WO2023134711A1 - 并环哌啶类化合物及其制备方法和用途 - Google Patents

并环哌啶类化合物及其制备方法和用途 Download PDF

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WO2023134711A1
WO2023134711A1 PCT/CN2023/071816 CN2023071816W WO2023134711A1 WO 2023134711 A1 WO2023134711 A1 WO 2023134711A1 CN 2023071816 W CN2023071816 W CN 2023071816W WO 2023134711 A1 WO2023134711 A1 WO 2023134711A1
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formula
compound
cyclopiperidine
compound shown
pharmaceutically acceptable
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PCT/CN2023/071816
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English (en)
French (fr)
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程建军
汪胜
王欢
曹冬梅
余竞
段文文
贺莉聪
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上海科技大学
中国科学院分子细胞科学卓越创新中心
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a cyclopiperidine compound and its preparation method and application.
  • Depression is a mental disease that seriously affects human health, affecting about 300 million people worldwide, and tens of thousands of depressed patients commit suicide every year. Depression is characterized by significant and persistent low mood, accompanied by symptoms such as loss of interest, sleep disturbance, and low self-evaluation. In severe cases, suicidal ideation or self-injury suicide behavior will appear.
  • SSRI drugs are widely used clinically, mainly including sertraline, escitalopram, fluoxetine, paroxetine and so on.
  • SSRI drugs play a role by inhibiting the reabsorption of the central neurotransmitter 5-hydroxytryptamine (5-HT) and increasing the concentration of 5-HT in the synaptic cleft.
  • 5-HT 5-hydroxytryptamine
  • SSRI drugs Although the efficacy of SSRI drugs has the advantages of better tolerance and higher safety compared with traditional tricyclic antidepressants, these drugs still have several obvious disadvantages: (1) slow onset, It takes several weeks to months to take the medicine to take effect; (2) the response rate is low, and more than one-third of the patients have no response; (3) adverse reactions are still relatively common, such as nausea, weight gain, and sexual dysfunction. Therefore, there is an urgent need to develop new antidepressant drugs.
  • esketamine is a non-competitive and subtype non-selective activity-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, which acts by antagonizing NMDA function (Zhang et al.; Nature, 2021, 596(7871):301-305).
  • NMDA N-methyl-D-aspartate
  • ketamine was able to remodel many synapses that had previously existed but had disappeared under chronic stress.
  • ketamine can cause side effects such as dissociative hallucinations, and it also has the risk of addiction, so its clinical application will be limited.
  • psychedelics have great potential in the treatment of depression, anxiety, drug addiction, post-traumatic stress disorder (PTSD) and other diseases (Nutt et al., Cell, 2020, 181( 1): 24-28).
  • Classic hallucinogens mainly include psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ibogaine and so on.
  • LSD lysergic acid diethylamide
  • DMT N,N-dimethyltryptamine
  • ibogaine ibogaine
  • Lumateperone is a compound with a tetracyclic piperidine core skeleton In December 2019, it was approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia in adults (Blair, Drugs, 80(4):417-423). In December 2021, the US FDA approved a new indication for lumepirone: as monotherapy, and as adjuvant therapy with lithium or valproate, for the treatment of adult patients with bipolar I or Depressive episodes associated with type II disorder (bipolar depression) (Calabrese; Am J Psychiatry, 2021, 178(12):1098-1106).
  • K i 0.54nM
  • K i 32nM
  • SERT 5-HT Transporter
  • K i 61 nM
  • lumepirone is only used for depressive episodes related to bipolar I or II disorder, and the patient response rate is only 51.1% (Calabrese et al., Am J Psychiatry 2021, 178:12); and in patients with treatment-resistant depression have not been reported.
  • the technical problem to be solved by the present invention is to overcome the defects of limited types of antidepressants or hallucinogenic side effects in the prior art. Therefore, a cyclopiperidine compound and its preparation method and application are provided.
  • the cyclopiperidine compound of the present invention has a better effect of suppressing depression, and further avoids hallucinogenic side effects.
  • the present invention overcomes the above-mentioned technical problems through the following technical solutions.
  • the present invention provides a cyclopiperidine compound or a pharmaceutically acceptable salt thereof as shown in formula I':
  • R a , R b and R c are independently hydrogen or C 1 -C 4 alkyl
  • R 1 and R 2 are independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is independently hydrogen, halogen, hydroxyl or C 1 -C 4 oxoalkyl
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • z is 1 or 2.
  • the cyclopiperidine compound shown in formula I' is not
  • the cyclopiperidine compound represented by formula I' is a cyclopiperidine compound represented by formula Ia, Ib, I or Ic:
  • X, R 1 , R 2 , R 3 , m and n are as defined above.
  • the cyclopiperidine compound shown in formula I' is a cyclopiperidine compound represented by formula I:
  • R a , R b and R c are independently hydrogen or C 1 -C 4 alkyl
  • R 1 and R 2 are independently hydrogen, halogen or C 1 -C 4 alkyl
  • R 3 is independently hydrogen, halogen, hydroxyl or C 1 -C 4 oxoalkyl
  • n 1, 2 or 3;
  • n 1, 2 or 3.
  • the C 1 -C 4 alkyl is independently preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl radical, sec-butyl or tert-butyl, such as methyl.
  • said halogen is independently preferably F, Cl, Br or I.
  • the C 1 -C 4 alkyl is independently preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl or tert-butyl.
  • said halogen is preferably F, Cl, Br or I.
  • the C 1 -C 4 alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , sec-butoxy or tert-butoxy, for example methoxy.
  • substitution position of R on the benzene ring is ortho, "ortho and para" or “ortho and meta", Wherein, ortho, para or meta all refer to R 3 relative to formula I' Substitution position on the benzene ring.
  • substitution position of R on the benzene ring is ortho, "ortho and para” or “ortho and meta", wherein the ortho, para or meta all mean that R is relative to in formula I Substitution position on the benzene ring.
  • X is
  • X is R a is C 1 -C 4 alkyl.
  • X is
  • X is R b and R c are independently hydrogen.
  • X is
  • R1 and R2 are hydrogen.
  • R 3 is independently hydrogen, hydroxyl, or C 1 -C 4 oxyalkyl.
  • n 1 or 2.
  • X is
  • X is
  • R a is C 1 -C 4 alkyl
  • R b and R c are independently hydrogen
  • R and R are hydrogen
  • R 3 is independently hydrogen, hydroxyl or C 1 -C 4 oxyalkyl
  • n 1 or 2;
  • z is 1 or 2;
  • substitution position of R 3 on the benzene ring is ortho, "ortho and para" or “ortho and meta”.
  • X is
  • R a is C 1 -C 4 alkyl
  • R and R are hydrogen
  • R 3 is independently hydrogen, hydroxyl or C 1 -C 4 oxyalkyl
  • n 1 or 2;
  • substitution position of R 3 on the benzene ring is ortho, "ortho and para" or “ortho and meta”.
  • cyclopiperidine compound as described in formula I' is any of the following compounds:
  • the present invention also provides the above-mentioned preparation method of the cyclopiperidine compound shown in formula I' or a pharmaceutically acceptable salt thereof, which includes method 1, method 2 or method 3:
  • R 3 is independently hydrogen, halogen or C 1 -C 4 oxyalkyl
  • the preparation method of the cyclopiperidine compound or its salt shown in formula I' is method 1 or method 2;
  • Method 1 includes the following steps: in the presence of a base, the compound shown in formula II' and the compound shown in formula III are subjected to the following substitution reaction in a solvent to obtain the compound shown in formula I' Piperidine compounds;
  • Method 2 comprises the following steps: in the presence of a reducing agent, the compound shown in formula II' and the compound shown in formula IV are subjected to the following reductive amination reaction in a solvent to obtain the compound shown in formula I' and cyclopiperidine compounds;
  • R3 is independently a hydroxyl group
  • the preparation method of the cyclopiperidine compound or its salt shown in formula I' is method 3;
  • Method 3 comprises the following steps: in the presence of BBr 3 , react the acyclic piperidine compound shown in formula I' as described in method 1 or 2 in a solvent to obtain the acyclic piperidine compound shown in formula I' Piperidine compounds (that is, R 3 is a hydroxyl group);
  • n-1 means one carbon less than m.
  • the conditions and operations of the substitution reaction can be the conventional conditions and operations of this type of reaction in the art, and the present invention particularly preferably follows the conditions and operations:
  • the base is preferably an organic base, such as diisopropylethylamine (DIPEA).
  • DIPEA diisopropylethylamine
  • the molar ratio of the base to the compound represented by formula II' is preferably (1-3):1, for example 1:1.
  • the molar ratio of the compound represented by formula III to the compound represented by formula II' is preferably (1-3):1, such as 1.5:1.
  • the solvent is preferably a polar aprotic organic solvent, such as dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the temperature of the substitution reaction is preferably room temperature to 80°C, more preferably 50-80°C, eg 60°C.
  • the conditions and operations of the described reaction can be the conventional conditions and operations of this type of reaction in the art field, and the present invention particularly preferably follows the conditions and operations:
  • the solvent is preferably an alcoholic solvent, such as methanol.
  • the reducing agent is preferably a borane reducing agent, such as sodium cyanoborohydride.
  • the reductive amination reaction temperature is preferably 0-60°C, such as room temperature.
  • the conditions and operations of the described reaction can be the conventional conditions and operations of this type of reaction in the art field, and the present invention particularly preferably follows the conditions and operations:
  • the solvent is preferably a halogenated hydrocarbon organic solvent, such as dichloromethane.
  • the reaction temperature is preferably -40°C to 40°C; more preferably 10-40°C, such as room temperature.
  • the present invention also provides a method for preparing the above-mentioned cyclopiperidine compound represented by formula I or a pharmaceutically acceptable salt thereof, which includes method 1 or method 2:
  • R 3 is independently hydrogen, halogen or C 1 -C 4 oxyalkyl
  • the preparation method of the cyclopiperidine compound or its salt shown in formula I is method 1;
  • Method 1 comprises the following steps: in the presence of a base, the compound shown in formula II and the compound shown in formula III are subjected to the following substitution reaction in a solvent to obtain the acyclopiperidine shown in formula I Compounds;
  • Method 2 comprises the following steps: in the presence of BBr 3 , the cyclopiperidine compound shown in formula I described in method 1 is reacted in a solvent to obtain the cyclopiperidine compound shown in formula I (i.e. R 3 is a hydroxyl group);
  • the conditions and operations of the substitution reaction can be the conventional conditions and operations of this type of reaction in the art, and the present invention particularly preferably follows the conditions and operations:
  • the base is preferably an organic base, such as diisopropylethylamine (DIPEA).
  • DIPEA diisopropylethylamine
  • the molar ratio of the base to the compound represented by formula II is preferably (1-3):1, for example 1:1.
  • 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.
  • the solvent is preferably a halogenated hydrocarbon organic solvent, such as dichloromethane.
  • the temperature of the substitution reaction is preferably 50-80°C, such as 60°C.
  • the conditions and operations of the described reaction can be the conventional conditions and operations of this type of reaction in the art field, and the present invention particularly preferably follows the conditions and operations:
  • the solvent is preferably a halogenated hydrocarbon organic solvent, such as dichloromethane.
  • the temperature of the substitution reaction is preferably 10-40°C, such as room temperature.
  • the present invention also provides a pharmaceutical composition, which comprises the cyclopiperidine compound represented by formula I' or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
  • the present invention also provides a pharmaceutical composition, which comprises the cyclopiperidine compound represented by formula I or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliary materials.
  • the present invention also provides the application of a substance A in the preparation of 5-HT 2A receptor agonists; the substance A is the cyclopiperidine compound shown in the formula I', which can be used pharmaceutically Accepted salts or pharmaceutical compositions described above.
  • the 5-HT 2A receptor agonist is preferably a 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling pathway agonist and/or a 5-HT 2A receptor downstream Gq protein activation signaling pathway agonist, such as 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling pathway agonist.
  • the present invention also provides an application of substance A in the preparation of 5-HT 2A receptor agonists; the substance A is the cyclopiperidine compound shown in formula I, which is pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition.
  • the 5-HT 2A receptor agonist is preferably a 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling pathway agonist and/or a 5-HT 2A receptor downstream Gq protein activation signaling pathway agonist, such as 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling pathway agonist.
  • the present invention also provides an application of substance A in the prepared medicine
  • Said substance A contains said cyclopiperidine compound shown in formula I', its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition;
  • the medicine is used for treating or preventing diseases related to 5-HT 2A receptors.
  • the diseases associated with 5-HT 2A receptors are preferably associated with 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling Diseases related to pathway and/or Gq protein activation signaling pathway downstream of 5-HT 2A receptor, preferably diseases related to ⁇ -arrestin2 recruitment signaling pathway downstream of 5-HT 2A receptor, such as depression.
  • the present invention also provides an application of substance A in the prepared medicine
  • the substance A is a cyclopiperidine compound as shown in formula I, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition;
  • the medicine is used for treating or preventing diseases related to 5-HT 2A receptors.
  • the disease associated with the 5-HT 2A receptor is preferably a disease related to the ⁇ -arrestin2 recruitment signaling pathway downstream of the 5-HT 2A receptor and/or the Gq protein activation signaling pathway downstream of the 5-HT 2A receptor, preferably Diseases associated with ⁇ -arrestin2 recruitment signaling pathway downstream of 5-HT 2A receptors, such as depression.
  • the present invention also provides the application of a substance A in the preparation of medicines for treating or preventing depression; the substance A contains the cyclopiperidine compound shown in formula I', its pharmaceutical acceptable salt or the above-mentioned pharmaceutical composition.
  • the present invention also provides the application of a substance A in the preparation of medicines for treating or preventing depression; the substance A contains the cyclopiperidine compound shown in formula I, and its pharmaceutical acceptable salt or the above-mentioned pharmaceutical composition.
  • the present invention also provides a method for treating or preventing depression, which comprises administering a therapeutically effective amount of substance A to a subject in need thereof (for example, a human or a mouse); said substance A is said as A cyclopiperidine compound represented by formula I', a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.
  • room temperature refers to 10-30°C. Overnight means 8-15 hours.
  • halogen is preferably fluorine, chlorine, bromine or iodine.
  • the alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • alkoxy represents a cyclic or acyclic alkyl group having the stated number of carbon atoms connected through an oxygen bridge.
  • Alkoxy thus includes the above definitions of alkyl and cycloalkyl.
  • the alkoxy group in the present invention is preferably C 1 -C 4 alkoxy group, more preferably methoxy group, ethoxy group, n-propoxy group, isopropoxy group or tert-butoxy group.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the cyclopiperidine compound of the present invention has a better inhibitory effect on depression and can effectively treat depression. Further, the cyclopiperidine compound of the present invention also avoids depression while treating depression. Avoid hallucinogenic side effects.
  • Fig. 1 is a diagram of the antidepressant effect of compound I-3 in the biological test example 5 in the mouse tail suspension test, wherein “*” indicates P ⁇ 0.05, and “****” indicates P ⁇ 0.0001.
  • Fig. 2 is a diagram of the antidepressant effect of compound I-3 in the biological test example 5 in the mouse forced swimming test, wherein “ns” means no significant difference, and “****” means P ⁇ 0.0001.
  • Fig. 3 is a diagram of the antidepressant effect of compound I-10 in the biological test example 5 in the mouse tail suspension test, wherein “ns” means no significant difference, and “****” means P ⁇ 0.0001.
  • Fig. 4 is a diagram of the antidepressant effect of compound I-10 in the biological test example 5 in the mouse forced swimming test, wherein “ns” means no significant difference, and “****” means P ⁇ 0.0001.
  • Fig. 5 is a graph showing the response of compound I-3 in the biological test Example 6 to mouse head twitching.
  • Fig. 6 is a graph showing the response of compound I-10 to head twitching in mice in biological test example 6.
  • Fig. 7 is a graph showing the head twitch response of compound I-23 mice in Biological Test Example 7.
  • Figure 8 is a graph of the antidepressant effect in the mouse tail suspension experiment after 1 day, 7 days and 14 days after a single injection of compound I-23 in biological test example 7, wherein “ns” means no significant difference, "* " indicates P ⁇ 0.05, “**” indicates P ⁇ 0.01, “***” indicates P ⁇ 0.001, and “****” indicates P ⁇ 0.0001.
  • Step 1 Add 2-methoxyphenylmethanol (0.54g, 3.91mmol), CBr 4 (1.94g, 5.87mmol), and solvent dichloromethane (20mL) into the round bottom flask, put it in an ice-water bath, add PPh3 (1.54g, 5.87mmol). The reaction system was stirred at room temperature for 5 hours. After the reaction, the solvent was removed under reduced pressure, and purified by a flash silica gel column (eluent: 10-30% ethyl acetate/petroleum ether) to obtain a colorless oil whc46 (0.75 g, yield 96%).
  • 2-methoxyphenylmethanol (0.54g, 3.91mmol
  • CBr 4 (1.94g, 5.87mmol
  • solvent dichloromethane 20mL
  • Step 2 Add 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,CAS#313368-85-3, purchased from Shanghai Pide Pharmaceutical Technology) (100mg, 0.44mmol), whc46 (130mg, 0.66 mmol), solvent DMSO (5 mL), and diisopropylethylamine (DIPEA) (1 mL). The reaction system was stirred overnight at 60 °C.
  • DIPEA diisopropylethylamine
  • Step 1 Add 3-(2-methoxyphenyl)propionic acid (2.0g, 11.1mmol), solvent DMF (10mL) and Cs 2 CO 3 (10.8g, 33.3mmol) into a round bottom flask, then add BnBr (2.85 g, 16.7 mmol). The reaction was stirred overnight at room temperature. After the reaction was completed, the solvent was removed and separated and purified with a flash silica gel column (eluent: 20-30% ethyl acetate/petroleum ether) to obtain a colorless oil whc31 (2.8 g, yield 97%).
  • Step 2 Add whc31 (3-(2-methoxyphenyl) benzyl propionate, 1.0 g, 3.7 mmol) to a dry round bottom flask, add THF (15 mL) to dissolve, protect under argon and place in - Stir in a low temperature reactor at 10°C. After 10 min DABAL-H (23 mL, 1M in hexane) was added. Subsequently, the reaction system was stirred at 0°C for 5 hours. After the reaction was completed, the reaction was quenched with saturated sodium potassium tartrate solution (5 mL) at low temperature (-10 °C).
  • Step 3 Following 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.
  • Step 4 Following the method of step 2 of Example 1, react whc52 (1-(3-bromopropyl)-2-methoxybenzene) with raw material (A) to obtain compound I-10 (80mg, 96%) , yellow oil.
  • Example 12 (8aS, 12aR)-11-(2-methoxyphenethyl)-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- Methoxyphenethyl)-4-methyl-4,5,6,7,8a,9,10,11,12,12a-decahydro-[1,4]diazepine[3,2, Preparation of 1-hi]pyrido[4,3-b]indole (Compound I-13)
  • Step 1 Add 1,3,4,5-tetrahydro-2H-1,5-benzodiazepine-2-one (1.6g, 10mmol) into a round bottom flask, add acetic acid:water (2:1 ) mixed solution (15mL) was stirred and dissolved, and the temperature was lowered to 0°C. An aqueous solution (5 mL) of sodium nitrite (770 mg, 11 mmol) was slowly added dropwise to the reaction solution. After the dropwise addition, the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the pale yellow solid DW05006 (1.7 g, yield 89%) was obtained by filtration.
  • Step 2 Add DW05006 (0.96g, 5mmol) to a round bottom flask, add acetic acid (10mL) and stir to dissolve at room temperature, then put it in an ice bath environment, and slowly add zinc powder (1.6g, 25mmol) to the reaction system in batches. After the addition was complete, the reaction system was stirred at room temperature for 1 hour, and the reaction ended.
  • Step 3 Filter out the insoluble matter in the reaction solution of the previous step, add N-ethoxycarbonyl-4-piperidone (0.75mL, 5mmol) and 0.3mL 1N hydrochloric acid aqueous solution to the filtrate, and heat the reaction system to reflux, Continue to stir the reaction. After 2 hours, the reaction was complete. The reaction was cooled to room temperature, most of the acetic acid was distilled off under reduced pressure, and then cold ethanol was slowly added, and a solid precipitated out. DW05007-2 (685 mg, yield 44%) was obtained as a light yellow solid by filtration.
  • Step 4 Add DW05007-2 (626mg, 2mmol) to the round bottom flask, add trifluoroacetic acid (10mL) and stir to dissolve at 0°C, slowly add sodium cyanoborohydride (151mg, 2.4mmol) to the reaction solution in batches ). After the addition was complete, the reaction system was stirred and reacted at room temperature for 1 hour. After the reaction was completed, 10 mL of water was added to the reaction system to quench the reaction. Most of the trifluoroacetic acid was distilled off under reduced pressure, and then the pH was adjusted to 9.0 with 2N aqueous sodium hydroxide solution.
  • Step 5 Add DW05008 (315mg, 1mmol), methyl iodide (0.1mL, 1.2mmol) and anhydrous N,N-dimethylformamide (10mL) into a round bottom flask and stir to dissolve at room temperature. 60% sodium hydride (45 mg, 1.1 mmol) was slowly added in portions, and the reaction was continued to stir 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. It was extracted three times with ethyl acetate, the organic phases were combined and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate.
  • 60% sodium hydride 45 mg, 1.1 mmol
  • Step 6 DW05009 (329 mg, 1 mmol) was added to a round bottom flask, and anhydrous tetrahydrofuran (10 mL) was added to dissolve it.
  • the reaction system was placed in an ice bath, and a solution of borane in tetrahydrofuran (1M, 2 mL) was added dropwise. After the addition was complete, the reaction system was heated to reflux for 1 hour. After the reaction was completed, the reaction system was cooled to room temperature, 2N hydrochloric acid aqueous solution (1 mL) was added, and the mixture was heated under reflux and stirred. After 30 minutes, the reaction system was placed at room temperature, and 4N aqueous sodium hydroxide solution was added to adjust the pH to 9.0.
  • 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. under reflux and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature. 10 mL of water was added to the reaction system, and extracted three times with ethyl acetate, the combined organic phases were washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 8 Add DW05011 (243 mg, 1 mmol), 4-methoxyphenylacetaldehyde (225 mg, 1.5 mmol) into a round bottom flask, add methanol (10 mL) to dissolve. Sodium cyanoborohydride (94 mg, 1.5 mmol) was added slowly in portions. After the addition was complete, stirring was continued overnight at room temperature. After the reaction was completed, 10 mL of water was added to quench the reaction. It was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 14, 15 (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 Preparation of ]diazepine[3,2,1-hi]pyrido[4,3-b]indole (I-15)
  • Step 1 Following the method of Step 8 in Examples 12 and 13, 4-methoxyphenylacetaldehyde was replaced by 4-methoxyphenylpropanal to obtain pale yellow oil DW05014 (278 mg, yield 81%).
  • Step 2 Chiral resolution of DW05014.
  • Step 1 Tetrahydroquinoline (4g, 30mmol) was dissolved in a mixed solvent of glacial acetic acid (40mL) and water (10mL), then NaNO2 (2.28g, 33mmol) in water (5mL) was slowly added dropwise, and the mixture was heated at room temperature Stir overnight. After the reaction, the solvent was removed under reduced pressure, the concentrate was dissolved in ethyl acetate, and washed once with saturated NaHCO 3 aqueous solution. The organic phase was concentrated and purified by flash silica gel column chromatography (eluent: 0-10% ethyl acetate/petroleum ether) to obtain orange-yellow oil WHE-119 (4.5 g, yield 92%).
  • Step 2 Under argon protection, LiAlH 4 (485 mg, 12.8 mmol) was suspended in anhydrous THF (25 mL). The temperature was cooled in an ice-water bath, and a solution of raw material WHE-119 (1.3 g, 7.98 mmol) in THF (5 mL) was added. The reaction was stirred for an additional 30 minutes in an ice-water bath, then slowly warmed to room temperature and stirred overnight. After the reaction, quench the reaction with sodium potassium tartrate solution, add water and filter. The filtrate was extracted three times with ethyl acetate, and the organic phases were combined.
  • Step 3 Dissolve WHE-115 (620mg, 4.19mmol) and 4,4-dihydroxypiperidine hydrochloride (650mg, 4.2mmol) in ethanol (15mL), then add concentrated hydrochloric acid (0.35mL) and heat to reflux for 3 hours . The reaction solution was cooled and filtered to obtain white solid WHE-109 (0.75 g, yield 84%).
  • Step 5 Crude product WHE-117 (1.3g, 6.42mmol) was dissolved in 1,4-dioxane (15mL), NaOH (500mg, 12.8mmol) aqueous solution (10mL) was added, followed by Boc2O (1.54g , 7.06mmol). The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, water (15 mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated. Purified by flash silica gel column chromatography to obtain WHE-125 (1.8 g, 89% yield in two steps).
  • Step 6 Chiral resolution of compound WHE-125 to obtain WHE-125-p1 and WHE-125-p2
  • stereo configurations of compounds WHE-125-P1 and WHE-125-p2 are obtained by comparing their optical rotation values with those of raw materials A and WHF-108 with known stereo configurations:
  • Step 7 WHE-125-p2 (120mg, 0.382mmol) was added to a round bottom flask, followed by the solvent dichloromethane (2mL), TFA (1mL), and stirred at room temperature for 1 hour. The solvent was removed by concentration under reduced pressure, the residue was dissolved in DMSO (3 mL), 1-(2-bromoethyl)-2-methoxybenzene (100 mg, 0.465 mmol) was added, and then diisopropylethylamine (3 mL ), the reaction system was stirred overnight (18 hours) under heating at 60°C.
  • the compound WHE-125-p2 was de-Boc-protected and alkylated with 1-(3-bromopropyl)-2-methoxybenzene to obtain I-18 (50 mg, yield rate 50%), brown-yellow oil.
  • Step 1 Add benzomorpholine (2.6g, 20mmol) into a round bottom flask, add tetrahydrofuran (40mL) to dissolve, and place the reaction system at 0°C to stir. 3M hydrochloric acid (13 mL) was slowly added dropwise to the reaction system, and the reaction was continued to stir at 0°C. After 1 hour, an aqueous solution (10 mL) of sodium nitrite (3.45 g, 50 mmol) was added dropwise to the reaction flask. After the dropwise addition was completed, stirring was continued overnight at room temperature. TLC detected that the reaction was complete.
  • Step 2 Add DW04027 (1.6g, 10mmol) to a round bottom flask, add a mixed solution (20mL) of acetic acid: water (1:1) to dissolve, and place the reaction system at 0-5°C to stir.
  • Zinc powder 2.6 g, 40 mmol was slowly added in batches, and after the addition was completed, the reaction was continued with stirring at room temperature for 1 hour.
  • the zinc powder was filtered off, and the filtrate was adjusted to pH 9.0 with 2N NaOH, and then washed with ethyl Acetate was extracted three times, the organic phases were combined and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate.
  • Step 3 Add DW04028 (1.5g, 10mmol) and 4,4-piperidinediol hydrochloride (1.2g, 10mmol) into a round bottom flask, add ethanol (20mL) to dissolve. Concentrated hydrochloric acid (1 mL) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was heated to 90° C. and stirred under reflux for 3 hours. The reaction solution was cooled to room temperature and filtered to obtain off-white solid DW04029 (1.6 g, yield 73%).
  • Step 4 Add DW04029 (2.1 g, 10 mmol) to a round bottom flask, add trifluoroacetic acid (20 mL) to dissolve, and place the reaction system at 0° C. to stir. Sodium cyanoborohydride (1.89 g, 30 mmol) was added in batches, and then stirred at room temperature for 2 hours. After the reaction was completed, most of the trifluoroacetic acid was distilled off under reduced pressure, 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 and washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate.
  • Step 5 Add DW04030 (2.1 g, 10 mmol), di-tert-butyl dicarbonyl (2.2 g, 10 mmol) into a round bottom flask, add dioxane (25 mL) and stir 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, it was 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 to obtain crude oil DW04032 (3.0 g, yield 94%). HRMS ( ESI ) m/z Calcd . for C18H25N2O3 + [M+H] + : 317.1860, found: 317.1871.
  • Step 6 Carry out chiral column resolution of DW04032.
  • Step 7 Add DW04032P1 (310 mg, 1 mmol) to a round bottom flask, add dichloromethane (5 mL) and stir at room temperature to dissolve, then add trifluoroacetic acid (1 mL). The reaction system continued to stir at room temperature for 2 hours. After the reaction was completed, 2N aqueous sodium hydroxide solution was added to the reaction system to adjust the pH to 9.0, extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The organic phase was concentrated to obtain crude DW04072P1 (208 mg, yield 96%) as a light yellow solid.
  • HRMS (ESI) m/z calcd for C13H17N2O + [ M +H] + : 217.1335 , found: 217.1343.
  • Step 8 Following the method of Step 7 of Example 16, DW04072P1 was alkylated with 1-(2-bromoethyl)-2-methoxybenzene to obtain light yellow oil I-20 (80 mg, yield 49 %).
  • Step 1 Add 2-mercaptoaniline (2.5g, 20mml), 1,3-dibromopropane (6.03g, 30mmol) and K 2 CO 3 (8.28g, 60mmol) into a round bottom flask, add the solvent DMF under nitrogen protection (20mL). The reaction system was heated and stirred overnight at 65°C. After the reaction, the solvent DMF was removed by concentration under reduced pressure, and the solvent was separated and purified by flash silica gel column chromatography (eluent: 0-20% ethyl acetate/petroleum ether) to obtain brown-red oil WHE148 (1.41 g, yield 50%).
  • Step 2 The raw material WHE-148 (1.59g, 9.63mmol) was dissolved in HOAc/H 2 O (15mL/5mL) in a round bottom flask, and then NaNO 2 (797mg, 11.6mmol) was added under cooling in an ice-water bath, The reaction system was slowly warmed to room temperature and then stirred overnight. After the reaction, the solvent was removed under reduced pressure, dissolved in ethyl acetate, washed once with NaHCO 3 saturated aqueous solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, concentrated and separated and purified by flash silica gel column chromatography to obtain WHF-12 (1.53 g, 82%) as a brown yellow oil.
  • Step 3 LiAlH 4 (600 mg, 15.8 mmol) was suspended in anhydrous THF (20 mL) under nitrogen 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 added slowly. reactant Stirring was continued for 30 minutes under ice-water bath conditions, and then stirred overnight under heating conditions at 50°C. After the reaction, the reaction solution was cooled in an ice-water bath, quenched with an aqueous solution of sodium potassium tartrate, filtered, added water to the filtrate, and separated the organic phase. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined.
  • Step 4 Dissolve WHE-136 in ethanol (10 mL), add 4,4-dihydroxypiperidine hydrochloride (1.85 g, 12.1 mmol), hydrochloric acid (0.6 mL), and heat the reaction system under reflux overnight. After the reaction, 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 NaHCO 3 aqueous solution, concentrated under reduced pressure and purified by flash silica gel column chromatography to obtain light yellow solid WHF-19 (1.4 g, yield 94%).
  • Step 5 Compound WHF-17 (1.09g, 6.05mmol) was dissolved in trifluoroacetic acid, cooled in an ice-water bath, and then NaBH 3 CN (1.1g, 17.2mmol) was added in batches within 30 minutes, and the reaction system was cooled at room temperature Stir for 2 hours. After the reaction was completed, ice was added to the reaction solution to quench the reaction, and the solution was made alkaline with NaOH aqueous solution. Extracted three times with ethyl acetate, combined the organic phases, and concentrated to obtain the crude product WHF-19 (1.5 g) as a tan solid, which was directly used in the next step.
  • NaBH 3 CN 1.1g, 17.2mmol
  • Step 6 The crude compound WHF-19 (1.5 g, 6.1 mmol) from the previous step was dissolved in dichloromethane (10 mL), and Et 3 N (2 mL) was added, followed by Boc 2 O (2.6 g, 12.2 mmol). The reaction system was stirred at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure, and the compound WHF-21 (1.4 g, two-step yield 67%) was separated and purified by flash silica gel column chromatography.
  • the stereo configurations of compounds WHF-21-p1 and WHF-21-p2 were obtained by comparing their optical rotation values with those of raw materials A and WHF-108 with known stereo configurations, respectively.
  • Step 8 Following the method of Step 7 of Example 16, the compound WHF-21-p1 was de-Boc-protected and alkylated with 1-(2-bromoethyl)-2-methoxybenzene to obtain I-24( 51 mg, yield 59%), orange-yellow oil.
  • the compound can be prepared I-29, yellow oil.
  • cell membrane fractions containing specific 5-HT 2A receptors are prepared.
  • a 10cm culture dish covered with HEK-293T cells (ATCC, CRL-11268) was transfected with 5-HT 2A receptor plasmid (10ng) and PEI (40 ⁇ L), After 48 hours, take out the 10 cm culture dish from the cell room in which the cultured cells have expressed the 5-HT 2A receptor.
  • Use a vacuum pump to suck off the culture medium, add 3mL of lysate to each well, and place the cells in a 4°C freezer for 10 minutes. After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant.
  • the cell pellet was transferred to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded.
  • the precipitate is the cell membrane fraction containing the 5-HT 2A receptor.
  • ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing 5-HT 2A receptors.
  • 30 ⁇ L of membrane protein suspension to each well of a 96-well plate.
  • 30 ⁇ L of different drugs were added to the 96-well plate from left to right to ensure that the final drug concentrations were 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates per treatment.
  • 30 ⁇ L of [ 3 H]-LSD was added to each well of the 96-well plate. Incubate at room temperature for 2 hours in the dark. detection. The machine reading value reflects the amount of [ 3 H]-LSD bound on the membrane, and after further data processing, the affinity K i value of different compounds for the 5-HT 2A receptor is obtained.
  • Table 1 shows the affinity K i values of the compounds of the present invention for 5-HT 2A receptors.
  • the compounds of the present invention have moderate to high affinity to the 5-HT 2A receptor, wherein, 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 Ki values for 5-HT 2A receptors less than 0.1 ⁇ M.
  • the next day digest the overgrown cells, spread a 96-well plate with the amount of cells in a 6cm culture dish full of cells, and use 100 ⁇ L of culture medium per well.
  • dosing test Take out the 96-well plate from the cell room to remove the culture medium, add 40 ⁇ L of the substrate coelenterazine 400a (final concentration 5 ⁇ M) to each well, and then add 20 ⁇ L of different concentrations of drugs from left to right to ensure that the final drug concentration is from bottom to top
  • the upper gradient was decreased, and each treatment was repeated twice, and finally, the computer was tested.
  • the machine reading value reflects the membrane condition of intracellular ⁇ -arrestin2 and the dissociation of G protein trimer.
  • the former indicates the activation degree of ⁇ -arrestin2 signaling pathway downstream of 5-HT 2A receptor
  • the latter indicates the G protein downstream of 5-HT 2A receptor.
  • the degree of activation of signaling pathways thus, various chemical
  • the agonistic effect of the drug on the 5-HT 2A receptor can be characterized.
  • the compounds of the present invention have moderate to strong agonistic activity on 5-HT 2A receptors, and compounds I-9, I-10, I-13, I-15, I-17, I- 19, I-21, I-23, I-25 and I-27 have selective activation effects on 5- HT2A receptor-mediated recruitment of ⁇ -arrestin2 and do not activate G protein signaling pathway.
  • the affinity of the compound of the present invention for dopamine D2 receptor is determined by radioligand competition experiment.
  • cell membrane fractions containing specific dopamine D2 receptors are prepared.
  • a 10 cm culture dish covered with HEK-293T cells (ATCC, CRL-11268) was transfected with 10 ng dopamine D2 receptor plasmid and 40 ⁇ L PEI. After 48 hours, the 10 cm culture dish was taken out from the cell room, and the cells cultured therein Dopamine D2 receptors are expressed.
  • Use a vacuum pump to suck off the culture medium, add 3mL of lysate to each well, and place the cells in a 4°C freezer for 10 minutes.
  • the cells After the cells are detached, transfer them to a 15 mL centrifuge tube, centrifuge at 1500 rpm for 5 minutes at 4°C, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3mL of lysate to it, and grind until the cells are broken. Then, the cell suspension was equally divided into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate is the cell membrane fraction containing dopamine D2 receptors. In the second step, ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing dopamine D2 receptors.
  • mice 60 male C57 mice (purchased from Suzhou Zhaoyan Experimental Animal Co., Ltd.) were randomly divided into groups according to body weight, with 3 mice in each group. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration. Administered by intraperitoneal injection, the administration concentration is 1 mg/mL, and the vehicle is 10% DMSO+90% normal saline.
  • Sample collection 0.1 mL of blood was collected through the orbit before and after isoflurane anesthesia, placed in an EDTAK2 centrifuge tube and placed on an ice bath. Centrifuge at 5000rpm at 4°C for 10 minutes to collect plasma.
  • Time points of IP blood collection and brain tissue 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h, 3 mice at each time point, all plasma samples were stored at -80°C before analysis and detection.
  • C max is the measured maximum blood drug concentration
  • AUC (0 ⁇ t) is calculated by the trapezoidal method
  • T max is the peak time of blood drug concentration after administration.
  • ARS Acute restraint stress
  • FST forced swim test
  • TST tail suspension test
  • C57/bl6j wild-type mice (over 8 weeks old, purchased from Shanghai Lingchang Biotechnology Co., Ltd.) were immobilized with a single rodent restraint device for 5 hours. mouse All body movement is restricted, but causes only minimal pain.
  • mice were deprived of food and water. After 5 hours of restraint, a separate group of mice was released and immediately followed by intraperitoneal injection of the compound being tested.
  • mice After recovering for 30 min, the behavioral changes of the mice were evaluated by forced swimming test or tail suspension test.
  • the control group simultaneously received saline injections but did not undergo the ARS step.
  • Forced swimming test the control group and the mice after ARS stress were placed in glass beakers filled with 15 cm deep water at a temperature of 25 ⁇ 1°C. All mice were forced to swim for 6 min and recorded with a video camera. Record the resting time for the last 4 min of the test. Immobility time is defined as the time during which the animal floats in the water without struggling, and only makes necessary movements to keep the head out of the water; tail suspension test: the mice in the control group and the mice after restraint stress were hung by sticking their tails with adhesive tape for 6 minutes, respectively. and recorded by the camera. The last 4 min of resting time was manually timed and assessed by a blinded observer.
  • the antidepressant effect of compound I-10 in the mouse tail suspension test is shown in Figure 3. It can be seen from Figure 3 that compound I-10 has obvious antidepressant effect.
  • the antidepressant effect of I-10 in the forced swimming test is shown in Figure 4. It can be seen from Figure 4 that compound I-10 has obvious antidepressant effect.
  • METHODS The hallucinogenic effects were characterized by detecting head twitch responses in mice based on magnetic signals.
  • Mice strain C57/BL6J, purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • Mice were anesthetized with 2% isoflurane.
  • a small section of scalp is excised in the center of the back of the skull.
  • a custom-made small neodymium magnet (4 mm x 4 mm x 2 mm) was attached to the center of the back of the cranium using dental resin.
  • the N-S poles of the magnets are parallel to the dorso-ventral surface of the implant. Mice were allowed to recover for 1 week before testing.
  • mice were placed in 12 cm diameter glass beakers surrounded by 150 turns of 30-gauge enamelled copper wire.
  • the output signal of the coil is recorded by the PowerLab/4SP instrument with LabChart V8.1.16 software.
  • the LabChart data was processed with a 40-200 Hz digital bandpass filter, and the mouse head twitch response was determined by retrieving sinusoidal wavelets satisfying the following conditions: 1, containing more than 2 bipolar Peak; 2, the amplitude exceeds the background noise level; 3, the duration is less than 120 ms.
  • the mice were transferred to the test room for acclimatization 1 hour before the test. Mice were then transferred to beakers for 30 minutes and baseline mouse head twitch response values were recorded. Immediately after baseline recordings, mice were injected (ip) with test compounds and further recorded for 1-2 hours depending on the compound used. 30 minutes before the numerical statistics.
  • Antidepressant efficacy test method For male C57BL/6 mice (8 weeks old, purchased from Shanghai Lingchang Biotechnology Co., Ltd.), corticosterone was dissolved in the drinking water of the mice at a concentration of 25 ⁇ g/mL. Mice were dosed with a corticosterone solution using a drinking water bottle for 21 days. Mice were maintained on a 12-hour photoperiod. Change fresh corticosterone-containing drinking water every other day for the first two weeks, and gradually replace it with corticosterone-free ordinary drinking water every two days in the last week.
  • mice After 21 days of corticosterone exposure, a single injection of compound I-23 was performed in mice, and the antidepressant activity of compound I-23 was tested by tail suspension test at three time periods after 1 day, 7 days and 14 days.
  • Tail suspension test the mice in the control group and the drug-administered group were respectively taped to their tails and hung for 6 minutes, and recorded by video camera. The last 4 min of resting time was manually timed and assessed by a blinded observer.
  • Hallucinogenic effect test method Refer to the method of biological test example 6 to test the effect of compound I-23 on causing head twitching in mice.

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Abstract

本发明公开了一种并环哌啶类化合物及其制备方法和用途。本发明的并环哌啶类化合物如式I'所示。本发明的并环哌啶类化合物具有较佳的抑制抑郁症的作用，具有良好的应用前景。

Description

并环哌啶类化合物及其制备方法和用途
本申请要求申请日为2022/1/14的中国专利申请2022100417955的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种并环哌啶类化合物及其制备方法和用途。
背景技术
抑郁症是一种严重影响人类健康的精神类疾病，影响全球约3亿人，每年有数万抑郁症患者自杀。抑郁症以显著而持久的心境低落为主要特征，伴以兴趣丧失、睡眠障碍、自我评价过低等症状，严重者会出现自杀意念或自伤自杀行为。
目前已知的抗抑郁症药物主要包括选择性5-羟色胺重摄取抑制剂(SSRI)、三环类抗抑郁药、单胺氧化酶抑制剂等几大类。SSRI类药物临床应用较为广泛，主要包括舍曲林(sertraline)、艾司西酞普兰(escitalopram)、氟西汀(fluoxetine)、帕罗西汀(paroxetine)等。SSRI类药物通过抑制中枢神经递质5-羟色胺(5-HT)的重吸收，增加5-HT在突触间隙的浓度而发挥作用。尽管SSRI类药物的药效相比传统的三环类抗抑郁药物具有耐受性更好、安全性更高的优点，但这类药物仍然存在几个明显的缺点：(1)起效慢，服药数星期至数月才起效；(2)响应率低，超过三分之一患者无响应；(3)不良反应仍较为普遍，如恶心、体重增加、性功能障碍等。因此，迫切需要开发新型抗抑郁药物。
本世纪初，临床试验意外发现了医用麻醉剂氯胺酮(ketamine)的快速抗抑郁效果。单次使用一剂亚麻醉剂量的氯胺酮能在几小时内快速缓解抑郁症状。2019年3月，美国FDA批准了S构型的氯胺酮(esketamine，艾氯胺酮)作为一种鼻腔喷雾剂，用于治疗难治性抑郁症患者(Swainson等；Expert Rev Neurother,2019,19(10):899-911)。在作用机制上，艾氯胺酮是一种非竞争性和亚型非选择性活动依赖性N-甲基-D天冬氨酸(NMDA)受体拮抗剂，通过拮抗NMDA功能发挥作用(Zhang等；Nature,2021,596(7871):301-305)。在抑郁症小鼠模型中，氯胺酮能够重塑许多之前曾存在、但在长期压力下消失了的突触。但是，氯胺酮作为抗抑郁药物会造成分离性幻觉等副作用，同时也有成瘾风险，临床应用会受到限制。
近期的研究还表明，迷幻剂(psychedelics)类药物在治疗抑郁症、焦虑症、药物成瘾、创伤后应激障碍(PTSD)等疾病方面存在巨大潜力(Nutt等，Cell,2020,181(1): 24-28)。经典迷幻剂主要包括赛洛西宾(psilocybin)、麦角酰二乙胺(LSD)、N,N-二甲基色胺(DMT)、伊博格碱(ibogaine)等。其中，赛洛西宾在二期临床中表现了快速起效、持久缓解抑郁症的效果，目前多项应用赛洛西宾快速治疗抑郁症的临床试验正在进行中。在作用机制上，迷幻剂类药物通过激活5-HT2A受体发挥作用，但如何通过调节激动剂的强度和信号通路选择性发现不具致幻作用的抗抑郁药物仍不明确。
卢美哌隆(Lumateperone)是一个具有四并环哌啶母核骨架的化合物2019年12月获得美国食品和药物管理局(FDA)批准，用于治疗成人精神分裂症(Blair,Drugs,80(4):417-423)。2021年12月，美国FDA批准了卢美哌隆一个新的适应症：作为单药疗法、以及作为锂盐或丙戊酸盐的辅助疗法，用于治疗成人患者以治疗与双相I型或II型障碍(双相抑郁症)相关抑郁发作(Calabrese；Am J Psychiatry,2021,178(12):1098-1106)。
在作用机制上，卢美哌隆是一种5-HT2A受体强效拮抗剂(Ki＝0.54nM)，突触后D2受体拮抗剂(Ki＝32nM)，和5-HT转运体(SERT)抑制剂(Ki＝61nM)(Li等；J Med Chem 2014,57,2670-2682)。作为抗抑郁药物，卢美哌隆仅用于双相I型或II型障碍的相关抑郁发作，病人响应率仅51.1％(Calabrese等，Am J Psychiatry 2021，178:12)；对于一般抑郁症病人和难治性抑郁症病人的效果尚未见报导。其抗抑郁的效果和作用机制类似于鲁拉西酮(lurasidone)、喹硫平(quetiapine)和卡利拉嗪(cariprazine)等抗精神分裂症药物(Calabrese等，Am J Psychiatry 2021，178:12)。
发明内容
本发明所要解决的技术问题是为了克服现有技术中的抗抑郁药物种类有限或者致幻副作用的缺陷，为此，而提供了一种并环哌啶类化合物及其制备方法和用途。本发明的并环哌啶类化合物具有较佳的抑制抑郁症的作用，进一步地还避免了致幻副作用。
本发明是通过如下的技术方案克服上述技术问题的。
本发明提供了一种如式I’所示的并环哌啶类化合物或其药学上可接受的盐：
其中，X为
Ra、Rb和Rc独立地为氢或C1-C4烷基；
R1和R2独立地为氢、卤素或C1-C4烷基；
R3独立地为氢、卤素、羟基或C1-C4氧烷基；
m为1、2或3；
n为1、2或3；
z为1或2。
在一实施方案中，所述如式I’所示的并环哌啶类化合物不为
在一实施方案中，所述如式I’所示的并环哌啶类化合物为如式I-a、I-b、I或I-c所示的并环哌啶类化合物：

其中，X、R1、R2、R3、m和n的定义同前所述。
在一实施方案中，所述如式I’所示的并环哌啶类化合物为如式I所示的并环哌啶类化合物：
其中，X为
Ra、Rb和Rc独立地为氢或C1-C4烷基；
R1和R2独立地为氢、卤素或C1-C4烷基；
R3独立地为氢、卤素、羟基或C1-C4氧烷基；
m为1、2或3；
n为1、2或3。
在一实施方案中，Ra、Rb和Rc中，所述的C1-C4烷基独立地优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基。
在一实施方案中，R1和R2中，所述的卤素独立地优选为F、Cl、Br或I。
在一实施方案中，R1和R2中，所述的C1-C4烷基独立地优选为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在一实施方案中，R3中，所述的卤素优选为F、Cl、Br或I。
在一实施方案中，R3中，所述的C1-C4烷氧基优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基。
在一实施方案中，R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”， 其中邻位、对位或间位均是指R3相对于式I’中的在苯环上的取代位置。
在一实施方案中，R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”，其中邻位、对位或间位均是指R3相对于式I中的在苯环上的取代位置。
在一实施方案中，X为
在一实施方案中，X为Ra为C1-C4烷基。
在一实施方案中，X为
在一实施方案中，X为Rb和Rc独立地为氢。
在一实施方案中，X为
在一实施方案中，R1和R2为氢。
在一实施方案中，R3独立地为氢、羟基或C1-C4氧烷基。
在一实施方案中，n为1或2。
在一实施方案中，X为
在一实施方案中，为
在一实施方案中，为
在一实施方案中，为
在一实施方案中，为
在一实施方案中，为
在一实施方案中，X为
Ra为C1-C4烷基；
Rb和Rc独立地为氢；
R1和R2为氢；
R3独立地为氢、羟基或C1-C4氧烷基；
n为1或2；
z为1或2；
R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”。
在一实施方案中，X为
Ra为C1-C4烷基；
R1和R2为氢；
R3独立地为氢、羟基或C1-C4氧烷基；
n为1或2；
R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”。
在一实施方案中，所述的如式I’所述的并环哌啶类化合物为如下任一化合物：


本发明还提供了上述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐的制备方法，其包括方法1、方法2或方法3：
当R3独立地为氢、卤素或C1-C4氧烷基时，所述的如式I’所示的并环哌啶类化合物或其盐的制备方法为方法1或方法2；
方法1包括如下步骤：在碱存在下，将如式II’所示的化合物和如式III所示的化合物在溶剂中进行如下的取代反应，得到所述的如式I’所示的并环哌啶类化合物；
方法2包括如下步骤：在还原剂存在下，将如式II’所示的化合物和如式IV所示的化合物在溶剂中进行如下的还原胺化反应，得到所述的如式I’所示的并环哌啶类化合物；
当R3独立地为羟基时，所述的如式I’所示的并环哌啶类化合物或其盐的制备方法为方法3；
方法3包括如下步骤：在BBr3存在下，将方法1或2中所述的如式I’所示的并环哌啶类化合物在溶剂中进行反应，得到如式I’所示的并环哌啶类化合物(即R3为羟基)；
方法1、2和3中X、Ra、Rb、Rc、R1、R2、m和n的定义均同前所述；
m-1是指比m少一个碳。
方法1中，所述的取代反应的条件和操作可以为本领领域此类反应常规的条件和操作，本发明特别优选如下条件和操作：
所述的碱优选为有机碱，例如二异丙基乙基胺(DIPEA)。所述的碱与所述的如式II’所示的化合物的摩尔比优选为(1-3):1，例如1:1。
所述的如式III所示的化合物与所述的如式II’所示的化合物的摩尔比优选为(1-3):1，例如1.5:1。
所述的溶剂优选为极性非质子性有机溶剂，例如二甲基亚砜(DMSO)。
所述的取代反应的温度优选为室温至80℃，更优选为50-80℃，例如60℃。
方法2中，所述的反应的条件和操作可以为本领领域此类反应常规的条件和操作，本发明特别优选如下条件和操作：
所述的溶剂优选为醇类溶剂，例如甲醇。
所述的还原剂优选为硼烷类还原剂，例如氰基硼氢化钠。
所述的还原胺化反应温度优选为0-60℃，例如室温。
方法3中，所述的反应的条件和操作可以为本领领域此类反应常规的条件和操作，本发明特别优选如下条件和操作：
所述的溶剂优选为卤代烃类有机溶剂，例如二氯甲烷。
所述的反应的温度优选为-40℃至40℃；更优选为10-40℃，例如室温。
本发明还提供了上述的如式I所示的并环哌啶类化合物或其药学上可接受的盐的制备方法，其包括方法1或方法2：
当R3独立地为氢、卤素或C1-C4氧烷基时，所述的如式I所示的并环哌啶类化合物或其盐的制备方法为方法1；
方法1包括如下步骤：在碱存在下，将如式II所示的化合物和如式III所示的化合物在溶剂中进行如下的取代反应，得到所述的如式I所示的并环哌啶类化合物；
当R3独立地为羟基时，所述的如式I所示的并环哌啶类化合物或其盐的制备方法为方法2；
方法2包括如下步骤：在BBr3存在下，将方法1中所述的如式I所示的并环哌啶类化合物在溶剂中进行反应，得到如式I所示的并环哌啶类化合物(即R3为羟基)；
方法1和2中X、Ra、Rb、Rc、R1、R2、m和n的定义均同前所述。
方法1中，所述的取代反应的条件和操作可以为本领领域此类反应常规的条件和操作，本发明特别优选如下条件和操作：
所述的碱优选为有机碱，例如二异丙基乙基胺(DIPEA)。所述的碱与所述的如式II所示的化合物的摩尔比优选为(1-3):1，例如1:1。
所述的如式III所示的化合物与所述的如式II所示的化合物的摩尔比优选为(1-3):1，例如1.5:1。
所述的溶剂优选为卤代烃类有机溶剂，例如二氯甲烷。
所述的取代反应的温度优选为50-80℃，例如60℃。
方法2中，所述的反应的条件和操作可以为本领领域此类反应常规的条件和操作，本发明特别优选如下条件和操作：
所述的溶剂优选为卤代烃类有机溶剂，例如二氯甲烷。
所述的取代反应的温度优选为10-40℃，例如室温。
本发明还提供一种药物组合物，其包含所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，和药学上可接受的辅料。
本发明还提供一种药物组合物，其包含所述的如式I所示的并环哌啶类化合物或其药学上可接受的盐，和药学上可接受的辅料。
本发明还提供了一种物质A在制备5-HT2A受体激动剂中的应用；所述的物质A为所述的如式I’所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物。
所述的5-HT2A受体激动剂优选为5-HT2A受体下游β-arrestin2招募信号通路激动剂和/或5-HT2A受体下游Gq蛋白激活信号通路激动剂，例如5-HT2A受体下游β-arrestin2招募信号通路激动剂。
本发明还提供了一种物质A在制备5-HT2A受体激动剂中的应用；所述的物质A为所述的如式I所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物。
所述的5-HT2A受体激动剂优选为5-HT2A受体下游β-arrestin2招募信号通路激动剂和/或5-HT2A受体下游Gq蛋白激活信号通路激动剂，例如5-HT2A受体下游β-arrestin2招募信号通路激动剂。
本发明还提供了一种物质A在制备的药物中的应用；
所述的物质A为含所述的如式I’所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物；
所述的药物为用于治疗或预防与5-HT2A受体相关的疾病。
所述的与5-HT2A受体相关的疾病优选为与5-HT2A受体下游β-arrestin2招募信号通 路和/或5-HT2A受体下游Gq蛋白激活信号通路相关的疾病，优选为与5-HT2A受体下游β-arrestin2招募信号通路相关的疾病，例如抑郁症。
本发明还提供了一种物质A在制备的药物中的应用；
所述的物质A为含所述的如式I所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物；
所述的药物为用于治疗或预防与5-HT2A受体相关的疾病。
所述的与5-HT2A受体相关的疾病优选为与5-HT2A受体下游β-arrestin2招募信号通路和/或5-HT2A受体下游Gq蛋白激活信号通路相关的疾病，优选为与5-HT2A受体下游β-arrestin2招募信号通路相关的疾病，例如抑郁症。
本发明还提供了一种物质A在制备用于治疗或预防抑郁症的药物中的应用；所述的物质A为含所述的如式I’所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物。
本发明还提供了一种物质A在制备用于治疗或预防抑郁症的药物中的应用；所述的物质A为含所述的如式I所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物。
本发明还提供了一种治疗或预防抑郁症的方法，其包括向有此需要的受试者(例如人或小鼠)给予治疗有效量的物质A；所述的物质A为所述的如式I’所示的并环哌啶类化合物、其药学上可接受的盐或上述的药物组合物。
本发明中，室温是指10-30℃。过夜是指8-15小时。
本发明中，卤素优选氟、氯、溴或碘。
本发明中，烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
本发明中，烷氧基表示通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基。由此，烷氧基包含以上烷基和环烷基的定义。本发明中烷氧基优选C1-C4烷氧基，更优选甲氧基、乙氧基、正丙氧基、异丙氧基或叔丁氧基。
本发明中，“ns”表示无显著差异，“*”表示P＜0.05，“**”表示P＜0.01，“***”表示P＜0.001，“****”表示P＜0.0001。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的并环哌啶化合物对抑郁症具有较佳的抑制作用，可以有效治疗抑郁症。进一步地，本发明的并环哌啶化合物在治疗抑郁症同时还避 免了致幻副作用。
附图说明
图1为生物测试实施例5中化合物I-3在小鼠悬尾实验中的抗抑郁作用图，其中“*”表示P＜0.05，“****”表示P＜0.0001。
图2为生物测试实施例5中化合物I-3在小鼠强制游泳实验中的抗抑郁作用图，其中“ns”表示无显著差异，“****”表示P＜0.0001。
图3为生物测试实施例5中化合物I-10在小鼠悬尾实验中的抗抑郁作用图，其中“ns”表示无显著差异，“****”表示P＜0.0001。
图4为生物测试实施例5中化合物I-10在小鼠强制游泳实验中的抗抑郁作用图，其中“ns”表示无显著差异，“****”表示P＜0.0001。
图5为生物测试实施例6中化合物I-3在小鼠头部抽搐的响应图。
图6为生物测试实施例6中化合物I-10在小鼠头部抽搐的响应图。
图7为生物测试实施例7中化合物I-23小鼠头部抽搐的响应图。
图8为生物测试实施例7中化合物I-23单次注射后在1天后、7天后和14天后在小鼠悬尾实验中的抗抑郁作用图，其中“ns”表示无显著差异，“*”表示P<0.05,“**”表示P<0.01,“***”表示P<0.001,“****”表示P＜0.0001。
具体实施方式
实施例1：(6bR,10aS)-8-(2-甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-1)的制备
步骤1：圆底烧瓶中加入2-甲氧基苯基甲醇(0.54g,3.91mmol)，CBr4(1.94g,5.87mmol),溶剂二氯甲烷(20mL)溶解，置于冰水浴中，加入PPh3(1.54g,5.87mmol)。反应体系在室温下搅拌5小时。反应结束后，减压除去溶剂，用快速硅胶柱纯化(洗脱剂为10-30％乙酸乙酯/石油醚)得到无色油状物whc46(0.75g，产率96％)。1H NMR(800MHz,CDCl3)δ7.33(d,J＝7.5Hz,1H),7.31–7.27(m,1H),6.92(t,J＝7.4Hz,1H),6.88(d, J＝8.3Hz,1H),4.57(s,2H),3.90(s,3H).
步骤2：圆底烧瓶中加入原料(A)((6bR,10aS)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉，CAS#313368-85-3，购自上海毕得医药科技)(100mg,0.44mmol)，whc46(130mg,0.66mmol)，溶剂DMSO(5mL)，及二异丙基乙基胺(DIPEA)(1mL)。反应体系在60℃下搅拌过夜。反应结束后加水，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗一次，浓缩后用快速硅胶柱分离纯化(洗脱剂为0-10％甲醇/二氯甲烷)得到黄色固体I-1(100mg,产率65％)。1H NMR(800MHz,CDCl3)δ7.50(d,J＝7.2Hz,1H),7.31–7.26(m,1H),6.96(t,J＝7.5Hz,1H),6.87(d,J＝8.3Hz,1H),6.64(t,J＝7.6Hz,1H),6.48(d,J＝7.4Hz,1H),6.39(d,J＝8.1Hz,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＝12.0,6.6Hz,1H),2.95–2.91(m,1H),2.85(s,3H),2.79(t,J＝9.9Hz,1H),2.61–2.56(m,1H),2.27–2.23(m,2H),1.98(d,J＝14.4Hz,1H).13C NMR(201MHz,CDCl3)δ157.99,137.70,135.08,131.85,129.43,129.02,128.88,120.71,120.65,112.74,110.69,109.08,63.97,55.51,55.48,55.11,50.49,48.16,44.39,40.58,37.46,23.81.HR-MS(ESI)m/z C22H28N3O+[M+H]+计算值:350.2227；实测值:350.2233.
实施例2：2-(((6bR,10aS)-3-甲基-2,3,6b,9,10,10a-六氢-1H-吡啶并-[3',4':4,5]吡咯并[1,2,3-de]喹喔啉-8(7H)-基)甲基)苯酚(化合物I-2)的制备
圆底烧瓶中加入I-1(47mg,0.13mmol)，无水二氯甲烷(15mL)，氩气保护下冷却至-78℃，加入BBr3(17％乙醚溶液,0.6mL)。随后反应体系在室温条件下搅拌3小时。反应结束后，在低温(-30℃)下加入饱和NaHCO3水溶液淬灭反应，除去溶剂后用快速硅胶柱纯化，随后用制备液相色谱进一步分离纯化(20-80％MeOH/H2O,tR＝18.5min)得黄色固体I-2(40mg,32％)。1H NMR(800MHz,CD3OD)δ7.34–7.29(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＝10.9Hz,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＝10.2Hz,1H),2.74(t,J＝12.4Hz,1H),2.32(d,J＝15.9Hz,1H),2.16–2.10(m,1H).HR-MS(ESI)m/z calcd for C21H26N3O+[M+H]+计算值:336.2070；实测值:336.2071.
实施例3：(6bR,10aS)-8-(2-甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并 [3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-3)的制备
仿照实施例1步骤2的方法，将1-(2-溴乙基)-2-甲氧基苯(CAS#36449-75-9)与原料(A)进行反应得化合物I-3(220mg,90％)，黄色油状物。1H NMR(800MHz,CDCl3)δ7.17(t,J＝7.8Hz,1H),7.13(d,J＝7.4Hz,1H),6.86(t,J＝7.4Hz,1H),6.83–6.80(m,1H),6.66(t,J＝7.7Hz,1H),6.54(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,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＝11.7,6.5Hz,1H),2.93–2.89(m,3H),2.86(s,3H),2.82(t,J＝10.0Hz,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).13C NMR(201MHz,CDCl3)δ157.51,137.87,135.12,130.39,129.53,127.85,127.63,120.59,112.76,110.38,109.11,64.31,58.45,55.61,55.28,50.64,48.74,44.44,41.15,37.55,27.40,24.37.HR-MS(ESI)m/z C23H30N3O+[M+H]+计算值:364.2383；实测值:364.2386.旋光值：[α]D 25＝–54°(c＝0.1，CHCl3)。
实施例4：(6bR,10aS)-8-(3-甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-4)的制备
仿照实施例1步骤2的方法，将1-(2-溴乙基)-3-甲氧基苯(CAS#2146-61-4)与原料(A)进行反应，得化合物I-4(80mg，84％)，黄色油状物。1H NMR(800MHz,CDCl3)δ7.21–7.17(m,1H),6.77(d,J＝7.5Hz,1H),6.76–6.72(m,2H),6.66(t,J＝7.6Hz,1H),6.54(d,J＝7.3Hz,1H),6.42(d,J＝8.0Hz,1H),3.78(s,3H),3.63–3.59(m,1H),3.32(dt,J＝10.1,2.9Hz,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＝10.0,3.0Hz,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＝11.2Hz,1H),2.00–1.93(m,2H).13C NMR(201MHz,CDCl3)δ159.70,142.13,138.03,135.06,130.04,129.38,121.16,120.38,114.54,112.75,111.37,109.01,64.58,60.63,56.30,55.16,50.71,49.07,44.41,41.79,37.61,33.67,25.06.HR-MS(ESI) m/z C23H30N3O+[M+H]+计算值:364.2383；实测值:364.2385.
实施例5：(6bR,10aS)-8-(4-甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-5)的制备
仿照实施例1步骤2的方法，将1-(2-溴乙基)-4-甲氧基苯(CAS#14425-64-0)与原料(A)进行反应得化合物I-5(40mg，42％)，黄色油状物。1H NMR(800MHz,CDCl3)δ7.13–7.08(m,2H),6.84–6.81(m,2H),6.66(t,J＝7.6Hz,1H),6.54(d,J＝7.3Hz,1H),6.42(d,J＝7.9Hz,1H),3.78(s,3H),3.61(td,J＝11.0,10.5,3.1Hz,1H),3.32(dt,J＝10.1,3.0Hz,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＝10.0,2.9Hz,1H),2.79–2.72(m,3H),2.60–2.50(m,2H),2.36–2.30(m,1H),2.04(t,J＝11.2Hz,1H),1.99–1.94(m,2H).13C NMR(201MHz,CDCl3)δ157.97,138.03,135.05,132.52,130.06,129.64,120.37,113.89,112.76,109.00,64.59,61.02,56.34,55.28,50.71,49.09,44.41,41.78,37.60,32.71,25.05.HR-MS(ESI)m/z C23H30N3O+[M+H]+计算值:364.2383；实测值:364.2388.
实施例6：(6bR,10aS)-8-(2,3-二甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-6)的制备
仿照实施例1步骤2的方法，将1-(2-溴乙基)-2，3-二甲氧基苯(CAS#709027-29-2)与原料(A)进行反应得化合物I-6(130mg,75％)，黄色油状物。1H NMR(800MHz,CDCl3)δ6.96(t,J＝7.9Hz,1H),6.78–6.75(m,2H),6.65(t,J＝7.6Hz,1H),6.54(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,1H),3.84(s,3H),3.81(s,3H),3.60(td,J＝10.5,3.0Hz,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＝11.6,6.2Hz,1H),2.86(s,3H),2.84(t,J＝8.2Hz,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).13C NMR(201MHz,CDCl3)δ152.80,147.35,138.07,135.05,134.21,130.12,123.88,122.31,120.34,112.81,110.53,108.98,64.63, 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 C24H32N3O2 +[M+H]+计算值：394.2489；实测值：394.2489.
实施例7：(6bR,10aS)-8-(2,4-甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-7)的制备
仿照实施例1步骤2的方法，将1-(2-溴乙基)-2，4-二甲氧基苯(CAS#37567-79-6)与原料(A)进行反应得化合物I-7(72mg,84％)，黄色油状物。1H NMR(800MHz,CDCl3)δ7.12(d,J＝8.0Hz,1H),6.71(t,J＝7.7Hz,1H),6.53(d,J＝7.4Hz,1H),6.44(d,J＝8.0Hz,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＝10.1Hz,1H),3.50(dd,J＝12.1,6.5Hz,1H),3.44–3.39(m,1H),3.36–3.32(m,1H),3.31(d,J＝10.3Hz,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(201MHz,CDCl3)δ160.33,158.12,137.07,135.43,131.05,127.07,121.49,116.60,112.53,109.59,104.43,98.62,62.94,56.98,55.37,55.30,53.37,50.31,47.85,44.38,38.77,37.33,24.75,21.94.HR-MS(ESI)m/z C24H32N3O2 +[M+H]+计算值：394.2489；实测值：394.2498.
实施例8：(6bR,10aS)-8-(2,5-二甲氧基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-8)的制备
仿照实施例1步骤2的方法，将1-(2-溴乙基)-2，5-二甲氧基苯(CAS#99187-42-5)与原料(A)进行反应得化合物I-8(50mg,13％)，黄色油状物。1H NMR(800MHz,CDCl3)δ6.75(d,J＝8.8Hz,1H),6.73(d,J＝3.1Hz,1H),6.69(dd,J＝8.8,3.1Hz,1H),6.66(t,J＝7.7Hz,1H),6.54(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,1H),3.75(s,3H),3.74(s,3H),3.60(td,J＝10.7,3.0Hz,1H),3.31(dt,J＝10.2,3.0Hz,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＝12.0Hz,1H),2.12(t,J＝11.3Hz,1H),2.09–2.02(m,1H),2.00–1.97(m,1H).13C NMR(201MHz,CDCl3)δ153.49, 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 C24H32N3O2 +[M+H]+计算值：394.2489；实测值：394.2489.
实施例9：2-(2-((6bR,10aS)-3-甲基-2,3,6b,9,10,10a-六氢-1H-吡啶并-[3',4':4,5]-吡咯并[1,2,3-de]喹喔啉-8(7H)-基)乙基)苯酚(化合物I-9)的制备
仿照实施例2的方法，将I-3进行脱甲基反应得化合物I-9(100mg,70％)，黄色固体。1H NMR(800MHz,CD3OD)δ6.98(t,J＝7.7Hz,1H),6.95(d,J＝7.5Hz,1H),6.71(d,J＝8.0Hz,1H),6.65(t,J＝7.4Hz,1H),6.54(t,J＝7.6Hz,1H),6.44(d,J＝7.3Hz,1H),6.36(d,J＝7.9Hz,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＝12.2Hz,1H),2.05–1.98(m,2H),1.96–1.92(m,1H).13C NMR(201MHz,CD3OD)δ157.45,139.31,136.51,131.74,130.77,128.82,128.79,121.76,120.44,117.55,114.08,110.78,65.79,60.28,57.16,51.86,49.93,45.67,42.65,38.06,31.08,25.37.HR-MS(ESI)m/z C22H28N3O+[M+H]+计算值:350.2227；实测值:350.2227.
实施例10：(6bR,10aS)-8-(3-(2-甲氧基)丙基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-10)的制备
步骤1：圆底烧瓶中加入3-(2-甲氧基苯基)丙酸(2.0g,11.1mmol)，溶剂DMF(10mL)及Cs2CO3(10.8g,33.3mmol)，随后加入BnBr(2.85g,16.7mmol)。反应体系在室温下搅拌过夜。反应结束后，除去溶剂并用快速硅胶柱(洗脱剂为20-30％乙酸乙酯/石油醚)分离纯化得无色油状物whc31(2.8g，产率97％)。1H NMR(800MHz,CDCl3)δ7.36–7.34 (m,2H),7.33–7.29(m,3H),7.21–7.18(m,1H),7.12(dd,J＝7.4,1.7Hz,1H),6.86(dd,J＝7.4,1.1Hz,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).
步骤2：干燥的圆底烧瓶中加入whc31(3-(2-甲氧基苯基)丙酸苄基酯，1.0g,3.7mmol)，加入THF(15mL)溶解，氩气保护并置于-10℃低温反应器中搅拌。10min后加入DABAL-H(23mL,1M in hexane)。随后，反应体系在0℃下搅拌5小时。反应结束后，在低温(-10℃)下用饱和酒石酸钠钾溶液(5mL)淬灭反应。除去溶剂后，用快速硅胶柱分离纯化(洗脱剂为20-50％乙酸乙酯/石油醚)得到无色油状物whc47(0.50g,产率81％)。1H NMR(800MHz,CDCl3)δ7.19(t,J＝7.8Hz,1H),7.14(d,J＝7.5Hz,1H),6.90(t,J＝7.4Hz,1H),6.86(d,J＝8.2Hz,1H),3.83(s,3H),3.60(t,J＝6.2Hz,2H),2.72(t,J＝7.4Hz,2H),1.88–1.82(m,2H).
步骤3：仿照实施例1步骤1的方法，将whc47进行溴代反应，得到化合物whc52(0.62g，产率90％)，无色油状物。1H NMR(800MHz,CDCl3)δ7.22–7.17(m,1H),7.15(dd,J＝7.4,1.7Hz,1H),6.91–6.87(td,J＝7.4,1.1Hz,1H),6.85(dd,J＝8.1,1.1Hz,1H),3.82(s,3H),3.40(t,J＝6.8Hz,2H),2.78–2.74(m,2H),2.18–2.12(m,2H).
步骤4：仿照实施例1步骤2的方法，将whc52(1-(3-溴丙基)-2-甲氧基苯)与原料(A)进行反应得化合物I-10(80mg,96％)，黄色油状物。1H NMR(800MHz,CD3OD)δ7.24–7.18(m,1H),7.13(d,J＝7.3Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(t,J＝7.4Hz,1H),6.67(d,J＝9.7Hz,1H),6.59(d,J＝7.3Hz,1H),6.53(d,J＝8.0Hz,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＝7.5Hz,2H),2.65(t,J＝12.3Hz,1H),2.36–2.31(m,1H),2.16–2.09(m,1H),2.07–1.99(m,2H).13C NMR(201MHz,CDCl3)δ157.02,137.25,134.89,129.50,128.97,128.28,127.07,120.46,120.11,112.22,110.02,108.89,63.48,57.39,54.94,54.52,50.15,48.05,43.99,39.96,37.13,27.50,25.02,23.11.HR-MS(ESI)m/z C24H32N3O+[M+H]+计算值:378.2540；实测值:378.2547.旋光值：[α]D 25＝–41°(c＝0.1，CHCl3)。
实施例11：2-(3-((6bR,10aS)-3-甲基-2,3,6b,9,10,10a-六氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉-8(7H)-基)丙基)苯酚(化合物I-11)的制备
仿照实施例2的方法，将I-10脱甲基反应得化合物I-11(20mg,34％)，灰色固体。1H NMR(800MHz,CD3OD)δ7.51(s,1H),7.10(dd,J＝7.4,1.7Hz,1H),7.05(td,J＝7.7,1.7Hz,1H),6.79–6.75(m,2H),6.69(d,J＝7.8Hz,1H),6.62–6.58(m,1H),6.54(d,J＝8.0Hz,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＝13.0Hz,1H),3.14–3.10(m,2H),2.89(s,3H),2.85–2.81(m,1H),2.70(t,J＝7.5Hz,2H),2.66(t,J＝12.3Hz,1H),2.35(d,J＝16.3Hz,1H),2.19–2.13(m,1H),2.10–2.06(m,3H).13C NMR(201MHz,CD3OD)δ153.62,136.36,133.00,128.48,126.02,124.86,119.73,118.03,113.29,111.74,109.11,61.41,55.44,52.00,49.00,42.49,37.94,35.47,27.55,25.44,22.75,20.56,18.11,11.71.HR-MS(ESI)m/z calcd for C23H30N3O+[M+H]+计算值:364.2383；实测值:364.2386.
实施例12、13：(8aS，12aR)-11-(2-甲氧基苯乙基)-4-甲基-4，5，6，7，8a，9，10，11，12，12a-十氢-[1，4]二氮杂卓[3，2，1-hi]吡啶并[4，3-b]吲哚(化合物I-12)与(8aR，12aS)-11-(2-甲氧基苯乙基)-4-甲基-4，5，6，7，8a，9，10，11，12，12a-十氢-[1，4]二氮杂卓[3，2，1-hi]吡啶并[4，3-b]吲哚(化合物I-13)的制备
步骤1：圆底烧瓶中加入1,3,4,5-四氢-2H-1,5-苯并二氮杂卓-2-酮(1.6g，10mmol)，加入醋酸：水(2：1)的混合溶液(15mL)搅拌溶解，降温至0℃。向反应液中缓慢滴加亚硝酸钠(770mg，11mmol)水溶液(5mL)。滴加完毕后，反应体系室温搅拌2小时。反应结束，过滤得淡黄色固体DW05006(1.7g，产率89％)。1H NMR(800MHz,DMSO-d6)δ10.06(s,1H),7.54(dd,J＝7.9,1.3Hz,1H),7.50(td,J＝7.8,1.4Hz,1H),7.31(td,J＝7.7,1.4Hz,1H),7.21(dd,J＝8.0,1.2Hz,1H),4.14–4.08(m,2H),2.65(dd,J＝7.5,5.4Hz,2H)。HRMS(ESI)m/z C9H10N3O2 +[M+H]+计算值：192.0768，实测值：192.0771。
步骤2：圆底烧瓶中加入DW05006(0.96g，5mmol)，加醋酸(10mL)室温搅拌溶解，后置于冰浴环境下，向反应体系中分批缓慢加入锌粉(1.6g，25mmol)。加毕，反应体系室温搅拌1小时，反应结束。
步骤3：滤除上步反应液中的不溶物，向滤液中加入N-乙氧羰基-4-哌啶酮(0.75mL，5mmol)和0.3mL 1N盐酸水溶液，并将反应体系加热至回流，继续搅拌反应。2小时后，反应结束。将反应冷却至室温，减压蒸馏除去大部分醋酸，后缓慢加入冷的乙醇，有固体析出。过滤得淡黄色固体DW05007-2(685mg，产率44％)。1H NMR(800MHz,DMSO- d6)δ10.10(s,1H),7.13(d,J＝7.6Hz,1H),6.93(t,J＝7.7Hz,1H),6.77(d,J＝7.3Hz,1H),4.57(s,2H),4.25–4.17(m,2H),4.09(q,J＝7.1Hz,2H),3.77(t,J＝5.7Hz,2H),2.91–2.84(m,2H),2.79(t,J＝5.6Hz,2H),1.25–1.17(m,3H)。HRMS(ESI)m/z C17H20N3O3 +[M+H]+计算值：314.1499，实测值：314.1521。
步骤4：圆底烧瓶中加入DW05007-2(626mg，2mmol)，加入三氟乙酸(10mL)于0℃下搅拌溶解，缓慢向反应液中分批缓慢加入氰基硼氢化钠(151mg，2.4mmol)。加毕，反应体系于室温继续搅拌反应1小时。反应结束，向反应体系中加10mL水淬灭反应。减压蒸馏除去大部分三氟乙酸，后用2N氢氧化钠水溶液调pH至9.0。用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥有机相。浓缩有机相后过快速硅胶柱分离纯化(洗脱剂为0-50％石油醚/乙酸乙酯)，得白色固体DW05008(441mg，产率70％)。1H NMR(800MHz,CDCl3)δ7.84(s,1H),6.88(d,J＝5.6Hz,1H),6.70(t,J＝7.4Hz,1H),6.63(d,J＝7.9Hz,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＝6.8Hz,3H)。HRMS(ESI)m/z C17H22N3O3 +[M+H]+计算值：316.1656，实测值：316.1670。
步骤5：圆底烧瓶中加入DW05008(315mg，1mmol)，碘甲烷(0.1mL，1.2mmol)加无水N,N-二甲基甲酰胺(10mL)室温搅拌溶解。缓慢分批加入60％氢化钠(45mg，1.1mmol)，继续室温搅拌反应2小时。反应结束，向反应体系中加入10mL水淬灭反应。用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥有机相。浓缩有机相后过快速硅胶柱分离纯化(洗脱剂为0-50％石油醚/乙酸乙酯)，得无色油状物DW05009(300mg，产率91％)。1H NMR(800MHz,CDCl3)δ6.94–6.92(m,2H),6.76(t,J＝7.0Hz,1H),4.17–4.07(m,2H),3.82(t,J＝11.6Hz,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＝12.4Hz,1H),2.55(dd,J＝13.4,4.7Hz,1H),1.98–1.86(m,2H),1.76(s,1H),1.24(t,J＝7.0Hz,3H)。HRMS(ESI)m/z C18H24N3O3 +[M+H]+计算值：330.1812，实测值：330.1833。
步骤6：圆底烧瓶中加入DW05009(329mg，1mmol)，加入无水四氢呋喃(10mL)溶解。将反应体系置于冰浴条件下，滴加硼烷的四氢呋喃溶液(1M,2mL)。加毕，将反应体系加热回流1小时。反应结束，反应体系冷却至室温，加入2N盐酸水溶液(1mL)，继续加热回流搅拌。30分钟后将反应体系置于室温，加4N氢氧化钠水溶液调pH至9.0。用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥。浓缩有机相后过快速硅胶柱层析纯化(洗脱剂为0-40％石油醚/乙酸乙酯)，得无色油状物DW05010 (300mg，产率69％)。HRMS(ESI)m/z C18H26N3O2 +[M+H]+计算值：316.2020，实测值：316.2031。
步骤7：DW05010(315mg，1mmol)溶解于正丁醇(10mL)，加入氢氧化钾(672mg，12mmol)。将体系加热至120℃回流搅拌5小时。反应结束，冷却至室温。反应体系中加入10mL水，并用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥。浓缩有机相后过快速硅胶柱层析纯化(洗脱剂为0-10％甲醇/二氯甲烷)，得淡黄色固体DW05011(137mg，产率56％)。1H NMR(800MHz,CDCl3)δ6.75(t,J＝7.6Hz,1H),6.66(d,J＝7.1Hz,1H),6.61(d,J＝8.0Hz,1H),3.50–3.45(m,1H),3.29–3.22(m,2H),3.14(dt,J＝10.3,6.6Hz,1H),3.05–3.02(m,1H),2.94(td,J＝12.1,3.0Hz,1H),2.90(s,3H),2.89–2.88(m,1H),2.87–2.84(m,1H),2.65(td,J＝11.7,3.5Hz,1H),2.52(dd,J＝12.6,10.4Hz,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 C15H22N3 +[M+H]+计算值：244.1808，实测值：244.1813。
步骤8：圆底烧瓶中加入DW05011(243mg，1mmol)，4-甲氧基苯乙醛(225mg，1.5mmol)，加甲醇(10mL)溶解。分批缓慢加入氰基硼氢化钠(94mg，1.5mmol)。加毕，继续室温搅拌过夜。反应结束，加入10mL水淬灭反应。用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥。浓缩有机相后过快速硅胶柱层析纯化(洗脱剂为0-10％甲醇/二氯甲烷)，得淡黄油状物体DW05015(302mg，产率80％)。1H NMR(800MHz,CDCl3)δ7.23(td,J＝8.2,1.5Hz,1H),7.16(d,J＝7.4Hz,1H),6.89(t,J＝7.4Hz,1H),6.84(d,J＝8.2Hz,1H),6.81(t,J＝7.7Hz,1H),6.71(d,J＝7.1Hz,1H),6.67(d,J＝8.1Hz,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＝8.1Hz,2H),2.96–2.84(m,4H),2.92(s,3H),2.82–2.78(m,1H),2.63(td,J＝12.0,3.0Hz,1H),2.36–2.34(m,1H),2.29–2.26(t,J＝10.5Hz,1H),2.19–2.17(m,1H),2.06–2.02(m,1H),1.91–1.87(m,1H).13C NMR(201MHz,CDCl3)δ157.44,142.97,140.15,130.71,128.66,121.61,121.00,115.85,115.56,110.57,62.71,60.54,57.60,55.44,55.12,49.97,48.66,42.43,39.25,29.64,26.55,23.34.HRMS(ESI)m/z C24H32N3O+[M+H]+计算值：378.2540，实测值：378.2559。
手性分析条件：仪器：UPCC(Waters)；手性柱：CHIRALPAK OD(Daicel)；柱体积：4.6×100mm(5μm粒径填料)；温度：40℃；流动相：CO2/MeOH[0.2％氨的甲醇溶液(7M)＝70/30]；流速：3.0mL/min；检测波长：214nm。
手性制备条件：仪器：SFC-150(Waters)；手性柱：OD(Daicel)；柱体积：20×250mm(10μm粒径填料)；温度：35℃；流动相：CO2/MeOH[0.2％氨的甲醇溶液(7M)＝60/40]； 流速：100.0mL/min；检测波长：214nm。制备得I-12(HRMS(ESI)m/z C24H32N3O+[M+H]+计算值：378.2540，实测值：378.2538；e.e.99.64％；旋光值：[α]D 25＝–65°(c＝0.1，CHCl3)，与化合物I-3的旋光方向一致，同为左旋，手性构型一致)和I-13(HRMS(ESI)m/z C24H32N3O+[M+H]+计算值：378.2540，实测值：378.2557；e.e.99.44％；旋光值：[α]D 25＝+103°(c＝0.1，CHCl3)，与化合物I-3的旋光方向相反，为右旋，手性构型相反)。
实施例14、15：(8aS，12aR)-11-(3-(2-甲氧基苯基)丙基)-4-甲基-4，5，6，7，8a，9，10，11，12，12a-十氢-[1，4]二氮杂卓[3，2，1-hi]吡啶并[4，3-b]吲哚(化合物I-14)与(8aR，12aS)-11-(3-(2-甲氧基苯基)丙基)-4-甲基-4，5，6，7，8a，9，10，11，12，12a-十氢-[1，4]二氮杂卓[3，2，1-hi]吡啶并[4，3-b]吲哚(I-15)的制备
步骤1：仿照实施例12、13中步骤8的方法，将4-甲氧基苯乙醛替换为4-甲氧基苯丙醛，得到淡黄色油状物DW05014(278mg，产率81％)。1H NMR(800MHz,CDCl3)δ7.19(t,J＝7.8Hz,1H),7.07(d,J＝7.3Hz,1H),6.87(t,J＝7.3Hz,1H),6.83(d,J＝8.2Hz,1H),6.80(t,J＝7.6Hz,1H),6.66–6.64(m,2H),3.81(s,3H),3.66–3.63(m,1H),3.48(t,J＝9.3Hz,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＝11.3Hz,1H),2.17(d,J＝15.8Hz,1H),2.07–2.05(m,2H),2.04–2.02(m,2H),1.88–1.84(m,1H).13C NMR(201MHz,CDCl3)δ157.32,1 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 C25H34N3O+[M+H]+计算值：392.2696，实测值：392.2712。
步骤2：将DW05014进行手性拆分。
手性分析方法：仪器：UPCC(Waters)；手性柱：CHIRALPAK IG(Daicel)；柱体积： 4.6×100mm(5μm粒径填料)；温度：40℃；流动相：CO2/MeOH[0.2％氨的甲醇溶液(7M)＝70/30]；流速：3.0mL/min；检测波长：214nm。
手性制备方法：仪器：SFC-150(Waters)手性柱：IG(Daicel)；柱体积：20×250mm(10μm粒径填料)；温度：35℃；流动相：CO2/MeOH[0.2％氨的甲醇溶液(7M)＝50/50]；流速：100.0mL/min；检测波长：214nm。制备得I-14(HRMS(ESI)m/z C25H34N3O+[M+H]+计算值：392.2697，实测值：392.2712；e.e.99.68％；旋光值：[α]D 25＝–55°(c＝0.1，CHCl3)，与化合物I-10的旋光方向一致，同为左旋，手性构型一致)和I-15(HRMS(ESI)m/z C25H34N3O+[M+H]+计算值：392.2696，实测值：392.2709；e.e.100％；旋光值：[α]D 25＝+95°(c＝0.1，CHCl3)，与化合物I-10的旋光方向相反，为右旋，手性构型相反)。
实施例16：(7aS,11aR)-10-(2-甲氧基苯乙基)-5,6,7a,8,9,10,11,11a-八氢-4H-吡啶并[3',4':4,5]吡咯并[3,2,1-ij]喹啉(化合物I-16)的制备
步骤1：四氢喹啉(4g，30mmol)溶解于冰醋酸(40mL)和水(10mL)的混合溶剂中，然后缓慢滴加NaNO2(2.28g,33mmol)的水溶液(5mL)，混合物在室温下搅拌过夜。反应结束后，减压除去溶剂，浓缩物溶于乙酸乙酯中，用饱和NaHCO3水溶液洗一次。浓缩有机相，快速硅胶柱层析纯化(洗脱剂为0-10％乙酸乙酯/石油醚)得橙黄色油状物WHE-119(4.5g，收率92％)。1H NMR(800MHz,CDCl3)δ8.06(d,J＝8.2Hz,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＝ 6.1Hz,2H).HR-MS(ESI)m/z C9H11N2O+[M+H]+计算值：163.0866，实测值：163.0873。
步骤2：氩气保护下，LiAlH4(485mg，12.8mmol)悬浮于无水THF(25mL)中。冰水浴降温，加入原料WHE-119(1.3g，7.98mmol)的THF(5mL)溶液。反应在冰水浴条件下继续搅拌30分钟，然后缓慢升至室温搅拌过夜。反应结束后，用酒石酸钠钾溶液淬灭反应，加水过滤。滤液用乙酸乙酯萃取三次，合并有机相。浓缩后快速硅胶柱层析纯化(洗脱剂为10-30％乙酸乙酯/石油醚)得黄色固体WHE-115(0.95g，收率81％)。1H NMR(600MHz,CDCl3)δ7.15(d,J＝8.2,1.4Hz,1H),7.14–7.09(m,1H),6.96(d,J＝7.4Hz,1H),3.34–3.30(m,2H),2.76(t,J＝6.6Hz,2H),2.09–2.02(m,2H).HR-MS(ESI)m/z C9H13N2 +[M+H]+计算值：149.1073，实测值：149.1075。
步骤3：WHE-115(620mg,4.19mmol)与4,4-二羟基哌啶盐酸盐(650mg,4.2mmol)溶于乙醇(15mL)，然后加入浓盐酸(0.35mL)，加热回流3小时。冷却反应液，过滤得白色固体WHE-109(0.75g，收率84％)。1H NMR(600MHz,CDCl3)δ10.15(s,2H),7.24–7.19(m,1H),7.01(dd,J＝8.0,7.1Hz,1H),6.95–6.90(m,1H),4.47(d,J＝4.6Hz,2H),3.99(t,J＝5.7Hz,2H),3.61–3.57(m,2H),3.18(t,J＝6.0Hz,2H),2.98(t,J＝6.1Hz,2H),2.25–2.213(m,2H).HR-MS(ESI)m/z C14H17N2 +[M+H]+计算值：213.1386，实测值：213.1386。
步骤4：圆底烧瓶中加入WHE-109(1.35g，6.42mmol)，TFA(13mL)，冰水浴冷却。然后缓慢分批加入NaBH3CN(1.2g，19.3mmol)，反应体系从冰水浴缓慢升至室温，搅拌2小时。反应结束后，加冰淬灭反应，并用NaOH溶液调为碱性(pH＝14)。加水，用二氯甲烷萃取三次，合并有机相。浓缩后得粗产物WHE-117(1.3g)直接用于下一步。1H NMR(800MHz,CDCl3)δ6.92(t,J＝6.7Hz,2H),6.68(t,J＝7.4Hz,1H),3.44–3.35(m,2H),3.34–3.26(m,3H),3.16(td,J＝13.0,3.3Hz,1H),2.76–2.67(m,3H),2.54–2.51(m,1H),2.28–2.23(m,1H),2.19–2.16(m,1H),2.15–2.09(m,2H).HR-MS(ESI)m/z C14H19N2 +[M+H]+计算值：215.1543，实测值：215.1546。
步骤5：粗产物WHE-117(1.3g,6.42mmol)溶于1,4-二氧六环(15mL)，加入NaOH(500mg,12.8mmol)水溶液(10mL)，然后加入Boc2O(1.54g，7.06mmol)。反应体系在室温下搅拌2小时。反应结束后加水(15mL)，分出有机相，用乙酸乙酯萃取水相，合并有机相后浓缩。快速硅胶柱层析纯化得WHE-125(1.8g，两步收率89％)。1H NMR(800MHz,CDCl3)δ6.96(d,J＝7.2Hz,1H),6.89(d,J＝7.6Hz,1H),6.66(t,J＝7.5Hz,1H),4.13–4.01&3.91–3.79(m,1H),3.73(d,J＝13.2Hz,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＝6.5Hz,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 C19H27N2O2 +[M+H]+计算值：315.2067，实测值：315.2067。
步骤6：化合物WHE-125的手性拆分，得WHE-125-p1和WHE-125-p2
手性分析条件：手性柱：OD-H(Daicel)；柱体积：4.6x100mm(5μm粒径填料)；流动相：CO2/异丙醇[0.5％氨的甲醇溶液(7M)]＝90/10；流速：3.0mL/min；波长：214nM；温度：40℃；HPLC仪器：UPCC(Waters)；Peak1(前峰)tR＝1.672min；peak2(后峰)tR＝1.941min.
手性制备条件：手性柱：OD(Daicel)；柱体积：20x250mm(10μm粒径填料)；流动相：CO2/异丙醇[0.5％氨的甲醇溶液(7M)]＝85/15；流速：80mL/min；波长：214nM；温度：35℃；HPLC仪器：SFC-150(Waters)。
WHE-125-P1：1H NMR(800MHz,CDCl3)δ6.94(d,J＝7.2Hz,1H),6.87(d,J＝7.5Hz,1H),6.64(t,J＝7.4Hz,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 C19H27N2O2 +[M+H]+计算值：315.2067；实测值：315.2082.旋光值：[α]D 25＝+128°(c＝0.1,CHCl3)。
WHE-125-p2：1H NMR(800MHz,CDCl3)δ6.93(d,J＝7.2Hz,1H),6.87(d,J＝7.6Hz,1H),6.64(t,J＝7.4Hz,1H),4.10–3.99&3.87–3.79(m,1H),3.72(dt,J＝13.2,4.4Hz,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＝8.2,5.1Hz,2H),2.64–2.56(m,1H),2.14–2.07(m,2H),1.93–1.88(m,1H),1.87–1.79(m,1H),1.49(s,9H).HR-MS(ESI)m/z C19H27N2O2 +[M+H]+计算值：315.2067，实测值：315.2063。旋光值：[α]D 25＝–115°(c＝0.1,CHCl3)。
化合物WHE-125-P1和WHE-125-p2的立体构型通过其旋光值与已知立体构型的原料A和WHF-108的旋光值对比得出：
圆底烧瓶中加入A(50mg，0.13mmol)，溶于DCM(3mL)，加入Et3N(1mL)，然后加入Boc2O(57mg，0.26mmol)，反应在室温下搅拌2小时。反应结束后，减压除 去溶剂，用快速硅胶柱层析(洗脱剂为0-30％乙酸乙酯/石油醚)分离纯化得无色油状物WHF108(32mg，收率74％)。1H NMR(800MHz,CDCl3)δ6.72-6.61(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 C19H27N3O2 +[M+H]+计算值:329.2098；实测值:329.2098。旋光值:[α]D 25＝–53°(c＝0.1,CHCl3)；原料A的旋光值：[α]D 25＝–165°(c＝0.1,CHCl3)。
步骤7：圆底烧瓶中加入WHE-125-p2(120mg，0.382mmol)，然后加入溶剂二氯甲烷(2mL)，TFA(1mL)，室温下搅拌1小时。减压浓缩除去溶剂，残余物溶于DMSO(3mL)，加入1-(2-溴乙基)-2-甲氧基苯(100mg，0.465mmol)，然后加入二异丙基乙基胺(3mL)，反应体系在60℃加热条件下搅拌过夜(18小时)。反应结束后，加水(50mL)，用乙酸乙酯萃取三次，合并有机相并浓缩，残余物用快速硅胶柱层析分离纯化(洗脱剂为0-10％乙酸乙酯/石油醚)得I-16(70mg，收率53％)，棕黄色油状物。1H NMR(800MHz,CDCl3)δ7.22–7.20(m,1H),7.16(d,J＝7.4Hz,1H),6.97(d,J＝7.2Hz,1H),6.91–6.89(m,2H),6.86(d,J＝8.2Hz,1H),6.68(t,J＝7.4Hz,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＝11.2,4.3Hz,1H),2.19–2.07(m,3H),2.07–1.99(m,2H).13C NMR(201MHz,CDCl3)δ157.62,149.80,131.09,130.41,128.68,127.47,126.84,121.07,120.58,120.56,118.68,110.38,64.13,58.90,55.91,55.34,48.88,44.67,40.88,27.91,24.91,24.26,23.16.HR-MS(ESI)m/z C23H29N2O+[M+H]+计算值：349.2274，实测值：349.2276。旋光值：[α]D 25＝–96°(c＝0.1,CHCl3)。
实施例17：(7aR,11aS)-10-(2-甲氧基苯乙基)-5,6,7a,8,9,10,11,11a-八氢-4H-吡啶并[3',4':4,5]吡咯并[3,2,1-ij]喹啉(化合物I-17)的制备
仿照实施例16步骤7的方法，将化合物WHE-125-p1脱Boc保护并与1-(2-溴乙基)-2-甲氧基苯进行烷基化反应得I-17(90mg，收率82％)，棕黄色油状物。1H NMR(800MHz,CDCl3)δ7.22–7.17(m,1H),7.14(d,J＝7.6Hz,1H),6.95(d,J＝7.2Hz,1H),6.88(t,J＝7.5Hz,2H),6.84(d,J＝8.1Hz,1H),6.66(t,J＝7.4Hz,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＝11.7,3.3Hz,1H),2.18–1.95(m,5H).13C NMR(201MHz,CDCl3)δ157.62,149.80,131.17,130.38,128.79,127.43,126.80,121.04,120.54,120.53,118.63,110.38,64.16,58.96,56.00,55.33,48.91,44.65,40.94,27.99,24.98,24.26,23.15.HR-MS(ESI)m/z C23H29N2O+[M+H]+计算值：349.2274，实测值：349.2282.旋光值：[α]D 25＝+104°(c＝0.1,CHCl3)。
实施例18：10-(3-(2-甲氧基苯基)丙基)-5,6,7a,8,9,10,11,11a-八氢-4H-吡啶并[3',4':4,5]吡咯并[3,2,1-ij]喹啉(化合物I-18)的制备
仿照实施例16步骤7的方法，将化合物WHE-125-p2脱Boc保护并与1-(3-溴丙基)-2-甲氧基苯进行烷基化反应得I-18(50mg，收率50％)，棕黄色油状物。1H NMR(800MHz,CDCl3)δ7.20(t,J＝7.8Hz,1H),7.16(d,J＝7.4Hz,1H),6.94(d,J＝7.2Hz,1H),6.92–6.88(m,2H),6.86(d,J＝8.2Hz,1H),6.66(t,J＝7.4Hz,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＝10.4,3.1Hz,1H),2.46–2.37(m,2H),2.29(td,J＝11.7,3.2Hz,1H),2.18–2.08(m,2H),2.03–1.92(m,3H),1.87–1.83(m,2H).13C NMR(201MHz,CDCl3)δ157.51,149.75,131.19,130.68,129.86,127.07,126.75,120.95,120.48,120.41,118.58,110.25,64.17,58.69,56.14,55.30,49.04,44.59,40.99,28.35,27.10,25.03,24.26,23.15.HR-MS(ESI)m/z C24H31N2O+[M+H]+计算值：363.2431，实测值：363.2439。旋光值：[α]D 25＝–108°(c＝0.1,CHCl3)。
实施例19：(7aR,11aS)-10-(3-(2-甲氧基苯基)丙基)-5,6,7a,8,9,10,11,11a-八氢-4H-吡啶并[3',4':4,5]吡咯并[3,2,1-ij]喹啉(化合物I-19)的制备
仿照实施例16步骤7的方法，将化合物WHE-125-p1脱Boc保护并与1-(3-溴丙基)-2-甲氧基苯进行烷基化反应得I-19(48mg，收率46％)，棕黄色油状物。1H NMR(800MHz,CDCl3)δ7.09(t,J＝7.7Hz,1H),7.05(d,J＝7.4Hz,1H),6.83(d,J＝7.2Hz,1H),6.80–6.77(m,2H),6.75(d,J＝8.2Hz,1H),6.55(t,J＝7.4Hz,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＝10.3,3.3Hz,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 C24H31N2O+[M+H]+计算值：363.2431，实测值：363.2438，旋光值：[α]D 25＝+101°(c＝0.1,CHCl3)。
实施例20：(6bR，10aS)-8-(2-甲氧基苯乙基)-1，2，6b，7，8，9，10，10a-八氢-[1，4]噁嗪并[2，3，4-hi]吡啶并[4，3-b]吲哚(化合物I-20)的制备
步骤1：圆底烧瓶中加入苯并吗啉(2.6g，20mmol)，加四氢呋喃(40mL)溶解，反应体系置于0℃搅拌。向反应体系中缓慢滴加3M盐酸(13mL)，继续在0℃搅拌反应。1小时后，向反应瓶中滴加亚硝酸钠(3.45g，50mmol)水溶液(10mL)。滴加完毕，继续室温搅拌过夜。TLC检测反应完全，减压蒸馏除去大部分溶剂，用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥有机相。浓缩有机相得粗品，过快速硅胶柱纯化(洗脱剂为0-25％乙酸乙酯/石油醚)，得黄色固体DW04027(3.0g，产率：91％)。1H NMR(800MHz,CDCl3)δ8.10(dd,J＝8.2,1.4Hz,1H),7.24–7.18(m,1H),7.09–7.05(m,1H),7.03(dd,J＝8.2,1.2Hz,1H),4.28–4.22(m,2H),4.08–4.04(m,2H)。HRMS(ESI)m/z C8H9N2O2 +[M+H]+计算值：165.0659，实测值：165.0672。
步骤2：圆底烧瓶中加入DW04027(1.6g，10mmol)，加醋酸：水(1：1)的混合溶液(20mL)溶解，并将反应体系置于0-5℃搅拌。缓慢分批加入锌粉(2.6g，40mmol)，加毕，室温继续搅拌反应1小时。滤除锌粉，滤液用2N NaOH调节pH至9.0，然后用乙 酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥有机相。浓缩有机相得粗品，过快速硅胶柱纯化(洗脱剂为0-35％乙酸乙酯/石油醚)，得淡黄色固体DW04028(1.2g，产率80％)。1H NMR(800MHz,CDCl3)δ7.11(dd,J＝8.0,1.0Hz,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 C8H11N2O+[M+H]+计算值：151.0866，实测值：151.0871。
步骤3：圆底烧瓶中加入DW04028(1.5g，10mmol)，4,4-哌啶二醇盐酸盐(1.2g，10mmol)，加乙醇(20mL)溶解。向反应体系中缓慢滴加浓盐酸(1mL)，滴加完毕，将反应体系加热至90℃回流搅拌3小时。反应液冷却至室温，过滤得灰白色固体DW04029(1.6g，产率73％)。HRMS(ESI)m/z C13H15N2O+[M+H]+计算值：215.1179；实测值：215.1185。
步骤4：圆底烧瓶中加入DW04029(2.1g，10mmol)，加三氟乙酸(20mL)溶解，将反应体系置于0℃搅拌。分批加入氰基硼氢化钠(1.89g，30mmol)，后置于室温继续搅拌反应2小时。反应结束，减压蒸馏除去大部分三氟乙酸，用2N氢氧化钠水溶液调pH至9.0，然后用乙酸乙酯萃取三次，合并有机相并用饱和食盐水清洗，无水硫酸钠干燥有机相。浓缩有机相得粗品，过快速硅胶柱纯化(洗脱剂为0-10％甲醇/二氯甲烷)，得黄色油状物DW04030(1.2g，产率61％)。1H NMR(800MHz,CDCl3)δ6.78–6.73(m,2H),6.73–6.71(m,1H),4.51(d,J＝11.1Hz,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＝11.8Hz,1H),2.82(td,J＝10.5,2.7Hz,1H),2.30–2.21(m,2H)。HRMS(ESI)m/z C13H17N2O+[M+H]+计算值：217.1335，实测值：217.1351。
步骤5：圆底烧瓶中加入DW04030(2.1g，10mmol)，二羰基二叔丁酯(2.2g，10mmol)，加二氧六环(25mL)室温搅拌溶解。然后加入1N氢氧化钠水溶液(10mL)，反应体系室温搅拌过夜。反应结束后，用乙酸乙酯萃取三次，合并有机相并用饱和食盐水洗，无水硫酸钠干燥。浓缩有机相得粗品油状物DW04032(3.0g，产率94％)。HRMS(ESI)m/z C18H25N2O3 +[M+H]+计算值：317.1860，实测值：317.1871.
步骤6：将DW04032进行手性柱拆分。
手性分析方法：仪器：Shimadzu；手性柱：OJ-H(Daicel)；柱体积：4.6×250mm(5μm粒径填料)；温度：40℃；流动相：正己烷(0.1％二乙胺):乙醇(0.1％二乙胺)＝70:30；流速：1.0mL/min；检测波长：214nm和254nm。
手性制备方法：仪器：Gilson-281；手性柱：OJ(Daicel)；柱体积：20×250mm(10μm粒径填料)；温度：35℃；流动相：正己烷(0.1％二乙胺):乙醇(0.1％二乙胺)＝75:25；流 速：40.0mL/min；检测波长：214nm。制备得DW04032P1(e.e.100％)和DW04032P2(e.e.100％)。
步骤7：圆底烧瓶中加入DW04032P1(310mg，1mmol)，加二氯甲烷(5mL)室温搅拌溶解，后加入三氟乙酸(1mL)。反应体系继续室温搅拌反应2小时。反应结束，向反应体系中加2N氢氧化钠水溶液调节pH至9.0，用乙酸乙酯萃取三次，合并有机相并用饱和食盐水洗涤。浓缩有机相，得粗品淡黄色固体DW04072P1(208mg，产率96％)。HRMS(ESI)m/z C13H17N2O+[M+H]+计算值：217.1335，实测值：217.1343。
步骤8：仿照实施例16步骤7的方法，将DW04072P1与1-(2-溴乙基)-2-甲氧基苯进行烷基化反应得淡黄色油状物I-20(80mg，产率49％)。1H NMR(800MHz,CDCl3)δ7.10(td,J＝8.0,1.6Hz,1H),7.06(dd,J＝7.4,1.4Hz,1H),6.79(t,J＝7.4Hz,1H),6.75(d,J＝8.1Hz,1H),6.65(d,J＝7.0Hz,1H),6.58–6.54(m,2H),4.39–4.34(m,2H),3.72(s,3H),3.21(dt,J＝10.7,2.0Hz,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＝11.5,3.7Hz,1H),2.05(t,J＝11.3Hz,1H),1.95–1.86(m,2H).13C NMR(201MHz,CDCl3)δ157.60,143.52,138.01,132.83,130.35,128.73,127.42,120.52,120.36,115.86,113.21,110.36,66.85,65.65,60.48,58.95,55.91,55.31,48.93,44.73,41.58,28.02.HRMS(ESI)m/z C22H27N2O2 +[M+H]+计算值：351.2067实测值：351.2079。旋光值：[α]D 25＝–11°(c＝0.1，CHCl3)，与化合物I-3的旋光方向一致，同为左旋，手性构型一致。
实施例21：(6bS，10aR)-8-(2-甲氧基苯乙基)-1，2，6b，7，8，9，10，10a-八氢-[1，4]噁嗪并[2，3，4-hi]吡啶并[4，3-b]吲哚(化合物I-21)的制备
仿照实施例20中步骤7的方法，以DW04032P2为原料，制备DW04072P2(淡黄色固体180mg，产率93％)。HRMS(ESI)m/z C13H17N2O+[M+H]+计算值：217.1335，实测值：217.1348。
仿照实施例20中步骤8的方法，将DW04072P2与1-(2-溴乙基)-2-甲氧基苯进行烷 基化反应得淡黄色油状物I-21(83mg，产率51％)。1H NMR(800MHz,CDCl3)δ7.10(td,J＝8.0,1.6Hz,1H),7.06(td,J＝7.1,2.0Hz,1H),6.82–6.78(m,1H),6.76(d,J＝8.1Hz,1H),6.65(d,J＝7.0Hz,1H),6.59–6.54(m,2H),4.41–4.34(m,2H),3.72(s,3H),3.22(dt,J＝10.7,2.1Hz,1H),3.20–3.18(m,1H),3.18–3.14(m,1H),2.98–2.94(m,1H),2.78(dt,J＝11.2,6.0Hz,2H),2.76–2.73(m,1H),2.69–2.65(m,1H),2.55–2.47(m,2H),2.32(td,J＝11.6,3.3Hz,1H),2.06(t,J＝11.2Hz,1H),1.95–1.87(m,2H).13C NMR(201MHz,CDCl3)δ157.61,143.53,138.01,132.80,130.36,128.69,127.45,120.53,120.39,115.88,113.23,110.37,66.86,65.64,60.49,58.92,55.87,55.32,48.92,44.75,41.55,28.01.HRMS(ESI)m/z C22H27N2O2 +[M+H]+计算值：351.2067，实测值：351.2082。旋光值：[α]D 25＝+41°(c＝0.1，CHCl3)，与I-3的旋光方向相反，为右旋，手性构型相反。
实施例22：(6bR，10aS)-8-(3-(2-甲氧基苯基)丙基)-1，2，6b，7，8，9，10，10a-八氢-[1，4]噁嗪并[2，3，4-hi]吡啶并[4，3-b]吲哚(化合物I-22)的制备
仿照实施例16步骤7的方法，将DW04072P1与1-(3-溴丙基)-2-甲氧基苯进行烷基化反应得淡黄色油状物I-22(105mg，产率58％)。1H NMR(800MHz,CDCl3)δ7.17(td,J＝8.0,1.6Hz,1H),7.14–7.12(m,1H),6.87(t,J＝7.3Hz,1H),6.83(d,J＝8.1Hz,1H),6.69(t,J＝6.7Hz,1H),6.66–6.60(m,2H),4.47–4.40(m,2H),3.81(s,3H),3.28(dt,J＝10.7,2.1Hz,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＝11.6,2.4Hz,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(201MHz,CDCl3)δ157.52,143.55,137.96,132.73,130.54,129.88,127.15,120.44,120.42,115.85,113.26,110.28,66.86,65.59,60.34,58.52,55.82,55.32,48.90,44.72,41.43,28.31,26.89.HRMS(ESI)m/z C23H29N2O2 +[M+H]+计算值：365.2224，实测值：365.2239。旋光值：[α]D 25＝–10°(c＝0.1，CHCl3)，与化合物I-10的旋光方向一致，同为左旋，手性构型一致。
实施例23：(6bS，10aR)-8-(3-(2-甲氧基苯基)丙基)-1，2，6b，7，8，9，10，10a-八氢-[1，4]噁嗪并[2，3，4-HI]吡啶并[4，3-b]吲哚(化合物I-23)的制备
仿照实施例16步骤7的方法，将DW04072P2与1-(3-溴丙基)-2-甲氧基苯进行烷基化反应得淡黄色油状物I-23(83mg，产率51％)。1H NMR(800MHz,CDCl3)δ7.17(td,J＝8.1,1.5Hz,1H),7.13–7.11(m,1H),6.87(t,J＝7.3Hz,1H),6.83(d,J＝8.2Hz,1H),6.70(d,J＝7.0Hz,1H),6.66–6.60(m,2H),4.43(dd,J＝11.3,6.1Hz,2H),3.80(d,J＝18.3Hz,3H),3.28(dt,J＝10.7,2.0Hz,1H),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＝10.3Hz,1H),2.07(t,J＝11.2Hz,1H),2.04–2.00(m,1H),1.97–1.91(m,1H),1.88–1.81(m,2H).13C NMR(201MHz,CDCl3)δ157.53,143.58,137.94,130.42,129.90,127.20,124.11,120.49,120.47,115.89,113.33,110.31,66.87,65.53,58.44,55.34,48.83,44.74,41.28,31.57,30.32,29.85,28.29.HRMS(ESI)m/z C23H29N2O2 +[M+H]+计算值：365.2224，实测值：365.2225。旋光值：[α]D 25＝+49°(c＝0.1，CHCl3)，与化合物I-10的旋光方向相反，为右旋，手性构型相反。
实施例24：(8aS,12aR)-11-(2-甲氧基苯乙基)-6,7,8a,9,10,11,12,12a-八氢-5H-吡啶并[4,3-b][1,4]噻唑呯并[2,3,4-hi]吲哚(化合物I-24)的制备
步骤1：圆底烧瓶中加入2-巯基苯胺(2.5g，20mml)，1,3-二溴丙烷(6.03g，30mmol)及K2CO3(8.28g，60mmol)，氮气保护下加入溶剂DMF(20mL)。反应体系在65℃下加热搅拌过夜。反应结束后，减压浓缩除去溶剂DMF，用快速硅胶柱层析分离纯化(洗脱剂0-20％乙酸乙酯/石油醚)得棕红色油状物WHE148(1.41g，收率50％)。1H NMR(800MHz,CDCl3)δ7.40(dd,J＝7.6,1.5Hz,1H),7.08–7.06(m,1H),6.82–6.80(m,1H),6.77(d,J＝7.8Hz,1H),3.30–3.27(m,2H),2.86–2.83(m,2H),2.12–2.07(m,2H).HR-MS(ESI)m/z C9H12NS+[M+H]+计算值：166.0685，实测值：166.0688。
步骤2：圆底烧瓶中将原料WHE-148(1.59g，9.63mmol)溶于HOAc/H2O(15mL/5mL)中，然后在冰水浴冷却条件下加入NaNO2(797mg，11.6mmol)，反应体系缓慢升至室温后搅拌过夜。反应结束后，减压除去溶剂，溶于乙酸乙酯，NaHCO3饱和水溶液洗一次，水相用乙酸乙酯萃取。合并有机相，浓缩后用快速硅胶柱层析分离纯化得棕黄色油状物WHF-12(1.53g，82％)。1H NMR(800MHz,CDCl3)δ7.55(dd,J＝7.8,1.5Hz,1H),7.47(dd,J＝7.7,1.6Hz,1H),7.35–7.27(m,2H),4.20(t,J＝6.0Hz,2H),2.91–2.86(m,2H),2.16(p,J＝6.0Hz,2H).HR-MS(ESI)m/z C9H11N2OS+[M+H]+计算值：195.0587，实测值：195.0587。
步骤3:氮气保护下LiAlH4(600mg，15.8mmol)悬浮于无水THF(20mL)中。冰水浴冷却，缓慢加入WHE-148(1.53g，7.89mmol)的无水THF(5mL)溶液。反应体 系在冰水浴条件下继续搅拌30分钟，然后在50℃加热条件下搅拌过夜。反应结束后，反应液以冰水浴冷却，酒石酸钠钾水溶液淬灭反应，过滤，滤液加水，分出有机相，水相用乙酸乙酯萃取三次，合并有机相。有机相浓缩后用快速硅胶柱层析分离纯化得橙黄色油状物WHE-136(1.1g,收率77％)。HR-MS(ESI)m/z C9H13N2S+[M+H]+计算值：181.0794，实测值：181.0794。
步骤4：将WHE-136溶于乙醇(10mL)，加入4,4-二羟基哌啶盐酸盐(1.85g，12.1mmol)，盐酸(0.6mL)，反应体系加热回流过夜。反应结束后，减压除去乙醇，残余物加水，用乙酸乙酯萃取。合并有机相，用饱和NaHCO3水溶液洗一次，减压浓缩后用快速硅胶柱层析分离纯化得淡黄色固体WHF-19(1.4g，收率94％)。1H NMR(800MHz,MeOD)δ7.24(dd,J＝7.8,1.0Hz,1H),7.02(dd,J＝7.4,1.0Hz,1H),6.90(t,J＝7.6Hz,1H),4.61–4.57(m,2H),4.38(d,J＝1.5Hz,2H),3.63(t,J＝6.2Hz,2H),3.35–3.31(m,2H),3.10(td,J＝6.5,3.3Hz,2H),2.38–2.32(m,2H).HR-MS(ESI)m/z C14H17N2S+[M+H]+计算值：245.1107，实测值：245.1108.
步骤5：化合物WHF-17(1.09g，6.05mmol)溶于三氟乙酸中，冰水浴冷却，然后30分钟内分批加入NaBH3CN(1.1g，17.2mmol)，然后反应体系在室温条件下搅拌2小时。反应结束后，反应液中加入冰淬灭反应，用NaOH水溶液调成碱性。乙酸乙酯萃取三次，合并有机相，浓缩得粗产物棕黄色固体WHF-19(1.5g)，直接用于下一步。
步骤6：上一步粗产物化合物WHF-19(1.5g，6.1mmol)溶于二氯甲烷(10mL)，加入Et3N(2mL)，然后加入Boc2O(2.6g，12.2mmol)。反应体系在室温下搅拌2小时。反应结束后，减压除去溶剂，用快速硅胶柱层析分离纯化得化合物WHF-21(1.4g，两步收率67％)。1H NMR(800MHz,CDCl3)δ6.94(d,J＝7.2Hz,1H),6.87(d,J＝7.6Hz,1H),6.64(t,J＝7.5Hz,1H),4.14–3.97&3.87–3.79(m,1H),3.71(d,J＝13.1Hz,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＝6.5Hz,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 C19H27N2O2S+[M+H]+计算值：347.1788，实测值：347.1788.
步骤7：化合物WHF-21的手性拆分
手性分析条件：手性柱：IG(Daicel)；柱体积：4.6x100mm(5μm粒径填料)；流动相：CO2/MeOH[0.2％氨的甲醇溶液(7M)]＝85/15；流速：3.0mL/min；波长：214nM；温度：40℃；HPLC仪器：UPCC(Waters)；Peak1(前峰)tR＝1.926min；peak2(后峰)tR＝2.344min.
手性制备条件：手性柱：IG(Daicel)；柱体积：20x250mm(10μm粒径填料)；流动相：CO2/MeOH[0.2％氨的甲醇溶液(7M)]＝75/25；流速：100mL/min；波长：214nM；温度：35℃；HPLC仪器：SFC-150(Waters)。
WHF-21-p1:1H NMR(800MHz,CDCl3)δ6.93(d,J＝7.8Hz,1H),6.86(d,J＝7.2Hz,1H),6.60(t,J＝7.5Hz,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).旋光值:[α]D 25＝–143°(c＝0.1,CHCl3)。
WHF-21-p2:1H NMR(800MHz,CDCl3)δ6.96–6.93(m,1H),6.87(d,J＝7.2Hz,1H),6.61(t,J＝7.5Hz,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).旋光值:[α]D 25＝+135°(c＝0.1,CHCl3)。
化合物WHF-21-p1与WHF-21-p2的立体构型通过其旋光值分别与已知立体构型的原料A和WHF-108的旋光值对比得出。
步骤8：仿照实施例16步骤7的方法，将化合物WHF-21-p1脱Boc保护并与1-(2-溴乙基)-2-甲氧基苯进行烷基化反应得I-24(51mg，收率59％)，橙黄色油状物。1H NMR(800MHz,CDCl3)δ7.19(t,J＝7.7Hz,1H),7.14(d,J＝7.4Hz,1H),6.96(d,J＝7.8Hz,1H),6.91–6.86(m,2H),6.84(d,J＝8.1Hz,1H),6.64(t,J＝7.5Hz,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＝8.2Hz,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).13C NMR(201MHz,CDCl3)δ157.59,152.31,133.86,130.37,128.84,128.66,127.45,121.31,120.53,119.79,119.72,110.37,63.98,58.96,56.52,55.33,49.10,47.22,40.94,32.03,30.61,28.04,25.73.HR-MS(ESI)m/z C23H29N2OS+[M+H]+计算值：381.1995，实测值：381.2013。旋光值：[α]D 25＝–134°(c＝0.1,CHCl3)。
实施例25：(8aR,12aS)-11-(2-甲氧基苯乙基)-6,7,8a,9,10,11,12,12a-八氢-5H-吡啶并[4,3-b][1,4]噻唑呯并[2,3,4-hi]吲哚(化合物I-25)的制备
仿照实施例16步骤7的方法，将化合物WHF-21-p2脱Boc保护并与1-(2-溴乙基)-2-甲氧基苯进行烷基化反应得I-25(62mg，收率67％)，橙黄色油状物。1H NMR(800MHz,CDCl3)δ7.20–7.18(m,1H),7.14(d,J＝7.4Hz,1H),6.96(d,J＝7.8Hz,1H),6.91–6.86(m,2H),6.84(d,J＝8.1Hz,1H),6.64(t,J＝7.5Hz,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＝8.2Hz,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(201MHz,CDCl3)δ157.60,152.30,133.85,130.37,128.85,128.63,127.46,121.31,120.54,119.80,119.73,110.37,63.98,58.95,56.50,55.34,49.10,47.23,40.93,32.03,30.61,28.03,25.72.HR-MS(ESI)m/z C23H29N2OS+[M+H]+计算值：381.1995，实测值：381.1997。旋光值：[α]D 25＝+142°(c＝0.1,CHCl3)。
实施例26：(8aS,12aR)-11-(3-(2-甲氧基苯基)丙基)-6,7,8a,9,10,11,12,12a-八氢-5H-吡啶并[4,3-b][1,4]噻唑呯并[2,3,4-hi]吲哚(化合物I-26)的制备
仿照实施例16步骤7的方法，将化合物WHF-21-p1脱Boc保护并与1-(3-溴丙基)-2-甲氧基苯进行烷基化反应得I-26(45mg，收率50％)，橙黄色油状物。1H NMR(800MHz,CDCl3)δ7.18–7.16(m,1H),7.12(dd,J＝7.3,1.7Hz,1H),6.94(dd,J＝7.8,1.2Hz,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＝7.7Hz,2H),2.44–2.35(m,2H),2.31–2.27(d,J＝13.2Hz,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).13C  NMR(201MHz,CDCl3)δ157.51,152.24,133.72,130.47,129.92,128.91,127.18,121.29,120.45,119.86,119.77,110.29,63.95,58.60,56.42,55.33,49.11,47.19,40.79,32.05,30.61,28.31,26.92,25.54.HR-MS(ESI)m/z C24H31N2OS+[M+H]+计算值：395.2152，实测值：395.2152。旋光值：[α]D 25＝–121°(c＝0.1,CHCl3)。
实施例27：(8aR,12aS)-11-(3-(2-甲氧基苯基)丙基)-6,7,8a,9,10,11,12,12a-八氢-5H-吡啶并[4,3-b][1,4]噻唑呯并[2,3,4-hi]吲哚(化合物I-27)的制备
仿照实施例16步骤7的方法，将化合物WHF-21-p2脱Boc保护并与1-(3-溴丙基)-2-甲氧基苯进行烷基化反应得I-27(87mg，收率94％)，橙黄色油状物。1H NMR(800MHz,CDCl3)δ7.17(t,J＝7.8Hz,1H),7.14–7.10(m,1H),6.95(d,J＝7.8Hz,1H),6.90–6.82(m,3H),6.62(t,J＝7.5Hz,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＝7.8Hz,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(201MHz,CDCl3)δ157.51,152.24,133.83,130.56,129.90,128.84,127.13,121.25,120.42,119.78,119.70,110.27,64.01,58.65,56.54,55.32,49.17,47.15,40.90,32.04,30.60,28.33,27.05,25.67.HR-MS(ESI)m/z C24H31N2OS+[M+H]+计算值：395.2152，实测值：395.2156。旋光值：[α]D 25＝+130°(c＝0.1,CHCl3)。
实施例28：(6bS,10aR)-8-(2-甲氧基苯基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-28)的制备
仿照实施例3的方法，以ent-A(参照J Med Chem 2014,57,2670-2682；Bioorganic&Medicinal Chemistry Letters 13(2003)767–770所描述的方法进行制备)和1-(2-溴乙基)- 2-甲氧基苯(CAS#36449-75-9)为原料，可制备得到化合物I-28。1H NMR(800MHz,CDCl3)δ7.18(t,J＝7.4Hz,1H),7.13(d,J＝7.4Hz,1H),6.86(t,J＝7.4Hz,1H),6.84–6.80(m,1H),6.67(t,J＝7.6Hz,1H),6.54(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,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＝11.4,6.4Hz,1H),2.92–2.89(m,3H),2.86(s,3H),2.82(t,J＝9.8Hz,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 C23H30N3O+[M+H]+计算值:364.2383；实测值:364.2390.旋光值：[α]D 25＝+53°(c＝0.1,CHCl3)。
实施例29：(6bS,10aR)-8-(3-(2-甲氧基)丙基)-3-甲基-2,3,6b,7,8,9,10,10a-八氢-1H-吡啶并[3',4':4,5]吡咯并[1,2,3-de]喹喔啉(化合物I-29)的制备
仿照实施例10的方法，以ent-A(参照J Med Chem 2014,57,2670-2682；Bioorganic&Medicinal Chemistry Letters 13(2003)767–770所描述的方法进行制备)和whc52为原料，可制备得到化合物I-29，黄色油状物。1H NMR(800MHz,CD3OD)δ7.23–7.18(m,1H),7.14(d,J＝7.4Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(t,J＝7.4Hz,1H),6.67(d,J＝9.4Hz,1H),6.58(d,J＝7.2Hz,1H),6.53(d,J＝8.0Hz,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＝7.4Hz,2H),2.65(t,J＝12.4Hz,1H),2.36–2.31(m,1H),2.16–2.09(m,1H),2.07–2.00(m,2H).HR-MS(ESI)m/z C24H32N3O+[M+H]+计算值:378.2540；实测值:378.2545.旋光值：[α]D 25＝+40°(c＝0.1,CHCl3)。
生物测试实施例1：本发明化合物对于5-HT2A受体的亲和力测试
方法：本发明化合物对于5-HT2A受体的亲和力采用放射性配体竞争性实验的方法进行测定。
第一步，制备含有特定5-HT2A受体的细胞膜组分。铺满HEK-293T细胞(ATCC，CRL-11268)的10cm培养皿以5-HT2A受体质粒(10ng)和PEI(40μL)进行转染， 48小时后，从细胞房拿出10厘米培养皿，其中培养的细胞已表达5-HT2A受体。用真空泵吸掉培液，每孔加入3mL裂解液，将细胞置于4℃冷库，静置10分钟。待细胞脱落后，将其转移到15mL离心管中，4℃离心机1500rpm离心5分钟，弃上清。将细胞沉淀转移到组织匀浆器中，再向其中加入3mL裂解液，充分研磨至细胞破碎。然后，将细胞悬液等分至多个EP管中，4℃离心机12000rpm离心5min，弃上清。沉淀即为含有5-HT2A受体的细胞膜组分。
第二步，对瞬时表达5-HT2A受体的293T膜组分进行配体受体结合实验。首先，向含有5-HT2A受体的细胞膜组分加入标准结合缓冲液，用电动组织匀浆器将细胞膜破碎重悬。96孔板每孔加入30μL膜蛋白悬液。然后，96孔板从左到右依次加入30μL不同药物，保证药物终浓度由下到上依次为10-5M、10-6M、10-7M、10-8M、10-9M、0M，每种处理两个重复。紧接着，96孔板每孔加入30μL[3H]-LSD。室温避光孵育2小时。检测。机器读值反应膜上结合[3H]-LSD的量，进一步数据处理后得到不同化合物对5-HT2A受体的亲和力Ki值。
结果：本发明化合物对5-HT2A受体的亲和力Ki值如表1所示。
表1.

从表1可以看出，本发明化合物对5-HT2A受体具有中等到高亲和力，其中，化合物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和I-27对5-HT2A受体的Ki值小于0.1μM。
生物测试实施例2：本发明化合物对于5-HT2A受体的功能活性测试
方法：为了检测5-HT2A受体介导的下游G蛋白信号通路，第一天，铺满HEK-293T细胞(ATCC，CRL-11268)的6cm培养皿以1μg 5-HT2A受体质粒、1μg含有C端海藻荧光素酶的Gαq(Gαq-Rluc)、1μg Gβ3、1μg含有C端绿色荧光蛋白的Gγ9(Gγ9-GFP)和16μL PEI进行转染。同时，为了检测5-HT2A受体介导的下游β-arrestin2信号通路，第一天，铺满HEK-293T细胞(ATCC，CRL-11268)的6cm培养皿以500μg含有C端海藻荧光素酶的5-HT2A受体质粒(5-HT2A-Rluc)、500μg G蛋白偶联受体激酶2(GRK2)、2500μg含有N端绿色荧光蛋白的β-arrestin2(GFP2-ARRB2)和14μL PEI进行转染。第二天，消化长满的细胞，以一个长满细胞的6cm培养皿细胞量铺一个96孔板，每孔100μL培液。第三天，加药检测。从细胞房中拿出96孔板去除培液，每孔加入40μL底物腔肠素400a(终浓度5μM)，紧接着从左到右依次加入20μL不同浓度的药物，保证药物终浓度由下到上梯度递减，每种处理两个重复，最后，上机检测。机器读值反应胞内β-arrestin2上膜情况以及G蛋白三聚体解离情况，前者表征5-HT2A受体下游β-arrestin2信号通路激活程度后者表征5-HT2A受体下游G蛋白信号通路激活程度，由此，各种化合 物对5-HT2A受体的激动作用可被表征。
结果：本发明化合物对5-HT2A受体的激动活性如表2所示(“NA”，无激动活性；“\”，无测试)。
表2

从表2可以看出，本发明化合物对5-HT2A受体具有中等到较强的激动活性，且化合物I-9，I-10，I-13，I-15，I-17，I-19，I-21，I-23，I-25和I-27对5-HT2A受体介导的β-arrestin2招募具有选择性激活作用，不激活G蛋白信号通路。
生物测试实施例3：化合物I-3和I-10对多巴胺D2受体的选择性测试
方法：本发明化合物对于多巴胺D2受体的亲和力采用放射性配体竞争性实验的方法进行测定。第一步，制备含有特定多巴胺D2受体的细胞膜组分。铺满HEK-293T细胞(ATCC，CRL-11268)的10cm培养皿以10ng多巴胺D2受体质粒和40μL PEI进行转染，48小时后，从细胞房拿出10厘米培养皿，其中培养的细胞已表达多巴胺D2受体。用真空泵吸掉培液，每孔加入3mL裂解液，将细胞置于4℃冷库，静置10分钟。待细胞脱落后，将其转移到15mL离心管中，4℃离心机1500rpm离心5分钟，弃上清。将细胞沉淀转移到组织匀浆器中，再向其中加入3mL裂解液，充分研磨至细胞破碎。然后，将细胞悬液等分至多个EP管中，4℃离心机12000rpm离心5min，弃上清。沉淀即为含有多巴胺D2受体的细胞膜组分。第二步，对瞬时表达多巴胺D2受体的293T膜组分进行配体受体结合实验。首先，向含有多巴胺D2受体的细胞膜组分加入标准结合缓冲液，用电动组织匀浆器将细胞膜破碎重悬。96孔板每孔加入30μL膜蛋白悬液。然后，96孔板从左到右依次加入30μL不同药物，保证药物终浓度由下到上依次为10-5M、10- 6M、10-7M、10-8M、10-9M、0M，每种处理两个重复。紧接着，96孔板每孔加入30μL[3H]-Methylspiperone。室温避光孵育2小时。检测。机器读值反应膜上结合[3H]-Methylspiperone的量，进一步数据处理后得到不同化合物对多巴胺D2受体的亲和力Ki值。
结果：化合物I-3对多巴胺D2受体的亲和力为Ki＝1.55μM，化合物I-10对多巴胺D2受体的亲和力为Ki＝1.86μM。因此，化合物I-3和I-10对多巴胺受体的亲和力很弱。相比于卢美哌隆，化合物I-3和I-10对5-HT2A具有更好的选择性。
生物测试实施例4：化合物I-10和I-23的小鼠代谢性质测试
化合物I-10在雄性小鼠体内单剂量腹腔注射给药后，于不同时间点采集血样，LC-MS/MS测定小鼠血浆中化合物的浓度并计算相关药代参数，考察化合物在小鼠体内药代特征。
实验设计：60只雄性C57小鼠(购自苏州昭衍实验动物有限责任公司)按体重随机分组，每组3只。给药前1天禁食不禁水12～14h，给药后4h给食。腹腔注射给药，给药浓度为1mg/mL，溶媒为10％DMSO+90％生理盐水。
样品采集：于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中并放置冰浴上。5000rpm，4℃离心10分钟，收集血浆。IP采血和脑组织时间点：0,5,15,30min,1,2,4,6,8,24h，每个时间点3只小鼠，分析检测前，所有血浆样品存于-80℃。
数据处理：血浆和脑组织药物浓度均使用LC-MS(API4000QTRAP三重四极杆串联质谱仪，电喷雾电离源(ESI))进行检测。数据采集及控制系统软件为Analyst1.5.1软件(Applied Biosystem)。图谱样品峰积分方式为自动积分；采用样品峰面积和内标峰面积的比值作为指标，和样品的浓度进行回归。回归方式：线性回归，权重系数为1/X2。药代动力学参数用WinNonlin Professional v6.3(Pharsight,USA)用非房室模型分析处理。Cmax为实测的最大血药浓度，血药浓度-时间曲线下面积AUC(0→t)由梯形法计算得到，Tmax为给药后血药浓度达峰时间。实验数据用“均数±标准差”(Mean±SD,n≥3)或“均数”(Mean,n＝2)表示。
实验结果：化合物I-10和I-23的药代参数见下表3(腹腔注射)：
表3
生物测试实施例5：化合物I-3和I-10的抗抑郁活性测试
方法：急性束缚应激(ARS)经常被用来诱导小鼠的抑郁状态。强迫游泳试验(FST)和尾悬试验(TST)是目前最常用的推断“抑郁样”行为的模型。将C57/bl6j野生型小鼠(8周以上，购自上海灵畅生物科技有限公司)用单个啮齿动物抑制装置固定5小时。小鼠 被限制所有的身体运动，但只造成最小的疼痛。在ARS实验期间，小鼠被剥夺了食物和水。在5小时的束缚后，一组独立的小鼠被释放，随后立即腹腔注射所测试的化合物。恢复30min后，通过强迫游泳试验或悬尾试验评价小鼠的行为变化。对照组同时接受生理盐水注射，但不进行ARS步骤。强制游泳测试：对照组和ARS应激后的小鼠分别置于盛有15厘米深的水的玻璃烧杯中，温度为25±1℃。所有小鼠被强迫游泳6分钟，并用摄像机记录。记录测试最后4分钟的静止时间。静止时间被定义为动物在水中漂浮而不挣扎，只做必要的动作以保持头部出水的时间；尾部悬挂试验：对照组和束缚应激后的小鼠分别用胶带粘住尾巴悬挂6分钟，并由摄像机记录下来。最后4分钟的静止时间由不知情的观察者手动计时和评估。
结果：化合物I-3在小鼠悬尾实验中的抗抑郁作用如图1所示。从图1可以看出，化合物I-3具有明显的抗抑郁作用。I-3在强制游泳实验中的抗抑郁作用如图2所示。从图2可以看出，化合物I-3具有明显的抗抑郁作用；
化合物I-10在小鼠悬尾实验中的抗抑郁作用如图3所示。从图3可以看出，化合物I-10具有明显的抗抑郁作用。I-10在强制游泳实验中的抗抑郁作用如图4所示。从图4可以看出，化合物I-10具有明显的抗抑郁作用。
生物测试实施例6：化合物I-3和I-10的致幻作用测试
方法：基于磁信号检测小鼠头部抽搐响应以表征致幻作用。小鼠(品系C57/BL6J，购自上海灵畅生物科技有限公司)用2％异氟烷麻醉。在头盖背面中心切除一小部分头皮。一个定制的小型钕磁铁(4毫米×4毫米×2毫米)使用牙科树脂附着在头盖背面的中心。磁体N-S极点与植入体的背腹面平行。试验前允许小鼠进行1周的恢复。为了记录精确的头部运动，老鼠被放置在直径12厘米的玻璃烧杯中，周围环绕着150圈30号漆包铜线。线圈的输出信号由PowerLab/4SP仪器用LabChart V8.1.16软件记录。放大线圈电压，10kHz低通滤波去除射频干扰，40khz采样。对于小鼠头部抽搐响应检测，LabChart数据用40-200赫兹的数字带通滤波器进行处理，通过检索满足以下条件的正弦小波来判定小鼠头部抽搐响应：1，含有2个以上双极峰；2，振幅超过背景噪声水平；3，持续时间小于120毫秒。试验前1小时将小鼠转移到试验室适应。随后将小鼠转移到烧杯中30分钟，记录基线小鼠头部抽搐响应数值。基线记录后，立即给小鼠注射(腹腔)测试化合物，根据使用的化合物，进一步记录1-2小时。数值统计前30分钟。
结果：化合物I-3对小鼠头部抽搐的响应如图5所示。从图5可以看出，化合物I-3在图示两个剂量下不引起小鼠的致幻作用。
化合物I-10对小鼠头部抽搐的响应如图6所示。从图6可以看出，化合物I-10在图 示两个剂量下也不引起小鼠的致幻作用。
生物测试实施例7：化合物I-23的抗抑郁与致幻作用测试
抗抑郁药效测试方法：对于雄性C57BL/6小鼠(8周龄，购自上海灵畅生物科技有限公司)，将皮质酮以25μg/mL的浓度溶解在小鼠饮用水中。用饮用水瓶给小鼠服用皮质酮溶液21天。小鼠被维持在12小时的光周期中。前两周每隔一天换新鲜含皮质酮的饮用水，最后一周每两天减半逐渐换成不含皮质酮的普通饮用水。皮质酮暴露21天后在小鼠中单次注射化合物I-23，于1天，7天和14天后三个时间段通过悬尾实验测试化合物I-23的抗抑郁活性。尾部悬挂试验：对照组和给药组的小鼠分别用胶带粘住尾巴悬挂6分钟，并由摄像机记录下来。最后4分钟的静止时间由不知情的观察者手动计时和评估。
致幻作用测试方法：参照生物测试实施例6的方法测试化合物I-23引起小鼠头部抽搐的效应。
结果：
化合物I-23对小鼠头部抽搐的响应如图7所示。从图7可以看出，化合物I-23在图示两个剂量下均不引起小鼠的致幻作用。
化合物I-23在小鼠悬尾实验中的抗抑郁作用如图8所示。从图8可以看出，化合物I-23单次给药一天后具有明显的抗抑郁作用，并且单针注射10mg/kg组的小鼠在7天后和14天后仍具有显著的抗抑郁作用。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (13)

  1. 一种如式I’所示的并环哌啶类化合物或其药学上可接受的盐：
    其中，X为
    Ra、Rb和Rc独立地为氢或C1-C4烷基；
    R1和R2独立地为氢、卤素或C1-C4烷基；
    R3独立地为氢、卤素、羟基或C1-C4氧烷基；
    m为1、2或3；
    n为1、2或3；
    z为1或2。
  2. 如权利要求1所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，所述如式I’所示的并环哌啶类化合物为如式I-a、I-b、I或I-c所示的并环哌啶类化合物：
    其中，X、R1、R2、R3、m和n的定义如权利要求1所述；
    例如，所述如式I’所示的并环哌啶类化合物为如式I所示的并环哌啶类化合物，
    其中，X为
    Ra、Rb和Rc独立地为氢或C1-C4烷基；
    R1和R2独立地为氢、卤素或C1-C4烷基；
    R3独立地为氢、卤素、羟基或C1-C4氧烷基；
    m为1、2或3；
    n为1、2或3。
  3. 如权利要求1所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，Ra、Rb和Rc中，所述的C1-C4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，例如甲基；
    和/或，R1和R2中，所述的卤素独立地为F、Cl、Br或I；
    和/或，R1和R2中，所述的C1-C4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，R3中，所述的卤素独立为F、Cl、Br或I；
    和/或，R3中，所述的C1-C4烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，例如甲氧基；
    和/或，R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”。
  4. 如权利要求1所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，X为例如X为
    和/或，Ra为C1-C4烷基；
    和/或，Rb和Rc独立地为氢；
    和/或，R1和R2为氢；
    和/或，R3独立地为氢、羟基或C1-C4氧烷基；
    和/或，n为1或2。
  5. 如权利要求1所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，X为例如X为
    和/或，为
    和/或，为
  6. 如权利要求5所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，为
  7. 如权利要求1所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，所述如式I’所示的并环哌啶类化合物为如下任一方案：
    方案一：
    X为
    Ra为C1-C4烷基；
    Rb和Rc独立地为氢；
    R1和R2为氢；
    R3独立地为氢、羟基或C1-C4氧烷基；
    n为1或2；
    z为1或2；
    R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”
    方案二：
    X为
    Ra为C1-C4烷基；
    R1和R2为氢；
    R3独立地为氢、羟基或C1-C4氧烷基；
    n为1或2；
    R3在苯环上的取代位置为邻位、“邻位和对位”或“邻位和间位”。
  8. 如权利要求1所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，其特征在于，所述的如式I’所述的并环哌啶类化合物为如下任一化合物：

  9. 一种如权利要求1-8中任一项所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐的制备方法，其包括方法1、方法2或方法3：
    当R3独立地为氢、卤素或C1-C4氧烷基时，所述的如式I’所示的并环哌啶类化合物或其盐的制备方法为方法1；
    方法1包括如下步骤：在碱存在下，将如式II’所示的化合物和如式III所示的化合物在溶剂中进行如下的取代反应，得到所述的如式I’所示的并环哌啶类化合物；
    方法2包括如下步骤：在还原剂存在下，将如式II’所示的化合物和如式IV所示的化合物在溶剂中进行如下的还原胺化反应，得到所述的如式I’所示的并环哌啶类化合物；
    当R3独立地为羟基时，所述的如式I’所示的并环哌啶类化合物或其盐的制备方法为方法3；
    方法3包括如下步骤：在BBr3存在下，将方法1或2中所述的如式I’所示的并环哌啶类化合物在溶剂中进行反应，得到如式I’所示的并环哌啶类化合物(即R3为羟基)；
    方法1、2和3中X、Ra、Rb、Rc、R1、R2、m和n的定义如权利要求1-8中任一项所述；
    优选的，所述的制备方法满足如下条件：
    方法1中，所述的碱优选为有机碱，例如二异丙基乙基胺；
    和/或，方法1中，所述的碱与所述的如式II’所示的化合物的摩尔比优选为(1-3):1，例如1:1；
    和/或，方法1中，所述的如式III所示的化合物与所述的如式II’所示的化合物的摩尔比优选为(1-3):1，例如1.5:1；
    和/或，方法1中，所述的溶剂优选为极性非质子性有机溶剂，例如二甲基亚砜；
    和/或，方法1中，所述的取代反应的温度优选为室温至80℃，更优选为50-80℃，例如60℃；
    和/或，方法2中，所述的溶剂优选为醇类溶剂，例如甲醇；
    和/或，方法2中，所述的还原剂优选为硼烷类还原剂，例如氰基硼氢化钠；
    和/或，方法2中，所述的反应温度优选为0-60℃，例如室温；
    和/或，方法3中，所述的溶剂优选为卤代烃类有机溶剂，例如二氯甲烷；
    和/或，方法3中，所述的反应的温度优选为-40℃至40℃，更优选为10-40℃，例如室温。
  10. 一种药物组合物，其包含如权利要求1-8中任一项所述的如式I’所示的并环哌啶类化合物或其药学上可接受的盐，和药学上可接受的辅料。
  11. 一种物质A在制备5-HT2A受体激动剂或药物中的应用；
    所述的物质A为如权利要求1-8中任一项所述的如式I’所示的并环哌啶类化合物、其药学上可接受的盐或如权利要求10所述的药物组合物；
    所述的药物为用于治疗或预防与5-HT2A受体相关的疾病。
  12. 如权利要求11所述的应用，其特征在于，所述的5-HT2A受体激动剂为5-HT2A受体下游β-arrestin2招募信号通路激动剂和/或5-HT2A受体下游Gq蛋白激活信号通路激动剂，优选为5-HT2A受体下游β-arrestin2招募信号通路激动剂；
    和/或，所述的与5-HT2A受体相关的疾病为与5-HT2A受体下游β-arrestin2招募信号通路和/或5-HT2A受体下游Gq蛋白激活信号通路相关的疾病，优选为与5-HT2A受体下游β-arrestin2招募信号通路相关的疾病，例如抑郁症。
  13. 一种物质A在制备用于治疗或预防抑郁症的药物中的应用，其特征在于，所述的物质A为如权利要求1-8中任一项所述的如式I’所示的并环哌啶类化合物、其药学上可接受的盐或如权利要求10所述的药物组合物。
PCT/CN2023/071816 2022-01-14 2023-01-11 并环哌啶类化合物及其制备方法和用途 WO2023134711A1 (zh)

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