Tetracyclic compound, and preparation method, pharmaceutical composition, and use thereof

Abstract

Disclosed in the present invention are a tetracyclic compound, and a preparation method, a pharmaceutical composition, and a use thereof. Specifically disclosed is a tetracyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention can effectively treat depression, has good pharmacokinetic properties, and has less drug interactions.

Description

[0001] This application claims the priority of Chinese patent application 2024101657033 with a filing date of February 5, 2024, the priority of Chinese patent application 2024111010693 with a filing date of August 12, 2024, the priority of Chinese patent application 2024117721951 with a filing date of December 4, 2024, and the priority of Chinese patent application 2025101190321 with a filing date of January 24, 2025. This application incorporates the full text of the aforementioned Chinese patent applications. Technical Field The present invention relates to tetracycline compounds, their preparation methods, pharmaceutical compositions, and applications. Background

[0002] Serotonin is a monoamine neurotransmitter that exerts various biological functions, including emotion, cognition, reward, learning, and memory, through different receptor subtypes (Young SN. ■ / PsychiatryNeurosci. 2007 Nov;32(6):394-9). The 5-HT2A receptor belongs to a family of serotonin receptors, which currently consists of more than 15 different receptors encoded by different genes and are divided into seven major categories: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 (Roth BL, Lopez E, The Neuroscientist. 2000;6(4):252-262).

[0003] The 5-HT2A receptor is one of the 5-HT2A receptors. Its downstream signaling pathways primarily involve two pathways. One is a Gq / 11-coupled pathway that activates phospholipase C, leading to increased formation of inositol triphosphate and diacylglycerol, and triggering these downstream signaling events. The other pathway involves (3-arrestin, which acts as a signal transduction scaffold and activates downstream ERK and other signaling pathways (McCorvy JD, Roth BL. Pharmacol Ther. 2015 Jun;150:129-42). Non-canonical signaling pathways related to the 5-HT2A receptor include the phospholipase A2- and (6-arrestin-coupled) Src / Akt pathway (Maroteaux L, Ayme-Dietrich E, Aubertin-Kirch G, et al. Pharmacol Ther. 2017 Feb;170:14-36).

[0004] Stimulation of 5-HT2A receptors can lead to neuronal excitation in various brain regions. Among all 14 serotonin receptor subtypes, 5-HT2A receptors are widely present in the central nervous system and have the highest concentration among monoamine receptors in the cerebral cortex. They are distributed in structural areas involved in emotion regulation, such as the median nucleus / dorsal raphe nucleus, locus coeruleus, and ventral tegmental area (Zi ?BaA, SRpnicki P, Matosiuk D, et al. IntJMol Sci. 2021 Dec 21;23(l):10)o Consistent with their location in the brain, they are not only related to various central physiological functions, including memory, sleep, nociception, eating and reward behavior, but also to many neuropsychiatric diseases, such as schizophrenia, depression and anxiety (Guiard BP, Di Giovanni G. Front Pharmacol. 2015 Mar 17;6:46). Many new antipsychotic drugs (such as aripiprazole, brepirazole and pimavanserin) have high affinity for 5-HT2A receptors, which may be the reason for their better efficacy and lower side effects (McCreary AC, Newman-Tancredi A. CurrPharm Des. 2015;21(26):3725-31). Experiments in mice with 5-HT2A receptor knockout have confirmed that cortical 5-HT2AR plays a role in anxiety regulation, and that serotonin signaling in the cortex can significantly influence behavior in conflict anxiety tests (Weisstaub NV, Zhou M, Lira A, et al. Science. 2006 Jul 28;313(5786):536-40). Depression is one of the chronic mental disorders currently affecting humans. Esketamine, approved by the US FDA in 2019, is the first rapidly acting antidepressant on the market. It can be used in combination with oral antidepressants to treat refractory depression. However, as a ketamine analog, esketamine carries a certain risk of addiction and requires medical supervision. Meanwhile, hallucinogens such as ergotamine and psilocybin, which target 5-HT2A, have been widely used by psychotherapists as adjunctive medications for treating depression, anxiety-related disorders, and addiction since the 1960s, with generally encouraging results. Current 5-HT2A-targeted depression treatments still suffer from issues such as slow onset of action, limited efficacy, significant individual variability, and significant side effects. SUMMARY OF THE INVENTION The present invention aims to overcome the shortcomings of existing antidepressants, such as slow onset of action or hallucinogenic side effects. To this end, the present invention provides a tetracycline compound, a preparation method, a pharmaceutical composition, and its use. While maintaining a strong antidepressant effect, the compounds of the present invention possess advantages such as rapid onset of action, no hallucinogenic side effects, and low drug interactions in vivo. The present invention overcomes these technical issues through the following technical solutions.The present invention provides a tetracyclic compound represented by formula I or a pharmaceutically acceptable salt thereof: A carbon atom with a "#" indicates a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof; a carbon atom with a "#" indicates a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof;

[0005] X] is -NRX1-, -O-, -CRX2RX3-, -S-, -S(O)- or -S(O)2-;

[0006] R X1 is H, Ci-C6 alkyl, Ci-C6 alkyl substituted by one or more R-XU, -C(0)-Ci-C6 alkyl, or "a 3-12 membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S";

[0007] RXU is independently OH;

[0008] RX2 and RX3 are independently H or C1-C6 alkyl;

[0009] X2 is N or CRX4;

[0010] RX4 is H or C1-C6 alkyl;

[0011] X3 is N or CRi;

[0012] X4 is N or CRL2;

[0013] X5 is N or CRH;

[0014] R 1 1 , R1-2 and R1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0015] L is -(CRURL2)n1-, -(CRLiRL2)n2-YL(CRLiRL2)n3-, or -(CRURL2)n4-Y2-(CRLiRL2)n5-;

[0016] R L1 and n1 are independently H or C1-C6 alkyl; n1 is 1, 2, 3 or 4; n2 is 0, 1, 2 or 3; n3 is 0, 1, 2 or 3; n2+n3=1, 2 or 3; γ2 is -OC-, -C(0)-NRL3-, -CRL6=CRL7-, n4 is 0, 1, or 2; n5 is 0, 1, or 2; n4+n5=1 or 2;

[0017] RL3 is independently H or C1-C6 alkyl;

[0018] RL4 is H or halogen;

[0019] RL5 is halogen, OH or C1-C6 alkoxy;

[0020] RL6 and RL7 are independently H or halogen;

[0021] R2 is independently C1-C6 alkyl, -C(O)-C1-C6 alkyl, or oxo (=0); m2 is 0, 1, 2, 3, or 4; Ring A is "a 9-12 membered bicyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S," "a 5-6 membered monocyclic heterocyclic group having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S," C6-C10 aryl, or C3-C6 cycloalkyl;

[0022]

[0023] R3 is independently oxo (=0), C1-C6 alkyl, C1-C6 alkoxy, -NR4R5, -C(0)R6, -SR 7 、 -S(O)2R\ halogen、 one or more R 9 Substituted C1-C6 alkoxy, C1-C6 alkyl substituted with one or more R1°, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR;

[0024] R4 is independently H or C1-C6 alkyl;

[0025] R 5 are independently H, Ci-C6 alkyl or -C(O)R 5 1 ;

[0026] R6, Rd, R 7and R8 are independently C1-C6 alkyl;

[0027] R 9 and R 10 are independently OH, -NR4R 5 or halogen; RH is H or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; m3 is 0, 1, 2, 3 or 4. The present invention also provides a tetracyclic compound represented by Formula 1-0 or a pharmaceutically acceptable salt thereof: A carbon atom with a "#" indicates a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof; a carbon atom with a "#" indicates a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof;

[0028] X] is -NRX1-, -O-, -CRX2RX3-, -S-, -S(O)- or -S(O)2-;

[0029] RXI is H, C1-C6 alkyl, C1-C6 alkyl substituted with one or more RXU, -C(O)-Ci-C6 alkyl, C3-C6 cycloalkyl, or "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S";

[0030] Rxi is independently sieve or OH;

[0031] RX2 and RX3 are independently H, alkyl, C1-C6 alkyl or C1-C6 halogenated alkyl;

[0032] X2 is N, N+O- or CRX4;

[0033] RX4 is H or C1-C6 alkyl;

[0034] X3 is N or CRi;

[0035] X4 is N or CRL2;

[0036] X5 is N or CRH;

[0037] R 1 1 , R1-2 and R1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0038] L is -(CRURL2)n1-, -(CRLiRL2)n2-YL(CRLiRL2)n3-, or -(CRURL2)n4-Y2-(CRLiRL2)n5-;

[0039] R L1 and n1 are independently H or C1-C6 alkyl; n1 is 3 or 4; n3 is 0, 1, 2 or 3; n2+n3=1, 2 or 3; γ2 is -OC-, -C(0)-NRL3-, -CRL6=CRL7-, n4 is 0, 1, or 2; n5 is 0, 1, or 2; n4+n5=1 or 2;

[0040] RL3 is independently H or C1-C6 alkyl;

[0041] RL4 is H or halogen;

[0042] RL5 is halogen, OH or C1-C6 alkoxy;

[0043] RL6 and RL7 are independently H or halogen;

[0044] R2 is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)-C1-C6 alkyl, oxo (=O), thioxo (=S) or hydroxy; m2 is 0, 1, 2, 3 or 4; Ring A is "an 8-12 membered bicyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from among N, O and S", "a 5-6 membered monocyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from among N, O and S", "a 9-16 membered polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from among N, O and S", or a C3-C6 cycloalkyl;

[0045] (R 3 )m3 and when L is -(CR L1 R L2 )nl-、 -(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, V is

[0046] R3 is independently oxo (=0), C1-C6 alkyl, C1-C6 alkoxy, -NR4R5, -C(0)R6, -SR 7 、 -S(O)2R\ halogen、 one or more R 9 Substituted C1-C6 alkoxy, C1-C6 alkyl substituted with one or more R1°, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR;

[0047] R4 is independently H or C1-C6 alkyl;

[0048] R 5 are independently H, C1-C6 alkyl or -C(O)R 5 1 ;

[0049] R6, Rd, R 7 and R8 are independently C1-C6 alkyl;

[0050] R 9 and R 10 are independently OH, -NR4R 5 or halogen;

[0051] RH is H or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; m3 is 0, 1, 2, 3 or 4; and m4 is 0, 1 or 2. In certain preferred embodiments of the present invention, certain groups in the tetracyclic compound or a pharmaceutically acceptable salt thereof are defined as follows. Unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention"); X is -NR*. In a certain embodiment of the present invention, RX2 and RX3 are independently H. In a certain embodiment of the present invention, RX4 is H. In a certain embodiment of the present invention, X3 is C14. In a certain embodiment of the present invention, X4 is C14. In a certain embodiment of the present invention, X5 is C14. In a certain embodiment of the present invention, R 1 1 , RU2 and R1-3 are independently H, CN, halogen or C1-C6 alkoxy; for example, RU and Ri. is independently & In a certain embodiment of the present invention, R 1 1, RLi and R2 are independently H, CN, or a C1-C6 alkoxy group; for example, RU and R* are H, and RD is H, CN, or a C1-C6 alkoxy group. In one embodiment of the present invention, m4 is 1. In one embodiment of the present invention, RLi and R2 are independently H. In one embodiment of the present invention, n1 is 3. For C(0) ■ or.

[0052] CRL4RL5=. In one embodiment of the present invention, n2 is 0, 1, or 2, for example, n2 is 1 or 2, and another embodiment, n2 is 2. In one embodiment of the present invention, n3 is 0, 1, or 2, for example, n3 is 1 or 1, and another embodiment, n3 is 0. In one embodiment of the present invention, n4 is 0 or 1, for example, n4 is 1. In one embodiment of the present invention, n5 is 0 or 1, for example, n5 is 0. In one embodiment of the present invention, n4+n5=1. In one embodiment of the present invention, RL3 is H. In one embodiment of the present invention, RL4 is H. In one embodiment of the present invention, R1 is halogen. In one embodiment of the present invention, RL6 and RL7 are independently H. In one embodiment of the present invention, R2 is independently alkyl, C1-C6 alkyl, oxo (=0), thio (=S) or hydroxyl; for example, oxo (=0). In one embodiment of the present invention, R 2 are independently oxo (=0). In one embodiment of the present invention, m2 is 0, 1, 2 or 3, for example, m2 is 1. In one embodiment of the present invention, m2 is 0 or 1; for example, m2 is 0. In one embodiment of the present invention, when L is -(CRLiRL2)nl-, -(CR L1 R L2 )n2-O- or -(CRLiRL2)n2-C(O)-, In one embodiment of the present invention, R 3 are independently oxo (=0), G-C6 alkoxy, -NR4R 5 、 -C(0)R6、 -SR 7 、 -S(O)2R\ halogen、 one or more R 9substituted C1-C6 alkoxy, C1-C6 alkyl substituted by one or more R®, CN, “a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S” or -0; for example, R 3 are independently C1-C6 alkoxy, 9 Substituted C1-C6 alkoxy or halogen. In one embodiment of the present invention, R 3 are independently -OR", C1-C6 alkyl, C1-C6 alkoxy, 9 Substituted C1-C6 alkoxy or halogen. In a certain embodiment of the present invention, R 4 are independently H. In a certain embodiment of the present invention, R 5 are independently H or -C(O)R 5 1 ; For example, R 5 are independently H. In a certain embodiment of the present invention, R 9 are independently halogen. In one embodiment of the present invention, m3 is . or 1, for example, m3 is 0. In one embodiment of the present invention, the "C1-C6 alkyl" in each "C1-C6 alkyl", "substituted C1-C6 alkyl" and "-C(O)-C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl. In one embodiment of the present invention, the "C1-C6 alkoxy" in each "C1-C6 alkoxy" and "substituted C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy or ethoxy. In one embodiment of the present invention, each "hetero atom is selected from 1, 2 or 3 of N, O and S, and the number of hetero atoms is 1, 2 or 3 3-membered heterocycloalkyl" is independently "hetero atom is selected from 1 or 2 of N and O, and the number of hetero atoms is 1 or 2

[0053] 5-6 membered heterocycloalkyl", such as piperidine (e.g. P Linky In one embodiment of the present invention, each halogen is independently F, Cl, Br or I, such as F or Cl. In one embodiment of the present invention, each C3-C6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclobutyl. In one embodiment of the present invention, in ring A, the "heteroatom" is selected from one, two or three of N, O and S, and the number of heteroatoms is A] is independently phenyl or pyridyl, and ring A? is independently "a 5- to 6-membered heterocycloalkyl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms" or "a 5- to 6-membered heteroaryl group having one or two heteroatoms selected from N and O"; for example, ring A 2 are independently "a 5-membered heterocycloalkyl group having 1 or 2 heteroatoms and a heteroatom selected from 0" or "a 5-6-membered heteroaryl group having 1 or 2 heteroatoms and a heteroatom selected from N and 1 or 2 heteroatoms"; for example, in ring A, the "heteroatoms selected from N, 0 and In one embodiment of the present invention, in ring A, the “8-12-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S” is “an 8-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S” or “a 9-12-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S”, wherein the “9-12-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S” is defined as described in any one of the present invention. For example, in ring A, the "heteroatom" is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 in an 8-12 membered diaryl ring.

[0054] In one embodiment of the present invention, in ring A, the “5-6 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S” is “a 5-6 membered monocyclic heteroaryl group having 1 or 2 heteroatoms selected from N and S” or “a 5-6 membered monocyclic heterocycloalkyl group having 1 or 2 heteroatoms selected from N”, for example, Preferably, in ring A, the "heteroatom" is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 In one embodiment of the present invention, in ring A, the "9-16 membered polycyclic heterocyclic group wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3" is "the heteroatoms are selected from 1 or 2 of N and O, and the number of heteroatoms is 1 In one embodiment of the present invention, the C6-C10 aryl group in Ring A is a phenyl group or a naphthyl group, for example, a phenyl group. In one embodiment of the present invention, the C3-C6 cycloalkyl group in Ring A is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclohexyl group. In one embodiment of the present invention, each "5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from N, O, and S" is independently a "5- to 6-membered heteroaryl group having one or two heteroatoms selected from N," for example,

[0055] In one embodiment of the present invention, the tetracyclic compound is a compound as shown in Formula 1, 2 or 3:

[0056] 1-2 wherein, *, #, X], ring A, R? and m3 are as defined in any one of the present invention. wherein, *, #, X], ring A, R? and m3 are as defined in any one of the present invention.

[0057] In one embodiment of the present invention, the compound of the present invention is not the following compound:

[0058] (1) A tetracyclic compound or a pharmaceutically acceptable salt thereof according to any one of the present invention, and

[0059] (2) Pharmaceutically acceptable excipients. The present invention also provides a use of the tetracycline compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition as described in any one of the present invention, wherein the use is selected from:

[0060] (1) preparing a 5-HT2A receptor agonist;

[0061] (2) Preparation for treatment and / or prevention with 5-HT 2A drugs for receptor-related diseases;

[0062] (3) Preparation of drugs for treating and / or preventing depression. The present invention also provides a method for treating and / or preventing diseases related to 5-HT2A receptors, comprising: administering to a patient in need thereof a therapeutically effective amount of a tetracycline compound as shown in Formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. The present invention also provides a method for treating and / or preventing depression, comprising: administering to a patient in need thereof a therapeutically effective amount of a tetracycline compound as shown in Formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. In a certain embodiment of the present invention, the disease related to 5-HT2A receptors is depression. Terminology Unless otherwise specified, the terms used in the present invention have the following meanings: The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients. The term "pharmaceutically acceptable salt" means a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition). When the linking groups listed in the present invention do not specify their connection direction, their connection direction is the same as the direction of reading from left to right. For example,

[0063] YL(CRLiRL2)n3 - when, at this time - (CRL^^-Y^CCRL 1 ^ 2 ^-^ is connected in the same direction as the reading order from left to right to form The term "one or more" means 1, 2 or 3. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "oxo group" means =0, where two hydrogen atoms on the same carbon atom are replaced by an oxygen atom, that is, a methylene group is replaced by a residue. The term "alkyl" means a straight-chain or branched-chain, saturated monovalent hydrocarbon group having a specified number of carbon atoms (for example, C1-C6). Alkyl includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. The term "haloalkyl" means an alkyl group substituted by one or more halogens, where the definition of halogen is the same as the term "halogen", and the definition of alkyl is the same as the term "alkyl". Haloalkyl includes but is not limited to: -CF3, -CHF2, -CH2CF3, etc. The term "alkoxy" means the group -O-RX, where the definition of RX is the same as the term "alkyl". Alkoxy includes but is not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc. The term "haloalkoxy" means the group -O-R x \ RX, where the definition of RX is the same as the term "haloalkyl". Haloalkoxy includes but is not limited to: -O-CF3, -O-CHF2, -O-CH2CF3, etc. The term "cycloalkyl" means a saturated cyclic hydrocarbon group having a specified number of carbon atoms (for example, C3-C6), which is a monocyclic ring. Cycloalkyl includes

[0064] / , f, / 顼, etc. The term "aryl" means an unsaturated cyclic hydrocarbon group having a specified number of carbon atoms (for example, C6-C10), which is a monocyclic or polycyclic ring (for example, 2 rings). When it is a polycyclic ring, two adjacent monocyclic rings share two atoms and one bond, and each ring has aromaticity. Aryl includes but is not limited to: phenyl, naphthyl, etc. The term "heterocycloalkyl" means a cyclic group having a specified number of ring atoms (for example, 3-12 membered), a specified number of heteroatoms (for example, 1, 2 or 3), and a specified type of heteroatom (one, two or three of N, O and S), which is a monocyclic, bridged or spiro ring, and each ring is saturated. Heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes but is not The term "monocyclic heterocyclyl" refers to a cyclic group with a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one, two, or three of N, O, and S), which is saturated or unsaturated, aromatic or non-aromatic, and is a monocyclic ring. The heterocyclyl is attached to the rest of the molecule through a carbon atom or a heteroatom. The term "bicyclic heterocyclyl" refers to a cyclic group with a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one, two, or three of N, O, and S), which is a bicyclic ring, each ring of which is independently saturated or unsaturated, aromatic or non-aromatic. The heterocyclyl is attached to the rest of the molecule through a carbon atom or a heteroatom. The term "heteroaryl" refers to a ring having a specified number of ring atoms (e.g., 5-10 members, 5-6 members), a specified number of heteroatoms (e.g., 1,

[0065] 2 or 3) and a specified heteroatom type (one, two or three of N, O and S), an unsaturated cyclic group, which is monocyclic or polycyclic. When it is polycyclic, the monocyclic rings share two atoms and one bond, and each ring has aromaticity. The term "therapeutically effective amount" refers to an amount administered to a patient sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, and other factors, but can be adjusted by those skilled in the art as appropriate. The term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical formulation other than the active pharmaceutical ingredient, and is generally divided into two categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical

[0066] Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition) □ The term “treatment” means eliminating the cause of a disease or alleviating its symptoms. The term “prevention” means reducing the risk of developing a disease. The term "patient" refers to any animal, typically a mammal, such as a human, in need of treatment or prevention of a disease. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans. The preferred conditions described above may be arbitrarily combined, without violating common knowledge in the art, to obtain preferred embodiments of the present invention. The reagents and raw materials used in the present invention are commercially available. The positive effects of the present invention are that the compounds of the present invention can reduce depression and hallucinations while maintaining a good antidepressant effect, and have low drug interactions in vivo. The following examples further illustrate the present invention, but the invention is not limited to the scope of the examples described. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications. Example 1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-2,3,6b,7, 8, 9, 10, 10a-Octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]pyr ... Step 1: Dissolve 2,3-dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.7 mmol) and methyl (triphenylphosphinoyl) acetate (3.36 g, 10.05 mmol) in anhydrous tetrahydrofuran (15 mL) at room temperature. Stir the reaction mixture at 80°C (2°C) for 2 h. Cool the reaction mixture to room temperature and concentrate in vacuo to obtain a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-10%) to obtain methyl (E)-3-(2,3-dihydrobenzofuran-7-yl)acrylate (1.18 g, yield: 76.1%) as a white solid. MS m / z (ESI): 205.1 [M+H] +Step 2: Methyl (E)-3-(2,3-dihydrobenzofuran-7-yl)propanoate (1.18 g, 5.8 mmol) was dissolved in methanol (10 mL) at room temperature, and 10% wet benzofuran (310 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with methanol, and the filtrates were combined and concentrated in vacuo to afford crude methyl 3-(2,3-dihydrobenzofuran-7-yl)propanoate (1.15 g, yield: 96.6%) as a colorless viscous oil. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 207.1 [M+H] + Step 3: Methyl 3-(2,3-dihydrobenzofuran-7-yl)propanoate (500 mg, 2.4 mmol) was added to the mixture at room temperature. Dissolve the product in tetrahydrofuran (8 mL) and cool to zero degrees Celsius under a nitrogen atmosphere. Add a 1M solution of lithium aluminum hydride in tetrahydrofuran (8 mL) and stir at room temperature for 1 hour. Stir the reaction mixture at zero degrees Celsius and slowly dilute it with ethyl acetate (20 mL). Add sodium sulfate decahydrate, filter through celite, wash with methanol, and concentrate in vacuo to obtain the crude product. Purify the crude product by column chromatography (EtOAc / PE = 0-15%) to obtain 3-(2,3-dihydrobenzofuran-7-yl)propan-1-ol (340 mg, yield: 78.7%) as a colorless oil. MS m / z (ESI): 179.1 [M+H] +Step 4: 3-(2,3-Dihydrobenzofuran-7-yl)propan-1-ol (150 mg, 0.841 mmol) and triethylamine (256 mg, 2.525 mmol) were dissolved in dichloromethane (4 mL) at room temperature and cooled to 0. (2, methanesulfonyl chloride (145 mg, 1.262 mmol) was added, and the mixture was returned to room temperature. After stirring for 1 hour, the reaction solution was concentrated in vacuo at room temperature. ((6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyrro[1,2, 3-de]oxathioline (97 mg, 0.421 mmol), potassium iodide (140 mg, 0.842 mmol), dioxane (3 mL) and triethylamine (256 mg, 2.525 mmol) were added. The reaction solution was stirred at 100. (2 for 18 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to obtain a crude product. The crude product was purified by alkaline method to obtain (6bR,10aS)-8-(3-(2,3 3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin (28.61 mg, yield: 17.32%) was obtained as a yellow oily liquid. E NMR (400 MHz, CDCL) δ 7.03 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 6.8 Hz, 1H), 6.40 (d, J = 7.7 Hz, 1H), 4.53 (t, J= 8.7 Hz, 2H), 3.63-3.55 (m, 1H), 3.32-3.15 (m, 6H), 2.92-2.79 (m, 5H), 2.69 (m, 1H), 2.57 (t, J= 7.6 Hz, 2H), 2.39 (s, 2H), 2.24 (s, 1H), 1.89 (d, ■7 = 35.6 Hz, 5H). MS m / z (ESI): 390.2 [M+H] + oExample 2: (6bR,10aS)-8-(3-(Benzo[d][1,3]dioxazol-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-<[3',4':4,5]<[1,2,3-de]oxazol-4-yl]-1H- ...

[0067] The preparation of E2 was carried out according to the synthesis method of Example 1. 1 H NMR(400 MHz, CDC13) 5 6.77-6.71 (m, 1H), 6.70-6.62 (m, 3H), 6.51 (d, J = 6.8 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 5.91 (s, 2H), 3.63-3.56 (m, 1H), 3.33-3.12 (m, 4H), 2.92-2.78 (m, 5H), 2.62-2.59 (m, 3H), 2.45-2.24 (m, 3H), 1.94-1.86 (m, 5H). MS m / z (ESI): 392.2 [M+H] + Example 3: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate Step 1: Compound 2,3-dihydrobenzofuran-4-carbaldehyde (200 mg, 1.35 mmol) and ethoxycarbonylmethylenetriphenylphosphine (940 mg, 2.7 mmol) were added to a 50 mL reaction flask, followed by the addition of THF (10 mL). The mixture was heated to 70°C and stirred for 2 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain ethyl (£)-3-(2,3-dihydrobenzofuran-4-yl)acrylate (colorless liquid, 200 mg, yield 68%). MS m / z (ESI): 219.3 [M+H] +Step 2: Add ethyl (E)-3-(2,3-dihydrobenzofuran-4-yl)acrylate (200 mg, 0.92 mmol) to a 50 mL reaction flask, followed by methanol (10 mL) and carbon-wetted (10%, 97 mg). Stir under a hydrogen atmosphere at room temperature for 1 hour. After completion of the reaction, as determined by LCMS, the reaction mixture was filtered and concentrated to yield ethyl 3-(2,3-dihydrobenzofuran-4-yl)propanoate (200 mg, 99% yield, colorless liquid). MS m / z (ESI): 221.4 [M+H] + Step 3: Ethyl 3-(2,3-dihydrobenzofuran-4-yl)propanoate (180 mg, 0.82 mmol) was added to a 50 mL three-necked reaction flask, followed by the addition of THF (5 mL). Lithium aluminum tetrahydride (1.5 mL, 1 mol / L) was slowly added dropwise at 0°C (200°F). The reaction mixture was stirred at 0°C for 20 min. The reaction solution was quenched with sodium sulfate decahydrate, filtered, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 3-(2,3-dihydrobenzofuran-4-yl)propan-1-ol (colorless liquid, 100 mg, yield 68.7%). MS m / z (ESI): 179.3 [M+H] + Step 4: Add 3-(2,3-dihydrochromen-4-yl)propan-1-ol (30 mg, 0.17 mmol) to a 25 mL reaction flask. DCM (5 mL) was then added, followed by DIEA (65 mg, 0.5 mmol) and MS2O (44 mg, 0.5 mmol). Stir at room temperature for 1 h. The reaction mixture was extracted with DCM (2 x 20 mL), and the organic phase was washed with saturated brine (2 x 20 mL). Concentration afforded 3-(2,3-dihydrochromen-4-yl)propyl methanesulfonate (colorless liquid, 35 mg, 81.4% yield). MS m / z (ESI): 257.3 [M+H] +Step 5: Add the compound 3-(2, 3-dihydrobenzofuran-4-yl)propyl methanesulfonate (35 mg, 0.14 mmol) and the raw material (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin (31 mg, 0.14 mmol) to a 25 mL reaction bottle, followed by DMSO (3 mL) and then DIPEA (52 mg, 0.4 mmol). After the addition is complete, stir at 60 °C for 16 h. The reaction mixture was concentrated and then purified by reverse phase column chromatography (acetonitrile / (water+0.05% NH4HCO3)) to give (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyro[1,2, 3-de]oxathioline (gray solid, 20 mg, yield 37.7%). H NMR (500 MHz, DMSO-%) δ 7.00 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.56 (t, J = 11.2 Hz, 1H), 6.51 (t, J = 7.6 Hz, 1H), 6.42 (d, J= 7.2 Hz, 1H), 6.33 (d, J= 7.6 Hz, 1H), 4.50 (s, 2H), 3.46-3.38 (m, 1H), 3.27 (d, J= 11.4 Hz, 1H), 3.12 (t, J= 8.4 Hz, 3H), 3.01 (s, 1H), 2.78 (s, 4H), 2.67 (ddd, J= 16.4, 6.8, 2.2 Hz, 1H), 2.61-2.51 (m, 4H), 2.24 (s, 2H), 2.08 (s, 1H), 1.88-1.70 (m, 5H). MS m / z (ESI): 390.8[M+H] + Example 4: (6bR,10aS)-8-(3-(chrome-8-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin Step 1: Compound 8-bromochroman (500 mg, 2.35 mmol), ethyl acrylate (260 mg, 2.58 mmol), Pd2(dba)3 (43 mg, 0.05 mmol), tri-tert-butylphosphine tetrafluoroborate (14 mg, 0.05 mmol), and N-methyldicyclohexylamine (1370 mg, 7.05 mmol) were added to a 50 mL single-necked reaction flask. Anhydrous dioxane (10 mL) was then added. After the addition, the atmosphere was replaced with nitrogen three times. The temperature was slowly raised to 100 °C and stirred for 16 h. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (Biotage-12 g, eluent gradient: 10% EA / PE) to afford ethyl (E)-3-(chroman-8-yl)acryloyl ester (pale yellow oil, 150 mg, 28% yield). Step 2: Ethyl (E)-3-(chroman-8-yl)acryloyl ester (150 mg, 0.65 mmol) was added to a 25 mL single-necked reaction flask. Ethyl acetate (15 mL) and 10% Pd / C (wet basis, 15 mg) were then added, respectively. After addition, the atmosphere was replaced with hydrogen three times, and the reaction was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to afford ethyl 3-(chroman-8-yl) propionate (crude, 150 mg, 99% yield). The crude product was used directly in the next reaction without further purification. MS m / z(ESI):235.5 [M+H] +Step 3: Ethyl 3-(chromen-8-yl)propionate (150 mg, 0.64 mmol) was added to a 25 mL three-necked reaction flask. Anhydrous tetrahydrofuran (10 mL) was then added. 1M lithium aluminum tetrahydride (THF) solution (48 mg, 1.28 mmol, 1 mol / L) was added portionwise under nitrogen and an ice-water bath. The reaction was stirred at 0°C for 0.5 h. After completion of the reaction, NaSO.10H2O was slowly added to the reaction mixture to quench the reaction. The mixture was filtered, and the filter cake was washed with 10% MeOH / DCM (30 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: 30% EA / PE) to afford 3-(chromen-8-yl)propan-1-ol (colorless oil, 110 mg, 89% yield). Step 4: 3-(Chroman-8-yl)propan-1-ol (15 mg, 0.08 mmol), DMAP (2 mg, 0.01 mmol), DIEA (30 mg, 0.24 mmol), and anhydrous dichloromethane (5 mL) were added to a 25 mL three-necked reaction flask. Methanesulfonic acid (27 mg, 0.16 mmol) was slowly added under nitrogen and in an ice-water bath. After addition, the mixture was stirred at room temperature for 2 h. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to afford 3-(Chroman-8-yl)propyl methanesulfonate (a colorless oil, crude product, 20 mg). The crude product was used directly in the next reaction without further purification. Step 5: Add compound 3-(chromen-8-yl)propyl methanesulfonate (20 mg, 0.07 mmol) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin (20 mg, 0.08 mmol) to a 10 mL reaction bottle, followed by anhydrous DMSO (2 mL) and DIPEA (30 mg, 0.21 mmol), respectively. After the addition is complete, slowly heat to 60 °C and stir the reaction for 16 h.After the reaction, the reaction mixture was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain (6bR,10aS)-8-(3-(chroman-8-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin (off-white solid, 4.5 mg, yield 15%). X H NMR (500 MHz, CDCL) S 6.93 (d, J= 7.3 Hz, 1H), 6.88 (d, J= 7.0 Hz, 1H), 6.74 (t, J= 7.4 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 7.1 Hz, 1H), 6.40 (d, J= 7.8 Hz, 1H), 4.21-4.14 (m, 2H), 3.64-3.56 (m, 1H), 3.33-3.16 (m, 4H), 2.95-2.89 (m, 1H), 2.86 (s, 3H), 2.85-2.76 (m, 3H), 2.75-2.69 (m, 1H), 2.60-2.51 (m, 2H), 2.48-2.34 (m, 2H), 2.32-2.22 (m, 1H), 2.02-1.90 (m, 5H), 1.84-1.78 (m, 2H). MS m / z (ESI): 404.7[M+H] + Example 5: (6bR,10aS)-8-(3-(benzofuran-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,1Oa-octahydro-1H-pyrido[3',4':4,5]<pyroximate[1,2,3-de]oxathiocarbamate The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase chromatography to obtain ethyl (E)-3-(benzofuran-7-yl) acrylate (yellow oil, 220 mg, yield 50%). MS m / z (ESI): 217.3.[M+H] +Step 2: Dissolve ethyl (E)-3-(benzofuran-7-yl)acrylate (45 mg, 0.2 mmol) in THF (2.0 mL), cool to 0°C, add 1M lithium aluminum tetrahydride solution in tetrahydrofuran (0.2 mL, 0.2 mmol), and stir at room temperature for 1 hour. Then, add sodium sulfate decahydrate and stir for 30 minutes. Filter, concentrate, and purify by normal phase chromatography to obtain 3-(benzofuran-7-yl)propan-1-ol (yellow oil, 25 mg, 70% yield). MS m / z (ESI): 177.2. [M+H] +Step 3: Dissolve compound 3-(benzofuran-7-yl)propan-1-ol (25 mg, 0.14 mmol) in DCM (2.0 mL), add DIEA (90 mg, 0.7 mmol), cool to 0 °C, add methanesulfonic acid tincture (45 mg, 0.26 mmol), and then warm to room temperature and stir for 3 h. Quench with water, extract with DCM, add sodium sulfate, dry, and filter to obtain compound 3-(4-fluoro-2-methoxyphenyl)propyl methanesulfonate (yellow oil, 23 mg), which is directly used in the next reaction. Step 4: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (25 mg, 0.10 mmol) was dissolved in DMSO (2.5 mL) at room temperature. DIEA (0.5 mL, 3.0 mmol) and 3-(4-fluoro-2-methoxyphenyl)propyl methanesulfonate (23 mg, 0.1 mmol) were added sequentially. The mixture was heated to 65 °C and stirred for 18 h. The mixture was cooled to room temperature and filtered. The product was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%). Obtained compound (6bR,10aS)-8-(3-(benzofuran-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,, 405]pyrrolo[1,2, 3-de]oxathioline (colorless oil, 2.0 mg, yield 5%). δ 5 NMR (500 MHz, DMSO-%) 7.98 (d, J = 5.0 Hz, 1H), 7.48 (dd, J = 10.0, 5.0 Hz, 1H), 7.19-7.12 (m, 2H), 6.95 (d, J = 5.0 Hz, 1H), 6.67-6.52 (m, 1H), 6.43 (d, J= 5.0 Hz, 1H), 6.34 (d, J = 10.0 Hz, 1H), 3.36-3.26 (m, 7H), 3.12-3.04 (m, 2H), 2.89-2.79 (m, 3H), 2.71 (s, 3H), 2.69-2.67 (m, 2H), 1.98- 1.79 (m, 4H)o MS m / z (ESI): 388.8[M+H]+ Example 6: (6bR,10aS)-8-(3-(Benzo[b]thiophen-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathiophene Step 1: 6-7-Bromobenzo[3-( ... Ethyl (E)-3-(benzo[b]thiophen-7-yl)acrylate (470 mg, 2.02 mmol), 50 mg of Pd / C, and 50 mg of Pd(OH)2 / C were added to a three-necked flask containing 30 mL of MeOH. The mixture was replaced three times and allowed to react at room temperature for 16 hours. TLC and Icms confirmed the reaction was complete. The product was filtered, concentrated, and then purified by normal phase column chromatography (PE / EA = 100:5 / 1) to afford ethyl 3-(benzo[b]thiophen-7-yl)propanoate (410 mg, colorless oil, yield: 87%). Step 3: Add ethyl 3-(benzo[epthiophen-7-yl)propionate (110 mg, 0.469 mmol) to a three-necked flask containing 5 mL of THF. Replace the atmosphere with nitrogen three times, cool to 100°C, inject 0.9 mL of 1M LAH THF solution, and continue the reaction for 1 hour. TLC confirms the reaction is complete. Sodium sulfate decahydrate is added to quench the reaction. EA and Na₂SO₄ are then added, stirring at room temperature for half an hour. Filter, concentrate, and analyze by normal phase column chromatography (PE / EA = 100% to 10 / 1) to obtain 3-(benzo[epthiophen-7-yl)propan-1-ol (90 mg, colorless oil, yield: 90%). Step 4: Preparation of 3-(Benzo[epthiophen-7-yl)propyl methanesulfonate: Refer to the synthesis method described in Step 4 of Example 3.Step 5: Preparation of (6bR,10aS)-8-(3-(benzo[b-thiophen-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone: Refer to the synthesis method of Step 5 of Example 3. I: HNMR (500 MHz, CDC13).

[0068] 57.68 (d, J = 8.0 Hz 1H), 7.42(d = 5.5Hz 1H), 7.35(d, = 5.5Hz, 1H), 7.31(t, = 8.0 Hz 1H), 7.16 (d, J =

[0069] 7.0 Hz 1H), 6.64(t, J= 7.5 Hz 1H), 6.51(d, J= 5.5 Hz 1H), 6.40(d, J= 7.5 Hz 1H), 3.62-3.56 (m, 1H), 3.31-

[0070] 3.20 (m, 4H), 2.92(t, « / = 8.0 Hz 1H)2.86 (s, 3H), 2.85-2.72 (m, 2H), 2.58-2.30 (m, 3H), 2.07-1.94 (m, 5H).

[0071] MS m / z (ESI): 405.4.[M+H] + . oh Step 1: Compound 2-amino-6-bromophenol (1000 mg, 5.32 mmol), anhydrous p-toluenesulfonic acid (100 mg, 0.53 mmol) and triethyl orthoformate (10 mL) were added to a 25 mL single-necked reaction flask. Under nitrogen protection, the temperature was slowly raised to 80 ° C and stirred for 16 h. After the reaction was completed, saturated NaHCO3 solution was added to the reaction solution to adjust the pH of the system to alkaline, followed by extraction with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by normal phase column chromatography (eluent gradient: 3% EA / PE) to obtain compound 7-bromobenzo[d]oxazolidine (pale yellow solid, 900 mg, yield 85%). Step 2: Compound 7-bromobenzo[d]oxazolidine (250 To a 25 mL single-necked reaction flask were added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate (340 mg, 1.51 mmol), Pd(dppf)C12.CH2C12 complex (20 mg, 0.03 mmol), and sodium carbonate (265 mg, 2.52 mmol). Dioxane (5 mL) and water (1 mL) were then added, respectively. After the additions were complete, the atmosphere was replaced with nitrogen three times, and the temperature was slowly raised to 80°C with stirring for 16 h. After the reaction was completed, the reaction solution was filtered, water (20 mL) was added, and extraction with ethyl acetate (3 x 10 mL) was performed. The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 10% EA / PE) to obtain ethyl (E)-3-(benzo[d-amino-7-yl)acrylate (pale yellow oil, 150 mg, yield 55%). MS m / z (ESI): 218.5 [M+H] +Step 3: Ethyl (E)-3-(benzo[d]oxazolidin-7-yl)propanoate (100 mg, 0.46 mmol) was added to a 25 mL single-necked reaction flask. Ethyl acetate (10 mL) and 10% Pd / C (wet 8, 10 mg) were then added. After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 3-(benzo[d]oxazolidin-7-yl)propanoate (crude product, 100 mg, 99% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 220.4 [M+H] + Step 4: Preparation of 3-(Benzo[d-azole-7-yl)propan-1-ol: Refer to the synthesis method of Step 3 of Example 3. Ethyl 3-(Benzo[d-azole-7-yl)propanoate (50 mg, 0.23 mmol) was added to a 25 mL three-necked reaction flask, followed by anhydrous tetrahydrofuran (3 mL). Lithium aluminum tetrahydride (17 mg, 0.46 mmol) was added portionwise under nitrogen and an ice-water bath, and the reaction was stirred under ice-water bath for 1 h. After the reaction was completed, the reaction solution was quenched by slowly adding Na2SO4.10H2O, filtered, and the filter cake was washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified and separated by normal phase column chromatography (eluent gradient: 40% EA / PE) to obtain compound 3-(benzo[d]oxazolidinone-7-yl)propane-1-ol (colorless oil, 25 mg, yield 62%). MS m / z (ESI): 178.4 [M+H] +Step 5: Compound 3-(Benzo[d]Bm-7-yl)propan-1-ol (10 mg, 0.06 mmol), triethylamine (12 mg, 0.12 mmol) and anhydrous dichloromethane (3 mL) were added to a 10 mL single-necked reaction flask. Methanesulfonic acid tincture (12 mg, 0.07 mmol) was added under ice-water bath. After the addition, the mixture was allowed to stir at room temperature for 3 h. After the reaction was completed by LCMS, saturated chromium chloride solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase purification (eluent gradient: 30% EA / PE) to obtain compound 3-(Benzo[d]Bm-7-yl)propyl methanesulfonate (pale yellow oil, 8 mg, yield 60%). Step 6: Add compound 3-(benzo[d-pyrazol-7-yl)propyl methanesulfonate (8 mg, 0.03 mmol, crude) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3 / :4,5]pyrrolo[1,2, 3-de]benzothiazolin (8 mg, 0.04 mmol) to a 10 mL reaction bottle, followed by addition of DIEA (11 mg, 0.09 mmol) and anhydrous DMSO (1 mL). After the addition, heat to 60 °C and stir for 6 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water+0.05% NH4HCO3)) to obtain compound 7-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3 / :4,5]pyrrolo[1,2,3-de]oxathiapiprolin-8(7H)-yl)propyl)benzo[d-piperidin-8(7H)-yl)propyl)benzo[d-piperidin-8(7H)-yl)propyl)benzo[d-piperidin-8(7H)-yl)propyl)benzo[d-piperidin-8(7H)-yl)propyl] ... XH NMR (500 MHz, CDCL) S 8.08 (s, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.29 (d, J= 7.6 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 6.65 (t, ■7= 7.6 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 7.8 Hz, 1H), 3.58 (dd, J = 14.7, 6.5 Hz, 1H), 3.33- 3.14 (m, 4H), 2.93 (t,J= 7.6 Hz, 3H), 2.87-2.78 (m, 4H), 2.78-2.64 (m, 1H), 2.52-2.26 (m, 3H), 2.06-1.96 (m, 5H). MS m / z (ESI): 389.7[M+H] + Example 8: (6bR,10aS)-3-methyl-8-(3-(oxazolidin-8-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxazolidin-8-yl)-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxazolidin-8-yl

[0072] Step 1: Compound 8-bromobenzothiazolidine (500 mg, 2.40 mmol), ethyl acrylate (480 mg, 4.80 mmol), Pd(PPh3)2Cl2 (17 mg, 0.02 mmol), and triethylamine (730 mg, 7.20 mmol) were added to a 25 mL single-necked reaction flask, followed by the addition of anhydrous DMF (8 mL). After the addition, the atmosphere was replaced with nitrogen three times, and the temperature was slowly raised to 120°C with stirring for 16 h. After the reaction was completed, LCMS analysis revealed that water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 5% EA / PE) to obtain ethyl (E)-3-(oxazolidin-8-yl)acrylate (reddish-brown oil, 350 mg, 64% yield). MS m / z (ESI): 228.4 [M+H] +Step 2: Ethyl (E)-3-(benzophenone-8-yl)propanoate (100 mg, 0.44 mmol) was added to a 25 mL single-necked reaction flask. Ethyl acetate (10 mL) and 10% Pd / C (wet basis, 10 mg) were then added, respectively. After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 3-(benzophenone-8-yl)propanoate (crude product, 100 mg, 99% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 230.4 [M+H] + Step 3: Ethyl 3-(benzophenone-8-yl)propionate (100 mg, 0.44 mmol) was added to a 25 mL three-necked reaction flask, followed by the addition of anhydrous tetrahydrofuran (5 mL). Lithium aluminum tetrahydride (33 mg, 0.88 mmol, 1 mol / L) was added in portions under nitrogen and an ice-water bath. The reaction was stirred for 0.5 h under an ice-water bath. After the reaction was completed, Na2SO4.10H2O was slowly added to the reaction solution to quench the mixture. The mixture was filtered, and the filter cake was washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified and separated by normal phase column chromatography (eluent gradient: 30% EA / PE) to obtain compound 3-(benzophenone-8-yl)propan-1-ol (colorless oil, 60 mg, yield 74%). MS m / z (ESI): 188.4 [M+H] + Step 4: Compound 3-(benzothiazolin-8-yl)propan-1-ol (30 mg, 0.16 mmol), pyridinium chloride (65 mg, 0.32 mmol), and anhydrous dichloromethane (3 mL) were added to a 10 mL single-necked reaction flask and stirred at room temperature for 2 h. After completion of the reaction, saturated sodium bicarbonate aqueous solution was added to the reaction solution to an alkaline pH. The mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound 3-(benzothiazolin-8-yl)propanal (a dark brown oil, crude product, 25 mg, 83% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 186.4 [M+H] +Step 5: Add compound 3-(benzothiazolin-8-yl)propanal (25 mg, 0.13 mmol) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin (32 mg, 0.14 mmol) to a 10 mL reaction bottle and stir at room temperature for 0.5 h. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was then added to the reaction solution, and the mixture was stirred at room temperature for 16 h. After the reaction, the reaction solvent was removed under reduced pressure, and the crude product was directly subjected to reverse-phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound (6bR,10aS)-3-methyl-8-(3-(benzothiazolin-8-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]-pyrro[1,2,3-de]benzothiazolin (off-white solid, 6.0 mg, yield 18%). ENMR (500 MHz, MeOD). 8.86 (dd, ■7= 4.2, 1.8 Hz, 1H), 8.29 (dd, ■7= 8.3, 1.7 Hz, 1H), 7.77 (dd = 8.2, 1.3 Hz, 1H), 7.62 (d, J= 7.0 Hz, 1H), 7.54-7.46 (m, 2H), 6.64-6.55 (m, 1H), 6.47 (d, J = 7.2 Hz, 1H), 6.40 (d, J= 7.9 Hz, 1H), 3.49 (ddd, J= 11.4, 10.1, 2.9 Hz, 1H), 3.36-3.32 (m, 1H), 3.29-3.25 (m, 1H), 3.25-3.21 (m, 2H), 3.14-3.05 (m, 2H), 2.92- 2.87 (m, 1H), 2.82 (s, 3H), 2.78-2.70 (m, 2H), 2.54-2.44 (m, 2H), 2.31 (td, J = 12.1, 3.0 Hz, 1H), 2.05-1.86 (m, 5H). MS m / z (ESI): 399.9[M+H] +Example 9: (6bR,10aS)-8-(3-isoquinolin-8-propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]quinolin-1H-ol 59.54 (s, 1H), 8.51 (d = 5.6 Hz, 1H), 7.87-7.76 (m, 2H), 7.69 (dd, = 8.2, 7.0 Hz, 1H), 7.51 (dd, = 7.0, 1.1 Hz, 1H), 6.51 (t, J= 7.6 Hz, 1H), 6.42 (d = 7.2 Hz, 1H), 6.33 (d = 7.9 Hz, 1H), 3.45-3.40 (m, 1H), 3.27 (dd = 11.5, 2.9 Hz, 3H), 3.19 (dd, J= 8.6, 6.6 Hz, 2H), 3.13 (s, 1H), 3.05 (s, 1H), 2.78 (s, 3H), 2.71-2.55 (m, 2H), 2.45-2.22 (m, 2H), 2.09 (d, J = 21.6 Hz, 1H), 1.84 (d, J = 29.7 Hz, 5H). MS m / z (ESI): 399.9[M+H] + . Step 1: Compound 5-bromo-3, 4-dihydro-2H-benzo[b][1, 4]oxazine (420 mg, 2.0 mmol) was dissolved in DMF (10.0 mL). Under nitrogen protection, triethylamine (1.6 g, 16.0 mmol), ethyl acrylate (300 mg, 1.5 mmol), o-trimethylphenylphosphine (120 mg, 0.4 mmol) and succinyl acetate (44 mg, 0.2 mmol) were added sequentially. The mixture was stirred at 100 °C for 3 h. After TLC detection, the reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase to obtain compound (E)-3-(3, 4-dihydro-2H-benzo[b][l, 4]oxazin-5-yl) ethyl acrylate (yellow oil, 230 mg, yield 49%). MS m / z (ESI): 234.3.[M+H] +Step 2: Dissolve (E)-3-(3, 4-dihydro-2H-benzo[b][l, 4]oxazin-5-yl)ethyl acrylate (190 mg, 0.81 mmol) in DCM (20.0 mL), add TEA (800 mg, 8.0 mmol) and then (Boc)2O (700 mg, 3.2 mmol), stir at 20°C for 16 h, concentrate under reduced pressure, and purify by normal phase to obtain (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2, 3-dihydro-4H-benzo[b][l, 4]oxazin-4-yl)tert-butyl ester (yellow oil, 180 mg, yield 67%). MS m / z (ESI): 334.4.[M+H] + Step 3: Dissolve (E)-5-(3-ethoxy-3-oxopropyl-1-en-1-yl)-2,3-dihydro-4H-benzo[b][l,4]oxazine-4-carboxylic acid tert-butyl ester in MeOH (10.0 mL). Add 10% nitrocarbon (90 mg). Stir at room temperature for 18 hours. Filter and concentrate to obtain 5-(3-ethoxy-3-oxopropyl)-2,3-dihydro-4H-benzo[b][l,4]oxazine-4-carboxylic acid tert-butyl ester (yellow oil, 160 mg, 88% yield). MS m / z (ESI): 336.4. [M+H] + Step 4: Dissolve tert-butyl 5-(3-ethoxy-3-oxopropyl)-2, 3-dihydro-4H-benzo[b][1, 4]oxazine-4-carboxylate (145 mg, 0.43 mmol) in THF (2.0 mL), cool to 0 °C, add lithium aluminum tetrahydride solution (0.45 mL, 0.15 mmol), and heat to 20 °C with stirring for 1 h. Dry with sodium sulfate decahydrate, filter, and purify by normal phase chromatography to obtain tert-butyl 5-(3-hydroxypropyl)-2, 3-dihydro-4H-benzo[b][1, 4]oxazine-4-carboxylate (yellow oil, 85 mg, yield 67%). MS m / z (ESI): 294.3.[M+H] +Step 5: Dissolve tert-butyl 5-(3-hydroxypropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-olate (85 mg, 0.29 mmol) in DCM (5.0 mL), add PCC (128 mg, 0.59 mmol), and stir for 3 h at 20 °C. Quench with saturated sodium bicarbonate, extract with DCM, dry over sodium sulfate, and filter and concentrate to obtain tert-butyl 5-(3-hydroxypropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-olate (colorless oil, 66 mg, 80% yield), which was used directly in the next reaction. MS m / z (ESI): 292.4. [M+H] + Step 6: (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathiocarbamate (62 mg, 0.27 mmol) and tert-butyl 5-(3-oxopropyl)-2, 3-dihydro-4H-benzo[b][l, 4]oxazine-4-oxazineate (66 mg, 0.23 mmol) were dissolved in DCM (3.0 mL). 5 mg each of triethylamine and acetic acid were added. After stirring for 10 min, sodium triacetoxyborohydride (230 mg, 4.0 mmol) was added. The mixture was stirred at 20 °C for 18 h, quenched by the addition of water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The intermediate was purified by normal phase chromatography and dissolved in DCM (3.0 mL). TFA (0.3 mL, 1.1 mmol) was added and stirred at room temperature for 0.5 h. After concentration, the product was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound (6bR,10aS)-3-methyl-8-(3-(1,2,3,4-tetrahydroquinolin-8-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]quinolin-1H-ol (off-white solid, 8.0 mg, yield 9%). XH NMR (500 MHz, CD3OD) 5 6.61-6.59 (m, 2H), 6.57-6.49 (m, 3H), 7.00 (d, J= 5.0 Hz, 1H), 4.15 (t, J= 5.0 Hz, 2H), 3.54-3.48 (m, 1H), 3.37 (t, J= 5.0 Hz, 3H), 3.23-3.16 (m, 2H), 3.06-3.00 (m, 1H), 2.93-2.88 (m, 1H), 2.84 (s, 3H), 2.79-2.72 (m, 1H), 2.57-2.47 (m, 5H), 2.17-2.07 (m, 2H) , 2.00-1.84 (m, 3H). MS m / z (ESI): 405.8[M+H] + Example 11: (6bR,10aS)-8-(3-(1H'indol-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathiocarbamate Step 1: 1H-indole-7-carboxaldehyde (500.0 mg, 3.44 mmol) and triphenylphosphinoyl methyl acetate (1.4 g, 4.13 mmol) were dissolved in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. 80 mL of water was added to the reaction solution and the mixture was washed with DCM (70 mL).

[0073] The organic phases were combined and concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 100 / 0-90 / 10) to obtain methyl

[0074] (E)-3-(1H-indol-7-yl)acryloyl ester (580 mg, yield: 83.7%) as a yellow solid. MS m / z (ESI): 202.1 [M+H] +Step 2: Methyl (E)-3-(1H-indol-7-yl)acryloyl ester (480.0 mg, 2.39 mmol) was added to methanol (5 mL) and 10% charcoal (101.5 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol to obtain methyl 3-(1H-indol-7-yl)propanoate (450 mg, 92.8% yield) as a gray solid. MS m / z (ESI): 204.1 [M+H] + Step 3: Methyl 3-(1H-indol-7-yl)propanoate (450.0 mg, 2.21 mmol) was added to methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature, and sodium borohydride (418.8 mg, 11.07 mmol) was added. The reaction solution was stirred at room temperature under nitrogen atmosphere for 16 hours. After completion of the reaction, excess methanol was added to quench the reaction, and the mixture was concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 0-60 / 40) to obtain 3-(1H-indol-7-yl)propan-1-ol (380 mg, yield: 97.9%) as a light yellow oil. MS m / z (ESI): 176.2 [M+H] + Step 4: At room temperature, 3-(1H-indol-7-yl)propan-1-ol (50.0 mg, 0.29 mmol) and carbon tetrabromide (141.9 mg, 0.43 mmol) were dissolved in dichloromethane (10 mL). Triphenylphosphine (112.2 mg, 0.43 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 0-90 / 10) to give 7-(3-bromopropyl)-1H-indole (40 mg, 58.9% yield) as a clear oil. MS m / z (ESI): 238.1 [M+H] +Step 5: Dissolve 7-(3-bromopropyl)-1H-indole (40.5 mg, 0.17 mmol) in 1,4-dioxane / toluene (1.5 mL / 1.5 mL). Add (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin (39.0 mg, 0.17 mmol), potassium iodide (56.4 mg, 0.34 mmol), and triethylamine (51.6 mg, 0.51 mmol). The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was prepared to give (6bR,10aS)-8-(3-(1H-naphthene-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin (13.51 mg, yield 20.16%) as a light yellow solid. E NMR (400 MHZ, CDC13) 5 10.85 (s, 1H), 7.52 (dd, J= 7.8, 0.8 Hz, 1H), 7.22 (d, J= 2.9 Hz, 1H), 7.06-7.01 (m, 1H), 6.96 (d, J= 6.8 Hz, 1H), 6.68 (t, J= 7.6 Hz, 1H), 6.55 (dd, J= 6.6, 5.4 Hz, 2H), 6.43 (d, J= 7.8 Hz, 1H), 3.64-3.58 (m, 1H), 3.39-3.28 (m, 4H), 3.04-2.96 (m, 3H), 2.92-2.86 (m, 4H), 2.78 (s, 1H), 2.41-2.38 (m, 3H), 2.11-2.07 (m, 3H), 2.02-1.97 (m, 2H). MS m / z (ESI): 387.3 [M+H] + Example 12: (6bR,10aS)-8-(3-(dihydroindole-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate At room temperature, (6bR,10aS)-8-(3-(1H-indol-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathioline (55.0 mg, 0.14 mmol) was dissolved in acetic acid (3 mL), and sodium acetate borohydride (13.4 mg, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated in vacuo, added to 10 mL of water, and sodium hydroxide solution was added dropwise to adjust the pH to 8. The mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL x 3) to obtain a crude product. The crude product was subjected to preparative purification to obtain (6bR,10aS)-8-(3-(dihydroindol-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathioline.

[0145] The product of 1,2-dimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3'-:4,5]pyrrolo[1,2,3-de]benzothiazolin carboxylate (14.04 mg, 24.2% yield) was obtained as a brown solid. X H NMR (400 MHz, CDC13) 58.50 (s, 1H), 6.99 (d, J= 7.2 Hz, 1H), 6.78 (d, J= 7.5 Hz, 1H), 6.69 (t, J = 7.7 Hz, 1H), 6.63 (t, J= 7.4 Hz, 1H), 6.52 (d, J = 7.4 Hz, 1H), 6.43 (d, J= 8.0 Hz, 1H), 3.65-3.50 (m, 4H), 3.41 (dd, J= 11.8, 6.2 Hz, 1H), 3.36-3.24 (m, 4H),

[0075] 3.03 (t, J = 8.4 Hz, 2H), 2.95-2.78 (m, 7H), 2.56 (t, J = 7.3 Hz, 2H), 2.39-2.34 (m, 2H), 2.09-2.03 (m, 3H). MS m / z (ESI): 389.3 [M+H] + Example 13: (6bR,10aS)-8-(3-(3-methoxypyridinyl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, [3',4':4,5]<[1,2,3 -take off]Chaohkoulin Step 1: 3-Fluoro-4-nitropyridine 1-oxide (5 g, 31.6 mmol) was dissolved in anhydrous methanol (55 mL) at room temperature. 5.4 M sodium methoxide in methanol (5.9 mL, 31.6 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and diluted with water (80 mL). The aqueous phase was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 3-methoxy-4-nitropyridine 1-oxide (5 g, yield: 77.8%) as a light yellow solid. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 171.1 [M+H] + Step 2: 3-Methoxy-4-nitropyridine 1-oxide (5.0 g, 29.4 mmol) was dissolved in ethyl acetate (50 mL) at room temperature, and phosphorus tribromide (22.1 mL, 235.2 mmol) was added dropwise. After stirring at room temperature for 10 minutes, the temperature was raised to 80°C and stirred at this temperature for 16 h. The reaction solution was cooled to room temperature and added dropwise to ice water. After extraction with ethyl acetate, the aqueous phase was adjusted to pH = 11 with 10 M aqueous NaOH and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-15%) to afford 4-bromo-3-methoxypyridine (470 mg, yield: 8.5%) as a brown solid. MS m / z (ESI): 188.1 [M+H] +Step 3: At room temperature, DMF (5 mL) was added to a reaction flask containing 4-bromo-3-methoxypyridinium chloride (470 mg, 2.5 mmol), ethyl acrylate (860.79 mg, 9.99 mmol), triethylamine (56.62 g, 0.25 mmol), triethylamine (2.53 g, 25.0 mmol), and tri-o-methylphenylphosphine (228.25 mg, 0.75 mmol). The reaction flask was purged with nitrogen three times, heated to 100°C, and stirred under nitrogen for 18 h. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-20%) to afford ethyl 3-(3-methoxypyridin-4-yl)acrylate (300 mg, yield: 60.3%) as a light yellow solid. MS m / z (ESI): 208.1 [M+H] + Step 4: Ethyl 3-(3-methoxypyridin-4-yl) acryloyl ester (270 mg, 14.5 mmol) was dissolved in methanol (5 mL) at room temperature, and 10% wet chloroform (69 mg, 0.65 mmol) was added. The reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with methanol, and the filtrates were combined and concentrated under vacuum to afford ethyl 3-(3-methoxypyridin-4-yl) propionate (50 mg, yield: 87.6%) as a yellow oil. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 210.1 [M+H] + Step 5: Ethyl 3-(3-methoxypyridin-4-yl)propionate (200.0 mg, 0.96 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at room temperature. The temperature was lowered to 0°C, and a 1M solution of lithium aluminum hydride in tetrahydrofuran (2.4 mL, 2.39 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with tetrahydrofuran, quenched with sodium sulfate decahydrate under an ice bath, and filtered through Celite. The filter cake was sonicated with methanol and filtered again. The combined filtrates were concentrated in vacuo to yield 3-(3-methoxypyridin-4-yl)propan-1-ol (160 mg, theoretical amount) as a yellow oil. MS m / z (ESI): 168.2 [M+H] +Step 6: Dissolve 3-(3-methoxypyridin-4-yl)propan-1-ol (130.0 mg, 0.78 mmol) and triethylamine (236.0 mg, 2.33 mmol) in anhydrous DCM (1.5 mL) at room temperature, and add a solution of MsCl (133.59 mg, 1.17 mmol) in DCM (0.5 mL) dropwise. The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is concentrated in vacuo to afford 3-(3-methoxypyridin-4-yl)propyl methanesulfonate (191 mg, theoretical amount) as a white solid. MS m / z (ESI): 246.1 [M+H] +Step 7: (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin (90.0 mg, 0.30 mmol), 3-(3-methoxypyrido-4-yl)propyl methanesulfonate (192.6 mg, 0.78 mmol) and potassium iodide (130.2 mg, 0.78 mmol) were dissolved in anhydrous 1, 4-dioxane (1.5 mL) and anhydrous toluene (1.5 mL) at room temperature, and triethylamine (238.3 mg, 2.36 mmol) was added. The reaction solution was stirred at 100 °C for 22 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford a crude product. The crude product was purified by formic acid preparative treatment to afford (6bR,10aS)-8-(3-(3-methoxypyridin-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]oxathiolin formate (6.53 mg, 3.8% yield) as a yellow oil. ENMR(400 MHz, CDC13) 5 8.41 (S, 1H), 8.19 (S, 1H), 8.16 (d, J = 4.7 HZ, 1H), 7.06 (d, J= 4.8 Hz, 1H), 6.69 (t, J = 7.7 Hz, 1H), 6.52 (d, J= 7.4 Hz, 1H), 6.43 (d, J= 7.9 Hz, 1H), 3.9O (s, 3H), 3.62-3.49 (m, 2H), 3.37 (dd, J= 11.6, 6.7 Hz, 1H), 3.28 (d, J= 9.4 Hz, 4H), 2.87-2.78 (m, 6H), 2.68-2.63 (m, 2H), 2.36 (s, 2H), 2.08-2.02 (m, 4H). MS m / z (ESI): 379.2 [M+H] + Example 14: (6bR,10aS)-8-(3-(2-methoxypyridin-3-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-2-yl) ... Step 1: To a reaction flask containing 3-bromo-2-methoxypyridinium chloride (5 g, 26.6 mmol), ethyl acrylate (10.65 g, 106.4 mmol), triethylamine (0.6 g, 2.66 mmol), triethylamine (26.92 g, 266 mmol), and tri-o-tolylphosphine (2.43 g, 7.98 mmol) was added DMF (100 mL) at room temperature. The reaction flask was purged with nitrogen three times, heated to 100°C, and stirred under nitrogen for 20 h. The reaction solution was cooled to room temperature and filtered through celite. The filtrate was diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-6%) to give ethyl (E)-3-(2-methoxypyridin-3-yl)acrylate (4 g, yield: 71.8%) as a light yellow oil. MS m / z (ESI): 208.1 [M+H] + Step 2: Ethyl (E)-3-(2-methoxypyridin-3-yl) acrylate (3 g, 14.5 mmol) was dissolved in methanol (30 mL) at room temperature, and 10% wet diatomaceous carbon (770 mg, 0.725 mmol) was added. The reaction mixture was stirred at room temperature for 7 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with methanol, and the filtrates were combined and concentrated in vacuo to afford ethyl 3-(2-methoxypyridin-3-yl) propionate (3 g, yield: 98.6%) as a colorless viscous oil. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 210.1 [M+H] +Step 3: Ethyl 3-(2-methoxypyridin-3-yl) propionate (1 g, 4.8 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. The temperature was lowered to 0°C, and a 1M solution of lithium aluminum hydride in tetrahydrofuran (12 mL, 12 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with tetrahydrofuran, quenched with sodium sulfate decahydrate in an ice bath, and filtered through celite. The filter cake was sonicated with methanol and filtered again. The combined filtrates were concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-18%) to obtain 3-(2-methoxypyridin-3-yl)propan-1-ol (705 mg, yield: 87.5%) as a colorless viscous oil. MS m / z (ESI): 168.2 [M+H] + Step 4: Dissolve 3-(2-methoxypyridin-3-yl)propan-1-ol (200 mg, 1.196 mmol) in anhydrous DCM (2 mL) at room temperature. Add dichloromethane (398.4 mg, 3.35 mmol) dropwise under ice. Stir the reaction mixture at room temperature for 1 h. Concentrate the mixture in vacuo to afford 3-(3-chloropropyl)-2-methoxypyridin-3-yl)propan-1-ol (220 mg, theoretical amount) as a white solid. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 186.1 [M+H] +Step 5: (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin (68 mg, 0.296 mmol), 3-(3-chloropropyl)-2-methoxypyrrole (110.09 mg, 0.593 mmol) and potassium iodide (98.36 mg, 0.593 mmol) were dissolved in anhydrous 1,4-dioxane (1.5 mL) and anhydrous toluene (1.5 mL) at room temperature, and triethylamine (180.02 mg, 1.779 mmol) was added. The reaction solution was stirred at 100°C for 22 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to yield a crude product. The crude product was purified by alkaline preparative method to afford rJ(6bR,10aS)-8-(3-(2-methoxypyridin-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyridin-3',4':4,5]pyrrolido[1,2,3-deoxy]benzothiazolin (12.10 g, 10.7% yield) as a yellow oil. 8.01 (dd, J= 5.0, 1.7 Hz, 1H), 7.38 (d, J= 5.8 Hz, 1H), 6.80 (dd, J= 7.1, 5.1 Hz, 1H), 6.65 (t, J= 7.6 Hz, 1H), 6.51 (d, J= 7.3 Hz, 1H), 6.41 (d, J= 7.9 Hz, 1H), 3.93 (s, 3H), 3.59 (dd, J= 14.9, 6.3 Hz, 1H), 3.46-3.00 (m, 5H), 2.91-2.69 (m, 6H), 2.58 (t, J= 7.6 Hz, 2H), 2.47-2.18 (m, 3H), 1.89-1.83 (m, 4H). MS m / z (ESI): 379.2 [M+H] + Example 15: (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-3', 4': 4, 5]pyrrolido[1, 2, 3-deoxy]oxazolidinone Step 1: Add 3-(4-methoxypyridin-3-yl)propan-2-ol (150 mg, 0.92 mmol) to a 50 mL three-necked reaction flask, followed by methanol (10 mL) and carbon-wetted (10%, 50 mg). The mixture was then heated to 60°C and stirred for 4 hours under a hydrogen atmosphere. After completion of the reaction, as determined by LCMS, the reaction mixture was filtered, concentrated, and purified by column chromatography (DCM:MeOH = 3:1) to afford the title compound, 3-(4-methoxypyridin-3-yl)propan-1-ol (colorless liquid, 80 mg, 80% yield). MS m / z (ESI): 168.4 [M+H] + Step 2: Preparation of 3-(4-methoxypyridin-3-yl)propyl methanesulfonate was carried out according to the synthesis method of the third step of Example 3. Step 3: Preparation of (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-3', 4': 4, 5] pyrrolido[1,2, 3-de]oxazolidinone was carried out according to the synthesis method of the fourth step of Example 3. 5 8.30 (d, J= 5.6 Hz, 1H), 8.20 (s, 1H), 6.98 (d, J= 5.6 Hz, 1H), 6.51 (t, J= 7.6 Hz, 1H), 6.42 (d, J= 7.2 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.45-3.39 (m, 1H), 3.31-3.25 (m, 2H), 3.11 (s, 1H), 3.02 (s, 1H),

[0076] 2.78 (s, 4H), 2.67-2.63 (m, 1H), 2.53-.2.49 (m, 3H), 2.18-2.10 (m, 2H), 2.03-1.85 (m, 2H), 1.81-1.61 (m, 4H). MS m / z (ESI): 379.6 [M+H] + Example 16: (6bR,10aS)-8-(3-(3-methoxypyridin-2-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-1H-[3',4':4,5]pyrrolido[1,2,3-de]oxathiocarbamate

[0077] (dd, J = 8.3, 1.3 Hz, 1H), 7.18 (dd, J = 8.2, 4.7 Hz, 1H), 6.54-6.46 (m, 1H), 6.41 (dd, J = 7.3, 0.9 Hz, 1H),

[0078] 6.32 (dd, J= 8.0, 1.0 Hz, 1H), 3.80 (s, 3H), 3.44-3.39 (m, 1H), 3.29 (m, 2H), 3.09 (m, 1H), 2.98 (m, 1H), 2.77

[0079] (s, 3H), 2.76-2.64 (m, 4H), 2.60-2.54 (m, 1H), 2.27 (m, 2H), 2.06 (m, 1H), 1.92-1.85 (m, 1H), 1.80-1.70 (m,

[0080] 4H). MS m / z (ESI): 379.8 [M+H] + Example 17: Preparation of (6bR,10aS)-8-((E)-3-(2-methoxypyridin-3-yl)allyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-1H-[3',4':4,5]pyrrolido[1,2,3-de]oxazolidinone Step 1: Ethyl (E)-3-(2-methoxypyridin-3-yl) acryloyl ester (800.0 mg, 3.82 mmol) was dissolved in dichloromethane (10 mL) at room temperature. The temperature was lowered to 0°C, and a 1M solution of diisobutylaluminum hydride (7.6 mL, 7.65 mmol) in THF was added dropwise. The reaction mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction mixture was diluted with dichloromethane and quenched by the dropwise addition of saturated chromium chloride solution under an ice bath. The mixture was diluted with 40 mL of water and extracted with dichloromethane (40 mL x 3). The organic phases were combined and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-18%) to obtain (E)-3-(2-methoxypyridin-3-yl)prop-2-en-1-ol (437 mg, yield: 69.3%). It is a light yellow oil. MS m / z (ESI): 166.2 [M+H] +Step 2: (E)-3-(2-methoxypyridin-3-yl)prop-2-en-1-ol (100 mg, 0.60 mmol) was dissolved in anhydrous DCM (3 mL) at room temperature. SOCl2 (144 mg, 1.21 mmol) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford (E)-3-(3-chloroprop-1-en-1-yl)-2-methoxypyridin-1-ol (400 mg, theoretical amount) as a white solid. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 184.1 [M+H] + Step 3: At room temperature, (E)-3-(3-chloroprop-1-en-1-yl)-2-methoxypyridine (112.1 mg, 0.61 mmol) was dissolved in 1,4-dioxane / toluene (1.5 mL / 1.5 mL). (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]pyrrolidine (70.0 mg, 0.30 mmol), potassium iodide (101 mg, 0.61 mmol), and triethylamine (185.3 mg, 1.83 mmol) were added. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified by alkaline preparation to give (6bR,10aS)-8-((E)-3-(2-methoxypyrrole-3-yl)allyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrole[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin (26.15 mg, yield: 22.5%) as a yellow solid. 5 8.05 (dd,

[0081] J = 4.9, 1.7 Hz, 1H), 7.67 (d = 6.4 Hz, 1H), 6.86 (dd, = 7.3, 5.0 Hz, 1H), 6.70-6.62 (m, 2H), 6.52 (d, = 6.8 Hz, 1H), 6.41 (d, = 7.6 Hz, 2H), 3.97 (s, 3H), 3.58-3.61 (m, 1H), 3.35-3.28 (m, 6H), 2.96 (s, 1H), 2.88- 2.73 (m, 5H), 2.30 (s, 1H), 1.97 (s, 3H). MS m / z (ESI): 377.2[M+H] + Example 18: (6bR,10aS)-8-(2-(2-methoxyphenoxy)ethyl)-3-methyl-2,3- Preparation of [3',4':4,5]<pyro[1,2,3-de]oxathiapiprolin At room temperature, (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (23 mg, 0.1 mmol) was dissolved in DMSO (2.5 mL), and DIEA (0.5 mL, 3.0 mmol) and 1-(2-bromoethoxy)-2-methoxybenzene (23 mg, 0.1 mmol) were added sequentially. The mixture was heated to 65 °C and stirred for 18 h. The mixture was cooled to room temperature and filtered. The mixture was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound (6bR,10aS)-8-(2-(2 8-(2-(2-(2-methoxyphenoxy)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (yellow solid, 10.2 mg, yield 27%). H NMR (500 MHz, CD3OD) δ 7.09-6.90 (m, 4H), 6.88-6.57 (m, 3H), 4.41 (t, J = 5.0 Hz, 1H),

[0082] 3.75-3.69 (m, 4H), 3.55-3.46 (m, 8H), 3.39-3.21 (m, 2H), 2.86 (s, 3H), 2.82-2.77 (m, 2H), 2.35-2.24 (m, 2H) O

[0083] MS m / z (ESI): 380.8[M+H] + Example 19: 2-Methoxy-N-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[3 ...

[0084] [1,2,3-deoxy]benzothiazolinone (8(7H)-yl)ethyl)aniline Step 1: Dissolve 2-methoxyaniline (505 mg, 2.0 mmol) and dibromoethane (1.104 g, 6.0 mmol) in DMF (5.0 mL) and stir at 60 °C for 3 h. After completion of the reaction, water was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by normal phase afforded 1-(2-bromoethoxy)-2-methoxybenzene (yellow solid, 115 mg, 25% yield). MS m / z (ESI): 232.3. [M+H] +Step 2: The synthesis of 2-methoxy-N-(2-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1,2, 3-de]oxathiapa 8(7H)-yl)ethyl)aniline was carried out according to the synthesis method of the fourth step of Example 3. g NMR (500 MHz, CD3OD) 5 6.81-6.77 (m, 2H), 6.59-6.50 (m, 3H), 6.44-6.42 (m, 1H), 6.35-6.33 (m, 1H), 4.78 (brs, 1H), 3.77 (s, 3H), 3.47- 3.42 (m, 1H), 3.32-3.26 (m, 3H), 3.15-3.05 (m, 4H), 2.79-2.75 (m, 4H), 2.72-2.55 (m, 3H), 2.26-2.24 (m, 1H), 1.98-1.75 (m, 3H)o MS m / z (ESI): 379.9[M+H] + Example 20: N-(2-methoxyphenyl)-2-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1, 2, 3-de]oxathiazolinone 8(7H)-acetamide Compound (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,,4,:4,5]pyrrolo[1,2, 3-de]oxathioline (25 mg, 0.11 mmol), 2-chloro-N-(2-methoxyphenyl)acetamide (22 mg, 0.11 mmol), DIEA (78 mg, 0.60 mmol) and sodium iodide (17 mg, 0.11 mmol) were dissolved in DMSO (3 mL) and heated at 60. The reaction mixture was filtered and subjected to reverse phase purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and the mixture was lyophilized to obtain the compound N-(2-methoxyphenyl)-2-(6bR, 10aS)-3-g-2,3,6b,9,10,10a-hexahydro-1H-pyrrolo[3 / :4,5]pyrrolo[1,2,3-de]oxathiazopa 8(7H)-acetamide (pale yellow solid, 20 mg, yield 46%). H NMR (C80 MHz, DMSO) 59.78 (s, 1H), 8.29-8.11 (m, 1H), 7.09-7.03 (m, 2H), 6.93 (m, 1H), 6.51 (t, J = 7.6 Hz, 1H), 6.43 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.45 (m, 1H), 3.36 (m, 1H), 3.29 (m, 1H), 3.24-3.18 (m, 1H), 3.16-3.11 (m, 1H), 3.09 (s, 2H), 2.84 (m, 1H), 2.79 (s, 3H), 2.71 (m, 1H), 2.62 (d, J = 11.4 Hz, 1H), 2.41 (m, 1H), 2.11 (t, J = 11.0 Hz, 1H), 2.01 (dd, J = 14.5, 2.8 Hz, 1H), 1.88 (m, 1H). MS m / z (ESI): 393.6[M+H] +Example 21: 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiolin-8(7H)-yl)-1-(pyrido-4-yl)propan-1-one Step 1: Ethyl 3-hydroxy-3-(pyridin-4-yl)propanoate (300 mg, 1.55 mmol) was added to a 50 mL three-necked reaction flask. THF (5 mL) was then added. LiHMDS (1.7 mL, 1 mol / L) was slowly added dropwise at -78 °C. The reaction was stirred at 0 °C for 0.5 h. Lithium aluminum tetrahydride (3.1 mL, 1 mol / L) was then slowly added dropwise at 0 °C. The temperature was slowly raised to 0 °C and the reaction was stirred for 1 h. The reaction solution was quenched with saturated aqueous chromium chloride solution, extracted with dichloromethane (2 x 50 mL), concentrated, and filtered to afford 1-(pyridin-4-yl)propane-1,3-diol (yellow liquid, 200 mg, 84.0% yield). MS m / z (ESI): 154.0 [M+H] + Step 2: 1-(Pyridin-4-yl)propane-1,3-diol (200 mg, 1.3 mmol) was added to a 100 mL reaction flask, followed by dichloromethane (20 mL) and MnO2 (568 mg, 6.5 mmol) and stirred at 40°C for 4 h. The reaction mixture was filtered, concentrated, and purified by reverse-phase column chromatography to afford 3-hydroxy-1-(pyridin-4-yl)propan-1-one (colorless solid, 100 mg, 50.1% yield). MS m / z (ESI): 152.1 [M+H] +Step 3: The preparation of 3-residue-3-(pyrido-4-yl)propyl methanesulfonate was carried out according to the synthesis method of the third step of Example 3. Step 4: The preparation of 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiolin-8(7H)-yl)-1-(pyrido-4-yl)propan-1-one was carried out according to the synthesis method of the fourth step of Example 3. iHNMR(500 MHz, CD30D) 5 8.90 (d, J = 6.0 Hz, 2H), 7.98 (t, J =8.0 Hz, 2H), 6.63 (t, J = 7.6 Hz, 1H), 6.52 (dd, J = 32.8, 7.6 Hz, 2H),

[0085] 3.75 (d, J = 7.2 Hz, 4H), 3.28-3.02 (m, 7H), 2.84 (s, 3H), 2.80-2.71 (m, 1H), 2.65 (dd, J = 3.7, 1.8 Hz, 1H),

[0086] 2.33 (dd, J = 45.0, 7.0 Hz, 3H). MS m / z (ESI): 363.6 [M+H] + Example 22: 1-(2-methoxyphenyl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[ Step 1: Dissolve 1-(2-methoxyphenyl)ethane-1-one (500 mg, 3.33 mmol) and paraformaldehyde (200 mg, 6.66 mmol) in tetrahydrofuran (10 mL). Add N,N-diisopropylethylamine trihydrofluoride (716 mg, 3.33 mmol) and TFA (40 mg, 0.33 mmol). Stir at 70°C for 12 h. Add water (80 mL) to the reaction solution, and extract with ethyl acetate (80 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 1-(2-methoxyphenyl)prop-2-en-1-one (yellow solid, 430 mg crude product, 80% yield). MS m / z (ESI): 163.2[M+H] +Step 2: Dissolve 1-(2-methoxyphenyl)prop-2-en-1-one (100 mg, 0.62 mmol) in acetonitrile (5 mL), then add water (67 mg, 3.70 mmol) and chromium trichloride (20 mg, 0.12 mmol) and stir at room temperature for 24 h. Add water (30 mL) to the reaction mixture, and extract with ethyl acetate (30 mL x 2). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated and subjected to reverse phase purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCC>3)). The acetonitrile is removed under reduced pressure, and the product is lyophilized to yield 3-hydroxy-1-(2-methoxyphenyl)propan-1-one (white solid, 10 mg, 9% yield). Step 3: Preparation of 3-(2-methoxyphenyl)-3-oxopropyl methanesulfonate follows the synthetic method described in Step 3 of Example 3. Step 4: The preparation of 1-(2-methoxyphenyl)-3-((6bR,10aS)3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3 / :4,5]pyrrolo[1,2,3-de]oxathiapa8(7H)yl)propan-1-one was carried out according to the synthesis method of the fourth step of Example 3. iHNMR (500 MHz, DMSO) 5 7.58-7.47 (m, 2H), 7.16 (d, J = 8.3 Hz, 1H), 7.05-6.99 (m, 1H), 6.58-6.49 (m, 1H), 6.42 (d, J= 6.9 Hz, 1H), 6.34 (d, J= 8.0 Hz, 1H), 3.87 (s, 3H), 3.46-3.42 (m, 3H), 3.30-3.25 (m, 2H), 3.25-3.14 (m, 2H), 3.10 (s, 2H), 2.98-2.87 (m, 1H), 2.80 (s, 1H), 2.78 (s, 3H), 2.71-2.63 (m, 2H), 2.03-1.89 (m, 2H), 1.87-1.72 (m, 1H). MS m / z (ESI): 392.9[M+H] +Example 23: 1-(2,3-Dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]<pyrro[1,2,3-de]oxathiapa8(7H)-yl)propan-1-one Compound 23-1 (115 mg, 0.5 mmol) was dissolved in EtOH (5 mL), and paraformaldehyde (120 mg, 4.0 mmol) and concentrated hydrochloric acid (0.125 mL, 1.5 mmol) were added. The mixture was heated and stirred under reflux for 16 h. After concentration, the mixture was purified by normal phase column chromatography to obtain compound 1-(2, 3-dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-yl)propan-1-one (gray solid, 45 mg, yield 22%). X H NMR (500 MHz, CD3OD) 5 7.63 (d, J= 5.0 Hz, 1H), 7.43 (d, J= 10.0 Hz, 1H), 6.91 (t, J= 7.5 Hz, 1H), 6.65-6.60 (m, 1H), 6.53-6.49 (m, 1H), 6.43 (d, J= 10.0 Hz, 1H), 4.70 (d, J= 7.5 Hz, 2H), 3.58-3.50 (m, 3H), 3.41-3.34 (m, 2H), 3.29-3.23 (m, 3H), 3.21-3.14 (m, 2H), 3.11- 3.04 (m, 1H), 2.87 (s, 3H), 2.84-2.80 (m, 2H), 2.65-2.58 (m, 2H), 2.22-2.18 (m, 1H), 2.12-2.09 (m, 1H), 2.03- 1.97 (m, 1H). MS m / z (ESI): 404.9[M+H] + Example 24: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1, 2, 3-de]benzothiazolin Step 1: Compound 1-(2, 3-dihydrobenzofuran-7-yl)-3-((6bR, 10aS)-3-methyl-2, 3, 6b, 9, 10, 10aS hexahydro-1H-pyrrolo[3,, 4':4, 5]pyrrolo[1, 2, 3-de]benzofuran-8(7H)-yl)propan-1-one (25 mg, 0.062 mmol) was dissolved in MeOH (2 mL), sodium borohydride (10 mg, 0.26 mmol) was added, and the mixture was stirred at 20 ° C for 1 h and then filtered. Prep-HP LC purification and separation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) was performed to obtain compound 1-(2, 3-dihydrobenzofuran-7-yl)-3-((6bR, 10aS)-3-methyl-2, 3, 6b, 9, 10, 10aS hexahydro-1H-pyrrolo[3,, 4':4, 5]pyrrolo[1, 2, 3-de]benzofuran-8(7H)-yl)propan-1-one -((6bR, 10aS)-3-methyl-2, 3, 6b, 9, 10, 10aS hexahydro-1H-pyrido[3′, 4′:4, 5]pyrrolo[1, 2, 3-de]benzothiazolin-8(7H)-yl)propan-1-ol (off-white solid, 12.5 mg, yield 50%). Step 2: Dissolve compound 1-(2, 3-dihydrobenzofuran-7-yl)-3-((6bR, 10aS)-3-methyl-2, 3, 6b, 9, 10, 10aS hexahydro-1H-pyrido[3′, 4′:4, 5]pyrrolo[1, 2, 3-de]benzothiazolin-8(7H)-yl)propan-1-ol in DCM (2 mL) and cool to 0. To the reaction mixture was added DAST (10 mg, 0.06 mmol) and stirred at 0 °C for 0.5 h. The mixture was quenched by the addition of saturated sodium bicarbonate, extracted with DCM, concentrated, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin (off-white solid, 2.23 mg, yield 18%). XH NMR (500 MHz, CD3OD) 5 7.17 (d, J = 5.0 Hz, 1H), 7.12 (d, J= 5.0 Hz, 1H), 6.85 (t, J= 7.5 Hz, 1H), 6.60 (t, J= 7.5 Hz, 1H), 6.48 (d, J= 5.0 Hz, 1H), 6.42 (d, J = 10.0 Hz, 1H), 5.68-5.59 (m, 2H), 5.25-5.15 (m, 2H), 4.66-4.55 (m, 1H), 3.52-3.48 (m, 1H), 3.34-3.31 (m, 4H), 3.22-3.14 (m, 4H), 2.91-2.73 (m, 5H), 2.67-2.54 (m, 1H), 2.37-2.16 (m, 2H), 2.05-1.93 (m, 2H), MS m / z (ESI): 408.8 [M+H] + Example 25: (6bR,10aS)-8-(2-(2,3-dihydrobenzofuran-3-yl)ethyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3',4':4,5]pyrrolo[1,2, 3-de]oxathiocarbamate Step 1: Compound 2-(benzofuran-3-yl)ethane-1-ol (150 mg, 1.3 mmol) was added to a 50 mL three-necked reaction flask, followed by the addition of methanol (10 mL), wet carbon (10%, 0.1 g), and carbon hydroxide (20%, 0.1 g). The mixture was then heated to 40 °C and stirred for 16 h under a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the title compound 2-(2, 3-dihydrobenzofuran-3-yl)ethane-1-ol (colorless liquid, 0.1 g, yield 66%). Step 2: Preparation of 2-(2, 3-dihydrobenzofuran-3-yl)ethyl methanesulfonate was prepared by referring to the third step of Example 3. Step 3: (6bR,10aS)-8-(2-(2,3 The preparation of (1,2,3-dihydrobenzofuran-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathioline was based on the synthesis method of the fourth step of Example 3. i:H NMR (500 MHz, CD3OD) 57.39-7.23 (m, 3H), 7.21-7.02 (m, 1H), 6.94 (t, J= 7.8 Hz, 1H), 6.89-6.81 (m, 1H), 6.72 (dd, J= 15.4, 7.9 Hz, 1H), 4.65-4.54 (m, 1H), 4.39-4.16 (m, 1H), 3.98-3.81 (m, 2H), 3.76-3.62 (m, 4H), 3.58-3.50 (m, 2H), 3.31 (dd, J = 3.2, 1.6 Hz, 4H), 3.29-3.06 (m, 3H), 2.83-2.69 (m, 1H), 2.51-2.19 (m, 3H), 2.17-2.00 (m, 1H). MS m / z (ESI): 376.8 [M+H] + Example 26: (6bR,10aS)-8-(2-(benzofuran-3-yl)ethyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3',4':4,5]pyrrolo[1,2, 3-deoxy]benzothiazolin Step 1: Add ethyl 2-(benzofuran-3-yl) acetate (1000 mg, 4.87 mmol) to a 50 mL three-necked reaction flask, followed by THF (20 mL). Slowly add lithium aluminum tetrahydride (2 ml, 1 mol / L) dropwise at 0 °C, and stir the reaction at 0 °C for 0.2 h. The reaction solution was quenched with sodium sulfate decahydrate, filtered, concentrated, and purified by normal phase column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound 2-(benzofuran-3-yl)ethane-1-ol (colorless liquid, 700 mg, yield 88.7%). Steps: Compound 2-(benzofuran-3-yl)ethane-1-ol (200 mg, 1.23 mmol) was added to a 25 mL reaction bottle, followed by DCM (50 mL), and then DIEA (635 mg, 4.9 mmol), Ms2O (430 mg, 2.47 mmol) were added in sequence. After the addition, the mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with DCM (2*20 mL), the organic phase was washed with saturated brine (2*20 mL), and concentrated to obtain compound 2-(benzofuran-3-yl)ethyl methanesulfonate (colorless liquid, 0.25 g, Yield 84.7%). Step 3: Compound 2-(benzofuran-3-yl)ethyl methanesulfonate (60 mg, 0.25 mmol), raw material (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2, 3-de]oxathioline (68 mg, 0.3 mmol) were added to a 25 mL reaction bottle, followed by DMSO (5 mL) and then DIPEA (0.2 g, 1.58 mmol). After the addition was complete, the mixture was stirred at 60 °C for 16 h. The reaction mixture was added with ethyl acetate (30 mL), washed with water (30 mL) and brine (50 mL). The organic phase was concentrated and purified by normal phase column chromatography (dichloromethane: methanol = The product was initially purified by HPLC (10:1) and then by reverse phase column chromatography (acetonitrile / (water + 0.05% HCl)) to give the compound (6bR, 10aS-8-(2-(benzofuran-3-yl)ethyl)-3-methyl-2,3,6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline) as a gray solid, 20 mg, yield 21.5%).ENMR (500 MHz, CD3OD) 57.73 (s, 1H), 7.70 (d,J= 7.4 Hz, 1H), 7.48 (d, J= 8.2 Hz, 1H), 7.37-7.13 (m, 4H), 6.93 (s, 1H), 3.81 (s, 2H), 3.67 (d, J= 10.7 Hz, 3H), 3.52-3.42 (m, 3H), 3.38-3.36 (m, 2H), 3.31 (d, J= 1.6 Hz, 3H), 3.27 (d, J= 8.3 Hz, 3H), 2.85 (d, J= 11.7 Hz, 1H), 2.47 (s, 2H). MS m / z (ESI): 374.6[M+H]. + Example 27: 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-yl)propyl)aniline Step 1: Add tert-butyl (2-bromophenyl)carbamate (1 g, 3.68 mmol), ethyl acrylate (400 mg, 4.00 mmol), tri(o-tolyl)phosphine (110 mg, 0.36 mmol), hydroxybenzoate (80 mg, 0.36 mmol) and triethylamine (728 mg, 7.19 mmol) to a 100 mL reaction bottle, followed by addition of DMF (15 mL) and stirring at 100 °C for 12 h. Water (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (2*80 mL). The organic phase was washed with brine (3*80 mL), concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound (Z)-3-(2-((tert-butyloxy)amino)phenylacrylate)ethyl ester (yellow oil, 290 mg, 27% yield). XHNMR (500 MHz, DMSO) 59.13 (s, 1H), 7.82-7.75 (m, 2H), 7.42-7.35 (m, 1H), 7.34- 7.29 (m, 1H), 7.25-7.17 (m, 1H), 6.53 (d, J = 16.0 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.45 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H). Step 2: Compound (Z)-ethyl 3-(2-((tert-butyloxy)amino)phenyl)acrylate (290 mg, 0.995 mmol) was added to a 100 mL reaction vial, followed by methanol (10 mL). 10% wet Pd / C (11 mg, 0.0995 mmol) and Pd(OH)2 / C (14 mg, 0.0995 mmol) were then added in sequence. After the addition was complete, the mixture was stirred at 60°C for 3 hours under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated and purified by normal phase column chromatography (petroleum nitrile: ethyl acetate = 3:1) to obtain ethyl 3-(2-((tert-butyloxy)amino)phenyl)propionate (white solid, 240 mg, yield 82%). MS m / z (ESI): 294.4[M+H] +Step 3: Add the compound ethyl 3-(2-((tert-butyloxy)amino)phenyl)propionate (140 mg, 0.48 mmol) to a 50 mL three-necked flask, followed by anhydrous tetrahydrofuran (5 mL), and then add 1M LiAlH4 tetrahydrofuran solution (0.95 mL, 0.95 mmol, 1M) at 0 °C under nitrogen protection. After addition, stir at room temperature for 2 h. Sodium sulfate decahydrate (50 mg) was added to the reaction solution, and after stirring at room temperature for 10 min, the reaction solution was filtered, and the filtrate was concentrated and purified and separated by normal phase column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the compound tert-butyl (2-(3-hydroxypropyl)phenyl)carbamate (colorless oil, 100 mg, yield 83%). Step 4: The compound tert-butyl (2-(3-hydroxypropyl)phenyl)carbamate (100 mg, 0.40 mmol) was added to a 50 mL reaction bottle, followed by dichloromethane (4 mL), followed by DIEA (155 mg, 1.20 mmol), DMAP (25 mg, 0.20 mmol) and Ms2O (174 mg, 1.00 mmol). After stirring at room temperature for 1 h, water (10 mL) was added to the reaction solution and extracted with dichloromethane (10 mL*2). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield 3-(2-(((tert-butyloxy)amino)phenyl)propyl methanesulfonate (yellow oil, 100 mg, 77% yield). MS m / z (ESI): 230.5 [M+H-Boc] +Step 5: Compound 3-(2-(((tert-butyloxy)amino)phenyl)propyl methanesulfonate (100 mg, 0.30 mmol) was added to a 50 mL reaction bottle, followed by DMSO (4 mL), followed by DIEA (118 mg, 0.91 mmol) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline (83 mg, 0.36 mmol). After stirring at 60 °C for 12 h, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL*2). The organic phase was washed with saturated brine (10 mL). After washing twice with 5% paraformaldehyde (5-nitropropane), the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified and separated by normal phase column chromatography (dichloromethane: methanol = 10:1) to obtain compound 2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10, 10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2, 3 -de]benzothiazolin-8(7H)-propyl)propyl)phenyl)carbamate (2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-5E[3',4':4,5]pyrrolo[1,2, 3 -de]benzothiazolin-8(7H)-propyl)phenyl)carbamate (white solid, 80 mg, yield 57%). MS m / z (ESI): 463.8[M+H] +Step 6: Compound 2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9,10,10,10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin-8(7H)-propyl)propyl)phenyl)carbamate (2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9,10,10a-hexahydro-1H-<5E[3',4':4,5]pyrrolo[1,2, 3-de]benzothiazolin-8(7H)-propyl)phenyl)carbamate (20 mg, 0.043 mmol) was dissolved in HCl / Dioxane (2 mL) and stirred at 25 °C for 1 h. The reaction solution was spin-dried and dissolved in MeOH (2 mL). The mixture was then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and the mixture was lyophilized to obtain compound 2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydropyrido[3',4':4,5]pyro[1,2, 3-de]oxathiazolinone-8(7H)-propyl)aniline (yellow solid, 7 mg, yield 25%). X H NMR (500 MHz, DMSO) 5 6.93-6.83 (m, 2H), 6.59 (dd, J= 7.9, 1.3 Hz, IH), 6.54-6.40 (m, 3H), 6.33 (d, J= 7.8 Hz, IH), 4.98 (s, 2H), 3.44-3.40 (m, IH), 3.31-3.25 (m, 2H), 3.16-3.10 (m, IH), 3.08-2.99 (m, IH), 2.78 (s, 4H), 2.72-2.65 (m, IH), 2.62 (d, J = 8.9 Hz, IH), 2.43 (t, J = 7.3 Hz, 2H), 2.18 (d, J= 64.8 Hz, 3H), 1.96-1.88 (m, IH), 1.84-1.74 (m, 2H), 1.72-1.63 (m, 2H). MS m / z (ESI): 363.8[M+H] +Example 28: N-(2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1, 2, 3-de]oxathiazolinone(7H)-propyl)propyl)phenyl)acetamide Compound 2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydropyrido[3',4':4,5]<pyrro[1,2, 3-de]oxathiazolinone(8(7H)-propyl)aniline (20 mg, 0.055 mmol), DIEA (22 mg, 0.17 mmol) and acetyl chloride (5 mg, 0.066 mmol) were dissolved in dichloromethane (3 mL) and stirred at 25.3 °C. (2) and stirred for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2*10 mL). The organic phase was concentrated, dissolved in MeOH (2 mL), and then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water+0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and lyophilized to obtain the compound N-(2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3 / :4,5]pyrrolo[1,2, 3-de]oxathiapiprolin-8(7H)-propyl)propyl)phenyl)acetamide (yellow oil, 5 mg, yield 22%). i: H NMR (500 MHz, DMSO) 5 9.42 (s, 1H), 7.32 (dd, J= 7.7, 1.5 Hz, 1H), 7.22 (dd, J= 7.3, 1.8 Hz, 1H), 7.13 (m, 2H), 6.52 (t, J = 7.6 Hz, 1H), 6.43 (d, J= 7.3 Hz, 1H), 6.34 (d, J= 7.9 Hz, 1H), 3.46-3.40 (m, 1H), 3.32 (d, J= 3.7 Hz, 2H), 3.27 (m, 2H), 3.13 (s, 2H), 2.78 (s, 3H), 2.68 (m, 1H), 2.57 (t, J= 7.6 Hz, 2H), 2.19 (d, J= 31.3 Hz, 2H), 2.04 (s, 3H), 1.95-1.62 (m, 5H), 1.23 (s, 1H). MS m / z (ESI): 405.9[M+H] +Example 29: 1-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1, 2, 3-de]oxathiazolin-8(7H)-yl)propyl)phenyl)ethan-1-one Step 1: Add 1-(2-iodophenyl)ethane-1-one (500 mg, 2.03 mmol), trimethyl orthoformate (1 mL) and anhydrous ethylene glycol (2 mL) into a 25 mL three-necked flask, followed by the addition of anhydrous dichloromethane (10 mL). Stir under nitrogen and an ice-water bath for 0.5 h. Finally, slowly add concentrated sulfuric acid (0.5 mL) dropwise. After completion of the addition, allow to stir at room temperature for 24 h. After TLC detection of the reaction completion, saturated NaHCO3 solution was slowly added dropwise to the reaction solution to adjust the system to alkaline, followed by DCM extraction (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by normal phase column chromatography (eluent gradient: 5% EA / PE) to obtain compound 2-(2-iodophenyl)-2-methyl-1,3-dioxopentanyl (pale yellow oil, 350 mg, yield 59%). Step 2: Add 2-(2-iodophenyl)-2-methyl-1,3-dioxolane (350 mg, 1.20 mmol), ethyl acrylate (360 mg, 3.60 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), tri(o-methylphenyl)phosphine (18 mg, 0.06 mmol), and triethylamine (360 mg, 3.60 mmol) to a 25 mL single-necked reaction flask, followed by anhydrous DMF (5 mL). After the addition, replace the atmosphere with nitrogen three times, slowly heat to 100 °C, and stir for 16 h.After the reaction was completed as determined by TLC, the reaction solution was filtered, and water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 3% EA / PE) to obtain compound (E)-ethyl 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (pale yellow oil, 200 mg, yield 63%). Step 3: Compound (E)-ethyl 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (200 mg, 0.76 mmol) was added to a 25 mL single-necked reaction flask, followed by the addition of ethyl acetate (15 mL) and 10% Pd / C (wet basis, 20 mg), respectively. After the addition was completed, the atmosphere was replaced with hydrogen three times. The reaction was stirred at room temperature for 0.5 h. After completion of the reaction as determined by TLC, the reaction solution was filtered and the filtrate concentrated under reduced pressure to yield ethyl 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)propanoate (crude product, 200 mg, 99% yield). The crude product was used directly in the next reaction without further purification. Step 4: Preparation of 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)propan-1-ol was performed according to the synthetic method of the first step in Example 26. Step 5: Compound 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)propan-1-ol (35 mg, 0.16 mmol), DMAP (2 mg, 0.02 mmol), DIEA (62 mg, 0.48 mmol), and anhydrous dichloromethane (5 mL) were added to a 25 mL three-necked reaction flask. After addition, the mixture was stirred at room temperature for 2 h. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 3-(2-(2-methyl-1,3-dioxopentan-2-yl)phenyl)propyl methanesulfonate (a colorless oil, crude product, 50 mg). The crude product was used directly in the next reaction without further purification. Step 6: The preparation of (6bR,10aS)-3-methyl-8-(3-(2-(2-methyl-1,3-dioxopentan-2-yl)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathiocarbamate was performed by referring to the synthesis method of the third step of Example 26. Step 7: Compound (6bR,10aS)-3-methyl-8-(3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin (5 mg, 0.75 mmol) was added to a 10 mL single-necked reaction flask, followed by the addition of 4M HCl / Dioxane (1 mL). The reaction mixture was stirred at room temperature for 1.0 h. After the reaction was completed, the solvent was removed under reduced pressure, the crude product was dissolved in MeOH (1 mL), and the solution was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound 1-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3',4':4,5]<pyrro[1,2, 3-de]oxathiapa 8(7H)-yl)propyl)phenyl)ethan-1-one (white solid, 3.0 mg, yield 66%).

[0087] NMR (500 MHz, MeOD) 8 7.78 (d, J= 7.3 Hz, 1H), 7.49-7.39 (m, 1H), 7.31 (t, J= 7.4 Hz, 2H), 6.59 (t, J= 7.6 Hz, 1H), 6.48 (d, J= 7.2 Hz, 1H), 6.41 (d, J= 7.6 Hz, 1H), 4.61 (s, 1H), 3.54-3.47 (m, 1H), 3.38-3.32 (m, 2H), 3.27 (t, J = 2.8 Hz, 1H), 3.18-3.06 (m, 2H), 2.92-2.86 (m, 1H), 2.85-2.80 (m, 5H), 2.78-2.72 (m, 2H), 2.57-2.53 (m, 1H), 2.48-2.42 (m, 2H), 2.30 (td, J= 12.3, 3.0 Hz, 1H), 2.04-1.99 (m, 1H), 1.96-1.88 (m, 2H), 1.84-1.76 (m, 2H)o MS m / z (ESI): 390.4[M+H] + Example 30: 3-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazol-8(7H)-yl)ethyl)benzo[d]isothiazol Compound 3-(2-bromoethyl)benzo[d]isothiazoline (15 mg, 0.07 mmol) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline (15 mg, 0.07 mmol) were added to a 10 mL reaction bottle. Anhydrous DMF (2 mL), K2CO3 (19 mg, 0.14 mmol) and Nal (10 mg, 0.07 mmol) were then added. After the addition was complete, the temperature was slowly raised to 45 °C and the reaction was stirred for 16 h. After the reaction, the reaction mixture was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound 3-(2-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiazolin-8(7H)-yl)ethyl)benzo[d]isothiazolin (pale yellow oil, 8 mg, yield 33%). X HNMR (500 MHz, CDC13) S 7.69 (d, J= 7.9 Hz, 1H), 7.59-7.51 (m, 2H), 7.30 (t, J= 7.1 Hz, 1H), 6.70-6.64 (m, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 7.9 Hz, 1H), 3.66-3.59 (m, 1H), 3.34-3.20 (m, 6H), 3.06-2.98 (m, 1H), 2.93-2.81 (m, 7H), 2.50-2.40 (m, 1H), 2.16 (t, J = 10.8 Hz, 1H), 2.02-1.96 (m, 2H). MS m / z (ESI): 375.6[M+H] + Example 31: 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiapiprolin-8(7H)-yl)-1-phenylpropane At room temperature, (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (18 mg, 0.078 mmol) was dissolved in DMSO (2.0 mL), and DIEA (0.5 mL, 3.0 mmol) and 3-chloro-1-phenylpropan-1-ol (14 mg, 0.08 mmol) were added sequentially. The mixture was heated to 65°C and stirred for 18 h. The mixture was cooled to room temperature and filtered. The mixture was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound 3-(6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline). 3, 6b, 9, 10, 10a-Hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa[8(7H)-yl)-1-phenylpropan-1-ol (pale yellow oil, 9.8 mg, yield 33%). 1H NMR (500 MHz, DMSO-%) δ 7.34-7.30 (m, 4H), 7.23-7.20 (m, 1H), 6.52 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 5.0 Hz, 1H), 6.33 (d, J = 5.0 Hz, 1H), 4.63-4.61 (m, 1H), 3.33-3.26 (m, 3H), 3.13-3.11 (m, 1H), 3.05-3.00 (m, 1H), 2.83-2.80 (m, 1H), 2.78 (s, 3H), 2.71-2.64 (m, 2H), 2.45-2.30 (m, 2H), 2.15-2.08 (m, 1H), 1.93-1.88 (m, 1H), 1.82-1.72 (m, 4H). MS m / z (ESI): 364.7[M+H] + Example 32: (6bR,10aS)-3-methyl-8-(3-(2-(methylthio)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3',4,4,5]pyrrolo[1,2,3-de]oxathioline)

[0088] The preparation of E32 refers to the synthetic method of Example 26. E NMR (500 MHz, CDCI3) 57.18 (dd, J = 4.5,1.0 Hz 2H), 7.14(d, J= 7.5, Hz 1H), 7.10~7.06(m, 1H), 6.64(t, J= 7.5 Hz 1H), 6.52 (d, J= 7.0 Hz 1H), 6.40(d, J= 8.0 Hz 1H), 3.62-3.57 (m, 1H), 3.32-3.17 (m, 4H), 32.93-2.80 (m, 5H), 2.71(t, J = 7.5 Hz,3H), 2.46-2.41 (m, 5H), 2.27-2.20(m, 1H), 1.99-1.95 (m, 3H), 1.88-1.82 (m, 2H). MS m / z (ESI):394.7[M+H] + Example 33: (6bR,10aS)-3-methyl-8-(3-(2-(methylsulfonyl)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-deoxy]benzothiazolin Step 1: Compound (2-iodophenyl)(methyl)sulfane 33-1 (1 g, 4 mmol), ethyl acrylate (1 g, 10 mmol), Pd(OAc)2 (50 mg, 0.22 mmol), K2CO3 (1.36 g, 9.86 mmol), and TBAB (1.32 g, 4.09 mmol) were added to a three-necked flask containing 10 mL of DMF. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 50°C for 16 h. After completion of the reaction as determined by TLC, water and EA were added, the layers were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (PE / EA = 100 μl / 1) to obtain compound (E)-ethyl 3-(2-(methylthio)phenyl)acrylate (920 mg, 90% yield). Step 2: Ethyl (E)-3-(2-(methylthio)phenyl)acrylate (800 mg, 3.6 mmol), 50 mg of 10% Pd / C, and 50 mg of Pd(OH)2 / C were added to a three-necked flask containing 30 mL of THF and 30 mL of EtOH. The atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed at room temperature for 16 h. After TLC and LCMS analysis, the reaction was complete, filtered, and concentrated to afford the crude product (860 mg) of ethyl 3-(2-(methylthio)phenyl)propanoate. MS m / z (ESI): 225.17 [M+H] +Step 3: Ethyl 3-(2-(methylthio)phenyl)propanoate (300 mg, 1.34 mmol) was added to a single-necked flask containing 5 mL of DCM, followed by the addition of m-CPBA (231 mg, 1.14 mmol). The mixture was allowed to react at room temperature for 16 h. TLC confirmed the reaction was complete. The mixture was washed three times with saturated NaHCO₃, separated, dried, filtered, concentrated, and then purified by normal phase column chromatography (PE / EA = 100% to 5 / 1) to obtain Ethyl 3-(2-(methylsulfonyl)phenyl)propanoate (150 mg, yield: 49%). Step 4: Ethyl 3-(2-(methylsulfonyl)phenyl)propanoate (116 mg, 0.45 mmol) was added to a three-necked flask containing 4 mL of THF. The atmosphere was replaced with nitrogen three times and the mixture was cooled to 0.5°C. (2, inject 0.9 mL 1M LAHTHF solution, continue the reaction for 1 h, and TLC detection shows that the reaction is complete. Sodium sulfate decahydrate is added to quench the reaction, and then EA and Na2SO4 are added. Stir at room temperature for half an hour, filter and concentrate to obtain the preparation of compound 3-(2-(methylsulfonyl)phenyl)propan-1-ol (70 mg, yield: 72%). Step 5: The preparation of 3-(2-(methylsulfonyl)phenyl)propyl methanesulfonate refers to the synthesis method of the third step of Example 3. Step 6: The preparation of (6bR,10aS)-3-methyl-8-(3-(2-(methylsulfonyl)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3',4,:4,5]pyrrolo[1,2,3-de]oxathioline refers to the synthesis method of the fourth step of Example 3. NMR (500 MHz, CDCL) 58.03 (dd, J= 8.0,1.0 Hz 1H), 7.58-7.55 (m, 1H), 7.42~7.37(m, 2H), 6.66(t, J = 7.5 Hz 1H), 6.52 (d, J = 7.0 Hz lH), 6.41(d, J= 8.0 Hz 1H), 3.61-3.56 (m, 1H), 3.31-3.25 (m, 4H), 3.10-3.05 (m, 6H), 2.86-2.81(m, 5H), 2.58 (s, 2H), 2.43(s, lH) 2.14-1.97 (m, 5H). m / z (ESI):426.8[M+H] +Example 34: (6bR,10aS)-8-(3-cyclohexylpropyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiophene

[0089] The preparation of E34 refers to the synthesis of Example 20 6.63 (t, J = 7.6 Hz, 1H), 6.58 (d, = 7.0 Hz, 1H), 6.52 (s, 1H), 3.52-3.47 (m, 2H), 3.47-3.42 (m, 2H), 3.37 (d, = 10.0 Hz, 2H), 3.02- 2.94 (m, 2H), 2.85 (d, = 5.8 Hz, 3H), 2.22 (t〃= 14.8 Hz, 2H), 1.77-1.57 (m, 9H), 1.33-1.03 (m, 8H), 0.85 (dd, = 21.5, 10.5 Hz, 2H). MS m / z (ESI): 348.6[M+H] + Example 35: (6bR,10aS)-3-methyl-8-(3-piperidinyl)propyl)-2, 3, 6b, 7, 8, 9, 10, Pyrohexadecene [1,2,3-deoxy]-pyrohexadecene

[0090] The preparation of E35 refers to the synthesis method of Example 20. XH NMR (500 MHz, DMSO-%) 5 6.51 (t, J = 7.5 Hz, 1H), 6.42 (d, J= 7.2 Hz, 1H), 6.34 (d, J= 7.5 Hz, 1H), 3.32-3.22 (m, 3H), 3.11 (dd, J= 4.2, 2.3 Hz, 1H), 3.03-2.97 (m, 1H), 2.82-2.76 (m, 4H), 2.71-2.66 (m, 1H), 2.60 (d, J= 11.0 Hz, 1H), 2.52 (t, J= 4.0 Hz, 2H), 2.48-2.33 (m, 4H), 2.31-2.20 (m, 2H), 2.11 (t, J= 10.5 Hz, 1H), 1.90 (dd, J= 14.5, 2.5 Hz, 1H), 1.80-1.72 (m, 2H), 1.61 (s, 2H), 1.56-1.47 (m, 4H), 1.37 (d, J= 24.9 Hz, 2H). MS m / z (ESI): 355.7[M+H] + Example 36: 3-(6bR, 10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydropyrido[3,4':4,5]<pyrro[1,2,3-de]oxathiolin-8(7H) yl)-1-(piperidin-1-yl)propan-1-one The preparation of compound E36 was carried out according to the synthesis method of Example 20. E NMR (500 MHz, DMSO) 5 6.53 (t, J = 7.6 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 7.9 Hz, 1H), 3.50-3.37 (m, 9H), 3.30-3.25 (m, 2H), 3.12 (s, 2H), 2.79 (s, 3H), 2.72-2.63 (m, 2H), 2.57 (s, 2H), 2.13-1.69 (m, 3H), 1.56 (q, J = 6.2 Hz, 2H), 1.51-1.45 (m, 2H), 1.42-1.36 (m, 2H). MS m / z (ESI): 369.9[M+H] +Example 37: 2-(((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1, 2, 3-de]benzothiazolin-8(7H)-yl)methyl)benzo[d]benzothiazolin

[0091] The preparation of E37 was carried out according to the synthesis method of Example 30. E NMR (500 MHz, CDC13) δ 7.74-7.68 (m, 1H), 7.58-7.50

[0092] (m, 1H), 7.36-7.30 (m, 2H), 6.64 (t, J= 7.6 Hz, 1H), 6.50 (d, J= 7.3 Hz, 1H), 6.40 (d, J= 7.9 Hz, 1H), 3.94 - 3.81 (m, 2H), 3.60 (td, J = 10.8, 2.8 Hz, 1H), 3.33-3.19 (m, 4H), 3.06-2.96 (m, 1H), 2.86 (s, 3H), 2.83-2.75

[0093] (m, 2H), 2.50 (td, J = 11.5, 3.3 Hz, 1H), 2.19 (t, J = 11.0 Hz, 1H), 2.05-1.93 (m, 2H). MS m / z (ESI): 361.6 [M+H] + Example 38: 2-(2-((6bR, 10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3,4':4,5]pyro[1,2,3-de]benzothiazolidine-8(7H)-yl)ethyl)benzo[d]benzothiazolidine Step 1: Dissolve ethyl 2-(benzoxazole-2-yl)acetate (60 mg, 0.29 mmol) in methanol (3 mL). Add sodium borohydride (55 mg, 1.45 mmol) under 1% CO and stir at room temperature for 2 h. Add water (10 mL) to the reaction mixture at 0.8°C and extract with ethyl acetate (10 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound, 2-(benzoxazole-2-yl)ethan-1-ol (yellow oil, 30 mg, 64% yield). MS m / z (ESI): 164.4 [M+H] + Step 2: Preparation of 2-(Benzo[d]oxazol-2-yl)ethyl methanesulfonate was performed by referring to the synthesis method of the third step of Example 3. Step 3: 2-(2-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3',4':4,5]pyro[1,2,3-de]oxazol-8(7H)-ethyl) -7.62 (m, 2H), 7.38-7.30 (m, 2H), 6.51 (t, J= 7.6 Hz, 1H), 6.42 (d, J= 7.2 Hz, 1H), 6.33 (d, J= 7.8 Hz, 1H), 3.47- 3.41 (m, 1H), 3.31 (t, J = 2.9 Hz, 2H), 3.28-3.24 (m, 1H), 3.18-3.05 (m, 3H), 3.00 (q, J = 6.3 Hz, 1H), 2.90- 2.80 (m, 2H), 2.78 (s, 3H), 2.74-2.61 (m, 2H), 2.23 (s, 1H), 2.07-1.83 (m, 2H), 1.75 (d, J= 13.5 Hz, 1H). MS m / z (ESI): 375.8[M+H] + Example 39: (6bR,10aS)-3-methyl-8-(3-(thiophen-2-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1, 2, 3-de]oxathiophene Step 1: Preparation of 3-(thiophene-2-yl)propyl methanesulfonate was carried out according to the synthesis method of the third step of Example 3. Step 2: (6bR,10aS)-3-methyl-8-(3-(thiophene-2-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, The preparation of [1,2,3-de] oxalool is as follows: 7.30 (dd, J= 5.0, 1.0 Hz, 1H), 6.95-6.91 (m, 1H), 6.85 (dd, J= 3.0, 1.0Hz, 1H), 6.51 (t, • / = 7.6 Hz, 1H), 6.42 (d, J= 7.0 Hz, 1H), 6.33 (d, = 7.6 Hz, 1H), 3.47-3.37 (m, 2H), 3.32-3.23 (m, 2H), 3.11 (d, 2.0 Hz, 1H), 3.06-2.99

[0094] (m, 1H), 2.83-2.79 (m, 2H), 2.78 (s, 3H), 2.67 (ddd〃= 20.5, 10.5, 2.5 Hz, 1H), 2.55 (d, • / = 25.5 Hz, 1H), 2.28 (s, 2H), 2.09 (d, = 16.8 Hz, 1H), 1.90 (d, = 13.1 Hz, 1H), 1.78 (dd, = 18.1, 10.8 Hz, 4H). MS m / z (ESI): 354.7[M+H] + Example 40: (6bR,10aS)-8-(3-(3-methoxythiophene-2-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10,

[0095] [3',4':4,5]<[1,2, 3 -take off]Chaohkoulin Step 1: Dissolve 3-methoxythiophene-2-carbaldehyde (350 mg, 2.46 mmol) in THF (25.0 mL). Add ethoxycarbonylmethylenetriphenylphosphine (1.20 g, 3.45 mmol) and 75° C. (2% ethanol) under nitrogen. Stir for 18 h. After completion of the reaction, confirm with TLC. Concentrate under reduced pressure and purify with normal phase chromatography to obtain ethyl (E)-3-(3-methoxythiophene-2-yl) acrylate (yellow oil, 420 mg, 74% yield). MS m / z (ESI): 213.3. [M+H] + Step 2: Dissolve ethyl (E)-3-(3-methoxythiophen-2-yl) acryloyl ester (270 mg, 1.27 mmol) in MeOH (15.0 mL), add 10% Pd / C (135 mg), and hydrogenate at room temperature for 18 h. Filter and concentrate to obtain ethyl 3-(3-methoxythiophen-2-yl) propionate (colorless oil, 230 mg, 85% yield). MS m / z (ESI): 215.3. [M+H] + Step 3: Dissolve ethyl 3-(3-methoxythiophen-2-yl) propionate (112 mg, 0.52 mmol) in THF (1.0 mL), cool to 0°C, add 1M lithium aluminum tetrahydride in tetrahydrofuran (0.5 mL, 0.5 mmol), and stir at room temperature for 1 h. Then, add sodium sulfate decahydrate and stir for 30 minutes. Filter, concentrate, and purify by normal phase chromatography to obtain 3-(3-methoxythiophen-2-yl)propan-1-ol (colorless oil, 68 mg, 76% yield). MS m / z (ESI): 173.3. [M+H] +Step 4: Dissolve 3-(3-methoxythiophen-2-yl)propan-1-ol (68 mg, 0.40 mmol) in DCM (3.0 mL), add DIEA (260 mg, 2.0 mmol), cool to 0 °C, add methanesulfonic acid tincture (140 mg, 0.8 mmol) and heat to 20. (2) The mixture was stirred for 3 h, quenched with water, extracted with DCM, dried over sodium sulfate, and filtered to obtain compound 3-(3-methoxythiophen-2-yl)propyl methanesulfonate (yellow oil, 100 mg), which was used directly in the next reaction. Step 5: (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (55 mg, 0.24 mmol) was dissolved in DMSO (3.0 mL) at room temperature, and DIEA (0.5 mL, 3.0 mmol) and 3-(3-methoxythiophen-2-yl)propyl methanesulfonate (100 mg, 0.4 mmol) were added sequentially. The mixture was heated to 65.degree. C.The mixture was stirred for 18 h, cooled to room temperature, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water+0.05% NH4HCO3) = 30%-70%) to give compound (6bR,10aS)-8-(3-(3-methoxythiophen-2-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3 / :4,5]pyrrolo[1,2, 3-de]oxathioline (pale yellow oil, 16.0 mg, yield 17%). δ 7.07 (d, J = 5.0 Hz, 1H), 6.86 (d, J = 5.0 Hz, 1H), 6.60 (t, J= 7.5 Hz, 1H), 6.48 (d, J= 5.0 Hz, 1H), 6.42 (d, J= 5.0 Hz, 1H), 3.79 (s, 3H), 3.53- 3.48 (m, 1H), 3.37-3.27 (m, 2H), 3.16-3.10 (m, 2H), 3.00-2.93 (m, 1H), 2.88-2.82 (m, 1H), 2.81 (s, 3H), 2.77- 2.65 (m, 3H), 2.53-2.38 (m, 3H), 2.07-1.82 (m, 5H). MS m / z (ESI): 384.9 [M+H]. + Example 41: (6bR, 10aS)-8-(3-(2-methoxythiophen-3-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathiophene Step 1: Dissolve 2-methoxythiophene (575 mg, 5.05 mmol) in DCM (20.0 mL), cool to 0.8°C, add NBS (1.78 g, 10.0 mmol), heat to 20.8°C, stir for 3 h, concentrate under reduced pressure, and purify by normal phase chromatography to obtain 3,5-dibromo-2-methoxythiophene (yellow oil, 380 mg, 27% yield). MS m / z (ESI): 272.4. [M+H] +Step 2: Dissolve 3,5-dibromo-2-methoxythiophene (380 mg, 1.40 mmol) in THF (5.0 mL), cool to -78 °C, add n-butyllithium solution (0.56 mL, 1.4 mmol), and stir at -78 °C for 30 min. Quench the reaction by adding methanol, extract with dichloromethane, and wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and purify by normal phase to obtain 3-bromo-2-methoxythiophene (yellow oil, 195 mg, yield 71%). MS m / z (ESI): 194.4. [M+H] + Step 3: Compound 3-bromo-2-methoxythiophene (190 mg, 1.0 mmol) was dissolved in DMF (5.0 mL). Under nitrogen, triethylamine (800 mg, 8.0 mmol), ethyl acrylate (120 mg, 1.2 mmol), o-trimethylphenylphosphine (60 mg, 0.2 mmol), and tweezers acetate (22 mg, 0.1 mmol) were added sequentially. The mixture was stirred at 100 °C for 3 h. After TLC, the reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase purification to obtain compound (E)-3-(2-methoxythiophen-3-yl)ethyl acrylate (yellow oil, 48 mg, yield 23%). MS m / z (ESI): 213.3. [M+H] + Step 4: Dissolve ethyl (E)-3-(2-methoxythiophen-3-yl)acrylate (48 mg, 0.23 mmol) in MeOH (5.0 mL), add 10% carbon chelate (30 mg), and stir at room temperature for 18 h. Filter and concentrate to obtain ethyl 3-(2-methoxythiophen-3-yl)propionate (yellow oil, 32 mg, 66% yield). MS m / z (ESI): 215.3. [M+H] +Step 5: Dissolve ethyl 3-(2-methoxythiophen-3-yl)propionate (32 mg, 0.15 mmol) in THF (1.5 mL), cool to 0.2°C, add lithium aluminum tetrahydride solution (0.15 mL, 0.15 mmol), and heat to 20.2°C. Stir for 1 h, quench with water, and dry over sodium sulfate. Filter and purify by normal phase chromatography to obtain 3-(2-methoxythiophen-3-yl)propan-1-ol (yellow oil, 18 mg, yield 69%). MS m / z (ESI): 173.3. [M+H] +Step 6: Dissolve 3-(2-methoxythiophen-3-yl)propan-1-ol (18 mg, 0.53 mmol) in DCM (3.0 mL), add TEA (50 mg, 0.5 mmol), cool to 0 °C, add methanesulfonic acid tincture (36 mg, 0.2 mmol) and heat to 20. (2) The mixture was stirred for 3 h, quenched with water, extracted with DCM, dried over sodium sulfate, and filtered to obtain compound 3-(2-methoxythiophen-3-yl)propyl methanesulfonate (colorless oil, 37 mg, yield 99%), which was used directly in the next reaction. Step 7: (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin (26 mg, 0.11 mmol) was dissolved in DMSO (3.0 mL) at room temperature, and DIEA (195 mg, 1.5 mmol) and compound 3-(2-methoxythiophen-3-yl)propyl methanesulfonate (37 mg, 0.15 mmol) were added sequentially. The mixture was heated to 65.degree. C.The mixture was stirred for 18 h, cooled to room temperature, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water+0.05% NH4HCO3) = 30%-70%) to give compound (6bR,10aS)-8-(3-(2-methoxythiophen-3-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline (yellow solid, 2.0 mg, yield 5.0%). δ 7.23 (d, J = 5.0 Hz, 1H), 6.95 (d, J = 5.0 Hz, 1H), 6.52 (t, J= 7.5 Hz, 1H), 6.43 (d, J= 10.0 Hz, 1H), 6.33 (d, J= 5.0 Hz, 1H), 3.76 (s, 3H), 3.45- 3.26 (m, 3H), 3.13-3.01 (m, 2H), 2.80-2.79 (m, 1H), 2.78 (s, 3H), 2.71-2.61 (m, 4H), 2.37-2.03 (m, 3H), 1.96- 1.65 (m, 5H)o MS m / z (ESI): 384.8[M+H]. + Example 42: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydro-[1,4]oxa-azino[2,3,4-hi]pyrido[4,3- Step 1: Benzomorph (815 mg, 6.0 mmol) was dissolved in acetic acid (12 mL) and cooled to 0°C. Aqueous NaNO2 (414 mg, 6.0 mmol, 4 mL of water) was added with stirring and stirred at 20°C for 3 h. After completion of the reaction by TLC, the mixture was quenched with water and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford 4-nitroso-3,4-dihydro-2H-benzo[b][l,4]B1-oxazine (yellow oil, 680 mg, 69% yield). MS m / z (ESI): 163.3. [M+H] +Step 2: Lithium aluminum tetrahydride (158 mg, 4.15 mmol) was suspended in THF (10 mL) and cooled to 0°C. A solution of 4-nitroso-3, 4-dihydro-2H-benzo[b][l,4]B®oxazine (680 mg, 4.15 mmol) in tetrahydrofuran (5 mL) was added with stirring. The mixture was heated to 20°C and stirred for 18 h. The mixture was quenched by addition of 2M aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by normal phase chromatography afforded 4-amino-3,4-dihydro-2H-benzo[b][l,4]B®oxazine (yellow oil, 413 mg, 67% yield). MS m / z (ESI): 164.3. [M+H] + Step 3: Compound 4-amino-3, 4-dihydro-2H-benzo[b][l,4]benzo[b][l,4]oxazine (413 mg, 2.77 mmol) and compound 4-piperidone hydrochloride (375 mg, 2.78 mmol) were added to a 25 mL reaction flask in isopropanol (15 mL). The mixture was heated to 88°C and stirred for 2 h. Concentrated HCl (0.23 mL, 2.8 mmol) was added and the mixture was heated to 88°C and stirred for 3 h. The mixture was cooled to room temperature and filtered to obtain compound 1,2,7,8,9,10-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-indole] (yellow solid, 335 mg, yield 55%). MS m / z (ESI): 213.4. [M+H] + Step 4: Compound 1,2, 7, 8, 9, 10-hexahydro-[1,4]oxazinyl[2,3,4-hi]pyrido[4, 3-b]indole (335 mg, 1.55 mmol) was dissolved in TFA (5 mL) and cooled to 0 °C. NaBH3CN (296 mg, 4.65 mmol) was added with stirring and stirred at 20 °C for 3 h. After the reaction was completed by TLC, saturated sodium bicarbonate solution was added and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by normal phase to obtain compound 1,2, 6b, 7, 8, 9, 10, 10a-octahydro-[1,4]oxazinyl[2,3,4-hi]pyrido[4,3-b]indole (pale yellow solid, 115 mg, yield 66%). MS m / z (ESI): 215.3. [M+H] +Step 5: At room temperature, 1,2, 6b, 7, 8, 9, 10, 10a-octahydro-[1,4]oxazinyl[2,3,4-hi]pyrido[4,3-"indole (40 mg, 0.185 mmol) was dissolved in DMSO (1.5 mL), DIEA (0.5 mL, 3.0 mmol) and 3-(2,3-dihydrobenzofuran-7-yl)propyl methanesulfonate (52 mg, 0.20 mmol) were added sequentially, and the mixture was heated to 65 ° C. and stirred for 18 h. After filtration, the mixture was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2, 6b, 7, 8, 9, 10, 10a-Octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (white solid, 14.0 mg, yield 20 %). 1H NMR (500 MHz, DMSO-d6) δ 7.05 (d, J = 5.0 Hz, 1H), 6.92 (d, J = 5.0 Hz, 1H), 6.73 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 10.0 Hz, 1H), 6.57-6.50 (m, 2H), 4.49 (t, J = 7.5 Hz, 2H), 4.42-4.39 (m, 1H), 4.31-4.26 (m, 1H), 3.36-3.34 (m, 1H), 3.19-3.07 (m, 4H), 2.81-2.79 (m, 1H), 2.65-2.60 (m, 2H), 2.49-2.47 (m, 2H), 2.26-2.14 (m, 3H), 1.89-1.70 (m, 5H). MS m / z (ESI): 375.8[M+H] + Example 43: 10-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5, 6, 7a, 8, 9, 10, 11, 11a-octahydro-4H-pyrido[3, 4, 4, 5]pyrrolo[3, 2, 1-hydroxybenzo ...

[0096] The preparation of E43 followed the synthetic method of Example 42. E NMR (500 MHz, DMSO-%) 5 7.04 (d, J= 10.0 Hz, 1H), 6.91 (d, J= 5.0 Hz, 1H), 6.86 (d, J= 5.0 Hz, 1H), 6.76 (d, J= 5.0 Hz, 1H), 6.73 (t, J= 7.5 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 4.49 (t, J = 10.0 Hz, 2H), 3.25-3.13 (m, 4H), 3.04-3.00 (m, 1H), 2.74-2.70 (m, 1H), 2.62-2.59 (m, 2H), 2.50-2.46 (m, 2H), 2.26-2.08 (m, 5H), 2.03-1.67 (m, 5H). MS m / z (ESI): 375.8[M+H] + Example 44: (6bR,10aS)-8-(3-(2,3-dihydrobenzo[b][l,4]dioxin-5-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiocarbamate

[0097] The preparation of E44 was carried out according to the synthesis method of Example 3. g NMR (500 MHz, CD3OD) 5 6.74-6.66 (m, 3H), 6.62 (t, J = 7.6 Hz, 1H), 6.51 (d, J= 7.2 Hz, 1H), 6.44 (d, J= 8.0 Hz, 1H), 4.24 (d, J= 6.0 Hz, 2H), 4.21 (d, J= 6.0 Hz, 2H), 3.56-3.48 (m, 1H), 3.37 (d, J= 10.0 Hz, 1H), 3.22 (d, J= 12.0 Hz, 3H), 3.07 (s, 1H), 2.84 (s, 3H), 2.79- 2.70 (m, 4H), 2.62 (dd, J = 10.0, 5.0 Hz, 2H), 2.31 (s, 1H), 2.19-2.12 (m, 1H), 2.17-1.99 (m, 2H), 1.96-1.89 (m, 2H). MS m / z (ESI): 406.9[M+H] + Example 45-1: 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydro-3H-pyrido[3',4':4,5]<pyro[1,2,3-de]benzothiazolin-3-yl)ethane-1-one Step 1: Ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-indole-2-carboxylate (2.08 g, 6.4 mmol), benzophenone imine (1.5 g, 7.7 mmol), NaOt-Bu (1.23 g, 12.8 mmol), BINAP (120 mg, 0.19 mmol), and 40 mL of toluene were added to a 250 mL three-necked flask. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C for 16 h. The reaction mixture was then cooled to room temperature, and Pd2(dba)3 (59 mg, 0.064 mmol) was added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 105°C for 16 h. A small amount of starting material remained, as monitored by LCMS. The reaction solution was cooled to room temperature. MTBE was added, filtered, and concentrated to afford ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-cheindol-2-carboxylate (3.4 g, crude), which was directly used in the next step. MS m / z (ESI): 426.5 [M+H] + Step 2: Ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-indole-2-carboxylate (3.4 g, 8.0 mmol), ethyl bromoacetate (2.67 g, 7.7 mmol), Na2CC)3 (1.7 g, 16.04 mmol), KI (1.99 g, 12.76 mmol), and 40 mL of acetone were added to a 250 mL three-necked flask. The atmosphere was replaced with nitrogen three times and the temperature was raised to 60°C. The reaction was allowed to proceed for 16 h. A small amount of starting material remained after Lems monitoring. The reaction solution was concentrated to dryness, and DCM and water were added. The organic phase was washed with saturated sodium chloride, dried, and filtered. The reaction mixture was concentrated to give ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4 g, crude product), which was directly used in the next step. MS m / z (ESI): 513.6 [M+H] +Step 3: Ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-indole-2-carboxylate (4 g, crude) was added to a single-necked flask containing 40 mL of THF. 8 mL of 2N HCl was added at room temperature and stirred at room temperature for another half hour. LCMS confirmed the reaction was complete. The THF was concentrated and added to DCM. The layers were separated and the organic phase was washed three times with saturated sodium chloride, dried, and concentrated. The sample was mixed with neutral alumina and passed through a column. Purification was performed using PE / EA = 100% to 1 / 10, followed by MeOH / DCM = 0-3% to obtain the compound ethyl (6bR,10aS)-2-M^-2,3,6b,9, 10,10a-Hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiolin-8(7H)-ester 800 mg MS m / z (ESI): 302.2[M+H] +Step 4: Ethyl (6bR, 10aS)-2-M^-2,3,6b,9,10,10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-acid ester (170 mg, 0.56 mmol) was added to a three-necked flask containing 10 mL of THF, and the atmosphere was replaced with N2 three times. 1.7 mL of 1M BH3Me2S was added at 2 °C. After the addition was complete, the temperature was raised to 70 °C and the reaction was allowed to proceed for 3 h. Completion was monitored by LCMS. The reaction solution was cooled to 50 °C and 6N HCl was added dropwise until no bubbles were generated. The THF was concentrated, and NaOH (aq) was added to adjust the pH to 9. The solution was extracted twice with DCM, dried, and concentrated through a column (MeOH / DCM = 0-5%) to obtain the compound ethyl (6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiazolinone 8(7H)-cobalt salt (100 mg, yellow oil, yield: 62.5%). Step 5: Ethyl (6bR, 10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin P#-8(7H)-coate (100 mg, 0.348 mmol) and 3 mL of HBr in HBr were reacted at 100°C for 16 h. The reaction was completed as monitored by LCMS. The product was concentrated to give 70 mg of (6bR, 10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin, which was used directly in the next step. Step 6: (6bR, 10aS)-2,3,6b,7,8,9, 10,10a-Octahydro-1H-pyrrolo[3′,4′:4,5]pyrrolo[1,2,3-de]oxathioline (70 mg, 0.33 mmol), 7 (110 mg, 0.4 mmol), and 0.1 mL of DIEA were added to a single-necked vial containing 1 mL of DMSO. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60° C. for 2 h. The reaction was completed after LCMS monitoring.Water and EA were added, the layers were separated, the aqueous phase was extracted with EA, and the organic phases were combined, washed three times with saturated sodium chloride solution, dried, concentrated, and filtered through a column chromatography (MeOH / DCM = 0-5%) to give compound (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3′, 4′:4,5]pyro[1,2, 3-de]benzothiazolin (40 mg, beige solid, yield: 32%). MS m / z (ESI): 376.6. [M+H]. +Step 7: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,, 4':4,5]<pyroximate[1,2, 3-de]benzothiazolin (40 mg, 0.10 mmol) and TEA (20 mg, 0.20 mmol) were added to a single-necked vial containing 1 mL of DCM. The atmosphere was replaced with nitrogen three times, the temperature was lowered to 0 °C, acetyl chloride (13 mg, 0.15 mmol) was added, and the reaction was carried out at this temperature for 0.5 h. The reaction was monitored by LCMS for completion. Water and DCM were added, the mixture was separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed three times with saturated sodium chloride solution, dried, concentrated, and purified by Prep-HPLC (30-70% CHCl 30 min, 0.05% NH4HCO3 in 0) to give compound 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydro-3H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiolin-3-yl)ethan-1-one (15 mg, yellow solid, yield: 36%). δ NMR (500 MHz, CDCI3) 67.03 (d, J = 8.0 Hz 1H), 6.92 (d, J= 7.5Hz 1H), 6.88(d, J = 7.0 Hz, 1H), 6.76(t, J= 7.5Hz, 1H), 6.67(s, 1H), 4.54(t, J = 8.5 Hz, 2H), 4.04-3.79 (m, 2H), 3.50-3.29 (m, 3H), 3.20 (t, J= 7.5Hz, 2H), 2.91-2.70 (m, 3H), 2.58 (t, J = 9.0 Hz, 2H), 2.42-2.26 (m, 6H), 2.06-1.84 (m, 5H). MS m / z (ESI):418.9[M+H] + Example 45-2: 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydro-3H-pyrido[3',4':4,5]<pyro[1,2,3-de]oxathiolin-3-yl)ethane-1-one Step 1: 45-2-1 was prepared by referring to the synthetic method of Step 2 of E73-1. Step 2: 45-2-1 (860 mg, 4 mmol), TEA (808 mg, 8 mmol), and 10 mL of MeOH were added to a 100 mL single-necked flask. BOC2O (872 mg, 4 mmol) was then added and the mixture was allowed to react at room temperature for 2 h. The reaction was complete by TLC. The residue was concentrated and passed through a column chromatography (PE / EA = 2 / 1) to afford 45-2-2 (yellow oil, 1.2 g). MS m / z (ESI): 316.5 [M+H] + Step 3: 45-2-2 (300 mg, 0.95 mmol), TEA (192 mg, 1.9 mmol), and 5 mL of DCM were added to a 50 mL single-necked flask. Acetyl chloride (90 mg, 1.14 mmol) was then added and the mixture was allowed to react at room temperature for 10 min. LCMS confirmed the reaction was complete. Saturated sodium chloride was added, the mixture was separated, and the resulting mixture was dried and concentrated by column chromatography (PE / EA = 1 / 1) to afford 45-2-3 (330 mg, yellow oil). MS m / z (ESI): 358.2 [M+H] + Step 4: 45-2-3 (330 mg, 0.924 mmol), 1 mL TFA, and 3 mL DCM were added to a 50 mL single-necked flask and reacted at room temperature for 2 h. LCMS confirmed the reaction was complete, and the product was concentrated. Saturated sodium bicarbonate was added to adjust the pH to 7-8, and the mixture was separated. The aqueous phase was extracted five times with DCM / MeOH (10 / 1 v / v), and then dried and concentrated to yield 45-2-4 (210 mg as a yellow solid). MS m / z (ESI): 258.2 [M+H] +Step 5: Under nitrogen, compound 45-2-4 (100 mg, 0.389 mmol) was dissolved in MeOH (50 mL) and DCM (30 mL), and 3-(2,3-dihydrobenzofuran-7-yl)propanal (86.7 mg, 0.492 mmol) and NaBH(OAc)3 (129.1 mg, 2.05 mmol) were added. The reaction was allowed to proceed at 25°C for 1 h. LCMS confirmed the completion of the reaction. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 45-2-5 (yellow solid, 100 mg, 61% yield). MS m / z (ESI): 418.2 [M+H] + Step 6: 45-2-5 (100 mg, 0.239 mmol) was separated by SFC (Daicel ChiralPak 1H, 40mm IDx250mm, 10gm; Mobile phase: Supercritical CO2 / Methanol [0.1% NH3.H2O (VA^)] = 65 / 35; Flow rate: 140 mL / min) to give white solid E45-2 (PK1: 26.0 mg, purity 99%, yield 26%, ee 100%, RT = 1.687, OROT = -97.9 and white solid E45-1 (PK2: 29.1 mg, purity 99%, yield 29%, ee 98%, RT = 2.267, OROT = + 89. l) o E45-2: XH NMR (400 MHz, DMSO-d6) 5 8.10 (s, 1H), 7.04 (d, J= 7.2 Hz, 1H), 6.91 (d, J= 7.2 Hz, 1H), 6.84 (d, J= 6.4 Hz, 1H), 6.73 (t, J= 7.2 Hz, 1H), 6.58 (dd, J = 8.0, 7.2 Hz, 1H), 4.49 (t, J = 8.8 Hz, 2H), 4.18-3.56 (m, 2H), 3.46-3.20 (m, 3H), 3.20-3.04 (m, 3H), 2.92-2.62 (m, 2H), 2.59-2.41 (m, 2H), 2.36-2.02 (m, 6H), 1.98-1.57 (m, 5H). E45-1: E NMR (400 MHz, DMSO-d6) 5 8.10 (s, 1H), 7.04 (d, J = 7.2, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.84 (d, J= 6.4 Hz, 1H), 6.73 (t, J= 7.2 Hz, 1H), 6.58 (dd, J= 8.0, 7.2 Hz, 1H), 4.49 (t, J = 8.8 Hz, 2H), 4.15- 3.62 (m, 2H), 3.46-3.21 (m, 3H), 3.21-3.05 (m, 3H), 2.93-2.61 (m, 2H), 2.52-2.35 (m, 2H), 2.35-2.01 (m, 6H), 1.99-1.54 (m, 5H). Example 46: (6bR,10aS)-8-(3-(3-chloropyridin-2-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-2-yl)propyl Step 1: Dissolve tert-butyl (2-formylpyridin-3-yl)carbamate (750 mg, 3.37 mmol) in tetrahydrofuran (20 mL). Add ethoxycarbonylmethylenetriphenylphosphine (1.4 g, 4.04 mmol) and stir at 70°C for 2 h. The reaction mixture is condensed and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain (E)-ethyl 3-(tert-butyloxy)amino)pyridin-2-ylacrylate (pale yellow oil, 940 mg, 96% yield). MS m / z (ESI): 293.6 [M+H] + Step 2: Dissolve (E)-3-(tert-Butyloxy)amino)pyridin-2-ylacrylate (940 mg, 3.22 mmol) in ethyl acetate (15 mL). Add 10% wet carbon (35 mg, 0.32 mmol). Stir under hydrogen at 28°C for 15 min. The reaction mixture was filtered and concentrated to yield ethyl 3-(3-(((tert-Butyloxy)amino)pyridin-2-yl)propanoate (pale yellow oil, 830 mg, 88% yield). MS m / z (ESI): 295.7 [M+H] + Step 3: Ethyl 3-(3-(((tert-butyloxy)amino)pyridin-2-yl)propanoate (830 mg, 2.82 mmol) was dissolved in tetrahydrofuran (15 mL). LiAlH₄ (4.23 mL, 1 M in THF, 4.23 mmol) was added to the solution under nitrogen at zero degrees Celsius. The reaction was allowed to react at room temperature for 30 min. Sodium sulfate decahydrate was then added to the reaction solution until no more bubbles were generated during stirring. The mixture was filtered, concentrated, and purified by normal phase column chromatography (dichloromethane:methanol = 10:1) to obtain tert-butyl (2-(3-hydroxypropyl)pyridin-3-yl)carbamate (colorless oil, 460 mg, yield 65%). MS m / z (ESI): 253.6 [M+H] +Step 4: Dissolve tert-butyl (2-(3-hydroxypropyl)pyridin-3-yl)carbamate (460 mg, 1.82 mmol) in hydrochloric acid / dioxane (10 mL). After reacting at room temperature for 30 min, the reaction mixture was subjected to reverse phase chromatography (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and lyophilized to afford 3-(3-aminopyridin-2-yl)propanol as a white solid (240 mg, 88% yield). MS m / z (ESI): 153.2 [M+H] + Step 5: Dissolve 3-(3-aminopyridin-2-yl)propanol (240 mg, 1.58 mmol), cupric chloride (45 mg, 0.32 mmol), cuprous chloride (311 mg, 3.15 mmol), and tert-butyl nitrite (325 mg, 3.15 mmol) in acetonitrile (15 mL). Under nitrogen, react at 25°C for 0.5 h and then at 50°C for an additional 2 h. The reaction mixture was filtered and purified by normal phase column chromatography (dichloromethane:methanol = 10:1) to obtain 3-(3-chloropyridin-2-yl)propanol (yellow oil, 50 mg, 19% yield). MS m / z (ESI): 172.1 [M+H] + Step 6: Dissolve 3-(3-chloropyridin-2-yl)propanol (50 mg, 0.29 mmol) in dichloromethane (5 mL). Add PCC (440 mg, 2.04 mmol). After reacting at room temperature for 0.5 h, filter the reaction solution and wash the filtrate with saturated sodium bicarbonate solution (10 mL x 2). Concentrate the organic phase to obtain the title compound, 3-(3-chloropyridin-2-yl)propanal (brown solid, 45 mg crude product, 92% yield). MS m / z (ESI): 170.1 [M+H] +Step 7: Compound 3-(3-chloropyridin-2-yl)propanal (35 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL), and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin (49 mg, 0.21 mmol) was added thereto. After reacting at room temperature for 0.5 h, sodium acetate borohydride (135 mg, 0.63 mmol) was added thereto. After reacting at room temperature for 0.5 h, the reaction solution was filtered and subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and lyophilized to obtain compound (6bR, 1H-octahydro-1H-pyrrolo[3,4,5]pyrrolo[1,2,3-de]oxathioline (yellow solid, 23 mg, yield 19%). 3 NMR (500 MHz, CDCI3) δ 8.41 (dd, J = 4.7, 1.6 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.09 (dd, J = 8.0, 4.7 Hz, 1H), 6.65 (t, J = 7.7 Hz, 1H), 6.51 (dd, J = 7.4, 1.0 Hz, 1H), 7.70 (dd, J = 7.9, 1.0 Hz, 1H), 7.97 (t, J = 7.8, 1.0 Hz, 1H), 7. 1H), 6.40 (dd, J = 7.9, 0.9 Hz, 1H), 3.65-3.56 (m, 1H), 3.32-3.20 (m, 4H), 2.97 (q, J = 8.0 Hz, 3H), 2.86 (s, 3H), 2.85-2.77 (m, 2H), 2.52 (d,J= 9.4 Hz, 2H), 2.34 (s, 1H), 2.04-1.93 (m, 5H). MS m / z (ESI): 383.7[M+H] + Example 47: 2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydropyrido[3',4':4,5]pyrro[1,2, 3-de]oxazolidinone(7H)-propyl)pyrido-3-amine Step 1: Dissolve tert-butyl (2-(3-hydroxypropyl)pyridin-3-yl)carbamate (20 mg, 0.079 mmol) in dichloromethane (2 mL). Add PCC (85 mg, 0.40 mmol). After reacting at room temperature for 12 h, filter the reaction solution and wash the filtrate with saturated sodium bicarbonate solution (10 mL x 2). Concentrate the organic phase to obtain tert-butyl (2-(3-oxopropyl)pyridin-3-yl)carbamate (brown solid, 20 mg crude product, 100% yield). MS m / z (ESI): 251.5 [M+H] + Step 2: Dissolve tert-butyl (2-(3-oxopropyl)pyridin-3-yl)carbamate (20 mg, 0.079 mmol) in dichloromethane (2 mL), add (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline (19 mg, 0.079 mmol), and react at room temperature for 0.5 h. Then, add sodium acetate borohydride (51 mg, 0.24 mmol) and react at room temperature for 0.5 h. The reaction solution is filtered and then subjected to reverse phase purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCC>3)). Remove acetonitrile under reduced pressure. Lyophilization gave the compound tert-butyl 2-(3-((6bR, 10aS)-3-g-2,3,6b,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiopalmus(H)-propyl)pyrrolo-3-carbamate (yellow solid, 8 mg, yield 22%). MS m / z (ESI): 464.9 [M+H] +Step 3: Compound 2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin-8(H)-propyl)pyrrolo-3-carbamic acid tert-butyl ester (8 mg, 0.017 mmol) was dissolved in dichloromethane (3 mL). Hydrochloric acid / dioxane (3 mL) was added thereto at 0 °C. After reacting under 0 °C for 10 min, the reaction solution was filtered and subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water+0.05% NH4HCC>3)). The acetonitrile was removed under reduced pressure and the mixture was lyophilized to obtain compound 2-(3-(6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a- Hexahydropyrimethoxy[3',4':4,5]pyroximate[1,2,3-de]oxazolidinone-8(7H)-propyl)pyrimethoxy-3-amine (yellow solid, 2 mg, yield 33%). E NMR (500 MHz, DMSO) δ 7.70 (dd, J = 4.1, 2.1 Hz, 1H), 6.92-6.85 (m, 2H), 6.50 (t, J = 7.6 Hz, 1H), 6.42 (dd, J = 7.4, 1.0 Hz, 1H), 6.33 (dd, J = 7.9, 1.0 Hz, 1H), 5.13 (s, 2H), 3.45-3.40 (m, 1H), 3.32-3.26 (m, 2H), 3.13-3.09 (m, 1H), 3.05-2.98 (m, 1H), 2.78 (s, 4H), 2.71-2.65 (m, 1H), 2.59 (q, J= 7.3, 6.0 Hz, 3H), 2.30-2.18 (m, 2H), 2.12-2.05 (m, 1H), 1.94-1.88 (m, 1H), 1.82-1.72 (m, 4H).MS m / z (ESI): 364.8[M+H] + Example 48: (6bR, 10aS)-8-(3-(5-fluoro-2, 3-dihydrobenzofuran-4-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1, 2, 3-de]benzothiazolin

[0098] The preparation of E48 was carried out according to the synthesis method of Example 3. g NMR (500 MHz, CDCh) 5 6.79-6.70 (m, 1H), 6.69-6.61 (m, 1H), 6.56-6.48 (m, 2H), 6.41 (d, J = 7.5 Hz, 1H), 4.57 (t, J = 8.8 Hz, 2H), 3.68-3.49 (m, 1H), 3.34-3.11 (m, 6H), 2.97-2.89 (m, 1H), 2.88-2.71 (m, 5H), 2.57 (dd, J= 26.0, 18.0 Hz, 2H), 2.47-2.29 (m, 3H), 2.04-1.93 (m, 3H), 1.84 (dt, J= 15.1, 7.6 Hz, 2H). MS m / z (ESI): 408.9[M+H] + Example 49: (6bR,10aS)-8-(3-(5-fluorobenzofuran-4-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyroximate[1,2,3-de]oxathiocarbamate

[0099] The preparation of E49 was carried out according to the synthesis method of Example 3. X H NMR (500 MHz, CDCb) 5 7.63 (d, J = 2.0 Hz, 1H), 7.28- 7.26 (m, 1H), 7.02-6.92 (m, 1H), 6.79 (dd, J= 2.0, 1.0 Hz, 1H), 6.69-6.57 (m, 1H), 6.50 (d, J= 7.0 Hz, 1H), 6.40 (d, J= 7.5 Hz, 1H), 3.58 (ddd, J= 13.0, 8.0, 2.5 Hz, 1H), 3.32-3.14 (m, 4H), 2.95-2.75 (m, 8H), 2.70 (d, J = 14.6 Hz, 1H), 2.41 (d, J = 9.0 Hz, 2H), 2.24 (dd, J = 25.5, 9.2 Hz, 1H), 1.94 (dd, J = 22.0, 9.0 Hz, 4H). MS m / z (ESI): 406.9[M+H] +Example 50: (6bR,10aS)-8-(2-(1H'indol-3-yl)ethyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathiocarbamate At room temperature, 2-(1H-indol-3-yl)ethane-1-ol (71.2 mg, 0.44 mmol) and triethylamine (220.6 mg, 2.18 mmol) were dissolved in dichloromethane (2 mL). The temperature was lowered to 0°C, and methanesulfonyl chloride (74.9 mg, 0.65 mmol) was added. The mixture was returned to room temperature and stirred for 1 hour before being concentrated in vacuo at room temperature. The crude product was dissolved in anhydrous dimethyl sulfoxide (3 mL), and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolinone (50.0 mg, 0.22 mmol) and potassium iodide (72.3 mg, 0.44 mmol) were added. and DIPEA (0.5 mL). The reaction mixture was stirred at 100°C for 16 hours. LCMS (ENBW230404-026-6-R1, 2023.8.8) indicated the formation of the product. The reaction mixture was cooled to room temperature, added to 50 mL of water, and extracted with ethyl acetate (40 mL x 3). The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated to yield the crude product. The crude product was purified to yield (6bR,10aS)-8-(2-(1H-indol-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (7.80 mg, 9.5% yield) as a white solid. XH NMR (400 MHz, CDCL) 5 8.09 (s, 1H), 7.59 (d, J= 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21-7.16 (m, 1H), 7.13-7.09 (m, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6.69 (t, J = 7.7 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 3.65-3.57 (m, 1H), 3.48 (s, 1H), 3.31-2.28 (m, 4H), 3.15-3.11 (m, 3H), 2.95-2.82 (m, 6H), 2.72-2.61 (m, 1H), 2.36-2.24 (m, 2H), 2.05 (d,J= 15.4 Hz, 1H). MS m / z (ESI): 373.2 [M+H] + Example 52: 2-Methyl-1-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1,2,3-de]oxathiapa8(7H)-yl)propyl)phenoxy)propan-2-ol Step 1: At room temperature, chroman-2-one (5.0 g, 33.7 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium borohydride (1.9 g, 50.5 mmol) was added. The reaction mixture was stirred at 60° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched by the addition of saturated chromium chloride solution. The mixture was concentrated in vacuo and slurried with 50 mL of dichloromethane. The mixture was filtered and the filtrate was concentrated in vacuo to afford 2-(3-hydroxypropyl)phenol (5.5 g, 99.1% yield) as a colorless oil. MS m / z (ESI): 153.2 [M+H] +Step 2: Dissolve 2-(3-hydroxypropyl)phenol (5.5 g, 36.1 mmol) in acetone (50 mL), add benzyl bromide (7.4 g, 43.3 mmol) and potassium carbonate (7.5 g, 54.2 mmol). The reaction mixture was stirred at 50°C (2°C) for 48 hours. The reaction mixture was cooled to room temperature, 120 mL of water was added, and extraction with ethyl acetate (100 mL x 3) afforded 3-(2-(benzyloxy)phenyl)propan-1-ol (3 g, 34.4% yield) as a clear oil. MS m / z (ESI): 243.2 [M+H] + Step 3: At room temperature, 3-(2-(benzyloxy)phenyl)propan-1-ol (1.3 g, 5.23 mmol) and triethylamine (1.6 g, 15.7 mmol) were dissolved in dichloromethane (10 mL). The temperature was lowered to 0°C, and methanesulfonyl chloride (899.1 mg, 7.8 mmol) was added. The mixture was returned to room temperature and stirred for 1 hour. The reaction solution was concentrated in vacuo at room temperature, added to water, and extracted with dichloromethane. The organic phase was spin-dried to dryness to obtain a white solid. (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (600.0 mg, 2.6 mmol) was dissolved in DMSO (9 mL). The white solid and DIPEA (1.5 mL) were added. The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, added to 50 mL of water, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 0 / 1.00-8 / 92) to obtain (6bR,10aS)-8-(3-(2-(benzyloxy)phenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3 / :4,5]pyrrolo[1,2,3-de]oxathioline (1.0 g, 84.3% yield) as a yellow oil. MS m / z (ESI): 454.2 [M+H] +Step 4: A dichloromethane solution of boron tribromide (22 mL, 22 mmol) was added dropwise to a solution of (6bR,10aS)-8-(3-(2-(benzyloxy)phenyl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1,2,3-de]oxathioline (1 g, 2.2 mmol) in DCM (30 mL) at room temperature under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, methanol was added to quench the reaction in an ice bath. The reaction mixture was concentrated in vacuo, and water (30 mL) was added. 1M sodium hydroxide solution was added to adjust the pH to 10, and ethyl acetate (40 mL x 3) was added for extraction. The combined organic phases were concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 100 / 0-90 / 10) to obtain 2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathiolin-8(7H)-yl)propyl)phenol (600 mg, yield: 77.3%) as a yellow solid. MS m / z (ESI): 364.2 [M+H] + Step 5: 2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3 / :4,5]pyrrolo[1,2, 3-de]oxathio[#-8(7H)-yl)propyl)phenol (100.0 mg, 0.28 mmol) and 1-chloropropane-2-one (50.9 mg, 0.55 mmol) were dissolved in DMF (1.5 mL) at room temperature, and anhydrous sodium carbonate (268.9 g, 0.83 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated in vacuo to obtain a crude product, which was then filtered through a silica gel column (PE / EA= The product was purified by HPLC (HPLC-MS / MS: 100 / 0-0 / 100) to give 1-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1,2, 3-de]oxathiapa8(7H)-yl)propyl)phenoxy)propan-2-one (36 mg, yield: 14.9%) as a yellow oil. MS m / z (ESI): 420.2 [M+H] +Step 6: At room temperature, 1-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2, 3-de]benzothiazol-8(7H)-yl)propyl)phenoxy)propan-2-one (50.0 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL). The system was filled with nitrogen. The reaction solution was cooled to 0°C, and methylmagnesium bromide (3 M, 0.1 mL, 0.36 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, saturated hydrazine chloride solution was added to quench the reaction, 40 mL of water was added to dilute the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and concentrated in vacuo to obtain a crude product. The crude product was prepared to obtain 2-methyl-1-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3,,4,:4,5]pyrrolo[1,2,3-de]oxathiapa 8(7H)-yl)propyl)phenoxy)propan-2-ol (5.77 mg, yield: 10.2%) as a brown solid. 1 HNMR(400 MHz, CDC13) 57.17-7.10 (m, 2H), 6.89 (t, J= 7.3 Hz, 1H), 6.82 (d, J= 8.1 Hz, 1H), 6.65 (t, J= 7.6 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 6.40 (d, J = 7.9 Hz, 1H), 3.79 (s, 2H), 3.64-3.56 (m, 1H), 3.30-3.20 (m, 4H), 3.01 (d, J= 10.7 Hz, 1H), 2.88-2.78 (m, 5H), 2.68 (t, J= 7.5 Hz, 2H), 2.55-2.33 (m, 4H), 2.05-2.01 (m, 2H), 1.94-1.89 (m, 2H), 1.36 (s, 6H). MS m / z (ESI): 436.3[M+H] + o Example 53: 2-(2-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1, 2, 3-de]benzothiazolin-8(7H)-yl)propyl)phenoxy)ethane At room temperature, 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-yl)propyl)phenol (50.0 mg, 0.14 mmol) and 1,3-dioxopentan-2-one (24.2 mg, 0.28 mmol) were dissolved in DMF (1 mL), potassium carbonate (38.0 g, 0.28 mmol) was added, and the reaction mixture was stirred at 110°C for 16 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and the crude product was extracted with ethyl acetate (30 mL x 3). The crude product was prepared to obtain 2-(2-(3-((6bR,10aS)-3-methyl-2, 3,6b,9,10,10a-Hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiolin-8(7H)-yl)propyl)phenoxy)ethan-1-ol (10.82 mg, 18.9% yield) was obtained as a yellow solid. E NMR (400 MHz, CDCL) δ 7.19-7.07 (m, 2H), 6.94-6.81 (m, 2H), 6.65 (t, δ = 7.6 Hz, 1H), 6.51 (d, J = 6.8 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 4.14-4.03 (m, 2H), 4.00-3.91 (m, 2H), 3.66-3.55 (m, 1H), 3.34-3.16 (m, 4H), 2.95 (d, J = 12.5 Hz, 1H), 2.86 (s, 3H), 2.85-2.72 (m, 2H), 2.68 (t, J= 7.5 Hz, 2H), 2.34 (d, J= 51.1 Hz, 4H), 1.98-1.85 (m, 4H). MS m / z (ESI): 408.2[M+H] + Example 54: (6bR, 10aS)-8-(3-(2,2-difluorobenzo[d][l,3]dioxazol-4-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,:4,5]pyrrolo[1,2,3-de]oxazol-4-yl) ... Step 1: At room temperature, 2, 2-difluorobenzo[d][l,3]dioxazole (500.0 mg, 3.16 mmol) was dissolved in tetrahydrofuran (8 mL), sec-butyllithium (202.6 mg, 3.16 mmol) was added, and the system was filled with nitrogen. The reaction solution was cooled to -65 ° C, and butyl ring (183.7 mg, 3.16 mmol) and trifluoroacetic boron (189.6 mg, 1.3 mmol) were added dropwise. The reaction solution was stirred at -65. (2) for 1 hour. After the reaction was completed, saturated aqueous chromium chloride solution was added to quench the reaction, 60 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was concentrated in vacuo to obtain a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 100 / 0-90 / 10) to obtain 3-(2, 2 4-Difluorobenzo[d][l,3]dioxazol-4-yl)propan-1-ol (470 mg, 68.8% yield) was obtained as a clear oil. 1HNMR (400 MHz, CDCI3) 57.02-6.96 (m, 1H), 6.94- 6.88 (m, 2H), 3.69 (t, J = 6.3 Hz, 2H), 2.84-2.56 (m, 2H), 1.93 (dq, J= 13.9, 6.4 Hz, 2H). Step 2: Dissolve 3-(2, 2-difluorobenzo[d][l,3]dioxazol-4-yl)propan-1-ol (94.3 mg, 0.44 mmol) and triethylamine (220.6 mg, 2.18 mmol) in dichloromethane (3 mL) and cool to 0. (2, methanesulfonyl chloride (74.9 mg, 0.65 mmol) was added, the mixture was returned to room temperature, stirred for 1 hour, and the reaction solution was concentrated in vacuo at room temperature. The crude product was dissolved in DMSO (3 mL), and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1,2, 3-de]oxathioline (50 mg, 0.22 mmol) and DIPEA (0.5 mL) were added. The reaction solution was stirred at 60. (2 for 18 hours. The reaction solution was cooled to room temperature, added to 50 mL of water, extracted with ethyl acetate (40 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to obtain a crude product. The crude product was purified by preparative method to obtain (6bR,10aS)- 8-(3-(2,2-Difluorobenzo[1,3]dioxazol-4-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3 / 4,5]pyrrolo[1,2, 3-de]oxathioline (41.33 mg, 43.72% yield) was obtained as a brown oil. E NMR (400 MHz, CDCh) δ 7.01-6.95 (m, 1H), 6.89 (dd, J = 7.5, 2.4 Hz, 2H), 6.65 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 6.9 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 3.63-3.56 (m, 1H), 3.34-3.14 (m, 4H), 2.84-2.79 (m, 5H), 2.69 (t, J = 7.6 Hz, 3H), 2.45-2.34 (m, 3H), 1.99-1.91 (m, 5H). 19F NMR (377 MHz, CDC13) 5 -49.80 (s, 2F). MS m / z (ESI): 428.2[M+H] + Example 55: (6bR,10aS)-3-methyl-8-(3-(2-(2,2,2-trifluoroethoxy)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyrobromo[1,2,3-de]oxathiocarbamate At room temperature, 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-yl)propyl)phenol (50.0 mg, 0.14 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (52.7 mg, 0.21 mmol) were dissolved in DMF (1 mL), potassium carbonate (57.1 mg, 0.41 mmol) was added, and the reaction mixture was stirred at 110°C for 16 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3) and concentrated to obtain a crude product. The crude product was prepared to obtain (6bR,10aS)- 3-Methyl-8-(3-(2-(2,2,2-trifluoroethoxy)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (5.32 mg, 8.2% yield) was obtained as a brown solid. X H NMR (400 MHz, CDCL) 5 7.20-7.15 (m, 2H), 6.99- 6.95 (m, 1H), 6.77 (d, J= 8.3 Hz, 1H), 6.65 (t, J= 7.6 Hz, 1H), 6.51 (d, J= 7.3 Hz, 1H), 6.40 (d, J= 7.6 Hz, 1H), 4.34 (q, J = 8.1 Hz, 2H), 3.64-3.55 (m, 1H), 3.35-3.17 (m, 4H), 2.94-2.79 (m, 5H), 2.75-2.64 (m, 3H), 2.41 (s, 2H), 2.27 (s, 1H), 1.96 (s, 2H), 1.73 (s, 3H). 19F NMR (377 MHz, CDCh) 5 -73.98 (s, 3F). MS m / z (ESI): 446.2[M+H] + o Example 56: (6bR,10aS)-3-methyl-8-(3-(2-(pyrido-4-oxy)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyrro[1,2,3-de]oxathioline 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-yl)propyl)phenol (60.0 mg, 0.16 mmol) and 4-bromopyrido[39.1 mg, 0.25 mmol) were dissolved in DMF (2 mL) at room temperature. Anhydrous sodium carbonate (107.6 g, 0.33 mmol) and cuprous iodide (6.3 mg, 0.03 mmol) were added. The reaction mixture was stirred at 120°C for 16 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and the crude product was extracted with ethyl acetate (30 mL×3). The crude product was prepared to obtain (6bR,10aS)-3-methyl-8-(3-(2-(pyrrole-4-oxy)phenyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrole[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin 2, 2, 2-trifluoroacetate (18.42 mg, yield 25.02%) as a black oil. 5 11.59 (s, 1H), 8.70 (d, J= 6.8 Hz, 2H), 7.44-7.34 (m, 3H), 7.24 (d, J= 6.7 Hz, 2H), 7.06 (d, J= 7.6 Hz, 1H), 6.78 (s, 1H), 6.59 (d, J = 8.1 Hz, 2H), 3.58-3.46 (m, 3H), 3.49-3.24 (m, 4H), 3.06-2.85 (m, 7H), 2.54 (t, J = 7.4 Hz, 3H), 2.39 (s, 1H), 2.29-1.90 (m, 3H). MS m / z (ESI): 441.1[M+H] +o Example 57: Preparation of (6bR,10aS)-8-(3-(2-(difluoromethoxy)phenyl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyro[1,2, 3-de]oxathioline 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazol-8(7H)-yl)propyl)phenol (50.0 mg, 0.14 mmol) and ((difluoromethyl)sulfonyl)benzene (60.8 mg, 0.32 mmol) were dissolved in acetonitrile (1 mL) at room temperature. A 25% solution of potassium hydroxide (84.9 mg, 1.5 mmol) in water (0.255 mL) was added, and the reaction system was purged with nitrogen. The reaction mixture was heated at 60.degree. C. (2) Stir for 16 hours. After the reaction is completed, 40 mL of water is added to dilute, extracted with ethyl acetate (30 mL x 3), the organic phases are combined, and concentrated in vacuo to obtain a crude product. The crude product is prepared to obtain (6bR, 10aS)-8-(3-(2-(difluoromethoxy)phenyl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline (6.39 mg, yield: 11.0%) as a brown solid. X H NMR (400 MHz, CDC13) 5 12.03 (s, 1H), 7.24-7.12 (m, 3H), 7.06 (d, J= 8.0 Hz, 1H), 6.73 (t, J =

[0100] 7.7 Hz, 1H), 6.58-6.32 (m, 3H), 3.63-3.46 (m, 4H), 3.32-3.29 (m, 3H), 3.03-2.86 (m, 7H), 2.71 (t, J= 7.4 Hz, 2H), 2.52-2.48 (m, 2H), 2.17-2.04 (m, 3H). 19 F NMR (377 MHz, CDCL) 5 -75.78 (s, 6F), -79.97 (d, J = 2.7 Hz, 2F). MS m / z (ESI): 414.2 [M+H]+ Example 58: (6bR,10aS)-3-methyl-8-(3-(pyridin-2-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyridin-3,4,4,5- Step 1: Dissolve 3-(Pyridin-2-yl)propan-1-ol (30.0 mg, 0.22 mmol) in dichloromethane (3 mL) at room temperature, cool to 0°C, add PCC (94.3 mg, 0.44 mmol), and return to room temperature with stirring for 16 hours. The reaction mixture was filtered through celite and added to 10 mL of water. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, diluted with 40 mL of water, and extracted with dichloromethane (30 mL x 3). The organic phases were dried over anhydrous sodium sulfate, and the combined organic phases were concentrated to yield 3-(Pyridin-2-yl)propanal (29 mg, 78.5% yield) as a clear oil. The crude product was used directly in the next reaction. MS m / z (ESI): 136.2 [M+H] +Step 2: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiophene (45.0 mg, 0.20 mmol) and 3-(pyrido-2-yl)propanal (29.2 mg, 0.22 mmol) were dissolved in dichloromethane (2 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. Sodium acetate borohydride (83.2 mg, 0.39 mmol) was added, and the reaction mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the mixture was added to 40 mL of water and extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated to yield the crude product. The crude product was purified by preparative method to give (6bR,10aS)-3-methyl-8-(3-(pyridin-2-yl)propyl)-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1,2, 3-de]benzothiazolin 2, 2, 2-trifluoroacetate (7.24 mg, 10.1% yield) as a brown oil. E NMR (400 MHZ, CDCh) 5 8.75 (d, J= 5.3 Hz, 1H), 8.25 (s, 1H), 7.79-7.67 (m, 2H), 6.72 (t, J = 7.7 Hz, 1H), 6.55-6.48 (m, 2H), 3.63-3.61 (m, 1H), 3.52-3.35 (m, 2H), 3.32 (t, J = 11.3 Hz, 3H), 3.23-3.17 (m, 2H), 3.14-3.09 (m, 3H), 2.90-2.78 (m, 5H), 2.42-2.36 (m, 2H), 2.27-2.13 (m, 2H), 2.02- 1.99 (m, 1H). 19 F NMR (376 MHz, CDCL) 5 -75.72 (s, 3F). MS m / z (ESI): 349.2[M+H] + Example 59: 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]benzothiazolin-8(7H)-yl)propyl)benzonitrile Step 1: Dissolve 3-(2-hydroxyphenyl)propanoic acid (500.0 mg, 2.85 mmol) in dichloromethane (5 mL) at room temperature, add oxalyl chloride (543.4 mg, 4.28 mmol), and stir at room temperature for 1 hour. Concentrate the reaction mixture in vacuo to obtain the crude product. Dissolve the crude product in THF / MeOH (4 mL / 4 mL) and add sodium borohydride (539.9 mg, 14.27 mmol). Stir the reaction mixture at room temperature for 16 hours. After the reaction, methanol was added for dilution, the mixture was concentrated in vacuo, and 50 mL of water was added. The mixture was extracted with ethyl acetate (40 mL x 3), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 0-60 / 40) to obtain 2-(3-hydroxypropyl)benzonitrile (300 mg, 59.2% yield) as a clear oil. MS m / z (ESI): 162.1 [M+H] + Step 2: At room temperature, 2-(3-hydroxypropyl)benzonitrile (300.0 mg, 1.86 mmol) and carbon tetrabromide (925.8 mg, 2.79 mmol) were dissolved in dichloromethane (35 mL). Triphenylphosphine (732.2 mg, 2.79 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 0-90 / 10) to obtain 2-(3-bromopropyl)benzonitrile (250 mg, 59.9% yield) as a clear oil. MS m / z (ESI): 226.1 [M+H] +Step 3: At room temperature, 2-(3-bromopropyl)benzonitrile (48.8 mg, 0.22 mmol) was dissolved in 1,4-dioxane / toluene (1.5 mL / 1.5 mL). (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3 / :4,5]pyrrolo[1,2,3-de]benzothiazolin (50.0 mg, 0.22 mmol), potassium iodide (72.4 mg, 0.44 mmol), and triethylamine (66.2 mg, 0.65 mmol) were added. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was prepared to give 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa[8(7H)-yl)propyl)benzonitrile (14.34 mg, yield 16.8%) as a yellow solid. X HNMR (400 MHz, CDC13) 57.61 (d, J= 7.7 Hz, 1H), 7.56-7.53 (m, 1H), 7.41 (d, J= 7.7 Hz, 1H), 7.32 (t, J= 7.6 Hz, 1H), 6.69 (t, J= 7.7 Hz, 1H), 6.52 (d, J= 7.3 Hz, 1H), 6.43 (d, J= 7.9 Hz, 1H), 3.66-3.57 (m, 2H), 3.29-3.24 (m, 4H), 3.22 (d, J= 10.8 Hz, 1H), 2.93-2.80 (m, 9H), 2.52 (t, J= 14.0 Hz, 1H), 2.38 (t, J= 11.8 Hz, 1H), 2.23-2.20 (m, 2H), 2.10 (d, J= 15.3 Hz, 1H). MS m / z (ESI): 373.2[M+H] + o Example 60: 7-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]benzothiazolinone P#-8(7H)-yl)propyl)-2, 3 -dihydropyrano[2,3-c]pyrrolo[1,2,3-d]pyrrolo[ ... Step 1: Add compound 7-chloropyro[2,3-c]pyrrolidone (300 mg, 1.96 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate (660 mg, 2.92 mmol), Pd(dppf)C12.CH2C12 complex (30 mg, 0.04 mmol) and potassium carbonate (540 mg, 3.92 mmol) into a 25 mL single-necked reaction bottle, followed by the addition of dioxane (4 mL) and water (1 mL). After the addition, replace the atmosphere with nitrogen three times, slowly heat to 100 °C and stir for 16 h. After the reaction was completed, the reaction solution was filtered, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 10% EA / PE) to obtain ethyl (E)-3-(furano[2,3-c]pyridin-7-yl)acrylate (white solid, 180 mg, yield 42%). MS m / z (ESI): 218.4 [M+H] + Step 2: Ethyl (E)-3-(furano[2,3-c]pyridin-7-yl) acrylate (50 mg, 0.23 mmol) was added to a 25 mL single-necked reaction flask. Methanol (10 mL) and 10% Pd / C (wet basis, 10 mg) were then added, respectively. After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the target compound, ethyl 3-(2,3-dihydrofurano[2,3-c]pyridin-7-yl) propionate (crude product, 50 mg, 99% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 222.5 [M+H] +Step 3: Add ethyl 3-(2,3-dihydrofurano[2,3-c]pyridin-7-yl)propionate (50 mg, 0.23 mmol) to a 25 mL three-necked reaction flask, followed by anhydrous tetrahydrofuran (3 mL). Lithium aluminum tetrahydride (25 mg, 0.69 mmol) was added in batches under nitrogen and an ice-water bath, and the reaction was stirred in an ice-water bath for 0.5 h. After the reaction was completed, LCMS detection was performed. Na2SO4.10H2O was slowly added to the reaction solution to quench it, and the mixture was filtered. The filter cake was washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified and separated by normal phase column chromatography (eluent gradient: 30% EA / PE) to obtain compound 3-(2,3-dihydrofurano[2,3-c]pyridin-7-yl)propan-1-ol (pale yellow oil, 25 mg, yield 62%). MS m / z (ESI): 180.5 [M+H] + Step 4: Compound 3-(2,3-dihydrofurano[2,3-c]pyridin-7-yl)propan-1-ol (25 mg, 0.14 mmol) and anhydrous dichloromethane (3 mL) were added to a 10 mL single-necked reaction flask. PCC (60 mg, 0.28 mmol) was then added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, dichloromethane (10 mL) was added to the reaction solution. The pH was then adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to afford crude 3-(2,3-dihydrofurano[2,3-c]pyridin-7-yl)propanal (a reddish-brown oil, 30 mg). The crude product was used directly in the next reaction without further purification. MS m / z(ESI): 258.5[M+H] +Step 5: Preparation of 7-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin-8(7H)-yl)propyl)-2, 3-dihydrofurano[2,3-c]pyridin-7-yl)propanal (10 mg, 0.06 mmol, crude) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin-8(7H)-yl)propyl)-2, 3-dihydrofurano[2,3-c]pyridin-7-yl)propanal (10 mg, 0.06 mmol, crude) and (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3,,4,:4,5]pyrrolo[1,2, 3-de]benzothiazolin-8(7H)-yl)propanol ( The product was added to a 10 mL reaction bottle, followed by the addition of DIEA (35 mg, 0.30 mmol) and anhydrous DCM (2 mL). After the addition was complete, the mixture was stirred at room temperature for 16 h. After the reaction was completed by LCMS, the reaction solution was evaporated to dryness under reduced pressure, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain the title compound 7-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrido[3',4':4,5]<pyrro[1,2,3-de]oxathiazolinone 8(7H)-yl)propyl)-2, 3-dihydrofurano[2,3-c]pyrido[1,2,3-c]pyrido[1,2,3-d ... Yield 36%)o E NMR (500 MHz, MeOD) 8 7.92 (d, J = 4.9 Hz, 1H), 7.17 (d, J = 4.9 Hz, 1H), 6.61-6.55 (m, 1H), 6.47 (d, J= 7.2 Hz, 1H), 6.40 (d, J= 7.9 Hz, 1H), 4.60 (t, J= 8.9 Hz, 2H), 3.52-3.46 (m, 1H), 3.36-3.32 (m, 1H), 3.30-3.24 (m, 3H), 3.14-3.10 (m, 1H), 3.10-3.04 (m, 1H), 2.88-2.81 (m, 4H), 2.76-2.69 (m, 4H), 2.44- 2.33 (m, 2H), 2.26 (td, J = 12.1, 3.0 Hz, 1H), 2.02-1.97 (m, 1H), 1.94-1.85 (m, 4H).MS m / z (ESI): 391.9 [M+H]. + Example 61: 4-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiocarbamate P#-8(7H)-yl)propyl)phenyl)morpholin

[0101] The preparation of E61 was carried out according to the synthesis method of Example 1. 1 H NMR(400 MHz, CDC13) 5 7.01 (t, J= 7.6 Hz, 1H), 6.92 (d, J

[0102] = 7.1 Hz, 1H), 6.66 (t, J= 7.6 Hz, 1H), 6.60-6.47 (m, 3H), 6.41 (d, J= 7.9 Hz, 1H), 3.73-3.57 (m, 5H), 3.46- 3.42 (m, 2H), 3.34-3.20 (m, 6H), 3.10-3.08 (m, 1H), 2.94 (d, J= 10.4 Hz, 1H), 2.87-2.82 (m, 4H), 2.73 (t, J = 5.9 Hz, 4H), 2.48 (t, J= 11.2 Hz, 1H), 2.18-2.09 (m, 2H), 1.92-1.89 (m, 3H). MS m / z (ESI): 433.2[M+H] + o Example 62: (6bR, 10aS)-8-(3-(4-methoxypyridin-3-yl)propan-2-hydroxy-1-yl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-[3', 4': 4, 5] pyrrolido[1, 2, 3 -de]oxathiocarbamate Step 1: 3-iodo-4-methoxypyranol (1.5 g, 6.38 mmol) was added to a 100 mL reaction flask, followed by the addition of bistriphenylphosphine dichloride (0.13 g, 0.19 mmol), cuprous iodide (0.12 g, 0.64 mmol), and then DMF (20 mL), TEA (30 mL), and 2-(propan-2-halogen-1-oxytetrahydro-2H-pyranol) (1.3 g, 9.6 mmol) were added under nitrogen protection, and then stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL x 3), washed with brine (50 mL x 3), and the organic phase was concentrated and purified by normal phase column chromatography (dichloromethane: methanol = 20: 1) to obtain compound 4-methoxy-3-(3-((tetrahydro-2H-pyranol)-2H-pyranol)-2H-pyranol) (4-(2-Yl)oxy)prop-1-hydroxy-1-yl)pyrrolidone (white solid, 1.2 g, yield 76%). MS m / z (ESI): 248.5 [M+H] + Step 2: 4-Methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol-1-yl)pyrimidine (400 mg, 1.62 mmol) was added to a 100 mL reaction flask, followed by dichloromethane (10 mL) and TFA (5 mL). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated, saturated sodium bicarbonate (50 mL) was added, and extracted with dichloromethane (2 x 50 mL). The concentrated solution was purified by normal phase column chromatography (dichloromethane:methanol = 10:1) to afford 3-(4-methoxypyrimidine-3-yl)propan-2-ol-1-ol (colorless liquid, 200 mg, yield 75.2%). MS m / z (ESI): 164.4. [M+H] +Step 3: 4-methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol-1-yl)pyrimidine (100 mg, 0.61 mmol) was added to a 25 mL reaction flask, followed by DCM (50 mL), followed by DIEA (390 mg, 3 mmol), and MS2O (320 mg, 1.84 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with DCM (2 x 20 mL), and the organic phase was washed with saturated brine (2 x 20 mL). After concentration, 3-(4-methoxypyrimidine-3-yl)propan-2-ol-1-yl methanesulfonate (colorless liquid, 120 mg, yield 81.3%) was obtained. MS m / z (ESI): 242.5 [M+H] +Step 4: Compound 3-(4-methoxypyridin-3-yl)propan-2-hydroxy-1-yl methanesulfonate (50 mg, 0.21 mmol) and starting material (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyridin-[3 / :4,5]pyrrolo[1,2, 3-de]benzothiazolin (57 mg, 0.25 mmol) were added to a 25 mL reaction bottle, followed by DMSO (5 mL) and then DIPEA (81 mg, 0.63 mmol). After complete addition, the mixture was stirred at 60 °C for 16 h. The reaction mixture was added to ethyl acetate (30 mL), washed with water (30 mL), and then with brine (50 mL). The organic phase was concentrated and initially purified by normal phase column chromatography (dichloromethane: methanol = 10:1) to obtain 50 mg of a crude product. 20 mg of the product was then purified by reverse phase column chromatography (acetonitrile / (water + 0.05% NH4HCO3)) to obtain the compound (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)propan-2-hydroxy-1-yl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyridin-[3,4,:4,5]pyrrolo[1,2,3-de]oxathioline (gray solid, 10 mg, yield 31.5%). g NMR (500 MHz, DMSO-%) 5 8.44 (s, 2H), 7.12 (d, J = 5.2 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.48 (d, J =6.4 Hz, 1H), 6.38 (d, J= 6.4 Hz, 1H), 3.83 (s, 3H), 3.47-3.40 (m, 2H), 3.29 (s, 3H), 3.17 (s, 2H), 2.79 (s, 3H), 2.76-2.61 (m, 2H), 2.51 (s, 2H), 2.25-1.70 (m, 3H). MS m / z (ESI): 375.6[M+H] + Example 63: (6bR, 10aS)-8-((E)-3-(benzofuran-7-yl)allyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2, 3-de]oxathiocarbamate Step 1: Dissolve ethyl (E)-3-(benzofuran-7-yl)acrylate (65 mg, 0.3 mmol) in THF (2.0 mL), cool to -78°C, add 1 M DABL-H in tetrahydrofuran (0.45 mL, 0.45 mmol), and stir at -78°C for 1 h. Then, add sodium sulfate decahydrate and stir for 15 minutes. Filter, concentrate, and purify by normal phase chromatography to obtain (E)-3-(benzofuran-7-yl)prop-2-en-1-ol (yellow oil, 21 mg, 40% yield). MS m / z (ESI): 175.3. [M+H] + Step 2: Dissolve (E)-3-(benzofuran-7-yl)prop-2-en-1-ol (21 mg, 0.12 mmol) in DCM (2.0 mL). Add activated MnO2 (104 mg, 1.2 mmol) and stir at 20 °C for 3 h. Filter to obtain (E)-3-(benzofuran-7-yl)acryloylaldehyde (yellow oil, 20 mg), which is used directly in the next reaction. MS m / z (ESI): 173.3. [M+H] + Step 3: (6bR,10aS)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2, 3-de]oxathioline (25 mg, 0.10 mmol) and (E)-3-(benzofuran-7-yl)acryloylaldehyde (20 mg, 0.12 mmol) were dissolved in DCM (2.5 mL) at room temperature. Triethylamine (5.0 mg, 0.05 mmol) and acetic acid (6.0 mg, 0.1 mmol) were added. After stirring for 10 minutes, NaBH(0Ac)3 (120 mg, 0.6 mmol) was added and stirred at 20 °C for 16 min. h, concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain the compound (6bR,10aS)-8-((E)-3-(benzofuran-7-yl)allyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3,,4,:4,5]pyrrolo[1,2,3-de]oxathioline (pale yellow oil, 10.1 mg, yield 26%). XH NMR (500 MHz, DMSO-J6) 5 8.05 (s, 1H), 7.55 (d, J= 5.0 Hz, 1H), 7.36 (d, J= 5.0 Hz, 1H), 7.23 (t, J= 7.5 Hz, 1H), 7.00 (s, 1H), 6.79-6.71 (m, 2H), 6.50 (t, J= 7.5 Hz, 1H), 6.41 (d, J= 5.0 Hz, 1H), 6.34 (d, J = 5.0 Hz, 1H), 3.47-3.26 (m, 4H), 3.21-3.04 (m, 3H), 2.89-2.85 (m, 1H), 2.71 (s, 3H), 2.69-2.66 (m, 2H), 2.24-2.21 (m, 1H), 1.95-1.82 (m, 3H). MS m / z (ESI): 386.9[M+H] + o Example 64: 4-(3-((6bR,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H-pyrrolo[3, 4, 4, 5]pyrrolo[1,2,3-de]benzothiazolinone P#-8(7H)-yl)propyl)-2, 3 -dihydropyrano[3,2-c]pyrrolo[3,2-c]pyrrolo[3,2-d ...

[0103] The preparation of E64 refers to the synthetic method of Example 60. E NMR (500 MHz, DMSO-%) 5 8.13 (d, J = 5.4 Hz, 1H), 6.66 (d, J= 5.4 Hz, 1H), 6.51 (t, J= 7.6 Hz, 1H), 6.42 (d, J= 7.2 Hz, 1H), 6.33 (d, J= 7.8 Hz, 1H), 4.60 (t, J = 8.8 Hz, 2H), 3.33-3.27 (m, 3H), 3.18 (t, J= 8.8 Hz, 2H), 3.12-3.08 (m, 1H), 3.01-2.95 (m, 1H), 2.78 (s, 3H), 2.74 (dd, J= 11.9, 6.1 Hz, 1H), 2.70-2.66 (m, 1H), 2.63 (dd, J= 8.6, 6.6 Hz, 2H), 2.56 (d, J= 11.4 Hz, 1H), 2.31-2.21 (m, 2H), 2.10-2.03 (m, 1H), 1.88 (dd,J= 14.4, 2.9 Hz, 1H), 1.84-1.71 (m, 4H). MS m / z (ESI): 391.8 [M+H] + Example 65-1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-ethyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]<pyro[1,2,3-de]oxathiocarbamate Step 1: At room temperature, compound 3-(2,3-dihydrobenzofuran-7-yl)propan-1-ol (3 g, 16.8 mmol) and dichloromethane (50 mL) were added to a 100 mL single-necked flask. Dess-Martin reagent (21.4 g, 50.5 mmol) was then added. After addition, the mixture was stirred at room temperature for 5 h. After TLC, the reaction solution was filtered through celite. The filtrate was adjusted to an alkaline pH with saturated sodium bicarbonate aqueous solution. The filtrate was extracted with DCM (50 mL x 1). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-20%) to obtain compound 65-1-1 (colorless oil, 2.5 g, yield: 84%). Step 2: Compound 45-1-5 (2.0 g, 7.0 mmol), acetaldehyde aqueous solution (40% wt, 10 mL) and methanol (40 mL) were added into a 100 mL single-necked flask. Na(OAc)3BH (8.8 g, 42 mmol) was then added in batches. After the addition, the mixture was stirred at room temperature for 3 h. After the reaction was complete as determined by LCMS, the reaction solution was concentrated under reduced pressure to remove most of the solvent. The crude product was then dissolved in EA, washed with water (50 mL x 1), washed with saturated NaHCO3 solution (50 mL x 1), and extracted with EA (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was separated by column chromatography (EtOAc / PE = 0-25%) to obtain compound 65-1-2 (pale yellow oil, 1.8 g, yield: 82%). X H NMR (500 MHz, CDC13) 3 6.65 (t, J = 7.7 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.40 (d, J= 7.9 Hz, 1H), 4.21-4.03 (m, 3H), 3.88 (s, 1H), 3.73-3.64 (m, 1H), 3.45-3.35 (m, 1H), 3.35- 3.27 (m, 3H), 3.26-3.07 (m, 3H), 2.93-2.72 (m, 2H), 1.92-1.80 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.15 (t, J =

[0104] 7.1 Hz, 3H). MS m / z (ESI): 316.4 [M+H]+. Step 3: 65-1-3 was prepared according to the synthesis method of the second step in Example 73-1. MS m / z (ESI): 244.5 [M+H] + Step 4: The preparation of E65-1 was carried out according to the synthesis method of the third step of Example 73-1. E NMR (500 MHz, CDCL). 7.03 (dd, J = 7.3, 0.8 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.64 (t, J = 7.7 Hz, 1H), 6.47 (d, J =

[0105] 7.2 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 3.72-3.64 (m, 1H), 3.44-3.36 (m, 1H), 3.32- 3.17 (m, 7H), 3.00-2.90 (m, 1H), 2.83-2.70 (m, 2H), 2.58 (dd, J= 14.5, 7.6 Hz, 2H), 2.50-2.28 (m, 3H), 2.07- 1.93 (m, 3H), 1.91-1.83 (m, 2H), 1.14 (t, J= 7.1 Hz, 3H). MS m / z (ESI): 404.9 [M+H] + Example 65-2: (6bS,10aR)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-ethyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate Step 1: Dissolve 67-2-6 (2.10 g, 7.31 mmol) in THF (20.0 mL), add BH3 / THF (21.9 mL, 1 M) o The reaction was continued at 70 °C for 3 h. LCMS confirmed the reaction was complete. Water was added, extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 5:1) to obtain compound 65-2-1 (yellow solid, 1.80 g, 90% yield). MS m / z (ESI): 274.4 [M+H]+ Step 2: Methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiapiprolin 8(9H)hydrazine (1.70 g, 6.22 mmol) was dissolved in MeOH (600.0 mL), and aqueous acetaldehyde (9.12 g, 62.1 mmol) was added. The mixture was reacted at 25 °C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 3:1) to afford compound 65-2-2 (yellow solid, 1.04 g, 55% yield). MS m / z (ESI): 302.2 [M+H] + Step 3: 65-2-2 (1.00 g, 3.31 mmol) was dissolved in a solution of hydrobromic acid in acetic acid (20 mL) and reacted at 25 °C for 20 h. The reaction was complete as determined by LCMS. The reaction solution was concentrated to give compound 65-2-3 (gray solid, 1.04 g, yield 96%). MS m / z (ESI): 244.2 [M+H] + Step 4: Under nitrogen, 65-2-3 (400 mg, 1.64 mmol) was dissolved in MeOH (200 mL) and DCM (120 mL), 3-(2,3-dihydrobenzofuran-7-yl)propanal (347 mg, 1.97 mmol) and NaBH(AcO)3 (1.73 mg, 8.21 mmol) were added and the mixture was reacted at -25 °C. Water was added, and the mixture was extracted with EA. The mixture was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to obtain compound 65-2-4 (yellow solid, 1.04 g, yield 55%). MS m / z (ESI): 404.3 [M+H] +Step 5: 65-2-4 (100 mg, 0.248 mmol) was separated by SFC (Daicel ChiralPak IJ, 40mm IDx250mm, 10 gm; Mobile phase: n-Hexane / Ethanol [0.1% NH3.H2. (V / O1 = 95 / 5; Flow rate: 80 mL / min) to give white solid E65-1 (PK1: 42.8 mg, purity 98%, yield 42%, ee 98%, RT = 4.512, OROT = + 0.13.8 and white solid E65-2 (PK2: 37.4 mg, purity 97%, yield 37%, ee 100%, RT = 5.303, OROT = -10.2)). o E65』: E NMR (400 MHz, DMSO-d6)] H NMR (400 MHz, DMSO) 5 7.04 (d〃= 7.3 Hz, 1H), 6.91 (d〃= 7.4 Hz, 1H), 6.73 (t〃= 7.4 Hz, 1H), 6.50 (t〃= 7.6 Hz, 1H), 6.37 (d, = 7.2 Hz, 1H), 6.31 (d, = 7.8 Hz, 1H), 4.49 (t, J= 8.7 Hz, 2H), 3.51 (d = 8.6 Hz, 1H), 3.35 (d, = 7.2 Hz, 1H), 3.30-3.22 (m, 2H), 3.21-3.11 (m, 3H), 3.07 (d, =

[0106] 4.0 Hz, 1H), 3.03-2.94 (m, 1H), 2.75 (d, • / = 4.3 Hz, 1H), 2.64-2.52 (m, 2H), 2.47 (s, 2H), 2.24 (dd, = 15.9, 7.1 Hz, 2H), 2.08 (s, 1H), 1.89 (d,J= 14.4 Hz, 1H), 1.81-1.62 (m, 4H), 1.04 (tj= 7.0 Hz, 3H). MS m / z (ESI): 404.3 5 7.04 (d, J = 7.2

[0107] Hz, 1H), 6.92 (d, = 7.6 Hz, 1H), 6.73 (t, J= 7.2 Hz, 1H), 6.50 (t, J= 7.6 Hz, 1H), 6.37 (d, = 7.2 Hz, 1H),

[0108] 6.31 (d, J = 7.6 Hz, 1H), 4.49 (t, J = 8.8 Hz, 2H), 3.60-3.45 (m, 1H), 3.41-3.23 (m, 3H), 3.23-3.11 (m, 3H),

[0109] 3.10-3.04 (m, 1H), 3.04-2.90 (m, 1H), 2.82-2.71 (m, 1H), 2.63-2.53 (m, 2H), 2.49-2.41 (m, 2H), 2.31-2.17 (m,

[0110] 2H), 2.15-2.01 (m, 1H), 1.95-1.83 (m, 1H), 1.83-1.60 (m, 4H), 1.05 (t, J= 7.2 Hz, 3H). MS m / z (ESI): 404.3 [M+H] + Example 66: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-(butylene-3-yl)-2, 3, 6b, 7, 8, 9, 10, 10a-octadecyl Step 1: 45-1-6 (1 g, 2.67 mmol) and TEA (13.5 g, 13.3 mmol) were dissolved in DCM / MeOH (10:1) (150 ml), followed by the addition of (BOC)2O (540 mg, 2.67 mmol). The reaction was allowed to proceed at room temperature for 6 h. LCMS indicated complete reaction. The product was extracted with DCM and purified by silica gel column chromatography (PE / EA = 100 / 0-70 / 30) to afford product 66-1 (600 mg, white solid, yield: 71.3%). MS m / z (ESI): 316.3 [M+H] +Step 2: Compound 66-1 (70 mg, 0.22 mmol) was dissolved in MeOH (50 ml), followed by the addition of oxadiazole-3-one (80 mg, 1.11 mmol). Na(OAc)3BH (71 mg, 1.11 mmol) was then quickly added and the reaction continued for 1 h. LCMS indicated complete reaction. The product was extracted with DCM and purified through a silica gel column (PE / EA = 100 / 0-60 / 40) to afford compound 66-2 (70 mg, colorless liquid, yield: 84.9%). MS m / z (ESI): 372.1 [M+H]+. Step 3: Compound 66-2 (60 mg, 0.16 mmol) was added to a 25 mL reaction vial. Dichloromethane (5 mL) and TFA (2 mL) were then added and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to give compound 66-3 (colorless liquid, 60 mg, TFA salt, yield 96.3%). MS m / z (ESI): 272.2 [M+H] + Step 4: 66-3 (30 mg, 0.11 mmol) was dissolved in MeOH (5 ml) and DCM (5 ml), and then 65-1-1 (21 mg, 0.12 mmol) was added. Na(OAc)3BH (116 mg, 0.55 mmol) was quickly added and the reaction was continued for 1 h. LCMS showed that the reaction was complete. The product was extracted with DCM, concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% -70%) to obtain compound E66 (10 mg, white solid, 7.3 Hz, IH), 6.92 (d, J= 7.5 Hz, lH), 6.76 (t, J= 7.4 Hz, IH), 6.59 (dt, J = 14.0, 7.0 Hz, 2H), 6.16 (d, J= 7.7 Hz, IH), 4.86 (tt, J = 19.2, 6.5 Hz, 4H), 4.75 (p, J = 6.9 Hz, IH), 4.53 (t, J = 8.7 Hz, 2H), 3.55-3.36 (m, 3H), 3.30-3.23 (m, IH), 3.19 (t, J= 8.7 Hz, 3H), 2.90 (s, IH), 2.82 (td, J= 9.8, 3.2 Hz, IH), 2.72 (s, IH), 2.60-2.50 (m, 2H), 2.41 (d, J= 7.8 Hz, 2H), 2.34-2.22 (m, IH), 1.97 (s, 3H), 1.85 (dt, J= 15.1, 7.5 Hz, 2H). MS m / z (ESI): 432.8 [M+H] + Example 67-1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one Step 1: Compound 45-1-4 (5 g, 16.6 mmol) and 50 mL of HBr in HOAc were reacted at 50°C for 16 h. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the solid was washed with EA and dried to afford compound 67-1-1 (6 g, brown solid). MS m / z (ESI): 230.2 [M+H] +Step 5: Compound 67-1-1 (2 g, 6.47 mmol) was dissolved in 100 mL DCM and 100 mL MeOH, followed by the addition of NaBH(OAc)3 (6.8 g, 32.2 mmol) and finally compound 65-1-1 (910 mg, 5.18 mmol). The mixture was reacted at room temperature for 0.5 h. LCMS showed that a small amount of compound 67-1-1 remained. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7-8. The DCM and MeOH were concentrated, and EA and water were added. The mixture was filtered, and the aqueous phase was extracted twice with EA. The organic phases were combined, dried, concentrated, and purified by column chromatography (100% DCM-2% MeOH / DCM) to give compound E67-1 (990 mg). The residue was then purified by HPLC (0-95% 30 min, 0.05% NH4HCO3 in H2O, basic C18 column) to give 790 mg of compound E67-1. Yield: 36%. X H NMR(400 MHz, CDCh) 5 7.66 (s,lH), 7.04 (d, J= 7.0 Hz, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.82 (d, J= 7.0 Hz, 1H), 6.76 (t, J= 7.5 Hz, 1H) , 6.72 (t, J= 7.5 Hz, 1H), 6.58 (d, J= 7.0 Hz, 1H), 4.53(t, J= 9.0 Hz, 2H), 3.95(d, J= 14.5 Hz, 1H), 3.39(d, J= 14.5 Hz, 1H), 3.34-3.32 (m, 2H), 3.20 (t, J= 8.5 Hz, 2H), 2.95-2.90 (m, 1H), 2.78-2.71 (m, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.43-2.33 (m, 2H), 2.26-2.19 (m, 1H), 2.03-1.92 (m, 2H), 1.86-1.80 (m, 3H). MS m / z (ESI): 390.7 [M+H] + o Example 67-2: (6bS, 10aR) -8- (3- (2,3 - dihydrobenzofuran-7-yl) propyl) -6b, 7, 8, 9, 10, 10a- hexahydro -1H- pyrido [3', 4': 4, 5] pyrro[1, 2, 3 - de] oxazolidinone 2 (3H) -one Step 1: Dissolve (2-bromophenyl)-2-nitropropane hydrochloride (16.0 g, 71.4 mmol) and piperidine-4-one hydrochloride (12.1 g, 89.8 mmol) in isopropanol (200.0 mL), and add concentrated hydrochloric acid solution (16.0 mL). The mixture was reacted at 100 °C for 12 h. The reaction was complete by LCMS. The product was filtered and concentrated to give compound 67-2-1 (yellow solid, 20.0 g, yield 98%). MS m / z (ESI): 251.0, 253.0 [M+H] + Step 2: Dissolve 67-2-1 (19.0 g, 60.5 mmol) in TFA (20 mL) and add triethylsilyl hydrochloride (70.3 g, 605 mmol).

[0111] The reaction was continued at 40 °C for 48 h. LCMS showed that the reaction was complete. The reaction solution was concentrated, and saturated sodium bicarbonate solution was added. The mixture was extracted with EA, dried over sodium sulfate, and filtered and concentrated to give compound 67-2-2 (gray solid, 15.0 g, yield 89%). MS m / z (ESI): 253.0, 255.0 [M+H] + Step 3: Under nitrogen, compound 67-2-2 (15.0 g, 59.5 mmol) was dissolved in DCM (200 mL), and TEA (13.1 mL, 94.8 mmol) and dimethyl dicarbonate (6.99 g, 52.1 mmol) were added. The mixture was reacted at 25 °C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 5:1) to afford compound 67-2-3 (white solid, 15.0 g, 81% yield). MS m / z (ESI): 311.0 [M+H] +Step 4: Under nitrogen, dissolve compound 67-2-3 (14.0 g, 26.9 mmol) in toluene (200 mL). Add benzophenone imine (5.87 g, 32.3 mmol), NaOt-Bu (5.19 g, 53.9 mmol), and BINAP (0.50 g, 0.810 mmol). React at 60 °C for 3 h. Then, add Pd2(dba)3 (0.25 g, 0.270 mmol) and continue the reaction at 105 °C for 16 h. The reaction was complete after LCMS detection. Water was added, extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE: EA = 5: 1) to obtain compound 67-2-4 (yellow solid, 8.10 g, yield 73%). MS m / z (ESI): 412.2 [M+H] + Step 5: Under nitrogen, compound 67-2-4 (8.10 g, 19.0 mmol) was dissolved in acetone (100 mL), and ethyl 2-bromoacetate (4.27 g, 25.5 mmol), Na2CO3 (3.13 g, 29.5 mmol), and KI (4.08 g, 24.6 mmol) were added. The reaction was incubated at 65 °C for 12 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 5:1) to afford compound 67-2-5 (yellow solid, 8.50 g, 86% yield). Step 6: Under nitrogen, compound 67-2-5 (3.00 g, 5.86 mmol) was dissolved in THF (10 mL), and hydrochloric acid (3.4 mL, 2 N) was added. The reaction was continued at 25 °C for 1.5 h. LCMS confirmed the reaction was complete and the product was concentrated to give compound 67-2-6 (yellow solid, 1.40 g, 80% yield). MS m / z (ESI): 288.2 [M+H] + Step 7: Under nitrogen, compound 67-2-6 (660 mg, 2.29 mmol) was dissolved in a solution of hydrobromic acid in acetic acid (5 mL) and reacted at 50 °C for 18 h. The reaction was complete by LCMS. The product was concentrated to afford compound 67-2-7 (yellow solid, 450 mg, 85% yield). MS m / z (ESI): 230.2 [M+H] +Step 8: Under nitrogen, compound 67-2-7 (200 mg, 0.872 mmol) was dissolved in THF (5 mL), and 3-(2,3-dihydrobenzofuran-7-yl)propanal (184 mg, 1.05 mmol) and NaBH3CN (274 mg, 4.36 mmol) were added. The mixture was reacted at 25 °C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 67-2-8 (yellow solid, 100 mg, 29% yield). MS m / z (ESI): 390.2 [M+H] + Step 9: 67-2-8 (100 mg, 0.257 mmol) was separated by SFC (Daicel ChiralPak 1H, 40mm IDx250mm, 10 gm; Mobile phase: n-Hexane+TFAO.1 / Ethanol = 60 / 40; Flow rate: 70 mL / min) to give compound E67-2 (PK1: 27.4 mg, purity 91%, yield 27%, ee 100%, RT = 3.441, OROT = -219.5) and compound E67-1 (PK2: 30.3 mg, purity 83%, yield 30%, ee 99%, RT = 4.936, OROT = +52.6) O E67-2: 1HNMR(400 MHz, DMSO) 5 10.35 (s, 1H), 7.08-7.02 (m, 1H), 6.92 (d, J= 7.2 Hz, 1H), 6.80-6.70 (m, 2H), 6.64 (t, J= 7.6 Hz, 1H), 6.58 (dd, , 2.31-2.15 (m, 2H), 2.10-1.99 (m, 1H), 1.97-1.85 (m, 1H), 1.86-1.75 (m, 1H), 1.73- 1.59 (m, 3H). MS m / z (ESI): 390.2 [M+H] + . E67-1: E NMR (400 MHz, DMSO) 5 10.36 (s, 1H), 7.04 (d, J =

[0112] 7.2 Hz, 1H), 6.92 (d, J= 7.6 Hz, 1H), 6.81-6.70 (m, 2H), 6.64 (t, J= 7.6 Hz, 1H), 6.60-6.55 (m, 1H), 4.49 (t, J = 8.8 Hz, 2H), 3.80 (d, J = 14.4 Hz, 1H), 3.34-3.06 (m, 7H), 2.90-2.77 (m, 1H), 2.66-2.54 (m, 1H), 2.35- 2.15 (m, 2H), 2.13-1.98 (m, 1H), 2.00-1.86 (m, 1H), 1.85-1.74 (m, 1H), 1.73-1.58 (m, 3H). MS m / z (ESI):

[0113] 390.2 [M+H] + Example 67-3: trans-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3 / :4,5]pyrrolo[1,2,3-de]oxathiapa 2(3H)-one Step 1: Compound 67-2-1 (20.00 g, 79.6 mmol) was dissolved in DMF (250.0 mL), and KCO (44.0 g, 318 mmol) was added. The mixture was reacted at -25°C for 0.5 h. Bian bromine (0.75 g, 4.380 mmol) was then added and the reaction continued at room temperature for 2 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE = 100%) to afford compound 67-3-1 (white solid, 11.0 g, 40.7% yield). MS m / z (ESI): 341.2, 343.2 [M+H] + Step 2: 67-3-1 (3.0 g, 8.79 mmol) was dissolved in THF (20.0 mL), and dimethyl borane sulfide (90.0 mL, 176 mmol, 2M) was added under nitrogen. The reaction was continued at 80°C for 48 h. LCMS analysis indicated that a quarter of the starting material remained in the reaction, and two peaks of the desired molecular weight were present. 6N HCl was added, and the reaction was continued at 100°C for another half an hour. The product was then pumped dry and purified by reverse phase chromatography (ACN:H2O = 25%) to afford compound 67-3-2 (yellow solid, 1.9 g, 63% yield). MS m / z (ESI): 343.2, 345.0 [M+H] + Step 3: 67-3-2 (1.9 g, 5.12 mmol) was dissolved in toluene (20.0 mL). LiHMDS (17 ml, 5.12 mmol) was added under nitrogen at 0°C for 0.5 h. 2-Chloroacetamide (510 mg, 5.448 mmol) was then added and allowed to react overnight at 25°C. LCMS confirmed the reaction was complete. The product was quenched with aqueous sodium sulfite solution, extracted with DCM and water, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 67-3-3 as a brown solid, 500 mg, 25% yield. MS m / z (ESI): 400.3, 402.4 [M+H] +Step 4: Compound 67-3-3 (500 mg, 1.25 mmol) was dissolved in dioxane (5.0 mL), and Cui (70 mg, 0.375 mmol), anhydrous carbonic acid (1.9 g, 3.74 mmol), and 2,5-dioxane (135 mg, 1.5 mmol) were added. The mixture was reacted at 110 °C for 2 h. LCMS confirmed the reaction was complete. The product was extracted with EA and water, filtered, concentrated, and purified on a silica gel column (EA:PE = 42%) to afford compound 67-3-4 as a brown solid (260 mg, 65% yield). MS m / z (ESI): 320.2 [M+H] + Step 5: Under nitrogen, compound 67-3-4 (260 mg, 0.814 mmol) was dissolved in MeOH (3.0 mL), and Pd / C (50 mg) and (Boc)2 (355 mg, 1.63 mmol) were added. The reaction was allowed to proceed at 25°C for 18 h. LCMS confirmed the reaction was complete. The carbon was filtered off, the sample was washed with silica gel, concentrated, and purified on a silica gel column (EA:PE = 56%) to afford compound 67-3-5 (yellow solid, 130 mg, 48% yield). MS m / z (ESI): 275.2 [M-56+H] + Step 6: Compound 67-3-5 (50 mg, 0.152 mmol) was dissolved in DCM (10 mL), and HCl-dioxane (0.5 mL) was added. The reaction was continued at 25°C for 3 h. LCMS confirmed the reaction was complete. The reaction solution was drained and directly used in the next step to obtain compound 67-3-6 (yellow solid, 35 mg, 100% yield). MS m / z (ESI): 230.4 [M+H] +Step 8: Under nitrogen, compound 67-3-6 (35 mg, 0.153 mmol) was dissolved in MeOH (20 mL) and DCM (12 mL). 3-(2,3-dihydro-1-benzofuran-7-yl)propanal (60 mg, 0.305 mmol) and sodium acetate borohydride (97 mg, 0.458 mmol) were added, and the mixture was reacted at 25 °C overnight. LCMS confirmed the completion of the reaction. The reaction solution was drained, filtered, concentrated, and then purified (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 25%-78%) to obtain compound E67-3 (white solid, 15.35 mg, yield 25.8%). E NMR (400 MHz, CD3OD) 5 7.06 (dd, J= 7A, 1.0 Hz, 1H), 6.94 (d, J= 7.6 Hz, 1H), 6.83 (d, ■ / = 7.4 Hz, 1H), 6.77 (td, J = 7.6, 5.5 Hz, 2H), 3.20 (t, J= 8.8 Hz, 2H), 2.95 (dd, 3H), 2.74 (t, J = 7.8 Hz, 2H), 2.63 (t, J = 7.6 Hz, 3H), 2.56-2.42 (m, 2H), 2.20 (dd, J = 12.6, 2.7 Hz, 1H), 1.94 (dd, J = 16.0, 12.0, 5.8 Hz, 3H). MS m / z (ESI): 390.2 [M+H]+. Example 68: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydropyri[4,3-b][l,4]thiazido[2,3,4-hi]

[0114] The preparation of E68 was carried out according to the synthesis method of Example 42. E NMR (500 MHz, CD3OD) 5 7.18-7.04 (m, 2H), 6.98-6.84 (m, 2H), 6.80-6.62 (m, 2H), 4.54-4.49 (m, 2H), 4.29-4.27 (m, 1H), 4.03 (d,J= 5.0 Hz, 1H), 3.65-3.61 (m, 1H), 3.48-3.44 (m, 1H), 3.35-3.33 (m, 1H), 3.26-3.16 (m, 5H), 3.10-2.84 (m, 3H), 2.75-2.58 (m, 4H), 2.31-2.18 (m, 1H), 2.08-1.94 (m, 2H). MS m / z (ESI): 392.9 [M+H] + o Example 69: (6bR, 10aS) -8- (3- (2,3 - dihydrobenzofuran-7 - yl) -2 - fluoropropyl) -3 - methyl -2, 3, 6b, 7, 8, 9, 10, 10a-octahydro- 1H- pyrrolo [3, 4, 4, 5] pyrrolo [1, 2, 3 - de] oxazolidinone Step 1: 7-Bromo-2,3-dihydrobenzofuran (2 g, 10 mmol), allyltributyltin (3.5 g, 11 mmol), Pd(PPh3)4, and CsF (3.04 g, 20 mmol) in 10 mL of 1,4-dioxane were purged with N2 three times. The temperature was raised to 110°C and the reaction was allowed to proceed for 16 h. The reaction was complete by TLC. The reaction was filtered, concentrated, and water and EA were added. The layers were separated, and the aqueous phase was extracted once with EA. The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 50 / 1) to afford 69-1 (1.3 g, colorless liquid). Step 2: 69-1 (1.1 g, 6.88 mmol) was added to a single-necked flask containing 20 mL of DCM, and m-CPBA (2.79 g, 13.75 mmol) was added portionwise. The reaction was allowed to react at room temperature for 16 h. TLC showed that the reaction was complete. The product was filtered and the solid was washed with DCM. Saturated sodium bicarbonate was added to the filtrate. The mixture was separated, dried, concentrated, and passed through a column (PE / EA = 50 / 1) to give 69-2 (600 mg, colorless liquid). Step 3: (6bR,10aS)-3-[3-(g-2,3,6b,7,8,9,10,10a- / k-hydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathioline (300 mg, 1.3 mmol), 69-2 (276 mg, 1.57 mmol), K2CC)3 (360 mg, 2.6 mmol) and 5 mL of DMF were microwave-treated at 150 °C for 1.5 h. LCMS indicated a small amount of starting material remained. Water and EA were added, the layers separated, and the aqueous phase was extracted once with EA. The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1) to afford 69-3 (430 mg, yellow liquid). MS m / z (ESI): 406.5 [M+H] +Step 4: BAST (55 mg, 0.24 mmol) was added to a three-necked flask containing 2 mL of DCM. The atmosphere was replaced with nitrogen three times, the reaction mixture was cooled to -78°C, and a solution of compound 69-3 (50 mg, 0.12 mmol) in DCM was added. The mixture was slowly warmed to room temperature and allowed to react for 16 h. LCMS indicated the main peak was the desired product. The reaction was quenched with saturated sodium bicarbonate. The layers were separated, and the aqueous phase was extracted once with DCM. The combined organic phases were dried, concentrated, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to afford compound E69 (7.5 mg, white solid, yield: 15.4%).

[0115] 1H NMR (500 MHz, CDCh) 5 7.08 (d, J= 7.1 Hz, 1H), 6.96 (d, J= 6.9 Hz, 1H), 6.78 (t, J= 8.2 Hz, 1H), 6.65 (t, J= 7.2 Hz, 1H), 6.50 (d, J= 7.3 Hz, 1H), 6.41 (d, J= 7.8 Hz, 1H), 5.23-4.87 (m, 1H), 4.54 (t, J= 8.7 Hz, 2H), 3.63-3.55 (m, 1H), 3.33-3.15 (m, 6H), 3.02-2.66 (m, 11H), 2.17-1.77 (m, 3H).MS m / z (ESI): 408.5[M+H] + Example 70: (6bR,10aS)-8-(3-(3-chloro-6-methylpyrrolo-2-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrrolo[3',4':4,5]pyrrolo[1,2,3-de ... Step 1: CuBr (832 mg, 5.8 mmol) was added to a three-necked flask containing 30 mL of THF. The atmosphere was replaced with nitrogen three times, the temperature was lowered to -78°C, and 0.5 M (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide (23 mL, 11.6 mmol) was added dropwise. The reaction was allowed to proceed at this temperature for 20 min. 2-Bromo-3-chloro-6-methylpyridine (300 mg, 1.45 mmol) was added, and the reaction was continued at -78°C for 3 h. The mixture was then warmed to room temperature and allowed to react for 16 h. LCMS confirmed the reaction was complete. Ammonia was added to adjust the pH to 9-10. EA and water were then added. The mixture was filtered and separated. The aqueous phase was extracted twice with EA. The combined organic phases were washed once with saturated sodium chloride solution, dried, concentrated, and column chromatography (PE / EA = 3 / 1) to yield 70-1 (300 mg, colorless liquid). MS m / z (ESI): 242.1, 243.9 [M+H] + Step 2: Compound 70-1 (300 mg, 1.24 mmol) was added to a single-necked vial containing 3 mL of THF. 4M HCl (1 mL, 4 mmol) was then added and the mixture was allowed to react at 50°C for 3 h. LCMS indicated completion of the reaction. The THF was concentrated, and the pH was adjusted to 8-9 with saturated sodium bicarbonate. EA and water were then added and the layers separated. The aqueous phase was extracted twice with EA. The combined organic phases were washed once with saturated sodium chloride solution, dried, concentrated, and filtered through a column chromatography column (PE / EA = 3 / 1) to yield 70-2 (90 mg, brown oil). MS m / z (ESI): 184.0, 185.9 [M+H] + . Step 3: The preparation of E70 refers to the synthetic method of step 7 of E46. 1HNMR (5OO MHz, CDC13) 57.47 (d,J= 8.0 Hz, lH), 6.92 (d, J= 8.0 Hz, 1H), 6.64 (t, J= 7.5 Hz, 1H), 6.51 (d, J= 7.0 Hz, 1H), 6.40 (d, J= 8.0 Hz, 1H), 3.62- 3.57 (m, 1H), 3.32-3.11 (m, 4H), 2.96-2.87 (m, 3H), 2.86 (s, 3H), 2.85 - 2.65 (m, 2H), 2.54-2.42 (m, 5H), 2.23- 2.21 (m, 1H), 2.07-1.88 (s, 5H).MS m / z (ESI): 398.2 [M+H]+ Example 71: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one Step 1: Dissolve 2,3-dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.76 mmol) in THF (50 mL), cool to -78 °C, add vinylmagnesium chloride (6.6 mL, 10 mmol), warm to room temperature, and stir for 2 hr. Quench the reaction by adding aqueous chromium chloride (50 mL). Extract with ethyl acetate (50 mL x 2), wash with saturated brine, and dry over anhydrous sodium sulfate. The organic phase is concentrated to obtain the crude product, which is then purified by normal phase column chromatography to afford compound 71-1 (colorless oil, 1.1 g, yield: 92%). MS m / z (ESI): 177.4 [M+H] + Step 2: The preparation of 71-2 followed the synthetic method of the first step in Example E65. Step 3: Compound 67-1-1 (150 mg, 0.66 mmol), compound 71-2 (135 mg, 0.79 mmol), and anhydrous DCM (15 mL) were added to a 50 mL single-necked flask. TEA (200 mg, 1.98 mmol) was then added. After the addition was complete, the mixture was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction mixture was washed with saturated NH4Cl solution (50 mL x 1) and extracted with DCM (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-5%) to afford compound 71-3 (pale yellow oil, 150 mg, yield: 57%). XHNMR (500 MHz, CDCh) 57.78 (s, 1H), 7.67 (d,J=7.6Hz, 1H), 7.36 (dd, J= 7.2, 1.1 Hz, 1H), 6.92-6.87 (m, 1H), 6.85 (d, J =7.4 Hz, 1H), 6.75 (t, J = 7.6 Hz, 1H), 6.62 (d, J= 7.7 Hz, 1H), 4.71 (t,J= 8.8 Hz, 2H), 3.95 (d,J= 14.5 Hz, 1H), 3.71-3.51 (m, 1H), 3.45-3.31 (m, 4H), 3.25 (t, J= 8.8 Hz, 2H), 3.21-2.93 (m, 4H), 2.67-2.49 (m, 1H), 2.37-2.07 (m, 2H), 2.05- 1.97 (m, 1H). MS m / z (ESI): 404.5 [M+H] + Step 4: Compound 71-3 (150 mg, 0.37 mmol) and anhydrous MeOH (10 mL) were added to a 50 mL single-necked flask. NaBH4 (45 mg, 1.11 mmol) was then added portionwise at room temperature. After addition, the mixture was stirred at room temperature for 1 h. After completion of the reaction as determined by LCMS, the reaction mixture was washed with saturated NH4Cl solution (20 mL x 1) and extracted with DCM (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-10%) to afford compound 71-4 (white solid, 120 mg, yield: 80%). XH NMR (500 MHz, MeOD) 57.18 (dd, J= 7.4, 3.6 Hz, 1H), 7.10 (dd, J= 7.3, 1.0 Hz, 1H), 6.87-6.79 (m, 2H), 6.72 (td,J= 7.6, 1.9 Hz, 1H), 6.65 (d,J= 7.8 Hz, 1H), 4.93-4.90 (m, 1H), 4.63-4.47 (m, 3H), 3.89 (d, J= 14.6 Hz, 1H), 3.34 (dd, J= 11.9,9.0 Hz, 2H), 3.18 (t, J = 8.6 Hz, 2H), 3.08-2.98 (m, 1H), 2.92-2.82 (m, 1H), 2.67-2.45 (m, 2H), 2.44-2.33 (m, 1H), 2.09-1.86 (m, 5H). MS m / z (ESI): 406.6 [M+H] + Step 5: Compound 71-4 (20 mg, 0.05 mmol) and anhydrous DCM (3 mL) were added together in a 25 mL three-necked flask. A dichloromethane solution of DAST (55 mg, 0.25 mmol) was slowly added dropwise under nitrogen and a dry ice-ethanol bath. After the addition, the mixture was allowed to stir at room temperature for 3 h. After the reaction was complete as determined by LCMS, a saturated NH4Cl solution was added to the reaction solution for washing (10 mL x 1) to quench the reaction mixture. The mixture was then extracted with DCM (10 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and dried under reduced pressure. The crude product was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain the target compound E71 (white solid, 6 mg, yield: 30%). XH NMR (500 MHz, MeOD) 57.18 (t, J = 6.8 Hz, 1H), 7.12 (t, J= 8.4 Hz, 1H), 6.84 (dt, J= 15.0, 7.4 Hz, 2H), 6.72 (dd, J= 15.7, 7.8 Hz, 1H), 6.66 (t, J= 8.0 Hz, 1H), 4.95-4.88 (m, 1H), 4.61-4.51 (m, 3H), 3.89 (dd, J= 14.5, 8.5 Hz, 1H), 3.49-3.33 (m, 4H), 3.21-3.13 (m, 3H), 3.06-2.94 (m, 1H), 2.82-2.54 (m, 3H), 2.16-2.03 (m, 3H). MS m / z (ESI): 408.8 [M+H] + Example 72: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-2-fluoropropyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiapiprolin 2

[0116] E72 was prepared according to the synthetic method of Example 69. g NMR (500 MHz, CDCL) 57.41 (s, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.84-6.68 (m, 3H), 6.57 (d, J= 7.8 Hz, 1H), 4.99 (d, J= 50.2 Hz, 1H), 4.57- 4.51 (m, 2H), 3.94 (dd, J= 14.6, 2.6 Hz, 1H), 3.54-3.28 (m, 3H), 3.21 (t, J= 8.7 Hz, 2H), 2.99-2.85 (m, 3H), 2.58 (t, J= 102.0 Hz, 4H), 1.97 (d, J = 33.6 Hz, 3H). MS m / z (ESI): 408.6[M+H] +Example 73-1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one Step 1: Under nitrogen, compound 45-1-4 (210 mg, 0.69 mmol) was dissolved in dry tetrahydrofuran (5.0 mL). Sodium hydroxide (55.7 mg, 1.39 mmol, 60% dispersion in mineral oil) was added. The reaction was allowed to proceed at 0°C for 0.5 h. Methyl iodide (55.7 mg, 1.39 mmol) was then added and the reaction continued at room temperature for 2 h. After completion of the reaction as determined by LCMS, the reaction was quenched with 10.0 mL of ice water and extracted with dichloromethane (10.0 mL x 2). The organic phase was evaporated to dryness, and the crude product was purified on a normal silica gel column to afford compound 73-1-1 (brown solid, 190 mg, 96% yield). MS m / z (ESI): 316.2 [M+H] + Step 2: Compound 73-1-1 (190 mg, 0.60 mmol) was dissolved in 30% hydrobromic acid / acetic acid solution (3.0 mL) and stirred at 50°C for 16 h. LCMS confirmed the disappearance of the starting material. After cooling to room temperature, the mixture was filtered to obtain compound 73-1-2 (brown solid, 45 mg, 20% yield). MS m / z (ESI): 244.2 [M+H] +Step 3: Under nitrogen protection, compound 73-1-2 (45.0 mg, 0.19 mmol), 3-(2, 3-dihydrobenzofuran-7-yl)propanal (31.0 mg, 0.19 mmol), and acetic acid (0.05 mL, 0.93 mmol) were dissolved in THF (3.0 mL), and sodium hydroxyborohydride (24.7 mg, 0.39 mmol) and 0. The reaction was allowed to proceed for 2 h. The reaction was complete after LCMS detection, and the product was filtered, dried by rotation, and purified by reverse phase purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to give compound E73-1 (white solid, 10.1 mg, yield 14%). 1H NMR (400 MHz, CDCh) δ 7.01 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.86-6.84 (m, 1H), 6.79-6.72 (m, 3H), 4.55 (t, J = 8.4 Hz, 2H), 4.01 (t, J = 14.0 Hz, 1H), 3.38-3.35 (m, 2H), 3.32 3-Hydroxy-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-d]-[4-(2-nitrobenzofuran-7-yl)propyl]-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-d]-[4-(2-nitrobenzofuran-7-yl)propyl]-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-d]-[4-(2-nitrobenzofuran-7-yl)propyl]-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-d]-[4-(2-nitrobenzofuran-7-yl)propyl]-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-d]-[4-(2-nitrobenzofuran-7-yl)propyl]-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3 -de]oxathia 2(3H)-one

[0117] Step 1: Compound 67-2-6 (840 mg, 2.92 mmol) was dissolved in THF (5.0 mL). NaH (9.12 g, 62.1 mmol) and iodomethane (77.3 mg, 0.636 mmol) were added under ice-cooling. The mixture was reacted at 0 °C for 2 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 20:1) to afford compound 73-2-1 (yellow solid, 770 mg, 87% yield). MS m / z (ESI): 302.1 [M+H] + Step 2: Compound 73-2-1 (770 mg, 2.55 mmol) was dissolved in a solution of hydrobromic acid in acetic acid (5 mL) and reacted at 50 °C for 18 h. LCMS confirmed the reaction was complete, and the reaction solution was concentrated to give compound 73-2-2 (gray solid, 526 mg, 84% yield). MS m / z (ESI): 244.2 [M+H] + Step 3: Under nitrogen, compound 73-2-2 (300 mg, 1.23 mmol) was dissolved in THF (5.0 mL), and 3-(2,3-dihydrobenzofuran-7-yl)propanal (260 mg, 1.48 mmol) and NaBH3CN (387 mg, 6.16 mmol) were added. The mixture was reacted at 25 °C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 73-2-3 (yellow solid, 30.0 mg, 6% yield). MS m / z (ESI): 404.2 [M+H] +Step 4: 73-2-3 (30.0 mg, 0.0744 mmol) was separated by SFC (Daicel ChiralCel OD, 40mm IDx250mm, 10gm; Mobile phase: n-Hexane / Ethanol [0.1% NH3.H2O (V / V)] = 70 / 30; Flow rate: 80 mL / min) to give white solid E73-2 (PK1: 2.20 mg, purity 96%, yield 7%, ee 100%, RT = 3.543, OROT = -205.3 and white solid E73-1 (PK2: 6.00 mg, purity 72%, yield 20%, ee 99%, RT = 4.604, OROT = + 163.3)o E73-2: ENMR (400 MHz, CDCh) 5 6.97 (d, J= 7.2 Hz, 1H), 6.85-6.74 (m, 3H), 6.72-6.65 (m, 2H), 4.45 (t, J= 8.8 Hz, 2H), 3.91 (d, J = 14.0 Hz, 1H), 3.42-3.27 (m, 2H), 3.26 (s, 3H), 3.20-3.00 (m, 3H), 2.75-2.40 (m, 4H), 2.15-1.82 (m, 4H), 1.61-1.37 (m, 3H), 1.26-1.07 (m, 1H). E73-1: XH NMR (400 MHz, CDC13) 5 7.01 (d, J = 7.2 Hz, 1H), 6.91 (d, J= 7.6 Hz, 1H), 6.86-6.84 (m, 1H), 6.79-6.72 (m, 3H), 4.55 (t, J= 8.4 Hz, 2H), 4.01 (t, J= 14.0 Hz, 1H), 3.38-3.35 (m, 2H), 3.32 (s, 3H), 3.30-3.29 (m, 1H), 3.19 (t, J= 8.8 Hz, 2H), 2.94-2.72 (m, 2H), 2.57 (t, J= 7.6 Hz, 2H), 2.39-2.16 (m, 3H), 2.02-1.77 (m, 5H). Example 74: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-ethyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one Step 1: Compound 45-1-4 (70 mg, 0.23 mmol) was added to a 50 mL three-necked reaction flask, followed by DMF (5 mL). The mixture was stirred at 0 °C for 5 min under a nitrogen atmosphere, followed by the addition of sodium hydride (9 mg, 0.35 mmol). Ethyl iodide (43 mg, 0.28 mmol) was then added dropwise, and the mixture was allowed to react at room temperature for 5 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl solution, as determined by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford compound 74-1 (a dark brown oil, 50 mg, 66% yield). MS m / z (ESI): 330.5 [M+H] +Step 2: The preparation of 74-2 refers to the synthesis method of the first step of Example 72. Step 3: The preparation of E74 refers to the synthesis method of the fifth step of Example 8. g NMR (500 MHz, CDCL) 5 7.06-7.01 (m, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.88-6.69 (m, 4H), 4.52 (t, J = 8.7 Hz, 2H), 4.03-3.84 (m, 3H), MS m / z (ESI):418.9 [M+H] + Example 75: (6bR,10aS)-8-(2-((2,3-dihydrobenzofuran-7-yl)oxy)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiapiperazine 2(3H)-one Step 1: 7-Methoxybenzofuran (500 mg, 3.37 mmol) and 10 mL of DCM were purged with N2 three times, cooled to -78°C, and 2M BBr3 (2.5 mL, 5 mmol) was added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 3 h. TLC indicated complete reaction of the starting material. Sat. NH4Cl was added to the reaction mixture, and the layers were separated. The aqueous phase was extracted once more with DCM. The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1) to afford 75-1 (280 mg, colorless liquid). MS m / z (ESI): 133.2 [MH]; Step 2: Compound 75-1 (280 mg, 2.09 mmol) was added to a 100 mL single-necked reaction flask. Methanol (10 mL), 10% Pd / C (wet basis, 50 mg), and 20% Pd(OH)2 / C (wet basis, 50 mg) were then added, respectively. The atmosphere was replaced with hydrogen three times, and the reaction was stirred at 60°C for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 75-2 (crude product, 260 mg, 92% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 135.2 [MH]-. Step 3: 75-2 (200 mg, 1.47 mmol), 1,2-dibromoethane (1.37 g, 7.35 mmol), NaOH (176 mg, 4.41 mmol), TBAB (142 mg, 0.44 mmol), and 10 mL of water were replaced with N2 three times. The temperature was raised to 90 °C and the reaction was allowed to proceed for 16 h. TLC showed a small amount of starting material remaining. EA was added to the reaction mixture, and the layers were separated. The aqueous phase was extracted twice more with EA. The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1) to afford 75-3 (130 mg, yellow oil). Step 4: 67-1-1 (20 mg, 0.087 mmol), 75-3 (32 mg, 0.131 mmol), DIEA (23 mg, 0.174 mmol), KI (29 mg, 0.174 mmol) and 2 mL DMF were replaced with N2 three times, heated to 80 °C, and reacted for 16 h. LCMS showed that the reaction was complete.The reaction solution was cooled to room temperature, filtered, and purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30% - 70%) to obtain compound E75 (8 mg, pink solid). 57.74 (s, 1H), 6.83 (d, J= 7.0 Hz, 2H), 6.81-6.69 (m, 3H), 6.59 (d, J = 7.5 Hz, 1H), 4.60 (t, J= 9.0 Hz, 2H), 4.19 (t, J = 6.0 Hz, 2H), 3.96 (d, J= 15.0 Hz, 1H), 3.50-3.30 (m, 3H), 3.22 (t, J= 8.5 Hz, 2H), 3.07-2.99 (m, 1H), 2.94-2.73 (m, 3H), 2.51-2.38 (m, 1H), 2.15-1.94 (m, 3H).MS m / z (ESI): 392.2[M+H] + Example 76: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-hydroxypropyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]<pyrro[1,2,3-de]benzothiazolidine-2(3H)-one (HJM-2119, CJJ120-093)

[0118] The preparation of E76 refers to the synthetic method of Example 71. XH NMR (500 MHz, CD3 OD) 5 7.18 (t, J = 6.8 Hz, 1 H), 7.11 (dd, J = 7.3, 0.9 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.84 (ddd, J = 8.7, 7.7, 1.5 Hz, 2H), 4.94-4.90 (m, 1H), 4.63-4.49 (m, 3H), 4.00 (d, J= 14.4 Hz, 1H), 3.45-3.38 (m, 2H), 3.37-3.31 (m, 3H), 3.24-3.14 (m, 3H), 3.08-3.00 (m, 1H), 2.85-2.55 (m, 3H), 2.17-1.99 (m, 5H). MS m / z (ESI):420.6[M+H] + Example 77: (6bR,10aS)-8-(3-(2,3-dihydropyrano[2,3-c]pyrrolo[7-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa 2(3H)-one

[0119] The preparation of E77 refers to the synthetic method of Example 60. E NMR (500 MHz, MeOD) 5 7.92 (d, J = 4.9 Hz, 1H), 7.17 (d, J= 4.9 Hz, 1H), 6.91-6.79 (m, 3H), 4.60 (t, J= 8.9 Hz, 2H), 3.97 (d, J= 14.4 Hz, 1H), 3.35 (t, J= 10.9 Hz, 1H), 3.31 (d, J = 1.3 Hz, 3H), 3.29-3.25 (m, 4H), 2.96-2.89 (m, 1H), 2.80-2.71 (m, 3H), 2.44-2.32 (m, 2H), 2.22 (td, J= 12.0, 3.3 Hz, 1H), 2.03-1.87 (m, 4H), 1.74 (t, J= 11.1 Hz, 1H). MS m / z (ESI): 405.7[M+H] +Example 78: (6bR,10aS)-8-(3-(3-chloropyridin-2-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyridin-[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa-2(3H)-one

[0120] The preparation of E78 refers to the synthetic method of step 5 of E67-1. 1H NMR (500 MHz, CD3OD) 5 8.54 (d, J = 4.5 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.50-7.41 (m, 1H), 7.04-6.99 (m, 1H), 6.96 (d, J= 7.4 Hz, 1H), 6.90 (t, J= 7.7 Hz, 1H), 4.07 (d, J= 14.5 Hz, 1H), 3.78-3.63 (m, 2H), 3.58-3.53 (m, 1H), 3.49-3.43 (m, 2H), 3.32 (s, 3H), 3.28- 3.19 (m, 3H), 3.12 (t, J = 7.5 Hz, 2H), 2.70 -2.56 (m,lH), 2.40 (d, J =16.0 Hz, 1H), 2.30-2.22 (m, 3H). MS m / z (ESI): 397.9, 399.9 [M+H] + Example 79: (6bR, 10aS) -3 - cyclobutyl-8-(3-(2,3 - dihydrobenzofuran-7-yl)propyl) -6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3', 4': 4, 5] pyrrolido[1, 2, 3 - de] oxazolidinone 2 (3H) -one Step 1: 2-bromoacetyl chloride (1 g, 6.36 mmol) and NaHCO 3 (1.07 g, 12.72 mmol) were added to a three-necked flask containing 10 mL of THF, the atmosphere was replaced with N 2 three times, and the mixture was cooled to 0. (2, cyclobutylamine (544 mg, 7.63 mmol) was added, the temperature was slowly raised to room temperature, and the reaction was carried out for 2 h. EA and saturated sodium chloride solution were added, the layers were separated, the aqueous phase was extracted once with EA, the organic phases were combined, dried and concentrated to obtain 79-1 (800 mg, white solid), which was used directly in the next step. Step 2: Ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-chenodeoxy-2-cortico[2-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1-[4-hydroxyethyl]-1- The liquid phase was separated, and the aqueous phase was extracted three times with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried, concentrated, and passed through a column (PE / EA = 3 / 1) to obtain 79-2 (180 mg, brown oil). MS m / z (ESI): 436.6, 438.6 [M+H] + Step 3: Compound 79-2 (180 mg, 0.414 mmol), Pd2(dba)3 (38 mg, 0.0414 mmol), NaOt-Bu (80 mg, 0.828 mmol), BINAP (77 mg, 0.124 mmol), and 10 mL of dioxane were added to a 100 mL single-necked flask. The atmosphere was replaced with nitrogen three times, the temperature was raised to 110°C, and the reaction was allowed to proceed for 16 hours. LCMS confirmed the complete reaction of the starting materials. The reaction solution was cooled to room temperature, and water and EA were added. The layers were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, dried, and concentrated to afford compound 79-3 (150 mg, crude), which was directly used in the next step. MS m / z (ESI): 356.2 [M+H] +Step 4: Compound 79-3 (150 mg, 0.422 mmol) and 2 mL of HBr in HOAc were reacted at 50 °C for 16 h. LCMS indicated completion of the reaction. The reaction solution was cooled to room temperature, the HOAc was concentrated, and the product was purified by HPLC (0.05% HCl in H2O, 0-95% ACN over 30 min) to afford compound 79-4 (45 mg, brown solid). MS m / z (ESI): 230.2 [M+H] + . Step 5: The preparation of E79 refers to the synthetic method of Step 5 of E67-1.

[0121] X H NMR (500 MHz, CDCb) 5 7.03 (d, J= 8.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.84 (dd, J = 6.5, 1.0 Hz, 1H), 6.80-6.73 (m, 3H), 4.66 (m, 1H), 4.53 (t, J= 8.5 Hz, 2H), 3.92 (d, J= 15.0 Hz, 1H), 3.42-3.30 (m, 1H), 3.26-3.15 (m, 4H), 3.01-2.92 (m, 1H), 2.82-2.75 (m, 1H), 2.72-2.63 (m, 1H), 2.61-2.53 (m, 4H), 2.49- 2.34 (m, 3H), 2.33-2.21 (m, 1H), 2.00-1.77 (m, 7H).MS m / z (ESI):444.8 [M+H] + Example 80: (6bR, 10aS)-8-(2-((2,3-dihydrobenzofuran-7-yl)amino)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one

[0122] 80-1 E80 Step 1: 2,3-Dihydrobenzofuran-7-amine (900 mg, 6.66 mmol) was dissolved in DMF (10.0 mL), and 1,2-dibromoethane (3.75 g, 19.9 mmol) was added. The mixture was reacted at 60°C for 2 h. TLC confirmed the reaction was complete, and the product was quenched with water, extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified (PE:EA = 10:1) to afford compound 80-1 (white solid, 300 mg, 18% yield). MS m / z (ESI): 242.0, 244.0 [M+H] +. Step 2: Compound 80-1 (135 mg, 0.591 mmol) was dissolved in DMSO (10.0 mL), and DIEA (208 mg, 1.61 mmol) and (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrrolo[3 / :4,5]pyrrolo[1,2, 3 -de]benzothiazolidine P#-2(3H)-one (130 mg, 0.537 mmol) were added. (2) The mixture was stirred for 16 h. TLC showed that the reaction was complete, and the mixture was quenched with water, extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified (eluent (v / v): acetonitrile / (water+0.05% NH4HCO3) = 30%-70%) to give compound E80 (white solid, 29.0 mg, yield 13%). 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 6.78 (d, J = 6.4 Hz, 1H), 6.65 (dd, J = 15.6, 7.6 Hz, 2H), 6.58 (dd, J = 7.6, 0.8 Hz, 1H), 6.51 (d, J = 6.8 Hz, 1H), 6.41 (d, J = 7.6 Hz, 1H), 4.65- 4.38 (m, 3H), 3.81 (d, J= 14.5 Hz, 1H), 3.35-3.17 (m, 4H), 3.18-3.04 (m, 4H), 2.96-2.83 (m, 1H), 2.71-2.59 (m, 1H), 2.49-2.38 (m, 1H), 2.22-2.07 (m, 1H), 2.01-1.87 (m, 1H), 1.87-1.75 (m, 1H), 1.72 (t, J = 11.2 Hz, 1H). MS m / z (ESI): 391.2 [M+H] + Example 81: (8aS, 12aR) -11- (3- (2,3 - dihydrobenzofuran-7-yl) propyl) -6, 7, 8a, 9, 10, 11, 12, 12a-octahydro- [1,4] diazoheptaquino [3,2,1-hi] pyrido [4,3-b"indole-5 (4H) -one

[0123] Step 1: The preparation of 81-1 refers to the synthesis method of step 5 of E83. Step 2: The preparation of 81-2 refers to the synthesis method of step 3 of E45-1. Step 3: The preparation of 81-3 refers to the synthesis method of step 4 of E67-1. Step 4: The preparation of E81 refers to the synthesis method of step 5 of E67-1. 5 1H NMR (500 MHz, CDC13) 5 7.48 (s, 1H),

[0124] 7.04 (d, J= 7.5 Hz, 1H), 6.91 (d, J= 8.0 Hz, 1H), 6.85 (d, J= 7.0 Hz, 1H), 6.77-6.71 (m, 2H), 6.60 (d, J= 8.0 Hz, 1H), 4.53 (t, J = 9.0 Hz, 2H), 3.62-3.31 (m, 3H), 3.24-3.09 (m, 3H), 3.05 -2.75 (m, 4H), 2.61-2.44 (m, 5H), 2.30-1.88 (m, 5H).MS m / z (ESI): 404.5 [M+H] + Example 82: (8aS, 12aR)-11-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-4-methyl-6, 7, 8a, 9, 10, 11, 12, 12a-octahydro-[1,4]diazoheptaquino[3,2,1-hi]pyrido[4,3-che-5(4H)-one Step 1: The preparation of 82-1 refers to the synthesis method of E73-1 step 1. Step 2: The preparation of 82-2 refers to the synthesis method of E73-1 step 2. Step 3: The preparation of E82 refers to the synthesis method of E73-1 step 3. 5 7.03 (d, J= 8.5 Hz, 1H), 6.94-6.89 (m, 3H), 6.76 (t, J = 7.5 Hz, 2H), 4.53 (t, J= 9.0 Hz, 2H), 3.74 (t, J= 12.5 Hz, 1H), 3.45-3.42 (m, 1H), 3.38-3.33 (m, 5H), 3.19 (t, J = 8.5 Hz, 2H), 2.84-2.77 (m, 1H), 2.75 -2.62 (m, 2H), 2.60 -2.52 (m, 3H), 2.45-2.34 (m, 2H), 2.32-2.21 (m, 1H), 2.06-1.94 (m, 2H), 1.88-1.81 (m, 3H). MS m / z (ESI): 418.5 [M+H] + Example 83: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5-fluoro-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa-2(3H)-one

[0125] Step 1: 4-Fluoro-2-bromoaniline (5.0 g, 26.3 mmol) and 5M HCl solution (50 mL) were added to a 250 mL three-necked flask and cooled to 0°C in an ice-water bath. 20 mL of NaNO2 (2.8 g, 39.4 mmol) solution was then slowly added dropwise. After the addition was complete, the mixture was stirred at 0.2°C for 2 h. A solution of SnCl2 (10 g, 52.6 mmol) in hydrochloric acid (5.5 mL) was then slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was stirred at room temperature overnight. After TLC detection, the reaction solution was directly filtered, the filter cake was washed with a small amount of concentrated HCl, and lyophilized to obtain the crude compound.

[0126] 83-1 (off-white solid, 4.4 g, 82% yield) The crude product was used directly in the next reaction without further purification. Step 2: Compound 83-1 (2.0 g, 9.8 mmol) was dissolved in isopropanol (30 mL), followed by the addition of 4-oxopiperazine hydrochloride (1.5 g, 10.7 mmol) and concentrated HCl (2 mL). After addition, the mixture was heated to 90°C under nitrogen and stirred overnight. After completion of the reaction, as determined by LCMS, the reaction mixture was cooled to room temperature. A large amount of solid precipitated, which was filtered, and the filter cake was washed with isopropanol and dried under reduced pressure to obtain the crude compound.

[0127] 83-2 (off-white solid, 2.0 g, yield: 76%) The crude product was used directly in the next step without further purification. MS m / z (ESI): 269.2, 271.2 [M+H] +Step 3: Crude compound 83-2 (200 mg, 0.74 mmol), TEA (225 mg, 2.22 mmol), and anhydrous DCM (10 mL) were added to a 25 mL three-necked flask. (BOC)2O (200 mg, 0.90 mmol) was then slowly added dropwise under N2 protection. The mixture was stirred at room temperature for 2 h. After completion of the reaction as determined by LCMS, water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 x 20 mL). The combined organic phases were washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 2% MeOH / DCM) to obtain compound 83-3 (white solid, 190 mg, 69% yield). Step 4: Compound 83-3 (100 mg, 0.27 mmol), benzophenone imine (60 mg, 0.32 mmol), t-BuONa (1.23 g, 12.8 mmol), t-BuXPhos-Pd-Gs (11 mg, 0.01 mmol), and toluene (5 mL) were added to a 35 mL microwave tube. Oxygen was bubbled through the tube for 2 minutes, followed by microwave heating at 120°C with stirring for 1 hour. After completion of the reaction as determined by LCMS, water (30 mL) was added to the reaction solution, and the mixture was extracted with EA (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0-20%) to afford compound 83-4 (pale yellow solid, 110 mg, yield: 70%). MS m / z (ESI):470.9 [M+H] +Step 5: Compound 83-4 (100 mg, 0.21 mmol), ethyl bromoacetate (70 mg, 0.42 mmol), CS2CO3 (240 mg, 0.63 mmol), KI (1.99 g, 12.76 mmol), and anhydrous CH3CN (10 mL) were added to a 25 mL single-necked flask and refluxed overnight under a nitrogen atmosphere. After completion of the reaction as determined by LCMS, the reaction solution was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted with EA (30 mL x 2). The combined organic phases were washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0-15%) to obtain compound 83-5 (yellow oil, 100 mg, yield: 85%). MS m / z (ESI): 556.6 [M+H] + Step 6: Compound 83-5 (100 mg, 0.18 mmol) and THF (10 mL) were added to a 25 mL single-necked flask, followed by the addition of 2N HCl solution (3 mL). After the addition was complete, the mixture was stirred at room temperature for 2 h. After completion of the reaction as monitored by LCMS, saturated NaHCO₃ solution was added to the reaction solution to adjust the pH to alkaline. The mixture was extracted with EA (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na₂SO₄, and dried under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-2%) to obtain compound 83-6 (yellow oil, 40 mg, yield: MS m / z (ESI): 246.5 [M-Boc] +Step 7: Compound 83-6 (40 mg, 0.12 mmol) and anhydrous DCM (5 mL) were added to a 25 mL single-necked flask. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 h. After completion of the reaction as determined by LCMS, the solvent was removed under reduced pressure. The crude product was then dissolved in 10% MeOH / DCM (20 mL). Saturated NaHCO₃ solution was added to adjust the pH to alkaline. Extraction was performed with 10% MeOH / DCM (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous Na₂SCM, and evaporated to dryness under reduced pressure to afford crude compound 83-7 (brown oil, 30 mg). The crude product was used directly in the next step without further purification. MS m / z (ESI): 246.7 [M+H] + Step 8: Compound 83-8 was prepared by referring to the synthesis method of Step 3 of Example E73-1. MS m / z (ESI): 406.7 [M+H] + Step 9: Crude compound 83-8 (20 mg, 0.05 mmol) and TFA (5 mL) were added to a 25 mL single-necked flask, followed by the addition of NaCN-BH₃ (30 mg, 0.50 mmol). After completion of the reaction, the reaction solvent was removed under reduced pressure. EA and water were then added to the crude product, followed by extraction with EA (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous Na₂SO₃, and evaporated to dryness under reduced pressure. The crude product was purified and isolated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH₄HCO₃) = 30%-70%) to afford compound E83 as a white solid, 4 mg, yield: 20%. XH NMR (500 MHz, CDCh) 57.49 (s, 1H), 7.07 (t,J= 8.2 Hz, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.77 (t,J= 7.4 Hz, 1H), 6.65 (dd,J= 8.0, 2.1 Hz, 1H), 6.45 (dd, J=9.2, 2.1 Hz, 1H), 4.52 (t, J=9.0 Hz, 2H), 3.90 (d, J= 14.3 Hz, 1H), 3.85-3.77 (m, 1H), 3.59-3.53 (m, 1H), 3.52-3.44 (m, 2H), 3.40 (d, J= 14.3 Hz, 1H), 3.20 (t,J= 8.8 Hz, 2H), 3.06-3.00 (m, 3H), 2.65 (t,J= 7.2 Hz, 2H), 2.52-2.41 (m, 2H), 2.21-2.15 (m, 1H), 2.13-2.07 (m, 2H). MS m / z (ESI): 408.7 [M+H] + Example 84: (6bR, 10aS)-8-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one

[0128] Step 1: At room temperature, 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (1.8 g, 11 mmol) was dissolved in dichloromethane (50 mL). Pyrrolidone (1.8 mL, 22.8 mmol) was added and the temperature was lowered to 0.2°C. TfzO (2.3 mL, 13.5 mmol) was then added and the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was washed with 1M HCl (50 mL), water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain compound 84-1 (yellow oil, 3.1 g). The crude product was used directly in the next step. MS m / z (ESI): 296.6 [M+H] +Step 2: Compound 84-1 (3.1 g, 10.5 mmol) was dissolved in DMF (24 mL) at room temperature. EtN (6 mL) and ethyl acrylate (2.0 g, 20 mmol) were added, followed by Pd(dppf)2Cl2 (770 mg, 1.05 mmol). The mixture was heated to 98°C under N2 protection for 18 hours. The mixture was concentrated to remove triethylamine and DMF, added to 50 mL of water, extracted with ethyl acetate (50 mL), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the crude product, which was purified by normal phase column chromatography to afford compound 84-2 (yellow oil, 760 mg, yield: 31%). MS m / z (ESI): 247.3 [M+H] + Step 3: Prepare according to the synthetic method of step 2 in Example 1. MS m / z (ESI): 249.1 [M+H] + Step 4: Prepare according to the synthetic method of step 3 of Example 1. MS m / z (ESI): 207.1 [M+H] +Step 5: Dissolve compound 84-4 (40 mg, 0.194 mmol) and triethylamine (78 mg, 0.78 mmol) in dichloromethane (4 mL) at room temperature and cool to 0. (2, methanesulfonic acid tincture (67 mg, 0.39 mmol), * returned to room temperature and stirred for 1.5 hours, DCM (15 mL) and water (15 mL) were added to separate the layers, the organic phase was washed with water (15 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was dissolved in acetonitrile (5 mL), compound 67-1-1 (30 mg, 0.194 mmol) and potassium carbonate (32 mg, 0.23 mmol), and heated to 80. (2) for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered and concentrated, and purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water+0.05%NH4HC03) = 30%-70%) to obtain compound E84 (white solid, 9.0 mg, yield: 10%). iHNMR (500 MHz, CD3OD) 5 6.96 (d, J= 10.0 Hz, 1H), 6.88 (d, J= 10.0 Hz, 1H), 6.82 (d, J= 5.0 Hz, 1H), 6.72-6.68 (m, 2H), 6.64 (d, J = 10.0 Hz, 1H), 3.87 (d, J= 10.0 Hz, 1H), 3.35 (d, J= 10.0 Hz, 1H), 3.03-2.94 (m, 4H), 2.86-2.77 (m, 1H), 2.66-2.63 (m, 1H), 2.55-2.52 (m, 2H), 2.43-2.26 (m, 3H), 2.05-1.82 (m, 5H), 1.42 (s, 6H). MS m / z (ESI): 418.6 [M+H] + Example 85: (6bR,10aS)-8-(3-(2H-spiro[benzofuran-3,1,-cyclopropane]-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]<pyro[1,2,3-de]oxazolidinone 2(3H)-one

[0129] Step 1: Methyltriphenylphosphine bromide (5.06 g, 14.2 mmol) was dissolved in THF (150 mL), cooled to 150°C, potassium tert-butoxide (1.67 g, 14.9 mmol) was added, the temperature was raised to 25°C and stirred for 1 hour, 7-bromo-3-benzofuranone (2.0 g, 9.39 mmol, dissolved in 150 mL THF) was added, and stirred at 25°C for 16 hours. 100 mL of water was added to quench the mixture, and ethyl acetate (150 mL) was used to dry the mixture. x 2) Extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration of the organic phase to obtain a crude product, which was purified by normal phase column chromatography to obtain compound 85-1 (colorless oil, 1.58 g, yield: 79%). MS m / z (ESI): 212.4 [M+H] + Step 2: Dissolve diethylzinc (27 mL, 27 mmol) in DCM (150 mL), cool to 0. (2), add TFA (2.32 mL,

[0130] The mixture was stirred at 0°C for 15 min, diiodomethane (8.0 g, 30 mmol) was added, and the mixture was stirred at 0°C for 15 min. Compound 85-1 (1.58 g, 7.49 mmol, dissolved in DCM (150 mL)) was added, and the mixture was stirred at 0°C for 15 min. The temperature was raised to 25°C and stirred for 16 hr. The reaction was quenched with 2 M HCl (150 mL), and the layers were separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain a crude product, which was purified and separated by normal phase column chromatography to obtain compound 85-2 (colorless oil, 390 mg, yield: 23%). MS m / z (ESI):

[0131] 226.4 [M+H] +Step 3: Compound 85-2 (350 mg, 1.54 mmol) was dissolved in DMF (15 mL). Triethylamine (3.5 mL) was added, followed by ethyl acrylate (308 mg, 3.08 mmol) and Pd(dppf)C12 (224 mg, 0.308 mmol). Under nitrogen, the reaction mixture was heated to 95°C and stirred for 18 hours. The solvent was evaporated to dryness, ethyl acetate (50 mL) was added, and the mixture was filtered. The filtrate was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Compound 85-3 (colorless oil, 300 mg, yield: 79%) was isolated and purified by normal phase column chromatography. MS m / z (ESI): 245.3 [M+H] + Step 4: Dissolve compound 85-3 (290 mg, 1.18 mmol) in ethyl acetate (30 mL). Add dioxygen tweezers (80 mg) and hydrogenate at 25°C for 16 hours. Filter and concentrate the filtrate to obtain the product (colorless oil, 220 mg, 76% yield). MS m / z (ESI): 247.1 [M+H] + Step 5: Prepare according to the synthetic method of step 3 of Example 1. MS m / z (ESI): 205.3 [M+H] + Step 6: Prepare by referring to the synthetic method of Step 5 of Example 84 to obtain compound E85. X H NMR (500 MHz, CD3OD) 5 6.88-6.83 (m, 2H), 6.73-6.71 (m, 2H), 6.65 (d, J= 5.0 Hz, 1H), 6.55 (d, J= 5.0 Hz, 1H), 4.44 (s, 2H), 3.87 (d, J= 15.0 Hz, 1H), 3.38-3.34 (m, 2H), 3.09-3.06 (m, 1H), 2.94-2.92 (m, 1H), 2.58-2.44 (m, 6H), 2.10-1.87 (m, 5H), 1.00 (s, 4H)o MS m / z (ESI): 416.6 [M+H] +Example 86: (6bR,10aS)-8-(3-(6-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one

[0132] Step 1: Under nitrogen protection, compound 2-bromo-3-fluorophenol (2 g, 10.5 mmol) and 2-bromo-1,1-diethoxyethane (2.47 g, 12.6 mmol) were dissolved in dry DMF (50 mL), and then K2CO3 (4.3 g, 31.4 mmol) was added and the reaction was carried out at 145 °C for 3h. After the reaction was completed, the reaction was quenched with 100.0 mL of ice water, extracted with ethyl acetate (100 mL * 3), washed with saturated brine (100 mL * 3), and the organic phase was spin-dried. The crude product was purified by normal silica gel column to obtain 86-1 (colorless liquid, 3 g, yield 93%). Step 2: Compound 86-1 (2 g, 9.77 mmol) was dissolved in toluene (30 mL), and PPA (3 mL) was added. The mixture was stirred at 90°C for 3 h and cooled to room temperature. The solvent was spin-dried, the mixture was quenched with 100.0 mL of ice water, extracted with ethyl acetate (100 mL * 3), washed with saturated brine (100 mL * 3), and the organic phase was spin-dried. The crude product was purified by normal silica gel column to obtain 86-2 (colorless liquid, 1 g, yield 47.6%). Step 3: Compound E86 was prepared according to the synthetic method of Steps 1-5 of Example 60. 1HNMR(400 MHz, CDC13) 57.48 (d, J= 15.5 Hz, 1H), 6.92 (dd, J= 8.0, 5.5 Hz, 1H), 6.83 (d, J= 7.5 Hz, 1H), 6.73 (t, J= 7.5 Hz, 1H), 6.58 (d, J= 7.5 Hz, 1H), 6.49 (dd, J= 10.0, 8.0 Hz, 1H), 4.61-4.54 (m, 2H), 3.94 (d, J= 14.5 Hz, 1H), 3.44-3.27 (m, 3H), 3.15 (t, J = 8.7 Hz, 2H), 3.08-2.76 (m, 2H), 2.60 (t, J = 7.4 Hz, 2H), 2.26 (d, J = 194.5 Hz, 4H), 2.06- 1.79 (m, 4H). MS m / z (ESI): 408.6 [M+H] + Example 87: (6bR,10aS)-8-(3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxazolidinone 2(3H)-one Step 1: The preparation of 87-1 follows the first step of Example 3. Step 2: The preparation of 87-2 follows the second step of Example 3. Step 3: The preparation of 87-3 follows the third step of Example 3. Step 4: The preparation of 87-4 follows the fourth step of Example 8. Step 5: The preparation of E87 follows the fifth step of Example 8. g NMR (500 MHz, CDCb) 5 7.55 (s, 1H), 6.89-6.80 (m, 2H), 6.72 (t, J= 7.6 Hz, 1H), 6.57 (dd, J = 7.9, 0.9 Hz, 1H), 6.48 (t, J= 8.4 Hz, 1H), 4.59 (t, J = 8.7 Hz, 2H), 3.95 (d, J= 14.5 Hz, 1H), 3.45-3.30 (m, 3H), 3.23 (t, J= 8.7 Hz, 2H), 2.94 (s, 1H), 2.84-2.68

[0133] (m, 1H), 2.53 (t,J= 7.6 Hz, 2H), 2.33 (d,J= 61.8 Hz, 3H), 2.06-1.79 (m, 5H). MS m / z (ESI): 408.6[M+H] + Example 88: (6bR,10aS)-8-(3-(5-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3-(5-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-

[0134] [3',4':4,5]<Pyrro[1,2, 3-de]oxathiapa 2(3H)-one

[0135] E88 was prepared according to the synthesis method of Example 60. g NMR (400 MHz, CDCL) δ 7.59 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.73 (t, J = 7.5 Hz, 2H), 6.63 (dd, J = 10.0, 2.5 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1H), 4.54 (t, J = 8.5 Hz, 2H),

[0136] 3.95 (d, J= 14.5 Hz, 1H), 3.44-3.27 (m, 3H), 3.17 (t, J= 8.6 Hz, 2H), 2.96 (s, 1H), 2.78 (s, 1H), 2.60-2.47 (m,

[0137] 2H), 2.35 (d, J= 60.3 Hz, 3H), 2.04 (s, 1H), 1.97-1.77 (m, 4H). MS m / z (ESI): 408.6 [M+H] + Example 89: (6bR,10aS)-8-(3-(6-chloro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3-(6-chloro-2,3-dihydrobenzofuran-7-yl)propyl)-

[0138] [3',4':4,5]<Pyrro[1,2, 3-de]oxathiapa 2(3H)-one

[0139] The preparation of E89 was carried out according to the synthesis method of Example 60. XH NMR(400 MHz, CDCI3) 5 7.42 (s, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.83 (dd, J= 12.5, 7.5 Hz, 2H), 6.76 (t, J = 7.5 Hz, 1H), 6.60 (d, J= 8.0 Hz, 1H), 4.55 (dt, J= 15.0, 8.5 Hz, 3H), 3.92 (s, 1H), 3.40 (d, J= 14.5 Hz, 3H), 3.17 (t, J= 8.7 Hz, 4H), 2.72 (d, J= 7.5 Hz, 3H), 2.67-2.43 (m, 2H), 2.11 (d, J= 94.6 Hz, 2H), 1.97-1.73 (m, 2H). MS m / z (ESI): 424.6 [M+H] + Example 90: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2-hydroxy-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]benzothiazolin-8-oxide Step 1: E67-1 (10 mg, 2.67 mmol) was dissolved in DCM (5 ml), and TM-CPBA (540 mg, 2.67 mmol) was added. The reaction was carried out at room temperature for 2 h. LCMS showed complete reaction. The product was extracted with DCM, concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E90 (5 mg, white solid, yield: 21.1%). XH NMR(400 MHz, CDCh) 5 8.61 (s, 1H), 7.07-7.00 (m, 1H), 6.89 (t, J = 10.5 Hz, 1H), 6.84 (d, J= 7.5 Hz, 1H), 6.76 (dq, J= 9.5, 7.5 Hz, 2H), 6.66 (d, J= 7.5 Hz, 1H), 4.49 (q, J= 9.0 Hz, 2H), 4.05-3.98 (m, 1H), 3.91 (d, J= 14.5 Hz, 1H), 3.41 (t, J= 14.6 Hz, 3H), 3.33-3.26 (m, 3H), 3.18 (q, J= MS m / z (ESI):406.6[M+H] + Example 91: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)6-fluoro-6b, 7, 8, 9, 10, [1,2,3-de]2-oxathioate 2(3H) ketone

[0140] The preparation of E91 refers to the synthetic method of Example 83. iH NMR(400 MHz, CDCb) 5 7.70 (s,lH), 7.04 (d, = 8.0 Hz, 1H), 6.93 (d, = 7.5 Hz, 1H), 6.76 (t〃= 7.5 Hz, 1H) , 6.50 (dd〃= 8.5, 3.5 Hz, 1H), 6.40 (t = 8.5 Hz, 1H), 4.54(t, • / = 9.0 Hz, 2H), 3.94(d, = 14.5 Hz, 1H), 3.62-3.50(m, 1H), 3.38 (d, = 14.5 Hz, 2H), 3.20 (t, J= 8.5 Hz, 2H), MS m / z (ESI):408.9[M+H] + . and [3',4':4,5] < pyro[1,2,3 -de] oxazolidinone 2(3H)

[0141] The preparation of E92 refers to the synthetic method of Example 60. iHNMR (500 MHz, CD3OD) d 8.13 (s, 1H), 8.05 (dj= 10.5 Hz, 1H), 6.83 (d, = 6.7 Hz, 1H), 6.70 (t, J= 7.6 Hz, 1H), 6.64 (dd, = 7.8, 0.8 Hz, 1H), 4.72-4.65 (m, 2H), 3.87 (d, = 14.6 Hz, 1H), 3.34 (d, J= 14.5 Hz, 1H), 3.28-3.24 (m, 2H), 3.21-3.08 (m, 1H), 2.94-2.90 (m, 1H), 2.80-2.74 (m, 1H), 2.60 (t, • / = 7.6 Hz, 2H), 2.40-2.32 (m, 2H), 2.28-2.22 (m, 1H), 2.04-1.96 (m, 2H), 1.94- 1.75 (m, 4H). MS m / z (ESI): 391.6[M+H] + oExample 93: Pyrro[1,2,3-de]oxathia 2(3H) ketone

[0142] Preparation of E93 Refer to the preparation of Example 40 5 7.09 (d = 5.0 Hz, 1H), 6.89- 6.87 (m, 2H), 6.75 (d, = 10.0 Hz, 1H), 6.69 (d, = 10.0 Hz, 1H), 3.91 (d, = 15.0 Hz, 1H), 3.79 (s, 3H), 3.51-3.46 (m, 1H), 3.40-3.35 (m, 2H), 3.19-3.13 (m, 1H), 2.84-2.77 (m, 3H), 2.75-2.71 (m, 2H), 2.31-2.08 (m, 3H), 1.95-1.82 (m, 3H) O MS m / z (ESI): 384.6[M+H] + Example 94: (6bR,10aS)-8-(4-(2,3-dihydrobenzofuran) [3',4':4,5]<Pyrro[1,2, 3-de]oxathiapa 2(3H)-one Step 1: Dissolve 1-3 (320 mg, 1.47 mmol) in methanol (5 mL) and saturated aqueous sodium hydroxide (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with water and ethyl acetate. The aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spin-dried to afford 94-1 (260 mg, 94% yield) as a white solid. Step 2: Dissolve 94-1 (260 mg, 1.35 mmol), N,O-dimethylhydroxylamine hydrochloride (158 mg, 1.62 mmol), HATU (772 mg, 2.03 mmol), and DIEA (525 mg, 4.06 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After concentration, the product was purified by column chromatography (PE: EA = 3:1) to obtain the title compound 94-2 (white solid, 300 mg, 94% yield). MS m / z (ESI): 236.4 [M+H] +Step 3: At -78 °C under nitrogen, 94-2 (250 mg, 1.06 mmol) was dissolved in THF (5 mL). A 3M solution of methylmagnesium bromide in tetrahydrofuran (0.7 mL, 2.13 mmol) was added dropwise. The reaction mixture was then gradually warmed and stirred at room temperature for 2 h. A saturated aqueous solution of chromium chloride (5 mL) was added to the reaction mixture, and the mixture was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 3:1) to obtain the title compound 94-3 (white solid, 180 mg, 90% yield). Step 4: At room temperature, 94-3 (50 mg, 0.26 mmol) and sodium borohydride (30 mg, 0.79 mmol) were dissolved in methanol (3 mL). The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain the title compound 94-4 (colorless oil, 40 mg, 82% yield). Step 5: The ester 94-5 was prepared according to the synthesis method of Step 4 of Example 3. Step 6: At room temperature, 94-5 (15 mg, 0.055 mmol), 67-1-1 (13 mg, 0.055 mmol), and sodium iodide (3 mg, 0.11 mmol) were dissolved in DMF (2 mL), and potassium carbonate (23 mg, 0.17 mmol) was added. The reaction mixture was stirred at 80°C for 12 h. The reaction solution was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water+0.05% NH4HCO3)) to obtain compound E94 (2 mg, yield: 9%) as a white solid. XH NMR (500 MHz, CDC13) 5 7.53 (s, 1H), 7.07-7.01 (m, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.87-6.81 (m, 1H), 6.80-6.69 (m, 2H), 6.58 (d, J= 7.8 Hz, 1H), 4.58-4.47 (m, 2H), 3.95 (dd, J= 14.5, 1.7 Hz, 1H), 3.40-3.33 (m, 2H), 3.23-3.17 (m, 2H), 2.87-2.57 (m, 5H), 2.22 (t, J= 7.6 Hz, 1H), 2.11-1.72 (m, 4H), 1.43-1.21 (m, 3H), 1.01 (s, 2H).MS m / z (ESI): 404.8[M+H] + Example 95: (6bR,10aS)-8-(3-(6-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]<pyrro[1,2,3-de]oxazolidinone 2(3H)-one

[0143] The preparation of E95 refers to the preparation method of Example 86. g NMR (500 MHz, CDCL) 5 6.95-6.89 (m, 1H), 6.86 (d, J = 7.1 Hz, 1H), 6.80 (t, J= 7.6 Hz, 1H), 6.76-6.70 (m, 1H), 6.49 (dd, J = 10.0, 8.1 Hz, 1H), 4.58 (t, J= 8.7 Hz, 2H), 4.01 (d, J= 14.2 Hz, 1H), 3.39-3.25 (m, 6H), 3.21-3.10 (m, 2H), 2.93 (dd, J= 11.0, 6.2 Hz, 1H), 2.75 (d, J = 10.7 Hz, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.44-2.31 (m, 2H), 2.21 (t, J = 10.3 Hz, 1H), 2.05-1.90 (m, 2H), 1.79 (dd, J = 15.5, 7.3 Hz, 3H). MS m / z (ESI): 422.7[M+H] + o Example 96: (6bR,10aS)-8-(2-((2,3-dihydrobenzofuran-7-yl)oxy)ethyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H- The reaction mixture was stirred at 80°C for 2 hours with 2,3-dihydrobenzofuran (10 mg, 0.041 mmol), sodium iodide (13 mg, 0.082 mmol), and DIEA (16 mg, 0.12 mmol). The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. The crude product was concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E96 (4.7 mg, 28% yield) as a white solid. 'H NMR (500 MHz, CDCh) δ 6.89-6.72 (m, 6H), 4.62 (q, J = 8.9 Hz, 3H), 4.38-4.33 (m, 1H), 4.18 (t, J= 6.0 Hz, 2H), 4.02 (d, J= 14.3 Hz, 1H), 3.68-3.60 (m, 1H), 3.36 (d, J= 30.0 Hz, 5H), 3.26-3.20 (m, 3H), 3.03 (s, 1H), 2.83 (s, 3H), 2.39 (s, 1H).MS m / z (ESI): 406.8[M+H] + Example 97: (6bR,10aS)-8-(3-(2,3-dihydropyrano[2,3-c]pyrrolo[7-yl]propyl)-3-(methyl-d3)-6b,7,8,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiapiprolin-2(3H)-one Step 1: Compound 45-1-4 (120 mg, 0.40 mmol) and anhydrous THF (5 mL) were added to a 25 mL three-necked reaction flask. NaH (30 mg, 0.80 mmol, 60% in oil) was then added. After addition, the mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 h. CD3I (170 mg, 1.20 mmol) was then added. After addition, the mixture was stirred at room temperature for 3 h. After completion of the reaction as determined by LCMS, water (30 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL x 2). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain crude compound 97-2 (pale yellow oil, 120 mg, yield: 95%). The crude product was used directly in the next step without further purification. MS m / z (ESI): 319.5 [M+H] + Step 2: The preparation of 97-3 was carried out according to the synthesis method of step 5 in Example 45-1. MS m / z (ESI): 247.6 [M+H] + Step 3: The preparation of E97 was carried out according to the synthetic method of Step 5 of Example E60. X H NMR (500 MHz, CD3OD) 6 7.83 (d, J = 4.9 Hz, 1H), 7.09 (d, J = 4.9 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 6.77 (dd, J = 7.9, 0.9 Hz, 1H), 6.75-6.70 (m, 1H), 4.51 (t, J= 8.9 Hz, 2H), 3.88 (d, J = 14.4 Hz, 1H), 3.28 (d, J = 14.3 Hz, 1H), 3.25-3.21 (m, 2H), 3.20 - 3.15 (m, 2H), 2.97-2.87 (m, 1H), 2.75 MS m / z (ESI): 409.0 [M+H] +Example 98: (6bR,10aS)-8-(3-(3-methoxypyridin-2-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyridin-1H-[3',4':4,5]pyrrolido[1,2,3-de]oxazolidin-2(3H)-one

[0144] E98 was prepared according to the synthesis method of Example 16. g NMR(400 MHz, CDCL) 5 7.42 (s, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.83 (dd, J= 12.5, 7.5 Hz, 2H), 6.76 (t, J = 7.5 Hz, 1H), 6.60 (d, J= 8.0 Hz, 1H), 4.55 (dt, J= 15.0, 8.5 Hz, 3H), 3.92 (s, 1H), 3.40 (d, J= 14.5 Hz, 3H), 3.17 (t, J= 8.7 Hz, 4H), 2.72 (d, J= 7.5 Hz, 3H), 2.67-2.43 (m, 2H), 2.11 (d, J= 94.6 Hz, 2H), 1.97-1.73 (m, 2H). MS m / z (ESI):393.6 [M+H] + Example 99: (6bR, 10aS)-8-(3-(2-methoxyphenyl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1,2,3-de]oxathiolin-2(3H)-one The preparation was carried out according to the synthesis method of Example 3. 0NMR (500 MHz, CD3OD) δ 7.23-7.15 (m, 2H), 7.00-6.87 (m, 5H), 4.05 (d, J = 15.0 Hz, 1H), 3.84 (s, 3H), 3.60-3.47 (m, 5H), 3.32 (s, 3H), 3.09-2.98 (m, 3H), 2.70 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 10.0 Hz, 1H), 2.33-2.16 (m, 2H), 2.06-2.00 (m, 2H). MS m / z (ESI): 393.9 [M+H] +Example 100: (6bR, 10aS)-8-(3-(3-methoxypyridin-2-yl)propyl)-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1, 2, 3-de]oxathiolin-2(3H)-one

[0145] E100 was prepared according to the synthesis method of Example 16. E NMR (400 MHz, CDCh) 5 8.09 (dd, J = 4.1, 1.9 Hz, 1H), 7.55 (s, 1H), 7.11-7.08 (m, 2H), 6.81 (dd, J= 12.9, 4.8 Hz, 1H), 6.73 (t, J= 7.6 Hz, 1H), 6.58 (d, J= 7.8 Hz, 1H), 3.93 (t, J= 14.6 Hz, 1H), 3.82 (s, 3H), 3.47-3.31 (m, 3H), 3.01 (s, 1H), 2.91-2.77 (m, 3H), 2.64-2.18 (m, 4H), 1.95 (d, J= 12.1 Hz, 4H). MS m / z (ESI):379.6 [M+H] + o Example 101: (6bR, 10aS)-8-(3-(3-methoxythiophen-2-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3', 4': 4,5]<pyroxo[1,2,3-de]oxathiolin-2(3H)-one The preparation was carried out according to the synthesis method of Example 3. 1HNMR (500 MHz, CD3OD) 66.88 (d, ■7= 5.0 Hz, 1H), 6.82-6.71 (m, 4H), 3.88 (d, J= 15.0 Hz, 1H), 3.73 (s, 3H), 3.29-3.24 (m, 3H), 3.22 (s, 3H), 2.94-2.90 (m, 1H), 2.77-2.75 (m, 1H), 2.60 (t, J= 7.5 Hz, 2H), 2.41-2.23 (m, 3H), 2.01-1.71 (m, 5H). MS m / z (ESI): 399.0[M+H] + oExample 102: (6bR,10aS)-8-(3-(2,3-dihydropyrano[3,2-c]pyridin-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin-1H-pyridin-2(3H)-one

[0146] The preparation of E102 was carried out according to the synthesis method of Example E60. E NMR (500 MHz, CD3OD) 3 8.13 (s, 1H), 8.05 (d, J = 10.5 Hz, 1H), 6.83 (d, J= 6.7 Hz, 1H), 6.70 (t, J= 7.6 Hz, 1H), 6.64 (dd, J= 7.8, 0.8 Hz, 1H), 4.72-4.65 (m, 2H), 3.87 (d, J= 14.6 Hz, 1H), 3.34 (d, J= 14.5 Hz, 1H), 3.28-3.24 (m, 2H), 3.21-3.08 (m, 1H), 2.94-2.90 (m, 1H), 2.80-2.74 (m, 1H), 2.60 (t, J = 7.6 Hz, 2H), 2.40-2.32 (m, 2H), 2.28-2.22 (m, 1H), 2.04-1.96 (m, 2H), 1.94-1.75 (m, 4H). MS m / z (ESI): 391.7[M+H] + Example 103: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-4-fluoro-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3,4,4,5]<pyroxo[1,2,3-de]oxathiolin-2(3H)-one The preparation was carried out according to the synthesis method of Example 83. XH NMR (500 MHz, CD3OD) 5 6.83-6.80 (m, 1H), 6.73 (d, J= 10.0 Hz, 1H), 6.61 (t, J= 10.0 Hz, 1H), 6.54 (d, J= 5.0 Hz, 1H), 6.38 (t, J= 7.5 Hz, 1H), 4.49 (t, J = 7.5 Hz, 2H), 3.77 (d, J = 15.0 Hz, 1H), 3.26-3.23 (m, 3H), 3.12 (t, J= 7.5 Hz, 2H), 2.85-2.82 (m, 1H), 2.70-2.68 (m, 1H), 2.43 (t, J= 7.5 Hz, 2H), 2.30-2.15 (m, 3H), 1.95-1.68 (m, 5H). MS m / z (ESI): 408.9[M+H] + Example 104: (5bR,9aS)-7-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5b, 6,7,8,9,9a-hexahydroimidazo[4,5,1-hi]pyrido[4,3-b]indol-1(2H)-one

[0147] Step 1: Preparation of 104-1 follows the synthetic method of step 3 of E45-1. MS m / z (ESI): 262.2 [M+H] + Step 2: The preparation of 104-2 was carried out according to the synthesis method of step 5 of E45-1. MS m / z (ESI): 190.3 [M+H] + Step 3: The preparation of 104-3 was carried out according to the synthesis method of step 2 of E67-1. MS m / z (ESI): 350.2 [M+H] + Step 4: 104-3 (140 mg, 0.4 mmol), DMAP (38 mg, 0.4 mmol) and pyrrolidone (2 mL) were added to a 25 mL three-necked flask. The atmosphere was replaced with N2 three times, cooled to 0 °C, and methyl chloroformate (38 mg, 0.4 mmol) was added. The reaction was incubated at 0 °C for 1 h. Water and DCM were added, the layers were separated, and the aqueous phase was extracted once with DCM. The organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated through a column chromatography (DCM / MeOH = 20 / 1) to afford 104-4 (90 mg, white solid, yield: 55%). MS m / z (ESI): 408.6 [M+H]+ . Step 5: 104-4 (90 mg, 0.22 mmol) and toluene (2 mL) were added to a 25 mL three-necked flask, N? replaced three times, 1M LiHMDS (0.9 mL, 0.9 mmol), and reacted at 75 ° C for 1 h. Water and EA were added, the liquid was separated, the aqueous phase was extracted once with EA, the organic phases were combined, washed three times with saturated sodium chloride, dried, concentrated, and purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HC03) = 30%-70%) to obtain E104 (13 mg, yellow solid, yield: 15.7%). g NMR (500 MHz, CDCL) 5 8.13 (s, 1H), 7.04 (d, J= 8.2 Hz, 1H), 6.97 - 6.84 (m, 3H), 6.82-6.73 (m, 2H), 4.64 (q, J= 5.2 Hz, 1H), 4.54 (t, J= 8.5 Hz, 2H), 3.92 (q, J= 6.5 Hz, 1H), 3.20 (t, J= 8.5 Hz, 2H), 2.98 (dd, J = 11.9, 5.8 Hz, 1H), 2.66-2.47(m, 4H), 2.42 (m, 3H), 2.36-2.22 (m, 2H), 1.85-1.78 (m, 2H). MS m / z (ESI):376.6 [M+H] + Example 105: (6bR,10aS)-8-(2-((2,3-dihydropyrano[2,3-c]pyrrolo[7-yl)oxy)ethyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa-2(3H)-one Step 1: Compound furan[2,3-c]pyridin-7(6H)-one (120 mg, 0.89 mmol), bromoethanol (330 mg, 2.64 mmol), and anhydrous toluene (10 mL) were added to a 25 mL single-necked reaction flask. Ag2CO3 (730 mg, 2.6 mmol) and Nal (330 mg, 2.6 mmol) were then added. After the addition, the atmosphere was replaced with nitrogen three times, and the temperature was slowly raised to 115°C (2°F) and stirred for 48 h. After the reaction was completed, the reaction solution was filtered, the filtrate was evaporated to dryness under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: 5% MeOH / DCM) to obtain compound 105-2 (pale yellow oil, 60 mg, yield 42%). X H NMR (500 MHz, CD3OD) 7.93 (d, J= 2.1 Hz, 1H), 7.86 (d, J= 5.5 Hz, 1H), 7.26 (d, J = 5.5 Hz, 1H), 6.92 (d, J= 2.1 Hz, 1H), 4.57 (dd, J= 5.4, 4.3 Hz, 2H), 4.01-3.95 (m, 2H). MS m / z (ESI): 180.4 [M+H] + Step 2: Preparation of 105-3: Refer to the synthetic method of Example E60, Step 2. MS m / z (ESI): 182.4 [M+H] + Step 3: Preparation of 105-4: Refer to the synthetic method of Step 3 of Example E60. MS m / z (ESI): 180.6 [M+H] +Step 4: Preparation of E105: Refer to the synthetic method of Example E60, Step 4. ENMR (500 MHz, CD3OD). 7.62 (d, J = 5.0 Hz, 1H), 6.95-6.91 (m, 2H), 6.90 (d, J = 7.1 Hz, 1H), 6.86-6.83 (m, 1H), 4.62 (t, J= 9.3 Hz, 2H), 4.51 (t, J= 5.7 Hz, 2H), 4.01 (d, J= 14.4 Hz, 1H), 3.42-3.36 (m, 3H), 3.37-3.34 (m, 3H), 3.26 (t, J = 9.0 Hz, 2H), 3.12-3.08 (m, 1H), 2.96-2.90 (m, 1H), 2.86-2.78 (m, 2H), 2.46-2.40 (m, 1H), 2.07-2.02 (m, 2H), 1.98-1.94 (m, 1H). MS m / z (ESI): 407.6 [M+H] + Example 106: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiolin-2(3H)-one Step 1: Preparation of 106-1 was carried out according to the synthesis method of step 4 of Example E8. Step 2: Preparation of E106 was carried out according to the synthesis method of step 5 of Example E8. ENMR (500 MHZ, CDC13) 57.53 (S, 1H), 7.04 (t, J= 7.8 Hz, 1H), 6.87-6.80 (m, 1H), 6.74 (t, ■7= 7.6 Hz, 1H), 6.65 (dd, J= 7.7, 6.0 Hz, 3.01 (s, 1H), 2.81 (d, J = 29.9 Hz, 1H), 2.66-2.26 (m, 5H), 2.17-1.82 (m, 5H).MS m / z (ESI): 390.9 [M+H] + o Example 107: (6bR,10aS)-8-(3-(5-hydroxy-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiolin-2(3H)-one

[0148] The preparation of steps 1-5 was carried out according to the synthetic method of steps 1-5 in Example 86. Step 6: The preparation of 107-6 was carried out according to the synthetic method of the sixth step in Example 13. Step 7: The preparation of 107-7 was carried out according to the synthetic method of the sixth step in Example 7. Step 8: Compound 107-7 (30 mg, 0.07 mmol) and anhydrous dichloromethane (3 mL) were added to a 25 mL three-necked reaction flask. BBr3 (2.1 mL, 2.1 mmol) was added at -78°C. After the addition, the temperature was slowly raised to -10°C and the reaction was continued with stirring at this temperature for 3 h. After the reaction was completed as determined by LCMS, aqueous ammonia (1 mL) was added to the reaction solution, and the solution was concentrated and filtered, followed by prep-HPLC purification and separation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E107 (5 mg, white solid, yield: 16.9%).

[0149] E NMR (400 MHz, CDCh) 5 7.49 (d, J = 16.3 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 6.74 (t, J = 7.6 Hz, 1H), 6.58 (dd, J = 12.8, 4.9 Hz, 2H), 6.43 (d, J= 2.4 Hz, 1H), 4.49 (t, J = 8.6 Hz, 2H), 3.94 (d, J = 14.5 Hz, 1H), 3.50 (s, 1H), 3.42-3.31 (m, 2H), 3.13 (dd, J= 19.9, 11.2 Hz, 2H), 3.07 (s, 1H), 2.90 (d, J= 12.4 Hz, 2H), 2.50 (dd,J= 33.2, 25.7 Hz, 5H), 2.18 (s, 1H), 1.98 (dd,J= 31.1, 16.2 Hz, 4H). MS m / z (ESI): 406.8 [M+H] + o Example 108: (6bR, 10aS)-8-(3-(6-hydroxy-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]<pyro[1,2,3-de]oxazolidinone 2(3H)-one hydrochloride

[0150] E108 was prepared according to the synthetic method of Example 107. XHNMR (500 MHz, DMSO-J6) 5 10.61 (s, 1H), 10.50 (s, 1H), 9.33 (s, 1H), 6.86 (d, J= 7.2 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.70 (d, J= 7.5 Hz, 1H), 6.66 (d, J= 7.8 Hz, 1H), 6.32 (d, J= 8.0 Hz, 1H), 5.33 (t, J= 5.1 Hz, 1H), 4.47 (t, J= 8.5 Hz, 2H), 3.90 (d, J= 14.5 Hz, 2H), 3.04 (t, J = 8.5 Hz, 4H), 2.48-2.35 (m, 4H), 2.24 (s, 2H), 2.03-1.97 (m, 3H), 1.90 (s, 2H). MS m / z (ESI): 406.6 [M+H] + Example 109: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,1-dimethyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrimidine Step 1: Compound 45-1-4 (300 mg, 1.0 mmol) was dissolved in DMF (10 mL), cooled to 0.2°C in an ice-water bath, and sodium hydroxide (120 mg, 3.0 mmol) was added. The mixture was stirred at 0.2°C for 30 minutes, followed by the addition of p-methoxybenzyl chloride (310 mg, 2.0 mmol) and stirring at room temperature for 16 hours. After the reaction was complete as determined by LCMS, water (20 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated brine (1 x 25 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was slurried with methyl tert-butyl amide to obtain compound 109-1 (white solid, 185 mg, yield 44%). MS m / z (ESI): 422.5 [M+H] +Step 2: Compound 109-1 (150 mg, 0.36 mmol) was dissolved in THF (5 mL), cooled to -78 °C, and LiHMDS (1.45 mL, 1.45 mmol) was added at -78. After stirring for 1 hour, iodomethane (200 mg, 1.42 mmol) was added, and the mixture was heated to room temperature and stirred for 18 hours. After the reaction was complete as determined by LCMS, water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated brine (1 x 25 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 0-50% EtOAc / Petroleum ether) to obtain compound 109-2 (yellow oil, 130 mg, yield 83%). MS m / z (ESI): 437.0 [M+H] + Step 3: Dissolve compound 109-2 (240 mg, 0.55 mmol) in THF (5 mL), cool to -78 °C, add n-BuLi (1 mL, 1.6 mmol), and heat at -78. After stirring for 1 h, iodomethane (235 mg, 1.6 mmol) was added, and the temperature was raised to room temperature and stirred for 16 h. After the reaction was complete as determined by LCMS, water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated brine (1 x 25 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by normal phase column chromatography (eluent gradient: 0-50% EtOAc / Petroleum ether) to obtain compound 109-3 (yellow oil, 66 mg, yield 26%). MS m / z (ESI): 450.5 [M+H] +Step 4: Compound 109-3 (66 mg, 0.15 mmol) was dissolved in TFA (205 μL), and TfOH (90 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 3 h. After completion of the reaction as determined by LCMS, the reaction mixture was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. HBr acetic acid solution (1.5 mL) was added and the mixture was heated to 50°C (2°F). The mixture was stirred for 3 h and concentrated. The crude product was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to afford compound 109-4 (colorless oil, 18 mg, 46% yield). MS m / z (ESI): 258.4 [M+H] + Step 5: Prepare according to the synthetic method of Step 5 in Example 8. ^NMR CSOO MHz, CD3OD) 56.94 (d, J= 5.0 Hz, 1H), 6.79 (d, J = 5.0 Hz, 1H), 6.70 (d, J= 10.0 Hz, 1H), 6.65-6.59 (m, 2H), 6.51 (d, J= 5.0 Hz, 1H), 4.40 (t, J= 7.5 Hz, 2H), 3.84 (d, J= 10.0 Hz, 1H), 3.31-3.26 (m, 1H), 3.07 (d, J= 10.0 Hz, 2H), 2.89 (d, J= 10.0 Hz, 1H), 2.78 (d, J= 10.0 Hz, 1H), 2.47-2.35 (m, 5H), 2.24-2.21 (m, 1H), 2.00-1.87 (m, 2H), 1.80-1.73 (m, 2H), 1.54 (s, 3H), 1.07 (s, 3H)o MS m / z (ESI): 418.8 [M+H] + Example 110: (6bR, 10aS)-8-(3-(2,3-hydroxybenzo[3,2-b]-7-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-

[0151] 110-3 110-4 E110 Step 1: Compound 7-chlorofurano[3,2-B]pyridinium chloride (500 mg, 3.3 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethyl acrylate (1.47 g, 6.5 mmol), Pd(dtbpf)C12 (425 mg, 0.65 mmol), and K2CO3 (1.4 g, 9.8 mmol) were added to a three-necked flask containing dioxane (6 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 110°C for 16 h. After the reaction was completed by LCMS, water and EA were added, the layers were separated, the aqueous phase was extracted twice with EA, the organic phases were combined, and washed twice with saturated sodium chloride. The residue was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 110-1 as a colorless oil (600 mg, 84% yield). Step 2: Preparation of 110-2 follows the synthesis method of Step 2 of Example 1. Step 3: Preparation of 110-3 follows the synthesis method of Step 3 of Example 1. Step 4: Preparation of 110-4 follows the synthesis method of Step 4 of Example 3. Step 5: Preparation of E110 follows the synthesis method of Step 5 of Example 3. E NMR (500 MHz, CDCI3) 5 7.93 (d, J = 5.0 Hz, 1H), 6.88-6.79 (m, 3H), 6.77-6.72 (m, 1H), 4.63 (t, J= 8.9 Hz, 2H), 4.01 (d, J = 14.2 Hz, 1H), 3.40- 3.28 (m, 8H), 2.92 (s, 1H), 2.73 (s, 1H), 2.57 (t,J= 7.6 Hz, 2H), 2.36 (s, 2H), 2.11-1.73 (m, 6H).MS m / z (ESI): 405.8[M+H] + o Example 111: (6bR, 10aS)-8-(3-(2,3-dihydropyrano[3,2-b]pyridin-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin-1H-[3',4':4,5]pyrrolido[1,2,3-de]oxathiocarbamate

[0152] E111 was prepared according to the synthetic method of Example 110. ^NMR (500 MHz, CDC13) 57.94 (d, 5.0 Hz, 1H), 7.59 (s, 1H),

[0153] 6.86-6.81 (m, 2H), 6.74 (t, J= 7.6 Hz, 1H), 6.59 (d, = 7.7 Hz, 1H), 4.63 (t, J= 8.9 Hz, 2H), 3.95 (d, = 14.5 Hz, 1H), 3.46-3.26 (m, 5H), 2.96 (s, 1H), 2.79 (s, 1H), 2.58 (t, J = 7.6 Hz, 2H), 2.42 (s, 2H), 2.14-1.81 (m, 6H).MS m / z (ESI):391.9 [M+H] + Example 112: (6bR, 10aS)-8-(3-(4-hydroxy-2,3-dihydrobenzofuran- pyro[3',4':4,5]pyro[1,2,3-de]oxathiolin-2(3H)-one The preparation was carried out according to the synthesis method of Example 107. E NMR (500 MHz, CDCh) 5 7.47 (d, J= 4.2 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.75 (t, J = 7.9 Hz, 2H), 6.60 (d, J= 7.8 Hz, 1H), 6.22 (d, J = 8.1 Hz, 1H), 4.57 (t, J= 8.7 Hz, 2H), 3.93 (d, J= 14.5 Hz, 1H), 3.58 (s, 1H), 3.40 (d, J= 14.5 Hz, 2H), 3.14 (t, J= 8.7 Hz, 4H), 2.52 (t, J= 7.4 Hz, 5H), 2.15-1.84 (m, 5H). MS m / z (ESI):406.8 [M+H] + Example 114: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiolin-2(3H)-one-1,14- Step 1: Add acetyl chloride (1.4 g, 17.2 mmol), nitric acid chloride (5 mL), and NCS (3.5 e, 25.7 mmol) into a 25 mL single-necked flask, followed by the addition of 2 drops of acetyl hydrochloric acid (35% wt in D2). After addition, slowly heat the mixture to 85°C under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 4 h. The reaction mixture was then cooled to 0°C and anhydrous ethanol (4 mL) was slowly added dropwise. After the addition was complete, stirring was continued at 0°C for 0.5 h. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with n-heptane (20 mL x 3). The organic phases were combined and washed with saturated NaHCO3 (20 mL x 1) and saturated brine (50 mL x 1), respectively, and dried over anhydrous sodium sulfate. The n-heptane was removed under reduced pressure to obtain compound 114-1 (yellow oil, 600 mg, yield 28%). The crude product was not further purified and was used directly in the next reaction. Step 2: Preparation of compound 114-2 Refer to the synthetic method of step 2 in Example 45-1. MS m / z (ESI): 514.8 [M+H] + Step 3: Compound 114-3 was prepared by referring to the synthetic method of Step 3 in Example 45-1. MS m / z (ESI): 304.4 [M+H] + - Step 4: Compound 114-4 was prepared by referring to the synthesis method of Step 5 in Example 45-1. MS m / z (ESI): 232.5 [M+H] +Step 5: Preparation of Compound E114: Refer to the synthetic method of Step 5 in Example E60. E NMR (500 MHz, CDCL). 7.55 (s, 1H), 7.04 (dd, J = 7.3, 0.9 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 6.74 (dt, J = 19.5, 7.5 Hz, 2H), 6.57 (d, J = 7.6 Hz, 1H), 4.53 (t, J = 8.7 Hz, 2H), 3.45-3.31 (m, 2H), 3.20 (t, J = 8.7 Hz, 2H), 3.00-2.90 (m, 1H), 2.86-2.74 (m, 1H), 2.60-2.54 (m, 2H), 2.48-2.20 (m, 3H), 2.10-1.98 (m, 1H), 1.97- 1.81 (m, 4H). MS m / z (ESI): 392.5 [M+H] + Example 116: 6bR, 10aS)-8-(3-(2,3-dihydrothiophene[3,4-b]furan-6-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3,4,:4,5]pyrrolo[1,2,3-de]oxolin-2(3H)-one

[0154] Step 1: 4-Bromo-3-hydroxythiophene-2-carboxylic acid methyl ester (5 g, 21.09 mmol), 1,2-dibromoethane (31.7 g, 168.7- mmol), potassium carbonate (11.6 g, 84.36 mmol) and anhydrous DMF (50 mL) were added into a 250 mL three-necked flask and kept at 80. (2) Stir for 16 h. After TLC detection, water (80 mL) was added to the reaction solution, extracted with ethyl acetate (80 mL x 3), and washed with brine (50 mL x 3). The organic phase was concentrated and purified by normal phase column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 116-1 (white solid, 6.2 g, yield 85%). Step 2: 116-1 (3.5 g, 10.17 mmol) and anhydrous THF (35 mL) were added together in a 250 mL three-necked flask, cooled to -78 °C, and then n-BuLi (2.5M in Hexanes, 4.5 mL, 11.19 mmol) was slowly added dropwise. After the addition was completed, the mixture was kept at -78 °C and stirred for 2 h. After LCMS detection, saturated aqueous chromium chloride solution (40 mL) was added to the reaction solution, extracted with ethyl acetate (60 mL x 3), washed with brine (50 mL x 3), and The organic phase was concentrated and purified by normal phase column chromatography (petroleum ether: ethyl acetate = 5:1) to afford compound 116-2 (colorless solid, 400 mg, yield 21%). MS m / z (ESI): 185.2 [M+H] + Step 3: For the preparation of 116-3, refer to the synthesis method of the third step in Example 1. Step 4: For the preparation of 116-4, refer to the synthesis method of the fourth step in Example 8. Step 5: For the preparation of 116-5, refer to the synthesis method of the first step in Example 1. Step 6: For the preparation of 116-6, refer to the synthesis method of the second step in Example 1. Step 7: For the preparation of 116-7, refer to the synthesis method of the third step in Example 1. Step 8: For the preparation of 116-8, refer to the synthesis method of the fourth step in Example 8. Step 9: For the preparation of E116, refer to the synthesis method of the fifth step in Example 8. XHNMR (500 MHz, CDC13) 56.89-6.85 (m, 1H), 6.82 (t, J= 7.6 Hz, 1H), 6.75 (dd, J= 7.9, 1.1 Hz, 1H), 6.52 (t, J= 1.5 Hz, 1H), 4.82 (t, J= 7.9 Hz, 2H), 4.01 (d, J= 14.2 Hz, 1H), 3.46 (d, J= 9.0 Hz, 1H), 3.38 (d, J= 14.3 Hz, 1H), 3.33 (s, 3H), 3.31 (s, 1H), 3.01 (s, 1H), 2.94 (td, J= 7.9, 1.5 Hz, MS m / z (ESI): 410.8 [M+H] + Example 117: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b, 7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate-1,2(3H)-dione Step 1: Compound 45-1-4 (60 mg, 0.2 mmol), NaIO4 (120 mg, 0.56 mmol), RuO2 (15 mg, 0.11 mmol), and CCl4 (5 mL) were added to a 50 mL single-necked flask and stirred at room temperature for 80 h. After completion of the reaction, water and EA were added, and the mixture was separated. The aqueous phase was extracted twice with EA. The combined organic phases were washed three times with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain compound 117-1 (gray solid, 40 mg, 63% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 316.5 [M+H]. Step 2: The preparation of E117-2 followed the synthesis method described in Step 5 of Example 45-1. Step 3: The preparation of E117 followed the synthesis method described in Step 5 of Example 8. iHNMR (500 MHz, CDC13) a i0.05 (s, 1H), 7.16 (t, J= 7.7 Hz, 1H), 7.10 (dt, J = 7.5, 1.1 Hz, 1H), 7.06-7.01 (m, 2H), 6.88 (d, J= 7.5 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 4.88 (td, J = 8.2, 6.2 Hz, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.71 (s, 1H), 3.21 (t, J= 8.7 Hz, 2H), 3.15 (d, J= 12.4 Hz, 1H), 2.72-2.60 (m, 2H), 2.59-2.35 (m, 5H), 2.24 (dd,J= 20.1, 12.5 Hz, 1H), 1.98 (s, 1H), 1.85-1.75 (m, 2H). MS m / z (ESI): 404.9 [M+H] + o Example 118: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]<pyro[1,2,3-de]oxathiolin-2(3H)-one Step 1: Compound (4aS,9bR)-6-bromo-1,3,4,4-[5,9i]-hexahydro-2-pyrido[4,3-indole-2-carboxylic acid] ethyl ester (320 mg, 1.0 mmol) was dissolved in dioxane (5 mL), and 2-bromopropionamide (228 mg, 1.5 mmol), KI (165 mg, 1.0 mmol), and DIEA (260 mg, 2.0 mmol) were added sequentially. The mixture was heated to 105° C. and stirred for 16 h. The reaction solution was cooled to room temperature, EtOAc (50 mL) was added, filtered, and dried under reduced pressure. The crude product was purified and separated by normal phase column chromatography (eluent gradient: 20-100% EtOAc / Petroleum ether) to obtain compound 118-1 (colorless oil, 180 mg, yield 45%). MS m / z (ESI): 398.5 [M+H] + Step 2: Compound 118-1 (145 mg, 0.37 mmol) was dissolved in dioxane (3 mL). Cui (18 mg, 0.092 mmol), K2CO3 (112 mg, 0.82 mmol), and 2V / V-dimethylethylenediamine (24 μL, 0.22 mmol) were added sequentially. The mixture was purged with nitrogen and heated to 117°C with stirring for 1 h. The reaction solution was cooled to room temperature, filtered, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 20-100% EtOAc / Petroleum ether) to obtain compound 118-2 (yellow oil, 86 mg, yield 73%). MS m / z (ESI): 317.8 [M+H] + Step 3: Compound 118-2 (86 mg, 0.273 mmol) was added to HBr acetic acid solution (2.0 mL) and heated to 50°C. Stir for 3 h and concentrate to obtain compound 118-3 (yellow oil, 80 mg, crude product). MS m / z (ESI): 244.4 [M+H] + Step 4: Prepare according to the synthetic method of Step 5 in Example 8. XH NMR (500 MHz, CD3OD) 5 7.14-7.10 (m, 1H), 6.90-6.70 (m, 5H) , 4.58 (t, J = 7.5 Hz, 2H), 3.60-3.55 (m, 3H), 3.27 (t, J = 7.5 Hz, 2H), 3.11-2.98 (m, 2H), 2.65-2.14 (m, 7H), 2.05-1.91 (m, 3H), 1.65 (d, J= 7.5 Hz, 3H). MS m / z (ESI): 404.8 [M+H] + o Example 119: (6bR, 10aS)-8-(2-((2,3-dihydropyrano[2,3-c]pyrrolo[7-yl)oxy)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrrolo[3,4,4,5]pyrrolo[1,2,3-de]oxolin-2(3H)-one

[0155] The preparation of E119 was carried out according to the synthetic method of Example E105. X H NMR (500 MHz, CD3OD) d 7.77 (d, J= 5.0 Hz, 1H), 7.07 (d, J = 5.0 Hz, 1H), 7.00 (d, J= 7.3 Hz, 1H), 6.88 (t, J= 7.6 Hz, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.76 (t, J = 8.9 Hz, 2H), 4.65 (t, J= 5.7 Hz, 2H), 4.05 (d, J= 14.6 Hz, 1H), 3.53-3.48 (m, 3H), 3.43-3.37 (m, 2H), 3.23 (dd, J = 11.8, 6.2 Hz, 1H), 3.10-3.03 (m, 1H), 3.02-2.92 (m, 2H), 2.63-2.55 (m, 1H), 2.22-2.09 (m, 3H). MS m / z (ESI): 393.9 [M+H] +Example 120: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate The preparation was carried out according to the synthetic method of Example 106. E NMR (500 MHz, CDCL) 5 7.04 (t, J= 7.8 Hz, 1H), 6.86 (dd, J = 7.3, 1.1 Hz, 1H), 6.81 (t, J= 7.6 Hz, 1H), 6.75 (dd, J= 7.9, 1.1 Hz, 1H), 6.65 (dd, J= 9.2, 7.8 Hz, 2H), 4.56 (t, J= 8.7 Hz, 2H), 4.01 (d, J= 14.2 Hz, 1H), 3.38 (d, J= 14.3 Hz, 2H), 3.33 (s, 4H), 3.14 (t, J= 8.7 Hz, 2H), 2.98 (s, 1H), 2.80 (s, 1H), 2.61-2.53 (m, 2H), 2.42 (d, J= 16.7 Hz, 2H), 2.26 (d, J = 21.4 Hz, 1H), 2.03-1.93 (m, 2H), 1.86 (q, J = 8.5, 7.3 Hz, 3H). MS m / z (ESI):404.6 [M+H] + Example 121: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-7, 8, 9, 10-tetrahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiapa 2(3H)-one

[0156] The preparation of E121 followed the synthetic method of step 2 of reference example E67-1. E NMR (500 MHz, CDCI3) 8 7.80 (s, 1H), 7.07 (t, J= 7.8 Hz, 2H), 6.99-6.90 (m, 2H), 6.79 (t, J = 7.4 Hz, 1H), 6.49 (d, J= 7.3 Hz, 1H), 4.83 (s, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.72 (s, 2H), 3.22 (t, J = 8.7 Hz, 2H), 2.94-2.88 (m, 2H), 2.84-2.80 (m, 2H), 2.74-2.63 (m, 4H), 2.01-1.94 (m, 2H). MS m / z (ESI): 388.7 [M+H] + Example 122: (6bR, 10aS)-8-(2-(benzofuran-7-yl)ethyl)-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido[3, 4, 4, 5]pyrrolo[1, 2, 3-de]oxathiolin-2(3H)-one Step 1: Benzofuran-7-carbaldehyde (1.0 g, 6.85 mmol), methyltriphenylphosphine bromide (3.0 g, 8.22 mmol), and anhydrous THF (20 mL) were added to a 100 mL three-necked flask. Anhydrous β-BuOK (1.15 g, 10.28 mmol) was added portionwise under an N₂ atmosphere (i.e., in an ice-water bath). After addition, the mixture was stirred at room temperature overnight. After TLC, saturated aqueous NH₄Cl (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-5%) to afford compound 122-1 as a pale yellow oil (0.70 g, yield: 71%). Step 2: Compound 122-1 (700 mg, 4.86 mmol) and anhydrous THF (15 mL) were added to a 100 mL three-necked flask. 2MB2H6 / dimethyl sulfide solution (4 mL) was slowly added dropwise under N2 and an ice-water bath. After completion, the mixture was stirred at room temperature for 5 h. Subsequently, 10% aqueous NaOH solution (5 mL) and 30% H2O2 solution (0.5 mL) were slowly added dropwise under an ice-water bath. After completion, the mixture was stirred at room temperature overnight. After TLC, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-10%) to obtain compound 122-2 (pale yellow oil, 400 mg, yield: R-δ: 7.62 (d, J = 2.2 Hz, 1H), 7.48 (dd, J= 7.5, 1.3 Hz, 1H), 7.17 (dt,J= 14.2,6.9 Hz, 2H), 6.77 (d, J=2.2 Hz, 1H), 3.99 (t, J = 6.5 Hz, 2H), 3.18 (t,J= 6.5 Hz, 2H). Step 3: Compound 122-2 (100 mg, 0.62 mmol) and anhydrous DCM (10 mL) were added to a 50 mL single-necked flask at room temperature, followed by the addition of Dess-Martin reagent (0.32 g, 0.74 mmol) and stirring at room temperature for 1 hour. After TLC confirmed the reaction was complete, the reaction solution was filtered and the filtrate was slowly added dropwise with saturated NaHCO₃ solution to adjust the pH to alkaline. The mixture was extracted with DCM (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and dried under reduced pressure to afford crude compound 112-3 (90 mg, 90% yield). The crude product was used in the next reaction without further purification. Step 4: Preparation of Compound E122: Refer to the synthetic method of Step 5 in Example E60. E NMR (500 MHz, CDCL) 5 7.68 (s, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.48-7.44 (m, 1H), 7.16 (t, J =7.5 Hz, 1H), 7.12 (d, J =6.7 Hz, 1H), 6.88 (d, J= 7.4 Hz, 1H), 6.78-6.73 (m, 2H), 6.61 (d, J= 7.7 Hz, 1H), 3.97 (d,J= 14.5 Hz, 1H), 3.60-3.46 (m, 1H), 3.45-3.37 (m, 2H), 3.24-3.12 (s, 3H), 3.06-2.94 (m, 1H), 2.91-2.76 (m, 2H), 2.58-2.42 (m, 1H), 2.20-2.06 (m, 2H), 2.04-2.00 (m, 1H). MS m / z (ESI): 374.6 [M+H] +Example 123: (6bR, 10aS)-8-(2-(benzofuran-7-yl)ethyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate

[0157] The preparation of E123 was carried out according to the synthetic method of Example E122. X H NMR (500 MHz, CDC13) 5 7.60 (d, J = 2.2 Hz, 1H), 7.45 (dd, J= 7.6, 1.2 Hz, 1H), 7.16 (t, J= 7.5 Hz, 1H), 7.11 (d, J = 6.6 Hz, 1H), 6.75 (d, J = 2.2 Hz, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 6.8 Hz, 1H), 6.43 (d, J= 7.6 Hz, 1H), 3.64-3.59 (m, 1H), 3.35-3.25 (m, 4H), 3.20-3.06 (m, 3H), 2.90-2.82 (m, 5H), 2.81-2.71 (m, 2H), 2.51-2.39 (m, 1H), 2.18-2.10 (m, 1H), 2.07-1.97 (m, 2H). MS m / z (ESI): 374.6 [M+H] + Example 124: (6bR, 10aS)-8-(3-(benzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3 / :4,5]pyrrolo[1,2,3-de]oxathiolin-2(3H)-one Step 1: Preparation of 124-1 Refer to the synthesis method of step 4 of Example E8. Step 2: Preparation of E124 Refer to the synthesis method of step 5 of Example E8. E NMR (500 MHz, CDCL) 5 7.61 (d, J = 2.1 Hz, 1H), 7.52 (s, 1H), 7.44 (dd, J = 7.8, 1.3 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.09 (dd, J = 7.3, 1.4 Hz, 1H), 6.83 (dd, J= 7.5, 0.9 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.72 (t, J= 7.6 Hz, 1H), 6.57 (dd, J= 7.8, 0.9 Hz, 1H), 3.95 (d, J= 14.6 Hz, 1H), MS m / z (ESI): 388.7[M+H] + O Example 125: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiophene 2(3H)-thione Compound E67-1 (40 mg, 0.103 mmol) was dissolved in THF (3 mL), and Lawesson's reagent (62 mg, 0.15 mmol) was added. The reaction mixture was stirred at 70°C for 1 hour. After vacuum concentration, ethyl acetate (25 mL) and water (25 mL) were added, and the layers were separated. The organic phase was washed with water and concentrated to obtain a crude product. The crude product was concentrated, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E125 (7.8 mg, white solid, yield 18%). 1H NMR (500 MHz, CD3OD) 56.91 (d, J = 5.0 Hz, 1H), 6.81-6.78 (m, 2H), 6.65-6.60 (m, 3H), 4.40 (t, J = 10.0 Hz, 2H), 4.23 (t, J = 15.0 Hz, 1H), 3.46 (t, J = 15.0 Hz, 1H), 3.19 (s, 2H), 3.07 (t, J = 10.0 Hz, 2H), 2.88-2.84 (m, 1H), 2.72-2.70 (m, 1H), 2.45 (t, J = 10.0 Hz, 2H), 2.34-2.12 (m, 3H), 1.96-1.69 (m, 5H). MS m / z (ESI): 406.9 [M+H]+ o Example 126: (6bR,10aS)-8-(3-(2,3-hydrobenzofuranyl)propyl)-2, 3, 6b, 7, 8, 9, 10, 4':4,5]<1,2,3-de]^Oh mouth Lin

[0158] Preparation of E126 was carried out according to the synthesis method of Example E45-1. E NMR (500 MHz, CDC13) δ 7.03 (d, J = 7.0 Hz 1H),

[0159] 6.93(d〃= 7.5Hz 1H), 6.76(t〃= 7.5Hz, 1H), 6.58(t, • / = 7.5 Hz 1H), 6.54 (d, • / = 7.0 6.38(d, • / = 7.5

[0160] Hz 1H), 4.53(t, • / = 8.5 Hz, 2H), 3.71-3.66 (m, 1H), 3.49-3.45 (m, 1H), 3.31-3.28 (m, 1H), 3.24-3.18 (m, 4H), 2.94-2.91 (m, [M+H] + . Step 1: Compound 66-1 (50 mg, 0.16 mmol) was dissolved in CH3CN (5 mL). Bromoethanol (98 mg, 0.8 mmol) and anhydrous sodium carbonate (204 mg, 0.63 mmol) were added sequentially. The mixture was heated to 80°C and stirred for 16 h. The reaction solution was cooled to room temperature and filtered. The crude product was purified on a reverse-phase C18 column to obtain compound 127-1 (colorless oil, 18 mg, yield 31.6%). MS m / z (ESI): 360.1 [M+H] + Step 2: Dissolve compound 127-1 (25 mg, 0.07 mmol) in methanol (3 mL), then add HCl / dioxane (3 mL, 12 mmol) and stir at room temperature for 2 h. Drain the reaction mixture to obtain compound 127-2 (brown solid, 20 mg, hydrochloride). MS m / z (ESI): 259.8 [M+H] + Step 3: Preparation of E127 The synthetic method of reference example E67-1 step 2 was used. E NMR (500 MHz, CD3OD) δ 7.06- 6.96 (m, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.58 (t, J = 7.7 Hz, 1H), 6.41 (dd, J = 16.5,

[0161] 7.6 Hz, 2H), 4.50 (t, J= 8.7 Hz, 2H), 3.85-3.55 (m, 3H), 3.49-3.35 (m, 2H), 3.34-3.31 (m, 2H), 3.17 (t, J= 8.7 Hz, 2H), 3.08 (dd, J= 11.0, 4.8 Hz, 2H), 2.95-2.83 (m, 1H), 2.77 (d, J= 11.5 Hz, 1H), 2.66-2.57 (m, 1H), 2.55 (t, J = 7.5 Hz, 2H), 2.46-2.29 (m, 3H), 2.06-1.89 (m, 3H), 1.85 (dt, J = 14.8, 7.3 Hz, 2H). MS m / z (ESI):

[0162] 420.6 [M+H] + Example 128: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyrobromo[1,2,3-de]benzothiazolin-5-carboxamide

[0163]

[0164] 128-7 E128 Step 1: 45-1-4 (600 mg, 2.0 mmol) and 6 mL of DMF were added to a 25 mL single-necked flask. The atmosphere was replaced with N2 three times and the mixture was cooled to 0.2°C. NBS (356 mL, 2.0 mmol) was added and the mixture was reacted at 0°C for 0.5 h. LC-MS showed the reaction was complete. Saturated NaHCO3 solution and EA were added, and the layers were separated. The aqueous phase was extracted three times with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated to afford 128-1 (750 mg, crude product). MS m / z (ESI): 380.2, 382.2 [M+H] +Step 2: Compound 128-1 (750 mg, 2.0 mmol), CH3I (5.1 g, 36.0 mmol), K2CO3 (552 mg, 4.0 mmol), and acetonitrile (20 mL) were added to a 100 mL single-necked flask. The mixture was replaced with N? three times and the temperature was raised to 80°C (2°F) for 16 h. LC-MS showed the reaction was complete. The solvent was concentrated to dryness, and water and EA were added. The layers were separated, and the aqueous phase was extracted once with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated to afford compound 128-2 (750 mg, crude product). MS m / z (ESI): 394.3, 396.4 [M+H] + Step 3: Preparation of 128-3 was carried out according to the synthetic method of step 4 of E45-1. MS m / z (ESI): 380.2, 382.2[M+H] + Step 4: Compound 128-3 (200 mg, 0.52 mmol), hydrated chlorinated ammonium chloride (60 mg, 1.04 mmol), KOH (112 mg, 2.08 mmol), and ethylene glycol (8 mL) were added to a 25 mL microwave tube and heated to 150 °C for 1.5 h. Water and EA were added, and the layers were separated. The aqueous phase was extracted three times with EA. The combined organic phases were washed three times with saturated sodium chloride, dried, and concentrated to afford compound 128-4 (140 mg, crude). MS m / z (ESI): 308.2, 310.2 [M+H] + Step 5: Preparation of 128-5 was carried out according to the synthetic method of E45-2 Step 2. MS m / z (ESI): 408.2, 410.2[M+H] + Step 6: Dissolve compound 128-5 (18.0 mg, 0.04 mmol) in DMF (2.0 mL). Under nitrogen, add tetrakis(triphenylphosphine)trigger (1.20 g, 3.45 mmol), zinc dichloride (5.18 mg, 0.044 mmol), and zinc powder (0.860 mg, 0.013 mmol). Microwave at 150 °C and stir for 3 h. After completion of the reaction, follow TLC monitoring and concentrate under reduced pressure. Purify by normal phase chromatography to obtain compound 128-6 (yellow solid, 150 mg, 74% yield). MS m / z (ESI): 355.2. [M+H] +Step 7: Dissolve compound 128-6 (15.0 mg, 0.04 mmol) in dichloromethane (3.0 mL) and add trifluoroacetic acid (1.0 mL). The mixture was allowed to react at room temperature for 1 h. After filtration and concentration, compound 128-7 was obtained as a brown oil (12.0 mg, 85% yield). MS m / z (ESI): 255.2. [M+H] + Step 8: Under nitrogen, compound 128-7 (15.0 mg, 0.05 mmol), 2-(2,3-dihydro-1-benzofuran-6-yl)acetaldehyde (9.57 mg, 0.05 mmol), and acetic acid (0.052 mL, 0.93 mmol) were dissolved in THF (2 mL). Sodium hydroxyborohydride (12.3 mg, 0.15 mmol) was added and the mixture was reacted at 0°C for 2 h. The reaction was confirmed to be complete by TLC. The product was filtered and purified by reverse phase preparative purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to afford E128 (white solid, 1.0 mg, 4% yield). X H NMR (400 MHz, CDC13) 57.04 (d,

[0165] J= 7.2 Hz, 1H), 6.91-6.88 (m, 1H), 6.79 - 6.74 (m, 2H), 6.56 (s, 1H), 4.55-4.50 (t, J= 8.8 Hz, 2H), 3.61-3.56 (m, 1H), 3.43-3.17 (m, 4H), 3.19 (t, J= 8.8 Hz, 2H), 3.02-2.91 (m, 2H), 2.87 (s, 3H), 2.75-2.60 (m, 3H), 2.05- 1.76 (m, 4H), 1.32-1.25 (m, 4H). MS m / z (ESI): 415.4 [M+H]+. Example 129: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5-methoxy-3-methyl-2, 3, 6b, 7, 8, 9, 10, 10a-octahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiocarbamate Step 1: Glycine methyl ester hydrochloride (7.2 g, 57.9 mmol) and K2CO3 (4.72 mg, 34.2 mmol) were dissolved in 90 mL of NMP, and 1-fluoro-4-methoxy-2-nitrobenzene (9.0 g, 52.6 mmol) was added. The mixture was heated to 80°C for 16 h. TLC confirmed the reaction was complete. Water and EtOAc were added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed three times with saturated sodium chloride solution, dried, concentrated, and filtered through a normal phase silica gel column (PE / EtOAc = 5 / 1) to afford compound 129-1 (2.2 g, yellow solid, 17% yield). MS m / z (ESI): 240.4 [M+H] + Step 2: Dissolve 129-1 (2.2 g, 9.17 mmol) in 30 mL of methanol, add 1 g of 10% Pd / C, and stir at room temperature for 16 h. Filter and concentrate to obtain 129-2 (1.6 g, off-white solid, 98% yield), which was used directly in the next step. MS m / z (ESI): 179.2 [M+H] + Step 3: The preparation of 129-3 was carried out according to the synthetic method of step 1 of E42. MS m / z (ESI): 208.3 [M+H] + Step 4: Dissolve compound 129-3 (320 mg, 1.54 mmol) in 10 mL of methanol. Add hydrazine chloride (447 mg, 7.7 mmol) and zinc powder (492 mg, 7.7 mmol) at room temperature. Stir at room temperature for 3 h. Filter and concentrate to obtain compound 129-4 (220 mg, off-white solid, 74% yield), which is used directly in the next step. MS m / z (ESI): 194.4 [M+H] + Step 5: The preparation of 129-5 was carried out according to the synthetic method of step 3 of E42. MS m / z (ESI): 357.4 [M+H] + Step 6: The preparation of 129-6 was carried out according to the synthetic method of step 1 of E73-1. MS m / z (ESI): 371.5 [M+H] + Step 7: The preparation of 129-7 was carried out according to the synthetic method of step 4 of E42. MS m / z (ESI): 273.3 [M+H] +Step 8: The preparation of 129-8 was carried out according to the synthetic method of step 4 of E45. MS m / z (ESI): 259.4 [M+H] + Step 9: The preparation of E129 was carried out according to the synthetic method of Step 5 of E42. X H NMR (500 MHz, CD3OD) 57.03 (d, J = 5.0 Hz, 1H), 6.90 (d, J= 5.0 Hz, 1H), 6.74 (t, J= 7.5 Hz, 1H), 6.08-6.02 (m, 2H), 4.51 (t, J= 10.0 Hz, 2H), 3.76- 3.68 (m, 4H), 3.22-3.19 (m, 1H), 3.16 (s, 3H), 3.07-2.91 (m, 6H), 2.66-2.56 (m, 6H), 2.19-1.92 (m, 6H). MS m / z (ESI): 419.9 [M+H] + o Example 130: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydropyrido[4,3-b][1,4]oxazine[2,3,4-dihydrobenzofuran-7-yl)propyl]-1, 2, 6b, 7, 8, 9, 10, 10a-octahydropyrido[4,3-b][1,4]oxazine[2,3,4-dihydrobenzofuran-7-yl] ... Step 1: Compound E68 (12 mg, 0.031 mmol) was dissolved in DCM (3 mL), cooled to 1°C, and m-CPBA (12 mg, 0.067 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo to obtain a crude product. The crude product was concentrated, filtered, and then purified and isolated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain compound E130 (5.0 mg, white solid, yield 38%). XH NMR (500 MHz, CD3OD) 5 7.03 (d, J= 5.0 Hz, 1H), 6.90 (d, J= 5.0 Hz, 1H), 6.73 (t, J = 7.5 Hz, 1H), 6.66 (d, J = 5.0 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.51 (d, J = 10.0 Hz, 1H), 4.50 (t, J = 10.0 Hz, 2H), 4.43-4.32 (m, 2H), 3.36-3.32 (m, 2H), 3.19-3.10 (m, 4H), 2.93-2.80 (m, 1H), 2.63-2.54 (m, 2H), 2.56 (t, J = 10.0 Hz, 2H), 2.42-2.26 (m, 3H), 2.19 (t, J = 10.0 Hz, 1H), 2.05-1.81 (m, 3H). MS m / z (ESI): 424.8 [M+H] + o Example 131: 1-((6bR,10aS)-8-((2-(2,3-dihydrobenzofuran-7-yl)cyclopropyl)methyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]oxathiapiprolin-3-yl)ethan-1-one Step 1: Compound 122-2 (1.6 g, 12.5 mmol) was dissolved in toluene (20 mL). Under nitrogen, ethyl diazoacetate (2.2 g, 18.75 mmol), NMI (3.08 g, 37.5 mmol), and Co(II) (Co(TPP)) (84 mg, 0.125 mmol) were added. The reaction was stirred at 80 °C for 48 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by normal phase chromatography to obtain compound 131-1 (purple solid, 1 g, yield 34.5%). MS m / z (ESI): 233.1. [M+H] + Step 2: The preparation of 131-2 refers to the synthesis method of step 3 of E60. Step 3: The preparation of 131-3 refers to the synthesis method of step 4 of E60. Step 4: The preparation of E131 refers to the synthesis method of step 45 of E60. NMR (500 MHz, CDCI3) 5 7.01 (d, J = 7.2 Hz, 1H), 6.88 (d, J= 7.3 Hz, 2H), 6.76 (t, J= 7.5 Hz, 1H), 6.69 (d, J= 7.5 Hz, 2H), 4.52 (t, J= 8.4 Hz, 2H), 3.92 (d, J= 85.9 Hz, 3H), 3.61-3.24 (m, 3H), 3.20 (dd, J= 15.7, 8.3 Hz, 3H), 2.78 (d, J= 165.2 Hz, 3H), 2.39 (d, J= 50.9 Hz, 5H), 1.99 (d, J= 18.0 Hz, 2H), 1.78 (s, 1H), 1.33 (s, 1H), 1.05 (s, 1H), 0.79 (s, 1H). MS m / z (ESI): 430.8 [M+H] + Example 132: 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxypropyl)-1, 2, 6b, 7, 8, 9, 10, 10a-octahydro-3H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiolin-3-yl)ethan-1-one Step 1: Preparation of 132-1 was carried out according to the synthetic method of step 3 of E45-2. MS m / z (ESI): 358.2 [M+H] + Step 2: Preparation of 132-2 was carried out according to the synthetic method of step 4 of E45-2. MS m / z (ESI): 258.2 [M+H] +Step 3: 132-2 (50 mg, 0.19 mmol), 69-2 (69 mg, 0.4 mmol), K2CO3 (52 mg, 0.4 mmol), and 2 mL of DMF were added to a 25 mL single-necked flask. The atmosphere was replaced with N2 three times, the temperature was raised to 120°C, and the reaction was continued for 16 h. Water and EA were added, the layers were separated, and the aqueous phase was extracted three times with EA. The combined organic phases were washed three times with saturated sodium chloride, dried, and concentrated to obtain E132 (30 mg, crude product). 15 mg of the crude product was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to obtain E132 (7.9 mg, white solid, yield: 19.3%). (500 MHz, CDC13)57.06 (t, J = 6.5 Hz, 1H), 6.99 (t, J= 7.3 Hz, 1H), 6.95-6.81 (m, 2H), 6.81-6.74 (m, 1H), 6.67 (s, 1H), 4.53 (t, J= 8.7 Hz, 2H), 4.15 0-3.76 (m, 3H), 3.66-3.09 (m, 6H), 3.06 -2.52 (m, 6H), 2.43-2.27 (m, 6H), 2.08-1.86 (m, 2H). MS m / z (ESI): 434.6 [M+H] + Example 133: (6bR, 10aS)-8-((2,3-dihydrobenzofuran-7-yl)methyl)-6b, 7,8,9,10,10a-hexahydro-1H-pyrido[3,4,4,5]pyrrolo[1,2,3-de]oxathiolin-2(3H)-one

[0166] E67-1-1 (50 mg, 0.16 mmol) was dissolved in MeOH (2.00 mL), and sodium hydroxyborohydride (30 mg, 0.484 mmol) was added. The mixture was stirred at room temperature for 20 minutes, and then 2, 3-dihydrobenzofuran-7-carbaldehyde (47 mg g, 0.322 mmol) was added and the reaction was continued at room temperature for 2 hours. The reaction was completed after LCMS detection and purified by HPLC (NH3.H2O system) to give compound E133 (white solid, 22 mg, yield 37.7%). 1H NMR (400 MHz, CDC13) δ 7.41 (s, 1H), 7.11 (d, J = 7.4 Hz, 2H), 6.80-6.78 (m, 2H), 6.70 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 4.54 (t, J = 8.8 Hz, 2H), 3.95 (d, J = 14.6 Hz, 1H), 3.49 (d, J = 2.0 Hz, 2H), 3.41-3.29 (m, 4H), 3.19 (d, J = 8.6 Hz, 2H), 2.96-2.90 (m, 1H), 2.79-2.72 (m, 1H), 2.29-2.22 (m, 1H), 1.94-1.86 (m, 2H). MS m / z (ESI): 362.4 [M+H] + Example 134: Preparation of (6bR, 10aS)-8-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)-6b, 7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyro[1,2,3-de]oxathiolin-2(3H)-one E134 Reference Example E67-1 Step 67.39 (s, 1H), 7.04 (d, J = 7.2 Hz, IH), 6.94 (d, J = 7.3 Hz, IH), 6.85 (d, J = 7.3 Hz, IH), 6.79-6.70 (m, 2H), 6.57 (d, J = 7.8 Hz, IH), 4.52 (t, J = 8.7 Hz, 2H), 3.97 (d, J = 14.6 Hz, IH), 3.38 (dd, J = 15.2, 8.0 Hz, 3H), 3.19 (t, J = 8.7 Hz, 2H), 3.04-2.98 (m, IH), 2.79 (dd, J = 21.4, 12.6 Hz, 3H), 2.59 (dd, J = 16.4, 8.0 Hz, 2H), 2.37-2.21 (m, 1H), 1.98 (dd, J = 22.3, 8.5 Hz, 3H). MS m / z (ESI): 376.4 [M+H]+. Example 135: (6bR,10aS)-8-(4-(2,3-dihydrobenzofuran) [3',4':4,5]<pyro[1,2,3-de]^oxoline-2(3H)-one Step 1: Dissolve 7-bromobenzofuran (600 mg, 3 mmol) and 3-butyn-1-ol (420 mg, 6 mmol) in DMF (5 mL). Add Et3N (5 mL), Cu2Cl2 (114 mg, 0.6 mmol), and Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) sequentially with stirring. Under nitrogen, stir at 90°C for 16 hours to complete the reaction. Pour the reaction mixture into ice water (30 mL), and the aqueous phase is extracted with ethyl acetate (30 mL x 2). The organic layer is washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether: 0% to 50%) to afford compound 135-1 as a white solid, 520 mg, 92% yield. MS m / z (ESI): 189.2 [M+H]+. Step 2: Compound 135-1 (360 mg, 2 mmol) was dissolved in MeOH (10 mL). Wet 20% Pd(OH)2 / C (50 mg) was added under nitrogen and stirred. The reaction was purged with hydrogen three times. The reaction was continued under hydrogen for 16 hours at 25°C. The reaction mixture was filtered and concentrated to afford product 135-2 (colorless oil, 190 mg, yield: 50%). MS m / z (ESI): 193.3 [M+H]+. Step 3: 135-2 was dissolved in DCM (5.0 mL), and Dess-Martin periodinane (390 mg, 0.91 mmol) was added. The reaction was allowed to proceed at 25°C for 1 h. LCMS confirmed the reaction was complete. Water was added, and the mixture was extracted with EA. The mixture was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (EA / PE = 5%) to obtain compound 135-3 (white solid, 35 mg, yield 35.4%). MS m / z (ESI): 162.2, [M+H]+. Step 4: Preparation of E135. Refer to the synthesis of step 2 in Example E67-1. 5 7.40 (s, IH), 7.03 (d, J = 7.2 Hz, IH), 6.92 (d, J = 7.6 Hz, IH), 6.83 (d, J = 7.6 Hz, IH), 6.74-6.68 (m, 2H), 6.56 (d, J = 7.6 Hz, IH), 4.53 (t, J = 8.8 Hz, 2H), 3.95 (d, J = 14.6 Hz, IH), 3.41-3.30 (m, 3H), 3.20 (t, J = 8.6 Hz, 2H), 2.92-2.67 (m, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.39-2.15 (m, 3H), 1.92-1.88 (m, 4H), 1.66-1.58 (m, 3H). MS m / z (ESI): 404.5 [M+H] + Example 136: (6bR,10aS)-8-(3-(3-hydroxy-2, 3-dihydrobenzofuran-7-yl)pro...

Claims

WO 2025 / 167894 PCT / CN2025 / 075755 Amended claims received by the International Bureau on June 27, 2025 (27.06.2025) 1. A tetracyclic compound of Formula I or a pharmaceutically acceptable salt thereof: A carbon atom with " represents a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof; a carbon atom with "#" represents a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof; Xi is -NRX1-, -O-, -CRX2RX3-, -S-, -S(O)- or -S(O)2-; R X1 is H, Ci-C6 alkyl, Ci-C6 alkyl substituted by one or more Rxu, -C(O)-Ci-C6 alkyl, or "a 3-12 membered heterocycloalkyl group wherein the heteroatoms are one, two or three selected from the group consisting of N, C, and S, and the number of heteroatoms is one, two or three"; RXU is independently OH; RX2 and RX3 are independently H or C1-C6 alkyl; X2 is N or CRX4; RX4 is H or G-C6 alkyl; X3 is N or CRU; X4 is N or CRL2; X5 is N or CRH; R 1 1 , R1-2 and R1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; L is -(CRURL2)n1-, -(CRLiRL2)n2-YL(CRLiRL2)n3-, or -(CRURL2)n4-Y2-(CRLiRL2)n5-; R L1 and n1 are independently H or C1-C6 alkyl; n1 is 1, 2, 3 or 4; n5 is 0, 1 or 2; n4+n5=1 or 2; 171 Amendment Page (Article 19 of the Treaty) RL3 is independently H or C1-C6 alkyl; RL4 is H or halogen; RL5 is halogen, OH or C1-C6 alkoxy; RL6 and RL7 are independently H or halogen; R 2 are independently C1-C6 alkyl, -C(O)-C1-C6 alkyl or oxo (=0); m2 is 0, 1, 2, 3 or 4; A] is independently phenyl or pyridyl, and ring A] is independently "a heteroatom selected from N and . One or two of the following, the number of heteroatoms is 1 or 2 5-6 membered heterocycloalkyl" or "heteroatoms are selected from N and. One or two of the following, the number of heteroatoms is 1 or 2 5-6 membered heteroaryl"; R3 is independently oxo (=0), C1-C6 alkyl, C1-C6 alkoxy, -NR4R5, -C(0)R6, -SR 7 、 -S(O)2R\ halogen、 one or more R 9 a substituted C1-C6 alkoxy group, a C1-C6 alkyl group substituted with one or more R1°, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, S and S" or -OR; R 4 are independently H or C1-C6 alkyl; R 5 are independently H, C1-C6 alkyl or -C(O)R 5 1 ; R6, Rd, R 7 and R8 are independently C1-C6 alkyl; R 9 and R 10 are independently OH, -NR4R 5 or halogen; 172 pages of amendments (Article 19 of the Treaty) RU is H or a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, N and S; m3 is 0, 1, 2, 3 or 4.

2. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) RX2 and RX3 are independently H; (2) RX4 is H; (3) X5 is CRT (4) R 11 , RID and RH are independently H, CN or G-C6 alkoxy; (5) RLi and W2 are independently H; (6) nl is 1, 2 or 3; (13) n5 is 1 or 1; (14) n4+n5=l; (15) 4 lying is H; (16) Lying 5 is halogen; (17) RL6 and RL7 are independently H; (18) R 2 are independently oxo; (19) m2 is 1 or 1; 173 pages of amendments (Article 19 of the Treaty) (21) R3 is independently oxo (=0), C1-C6 alkoxy, -NR4R5, -C(0)R6, -SR 7 、 -S(O)2R8、 halogen、 one or more R 9 a substituted C1-C6 alkoxy group, a C1-C6 alkyl group substituted with one or more R1°, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, S and S" or -OR; (22) R4 is independently H; (23 ) R 5 are independently H or -C(O)R 5 1 ; (24) R 9 are independently halogen; and (25) m3 is . or 1.

3. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) RU and R3 are H, KJ is H, CN or C-C6 alkoxy; (2) nl is 3; (3) Y 1 is -C(0)- or -CRL4RL5-; (4) n2 is 2; (5) n3 is 0; (6) Y2 is - CRL6=CRL7-; (7) n4 is 1; (8) n5 is 0; (9) m2 is 0; ( 10) R 3 are independently C1-C6 alkoxy, 9 Substituted C1-C6 alkoxy or halogen; (11) R5 is independently H; and (12) m3 is 0.

4. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The "C1-C6 alkyl" in each of "C1-C6 alkyl", "substituted C1-C6 alkyl" and "-C(O)-C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) The "C1-C6 alkoxy" in each "C1-C6 alkoxy" and "substituted C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (3) Each "3-12 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, S and S" is independently "a 5-6 membered heterocycloalkyl group having one or two heteroatoms selected from N and S and having one or two heteroatoms"; (4) Each halogen is independently F, Cl, Br or I; (5) Ring A is independently "a 5-membered heterocycloalkyl group having 1 or 2 heteroatoms and a heteroatom selected from 0" or "a 5- to 6-membered heteroaryl group having 1 or 2 heteroatoms and a heteroatom selected from N and ." (6) Each "5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, S and S" is independently "a 5-6 membered heteroaryl group having one or two heteroatoms selected from N"; and 174 pages of amendments (Article 19 of the Treaty) (7) 5. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) each "C1-C6 alkyl", "substituted C1-C6 alkyl' ' and "-C (O) -C1-C6 alkyl' ' in the "C1-C6 alkyl' ' is independently methyl or ethyl; (2) each "C1-C6 alkoxy" and "substituted C1-C6 alkoxy" in the "C1-C6 alkoxy" is independently a methoxy group or an ethoxy group; (3) Each "heteroatom is selected from one, two or three of N, S and S, and the number of heteroatoms is 1, 2 or 3, 3-12 membered heterocycloalkyl" is independently a piperyl (e.g. Makou Linki (For example (4) Each halogen is independently F or Cl; Amendment Page (Article 19 of the Treaty) 6. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: Amendment Page (Article 19 of the Treaty) 7. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that , m2 is . or 1; R 2 are independently oxo; X3 is CRU; X4 is CRL2; X5 is CRL3; R 1 1 , R 1 2 and R 1 3 independently H; 8. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: 177 Amendment Page (Article 19 of the Treaty) Amendment Page (Article 19 of the Treaty) 9. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The tetracyclic compound as shown in Formula I is a compound as shown in Formula 1-1, 1-2 or 1-3: I-3 Among them, *, #, X, Ring A, R3 and m3 are as defined in any one of claims 1-8.

10. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that , 179 Amendment Page (Article 19 of the Treaty) 11. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Place 12. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized in that: Replace the tetracyclic compound represented by Formula I with the tetracyclic compound represented by Formula 1-0: Amendment Page (Article 19 of the Treaty) A carbon atom with " represents a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof; a carbon atom with "#" represents a chiral carbon atom, which is in S configuration, R configuration, or a mixture thereof; Xi is -NRX1-, -O-, -CRX2RX3-, -S-, -S(O)- or -S(O)2-; RXI is H, G-C6 alkyl, G-C6 alkyl substituted by one or more Rxu, -C(O)-Ci-C6 alkyl, C3-C6 cycloalkyl, or "a 3-12 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, C, and S, with one, two or three heteroatoms"; RXU is independently 0H or 0H; RX2 and RX3 are independently H, alkyl, C1-C6 alkyl or C1-C6 halogenated alkyl; X2 is N, N+0- or CRX4; RX4 is H or G-C6 alkyl; X3 is N or CRU; X4 is N or CRL2; X5 is N or CRH; R 1 1 , R1-2 and R1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 halogenated alkoxy; L is -(CRURL2)n1-, -(CRLiRL2)n2-YL(CRLiRL2)n3-, or -(CRURL2)n4-Y2-(CRLiRL2)n5-; R L1 and 2 are independently H or C1-C6 alkyl; n4 is 0, 1 or 2; n5 is 0, 1 or 2; n4+n5=1 or 2; Amendment Page (Article 19 of the Treaty) RL3 is independently H or C1-C6 alkyl; RL4 is H or halogen; lying 5 is halogen, 0H or G-C6 alkoxy; R L6 and R L7 are independently H or halogen; R 2 are independently hydrazine, C1-C6 alkyl, C1-C6 haloalkyl, -C(O)-C1-C6 alkyl, oxo (=O), thio (=S) or hydroxy; m2 is 0, 1, 2, 3 or 4; A 10-12 membered tricyclic heterocyclic group having 1 or 2 heteroatoms; wherein Ring A1 is independently phenyl or pyridyl, and Ring A2 is independently "a 5-6 membered heterocycloalkyl group having 1 or 2 heteroatoms selected from N and O" or "a 5-6 membered heteroaryl group having 1 or 2 heteroatoms selected from N and O"; R3 is independently oxo (=0), C1-C6 alkyl, C1-C6 alkoxy, -NR4R5, -C(0)R6, -SR 7 , -S(O)2R\ halogen, C1-C6 alkoxy substituted by one or more R9, C1-C6 alkyl substituted by one or more R1°, CN, "heteroatom selected from N, and 1, 2 or 3 of S, 3-12 membered heterocycloalkyl with 1, 2 or 3 heteroatoms "or -OR"; R 4 Independently H or Ci-C6 alkyl; R 5 are independently H, Ci-C6 alkyl or -C(O)R 5 1 ; 182 pages of amendments (Article 19 of the Treaty) R6, R54, R7 and R8 are independently C1-C6 alkyl; R 9 and R 10 are independently OH, -NR4R 5 or halogen; RU is H or a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, N and S; m3 is 0, 1, 2, 3 or 4; and m4 is 0, 1 or 2.

13. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that: It meets one or more of the following conditions: (1) X] is -NRX1-; (2) X3 is CRU; (3) X4 is CR "2; (4) R 1 1 , RID and RH are independently CN, halogen or C-C6 alkoxy; for example, Ri and W are H, R 1 2 is H, F, CN or G-C6 alkoxy; for example, R 1 1 , Rm and RH are independently H; (5) m4 is 1; (6) n2 is 1 or 2; (7) n3 is 0 or 1; (8) 3 lying is H; (9) R 2 Independently amine, G-C6 alkyl, oxo, thio or hydroxy; for example, oxo; (10) m2 is 0, 1, 2 or 3; for example, m2 is 1; ( 12) R 3 are independently -OR", C-C6 alkyl, C-C6 alkoxy, 9 Substituted G-C6 alkoxy or halogen O 183 Page of amendments (Article 19 of the Treaty) 14. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that: It meets one or more of the following conditions: (1) Each C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclobutyl; (3) In ring A, the "heteroatom" is selected from one or two of N and , and the number of heteroatoms is 1 or 2 in the range of 10-12 One or more of the following conditions are met: 184 Amendment Page (Article 19 of the Treaty) 185 Amendment Page (Article 19 of the Treaty) 186 Amendment Page (Article 19 of the Treaty) 187 Amendment Page (Article 19 of the Treaty) 17. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that , m2 is . or 1; R 2 are independently oxo; m4 is 1; X3 is CRU; X4 is CR1-2; X5 is CRL3; R1-1, R1-2 and R1-3 are independently H; 18. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that , Amendment Page (Article 19 of the Treaty) Amendment Page (Article 19 of the Treaty) 19. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, characterized in that: The tetracyclic compound is a compound as shown in Formula 1-4: wherein, *, #, X, ring A, R? and m3 are as defined in any one of claims 12-18.

20. A tetracyclic compound or a pharmaceutically acceptable salt thereof as shown below: Amendment Page (Article 19 of the Treaty) Amendment Page (Article 19 of the Treaty) 193 Amendment Page (Article 19 of the Treaty) 21. A pharmaceutical composition comprising: (1) The tetracycline compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

22. Use of the tetracycline compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21, wherein the use is selected from: (1) preparing a 5-HT2A receptor agonist; (2) Preparation for treatment and / or prevention with 5-HT 2A Drugs for diseases related to 5-HT receptors; for example, 2A Receptor-related diseases are depression; (3) Preparation of medicaments for the treatment and / or prevention of depression.