydrogen, hydroxyl or C １ ~C ４ is an alkoxy; and / or n is 1 or 2; and / or n is 1 or 2;

5. X is 【Chemistry 8】 For example, X is 【Chemistry 9】 and and / or 【Chemistry 10】 teeth, 【Chemistry 11】 and and / or 【Chemistry 12】 teeth, 【Chemistry 13】 The fused ring piperidine compound of formula I' according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R1 is an integer of 1 to 5;

6. 【Catalogue 14】 teeth, 【Chemistry 15】 6. The fused ring piperidine compound of formula I' according to claim 5, or a pharma- ceutically acceptable salt thereof, wherein:

7. The fused ring piperidine compound represented by formula I' is Scheme 1: X is 【Chemistry 16】 and R ａ is C １ ~C ４ is alkyl, R ｂ and R ｃ are independently hydrogen; R １ and R ２ is hydrogen, R ３ are independently hydrogen, hydroxyl or C １ ~C ４ is an alkoxy; n is 1 or 2; z is 1 or 2; R on the benzene ring ３ The substitution positions are the ortho positions, the ortho and para positions, or the ortho and meta positions; Scheme 2: X is 【Chemistry 17】 and R ａ is C １ ~C ４ is alkyl, R １ and R ２ is hydrogen, R ３ are independently hydrogen, hydroxyl or C １ ~C ４ is an alkoxy; n is 1 or 2; R on the benzene ring ３ The substitution position is the ortho position, the ortho and para positions, or the ortho and meta positions. The fused ring piperidine compound or its pharma- ceutically acceptable salt thereof represented by formula I' according to claim 1, wherein the compound is any one of the following formulas:

8. The fused ring piperidine compound represented by formula I' according to claim 1, which is any one of the following compounds: 【Chemistry 18】 【change】

9. Method 1, Method 2 or Method 3, R ３ are independently hydrogen, halogen or C １ ~C ４ When it is alkoxy, the preparation method of the fused ring piperidine compound or a salt thereof represented by the formula I' is Method 1, Method 1 includes the steps of subjecting a compound represented by formula II′ and a compound represented by formula III to the following substitution reaction in a solvent in the presence of a base to obtain the fused ring piperidine compound represented by formula I′: 【Chemistry 19】 Method 2 includes the steps of subjecting a compound represented by formula II′ and a compound represented by formula IV to the following reductive amination reaction in a solvent in the presence of a reducing agent to obtain the fused ring piperidine compound represented by formula I′: 【Chemistry 20】 R ３ are independently hydroxyl, the method for preparing the fused ring piperidine compound or a salt thereof represented by formula I' is method 3, Method 3 is BBr ３ In the presence of ３ is hydroxyl, X, R in Methods 1, 2 and 3 ａ , R ｂ , R ｃ , R １ , R ２ , m and n are defined as in any one of claims 1 to 8, Preferably, the preparation method comprises: In the method 1, the base is preferably an organic base, for example, diisopropylethylamine. and / or, in the method 1, the molar ratio of the base to the compound represented by formula II' is preferably (1-3):1, for example, 1:1; and / or, in the method 1, the molar ratio of the compound represented by formula III to the compound represented by formula II' is preferably (1-3):1, for example, 1.5:1; and / or, in method 1, the solvent is preferably a polar aprotic organic solvent, e.g., dimethylsulfoxide; and / or, in the method 1, the temperature of the substitution reaction is preferably room temperature to 80° C., more preferably 50 to 80° C., for example, 60° C.; and / or, in the method 2, the solvent is preferably an alcoholic solvent, for example, methanol; and / or in the method 2, the reducing agent is preferably a borane-based reducing agent, for example, sodium cyanoborohydride; and / or, in the method 2, the reaction temperature is preferably 0 to 60° C., for example, room temperature; and / or in method 3, the solvent is preferably a halogenated hydrocarbon organic solvent, for example dichloromethane; and / or, in the method 3, the reaction temperature is preferably −40° C. to 40° C., more preferably 10° C. to 40° C., for example, room temperature; 9. A method for preparing a fused ring piperidine compound represented by formula I' according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof, which satisfies the above.

10. A pharmaceutical composition comprising a fused ring piperidine compound of formula I' according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

11. 5-HT ２Ａ In the preparation of a receptor agonist or a medicament, Use of a substance A which is a fused ring piperidine compound of formula I' according to any one of claims 1 to 8, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, comprising: The drug is 5-HT ２Ａ Use in the treatment or prevention of a disease associated with the receptor.

12. The 5-HT ２Ａ Receptor agonists are 5-HT ２Ａ Receptor downstream β-arrestin 2 recruitment signaling pathway agonists, and / or 5-HT ２Ａ Agonists of the downstream Gq protein-activated signaling pathway of the receptor, preferably 5-HT ２Ａ Agonists of the receptor downstream β-arrestin 2 recruitment signaling pathway; And / or the 5-HT ２Ａ Receptor-related diseases include 5-HT ２Ａ Receptor downstream β-arrestin 2 recruitment signaling pathway and / or 5-HT ２Ａ The disease is related to the downstream Gq protein-activated signal transduction pathway of the receptor, preferably 5-HT ２Ａ The use according to claim 11, characterized in that the disease is associated with a downstream β-arrestin 2 recruitment signalling pathway of the receptor, for example depression.

13. Use of a substance A, which is a fused ring piperidine compound of formula I' according to any one of claims 1 to 8, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, in the preparation of a medicament for treating or preventing depression.

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