CN119930620A

CN119930620A - Tetracyclic compounds, preparation methods, pharmaceutical compositions and applications thereof

Info

Publication number: CN119930620A
Application number: CN202510119032.1A
Authority: CN
Inventors: 寻国良; 席建备; 刘瑶; 刘志; 陈金聚; 方韬; 赵舒; 赵存良; 陈燕妮; 周远
Original assignee: Hejing Pharmaceutical Technology Shanghai Co ltd
Current assignee: Hejing Pharmaceutical Technology Shanghai Co ltd
Priority date: 2024-02-05
Filing date: 2025-01-24
Publication date: 2025-05-06
Also published as: WO2025167894A1

Abstract

本发明公开了一种四并环类化合物、其制备方法、药物组合物及应用。并具体公开了如式I所示的四并环类化合物或其药学上可接受的盐。本发明的化合物能有效治疗抑郁症，具有良好的药代动力学性质，较小的药物相互作用。 The present invention discloses a tetracyclic compound, a preparation method, a pharmaceutical composition and an application 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 less drug interaction.

Description

Tetrafused ring compound, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to a tetrakiscyclic compound, a preparation method, a pharmaceutical composition and application thereof.

Background

5-Hydroxytryptamine is a monoamine neurotransmitter that performs a variety of biological functions through different receptor subtypes, including emotion, cognition, rewards, learning, memory, etc. (Young SN. J Psychiatry neurosci.2007Nov;32 (6): 394-9). The 5-HT2A receptor belongs to a family of 5-hydroxytryptamine receptors, currently consisting of more than 15 different receptors encoded by different genes, and is classified into 7 general classes 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).

The 5-hydroxytryptamine 2A receptor is one of the 5-hydroxytryptamine receptors, and the downstream signal has mainly two pathways, one of which is Gq/11 coupled, activating phospholipase C, leading to an increase in the formation of inositol triphosphate and diacylglycerol and triggering their downstream signal events. The other is through beta-blocker protein as a signaling scaffold, activating downstream ERK and other signals (McCorvy JD, roth BL. Pharmacol Ther.2015Jun; 150:129-42). Non-classical pathways also include atypical signaling pathways associated with the 5-HT2A receptor, including the phospholipase A2 and beta-blocker protein coupled Src/Akt pathway, et al (Maroteaux L, ayme-DIETRICH E, aubertin-Kirch G, et al Pharmacol Ther.2017Feb; 170:14-36).

Stimulation of 5-HT2A receptors results in neuronal excitation of various brain regions, and among all 14 5-hydroxytryptamine receptor subtypes, 5-HT2A receptors are widely present in the central system, being the highest concentration levels of monoaminergic receptors in the cerebral cortex, distributed in structural regions involved in mood regulation such as the median/dorsal nucleus of the central/central slit, the locus cerulosa and the ventral tegmental areaA,P, matosiuk D, et al int J Mol Sci.2021Dec 21;23 (1): 10). Consistent with their location in the brain, they are associated not only with a variety of central physiological functions, including memory, sleep, nociception, eating and rewarding actions, but also with many neuropsychiatric disorders such as schizophrenia, depression and anxiety etc. (Guiard BP, di Giovanni G. Front pharmacol. 2015Mar17; 6:46). Many new antipsychotics, such as aripiprazole, bripiprazole and pimavanserin, have a high affinity for 5-HT2A receptors, which may also be responsible for their better therapeutic efficacy and lower side effects (MCCREARY AC, newman-Tancredi A. Curr Pharm Des.2015;21 (26): 3725-31). Mouse experiments with 5-HT2A receptor knockdown demonstrated that cortical 5-HT2AR can play a role in anxiety regulation, and that 5-hydroxytryptamine signaling in the cortex can have a significant effect on behavior in conflicting anxiety tests (Weisstaub NV, zhou M, lira A, et al science.2006Jul 28;313 (5786): 536-40).

Depression is one of the chronic mental disorders currently affecting humans, and esketamine, approved by the FDA in the united states in 2019, is the first fast-acting antidepressant on the market, which can be combined with oral antidepressant drugs to treat refractory depression. However, esketamine, as an analogue of ketamine, has a certain risk of addiction, requiring use under supervision of medical staff. Meanwhile, the hallucinogens such as ergoline ethylenediamine and nupharin act on the target of 5-HT2A, and in the 60 th century, are widely used by psychotherapists as auxiliary drugs for treating depression, anxiety-related diseases and addiction, and as a result, are generally encouraging. At present, the existing medicines for treating depression by aiming at 5-HT2A still have the problems of slow medicine effect, limited curative effect, large individual difference, large side effect and the like.

Disclosure of Invention

The invention aims to overcome the defects of slow effect or magic side effect of the existing antidepressant drugs, and provides a tetrakis ring compound, a preparation method, a pharmaceutical composition and application thereof. The compound has the advantages of quick response, no illusion side effect and the like while keeping better antidepressant effect, and has lower drug interaction in vivo.

The invention overcomes the technical problems by the following technical proposal.

The invention provides a tetrakiscyclic compound shown in a formula I or pharmaceutically acceptable salt thereof:

the carbon atom with "×" represents a chiral carbon atom, which is in the S configuration, R configuration, or mixtures thereof;

The "#" carbon atom represents a chiral carbon atom in the S configuration, R configuration, or mixtures thereof;

X ¹ is-NR ^X1-、-O-、-CR^X2R^X3 -, -S-, -S (O) -or-S (O) ₂ -;

R ^X1 is H, C ₁-C₆ alkyl, C ₁-C₆ alkyl substituted by one or more R ^X1-1, -C (O) -C ₁-C₆ alkyl or "3-to 12-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of N, O and S";

r ^X1-1 is independently OH;

R ^X2 and R ^X3 are independently H or C ₁-C₆ alkyl;

X ² is N or CR ^X4;

R ^X4 is H or C ₁-C₆ alkyl;

x ³ is N or CR ^1-1;

X ⁴ is N or CR ^1-2;

X ⁵ is N or CR ^1-3;

R ^1-1、R^1-2 and R ^1-3 are independently H, CN, halogen, C ₁-C₆ alkyl, C ₁-C₆ haloalkyl, C ₁-C₆ alkoxy or C ₁-C₆ haloalkoxy;

L is- (CR ^L1R^L2)n1-、-(CR^L1R^L2)n2-Y¹-(CR^L1R^L2) n 3-or- (CR ^L1R^L2)n4-Y²-(CR^L1R^L2) n5-;

r ^L1 and R ^L2 are independently H or C ₁-C₆ alkyl;

n1 is 1,2, 3 or 4;

Y ¹ is-O-, -NR ^L3-、-C(O)-、-CR^L4R^L5 -

N2 is 0, 1,2 or 3;

n3 is 0, 1,2 or 3;

n2+n3=1, 2 or 3;

y ² is-C.ident.C-, -C (O) -NR ^L3-、-CR^L6＝CR^L7 -

N4 is 0,1 or 2;

n5 is 0,1 or 2;

n4+n5= 1 or 2;

R ^L3 is independently H or C ₁-C₆ alkyl;

R ^L4 is H or halogen;

R ^L5 is halogen, OH or C ₁-C₆ alkoxy;

R ^L6 and R ^L7 are independently H or halogen;

R ² is independently C ₁-C₆ alkyl, -C (O) -C ₁-C₆ alkyl or oxo (=o);

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 N, O and S", "a 5-6 membered monocyclic heterocyclic group having 1,2 or 3 heteroatoms selected from N, O and S", "a C ₆-C₁₀ aryl group or a C ₃-C₆ cycloalkyl group;

And when L is- (CR ^L1R^L2)n1-、-(CR^L1R^L2) n 2-O-or- (CR ^L1R^L2) n2-C (O) -, Is that

R ³ is independently oxo (=o), C ₁-C₆ alkyl, C ₁-C₆ alkoxy, -NR ⁴R⁵、-C(O)R⁶、-SR⁷、-S(O)₂R⁸, halogen, C ₁-C₆ alkoxy substituted by one OR more R ⁹, C ₁-C₆ alkyl substituted by one OR more R ¹⁰, CN, 3-12 membered heterocycloalkyl having 1,2 OR 3 heteroatoms selected from N, O and S, OR-OR ¹¹;

r ⁴ is independently H or C ₁-C₆ alkyl;

R ⁵ is independently H, C ₁-C₆ alkyl or-C (O) R ^5-1;

r ⁶、R^5-1、R⁷ and R ⁸ are independently C ₁-C₆ alkyl;

R ⁹ and R ¹⁰ are independently OH, -NR ⁴R⁵ or halogen;

r ¹¹ is H or "a 5-to 10-membered heteroaryl group having 1,2 or 3 heteroatoms selected from 1,2 or 3 of N, O and S";

m3 is 0,1, 2,3 or 4.

The invention also provides a tetrakiscyclic compound shown as a formula I-0 or pharmaceutically acceptable salt thereof:

X ¹ is-NR ^X1-、-O-、-CR^X2R^X3 -, -S-, -S (O) -or-S (O) ₂ -;

R ^X1 is H, C ₁-C₆ alkyl, C ₁-C₆ alkyl substituted by one or more R ^X1-1, -C (O) -C ₁-C₆ alkyl, C ₃-C₆ cycloalkyl or "3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of N, O and S";

R ^X1-1 is independently deuterium or OH;

R ^X2 and R ^X3 are independently H, deuterium, C ₁-C₆ alkyl or C ₁-C₆ deuterated alkyl;

x ² is N, N ⁺O^- or CR ^X4;

R ^X4 is H or C ₁-C₆ alkyl;

x ³ is N or CR ^1-1;

X ⁴ is N or CR ^1-2;

X ⁵ is N or CR ^1-3;

r ^L1 and R ^L2 are independently H or C ₁-C₆ alkyl;

n1 is 3 or 4;

Y ¹ is-O-, -NR ^L3-、-C(O)-、-CR^L4R^L5 -

N2 is 0, 1,2 or 3;

n3 is 0, 1,2 or 3;

n2+n3=1, 2 or 3;

y ² is-C.ident.C-, -C (O) -NR ^L3-、-CR^L6＝CR^L7 -

N4 is 0,1 or 2;

n5 is 0,1 or 2;

n4+n5= 1 or 2;

R ^L3 is independently H or C ₁-C₆ alkyl;

R ^L4 is H or halogen;

R ^L5 is halogen, OH or C ₁-C₆ alkoxy;

R ^L6 and R ^L7 are independently H or halogen;

R ² is independently deuterium, C ₁-C₆ alkyl, C ₁-C₆ deuterated alkyl, -C (O) -C ₁-C₆ alkyl, oxo (=o), thio (=s) or hydroxy;

m2 is 0,1, 2,3 or 4;

Ring a is "a 8-12 membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms selected from N, O and S", "a 5-6 membered monocyclic heterocyclic group having 1,2 or 3 heteroatoms selected from N, O and S", "a 9-16 membered polycyclic heterocyclic group having 1,2 or 3 heteroatoms selected from N, O and S", or C ₃-C₆ cycloalkyl;

r ⁴ is independently H or C ₁-C₆ alkyl;

R ⁵ is independently H, C ₁-C₆ alkyl or-C (O) R ^5-1;

r ⁶、R^5-1、R⁷ and R ⁸ are independently C ₁-C₆ alkyl;

R ⁹ and R ¹⁰ are independently OH, -NR ⁴R⁵ or halogen;

m3 is 0,1, 2,3 or 4;

m4 is 0,1 or 2.

In certain preferred embodiments of the invention, certain groups in the tetrakiscyclic compounds or pharmaceutically acceptable salts thereof are defined as follows, and the non-mentioned groups are as described in any of the embodiments of the invention (abbreviated as "in one embodiment of the invention"), and X ¹ is-NR ^X1 -.

In one embodiment of the invention, R ^X2 and R ^X3 are independently H.

In one embodiment of the invention, R ^X4 is H.

In one embodiment of the invention, X ³ is CR ^1-1.

In one embodiment of the invention, X ⁴ is CR ^1-2.

In one embodiment of the invention, X ⁵ is CR ^1-3.

In one embodiment of the invention, R ^1-1、R^1-2 and R ^1-3 are independently H, CN, halogen or C ₁-C₆ alkoxy, e.g., R ^1-1 and R ^1-3 are H, R ^1-2 is H, F, CN or C ₁-C₆ alkoxy, and e.g., R ^1-1、R^1-2 and R ^1-3 are independently H.

In one embodiment of the invention, R ^1-1、R^1-2 and R ^1-3 are independently H, CN or C ₁-C₆ alkoxy, e.g., R ^1-1 and R ^1-3 are H and R ^1-2 is H, CN or C ₁-C₆ alkoxy.

In one embodiment of the invention, m4 is 1.

In one embodiment of the invention, R ^L1 and R ^L2 are independently H.

In one embodiment of the invention, n1 is 3.

In one embodiment of the invention, Y ¹ is-O-, -NR ^L3-、-C(O)-、-CR^L4R^L5 -orFor example, Y ¹ is-C (O) -or-CR ^L4R^L5 -.

In one embodiment of the invention, n2 is 0, 1 or 2, for example n2 is 2.

In one embodiment of the invention, n3 is 0, 1 or 2, e.g., n3 is 0 or 1, and e.g., n3 is 0.

In one embodiment of the present invention, n2+n3=2.

In one embodiment of the invention, Y ² is-C.ident.C-, -C (O) -NR ^L3-、-CR^L6＝CR^L7 -orFor example, Y ² is-CR ^L6＝CR^L7 -.

In one embodiment of the invention, n4 is 0 or 1, e.g., n4 is 1.

In one embodiment of the invention, n5 is 0 or 1, e.g., n5 is 0.

In one embodiment of the present invention, n4+n5=1.

In one embodiment of the invention, R ^L3 is H.

In one embodiment of the invention, R ^L4 is H.

In one embodiment of the invention, R ^L5 is halogen.

In one embodiment of the invention, R ^L6 and R ^L7 are independently H.

In one embodiment of the invention, R ² is independently deuterium, C ₁-C₆ alkyl, oxo (=o), thio (=s) or hydroxy, for example oxo (=o).

In one embodiment of the invention, R ² is independently oxo (=o).

In one embodiment of the invention, m2 is 0, 1,2 or 3, e.g. m2 is 1.

In one embodiment of the invention, m2 is 0 or 1, for example, m2 is 0.

In one aspect of the present invention, when L is- (CR ^L1R^L2)n1-、-(CR^L1R^L2) n 2-O-or- (CR ^L1R^L2) n2-C (O) -,

Is that

In one aspect of the present invention, when L is- (CR ^L1R^L2)n1-、-(CR^L1R^L2) n 2-O-or- (CR ^L1R^L2) n2-C (O) -,Is that

In one embodiment of the invention, R ³ is independently oxo (= O), C ₁-C₆ alkoxy, -NR ⁴R⁵、-C(O)R⁶、-SR⁷、-S(O)₂R⁸, halogen, C ₁-C₆ alkoxy substituted with one OR more R ⁹, C ₁-C₆ alkyl substituted with one OR more R ¹⁰, CN, 3-12 membered heterocycloalkyl having 1, 2 OR 3 heteroatoms selected from N, O and S, OR-OR ¹¹, for example, R ³ is independently C ₁-C₆ alkoxy, C ₁-C₆ alkoxy substituted with one OR more R ⁹, OR halogen.

In one embodiment of the invention, R ³ is independently-OR ¹¹、C₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkoxy substituted with one OR more R ⁹, OR halogen.

In one embodiment of the invention, R ⁴ is independently H.

In one embodiment of the invention, R ⁵ is independently H or-C (O) R ^5-1, for example, R ⁵ is independently H.

In one embodiment of the invention, R ⁹ is independently halogen.

In one embodiment of the invention, m3 is 0 or 1, e.g., m3 is 0.

In one embodiment of the invention, the "C ₁-C₆ alkyl" in each of "C ₁-C₆ alkyl", "substituted C ₁-C₆ alkyl" and "-C (O) -C ₁-C₆ alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl.

In one embodiment of the invention, each "C ₁-C₆ alkoxy" of the "C ₁-C₆ alkoxy" and "substituted C ₁-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 invention, each "3-to 12-membered heterocycloalkyl having 1,2 or 3 heteroatoms" is independently "5-to 6-membered heterocycloalkyl having 1 or 2 heteroatoms" selected from 1 or 2 heteroatoms in N and O, e.g., piperidinyl (e.g.) Morpholinyl groupOr oxetanyl (e.g)。

In one embodiment of the invention, each halogen is independently F, cl, br or I, such as F or Cl.

In one embodiment of the invention, each C ₃-C₆ cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, e.g., cyclobutyl.

In one embodiment of the invention, the "heteroatom is 1,2 or 3 of N, O and S, and the 9-12 membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms" isWherein ring A ¹ is independently phenyl or pyridinyl, ring A ² is independently "A5-6 membered heterocycloalkyl group having 1 or 2 heteroatoms selected from 1 or 2 of N and O" or "A5-6 membered heteroaryl group having 1 or 2 heteroatoms selected from 1 or 2 of N and O", e.g., ring A ² is independently "A5-6 membered heterocycloalkyl group having 1 or 2 heteroatoms selected from O, or" A5-6 membered heteroaryl group having 1 or 2 heteroatoms selected from 1 or 2 of N and O ", e.g., in ring A, the" a 9-12 membered bicyclic heterocyclyl group having 1, 2 or 3 heteroatoms selected from 1, 2 or 3 of N, O and S "is

In one embodiment of the present invention, in ring a, the "heteroatom is selected from 1,2 or 3 of N, O and S, the 8-12 membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms is" heteroatom is selected from 1,2 or 3 of N, O and S, the 8-membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms is "heteroatom is selected from 1,2 or 3 of N, O and S, the 9-12 membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms is" heteroatom is selected from 1,2 or 3 of N, O and S, and the 9-12 membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms is defined as 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 an 8-12 membered bicyclic heterocyclic group having 1,2 or 3 heteroatoms" is

In one embodiment of the invention, in ring A, the "heteroatom is selected from 1,2 or 3 of N, O and S, the 5-6 membered monocyclic heterocyclic group having 1,2 or 3 heteroatoms is" heteroatom is selected from 1 or 2 of N and S, the 5-6 membered monocyclic heteroaryl group having 1 or 2 heteroatoms is "heteroatom is selected from N, the 5-6 membered monocyclic heterocyclic group having 1 or 2 heteroatoms is" heteroatom is "5-6 membered monocyclic heterocyclic group having 1 or 2 heteroatoms is" for example pyridyl (e.g.)) Thienyl (e.g) Or piperidinyl (e.g) Preferably, in ring A, the "heteroatom is selected from 1, 2 or 3 of N, O and S, and the 5-6 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms" is

In one embodiment of the invention, in ring A, the "heteroatom is selected from 1,2 or 3 of N, O and S, the 9-16 membered polycyclic heterocyclic group having 1,2 or 3 heteroatoms" is "heteroatom is selected from 1 or 2 of N and O, the 10-12 membered tricyclic heterocyclic group having 1 or 2 heteroatoms" for example

In one embodiment of the invention, in ring A, the C ₆-C₁₀ aryl is phenyl or naphthyl, e.g., phenyl.

In one embodiment of the invention, in ring a, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclohexyl.

In one embodiment of the invention, each "heteroatom is selected from 1,2 or 3 of N, O and S, a 5-to 10-membered heteroaryl" having 1,2 or 3 heteroatoms is independently "heteroatom is selected from N, a 5-to 6-membered heteroaryl having 1 or 2 heteroatoms", e.g., pyridinyl (e.g.)。

In one aspect of the present invention,Is that One or more of (a) and (b), e.gIn one aspect of the present invention,Is that For exampleIn one aspect of the present invention,Is thatIn one aspect of the present invention,Is that

In one aspect of the present invention,Is that

In one embodiment of the invention, L is For example

In one embodiment of the invention, L is

In one aspect of the present invention,Is that

In one embodiment of the invention, the tetracyclic compound is a compound shown in formula I-1, formula I-2 or formula I-3:

Wherein, #, X ¹, ring A, R ³ and m3 are as defined in any one of the present inventions.

In one embodiment of the invention, the tetracyclic compound is a compound shown in formula I-4:

In one aspect of the present invention,Is that

In one embodiment of the invention, the compounds of the invention are not:

And stereoisomers thereof.

The invention also provides a tetrakiscyclic compound shown in any one of the following or pharmaceutically acceptable salts thereof:

the present invention provides a pharmaceutical composition comprising:

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

(2) Pharmaceutically acceptable auxiliary materials.

The invention also provides the use of a tetrakiscyclic compound according to any one of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described hereinbefore, selected from the group consisting of:

(1) Preparing a 5-HT _2A receptor agonist;

(2) Preparing a medicament for treating and/or preventing a disease associated with a 5-HT _2A receptor;

(3) Preparing the medicine for treating and/or preventing depression.

The present invention also provides a method for the treatment and/or prophylaxis of a disease associated with the 5-HT _2A receptor, which comprises administering to a patient in need thereof a therapeutically effective amount of a tetrakiscyclic compound according to any one of the present invention as defined in formula I, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described hereinbefore.

The present invention also provides a method for the treatment and/or prophylaxis of depression comprising administering to a patient in need thereof a therapeutically effective amount of a tetrakiscyclic compound according to any of the present invention as defined in formula I, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above.

In one embodiment of the invention, the disorder associated with the 5-HT _2A receptor is depression.

Description of the terms

Unless otherwise indicated, the terms used in the present invention have the following meanings:

The term "pharmaceutically acceptable" refers to those compositions which are relatively non-toxic, safe, and suitable for use by a patient.

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

The term "-" at the end of a group means that the group is attached to the remainder of the molecule at that site, in the end of a structural fragmentMeaning that the structural fragment is attached to the remainder of the molecule via this site, e.g.,Refers to cyclohexyl.

When the linking group exemplified in the present invention does not indicate its linking direction, the linking direction is linked in the same direction as the reading order from left to right, for example,When the linking group L is- (CR ^L1R^L2)n2-Y¹-(CR^L1R^L2) n3-, the linking groups- (CR ^L1R^L2)n2-Y¹-(CR^L1R^L2) n 3-are linked in the same direction as the reading sequence from left to rightWithout making up

The term "one or more" means 1, 2 or 3.

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

The term "oxo" refers to =o, the oxygen atom replacing two hydrogens on the same carbon atom, i.e. replacing a methylene group with a carbonyl group.

The term "alkyl" refers to a straight or branched, saturated monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C ₁-C₆). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where halogen is defined as the term "halogen" and alkyl is defined as the term "alkyl". Haloalkyl includes, but is not limited to, -CF ₃、-CHF₂、-CH₂CF₃, and the like.

The term "alkoxy" refers to the group-O-R ^X,R^X as defined under the term "alkyl". Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "haloalkoxy" refers to the group-O-R ^X',R^X' as defined by the term "haloalkyl". Haloalkoxy groups include, but are not limited to, -O-CF ₃、-O-CHF₂、-O-CH₂CF₃, and the like.

The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having the specified number of carbon atoms (e.g., C ₃-C₆), which is a single ring. Cycloalkyl groups include, but are not limited to: Etc.

The term "aryl" refers to an unsaturated cyclic hydrocarbon group of a specified number of carbon atoms (e.g., C ₆-C₁₀) which is a single ring or multiple rings (e.g., 2), where multiple rings are provided, two atoms and a bond are shared between adjacent single rings, and each ring has aromaticity. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group of a specified number of heteroatoms (e.g., 1, 2, or 3) of a specified number of ring atoms (e.g., 3-12 members), of a specified heteroatom species (one, two, or three of N, O and S), which is a single ring, bridged ring, or spiro ring, and each ring is saturated. The heterocycloalkyl group is attached to the remainder of the molecule via a carbon atom or heteroatom. Heterocycloalkyl groups include, but are not limited to: Etc.

The term "monocyclic heterocyclyl" refers to a saturated or unsaturated, aromatic or non-aromatic cyclic group of a specified number of ring atoms (e.g., 5-6 membered), of specified number of heteroatoms (e.g., 1, 2 or 3), of specified heteroatom species (one, two or three of N, O and S), which is monocyclic. The heterocyclic group is attached to the remainder of the molecule via a carbon atom or heteroatom.

The term "bicyclic heterocyclyl" refers to a cyclic group of a specified number of heteroatoms (e.g., 1, 2, or 3) of a specified number of ring atoms (e.g., 5-6 membered), of a specified heteroatom species (one, two, or three of N, O and S), which is bicyclic, each ring independently being saturated or unsaturated, aromatic, or non-aromatic. The heterocyclic group is attached to the remainder of the molecule via a carbon atom or heteroatom. Bicyclic heterocyclyl groups include, but are not limited to: Etc.

The term "heteroaryl" refers to an unsaturated cyclic group of a specified number of ring atoms (e.g., 5-10, 5-6) of specified number of heteroatoms (e.g., 1, 2, or 3), of specified heteroatom types (one, two, or three of N, O and S), which is a single ring or multiple rings, where two atoms and one bond are shared between the single rings, and each ring has aromaticity. Heteroaryl is linked to the remainder of the molecule through a carbon atom or heteroatom, and in the case of polycyclic, heteroaryl is linked to the remainder of the molecule through a ring with a heteroatom or a ring without a heteroatom. Heteroaryl groups include, but are not limited to: Etc.

The term "therapeutically effective amount" refers to an amount administered to a patient that is 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, etc., but can be adjusted as appropriate by one skilled in the art.

The term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical formulation, except for the active pharmaceutical ingredient, which generally fall into two broad categories, excipients and additives. See in particular the pharmacopoeia of the people's republic of China (2020 edition) )"、Handbook of Pharmaceutical Excipients(Paul J Sheskey,Bruno C Hancock,Gary P Moss,David J Goldfarb,2020,9th Edition).

The term "treatment" refers to the elimination of etiology or alleviation of symptoms.

The term "preventing" refers to 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, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The compound has the positive progress effects that the compound can reduce depression and illusion while keeping good antidepressant effect, and has lower drug interaction in vivo.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 12, 3-Dihydrobenzofuran-7-carbaldehyde (1.0 g,6.7 mmol) and methyl (triphenylphosphine) acetate (3.36 g,10.05 mmol) were dissolved in anhydrous tetrahydrofuran (15 mL) at room temperature. The reaction solution was stirred at 80 ℃ for 2h. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. The crude product was purified by column chromatography (EtOAc/pe=0-10%) to give 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) acrylate (1.18 g,5.8 mmol) was dissolved in methanol (10 mL) at room temperature and 10% wet palladium on carbon (310 mg,0.29 mmol) was added. The reaction solution was stirred at room temperature for 1h under a hydrogen atmosphere. The reaction solution was filtered through celite, washed with methanol, and the filtrates were combined and concentrated in vacuo to give crude methyl 3- (2, 3-dihydrobenzofuran-7-yl) propionate (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) propionate (500 mg,2.4 mmol) was dissolved in tetrahydrofuran (8 mL) at room temperature, cooled to zero under nitrogen, and then added with 1M lithium aluminum hydride in tetrahydrofuran (8 mL) and stirred at room temperature for 1 hour. The reaction was stirred at zero degrees, diluted with ethyl acetate (20 mL), added with sodium sulfate decahydrate, filtered through celite, washed with methanol and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (EtOAc/pe=0-15%) to give 3- (2, 3-dihydrobenzofuran-7-yl) propan-1-ol (340 mg, yield: 78.7%) as a colorless oily liquid. 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, cooled to 0℃and methanesulfonyl chloride (145 mg,1.262 mmol) was added, the reaction solution was returned to room temperature after stirring for 1 hour and concentrated in vacuo at room temperature, ((6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (97 mg, 0.426 mmol), potassium iodide (140 mg,0.842 mmol) dioxane (256 mg,2.525 mmol) was cooled to room temperature at 100℃for 18 hours, the reaction solution was concentrated in vacuo to give a crude product, and the crude product was purified (6 bR) -3- (3, 7,8,9,10 a-octahydro-1H-pyrido [3',4, 5] pyrrolo [1,2, 3-dihydro-5 ] quinoxaline (97 mg, 0.426 mmol) and potassium iodide (140 mg,0.842 mmol) were prepared as yellow liquid by an alkaline method .¹H NMR(400MHz,CDCl₃)δ7.03(d,J＝7.3Hz,1H),6.92(d,J＝7.5Hz,1H),6.76(t,J＝7.4Hz,1H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝6.8Hz,1H),6.40(d,J＝7.7Hz,1H),4.53(t,J＝8.7Hz,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＝7.6Hz,2H),2.39(s,2H),2.24(s,1H),1.89(d,J＝35.6Hz,5H).MS m/z(ESI):390.2[M+H]⁺.

Example 2 (6 bR,10 aS) -8- (3- (benzo [ d ] [1,3] dioxazol-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Preparation of E2 reference is made to the synthetic method of example 1 .¹H NMR(400MHz,CDCl₃)δ6.77-6.71(m,1H),6.70-6.62(m,3H),6.51(d,J＝6.8Hz,1H),6.40(d,J＝7.9Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1. The compound 2, 3-dihydrobenzofuran-4-carbaldehyde (200 mg,1.35 mmol), ethoxyformylmethylene triphenylphosphine (940 mg,2.7 mmol) was added to a 50mL reaction flask followed by THF (10 mL) and then stirred for 2h at 70 ℃. After completion of LCMS detection, the reaction mixture was concentrated and purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give ethyl (E) -3- (2, 3-dihydrobenzofuran-4-yl) acrylate (colorless liquid, 200mg, yield 68%). MS m/z (ESI): 219.3[ M+H ] ⁺

Step 2 Ethyl (E) -3- (2, 3-Dihydrobenzofuran-4-yl) acrylate (200 mg,0.92 mmol) was added to a 50mL reaction flask, followed by methanol (10 mL), wet palladium on carbon (10%, 97 mg) and then stirred at room temperature under hydrogen atmosphere for 1h. After completion of the reaction by LCMS, the reaction mixture was concentrated by filtration to give ethyl 3- (2, 3-dihydrobenzofuran-4-yl) propionate (200 mg, 99% yield) as a colorless liquid. MS m/z (ESI): 221.4[ M+H ] ⁺

Step 3 Ethyl 3- (2, 3-Dihydrobenzofuran-4-yl) propionate (180 mg,0.82 mmol) was added to a 50mL three-port reaction flask, followed by THF (5 mL) at 0deg.C and lithium aluminum hydride (1.5 mL,1 mol/L) was slowly added dropwise, and the reaction was stirred at 0deg.C for 20min. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and concentrated to dryness by normal phase column chromatography (petroleum ether: ethyl acetate=3:1) to give 3- (2, 3-dihydrobenzofuran-4-yl) propan-1-ol (colorless liquid, 100mg, yield 68.7%). MS m/z (ESI): 179.3[ M+H ] ⁺

Step 4-Compound 3- (2, 3-Dihydrobenzofuran-4-yl) propan-1-ol (30 mg,0.17 mmol) was added to a 25mL reaction flask, followed by DCM (5 mL) and then DIEA (65 mg,0.5 mmol), ms ₂ O (44 mg,0.5 mmol) were added sequentially and stirred at room temperature for 1h after addition. The reaction mixture was extracted with DCM (2×20 ml), and the organic phase was saturated brine (2×20 ml) and concentrated to give 3- (2, 3-dihydrobenzofuran-4-yl) propyl methanesulfonate (colorless liquid, 35mg, yield 81.4%). MS m/z (ESI): 257.3[ M+H ] ⁺

Step 5-3- (2, 3-Dihydrobenzofuran-4-yl) propyl methanesulfonate (35 mg,0.14 mmol), starting material (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (31 mg,0.14 mmol) was added to a 25mL reaction flask, followed by DMSO (3 mL) and then DIPEA (52 mg,0.4 mmol) and stirred at 60℃for 16H. The reaction mixture was concentrated and the column was reversed phase (acetonitrile/(water+0.05% NH ₄HCO₃)) to give (6 br,10 as) -8- (3- (2, 3-dihydrobenzofuran-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration (grey solid, 20mg, yield) 37.7％).¹H NMR(500MHz,DMSO-d₆)δ7.00(t,J＝7.6Hz,1H),6.66(d,J＝7.6Hz,1H),6.56(t,J＝11.2Hz,1H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),6.33(d,J＝7.6Hz,1H),4.50(s,2H),3.46-3.38(m,1H),3.27(d,J＝11.4Hz,1H),3.12(t,J＝8.4Hz,3H),3.01(s,1H),2.78(s,4H),2.67(ddd,J＝16.4,6.8,2.2Hz,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 (6 bR,10 aS) -8- (3- (chroman-8-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1. Compound 8-Bromobenzodihydropyran (500 mg,2.35 mmol), ethyl acrylate (260 mg,2.58 mmol), pd ₂(dba)₃ (43 mg,0.05 mmol), tri-tert-butylphosphine tetrafluoroborate (14 mg,0.05 mmol), N-methyldicyclohexylamine (1370 mg,7.05 mmol) were added together in a 50mL single-port reaction flask, followed by anhydrous dioxane (10 mL), nitrogen substitution 3 times, and the reaction was stirred at 100℃slowly warmed to 16h. After completion of TLC detection, water (20 mL) was added to the reaction mixture, ethyl acetate was used for extraction (3X 20 mL), the organic phases were combined, washed with saturated brine (1X 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure, and the crude product was isolated by normal phase column purification (Biotage-12 g, eluent gradient: 10% EA/PE) to give ethyl (E) -3- (chroman-8-yl) acrylate (pale yellow oil, 150mg, yield 28%).

Step 2. Ethyl (E) -3- (chroman-8-yl) acrylate (150 mg,0.65 mmol) was added to a 25mL single port reaction flask followed by ethyl acetate (15 mL) and 10% Pd/C (wet base, 15 mg) respectively, and the addition was completed, hydrogen was replaced 3 times and the reaction was stirred at room temperature for 16h. After completion of the reaction by LCMS, the reaction solution was filtered with suction, and the filtrate was concentrated under reduced pressure to give ethyl 3- (chroman-8-yl) propionate (crude, 150mg, yield 99%). 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- (chroman-8-yl) propionate (150 mg,0.64 mmol) was added to a 25mL three-port reaction flask, followed by anhydrous tetrahydrofuran (10 mL), 1M lithium aluminum tetrahydrofuran solution (48 mg,1.28mmol,1 mol/L) was added in portions under a nitrogen and ice-water bath, and the reaction was stirred at 0℃for 0.5h. After completion of the TLC detection, the reaction was quenched by slow addition of Na ₂SO₄.10H₂ O, filtered, 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 give 3- (chroman-8-yl) propan-1-ol (colorless oil, 110mg, 89% yield).

Step 4 Compound 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 together in a 25mL three-port reaction flask, and methylsulfonic anhydride (27 mg,0.16 mmol) was slowly added under nitrogen and ice-water bath, and the addition was complete, allowing the reaction to stir at room temperature for 2h. After completion of the TLC detection reaction, water (10 mL) was added to the reaction solution, dichloromethane extraction (2X 10 mL), the organic phases were combined, washed with saturated brine (1X 10 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give 3- (chroman-8-yl) propylmethanesulfonate (colorless oil, crude product, 20 mg). The crude product was used directly in the next reaction without further purification.

Step 5-Compounds 3- (chroman-8-yl) propylmethanesulfonate (20 mg,0.07 mmol) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (20 mg,0.08 mmol) were added to a 10mL reaction flask, followed by the addition of anhydrous DMSO (2 mL) and DIPEA (30 mg,0.21 mmol), respectively, and slowly warmed to 60℃after the addition and stirred for 16H. After the reaction, the reaction mixture was filtered and the filtrate was directly separated by reverse phase preparation (C18 column, eluent gradient: acetonitrile/(water +0.05% NH ₄HCO₃)) to give ((6 bR,10 aS) -8- (3- (chroman-8-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration ] quinoxaline (off-white solid, 4.5mg, yield) 15％).¹H NMR(500MHz,CDCl₃)δ6.93(d,J＝7.3Hz,1H),6.88(d,J＝7.0Hz,1H),6.74(t,J＝7.4Hz,1H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝7.1Hz,1H),6.40(d,J＝7.8Hz,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 (6 bR,10 aS) -8- (3- (benzofuran-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ] quinoxaline

Step 1) Compound 7-bromobenzofuran (400 mg,2.0 mmol) was dissolved in DMF (5.0 mL), triethylamine (1.40 g,14.0 mmol), ethyl acrylate (220 mg,2.2 mmol), o-trimethylphenylphosphine (122 mg,0.4 mmol) and palladium acetate (44 mg,0.2 mmol) were added sequentially under nitrogen protection, stirred for 4h at 100℃after completion of TLC detection reaction, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and purified in normal phase to give Compound ethyl (E) -3- (benzofuran-7-yl) acrylate (yellow oil, 220mg, yield 50%). MS M/z (ESI): 217.3.[ M+H ] ⁺.

Step 2 Ethyl (E) -3- (benzofuran-7-yl) acrylate (45 mg,0.2 mmol) was dissolved in THF (2.0 mL), cooled to 0deg.C, 1M solution of lithium aluminum in tetrahydrofuran (0.2 mL,0.2 mmol) was added, stirred at room temperature for 1h, sodium sulfate decahydrate was added, stirred for 30min, filtered and concentrated and the normal phase purified to give compound 3- (benzofuran-7-yl) propan-1-ol (yellow oil, 25mg, 70% yield). MS M/z (ESI): 177.2.[ M+H ] ⁺.

Step 3 Compound 3- (benzofuran-7-yl) propan-1-ol (25 mg,0.14 mmol) was dissolved in DCM (2.0 mL), DIEA (90 mg,0.7 mmol) was added to cool to 0deg.C, methanesulfonic anhydride (45 mg,0.26 mmol) was added and then warmed to room temperature and stirred for 3h, quenched with water, extracted with DCM, dried over sodium sulfate and filtered to give Compound 3- (4-fluoro-2-methoxyphenyl) propylmethanesulfonate (yellow oil, 23 mg) which was used directly in the next reaction.

Step 4 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (25 mg,0.10 mmol) was dissolved in DMSO (2.5 mL) at room temperature, DIEA (0.5 mL,3.0 mmol) was added sequentially, 3- (4-fluoro-2-methoxyphenyl) propylmethanesulfonate (23 mg,0.1 mmol), heated to 65℃with stirring for 18H, cooled to room temperature, and prep-HPLC purification separation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) was performed to give the compound (6 bR,10 aS) -8- (3- (benzofuran-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4': 1, 5] pyrrolo [3, 3' ] 2, 5] quinoxaline (0.0 mg) colorless oil 5％).¹H NMR(500MHz,DMSO-d₆)δ7.98(d,J＝5.0Hz,1H),7.48(dd,J＝10.0,5.0Hz,1H),7.19-7.12(m,2H),6.95(d,J＝5.0Hz,1H),6.67-6.52(m,1H),6.43(d,J＝5.0Hz,1H),6.34(d,J＝10.0Hz,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).MS m/z(ESI):388.8[M+H]⁺.

Example 6 (6 bR,10 aS) -8- (3- (benzo [ b ] thiophen-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1-6-7-bromobenzo [ b ] thiophene (500 mg,2.35 mmol), ethyl acrylate (580 mg,5.79 mmol), pd ₂(dab)₃ (110 mg,0.12 mmol), tris (o-tolyl) phosphine (220 mg,0.72 mmol) were added to a three-necked flask containing 10mL of DMF, the reaction was performed three times under nitrogen, 16h at 105℃after completion of the TLC detection reaction, water and EA were added, the liquid was separated, 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 and concentrated, and then normal phase column chromatography (PE/EA=100%. About.10/1) was performed to give ethyl (E) -3- (benzo [ b ] thiophen-7-yl) acrylate (yellow solid, 487mg, yield: 87%).

Step2 Ethyl (E) -3- (benzo [ b ] thiophen-7-yl) acrylate (470 mg,2.02 mmol), 50mg Pd/C and 50mg Pd (OH) ₂/C were added to a three-necked flask containing 30mL MeOH, H ₂ was replaced three times, and the reaction was allowed to proceed at room temperature for 16H, and was complete by TLC and lcms. After filtration and concentration, normal phase column chromatography (PE/ea=100% -5/1) gives the compound ethyl 3- (benzo [ b ] thiophen-7-yl) propionate (410mg,colorless oil, yield: 87%).

Step 3 Ethyl 3- (benzo [ b ] thiophen-7-yl) propionate (110 mg,0.469 mmol) was added to a three-necked flask containing 5mL of THF, replaced with nitrogen three times, cooled to 0℃and injected with 0.9mL of 1M LAH THF solution, and the reaction was continued for 1h and the completion of TLC detection. Adding sodium sulfate decahydrate to quench the reaction, adding EA and Na ₂SO₄, stirring at room temperature for half an hour, filtering, concentrating normal phase column chromatography (PE/EA=100% -10/1) to obtain the compound 3- (benzo [ b ] thiophen-7-yl) propan-1-ol (90mg,colorless oil, yield: 90%).

Step 4 preparation of the Compound 3- (benzo [ b ] thiophen-7-yl) propylmethanesulfonate reference example 3 the fourth step of the synthesis.

Step 5 preparation of the Compound (6 bR,10 aS) -8- (3- (benzo [ b ] thiophen-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline reference example 3 Synthesis method in the fifth step .¹H NMR(500MHz,CDCl₃)δ7.68(d,J＝8.0Hz 1H),7.42(d,J＝5.5Hz 1H),7.35(d,J＝5.5Hz,1H),7.31(t,J＝8.0Hz 1H),7.16(d,J＝7.0Hz 1H),6.64(t,J＝7.5Hz 1H),6.51(d,J＝5.5Hz 1H),6.40(d,J＝7.5Hz 1H),3.62-3.56(m,1H),3.31-3.20(m,4H),2.92(t,J＝8.0Hz 1H)2.86(s,3H),2.85-2.72(m,2H),2.58-2.30(m,3H),2.07-1.94(m,5H).MS m/z(ESI):405.4.[M+H]⁺.

EXAMPLE 7- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) benzo [ d ] oxazole

Step 1. 2-amino-6-bromophenol (1000 mg,5.32 mmol) as a compound, anhydrous p-toluenesulfonic acid (100 mg,0.53 mmol) and triethyl orthoformate (10 mL) were added together in a 25mL single-port reaction flask, and the temperature was slowly raised to 80℃under nitrogen protection, followed by stirring for 16h. After the TLC detection reaction was completed, saturated NaHCO ₃ solution was added to the reaction solution to adjust the pH of the system to be alkaline, followed by extraction with ethyl acetate (3X 20 mL), the organic phases were combined, washed with saturated brine (1X 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure by spin-drying, and the crude product was purified and separated by normal phase column (eluent gradient: 3% EA/PE) to obtain the compound 7-bromobenzo [ d ] oxazole (pale yellow solid, 900mg, yield 85%).

Step 2. 7-bromobenzo [ d ] oxazole (250 mg,1.26 mmol), ethyl (E) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) acrylate (340 mg,1.51 mmol), pd (dppf) Cl ₂.CH₂Cl₂ complex (20 mg,0.03 mmol) and sodium carbonate (265 mg,2.52 mmol) were added together in a 25mL single port reaction flask followed by dioxane (5 mL) and water (1 mL), displacement with nitrogen 3 times, and stirring at 80℃for 16h. After completion of LCMS detection, the reaction mixture was filtered, then water (20 mL) was added to the mixture, ethyl acetate was extracted (3 x 10 mL), the organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried by spin-drying under reduced pressure, and the crude product was isolated by normal phase column purification (eluent gradient: 10% ea/PE) to give ethyl (E) -3- (benzo [ d ] oxazol-7-yl) acrylate (pale yellow oil, 150mg, yield 55%). MS m/z (ESI): 218.5[ M+H ] ⁺.

Step 3. Ethyl (E) -3- (benzo [ d ] oxazol-7-yl) acrylate (100 mg,0.46 mmol) was added to a 25mL single port reaction flask followed by ethyl acetate (10 mL) and 10% Pd/C (wet base, 10 mg) respectively, the addition was completed, hydrogen was replaced 3 times and the reaction was stirred at room temperature for 16h. After completion of the LCMS detection reaction, the reaction solution was filtered with suction, and the filtrate was concentrated under reduced pressure to give ethyl 3- (benzo [ d ] oxazol-7-yl) propionate (crude, 100mg, yield 99%). 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 ] oxazol-7-yl) propan-1-ol reference example 3 third step synthesis method. The compound ethyl 3- (benzo [ d ] oxazol-7-yl) propionate (50 mg,0.23 mmol) was added to a 25mL three-port reaction flask, then anhydrous tetrahydrofuran (3 mL), lithium aluminum hydride (17 mg,0.46 mmol) was added in portions under nitrogen and ice-water bath, and the reaction was stirred under ice-water bath for 1h. After completion of LCMS detection, na ₂SO₄.10H₂ O was slowly added to the reaction, quenched, filtered, the filter cake was washed with 10% MeOH/DCM (10 mL), the filtrate concentrated under reduced pressure and the crude product purified by normal phase column chromatography (eluent gradient: 40% EA/PE) to give compound 3- (benzo [ d ] oxazol-7-yl) propan-1-ol (colorless oil, 25mg, yield 62%). MS m/z (ESI): 178.4[ M+H ] ⁺

Step 5 Compound 3- (benzo [ d ] oxazol-7-yl) propan-1-ol (10 mg,0.06 mmol), triethylamine (12 mg,0.12 mmol) and anhydrous dichloromethane (3 mL) were added together in a 10mL single port reaction flask, methanesulfonic anhydride (12 mg,0.07 mmol) was added under ice water bath, and after addition, stirring was allowed for 3h at room temperature. After LCMS detection, saturated ammonium chloride solution (5 mL) was added to the reaction solution, dichloromethane extraction (2 x10 mL), the organic phases were combined, washed with saturated brine (1 x10 mL), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product purified by normal phase purification (eluent gradient: 30% EA/PE) to give 3- (benzo [ d ] oxazol-7-yl) propylmethanesulfonate (pale yellow oil, 8mg, 60% yield).

Step 6. 3- (benzo [ d ] oxazol-7-yl) propylmethanesulfonate (8 mg,0.03mmol, crude) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (8 mg,0.04 mmol) were added to a 10mL reaction flask, followed by DIEA (11 mg,0.09 mmol) and anhydrous DMSO (1 mL) and stirred for 6H at 60 ℃. After completion of LCMS detection reaction, the reaction solution was filtered and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile/(water+0.05% NH ₄HCO₃)) to give the compound 7- (3- ((6bR, 10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) benzo [ d ] oxazole (pale yellow solid, 2.0mg, yield) 15％).¹HNMR(500MHz,CDCl₃)δ8.08(s,1H),7.63(d,J＝8.0Hz,1H),7.29(d,J＝7.6Hz,1H),7.19(d,J＝7.4Hz,1H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝7.2Hz,1H),6.40(d,J＝7.8Hz,1H),3.58(dd,J＝14.7,6.5Hz,1H),3.33-3.14(m,4H),2.93(t,J＝7.6Hz,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 (6 bR,10 aS) -3-methyl-8- (3- (quinolin-8-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ]

Step 1-Compound 8-bromoquinoline (500 mg,2.40 mmol), ethyl acrylate (480 mg,4.80 mmol), pd (PPh ₃)₂Cl₂ (17 mg,0.02 mmol), triethylamine (730 mg,7.20 mmol) were added together to a 25mL single port reaction flask followed by anhydrous DMF (8 mL), after 3 changes in nitrogen, and the reaction mixture was slowly warmed to 120℃under stirring for 16h.LCMS detection, water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (3X 20 mL), the organic phases were combined, washed with saturated saline (1X 20 mL), dried over anhydrous sodium sulfate, and the crude product was isolated by normal phase column purification (eluent gradient: 5% EA/PE) to give the compound ethyl (E) -3- (quinolin-8-yl) acrylate (reddish brown oil, 350mg, 64% yield. MS m/z (ESI): 228.4[ M+H ] ⁺).

Step 2. Ethyl (E) -3- (quinolin-8-yl) acrylate (100 mg,0.44 mmol) was added to a 25mL single port reaction flask, followed by ethyl acetate (10 mL) and 10% Pd/C (wet base, 10 mg) respectively, and the addition was completed, hydrogen was replaced 3 times and the reaction was stirred at room temperature for 0.5h. After completion of the reaction by LCMS, the reaction solution was filtered with suction, and the filtrate was concentrated under reduced pressure to give ethyl 3- (quinolin-8-yl) propionate (crude, 100mg, yield 99%). 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- (quinolin-8-yl) propionate (100 mg,0.44 mmol) was added to a 25mL three-port reaction flask, and then anhydrous tetrahydrofuran (5 mL) was added, lithium aluminum hydride (33 mg,0.88mmol,1 mol/L) was added in portions under a nitrogen and ice-water bath, and the reaction was stirred under an ice-water bath for 0.5h. After completion of LCMS detection, na ₂SO₄.10H₂ O was slowly added to the reaction, quenched, filtered, the filter cake was washed with 10% MeOH/DCM (10 mL), the filtrate concentrated under reduced pressure and the crude product purified by normal phase column chromatography (eluent gradient: 30% EA/PE) to give compound 3- (quinolin-8-yl) propan-1-ol (colorless oil, 60mg, yield 74%). MS m/z (ESI): 188.4[ M+H ] ⁺.

Step 4 Compound 3- (quinolin-8-yl) propan-1-ol (30 mg,0.16 mmol), pyridinium chlorochromate (65 mg,0.32 mmol) and anhydrous dichloromethane (3 mL) were added together to a 10mL single port reaction flask and reacted at room temperature under stirring for 2h. After LCMS detection was completed, saturated aqueous sodium bicarbonate was added to the reaction to adjust the pH of the system to alkaline, dichloromethane extraction (2 x 10 ml), the organic phases were combined, washed with saturated brine (1 x 10 ml), dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give compound 3- (quinolin-8-yl) propanal (dark brown oil, crude product, 25mg, yield 83%). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 186.4[ M+H ] ⁺.

Step 5 the compounds 3- (quinolin-8-yl) propanal (25 mg,0.13 mmol) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (32 mg,0.14 mmol) were added to a 10mL reaction flask and stirred at room temperature for 0.5H. Sodium triacetoxyborohydride (55 mg,0.26 mmol) was then added to the reaction solution, and the mixture was stirred at room temperature for 16 hours after the completion of the addition. After the reaction, the reaction solvent was removed under reduced pressure, and then the crude product was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile/(water+0.05% NH ₄HCO₃)) to give the compound (6 bR,10 aS) -3-methyl-8- (3- (quinolin-8-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration (off-white solid, 6.0mg, yield) 18％).¹H NMR(500MHz,MeOD)δ8.86(dd,J＝4.2,1.8Hz,1H),8.29(dd,J＝8.3,1.7Hz,1H),7.77(dd,J＝8.2,1.3Hz,1H),7.62(d,J＝7.0Hz,1H),7.54-7.46(m,2H),6.64-6.55(m,1H),6.47(d,J＝7.2Hz,1H),6.40(d,J＝7.9Hz,1H),3.49(ddd,J＝11.4,10.1,2.9Hz,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＝12.1,3.0Hz,1H),2.05-1.86(m,5H).MS m/z(ESI):399.9[M+H]⁺.

Example 9 (6 bR,10 aS) -8- (3-isoquinolin-8-propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Preparation of E9 reference is made to the synthetic method of example 3 .¹H NMR(500MHz,DMSO)δ9.54(s,1H),8.51(d,J＝5.6Hz,1H),7.87-7.76(m,2H),7.69(dd,J＝8.2,7.0Hz,1H),7.51(dd,J＝7.0,1.1Hz,1H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),6.33(d,J＝7.9Hz,1H),3.45-3.40(m,1H),3.27(dd,J＝11.5,2.9Hz,3H),3.19(dd,J＝8.6,6.6Hz,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＝21.6Hz,1H),1.84(d,J＝29.7Hz,5H).MS m/z(ESI):399.9[M+H]⁺.

Example 10 (6 bR,10 aS) -3-methyl-8- (3- (1, 2,3, 4-tetrahydroquinolin-8-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

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), triethylamine (1.6 g,16.0 mmol), ethyl acrylate (300 mg,1.5 mmol), o-trimethylphenylphosphine (120 mg,0.4 mmol) and palladium acetate (44 mg,0.2 mmol) were added sequentially under nitrogen protection, stirred at 100℃for 3H, after completion of TLC detection reaction, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the normal phase was purified to give Compound (E) -ethyl 3- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-5-yl) acrylate (yellow oil, 230mg, yield 49%). MS M/z (ESI): 234.3.[ M+H ] ⁺ _.

Step 2 Ethyl (190 mg,0.81 mmol) of compound (E) -3- (3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-5-yl) acrylate was dissolved in DCM (20.0 mL), TEA (800 mg,8.0 mmol) was added followed by (Boc) ₂ O (700 mg,3.2 mmol), stirring at 20℃for 16H, and normal phase purification by vacuum concentration gave tert-butyl (E) -5- (3-ethoxy-3-oxoprop-1-en-1-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-carboxylate (yellow oil, 180mg, 67% yield). MS M/z (ESI): 334.4.[ M+H ] ⁺.

Step 3. Compound (E) -5- (3-ethoxy-3-oxoprop-1-en-1-yl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester was dissolved in MeOH (10.0 mL), 10% palladium on carbon (90 mg) was added, stirred at room temperature for 18H, and concentrated by filtration to give Compound 5- (3-ethoxy-3-oxopropyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester (yellow oil, 160mg, yield 88%). MS M/z (ESI): 336.4 [ M+H ] ⁺.

Step 4. Compound 5- (3-ethoxy-3-oxypropyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester (145 mg,0.43 mmol) was dissolved in THF (2.0 mL), cooled to 0deg.C, added to lithium aluminum tetrahydrosolution (0.45 mL,0.15 mmol) and warmed to 20deg.C, stirred for 1H, dried over sodium sulfate decahydrate, filtered and normal phase purified to give Compound 5- (3-hydroxypropyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester (yellow oil, 85mg, 67% yield). MS M/z (ESI): 294.3.[ M+H ] ⁺.

Step 5 Compound 5- (3-hydroxypropyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylic acid tert-butyl ester (85 mg,0.29 mmol) was dissolved in DCM (5.0 mL), PCC (128 mg,0.59 mmol) was added and stirred at 20℃for 3H. Quenched with saturated sodium bicarbonate, extracted with DCM, dried over sodium sulfate, filtered and concentrated to give the compound tert-butyl 5- (3-oxypropyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylate (colorless oil, 66mg, 80% yield) which is used directly in the next reaction. MS M/z (ESI): 292.4.[ M+H ] ⁺.

Step 6: (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-desquinoxaline (62 mg,0.27 mmol), tert-butyl 5- (3-oxypropyl) -2, 3-dihydro-4H-benzo [ b ] [1,4] oxazine-4-carboxylate (66 mg,0.23 mmol) was dissolved in DCM (3.0 mL), 5mg each of triethylamine and acetic acid was added, after stirring for 10min, sodium triacetoxyborohydride (230 mg,4.0 mmol) was added, stirring for 18H at 20 ℃, water quenching was added, ethyl acetate extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the normal phase was purified to give an intermediate, dissolved in DCM (3.0 mL), TFA (0.3 mL,1.1 mmol) was added, and after concentration, prep-HPLC purification separation (eluent (v/v: acetonitrile/(water+0.05% NH ₄HCO₃) 30% -70%) was obtained as compound (6 bR,10 aS) -3-methyl-8- (3, 4, 3-tetrahydroquinoline-2, 3, 1.27 mmol) =5, 8 ' - [1, 3-5 ] quinoline, 3, 8 ' ] and (3.7 mg, 8 ' - [2, 3-quinoxaline ] were obtained by stirring at room temperature 9％).¹H NMR(500MHz,CD₃OD)δ6.61-6.59(m,2H),6.57-6.49(m,3H),7.00(d,J＝5.0Hz,1H),4.15(t,J＝5.0Hz,2H),3.54-3.48(m,1H),3.37(t,J＝5.0Hz,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 (6 bR,10 aS) -8- (3- (1H-indol-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1H-indole-7-carbaldehyde (500.0 mg,3.44 mmol) and methyl triphenylphosphine-acetate (1.4 g,4.13 mmol) were dissolved in DCM (3 mL) and the reaction mixture stirred at room temperature for 16H. The reaction was taken up in 80mL of water, extracted with DCM (70 mL X3), the organic phases were combined and concentrated in vacuo to give the crude product which was purified by column on silica gel (PE/EA=100/0-90/10) to give methyl (E) -3- (1H-indol-7-yl) acrylate (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) acrylate (480.0 mg,2.39 mmol) was added to methanol (5 mL), 10% palladium on charcoal (101.5 mg) was added, and the reaction was stirred at room temperature under hydrogen atmosphere for 1 hour. After the reaction was completed, the reaction mixture was filtered through celite, and washed with methanol to give methyl 3- (1H-indol-7-yl) propionate (450 mg, yield 92.8%) as a gray solid. MS m/z (ESI): 204.1[ M+H ] ⁺

Step 3 methyl 3- (1H-indol-7-yl) propionate (450.0 mg,2.21 mmol) was added to methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature, sodium borohydride (418.8 mg,11.07 mmol) was added, and the reaction was stirred at room temperature under nitrogen atmosphere for 16 hours. After the reaction, excess methanol was added for quenching, and concentrated in vacuo to give a crude product, which was purified by silica gel column (PE/ea=100/0-60/40) to give 3- (1H-indol-7-yl) propan-1-ol (380 mg, yield: 97.9%) as a pale yellow oil. MS m/z (ESI): 176.2[ M+H ] ⁺

Step 4 3- (1H-indol-7-yl) propan-1-ol (50.0 mg,0.29 mmol) and carbon tetrabromide (141.9 mg,0.43 mmol) are dissolved in dichloromethane (10 mL) at room temperature, triphenylphosphine (112.2 mg,0.43 mmol) is added and the reaction stirred at room temperature for 16 hours. After the reaction is finished, the crude product is obtained by vacuum concentration. Purification of the crude product over silica gel (PE/ea=100/0-90/10) afforded 7- (3-bromopropyl) -1H-indole (40 mg, 58.9% yield) as a clear oil. MS m/z (ESI): 238.1[ M+H ] ⁺.

Step 5 7- (3-bromopropyl) -1H-indole (40.5 mg,0.17 mmol) was dissolved in 1, 4-dioxane/toluene (1.5 mL/1.5 mL), and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (39.0 mg,0.17 mmol), potassium iodide (56.4 mg,0.34 mmol) and triethylamine (51.6 mg,0.51 mmol) were added. The reaction solution was stirred at 100 ℃ for 18 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. The crude product was prepared to give (6 bR,10 aS) -8- (3- (1H-indol-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (13.51 mg, yield 20.16%) as a pale yellow solid .¹H NMR(400MHz,CDCl₃)δ10.85(s,1H),7.52(dd,J＝7.8,0.8Hz,1H),7.22(d,J＝2.9Hz,1H)7.06-7.01(m,1H)6.96(d,J＝6.8Hz,1H),6.68(t,J＝7.6Hz,1H),6.55(dd,J＝6.6,5.4Hz,2H),6.43(d,J＝7.8Hz,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 (6 bR,10 aS) -8- (3- (indolin-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

(6 BR,10 aS) -8- (3- (1H-indol-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (55.0 mg,0.14 mmol) is dissolved in acetic acid (3 mL) at room temperature, and sodium borohydride acetate (13.4 mg,0.21 mmol) is added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction, the mixture was concentrated in vacuo, added to 10mL of water, added dropwise with sodium hydroxide solution to adjust the pH to 8, diluted with 30mL of water, extracted with ethyl acetate (30 mL of X3) to give a crude product, which was purified to give (6 bR,10 aS) -8- (3- (indolin-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline formate (14.04 mg yield 24.2%) as a brown solid .¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),6.99(d,J＝7.2Hz,1H),6.78(d,J＝7.5Hz,1H),6.69(t,J＝7.7Hz,1H),6.63(t,J＝7.4Hz,1H),6.52(d,J＝7.4Hz,1H),6.43(d,J＝8.0Hz,1H),3.65-3.50(m,4H),3.41(dd,J＝11.8,6.2Hz,1H),3.36-3.24(m,4H),3.03(t,J＝8.4Hz,2H),2.95-2.78(m,7H),2.56(t,J＝7.3Hz,2H),2.39-2.34(m,2H),2.09-2.03(m,3H).MS m/z(ESI):389.3[M+H]⁺.

Example 13 (6 bR,10 aS) -8- (3- (3-methoxypyridin-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 3-fluoro-4-nitropyridine 1-oxide (5 g,31.6 mmol) was dissolved in anhydrous methanol (55 mL) at room temperature, and 5.4M sodium methoxide methanol solution (5.9 mL,31.6 mmol) was added at 0deg.C. The reaction was stirred at room temperature for 2h. The reaction was concentrated in vacuo 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 in vacuo to give 3-methoxy-4-nitropyridine 1-oxide (5 g, yield: 77.8%) as a pale 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, followed by dropwise addition of phosphorus tribromide (22.1 mL,235.2 mmol), stirring at room temperature for 10 min, then raising to 80℃and stirring at this temperature for 16h. The reaction solution was cooled to room temperature, added dropwise to ice water, and extracted with ethyl acetate. The aqueous phase was ph=11 with 10M aqueous NaOH and extracted three more times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (EtOAc/pe=0-15%) to give 4-bromo-3-methoxypyridine (470 mg, yield: 8.5%) as a brown solid. MS m/z (ESI): 188.1[ M+H ] ⁺.

Step 3 to a reaction flask of 4-bromo-3-methoxypyridine (470 mg,2.5 mmol), ethyl acrylate (860.79 mg,9.99 mmol), palladium acetate (56.62 g,0.25 mmol), triethylamine (2.53 g,25.0 mmol), and trioxymethylphosphine (228.25 mg,0.75 mmol) was charged DMF (5 mL) at room temperature. After the reaction flask was replaced with nitrogen three times, the temperature was raised to 100℃and stirred under nitrogen atmosphere for 18 hours. 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. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (EtOAc/pe=0-20%) to give ethyl-3- (3-methoxypyridin-4-yl) acrylate (300 mg, yield: 60.3%) as a pale yellow solid. MS m/z (ESI): 208.1[ M+H ] ⁺.

Step 4 Ethyl-3- (3-methoxypyridin-4-yl) acrylate (270 mg,14.5 mmol) was dissolved in methanol (5 mL) at room temperature, and 10% wet palladium on carbon (69 mg,0.65 mmol) was added. The reaction solution was stirred at room temperature for 16h under a hydrogen atmosphere. The reaction solution was filtered through celite. Washing with methanol, combining the filtrates and concentrating in vacuo gave 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, and a 1M solution of aluminum lithium hydrogen in tetrahydrofuran (2.4 mL,2.39 mmol) was added dropwise at a reduced temperature to 0 ℃. The reaction solution was stirred at room temperature under nitrogen atmosphere for 1h. The reaction solution was diluted with tetrahydrofuran, quenched with sodium sulfate decahydrate in ice bath, and filtered through celite. The filter cake was filtered again after methanol sonication. The combined filtrates were concentrated in vacuo to give 3- (3-methoxypyridin-4-yl) propan-1-ol (160 mg, theory) as a yellow oil. MS m/z (ESI): 168.2[ M+H ] ⁺.

Step 6 3- (3-methoxypyridin-4-yl) propan-1-ol (130.0 mg,0.78 mmol) and triethylamine (236.0 mg,2.33 mmol) were dissolved in dry DCM (1.5 mL) at room temperature and a solution of MsCl (133.59 mg,1.17 mmol) in DCM (0.5 mL) was added dropwise. The reaction solution was stirred at room temperature for 1h. The reaction solution was concentrated in vacuo to give 3- (3-methoxypyridin-4-yl) propylmethanesulfonate (191 mg, theory) as a white solid. MS m/z (ESI): 246.1[ M+H ] ⁺.

Step 7, (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (90.0 mg,0.30 mmol), 3- (3-methoxypyridin-4-yl) propylmethanesulfonate (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 ℃ for 22h. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. Purification of the crude product by formic acid gave (6 bR,10 aS) -8- (3- (3-methoxypyridin-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline formate (6.53 mg, yield: 3.8%) as a yellow oil .¹H NMR(400MHz,CDCl₃)δ8.41(s,1H),8.19(s,1H),8.16(d,J＝4.7Hz,1H),7.06(d,J＝4.8Hz,1H),6.69(t,J＝7.7Hz,1H),6.52(d,J＝7.4Hz,1H),6.43(d,J＝7.9Hz,1H),3.90(s,3H),3.62-3.49(m,2H),3.37(dd,J＝11.6,6.7Hz,1H),3.28(d,J＝9.4Hz,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 (6 bR,10 aS) -8- (3- (2-methoxypyridin-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 to a reaction flask of 3-bromo-2-methoxypyridine (5 g,26.6 mmol), ethyl acrylate (10.65 g,106.4 mmol), palladium acetate (0.6 g,2.66 mmol), triethylamine (26.92 g,266 mmol) and triorthotolylphosphine (2.43 g,7.98 mmol) was charged DMF (100 mL) at room temperature. After the reaction flask was replaced with nitrogen three times, the temperature was raised to 100℃and stirred under nitrogen atmosphere for 20 hours. 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. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 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 pale 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 palladium on carbon (770 mg, 0.720 mmol) was added. The reaction solution was stirred at room temperature for 7h under hydrogen atmosphere. The reaction solution was filtered through celite. Washing with methanol, combining the filtrates, and concentrating in vacuo gave 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, and a 1M solution of aluminum lithium hydrogen in tetrahydrofuran (12 mL,12 mmol) was added dropwise at a reduced temperature to 0 ℃. The reaction solution was stirred at room temperature under nitrogen atmosphere for 1h. The reaction solution was diluted with tetrahydrofuran, quenched with sodium sulfate decahydrate in ice bath, and filtered through celite. After the filter cake is subjected to methanol ultrasonic treatment, filtering again, and concentrating the combined filtrate in vacuum to obtain a crude product. The crude product was purified by column chromatography (EtOAc/pe=0-18%) to give 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 3- (2-methoxypyridin-3-yl) propan-1-ol (200 mg,1.196 mmol) was dissolved in anhydrous DCM (2 mL) at room temperature, and thionyl chloride (398.4 mg,3.35 mmol) was added dropwise under ice-bath. The reaction solution was stirred at room temperature for 1h. The reaction solution was concentrated in vacuo to give 3- (3-chloropropyl) -2-methoxypyridine (220 mg, theory) 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 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (68 mg, 0.298 mmol), 3- (3-chloropropyl) -2-methoxypyridine (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℃for 22h. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. The crude product was purified by alkaline method to give (6 bR,10 aS) -8- (3- (2-methoxypyridin-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (12.10 g, yield: 10.7%) as a yellow oil .¹H NMR(400MHz,CDCl₃)δ8.01(dd,J＝5.0,1.7Hz,1H),7.38(d,J＝5.8Hz,1H),6.80(dd,J＝7.1,5.1Hz,1H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝7.3Hz,1H),6.41(d,J＝7.9Hz,1H),3.93(s,3H),3.59(dd,J＝14.9,6.3Hz,

1H),3.46-3.00(m,5H),2.91-2.69(m,6H),2.58(t,J＝7.6Hz,2H),2.47-2.18(m,3H),1.89-1.83(m,4H).MS m/z(ESI):379.2[M+H]⁺.

Example 15 (6 bR,10 aS) -8- (3- (4-methoxypyridin-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1-3- (4-methoxypyridin-3-yl) prop-2-yn-1-ol (150 mg,0.92 mmol) was added to a 50mL three-port reaction flask followed by methanol (10 mL), wet palladium on carbon (10%, 50 mg) and then stirred under hydrogen atmosphere at 60℃for 4h. After completion of LCMS detection, the reaction mixture was concentrated by filtration and purified by column chromatography (DCM: meoh=3:1) to give the title compound 3- (4-methoxypyridin-3-yl) propan-1-ol (colorless liquid, 80mg, yield 80%). MS m/z (ESI): 168.4[ M+H ] ⁺ _.

Step 2 preparation of 3- (4-methoxypyridin-3-yl) propylmethanesulfonate the synthesis of the third step of example 3 was referred to.

Step 3 preparation of (6 bR,10 aS) -8- (3- (4-methoxypyridin-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline by the fourth step of the synthesis method of example 3 .¹H NMR(500MHz,DMSO)δ8.30(d,J＝5.6Hz,1H),8.20(s,1H),6.98(d,J＝5.6Hz,1H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),6.33(d,J＝7.6Hz,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),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 (6 bR,10 aS) -8- (3- (3-methoxypyridin-2-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Preparation of Synthesis method of reference example 8 .1H NMR(500MHz,DMSO)δ8.03(dd,J＝4.7,1.3Hz,1H),7.31(dd,J＝8.3,1.3Hz,1H),7.18(dd,J＝8.2,4.7Hz,1H),6.54-6.46(m,1H),6.41(dd,J＝7.3,0.9Hz,1H),6.32(dd,J＝8.0,1.0Hz,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(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,4H).MS m/z(ESI):379.8[M+H]⁺

EXAMPLE 17 preparation of (6 bR,10 aS) -8- ((E) -3- (2-methoxypyridin-3-yl) allyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 Ethyl (E) -3- (2-methoxypyridin-3-yl) acrylate (800.0 mg,3.82 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and a 1M solution of diisobutylaluminum hydride (7.6 mL,7.65 mmol) in THF was added dropwise at a reduced temperature to 0 ℃. The reaction solution was stirred at room temperature under nitrogen atmosphere for 1h. The reaction was diluted with dichloromethane, quenched by dropwise addition of saturated ammonium chloride solution in ice bath, diluted with 40mL of water, extracted with dichloromethane (40 mL x 3), the organic phases combined and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (EtOAc/pe=0-18%) to give (E) -3- (2-methoxypyridin-3-yl) prop-2-en-1-ol (437 mg, yield: 69.3%) as a pale 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, and SOCl ₂ (144 mg,1.21 mmol) was added dropwise under ice-bath. The reaction solution was stirred at room temperature for 1h. The reaction solution was concentrated in vacuo to give (E) -3- (3-chloropro-1-en-1-yl) -2-methoxypyridine (110 mg, theory) 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, (E) -3- (3-Chloropropan-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) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (70.0 mg,0.30 mmol), potassium iodide (101 mg,0.61 mmol) and triethylamine (185.3 mg,1.83 mmol) were added at room temperature. The reaction solution was stirred at 100 degrees celsius for 18 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. The crude product was purified by alkaline method to give (6 bR,10 aS) -8- ((E) -3- (2-methoxypyridin-3-yl) allyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (26.15 mg, yield: 22.5%) as a yellow solid .¹H NMR(400MHz,CDCl₃)δ8.05(dd,J＝4.9,1.7Hz,1H),7.67(d,J＝6.4Hz,1H),6.86(dd,J＝7.3,5.0Hz,1H),6.70-6.62(m,2H),6.52(d,J＝6.8Hz,1H),6.41(d,J＝7.6Hz,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 preparation of (6 bR,10 aS) -8- (2- (2-methoxyphenoxy) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ] quinoxaline

(6 BR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (23 mg,0.1 mmol) was dissolved in DMSO (2.5 mL) at room temperature, DIEA (0.5 mL,3.0 mmol) was added in sequence, 1- (2-bromoethoxy) -2-methoxybenzene (23 mg,0.1 mmol) was heated to 65℃for 18H, cooled to room temperature, and prep-HPLC purification was performed after filtration to isolate (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give compound (6 bR,10 aS) -8- (2- (2-methoxyphenoxy) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (2.10 mg) as yellow solid (yellow solid) 27％).¹H NMR(500MHz,CD₃OD)δ7.09-6.90(m,4H),6.88-6.57(m,3H),4.41(t,J＝5.0Hz,1H),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).MS m/z(ESI):380.8[M+H]⁺.

EXAMPLE 19 2-methoxy-N- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) ethyl) aniline

Step 1 Compound 2-methoxyaniline (505 mg,2.0 mmol) and dibromoethane (1.104 g,6.0 mmol) were dissolved in DMF (5.0 mL), stirred at 60℃for 3h, after completion of TLC detection reaction, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, and the normal phase was purified to give Compound 1- (2-bromoethoxy) -2-methoxybenzene (yellow solid, 115mg, yield 25%). MS M/z (ESI): 232.3 [ M+H ] ⁺ _.

Step 2 Synthesis of 2-methoxy-N- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxalin-8 (7H) -yl) ethyl) aniline the fourth step of Synthesis method of reference example 3 .¹H NMR(500MHz,CD₃OD)δ6.81-6.77(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).MS m/z(ESI):379.9[M+H]⁺.

EXAMPLE 20N- (2-methoxyphenyl) -2- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -acetamide

The compound (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (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 stirred for 12H at 60 ℃. The reaction solution was filtered and then was subjected to reverse phase preparation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃)), acetonitrile was removed under reduced pressure, and lyophilized to give the compound N- (2-methoxyphenyl) -2- (6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -acetamide (pale yellow solid, 20mg, yield) 46％).¹H NMR(500MHz,DMSO)δ9.78(s,1H),8.29-8.11(m,1H),7.09-7.03(m,2H),6.93(m,1H),6.51(t,J＝7.6Hz,1H),6.43(d,J＝7.2Hz,1H),6.35(d,J＝7.8Hz,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＝11.4Hz,1H),2.41(m,1H),2.11(t,J＝11.0Hz,1H),2.01(dd,J＝14.5,2.8Hz,1H),1.88(m,1H).MS m/z(ESI):393.6[M+H]⁺.

EXAMPLE 21 3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) -1- (pyridin-4-yl) propan-1-one

Step 1. Ethyl 3-carbonyl-3- (pyridin-4-yl) propionate (300 mg,1.55 mmol) was added to a 50mL three-port reaction flask followed by THF (5 mL), -LiHMDS (1.7 mL,1 mol/L) was slowly added dropwise at 78℃and the reaction stirred at 0℃for 0.5h, then lithium aluminum hydride (3.1 mL,1 mol/L) was slowly added dropwise at 0℃and the reaction stirred continuously at 0℃for 1h. The reaction was quenched with saturated aqueous ammonium chloride, extracted with dichloromethane (2 x 50 ml), concentrated and passed through a column to give the compound 1- (pyridin-4-yl) propane-1, 3-diol (yellow liquid, 200mg, yield 84.0%). MS m/z (ESI) 154.0[ M+H ] ⁺ _.

Step 2 Compound 1- (pyridin-4-yl) propane-1, 3-diol (200 mg,1.3 mmol) was added to a 100mL reaction flask followed by dichloromethane (20 mL) and MnO ₂ (565 mg,6.5 mmol) at 40℃with stirring for 4h. The reaction solution was filtered, concentrated and then reversed-phase column chromatography to give the compound 3-hydroxy-1- (pyridin-4-yl) propan-1-one (colorless solid, 100mg, yield 50.1%). MS m/z (ESI) 152.1[ M+H ] ⁺ _.

Step 3 preparation of 3-carbonyl-3- (pyridin-4-yl) propylmethanesulfonate the synthesis of the third step of example 3 was referenced.

Step 4 preparation of 3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) -1- (pyridin-4-yl) propan-1-one the fourth step of the synthetic method according to example 3 is referred to .¹H NMR(500MHz,CD₃OD)δ8.90(d,J＝6.0Hz,2H),7.98(t,J＝8.0Hz,2H),6.63(t,J＝7.6Hz,1H),6.52(dd,J＝32.8,7.6Hz,2H),3.75(d,J＝7.2Hz,4H),3.28-3.02(m,7H),2.84(s,3H),2.80-2.71(m,1H),2.65(dd,J＝3.7,1.8Hz,1H),2.33(dd,J＝45.0,7.0Hz,3H).MS m/z(ESI):363.6[M+H]⁺.

EXAMPLE 22 1- (2-methoxyphenyl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) yl) propan-1-one

Step 1 Compound 1- (2-methoxyphenyl) ethan-1-one (500 mg,3.33 mmol) and paraformaldehyde (200 mg,6.66 mmol) were dissolved in tetrahydrofuran (10 mL), followed by addition of N, N-diisopropylethylamine trihydrofluoride salt (710 mg,3.33 mmol) and TFA (40 mg,0.33 mmol) and stirring at 70℃for 12h. To the reaction was added water (80 mL) and extracted with ethyl acetate (80 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate concentrated and purified by normal phase column chromatography to give the compound 1- (2-methoxyphenyl) prop-2-en-1-one (yellow solid, 430mg crude product, yield 80%). MS m/z (ESI): 163.2[ M+H ] ⁺

Step 2 Compound 1- (2-methoxyphenyl) prop-2-en-1-one (100 mg,0.62 mmol) was dissolved in acetonitrile (5 mL), followed by addition of water (67 mg,3.70 mmol) and chromium trichloride (20 mg,0.12 mmol) and stirring at room temperature for 24h. To the reaction was added water (30 mL) and extracted with ethyl acetate (30 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and prepared in reverse phase (eluent (v/v): acetonitrile/(water +0.05% NH ₄HCO₃)), acetonitrile was removed under reduced pressure, and lyophilized to give compound 3-hydroxy-1- (2-methoxyphenyl) propan-1-one (white solid, 10mg, yield 9%).

Step 3 preparation of 3- (2-methoxyphenyl) -3-oxopropanesulfonate the synthesis of the third step of example 3 is referred to.

Step 4 preparation of 1- (2-methoxyphenyl) -3- ((6 bR,10 aS) 3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) yl) propan-1-one the fourth step of the synthesis method of example 3 is referenced .¹H NMR(500MHz,DMSO)δ7.58-7.47(m,2H),7.16(d,J＝8.3Hz,1H),7.05-6.99(m,1H),6.58-6.49(m,1H),6.42(d,J＝6.9Hz,1H),6.34(d,J＝8.0Hz,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- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propan-1-one

Compound 23-1 (115 mg,0.5 mmol) was dissolved in EtOH (5 mL), paraformaldehyde (120 mg,4.0 mmol) and concentrated hydrochloric acid (0.125 mL,1.5 mmol) were added, heated under stirring and reflux for 16H, and after concentration, the normal phase column chromatography was purified to give compound 1- (2, 3-dihydrobenzofuran-7-yl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propan-1-one (grey solid, 45mg, yield) 22％).¹H NMR(500MHz,CD₃OD)δ7.63(d,J＝5.0Hz,1H),7.43(d,J＝10.0Hz,1H),6.91(t,J＝7.5Hz,1H),6.65-6.60(m,1H),6.53-6.49(m,1H),6.43(d,J＝10.0Hz,1H),4.70(d,J＝7.5Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) -3-fluoropropyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1-Compound 1- (2, 3-Dihydrobenzofuran-7-yl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 aS hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-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, filtered after stirring at 20℃for 1H, prep-HPLC purification was performed (eluent (v/v): acetonitrile/(water +0.05% NH ₄HCO₃) =30% -70%) to give Compound 1- (2, 3-Dihydrobenzofuran-7-yl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 aS hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1, 3-des ] quinoxalin-8 (7H) -yl) as a white solid (50 mg, 12%).

Step 2: dissolving the compound 1- (2, 3-dihydrobenzofuran-7-yl) -3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 aS hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propan-1-ol in DCM (2 mL), cooling to 0 ℃, adding DAST (10 mg,0.06 mmol), stirring at 0 ℃ for 0.5H, quenching with saturated sodium bicarbonate, extracting with DCM, concentrating, and purifying and separating prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give the compound (6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) -3-fluoropropyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4, 3': 1, 5] pyrrol [3, 3-1-d-e ] 1-ol as a white solid (23 mg, 23:23:1:1:1:1:1:1: 18％)¹H NMR(500 MHz,CD₃OD)δ7.17(d,J＝5.0Hz,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 (6 bR,10 aS) -8- (2, 3-Dihydrobenzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 Compounds 2- (benzofuran-3-yl) ethan-1-ol (150 mg,1.3 mmol) was added to a 50mL three-port reaction flask, followed by methanol (10 mL), wet palladium on carbon (10%, 0.1 g), palladium on carbon hydroxide (20%, 0.1 g) and then warmed to 40℃under hydrogen atmosphere and stirred for 16h. After completion of LCMS detection, the reaction mixture was concentrated by filtration and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give the title compound 2- (2, 3-dihydrobenzofuran-3-yl) ethan-1-ol (colorless liquid, 0.1g, yield 66%).

Step 2 preparation of 2- (2, 3-Dihydrobenzofuran-3-yl) ethylmethanesulfonate reference is made to the synthetic method of the third step of example 3

Step 3 preparation of (6 bR,10 aS) -8- (2, 3-Dihydrobenzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline reference to the fourth step of the synthesis method of example 3 .¹H NMR(500 MHz,CD₃OD)δ7.39-7.23(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 (6 bR,10 aS) -8- (2- (benzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ] quinoxaline

Step 1 Ethyl 2- (benzofuran-3-yl) acetate (1000 mg,4.87 mmol) was added to a 50mL three-port reaction flask, followed by THF (20 mL) at 0deg.C and lithium aluminum hydride (2 mL,1 mol/L) dropwise, and the reaction was stirred at 0deg.C for 0.2h. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and concentrated to dryness by normal phase column chromatography to obtain compound 2- (benzofuran-3-yl) ethan-1-ol (colorless liquid, 700mg, yield 88.7%).

Step 2- (benzofuran-3-yl) ethan-1-ol (200 mg,1.23 mmol) was added to a 25mL reaction flask, followed by DCM (50 mL) and then DIEA (635 mg,4.9 mmol), ms ₂ O (430 mg,2.47 mmol) and stirred at room temperature for 1h after completion of the addition. The reaction mixture was extracted with DCM (2×20 ml), and the organic phase was saturated brine (2×20 ml) and concentrated to give compound 2- (benzofuran-3-yl) ethylmethanesulfonate (colorless liquid, 0.25g, yield 84.7%).

Step 3. 2- (benzofuran-3-yl) ethylmethanesulfonate (60 mg,0.25 mmol), starting (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (68 mg,0.3 mmol) was added to a 25mL reaction flask, followed by DMSO (5 mL) and DIPEA (0.2 g,1.58 mmol) was then added and stirred at 60℃for 16H. The reaction mixture was added to (30 mL) ethyl acetate, washed with water (30 mL), brine (50 mL), and the organic phase concentrated and then initially purified by normal phase column chromatography (dichloromethane: methanol=10:1) followed by reverse phase column chromatography (acetonitrile/(water+0.05% HCl)) to give the compound (6 br,10as-8- (2- (benzofuran-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration ] quinoxaline (grey solid, 20mg, yield 21.5％).¹H NMR(500MHz,CD₃OD)δ7.73(s,1H),7.70(d,J＝7.4Hz,1H),7.48(d,J＝8.2Hz,1H),7.37-7.13(m,4H),6.93(s,1H),3.81(s,2H),3.67(d,J＝10.7Hz,3H),3.52-3.42(m,3H),3.38-3.36(m,2H),3.31(d,J＝1.6Hz,3H),3.27(d,J＝8.3Hz,3H),2.85(d,J＝11.7Hz,1H),2.47(s,2H).MS m/z(ESI):374.6[M+H]⁺.

EXAMPLE 27 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) aniline

Step 1. Compound (2-bromophenyl) carbamic acid tert-butyl ester (1 g,3.68 mmol), ethyl acrylate (400 mg,4.00 mmol), tris (o-tolyl) phosphine (110 mg,0.36 mmol), palladium acetate (80 mg,0.36 mmol) and triethylamine (178 mg,7.19 mmol) were added to a 100mL reaction flask followed by DMF (15 mL) and stirred at 100℃for 12h. Water (80 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (2X 80 mL), the organic phase was washed with brine (3X 80 mL), and the organic phase was concentrated and purified by normal phase column chromatography to isolate (petroleum ether: ethyl acetate=10:1) ethyl phenyl acrylate (compound (Z) -3- (2- ((t-butoxycarbonyl) amino) (yellow oil, 290mg, yield) 27％).¹H NMR(500MHz,DMSO)δ9.13(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＝16.0Hz,1H),4.19(q,J＝7.1Hz,2H),1.45(s,9H),1.26(t,J＝7.1Hz,3H).

Step 2 Ethyl (Z) -3- (2- ((tert-butoxycarbonyl) amino) phenyl) acrylate (290 mg,0.995 mmol) was added to a 100mL reaction flask followed by methanol (10 mL) followed by 10% wet Pd/C (11 mg,0.0995 mmol) and Pd (OH) ₂/C (14 mg,0.0995 mmol) in sequence and stirred under hydrogen at 60℃for 3h after completion of the addition. The reaction solution was filtered, and the filtrate was concentrated and purified by normal phase column chromatography to isolate (petroleum ether: ethyl acetate=3:1) to give ethyl 3- (2- ((t-butoxycarbonyl) amino) phenyl) propanoate (white solid, 240mg, yield 82%). MS m/z (ESI) 294.4[ M+H ] ⁺ _.

Step 3 Ethyl 3- (2- ((t-Butoxycarbonyl) amino) phenyl) propionate (140 mg,0.48 mmol) was added to a 50mL three-necked flask, followed by anhydrous tetrahydrofuran (5 mL) and then 1M LiAlH ₄ in tetrahydrofuran (0.95 mL,0.95mmol, 1M) under nitrogen at 0deg.C, and after addition was stirred at room temperature for 2h. Sodium sulfate decahydrate (50 mg) was added to the reaction solution, the reaction solution was stirred at room temperature for 10min, and then the reaction solution was filtered, and the filtrate was concentrated and purified by normal phase column chromatography to isolate (petroleum ether: ethyl acetate=3:1) t-butyl (2- (3-hydroxypropyl) phenyl) carbamate (colorless oil, 100mg, yield 83%).

Step 4. Tert-butyl 2- (3-hydroxypropyl) phenyl) carbamate (100 mg,0.40 mmol) was added to a 50mL reaction flask followed by dichloromethane (4 mL), DIEA (155 mg,1.20 mmol), DMAP (25 mg,0.20 mmol) and Ms ₂ O (174 mg,1.00 mmol), after stirring at room temperature for 1h, water (10 mL) was added to the reaction and extracted with dichloromethane (10 mL. Times.2), and after washing the organic phase with saturated brine (10 mL) 2 times, the organic phase was dried over anhydrous sodium sulfate and concentrated to give 3- (2- (((tert-butoxycarbonyl) amino) phenyl) propylmethanesulfonate (yellow oil, 100mg, 77% yield) MS m/z (ESI): 230.5 M+H-Boc) ⁺

Step 5: the compound 3- (2- (((tert-butoxycarbonyl) amino) phenyl) propylmethanesulfonate (100 mg,0.30 mmol) was added to a 50mL reaction flask followed by DMSO (4 mL) and then DIEA (118 mg,0.91 mmol) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (83 mg,0.36 mmol), after stirring for 12H at 60 ℃, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL x 2), after washing the organic phase 2 times with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated, and the separated (dichloromethane: methanol=10:1) was purified by normal phase column chromatography to give the compound 2- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4, 5] pyrrolo [1,2, 3-deoxoquinoxaline-8 (7H) -propyl) phenyl) carbamic acid butyl ester (2- (3- (6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4, 5 ': 1H-quinoxaline-8 (7H) -propyl) phenyl) carbamate (57 mg, white solid, yield). MS m/z (ESI): 463.8[ M+H ] ⁺ _.

Step 6 butyl 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -propyl) phenyl) carbamate (2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -propyl) phenyl) carbamate (20 mg,0.043 mmol) is dissolved in HCl/Dioxane (2 mL) and stirred at 25℃for 1H. After the reaction solution was dried by spin-drying, dissolved in MeOH (2 mL) and then prepared by reverse phase (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃)), acetonitrile was removed under reduced pressure, and the compound 2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydropyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -propyl) aniline (yellow solid, 7mg, yield) was obtained by lyophilization 25％).¹H NMR(500MHz,DMSO)δ6.93-6.83(m,2H),6.59(dd,J＝7.9,1.3Hz,1H),6.54-6.40(m,3H),6.33(d,J＝7.8Hz,1H),4.98(s,2H),3.44-3.40(m,1H),3.31-3.25(m,2H),3.16-3.10(m,1H),3.08-2.99(m,1H),2.78(s,4H),2.72-2.65(m,1H),2.62(d,J＝8.9Hz,1H),2.43(t,J＝7.3Hz,2H),2.18(d,J＝64.8Hz,3H),1.96-1.88(m,1H),1.84-1.74(m,2H),1.72-1.63(m,2H).MS m/z(ESI):363.8[M+H]⁺.

EXAMPLE 28N- (2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -propyl) phenyl) acetamide

The compound 2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydropyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline-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 for 2H at 25 ℃. Water (10 mL) was added to the reaction, extracted with dichloromethane (2X 10 mL), the organic phase concentrated and dissolved with MeOH (2 mL) and prepared in reverse phase (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃)), acetonitrile was removed under reduced pressure, and the compound N- (2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -propyl) phenyl) acetamide (yellow oil, 5mg, yield 22％).¹H NMR(500MHz,DMSO)δ9.42(s,1H),7.32(dd,J＝7.7,1.5Hz,1H),7.22(dd,J＝7.3,1.8Hz,1H),7.13(m,2H),6.52(t,J＝7.6Hz,1H),6.43(d,J＝7.3Hz,1H),6.34(d,J＝7.9Hz,1H),3.46-3.40(m,1H),3.32(d,J＝3.7Hz,2H),3.27(m,2H),3.13(s,2H),2.78(s,3H),2.68(m,1H),2.57(t,J＝7.6Hz,2H),2.19(d,J＝31.3Hz,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- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenyl) ethan-1-one

Step 1 Tri-methyl orthoformate (1 mL) was added to a 25mL three-necked flask together with anhydrous ethylene glycol (2 mL) and 1- (2-iodophenyl) ethan-1-one (500 mg,2.03 mmol), followed by addition of anhydrous dichloromethane (10 mL) and stirring under nitrogen and ice-water bath for 0.5h. Finally, concentrated sulfuric acid (0.5 mL) was slowly added dropwise, and the mixture was allowed to stir at room temperature for 24h. After completion of TLC detection, saturated NaHCO ₃ solution was slowly added dropwise to the reaction to adjust the system to basic, followed by DCM extraction (3×20 ml), the combined organic phases were washed with saturated brine (1×20 ml), dried over anhydrous sodium sulfate, and dried by spin-drying under reduced pressure, and the crude product was isolated by normal phase column purification (eluent gradient: 5% ea/PE) to give compound 2- (2-iodophenyl) -2-methyl-1, 3-dioxolane (pale yellow oil, 350mg, yield 59%).

Step 2 Ethyl acrylate (360 mg,3.60 mmol), pd (OAc) 2 (13 mg,0.06 mmol), tris (o-methylphenyl) phosphorus (18 mg,0.06 mmol) and triethylamine (360 mg,3.60 mmol) were added together to a 25mL single port reaction flask followed by anhydrous DMF (5 mL) and replaced 3 times with nitrogen and the reaction was stirred at 100℃for 16h. After completion of TLC detection, the reaction solution was filtered, then water (20 mL), ethyl acetate extraction (3X 20 mL) and the combined organic phases were washed with saturated brine (1X 20 mL), dried over anhydrous sodium sulfate and spun-dried under reduced pressure, and the crude product was separated by normal phase column purification (eluent gradient: 3% EA/PE) to give ethyl (E) -3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) acrylate (pale yellow oil, 200mg, yield 63%).

Step 3 Ethyl (200 mg,0.76 mmol) of the compound (E) -3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) acrylate was added to a 25mL single port reaction flask, followed by addition of ethyl acetate (15 mL) and 10% Pd/C (wet base, 20 mg) respectively, displacement of hydrogen 3 times, and stirring at room temperature for 0.5h. After completion of TLC detection, the reaction solution was filtered under suction, and the filtrate was concentrated under reduced pressure to give ethyl 3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) propionate (crude product, 200mg, yield 99%). 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 reference is made to the synthetic procedure of the first step of 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 together in a 25mL three-port reaction flask, and methylsulfonic anhydride (55 mg,0.32 mmol) was slowly added under nitrogen and ice water bath, and the addition was completed, allowing the reaction to stir at room temperature for 2h. After completion of the TLC detection reaction, water (10 mL) was added to the reaction solution, dichloromethane extraction (2X 10 mL), the organic phases were combined, washed with saturated brine (1X 10 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give the compound 3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) propylmethanesulfonate (colorless oil, crude product, 50 mg). The crude product was used directly in the next reaction without further purification.

Step 6 preparation of (6 bR,10 aS) -3-methyl-8- (3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline by the method of the third step of example 26.

Step 7. The compound (6 bR,10 aS) -3-methyl-8- (3- (2- (2-methyl-1, 3-dioxolan-2-yl) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (5 mg,0.75 mmol) was added to a 10mL one-port reaction flask, followed by 4M HCl/Dioxane (1 mL) and the reaction was stirred at room temperature for 1.0H after addition. After completion of LCMS detection, the solvent was removed under reduced pressure, the crude product was dissolved in MeOH (1 mL) and the solution was directly isolated by reverse phase preparation (C18 column, eluent gradient: acetonitrile/(water+0.05% NH ₄HCO₃)) to give compound 1- (2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenyl) ethan-1-one (white solid, 3.0mg, yield 66％).¹H NMR(500MHz,MeOD)δ7.78(d,J＝7.3Hz,1H),7.49-7.39(m,1H),7.31(t,J＝7.4Hz,2H),6.59(t,J＝7.6Hz,1H),6.48(d,J＝7.2Hz,1H),6.41(d,J＝7.6Hz,1H),4.61(s,1H),3.54-3.47(m,1H),3.38-3.32(m,2H),3.27(t,J＝2.8Hz,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＝12.3,3.0Hz,1H),2.04-1.99(m,1H),1.96-1.88(m,2H),1.84-1.76(m,2H).MS m/z(ESI):390.4[M+H]⁺.

EXAMPLE 30 3- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) ethyl) benzo [ d ] isothiazole

The compounds 3- (2-bromoethyl) benzo [ d ] isothiazole (15 mg,0.07 mmol) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (15 mg,0.07 mmol) were added to a10 mL reaction flask, followed by the addition of anhydrous DMF (2 mL), K ₂CO₃ (19 mg,0.14 mmol) and NaI (10 mg,0.07 mmol), respectively, slowly warmed to 45℃after the addition and stirred for 16H. After the reaction was completed, the reaction mixture was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile/(water+0.05% NH ₄HCO₃)) to give the compound 3- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxalin-8 (7H) -yl) ethyl) benzo [ d ] isothiazole (pale yellow oil, 8mg, yield 33％).¹H NMR(500MHz,CDCl₃)δ7.69(d,J＝7.9Hz,1H),7.59-7.51(m,2H),7.30(t,J＝7.1Hz,1H),6.70-6.64(m,1H),6.54(d,J＝7.3Hz,1H),6.42(d,J＝7.9Hz,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＝10.8Hz,1H),2.02-1.96(m,2H).MS m/z(ESI):375.6[M+H]⁺.

EXAMPLE 31 3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) -1-phenylpropan-1-ol

(6 BR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (18 mg,0.078 mmol) was dissolved in DMSO (2.0 mL) at room temperature, DIEA (0.5 mL,3.0 mmol) was added in sequence, 3-chloro-1-phenylpropan-1-ol (14 mg,0.08 mmol) was heated to 65℃with stirring for 18H, cooled to room temperature, and prep-HPLC purification was performed after filtration (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give the compound 3 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline-7-1-ol (8 mg, 8H) -1-quinol as a pale yellow oil, yield (8/v) was obtained as a 33％).¹H NMR(500MHz,DMSO-d₆)δ7.34-7.30(m,4H),7.23-7.20(m,1H),6.52(t,J＝7.5Hz,1H),6.43(d,J＝5.0Hz,1H),6.33(d,J＝5.0Hz,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 (6 bR,10 aS) -3-methyl-8- (3- (2- (methylthio) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazaline)

Preparation of E32 reference example 26 Synthesis method .¹H NMR(500MHz,CDCl₃)δ7.18(dd,J＝4.5,1.0Hz 2H),7.14(d,J＝7.5,Hz 1H),7.10～7.06(m,1H),6.64(t,J＝7.5Hz 1H),6.52(d,J＝7.0Hz 1H),6.40(d,J＝8.0Hz1H),3.62-3.57(m,1H),3.32-3.17(m,4H),32.93-2.80(m,5H),2.71(t,J＝7.5Hz,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 (6 bR,10 aS) -3-methyl-8- (3- (2- (methylsulfonyl) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1. Compound (2-iodophenyl) (methyl) sulfane 33-1 (1 g,4 mmol), ethyl acrylate (1g,10mmol),Pd(OAc)₂(50mg,0.22mmol),K₂CO₃(1.36g,9.86mmol),TBAB(1.32g,4.09mmol) is added into a three-port flask containing 10mL DMF, the reaction is carried out for 16h at 50 ℃ with nitrogen displacement, after TLC detection reaction is completed, water and EA are added, the liquid is separated, the aqueous phase is extracted twice with EA, the organic phases are combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated, and normal phase column chromatography (PE/EA=100% -5/1) is carried out to obtain Compound (E) -3- (2- (methylthio) phenyl) ethyl acrylate (920 mg, yield 90%).

Step 2 Ethyl (E) -3- (2- (methylthio) phenyl) acrylate (800 mg,3.6 mmol), 50mg of 10% Pd/C and 50mg of Pd (OH) ₂/C were added to a three-necked flask containing 30mL of THF and 30mL of EtOH, the reaction was performed three times with hydrogen, at room temperature for 16h, after completion of the reaction by TLC and LCMS, filtration and concentration gave a crude product (860 mg) of the preparation of ethyl 3- (2- (methylthio) phenyl) propionate. MS m/z (ESI) 225.17[ M+H ] ⁺ _.

Step 3 preparation of ethyl 3- (2- (methylthio) phenyl) propionate (300 mg,1.34 mmol) was added to a single vial with 5mL DCM and m-CPBA (231 mg,1.14 mmol) was added and reacted at room temperature for 16h, and the reaction was complete by TLC. Saturated NaHCO ₃ was added to wash three times, the mixture was separated, dried, filtered and concentrated, and then the mixture was subjected to normal phase column chromatography (PE/ea=100% -5/1) to give a preparation of ethyl 3- (2- (methylsulfonyl) phenyl) propionate (150 mg, yield: 49%).

Step 4 Ethyl 3- (2- (methylsulfonyl) phenyl) propionate (116 mg,0.45 mmol) was added to a three-necked flask containing 4mL of THF, replaced with nitrogen three times, cooled to 0℃and injected with 0.9mL of a 1M LAH THF solution, and the reaction was continued for 1h and complete by TLC. The reaction was quenched by the addition of sodium sulfate decahydrate, followed by addition of EA and Na ₂SO₄, stirring at room temperature for half an hour, and concentration by filtration to give the compound 3- (2- (methylsulfonyl) phenyl) propan-1-ol (70 mg, yield: 72%).

Step 5 preparation of 3- (2- (methylsulfonyl) phenyl) propyl methanesulfonate the synthetic method of the third step of example 3 is referenced.

Step 6 preparation of (6 bR,10 aS) -3-methyl-8- (3- (2- (methylsulfonyl) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline by the fourth step of the synthesis method of example 3 .¹H NMR(500MHz,CDCl₃)δ8.03(dd,J＝8.0,1.0Hz 1H),7.58～7.55(m,1H),7.42～7.37(m,2H),6.66(t,J＝7.5Hz 1H),6.52(d,J＝7.0Hz 1H),6.41(d,J＝8.0Hz 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,1H)2.14-1.97(m,5H).MS m/z(ESI):426.8[M+H]⁺.

EXAMPLE 34 (6 bR,10 aS) -8- (3-cyclohexylpropyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-dearomatization ] quinoxaline

Preparation of E34 reference example 20 Synthesis method .¹H NMR(500MHz,DMSO-d₆)δ6.63(t,J＝7.6Hz,1H),6.58(d,J＝7.0Hz,1H),6.52(s,1H),3.52-3.47(m,2H),3.47-3.42(m,2H),3.37(d,J＝10.0Hz,2H),3.02-

2.94(m,2H),2.85(d,J＝5.8Hz,3H),2.22(t,J＝14.8Hz,2H),1.77-1.57(m,9H),1.33-1.03(m,8H),0.85(dd,J＝21.5,10.5Hz,2H).MS m/z(ESI):348.6[M+H]⁺.

Example 35 (6 bR,10 aS) -3-methyl-8- (3- (piperidin-1-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazate ] quinoxaline

Preparation of E35 reference example 20 Synthesis method .¹H NMR(500MHz,DMSO-d₆)δ6.51(t,J＝7.5Hz,1H),6.42(d,J＝7.2Hz,1H),6.34(d,J＝7.5Hz,1H),3.32-3.22(m,3H),3.11(dd,J＝4.2,2.3Hz,1H),3.03-2.97(m,1H),2.82-2.76(m,4H),2.71-2.66(m,1H),2.60(d,J＝11.0Hz,1H),2.52(t,J＝4.0Hz,2H),2.48-2.33(m,4H),2.31-2.20(m,2H),2.11(t,J＝10.5Hz,1H),1.90(dd,J＝14.5,2.5Hz,1H),1.80-1.72(m,2H),1.61(s,2H),1.56-1.47(m,4H),1.37(d,J＝24.9Hz,2H).MS m/z(ESI):355.7[M+H]⁺.

EXAMPLE 36 3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydropyrido [3,4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) yl) -1- (piperidin-1-yl) propan-1-one

Preparation of Compound E36 reference example 20 Synthesis method .¹H NMR(500MHz,DMSO)δ6.53(t,J＝7.6Hz,1H),6.44(d,J＝7.2Hz,1H),6.35(d,J＝7.9Hz,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＝6.2Hz,2H),1.51-1.45(m,2H),1.42-1.36(m,2H).MS m/z(ESI):369.9[M+H]⁺.

EXAMPLE 37 2- (((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) methyl) benzo [ d ] oxazole

Preparation of E37 reference example 30 Synthesis method .¹H NMR(500MHz,CDCl₃)δ7.74-7.68(m,1H),7.58-7.50(m,1H),7.36-7.30(m,2H),6.64(t,J＝7.6Hz,1H),6.50(d,J＝7.3Hz,1H),6.40(d,J＝7.9Hz,1H),3.94-3.81(m,2H),3.60(td,J＝10.8,2.8Hz,1H),3.33-3.19(m,4H),3.06-2.96(m,1H),2.86(s,3H),2.83-2.75(m,2H),2.50(td,J＝11.5,3.3Hz,1H),2.19(t,J＝11.0Hz,1H),2.05-1.93(m,2H).MS m/z(ESI):361.6[M+H]⁺.

EXAMPLE 38 2- (2- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) ethyl) benzo [ d ] oxazole

Step 1 Compound 2- (Benzoxazol-2-yl) ethyl acetate (60 mg,0.29 mmol) was dissolved in methanol (3 mL), and sodium borohydride (55 mg,1.45 mmol) was added at 0℃and stirred at room temperature for 2h. The reaction was added water (10 mL) at 0 ℃ and extracted with ethyl acetate (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and the organic phase concentrated and purified by normal phase column chromatography to give the title compound 2- (benzo [ d ] oxazol-2-yl) ethan-1-ol (yellow oil, 30mg, 64% yield). MS m/z (ESI) 164.4[ M+H ] ⁺

Step 2 preparation of 2- (benzo [ d ] oxazol-2-yl) ethylmethanesulfonate reference is made to the synthetic method of the third step of example 3.

Step 3 preparation of 2- (2- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydropyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -ethyl) benzoxazole reference is made to the synthetic procedure of the fourth step of example 3 .¹H NMR(500MHz,DMSO)δ7.73-7.62(m,2H),7.38-7.30(m,2H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),6.33(d,J＝7.8Hz,1H),3.47-3.41(m,1H),3.31(t,J＝2.9Hz,2H),3.28-3.24(m,1H),3.18-3.05(m,3H),3.00(q,J＝6.3Hz,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＝13.5Hz,1H).MS m/z(ESI):375.8[M+H]⁺.

Example 39 (6 bR,10 aS) -3-methyl-8- (3- (thiophen-2-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 preparation of 3- (thiophen-2-yl) propylmethanesulfonate reference was made to the synthetic procedure of the third step of example 3.

Step 2 preparation of (6 bR,10 aS) -3-methyl-8- (3- (thiophen-2-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline by the fourth step of the synthesis method of example 3 .¹H NMR(500MHz,DMSO-d₆)δ7.30(dd,J＝5.0,1.0Hz,1H),6.95-6.91(m,1H),6.85(dd,J＝3.0,1.0Hz,1H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.0Hz,1H),6.33(d,J＝7.6Hz,1H),3.47-3.37(m,2H),3.32-3.23(m,2H),3.11(d,J＝2.0Hz,1H),3.06-2.99(m,1H),2.83-2.79(m,2H),2.78(s,3H),2.67(ddd,J＝20.5,10.5,2.5Hz,1H),2.55(d,J＝25.5Hz,1H),2.28(s,2H),2.09(d,J＝16.8Hz,1H),1.90(d,J＝13.1Hz,1H),1.78(dd,J＝18.1,10.8Hz,4H).MS m/z(ESI):354.7[M+H]⁺.

Example 40 (6 bR,10 aS) -8- (3- (3-methoxythiophen-2-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 Compound 3-methoxythiophene-2-carbaldehyde (350 mg,2.46 mmol) was dissolved in THF (25.0 mL), ethoxyformylmethylene triphenylphosphine (1.20 g,3.45 mmol) was added under nitrogen, stirring was carried out at 75℃for 18h, after TLC detection reaction was completed, concentrated under reduced pressure and then purified in normal phase to give ethyl (E) -3- (3-methoxythiophen-2-yl) acrylate (yellow oil, 420mg, yield 74%). MS M/z (ESI): 213.3.[ M+H ] ⁺.

Step 2 Ethyl (E) -3- (3-methoxythiophen-2-yl) acrylate (270 mg,1.27 mmol) was dissolved in MeOH (15.0 mL), 10% Pd/C (135 mg) was added, hydrogenated at room temperature for 18h, and concentrated by filtration to give the compound ethyl 3- (3-methoxythiophen-2-yl) propionate (colorless oil, 230mg, yield 85%). MS M/z (ESI): 215.3 [ M+H ] ⁺.

Step 3 Compound ethyl 3- (3-methoxythiophen-2-yl) propionate (112 mg,0.52 mmol) was dissolved in THF (1.0 mL), cooled to 0deg.C, 1M solution of lithium aluminum in tetrahydrofuran (0.5 mL,0.5 mmol) was added, stirred at room temperature for 1h, sodium sulfate decahydrate was added, stirred for 30 min, and after filtration and concentration the normal phase was purified to give compound 3- (3-methoxythiophen-2-yl) propan-1-ol (colorless oil, 68mg, yield 76%). MS M/z (ESI): 173.3.[ M+H ] ⁺.

Step 4 Compound 3- (3-methoxythiophen-2-yl) propan-1-ol (68 mg,0.40 mmol) was dissolved in DCM (3.0 mL), DIEA (260 mg,2.0 mmol) was added to cool to 0 ℃, methanesulfonic anhydride (140 mg,0.8 mmol) was added and then warmed to 20 ℃ and stirred for 3h, quenched with water, extracted with DCM, dried over sodium sulfate and filtered to give compound 3- (3-methoxythiophen-2-yl) propylmethanesulfonate (yellow oil, 100 mg) which was used directly in the next reaction.

Step 5 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (55 mg,0.24 mmol) was dissolved in DMSO (3.0 mL) at room temperature, DIEA (0.5 mL,3.0 mmol) was added in sequence, 3- (3-methoxythiophen-2-yl) propylmethanesulfonate (100 mg,0.4 mmol), heated to 65℃with stirring for 18H, cooled to room temperature, and after filtration prep-HPLC purification isolation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) gave the compound (6 bR,10 aS) -8- (3- (3-methoxythiophen-2-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4, 5' ] [3, 5] quinoxaline (1, 4mg, 16%) was pale yellow oil 17％).¹H NMR(500MHz,CD₃OD)δ7.07(d,J＝5.0Hz,1H),6.86(d,J＝5.0Hz,1H),6.60(t,J＝7.5Hz,1H),6.48(d,J＝5.0Hz,1H),6.42(d,J＝5.0Hz,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 (6 bR,10 aS) -8- (3- (2-methoxythiophen-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 Compound 2-methoxythiophene (575 mg,5.05 mmol) was dissolved in DCM (20.0 mL), cooled to 0deg.C, NBS (1.78 g,10.0 mmol) was added, warmed to 20deg.C and stirred for 3h, concentrated under reduced pressure, and purified in normal phase to give Compound 3, 5-dibromo-2-methoxythiophene (yellow oil, 380mg, yield 27%). MS M/z (ESI): 272.4 [ M+H ] ⁺ _.

Step 2 Compound 3, 5-dibromo-2-methoxythiophene (380 mg,1.40 mmol) was dissolved in THF (5.0 mL), cooled to-78 ℃, n-butyllithium solution (0.56 mL,1.4 mmol) was added, stirred at-78 ℃ for 30min, quenched with methanol, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified normal phase to give Compound 3-bromo-2-methoxythiophene (yellow oil, 195mg, 71% yield). 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), triethylamine (800 mg,8.0 mmol), ethyl acrylate (120 mg,1.2 mmol), o-trimethylphenylphosphine (60 mg,0.2 mmol) and palladium acetate (22 mg,0.1 mmol) were added sequentially under nitrogen, stirred for 3h at 100 ℃, after completion of TLC detection reaction, quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified in normal phase to give Compound (E) -3- (2-methoxythiophen-3-yl) ethyl acrylate (yellow oil, 48mg, yield 23%). MS M/z (ESI): 213.3.[ M+H ] ⁺.

Step 4 Compound (E) -ethyl 3- (2-methoxythiophen-3-yl) acrylate (48 mg,0.23 mmol) was dissolved in MeOH (5.0 mL), 10% palladium on carbon (30 mg) was added, stirred at room temperature for 18h, and concentrated by filtration to give Compound ethyl 3- (2-methoxythiophen-3-yl) propionate (yellow oil, 32mg, yield 66%). MS M/z (ESI): 215.3 [ M+H ] ⁺.

Step 5 Ethyl 3- (2-methoxythiophen-3-yl) propionate (32 mg,0.15 mmol) was dissolved in THF (1.5 mL), cooled to 0deg.C, added with lithium aluminum tetrahydrolate solution (0.15 mL,0.15 mmol) and warmed to 20deg.C and stirred for 1h, quenched with water, dried over sodium sulfate, filtered and purified normal phase to give 3- (2-methoxythiophen-3-yl) propan-1-ol (yellow oil, 18mg, 69%). MS M/z (ESI): 173.3 [ M+H ] ⁺ _.

Step 6 Compound 3- (2-Methoxythiophen-3-yl) propan-1-ol (18 mg,0.53 mmol) was dissolved in DCM (3.0 mL), TEA (50 mg,0.5 mmol) was added to cool to 0℃and methanesulfonic anhydride (36 mg,0.2 mmol) was added followed by warming to 20℃and stirring for 3h, quenched with water, extracted with DCM, dried over sodium sulfate and filtered to give Compound 3- (2-Methoxythiophen-3-yl) propylmethylsulfonate (colorless oil, 37mg, 99% yield) which was used directly in the next reaction.

Step 7 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (26 mg,0.11 mmol) was dissolved in DMSO (3.0 mL) at room temperature, DIEA (195 mg,1.5 mmol) was added in sequence, compound 3- (2-methoxythiophen-3-yl) propylmethylsulfonate (37 mg,0.15 mmol) was heated to 65℃with stirring for 18H, cooled to room temperature, and prep-HPLC purification isolation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) was performed to give compound (6 bR,10 aS) -8- (3- (2-methoxythiophen-3-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4' ] [3, 5] pyrrolo [3',4, 5] quinoxaline (1.5 mg, 3 mg) of a yellow solid 5.0％).¹H NMR(500MHz,DMSO-d₆)δ7.23(d,J＝5.0Hz,1H),6.95(d,J＝5.0Hz,1H),6.52(t,J＝7.5Hz,1H),6.43(d,J＝10.0Hz,1H),6.33(d,J＝5.0Hz,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).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 a-octahydro- [1,4] oxadiazepino [2,3,4-hi ] pyrido [4,3-b ] indole

Step 1. Benzomorpholine (815 mg,6.0 mmol) was dissolved in acetic acid (12 mL) and cooled to 0deg.C, naNO ₂ aqueous solution (414 mg,6.0mmol,4mL water) was added under stirring, stirring was performed for 3H at 20deg.C, after TLC detection was complete, water quenching was added, DCM extraction was performed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 4-nitroso-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (yellow oil, 680mg, 69% yield). MS M/z (ESI): 163.3.[ M+H ] ⁺ _.

Step 2 lithium aluminum hydride (158 mg,4.15 mmol) was suspended in THF (10 mL) and cooled to 0deg.C, a solution of 4-nitroso-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (680 mg,4.15 mmol) in tetrahydrofuran (5 mL) was added with stirring, the temperature was raised to 20deg.C and stirred for 18H, 2M aqueous sodium hydroxide solution was added to quench, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product, and normal phase purification gave compound 4-amino-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (yellow oil, 413mg, 67% yield). MS M/z (ESI): 164.3.[ M+H ] ⁺ _.

Step 3-4-amino-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (413 mg,2.77 mmol) and 4-piperidone hydrochloride (375 mg,2.78 mmol) were added as solvent isopropanol (15 mL) to a 25mL reaction flask, heated to 88 ℃ and stirred for 2H, concentrated HCl (0.23 mL,2.8 mmol) was added and heated to 88 ℃ and stirred for 3H, cooled to room temperature, and suction filtered to give the compound 1,2,7,8,9, 10-hexahydro- [1,4] oxazino [2,3,4-hi ] pyrido [4,3-b ] indole (yellow solid, 335mg, yield 55%). MS M/z (ESI): 213.4.[ M+H ] ⁺ _.

Step 4 dissolving the compound 1,2,7,8,9, 10-hexahydro- [1,4] oxazino [2,3,4-hi ] pyrido [4,3-b ] indole (335 mg,1.55 mmol) in TFA (5 mL) cooled to 0 ℃, adding NaBH ₃ CN (298 mg,4.65 mmol) with stirring, stirring at 20 ℃ for 3h, after completion of the TLC detection reaction, adding saturated sodium bicarbonate solution, DCM extraction, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtering and concentrating to give the crude product, and purifying the normal phase to give the compound 1,2,6b,7,8,9,10 a-octahydro- [1,4] oxazino [2,3,4-hi ] pyrido [4,3-b ] indole (pale yellow solid, 115mg, yield 66%). MS M/z (ESI): 215.3 [ M+H ] ⁺ _.

Step 51, 2,6b,7,8,9,10 a-octahydro- [1,4] oxazinyl [2,3,4-hi ] pyrido [4,3-b ] indole (40 mg,0.185 mmol) was dissolved in DMSO (1.5 mL) at room temperature, DIEA (0.5 mL,3.0 mmol) was added sequentially, 3- (2, 3-dihydrobenzofuran-7-yl) propylmethanesulfonate (52 mg,0.20 mmol) was heated to 65℃with stirring for 18h, and prep-HPLC purification was performed after filtration to isolate (eluent (v/v): acetonitrile/(water+0.05% NH4HCO 3) =30% -70%) to give the compound 8- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) -1,2,6b,7,8,9,10 a-octahydro- [1,4] oxadiazepino [2, 3-b ] indole (14.0 mg ) as a white solid 20％).1H NMR(500MHz,DMSO-d6)δ7.05(d,J＝5.0Hz,1H),6.92(d,J＝5.0Hz,1H),6.73(t,J＝7.5Hz,1H),6.67(d,J＝10.0Hz,1H),6.57-6.50(m,2H),4.49(t,J＝7.5Hz,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 a-octahydro-4H-pyrido [3',4':4,5] pyrrolo [3,2,1-iJ ] quinoline

Preparation of E43 Synthesis method of reference example 42 .¹H NMR(500MHz,DMSO-d₆)δ7.04(d,J＝10.0Hz,1H),6.91(d,J＝5.0Hz,1H),6.86(d,J＝5.0Hz,1H),6.76(d,J＝5.0Hz,1H),6.73(t,J＝7.5Hz,1H),6.53(t,J＝7.5Hz,1H),4.49(t,J＝10.0Hz,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 (6 bR,10 aS) -8- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-5-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Preparation of E44 reference is made to the synthetic method of example 3 .¹H NMR(500MHz,CD₃OD)δ6.74-6.66(m,3H),6.62(t,J＝7.6Hz,1H),6.51(d,J＝7.2Hz,1H),6.44(d,J＝8.0Hz,1H),4.24(d,J＝6.0Hz,2H),4.21(d,J＝6.0Hz,2H),3.56-3.48(m,1H),3.37(d,J＝10.0Hz,1H),3.22(d,J＝12.0Hz,3H),3.07(s,1H),2.84(s,3H),2.79-2.70(m,4H),2.62(dd,J＝10.0,5.0Hz,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- ((6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1,2,6b,7,8,9,10 a-octahydro-3H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-3-yl) ethan-1-one

Step 1 Ethyl (4 aS,9 bR) -6-bromo-1, 3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (2.08 g,6.4 mmol), benzophenone imine (1.5 g,7.7 mmol) and NaOt-Bu (1.23 g,12.8 mmol), BINAP (120 mg,0.19 mmol), 40mL tolene were added to a 250mL three-necked flask, N ₂ was replaced three times, warmed to 60 ℃, reacted for 16H, cooled to room temperature, pd ₂(dba)₃(59mg,0.064mmol),N₂ was added to replace three times, warmed to 105 ℃, reacted 16h.LCMS monitors a small amount of starting material remaining, the reaction solution was cooled to room temperature, MTBE was added, filtered, and concentrated to give the compound (4 aS,9 bR) -6- ((diphenylmethylene) amino) -1,3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (3.4 g, the next step) was directly obtained as a crude product. MS m/z (ESI): 426.5[ M+H ] ⁺.

Step 2 Ethyl (4 aS,9 bR) -6- ((diphenylmethylene) amino) -1,3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (3.4 g,8.0 mmol), ethyl bromoacetate (2.67 g,7.7 mmol) and Na ₂CO₃ (1.7 g,16.04 mmol), KI (1.99 g,12.76 mmol), 40mL Acetone were added to a 250mL three-necked flask, N2 was replaced three times, warmed to 60 ℃, reacted for 16H, lcms was monitored for a small amount of starting material remaining, the reaction solution was concentrated to dryness, DCM and water were added, the split organic phase was washed with saturated sodium chloride, dried, filtered, concentrated to give the compound (4 aS,9 bR) -6- ((diphenylmethylene) amino) -1,3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (4 g), crude product, and the next step was direct. MS m/z (ESI): 513.6[ M+H ] ⁺.

Step 3 Ethyl (4 aS,9 bR) -6- ((diphenylmethylene) amino) -1,3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (4 g, crude) was added to a single vial with 40mL of THF, 8mL of 2N HCl was added at room temperature and stirring was continued for another half hour at room temperature. LCMS monitored completion of the reaction, THF was concentrated to DCM, the organic phase was washed three times with saturated sodium chloride, dried, concentrated, and column loaded with neutral alumina, and purified with PE/ea=100% -1/10 followed by MeOH/dcm=0-3% to give the compound ethyl (6 br,10 as) -2-oxo-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration-8 (7H) -carboxylate 800mg MS m/z (ESI): 302.2[ m+h ] ⁺.

Step 4 Ethyl (6 bR,10 aS) -2-oxo-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -carboxylate (170 mg,0.56 mmol) was added to a three-necked flask containing 10mL THF, N2 was replaced three times, 1.7mL 1M BH ₃Me₂ S was added at 0℃and the temperature was raised to 70℃after the completion of the dropwise addition, and the reaction was monitored to completion by 3 h.LCMS. The reaction solution was cooled to 0 ℃, 6N HCl was added dropwise until no bubbles were generated, THF was concentrated, naOH (aq) was further added to adjust ph=9, extracted twice with DCM, dried, concentrated and passed through a column (MeOH/dcm=0 to 5%) to give the compound ethyl (6 br,10 as) -2,3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -carboxylate (100 mg, yellow oil, yield: 62.5%).

Step 5 Ethyl (6 bR,10 aS) -2,3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline-8 (7H) -carboxylate (100 mg,0.348 mmol) and 3mL HBr in HBr were reacted at 100℃for 16H, LCMS monitored for reaction completion, and concentrated to give compound (6 bR,10 aS) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline 70mg, which was used directly in the next step.

Step 6, (6 bR,10 aS) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (70 mg,0.33 mmol), 7 (110 mg,0.4 mmol), and 0.1mL DIEA were added to a single-necked flask containing 1mL DMSO, nitrogen was purged three times, and the temperature was raised to 60℃for 2H, and LCMS monitored the reaction was complete. Water and EA were added, the aqueous phase was extracted with EA, the organic phases were combined, washed three times with saturated sodium chloride solution, and dried and concentrated over (MeOH/DCM=0-5%) to give the compound (6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration (40 mg, beige solid, yield: 32%). MS M/z (ESI): 376.6.[ M+H ] ⁺.

Step 7, (6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (40 mg,0.10 mmol), TEA (20 mg,0.20 mmol) were added to a single-necked flask containing 1mL DCM, replaced three times with nitrogen, cooled to 0 ℃, and Acetyl chloride (13 mg,0.15 mmol) was added and the reaction was carried out at this temperature for 0.5H, with LCMS monitoring the reaction completion. Adding water and DCM, separating the aqueous phase, extracting with DCM, combining the organic phases, washing with saturated sodium chloride solution three times, drying and concentrating to obtain the compound 1- ((6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) -1,2,6b,7,8,9,10 a-octahydro-3H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxalin-3-yl) ethane-1-one (15 mg, yellow solid, yield) by Prep-HPLC (30-70% CJJ 30min,0.05% NH ₄HCO₃ in H₂ O) ：36％).¹H NMR(500MHz,CDCl₃)δ7.03(d,J＝8.0Hz 1H),6.92(d,J＝7.5Hz 1H),6.88(d,J＝7.0Hz,1H),6.76(t,J＝7.5Hz,1H),6.67(s,1H),4.54(t,J＝8.5Hz,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＝9.0Hz,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- ((6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1,2,6b,7,8,9,10 a-octahydro-3H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-3-yl) ethan-1-one

Preparation of step 1:45-2-1 reference is made to the synthetic method of step 2 of E73-1.

Step 2-45-2-1 (860 mg,4 mmol), TEA (806 mg,8 mmol) and 10mL MeOH were added to a 100mL single port flask and Boc ₂ O (872 mg,4 mmol) was added and reacted at room temperature for 2h. TLC detection was complete and concentrated through the column (PE/EA=2/1) to give 45-2-2 (yellow oil, 1.2 g). MS m/z (ESI): 316.5[ M+H ] ⁺.

Step 3-45-2 (300 mg,0.95 mmol), TEA (192 mg,1.9 mmol) and 5mL DCM were added to a 50mL single-necked flask, and acetyl chloride (90 mg,1.14 mmol) was added and reacted at room temperature for 10min. LCMS checked for completion, saturated sodium chloride was added, the solution was separated, and dried, concentrated over a column (PE/ea=1/1) to give 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), 1mL TFA and 3mL DCM were added to a 50mL single-port bottle and reacted at room temperature for 2h. LCMS detection reaction was complete, concentrated, ph=7-8 adjusted with saturated sodium bicarbonate, separated, aqueous phase extracted five times with DCM/meoh=10/1 (v/v), dried and concentrated to 45-2-4 (210 mg yellow solid). MS m/z (ESI): 258.2[ M+H ] ⁺.

Step 5 45-2-4 (100 mg,0.389 mmol) was dissolved in MeOH (50 mL) and DCM (30 mL) under nitrogen, 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 carried out at 25℃for 1h. LCMS detected completion of the reaction, water was added, EA extracted, dried over sodium sulfate, filtered and concentrated, and purified on silica gel column (DCM: meoh=10:1) to give compound 45-2-5 (yellow solid, 100mg, yield 61%). MS m/z (ESI) 418.2[ M+H ] ⁺.

Step 6:45-2-5 (100 mg,0.239 mmol) was resolved by SFC(Daicel ChiralPak IH,40mm I.D.×250mm,10μm;Mobile phase：Supercritical CO₂/Methanol[0.1％ NH_3.H₂O(V/V)]＝65/35;Flow rate:140mL/min) to give E45-2 (PK 1:26.0mg, 99% pure, 26% yield, ee 100%, RT=1.687, OROT= -97.9 and E45-1 (PK 2:29.1mg, 99% pure) as a white solid 29％,ee 98％,RT＝2.267,OROT＝+89.1).E45-2:¹HNMR(400MHz,DMSO-d6)δ8.10(s,1H),7.04(d,J＝7.2Hz,1H),6.91(d,J＝7.2Hz,1H),6.84(d,J＝6.4Hz,1H),6.73(t,J＝7.2Hz,1H),6.58(dd,J＝8.0,7.2Hz,1H),4.49(t,J＝8.8Hz,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).E45-1:¹H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.04(d,J＝7.2,1H),6.91(d,J＝7.2Hz,1H),6.84(d,J＝6.4Hz,1H),6.73(t,J＝7.2Hz,1H),6.58(dd,J＝8.0,7.2Hz,1H),4.49(t,J＝8.8Hz,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 (6 bR,10 aS) -8- (3- (3-chloropyridin-2-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1. Compound (2-formylpyridin-3-yl) carbamic acid tert-butyl ester (750 mg,3.37 mmol) was dissolved in tetrahydrofuran (20 mL), and after adding ethoxyformylmethylene triphenylphosphine (1.4 g,4.04 mmol), it was stirred at 70℃for 2h. The reaction solution was concentrated and then purified by normal phase column chromatography to give ethyl (E) -3- (t-butoxycarbonyl) amino) pyridin-2-ylacrylate (940 mg, 96% yield) as a compound (petroleum ether: ethyl acetate=3:1). MS m/z (ESI): 293.6[ M+H ] ⁺.

Step 2 Ethyl (E) -3- (t-Butoxycarbonyl) amino) pyridin-2-ylacrylate (940 mg,3.22 mmol) was dissolved in ethyl acetate (15 mL) and 10% wet palladium on carbon (35 mg,0.32 mmol) was added and stirred under hydrogen at 28℃for 15min. The reaction solution was filtered and concentrated to give ethyl 3- (3- (((t-butoxycarbonyl) amino) pyridin-2-yl) propionate (pale yellow oil, 830mg, yield 88%) MS m/z (ESI): 295.7[ M+H ] ⁺.

Step 3 Ethyl 3- (3- (((t-butoxycarbonyl) amino) pyridin-2-yl) propionate (830 mg,2.82 mmol) was dissolved in tetrahydrofuran (15 mL), liAlH ₄ (4.23mL,1M in THF,4.23mmol) was added thereto under nitrogen protection at zero degrees Celsius, after 30min of reaction at room temperature, sodium sulfate decahydrate was added to the reaction solution until no more bubbles were generated under stirring, after filtration and the filtrate was concentrated and purified by normal phase column chromatography to isolate (dichloromethane: methanol=10:1) t-butyl (2- (3-hydroxypropyl) pyridin-3-yl) carbamate (colorless oil, 460mg, 65% yield) MS m/z (ESI): 253.6[ M+H ] ⁺.

Step 4. Compound (2- (3-hydroxypropyl) pyridin-3-yl) carbamic acid tert-butyl ester (460 mg,1.82 mmol) was dissolved in hydrochloric acid/dioxane (10 mL), and after reaction at room temperature for 30min, the reaction solution was prepared in reverse phase (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃)), acetonitrile was removed under reduced pressure, and lyophilized to give Compound 3- (3-aminopyridin-2-yl) propanol (white solid, 240mg, yield 88%). MS m/z (ESI): 153.2[ M+H ] ⁺.

Step 5 Compound 3- (3-aminopyridin-2-yl) propanol (240 mg,1.58 mmol), copper chloride (45 mg,0.32 mmol), cuprous chloride (311 mg,3.15 mmol) and t-butyl nitrite (325 mg,3.15 mmol) were dissolved in acetonitrile (15 mL), reacted at 25℃for 0.5h under nitrogen protection, reacted for 2h under 50℃again, and the reaction mixture was purified by normal phase column chromatography after filtration to give compound 3- (3-chloropyridin-2-yl) propanol (yellow oily, 50mg, yield 19%). MS m/z (ESI): 172.1[ M+H ] ⁺.

Step 6 Compound 3- (3-chloropyridin-2-yl) propanol (50 mg,0.29 mmol) was dissolved in dichloromethane (5 mL) to which PCC (440 mg,2.04 mmol) was added, after 0.5h at room temperature the reaction solution was filtered and the filtrate was washed with saturated aqueous sodium bicarbonate (10 mL. Times.2) and the organic phase was concentrated to give the title compound 3- (3-chloropyridin-2-yl) propanal (brown solid, 45mg crude, 92% yield). MS m/z (ESI): 170.1[ M+H ] ⁺.

Step 7) dissolving the Compound 3- (3-chloropyridin-2-yl) propanal (35 mg,0.31 mmol) in dichloromethane (2 mL), adding thereto (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (49 mg,0.21 mmol), reacting at room temperature for 0.5H, adding thereto sodium borohydride acetate (135 mg,0.63 mmol) reacting at room temperature for 0.5H, filtering the reaction solution, preparing by reverse phase (eluent (v/v)/(water+0.05% NH ₄HCO₃)), removing acetonitrile under reduced pressure, lyophilizing to obtain the Compound (6 bR,10 aS) -8- (3-chloropyridin-2-propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4': 1, 5] quinoxaline (23 mg, 3 ': 1, 5 mg) in yellow solid 19％).¹H NMR(500MHz,CDCl₃)δ8.41(dd,J＝4.7,1.6Hz,1H),7.62(dd,J＝8.0,1.6Hz,1H),7.09(dd,J＝8.0,4.7Hz,1H),6.65(t,J＝7.7Hz,1H),6.51(dd,J＝7.4,1.0Hz,1H),6.40(dd,J＝7.9,0.9Hz,1H),3.65-3.56(m,1H),3.32-3.20(m,4H),2.97(q,J＝8.0Hz,3H),2.86(s,3H),2.85-2.77(m,2H),2.52(d,J＝9.4Hz,2H),2.34(s,1H),2.04-1.93(m,5H).MS m/z(ESI):383.7[M+H]⁺.

EXAMPLE 47 2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydropyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -propyl) pyridin-3-amine

Step 1. Compound (2- (3-hydroxypropyl) pyridin-3-yl) carbamic acid tert-butyl ester (20 mg,0.079 mmol) was dissolved in dichloromethane (2 mL), PCC (85 mg,0.40 mmol) was added thereto, after reaction at room temperature for 12h, the reaction solution was filtered, and after washing the filtrate with saturated aqueous sodium bicarbonate (10 mL. Times.2), the organic phase was concentrated to give Compound (2- (3-oxopropyl) pyridin-3-yl) carbamic acid tert-butyl ester (brown solid, 20mg crude product, yield 100%). MS m/z (ESI): 251.5[ M+H ] ⁺.

Step 2. Tert-butyl (2- (3-oxopropyl) pyridin-3-yl) carbamate (20 mg,0.079 mmol) was dissolved in dichloromethane (2 mL), and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (19 mg,0.079 mmol) was added thereto, followed by reaction at room temperature for 0.5H, and after adding sodium borohydride acetate (51 mg,0.24 mmol) thereto and reaction at room temperature for 0.5H, the reaction solution was filtered and then prepared by reverse phase (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃)), acetonitrile was removed under reduced pressure, and lyophilized to give 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4, 3': quinoxaline (19 mg,0.079 mmol) and (58 mg,0.24 mmol) of solid (i) which was prepared by filtration at room temperature.

Step 3 preparation of the reaction solution after filtration of the reaction solution in reverse phase (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃)), removal of acetonitrile under reduced pressure and lyophilization to give the compound 2- (3- (6 bR,10 aS) -3-methyl-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (H) -propyl) pyridine-3-carbamic acid tert-butyl ester (8 mg,0.017 mmol) in dichloromethane (3 mL), addition of hydrochloric acid/dioxane (3 mL) thereto at 0℃and reaction at 0℃for 10min, removal of acetonitrile (eluent (v/v)) to give the compound 2- (3- (6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydropyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (7H) -propyl) pyridine (2 mg) in yellow yield of 2, 10 mg 33％).¹H NMR(500MHz,DMSO)δ7.70(dd,J＝4.1,2.1Hz,1H),6.92-6.85(m,2H),6.50(t,J＝7.6Hz,1H),6.42(dd,J＝7.4,1.0Hz,1H),6.33(dd,J＝7.9,1.0Hz,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＝7.3,6.0Hz,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 (6 bR,10 aS) -8- (3- (5-fluoro-2, 3-dihydrobenzofuran-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Preparation of E48 reference is made to the synthetic method of example 3 .¹H NMR(500MHz,CDCl₃)δ6.79-6.70(m,1H),6.69-6.61(m,1H),6.56-6.48(m,2H),6.41(d,J＝7.5Hz,1H),4.57(t,J＝8.8Hz,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＝26.0,18.0Hz,2H),2.47-2.29(m,3H),2.04-1.93(m,3H),1.84(dt,J＝15.1,7.6Hz,2H).MS m/z(ESI):408.9[M+H]⁺.

Example 49 (6 bR,10 aS) -8- (3- (5-fluorobenzofuran-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Preparation of E49 reference was made to the synthetic method of example 3 .¹H NMR(500MHz,CDCl₃)δ7.63(d,J＝2.0Hz,1H),7.28-7.26(m,1H),7.02-6.92(m,1H),6.79(dd,J＝2.0,1.0Hz,1H),6.69-6.57(m,1H),6.50(d,J＝7.0Hz,1H),6.40(d,J＝7.5Hz,1H),3.58(ddd,J＝13.0,8.0,2.5Hz,1H),3.32-3.14(m,4H),2.95-2.75(m,8H),2.70(d,J＝14.6Hz,1H),2.41(d,J＝9.0Hz,2H),2.24(dd,J＝25.5,9.2Hz,1H),1.94(dd,J＝22.0,9.0Hz,4H).MS m/z(ESI):406.9[M+H]⁺.

Example 50 (6 bR,10 aS) -8- (2- (1H-indol-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

2- (1H-indol-3-yl) ethan-1-ol (71.2 mg,0.44 mmol) and triethylamine (220.6 mg,2.18 mmol) were dissolved in dichloromethane (2 mL) at room temperature, cooled to 0℃and methanesulfonyl chloride (74.9 mg,0.65 mmol) was added to restore room temperature, after stirring for 1 hour the reaction was concentrated in vacuo at room temperature. The crude product was dissolved in anhydrous dimethyl sulfoxide (3 mL), and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (50.0 mg,0.22 mmol), potassium iodide (72.3 mg,0.44 mmol) and DIPEA (0.5 mL) were added. The reaction was stirred at 100℃for 16 hours and LCMS (ENBW 230404-026-6-R1,2023.8.8) showed product formation. The reaction mixture was cooled to room temperature, extracted with 50mL of water, washed with ethyl acetate (40 mL. Times.3), dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to give the crude product. Crude preparation purification gave (6 bR,10 aS) -8- (2- (1H-indol-3-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (7.80 mg, yield 9.5%) as a white solid .¹H NMR(400MHz,CDCl₃)δ8.09(s,1H),7.59(d,J＝7.9Hz,1H),7.36(d,J＝8.1Hz,1H),7.21-7.16(m,1H),7.13-7.09(m,1H),7.05(d,J＝2.1Hz,1H),6.69(t,J＝7.7Hz,1H),6.54(d,J＝7.2Hz,1H),6.43(d,J＝7.6Hz,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＝15.4Hz,1H).MS m/z(ESI):373.2[M+H]⁺.

EXAMPLE 52 2-methyl-1- (2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenoxy) propan-2-ol

Step 1 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 at room temperature. The reaction mixture was stirred at 60 ℃ for 2 hours. After the reaction, cooling to room temperature, adding saturated ammonium chloride solution for quenching, adding 50mL of dichloromethane for beating after vacuum concentration, filtering, and vacuum concentrating the filtrate to obtain 2- (3-hydroxypropyl) phenol (5.5 g, yield 99.1%) as colorless oil. MS m/z (ESI): 153.2[ M+H ] ⁺

Step 2- (3-hydroxypropyl) phenol (5.5 g,36.1 mmol) was dissolved in acetone (50 mL) and benzyl bromide (7.4 g,43.3 mmol) and potassium carbonate (7.5 g,54.2 mmol) were added. The reaction mixture was stirred at 50 ℃ for 48 hours. The reaction solution was cooled to room temperature, 120mL of water was added, and extraction was performed with ethyl acetate (100 mL X3) to give 3- (2- (benzyloxy) phenyl) propan-1-ol (3 g, yield 34.4%) as a transparent oil. MS m/z (ESI): 243.2[ M+H ] ⁺

Step 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) at room temperature, cooled to 0℃and methanesulfonyl chloride (899.1 mg,7.8 mmol) was added and brought to room temperature, after stirring for 1 hour the reaction solution was concentrated in vacuo at room temperature, extracted with dichloro and the organic phase was dried by spin to give a white solid. (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-off ] quinoxaline (600.0 mg,2.6 mmol) was dissolved in DMSO (9 mL), and the white solid and DIPEA (1.5 mL) were added before. The reaction solution was stirred at 60 ℃ for 18 hours. The reaction mixture was cooled to room temperature, extracted with 50mL of water, washed with ethyl acetate (40 mL. Times.3), dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to give the crude product. Purification of the crude product over silica gel (DCM/meoh=0/100-8/92) afforded (6 br,10 as) -8- (3- (2- (benzyloxy) phenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (1.0 g, 84.3%) as a yellow oil. MS m/z (ESI): 454.2[ M+H ] ⁺

Step 4A solution of boron tribromide in methylene chloride (22 mL,22 mmol) was added dropwise to (6 bR,10 aS) -8- (3- (2- (benzyloxy) phenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (1 g,2.2 mmol) in DCM (30 mL) at 0℃under nitrogen atmosphere, and the reaction was stirred at room temperature for 2 hours. After the reaction was quenched by addition of methanol in an ice bath, concentrated in vacuo, added with water (30 mL), adjusted to pH 10 by addition of 1M sodium hydroxide solution, extracted with ethyl acetate (40 mL X3), the combined organic phases concentrated in vacuo to give crude product, which was purified by column (DCM/meoh=100/0-90/10) to give 2- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-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- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-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, cesium carbonate (268.9 g,0.83 mmol) was added. The reaction mixture was stirred at 60 ℃ for 16 hours. The reaction solution was cooled to room temperature, 40mL of water was added, extraction was performed with ethyl acetate (30 mL X3), the combined organic phases were concentrated in vacuo to give a crude product, which was purified by column chromatography (PE/ea=100/0-0/100) to give 1- (2- (3- ((6 br,10 as) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deno ] quinoxalin-8 (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 1- (2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxalin-8 (7H) -yl) propyl) phenoxy) propan-2-one (50.0 mg,0.12 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, the system was filled with nitrogen, the reaction solution was cooled to 0℃and methylmagnesium bromide (3M, 0.1mL,0.36 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, a saturated ammonium chloride solution was added to quench it, 40mL of water was added to dilute it, extracted with ethyl acetate (30 mL of X3), the organic phases were combined and concentrated in vacuo to give a crude product, which was prepared as a brown solid 2-methyl-1- (2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxalin-8 (7H) -yl) propyl) phenoxy) propan-2-ol (5.77 mg, yield: 10.2%) .¹H NMR(400MHz,CDCl₃)δ7.17-7.10(m,2H),6.89(t,J＝7.3Hz,1H),6.82(d,J＝8.1Hz,1H),6.65(t,J＝7.6Hz,1H),6.50(d,J＝7.3Hz,1H),6.40(d,J＝7.9Hz,1H),3.79(s,2H),3.64-3.56(m,1H),3.30-3.20(m,4H),3.01(d,J＝10.7Hz,1H),2.88-2.78(m,5H),2.68(t,J＝7.5Hz,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]⁺.

EXAMPLE 53 2- (2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenoxy) ethane-1-ol

2- (3- ((6 BR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenol (50.0 mg,0.14 mmol) and 1, 3-dioxolan-2-one (24.2 mg,0.28 mmol) were dissolved in DMF (1 mL) at room temperature, and potassium carbonate (38.0 g,0.28 mmol) was added. The reaction mixture was stirred at 110 ℃ for 16 hours. The reaction solution was cooled to room temperature, 40mL of water was added, and the crude product was extracted with ethyl acetate (30 mL X3), and the crude product was prepared to give 2- (2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenoxy) ethan-1-ol (10.82 mg, yield 18.9%) as a yellow solid .¹H NMR(400MHz,CDCl₃)δ7.19-7.07(m,2H),6.94-6.81(m,2H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝6.8Hz,1H),6.40(d,J＝7.6Hz,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＝12.5Hz,1H),2.86(s,3H),2.85-2.72(m,2H),2.68(t,J＝7.5Hz,2H),2.34(d,J＝51.1Hz,4H),1.98-1.85(m,4H).MS m/z(ESI):408.2[M+H]⁺.

EXAMPLE 54 (6 bR,10 aS) -8- (3- (2, 2-difluorobenzo [ d ] [1,3] dioxazol-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 12, 2-Difluorobenzo [ d ] [1,3] dioxazole (500.0 mg,3.16 mmol) was dissolved in tetrahydrofuran (8 mL), sec-butyllithium (202.6 mg,3.16 mmol) was added thereto at room temperature, the system was filled with nitrogen gas, the reaction solution was cooled to-65℃and oxetane (183.7 mg,3.16 mmol) and boron trifluoride diethyl ether (189.6 mg,1.3 mmol) were successively added dropwise. The reaction was stirred at-65 ℃ for 1 hour. After the reaction, quench with saturated aqueous ammonium chloride, add 60mL of water, extract with ethyl acetate (50 mL X3), concentrate the organic phase in vacuo to give crude product, purify the crude product over silica gel column (DCM/meoh=100/0-90/10) to give 3- (2, 2-difluorobenzo [ d ] [1,3] dioxan-4-yl) propan-1-ol (470 mg, yield 68.8%) as a clear oil .¹H NMR(400MHz,CDCl₃)δ7.02-6.96(m,1H),6.94-6.88(m,2H),3.69(t,J＝6.3Hz,2H),2.84-2.56(m,2H),1.93(dq,J＝13.9,6.4Hz,2H).

Step 2 3- (2, 2-difluorobenzo [ d ] [1,3] dioxan-4-yl) propan-1-ol (94.3 mg,0.44 mmol) and triethylamine (220.6 mg,2.18 mmol) were dissolved in dichloromethane (3 mL), cooled to 0℃and methanesulfonyl chloride (74.9 mg,0.65 mmol) was added, the reaction mixture was brought to room temperature, stirred for 1 hour, concentrated in vacuo at room temperature, the crude product was dissolved in DMSO (3 mL), and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazaquinoxaline (50 mg,0.22 mmol) and DIPEA (0.5 mL) were added. The reaction solution was stirred at 60 ℃ for 18 hours. The reaction mixture was cooled to room temperature, extracted with 50mL of water, washed with ethyl acetate (40 mL. Times.3), dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to give the crude product. The crude product was purified by preparative method to give (6 bR,10 aS) -8- (3- (2, 2-difluorobenzo [ d ] [1,3] dioxazol-4-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (41.33 mg, yield 43.72%) as a brown oil .¹H NMR(400MHz,CDCl₃)δ7.01-6.95(m,1H),6.89(dd,J＝7.5,2.4Hz,2H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝6.9Hz,1H),6.41(d,J＝7.8Hz,1H),3.63-3.56(m,1H),3.34-3.14(m,4H),2.84-2.79(m,5H),2.69(t,J＝7.6Hz,3H),2.45-2.34(m,3H),1.99-1.91(m,5H).¹⁹F NMR(377MHz,CDCl₃)δ-49.80(s,2F).MS m/z(ESI):428.2[M+H]⁺.

Example 55 (6 bR,10 aS) -3-methyl-8- (3- (2, 2-trifluoroethoxy) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

2- (3- ((6 BR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenol (50.0 mg,0.14 mmol) and 2, 2-trifluoroethyl 4-methylbenzenesulfonate (52.7 mg,0.21 mmol) were dissolved in DMF (1 mL) at room temperature, and potassium carbonate (57.1 mg,0.41 mmol) was added. The reaction mixture was stirred at 110 ℃ for 16 hours. The reaction was cooled to room temperature, 40mL of water was added, extracted with ethyl acetate (30 mL X3), and concentrated to give the crude product. The crude product was prepared to give (6 bR,10 aS) -3-methyl-8- (3- (2, 2-trifluoroethoxy) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (5.32 mg, yield 8.2%) as a brown solid .¹H NMR(400MHz,CDCl₃)δ7.20-7.15(m,2H),6.99-6.95(m,1H),6.77(d,J＝8.3Hz,1H),6.65(t,J＝7.6Hz,1H),6.51(d,J＝7.3Hz,1H),6.40(d,J＝7.6Hz,1H),4.34(q,J＝8.1Hz,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(377MHz,CDCl₃)δ-73.98(s,3F).MS m/z(ESI):446.2[M+H]⁺.

Example 56 (6 bR,10 aS) -3-methyl-8- (3- (2- (pyridin-4-yloxy) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

2- (3- ((6 BR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenol (60.0 mg,0.16 mmol) and 4-bromopyridine (39.1 mg,0.25 mmol) were dissolved in DMF (2 mL) at room temperature, cesium 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 ℃ for 16 hours. The reaction solution was cooled to room temperature, 40mL of water was added, and the crude product was extracted with ethyl acetate (30 mL of X3), and (6 bR,10 aS) -3-methyl-8- (3- (2- (pyridin-4-yloxy) phenyl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazalin 2, 2-trifluoroacetate (18.42 mg, yield 25.02%) was obtained as a black oil .¹H NMR(400MHz,CDCl₃)δ11.59(s,1H),8.70(d,J＝6.8Hz,2H),7.44-7.34(m,3H),7.24(d,J＝6.7Hz,2H),7.06(d,J＝7.6Hz,1H),6.78(s,1H),6.59(d,J＝8.1Hz,2H),3.58-3.46(m,3H),3.49-3.24(m,4H),3.06-2.85(m,7H),2.54(t,J＝7.4Hz,3H),2.39(s,1H),2.29-1.90(m,3H).MS m/z(ESI):441.1[M+H]⁺.

EXAMPLE 57 preparation of (6 bR,10 aS) -8- (3- (2- (difluoromethoxy) phenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

2- (3- ((6 BR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-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, and a 25% potassium hydroxide (84.9 mg,1.5 mmol) in water (0.255 mL) was added to fill the reaction system with nitrogen. The reaction mixture was stirred at 60 ℃ for 16 hours. After the reaction was completed, 40mL of water was added to dilute, extracted with ethyl acetate (30 mL of X3), the organic phases were combined and concentrated in vacuo to give a crude product, which was prepared to give (6 bR,10 aS) -8- (3- (2- (difluoromethoxy) phenyl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deoxoquinoxaline (6.39 mg, yield: 11.0%) as a brown solid .¹H NMR(400MHz,CDCl₃)δ12.03(s,1H),7.24-7.12(m,3H),7.06(d,J＝8.0Hz,1H),6.73(t,J＝7.7Hz,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＝7.4Hz,2H),2.52-2.48(m,2H),2.17-2.04(m,3H).¹⁹F NMR(377MHz,CDCl₃)δ-75.78(s,6F),-79.97(d,J＝2.7Hz,2F).MS m/z(ESI):414.2[M+H]⁺.

EXAMPLE 58 (6 bR,10 aS) -3-methyl-8- (3- (pyridin-2-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 13- (pyridin-2-yl) propan-1-ol (30.0 mg,0.22 mmol) was dissolved in dichloromethane (3 mL) at room temperature, cooled to 0℃and PCC (94.3 mg,0.44 mmol) was added and the mixture was returned to room temperature and stirred for 16 hours. The reaction solution was filtered through celite, added to 10mL of water, adjusted to pH 8 with saturated aqueous sodium bicarbonate, diluted with 40mL of water, extracted with dichloromethane (30 mL X3), dried over anhydrous sodium sulfate, the organic phases combined and concentrated to give 3- (pyridin-2-yl) propanal (29 mg, 78.5% yield) as a clear oil, the crude was directly put into the next reaction. MS m/z (ESI): 136.2[ M+H ] ⁺

Step 2 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (45.0 mg,0.20 mmol) and 3- (pyridin-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 borohydride acetate (83.2 mg,0.39 mmol) was added, and the reaction solution was stirred at room temperature for 3.5 hours. After completion of the reaction, 40mL of water was added, the mixture was extracted with ethyl acetate (30 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to give a crude product. The crude product was purified by preparative purification to give (6 bR,10 aS) -3-methyl-8- (3- (pyridin-2-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline 2, 2-trifluoroacetate (7.24 mg, yield 10.1%) as a brown oil .¹H NMR(400MHz,CDCl₃)δ8.75(d,J＝5.3Hz,1H),8.25(s,1H),7.79-7.67(m,2H),6.72(t,J＝7.7Hz,1H),6.55-6.48(m,2H),3.63-3.61(m,1H),3.52-3.35(m,2H),3.32(t,J＝11.3Hz,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).¹⁹F NMR(376MHz,CDCl₃)δ-75.72(s,3F).MS m/z(ESI):349.2[M+H]⁺.

EXAMPLE 59 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) benzonitrile

Step 13- (2-cyanophenyl) propionic acid (500.0 mg,2.85 mmol) was dissolved in dichloromethane (5 mL) at room temperature, oxalyl chloride (543.4 mg,4.28 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to give crude product. The crude product was dissolved in THF/MeOH (4 mL/4 mL) and sodium borohydride (539.9 mg,14.27 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, methanol was added to dilute, vacuum-concentrated, added to 50mL of water, extracted with ethyl acetate (40 mL X3), washed with saturated brine, dried over anhydrous sodium sulfate, the organic phases were combined and concentrated to give a crude product, which was purified by silica gel column (PE/ea=100/0-60/40) to give 2- (3-hydroxypropyl) benzonitrile (300 mg, yield 59.2%) as a transparent oil. MS m/z (ESI): 162.1[ M+H ] ⁺

Step 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) at room temperature, triphenylphosphine (732.2 mg,2.79 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours. After the reaction is finished, the crude product is obtained by vacuum concentration. The crude product was purified by column chromatography (PE/ea=100/0-90/10) to give 2- (3-bromopropyl) benzonitrile (250 mg, 59.9% yield) as a clear oil. MS m/z (ESI): 226.1[ M+H ] ⁺

Step 3 2- (3-bromopropyl) benzonitrile (48.8 mg,0.22 mmol) was dissolved in 1, 4-dioxane/toluene (1.5 mL/1.5 mL) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (50.0 mg,0.22 mmol), potassium iodide (72.4 mg,0.44 mmol) and triethylamine (66.2 mg,0.65 mmol) were added at room temperature. The reaction solution was stirred at 100 ℃ for 18 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. The crude product was prepared to give 2- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) benzonitrile (14.34 mg, 16.8% yield) as a yellow solid .¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝7.7Hz,1H),7.56-7.53(m,1H),7.41(d,J＝7.7Hz,1H),7.32(t,J＝7.6Hz,1H),6.69(t,J＝7.7Hz,1H),6.52(d,J＝7.3Hz,1H),6.43(d,J＝7.9Hz,1H),3.66-3.57(m,2H),3.29-3.24(m,4H),3.22(d,J＝10.8Hz,1H),2.93-2.80(m,9H),2.52(t,J＝14.0Hz,1H),2.38(t,J＝11.8Hz,1H),2.23-2.20(m,2H),2.10(d,J＝15.3Hz,1H).MS m/z(ESI):373.2[M+H]⁺.

EXAMPLE 60 7- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) -2, 3-dihydrofuro [2,3-c ] pyridine

Step 1. Compound 7-chlorofuro [2,3-C ] pyridine (300 mg,1.96 mmol), ethyl (E) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) acrylate (660 mg,2.92 mmol), pd (dppf) Cl ₂.CH₂Cl₂ complex (30 mg,0.04 mmol) and potassium carbonate (540 mg,3.92 mmol) were added together in a 25mL single port reaction flask, followed by dioxane (4 mL) and water (1 mL) respectively, replaced with nitrogen 3 times, and the reaction was stirred at 100℃for 16h with slow warming. After completion of the reaction by LCMS, the reaction mixture was filtered, then water (30 mL), ethyl acetate extraction (3 x 20 mL) and the combined organic phases were washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate and spun-dried under reduced pressure to give the crude compound ethyl (E) -3- (furo [2,3-c ] pyridin-7-yl) acrylate (white solid, 180mg, 42% yield) as a pure phase column purification isolation (eluent gradient: 10% ea/PE). MS m/z (ESI): 218.4[ M+H ] ⁺

Step 2. Ethyl (E) -3- (furo [2,3-C ] pyridin-7-yl) acrylate (50 mg,0.23 mmol) was added to a 25mL single port reaction flask followed by methanol (10 mL) and 10% Pd/C (wet base, 10 mg) respectively, the addition was completed, hydrogen was replaced 3 times and the reaction was stirred at room temperature for 16h. After completion of the LCMS detection reaction, the reaction solution was filtered with suction, and the filtrate was concentrated under reduced pressure to give ethyl 3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propionate (crude product, 50mg, yield 99%). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 222.5[ M+H ] ⁺

Step 3 Ethyl 3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propionate (50 mg,0.23 mmol) was added to a 25mL three-port reaction flask followed by anhydrous tetrahydrofuran (3 mL), lithium aluminum hydride (25 mg,0.69 mmol) was added in portions under nitrogen and ice water bath, and the reaction was stirred under ice water bath for 0.5h. After completion of LCMS detection, na ₂SO₄.10H₂ O was slowly added to the reaction, quenched, filtered, the filter cake washed with 10% MeOH/DCM (10 mL), and the filtrate concentrated under reduced pressure to give the crude product, which was purified by normal phase column chromatography (eluent gradient: 30% EA/PE) to give compound 3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propan-1-ol (pale yellow oil, 25mg, yield 62%). MS m/z (ESI) 180.5[ M+H ] ⁺

Step 4 Compound 3- (2, 3-Dihydrofuran [2,3-c ] pyridin-7-yl) propan-1-ol (25 mg,0.14 mmol) and anhydrous dichloromethane (3 mL) were added together in a 10mL single port reaction flask followed by PCC (60 mg,0.28 mmol) and stirred at room temperature for 16h. After completion of the reaction by LCMS, methylene chloride (10 mL) was added to the reaction mixture, followed by adjustment of the pH of the system to alkaline with saturated sodium bicarbonate solution, extraction with methylene chloride (2 x 10 mL), combination of the organic phases, washing with saturated brine (1 x 10 mL), drying over anhydrous sodium sulfate, and spin-drying under reduced pressure to give the crude compound 3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propanal (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- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) -2, 3-dihydrofuro [2,3-c ] pyridine

The compound 3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propanal (10 mg,0.06mmol, crude) and (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (13 mg,0.06 mmol) were added to a 10mL reaction flask, followed by DIEA (35 mg,0.30 mmol) and anhydrous DCM (2 mL), and stirred at room temperature for 16H. After completion of LCMS detection, the reaction mixture was dried under reduced pressure and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile/(water+0.05% NH ₄HCO₃)) to give the title compound 7- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) -2, 3-dihydrofuro [2,3-C ] pyridine (pale yellow solid, 8.0mg, yield) 36％).¹H NMR(500MHz,MeOD)δ7.92(d,J＝4.9Hz,1H),7.17(d,J＝4.9Hz,1H),6.61-6.55(m,1H),6.47(d,J＝7.2Hz,1H),6.40(d,J＝7.9Hz,1H),4.60(t,J＝8.9Hz,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＝12.1,3.0Hz,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- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) phenyl) morpholine

Preparation of E61 Synthesis method of example 1 .¹H NMR(400MHz,CDCl₃)δ7.01(t,J＝7.6Hz,1H),6.92(d,J＝7.1Hz,1H),6.66(t,J＝7.6Hz,1H),6.60-6.47(m,3H),6.41(d,J＝7.9Hz,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＝10.4Hz,1H),2.87-2.82(m,4H),2.73(t,J＝5.9Hz,4H),2.48(t,J＝11.2Hz,1H),2.18-2.09(m,2H),1.92-1.89(m,3H).MS m/z(ESI):433.2[M+H]⁺.

Example 62 (6 bR,10 aS) -8- (3- (4-methoxypyridin-3-yl) prop-2-yn-1-yl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 3-iodo-4-methoxypyridine (1.5 g,6.38 mmol) was added to a 100mL reaction flask, followed by bis-triphenylphosphine palladium 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- (prop-2-yn-1-oxy) tetrahydro-2H-pyran (1.3 g,9.6 mmol) under nitrogen, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated, then water (50 mL) was added to the reaction mixture, ethyl acetate was extracted (50 mL x 3), brine was washed (50 mL x 3), and the organic phase was concentrated and purified by normal phase column chromatography (dichloromethane: methanol=20:1) to give the compound 4-methoxy-3- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) pyridine (white solid, 1.2g, yield 76%). MS m/z (ESI) 248.5[ M+H ] ⁺ _.

Step 2-4-methoxy-3- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) pyridine (400 mg,1.62 mmol) was added to a 100mL reaction flask followed by dichloromethane (10 mL) and TFA (5 mL) and stirred at room temperature for 1H. The reaction was concentrated and then extracted with saturated sodium bicarbonate (50 mL), dichloromethane (2 x 50 mL) and concentrated to dryness by normal phase column chromatography to give the compound 3- (4-methoxypyridin-3-yl) prop-2-yn-1-ol (colorless liquid, 200mg, 75.2% yield). MS M/z (ESI): 164.4.[ M+H ] ⁺ _.

Step 3-4-methoxy-3- (3- ((tetrahydro-2H-pyran-2-yl) oxo) prop-1-yn-1-yl) pyridine (100 mg,0.61 mmol) was added to a 25mL reaction flask followed by DCM (50 mL) followed by DIEA (390 mg,3 mmol) and Ms ₂ O (320 mg,1.84 mmol) in sequence and stirred at room temperature for 1H after addition. The reaction mixture was extracted with DCM (2×20 ml), and the organic phase was saturated brine (2×20 ml) and concentrated to give compound 3- (4-methoxypyridin-3-yl) prop-2-yn-1-ylmethane sulfonate (colorless liquid, 120mg, yield 81.3%). MS m/z (ESI) 242.5[ M+H ] ⁺ _.

Step 4-3- (4-methoxypyridin-3-yl) prop-2-yn-1-ylmethylsulfonate (50 mg,0.21 mmol), starting (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (57 mg,0.25 mmol) was added to a 25mL reaction flask, followed by DMSO (5 mL) and then DIPEA (81 mg,0.63 mmol) and stirred at 60℃for 16H after the addition. The reaction mixture was added to (30 mL) ethyl acetate, washed with water (30 mL), brine (50 mL), and the organic phase concentrated and initially purified by normal phase column chromatography (dichloromethane: methanol=10:1) to give crude product 5mg, which was taken out of 20mg and then reversed phase column (acetonitrile/(water+0.05% NH ₄HCO₃)) to give compound (6 br,10 as) -8- (3- (4-methoxypyridin-3-yl) prop-2-yn-1-yl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deazaquinoxaline (gray solid, 10mg, yield 31.5％).¹H NMR(500MHz,DMSO-d₆)δ8.44(s,2H),7.12(d,J＝5.2Hz,1H),6.55(d,J＝8.4Hz,1H),6.48(d,J＝6.4Hz,1H),6.38(d,J＝6.4Hz,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 (6 bR,10 aS) -8- ((E) -3- (benzofuran-7-yl) allyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deaggregation ] quinoxaline

Step 1 Ethyl (E) -3- (benzofuran-7-yl) acrylate (65 mg,0.3 mmol) was dissolved in THF (2.0 mL), cooled to-78℃and 1M DABL-H in tetrahydrofuran (0.45 mL,0.45 mmol) was added, stirred at-78℃for 1H, sodium sulfate decahydrate was added and stirred for 15 min, and after filtration and concentration the normal phase was purified to give compound (E) -3- (benzofuran-7-yl) prop-2-en-1-ol (yellow oil, 21mg, 40% yield). MS M/z (ESI): 175.3.[ M+H ] ⁺ _.

Step 2 Compound (E) -3- (benzofuran-7-yl) prop-2-en-1-ol (21 mg,0.12 mmol) was dissolved in DCM (2.0 mL), active MnO ₂ (104 mg,1.2 mmol) was added and stirred at 20deg.C for 3h, filtered to give Compound (E) -3- (benzofuran-7-yl) propenal (yellow oil, 20 mg) which was used directly in the next reaction. MS M/z (ESI): 173.3 [ M+H ] ⁺ _.

Step 3 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (25 mg,0.10 mmol) and (E) -3- (benzofuran-7-yl) acrolein (20 mg,0.12 mmol) were dissolved in DCM (2.5 mL), triethylamine (5.0 mg,0.05 mmol) was added, acetic acid (6.0 mg,0.1 mmol) was added, naBH (OAc) ₃ (120 mg,0.6 mmol) was added after stirring for 10min, 20 ℃ stirring 16H, prep-HPLC purification separation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) was obtained as compound (6 bR,10 aS) -8- ((E) -3- (benzofuran-7-yl) allyl) -3-methyl-2, 3, 7, 6b, 8,9,10 a-octahydro [1, 6H ] pyrido [3, 6, 5] pyrido [3, 5] 1, 5] pyrido [3, 5] by concentration filtration 26％).¹H NMR(500MHz,DMSO-d₆)δ8.05(s,1H),7.55(d,J＝5.0Hz,1H),7.36(d,J＝5.0Hz,1H),7.23(t,J＝7.5Hz,1H),7.00(s,1H),6.79-6.71(m,2H),6.50(t,J＝7.5Hz,1H),6.41(d,J＝5.0Hz,1H),6.34(d,J＝5.0Hz,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]⁺.

EXAMPLE 64 4- (3- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-8 (7H) -yl) propyl) -2, 3-dihydrofuro [3,2-c ] pyridine

Preparation of E64 reference example 60 Synthesis method .¹H NMR(500MHz,DMSO-d₆)δ8.13(d,J＝5.4Hz,1H),6.66(d,J＝5.4Hz,1H),6.51(t,J＝7.6Hz,1H),6.42(d,J＝7.2Hz,1H),6.33(d,J＝7.8Hz,1H),4.60(t,J＝8.8Hz,2H),3.33-3.27(m,3H),3.18(t,J＝8.8Hz,2H),3.12-3.08(m,1H),3.01-2.95(m,1H),2.78(s,3H),2.74(dd,J＝11.9,6.1Hz,1H),2.70-2.66(m,1H),2.63(dd,J＝8.6,6.6Hz,2H),2.56(d,J＝11.4Hz,1H),2.31-2.21(m,2H),2.10-2.03(m,1H),1.88(dd,J＝14.4,2.9Hz,1H),1.84-1.71(m,4H).MS m/z(ESI):391.8[M+H]⁺

Example 65-1 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-ethyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 Compound 3- (2, 3-Dihydrobenzofuran-7-yl) propan-1-ol (3 g,16.8 mmol) was added to a 100mL single-port flask at room temperature, followed by the addition of dessert-martin reagent (21.4 g,50.5 mmol) and stirring at room temperature for 5h. After completion of the TLC reaction, the reaction was filtered through celite, the filtrate was adjusted to basic pH with saturated aqueous sodium bicarbonate, DCM extracted (50 ml x 2), the combined organic phases were washed with saturated brine (50 ml x 1), dried over anhydrous Na ₂SO₄, dried under reduced pressure and the crude was isolated by chromatography (EtOAc/pe=0-20%) and purified to give compound 65-1-1 (colorless oil, 2.5g, yield: 84%).

Step 2 Compounds 45-1-5 (2.0 g,7.0 mmol), aqueous acetaldehyde (40% wt,10 mL) and methanol (40 mL) were added together in a 100mL single-necked flask followed by addition of Na (OAc) ₃ BH (8.8 g,42 mmol) in portions and stirring at room temperature for 3h. After completion of the reaction by LCMS, the reaction mixture was concentrated under reduced pressure to remove most of the solvent, then the crude product was dissolved in EA, washed with water (50 ml x 1), saturated NaHCO ₃ solution (50 ml x 1), EA extracted (30 ml x 2), the combined organic phases were washed with saturated brine (50 ml x 1), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product was purified by chromatography (EtOAc/pe=0-25%) to give compound 65-1-2 (pale yellow oil, 1.8g, yield) :82％).¹H NMR(500MHz,CDCl₃)δ6.65(t,J＝7.7Hz,1H),6.51(d,J＝7.3Hz,1H),6.40(d,J＝7.9Hz,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＝7.1Hz,3H),1.15(t,J＝7.1Hz,3H).MS m/z(ESI):316.4[M+H]⁺.

Step 3:65-1-3 preparation of the Synthesis method of the second step in reference example 73-1. MS m/z (ESI): 244.5[ M+H ] ⁺.

Step 4 preparation of E65-1 reference is made to the synthetic method of the third step of example 73-1 .¹H NMR(500MHz,CDCl₃)δ7.03(dd,J＝7.3,0.8Hz,1H),6.92(d,J＝7.5Hz,1H),6.76(t,J＝7.4Hz,1H),6.64(t,J＝7.7Hz,1H),6.47(d,J＝7.2Hz,1H),6.39(d,J＝7.9Hz,1H),4.53(t,J＝8.7Hz,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＝14.5,7.6Hz,2H),2.50-2.28(m,3H),2.07-1.93(m,3H),1.91-1.83(m,2H),1.14(t,J＝7.1Hz,3H).MS m/z(ESI):404.9[M+H]⁺.

Example 65-2 (6 bS,10 aR) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-ethyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 67-2-6 (2.10 g,7.31 mmol) was dissolved in THF (20.0 mL) and BH ₃/THF (21.9 mL, 1M) was added. The reaction was carried out at 70℃for 3h. LCMS detected completion of the reaction, water was added, EA was extracted, dried over sodium sulfate, filtered and concentrated, and silica gel column purified (PE: ea=5:1) to afford compound 65-2-1 (yellow solid, 1.80g, 90% yield). MS m/z (ESI): 274.4[ M+H ] ⁺.

Step 2 methyl-2, 3,6b,7,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-8 (9H) -carboxylate (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 reaction was carried out at 25℃for 3h. LCMS detected completion of the reaction, water was added, EA was extracted, dried over sodium sulfate, filtered and concentrated, and silica gel column purified (PE: ea=3:1) to afford compound 65-2-2 (yellow solid, 1.04g, yield 55%). MS m/z (ESI): 302.2[ M+H ] ⁺.

Step 3 65-2-2 (1.00 g,3.31 mmol) was dissolved in hydrobromic acid in acetic acid (20 mL) and reacted at 25℃for 20h. LCMS detected completion of the reaction and concentrated the reaction solution to give compound 65-2-3 (gray solid, 1.04g, 96% yield). MS m/z (ESI): 244.2[ M+H ] ⁺.

Step 4 65-2-3 (400 mg,1.64 mmol) was dissolved in MeOH (200 mL) and DCM (120 mL) under nitrogen, 3- (2, 3-dihydrobenzofuran-7-yl) propanal (277 mg,1.97 mmol) and NaBH (AcO) ₃ (1.73 mg,8.21 mmol) were added. The reaction was carried out at 25℃for 1h. LCMS detected completion of the reaction, water was added, EA extracted, dried over sodium sulfate, filtered and concentrated, and purified on a silica gel column (DCM: meoh=10:1) to afford compound 65-2-4 (yellow solid, 1.04g, yield 55%). MS m/z (ESI): 404.3[ M+H ] ⁺.

Step 5:65-2-4 (100 mg,0.248 mmol) was resolved by SFC(Daicel ChiralPak IJ,40mm I.D.×250mm,10μm;Mobile phase：n-Hexane/Ethanol[0.1％ NH_3.H₂O(V/V)]＝95/5;Flow rate:80mL/min) to give E65-1 as a white solid (PK 1:42.8mg, 98% pure, 42% yield, ee 98%, RT=4.512, OROT= +0.13.8 and E65-2 as a white solid (PK 2:37.4mg, 97% pure, yield) 37％,ee 100％,RT＝5.303,OROT＝-10.2)).E65-1:¹H NMR(400MHz,DMSO-d6)¹H NMR(400MHz,DMSO)δ7.04(d,J＝7.3Hz,1H),6.91(d,J＝7.4Hz,1H),6.73(t,J＝7.4Hz,1H),6.50(t,J＝7.6Hz,1H),6.37(d,J＝7.2Hz,1H),6.31(d,J＝7.8Hz,1H),4.49(t,J＝8.7Hz,2H),3.51(d,J＝8.6Hz,1H),3.35(d,J＝7.2Hz,1H),3.30-3.22(m,2H),3.21-3.11(m,3H),3.07(d,J＝4.0Hz,1H),3.03-2.94(m,1H),2.75(d,J＝4.3Hz,1H),2.64-2.52(m,2H),2.47(s,2H),2.24(dd,J＝15.9,7.1Hz,2H),2.08(s,1H),1.89(d,J＝14.4Hz,1H),1.81-1.62(m,4H),1.04(t,J＝7.0Hz,3H).MS m/z(ESI):404.3[M+H]⁺.E65-2:¹H NMR(400MHz,DMSO-d6)δ¹H NMR(400MHz,DMSO-d6)δ7.04(d,J＝7.2Hz,1H),6.92(d,J＝7.6Hz,1H),6.73(t,J＝7.2Hz,1H),6.50(t,J＝7.6Hz,1H),6.37(d,J＝7.2Hz,1H),6.31(d,J＝7.6Hz,1H),4.49(t,J＝8.8Hz,2H),3.60-3.45(m,1H),3.41-3.23(m,3H),3.23-3.11(m,3H),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,2H),2.15-2.01(m,1H),1.95-1.83(m,1H),1.83-1.60(m,4H),1.05(t,J＝7.2Hz,3H).MS m/z(ESI):404.3[M+H]⁺.

Example 66 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3- (oxetan-3-yl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1-45-1-6 (1 g,2.67 mmol), TEA (13.5 g,13.3 mmol) was dissolved in DCM/MeOH=10:1 (150 ml), then (Boc) ₂ O (540 mg,2.67 mmol) was added, the reaction was reacted at room temperature for 6h, LCMS showed complete reaction, DCM extraction, and silica gel column (PE/EA=100/0-70/30) gave product 66-1 (600 mg, white solid, yield: 71.3%). MS m/z (ESI) 316.3[ M+H ] ⁺ _.

Step 2-66-1 (70 mg,0.22 mmol) was dissolved in MeOH (50 ml) followed by the addition of oxetan-3-one (80 mg,1.11 mmol) and rapid addition of Na (OAc) ₃ BH (71 mg,1.11 mmol) for 1h, LCMS showed complete reaction, DCM extraction and passage through a silica gel column (PE/EA=100/0-60/40) afforded product 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 25mL reaction flask followed by dichloromethane (5 mL) and TFA (2 mL) and stirred at room temperature for 1h. The reaction was concentrated to give compound 66-3 (colorless liquid, 60mg, tfa salt, yield 96.3%). MS m/z (ESI) 272.2[ M+H ] ⁺ _.

Step 4 dissolving 66-3 (30 mg,0.11 mmol) in MeOH (5 ml) and DCM (5 ml), then adding 65-1-1 (21 mg,0.12 mmol), adding Na (OAc) ₃ BH (116 mg,0.55 mmol) rapidly for 1h, LCMS showing complete reaction, DCM extraction, concentrating and filtering followed by prep-HPLC purification isolation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give compound E66 (10 mg, white solid, yield) ：21.1％).¹H NMR(500MHz,CDCl₃)δ7.03(d,J＝7.3Hz,1H),6.92(d,J＝7.5Hz,1H),6.76(t,J＝7.4Hz,1H),6.59(dt,J＝14.0,7.0Hz,2H),6.16(d,J＝7.7Hz,1H),4.86(tt,J＝19.2,6.5Hz,4H),4.75(p,J＝6.9Hz,1H),4.53(t,J＝8.7Hz,2H),3.55-3.36(m,3H),3.30-3.23(m,1H),3.19(t,J＝8.7Hz,3H),2.90(s,1H),2.82(td,J＝9.8,3.2Hz,1H),2.72(s,1H),2.60-2.50(m,2H),2.41(d,J＝7.8Hz,2H),2.34-2.22(m,1H),1.97(s,3H),1.85(dt,J＝15.1,7.5Hz,2H).MS m/z(ESI):432.8[M+H]⁺.

Example 67-1 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1-45-1-4 (5 g,16.6 mmol) and 50mL of HBr in HOAc were reacted at 50deg.C for 16h. LCMS showed complete reaction, the reaction was cooled to room temperature, filtered, and the solid was washed with EA and dried to give 67-1-1 (6 g, brown solid). MS m/z (ESI) 230.2[ M+H ] ⁺.

Step 5-dissolving 67-1-1 (2 g,6.47 mmol) in 100mL DCM and 100mL MeOH, adding NaBH (OAc) ₃ (6.8 g,32.2 mmol), finally adding 65-1-1 (910 mg,5.18 mmol), reacting at room temperature for 0.5h. LCMS showed a small amount of 67-1-1 remaining, adding saturated sodium bicarbonate solution to adjust pH=7-8, concentrating DCM and MeOH, adding EA and water, filtering, extracting the aqueous phase twice with EA, combining the organic phases, drying and concentrating the column (100% DCM-2% MeOH/DCM) to obtain compound E67-1 (990 mg). Purifying with HPLC (0-95% 30min,0.05% NH ₄HCO₃ in H₂ O, basic C18 column) to obtain 790mg compound E67-1 yield :36％.¹H NMR(400MHz,CDCl₃)δ7.66(s,1H),7.04(d,J＝7.0Hz,1H),6.92(d,J＝7.5Hz,1H),6.82(d,J＝7.0Hz,1H),6.76(t,J＝7.5Hz,1H),6.72(t,J＝7.5Hz,1H),6.58(d,J＝7.0Hz,1H),4.53(t,J＝9.0Hz,2H),3.95(d,J＝14.5Hz,1H),3.39(d,J＝14.5Hz,1H),3.34-3.32(m,2H),3.20(t,J＝8.5Hz,2H),2.95-2.90(m,1H),2.78-2.71(m,1H),2.57(t,J＝7.5Hz,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]⁺.

Example 67-2 (6 bS,10 aR) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 (2-bromophenyl) hydrazine hydrochloride (16.0 g,71.4 mmol) and piperidin-4-one hydrochloride (12.1 g,89.8 mmol) were dissolved in isopropanol (200.0 mL) and concentrated hydrochloric acid solution (16.0 mL) was added. The reaction was carried out at 100℃for 12h. LCMS detected completion of the reaction and was concentrated by filtration to give compound 67-2-1 (yellow solid, 20.0g, 98% yield). MS m/z (ESI): 251.0,253.0[ M+H ] ⁺.

Step 2 67-2-1 (19.0 g,60.5 mmol) was dissolved in TFA (20 mL) and triethylsilane (70.3 g,605 mmol) was added. The reaction was carried out at 40℃for 48h. LCMS detected completion of the reaction, concentrated the reaction, extracted with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give compound 67-2-2 (grey solid, 15.0g, 89% yield). MS m/z (ESI): 253.0,255.0[ M+H ] ⁺.

Step 3 67-2-2 (15.0 g,59.5 mmol) was dissolved in DCM (200 mL) under nitrogen and TEA (13.1 mL,94.8 mmol) and dimethyl dicarbonate (6.99 g,52.1 mmol) were added. The reaction was carried out at 25℃for 3h. LCMS detected completion of the reaction, water was added, EA was extracted, dried over sodium sulfate, filtered and concentrated, and silica gel column purified (PE: ea=5:1) to afford compound 67-2-3 (white solid, 15.0g, 81% yield). MS m/z (ESI): 311.0[ M+H ] ⁺.

Step 4 67-2-3 (14.0 g,26.9 mmol) was dissolved in toluene (200 mL) under nitrogen and benzophenone imine (5.87 g,32.3 mmol), naOt-Bu (5.19 g,53.9 mmol) and BINAP (0.50 g, 0.81mmol) were added. Pd ₂(dba)₃ (0.25 g,0.270 mmol) was added to the reaction mixture at 60℃for 3 h. The reaction was carried out at 105℃for 16h. LCMS detected completion of the reaction, water was added, EA was extracted, dried over sodium sulfate, filtered and concentrated, and silica gel column purified (PE: ea=5:1) to afford compound 67-2-4 (yellow solid, 8.10g, 73% yield). MS m/z (ESI): 412.2[ M+H ] ⁺.

Step 5 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), na ₂CO₃ (3.13 g,29.5 mmol) and KI (4.08 g,24.6 mmol) were added under nitrogen. The reaction was carried out at 65℃for 12h. LCMS detected completion of the reaction, water was added, EA was extracted, dried over sodium sulfate, filtered and concentrated, and silica gel column purified (PE: ea=5:1) to afford compound 67-2-5 (yellow solid, 8.50g, 86% yield).

Step 6 67-2-5 (3.00 g,5.86 mmol) was dissolved in THF (10 mL) under nitrogen and hydrochloric acid (3.4 mL, 2N) was added. The reaction was carried out at 25℃for 1.5h. LCMS detected completion of the reaction and concentrated to give compound 67-2-6 (yellow solid, 1.40g, 80% yield). MS m/z (ESI) 288.2[ M+H ] ⁺.

Step 7 67-2-6 (660 mg,2.29 mmol) was dissolved in hydrobromic acid in acetic acid (5 mL) under nitrogen. The reaction was carried out at 50℃for 18h. LCMS detected completion of the reaction and concentrated to give compound 67-2-7 (yellow solid, 450mg, 85% yield). MS m/z (ESI) 230.2[ M+H ] ⁺.

Step 8 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 NaBH ₃ CN (274 mg,4.36 mmol) were added under nitrogen. The reaction was carried out at 25℃for 3h. LCMS detected completion of the reaction, water was added, EA extracted, dried over sodium sulfate, filtered and concentrated, and silica gel column purified (DCM: meoh=10:1) to afford compound 67-2-8 (yellow solid, 100mg, 29% yield). MS m/z (ESI): 390.2[ M+H ] ⁺.

Step 9 resolution of 67-2-8 (100 mg,0.257 mmol) by SFC(Daicel ChiralPak IH,40mm I.D.×250mm,10μm;Mobile phase：n-Hexane+TFA0.1/Ethanol＝60/40;Flow rate:70mL/min) gave compound E67-2 (PK 1:27.4mg, purity 91%, yield 27%, ee 100%, RT=3.441, OROT= -219.5 and compound E67-1 (PK 2:30.3mg, purity 83%, yield) 30％,ee 99％,RT＝4.936,OROT＝+52.6).E67-2:¹H NMR(400MHz,DMSO)δ10.35(s,1H),7.08-7.02(m,1H),6.92(d,J＝7.2Hz,1H),6.80-6.70(m,2H),6.64(t,J＝7.6Hz,1H),6.58(dd,J＝7.6,0.8Hz,1H),4.49(t,J＝8.8Hz,2H),3.80(d,J＝14.0Hz,1H),3.30-3.03(m,7H),2.90-2.77(m,1H),2.64-2.55(m,1H),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]⁺.E67-1:¹H NMR(400MHz,DMSO)δ10.36(s,1H),7.04(d,J＝7.2Hz,1H),6.92(d,J＝7.6Hz,1H),6.81-6.70(m,2H),6.64(t,J＝7.6Hz,1H),6.60-6.55(m,1H),4.49(t,J＝8.8Hz,2H),3.80(d,J＝14.4Hz,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):390.2[M+H]⁺.

Example 67-3 trans-8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 67-2-1 (20.00 g,79.6 mmol) was dissolved in DMF (250.0 mL) and K ₂CO₃ (44.0 g,318 mmol) was added. The reaction was continued for 0.5h at 25℃and then Xiu (0.75 g,4.380 mmol) was added and the reaction continued for 2h at room temperature. LCMS checked the completion of the reaction, water was added, EA extracted, dried over sodium sulfate, filtered and concentrated, and purified on a silica gel column (pe=100%) to give compound 67-3-1 (white solid, 11.0g, 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 borane dimethyl sulfide (90.0 mL,176mmol, 2M) was added under nitrogen. The reaction was carried out at 80℃for 48h. There was also a quarter of the starting material in the LCMS reaction and the desired molecular weight had 2 peaks, 6n hcl was added and after half an hour of further reaction at 100 ℃, it was dried by water pump and purified in reverse phase (ACN: H ₂ o=25%) to give compound 67-3-2 (yellow solid, 1.9g, yield 63%). 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) and LiHMDS (17 mL,5.12 mmol) was added under nitrogen at 0deg.C for 0.5h. 2-chloroacetamide (510 mg, 5.4478 mmol) was then added and reacted overnight at 25 ℃. LCMS detected completion of the reaction, quenched with aqueous sodium sulfite, extracted with DCM and water, concentrated by filtration, and purified by silica gel column (DCM: meoh=10:1) to give compound 67-3-3 (brown solid, 500mg, yield 25%). MS m/z (ESI): 400.3,402.4[ M+H ] ⁺.

Step 4 67-3-3 (500 mg,1.25 mmol) was dissolved in dioxane (5.0 mL), cuI (70 mg,0.375 mmol), cesium carbonate (1.9 g,3.74 mmol) and 2, 5-diazahexane (135 mg,1.5 mmol) were added and reacted at 110℃for 2h. LCMS detected completion of the reaction, was washed with EA and water, filtered, concentrated, and purified on a silica gel column (EA: pe=42%) to afford compound 67-3-4 (brown solid, 260mg, 65% yield). Ms M/z (ESI) 320.2[ M+H ] ⁺.

Step 5 67-3-4 (260 mg,0.814 mmol) was dissolved in MeOH (3.0 mL), pd/C (50 mg) was added, and (Boc) ₂ O (355 mg,1.63 mmol) was added under nitrogen. The reaction was carried out at 25℃for 18h. LCMS detected completion of the reaction, palladium on carbon was filtered off, silica gel was sampled, concentrated, and silica gel column purified (EA: pe=56%) to afford compound 67-3-5 (yellow solid, 130mg, yield 48%). MS m/z (ESI): 275.2[ M-56+H ] ⁺.

Step 6-67-3-5 (50 mg,0.152 mmol) was dissolved in DCM (1.0 mL) and HCl-dioxane (0.5 mL) was added and reacted at 25℃for 3h. LCMS detected completion of the reaction, and the reaction was pulled dry and directly thrown to the next step to give compound 67-3-6 (yellow solid, 35mg, 100% yield). MS m/z (ESI) 230.4[ M+H ] ⁺.

Step 8 67-3-6 (35 mg,0.153 mmol) was dissolved in MeOH (20 mL) and DCM (12 mL) under nitrogen, 3- (2, 3-dihydro-1-benzofuran-7-yl) propanal (60 mg,0.305 mmol) and sodium borohydride acetate (97 mg,0.458 mmol) were added and reacted overnight at 25 ℃. LCMS detection of completion of reaction, drying the reaction solution, filtering, concentrating, and purifying (eluent (v/v): acetonitrile/(water+0.05% nh ₄HCO₃) =25% -78%) to give compound E67-3 (white solid, 15.35mg, yield) 25.8％).¹H NMR(400MHz,CD₃OD)δ7.06(dd,J＝7.4,1.0Hz,1H),6.94(d,J＝7.6Hz,1H),6.83(d,J＝7.4Hz,1H),6.77(td,J＝7.6,5.5Hz,2H),6.67(d,J＝7.8Hz,1H),4.54(t,J＝8.6Hz,2H),3.89(d,J＝14Hz,1H),3.78(d,J＝9.6Hz,1H),3.36(d,J＝14.4Hz,2H),3.20(t,J＝8.8Hz,2H),2.95(dd,J＝18.0,6.1Hz,1H),2.74(t,J＝7.8Hz,2H),2.63(t,J＝7.6Hz,3H),2.56-2.42(m,2H),2.20(dd,J＝12.6,2.7Hz,1H),1.94(dd,J＝16.0,12.0,5.8Hz,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 a-octahydropyrido [4,3-b ] [1,4] thiadiazepinyl [2,3,4-hi ] indole

Preparation of E68 reference example 42 Synthesis method .¹H NMR(500MHz,CD₃OD)δ7.18-7.04(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＝5.0Hz,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]⁺.

Example 69 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) -2-fluoropropyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 7-bromo-2, 3-dihydrobenzofuran (2 g,10 mmol), allyltributyltin (3.5 g,11 mmol), pd (PPh ₃)₄ and CsF (3.04 g,20 mmol), 10mL 1,4-dioxane were replaced three times with N ₂, warmed to 110 ℃, reacted 16h. TLC to detect completion, filtered, concentrated, separated in water and EA, the aqueous phase extracted once with EA, the organic phases combined, dried and concentrated over column (PE/EA=50/1) to give 69-1 (1.3 g, colorless liquid).

Step 2. 69-1 (1.1 g,6.88 mmol) was added to a single vial containing 20mL DCM, m-CPBA (2.79 g,13.75 mmol) was added in portions, room temperature reaction for 16h. TLC showed complete reaction, filtration, washing of the solid with DCM, adding saturated sodium bicarbonate to the filtrate, separating the liquid, and drying concentration over the column (PE/EA=50/1 to give 69-2 (600 mg, colorless liquid).

Step 3 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline (300 mg,1.3 mmol), 69-2 (276 mg,1.57 mmol), K ₂CO₃ (360 mg,2.6 mmol) and 5mL DMF were reacted by microwaves at 150℃for 1.5H. LCMS showed little starting material remaining, water and EA were added, the aqueous phase was extracted once with EA, the organic phases were combined, dried and concentrated over column (DCM/meoh=50/1) to give 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 with 2mL DCM, N ₂ was replaced three times, cooled to-78℃and a solution of 69-3 (50 mg,0.12 mmol) in DCM was added and slowly warmed to room temperature for 16h. LCMS showed the main peak as the target product, quenched with saturated sodium bicarbonate, separated, aqueous phase extracted once with DCM, combined organic phases, and dried concentrated prep-HPLC purification isolation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give compound E69 (7.5 mg, white solid, yield: 15.4%).

¹H NMR(500MHz,CDCl₃)δ7.08(d,J＝7.1Hz,1H),6.96(d,J＝6.9Hz,1H),6.78(t,J＝8.2Hz,1H),6.65(t,J＝7.2Hz,1H),6.50(d,J＝7.3Hz,1H),6.41(d,J＝7.8Hz,1H),5.23-4.87(m,1H),4.54(t,J＝8.7Hz,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 (6 bR,10 aS) -8- (3- (3-chloro-6-methylpyridin-2-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline

Step 1 CuBr (832 mg,5.8 mmol) was added to a three-necked flask containing 30mL of THF, N ₂ was replaced three times, cooled to-78℃and 0.5M (2- (1, 3-dioxan-2-yl) ethyl) magnesium bromide (23 mL,11.6 mmol) was added dropwise and reacted at this temperature for 20min. 2-bromo-3-chloro-6-methylpyridine (300 mg,1.45 mmol) was added, the reaction was continued at-78 ℃ for 3h, warmed to room temperature, 16h lcms detected completion, aqueous ammonia was added to adjust ph=9-10, EA and water were added, filtration, separation of the liquid, extraction of the aqueous phase with EA twice, washing of the combined organic phases with saturated sodium chloride solution once, drying concentration through the column (PE/ea=3/1) to give 70-1 (300 mg colorless liquid). MS m/z (ESI): 242.1,243.9[ M+H ] ⁺.

Step 2. 70-1 (300 mg,1.24 mmol) was added to a single vial containing 3mL of THF, 4M HCl (1 mL,4 mmol) was added, 50 ℃ 3h. LCMS showed complete reaction, THF was concentrated off, pH=8-9 was adjusted with saturated sodium bicarbonate, EA and water were added, the aqueous phase was separated, extracted twice with EA, the organic phases were combined, washed once with saturated sodium chloride solution, and concentrated by drying through the column (PE/EA=3/1) to give 70-2 (90 mg, brown oil). MS m/z (ESI): 184.0,185.9[ M+H ] ⁺.

Step 3 preparation of E70 reference E46 step 7 Synthesis method .1H NMR(500MHz,CDCl3)δ7.47(d,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,1H),6.64(t,J＝7.5Hz,1H),6.51(d,J＝7.0Hz,1H),6.40(d,J＝8.0Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) -3-fluoropropyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 Compound 2, 3-Dihydrobenzofuran-7-carbaldehyde (1.0 g,6.76 mmol) was dissolved in THF (50 mL), cooled to-78deg.C, vinylmagnesium chloride (6.6 mL,10 mmol) was added, and the mixture was warmed to room temperature and stirred for 2hr. The reaction was quenched with aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL. Times.2), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give crude product, which was purified and separated by normal phase column to give compound 71-1 (colorless oil, 1.1g, yield: 92%). MS m/z (ESI): 177.4[ M+H ] ⁺.

Step 2 preparation of 71-2 reference is made to the synthetic procedure of the first step in example E65.

Step 3 67-1-1 (150 mg,0.66 mmol), 71-2 (135 mg,0.79 mmol) and anhydrous DCM (15 mL) were added together in a 50mL single-necked flask followed by TEA (200 mg,1.98 mmol) and stirred at room temperature for 16h. After completion of LCMS detection, the reaction mixture was washed with saturated NH ₄ Cl solution (50 ml x 1), extracted with DCM (30 ml x 2), the combined organic phases washed with saturated brine (50 ml x 1), dried over anhydrous Na ₂SO₄, dried under reduced pressure, and the crude was purified by chromatography (MeOH/dcm=0-5%) to give 71-3 (pale yellow oil, 150mg, yield :57％).¹H NMR(500MHz,CDCl₃)δ7.78(s,1H),7.67(d,J＝7.6Hz,1H),7.36(dd,J＝7.2,1.1Hz,1H),6.92-6.87(m,1H),6.85(d,J＝7.4Hz,1H),6.75(t,J＝7.6Hz,1H),6.62(d,J＝7.7Hz,1H),4.71(t,J＝8.8Hz,2H),3.95(d,J＝14.5Hz,1H),3.71-3.51(m,1H),3.45-3.31(m,4H),3.25(t,J＝8.8Hz,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) was added to a 50mL single-necked flask with anhydrous MeOH (10 mL), followed by addition of NaBH ₄ (45 mg,1.11 mmol) in portions at room temperature, and stirring at room temperature for 1h. After completion of LCMS detection, the reaction mixture was washed with saturated NH ₄ Cl solution (20 ml x 1), DCM extracted (20 ml x 2), the combined organic phases washed with saturated brine (30 ml x 1), dried over anhydrous Na ₂SO₄, dried under reduced pressure, and the crude was purified by column chromatography (MeOH/dcm=0-10%) to give 71-4 (white solid, 120mg, yield :80％).¹H NMR(500MHz,MeOD)δ7.18(dd,J＝7.4,3.6Hz,1H),7.10(dd,J＝7.3,1.0Hz,1H),6.87-6.79(m,2H),6.72(td,J＝7.6,1.9Hz,1H),6.65(d,J＝7.8Hz,1H),4.93-4.90(m,1H),4.63-4.47(m,3H),3.89(d,J＝14.6Hz,1H),3.34(dd,J＝11.9,9.0Hz,2H),3.18(t,J＝8.6Hz,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) was added to a 25mL three-necked flask with anhydrous DCM (3 mL), and DAST (55 mg,0.25 mmol) in dichloromethane was slowly added dropwise under a bath of nitrogen and dry ice ethanol, after which the mixture was allowed to stir at room temperature for 3h. After completion of LCMS detection, the reaction mixture was quenched by addition of saturated NH ₄ Cl solution (10 ml x 1), followed by DCM extraction (10 ml x 2), the combined organic phases, saturated brine wash (30 ml x 1), dry Na ₂SO₄, spin-dry under reduced pressure, and the crude product was purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give the target compound E71 (white solid, 6mg, yield :30％).¹H NMR(500MHz,MeOD)δ7.18(t,J＝6.8Hz,1H),7.12(t,J＝8.4Hz,1H),6.84(dt,J＝15.0,7.4Hz,2H),6.72(dd,J＝15.7,7.8Hz,1H),6.66(t,J＝8.0Hz,1H),4.95-4.88(m,1H),4.61-4.51(m,3H),3.89(dd,J＝14.5,8.5Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) -2-fluoropropyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

E72 preparation Synthesis method of reference example 69 ¹H NMR(500MHz,CDCl₃)δ7.41(s,1H),7.08(d,J＝7.3Hz,1H),6.97(d,J＝7.6Hz,1H),6.84-6.68(m,3H),6.57(d,J＝7.8Hz,1H),4.99(d,J＝50.2Hz,1H),4.57-4.51(m,2H),3.94(dd,J＝14.6,2.6Hz,1H),3.54-3.28(m,3H),3.21(t,J＝8.7Hz,2H),2.99-2.85(m,3H),2.58(t,J＝102.0Hz,4H),1.97(d,J＝33.6Hz,3H).MS m/z(ESI):408.6[M+H]⁺.

Example 73-1 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 Compounds 45-1-4 (210 mg,0.69 mmol) were dissolved in dry tetrahydrofuran (5.0 mL) under nitrogen and sodium hydrogen (55.7 mg,1.39mmol,60% dispersed in mineral oil) was added. After 0.5h of reaction at 0 ℃, methyl iodide (55.7 mg,1.39 mmol) was added and the reaction was continued at room temperature for 2h. After completion of LCMS detection reaction, quenched with 10.0mL of ice water, extracted with dichloromethane (10.0 mL x 2), and the organic phase was dried by spin-drying, the crude product was purified on a forward silica gel column to give 73-1-1 (brown solid, 190mg, 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℃for 16h. LCMS detects disappearance of starting material. After cooling to room temperature, compound 73-1-2 (brown solid, 45mg, yield 20%) was obtained by filtration. MS m/z (ESI): 244.2[ M+H ] ⁺.

Step 3 Compounds 73-1-2 (45.0 mg,0.19 mmol), 3- (2, 3-dihydrobenzofuran-7-yl) propanal (31.0 mg,0.19 mmol), acetic acid (0.05 mL,0.93 mmol) were dissolved in THF (3.0 mL) under nitrogen, sodium cyanoborohydride (24.7 mg,0.39 mmol) was added and reacted at 0℃for 2h. LCMS detection of completion of reaction, filtration, spin-drying, reverse phase purification (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) gave compound E73-1 (white solid, 10.1mg, yield) 14％).1H NMR(400MHz,CDCl₃)δ7.01(d,J＝7.2Hz,1H),6.91(d,J＝7.6Hz,1H),6.86-6.84(m,1H),6.79-6.72(m,3H),4.55(t,J＝8.4Hz,2H),4.01(t,J＝14.0Hz,1H),3.38-3.35(m,2H),3.32(s,3H),3.30-3.29(m,1H),3.19(t,J＝8.8Hz,2H),2.94-2.72(m,2H),2.57(t,J＝7.6Hz,2H),2.39-2.16(m,3H),2.02-1.77(m,5H).MS m/z(ESI):404.4[M+H]+.

Example 73-2 (6 bS,10 aR) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 67-2-6 (840 mg,2.92 mmol) was dissolved in THF (5.0 mL) and NaH (9.12 g,62.1 mmol) and methyl iodide (77.3 mg,0.636 mmol) were added under ice-bath. The reaction was carried out at 0℃for 2h. LCMS detected completion of the reaction, water was added, EA extracted, dried over sodium sulfate, filtered and concentrated, and purified on a silica gel column (DCM: meoh=20:1) to afford compound 73-2-1 (yellow solid, 770mg, 87% yield). MS m/z (ESI): 302.1[ M+H ] ⁺.

Step 2 73-2-1 (770 mg,2.55 mmol) was dissolved in hydrobromic acid in acetic acid (5 mL) and reacted at 50℃for 18h. LCMS detected completion of the reaction and concentrated the reaction to give compound 73-2-2 (grey solid, 526mg, 84% yield). MS m/z (ESI): 244.2[ M+H ] ⁺.

Step 3 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 NaBH ₃ CN (387 mg,6.16 mmol) were added under nitrogen. The reaction was carried out at 25℃for 3h. LCMS detected completion of the reaction, water was added, EA extracted, dried over sodium sulfate, filtered and concentrated, and purified on a silica gel column (DCM: meoh=10:1) to afford compound 73-2-3 (yellow solid, 30.0mg, 6% yield). MS m/z (ESI): 404.2[ M+H ] ⁺.

Step 4:73-2-3 (30.0 mg,0.0744 mmol) was resolved by SFC(Daicel ChiralCel OD,40mm I.D.×250mm,10μm;Mobile phase：n-Hexane/Ethanol[0.1％ NH_3.H₂O(V/V)]＝70/30;Flow rate:80mL/min) to give E73-2 (PK 1:2.20mg, 96% pure, 7% yield, ee 100%, RT=3.543, OROT= -205.3 and E73-1 (PK 2:6.00mg, 72% pure) as a white solid 20％,ee 99％,RT＝4.604,OROT＝+163.3).E73-2:¹HNMR(400MHz,CDCl₃)δ6.97(d,J＝7.2Hz,1H),6.85-6.74(m,3H),6.72-6.65(m,2H),4.45(t,J＝8.8Hz,2H),3.91(d,J＝14.0Hz,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).E73-1:¹H NMR(400MHz,CDCl₃)δ7.01(d,J＝7.2Hz,1H),6.91(d,J＝7.6Hz,1H),6.86-6.84(m,1H),6.79-6.72(m,3H),4.55(t,J＝8.4Hz,2H),4.01(t,J＝14.0Hz,1H),3.38-3.35(m,2H),3.32(s,3H),3.30-3.29(m,1H),3.19(t,J＝8.8Hz,2H),2.94-2.72(m,2H),2.57(t,J＝7.6Hz,2H),2.39-2.16(m,3H),2.02-1.77(m,5H).

Example 74 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-ethyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 45-1-4 (70 mg,0.23 mmol) was added to a 50mL three-port reaction flask, followed by DMF (5 mL), then sodium hydride (9 mg,0.35 mmol) was added thereto after stirring under nitrogen atmosphere at 0℃for 5min, followed by iodoethane (43 mg,0.28 mmol) dropwise, and reacted at room temperature for 5h. After completion of LCMS detection, the reaction mixture was quenched with saturated NH ₄ Cl aqueous solution, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL x 2), the organic phase was washed 2 times with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated to give compound 74-1 (dark brown oil, 50mg, yield 66%). MS m/z (ESI) 330.5[ M+H ] ⁺ _.

Preparation of step 2:74-2 reference is made to the synthetic method of the first step of example 72

Step 3 preparation of E74 reference is made to the fifth Synthesis method of example 8 .¹H NMR(500MHz,CDCl₃)δ7.06-7.01(m,1H),6.91(d,J＝7.5Hz,1H),6.88-6.69(m,4H),4.52(t,J＝8.7Hz,2H),4.03-3.84(m,3H),3.59-3.24(m,3H),3.19(t,J＝8.7Hz,4H),2.59(t,J＝7.6Hz,5H),1.99(d,J＝22.6Hz,5H),1.26(t,J＝7.1Hz,3H).MS m/z(ESI):418.9[M+H]⁺.

Example 75 (6 bR,10 aS) -8- (2- ((2, 3-Dihydrobenzofuran-7-yl) oxo) ethyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1, 7-methoxybenzofuran (500 mg,3.37 mmol), 10mLDCM replaced with N ₂ for three times, cooled to-78 ℃, 2M BBr3 (2.5 mL,5 mmol) is added dropwise, and the mixture is naturally warmed to room temperature and reacted for 3h. TLC showed complete reaction of the starting material, sat.nh ₄ Cl was added to the reaction, the solution was separated, the aqueous phase was extracted once more with DCM, the organic phases were combined, dried and concentrated and passed through a column (PE/ea=10/1) to give 75-1 (280 mg, colorless liquid). MS m/z (ESI): 133.2[ M-H ] ^-.

Step 2 Compound 75-1 (280 mg,2.09 mmol) was added to a 100mL single port reaction flask, followed by methanol (10 mL) and 10% Pd/C (wet base, 50 mg), 20% Pd (OH) ₂/C (wet base, 50 mg) were added, and the reaction was stirred at 60℃for 16h after 3 substitutions of hydrogen. After completion of the reaction by LCMS, the reaction solution was filtered with suction, and the filtrate was concentrated under reduced pressure to give the target compound 75-2 (crude, 260mg, yield 92%). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 135.2

[M-H]^-.

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 10mL of water were replaced three times with N ₂, warmed to 90℃and reacted for 16h. TLC showed little starting material remained, EA was added to the reaction, the solution was separated, the aqueous phase was extracted twice more with EA, the organic phases were combined, dried and concentrated, and passed through a column (PE/ea=10/1) to give 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 2mL DMF were replaced three times with N ₂, warmed to 80℃and reacted 16h. LCMS showed complete reaction. The reaction solution was cooled to room temperature, filtered, and purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give compound E75 (8 mg, pink solid, yield) ：23.5％).¹H NMR(500MHz,CDCl₃)δ7.74(s,1H),6.83(d,J＝7.0Hz,2H),6.81-6.69(m,3H),6.59(d,J＝7.5Hz,1H),4.60(t,J＝9.0Hz,2H),4.19(t,J＝6.0Hz,2H),3.96(d,J＝15.0Hz,1H),3.50-3.30(m,3H),3.22(t,J＝8.5Hz,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 (6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) -3-hydroxypropyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one (HJM-2119, CJJ 120-093)

Preparation of E76 reference example 71 Synthesis method .¹H NMR(500MHz,CD3OD)δ7.18(t,J＝6.8Hz,1H),7.11(dd,J＝7.3,0.9Hz,1H),6.94(d,J＝7.2Hz,1H),6.90(d,J＝8.0Hz,1H),6.84(ddd,J＝8.7,7.7,1.5Hz,2H),4.94-4.90(m,1H),4.63-4.49(m,3H),4.00(d,J＝14.4Hz,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 (6 bR,10 aS) -8- (3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Preparation of E77 reference example 60 Synthesis method .¹H NMR(500MHz,MeOD)δ7.92(d,J＝4.9Hz,1H),7.17(d,J＝4.9Hz,1H),6.91-6.79(m,3H),4.60(t,J＝8.9Hz,2H),3.97(d,J＝14.4Hz,1H),3.35(t,J＝10.9Hz,1H),3.31(d,J＝1.3Hz,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＝12.0,3.3Hz,1H),2.03-1.87(m,4H),1.74(t,J＝11.1Hz,1H).MS m/z(ESI):405.7[M+H]⁺.

Example 78 (6 bR,10 aS) -8- (3- (3-chloropyridin-2-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Preparation of E78 reference E67-1 step 5 Synthesis method .1H NMR(500MHz,CD₃OD)δ8.54(d,J＝4.5Hz,1H),8.06(d,J＝8.1Hz,1H),7.50-7.41(m,1H),7.04-6.99(m,1H),6.96(d,J＝7.4Hz,1H),6.90(t,J＝7.7Hz,1H),4.07(d,J＝14.5Hz,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＝7.5Hz,2H),2.70 -2.56(m,1H),2.40(d,J＝16.0Hz,1H),2.30-2.22(m,3H).MS m/z(ESI):397.9,399.9[M+H]⁺.

Example 79 (6 bR,10 aS) -3-cyclobutyl-8- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-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 10mL THF, N ₂ was replaced three times, cooled to 0℃and cyclobutylamine (544 mg,7.63 mmol) was added, slowly warmed to room temperature and reacted for 2h. EA and saturated sodium chloride solution were added, separated, the aqueous phase was extracted once with EA, the organic phases were combined, dried and concentrated to 79-1 (800 mg, white solid) and used directly in the next step.

Step 2 Ethyl (4 aS,9 bR) -6-bromo-1, 3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (200 mg,0.6 mmol), 79-1 (370 mg,0.9 mmol), DIEA (156 mg,1.2 mmol), TBAB (200 mg,0.6 mmol) were added to a single-port flask with 5mL DMAc, replaced three times with N ₂, warmed to 110℃and reacted for 48H, EA and water were added, the aqueous phase was separated, extracted three times with EA, the combined organic phases were washed three times with saturated sodium chloride, and concentrated over the column (PE/EA=3/1) to give 79-2 (180 mg, brown oil). MS m/z (ESI): 436.6,438.6[ M+H ] ⁺.

Step 3-79-2 (180 mg,0.414 mmol), pd ₂(dba)₃ (38 mg,0.0414 mmol) and NaOt-Bu (80 mg, 0.8238 mmol), BINAP (77 mg,0.124 mmol), 10mL dioxane were added to a 100mL single neck flask, N ₂ was replaced three times, and the temperature was raised to 110℃and reacted for 16h. LCMS monitored complete reaction of the starting materials, cooled the reaction to room temperature, added water and EA, separated, the aqueous phase extracted twice with EA, the organic phases combined, dried, and concentrated to give compound 79-3 (150 mg, crude) as the next step. MS m/z (ESI) 356.2[ M+H ] ⁺.

Step 4. 79-3 (150 mg,0.422 mmol) and 2mL of HBr in HOAc were reacted at 50℃for 16h. LCMS showed complete reaction, the reaction was cooled to room temperature, most HOAc was concentrated and purified by HPLC (0.05% HCl in H ₂ O, 0-95% acn 30 min) to yield 79-4 (45 mg, brown solid). MS m/z (ESI) 230.2[ M+H ] ⁺.

Preparation of E79 reference E67-1, step 5 Synthesis method.

¹H NMR(500MHz,CDCl₃)δ7.03(d,J＝8.5Hz,1H),6.92(d,J＝7.5Hz,1H),6.84(dd,J＝6.5,1.0Hz,1H),6.80-6.73(m,3H),4.66(m,1H),4.53(t,J＝8.5Hz,2H),3.92(d,J＝15.0Hz,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 (6 bR,10 aS) -8- (2- ((2, 3-Dihydrobenzofuran-7-yl) amino) ethyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 12, 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 reaction was carried out at 60℃for 2h. TLC checked completion of the reaction, quenched with water, extracted with EA, dried over sodium sulfate, filtered and concentrated to give compound 80-1 (white solid, 300mg, yield 18%). 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), DIEA (208 mg,1.61 mmol) and (6 bR,10 aS) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one (130 mg,0.537 mmol) were added and stirred at 65℃for 16H. TLC detection of completion of the reaction, water quenching, EA extraction, drying with sodium sulfate, filtration and concentration to give purified (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) compound E80 (white solid, 29.0mg, yield) 13％).¹H NMR(400MHz,DMSO-d6)δ10.36(s,1H),6.78(d,J＝6.4Hz,1H),6.65(dd,J＝15.6,7.6Hz,2H),6.58(dd,J＝7.6,0.8Hz,1H),6.51(d,J＝6.8Hz,1H),6.41(d,J＝7.6Hz,1H),4.65-4.38(m,3H),3.81(d,J＝14.5Hz,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＝11.2Hz,1H).MS m/z(ESI):391.2[M+H]⁺.

EXAMPLE 81 (8 aS,12 aR) -11- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6,7,8a,9,10,11,12 a-octahydro- [1,4] diazoheptano [3,2,1-hi ] pyrido [4,3-b ] indol-5 (4H) -one

Preparation of step 1:81-1 reference E83 step 5 Synthesis method.

Preparation of step 2:81-2 reference is made to the synthetic method of step 3, E45-1.

Step 3:81-3 preparation of reference E67-1 synthetic method step 4.

Preparation of E81 reference E67-1 Synthesis method of step 5 .δ1H NMR(500MHz,CDCl₃)δ7.48(s,1H),7.04(d,J＝7.5Hz,1H),6.91(d,J＝8.0Hz,1H),6.85(d,J＝7.0Hz,1H),6.77-6.71(m,2H),6.60(d,J＝8.0Hz,1H),4.53(t,J＝9.0Hz,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 (8 aS,12 aR) -11- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -4-methyl-6, 7,8a,9,10,11,12 a-octahydro- [1,4] diazepino [3,2,1-hi ] pyrido [4,3-b ] indol-5 (4H) -one

Preparation of step 1:82-1 reference is made to the synthetic method of step 1, E73-1.

Preparation of step 2:82-2 reference is made to the synthetic method of step 2 of E73-1.

Step 3 preparation of E82 reference E73-1 Synthesis method of step 3 ¹H NMR(500MHz,CDCl₃)δ7.03(d,J＝8.5Hz,1H),6.94-6.89(m,3H),6.76(t,J＝7.5Hz,2H),4.53(t,J＝9.0Hz,2H),3.74(t,J＝12.5Hz,1H),3.45-3.42(m,1H),3.38-3.33(m,5H),3.19(t,J＝8.5Hz,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-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 4-fluoro-2-bromoaniline (5.0 g,26.3 mmol) and 5M HCl solution (50 mL) were added together in a 250mL three-necked flask, cooled to 0℃in an ice-water bath, followed by slow dropwise addition of 20mL NaNO ₂ (2.8 g,39.4 mmol) solution, after which stirring was maintained at 0℃for 2h, followed by slow dropwise addition of SnCl ₂ (10 g,52.6 mmol) in hydrochloric acid (5.5 mL) under an ice-water bath, after which stirring was allowed overnight at room temperature. After completion of TLC detection, the reaction solution was directly filtered, and the cake was washed with a little concentrated HCl and lyophilized with water to give crude compound 83-1 (off-white solid, 4.4g, yield 82%). 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-oxopiperidone hydrochloride (1.5 g,10.7 mmol) and concentrated HCl (2 mL), respectively, and after addition, the temperature was raised to 90℃under nitrogen and stirred overnight. After completion of the LCMS detection reaction, the reaction mixture was cooled to room temperature, a large amount of solids were precipitated, filtered, and the cake was washed with isopropyl alcohol and dried under reduced pressure to give crude compound 83-2 (off-white solid, 2.0g, yield: 76%). The crude product was used directly in the next reaction 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 together in a 25mL three-necked flask followed by slow dropwise addition (Boc) of ₂ O (200 mg,0.90 mmol) under N ₂ protection and stirring at room temperature for 2h. After completion of LCMS detection, water (20 mL) was added to the reaction, DCM extracted (2×20 mL), the organic phases were combined, washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give compound 83-3 (white solid, 190mg, 69% yield) as crude product by purification on normal phase column (eluent gradient: 2% MeOH/DCM).

Step 4. Compound 83-3 (100 mg,0.27 mmol), benzophenone imine (60 mg,0.32 mmol) and t-Buona (1.23G, 12.8 mmol), t-BuXPhos-Pd-G ₃ (11 mg,0.01 mmol) and toluene (5 mL) were added together in a 35mL microwave tube, argon bubbled for 2min, followed by microwave heating to 120℃with stirring for 1h. After completion of LCMS detection, water (30 mL) was added to the reaction, EA was extracted (20 ml×2), the organic phases were combined, washed with saturated brine (30 ml×1), dried over anhydrous Na ₂SO₄, dried under reduced pressure, and the crude product was isolated by chromatography (EA/pe=0-20%) and purified to give compound 83-4 (pale yellow solid, 110mg, 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), cs ₂CO₃ (240 mg,0.63 mmol), KI (1.99 g,12.76 mmol) and anhydrous CH ₃ CN (10 mL) were added together to a 25mL single vial and refluxed overnight under N ₂. After completion of LCMS detection, the reaction was filtered, water (20 mL) was added to the filtrate, EA was extracted (30 mL x 2), the combined organic phases were washed with saturated brine (30 mL x 1), dried over anhydrous Na ₂SO₄, dried under reduced pressure, and the crude was purified by column chromatography (EA/pe=0-15%) to give compound 83-5 (yellow oil, 100mg, yield: 85%). MS m/z (ESI): 556.6[ M+H ] ⁺.

Step 6 Compound 83-5 (100 mg,0.18 mmol) was added to a 25mL single vial with THF (10 mL) followed by 2N HCl solution (3 mL) and stirred at room temperature for 2h. After completion of the LCMS reaction, saturated NaHCO ₃ solution was added to the reaction to adjust the pH of the system to basic, EA was extracted (20 ml×3), the organic phases were combined, washed with saturated brine (30 ml×1), dried over anhydrous Na ₂SO₄, dried under reduced pressure, and the crude was purified by chromatography (MeOH/dcm=0-2%) to give compound 83-6 (yellow oil, 40mg, yield ：90％).¹H NMR(500MHz,CDCl₃)δ7.85(s,1H),6.78(d,J＝8.5Hz,1H),6.33(s,1H),4.85(s,2H),4.63-4.53(m,2H),3.86-3.76(m,2H),2.76(s,2H),1.50(s,9H).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 together in a 25mL single-port bottle followed by TFA (1 mL) and the reaction stirred at room temperature for 1h. After completion of LCMS detection, the reaction solvent was removed under reduced pressure, then the crude was dissolved with 10% MeOH/DCM (20 mL), saturated NaHCO ₃ solution was added to adjust the pH of the system to basic, 10% MeOH/DCM was extracted (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous Na ₂SO₄ and spun dry under reduced pressure to give crude compound 83-7 (brown oil, 30 mg). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 246.7[ M+H ] ⁺.

Step 8 preparation of Compound 83-8 reference is made to the synthetic procedure 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) was added to a 25mL single vial with TFA (5 mL) followed by NaCN) BH ₃ (30 mg,0.50 mmol) and stirred overnight at room temperature. After completion of the reaction by LCMS, the reaction solvent was removed under reduced pressure, then EA and water were added to the crude product, EA was extracted (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous Na ₂SO₄, and spun-dried under reduced pressure, and the crude product was purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% nh ₄HCO₃) =30% -70%) to give compound E83 as a white solid, 4mg, yield :20％).¹H NMR(500MHz,CDCl₃)δ7.49(s,1H),7.07(t,J＝8.2Hz,1H),6.86(d,J＝7.4Hz,1H),6.77(t,J＝7.4Hz,1H),6.65(dd,J＝8.0,2.1Hz,1H),6.45(dd,J＝9.2,2.1Hz,1H),4.52(t,J＝9.0Hz,2H),3.90(d,J＝14.3Hz,1H),3.85-3.77(m,1H),3.59-3.53(m,1H),3.52-3.44(m,2H),3.40(d,J＝14.3Hz,1H),3.20(t,J＝8.8Hz,2H),3.06-3.00(m,3H),2.65(t,J＝7.2Hz,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 (6 bR,10 aS) -8- (3- (2, 2-dimethyl-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) one

Step 12, 2-dimethyl-2, 3-dihydrobenzofuran-7-ol (1.8 g,11 mmol) was dissolved in dichloromethane (50 mL), pyridine (1.8 mL,22.8 mmol) was added, cooled to 0deg.C, tf ₂ O (2.3 mL,13.5 mmol) was added, and the mixture was returned to room temperature and stirred for 1 hour. The reaction was washed with 1M HCl (50 mL), water (50 mL), saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated to give compound 84-1 (yellow oil, 3.1 g), the crude 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), et ₃ N (6 mL) and ethyl acrylate (2.0 g,20 mmol) were added and reacted for 18hr under the protection of Pd (dppf) ₂Cl₂(770mg,1.05mmol),N₂ under heating to 98 ℃. Triethylamine and DMF were removed by concentration, and the mixture was added to 50mL of water, extracted with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a crude product, which was purified and separated by normal phase column to give compound 84-2 (yellow oil, 760mg, yield: 31%). MS m/z (ESI): 247.3[ M+H ] ⁺

Step3 preparation of the synthetic method of step2 of reference example 1. MS m/z (ESI): 249.1[ M+H ] ⁺

Step 4. Preparation of the synthetic method of step 3 of reference example 1. MS m/z (ESI): 207.1[ M+H ] ⁺

Step 5 Compound 84-4 (40 mg,0.194 mmol) and triethylamine (78 mg,0.78 mmol) were dissolved in dichloromethane (4 mL), cooled to 0℃and methanesulfonic anhydride (67 mg,0.39 mmol) was added, stirred at room temperature for 1.5 hours, DCM (15 mL) and water (15 mL) were added and the layers were separated, the organic phase was washed with water (15 mL), dried over anhydrous sodium sulfate, concentrated to give crude product, dissolved in acetonitrile (5 mL) and then Compound 67-1-1 (30 mg,0.194 mmol) and potassium carbonate (32 mg,0.23 mmol) were added and heated to 80℃for 16hr. After the reaction, the mixture was cooled to room temperature, filtered and concentrated, and purified and separated (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) by prep-HPLC to give compound E84 (white solid, 9.0mg, yield ：10％).¹H NMR(500MHz,CD₃OD)δ6.96(d,J＝10.0Hz,1H),6.88(d,J＝10.0Hz,1H),6.82(d,J＝5.0Hz,1H),6.72-6.68(m,2H),6.64(d,J＝10.0Hz,1H),3.87(d,J＝10.0Hz,1H),3.35(d,J＝10.0Hz,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 (6 bR,10 aS) -8- (3- (2H-spiro [ benzofuran-3, 1' -cyclopropan ] -7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 methyl triphenylphosphine bromide (5.06 g,14.2 mmol) was dissolved in THF (150 mL), cooled to 0deg.C, potassium tert-butoxide (1.67 g,14.9 mmol) was added, warmed to 25deg.C and stirred for 1hr, 7-bromo-3-benzofuranone (2.0 g,9.39mmol, dissolved in 150mL THF) was added and stirred for 16hr at 25deg.C. 100mL of water was added, the mixture was extracted with ethyl acetate (150 mL _X 2), washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a crude product, which was purified and separated by a normal phase column to give Compound 85-1 (colorless oil, 1.58g, yield: 79%). MS m/z (ESI) 212.4[ M+H ] ⁺

Step 2 diethyl zinc (27 mL,27 mmol) was dissolved in DCM (150 mL), cooled to 0deg.C, TFA (2.32 mL,31.4 mmol) was added, stirred at 0deg.C for 15min, diiodomethane (8.0 g,30 mmol) was added and then stirred at 0deg.C for 15min, compound 85-1 (1.58 g,7.49mmol, dissolved in DCM (150 mL)) was added, stirred at 0deg.C for 15min, and warmed to 25deg.C and stirred for 16hr. The reaction was quenched with 2M HCl (150 mL) and then separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give crude product, which was purified by normal phase column to give compound 85-2 (colorless oil, 390mg, yield: 23%). MS m/z (ESI): 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) Cl ₂ (224 mg,0.308 mmol) under nitrogen, and the reaction was heated to 95deg.C and stirred for 18hr. The solvent was dried by spin, ethyl acetate (50 mL) was added, the filtrate was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified and separated by normal phase column to give Compound 85-3 (colorless oil, 300mg, yield: 79%). MS m/z (ESI): 245.3[ M+H ] ⁺

Step 4 Compound 85-3 (290 mg,1.18 mmol) was dissolved in ethyl acetate (30 mL), and platinum dioxide (80 mg) was added to hydrogenate at 25℃for 16 hours, followed by filtration and concentration of the filtrate to give the product (colorless oil, 220mg, yield 76%). MSm/z (ESI): 247.1[ M+H ] ⁺

Step 5 preparation of the synthetic method of step 3 of reference example 1. MS m/z (ESI): 205.3[ M+H ] ⁺

Step 6 preparation of the synthetic method of step 5 of reference example 84. Obtaining the compound E85.¹H NMR(500MHz,CD₃OD)δ6.88-6.83(m,2H),6.73-6.71(m,2H),6.65(d,J＝5.0Hz,1H),6.55(d,J＝5.0Hz,1H),4.44(s,2H),3.87(d,J＝15.0Hz,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).MS m/z(ESI):416.6[M+H]⁺.

Example 86 (6 bR,10 aS) -8- (3- (6-fluoro-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 Compound 2-bromo-3-fluorophenol (2 g,10.5 mmol), 2-bromo-1, 1-diethoxyethane (2.47 g,12.6 mmol) was dissolved in dry DMF (50 mL) under nitrogen, and then K ₂CO₃ (4.3 g,31.4 mmol) was added. The reaction was carried out at 145℃for 3h. After completion of LCMS detection reaction, 100.0mL of ice water was added for quenching, extraction with ethyl acetate (100 mL x 3), washing with saturated brine (100 mL x 3), spin-drying the organic phase and purification of crude product on silica gel column afforded 86-1 (colorless liquid, 3g, 93% yield).

Step 2 Compound 86-1 (2 g,9.77 mmol) was dissolved in toluene (30 mL) and PPA (3 mL) was added and stirred at 90℃for 3h. After cooling to room temperature, the solvent was dried by spinning, quenched with 100.0mL of ice water, extracted with ethyl acetate (100 mL x 3), washed with saturated brine (100 mL x 3), and the organic phase was dried by spinning, and the crude product was purified on a silica gel column to give 86-2 (colorless liquid, 1g, yield 47.6%).

Step 3 Synthesis method for Compound E86 preparation of Steps 1-5 of reference example 60 .¹H NMR(400MHz,CDCl₃)δ7.48(d,J＝15.5Hz,1H),6.92(dd,J＝8.0,5.5Hz,1H),6.83(d,J＝7.5Hz,1H),6.73(t,J＝7.5Hz,1H),6.58(d,J＝7.5Hz,1H),6.49(dd,J＝10.0,8.0Hz,1H),4.61-4.54(m,2H),3.94(d,J＝14.5Hz,1H),3.44-3.27(m,3H),3.15(t,J＝8.7Hz,2H),3.08-2.76(m,2H),2.60(t,J＝7.4Hz,2H),2.26(d,J＝194.5Hz,4H),2.06-1.79(m,4H).MS m/z(ESI):408.6[M+H]⁺.

Example 87 (6 bR,10 aS) -8- (3- (4-fluoro-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Preparation of step 1:87-1 reference is made to the synthetic procedure of the first step of example 3.

Step 2:87-2 preparation reference is made to the synthesis of the second step of example 3.

Preparation of step 3:87-3 reference is made to the synthetic procedure of the third step of example 3.

Preparation of step 4:87-4 reference is made to the synthetic procedure of the fourth step of example 8.

Step 5 preparation of E87 reference is made to the fifth step of the synthetic method of example 8 .¹H NMR(500MHz,CDCl₃)δ7.55(s,1H),6.89-6.80(m,2H),6.72(t,J＝7.6Hz,1H),6.57(dd,J＝7.9,0.9Hz,1H),6.48(t,J＝8.4Hz,1H),4.59(t,J＝8.7Hz,2H),3.95(d,J＝14.5Hz,1H),3.45-3.30(m,3H),3.23(t,J＝8.7Hz,2H),2.94(s,1H),2.84-2.68(m,1H),2.53(t,J＝7.6Hz,2H),2.33(d,J＝61.8Hz,3H),2.06-1.79(m,5H).MS m/z(ESI):408.6[M+H]⁺.

Example 88 (6 bR,10 aS) -8- (3- (5-fluoro-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

E88 preparation Synthesis method of reference example 60 .¹H NMR(400MHz,CDCl₃)δ7.59(s,1H),6.83(d,J＝7.5Hz,1H),6.73(t,J＝7.5Hz,2H),6.63(dd,J＝10.0,2.5Hz,1H),6.58(d,J＝7.5Hz,1H),4.54(t,J＝8.5Hz,2H),3.95(d,J＝14.5Hz,1H),3.44-3.27(m,3H),3.17(t,J＝8.6Hz,2H),2.96(s,1H),2.78(s,1H),2.60-2.47(m,2H),2.35(d,J＝60.3Hz,3H),2.04(s,1H),1.97-1.77(m,4H).MS m/z(ESI):408.6[M+H]⁺.

Example 89 (6 bR,10 aS) -8- (3- (6-chloro-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

E89 preparation Synthesis method of reference example 60 .¹H NMR(400MHz,CDCl₃)δ7.42(s,1H),6.94(d,J＝8.0Hz,1H),6.83(dd,J＝12.5,7.5Hz,2H),6.76(t,J＝7.5Hz,1H),6.60(d,J＝8.0Hz,1H),4.55(dt,J＝15.0,8.5Hz,3H),3.92(s,1H),3.40(d,J＝14.5Hz,3H),3.17(t,J＝8.7Hz,4H),2.72(d,J＝7.5Hz,3H),2.67-2.43(m,2H),2.11(d,J＝94.6Hz,2H),1.97-1.73(m,2H).MS m/z(ESI):424.6[M+H]⁺.

Example 90 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -2-carbonyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline 8-oxide

Step 1E 67-1 (10 mg,2.67 mmol) was dissolved in DCM (5 ml) and then m-CPBA (540 mg,2.67 mmol) was added, this reaction was reacted at room temperature for 2h, LCMS showed complete reaction, DCM was extracted, prep-HPLC purification isolation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) after concentration filtration gave compound E90 (5 mg, white solid, yield) ：21.1％).¹H NMR(400MHz,CDCl₃)δ8.61(s,1H),7.07-7.00(m,1H),6.89(t,J＝10.5Hz,1H),6.84(d,J＝7.5Hz,1H),6.76(dq,J＝9.5,7.5Hz,2H),6.66(d,J＝7.5Hz,1H),4.49(q,J＝9.0Hz,2H),4.05-3.98(m,1H),3.91(d,J＝14.5Hz,1H),3.41(t,J＝14.6Hz,3H),3.33-3.26(m,3H),3.18(q,J＝8.4Hz,2H),2.96-2.86(m,1H),2.73(t,J＝11.6Hz,1H),2.62(t,J＝7.3Hz,2H),2.25-2.17(m,2H),1.92(d,J＝15.0Hz,2H).MS m/z(ESI):406.6[M+H]⁺.

EXAMPLE 91 8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6-fluoro-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

E91 preparation Synthesis method of reference example 83 .¹H NMR(400MHz,CDCl₃)δ7.70(s,1H),7.04(d,J＝8.0Hz,1H),6.93(d,J＝7.5Hz,1H),6.76(t,J＝7.5Hz,1H),6.50(dd,J＝8.5,3.5Hz,1H),6.40(t,J＝8.5Hz,1H),4.54(t,J＝9.0Hz,2H),3.94(d,J＝14.5Hz,1H),3.62-3.50(m,1H),3.38(d,J＝14.5Hz,2H),3.20(t,J＝8.5Hz,2H),3.11-3.02(m,1H),2.82-2.70(m,1H),2.62-2.53(m,2H),2.47-2.33(m,2H),2.27-2.17(m,1H),2.07-1.80(m,5H).MS m/z(ESI):408.9[M+H]⁺.

Example 92 (6 bR,10 aS) -8- (3- (2, 3-dihydrofuro [3,2-c ] pyridin-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Preparation of E92 reference example 60 Synthesis method .¹H NMR(500MHz,CD₃OD)δ8.13(s,1H),8.05(d,J＝10.5Hz,1H),6.83(d,J＝6.7Hz,1H),6.70(t,J＝7.6Hz,1H),6.64(dd,J＝7.8,0.8Hz,1H),4.72-4.65(m,2H),3.87(d,J＝14.6Hz,1H),3.34(d,J＝14.5Hz,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＝7.6Hz,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]⁺.

Example 93 (6 bR,10 aS) -8- (3- (3-methoxythiophen-2-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Preparation of E93 reference example 40 preparation method .¹H NMR(500MHz,CD₃OD)δ7.09(d,J＝5.0Hz,1H),6.89-6.87(m,2H),6.75(d,J＝10.0Hz,1H),6.69(d,J＝10.0Hz,1H),3.91(d,J＝15.0Hz,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).MS m/z(ESI):384.6[M+H]⁺.

Example 94 (6 bR,10 aS) -8- (4- (2, 3-Dihydrobenzofuran-7-yl) butan-2-yl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1-3 (320 mg,1.47 mmol) were dissolved in methanol (5 mL) and saturated aqueous sodium hydroxide (2 mL) at room temperature. The reaction solution was stirred at room temperature for 12h. The reaction solution was extracted with water and ethyl acetate, the aqueous phase was adjusted to pH 3 to 4 with dilute hydrochloric acid, then extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and dried by spin-drying to give 94-1 (260 mg, yield: 94%) as a white solid.

Step 2 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) were dissolved in DMF (5 mL) at room temperature. The reaction was stirred at room temperature for 2h. The reaction solution was extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography (PE: ea=3:1) to give the title compound 94-2 (white solid, 300mg, yield 94%). MS m/z (ESI): 236.4[ M+H ] ⁺

Step 3 94-2 (250 mg,1.06 mmol) was dissolved in THF (5 mL) at-78℃under nitrogen, a tetrahydrofuran (3M) solution of methylmagnesium bromide (0.7 mL,2.13 mmol) was added dropwise thereto, and then the reaction solution was gradually warmed and stirred at room temperature for 2h. To the reaction solution was added saturated aqueous ammonium chloride (5 mL), the reaction solution was extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, and purified by column chromatography (PE: ea=3:1) to give the title compound 94-3 (white solid, 180mg, yield 90%).

Step 4 94-3 (50 mg,0.26 mmol) and sodium borohydride (30 mg,0.79 mmol) were dissolved in methanol (3 mL) at room temperature. The reaction solution was stirred at room temperature for 20min. The reaction solution was extracted with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then dried by spin to give the title compound 94-4 (colorless oil, 40mg, yield 82%).

Step 5 preparation of 94-5 esters reference is made to the fourth synthetic procedure of example 3.

Step 6 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) at room temperature and potassium carbonate (23 mg,0.17 mmol) was added. The reaction solution was stirred at 80 ℃ for 12h. The reaction solution was suction-filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile/(water+0.05% NH ₄HCO₃)) to give Compound E94 (2 mg, yield: 9%) as a white solid .¹H NMR(500MHz,CDCl₃)δ7.53(s,1H),7.07-7.01(m,1H),6.94(d,J＝7.5Hz,1H),6.87-6.81(m,1H),6.80-6.69(m,2H),6.58(d,J＝7.8Hz,1H),4.58-4.47(m,2H),3.95(dd,J＝14.5,1.7Hz,1H),3.40-3.33(m,2H),3.23-3.17(m,2H),2.87-2.57(m,5H),2.22(t,J＝7.6Hz,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 (6 bR,10 aS) -8- (3- (6-fluoro-2, 3-dihydrobenzofuran-7-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

E95 preparation method for reference example 86 .¹H NMR(500MHz,CDCl₃)δ6.95-6.89(m,1H),6.86(d,J＝7.1Hz,1H),6.80(t,J＝7.6Hz,1H),6.76-6.70(m,1H),6.49(dd,J＝10.0,8.1Hz,1H),4.58(t,J＝8.7Hz,2H),4.01(d,J＝14.2Hz,1H),3.39-3.25(m,6H),3.21-3.10(m,2H),2.93(dd,J＝11.0,6.2Hz,1H),2.75(d,J＝10.7Hz,1H),2.58(t,J＝7.5Hz,2H),2.44-2.31(m,2H),2.21(t,J＝10.3Hz,1H),2.05-1.90(m,2H),1.79(dd,J＝15.5,7.3Hz,3H).MS m/z(ESI):422.7[M+H]⁺.

Example 96 (6 bR,10 aS) -8- (2- ((2, 3-Dihydrobenzofuran-7-yl) oxo) ethyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step1 73-1-2 (10 mg,0.041 mmol) was dissolved in DMF (2 mL) and 7- (2-bromoethoxy) -2, 3-dihydrobenzofuran (10 mg,0.041 mmol), sodium iodide (13 mg,0.082 mmol) and DIEA (16 mg,0.12 mmol) were added at room temperature. The reaction solution was stirred at 80 ℃ for 2 hours. The reaction solution was cooled to room temperature and concentrated in vacuo to give crude product. The crude product was concentrated and filtered and purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give compound E96 (4.7 mg, 28% yield) as a white solid .¹H NMR(500MHz,CDCl₃)δ6.89-6.72(m,6H),4.62(q,J＝8.9Hz,3H),4.38-4.33(m,1H),4.18(t,J＝6.0Hz,2H),4.02(d,J＝14.3Hz,1H),3.68-3.60(m,1H),3.36(d,J＝30.0Hz,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 (6 bR,10 aS) -8- (3- (2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) propyl) -3- (methyl-d ₃) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 Compounds 45-1-4 (120 mg,0.40 mmol) and anhydrous THF (5 mL) were added together in a 25mL three-port reaction flask followed by NaH (30mg,0.80mmol,60%in oil), and then stirred at room temperature under nitrogen atmosphere for 0.5h after addition, followed by CD ₃ I (170 mg,1.20 mmol) and stirred at room temperature for 3h after addition. After completion of the reaction by LCMS, water (30 mL) was added to the reaction mixture, etOAc extraction (20 ml×2), the organic phases were combined, washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, and spun-dried under reduced pressure to give crude compound 97-2 (pale yellow oil, 120mg, yield: 95%). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 319.5[ M+H ] ⁺.

Preparation of step 2:97-3 reference is made to the synthetic procedure of step 5 in example 45-1. MS m/z (ESI): 247.6[ M+H ] ⁺.

Step 3 preparation of E97 reference is made to the synthetic method of example E60 step 5 .¹H NMR(500MHz,CD₃OD)δ7.83(d,J＝4.9Hz,1H),7.09(d,J＝4.9Hz,1H),6.81(d,J＝7.2Hz,1H),6.77(dd,J＝7.9,0.9Hz,1H),6.75-6.70(m,1H),4.51(t,J＝8.9Hz,2H),3.88(d,J＝14.4Hz,1H),3.28(d,J＝14.3Hz,1H),3.25-3.21(m,2H),3.20-3.15(m,2H),2.97-2.87(m,1H),2.75(d,J＝9.5Hz,1H),2.65(t,J＝7.6Hz,2H),2.42-2.30(m,2H),2.28-2.18(m,1H),1.99-1.81(m,4H),1.78-1.68(m,1H).MS m/z(ESI):409.0[M+H]⁺.

Example 98 (6 bR,10 aS) -8- (3- (3-methoxypyridin-2-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

E98 preparation Synthesis method of reference example 16 .¹H NMR(400MHz,CDCl₃)δ7.42(s,1H),6.94(d,J＝8.0Hz,1H),6.83(dd,J＝12.5,7.5Hz,2H),6.76(t,J＝7.5Hz,1H),6.60(d,J＝8.0Hz,1H),4.55(dt,J＝15.0,8.5Hz,3H),3.92(s,1H),3.40(d,J＝14.5Hz,3H),3.17(t,J＝8.7Hz,4H),2.72(d,J＝7.5Hz,3H),2.67-2.43(m,2H),2.11(d,J＝94.6Hz,2H),1.97-1.73(m,2H).MS m/z(ESI):393.6[M+H]⁺.

Example 99 (6 bR,10 aS) -8- (3- (2-methoxyphenyl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of Synthesis method of reference example 3 .¹H NMR(500MHz,CD₃OD)δ7.23-7.15(m,2H),7.00-6.87(m,5H),4.05(d,J＝15.0Hz,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＝7.5Hz,2H),2.50(t,J＝10.0Hz,1H),2.33-2.16(m,2H),2.06-2.00(m,2H).MS m/z(ESI):393.9[M+H]⁺.

Example 100 (6 bR,10 aS) -8- (3- (3-methoxypyridin-2-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

E100 preparation Synthesis method of reference example 16 .¹H NMR(400MHz,CDCl₃)δ8.09(dd,J＝4.1,1.9Hz,1H),7.55(s,1H),7.11-7.08(m,2H),6.81(dd,J＝12.9,4.8Hz,1H),6.73(t,J＝7.6Hz,1H),6.58(d,J＝7.8Hz,1H),3.93(t,J＝14.6Hz,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＝12.1Hz,4H).MS m/z(ESI):379.6[M+H]⁺.

Example 101 (6 bR,10 aS) -8- (3- (3-methoxythiophen-2-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of Synthesis method of reference example 3 .¹H NMR(500MHz,CD₃OD)δ6.88(d,J＝5.0Hz,1H),6.82-6.71(m,4H),3.88(d,J＝15.0Hz,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＝7.5Hz,2H),2.41-2.23(m,3H),2.01-1.71(m,5H).MS m/z(ESI):399.0[M+H]⁺.

Example 102 (6 bR,10 aS) -8- (3- (2, 3-dihydrofuro [3,2-c ] pyridin-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of E102 reference example E60 Synthesis method .¹H NMR(500MHz,CD₃OD)δ8.13(s,1H),8.05(d,J＝10.5Hz,1H),6.83(d,J＝6.7Hz,1H),6.70(t,J＝7.6Hz,1H),6.64(dd,J＝7.8,0.8Hz,1H),4.72-4.65(m,2H),3.87(d,J＝14.6Hz,1H),3.34(d,J＝14.5Hz,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＝7.6Hz,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-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Synthesis method for preparing reference example 83 .¹H NMR(500MHz,CD₃OD)δ6.83-6.80(m,1H),6.73(d,J＝10.0Hz,1H),6.61(t,J＝10.0Hz,1H),6.54(d,J＝5.0Hz,1H),6.38(t,J＝7.5Hz,1H),4.49(t,J＝7.5Hz,2H),3.77(d,J＝15.0Hz,1H),3.26-3.23(m,3H),3.12(t,J＝7.5Hz,2H),2.85-2.82(m,1H),2.70-2.68(m,1H),2.43(t,J＝7.5Hz,2H),2.30-2.15(m,3H),1.95-1.68(m,5H).MS m/z(ESI):408.9[M+H]⁺.

Example 104 (5 bR,9 aS) -7- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -5b,6,7,8,9 a-hexahydroimidazo [4,5,1-hi ] pyrido [4,3-b ] indol-1 (2H) -one

Preparation of step 1:104-1 reference E45-1 Synthesis method of step 3 MS m/z (ESI): 262.2[ M+H ] ⁺.

Preparation of step 2:104-2 reference is made to the synthetic method of step 5, E45-1. MS m/z (ESI): 190.3[ M+H ] ⁺.

Preparation of step 3:104-3 reference E67-1 the synthetic method of step 2. MS m/z (ESI): 350.2[ M+H ] ⁺

Step 4-104-3 (140 mg,0.4 mmol), DMAP (38 mg,0.4 mmol) and pyridine (2 mL) were added to a 25mL three-necked flask, replaced three times with N ₂, cooled to 0℃and methyl chloroformate (38 mg,0.4 mmol) was added and reacted at 0℃for 1h, water and DCM were added, the aqueous phase was separated, extracted once with DCM, the organic phases were combined, washed three times with saturated sodium chloride, dried and concentrated over column (DCM/MeOH=20/1) to give 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 25mL three-necked flask, N ₂ was replaced three times, 1M LiHMDS (0.9 mL,0.9 mmol) was reacted at 75℃for 1h, water and EA were added, the aqueous phase was extracted once with EA, the organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated to prep-HPLC purification isolate (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to afford E104 (13 mg, yellow solid, yield: 15.7%).

¹H NMR(500MHz,CDCl₃)δ8.13(s,1H),7.04(d,J＝8.2Hz,1H),6.97–6.84(m,3H),6.82-6.73(m,2H),4.64(q,J＝5.2Hz,1H),4.54(t,J＝8.5Hz,2H),3.92(q,J＝6.5Hz,1H),3.20(t,J＝8.5Hz,2H),2.98(dd,J＝11.9,5.8Hz,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 (6 bR,10 aS) -8- (2- ((2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) oxy) ethyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 the 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 together in a 25mL single port reaction flask followed by Ag ₂CO₃ (730 mg,2.6 mmol) and NaI (330 mg,2.6 mmol), respectively, with nitrogen substitution 3 times, and stirred at 115℃for 48H. After completion of LCMS detection, the reaction mixture was filtered, the filtrate was dried under reduced pressure, and the crude product was purified by normal phase column (eluent gradient: 5% MeOH/DCM) to give compound 105-2 (pale yellow oil, 60mg, yield) 42％).¹H NMR(500MHz,CD₃OD)δ7.93(d,J＝2.1Hz,1H),7.86(d,J＝5.5Hz,1H),7.26(d,J＝5.5Hz,1H),6.92(d,J＝2.1Hz,1H),4.57(dd,J＝5.4,4.3Hz,2H),4.01-3.95(m,2H).MS m/z(ESI):180.4[M+H]⁺

Preparation of step 2:105-3 reference example E60 Synthesis method of step 2. MS m/z (ESI) 182.4[ M+H ] ⁺.

Preparation of step 3:105-4 reference example E60 Synthesis method of step 3. MS m/z (ESI) 180.6[ M+H ] ⁺.

Step 4 preparation of E105 reference example E60 Synthesis method of step 4 .¹H NMR(500MHz,CD₃OD)δ7.62(d,J＝5.0Hz,1H),6.95-6.91(m,2H),6.90(d,J＝7.1Hz,1H),6.86-6.83(m,1H),4.62(t,J＝9.3Hz,2H),4.51(t,J＝5.7Hz,2H),4.01(d,J＝14.4Hz,1H),3.42-3.36(m,3H),3.37-3.34(m,3H),3.26(t,J＝9.0Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-4-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of step 1:106-1 reference example E8 fourth step synthesis method.

Step 2 preparation of E106 reference example E8 Synthesis method in the fifth step .¹H NMR(500MHz,CDCl₃)δ7.53(s,1H),7.04(t,J＝7.8Hz,1H),6.87-6.80(m,1H),6.74(t,J＝7.6Hz,1H),6.65(dd,J＝7.7,6.0Hz,2H),6.59(d,J＝7.7Hz,1H),4.56(t,J＝8.7Hz,2H),3.95(d,J＝14.5Hz,1H),3.56-3.29(m,3H),3.15(t,J＝8.6Hz,2H),3.01(s,1H),2.81(d,J＝29.9Hz,1H),2.66-2.26(m,5H),2.17-1.82(m,5H).MS m/z(ESI):390.9[M+H]⁺.

Example 107 (6 bR,10 aS) -8- (3- (5-hydroxy-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1-5 the synthetic method of step 1-5 of reference example 86 was prepared.

Preparation of step 6:107-6 reference is made to the sixth step of the synthetic method of example 13

Preparation of step 7:107-7 reference is made to the sixth step of the synthetic method of example 7

Step 8-Compound 107-7 (30 mg,0.07 mmol), anhydrous dichloromethane (3 mL) were added together in a 25mL three port flask, BBr ₃ (2.1 mL,2.1 mmol) was added at-78℃and the addition was completed, slowly raised to-10℃and the reaction was continued with stirring at this temperature for 3h. After completion of LCMS detection reaction, ammonia (1 mL) was added to the reaction solution, and prep-HPLC purification and separation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) gave compound E107 (5 mg, white solid, yield: 16.9%) after concentration and filtration.

¹H NMR(400MHz,CDCl₃)δ7.49(d,J＝16.3Hz,1H),6.83(d,J＝7.3Hz,1H),6.74(t,J＝7.6Hz,1H),6.58(dd,J＝12.8,4.9Hz,2H),6.43(d,J＝2.4Hz,1H),4.49(t,J＝8.6Hz,2H),3.94(d,J＝14.5Hz,1H),3.50(s,1H),3.42-3.31(m,2H),3.13(dd,J＝19.9,11.2Hz,2H),3.07(s,1H),2.90(d,J＝12.4Hz,2H),2.50(dd,J＝33.2,25.7Hz,5H),2.18(s,1H),1.98(dd,J＝31.1,16.2Hz,4H).MS m/z(ESI):406.8[M+H]⁺.

Example 108 (6 bR,10 aS) -8- (3- (6-hydroxy-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one hydrochloride

Preparation of Synthesis method of reference example 107 .¹H NMR(500MHz,DMSO-d₆)δ10.61(s,1H),10.50(s,1H),9.33(s,1H),6.86(d,J＝7.2Hz,1H),6.82(d,J＝7.9Hz,1H),6.70(d,J＝7.5Hz,1H),6.66(d,J＝7.8Hz,1H),6.32(d,J＝8.0Hz,1H),5.33(t,J＝5.1Hz,1H),4.47(t,J＝8.5Hz,2H),3.90(d,J＝14.5Hz,2H),3.04(t,J＝8.5Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1, 1-dimethyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 Compound 45-1-4 (300 mg,1.0 mmol) was dissolved in DMF (10 mL), cooled to 0deg.C with an ice-water bath, sodium hydrogen (120 mg,3.0 mmol) was added, stirred at 0deg.C for 30min, then p-methoxybenzyl chloride (310 mg,2.0 mmol) was added, and stirred at room temperature for 16 h. After completion of the reaction by LCMS, water (20 mL) was added to the reaction mixture, etOAc extraction (2×25 mL), the organic phases were combined, washed with saturated brine (1×25 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure, and the crude product was slurried with methyl tert-butyl ether to give compound 109-1 (white solid, 185mg, 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 ℃, liHMDS (1.45 mL,1.45 mmol) was added, stirred at-78 ℃ for 1 hour, then methyl iodide (200 mg,1.42 mmol) was added, and the mixture was warmed to room temperature and stirred for 18 hours. After completion of the LCMS reaction, water (15 mL) was added to the reaction mixture, etOAc extraction (2X 25 mL), the organic phases were combined, washed with saturated brine (1X 25 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure, and the crude product was isolated by normal phase column purification (eluent gradient: 0 to 50% EtOAc/Petroleum ether) to give compound 109-2 (yellow oil, 130mg, yield 83%). MS m/z (ESI): 437.0[ M+H ] ⁺

Step 3 Compound 109-2 (240 mg,0.55 mmol) was dissolved in THF (5 mL), cooled to-78 ℃, n-BuLi (1 mL,1.6 mmol) was added, stirred at-78 ℃ for 1h, then methyl iodide (235 mg,1.6 mmol) was added, and the mixture was warmed to room temperature and stirred for 16h. After completion of the LCMS reaction, water (15 mL) was added to the reaction mixture, etOAc extraction (2X 25 mL), the organic phases were combined, washed with saturated brine (1X 25 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give compound 109-3 (yellow oil, 66mg, 26% yield) as a crude product by purification on a normal phase column (eluent gradient: 0 to 50% EtOAc/Petroleum ether). MS m/z (ESI) 450.5[ M+H ] ⁺

Step 4 Compound 109-3 (66 mg,0.15 mmol) was dissolved in TFA (205 uL), tfOH (90 mg,0.6 mmol) was added and stirred at room temperature for 3h. After completion of LCMS detection reaction, the reaction was diluted with DCM (20 mL), washed with saturated aqueous sodium bicarbonate (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, dried by spin-drying under reduced pressure, and HBr acetic acid solution (1.5 mL) was added, heated to 50 ℃ and stirred for 3h for concentration, and the crude product was purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% nh ₄ HCO 3) =30% -70%) to give compound 109-4 (colorless oil, 18mg, yield 46%). MS m/z (ESI): 258.4[ M+H ] ⁺

Step 5 preparation of the Synthesis method of step 5 of reference example 8 .¹H NMR(500MHz,CD₃OD)δ6.94(d,J＝5.0Hz,1H),6.79(d,J＝5.0Hz,1H),6.70(d,J＝10.0Hz,1H),6.65-6.59(m,2H),6.51(d,J＝5.0Hz,1H),4.40(t,J＝7.5Hz,2H),3.84(d,J＝10.0Hz,1H),3.31-3.26(m,1H),3.07(d,J＝10.0Hz,2H),2.89(d,J＝10.0Hz,1H),2.78(d,J＝10.0Hz,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).MS m/z(ESI):418.8[M+H]⁺.

Example 110 (6 bR,10 aS) -8- (3- (2, 3-dihydrofuro [3,2-b ] pyridin-7-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 Ethyl (E) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) acrylate (1.47 g,6.5 mmol) as a compound 7-chlorofuro [3,2-B ] pyridine (500 mg,3.3 mmol), pd (dtbpf) Cl ₂(425mg,0.65mmol),K₂CO₃ (1.4 g,9.8 mmol) was added to a three-necked flask containing dioxane (6 mL) and water (1 mL), nitrogen was replaced three times, reacted at 110℃for 16h, after completion of LCMS detection, water and EA were added, the aqueous phase was separated, extracted twice with EA, the organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated by filtration to give 110-1 (colorless oil, 600mg, yield 84%).

Step 2 preparation of 110-2 reference is made to the second step of the synthetic method of example 1.

Step 3 preparation of 110-3 reference is made to the synthetic method of the third step of example 1.

Preparation of step 4:110-4 reference is made to the fourth step of the synthetic method of example 3.

Step 5 preparation of E110 reference example 3 Synthesis method in the fifth step .¹H NMR(500MHz,CDCl₃)δ7.93(d,J＝5.0Hz,1H),6.88-6.79(m,3H),6.77-6.72(m,1H),4.63(t,J＝8.9Hz,2H),4.01(d,J＝14.2Hz,1H),3.40-3.28(m,8H),2.92(s,1H),2.73(s,1H),2.57(t,J＝7.6Hz,2H),2.36(s,2H),2.11-1.73(m,6H).MS m/z(ESI):405.8[M+H]⁺.

EXAMPLE 111 (6 bR,10 aS) -8- (3- (2, 3-dihydrofuro [3,2-b ] pyridin-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Synthesis method for preparing reference example 110 .¹H NMR(500MHz,CDCl₃)δ7.94(d,J＝5.0Hz,1H),7.59(s,1H),6.86-6.81(m,2H),6.74(t,J＝7.6Hz,1H),6.59(d,J＝7.7Hz,1H),4.63(t,J＝8.9Hz,2H),3.95(d,J＝14.5Hz,1H),3.46-3.26(m,5H),2.96(s,1H),2.79(s,1H),2.58(t,J＝7.6Hz,2H),2.42(s,2H),2.14-1.81(m,6H).MS m/z(ESI):391.9[M+H]⁺.

Example 112 (6 bR,10 aS) -8- (3- (4-hydroxy-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of Synthesis method of reference example 107 .¹H NMR(500MHz,CDCl₃)δ7.47(d,J＝4.2Hz,1H),6.83(d,J＝7.4Hz,1H),6.75(t,J＝7.9Hz,2H),6.60(d,J＝7.8Hz,1H),6.22(d,J＝8.1Hz,1H),4.57(t,J＝8.7Hz,2H),3.93(d,J＝14.5Hz,1H),3.58(s,1H),3.40(d,J＝14.5Hz,2H),3.14(t,J＝8.7Hz,4H),2.52(t,J＝7.4Hz,5H),2.15-1.84(m,5H).MS m/z(ESI):406.8[M+H]⁺

Example 114 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one-1, 1-d ₂

Step 1 deuterated acetyl chloride (1.4 g,17.2 mmol), thionyl chloride (5 mL), NCS (3.5 g,25.7 mmol) were added together in a 25mL single-port bottle followed by 2 drops of deuterated hydrochloric acid (35% wt in D ₂ O) and after the drops were added, the temperature was slowly raised to 85℃under nitrogen atmosphere and stirred for 4h. Subsequently, the reaction mixture was cooled to 0℃and absolute ethanol (4 mL) was slowly added dropwise, and stirring was continued for 0.5h at 0 ℃. After completion of the reaction, water (20 mL) was added to the reaction mixture, n-heptane was extracted (20 ml×3), and the organic phases were combined, washed with saturated NaHCO ₃ (20 ml×1) and saturated brine (50 ml×1), dried over anhydrous sodium sulfate, and n-heptane was removed under reduced pressure to give compound 114-1 (yellow oil, 600mg, yield 28%), and the crude product was used for the next reaction without further purification.

Step 2 preparation of Compound 114-2 reference example 45-1, synthetic method of step 2. MS m/z (ESI): 514.8[ M+H ] ⁺.

Step 3 preparation of Compound 114-3 reference example 45-1, synthetic method of step 3. MS m/z (ESI) 304.4[ M+H ] ⁺.

Step 4 preparation of Compound 114-4 reference example 45-1, synthetic method of step 5. MS m/z (ESI) 232.5[ M+H ] ⁺.

Step 5 preparation of Compound E114 Synthesis method of reference example E60 at step 5 .¹H NMR(500MHz,CDCl₃)δ7.55(s,1H),7.04(dd,J＝7.3,0.9Hz,1H),6.92(d,J＝7.5Hz,1H),6.83(d,J＝7.3Hz,1H),6.74(dt,J＝19.5,7.5Hz,2H),6.57(d,J＝7.6Hz,1H),4.53(t,J＝8.7Hz,2H),3.45-3.31(m,2H),3.20(t,J＝8.7Hz,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 bR,10 aS) -8- (3- (2, 3-Dihydrothieno [3,4-b ] furan-6-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 methyl 4-bromo-3-hydroxythiophene-2-carboxylate (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 together to a 250mL three-necked flask and stirred at 80℃for 16h. After completion of TLC detection, water (80 mL) was added to the reaction solution, extracted with ethyl acetate (80 ml×3), washed with brine (50 ml×3), and the organic phase was concentrated and purified by normal phase column chromatography (petroleum ether: ethyl acetate=5:1) to give 116-1 (white solid, 6.2g, yield 85%).

Step 2 116-1 (3.5 g,10.17 mmol) and anhydrous THF (35 mL) were added together in a 250mL three-necked flask, cooled to-78℃and then slowly added dropwise with n-BuLi (2.5M in Hexanes,4.5mL,11.19mmol), and the mixture was stirred for 2h at-78 ℃. After completion of LCMS detection, saturated aqueous ammonium chloride (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 give 116-2 (white solid, 400mg, yield 21%). MS m/z (ESI): 185.2[ M+H ] ⁺ _.

Preparation of step 3:116-3 reference is made to the synthetic method of the third step of example 1.

Preparation of step 4:116-4 reference is made to the fourth step of the synthetic method of example 8.

Preparation of step 5:116-5 reference is made to the synthetic procedure of the first step of example 1.

Preparation of step 6:116-6 reference is made to the second step of the synthetic procedure of example 1.

Preparation of step 7:116-7 reference is made to the synthetic method of the third step of example 1.

Preparation of step 8:116-8 reference is made to the fourth step of the synthetic method of example 8.

Step 9 preparation of E116 reference example 8 Synthesis method in the fifth step .¹H NMR(500MHz,CDCl₃)δ6.89-6.85(m,1H),6.82(t,J＝7.6Hz,1H),6.75(dd,J＝7.9,1.1Hz,1H),6.52(t,J＝1.5Hz,1H),4.82(t,J＝7.9Hz,2H),4.01(d,J＝14.2Hz,1H),3.46(d,J＝9.0Hz,1H),3.38(d,J＝14.3Hz,1H),3.33(s,3H),3.31(s,1H),3.01(s,1H),2.94(td,J＝7.9,1.5Hz,2H),2.85(s,1H),2.63(t,J＝7.3Hz,2H),2.47(s,2H),2.32(s,1H),2.10(s,1H),1.91(d,J＝36.5Hz,4H).MS m/z(ESI):410.8[M+H]⁺.

EXAMPLE 117 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-1, 2 (3H) -dione

Step 1 45-1-4 (60 mg,0.2 mmol), naIO ₄(120mg,0.56mmol),RuO₂ (15 mg,0.11 mmol) and CCl ₄ (5 mL) were added together in a 50mL single-necked flask and stirred at room temperature for 80h. After completion of LCMS detection reaction, water and EA were added, the solution was separated, the aqueous phase was extracted twice with EA, the organic phases were combined, washed three times with saturated sodium chloride, and dried over anhydrous sodium sulfate to give 117-1 (grey solid, 40mg, yield 63%). The crude product was used directly in the next reaction without further purification. MS m/z (ESI): 316.5[ M+H ] ⁺.

Step 2 preparation of E117-2 reference example 45-1 the fifth step of the synthesis method.

Step 3 preparation of E117 reference example 8 Synthesis method in the fifth step .¹H NMR(500MHz,CDCl₃)δ10.05(s,1H),7.16(t,J＝7.7Hz,1H),7.10(dt,J＝7.5,1.1Hz,1H),7.06-7.01(m,2H),6.88(d,J＝7.5Hz,1H),6.76(t,J＝7.4Hz,1H),4.88(td,J＝8.2,6.2Hz,1H),4.55(t,J＝8.7Hz,2H),3.71(s,1H),3.21(t,J＝8.7Hz,2H),3.15(d,J＝12.4Hz,1H),2.72-2.60(m,2H),2.59-2.35(m,5H),2.24(dd,J＝20.1,12.5Hz,1H),1.98(s,1H),1.85-1.75(m,2H).MS m/z(ESI):404.9[M+H]⁺.

EXAMPLE 118 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 Ethyl (4 aS,9 bR) -6-bromo-1, 3, 4a,5,9 b-hexahydro-2H-pyrido [4,3-b ] indole-2-carboxylate (320 mg,1.0 mmol) was dissolved in dioxane (5 mL), 2-bromopropionamide (228 mg,1.5 mmol), KI (165 mg,1.0 mmol), DIEA (260 mg,2.0 mmol) was added sequentially, and the mixture was heated to 105℃and stirred for 16H. The reaction solution was cooled to room temperature, etOAc (50 mL) was added, the mixture was dried under reduced pressure, and the crude product was isolated by normal phase column purification (eluent gradient: 20 to 100% EtOAc/Petroleum ether) to give compound 118-1 (colorless oil, 180mg, 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), K ₂CO₃ (112 mg,0.82 mmol), N, N-dimethylethylenediamine (24 uL,0.22 mmol) was added sequentially, nitrogen was added and the mixture was heated to 110℃and stirred for 18h. The reaction solution was cooled to room temperature, filtered and dried under reduced pressure, and the crude product was purified and separated by normal phase column (eluent gradient: 20-100% EtOAc/Petroleum ether) to give compound 118-2 (yellow oil, 86mg, 73% yield). 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 50deg.C and stirred for 3h to concentrate to give Compound 118-3 (yellow oil, 80mg, crude). MS m/z (ESI): 244.4[ M+H ] ⁺

Step 4 preparation of the Synthesis method of step 5 of reference example 8 .¹H NMR(500MHz,CD₃OD)δ7.14-7.10(m,1H),6.90-6.70(m,5H),4.58(t,J＝7.5Hz,2H),3.60-3.55(m,3H),3.27(t,J＝7.5Hz,2H),3.11-2.98(m,2H),2.65-2.14(m,7H),2.05-1.91(m,3H),1.65(d,J＝7.5Hz,3H).MS m/z(ESI):404.8[M+H]⁺.

Example 119 (6 bR,10 aS) -8- (2- ((2, 3-dihydrofuro [2,3-c ] pyridin-7-yl) oxy) ethyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of E119 reference example E105 Synthesis method .¹H NMR(500MHz,CD₃OD)δ7.77(d,J＝5.0Hz,1H),7.07(d,J＝5.0Hz,1H),7.00(d,J＝7.3Hz,1H),6.88(t,J＝7.6Hz,1H),6.81(d,J＝7.2Hz,1H),4.76(t,J＝8.9Hz,2H),4.65(t,J＝5.7Hz,2H),4.05(d,J＝14.6Hz,1H),3.53-3.48(m,3H),3.43-3.37(m,2H),3.23(dd,J＝11.8,6.2Hz,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 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-4-yl) propyl) -3-methyl-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of Synthesis method of reference example 106 .¹H NMR(500MHz,CDCl₃)δ7.04(t,J＝7.8Hz,1H),6.86(dd,J＝7.3,1.1Hz,1H),6.81(t,J＝7.6Hz,1H),6.75(dd,J＝7.9,1.1Hz,1H),6.65(dd,J＝9.2,7.8Hz,2H),4.56(t,J＝8.7Hz,2H),4.01(d,J＝14.2Hz,1H),3.38(d,J＝14.3Hz,2H),3.33(s,4H),3.14(t,J＝8.7Hz,2H),2.98(s,1H),2.80(s,1H),2.61-2.53(m,2H),2.42(d,J＝16.7Hz,2H),2.26(d,J＝21.4Hz,1H),2.03-1.93(m,2H),1.86(q,J＝8.5,7.3Hz,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 ] quinoxalin-2 (3H) -one

Preparation of E121 reference example E67-1 Synthesis method of step 2 .¹H NMR(500MHz,CDCl₃)δ7.80(s,1H),7.07(t,J＝7.8Hz,2H),6.99-6.90(m,2H),6.79(t,J＝7.4Hz,1H),6.49(d,J＝7.3Hz,1H),4.83(s,2H),4.56(t,J＝8.7Hz,2H),3.72(s,2H),3.22(t,J＝8.7Hz,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 (6 bR,10 aS) -8- (2- (benzofuran-7-yl) ethyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1. The compound benzofuran-7-carbaldehyde (1.0 g,6.85 mmol), methyltriphenylphosphine bromide (3.0 g,8.22 mmol) and anhydrous THF (20 mL) were added together in a 100mL three-necked flask, and anhydrous t-BuOK (1.15 g,10.28 mmol) was added in portions under N ₂ atmosphere, i.e., ice-water bath, and after addition, allowed to stir overnight at room temperature. After completion of the TLC detection, saturated aqueous NH ₄ Cl (50 mL), extraction with ethyl acetate (50 mL. Times.2) and washing with saturated brine (50 mL. Times.1), drying over anhydrous sodium sulfate, spin-drying under reduced pressure were added to the reaction mixture, and the crude product was purified by column chromatography (EtOAc/PE=0-5%) to give 122-1 (0.70 g, yield: 71%) as a pale yellow oil.

Step2 Compound 122-1 (700 mg,4.86 mmol) and anhydrous THF (15 mL) were added together in a 100mL three-necked flask, and 2M B ₂H₆/dimethyl sulfide solution (4 mL) was slowly added dropwise under N ₂ and ice-water bath, and after the dropwise addition, the mixture was allowed to stir at room temperature for 5h. Subsequently, 10% aqueous NaOH (5 mL) and 30% H ₂O₂ (0.5 mL) were slowly added dropwise, respectively, under an ice-water bath, and after the addition, the mixture was allowed to stir at room temperature overnight. After completion of TLC detection, water (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL. Times.1), dried over anhydrous sodium sulfate, dried under reduced pressure, and the crude product was purified by column chromatography (EtOAc/PE=0-10%) to give compound 122-2 (light yellow oil, 400mg, yield) :50％).¹H NMR(500MHz,CDCl₃)δ7.62(d,J＝2.2Hz,1H),7.48(dd,J＝7.5,1.3Hz,1H),7.17(dt,J＝14.2,6.9Hz,2H),6.77(d,J＝2.2Hz,1H),3.99(t,J＝6.5Hz,2H),3.18(t,J＝6.5Hz,2H).

Step 3. 122-2 (100 mg,0.62 mmol) was added to a 50mL single-port flask with anhydrous DCM (10 mL) at room temperature, followed by the addition of the dessmartin reagent (0.32 g,0.74 mmol) and stirring at room temperature for 1 hour. After completion of the TLC detection, the reaction solution was filtered, and the filtrate was slowly added dropwise with a saturated NaHCO ₃ solution to adjust the pH of the system to alkaline, DCM was extracted (20 mL. Times.2), the organic phases were combined, washed with a saturated brine (20 mL. Times.1), dried over anhydrous sodium sulfate, and dried under reduced pressure to give crude compound 112-3 (90 mg, yield: 90%). The crude product was used in the next reaction without further purification.

Step 4 preparation of Compound E122 Synthesis method of reference example E60 at step 5 .¹H NMR(500MHz,CDCl₃)δ7.68(s,1H),7.60(d,J＝2.2Hz,1H),7.48-7.44(m,1H),7.16(t,J＝7.5Hz,1H),7.12(d,J＝6.7Hz,1H),6.88(d,J＝7.4Hz,1H),6.78-6.73(m,2H),6.61(d,J＝7.7Hz,1H),3.97(d,J＝14.5Hz,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 (6 bR,10 aS) -8- (2- (benzofuran-7-yl) ethyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline

Preparation of E123 reference example E122 Synthesis method .¹H NMR(500MHz,CDCl3)δ7.60(d,J＝2.2Hz,1H),7.45(dd,J＝7.6,1.2Hz,1H),7.16(t,J＝7.5Hz,1H),7.11(d,J＝6.6Hz,1H),6.75(d,J＝2.2Hz,1H),6.68(t,J＝7.6Hz,1H),6.56(d,J＝6.8Hz,1H),6.43(d,J＝7.6Hz,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 (6 bR,10 aS) -8- (3- (benzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of step 1:124-1 reference example E8 fourth step synthesis method.

Step 2 preparation of E124 reference example E8 Synthesis method in the fifth step .¹H NMR(500MHz,CDCl₃)δ7.61(d,J＝2.1Hz,1H),7.52(s,1H),7.44(dd,J＝7.8,1.3Hz,1H),7.15(t,J＝7.5Hz,1H),7.09(dd,J＝7.3,1.4Hz,1H),6.83(dd,J＝7.5,0.9Hz,1H),6.76(d,J＝2.2Hz,1H),6.72(t,J＝7.6Hz,1H),6.57(dd,J＝7.8,0.9Hz,1H),3.95(d,J＝14.6Hz,1H),3.45-3.27(m,3H),2.93(t,J＝7.7Hz,3H),2.79(d,J＝7.7Hz,1H),2.45(s,2H),2.25(d,J＝15.2Hz,1H),2.03-1.83(m,5H).MS m/z(ESI):388.7[M+H]⁺.

Example 125 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxaline-2 (3H) -thione

Compound E67-1 (40 mg,0.103 mmol) was dissolved in THF (3 mL), lawsonia reagent (62 mg,0.15 mmol) was added, the reaction stirred at 70℃for 1 hour, concentrated in vacuo, then partitioned with ethyl acetate (25 mL) and water (25 mL), and the organic phase was water washed and concentrated to give crude product. The crude product is concentrated, filtered, purified by prep-HPLC and separated (eluent (v/v): acetonitrile/(water+0.05% NH4HCO 3) =30% -70%) to give compound E125 (7.8 mg, white solid, yield 18％).1H NMR(500MHz,CD3OD)δ6.91(d,J＝5.0Hz,1H),6.81-6.78(m,2H),6.65-6.60(m,3H),4.40(t,J＝10.0Hz,2H),4.23(t,J＝15.0Hz,1H),3.46(t,J＝15.0Hz,1H),3.19(s,2H),3.07(t,J＝10.0Hz,2H),2.88-2.84(m,1H),2.72-2.70(m,1H),2.45(t,J＝10.0Hz,2H),2.34-2.12(m,3H),1.96-1.69(m,5H).MS m/z(ESI):406.9[M+H]+.

EXAMPLE 126 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -2,3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline

Preparation of E126 reference example E45-1 Synthesis method .¹H NMR(500MHz,CDCl₃)δ7.03(d,J＝7.0Hz 1H),6.93(d,J＝7.5Hz 1H),6.76(t,J＝7.5Hz,1H),6.58(t,J＝7.5Hz 1H),6.54(d,J＝7.0Hz,1H),6.38(d,J＝7.5Hz 1H),4.53(t,J＝8.5Hz,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,1H),2.74-2.72(m,1H),2.68-2.63(m,1H),2.59-2.56(m,2H),2.47-2.29(m,3H),2.05-1.83(m,6H).MS m/z(ESI):376.6.[M+H]⁺.

EXAMPLE 127- ((6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) propyl) -1,2,6b,7,8,9,10 a-octahydro-3H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-3-yl) ethan-1-ol

Step 1 Compound 66-1 (50 mg,0.16 mmol) was dissolved in CH ₃ CN (5 mL), bromoethanol (98 mg,0.8 mmol) was added sequentially, cesium carbonate (204 mg,0.63 mmol) was heated to 80℃and stirred for 16h. The reaction solution was cooled to room temperature, filtered, and the crude product was purified and separated by reverse phase column C18 to give compound 127-1 (colorless oil, 18mg, yield 31.6%). MS m/z (ESI): 360.1[ M+H ] ⁺

Step 2 Compound 127-1 (25 mg,0.07 mmol) was dissolved in methanol (3 mL), then HCl/dioxane (3 mL,12 mmol) was added and the reaction was stirred at room temperature for 2h. The reaction solution was dried to give compound 127-2 (brown solid, 20mg, hydrochloride). MS m/z (ESI): 259.8[ M+H ] ⁺

Step 3 preparation of E127 reference example E67-1 Synthesis method of step 2 .¹H NMR(500MHz,CD₃OD)δ7.06-6.96(m,1H),6.89(d,J＝7.5Hz,1H),6.73(t,J＝7.4Hz,1H),6.58(t,J＝7.7Hz,1H),6.41(dd,J＝16.5,7.6Hz,2H),4.50(t,J＝8.7Hz,2H),3.85-3.55(m,3H),3.49-3.35(m,2H),3.34-3.31(m,2H),3.17(t,J＝8.7Hz,2H),3.08(dd,J＝11.0,4.8Hz,2H),2.95-2.83(m,1H),2.77(d,J＝11.5Hz,1H),2.66-2.57(m,1H),2.55(t,J＝7.5Hz,2H),2.46-2.29(m,3H),2.06-1.89(m,3H),1.85(dt,J＝14.8,7.3Hz,2H).MS m/z(ESI):420.6[M+H]⁺.

Example 128 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-deagglomeration ] quinoxaline-5-carbonitrile

Step 1 45-1-4 (600 mg,2.0 mmol) and 6mL DMF were added to a 25mL single-necked flask, N ₂ was replaced three times, cooled to 0 ℃, NBS (356 m,2.0 mmol) was added, 0 ℃ 0.5h.LC-MS indicated complete reaction, saturated NaHCO ₃ solution and EA were added, the aqueous phase was separated, extracted three times with EA, the organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated to 128-1 (750 mg, crude). MS m/z (ESI): 380.2,382.2[ M+H ] ⁺.

Step 2-128-1 (750 mg,2.0 mmol), CH ₃I(5.1g,36.0mmol),K₂CO₃ (552 mg,4.0 mmol) and acetonitrile (20 mL) were added to a 100mL single-necked flask, N ₂ was replaced three times, warmed to 80℃and reacted 16h.LC-MS showed complete reaction, the solvent was concentrated to dryness, water and EA were added, the liquid separated, the aqueous phase was extracted once with EA, the organic phases were combined, washed three times with saturated sodium chloride, dried and concentrated to give 128-2 (750 mg, crude). MS m/z (ESI): 394.3,396.4[ M+H ] ⁺.

Step 3:128-3 preparation of reference E45-1 the synthetic method of step 4. MS m/z (ESI): 380.2,382.2[ M+H ] ⁺.

Step 4-128-3 (200 mg,0.52 mmol), hydrazine hydrate (60 mg,1.04 mmol), KOH (112 mg,2.08 mmol) and ethylene glycol (8 mL) were added to a 25mL microwave tube, warmed to 150℃and reacted for 1.5h. MS m/z (ESI): 308.2,310.2[ M+H ] ⁺.

Step 5:128-5 preparation of reference E45-2 Synthesis method of step 2. MS m/z (ESI): 408.2,410.2[ M+H ] ⁺.

Step 6 Compound 128-5 (18.0 mg,0.04 mmol) was dissolved in DMF (2.0 mL) and tetrakis (triphenylphosphine) palladium (1.20 g,3.45 mmol), zinc cyanide (5.18 mg,0.044 mmol), zinc powder (0.860 mg,0.013 mmol) was added under nitrogen. The mixture was stirred for 3h at 150 ℃. After completion of TLC detection, concentration under reduced pressure and normal phase purification gave compound 128-6 (yellow solid, 150mg, yield 74%). MS M/z (ESI): 355.2 [ M+H ] ⁺ _.

Step 7 128-6 (15.0 mg,0.04 mmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (1.0 mL) was added. The reaction was carried out at room temperature for 1h. Concentration by filtration gave compound 128-7 (brown oil, 12.0mg, 85% yield). MS M/z (ESI): 255.2.[ M+H ] ⁺ _.

Step 8 Compound 128-7 (15.0 mg,0.05 mmol), 2- (2, 3-dihydro-1-benzofuran-6-yl) acetaldehyde (9.57 mg,0.05 mmol), acetic acid (0.052 mL,0.93 mmol) were dissolved in THF (2 mL) under nitrogen, and sodium cyanoborohydride (12.3 mg,0.15 mmol) was added. The reaction was carried out at 0℃for 2h. TLC detection of completion of the reaction, filtration, reverse phase purification (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) gave E128 (white solid, 1.0mg, yield) 4％).¹H NMR(400MHz,CDCl₃)δ7.04(d,J＝7.2Hz,1H),6.91-6.88(m,1H),6.79-6.74(m,2H),6.56(s,1H),4.55-4.50(t,J＝8.8Hz,2H),3.61-3.56(m,1H),3.43-3.17(m,4H),3.19(t,J＝8.8Hz,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 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline

Step 1 methyl glycine hydrochloride (7.2 g,57.9 mmol) and K ₂CO₃ (4.72 mg,34.2 mmol) were dissolved in 90mL NMP and 1-fluoro-4-methoxy-2-nitrobenzene (9.0 g,52.6 mmol) was added and heated to 80℃for 16h. TLC checked completion of the reaction, water and EtOAc were added to separate the layers, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed three times with saturated sodium chloride solution, and dried and concentrated to give compound 129-1 (2.2 g, yellow solid, 17% yield) by column chromatography on normal phase silica gel (PE/etoac=5/1). MS m/z (ESI) 240.4[ M+H ] ⁺.

Step 2 129-1 (2.2 g,9.17 mmol) was dissolved in 30mL of methanol, 1g of 10% Pd/C was added, stirred at room temperature for 16h, and concentrated by filtration to give 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 3:129-3 preparation reference E42, synthetic method of step 1. MS m/z (ESI): 208.3[ M+H ] ⁺.

Step 4 Compound 129-3 (320 mg,1.54 mmol) was dissolved in 10mL of methanol, ammonium chloride (447 mg,7.7 mmol) was added at room temperature, zinc powder (492 mg,7.7 mmol) was further added, stirred at room temperature for 3h, and after filtration and concentration 129-4 (220 mg, off-white solid, yield 74%) was obtained and used directly in the next step. MS m/z (ESI): 194.4[ M+H ] ⁺.

Preparation of step 5:129-5 reference E42 the synthetic method of step 3. MS m/z (ESI): 357.4[ M+H ] ⁺.

Preparation of step 6:129-6 reference is made to the synthetic method of step 1 of E73-1. MS m/z (ESI) 371.5[ M+H ] ⁺.

Preparation of step 7:129-7 reference E42 the synthetic method of step 4. MS m/z (ESI): 273.3[ M+H ] ⁺.

Step 8:129-8 preparation reference E45 step 4 synthesis method. MS m/z (ESI): 259.4[ M+H ] ⁺.

Step 9 preparation of E129 reference E42 Synthesis method of step 5 .¹H NMR(500MHz,CD₃OD)δ7.03(d,J＝5.0Hz,1H),6.90(d,J＝5.0Hz,1H),6.74(t,J＝7.5Hz,1H),6.08-6.02(m,2H),4.51(t,J＝10.0Hz,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]⁺.

EXAMPLE 130 8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1,2,6b,7,8,9,10 a-octahydropyrido [4,3-b ] [1,4] thiazine [2,3,4-hi ] indole 3, 3-dioxide

Step 1 Compound E68 (12 mg,0.031 mmol) was dissolved in DCM (3 mL), cooled to reflux, m-CPBA (12 mg,0.067 mmol) was added and the reaction stirred at room temperature for 2h and concentrated in vacuo to give the crude product. The crude product is concentrated, filtered, purified by prep-HPLC and separated (eluent (v/v): acetonitrile/(water+0.05% NH ₄ HCO 3) =30-70%) to give compound E130 (5.0 mg, white solid, yield 38％).¹H NMR(500MHz,CD₃OD)δ7.03(d,J＝5.0Hz,1H),6.90(d,J＝5.0Hz,1H),6.73(t,J＝7.5Hz,1H),6.66(d,J＝5.0Hz,1H),6.59(d,J＝7.5Hz,1H),6.51(d,J＝10.0Hz,1H),4.50(t,J＝10.0Hz,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＝10.0Hz,2H),2.42-2.26(m,3H),2.19(t,J＝10.0Hz,1H),2.05-1.81(m,3H).MS m/z(ESI):424.8[M+H]⁺.

EXAMPLE 131:1- ((6 bR,10 aS) -8- ((2- (2, 3-dihydrobenzofuran-7-yl) cyclopropyl) methyl) -1,2,6b,7,8,9,10 a-octahydro-3H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-3-yl) ethan-1-one

Step 1 dissolving Compound 122-2 (1.6 g,12.5 mmol) in toluene (20 mL), adding ethyl diazoacetate (2.2 g,18.75 mmol), NMI (3.08 g,37.5 mmol), co (II) (Co (TPP) (84 mg,0.125 mmol) 80 ℃ stirring reaction 48H after TLC detection, concentrating under reduced pressure, and purifying normal phase to give Compound 131-1 (purple solid, 1g, yield 34.5%) MS M/z (ESI): 233.1.[ M+H ] ⁺ _.

Step 2:131-2 preparation reference E60 step 3 synthesis method.

Step 3:131-3 Synthesis method of step 4 for preparing reference E60

Step 4 Synthesis method of step 45 of E131 preparation reference E60 ¹H NMR(500MHz,CDCl₃)δ7.01(d,J＝7.2Hz,1H),6.88(d,J＝7.3Hz,2H),6.76(t,J＝7.5Hz,1H),6.69(d,J＝7.5Hz,2H),4.52(t,J＝8.4Hz,2H),3.92(d,J＝85.9Hz,3H),3.61-3.24(m,3H),3.20(dd,J＝15.7,8.3Hz,3H),2.78(d,J＝165.2Hz,3H),2.39(d,J＝50.9Hz,5H),1.99(d,J＝18.0Hz,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- ((6 bR,10 aS) -8- (3- (2, 3-dihydrobenzofuran-7-yl) -2-hydroxypropyl) -1,2,6b,7,8,9,10 a-octahydro-3H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-3-yl) ethan-1-one

Step 1:132-1 preparation of reference E45-2 step 3 Synthesis method. MS m/z (ESI) 358.2[ M+H ] ⁺.

Step 2:132-2 preparation of reference E45-2 Synthesis method of step 4. MS m/z (ESI): 258.2[ M+H ] ⁺.

Step 3-132-2 (50 mg,0.19 mmol), 69-2 (69 mg,0.4 mmol), K ₂CO₃ (52 mg,0.4 mmol) and 2mL DMF were added to a 25mL single port flask, N ₂ was replaced three times, warmed to 120 ℃, reacted for 16h, water and EA were added, the aqueous phase was separated three times, the organic phases were combined, washed three times with saturated sodium chloride, dried, concentrated over column (DCM/MeOH=20/1) to give E132 (30 mg, crude). 15mg of crude product was purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH4HCO 3) =30% -70%) to give E132 (7.9 mg, white solid, yield ：19.3％).¹H NMR(500MHz,CDCl₃)δ7.06(t,J＝6.5Hz,1H),6.99(t,J＝7.3Hz,1H),6.95-6.81(m,2H),6.81-6.74(m,1H),6.67(s,1H),4.53(t,J＝8.7Hz,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 (6 bR,10 aS) -8- ((2, 3-Dihydrobenzofuran-7-yl) methyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

E67-1-1 (50 mg,0.16 mmol) was dissolved in MeOH (2.00 mL), sodium cyanoborohydride (30 mg, 0.284 mmol) was added and stirred at room temperature for 20min, followed by the continued addition of 2, 3-dihydrobenzofuran-7-carbaldehyde (47 mg, 0.322 mmol) and reaction at room temperature for 2h. LCMS checked completion of the reaction and HPLC purification (nh3.h2o system) gave compound E133 (white solid, 22mg, yield 37.7％).1H NMR(400MHz,CDCl3)δ7.41(s,1H),7.11(d,J＝7.4Hz,2H),6.80-6.78(m,2H),6.70(t,J＝7.6Hz,1H),6.55(d,J＝7.2Hz,1H),4.54(t,J＝8.8Hz,2H),3.95(d,J＝14.6Hz,1H),3.49(d,J＝2.0Hz,2H),3.41-3.29(m,4H),3.19(d,J＝8.6Hz,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 (6 bR,10 aS) -8- (2, 3-Dihydrobenzofuran-7-yl) ethyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Preparation of E134 reference example E67-1 Synthesis method of step 2 .1H NMR(400MHz,CDCl3)δ7.39(s,1H),7.04(d,J＝7.2Hz,1H),6.94(d,J＝7.3Hz,1H),6.85(d,J＝7.3Hz,1H),6.79-6.70(m,2H),6.57(d,J＝7.8Hz,1H),4.52(t,J＝8.7Hz,2H),3.97(d,J＝14.6Hz,1H),3.38(dd,J＝15.2,8.0Hz,3H),3.19(t,J＝8.7Hz,2H),3.04-2.98(m,1H),2.79(dd,J＝21.4,12.6Hz,3H),2.59(dd,J＝16.4,8.0Hz,2H),2.37-2.21(m,1H),1.98(dd,J＝22.3,8.5Hz,3H).MS m/z(ESI):376.4[M+H]+.

Example 135 (6 bR,10 aS) -8- (4- (2, 3-Dihydrobenzofuran-7-yl) butyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

Step 1 7-bromobenzofuran (600 mg,3 mmol) and 3-butyn-1-ol (420 mg,6 mmol) were dissolved in DMF (5 mL) and Et3N (5 mL), cuI (114 mg,0.6 mmol) and Pd (PPh 3) 2Cl2 (210 mg,0.3 mmol) were added sequentially with stirring. The reaction was stirred for 16 hours at 90 ℃ under nitrogen protection, and the reaction was completed. The reaction solution was poured into ice water (30 mL), the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic layer was dried over brine (30 mL. Times.2), and concentrated by filtration, and column chromatography (ethyl acetate/petroleum ether: 0% -50%) gave compound 135-1 (white solid, 520mg, yield 92%). MS m/z (ESI): 189.2[ M+H ] +.

Step 2 Compound 135-1 (360 mg,2 mmol) was dissolved in MeOH (10 mL) and wet 20% Pd (OH) 2/C (50 mg) was added under nitrogen blanket. Three substitutions with hydrogen were made and the reaction was stirred under hydrogen for 16 hours at 25 ℃ and the reaction was completed. The reaction system was concentrated by filtration to give 135-2 (colorless oil, 190mg, yield: 50%). MS m/z (ESI): 193.3[ M+H ] +.

Step 3. 135-2 was dissolved in DCM (5.0 mL) and dess-Martin oxidizer (390 mg,0.91 mmol) was added. The reaction was carried out at 25 ℃ for 1h, lcms detected completion of the reaction, water was added, EA was extracted, sodium sulfate was added, dried, filtered, concentrated, and purified by silica gel column (EA/pe=5%) to give compound 135-3 (white solid, 35mg, yield 35.4%). MS M/z (ESI): 162.2, [ M+H ] +.

Preparation of E135 reference example E67-1 Synthesis method of step 2 .¹H NMR(400MHz,CDCl3)δ7.40(s,1H),7.03(d,J＝7.2Hz,1H),6.92(d,J＝7.6Hz,1H),6.83(d,J＝7.6Hz,1H),6.74–6.68(m,2H),6.56(d,J＝7.6Hz,1H),4.53(t,J＝8.8Hz,2H),3.95(d,J＝14.6Hz,1H),3.41-3.30(m,3H),3.20(t,J＝8.6Hz,2H),2.92-2.67(m,2H),2.57(t,J＝7.2Hz,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 (6 bR,10 aS) -8- (3- (3-hydroxy-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2, 3-des ] quinoxalin-2 (3H) -one

Step 1 7-bromo-3-benzofuranone (1.28 g,6.0 mmol) was dissolved in methanol (10 mL), cooled to 0deg.C, sodium borohydride (295 mg,7.8 mmol) was added and the reaction stirred at room temperature for 2h. The solvent was removed by concentration under reduced pressure, ethyl acetate (30 mL) and water (30 mL) were added to separate the layers, and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give crude compound 137-1 (980 mg, yield: 76.1%) as a colorless oil, which was used directly in the next reaction. MS m/z (ESI) 216.2[ M+H ] ⁺

Step 2 Compound 136-1 (480 mg,4.56 mmol) was dissolved in DCM (10 mL) at room temperature, imidazole (930 mg,13.7 mmol) was added followed by TBDPSCl (1.88 g,6.84 mmol). The reaction solution was stirred at room temperature for 16h. After completion of LCMS monitoring the reaction, the reaction was quenched by addition of water (25 mL), extracted with DCM (25 mL), the organic phase was washed with water (25 mL) and dried over anhydrous sodium sulfate, concentrated to give crude product, which was purified by normal phase column chromatography (EtOAc/pe=0-10%) to give compound 136-2 (1.36 g, yield: 66%) as a colorless oil. MS m/z (ESI): 481.4[ M+H ] ⁺

Step 3 Compound 136-2 (1.36 g,3.0 mmol) was dissolved in DMF (15 mL), triethylamine (3.5 mL) was added, followed by ethyl acrylate (600 mg,6.0 mmol) and Pd (dtbpf) Cl ₂ (19 mg,0.3 mmol) under nitrogen, and the reaction was heated to 98℃and stirred for 18hr. The solvent was dried by spin, ethyl acetate (50 mL) was added, the filtrate was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by normal phase column chromatography (EtOAc/PE=0-10%) to give compound 136-3 (325 mg, yield: 23%) as a colorless oil. MS m/z (ESI): 473.6[ M+H ] ⁺

Step 4 preparation of 136-4 reference is made to the synthetic procedure of the second step of example 3.

Step 5 preparation of 136-5 reference is made to the synthetic method of the third step of example 3.

Step 6 preparation of 136-6 reference is made to the fourth synthetic procedure of example 8.

Step 7:136-7 preparation reference is made to the synthetic procedure of the fifth step of example 8.

Step 8 Compound 136-7 (33 mg,0.1 mmol) was dissolved in THF (2 mL), TBAF (0.15 mL,0.15 mmol) was added, and the reaction was stirred at room temperature for 2h. The solvent was removed by concentrating under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added to separate the layers, the organic phase was washed with saturated brine (10 mL) again, and the prep-HPLC purification and separation (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) was performed after concentration filtration to give compound E136 (6.6 mg, white solid, yield) ：16％).¹H NMR(500MHz,CD₃OD)δ7.23(d,J＝5.0Hz,1H),7.05(d,J＝5.0Hz,1H),6.85-6.81(m,2H),6.70(t,J＝7.5Hz,1H),6.63(d,J＝10.0Hz,1H),5.31-5.29(m,1H),4.50-4.47(m,1H),4.34-4.31(m,1H),3.86(d,J＝15.0Hz,1H),3.33-3.26(m,3H),2.93-2.90(m,1H),2.78-2.76(m,1H),2.59(t,J＝7.5Hz,2H),2.39-2.32(m,2H),2.26-2.21(m,1H),2.05-1.75(m,5H).MS m/z(ESI):406.8[M+H]⁺.

Example 137 (6 bR,10 aS) -8- (3- (2, 3-Dihydrobenzofuran-7-yl) propyl) -1-hydroxy-6 b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-2 (3H) -one

E67-1 (500 mg,1.24 mmol) was dissolved in HCl (pH=2, 10.0 mL) and reacted at 25℃for 0.5h (the reaction gradually worsened in the reaction solution with the lapse of time). LCMS checked completion of the reaction, filtered, HPLC purified (HCOOH system) to afford compound E137 (grey solid, 7.5mg, yield 2.36％).¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),7.03(d,J＝7.3Hz,1H),6.87(dd,J＝21.4,9.8Hz,2H),6.81-6.71(m,2H),6.66(t,J＝7.8Hz,1H),4.58-4.47(m,2H),3.60(dd,J＝14.0,7.7Hz,2H),3.13(dt,J＝87.9,33.5Hz,4H),2.76-2.57(m,3H),2.14(d,J＝103.4Hz,8H).

Example 138 (6 bR,10 aS) -8- (3- (3-hydroxy-2, 3-dihydrobenzofuran-7-yl) propyl) -6b,7,8,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline-1, 2 (3H) -dione

Preparation of E138 reference example E137 Synthesis method .¹H NMR(500MHz,CDCl₃)δ11.95(s,1H),7.21(d,J＝40.4Hz,3H),7.01(d,J＝19.1Hz,2H),6.86(s,1H),5.63(s,1H),5.31(s,1H),4.81(s,1H),4.57–4.50(m,1H),4.28(d,J＝10.1Hz,1H),3.73(s,1H),3.13(s,1H),2.66(d,J＝42.7Hz,2H),2.43(s,2H),2.28(d,J＝65.2Hz,3H),2.21(s,1H),1.97(s,1H),1.74(s,2H).MS m/z(ESI):420.6[M+H]⁺.

In the following effect examples, the control compounds used had the following structures:

control compound 1:

Control Compound 2 Lu Meipai long

Control compound 3:

Control compound 1 was prepared with reference to CN116444520 a.

Control Compound 2:1- (4-fluorophenyl) -4- ((6 bR,10 aS) -3-methyl-2, 3,6b,9,10 a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxalin-8 (7H) -yl) butan-1-one was prepared as follows:

Step 1 (6 bR,10 aS) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline (2 g,8.72 mmol), 4-chloro-1- (4-fluorophenyl) -1-butanone (2.6 g,13.08 mmol), DIEA (3.4 g,26.16 mmol) and sodium iodide (1.96 g,13.08 mmol) were dissolved in DMSO (20 mL) at room temperature. The reaction solution was stirred at 60 ℃ for 16 hours. The reaction was cooled to room temperature, water (80 mL) was added, the aqueous phase was extracted with EA (80 mL x 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride (80 mL x 3), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was concentrated and filtered and purified by prep-HPLC (eluent (v/v): acetonitrile/(water+0.05% NH ₄HCO₃) =30% -70%) to give control compound 2 (1 g, 29% yield, yellow oil) ).¹H NMR(500MHz,CDCl₃)δ8.05–7.94(m,2H),7.16–7.09(m,2H),6.65(t,J＝7.6Hz,1H),6.51(dd,J＝7.4,0.9Hz,1H),6.40(dd,J＝8.0,0.9Hz,1H),3.63–3.54(m,1H),3.35–3.24(m,2H),3.23–3.17(m,1H),3.10(s,1H),2.99(t,J＝7.1Hz,2H),2.92–2.77(m,5H),2.66(s,1H),2.40(s,2H),2.25(s,1H),2.06–1.78(m,5H).MS m/z(ESI):394.9[M+H]⁺.

Control Compound 3 (6 bR,10 aS) -8- ((2, 3-Dihydrobenzofuran-7-yl) methyl) -3-methyl-2, 3,6b,7,8,9,10 a-octahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de ] quinoxaline

Preparation of control Compound 3 reference example E133 preparation method .1H NMR(400MHz,CDCl3)δ7.16-7.05(m,2H),6.81(t,J＝7.4Hz,1H),6.69-6.59(m,1H),6.49(d,J＝6.8Hz,1H),6.39(d,J＝7.4Hz,1H),4.54(dd,J＝13.4,4.9Hz,2H),3.66-3.55(m,1H),3.48(d,J＝2.1Hz,2H),3.34-3.14(m,6H),2.90(dd,J＝10.7,5.3Hz,1H),2.86(s,3H),2.84-2.77(m,1H),2.71(d,J＝12.1Hz,1H),2.30(td,J＝10.8,5.1Hz,1H),2.08-1.98(m,1H),1.97-1.87(m,2H).MS m/z(ESI):362.3[M+H]+.

Effect example 1 affinity test of Compounds for 5-HT2A receptor

Affinity was determined by means of a radioligand competition assay. Plasmid vector containing 5-HT2A receptor sequence was transfected into HEK293 cells (ATCC, CRL-1573), HEK293 cells stably expressing 5-HT2A receptor were obtained by screening, and cultured in 10cm dishes overnight, after which the medium was aspirated, 3mL of lysate was added, and allowed to stand at 4℃for 10 minutes. After cell detachment, the supernatant was discarded by centrifugation at 1500rpm for 5 minutes in a centrifuge at 4 ℃. The cell pellet was transferred to a tissue homogenizer, to which 3mL of lysate was added, ground well until the cells were disrupted, and centrifuged at 12000rpm at 4℃for 5 minutes, and the supernatant was discarded. The pellet is a component of the cell membrane containing 5-HT2A receptor and resuspended in 10ml binding buffer. 96-well plates were prepared, and gradient diluted test compounds were added to the plates and 100. Mu.l of membrane stock solution and 100ul of [3H ] -ketanserin radioligand were added and incubated at 300rpm for 1 hour. Simultaneously, uniFilter ^TM plates (GF/B) were prepared, uniFilter ^TM plates were soaked with 50. Mu.l of 0.3% PEI for 0.5 hours, and the membrane and ligand incubation mixtures were filtered through UniFilter ^TM plates and rinsed 4 times. The filter plates were dried at 50 degrees for 1 hour. After drying, the bottom of the filter plate was sealed with a sealing plate membrane, 50. Mu.l of liquid flash buffer was added, and the amount of [3H ] -ketanserin bound to the filter plate was read on the instrument, and the binding inhibition rate was calculated as compared to the control wells. The data were analyzed using Prism software, and the data were fitted using the "log (inhibitor) vs. response-Variable slope" model to give IC ₅₀, and further processed to give Ki values for the affinities of different compounds for the 5-HT2A receptor. The compounds of the invention have a better affinity for the 5-HT2A receptor and the data for a portion of the compounds are set forth in Table 1.

TABLE 1

Effect example 2 downstream beta-arestin functional Activity test of 5-HT2A receptor

2.1 Method one was performed mainly using Promega NanoBit kit. Specifically, a 5HT2A receptor plasmid with LgBiT at the C end and a beta-arestin plasmid with SmBiT at the N end are respectively constructed. Before transfection, 4X10e6 HEK293 cells (ATCC, CRL-1573) were seeded in 10cm dishes, after overnight incubation, 10ug of 5HT2AR-LgBiT was mixed with 10ug of pBiT2.1-N-SmBiT-beta arestin plasmid and transfection reagent and added to the dishes for transfection. After 24 hours of incubation, cells were transferred to 384 well plates, 20000 cells per well, and the test compound or 5-HT was added as positive control and incubation was continued overnight at 37 ℃,5% co ₂. And after the next day of taking out, adding diluted 5uLNanoBit detection liquid, and reading the luminescence value on an enzyme-labeled instrument. The data were analyzed using Prism software with the read at the highest concentration of 5-HT as 100% of downstream pathway activation, and the "log (ag) vs. response-Variable slope (four parameters)" model was used to fit the data to give EC ₅₀ and E _max.

2.2 Method two, mainly using Promega NanoBret kit. Specifically, a 5HT2A receptor plasmid with Nanoluc at the C end, a beta-arestin plasmid with Halo-tag at the C end and a pcDNA3.1 plasmid for expressing GRK2 are respectively constructed. HEK293 cells (ATCC, CRL-1573) were seeded in 6-well plates before transfection, and after overnight incubation, plasmids of Nanoluc-5HT2AR, GRK2, beta-arestin-halotag were mixed at a ratio of 1:1:10 and added to 6-well plates together with the transfection reagent at a transfection amount of 2ug per well. After 4 hours, cells were transferred to 384 well plates after digestion, 20000 cells per well, and the test compound or 5-HT was added as positive control and incubation was continued overnight at 37 ℃,5% co ₂. After the next day of removal, diluted NanoBRET ^TM Nano-Glo substrate was added and read on a microplate reader at 618nm/460 nm. The data were analyzed using Prism software with the read at the highest concentration of 5-HT as 100% of downstream pathway activation, and the "log (ag) vs. response-Variable slope (four parameters)" model was used to fit the data to give EC ₅₀ and E _max. The following data all used method one. The compounds of the present invention can better activate the downstream signaling activity of 5HT2A receptor, and the data of a part of the compounds are shown in Table 2:

TABLE 2

Effect example 3 downstream calcium stream functional Activity test of 5-HT2A receptor

3.1 Method one downstream calcium flux activity assay of compounds with 5-HT2A receptor was performed using HEK293 cells (ATCC, CRL-1573) stably expressing 5-HT2A receptor. The 5-HT2A receptor was stably expressed in HEK293 by lentiviral infection to form HEK293-5HT2AR cells which were seeded at 25000 cells/well in 384 well plates and incubated overnight at 37℃in a 5% CO ₂ environment. The next day, the cell culture medium was aspirated, buffer containing FLIPR Calcium 6 dye was added and incubated for 30min at room temperature. Simultaneously, 384 well plates with the compound added were placed in the MD FLIPR instrument, and the calcium flux signal values were read. When analyzing the data, the data were analyzed using Prism software with the read value of the highest concentration of 5-HT as 100% of the activation of the downstream pathway, and the "log (ag) vs. response-Variable slope (four parameters)" model was used to fit the data to obtain EC ₅₀ and E _max.

3.2 Methods two downstream calcium flux activity assays of compounds with 5-HT2A receptor were performed using HEK293 cells transiently transfected with 5-HT2A receptor (ATCC, CRL-1573). The full length gene of 5-HT2A was inserted into pcDNA3.1 vector, transfected into HEK293 cells with lipofectamine3000 reagent, and after 4-6 hours, the cells were seeded into 384 well plates at 20000 cells/well and incubated overnight at 37℃in 5% CO ₂. The next day, the cell culture medium was aspirated, buffer containing FLIPR Calcium 6 dye was added and incubated for 30 min at room temperature. Simultaneously, compound 384 well plates were prepared and placed in an MD FLIPR instrument to read the calcium flux signal values. When analyzing the data, the data were analyzed using Prism software with the read value of the highest concentration of 5-HT as 100% of the activation of the downstream pathway, and the "log (ag) vs. response-Variable slope (four parameters)" model was used to fit the data to obtain EC ₅₀ and E _max. The compounds of the present invention are not generally shown to have a magic effect while being antidepressant, and the data for some of the compounds are listed in table 3:

TABLE 3 Table 3

ND means undetected.

The data is derived from the second method, and the rest adopts the first method. Effect example 4 animal Depression-like behavior test (FST)

Forced swimming tests are commonly used to evaluate mouse depression-like moods, with 7-8 week old C57BL/6J male mice in groups of 12 animals. The mice were placed in a 5L glass beaker with a water level of 15cm for 15 minutes 24hr before testing. On the day of testing, mice were placed in the same beaker for 6 minutes after 30 minutes of intraperitoneal injection of either blank vehicle (5% DMSO,10% polyethylene glycol-15-hydroxystearate, 85% physiological saline) ketamine (20 mpk) or test subject (15 mpk). Four minutes after the software (Shanghai Ji amount, JLBehv-FSG-4) analysis, mice were stationary. The percentage of the immobility time of each administration group and the immobility time of the solvent control group in the same batch is calculated for statistical analysis, if the data meet the normal distribution, the statistical method adopts parameter test, namely independent sample t test, and if the data do not meet the normal distribution, the statistical method adopts non-parameter test, the compound has better antidepressant effect, and the data of partial compounds are listed in the table 4-1 and the table 4-2.

TABLE 4-1

TABLE 4-2

NA=Not Available

Data are averages of multiple experiments.

Experimental results show that the compounds of the embodiment of the invention can obviously reduce the immobility time (not shown) and the immobility time ratio of the compounds to the solvent contrast, and the compounds are suggested to improve the depression-like emotion of mice. Meanwhile, under the experimental condition, the positive control compound ketamine obviously reduces the immobility time and the ratio of the positive control compound ketamine to the solvent control immobility time, and the control compound 1 has no obvious effect on the behavior of a mouse depression sample.

Effect example 5 Metabolic Property test

5.1 Test animals 9C 57 mice were divided into 3 groups and alternately sampled, and 15mg/kg of the compound was administered by single intraperitoneal injection at a dose volume of 10 mL/kg. 5min,15min,30min,1h,2h,4h,6h,8h,24h after administration a sample of the test sample is collected. Biological sample collection and storage 0.08mL of blood was placed in an EDTA-2K anticoagulant tube containing a label. After thoroughly mixing the anticoagulant (EDTA-2K) with blood by gentle inversion, the mixture was immediately placed in wet ice and the plasma was centrifuged within 30min after blood collection, with centrifugation conditions set at 4℃6800g for 6 min. The plasma separated after centrifugation was placed in a labeled EP tube and stored in a refrigerator at no higher than-20℃for 30min until the sample was analyzed. Sample analysis, namely establishing an LC-MS/MS analysis method for measuring the concentration of the crude drug in the plasma of the mice, and measuring the concentration of the biological sample obtained by the experiment, wherein the pretreatment process of the biological sample is carried out on yellow light and ice water bath. PK parameters were calculated using WinNonlin software. The compounds of the invention have better metabolic performance, and the data of partial compounds are shown in Table 5-1:

TABLE 5-1

In contrast, compounds 45-1 and 46 achieved higher plasma free exposures due to higher plasma free fractions (PPB, fu%) at close plasma exposures.

5.2 Test animals C57/6J mice, SPF grade, male, 9 animals/group.

The experimental design is that the intravenous injection group (i.v) animals are not fasted before administration, the gastric lavage group (P.O) is fasted, the fasted animals are fasted overnight (10-14 hours) before the experiment, and the animals are fed with free drinking water and empty stomach 4 hours after administration. The administration dosage is 2mg/kg of intravenous injection group, the administration concentration is 0.4mg/mL, the administration volume is 5mL/kg, the administration concentration is 1.0mg/mL, and the administration volume is 10mL/kg. Dosing mode, weighing before dosing, and calculating dosing amount according to the body weight. Single administration, cross-collection of plasma samples. Dosing vehicle 5% dmso+10% solutol+85% saline.

Intravenous group blood collection time point: 0.083h,0.25h,0.5h,1h,2h,4h,6h,8h,24h; time point of blood collection for the lavage group: 0.25h,0.5h,1h,2h,4h,6h,8h,24h; blood was collected via the jugular vein or other suitable vein, each sample was collected at approximately 0.08ml, anticoagulated with k2-EDTA, and placed on ice after collection.

Plasma sample treatment, namely, centrifugally separating plasma within 30min after blood collection, wherein the centrifugal condition is set to be 4 ℃ and 6800g for 6 min. The plasma separated after centrifugation was placed in a labeled EP tube and stored in a refrigerator at no higher than-20℃for 30min until the sample was analyzed. An LC-MS/MS analysis method for measuring the concentration of the crude drug in the plasma of the mice is established and is used for measuring the concentration of the biological sample obtained in the experiment, and the pretreatment process of the biological sample is required to be carried out on yellow light and ice water bath.

Analysis of results by calculation of pharmacokinetic parameters using Phoenix winnonlin7.0, providing parameters such as AUC _0-t、MRT_0-t、C_max、T_max and T _1/2, from blood concentration data at different time points. The pharmacokinetic parameters of mice are shown that the compounds of the invention have better metabolic properties, and the data of a part of the compounds are listed in Table 5-2.

TABLE 5-2

The compound of the present invention has better in vivo bioavailability than the control compound 2. F (%) = (AUC _0-inf-PO/AUC_0-inf -IV)/(DosePO/DoseIV) ×100

Effect example 6 drug interaction test

The in vitro inhibition of CYP2D6 enzyme by drugs was investigated by human liver microsomal incubation and its potential metabolic drug-drug interactions were assessed. The test substance and dextromethorphan hydrobromide (DM) probe substrate are incubated for a certain time in an incubation system of human liver microsomes (source: BIOIVT, batch number: CDN), and the residual enzyme activity percentage content at each administration concentration is calculated. The liver microsome incubation system medium was Phosphate Buffered Saline (PBS), containing the test substance or positive inhibitor, probe substrate, liver microsome (final concentration 0.1 mg/mL) and NADPH (1 mM). The metabolite production of the probe substrate was measured by LC-MS/MS method. The enzyme activity was reflected by the metabolite production, the residual percentage (%) of CYP2D6 at different analyte concentration levels was calculated, the ordinate was taken as the ordinate, the semi-logarithmic inhibition plot was taken as the abscissa, and the IC ₅₀ value was calculated using Prism software. At different concentration points of the test compound or positive inhibitor, the percentage of activity remaining is determined by the ratio of the amount of the characteristic metabolite of the probe substrate produced to the amount produced in the absence of the test compound or positive inhibitor. If a significant decrease in metabolite production was found at the highest concentration set point, the log (inhibitor) vs. response-Variable slope formula of GRAPHPAD PRISM software was used to calculate the median inhibitory concentration (IC 50):

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

Log (test compound or positive inhibitor concentration);

Y: percent activity remaining;

Top and Bottom, respectively, refers to the theoretical maximum and minimum residual activity percentages;

Hillslope gradient coefficient or slope.

If the amount of time product produced is not significantly reduced (percentage of enzyme activity remaining > 50%) at the maximum concentration set point, the half inhibition concentration (IC 50) cannot be accurately calculated, reporting that the IC50 is greater than the test maximum concentration.

It is believed that compounds have a strong inhibition of CYP enzyme inhibition with IC ₅₀ values < 1. Mu.M, a moderate inhibition with 1. Mu.M < IC ₅₀ < 10. Mu.M, and a weak inhibition with IC ₅₀ > 10. Mu.M.

The compounds of the present invention have less drug interactions and the results for some of the compounds are listed in table 6 below.

TABLE 6

The CYP2D6 gene codes for CYP2D6 enzyme, and the CYP2D6 enzyme is an important member of cytochrome P450 system and is a key enzyme for metabolism of various medicines. The smaller the inhibition effect of the drug on CYP2D6 enzyme, the smaller the metabolic influence on other drugs, and the stronger the inhibition effect is indicated by CYP2D6inhibition IC50< 1. The data in the table shows that the test compound has less inhibition effect on CYP2D6 enzyme than the control compound, especially compound 45-1, and has weaker inhibition effect on other medicines, so that the effects of medicine interaction are less. Effect example 7 mice head twitch response experiments (HTR)

The experiment adopts 6-8 weeks old C57BL/6J mice, and 10 mice are used in each group. On the day D1, animals of each group are firstly put into a test box to adapt for 20min, then the animals of each group are intraperitoneally injected with blank solvent (5% DMSO,10% polyethylene glycol-15-hydroxystearate, 85% physiological saline) or positive compound DOI (1- (4-iodo-2, 5-dimethoxyphenyl) -2-aminopropane) (1 mg/kg) or test substance (50 mg/kg) for intraperitoneal injection video and observing the number of times of head twitches of mice in 70min (0-70 min after drug recording), and on the day D2, the number of times of head twitches of mice in 30min is recorded and observed after 24 h+ -5 min after drug administration.

Data analysis, namely describing the head pumping times by adopting average value +/-standard error. Quantitative index the statistical analysis is performed by single factor analysis of variance (ONE-WAY ANOVA) when the data meet normal distribution and the variance is uniform, by Kruskal-Wallis H rank sum test (K-W method) when the variance is not uniform, and all the statistical analysis is completed by GRAPHPAD PRISM 9.0.0 software.

The compounds of the present invention have no apparent magic effect, and the results of some of the compounds are shown in Table 7 below.

TABLE 7

The results show that within 70 minutes after dosing, the positive compound DOI produced a pronounced illusion effect, whereas none of the compounds of the invention produced a pronounced illusion effect consistent with the blank, and no illusion was observed with the compounds of the invention after 24 hours after dosing.

Claims

1. A tetrakiscyclic compound represented by formula I or a pharmaceutically acceptable salt thereof:

X ¹ is-NR ^X1-、-O-、-CR^X2R^X3 -, -S-, -S (O) -or-S (O) ₂ -;

r ^X1-1 is independently OH;

R ^X2 and R ^X3 are independently H or C ₁-C₆ alkyl;

X ² is N or CR ^X4;

R ^X4 is H or C ₁-C₆ alkyl;

x ³ is N or CR ^1-1;

X ⁴ is N or CR ^1-2;

X ⁵ is N or CR ^1-3;

r ^L1 and R ^L2 are independently H or C ₁-C₆ alkyl;

n1 is 1,2, 3 or 4;

Y ¹ is-O-, -NR ^L3-、-C(O)-、-CR^L4R^L5 -

N2 is 0, 1,2 or 3;

n3 is 0, 1,2 or 3;

n2+n3=1, 2 or 3;

y ² is-C.ident.C-, -C (O) -NR ^L3-、-CR^L6＝CR^L7 -

N4 is 0,1 or 2;

n5 is 0,1 or 2;

n4+n5= 1 or 2;

R ^L3 is independently H or C ₁-C₆ alkyl;

R ^L4 is H or halogen;

R ^L5 is halogen, OH or C ₁-C₆ alkoxy;

R ^L6 and R ^L7 are independently H or halogen;

R ² is independently C ₁-C₆ alkyl, -C (O) -C ₁-C₆ alkyl or oxo (=o);

m2 is 0,1, 2,3 or 4;

r ⁴ is independently H or C ₁-C₆ alkyl;

R ⁵ is independently H, C ₁-C₆ alkyl or-C (O) R ^5-1;

r ⁶、R^5-1、R⁷ and R ⁸ are independently C ₁-C₆ alkyl;

R ⁹ and R ¹⁰ are independently OH, -NR ⁴R⁵ or halogen;

m3 is 0,1, 2,3 or 4.

2. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions:

(1) R ^X2 and R ^X3 are independently H;

(2) R ^X4 is H;

(3) X ⁵ is CR ^1-3;

(4) R ^1-1、R^1-2 and R ^1-3 are independently H, CN or C ₁-C₆ alkoxy;

(5) R ^L1 and R ^L2 are independently H;

(6) n1 is 1,2 or 3;

(7) Y ¹ is-O-, -NR ^L3-、-C(O)-、-CR^L4R^L5 -, or

(8) N2 is 0,1 or 2;

(9) n3 is 0,1 or 2;

(10)n2+n3=2;

(11) Y ² is-C.ident.C-, -C (O) -NR ^L3-、-CR^L6＝CR^L7 -or

(12) N4 is 0 or 1;

(13) n5 is 0 or 1;

(14)n4+n5=1;

(15) R ^L4 is H;

(16) R ^L5 is halogen;

(17) R ^L6 and R ^L7 are independently H;

(18) R ² is independently oxo;

(19) m2 is 0 or 1;

(20) When L is- (CR ^L1R^L2)n1-、-(CR^L1R^L2) n 2-O-or- (CR ^L1R^L2) n2-C (O) -, Is that

(21) R ³ is independently oxo (=o), C ₁-C₆ alkoxy, -NR ⁴R⁵、-C(O)R⁶、-SR⁷、-S(O)₂R⁸, halogen, C ₁-C₆ alkoxy substituted with one OR more R ⁹, C ₁-C₆ alkyl substituted with one OR more R ¹⁰, CN, 3-12 membered heterocycloalkyl having 1, 2 OR 3 heteroatoms selected from N, O and S, OR-OR ¹¹;

(22) R ⁴ is independently H;

(23) R ⁵ is independently H or-C (O) R ^5-1;

(24) R ⁹ is independently halogen, and

(25) M3 is 0 or 1.

3. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions:

(1) R ^1-1 and R ^1-3 are H, R ^1-2 is H, CN or C ₁-C₆ alkoxy;

(2) n1 is 3;

(3) Y ¹ is-C (O) -or-CR ^L4R^L5 -;

(4) n2 is 2;

(5) n3 is 0;

(6) Y ² is-CR ^L6＝CR^L7 -;

(7) n4 is 1;

(8) n5 is 0;

(9) m2 is 0;

(10) R ³ is independently C ₁-C₆ alkoxy, C ₁-C₆ alkoxy substituted with one or more R ⁹, or halogen;

(11) R ⁵ is independently H, and

(12) M3 is 0.

4. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions:

(1) "C ₁-C₆ alkyl" in each of "C ₁-C₆ alkyl", "substituted C ₁-C₆ alkyl" and "-C (O) -C ₁-C₆ alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

(2) The "C ₁-C₆ alkoxy" in each of "C ₁-C₆ alkoxy" and "substituted C ₁-C₆ alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

(3) Each "3-to 12-membered heterocycloalkyl having 1,2 or 3 heteroatoms selected from N, O and S" is independently "5-to 6-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N and O";

(4) Each halogen is independently F, cl, br or I;

(5) In ring A, the "heteroatom is selected from 1,2 or 3 of N, O and S, and 9-12 membered bicyclic heterocyclic group with 1,2 or 3 heteroatoms" is Wherein ring A ¹ is independently phenyl or pyridinyl, ring A ² is independently "heteroatom selected from 1 or 2 of N and O, 5-6 membered heterocycloalkyl of 1 or 2 heteroatoms selected from 1 or 2 of N and O," or "5-6 membered heteroaryl of 1 or 2 heteroatoms" for example, ring A ² is independently "heteroatom selected from O, 5-membered heterocycloalkyl of 1 or 2 heteroatoms selected from 1 or 2 of N and O," or "5-6 membered heteroaryl of 1 or 2 heteroatoms;

(6) In ring a, the "5-6 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms" is a "5-6 membered monocyclic heteroaryl group having 1 or 2 heteroatoms" or "heteroatom" is a "5-6 membered monocyclic heterocyclic group having 1 or 2 heteroatoms" is selected from 1 or 2 heteroatoms "in N, O and S, such as pyridyl (e.g. ) Thienyl (e.g) Or piperidinyl (e.g);

(7) In ring a, the C ₆-C₁₀ aryl is phenyl or naphthyl;

(8) In ring a, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

(9) Each "5-to 10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S" is independently "a heteroatom selected from N, a 5-to 6-membered heteroaryl having 1 or 2 heteroatoms"

(10)Is thatAnd/or

5. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions:

(1) "C ₁-C₆ alkyl" in each of "C ₁-C₆ alkyl", "substituted C ₁-C₆ alkyl" and "-C (O) -C ₁-C₆ alkyl" is independently methyl or ethyl;

(2) The "C ₁-C₆ alkoxy" in each of the "C ₁-C₆ alkoxy" and the "substituted C ₁-C₆ alkoxy" is independently methoxy or ethoxy;

(3) Each "3-to 12-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" is independently piperidinyl (e.g.) ) Morpholinyl groupOr oxetanyl (e.g);

(4) Each halogen is independently F or Cl;

(5) In ring A, the "heteroatom is selected from 1,2 or 3 of N, O and S, and 9-12 membered bicyclic heterocyclic group with 1,2 or 3 heteroatoms" is

(6) In ring A, the "heteroatom is selected from 1,2 or 3 of N, O and S, and the 5-6 membered monocyclic heterocyclic group with 1,2 or 3 heteroatoms" is

(7) In ring a, the C ₆-C₁₀ aryl is phenyl;

(8) In ring a, the C ₃-C₆ cycloalkyl is cyclohexyl;

(9) Each "heteroatom is selected from 1,2 or 3 of N, O and S, and a 5-to 10-membered heteroaryl group having 1,2 or 3 heteroatoms" is independently pyridinyl (e.g ) And (C) sum

(10)Is that

6. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions:

(1) L is

And

(2)Is that

7. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions:

(1) Is that

And

(2)Is that

8. The tetrakiscyclic compound shown in formula I or pharmaceutically acceptable salt thereof according to claim 1, wherein the tetrakiscyclic compound shown in formula I is a compound shown in formula I-1, I-2 or I-3:

wherein, #, X ¹, ring A, R ³ and m3 are as defined in any one of claims 1 to 7.

9. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1,Is that

10. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the tetrakiscyclic compound of formula I is not:

And stereoisomers thereof.

11. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the tetrakiscyclic compound of formula I is replaced by a tetrakiscyclic compound of formula I-0:

X ¹ is-NR ^X1-、-O-、-CR^X2R^X3 -, -S-, -S (O) -or-S (O) ₂ -;

R ^X1-1 is independently deuterium or OH;

x ² is N, N ⁺O^- or CR ^X4;

R ^X4 is H or C ₁-C₆ alkyl;

x ³ is N or CR ^1-1;

X ⁴ is N or CR ^1-2;

X ⁵ is N or CR ^1-3;

r ^L1 and R ^L2 are independently H or C ₁-C₆ alkyl;

n1 is 3 or 4;

Y ¹ is-O-, -NR ^L3-、-C(O)-、-CR^L4R^L5 -

N2 is 0, 1,2 or 3;

n3 is 0, 1,2 or 3;

n2+n3=1, 2 or 3;

y ² is-C.ident.C-, -C (O) -NR ^L3-、-CR^L6＝CR^L7 -

N4 is 0,1 or 2;

n5 is 0,1 or 2;

n4+n5= 1 or 2;

R ^L3 is independently H or C ₁-C₆ alkyl;

R ^L4 is H or halogen;

R ^L5 is halogen, OH or C ₁-C₆ alkoxy;

R ^L6 and R ^L7 are independently H or halogen;

m2 is 0,1, 2,3 or 4;

r ⁴ is independently H or C ₁-C₆ alkyl;

R ⁵ is independently H, C ₁-C₆ alkyl or-C (O) R ^5-1;

r ⁶、R^5-1、R⁷ and R ⁸ are independently C ₁-C₆ alkyl;

R ⁹ and R ¹⁰ are independently OH, -NR ⁴R⁵ or halogen;

m3 is 0,1, 2,3 or 4;

m4 is 0,1 or 2.

12. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, which satisfies one or more of the following conditions:

(1) X ¹ is-NR ^X1 -;

(2) X ³ is CR ^1-1;

(3) X ⁴ is CR ^1-2;

(4) R ^1-1、R^1-2 and R ^1-3 are independently H, CN, halogen or C ₁-C₆ alkoxy, for example, R ^1-1 and R ^1-3 are H, R ^1-2 is H, F, CN or C ₁-C₆ alkoxy, and for example, R ^1-1、R^1-2 and R ^1-3 are independently H;

(5) m4 is 1;

(6) n2 is 1 or 2;

(7) n3 is 0 or 1;

(8) R ^L3 is H;

(9) R ² is independently deuterium, C ₁-C₆ alkyl, oxo, thio or hydroxy, for example oxo;

(10) m2 is 0, 1, 2 or 3, e.g. m2 is 1;

(11) When L is- (CR ^L1R^L2)n1-、-(CR^L1R^L2) n 2-O-or- (CR ^L1R^L2) n2-C (O) -, Is that

And

(12) R ³ is independently-OR ¹¹、C₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkoxy substituted with one OR more R ⁹, OR halogen.

13. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, which satisfies one or more of the following conditions:

(1) Each C ₃-C₆ cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl;

(2) In ring A, the "heteroatom is selected from 1,2 or 3 of N, O and S, and the 8-12 membered bicyclic heterocyclic group with 1,2 or 3 heteroatoms" is

(3) In ring A, the "9-16 membered polycyclic heterocyclic group having 1, 2 or 3 hetero atoms" selected from 1, 2 or 3 of N, O and S "is" 10-12 membered tricyclic heterocyclic group having 1 or 2 hetero atoms "selected from 1 or 2 of N and O, for exampleAnd

(4)Is that One or more of (a) and (b), e.gAlso e.g. as

14. The tetrakiscyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, which satisfies one or more of the following conditions:

(1) Is that

(2) L is

For exampleAnd

(3)Is that

15. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11,Is that

16. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11,Is that

17. The tetrakis-cyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, wherein the tetrakis-cyclic compound is a compound of formula I-4:

Wherein, #, X ¹, ring A, R ³ and m3 are as defined in any one of claims 11 to 16.

18. A tetrakiscyclic compound as shown in any one of the following or a pharmaceutically acceptable salt thereof:

19. A pharmaceutical composition, the pharmaceutical composition comprising:

(1) A tetrakiscyclic compound as claimed in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and

(2) Pharmaceutically acceptable auxiliary materials.

20. Use of the tetrakiscyclic compound according to any of claims 1-18, a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19, selected from the group consisting of:

(1) Preparing a 5-HT _2A receptor agonist;

(2) Preparing a medicament for the treatment and/or prophylaxis of a 5-HT _2A receptor associated disease, for example, wherein the 5-HT _2A receptor associated disease is depression;

(3) Preparing the medicine for treating and/or preventing depression.